Ophthalmology [4 ed.] 9781455739844, 9781455750016, 9781455739837

Table of contents :
Front cover
Ophthalmology
Copyright page
User Guide
Color Coding
ExpertConsult.com Website
Video Contents
Table of Contents
Preface
Preface to First Edition
List of Contributors
Acknowledgments
Dedication
1 Genetics
1.1 Fundamentals of Human Genetics
DNA and the Central Dogma of Human Genetics
Human Genome
Mitosis and Meiosis
Basic Mendelian Principles
Mutations
Genes and Phenotypes
Patterns of Human Inheritance
Autosomal Dominant
Autosomal Recessive
X-Linked Recessive
Mitochondrial Inheritance
Pseudodominance
X-Linked Dominant Inheritance
Digenic Inheritance and Polygenic Inheritance
Imprinting
Molecular Mechanisms of Disease
Autosomal Dominant
Autosomal and X-Linked Recessive
Gene Therapy
References
Key References
1.2 Molecular Genetics of Selected Ocular Disorders
Introduction
Dominant Corneal Dystrophies
Aniridia, Peter’s Anomaly, Autosomal Dominant Keratitis
Rieger’s Syndrome
Juvenile Glaucoma
Congenital Glaucoma
Nonsyndromic Congenital Cataract
Retinitis Pigmentosa
Stargardt’s Disease
X-Linked Juvenile Retinoschisis
Norrie’s Disease
Sorsby’s Macular Dystrophy
Gyrate Atrophy
Color Vision
Retinoblastoma
Albinism
Leber’s Optic Neuropathy
Congenital Fibrosis Syndromes and Disorders of Axon Guidance
Autosomal Dominant Optic Atrophy
Complex Traits
References
Key References
1.3 Genetic Testing and Genetic Counseling
Genetic Testing
Role of Genetic Testing in the Clinic
Methods for DNA-based Genetic Testing
Current Recommendations for Genetic Testing for Ophthalmic Diseases
CLIA Laboratories
Genetic Reports
Genetic Counseling
Clinical Evaluation and Family History
Risk Prediction Based on Inheritance
Indications to Refer for Genetic Counseling
Confidentiality
References
Key References
2 Optics and Refraction
2.1 Visible Light
Origin of Visible Light
Source
Effect of Earth’s Atmosphere
Visible Light Sensing
Visible Light Receptors and the Ocular Media
Receptors
Dioptric Media
Photonics
Summary
Key References
References
2.2 Physical Optics for Clinicians
Overview
Electromagnetic and Scalar Waves
Polarization
Diffraction and Interference
The Speed of Light and Dispersion
Quantum Model of Light
Fluorescence and Phosphorescence
Laser Fundamentals
Light–Tissue Interactions
Light Scattering
Key References
References
2.3 Light Damage to the Eye
Ultraviolet Filtration
Ultraviolet Profile
Ultraviolet Vulnerability
Older Individuals
Lightly Pigmented Individuals
Aphakia
Use of Photosensitizing Drugs
Outer Segment Turnover
Biochemical Mechanism of UV Radiation Damage
Molecular Fragmentation
Free Radical Generation
Light Protection
During Surgery
Ultraviolet Filters in Intraocular Lenses
Absorptive Lenses
Improvement of Contrast Sensitivity
Improvement of Dark Adaptation
Reduction of Glare Sensitivity
Improvement of Color Contrast
Use of Photochromic Lenses
Ultraviolet-Absorbing Lenses
Key References
References
2.4 Principles of Lasers
Introduction
How Lasers Work
Continuous and Pulsed Lasers
What Color is Your Laser?
Clinical Use of Lasers
Clinical Use of Laser Photocoagulation
Clinical Use of Photodisruption
Clinical Use of Laser Photoablation
Photodynamic Therapy
Diagnostic Use of Lasers
Scanning Laser Ophthalmoscopy
Optical Coherence Tomography
Wavefront Analysis and Photorefractive Keratectomy
Conclusion
Key References
References
2.5 Optics of the Normal Eye
Introduction
Individual Optical Elements of the Eye
Corneal Factors
Pupillary Factors
Crystalline Lens Factors
Ocular Aberrations
Retinal Factors
Resolution and Focal Length Factors
Depth of Focus
Pinhole Optics
Visual Acuity Testing
Testing Distance
Other Considerations
Contrast Sensitivity Testing
Contrast
Contrast Sensitivity
Targets
Sine Waves
Recording Contrast Sensitivity
Modulation Transfer Function Testing
Wavefront Testing
Retina–Brain Image Processing
Vernier Acuity
Fast-Moving Objects
Flicker
Dark Adaptation
Key References
References
2.6 Testing of Refraction
Introduction
Historical Review
Purpose of the Test
Utility of the Test
Procedure
Instrumentation
Monocular Subjective Refraction
Binocular Balance
Near Refraction
Alternative Tests
Key References
References
2.7 Contact Lenses
Introduction
Lens Types and Usage
Lens Categories
Disposable Contact Lenses
Colored Lenses
Contact Lenses for Astigmatism
Contact Lens Asphericity
Contact Lenses for Presbyopia
Unusual Surface Configuration
Initial Fitting
Follow-Up Care
Corneal and Conjunctival Tissue Problems
Silicone Hydrogel Lenses
Spectacle Blur
Mechanical or Physical Problems
Key References
References
2.8 Ophthalmic Instrumentation
Introduction
Keratometer and Corneal Topographer
Slit-Lamp Biomicroscope
Illumination
Improving Tissue Contrast
Observation System
Slit-Lamp Fundus Lenses
Goldmann Applanation Tonometer
Optical Pachymeter
Specular Microscope
Optics of Endothelial Microscopy
Operating Microscope
Retinoscope
Optics of Retinoscopy
Neutrality
With and Against Motion
Other Clues
Enhancement
Myopia Estimation
Astigmatism
Automated Objective Refractometer
Characteristics of Contemporary Objective Refractors
Possible Problems
Lensmeter
Binocular Indirect Ophthalmoscope
Illumination System
Observation System
Direct Ophthalmoscope
Important Considerations when Using the Direct Ophthalmoscope
Light Safety
Fundus Camera
Lighting
Reducing Reflections from the Cornea and Instrument
The Observation System
Field of View
Fluorescein Angiography
Magnifying Devices
Angular Magnification
Magnifying Glass
Galilean Telescope
Simple Microscope (Operating Loupe)
Effects of Lens Aberrations
Optical Coherence Tomography
Wavefront Aberrometers
Wavefront Analysis
Hartmann–Shack Aberrometry
Tscherning Aberrometry
Retinal Raytracing Technique
Key References
References
2.9 Perspectives on Aberrations of the Eye
Introduction
The Wavefront Approach to Aberrations
Defocus
Regular Astigmatism (RA)
Spherical Aberration (SA)
Distortion
Coma
Astigmatism of Oblique Incidence
Piston Error
Higher-Order Aberrations
Mathematical Considerations
Chromatic Aberration
Clinical Measurement of Aberrations
Clinical Application of Aberration Theory
An Overall Perspective on Aberration Theory
Key References
References
3 Refractive Surgery
3.1 Current Concepts, Classification, and History of Refractive Surgery
Introduction
Excimer Laser and Ablation Profiles
Laser Ablation Profiles
Munnerlyn’s Formula
Wavefront-Guided Ablation
Topography-Guided Ablation
Wavefront-Optimized/Aspheric/ Q-Factor-Adjusted Laser Profiles
Presbyopia Correction
Concepts in Development and Optical Ray-Tracing
Classification of Refractive Procedures
Cornea
Intraocular Lenses and Refractive Lensectomy
Electronic IOLS
New or Alternative Approaches
Summary
Key References
References
3.2 Preoperative Evaluation for Refractive Surgery
Introduction
Systemic Contraindications for Keratorefractive Surgery
Ophthalmic Contraindications
Ophthalmic Examination
Ancillary Testing
Wavefront Measurement (Aberrometry)
Computerized Videokeratography
Pachymetry
Counseling
Key References
References
3.3 Excimer Laser Photorefractive Keratectomy
Introduction
History and Fundamentals of the Excimer Laser
Excimer Laser Keratomileusis
Surface ablation
Ablation Profiles
Tracking Systems
Iris Registration (IR) System
Preoperative Evaluation
Surgical Treatment
Patient Preparation and Epithelial Removal
Stromal Ablation
Postoperative Management
Photorefractive Keratectomy with Mitomycin-C
Wavefront-Guided PRK
Results
Photorefractive Keratectomy for Myopia and Astigmatism
Photorefractive Keratectomy for Hyperopia
Photorefractive Keratectomy Following Previous Refractive Surgery
Wavefront-Guided PRK
Complications
Undercorrection or Overcorrection
Epithelial Problems
Corneal Haze/Scar Formation
Dry Eyes
Infectious Keratitis
Conclusions
Key References
References
3.4 Laser Subepithelial Keratomileusis (LASEK) and Epi-LASIK
Introduction
Indications
Advantages
LASEK and Epi-LASIK Surgical Techniques
Preoperative Evaluation
LASEK Surgical Technique (see Fig. 3-4-1)
Epi-LASIK Surgical Technique (Fig. 3-4-2)
Postoperative Management
Complications
LASEK-Related Intraoperative Complications
Epi-LASIK-Related Intraoperative Complications
Early Postoperative Complications of LASEK and Epi-LASIK
Epithelial Healing
Pain
Infiltrates and Infection
Dry Eye
Long-Term Postoperative Complications
Corneal Haze
Laser-Related Complications
Clinical Outcomes
Clinical Results of LASEK and Epi-LASIK
LASEK and Epi-LASIK Versus PRK and LASIK
Key References
References
3.5 LASIK
Historical Review
LASIK
Excimer Lasers
Wavefront-Guided Technology and Custom Ablations
Wavefront-Optimized Technology and Ablations
Topography-Guided LASIK
Patient Selection
Microkeratomes and Femtosecond Lasers
Operative Technique
Postoperative Care
Complications
Results
LASIK Enhancements
LASIK in Complex Cases
LASIK after Radial Keratotomy
LASIK after Photorefractive Keratectomy
LASIK after Penetrating Keratoplasty
Intraocular Lens Calculations after LASIK
Bioptics
Summary
Key References
References
3.6 Wavefront-Based Excimer Laser Refractive Surgery
Introduction
Wavefront Optics
Higher-Order Aberrations
Ideal Corneal Shape
Measurements of Wavefront Aberrations
Quality of Vision and Measures of Optical Quality
Wavefront-Measuring Devices
Wavefront-Based Surgery
Results
Wavefront Platforms (Table 3-6-1)
Conclusion
Key References
References
3.7 Phakic Intraocular Lenses
Introduction
History of Phakic Lenses
Indications of Phakic Lenses
High Myopia
High Hyperopia
High Astigmatism
Advantages and Disadvantages of Phakic IOLs
Intraocular Lens Power Calculation
Ancillary Tests
Sizing the Anterior Chamber Angle-Supported Phakic IOLs
Sizing the Anterior Chamber Iris-Fixated Phakic IOLs
Sizing the Posterior Chamber Phakic IOLs
Visual Outcomes (Table 3-7-3)
Anterior Chamber Angle-Supported Phakic Intraocular Lenses
Surgical Procedure for the AcrySof Cachet
Complications
Iris-Fixated Phakic Intraocular Lenses
Surgical Procedure
Complications
Posterior Chamber Phakic Intraocular Lenses
Surgical Technique
Complications
Bioptics
Conclusion
Key References
References
3.8 Astigmatic and Radial Incisional Keratotomy
Historical Review
Incisional Keratotomy
Corneal Wound Healing after Incisional Keratotomy
Phases of Normal Epithelial and Stromal Wound Healing
Postoperative Side-Effects Related to Wound Healing
Surgical Techniques for Astigmatic and Radial Keratotomy
Preoperative Considerations
Incision Technique
Surgical Protocol
Postoperative Protocol
Complications of Astigmatic and Radial Incisional Keratotomy
Complications Related to Corneal Incisions
Complications Related to Corneal Perforations
Postoperative Complications
Sight-Threatening Complications
Complications Associated with Adjunctive Therapy
Conclusions
Key References
References
3.9 Intrastromal Corneal Ring Segments and Collagen Crosslinking
Introduction
Surgical Technique
ICRS Channel Formation
ICRS Channeling with Femtosecond Laser
Segment Insertion
Injection Adjustable Keratoplasty
Corneal Collagen Crosslinking (CXL)
Clinical Outcome
Wound Healing
Postoperative Care and Management
ICRS for Keratoconus and after LASIK
Combination Treatment with Corneal Collagen Crosslinking
Conclusions
Key References
References
3.10 Surgical Correction of Presbyopia
Introduction
Corneal Surgery
Excimer Laser Correction of Presbyopia Using the Concept of Multifocal Cornea
Intrastromal Correction of Presbyopia Using a Femtosecond Laser System (INTRACOR Procedure)
Surgical Correction of Presbyopia with Intracorneal Inlay
Hydrogel Refractive Presbyopic Implants
Lens Surgery
Pseudophakic Presbyopia Correction with Multifocal IOLs
Presbyopic Pseudophakic Correction with Accommodative Iols
Scleral Surgery for the Correction of Presbyopia
Conclusion
References
Key References
4 Cornea and Ocular Surface Diseases
1 Basic Principles
4.1 Corneal Anatomy, Physiology, and Wound Healing
Introduction
Corneal Wound Healing
Key References
References
4.2 Corneal Topography and Wavefront Imaging
Corneal Topography
Wavefront Analysis
Summary
Key References
References
2 Congenital Abnormailities
4.3 Congenital Corneal Anomalies
Introduction
Size and Shape Anomalies
Anomalies of Corneal Clarity
Key References
References
3 External Diseases
4.4 Blepharitis
Introduction
Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Treatment
Key References
References
4.5 Herpes Zoster Ophthalmicus (HZO)
Epidemiology and Pathogenesis
Clinical Manifestations
Herpes Zoster Ophthalmicus in Acquired Immune Deficiency Syndrome (AIDS)
Diagnosis
Management
Prevention
Key References
References
4 Conjunctival Diseases
4.6 Conjunctivitis:
Infectious Conjunctivitis
Noninfectious Conjunctivitis
Key References
References
4.7 Allergic Conjunctivitis
Acute Allergic Conjunctivitis: Seasonal/Perennial
Chronic Atopic Keratoconjunctivitis
Vernal Conjunctivitis
Treatment of Allergic/Atopic Keratoconjunctivitis
Allergic Dermatoconjunctivitis
Microbiallergic Conjunctivitis
Giant Papillary Conjunctivitis
Key References
References
4.8 Tumors of Conjunctiva and Cornea
Introduction
Tumors of Stratified Squamous Epithelium (SSE)
Melanocytic Tumors
Lymphoid Tumors
Miscellaneous Other Tumors
Key References
References
4.9 Pterygium and Conjunctival Degenerations
Introduction
Pinguecula
Pterygium
Senile Scleral Plaques
Conjunctival Amyloid
Conjunctival Melanosis
Key References
References
4.10 Ocular Cicatricial Pemphigoid/Mucous Membrane Pemphigoid
Introduction
Pathogenesis
Clinical Findings
Diagnosis
Treatment
Conclusions
Key References
References
5 Scleral and Episcleral Diseases
4.11 Episcleritis and Scleritis
Episcleritis
Scleritis
Inflammatory Diseases
Key References
References
6 Corneal Diseases
4.12 Bacterial Keratitis
Introduction
Epidemiology and Pathogenesis
Clinical Features
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Outcome
Key References
References
4.13 Fungal Keratitis
Introduction
Epidemiology and Pathogenesis
Clinical Features
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Outcome
References
Key References
4.14 Parasitic Keratitis
Introduction
Acanthamoeba
Microsporidiosis
Onchocerciasis
References
Key References
4.15 Herpes Simplex Keratitis
Epidemiology
Herpes Simplex Virus
Primary HSV Infection
Recurrent HSV Infections
Diagnosis
Herpetic Eye Disease Study (HEDS)
Treatment
Future Directions
References
Key References
4.16 Peripheral Ulcerative Keratitis
Introduction
Anatomy and Pathogenesis
Ocular Manifestations
Systemic Associations
Differential Diagnosis
Diagnostic and Ancillary Testing
Treatment
Course and Outcome
Key References
References
4.17 Noninfectious Keratitis
Introduction
Thygeson’s Superficial Punctate Keratitis
Superior Limbic Keratoconjunctivitis of Theodore
Mooren’s Ulcer
Nonsyphilitic Interstitial Keratitis (Cogan’s Syndrome)
Neurotrophic Keratitis
Terrien’s Marginal Degeneration
Rheumatoid-Associated Corneal Ulceration
Key References
References
4.18 Keratoconus and Other Ectasias
KER Atoconus
Keratoglobus
Key References
References
4.19 Anterior Corneal Dystrophies
Introduction
Anterior Basement Membrane Dystrophy
Meesmann’s Epithelial Dystrophy
Reis–Bückler’s Dystrophy
Honeycomb Dystrophy
Superficial Granular Dystrophy
Key References
References
4.20 Stromal Corneal Dystrophies
Introduction
Lattice Dystrophy Type I
Lattice Dystrophy Type II
Lattice Dystrophy Type III
Gelatinous Drop-Like Dystrophy
Granular Corneal Dystrophy (Groenouw Type I)
Avellino Dystrophy
Macular Corneal Dystrophy
Schnyder Crystalline Dystrophy
Central Cloudy Dystrophy
Fleck Dystrophy
Posterior Amorphous Corneal Dystrophy
Congenital Hereditary Stromal Dystrophy
Key References
References
4.21 Corneal Endothelium
Introduction
Fuchs’ Dystrophy
Congenital Hereditary Endothelial Dystrophy
Posterior Polymorphous Corneal Dystrophy
Key References
References
4.22 Corneal Degenerations
Introduction
Corneal Arcus (Arcus Senilis)
Lipid Keratopathy
Vogt’s White Limbal Girdle
Senile Corneal Furrow Degeneration
Terrien’s Marginal Corneal Degeneration
Peripheral Corneal Guttae
Calcific Band Keratopathy
Spheroidal Degeneration
Iron Deposition
Crocodile Shagreen
Cornea Farinata
Salzmann’s Corneal Degeneration
Corneal Keloids
Corneal Amyloid Degeneration
Key References
References
4.23 Dry Eye
Introduction
Epidemiology
Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Treatment
Key References
References
7 Miscellaneous Conditions
4.24 Contact Lens-Related Complications
Introduction
Contact Lenses and Corneal Physiology
Risk Factors for Contact Lens Complications
Contact Lens Complications
Key References
References
4.25 Corneal and External Eye Manifestations of Systemic Disease
Introduction
Congenital Disorders
Chromosomal Disorders
Inherited Connective Tissue Disorders
Metabolic Disorders
Ocular Anatomical Disorders
Conclusion
Key References
References
8 Trauma
4.26 Acid and Alkali Burns
Introduction
Alkali Injuries
Acid Injuries
Pathophysiology
Clinical Course
Therapy
Key References
References
9 Surgery
4.27 Corneal Surgery
Keratoplasty
Superficial Corneal Procedures
Key References
References
4.28 Excimer Laser Treatment of Corneal Pathology
Introduction
Preoperative Evaluation and Diagnostic Approach
Surgical Techniques
Complications
Outcome
Conclusion
Key References
References
4.29 Conjunctival Surgery
Historical Review
Anesthesia
Specific Techniques
Key References
References
4.30 Endothelial Keratoplasty:
Introduction
Evolution of EK Techniques
Indications
Surgical Technique
Combined Procedures
Outcomes
Outlook
Key References
References
4.31 Surgical Ocular Surface Reconstruction
Introduction
Historical Perspectives
General Concepts
Preoperative Considerations
Operative Procedures
Special Considerations in Ocular Surface Reconstruction
Key References
References
4.32 Management of Corneal Thinning, Melting, and Perforation
Introduction
Corneal Thinning From Noninflammatory Disorders
Corneal Thinning and Melting From Inflammatory Disorders
Surgical Treatment of Corneal Perforations
Conclusion
Key References
References
5 The Lens
5.1 Basic Science of the Lens
References
Key References
5.1 Basic Science of the Lens
Introduction
Anatomy of the Lens
Capsule
Epithelial Cells
Lens Substance
Sutures
Growth
Mass
Dimensions
Physiology of the Lens
Permeability, Diffusion, and Transport
Biophysics
Light Transmission
Transparency
Refractive Indices
Chromatic Aberration
Spherical Aberration
Accommodation
Biochemistry
Sugar Metabolism
Protein Metabolism
Glutathione
Antioxidant Mechanisms
Lens Crystallins
Crystallin Structure
Crystallin Gene Expression during Lens Growth
Crystallin Function
Age Changes
Morphology
Physiological Changes
Biophysical Changes
Accommodation Changes
Biochemical Changes
Crystallins
Secondary Cataract
Fibrosis-Type Posterior Capsule Opacification
Pearl-Type Posterior Capsule Opacification
Soemmerring’s Ring
Prevention and Treatment of Posterior Capsule Opacification
Key References
References
5.2 Evolution of Intraocular Lens Implantation
Introduction
Lens Design and Fixation
Generation I (Original Ridley Posterior Chamber Lens)
Generation II (Early Anterior Chamber Lenses)
Generation III (Iris-Supported Lenses)
Generation IV (Intermediate Anterior Chamber Lenses)
Generation V (Improved Posterior Chamber Lenses)
Generation VI (Modern Capsular Lenses – Rigid PMMA, Soft Foldable, and Modern Anterior Chamber)
Recent Advances
References
Key References
5.2 Evolution of Intraocular Lens Implantation
Introduction
Lens Design and Fixation
Generation I (Original Ridley Posterior Chamber Lens)
Generation II (Early Anterior Chamber Lenses)
Generation III (Iris-Supported Lenses)
Generation IV (Intermediate Anterior Chamber Lenses)
Generation V (Improved Posterior Chamber Lenses)
Generation VI (Modern Capsular Lenses—Rigid PMMA, Soft Foldable, and Modern Anterior Chamber)
Recent Advances
Key References
References
5.3 Patient Workup for Cataract Surgery
Introduction
Medical History and Current Therapeutic Regimen
General Ophthalmic History and Examination
Specific Ophthalmic Examination
Assessment of Lens Opacities
Introduction
Diagnosis of Lens Opacities
Classification of Lens Opacities
Grading of Lens Opacities
Effects of Opacities on Vision
Measurements
Introduction
IOL Calculations That Require Axial Length
Methods to Determine Axial Length
IOL Calculations Using k Values and Preoperative Refraction
Investigations for Further Surgical Refinement
Corneal Topography
Preoperative Topography
Calculation of IOL Power
Planning the Incision
Good Clinical Practice (Social and Legal Aspects)
References
Key References
5.4 Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques
Introduction
Medical Indications for Lens Surgery
Lenticular Opacification (Cataract)
Lenticular Malposition
Lenticular Malformation
Lens-Induced Ocular Inflammation
Lens-Induced Glaucoma
Refractive Indications for Lens Surgery
Indications for Different Lens Surgery Techniques
Intracapsular Extraction
Extracapsular Extraction (Large-Incision Nuclear Expression Cataract Surgery)
Small-Incision Nuclear Expression Cataract Surgery (‘Mini-nuc’ and Other Techniques)
Phacoemulsification
Surgery of the Lens Capsule
Zonular Surgery
Surgery for Presbyopia
Monovision
Astigmatism
Acknowledgment
References
Key References
5.5 The Pharmacotherapy of Cataract Surgery
Introduction
Preoperative Medications
Pupil Dilatation
Anti-Infective Prophylaxis
Anesthetics
Intraoperative Medications
Additives to Irrigating Solutions, Intracameral Antibiotics, and Other Intraocular Drugs Used During the Surgical Procedure
Irrigating Solutions
Ophthalmic Viscosurgical Devices
Postoperative Medications
Antibiotics
Corticosteroids and Nonsteroidal Anti-Inflammatory Drugs
Late Postoperative Medications
Treatment of Endophthalmitis
Treatment of Cystoid Macular Edema
References
Key References
5.6 Anesthesia for Cataract Surgery
Introduction
Medical Aspects of Anesthesia for Cataract Surgery
Cataract Type and Associated Medical Conditions
Specific Conditions
Local Anesthesia
General Considerations
Topical Anesthesia (see Box 5-6-1)
Retrobulbar Block (see Box 5-6-2)
Peribulbar Block (see also Table 5-6-1)
Sub-Tenon’s Block (see also Table 5-6-1)
Sedative Agents
General Anesthesia
Technique
Postoperative Care
References
Key References
5.7 Phacoemulsification
Introduction
Historical Review
Handpieces and Tips
Power Modulation
Pumps and Fluidics
Flow-Based (Peristaltic)
Vacuum-Based
Anterior Chamber Hydrodynamics
Fluidics of Micro-incisional Phaco
Post-Occlusion Surge
References
Key References
5.8 Refractive Aspects of Cataract Surgery
Introduction
Value of Corneal Topography
Intra-Operative Management of Preoperative Corneal Astigmatism to Prevent Induction of Corneal Astigmatism
Corneal Incisions
To Treat Preoperative Corneal Astigmatism
Astigmatic Incisions
Limbal Relaxing Incisions
Opposite Clear Corneal Incisions (OCCIs)
Toric Intraocular Lens Implantation
Postoperative Management of Residual or Induced Corneal Astigmatism
Corneal Laser Ablative Techniques
Post-Cataract Piggyback IOLS
Light Adjustable Intraocular Lens Implant (LAL)
References
Key References
5.9 Small Incision and Femtosecond Laser Cataract Surgery
Introduction
Incision Construction and Architecture
Continuous Curvilinear Capsulorrhexis
Hydrodissection and Hydrodelineation
Nucleofractis Techniques
Divide and Conquer
Phaco Chop
Power Modulations
Biaxial Micro-Incision Cataract Surgery
B-MICS Vertical Chop Technique
Femtosecond Laser-Assisted Cataract Surgery
Anterior Capsulectomy
Lens Fragmentation
Corneal Incisions
Conclusion
References
Key References
5.10 Manual Cataract Extraction
Introduction
Historical Issues
Manual (Large Incision) Cataract Surgery
Incision
Wound Closure
Intracapsular Cataract Extraction
General Comments
Specific Techniques
Extracapsular Cataract Extraction
Anterior Capsulectomy
Mininuc Technique
Complications
Discussion
References
Key References
5.11 Combined Procedures
Introduction
Combined Phacotrabeculectomy
Preoperative Evaluation and Diagnostic Approach
Specific Techniques
Complications
Outcomes
Lens Surgery Combined with Keratoplasty
Historical Review
Surgical Options
Specific Techniques
Complications
Outcomes
Combined Phacovitrectomy
Introduction
Historical Review
Indications and Advantages Over Noncombined Surgery
Disadvantages
Specific Techniques
Conclusion
References
Key References
5.12 Cataract Surgery in Complicated Eyes
Introduction
Zonular Instability
Uveitis
Compromised Endothelium
References
Key References
5.13 Pediatric Cataract Surgery
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Alternatives to Surgery
Anesthesia
General Techniques
Specific Techniques
Pars Plana Approach
Limbal Approach
Choice of Aphakic Correction in Children
Spectacles
Contact Lenses
Intraocular Lenses
Complications
Amblyopia Management
Intraocular Lens Exchange and Alternative Options
Outcome
References
Key References
5.14 Complications of Cataract Surgery
Introduction
Intra-Operative Complications
Cataract Incision
Tunnel Perforation
Descemet’s Detachment
Thermal Burns
Anterior Capsulectomy
Nuclear Expression Cataract Extraction
Complications During Phaco
Ruptured Posterior Capsule
Dropped Nucleus
Anterior Segment Hemorrhage
Post-Operative Complications
Wound Dehiscence
Wound Leakage
Inadvertent Filtering Bleb
Epithelial Ingrowth
Post-operative Astigmatism
Corneal Edema and Bullous Keratopathy
Hyphema
Endocapsular Hematoma
Intraocular Pressure Elevation
Capsular Block Syndrome
Intraocular Lens Miscalculation
Intraocular Lens Decentration and Dislocation
Sulcus-Fixated Intraocular Lens Dislocation
Posterior and Anterior Dislocation
Intraocular Lens Exchange
Cystoid Macular Edema
Endophthalmitis
Posterior Capsular Opacification – see Chapter 5.16
Retinal Detachment
References
Key References
5.15 Outcomes of Cataract Surgery
Introduction
Evaluation of Outcomes
Five Parameters That Describe Visual Function
Visual Acuity Testing
Contrast Sensitivity Testing
Glare Testing
Visual Fields
Color Vision
Objective Findings of Cataract Surgery Outcomes
Best-Corrected Distance Visual Acuity
Uncorrected Visual Acuity
Target Refraction Prediction Error
Contrast Sensitivity
Glare
Visual Fields
Color Vision
Subjective Findings of Cataract Surgery Outcomes
Patients’ Self-Assessment of the Visual Outcome
Cataract Surgery of One or Both Eyes
Cataract Surgery in Eyes with Ocular Comorbidity
Summary
References
Key References
5.16 Secondary Cataract
Introduction
Pathogenesis
Treatment and Prevention
Iols Maintaining the Capsular Bag Open or Expanded
References
Key References
5.17 Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract
Epidemiology of Cataracts
Genetics
Nutrition, Health, and Diabetes
Antioxidants
Sunlight and Irradiation
Smoking and Alcohol
Age, Education, and Other Factors
Myopia
Pharmacological Prevention of Cataracts
Pathophysiology of Cataracts
Cell Proliferation and Differentiation
Metabolic Disturbance and Osmotic Regulation Failure
Calpains
Protein Modification
Oxidation
Defensive Mechanisms
Other Factors
Causes of Cataract
Age
Trauma
Systemic Disorders
Dermatological Disorders
Central Nervous System Disorders
Ocular Disease and Cataracts
Toxic Causes
Congenital and Juvenile Cataracts
Morphology
Assessment and Grading of Cataracts
Visual Effects of Cataracts
Visual Acuity
Contrast Sensitivity, Glare, and Wavefront Aberrometry
Other Effects
Anomalies of Lens Growth
Aphakia
Microspherophakia
Lenticonus and Lentiglobus
Lens Coloboma
Ectopia Lentis
References
Key References
6 Retina and Vitreous
1 Anatomy
6.1 Structure of the Neural Retina
Introduction
Center of the Macula: Umbo
Foveola
Fovea
Parafovea
Perifovea
Macula, or Central Area
Extra-Areal Periphery
Layers of the Neural Retina
References
Key References
6.2 Retinal Pigment Epithelium
Introduction
Structure
Membrane Properties and Fluid Transport
Photoreceptor-Retinal Pigment Epithelium Interactions
Repair and Regeneration
Key References
References
6.3 Retinal and Choroidal Circulation
Introduction
Posterior Segment Vascular Anatomy
Blood-Retinal Barrier
Retinal and Choroidal Blood Flow
Future Perspectives for Retinal and Choroidal Assessment
Regulation of Retinal and Choroidal Blood Flows
Key References
References
6.4 Vitreous Anatomy and Pathology
Introduction
Molecular Morphology
Vitreous Anatomy
Age-Related Changes
Metabolic Disorders of Vitreous
References
Key References
2 Ancillary Tests
6.5 Contact B-Scan Ultrasonography
Introduction
Devices
Technique of Examination
Concepts of B-Scan Interpretation
Display Presentation and Documentation
Digital Contact Ultrasound
Summary
Key References
References
6.6 Fluorescein Angiography and Indocyanine Green Angiography
Fluorescein Angiography
Indocyanine Green Angiography
Fluorescein Angiography
Indocyanine Green Angiography
Key References
References
6.7 Optical Coherence Tomography
Introduction
OCT Technology Platforms
Anatomic Results
Image Optimization
OCT Image Interpretation
Key References
References
6.8 Electrophysiology
Introduction
Historical Review
Full-Field ERG
Multifocal ERG (mfERG)
Electro-Oculography (EOG)
References
Key References
3 Basic Principles of Retinal Surgery
6.9 Light and Laser Injury
Introduction
Light Interaction with the Retina
Photic Retinopathy
Light Exposure and Age-Related Macular Degeneration
Laser Injury
Laser Pointers
Complications of Therapeutic Retinal Laser Photocogulation
Key References
References
6.10 Scleral Buckling Surgery
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Differential Diagnosis
Alternatives to Scleral Buckling
Anesthesia
General Techniques
Complications
Outcome
Key References
References
6.11 Vitrectomy
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Indications and Alternatives to Surgery
Anesthesia
General Techniques
Specific Techniques
Complications
Outcomes
Key References
References
6.12 Intravitreal Injections and Medication Implants
Introduction
Pre-Injection Preparation
Injection
Post-Injection
Complications
Other Considerations
Implants
Conclusion
Key References
References
4 Dystrophies
6.13 Progressive and ‘Stationary’ Inherited Retinal Degenerations
Progressive Diffuse/ Pan-Retinal Degenerations
‘Stationary’ Retinal Disorders
6.14 Macular Dystrophies
Introduction
Stargardt Disease and Fundus Flavimaculatis
Vitelliform Macular Dystrophy (Best’s Disease)
Adult Vitelliform Macular Dystrophy/ Adult-Onset Foveomacular Dystrophy (Pattern Dystrophy)
Familial Drusen
Pattern Dystrophy
Dominant Cystoid Macular Edema
Sorsby’s Macular Dystrophy
North Carolina Macular Dystrophy
Atrophia Areata
Cone Dystrophy
Central Areolar Choroidal Dystrophy
6.15 Choroidal Dystrophies
Introduction
Choroideremia
Gyrate Atrophy
6.16 Hereditary Vitreoretinopathies
Introduction
Stickler’s Syndrome
X-Linked Juvenile Retinoschisis
Autosomal Dominant Vitreoretinochoroidopathy
Familial Exudative Vitreoretinopathy
Norrie’s Disease
References
Key References
5 Vascular Disorders
6.17 Hypertensive Retinopathy
Chronic Hypertensive Retinopathy
Malignant Acute Hypertensive Retinopathy
References
Key References
6.18 Retinal Arterial Obstruction
Central Retinal Artery Obstruction
Branch Retinal Artery Obstruction
Central Retinal Artery Obstruction
Branch Retinal Artery Obstruction
Ophthalmic Artery Obstruction
Cilioretinal Artery Obstruction
Combined Artery and Vein Obstructions
References
Key References
6.19 Venous Occlusive Disease of the Retina
Central Retinal Vein Occlusion
Branch Retinal Vein Occlusion
Central Retinal Vein Occlusion
Branch Retinal Vein Occlusion
References
Key References
6.20 Retinopathy of Prematurity
Introduction
Epidemiology and Pathogenesis
Clinical Features and Classification
Systemic Associations
Pathology
Diagnosis and Ancillary Testing
Differential Diagnosis
Treatment
Ablation of Peripheral Avascular Retina
Role of Anti-VEGF Therapy in ROP Treatment
Surgery in ROP Treatment
Role of Telemedicine in ROP Screening
Summary and Future Directions
References
Key References
6.21 Diabetic Retinopathy
Introduction
Epidemiology
Pathogenesis
Ocular Manifestations
Other Ocular Complications of Diabetes Mellitus
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Conclusions
References
Key References
6.22 Ocular Ischemic Syndrome
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment, Course, and Outcome
References
Key References
6.23 Hemoglobinopathies
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Treatment
Course and Outcome
References
Key References
6.24 Coats’ Disease and Retinal Telangiectasia
Introduction
Epidemiology
Ocular Manifestations
Diagnosis
Ancillary Testing
Differential Diagnosis
Systemic Associations
Treatment
Complications of Treatment
Course and Outcome
References
Key References
6.25 Radiation Retinopathy and Papillopathy
Radiation Retinopathy
Radiation Papillopathy
References
Key References
6.26 Proliferative Retinopathies
Introduction
Retinal Angiogenesis
Entities Associated with Retinal Neovascularization
Overview of Diagnosing and Treating Neovascularization
References
Key References
6.27 Retinal Arterial Macroaneurysms
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment, Course, and Outcome
Summary
References
Key References
6 Macular Disorders
6.28 Age-Related Macular Degeneration
Introduction
Epidemiology
Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Natural History and Prognosis
Treatment and Prevention
Conclusion
References
Key References
6.29 Secondary Causes of Choroidal Neovascularization:
Traumatic Ruptures of Bruch’s Membrane
Angioid Streaks
Pathologic Myopia
Inflammatory Disorders
References
Key References
6.30 Central Serous Chorioretinopathy
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
6.31 Macular Hole
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Course and Outcome
References
Key References
6.32 Epiretinal Membrane
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Course and Outcomes
References
Key References
6.33 Vitreomacular Traction Syndrome
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Postoperative Course and Outcome
Vitreofoveal Traction Syndrome
References
Key References
6.34 Cystoid Macular Edema
Introduction
Pathogenesis and Etiology
Diagnosis and Ancillary Testing
Treatment
Conclusion
References
Key References
6.35 Coexistent Optic Nerve and Macular Abnormalities
Introduction
Congenital Anomalies of the Optic Disc
Other Optic Nerve Abnormalities Associated with Macular Pathology
References
Key References
7 Retinal Detachment
6.36 Peripheral Retinal Lesions
Introduction and Anatomy
Ocular Manifestations and Diagnosis of Peripheral Retinal Lesions
References
Key References
6.37 Retinal Breaks
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Treatment
Course and Outcome
References
Key References
6.38 Rhegmatogenous Retinal Detachment
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
6.39 Serous Detachments of the Neural Retina
Introduction
Pathophysiology
Alterations in Choroidal Flow
Poor Scleral Outflow
Breakdown of the RPE and Retina
Miscellaneous
Diagnostic and Ancillary Testing
Differential Diagnosis
Treatment
Course and Outcome
References
Key References
6.40 Choroidal Hemorrhage
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Treatment
Course and Outcome
References
Key References
6.41 Proliferative Vitreoretinopathy
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8 Trauma
6.42 Posterior Segment Ocular Trauma
Introduction
Ocular Manifestations and Clinical Examination
Nonpenetrating Trauma
Penetrating Trauma
Course and Outcome
References
Key References
6.43 Distant Trauma with Posterior Segment Effects
Terson’s Syndrome
Purtscher’s Retinopathy
Shaken Baby Syndrome
Terson’s Syndrome
Purtscher’s Retinopathy
Shaken Baby Syndrome
Miscellaneous Conditions
References
Key References
6.44 Retinal Toxicity of Systemically Administered Drugs
Introduction
Chloroquine and Hydroxychloroquine
Sildenafil
Thioridazine
Niacin
Canthaxanthine
Tamoxifen
Fingolimod
Paclitaxel
Deferoxamine
Didanosine
Clofazimine
Thiazolidinediones
Imatinib
References
Key References
7 Uveitis and Other Intraocular Inflammations
1 Basic Principles
7.1 Anatomy of the Uvea
Introduction
Iris
Ciliary Body
Choroid
References
Key References
7.2 Mechanisms of Uveitis
Introduction
Innate and Adaptive Immunities
Cells of the Immune System
Molecules of the Immune System Involved in Uveitis
Tolerance and Autoimmunity
Mechanisms That Trigger and Promote Uveitogenic Processes
Mechanisms of Inflammation
Immunopathogenic Processes of Uveitis in Humans
Mechanisms That Inhibit Inflammation in the Eye
References
Key References
7.3 General Approach to the Uveitis Patient and Treatment Strategies
Introduction
Classification
Epidemiology
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Treatment
Course and Outcome
References
Key References
2 Infectious Causes of Uveitis–Viral
7.4 Herpes and Other Viral Infections
Varicella-Zoster and Herpes Simplex Virus-Induced Acute Retinal Necrosis
Progressive Outer Retinal Necrosis
Varicella-Zoster and Herpes Simplex Virus
Epstein-Barr Virus
Human T Cell Lymphotropic Virus Type I
Influenza a Virus
Measles Virus
References
Key References
7.5 Ocular Infections with Cytomegalovirus (CMV)
Introduction
Epidemiology, Pathogenesis, and Histopathology
Clinical Presentation: CMV Retinitis
CMVR in the HAART Era
Diagnosis
Differential Diagnosis
Treatment
Clinical Presentation: CMV Anterior Uveitis and Endothelitis
References
Key References
3 Infectious Causes of Uveitis–Bacterial
7.6 Syphilitic and Other Spirochetal Uveitis
Syphilitic Uveitis
Lyme Disease
Leptospirosis
References
Key References
7.7 Tuberculosis, Leprosy, and Brucellosis
Tuberculosis
Leprosy
Brucellosis
References
Key References
7.8 Cat Scratch and Whipple’s Disease:
Introduction
Cat Scratch Disease: Bartonella Henselae Associated Uveitis
Whipple’s Disease: Tropheryma Whippelii Associated Uveitis
References
Key References
7.9 Infectious Endophthalmitis
Introduction
Epidemiology and Risk Factors
Pathology and Pathogenesis
Clinical Presentation and Evaluation
Microbiologic Testing
Differential Diagnosis
Treatment
Outcomes
Conclusion
References
Key References
4 Infectious Causes of Uveitis–Fungal
7.10 Histoplasmosis
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Pathology
Treatment
Course and Outcome
References
Key References
7.11 Fungal Endophthalmitis
Candida
Aspergillus
Fusarium
Coccidioides Immitis – Ocular Coccidiodomycosis
Cryptococcal Endophthalmitis
Histoplasma Endophthalmitis
References
Key References
5 Infectious Causes of Uveitis–Protozoal and Parasitic
7.12 Ocular Toxoplasmosis
Introduction
Organism and Life Cycle
Epidemiology
Pathology and Pathogenesis
Clinical Manifestations
Diagnosis
Differential Diagnosis
Therapy
Course and Prognosis
References
Key References
7.13 Posterior Parasitic Uveitis
Introduction
Toxocariasis
Cysticercosis
Onchocerciasis
Gnathostomiasis
References
Key References
6 Uveitis Associated with Systemic Disease
7.14 Uveitis Related to HLA-B27
Uveitis Related to HLA-B27
Juvenile Idiopathic Arthritis (JIA)
Uveitis Related to HLA-B27
Juvenile Idiopathic Arthritis (JIA)
References
Key References
7.15 Sarcoidosis
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
7.16 Behçet’s Disease
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
7.17 Vogt-Koyanagi-Harada Disease
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
7 Traumatic Uveitis
7.18 Phacogenic Uveitis
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Pathology
Treatment
Course and Outcome
References
Key References
7.19 Sympathetic Uveitis
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8 Uveitis of Unknown Causes
7.20 Idiopathic and Other Anterior Uveitis Syndromes
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Fuchs’ Heterochromic Iridocyclitis
Possner Schlossman Syndrome
Drug-Induced Anterior Uveitis
Schwartz-Matsuo Syndrome
References
Key References
7.21 Pars Planitis and Other Intermediate Uveitis
Introduction
Epidemiology and Pathogenesis
Ocular Findings and Complications
Diagnosis
Management
Prognosis
References
Key References
7.22 Posterior Uveitis of Unknown Cause – White Spot Syndromes
Introduction
Birdshot Chorioretinopathy
Acute Posterior Multifocal Placoid Pigment Epitheliopathy
Serpiginous Choroiditis
Relentless Placoid Chorioretinitis
Persistent Placoid Maculopathy
Multifocal Choroiditis and Panuveitis, Punctate Inner Choroidopathy, and Subretinal Fibrosis and Uveitis Syndrome
Multifocal Choroiditis and Panuveitis
Punctate Inner Choroidopathy
Progressive Subretinal Fibrosis and Uveitis Syndrome
Multiple Evanescent White Dot Syndrome
Acute Zonal Occult Outer Retinopathy
Acute Macular Neuoretinopathy
References
Key References
9 Masquerade Syndromes
7.23 Masquerade Syndromes:
Introduction
Primary Neoplasms
Secondary Neoplasms and Metastases
Conclusion
References
Key References
8 Intraocular Tumors
1 Malignant and Intraocular Tumors
8.1 Retinoblastoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.2 Uveal Melanoma
Introduction
Epidemiology and Pathogenesis
Iris Melanomas
Choroidal and Ciliary Body Melanomas
References
Key References
8.3 Metastatic Cancer to the Eye
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.4 Lymphoma and Leukemia
Introduction
Primary Intraocular Lymphoma
Intraocular Leukemia
References
Key References
8.5 Medulloepithelioma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
2 Benign Intraocular Tumors
8.6 Uveal Nevus
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Management (Box 8-6-2)
Course and Outcome
References
Key References
8.7 Choroidal Hemangiomas
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.8 Choroidal Osteoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.9 Astrocytoma of Retina
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.10 Hemangiomas of Retina
Capillary Hemangioma of Retina
Cavernous Hemangioma of Retina
References
Key References
8.11 Combined Hamartoma of Retina
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
8.12 Hypertrophy of Retinal Pigment Epithelium
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
3 Phakomatoses
8.13 Phakomatoses
Introduction
Neurofibromatosis
Tuberous Sclerosis
Von Hippel-Lindau Syndrome
Sturge-Weber Syndrome
Wyburn-Mason Syndrome
References
Key References
9 Neuro-Ophthalmology
1 Imaging in Neuro–Ophthalmology
9.1 Principles of Imaging in Neuro-Ophthalmology
Introduction
Computed Tomography
Magnetic Resonance Imaging
Angiography
Functional Imaging
Imaging Strategies in Neuro-Ophthalmology
References
Key References
9.2 Optical Coherence Tomography in Neuro-Ophthalmology
Papilledema
Compressive Optic Neuropathy
Multiple Sclerosis
Neurodegenerative Diseases
Hereditary Optic Neuropathies
2 The Afferent Visual System
9.3 Anatomy and Physiology
Historical Review
General Anatomy
Constituent Elements
Four Portions of the Optic Nerve
Circulation of the Optic Nerve
References
Key References
9.4 Differentiation of Optic Nerve from Macular Retinal Disease
Introduction
Ocular Features
Diagnosis and Ancillary Testing
References
Key References
9.5 Congenital Optic Disc Anomalies
Introduction
Optic Nerve Hypoplasia
Morning Glory Disc Anomaly
Optic Disc Coloboma
Optic Pit
Megalopapilla
Congenital Tilted Disc Syndrome
Congenital Optic Disc Pigmentation
Aicardi Syndrome
References
Key References
9.6 Papilledema and Raised Intracranial Pressure
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
9.7 Inflammatory Optic Neuropathies and Neuroretinitis
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Course and Outcome
References
Key References
9.8 Ischemic Optic Neuropathies
Ischemic Optic Neuropathies
Diabetic Papillopathy
References
Key References
9.9 Hereditary, Nutritional, and Toxic Optic Atrophies
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Systemic Associations
Pathology
Treatment
Course and Outcome
References
Key References
9.10 Prechiasmal Pathways – Compression by Optic Nerve and Sheath Tumors
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Treatment
Optic Nerve Compression by Optic Nerve and Sheath Tumors
Optic Nerve Sheath Meningiomas
Intracanalicular and Intracranial Compressive Lesions
References
Key References
9.11 Traumatic Optic Neuropathies
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
References
Key References
9.12 Optic Chiasm, Parasellar Region, and Pituitary Fossa
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Pathology
Treatment, Course, and Outcome
Optic Gliomas
References
Key References
9.13 Retrochiasmal Pathways, Higher Cortical Function, and Non-Organic Visual Loss
Etrochiasmal Pathways and Higher Cortical Function
Cortical Representation of Vision
References
Key References
3 The Efferent Visual System
9.14 Disorders of Supranuclear Control of Ocular Motility
Introduction
Anatomy of Eye Movement
Diagnostic Testing
Disorders of Supranuclear Ocular Motility
Ocular Motility Disorders and the Cerebellum
Ocular Motility Disorders and the Vestibular System
Vergence Disorders
Development of the Ocular Motor System
References
Key References
9.15 Nuclear and Fascicular Disorders of Eye Movement
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Treatment, Course, and Outcome
References
Key References
9.16 Paresis of Isolated and Multiple Cranial Nerves and Painful Ophthalmoplegia
Introduction
Anatomy
Ocular Manifestations
Diagnosis
Differential Diagnosis
Treatment
Key References
References
9.17 Disorders of the Neuromuscular Junction
Myasthenia Gravis
Botulism
Lambert-Eaton Myasthenic Syndrome
Key References
References
9.18 Ocular Myopathies
Introduction
Mitochondrial Disorders
Dystrophic Myopathies
Graves’ Dysthyroid Ophthalmopathy
Other Inflammatory and Infiltrative Myopathies
Key References
References
9.19 Nystagmus, Saccadic Intrusions, and Oscillations
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Treatment
Key References
References
9.20 The Pupils
Introduction
Relative Afferent Pupillary Defects
Efferent Pupillary Defects
Poor Pupil Dilatation
Recent Discoveries in the Retinal Origin of the Pupil Light Reflex – the Melanopsin-Containing Retinal Ganglion Cell
Key References
References
9.21 Presbyopia and Loss of Accommodation
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Treatment
Course and Outcome
Key References
References
4 The Brain
9.22 Headache and Facial Pain
Introduction
Differential Diagnosis of Headache Syndromes
Differential Diagnosis of Facial Pain
References
Key References
9.23 Tumors, Infections, Inflammations, and Neurodegenerations
Tumors
Infections
Inflammations
Neurodegenerations
References
Key References
5 Neuro-Ophthalmologic Emergencies
9.24 Urgent Neuro-Ophthalmic Disorders
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Pathology
Treatment
Course and Outcomes
References
Key References
9.25 Trauma, Drugs, and Toxins
Trauma and the Brain
Drugs, Toxins, and the Brain
References
Key References
9.26 Vascular Disorders
Introduction
Aneurysms
Carotid-Cavernous Sinus Fistulas and Dural Shunts
Arteriovenous Malformations
Transient Visual Loss
Strokes
References
Key References
10 Glaucoma
1 Epidemiology and Mechanisms of Glaucoma
10.1 Epidemiology of Glaucoma
Introduction
Prevalence and Rates of Associated Blindness
Primary Open-Angle Glaucoma
Primary Angle-Closure Glaucoma
Secondary Glaucomas
Ocular Hypertension
Glaucoma Suspects
Key References
References
10.2 Screening for Glaucoma
Introduction
Historical Review
Purpose of the Test
Utility of the Test and Interpretation of Results
Procedure
Complications
Alternative Tests
Future Direction of Glaucoma Screening
Key References
References
10.3 Mechanisms of Glaucoma
Introduction
Glaucomatous Damage to the Aqueous Humor Outflow Pathway
Physiology of Inflow
Pathophysiology of Glaucomatous Optic Neuropathy
Conclusion
Key References
References
2 Evaluation and Diagnosis
10.4 Clinical Examination of Glaucoma
Introduction
Obtaining Clinically Relevant Information
Examination Techniques
Testing for Glaucoma
Key References
References
10.5 Visual Field Testing in Glaucoma
Introduction
Standard Automated Perimetry
Key References
References
10.6 Advanced Psychophysical Tests for Glaucoma
Introduction
New Test Strategies
New Test Procedures
New Analysis Methods
Conclusion
Key References
References
10.7 Optic Nerve Analysis
Introduction
Normal Anatomy
Clinical Examination: Glaucomatous Features
Imaging
Optic Disc Photographs
Confocal Scanning Laser Ophthalmoscopy
Optical Coherence Tomography
Conclusion
Key References
References
10.8 Optic Nerve Blood Flow Measurement
Introduction
Applied Anatomy
Physiology
Experimental Investigations
Clinical Studies
Systemic Vascular Disease and Glaucoma
Pharmacology
Key References
References
10.9 Ocular Hypertension
Introduction
Epidemiology and Pathogenesis
Diagnosis
Differential Diagnosis
Treatment
Course and Outcome
Key References
References
3 Specific Types of Glaucoma
10.10 Primary Open-Angle Glaucoma
Definition and Classification
Intraocular Pressure and Other Risk Factors for POAG
Diagnosis
Nature of Progressive Visual Loss
Treatment and Monitoring
Key References
References
10.11 Normal-Tension Glaucoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Treatment
Course and Outcome
Key References
References
10.12 Angle-Closure Glaucoma
Introduction
Epidemiology and Pathogenesis
Diagnosis
Differential Diagnosis
Management of Acute Angle Closure
Management of Chronic ACG
Management of Angle-Closure Glaucoma
Prognosis
Key References
References
10.13 Glaucoma Associated with Pseudoexfoliation Syndrome
Introduction
Epidemiology and Genetics
Systemic Manifestations
Clinical Presentation and Ocular Manifestations
Differential Diagnosis
Treatment and Outcome
Key References
References
10.14 Pigmentary Glaucoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Differential Diagnosis
Treatment
Course and Outcome
Key References
References
10.15 Neovascular Glaucoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Treatment
Course and Outcome
Emerging Treatments
Key References
References
10.16 Inflammatory and Corticosteroid-Induced Glaucoma
Introduction
Pathophysiology
Mechanisms of Elevated IOP
Principles of Management
Uveitis
Glaucoma
Specific Entities
Key References
References
10.17 Glaucoma Associated with Ocular Trauma
Introduction
Immediate or Early-Onset Glaucoma after Ocular Trauma
Late-Onset Glaucoma after Ocular Trauma
Key References
References
10.18 Glaucoma with Raised Episcleral Venous Pressure
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Systemic Associations
Treatment
Course and Outcome
Key References
References
10.19 Aqueous Misdirection Syndrome
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis
Differential Diagnosis
Treatment
Key References
References
10.20 Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors
Ghost Cell Hemolytic Glaucoma
Schwartz’s Syndrome
Iridocorneal Endothelial Syndrome
Axenfeld–Rieger Syndrome
Epithelial Downgrowth and Fibrous Ingrowth (Proliferation)
Aniridia
Tumors and Glaucoma
Penetrating Keratoplasty
Alkali Chemical Trauma
Key References
References
10.21 Congenital Glaucoma
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Classification Schemes
Pathology
Treatment
Course and Outcome
Key References
References
4 Therapy
10.22 When to Treat Glaucoma
Introduction
Analysis of Risk Factors
Risk Factors
Principles of Initiation of Therapy
Initiation of Therapy in the Glaucoma Patient
Initiation of Therapy in the Glaucoma Suspect
Conclusion
Key References
References
10.23 Which Therapy to Use in Glaucoma?
Introduction
Historical Review
Treatment Modalities
Treatment Algorithms
Conclusions
Key References
References
10.24 Current Medical Management of Glaucoma
Introduction
Drugs That Decrease Aqueous Production
Drugs That Increase Aqueous Outflow
Fixed Combination Medications
The Medical Armamentarium of Glaucoma Treatment
Key References
References
10.25 Laser Trabeculoplasty and Laser Peripheral Iridectomy
Laser Trabeculoplasty
Laser Peripheral Iridectomy
Laser Iridoplasty
Key References
References
10.26 Cyclodestructive Procedures in Glaucoma
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Mechanism of Action
Alternatives to a Cyclodestructive Procedure
Anesthesia
Specific Techniques
Endoscopic Laser Cyclophotocoagulation
Complications
Outcome
Key References
References
10.27 Goniotomy and Trabeculotomy
Introduction
Indications
Instruments
Preoperative Care
Examination Under Anesthesia (EUA)
Procedures
Postoperative Care
Results
Complications
Key References
References
10.28 Minimally Invasive and Nonpenetrating Glaucoma Surgeries
Introduction
Considerations for Patient Selection
Angle Surgeries: Minimally Invasive and Nonpenetrating Glaucoma Surgeries
Suprachoroidal Drainage Devices
Conclusions
Key References
References
10.29 Trabeculectomy
Introduction
Indications
Surgical Planning
Preoperative Factors to Consider
Patient Counseling
Surgical Techniques
Postoperative Care
Conclusion
Key References
References
10.30 Antifibrotic Agents in Glaucoma Surgery
Introduction
Types of Antifibrotic Agents
Indications for Antimetabolite Use
Application Techniques
Position of Drainage Area Under Eyelid
Closure of Scleral Flap and Associated Surgical Techniques
Postoperative Injections
Complications
Future Strategies to Prevent Fibrosis
References
Key References
10.31 Drainage Implants
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Alternatives
Surgical Technique
Complications
Outcome
References
Key References
10.32 Complications of Glaucoma Surgery and their Management
Introduction
Trabeculectomy
Glaucoma Drainage Implants
References
Key References
10.33 Genes Associated with Human Glaucoma
Introduction
Congenital Glaucoma
Developmental Glaucoma
Primary Open-Angle Glaucoma: Juvenile Onset
Pigment Dispersion Syndrome and Glaucoma
Primary Open-Angle Glaucoma: Adult Onset
Low-Tension Glaucoma
Pseudoexfoliation Syndrome and Glaucoma
Angle-Closure Glaucoma
References
Key References
10.34 Evidence-Based Medicine in Glaucoma
Introduction
The Tools of Evidence-Based Medicine
Evaluation of Diagnostic Testing in Glaucoma
Examples of Evidence-Based Medicine in Glaucoma Therapy
Barriers to the Practice of Evidence-Based Medicine
Future Directions
Conclusion
References
Key References
11 Pediatric and Adult Strabismus
1 Basic Science
11.1 Anatomy and Physiology of the Extraocular Muscles and Surrounding Tissues
Embryology
Gross Anatomy of the Extraocular Muscles
The Orbital Infrastructure and Anatomy
Clinical Correlates
Extraocular Muscle Physiology
Key References
References
2 Evaluation and Diagnosis
11.2 Evaluating Vision in Preverbal and Preliterate Infants and Children
Introduction
Historical and Observational Techniques
Fixation Targets
Opticokinetic Nystagmus
Visual Evoked Potentials
Forced-Choice Preferential Looking
Graded Optotypes
Maturation of Visual Acuity
Key References
References
11.3 Examination of Ocular Alignment and Eye Movements
Evaluation of Ocular Alignment
Eye Movement Examinations
Key References
References
11.4 Sensory Adaptations in Strabismus
Visual Confusion and Diplopia
Suppression and Anomalous Retinal Correspondence
Monofixation Syndrome
Key References
References
3 Ocular Manifestations
11.5 Sensory Status in Strabismus
Introduction
Sensory Fusion
Depth Perception and Stereopsis
Clinical Testing
Key References
References
11.6 Esotropia
Congenital Esotropia
Accommodative Esotropia
Duane’s Syndrome
Introduction
Congenital Esotropia
Accommodative Esotropia
Cyclic Esotropia
Möbius’ Syndrome
Duane’s Syndrome
Strabismus Fixus
Esotropia in the Neurologically Impaired
Esotropia Associated with Visual Deficit
Head-Tilt Dependent Esotropia Associated with Trisomy 21
Esotropia Caused by High Myopia and Globe Prolapse From the Muscle Cone
Key References
References
11.7 Exotropia
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Treatment
Course and Outcome
References
Key References
11.8 Oblique Muscle Dysfunctions
Introduction
Primary Inferior Oblique Overaction
Secondary Inferior Oblique Overaction
Inferior Oblique Underaction
Primary Superior Oblique Overaction
Secondary Superior Oblique Overaction
Superior Oblique Underaction
References
Key References
11.9 Alphabet-Pattern Strabismus
Introduction
V-Pattern Esotropia
V-Pattern Exotropia
A-Pattern Esotropia
A-Pattern Exotropia
X-Pattern Strabismus
References
Key References
11.10 Paralytic Strabismus
Introduction
Third Nerve Palsy
Fourth Nerve Palsy
Sixth Nerve Palsy
Summary
Key References
References
11.11 Other Vertical Strabismus Forms
Introduction
Dissociated Vertical Divergence
Primary Inferior Oblique Overaction
Double Elevator Palsy
Brown’s Syndrome
Congenital Fibrosis
Fractures of the Orbital Floor
Graves’ Ophthalmopathy (Dysthyroid Orbitopathy)
Heavy Eye Syndrome
Key References
References
11.12 Amblyopia
Introduction
Epidemiology and Pathogenesis
Ocular Manifestations
Diagnosis and Ancillary Testing
Differential Diagnosis
Treatment
Course and Outcome
Key References
References
4 Treatment
11.13 Forms of Nonsurgical Strabismus Management
Sector Occlusion
Orthoptics
Prisms
Botulinum Toxin
References
Key References
11.14 Techniques of Strabismus Surgery
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Anesthesia
General Techniques
Specific Techniques
Complications
Outcomes
References
Key References
12 Orbit and Oculoplastics
1 Orbital Anatomy and Imaging
12.1 Clinical Anatomy of the Eyelids
Introduction
Anatomy of the Eyelids
Nerves to the Eyelids
Vascular Supply to the Eyelids
References
Key References
12.2 Clinical Anatomy of the Orbit
Introduction
General Organization
Osteology of the Orbit
Connective Tissue System
Muscles of Ocular Motility
Motor Nerves of the Orbit
Sensory Nerves of the Orbit
Arterial Supply to the Orbit
Venous Drainage From the Orbit
Key References
References
12.3 Orbital Imaging Techniques
Introduction
Normal Orbital Anatomy in the Axial Plane
Normal Orbital Anatomy in the Coronal Plane
Orbital Echography
Key References
References
2 Eyelids
12.4 Eyelid Retraction
Introduction
Preoperative Evaluation and Diagnostic Approach
Differential Diagnosis
Alternatives to Surgery
Anesthesia
Surgical Techniques
Complications
Outcome
Key References
References
12.5 Blepharoptosis
Introduction
Preoperative Evaluation and Diagnostic Approach
Differential Diagnosis
Ptosis Repair
Anesthesia
General Techniques
Specific Techniques
Complications
Outcome
Key References
References
12.6 Entropion
Introduction
Preoperative Evaluation and Diagnostic Approach
Differential Diagnosis
Alternatives to Surgery
Anesthesia
General Technique
Specific Techniques
Complications
Outcome
Key References
References
12.7 Ectropion
Introduction
Historical Review
Preoperative Evaluation and Diagnostic Approach
Alternatives to Surgery
Anesthesia
General Techniques
Specific Techniques
Complications
Outcome
Key References
References
12.8 Essential Blepharospasm
Introduction
Ocular Manifestations
Diagnosis
Differential Diagnosis
Pathology
Treatment
Course and Outcome
Key References
References
12.9 Benign Eyelid Lesions
Introduction
Epithelial Tumors
Adnexal Tumors
Vascular Tumors
Tumors of Neural Origin
Xanthomatous Lesions
Pigmented Lesions of Melanocytic Origin
Inflammatory Lesions
Infectious Lesions
Conclusion
Outcomes
Key References
References
12.10 Eyelid Malignancies
Introduction
Basal Cell Carcinoma
Squamous Cell Carcinoma
Sebaceous Gland Carcinoma
Malignant Melanoma
Key References
References
12.11 Eyelid Trauma and Reconstruction Techniques
Introduction
Preoperative Evaluation and Diagnostic Approach
Anesthesia
General Techniques
Specific Techniques
Outcome
References
Key References
3 Orbit and Lacrimal Gland
12.12 Orbital Diseases
Introduction
Clinical Evaluation
Metastatic Tumors
Lacrimal Gland Lesions
Mesenchymal Tumors
Neurogenic Tumors
Lymphoproliferative Diseases
Histiocytic Tumors
Inflammations and Infections
Sturctural Lesions
Vascular Neoplastic Lesions
References
Key References
12.13 Orbital Surgery
Introduction
Preoperative Evaluation and Diagnostic Approach
General Techniques
Specific Techniques
Complications
Outcome
References
Key References
12.14 Enucleation, Evisceration, and Exenteration
Introduction
Preoperative Evaluation and Diagnostic Approach
Anesthesia
Specific Techniques
Complications
References
Key References
12.15 The Lacrimal Drainage System
Introduction
Anatomy and Physiology
Evaluation of Epiphora
Obstructions of the Lacrimal Sac and Duct
Treatment of Lacrimal Sac and Duct Obstruction
Tumors of the Lacrimal Sac
Diseases of the Canaliculi
Punctal Stenosis
References
Key References
4 Periorbital Aesthetic Procedures
12.16 Cosmetic Blepharoplasty and Browplasty
Introduction
Anatomic Considerations
Blepharoplasty
Brow Malposition
References
Key References
12.17 Injectable Skin Fillers
Introduction
Collagen
Hyaluronic Acid
Calcium Hydroxyapatite
Poly-L-Lactic Acid
Treatment Techniques
Contraindications and Adverse Reactions
Key References
References
12.18 Cosmetic Wrinkle Reduction with Botulinum Toxin
Introduction
Botulinum Neurotoxin
Mechanism of Action
Contraindications and Precautions
Adverse Reactions
Commercially Available Botulinum Toxin Agents
Suggested Dilution Protocols
Cosmetic Applications of Botulinum Toxin
Treatment of Glabellar Furrows
Transverse Forehead Lines
Treatment of Orbicularis Rhytids or ‘Crow’s-Feet’
Key References
References
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z

Citation preview

Fourth Edition

OPHTHALMOLOGY

Content Strategist: Russell Gabbedy Content Development Specialist: Sharon Nash Content Coordinator: Trinity Hutton Project Manager(s): Caroline Jones, Joanna Souch Design: Christian Bilbow Illustration Manager: Jennifer Rose Illustrator: Antbits Marketing Manager(s) (UK/USA): Gaynor Jones/Abigail Swartz Original cover image SS OCT: Courtesy James G. Fujimoto PHD

Fourth Edition

OPHTHALMOLOGY LEAD EDITORS Myron Yanoff MD

Professor and Chair Department of Ophthalmology Drexel University College of Medicine Adjunct Professor of Ophthalmology University of Pennsylvania Philadelphia, PA, USA

Jay S. Duker MD

Director, New England Eye Center Chairman and Professor of Ophthalmology Tufts Medical Center Tufts University School of Medicine Boston, MA, USA

SECTION EDITORS James J. Augsburger MD

Michael H. Goldstein MD MBA

Alfredo A. Sadun MD PhD

Professor and Chairman Department of Ophthalmology University of Cincinnati College of Medicine Cincinnati, OH, USA

Co-Director, Cornea and External Diseases Service New England Eye Center Tufts Medical Center Boston, MA, USA

Flora Thornton Chair of Vision Research Professor of Ophthalmology and Neurological Surgery Doheny Eye Institute USC-Keck School of Medicine Director, Neuro-Ophthalmology Vice Chair, Education Los Angeles, CA, USA

Dimitri T. Azar MD MBA Dean of the College of Medicine University of Illinois at Chicago Chicago, IL, USA

Sophie J. Bakri MD Associate Professor of Ophthalmology Director of Vitreoretinal Surgery Fellowship Vitreoretinal Diseases and Surgery Mayo Clinic Rochester, MN, USA

Gary R. Diamond MD Former Professor of Ophthalmology and Pediatrics Drexel University School of Medicine Philadelphia, PA, USA

Jonathan J. Dutton MD PhD Professor and Vice Chair Department of Ophthalmology University of North Carolina Chapel Hill, NC, USA

David Miller MD Associate Clinical Professor of Ophthalmology Harvard Medical School Boston, MA, USA

Narsing A. Rao MD Professor of Ophthalmology and Pathology, Doheny Eye Institute University of Southern California Los Angeles, CA, USA

Emanuel S. Rosen MD FRCS FRCOphth Private Practice Co-editor of the Journal of Cataract & Refractive Surgery Manchester, UK

Joel S. Schuman MD FACS Eye and Ear Foundation Professor and Chairman, Department of Ophthalmology University of Pittsburgh School of Medicine Director, UPMC Eye Center Professor of Bioengineering Pittsburgh, PA, USA

Janey L. Wiggs MD PhD Associate Professor of Ophthalmology Harvard Medical School Massachusetts Eye and Ear Infirmary Boston, MA, USA

SAUNDERS is an imprint of Elsevier Inc. © 2014, Elsevier Inc. All rights reserved. First edition 1999 Second edition 2004 Third edition 2009 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Chapter 4.30: ‘Endothelial Keratoplasty: Targeted treatment for corneal endothelial dysfunction’ by Francis W. Price, Jr., Marianne O. Price Marianne O. Price and Francis W. Price Jr. retain copyright of the video accompanying this chapter. Chapter 6.5: ‘Contact B-Scan Ultrasonography’ by Yale L. Fisher, James M. Klancnik Jr, Hanna Rodriguez-Coleman, Antonio P. Ciardella, Nicole E. Gross, David Y. Kim Yale L. Fisher retains copyright of the video accompanying this chapter. The remainder of this lecture as well as additional lectures on ophthalmology can be found at www.OphthalmicEdge.org. Chapter 7.2: ‘Mechanisms of uveitis’ by Igal Gery, Chi-Chao Chan This chapter is in the Public Domain. Chapter 7.23: ‘Masquerade Syndromes: Neoplasms’ by H. Nida Sen, Chi-Chao Chan This chapter is in the Public Domain.

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-1-4557-3984-4 e-book ISBN: 978-1-4557-5001-6 International Edition ISBN: 978-1-4557-3983-7

Printed in China Last digit is the print number:  9  8  7  6  5  4  3  2  1 

User Guide COLOR CODING

ExpertConsult.com Website

Ophthalmology is organized into 12 parts, which are color-coded as follows for quick and easy reference:

■ Fully searchable

Part 1: Genetics

■ Full reference lists for each chapter ■ Additional online content including text, figures & video clips

Part 2: Optics and Refraction Part 3: Refractive Surgery Part 4: Cornea and Ocular Surface Diseases Part 5: The Lens Part 6: Retina and Vitreous Part 7: Uveitis and Other Intraocular Inflammations Part 8: Intraocular Tumors Part 9: Neuro-ophthalmology Part 10: Glaucoma Part 11: Pediatric and Adult Strabismus Part 12: Orbit and Oculoplastics

v

Video Contents Video available at

Part 3: Refractive Surgery Chapter 3.5 LASIK

Chapter 6.11 Vitrectomy

3.5.1

6.11.1

iLASIK

Chapter 3.7 Phakic Intraocular Lenses

Chapter 6.31 Macular Hole

3.7.1

Cachet Lens

6.31.1

3.7.2

Artiflex Lens

Macular Hole Surgery

Chapter 6.32 Epiretinal Membrane

Part 4: Cornea and Ocular Surface Diseases

6.32.1

Chapter 4.30 Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

Chapter 6.33 Vitreomacular Traction Syndrome 6.33.1

Epiretinal Membrane Removal

Vitreomacular Traction Syndrome

4.30.1

DSEK Pull Through

4.30.2

DMEK Donor Preparation

Chapter 6.38 Rhegmatogenous Retinal Detachment

4.30.3

Descemet’s Membrane Endothelial Keratoplasty (DMEK)

6.38.1

Part 5: The Lens Chapter 5.6 Anesthesia for Cataract Surgery 5.6.1

Standard Technique for Sub-Tenon’s Anesthesia

5.6.2

“Incisionless” Technique for Sub-Tenon’s Anesthesia

Chapter 5.9 Small Incision and Femtosecond Laser Cataract Surgery 5.9.1

Unexpected Subluxation

5.9.2

Micro Incision Phaco

5.9.3

Micro Incision Refractive Lens Exchange

5.9.4

700 Micron Phaco

Chapter 5.11 Combined Procedures 5.11.1

Combined Phaco and Descemet Stripping Endothelial Keratoplasty (DSEK)

5.11.2

Combined Phacovitrectomy

Chapter 5.13 Pediatric Cataract Surgery 5.13.1

Congenital Cataract Surgery

Internal Limiting Membrane Peeling for Primary Rhegmatogenous Repair to Reduce Postoperative Macular Pucker

Chapter 6.40 Choroidal Hemorrhage 6.40.1

Transconjunctival Trocar/Cannula Drainage of Suprachoroidal Fluid

Chapter 6.42 Posterior Segment Ocular Trauma 6.42.1

Intraocular Foreign Body Removal

6.42.2

Intraocular Foreign Body Removal with Rare Earth Magnet

Part 7: Uveitis and Other Intraocular Inflammations Chapter 7.13 Posterior Parasitic Uveitis 7.13.1

Intraocular Gnathostomiasis

Part 10: Glaucoma Chapter 10.7 Optic Nerve Analysis 10.7.1

Three-Dimensional Imaging of the Optic Nerve Head

Chapter 10.28 Minimally Invasive and Nonpenetrating Glaucoma Surgeries 10.28.1 iStent G1 Implantation

Chapter 5.14 Complications of Cataract Surgery

10.28.2 Key Steps in Trabectome Surgery

5.14.1

10.28.3 Canaloplasty

Artisan Implantation

Part 6: Retina and Vitreous

10.28.4 SOLX Gold Shunt Implantation

Chapter 6.3 Retinal and Choroidal Circulation

Chapter 10.29 Trabeculectomy

6.3.1

10.29.1 Bleb Leak Detection Using Concentrated Fluorescein Dye

Retinal and Choroidal Circulation

Chapter 6.5 Contact B-Scan Ultrasonography 6.5.1

Examination Techniques for Contact B-Scan Ultrasonography

Chapter 6.10 Scleral Buckling Surgery

vi

Vitrectomy for Non-Clearing Vitreous Hemorrhage

6.10.1

Scleral Buckle

6.10.2

Suture

6.10.3

Drain

10.29.2 Trabeculectomy with Mitomycin C 10.29.3 5-Fluorouracil Subconjunctival Injection Chapter 10.31 Drainage Implants 10.31.1 Placement of the New Molteno 3 Glaucoma Draining Device into a Supra-Tenon Pocket Total running time approximately 130 minutes

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii Preface to First Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii

3.9

PART 1: GENETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

PART 4: CORNEA AND OCULAR SURFACE DISEASES . . . . . . . . . . . . 163

1.1

Fundamentals of human genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Janey L. Wiggs

1.2

Molecular genetics of selected ocular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Janey L. Wiggs

SECTION 1: BASIC PRINCIPLES 4.1 Corneal anatomy, physiology, and wound healing . . . . . . . . . . . . . . . . . . . . . 163 Ayad A. Farjo, Matthew V. Brumm, H. Kaz Soong

1.3

Genetic testing and genetic counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Janey L. Wiggs

PART 2: OPTICS AND REFRACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Intrastromal corneal ring segments and collagen crosslinking . . . . . . . . . . 147 Takashi Kojima, Jonathan D. Primack, Dimitri T. Azar

3.10 Surgical correction of presbyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Jorge L. Alió, Dimitri T. Azar, Kalliopi Stasi, Felipe A. Soria

4.2

Corneal topography and wavefront imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Michael J. Taravella, Richard S. Davidson

SECTION 2: CONGENITAL ABNORMAILITIES 4.3 Congenital Corneal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Joel Sugar, Hormuz P. Wadia, Roshni A. Vasaiwala SECTION 3: EXTERNAL DISEASES 4.4 Blepharitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Neha Gadaria-Rathod, Karen B. Fernandez, Penny A. Asbell

2.1

Visible light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 David Miller, Stephen K. Burns

2.2

Physical optics for clinicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Edmond H. Thall

2.3

Light damage to the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 David Miller, Clifford A. Scott

2.4

Principles of lasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Neal H. Atebara, Edmond H. Thall

2.5

Optics of the normal eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 David Miller, Paulo Schor, Peter Magnante†

4.7

Allergic conjunctivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Jonathan B. Rubenstein, Anjali Tannan

2.6

Testing of refraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Clifford A. Scott

4.8

Tumors of conjunctiva and cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 James J. Augsburger, Zélia M. Corrêa

2.7

Contact lenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Paul F. White, Clifford A. Scott

4.9

Pterygium and conjunctival degenerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Roni M. Shtein, Alan Sugar

2.8

Ophthalmic instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 David Miller, Edmond H. Thall, Neal H. Atebara

4.10 Ocular cicatricial pemphigoid/Mucous membrane pemphigoid . . . . . . . . 206 Ahmed R. Al-Ghoul, Gene Kim, Alex Mammen, Deepinder K. Dhaliwal

2.9

Perspectives on aberrations of the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Edmond H. Thall, David Miller

SECTION 5: SCLERAL AND EPISCLERAL DISEASES 4.11 Episcleritis and scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Debra A. Goldstein, Sarju S. Patel, Howard H. Tessler

PART 3: REFRACTIVE SURGERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 3.1

Current concepts, classification, and history of refractive surgery . . . . . . . . . 81 Suphi Taneri, Tatsuya Mimura, Dimitri T. Azar

3.2

Preoperative evaluation for refractive surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Joshua H. Hou, Joshua A. Young, Ernest W. Kornmehl, Jose de la Cruz

3.3

Excimer laser photorefractive keratectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Sandeep Jain, Sapna Tibrewal, Natalia Y. Kramarevsky, David R. Hardten

3.4

Laser subepithelial keratomileusis (LASEK) and Epi-LASIK . . . . . . . . . . . . . . . 102 Leonard P.K. Ang, Dimitri T. Azar

3.5

LASIK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Patricia B. Sierra, David R. Hardten, Elizabeth A. Davis

3.6

Wavefront-based excimer laser refractive surgery . . . . . . . . . . . . . . . . . . . . . . 120 Faisal M. Tobaigy, Daoud Fahd, Wallace Chamon

3.7

Phakic intraocular lenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Ramon C. Ghanem, Norma Allemann, Dimitri T. Azar

3.8

Astigmatic and radial incisional keratotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Kerry K. Assil, Joelle A. Hallak, Dimitri T. Azar

†Deceased

4.5

Herpes zoster ophthalmicus (HZO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 Gene Kim, Majid Moshirfar

SECTION 4: CONJUNCTIVAL DISEASES 4.6 Conjunctivitis: infectious and noninfectious . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Jonathan B. Rubenstein, Anjali Tannan

SECTION 6: CORNEAL DISEASES 4.12 Bacterial keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Jeremy D. Keenan, Stephen D. McLeod 4.13 Fungal keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Jeremy D. Keenan, Stephen D. McLeod 4.14 Parasitic keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Jeremy D. Keenan, Stephen D. McLeod 4.15 Herpes simplex keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Sonal S. Tuli, Anup A. Kubal 4.16 Peripheral ulcerative keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Sarkis H. Soukiasian 4.17 Noninfectious keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Amy Lin, Charles S. Bouchard 4.18 Keratoconus and other ectasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Joel Sugar, Priti Batta 4.19 Anterior corneal dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Michael H. Goldstein, Joel Sugar, Amy T. Kelmenson, Hormuz P. Wadia, Bryan Edgington

vii

Contents

4.20 Stromal corneal dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Joel Sugar, Hormuz P. Wadia, Roshni A. Vasaiwala

5.16 Secondary cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Liliana Werner

4.21 Corneal endothelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Noel Rosado-Adames, Natalie A. Afshari

5.17 Epidemiology, pathophysiology, causes, morphology, and visual effects of cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Mark Wevill

4.22 Corneal degenerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 Maria A. Woodward, Shahzad I. Mian, Alan Sugar 4.23 Dry eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Naveen K. Rao, Michael H. Goldstein, Elmer Y. Tu SECTION 7: MISCELLANEOUS CONDITIONS 4.24 Contact lens-related complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 William Ehlers, Jeanine Suchecki, Thomas L. Steinemann, Peter Donshik

SECTION 1: ANATOMY 6.1 Structure of the neural retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Hermann D. Schubert 6.2

Retinal pigment epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Michael F. Marmor

6.3

SECTION 8: TRAUMA 4.26 Acid and alkali burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 Naveen K. Rao, Michael H. Goldstein

Retinal and choroidal circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 Caio Vinícius Saito Regatieri, Shiyoung Roh, John J. Weiter

6.4

Vitreous anatomy and pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 J. Sebag

SECTION 9: SURGERY 4.27 Corneal surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Lana Srur, Lisa Martén, Ming X. Wang, Robert P. Selkin, Carol L. Karp

SECTION 2: ANCILLARY TESTS 6.5 Contact B-scan ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Yale L. Fisher, James M. Klancnik Jr, Hanna Rodriguez-Coleman, Antonio P. Ciardella, Nicole E. Gross, David Y. Kim

4.25 Corneal and external eye manifestations of systemic disease . . . . . . . . . . . 290 Priti Batta, Hormuz P. Wadia, Joel Sugar

4.28 Excimer laser treatment of corneal pathology . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Lana Srur, Robert P. Selkin, Dimitri T. Azar, Lisa Martén, Ming X. Wang, Carol L. Karp

6.6

Fluorescein angiography and indocyanine green angiography . . . . . . . . . 440 Raul Velez-Montoya, Jeffrey L. Olson, Naresh Mandava

4.29 Conjunctival surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Lana Srur, Lisa Martén, Ming X. Wang, Robert P. Selkin, Carol L. Karp

6.7

Optical coherence tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448 Miriam Englander, David Xu, Peter K. Kaiser

4.30 Endothelial keratoplasty: Targeted treatment for corneal endothelial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Marianne O. Price, Francis W. Price Jr

6.8

Electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Darin R. Goldman, Elias Reichel

4.31 Surgical ocular surface reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Matthew J. Weiss, Victor L. Perez 4.32 Management of corneal thinning, melting, and perforation . . . . . . . . . . . . 325 Nicoletta Fynn-Thompson, Michael H. Goldstein

PART 5: THE LENS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 5.1

Basic science of the lens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Jonathan Schell, Michael E. Boulton

5.2

Evolution of intraocular lens implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Liliana Werner, Andrea M. Izak, Suresh K. Pandey, David J. Apple†

5.3

Patient workup for cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 Frank W. Howes

5.4

Indications for lens surgery/Indications for application of different lens surgery techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Frank W. Howes

5.5

The pharmacotherapy of cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 Steve A. Arshinoff, Yvonne A.V. Opalinski, Dominik W. Podbielski

5.6

Anesthesia for cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356 Keith G. Allman

5.7

Phacoemulsification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 David Allen

5.8

Refractive aspects of cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 Emanuel S. Rosen

5.9

Small incision and femtosecond laser cataract surgery . . . . . . . . . . . . . . . . . 371 Mark Packer

5.10 Manual cataract extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 Frank W. Howes 5.11 Combined procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382 David Allen, David H.W. Steel

viii

PART 6: RETINA AND VITREOUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419

SECTION 3: BASIC PRINCIPLES OF RETINAL SURGERY 6.9 Light and laser injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Caroline R. Baumal, Michael Ip, Carmen A. Puliafito 6.10 Scleral buckling surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 Lisa J. Faia, George A. Williams 6.11 Vitrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Michael Engelbert, Stanley Chang 6.12 Intravitreal injections and medication implants . . . . . . . . . . . . . . . . . . . . . . . . 476 Ryan W Shultz, Sophie J. Bakri SECTION 4: DYSTROPHIES 6.13 Progressive and ‘stationary’ inherited retinal degenerations . . . . . . . . . . . . 480 Catherine A. Cukras, Wadih M. Zein, Rafael C. Caruso, Paul A Sieving 6.14 Macular dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 David G. Telander, Kent W. Small 6.15 Choroidal dystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 Sandeep Grover, Gerald A. Fishman, Mohamed A. Genead 6.16 Hereditary vitreoretinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Alan E. Kimura SECTION 5: VASCULAR DISORDERS 6.17 Hypertensive retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 Adam H. Rogers 6.18 Retinal arterial obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 Jay S. Duker 6.19 Venous occlusive disease of the retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Darin R. Goldman, Chirag P. Shah, Michael G. Morley, Jeffrey S. Heier 6.20 Retinopathy of prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 Amir H. Kashani, Kimberly A. Drenser, Antonio Capone Jr 6.21 Diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 Jennifer I. Lim, Brett J. Rosenblatt, William E. Benson

5.12 Cataract surgery in complicated eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386 Gary S. Schwartz, Stephen S. Lane

6.22 Ocular ischemic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551 Jorge A. Fortun, Matthew T.S. Tennant, Arunan Sivalingam, Gregory M. Fox, Gary C. Brown

5.13 Pediatric cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 Elie Dahan

6.23 Hemoglobinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Michael D. Tibbetts, Allen C. Ho

5.14 Complications of cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 Thomas Kohnen, Marko Ostovic, Li Wang, Neil J. Friedman, Douglas D. Koch

6.24 Coats’ disease and retinal telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560 Diana V. Do, Julia A. Haller

5.15 Outcomes of cataract surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Mats Lundström

6.25 Radiation retinopathy and papillopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 Ahmet Kaan Gűndűz, Carol L. Shields 6.26 Proliferative retinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Jeevan R. Mathura Jr, Srilaxmi Bearelly, Lee M. Jampol

7.9

SECTION 6: MACULAR DISORDERS 6.28 Age-related macular degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 Renata Portella Nunes, Philip J. Rosenfeld, Carlos Alexandre de Amorim Garcia Filho, Zohar Yehoshua, Adam Martidis, Matthew T.S. Tennant

SECTION 4: INFECTIOUS CAUSES OF UVEITIS – FUNGAL 7.10 Histoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729 Ramana S. Moorthy

6.29 Secondary causes of choroidal neovascularization: Conditions associated with breaks in Bruch’s membrane . . . . . . . . . . . . . . . 600 Richard F. Spaide 6.30 Central serous chorioretinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 Jose S. Pulido, Anna S. Kitzmann, William J. Wirostko 6.31 Macular hole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610 Andrew A. Moshfeghi, Jay S. Duker

Infectious endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723 Yevgeniy (Eugene) Shildkrot, Dean Eliott

7.11 Fungal endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733 Dimitra Skondra, Dean Eliott SECTION 5: INFECTIOUS CAUSES OF UVEITIS – PROTOZOAL AND PARASITIC 7.12 Ocular toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738 Daniel Vitor Vasconcelos-Santos 7.13 Posterior parasitic uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744 Jyotirmay Biswas

6.32 Epiretinal membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 T. Mark Johnson, Mark W. Johnson

SECTION 6: UVEITIS ASSOCIATED WITH SYSTEMIC DISEASE 7.14 Uveitis related to HLA-B27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748 Carlos E. Pavesio, Nicholas Jones

6.33 Vitreomacular traction syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 William E. Smiddy

7.15 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 Claude L. Cowan Jr

6.34 Cystoid macular edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625 Matthew T. Witmer, Szilárd Kiss

7.16 Behçet’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758 Annabelle A. Okada

6.35 Coexistent optic nerve and macular abnormalities . . . . . . . . . . . . . . . . . . . . . 632 Odette M. Houghton, Gary C. Brown, Melissa M. Brown

7.17 Vogt–Koyanagi–Harada disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761 Narsing A. Rao

SECTION 7: RETINAL DETACHMENT 6.36 Peripheral retinal lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638 William Tasman

SECTION 7: TRAUMATIC UVEITIS 7.18 Phacogenic uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764 Julie Gueudry, Bahram Bodaghi

6.37 Retinal breaks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 Craig M. Greven

7.19 Sympathetic uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 Veena Rao Raiji, Narsing A. Rao

6.38 Rhegmatogenous retinal detachment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646 Rajesh C. Rao, Gaurav K. Shah 6.39 Serous detachments of the neural retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 Benjamin J. Thomas, Thomas A. Albini 6.40 Choroidal hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660 Michael A. Kapusta, Radwan S. Ajlan, Pedro F. Lopez 6.41 Proliferative vitreoretinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665 David G. Charteris, G. William Aylward SECTION 8: TRAUMA 6.42 Posterior segment ocular trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 John W. Kitchens, Patrick E. Rubsamen 6.43 Distant trauma with posterior segment effects . . . . . . . . . . . . . . . . . . . . . . . . . 678 Jason Hsu, Carl D. Regillo

SECTION 8: UVEITIS OF UNKNOWN CAUSES 7.20 Idiopathic and other anterior uveitis syndromes . . . . . . . . . . . . . . . . . . . . . . . 770 Olivia L. Lee 7.21 Pars planitis and other intermediate uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774 Aliza Jap, Soon-Phaik Chee 7.22 Posterior uveitis of unknown cause – White spot syndromes . . . . . . . . . . . 778 Rukhsana G. Mirza, Ramana S. Moorthy, Lee M. Jampol SECTION 9: MASQUERADE SYNDROMES 7.23 Masquerade syndromes: Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788 H. Nida Sen, Chi-Chao Chan

PART 8: INTRAOCULAR TUMORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793

6.44 Retinal toxicity of systemically administered drugs . . . . . . . . . . . . . . . . . . . . . 683 Ravi S. Singh, David V. Weinberg

SECTION 1: MALIGNANT AND INTRAOCULAR TUMORS 8.1 Retinoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793 James J. Augsburger, Norbert Bornfeld, Zélia M. Corrêa

PART 7: UVEITIS AND OTHER INTRAOCULAR INFLAMMATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687

8.2

Uveal melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801 James J. Augsburger, Bertil E. Damato, Norbert Bornfeld, Zélia M. Corrêa

8.3

Metastatic cancer to the eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810 James J. Augsburger, Rudolf Guthoff, Zélia M. Corrêa

8.4

Lymphoma and leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815 James J. Augsburger, William G. Tsiaras, Zélia M. Corrêa

8.5

Medulloepithelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819 James J. Augsburger, Zélia M. Corrêa

SECTION 1: BASIC PRINCIPLES 7.1 Anatomy of the uvea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687 Monica Evans 7.2

Mechanisms of uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690 Igal Gery, Chi-Chao Chan

7.3

General approach to the uveitis patient and treatment strategies . . . . . . . 694 Russell W. Read

SECTION 2: INFECTIOUS CAUSES OF UVEITIS – VIRAL 7.4 Herpes and other viral infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700 P. Kumar Rao 7.5

Ocular infections with cytomegalovirus (CMV) . . . . . . . . . . . . . . . . . . . . . . . . . 704 Ehud Zamir

SECTION 3: INFECTIOUS CAUSES OF UVEITIS – BACTERIAL 7.6 Syphilitic and other spirochetal uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709 Julie H. Tsai 7.7

Tuberculosis, leprosy, and brucellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716 Amod Gupta, Reema Bansal, Vishali Gupta

7.8

Cat scratch and Whipple’s disease: bartonella-related infectious uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720 Robert C. Wang

Contents

6.27 Retinal arterial macroaneurysms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Clement C. Chow, William F. Mieler, Robert A. Mittra, John S. Pollack

SECTION 2: BENIGN INTRAOCULAR TUMORS 8.6 Uveal nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821 James J. Augsburger, J. William Harbour, John R. Gonder, Zélia M. Corrêa 8.7

Choroidal hemangiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825 James J. Augsburger, Rajiv Anand, George E. Sanborn, Zélia M. Corrêa

8.8

Choroidal osteoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830 James J. Augsburger, Rudolf Guthoff, Zélia M. Corrêa

8.9

Astrocytoma of retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 James J. Augsburger, Alan F. Cruess, Zélia M. Corrêa

8.10 Hemangiomas of retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836 James J. Augsburger, Norbert Bornfeld, Zélia M. Corrêa 8.11 Combined hamartoma of retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840 James J. Augsburger, Sanford M. Meyers, Zélia M. Corrêa 8.12 Hypertrophy of retinal pigment epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 James J. Augsburger, James P. Bolling, Zélia M. Corrêa

ix

Contents

SECTION 3: PHAKOMATOSES 8.13 Phakomatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844 James J. Augsburger, James P. Bolling, Zélia M. Corrêa

PART 9: NEURO-OPHTHALMOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . 851 SECTION 1: IMAGING IN NEURO-OPHTHALMOLOGY 9.1 Principles of imaging in neuro-ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . 851 Swaraj Bose 9.2

Optical coherence tomography in neuro-ophthalmology . . . . . . . . . . . . . . 858 Piero Barboni, Giacomo Savini, Michelle Y. Wang

SECTION 2: THE AFFERENT VISUAL SYSTEM 9.3 Anatomy and physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866 Alfredo A. Sadun

SECTION 1: EPIDEMIOLOGY AND MECHANISMS OF GLAUCOMA 10.1 Epidemiology of glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 Osamah Jawaid Saeedi, Pradeep Ramulu, David S. Friedman 10.2 Screening for glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 Joshua D. Stein, Paul P. Lee 10.3 Mechanisms of glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 Martin Wax, Abe Clark, Mortimer M. Civan SECTION 2: EVALUATION AND DIAGNOSIS 10.4 Clinical examination of glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1019 Mohsin Ali, Jerome C. Ramos-Esteban, L. Jay Katz 10.5 Visual field testing in glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029 Donald L. Budenz

9.4

Differentiation of optic nerve from macular retinal disease . . . . . . . . . . . . . 869 Alfredo A. Sadun, Vivek R. Patel

9.5

Congenital optic disc anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871 Michael C. Brodsky

9.6

Papilledema and raised intracranial pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . 875 Alfredo A. Sadun

9.7

Inflammatory optic neuropathies and neuroretinitis . . . . . . . . . . . . . . . . . . . 879 Dina A. Jacobs, Jason R. Guercio, Laura J. Balcer

9.8

Ischemic optic neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884 Anthony C. Arnold, Michelle Y. Wang

9.9

Hereditary, nutritional, and toxic optic atrophies . . . . . . . . . . . . . . . . . . . . . . . 890 Alfredo A. Sadun, Sevgi Gurkan, Vivek R. Patel

SECTION 3: SPECIFIC TYPES OF GLAUCOMA 10.10 Primary open-angle glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1052 James C.H Tan, Paul L. Kaufman

9.10 Prechiasmal pathways – compression by optic nerve and sheath tumors 894 Thomas C. Spoor, Michelle Y. Wang

10.11 Normal-tension glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057 Deborah S. Kamal, Roger A. Hitchings

9.11 Traumatic optic neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898 Michelle Y. Wang, Thomas C. Spoor

10.12 Angle-closure glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060 Jovina L.S. See, Maria Cecilia D. Aquino, Paul T.K. Chew

9.12 Optic chiasm, parasellar region, and pituitary fossa . . . . . . . . . . . . . . . . . . . . 900 Richard M. Rubin, Alfredo A. Sadun, Alfio P. Piva

10.13 Glaucoma associated with pseudoexfoliation syndrome . . . . . . . . . . . . . . .1070 Bryan S. Lee, Thomas W. Samuelson

9.13 Retrochiasmal pathways, higher cortical function, and non-organic visual loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 Andrew W. Lawton, Michelle Y. Wang

10.14 Pigmentary glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 M. Bruce Shields

SECTION 3: THE EFFERENT VISUAL SYSTEM 9.14 Disorders of supranuclear control of ocular motility . . . . . . . . . . . . . . . . . . . . 915 Patrick J.M. Lavin, Sean P. Donahue

10.6 Advanced psychophysical tests for glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . 1036 Chris A. Johnson 10.7 Optic nerve analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040 Gadi Wollstein, Joel S. Schuman 10.8 Optic nerve blood flow measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047 Brian Milan Marek, Alon Harris, Brent Siesky 10.9 Ocular hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050 Arsham Sheybani, Michael A. Kass

10.15 Neovascular glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076 Malik Y. Kahook 10.16 Inflammatory and corticosteroid-induced glaucoma . . . . . . . . . . . . . . . . . . 1080 Ridia Lim, Ivan Goldberg

9.15 Nuclear and fascicular disorders of eye movement . . . . . . . . . . . . . . . . . . . . . 922 Sean P. Donahue

10.17 Glaucoma associated with ocular trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084 David P. Tingey, Bradford J. Shingleton

9.16 Paresis of isolated and multiple cranial nerves and painful ophthalmoplegia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 David H. Perlmutter, Mark L. Moster

10.18 Glaucoma with raised episcleral venous pressure . . . . . . . . . . . . . . . . . . . . . 1090 E. Randy Craven

9.17 Disorders of the neuromuscular junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937 Deborah I. Friedman

10.19 Aqueous misdirection syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092 Nishat P. Alvi, Louis B. Cantor

9.18 Ocular myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943 Richard M. Rubin, Michelle Y. Wang, Alfredo A. Sadun

10.20 Glaucomas secondary to abnormalities of the cornea, iris, retina, and intraocular tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094 Elliott M. Kanner, James C. Tsai

9.19 Nystagmus, saccadic intrusions, and oscillations . . . . . . . . . . . . . . . . . . . . . . . 950 Peter A. Quiros, Robert D. Yee

10.21 Congenital glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101 James D. Brandt

9.20 The pupils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958 Randy H. Kardon

SECTION 4: THERAPY 10.22 When to treat glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1107 Rebecca S. Walker, Jody R. Piltz-Seymour

9.21 Presbyopia and loss of accommodation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967 Sean P. Donahue SECTION 4: THE BRAIN 9.22 Headache and facial pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969 Joel M. Weinstein, Michelle Y. Wang 9.23 Tumors, infections, inflammations, and neurodegenerations . . . . . . . . . . . 976 Hossein G. Saadati, Alfredo A. Sadun SECTION 5: NEURO-OPHTHALMOLOGIC EMERGENCIES 9.24 Urgent neuro-ophthalmic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983 Peter A. Quiros 9.25 Trauma, drugs, and toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988 Deborah I. Friedman, Luis J. Mejico

x

PART 10: GLAUCOMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001

9.26 Vascular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992 Peter A. Quiros, Thomas R. Hedges Jr

10.23 Which therapy to use in glaucoma? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111 Douglas J. Rhee 10.24 Current medical management of glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114 Ronald L. Gross 10.25 Laser trabeculoplasty and laser peripheral iridectomy . . . . . . . . . . . . . . . . 1120 Karim F. Damji, Fisseha A. Ayele 10.26 Cyclodestructive procedures in glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125 Ian P. Conner, Robert J. Noecker, Joel S. Schuman 10.27 Goniotomy and trabeculotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129 Sarwat Salim, David S. Walton 10.28 Minimally invasive and nonpenetrating glaucoma surgeries . . . . . . . . . . . 1133 Kevin Kaplowitz, Igor I. Bussel, Nils A. Loewen 10.29 Trabeculectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146 Cynthia Mattox

10.31 Drainage implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159 Jeffrey Freedman 10.32 Complications of glaucoma surgery and their management . . . . . . . . . . . 1164 Leon W. Herndon 10.33 Genes associated with human glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170 Janey L. Wiggs 10.34 Evidence-based medicine in glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173 Henry D. Jampel, Kimberly Brown Smith

PART 11: PEDIATRIC AND ADULT STRABISMUS . . . . . . . . . . . . . . . . 1181 SECTION 1: BASIC SCIENCE 11.1 Anatomy and physiology of the extraocular muscles and surrounding tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181 Anthony J. Panarelli, Brian N. Campolattaro, Frederick M. Wang, Raza M. Shah SECTION 2: EVALUATION AND DIAGNOSIS 11.2 Evaluating vision in preverbal and preliterate infants and children . . . . . 1188 Gary R. Diamond, Raza M. Shah

PART 12: ORBIT AND OCULOPLASTICS . . . . . . . . . . . . . . . . . . . . . . . 1255 SECTION 1: ORBITAL ANATOMY AND IMAGING 12.1 Clinical anatomy of the eyelids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255 Jonathan J. Dutton 12.2 Clinical anatomy of the orbit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1258 Jonathan J. Dutton 12.3 Orbital imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264 Jonathan J. Dutton SECTION 2: EYELIDS 12.4 Eyelid retraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1268 Gene R. Howard 12.5 Blepharoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272 Philip L. Custer 12.6 Entropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1278 James W. Gigantelli 12.7 Ectropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284 Fiona O. Robinson, J. Richard O. Collin 12.8 Essential blepharospasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1292 Donald C. Faucett

11.3 Examination of ocular alignment and eye movements . . . . . . . . . . . . . . . . 1192 Gary R. Diamond, Raza M. Shah

12.9 Benign eyelid lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1295 Ann G. Neff, Keith D. Carter

11.4 Sensory adaptations in strabismus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197 Gary R. Diamond, Raza M. Shah

12.10 Eyelid malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306 Gregory J. Vaughn, Richard K. Dortzbach, Gregg S. Gayre

SECTION 3: OCULAR MANIFESTATIONS 11.5 Sensory status in strabismus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 Gary R. Diamond, Raza M. Shah

12.11 Eyelid trauma and reconstruction techniques . . . . . . . . . . . . . . . . . . . . . . . . . 1312 Jeffrey P. Green, George C. Charonis, Robert A. Goldberg

11.6 Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206 Gary R. Diamond, Raza M. Shah

SECTION 3: ORBIT AND LACRIMAL GLAND 12.12 Orbital diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 Jonathan J. Dutton

11.7 Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214 Gary R. Diamond, Raza M. Shah

12.13 Orbital surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333 Jonathan J. Dutton

11.8 Oblique muscle dysfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217 Gary R. Diamond, Raza M. Shah

12.14 Enucleation, evisceration, and exenteration . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339 Myron Tanenbaum

11.9 Alphabet-pattern strabismus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221 Gary R. Diamond, Raza M. Shah

12.15 The lacrimal drainage system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346 Jeffrey J. Hurwitz

11.10 Paralytic strabismus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 Steven E. Rubin, Raza M. Shah

SECTION 4: PERIORBITAL AESTHETIC PROCEDURES 12.16 Cosmetic blepharoplasty and browplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1352 François Codère, Nancy Tucker

11.11 Other vertical strabismus forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233 Mitchell B. Strominger, Howard M. Eggers 11.12 Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1238 Gary R. Diamond, Raza M. Shah SECTION 4: TREATMENT 11.13 Forms of nonsurgical strabismus management . . . . . . . . . . . . . . . . . . . . . . . 1244 Gary R. Diamond, Raza M. Shah

Contents

10.30 Antifibrotic agents in glaucoma surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152 Peng Tee Khaw, Jonathan Clarke, Alastair Lockwood

12.17 Injectable skin fillers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359 Gregg S. Gayre 12.18 Cosmetic wrinkle reduction with botulinum toxin . . . . . . . . . . . . . . . . . . . . . 1362 William J. Lipham Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1367

11.14 Techniques of strabismus surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247 Robert W. Lingua, Gary R. Diamond, Raza M. Shah

xi

Preface We are delighted that our textbook Ophthalmology has gone to a fourth edition. The longevity of this title reflects the uniqueness and utility of its format, the hard work of our authors, editors, and publishers, and the pressing need in our field for updated, clinically relevant information. We continue to recognize the advantage of a complete textbook of ophthalmology in a single volume, rather than a multivolume textbook. The basic visual science is admixed with clinical information throughout and we have maintained an entire separate section dedicated to genetics and the eye.

xii

Once again, we do not intend this edition of Ophthalmology to be encyclopedic, but have strived to make it quite comprehensive, readable, and easy to access. Like the third edition, this book is thoroughly revised with new section editors and many new authors. Chapters have been re-written and restricted to reflect the new way diseases are diagnosed, categorized, and treated. We have discarded out-of-date material and have added numerous new items. Extra references and other material have been moved on-line to keep the book itself as one volume and now 100 pages shorter.

Preface to First Edition Over the past 30 years, enormous technologic advances have occurred in many different areas of medicine—lasers, molecular genetics, and immunology to name a few. This progress has fueled similar advances in almost every aspect of ophthalmic practice. The assimilation and integration of so much new information makes narrower and more focused ophthalmic practices a necessity. As a direct consequence, many subspecialty textbooks with extremely narrow focus are now available, covering every aspect of ophthalmic practice. Concurrently, several excellent multivolume textbooks detailing all aspects of ophthalmic practice have been developed. Yet there remains a need for a complete single-volume textbook of ophthalmology for trainees, nonophthalmologists, and those general ophthalmologists (and perhaps specialists) who need an update in which they are not expert. Ophthalmology was created to fill this void between the multivolume and narrow subspecialty book. This book is an entirely new, comprehensive, clinically relevant, single-volume textbook of ophthalmology, with a new approach to content and presentation that allows the reader to access key information quickly. Our approach, from the outset, has been to use templates to maintain a uniform chapter structure throughout the book so that the material is presented in a logical, consistent manner, without repetition. The majority of chapters in the book follow one of three templates: the disease-oriented template, the surgical procedure template, or the diagnostic testing template. Meticulous planning went into the content, sectioning and chaptering of the book, with the aim of presenting ophthalmology as it is practiced rather than as a collection of artificially divided aspects. Thus, pediatric ophthalmology is not in a separate section but is integrated into relevant sections across the book. The basic visual science and clinical information, including systemic manifestations, is integrated throughout, with only two exceptions. We dedicated an entire section to genetics and the eye, in recognition of the increasing importance of genetics in ophthalmology. Optics and refraction are included in a single section as well, because an understanding of these subjects is fundamental to all of ophthalmology.

To achieve the same continuity of presentation in the figures as well as in the text, all of the artworks have been redesigned from the author’s originals, maximizing their accessibility for the reader. Each section is color coded for easy cross-referencing and navigation through the book. Despite the extensive use of color in artworks and photographs throughout, the cost of this comprehensive book has been kept to a fraction of the multivolume sets. We hope to make this volume more accessible to more practitioners throughout the world. Although comprehensive, Ophthalmology is not intended to be encyclopedic. In particular, in dealing with surgery, we do not stress specific techniques or describe rarer ones in meticulous detail. The rapidly changing nature of surgical aspects of ophthalmic practice is such that the reader will need to refer to one or more of the plethora of excellent books that cover specific current techniques in depth. We concentrate instead on the areas that are less volatile but nevertheless vital: surgical indications, general principles of surgical technique, and complications. The approach to referencing is parallel to this: for every topic, all the key references are listed, but with the aim of avoiding pages of redundant references where a smaller number of recent classic reviews will suffice. The overall emphasis of Ophthalmology is current information that is relevant to clinical practice superimposed on the broad framework that comprises ophthalmology as a subspecialty. Essential to the realization of this ambitious project is the ream of Section Editors, each bringing unique insight and expertise to the book. They have coordinated their efforts in shaping the contents list, finding contributors, and editing chapters to produce a book that we hope will make a great contribution to ophthalmology. We are grateful to the editors and authors who have contributed to Ophthalmology and to the superb, dedicated Ophthalmology team at Mosby. Myron Yanoff Jay S. Duker July 1998

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List of Contributors Natalie A. Afshari MD FACS Professor of Ophthalmology Chief of Cornea and Refractive Surgery Shiley Eye Center University of California San Diego San Diego, CA, USA Ike K. Ahmed MD FRCSC Assistant Professor Fellowship Director, Glaucoma and Anterior Segment Surgery (GAASS) Research Fellowship Director, University of Toronto, Department of Ophthalmology and Vision Sciences Toronto, ON Chief, Division of Ophthalmology. The Credit Valley Hospital, Mississauga, Ontario Co-Medical Director, TLC Laser Eye Center Mississauga, ON, Canada Radwan S. Ajlan MBBCh Clinical Fellow Department of Ophthalmology McGill University Montreal, Quebec, Canada Thomas A. Albini MD Associate Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Ahmed R. Al-Ghoul MD FRCSC DipABO Ophthalmologist University of Calgary Division of Ophthalmology, Seema Eye Care Centre Alberta, Canada Mohsin Ali MD Research Fellow Glaucoma Service Wills Eye Institute, Jefferson Medical College Philadelphia, PA, USA Jorge L. Alió MD PhD Professor and Chairman President Vissum Corporation Ophthalmology Universidad Miguel Hernandez Alicante, Spain

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Norma Allemann MD Professor Department of Ophthalmology Federal University of São Paulo (UNIFESP) São Paulo, Brazil Adjunct Professor Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago, IL, USA

David Allen BSc FRCS FRCOphth Consultant Ophthalmologist Cataract Treatment Centre Sunderland Eye Infirmary Sunderland, UK Keith G. Allman MD FRCA Consultant Anaesthetist Anaesthesia and Critical Care West of England Eye Unit Exeter, UK Carlos Alexandre de Amorim Garcia Filho MD Physician (Ophthalmologist) Department of Ophthalmology, Federal University of Rio Grande Do Norte Natal, RN, Brazil, Post-doctoral Associate Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Nishat P. Alvi MD Glaucoma Specialist Specialty Care Institute, SC Barrington, IL, USA Rajiv Anand MD FRCS FRCSOphth Vitreoretinal Specialist Texas Retina Associates Dallas, TX, USA Leonard Pek-Kiang Ang MBBS Doctorate Med FRCS(Ed) MRCOphth(Lond) MMed(Ophth) FAMS(Ophth) Associate Professor Medical Director Lang Eye Center Mount Elizabeth Novena Hospital Singapore David J. Apple, MD† Former Professor of Ophthalmology and Pathology Director, Laboratories for Ophthalmic Devices Research John A. Moran Eye Center University of Utah Salt Lake City, UT, USA Maria Cecilia D. Aquino MD MMED(Ophth) Glaucoma Specialist Department of Ophthalmology National University Hospital National University Health System Singapore Anthony C. Arnold MD Jerome and Joan Snyder Professor of Ophthalmology Chief, Neuro-Ophthalmology Division Director, Optic Neuropathy Center Jules Stein Eye Institute Los Angeles, CA, USA

Steve A. Arshinoff MD FRCSC Clinical Instructor University of Toronto Assistant Clinical Professor (Adjunct), Department of Surgery, McMaster University Senior Lecturer, Ben Gurion University of the Negev Toronto, Ontario, Canada Penny A. Asbell MD FACS MBA Professor Department of Ophthalmology Mount Sinai School of Medicine New York, NY, USA Kerry K. Assil MD Corneal, Cataract and Refractive Surgeon Medical Director The Assil Eye Institute Beverly Hills, CA, USA Neal H. Atebara MS MD FACS Assistant Professor of Surgery Department of Surgery John A. Burns School of Medicine Honolulu, HI, USA James J. Augsburger MD Professor and Chairman Department of Ophthalmology University of Cincinnati College of Medicine Director of Ocular Oncology Service, University of Cincinnati Academic Health Center Cincinnati, OH, USA Fisseha A. Ayele MD Assistant Professor in Ophthalmology Department of Ophthalmology University of Gondar Gondar, Ethiopia G. William Aylward FRCS FRCOphth MD Consultant Vitreoretinal Surgeon Moorfields Eye Hospital London, UK Dimitri T. Azar MD MBA Dean, College of Medicine BA Field Chair of Ophthalmologic Research Distinguished Professor of Ophthalmology, Pharmacology and Bioengineering University of Illinois at Chicago Chicago, IL, USA Sophie J. Bakri MD Professor of Ophthalmology Director of Vitreoretinal Surgery Fellowship Vitreoretinal Diseases and Surgery Mayo Clinic Rochester, MN, USA

Laura J. Balcer MD MSCE Professor and Vice-Chair Department of Neurology New York University School of Medicine New York, NY, USA Reema Bansal MBBS MS Assistant Professor Advanced Eye Centre Post Graduate Institution of Medical Education and Research Sector Chandigarh, India Piero Barboni MD Consultant Department of Ophthalmology University Vita-Salute, Scientific Institute San Raffaele Milan, Italy Priti Batta MD Assistant Professor of Ophthalmology Department of Ophthalmology New York Medical College New York Eye and Ear Infirmary New York, NY, USA Caroline R. Baumal MD, FRCSC Assistant Professor, Tufts University School of Medicine Dept of Vitreoretinal Surgery, New England Eye Center Tufts University School of Medicine Boston, MA, USA Warwick Bayly BVSc (Hons) MS PhD Dip ACVIMProvost and Executive Vice-President, Washington State University, Pullman, WA, USA Srilaxmi Bearelly MD MHS Assistant Professor of Ophthalmology Columbia University Medical Center Edward S. Harkness Eye Institute New York, NY, USA William E. Benson MD Professor of Ophthalmology Thomas Jefferson University Attending Surgeon Wills Eye Hospital Philadelphia, PA, USA Jyotirmay Biswas MS FMRF FNAMS FICPath FAICO Director, Uveitis and Ocular Pathology Department, Sankara Nethralaya, Chennai Tamil Nadu, India Bahram Bodaghi MD PhD Professor of Ophthalmology University of Pierre and Marie Curie Pitié-Salpêtrière Hospital Paris, France

Norbert Bornfeld MD Professor Director, Department of Ophthalmology Universitätsklinikum Essen, Germany Swaraj Bose MD Director, Neuro-Ophthalmology Orbital Surgery Associate Professor of Ophthalmology University of California, Irvine and Cedars Sinai Medical Center Los Angeles, CA, USA Charles S. Bouchard MD MA Professor and Chairman Department of Ophthalmology Loyola University Medical Center Maywood, IL, USA Michael E. Boulton PhD Professor Department of Anatomy and Cell Biology University of Florida Gainesville, FL, USA James D. Brandt MD Professor and Director, Glaucoma Service Department of Ophthalmology and Vision Science University of California, Davis Eye Center Sacramento, CA, USA Michael C. Brodsky MD Professor of Ophthalmology and Neurology Mayo Clinic Rochester, MN, USA Gary C. Brown MD MBA Director of Healthcare Economics Center for Value-Based Medicine Flourtown, PA, USA Melissa M. Brown MD MN MBA Professor of Ophthalmology Thomas Jefferson University Senior Research Associate Wills Eye Institute President and CEO, Center for ValueBased Medicine Flourtown, PA, USA Kimberly Brown Smith MD PhD Medical Officer Center for Devices and Radiological Health US Food and Drug Administration Silver Spring, MD, USA Matthew V. Brumm MD Fellow in Cornea, Refractive Surgery, and External Diseases Department of Ophthalmology and Visual Sciences W.K. Kellogg Eye Center University of Michigan Ann Arbor, MI, USA Donald L. Budenz MD MPH Kittner Distinguished Professor Chair, Department of Ophthalmology University of North Carolina Chapel Hill, NC, USA

Igor I. Bussel MS MHA Doris Duke Clinical Research Fellow Department of Ophthalmology University of Pittsburgh School of Medicine Pittsburgh, PA, USA Stephen K. Burns PhD Senior Lecturer Division of Health Sciences and Technology Massachusetts Institute of Technology Cambridge, MA, USA Brian N. Campolattaro MD Clinical Assistant Professor Department of Ophthalmology New York Medical College Valhalla, NY Associate Attending New York Eye and Ear Infirmary New York, NY USA Louis B. Cantor MD Chair and Professor of Ophthalmology Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education Director of Glaucoma Service Eugene and Marilyn Glick Eye Institute Department of Ophthalmology Indiana University School of Medicine Indianapolis, IN, USA Antonio Capone Jr MD Professor Department of Ophthalmology Oakland University – William Beaumont Hospital School of Medicine Rochester, MI, USA Keith D. Carter MD FACS Lillian C & Dr. CS O'Brien Professor of Ophthalmology Professor and Department Chairman Department of Ophthalmology and Visual Sciences University of Iowa Hospitals and Clinics Iowa City, IA, USA Rafael C. Caruso MD Guest Researcher Princeton Neuroscience Institute Princeton University Princeton, NJ, USA Wallace Chamon MD Adjunct Professor Department of Ophthalmology and Visual Sciences College of Medicine University of Illinois at Chicago Chicago, IL, USA Adjunct Professor, Department of Ophthalmology Paulista School of Medicine Federal University of São Paulo (UNIFESP) Chief-editor, ABO – Arquivos Brasileiros de Oftalmologia São Paulo, SP, Brazil Chi-Chao Chan MD Chief, Immunopathology Section Laboratory of Immunology Head, Histopathology Core National Eye Institute National Institutes of Health Bethesda, MD, USA Stanley Chang MD KK Tse and Ku Teh Ying Professor of Ophthalmology Department of Ophthalmology Columbia University Edward Harkness Eye Institute New York, NY, USA

George C. Charonis MD PhD Director, Department of Orbitofacial Surgery Athens Vision Eye Institute Athens, Greece

Ian P. Conner MD PhD Assistant Professor of Ophthalmology University of Pittsburgh Medical Center School Pittsburgh, PA, USA

David G. Charteris MD FRCS(Ed) FRCOphth Consultant Vitreoretinal Surgeon Vitreoretinal Unit Moorfields Eye Hospital London, UK

Zélia M. Corrêa MD PhD Mary Knight Asbury Chair of Ophthalmic Pathology Associate Professor of Ophthalmology – Ocular Oncology University of Cincinnati College of Medicine Cincinnati, OH, USA

Soon-Phaik Chee FRCOphth FRCS(G) FRCS(Ed) MMed(Ophth) Senior Consultant and Head Ocular Inflammation and Immunology Singapore National Eye Centre Singapore Eye Research Institute Associate Professor, Department of Ophthalmology, Yong Loo Lin School of Medicine National University of Singapore, Singapore Duke-National University of Singapore Post Graduate Medical Institute, Singapore Paul T.K. Chew MBBS(Singapore) MMed(Ophth) FRCS(Ed) FRCOphth (Ed) Senior Consultant and Head, Glaucoma Division National University Hospital National University Health System Singapore Clement C. Chow MD Retina Fellow Department of Ophthalmology and Visual Sciences University of Illinois Chicago, IL, USA Antonio P. Ciardella MD Chair of Ophthalmology Policlinico S. Orsola-Malpighi Bologna, Italy Mortimer M. Civan MD Professor of Physiology and Professor of Medicine Department of Physiology University of Pennsylvania Perelman School of Medicine Philadelphia, PA, USA Abbot F. Clark PhD Professor of Cell Biology and Anatomy Director, North Texas Eye Research Institute Cell Biology and Anatomy University of North Texas Health Science Center Ft. Worth, TX, USA Jonathan Clarke MD FRCOphth Consultant Ophthalmologist National Institute for Health Research Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital and UCL Institute of Ophthalmology London, UK François Codère MD Associate Professor of Ophthalmology Department of Ophthalmology Université de Montréal Adjunct Professor McGill University Mount-Royal, Québec, Canada J. Richard O. Collin MA FRCS DO Consultant Moorfields Eye Hospital London, UK

List of Contributors

James P. Bolling MD Associate Professor Department of Ophthalmology Mayo Clinic Jacksonville, FL, USA

Claude L. Cowan Jr MD MPH Clinical Professor of Ophthalmology Staff Physician Department of Ophthalmology Georgetown University Medical Center Washington, DC Veterans Affairs Medical Center Washington, DC, USA E. Randy Craven MD FACS Chief of Glaucoma, King Khaled Eye Specialist Hospital, Saudi Arabia Associate Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA Alan F. Cruess MD FRCSC Professor and Head, District Chief, Capital Health Department of Ophthalmology and Visual Sciences Dalhousie University Halifax, Nova Scotia, Canada Jose de la Cruz MD Assistant Professor of Ophthalmology, Cornea and Refractive Surgery Department of Ophthalmology University of Illinois Eye & Ear Infirmary, Chicago Chicago, IL, USA Catherine A. Cukras MD PhD Staff Clinician National Eye Institute National Institutes of Health Bethesda, MD, USA Philip L. Custer MD Professor Department of Ophthalmology and Visual Sciences Washington University School of Medicine St Louis, MI, USA Elie Dahan MD MMed (Ophth)† Senior Consultant Pediatric Ophthalmology and Glaucoma Department of Ophthalmology Ein Tal Eye Hospital Tel Aviv, Israel Bertil E. Damato MD PhD FRCOphth Honorary Professor Department of Molecular and Clinical Cancer Medicine Consultant Ophthalmologist, Ocular Oncology Service Royal Liverpool University Hospital Liverpool, UK Karim F. Damji MD FRCSC MBA Professor Department of Ophthalmology University of Alberta Edmonton, Alberta, Canada

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List of Contributors

Richard S. Davidson MD Associate Professor and Vice Chair for Quality and Clinical Affairs Cataract, Cornea, and Refractive Surgery University of Colorado Eye Center University of Colorado School of Medicine Aurora, CO, USA Elizabeth A. Davis MD Managing Partner Minnesota Eye Consultants Assistant Clinical Professor University of Minnesota Bloomington, MN, USA Deepinder K. Dhaliwal MD LAc Associate Professor Department of Ophthalmology University of Pittsburgh School of Medicine Director, Cornea and Refractive Surgery Director, UPMC Eye Center, Monroeville Director and Founder, Center for Integrative Eye Care Medical Director, UPMC Laser/ Aesthetic Center Eye and Ear Institute, University of Pittsburgh Medical Center Pittsburgh, PA, USA Gary R. Diamond MD Formerly Professor of Ophthalmology and Pediatrics Drexel University College of Medicine Philadelphia, PA, USA Diana V. Do MD Associate Professor of Ophthalmology Vice Chair for Education Director of the Carl Camras Center for Innovative Clinical Research Truhlsen Eye Institute University of Nebraska Medical Center Omaha, Nebraska, USA Sean P. Donahue MD PhD Sam and Darthea Coleman Chair Vice Chair of Clinical Affairs, Department of Ophthalmology Professor of Pediatrics, Ophthalmology, and Neurology Chief of Pediatric Ophthalmology Vanderbilt University Medical Center Nashville, TN, USA Peter Donshik MD Clinical Professor University of Connecticut Health Center Bloomfield, CT, USA Richard K. Dortzbach MD Professor Emeritus Department of Ophthalmology and Visual Sciences University of Wisconsin School of Medicine and Public Health Madison, WI, USA Kimberly A. Drenser MD PhD Vitreoretinal Surgeon Associated Retinal Consultants Director of Ophthalmic Research, Department of Ophthalmology, William Beaumont Hospital Assistant Professor, Eye Research Institute, Oakland University, Rochester, MI, USA

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Jay S. Duker MD Director, New England Eye Center Chairman and Professor of Ophthalmology Tufts Medical Center Tufts University School of Medicine Boston, MA, USA Jonathan J. Dutton MD PhD Professor and Vice Chair Department of Ophthalmology University of North Carolina Chapel Hill, NC, USA Bryan Edgington MD Assistant Professor of Ophthalmology George Washington University Medical Faculty Associates Washington, DC, USA Howard M. Eggers MD Professor of Clinical Ophthalmology Harkness Eye Institute New York, NY, USA William Ehlers MD Associate Professor University of Connecticut Health Center Farmington, CT, USA Dean Eliott MD Associate Director, Retina Service Department of Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, MA, USA Michael Engelbert MD PhD Assistant Professor of Ophthalmology New York University Vitreous-Retina–Macula Consultants New York, NY, USA Miriam Englander MD Vitreoretinal Fellow Retina Division Cole Eye Institute Cleveland Clinic Cleveland, OH, USA Monica Evans MD Ophthalmologist Uveitis Clinic Ocular Pathology Laboratory San Jose, Costa Rica Daoud Fahd MD Visiting Fellow in Cornea Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago, IL, USA Lisa J. Faia MD Assistant Professor Department of Ophthalmology Oakland University – William Beaumont School of Medicine Royal Oak, MI Associated Retinal Consultants, PC Rochester, MI, USA Ayad A. Farjo MD Director Brighton Vision Center Brighton, MI, USA Donald C. Faucett MD Ophthalmologist Trio Eye Lid and Facial Clinic Flowood, MS, USA

Karen B. Fernandez MD Clinical Fellow Department of Ophthalmology Mount Sinai School of Medicine New York, NY, USA

Neil J. Friedman MD Adjunct Clinical Associate Professor Department of Ophthalmology Stanford University School of Medicine Stanford, CA, USA

Carlos Alexandre de Amorim Garcia Filho MD Physician (Ophthalmologist) Department of Ophthalmology Federal University of Rio Grande Do Norte Natal, RN, Brazil Post-doctoral Associate Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

Nicoletta Fynn-Thompson MD Partner, Cornea, Cataract, and Refractive Surgery Ophthalmic Consultants of Boston Boston, MA, USA

Yale L. Fisher MD Clinical Professor of Ophthalmology Department of Ophthalmology New York Presbyterian Hospital New York, NY, USA Clinical Professor of Ophthalmology (Voluntary) Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

Neha Gadaria-Rathod MD Research Fellow Department of Ophthalmology Mount Sinai School of Medicine New York, NY, USA Gregg S. Gayre MD Chief of Ophthalmology Eye Care Services San Rafael/Novato/ Petaluma Kaiser Permanente San Rafael, CA, USA Mohamed A. Genead MD Ophthalmologist, Retinal Specialist The Pangere Center for Hereditary Retinal Diseases The Chicago Lighthouse for People Who Are Blind or Visually Impaired Chicago, IL, USA

Gerald A. Fishman MD Director Pangere Center for Inherited Retinal Diseases The Chicago Lighthouse for People Who Are Blind or Visually Impaired Professor Emeritus of Ophthalmology Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago, IL, USA

Igal Gery PhD Senior Investigator Laboratory of Immunology National Eye Institute, NIH Bethesda, MD, USA

Jorge A. Fortun MD Assistant Professor of Clinical Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

James W. Gigantelli MD FACS Professor of Ophthalmology Truhlsen Eye Institute University of Nebraska Medical Center Omaha, NE, USA

Gregory M. Fox MD FACS Retina Specialist Retina Associates, PA Shawnee Mission, KS, USA Jeffrey Freedman MBBCh PhD FRCS(Ed) FCS(SA) Professor of Clinical Ophthalmology Department of Ophthalmology SUNY Downstate Medical Center Brooklyn, New York Great Neck, NY, USA David S. Friedman MD MPH PhD Alfred Sommer Professor of Ophthalmology, Director of Dana Center for Preventive Ophthalmology The Wilmer Eye Institute Baltimore, MD, USA Deborah I. Friedman MD MPH FAAN Professor, Neurology and Neurotherapeutics and Ophthalmology University of Texas Southwestern Medical Center Dallas, TX, USA

Ramon C. Ghanem MD PhD Director of Cornea and Refractive Surgery Department Sadalla Amin Ghanem Eye Hospital Joinville, SC, Brazil

Ivan Goldberg, AM MBBS (Syd) FRANZCO FRACS Clinical Associate Professor University of Sydney Head, Glaucoma Unit, Sydney Eye Hospital Director, Eye Associates Sydney, NSW, Australia Robert A. Goldberg MD Karen and Frank Dabby Professor of Ophthalmology David Geffen School of Medicine at UCLA Chief, Orbital and Ophthalmic Plastic Surgery Jules Stein Eye Institute Los Angeles, CA, USA Darin R. Goldman MD Vitreoretinal Fellow, Ophthalmic Consultants of Boston New England Eye Center at Tufts Medical Center Clinical Associate Department of Ophthalmology Tufts University School of Medicine Boston, MA, USA

Sevgi Gurkan MD Assistant Professor Department of Pediatrics Child Health Institute of New Jersey, UMDNJ–Robert Wood Johnson Medical School New Brunswick, NJ, USA

Michael H. Goldstein MD MBA Co-Director Cornea and External Diseases Service New England Eye Center Tufts Medical Center Tufts University School of Medicine Boston, MA, USA

Rudolf Guthoff MD Professor Department of Ophthalmology Universty of Rostock Rostock, Germany

John R. Gonder M.D. Associate Professor Ivey Eye Institute University of Western Ontario Ontario, Canada Jeffrey P. Green MD MBA Managing Director HealthCor Management LP Dallas, TX, USA Craig M. Greven MD Professor and Chairman Department of Ophthalmology Wake Forest Baptist Health Winston-Salem, NC, USA Nicole E. Gross MD Clinical Instructor Department of Ophthalmology Mount Sinai Medical Center New York, NY, USA Ronald L. Gross MD Professor and Chair WVU Eye Institute Department of Ophthalmology Morgantown, WV, USA Sandeep Grover MD Associate Professor Department of Ophthalmology University of Florida at Jacksonville Jacksonville, FL, USA Jason R. Guercio MD MBA Senior Resident in Anesthesiology Department of Anesthesiology Duke University Medical Center Durham, NC, USA Julie Gueudry MD Hospital Practitioner Ophthalmology Department Charles Nicolle Hospital Rouen, France Ahmet Kaan Gündüz MD Professor in Ophthalmology Department of Ophthalmology Ankara University Faculty of Medicine Ankara, Turkey Amod Gupta MBBS MS Professor Advanced Eye Centre Post Graduate Institution of Medical Education and Research Chandigarh, India Vishali Gupta MD Additional Professor Advanced Eye Centre Post Graduate Institute of Medical Education and Research Chandigarh, India

Joelle A. Hallak MS PhD candidate Research Specialist University of Illinois at Chicago Chicago, IL, USA Julia A. Haller MD Professor of Ophthalmology Ophthalmologist-in-Chief, Wills Eye Institute Chair, Department of Ophthalmology, Thomas Jefferson University School of Medicine Philadelphia, PA, USA J. William Harbour MD Vice Chairman for Translational Research Professor of Ophthalmology Director, Ocular Oncology Service Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA David R. Hardten MD Director of Refractive Surgery Department of Ophthalmology Minnesota Eye Consultants Adjunct Associate Professor of Ophthalmology University of Minnesota Minneapolis, MN, USA Alon Harris MS PhD FARVO Lois Letzter Professor of Ophthalmology Professor of Cellular and Integrative Physiology Director, Glaucoma Research and Diagnostic Center Indiana University School of Medicine Indianapolis, IN, USA Thomas R. Hedges Jr MD† Formerly Emeritus Professor of Ophthalmology School of Medicine The University of Pennsylvania Philadelphia, PA, USA Jeffrey S. Heier MD Director, Vitreoretinal Service Ophthalmic Consultants of Boston Boston, MA, USA Leon W. Herndon Jr MD Associate Professor of Ophthalmology Medical Director Duke Eye Center Durham, NC, USA Roger A. Hitchings FRCOphth FRCS Professor Emeritus University of London Consultant Ophthalmologist Moorfields Eye Hospital London, UK

Allen C. Ho MD Professor of Ophthalmology Thomas Jefferson University Mid Atlantic Retina Director of Retina Research, Wills Eye Hospital Attending Surgeon, Retina Service of Wills Eye Hospital Philadelphia, PA, USA Joshua H. Hou MD Ophthalmology Resident Department of Ophthalmology and Visual Sciences University of Illinois Eye and Ear Infirmary Chicago, IL, USA Odette M. Houghton MD Associate Professor of Ophthalmology Department of Ophthalmology University of North Carolina Chapel Hill, NC, USA Gene R. Howard MD Private Practice Oculoplastic Surgery Charleston Eyecare Physicians Clinical Professor of Ophthalmology Storm Eye Institute Charleston, SC, USA Frank W. Howes FCS FRCS FRCOphth FRANZCO Cataract Refractive & Glaucoma Surgeon Vision Eye Institute Associate Professor Faculty of Health Sciences Bond University, Gold Coast Queensland, Australia Jason Hsu MD Clinical Instructor Retina Service, Wills Eye Institute Thomas Jefferson University Philadelphia, PA, USA Jeffrey J. Hurwitz MD FRCS(C) Ophthalmologist-in-Chief Ophthalmology and Vision Sciences Mount Sinai Hospital and University of Toronto Toronto, ON, Canada Michael Ip MD Co-Director, Fundus Photograph Reading Center University of Wisconsin Madison, WI, USA Andrea M. Izak MD Post-Doctoral Fellow Storm Eye Institute Medical University of South Carolina Charleston, SC, USA Dina A. Jacobs MD Assistant Professor of Neurology Department of Neurology Perelman School of Medicine Hospital of the University of Pennsylvania Philadelphia, PA, USA Sandeep Jain MD Associate Professor Department of Ophthalmology College of Medicine, University of Illinois at Chicago Chicago, IL, USA

Henry D. Jampel MD MHS Odd Fellows Professor of Ophthalmology Glaucoma Center of Excellence at the Wilmer Eye Institute Johns Hopkins University School of Medicine Baltimore, MD, USA Lee M. Jampol MD Louis Feinberg Professor of Ophthalmology Department of Ophthalmology Northwestern University Chicago, IL, USA

List of Contributors

Debra A. Goldstein MD Professor and Director Uveitis Service Department of Ophthalmology Northwestern Memorial Hospital Northwestern Feinberg School of Medicine Chicago, IL, USA

Aliza Jap FRCS(G) FRCOphth FRCS (Ed) Senior Consultant Ophthalmologist Division of Ophthalmology Changi General Hospital, Singapore Singapore National Eye Centre, Singapore Chris A. Johnson PhD DSc Professor, Department of Ophthalmology and Visual Sciences University of Iowa Hospitals and Clinics Iowa City, IA, USA Mark W. Johnson MD Professor of Ophthalmology and Visual Science Chief, Vitreoretinal Service Department of Ophthalmology and Visual Science W.K. Kellogg Eye Center University of Michigan Medical School Ann Arbor, MI, USA T. Mark Johnson MD FRCSC Attending Surgeon Retina Group of Washington Washington, DC, USA Nicholas Jones BSc MB ChB DO FRCS FRCOphth Consultant Ophthalmic Surgeon Manchester Royal Eye Hospital Manchester, UK Malik Y. Kahook MD The Slater Family Endowed Chair in Ophthalmology Professor of Ophthalmology & Chief of the Glaucoma Service Director of Clinical and Translational Research University of Colorado School of Medicine Denver, CO, USA Peter K. Kaiser MD Chaney Family Endowed Chair for Ophthalmology Research Professor of Ophthalmology Cleveland Clinic Lerner College of Medicine Vitreoretinal Staff, Cole Eye Institute Cleveland, OH, USA Deborah S. Kamal MD MBBS Consultant Ophthalmologist Moorfields Eye Hospital NHS Foundation Trust London, UK

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List of Contributors

Elliott M. Kanner MD PhD Assistant Professor of Ophthalmology Hamilton Eye Institute Memphis, TN, USA Kevin Kaplowitz MD Assistant Professor of Ophthalmology Stony Brook School of Medicine Stony Brook, NY, USA Michael A. Kapusta MD Associate Professor Director of Vitreoretinal Surgery Fellowship McGill University, Montreal, Quebec, Canada Randy H. Kardon MD PhD Professor and Director of Neuro-ophthalmology Director of Iowa City VA Center for Prevention and Treatment of Visual Loss Pomerantz Family Chair of Ophthalmology Department of Ophthalmology and Visual Sciences, University of Iowa Hospital and Clinics and College of Medicine Department of Veterans Affairs Hospital Iowa City, IA, USA Carol L. Karp MD Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Amir H. Kashani MD PhD Assistant Professor of Ophthalmology Department of Ophthalmology University of Southern California Los Angeles, CA, USA Michael A. Kass MD Bernard Becker Professor and Chair Department of Ophthalmology and Visual Sciences Washington University School of Medicine St Louis, MO, USA L. Jay Katz MD FACS Director of Glaucoma Service Wills Eye Institute Professor of Ophthalmology, Jefferson Medical College Philadelphia, PA, USA Paul L. Kaufman MD Peter A. Duehr Professor and Chair Department of Ophthalmology and Visual Sciences University of Wisconsin School of Medicine and Public Health Madison, WI, USA Jeremy D. Keenan MD MPH Associate Professor of Ophthalmology Francis I. Proctor Foundation and Department of Ophthalmology University of California, San Francisco San Francisco, CA, USA Amy T. Kelmenson MD Cornea Fellow Department of Ophthalmology University of Florida College of Medicine Gainesville, FL, USA

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Peng Tee Khaw PhD FRCP FRCS FRCOphth FRCPath FCOptom CBiol FSB FMedSci Professor of Glaucoma and Ocular Healing Consultant Ophthalmic Surgeon Director, National Institute for Health Research Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital and UCL Institute of Ophthalmology London, UK David Y. Kim MD Chief Retina Fellow Massachusetts Eye and Ear Infirmary Harvard Medical School Boston, MA, USA Gene Kim MD Clinical Assistant Professor Department of Ophthalmology and Visual Sciences Robert Cizik Eye Clinic University of Texas, Health Science Center at Houston Houston, TX, USA Alan E. Kimura MD MPH Clinical Associate Professor Department of Ophthalmology University of Colorado Health Sciences Center Colorado Retina Associates, PC Denver, CO, USA Szilárd Kiss MD Director of Clinical Research Assistant Professor of Ophthalmology Weill Cornell Medical College New York, NY NewYork–Presbyterian Hospital New York, NY, USA John W. Kitchens MD Partner Retina Associates of Kentucky Lexington, KY, USA Anna S. Kitzmann MD Assistant Professor of Ophthalmology Department of Ophthalmology University of Iowa Iowa City, IA, USA James M. Klancnik Jr MD Partner, Vitreous Retina Macula Consultants of New York Clinical Assistant Professor Department of Ophthalmology NYU Langone Medical Center and School of Medicine New York, NY, USA Douglas D. Koch MD Professor, Ophthalmology Allen, Mosbacher and Law Chair Baylor College of Medicine Cullen Eye Institute Houston, TX, USA Thomas Kohnen MD PhD FEBO Professor and Chair Department of Ophthalmology Goethe University Frankfurt, Germany Ernest W. Kornmehl MD Associate Clinical Professor of Ophthalmology Tufts Medical Center Tufts University School of Medicine Boston, MA Clinical Instructor of Ophthalmology Harvard Medical School Boston, MA, USA

Takashi Kojima MD PhD Visiting Assistant Professor Department of Ophthalmology Keio University School of Medicine Tokyo, Japan

William J. Lipham MD FACS Ophthalmic Plastic and Reconstructive Surgeon Partner, Minnesota Eye Consultants PA Minneapolis, MN, USA

Natalia Y. Kramarevsky MD Assistant Professor of Clinical Ophthalmology Eastern Virginia Medical School Virginia Beach, VA, USA

Alastair Lockwood MA (Hons) BM BChir MRCOphth Research Fellow National Institute for Health Research Biomedical Research Centre for Ophthalmology Moorfields Eye Hospital and UCL Institute of Ophthalmology London, UK

Anup A. Kubal MD Assistant Professor of Clinical Ophthalmology Department of Ophthalmology University of Florida College of Medicine Gainesville, FL, USA Stephen S. Lane MD Medical Director, Associated Eye Care Adjunct Clinical Professor Department of Ophthalmology University of Minnesota Stillwater, MN, USA Patrick J.M. Lavin MD Professor of Neurology and Ophthalmology Department of Neurology Vanderbilt University Medical Center Nashville, TN, USA Andrew W. Lawton MD Associate Clinical Professor in Ophthalmology University of Tennessee Health Science Center Memphis, TN Private Practice, Little Rock Eye Clinic Little Rock, AR, USA

Nils A. Loewen MD PhD Assistant Professor of Ophthalmology Director, Glaucoma and Cataract Service Director, Glaucoma Fellowship Department of Ophthalmology University of Pittsburgh School of Medicine Pittsburgh, PA, USA Pedro F. Lopez MD Founding Chair and Professor Department of Ophthalmology Herbert Wertheim College of Medicine Florida International University Miami, FL Director Vireoretinal Service Center for Excellence in Eye Care Miami, FL, USA Mats Lundström MD PhD Adjunct Professor Emeritus Department of Clinical Sciences Ophthalmology, Faculty of Medicine Lund University Lund, Sweden

Bryan S. Lee MD JD Assistant Professor of Ophthalmology Department of Ophthalmology University of Washington Seattle, WA, USA

Peter Magnante MD† Formerly Optical Physicist Ophthalmic Instrument Development Broofield Optical Systems West Brookfield, MA, USA

Olivia L. Lee MD Assistant Professor of Ophthalmology Doheny Eye Institute Keck School of Medicine University of Southern California Los Angeles, CA, USA

Alex Mammen MD Clinical Assistant Professor of Ophthalmology Department of Ophthalmology, University of Pittsburgh School of Medicine Pittsburgh, PA, USA

Paul P. Lee MD JD Ophthalmology and Visual Sciences Director, W.K. Kellogg Eye Cente Ann Arbor, MI, USA Jennifer I. Lim MD Professor of Ophthalmology Marion H. Schenk, Esq., Chair in Ophthalmology for Research of the Aging Eye Director of the Retina Service University of Illinois at Chicago Illinois Eye and Ear Infirmary Chicago, IL, USA Ridia Lim MB BS MPH FRANZCO Glaucoma Service Sydney Eye Hospital Sydney, Australia Amy Lin MD Assistant Professor Department of Ophthalmology Loyola University Medical Center Maywood, IL, USA Robert W. Lingua MD Clinical Professor in Ophthalmology Gavin Herbert Eye Institute University of California, Irvine Irvine, CA, USA

Naresh Mandava MD Professor and Chair Department of Ophthalmology Rocky Mountain Lions Eye Institute University of Colorado School of Medicine Aurora, CO, USA Brian Milan Marek BS Medical Student Department of Ophthalmology Eugene and Marilyn Glick Eye Institute Indiana University School of Medicine Indianapolis, IN, USA Michael F. Marmor MD Professor of Ophthalmology Stanford University School of Medicine Byers Eye Institute at Stanford Palo Alto, CA, USA Lisa Martén MD MPH Medical Director South Texas Eye Institute San Antonio, TX, USA Adam Martidis MD Ophthalmologist Miramar Eye Specialists Medical Group Ventura, CA

Cynthia Mattox MD Associate Professor and Vice Chair of Ophthalmology Director, Glaucoma and Cataract Service Tufts University School of Medicine New England Eye Center Boston, MA, USA Stephen D. McLeod MD Professor and Chairman Department of Ophthalmology University of California San Francisco San Francisco, CA, USA Luis J. Mejico MD Director, Neuro-Ophthalmology Division Associate Professor Neurology and Ophthalmology SUNY Upstate Medical University Syracuse, NY, USA Sanford M. Meyers MD Ophthalmologist Retina Consultants Ltd Buffalo Grove, IL, USA Shahzad I. Mian MD Associate Chair, Terry J. Bergstrom Professor, Associate Professor Ophthalmology and Visual Sciences University of Michigan Ann Arbor, MI, USA William F. Mieler MD Professor and Vice-Chairman Director, Residency and Vitreoretinal Fellowship Training Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago, IL, USA David Miller MD Associate Clinical Professor of Ophthalmology Harvard Medical School Jamaica Plain, MA, USA Tatsuya Mimura MD PhD Tokyo Women’s Medical University Medical Center East Tokyo, Japan Rukhsana G. Mirza MD Assistant Professor Department of Ophthalmology Northwestern University Chicago, IL, USA Robert A. Mittra MD Vitreoretinal Surgeon VitreoRetinal Surgery, P.A. Minneapolis, MN, USA Ramana S. Moorthy MD FACS Associated Vitreoretinal and Uveitis ConsultantsFounding PartnerAssociate Clinical Professor of Ophthalmology Eugene and Marilyn Glick Eye InstituteIndiana University School of MedicineIndianapolis, Indiana Michael G. Morley MD MHCM Assistant Clinical Professor of Ophthalmology Harvard Medical School Boston, MA, USA

Andrew A. Moshfeghi MD MBA Associate Retina Associates of Kentucky Lexington, Kentucky, USA Majid Moshirfar MD FACS Professor of Ophthalmology Director of Cornea and Refractive Surgery Division Department of Ophthalmology and Visual Sciences John A. Moran Eye Center University of Utah, School of Medicine Salt Lake City, UT, USA Mark L. Moster MD Attending Surgeon Neuro-Ophthalmology Service Wills Eye Institute Professor of Ophthalmology and Neurology Thomas Jefferson University School of Medicine Philadelphia, PA, USA Ann G. Neff MD Dermatology Associates Sarasota, FL, USA Robert J. Noecker MD MBA Director of Glaucoma Ophthalmic Consultants of Connecticut Fairfield, CT, USA Annabelle A. Okada MD Professor of Ophthalmology Department of Ophthalmology Kyorin University School of Medicine Tokyo, Japan Jeffrey L. Olson MD Associate Professor Department of Ophthalmology Rocky Mountain Lions Eye Institute University of Colorado School of Medicine Aurora, CO, USA Yvonne A.V. Opalinski BSc MD BFA Clinical Associate Cardiovascular Surgery Southlake Regional Health Centre Toronto, ON, Canada Marko Ostovic MD Medical Study Center Manager Department of Ophthalmology Goethe-University Frankfurt, Germany Mark Packer MD FACS CPI Clinical Associate Professor of Ophthalmology Oregon Health and Science University Portland, OR, USA Anthony J. Panarelli MD Associate Attending New York Eye and Ear Infirmary New York, NY, USA Suresh K Pandey MB BS MS ASF Director SuVi Eye Institute and Lasik Laser Center Kota, Rajasthan, India Visiting Assistant Professor, John A Moran Eye Center Salt Lake City, Utah, USA Visiting Assistant Professor, Sydney Eye Hospital, Save Sight Institute, University of Sydney Sydney, NSW, Australia

Sarju S. Patel MD MPH MSc Assistant Professor of Ophthalmology Director of Uveitis Department of Ophthalmology Weill Cornell Medical College New York, NY, USA Vivek R. Patel MD FRCSC Neuro-Ophthalmology and Adult Strabismus Assistant Professor University of Ottawa Faculty of Medicine Ottawa, ON, Canada Carlos E. Pavesio MD FRCOphth Consultant Ophthalmic Surgeon Medical Retina Moorfields Eye Hospital London, UK Victor L. Perez MD Associate Professor Ophthalmology, Microbiology and Immunology, Director, Ocular Surface Center Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA David H. Perlmutter MD Ophthalmology Resident Wills Eye Institute Philadelphia, PA, USA Jody R. Piltz-Seymour MD Clinical Professor Perelman School of Medicine University of Pennsylvania Director, Glaucoma Care Center, PC Philadelphia, PA Alfio P. Piva MD Neurosurgeon and Eye Doctor Department of Ophthalmology and Neurosurgery CCSS University of Costa Rica Hospital Mexico San Jose, Costa Rica Dominik W. Podbielski BSc MD Senior Resident Department of Ophthalmology and Vision Sciences University of Toronto Toronto, ON, Canada John S. Pollack MD Assistant Professor of Ophthalmology Rush University Medical Center Chicago, IL, USA Renata Portella Nunes MD Post-Doctoral Associate Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Francis W. Price Jr MD President Price Vision Group Indianapolis, IN, USA Marianne O. Price PhD Executive Director Cornea Research Foundation of America Indianapolis, IN, USA Jonathan D. Primack MD Corneal Specialist The Eye Consultants of Pennsylvania Wyomissing, PA, USA

Carmen A. Puliafito MD MBA Dean of the Keck School of Medicine University of Southern California May S. and John Hooval Dean’s Chair in Medicine Professor of Ophthalmology and Health Management Doheny Eye Institute Los Angeles, CA, USA Jose S. Pulido MD MS MPH MBA Professor Department of Ophthalmology Mayo Clinic Rochester, MN, USA

List of Contributors

Jeevan R. Mathura Jr MD Assistant Professor of Ophthalmology Department of Ophthalmology The George Washington University Washington, DC, USA

Peter A. Quiros MD Residency Program Director Assistant Professor, Ophthalmology Doheny Eye Institute Keck School of Medicine University of Southern California Jerome C. Ramos-Esteban MD Fellow Cornea and Refractive Surgery, Cole Eye Institute Cleveland Clinic Cleveland, OH, USA Pradeep Ramulu MD MHS PhD Assistant Professor of Ophthalmology Wilmer Eye Institute Johns Hopkins University Baltimore, MD, USA Narsing A. Rao MD Professor of Ophthalmology and Experimental Ophthalmic Pathology Keck School of Medicine University of Southern California Director of Uveitis Service Doheny Eye Institute Los Angeles, CA, USA Naveen K. Rao MD Assistant Professor of Ophthalmology Tufts University School of Medicine Boston, MA, USA Cornea and Anterior Segment Surgeon Lahey Clinic Burlington, MA, USA P. Kumar Rao MD Associate Professor Ophthalmology and Visual Sciences Washington University St Louis, MO, USA Rajesh C. Rao MD Assistant Professor Department of Ophthalmology and Visual Sciences W.E. Kellogg Eye Center University of Michigan Medical School Ann Arbor, MI, USA Veena Rao Raiji MD MPH Assistant Professor of Ophthalmology George Washington University Washington, DC, USA Russell W. Read MD PhD Professor of Ophthalmology and Pathology University of Alabama at Birmingham Birmingham, AL, USA Caio Vinícius Saito Regatieri MD PhD Assistant Professor of Ophthalmology Tufts University School of Medicine New England Eye Center Boston, MA, USA Assistant Professor of Ophthalmology Federal University of São Paolo São Paolo, SP, Brazil

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List of Contributors

Carl D. Regillo MD FACS Director, Retina Service Wills Eye Hospital Professor of Ophthalmology Thomas Jefferson University Philadelphia, PA, USA

Steven E Rubin MD Vice Chair, Residency Program Director and Co-Chief, Pediatric Ophthalmology Hofstra North Shore–Long Island Jewish School of Medicine Great Neck, NY, USA

Joel S. Schuman MD Chairman Department of Ophthalmology University of Pittsburgh Medical Center Pittsburgh, PA, USA

Elias Reichel MD Professor and Vice Chair of Ophthalmology Director, Vitreoretinal Service New England Eye Center Tufts Medical Center Tufts University School of Medicine Boston, MA, USA

Richard M. Rubin LTC USAF MC SFS Ophthalmologist 92nd Medical Group Fairchild Air Force Base, WA, USA

Gary S. Schwartz MD Adjunct Associate Professor Department of Ophthalmology University of Minnesota Minneapolis, MN, USA

Douglas J. Rhee MD Associate Chief, Operations and Practice Development Medical Director, Strategic Network Development Massachusetts Eye and Ear Infirmary Associate Professor, Harvard Medical School Massachusetts Eye and Ear Infirmary Boston, MA, USA Fiona O. Robinson MB BCh BAO MRCP DO FRCOphth Consultant Ophthalmologist King’s College Hospital NHS Trust London, UK Hanna Rodriguez-Coleman MD Ophthalmologist New York Presbyterian Hospital/ Columbia New York, NY, USA Adam H. Rogers MD Assistant Professor of Ophthalmology New England Eye Center Tufts Medical Center Tufts University School of Medicine Boston, MA, USA

Hossein G. Saadati MD Ophthalmic Plastic/Orbital and Reconstructive Surgery Department of Ophthalmology The Permanente Medical Group Stockton, CA, USA Alfredo A. Sadun MD PhD Professor and Thornton Endowed Chair Ophthalmology and Neurosurgery USC Keck School of Medicine Doheny Eye Institute Los Angeles, CA, USA Osamah Jawaid Saeedi MD Assistant Professor Department of Ophthalmology and Visual Sciences University of Maryland Baltimore, MD, USA Sarwat Salim MD FACS Associate Professor of Ophthalmology and Director, Glaucoma Service Hamilton Eye Institute University of Tennessee Memphis, TN, USA

Shiyoung Roh MD Associate Clinical Professor Tufts University School of Medicine Boston, MA Vice-Chair, Division of Surgery and Department of Ophthalmology Lahey Hospital and Medical Center Peabody, MA, USA

Thomas W. Samuelson MD Attending Surgeon Glaucoma and Anterior Segment Surgery Minnesota Eye Consultants, PA Adjunct Associate Professor Department of Ophthalmology University of Minnesota Minneapolis, MN, USA

Noel Rosado-Adames MD Clinical Associate Duke University Eye Center Duke University Medical Center Durham, NC, USA

George E. Sanborn MD Clinical Professor of Ophthalmology Medical College of Virginia Virginia Commonwealth University Richmond, VA, USA

Emanuel S. Rosen BSc MD FRCS(Ed) FRCOphth FRPS Consultant Ophthalmologist in Private Practice Manchester, UK

Giacomo Savini MD GB Bietti Foundation IRCCS Rome, Italy

Brett J. Rosenblatt MD Partner, Long Island Vitreoretinal Consultants Great Neck, NY, USA Philip J. Rosenfeld MD PhD Professor, Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

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Patrick E. Rubsamen MD Retina Specialist Retina Group of Florida Boca Raton, FL, USA

Jonathan B. Rubenstein MD Deutsch Family Professor and ViceChairman of Ophthalmology Rush University Medical Center Chicago, IL, USA

Jonathan Schell MD Associate Physician Pernoud Eye Institute St Louis, MI, USA Paulo Schor MD PhD Tenured Adjunct Professor of Ophthalmology and Visual Sciences Department of Ophthalmology Paulista School of Medicine – Federal University of São Paulo (UNIFESP) São Paulo, SP, Brazil Hermann D. Schubert MD Professor of Clinical Ophthalmology and Pathology E.S. Harkness Eye Institute Columbia University Medical Center New York, NY, USA

Clifford A. Scott OD MPH President New England College of Optometry Boston, MA, USA J. Sebag MD FACS, FRCOphth, FARVO Professor of Clinical Ophthalmology Doheny Eye Institute Founding Director, VMR Institute Huntington Beach, CA, USA Jovina LS See MBBChir(Camb) MA(Camb) MMed(Ophth) FRCS(Edin) FAMS(Singapore) Senior Consultant and Glaucoma Specialist Dept of Ophthalmology, National University Hospital Shinagawa LASIK & Eye Centre Singapore Robert P. Selkin MD Private Practitioner Selkin Laser Centre Brentwood, TN, USA H. Nida Sen MD MHSc Director, Uveitis and Ocular Immunology Fellowship Program National Eye Institute, National Institutes of Health Bethesda, MD Associate Clinical Professor, Department of Ophthalmology The George Washington University Washington, DC, USA Chirag P. Shah MD MPH Assistant Professor, Department of Ophthalmology Tufts University School of Medicine Attending Vitreoretinal Surgeon, Ophthalmic Consultants of Boston Tufts Medical Center Boston, MA, USA Gaurav K. Shah MD Professor of Clinical Ophthalmology and Visual Sciences The Retina Institute Washington University School of Medicine St Louis, MO, USA Raza M. Shah MD PGY-4 Ophthalmology Resident Department of Ophthalmology Drexel University College of Medicine Philadelphia, PA, USA Arsham Sheybani MD Chief Resident of Ophthalmology Department of Ophthalmology and Visual Sciences Washington University in St Louis School of Medicine St Louis, MO, USA

Carol L. Shields MD Co-Director Ocular Oncology Professor, Thomas Jefferson University Wills Eye Institute Philadelphia, PA, USA M. Bruce Shields MD Marvin L. Sears Professor Emeritus Yale University School of Medicine Burlington, NC, USA Yevgeniy (Eugene) Shildkrot MD Assistant Professor of Ophthalmology Ocular Oncology and Vitreoretinal Diseases and Surgery University of Virginia Charlottesville, VA, USA Bradford J. Shingleton MD Surgeon in Ophthalmology Ophthalmic Consultants of Boston Associate Clinical Professor of Ophthalmology Department of Ophthalmology Harvard Medical School Clinical Instructor of Ophthalmology Department of Ophthalmology Tufts University School of Medicine Boston, MA, USA Roni M. Shtein MD MS Assistant Professor Department of Ophthalmology and Visual Sciences University of Michigan Ann Arbor, MI, USA Ryan W. Shultz MD Retina Specialist Everett & Hurite Ophthalmic Assocation Pittsburgh, PA, USA Patricia B. Sierra MD Private Practitioner Grutzmacher, Lewis and Sierra Cornea, External Diseases and Refractive Surgery Sacramento, CA, USA Brent Siesky BS PhD Research Associate Assistant Director Glaucoma Research Department of Ophthalmology Indiana University Indianapolis, IN, USA Paul A. Sieving MD PhD Director National Eye Institute National Institutes of Health Bethesda, MD, USA Ravi S. Singh MD Vitreo-Retinal Fellow Eye Institute Medical College of Wisconsin Milwaukee, WI, USA Arunan Sivalingam MD Clinical Associate Professor Thomas Jefferson University Hospital Philadelphia, PA, USA Dimitra Skondra MD Vitreoretinal Fellow Retina Service Massachusetts Eye and Ear Infirmary Boston, MA, USA

Thomas L. Steinemann MD Director, Cornea and External Disease Division of Ophthalmology MetroHealth Medical Center Professor of Ophthalmology Case Western Reserve University Cleveland, OH, USA

William E. Smiddy MD Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

Mitchell B. Strominger MD Chief, Pediatric Ophthalmology and Ocular Motility Neuro-ophthalmology Clinical Professor of Ophthalmology and Pediatrics Tufts Medical Center/Floating Hospital for Children Tufts University Medical School Boston, MA, USA

H. Kaz Soong MD Professor, Ophthalmology W.K. Kellogg Eye Center University of Michigan Medical School Ann Arbor, MI, USA

Jeanine Suchecki MD Associate Professor University of Connecticut Health Center Farmington, CT, USA

Felipe A. Soria MD Cornea, Refractive and Cataract Surgeon Vissum, Alicante-Spain Director, Clinical Research Program Instituto de la Vision Montemorelos, Mexico

Alan Sugar MD Professor and Vice Chair Ophthalmology and Visual Sciences W.K. Kellogg Eye Center University of Michigan Medical School Ann Arbor, MI, USA

Sarkis H. Soukiasian MD Director, Cornea and External Diseases, Director, Ocular Inflammation and Uveitis Lahey Clinic Burlington, MA Clinical Assistant Professor Tufts University School of Medicine Ophthalmology Burlington, MA, USA Richard F. Spaide MD Private Practitioner Vitreous, Retina, Macula Consultants of New York New York, NY, USA Thomas C. Spoor MD FACS Private Practitioner Neuro-Ophthalmology and OculoPlastic Surgery Sarasota Retina Institute Sarasota, FL, USA Lana Srur MD Assistant Professor of Clinical Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Kalliopi Stasi MD PhD Instructor of Ophthalmology University of Pennsylvania Scheie Eye Institute Philadelphia, PA, USA David H.W. Steel MB BS FRCOphth Consultant Ophthalmologist Sunderland Eye Infirmary Sunderland, UK Joshua D. Stein MD MS Assistant Professor of Ophthalmology and Visual Sciences University of Michigan Department of Ophthalmology and Visual Sciences Ann Arbor, MI, USA

Joel Sugar MD Professor and Vice-Head Department of Ophthalmology and Visual Sciences Illinois Eye and Ear Infirmary Chicago, IL, USA James C.H. Tan MD PhD FRCOphth Assistant Professor Doheny Eye Institute Department of Ophthalmology Keck School of Medicine University of Southern California Los Angeles, CA, USA Anjali Tannan MD Ophthalmology Resident Department of Ophthalmology Rush University Medical Center Chicago, IL, USA Myron Tanenbaum MD FACS Ophthalmologist Private Practice Miami, FL, USA Suphi Taneri MD Director, Center for Refractive Surgery Eye Department at the St Francis Hospital Münster, Germany Michael J. Taravella MD Professor Director: Cornea and Refractive Surgery University of Colorado Department of Ophthalmology Aurora, CO, USA William Tasman MD Professor and Emeritus Chairman Department of Ophthalmology Wills Eye Hospital and Jefferson Medical College Philadelphia, PA, USA

David G. Telander MD PhD Retinal Consultants Volunteer Clinical Professor University of California Davis Medical School Sacramento, CA, USA Matthew T.S. Tennant BA MD FRCSC Associate Clinical Professor Ophthalmology University of Alberta Edmonton, Alberta, Canada Howard H. Tessler MD Professor of Ophthalmology University of Illinois at Chicago Gurnee, IL, USA Edmond H. Thall MD MS Consultant in Aerospace Ophthalmology Aeromedical Consultation Service Ophthalmology Branch United States Air Force School of Aerospace Medicine Wright–Patterson Air Force Base Dayton, OH, USA Benjamin J. Thomas MD Resident Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Michael D. Tibbetts MD Resident Wills Eye Institute Philadelphia, PA, USA Sapna Tibrewal MD Post-Doc Research Fellow, Corneal Neurobiology Laboratory Department of Ophthalmology and Visual Sciences University of Illinois at Chicago Chicago, IL, USA David P. Tingey MD FRCSC Associate Professor of Ophthalmology Department of Ophthalmology University of Western Ontario Ontario, Canada Faisal M. Tobaigy MD Assistant Professor of Ophthalmology Dean, College of Dental and Applied Medical Science Jazan University Jazan, Saudi Arabia James C. Tsai MD MBA Robert R. Young Professor of Ophthalmology and Visual Science Chairman, Department of Ophthalmology and Visual Science Yale University School of Medicine Chief of Ophthalmology, Yale–New Haven Hospital New Haven, CT, USA Julie H. Tsai MD Assistant Professor Department of Ophthalmology Albany Medical College Albany, NY, USA William G. Tsiaras MD Clinical Professor of Surgery Brown University School of Medicine Providence, Rhode Island Providence, RI, USA

Elmer Y. Tu MD Associate Professor of Clinical Ophthalmology Department of Ophthalmology and Visual Sciences University of Illinois Eye and Ear Infirmary Chicago, IL, USA Nancy Tucker MD Assistant Professor Oculoplastics Service Department of Ophthalmology University of Toronto Toronto, Ontario, Canada

List of Contributors

Kent W. Small MD President/Founder Macula & Retina Institute Molecular Insight Research Foundation 8635 W 3rd Street, suite 395 W Los Angeles, CA, USA 501 N Orange Street suite 250 Glendale, CA, USA Regenerative Medicine Institute, Cedars Sinai Medical Institute, Los Angeles, CA, USA

Sonal S. Tuli MD MEd Associate Professor and Residency Program Director Department of Ophthalmology University of Florida Gainesville, FL, USA Roshni A. Vasaiwala MD Cornea and Refractive Surgery Fellow Department of Ophthalmology and Visual Sciences University of Illinois Eye and Ear Infirmary Chicago, IL, USA Daniel Vítor Vasconcelos-Santos MD PhD Associate Professor of Ophthalmology Department of Ophthalmology Universidade Federal de Minas Gerais Horizonte, MG, Brazil Gregory J. Vaughn MD District Manager Interventional Restorative Therapies Group Medtronic, Inc. Atlanta, GA, USA Raul Velez-Montoya MD International Associate Department of Ophthalmology Rocky Mountain Lions Eye Institute University of Colorado School of Medicine Aurora, CO, USA Hormuz P. Wadia MD Assistant Clinical Professor Department of Ophthalmology James A Haley VAMC Morsani School of Medicine University of South Florida Eye Institute Tampa, FL, USA Rebecca S. Walker MD FACS Private Practitioner Glaucoma Service, Wills Eye Hospital Philadelphia, PA, USA David S. Walton MD President, Children’s Glaucoma Foundation Clinical Professor of Ophthalmology, Harvard Medical School Surgeon in Ophthalmology Massachusetts Eye and Ear Infirmary Boston, MA, USA Frederick M. Wang MD Clinical Professor of Ophthalmology Department of Ophthalmology and Visual Sciences Albert Einstein College of Medicine The Bronx, NY Attending Surgeon New York Eye and Ear Infirmary New York, NY, USA

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List of Contributors

Li Wang MD PhD Assistant Professor of Ophthalmology Department of Ophthalmology Cullen Eye Institute Baylor College of Medicine Houston, TX, USA

Joel M. Weinstein MD Professor of Ophthalmology and Pediatrics Penn State University M.S. Hershey Medical Center Hershey PA, USA

George A. Williams MD Professor and Chair Department of Ophthalmology Oakland University – William Beaumont School of Medicine Royal Oak, MI, USA

Michelle Y. Wang MD PGY-4 Ophthalmology Resident Department of Ophthalmology Doheny Eye Institute Keck School of Medicine University of Southern California Los Angeles, CA, USA

Matthew J. Weiss MD Cornea and Refractive Surgery Fellow Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

William J. Wirostko MD Associate Professor of Ophthalmology The Eye Institute Milwaukee, WI, USA

Ming X. Wang MD PhD Clinical Associate Professor of Ophthalmology University of Tennessee Director, Wang Vision Cataract & LASIK Center Nashville, TN, USA International President Shanghai Aier Eye Hospital Shanghai, China

John J. Weiter MD PhD Associate Professor of Ophthalmology Harvard Medical School Boston, MA, USA

Robert C. Wang MD Vitreoretinal/uveitis specialist Texas Retina Associates Dallas, Texas, USA Clinical Associate Professor University Texas Southwestern Dallas, TX, USA Martin Wax MD Chief Medical Officer and Executive Vice-President R&D PanOptica, Inc. Bernardsville, NJ, USA David V. Weinberg MD Professor of Ophthalmology Medical College of Wisconsin Milwaukee, WI, USA

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Liliana Werner MD PhD Associate Professor Co-Director, Intermountain Ocular Research Center John A. Moran Eye Center University of Utah Salt Lake City, UT, USA Mark Wevill MB ChB FRCSE Ultralase Clinics Birmingham, UK Paul F. White, OD Adjunct Professor of Optometry New England College of Optometry Boston, MA, USA Janey L. Wiggs MD PhD Paul Austin Chandler Associate Professor of Ophthalmology Harvard Medical School Massachusetts Eye and Ear Infirmary Boston, MA, USA

Matthew T. Witmer MD Vitreoretinal Specialist Retinal Consultants of Arizona Phoenix, AZ, USA Gadi Wollstein MD Associate Professor of Ophthalmology Director, Ophthalmic Imaging Research Laboratories UPMC Eye Center University of Pittsburgh School of Medicine Pittsburgh, PA, USA Maria A. Woodward MD Clinical Lecturer in Ophthalmology Department of Ophthalmology University of Michigan Ann Arbor, MI, USA David Xu BS Medical student Cole Eye Institute Cleveland Clinic Cleveland, OH, USA Robert D. Yee MD FACS Chief of Ophthalmology Roudebush VA Medical Center Merrill Grayson Professor of Ophthalmology – Emeritus Indiana University School of Medicine Indianapolis, IN, USA

Zohar Yehoshua MD MHA Assistant Professor of Clinical Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA Elmer Y. Tu MD Associate Professor of Clinical Ophthalmology Department of Ophthalmology and Visual Sciences University of Illinois Eye and Ear Infirmary Chicago, IL, USA Joshua A. Young MD Clinical Professor of Ophthalmology New York University School of Medicine New York, NY, USA Ehud Zamir MD FRANZCO Clinical Senior Lecturer Centre for Eye Research Australia and the Royal Victorian Eye and Ear Hospital Melbourne, VIC, Australia Wadih M. Zein MD Staff Clinician Ophthalmic Genetics and Visual Function Branch National Eye Institute National Institutes of Health Bethesda, MD, USA

Acknowledgments We are grateful to the editors and authors who have contributed to Ophthalmology and to the superb, dedicated Ophthalmology team at Elsevier. We especially would like to thank Sharon Nash and Russell Gabbedy for their tireless efforts in keeping us on track and making our job much easier. We would also like to thank Trinity Hutton, Content

Coordinator; Caroline Jones and Joanna Souch, Project Managers; Elaine Leek and Helen Stedman, Copy Editors; Christian Bilbow, Designer; Jennifer Rose, Illustration Manager; Richard Tibbitts, Illustrator; Megan Graieg, Multimedia Producer; Gaynor Jones and Abigail Swartz, Marketing.

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PART 1 GENETICS

1.1

Fundamentals of Human Genetics Janey L. Wiggs

DNA AND THE CENTRAL DOGMA OF HUMAN GENETICS

HUMAN GENOME Human DNA is packaged as chromosomes located in the nuclei of cells. Chromosomes are composed of individual strands of DNA wound about proteins called histones. The complex winding and coiling process culminates in the formation of a chromosome. The entire collection of human chromosomes includes 22 paired autosomes and two sex chromosomes. Women have two copies of the X chromosome, and men have one X and one Y chromosome (Fig. 1-1-3). The set consisting of one of each autosome as well as both sex chromosomes is called the human genome. The chromosomal molecules of DNA from one human genome, if arranged in tandem end to end,

Sugar–phosphate backbone and nitrogenous bases

Separation of individual strands allows DNA replication

sugar– phosphate backbone

one helical turn = 3.4 nm

The regulation of cellular growth and function in all human tissue is dependent on the activities of specific protein molecules. In turn, protein activity is dependent on the expression of the genes that contain the correct DNA sequence for protein synthesis. The DNA molecule is a double-stranded helix. Each strand is composed of a sequence of four nucleotide bases – adenine (A), guanine (G), cytosine (C), and thymine (T) – joined to a sugar and a phosphate. The order of the bases in the DNA sequence forms the genetic code that directs the expression of genes. The double-stranded helix is formed as a result of hydrogen bonding between the nucleotide bases of opposite strands.1 The bonding is specific, such that A always pairs with T, and G always pairs with C. The specificity of the hydrogen bonding is the molecular basis of the accurate copying of the DNA sequence that is required during the processes of DNA replication (necessary for cell division) and transcription of DNA into RNA (necessary for gene expression and protein synthesis; Fig. 1-1-1). Gene expression begins with the recognition of a particular DNA sequence, called the promoter sequence, as the start site for RNA synthesis by the enzyme RNA polymerase. The RNA polymerase “reads” the DNA sequence and assembles a strand of RNA that is complementary to the DNA sequence. RNA is a single-stranded nucleic acid composed of the same nucleotide bases as DNA, except that uracil takes the place of thymine. Human genes (and genes found in other eukaryotic organisms) contain many DNA sequences that are not translated into polypeptides and proteins. These sequences are called intervening sequences or introns. Introns do not have a specific function, and although they are transcribed into RNA by RNA polymerase, they are spliced out of the initial RNA product (termed heteronuclear RNA, or hnRNA) to form the completed messenger RNA (mRNA). Untranslated RNA may have specific functions. For example, antisense RNA and micro RNAs (miRNA) appear to regulate expression of genes.2 The mRNA is the template for protein synthesis. Proteins consist of one or more polypeptide chains, which are sequences of specific amino acids. The sequence of bases in the mRNA directs the order of amino acids that make up the polypeptide chain. Individual amino acids are encoded by units of three mRNA bases, termed codons. Transfer RNA (tRNA) molecules bind specific amino acids and recognize the corresponding three-base codon in the mRNA. Cellular organelles called ribosomes bind the mRNA in such a configuration that the RNA sequence is accessible to tRNA molecules and the amino acids are aligned to form the polypeptide. The polypeptide chain may be processed by a number of other chemical reactions to form the mature protein (Fig. 1-1-2).

STRUCTURE OF THE DNA DOUBLE HELIX

bases

5l 3l 5l original new chains chain forming adenine

thymine

guanine

3l original chain cytosine

Fig. 1-1-1  Structure of the DNA double helix. The sugar–phosphate backbone and nitrogenous bases of each individual strand are arranged as shown. The two strands of DNA pair by hydrogen bonding between the appropriate bases to form the double-helical structure. Separation of individual strands of the DNA molecule allows DNA replication, catalyzed by DNA polymerase. As the new complementary strands of DNA are synthesized, hydrogen bonds are formed between the appropriate nitrogenous bases.

contain approximately 3.2 billion base pairs (bp). The Human Genome Project was formally begun in 1990 with the defined goals to: identify all the approximately 20 000–25 000 genes in human DNA; determine the sequences of the 3 billion chemical base pairs that make up human DNA; store this information in publicly available databases; improve tools for data analysis; transfer related technologies to the private sector; and address the ethical, legal, and social issues that may arise from the project. One of the most important goals, the complete sequence of the human genome, was completed in draft form in 2001.3 Catalogues of variation in the human genome sequence have also been completed, with the microsatellite repeat map in 1994,4 the release of the HapMap from the International HapMap Consortium in 2004,5 and more recently a catalogue of variants from the 1000 genomes project6. dbSNP (www.ncbi.nlm.nih.gov/projects/SNP/) is a database listing single nucleotide polymorphisms (SNPs) that are single-letter variations in a DNA base sequence. There are over 10 million SNPs present in the human genome with a density of one SNP every 100 bases of DNA. SNPs are

1

1

PACKAGING OF DNA INTO CHROMOSOMES

CENTRAL DOGMA OF MOLECULAR GENETICS

Genetics

nucleus

DNA double helix

cytoplasm

chromosome DNA transcription primary mRNA

processing

mature mRNA

Nucleosome histone

translation nuclear pore plasma membrane

nuclear envelope

nucleosome

DNA 200 bp of DNA

protein Solenoid exon

intron

intron spliced out

Fig. 1-1-2  The central dogma of molecular genetics. Transcription of DNA into RNA occurs in the nucleus of the cell, catalyzed by the enzyme RNA polymerase. Mature mRNA is transported to the cytoplasm, where translation of the code produces amino acids linked to form a polypeptide chain, and ultimately a mature protein is produced. Chromosome

bound together to form haplotypes, which are blocks of SNPs that are commonly inherited together. This binding occurs through the phenomenon of linkage disequilibrium. Within a haplotype block, which may extend for 10 000 to 100 000 bases of DNA, the analysis of only a subset of all SNPs may ‘tag’ the entire haplotype. The International HapMap project has performed an initial characterization of the linkage disequilibrium patterns between SNPs in multiple different populations. The SNP haplotype blocks identified can be examined for association with human disease, especially common disorders with complex inheritance. Knowledge about the effects of DNA variations among individuals can lead to new ways to diagnose, treat, and prevent human disease. This approach has been successfully used to identify the complement factor H risk allele in age-related macular degeneration7–9 as well as risk alleles for myopia,10,11 primary openangle glaucoma,12–14 and Fuchs’ endothelial dystrophy.15

Mitosis and Meiosis

2

In order for cells to divide, the entire DNA sequence must be copied so that each daughter cell can receive a complete complement of DNA. The growth phase of the cell cycle terminates with the separation of the two sister chromatids of each chromosome, and the cell divides during mitosis. Prior to cell division, the complete DNA sequence is copied by the enzyme DNA polymerase in a process called DNA replication. DNA polymerase is an enzyme capable of the synthesis of new strands of DNA using the exact sequence of the original DNA as a template. Once the DNA is copied, the old and new copies of the chromosomes form their respective pairs, and the cell divides such that one copy of each chromosome pair belongs to each cell (Fig. 1-1-4). Mitotic cell division produces a daughter cell that is an exact replica of the dividing cell. Meiotic cell division is a special type of cell division that results in a reduction of the genetic material in the daughter cells, which become the reproductive cells – eggs (women) and sperm (men). Meiosis begins with DNA replication, followed by a pairing of the maternal and paternal chromosomes (homologous pairing) and an exchange of genetic material between chromosomes by recombination (Fig. 1-1-5). The homologous chromosome pairs line up on the microtubule spindle and divide such that the maternal and paternal copies of the doubled chromosomes are distributed to separate daughter cells. A second cell division occurs, and the doubled chromosomes divide, which results in daughter cells that have half the genetic material of somatic (tissue) cells.

chromatin loop contains approximately 100, 000 bp of DNA

chromatin strand

chromatid

Fig. 1-1-3  The packaging of DNA into chromosomes. Strands of DNA are wound tightly around proteins called histones. The DNA–histone complex becomes further coiled to form a nucleosome, which in turn coils to form a solenoid. Solenoids then form complexes with additional proteins to become the chromatin that ultimately forms the chromosome.

BASIC MENDELIAN PRINCIPLES Two important rules central to human genetics emerged from the work of Gregor Mendel, a nineteenth-century Austrian monk. The first is the principle of segregation, which states that genes exist in pairs and that only one member of each pair is transmitted to the offspring of a mating couple. The principle of segregation describes the behavior of chromosomes in meiosis. Mendel’s second rule is the law of independent assortment, which states that genes at different loci are transmitted independently. This work also demonstrated the concepts of dominant and recessive traits. Mendel found that certain traits were dominant and could mask the presence of a recessive gene. At the same time that Mendel observed that most traits segregate independently, according to the law of independent assortment, he unexpectedly found that some traits frequently segregate together. The physical arrangement of genes in a linear array along a chromosome is the explanation for this surprising observation. On average, a recombination event occurs once or twice between two paired homologous chromosomes during meiosis (Fig. 1-1-6). Most observable traits, by chance, are located far away from one another on a chromosome, such that recombination is likely to occur between them, or they are located on entirely different chromosomes. If two traits are on separate

MEIOTIC CELL CYCLE

MITOTIC CELL CYCLE

1.1

Interphase plasma membrane cytoplasm nucleolus

nucleus nuclear envelope

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chiasmata Daughter cells

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Fundamentals of Human Genetics

centrioles

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Prometaphase microtubule spindle pole centromere chromatid

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large egg and polar bodies spermatids of equal size

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Fig. 1-1-4  The mitotic cell cycle. During mitosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides to form two identical diploid daughter cells.

chromosomes, or a recombination event is likely to occur between them on the same chromosome, the resultant gamete formed during meiosis has a 50% chance of inheriting different alleles from each loci, and the two traits respect the law of independent assortment. If, however, the loci for these two traits are close together on a chromosome, with the result that a recombination event occurs between them only rarely, the alleles at each loci are passed to descendent gametes ‘in phase.’ This means that the particular alleles present at each loci in the offspring reflect the orientation in the parent, and the traits appear to be ‘linked.’ For example, in Mendel’s study of pea plants, curly leaves were always found with pink flowers, even though the genes for curly leaves and pink flowers are located at distinct loci. These traits are linked, because the curly-leaf gene and the pink-flower gene are located close to each other on a chromosome, and a recombination event only rarely occurs between them. Recombination and linkage are the fundamental concepts behind genetic linkage analysis.

Haploid gametes

Fig. 1-1-5  The meiotic cell cycle. During meiosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides twice to form four haploid cells (gametes). As a consequence of the crossing over and recombination events that occur during the pairing of homologous chromosomes prior to the first division, the four haploid cells may contain different segments of the original parental chromosomes. For brevity, prophase II and telophase II are not shown.

GENETIC RECOMBINATION BY CROSSING OVER A

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Fig. 1-1-6  Genetic recombination by crossing over. Two copies of a chromosome are copied by DNA replication. During meiosis, pairing of homologous chromosomes occurs, which enables a crossover between chromosomes to take place. During cell division, the recombined chromosomes separate into individual daughter cells.

Mutations are changes in the gene DNA sequence that result in a biologically significant change in the function of the encoded protein. If a particular gene is mutated, the protein product might not be produced, or it might be produced but function poorly or even pathologically (dominant negative effect). Point mutations (the substitution of a single base pair) are the most common mutations encountered in human

genetics. Missense mutations are point mutations that cause a change in the amino acid sequence of the polypeptide chain. The severity of the missense mutation is dependent on the chemical properties of the switched amino acids and on the importance of a particular amino acid in the function of the mature protein. Point mutations also may

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decrease the level of polypeptide production because they interrupt the promoter sequence, splice site sequences, or create a premature stop codon. Gene expression can be affected by the insertion or deletion of large blocks of DNA sequence. These types of mutations are less common than point mutations but may result in a more severe change in the activity of the protein product. A specific category of insertion mutations is the expansion of trinucleotide repeats found in patients affected by certain neurodegenerative disorders. An interesting clinical phenomenon, ‘anticipation,’ was understood on a molecular level with the discovery of trinucleotide repeats as the cause of myotonic dystrophy.16 Frequently, offspring with myotonic dystrophy were affected more severely and at an earlier age than their affected parents and grandparents. Examination of the disease-causing trinucleotide repeat in affected pedigrees demonstrated that the severity of the disease correlated with the number of repeats found in the myotonic dystrophy gene in affected individuals. This phenomenon has been observed in a number of other diseases, including Huntington’s disease.17 Chromosomal rearrangements may result in breaks in specific genes that cause an interruption in the DNA sequence. Usually, the break in DNA sequence results in a truncated, unstable, dysfunctional protein product; occasionally, the broken gene fuses with another gene to cause a ‘fusion polypeptide product,’ which may have a novel activity in the cell. Often, such a novel activity results in an abnormality in the function of the cell. An example of such a fusion protein is the product of the chromosome 9;22 translocation that is associated with many cases of leukemia (Fig. 1-1-7).18,19 A set consisting of one of each autosome as well as an X or a Y chromosome is called a haploid set of chromosomes. The normal complement of two copies of each gene (or two copies of each chromosome) is called diploidy. Rarely, as a result of abnormal chromosome separation during cell division, a cell or organism may have three copies of each chromosome, which is called triploidy. A triploid human is not viable; however, some patients have an extra chromosome or an extra segment of a chromosome. In such a situation, the abnormality is called trisomy for the chromosome involved. For example, patients with Down syndrome have three copies of chromosome 21, also referred to as trisomy 21.20 If one copy of a pair of chromosomes is absent, the defect is called haploidy. Haploidy for an entire human chromosome is probably lethal, but deletions of a segment of a chromosome are common in the human population. Deletions of the X chromosome are frequently the cause of Duchenne’s muscular dystrophy.21 Polymorphisms are changes in DNA sequence that don’t have a significant biological effect. These DNA sequence variants may modify disease processes, but alone are not sufficient to cause disease. Human DNA sequence is highly variable and includes single nucleotide polymorphisms (SNPs), microsatellite repeat polymorphisms (20–50 bp repeats of CA or GT sequence), variable number of tandem repeat

RECIPROCAL TRANSLOCATION

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Fig. 1-1-7  Reciprocal translocation between two chromosomes. The Philadelphia chromosome (responsible for chronic myelogenous leukemia) is shown as an example of a reciprocal chromosomal translocation that results in an abnormal gene product responsible for a clinical disorder. In this case, an exchange occurs between the long arm of chromosome 9 and   the long arm of chromosome 22.

polymorphisms (VNTR, repeats of 50–100 bp of DNA), or larger insertion deletions.22

GENES AND PHENOTYPES The relationship between genes and phenotypes is complex: more than one genetic defect can lead to the same clinical phenotype (genetic heterogeneity), and different phenotypes can result from the same genetic defect (variable expressivity). Retinitis pigmentosa is an excellent example of genetic heterogeneity as it may be inherited as an X-linked, autosomal dominant, autosomal recessive, or digenic trait, and more than 165 causative genes have been identified.23 Other ocular disorders that are genetically heterogeneous include congenital cataract, glaucoma, and age-related macular degeneration. Different genes may contribute to a common phenotype because they affect different steps in a common pathway. Understanding the role of each gene in the disease process can help define the cellular mechanisms that are responsible for the disease. For many genes, a single mutation that alters a critical site in the protein results in an abnormal phenotype. For some diseases, the resulting phenotypes are remarkably similar regardless of the nature of the mutation. For example, a wide variety of mutations in RB1 cause retinoblastoma. Other diseases, however, exhibit variable expressivity, where an individual’s mutation may be responsible for severe disease, mild disease, or disease that is not clinically detectable (incomplete penetrance). There are many examples of ocular disease demonstrating variable expressivity, including Kjer’s autosomal dominant optic atrophy,24 Axenfeld–Rieger syndrome,25and aniridia.26 Different mutations in the same gene can also result in different phenotypes (allelic heterogeneity). Allelic heterogeneity accounts for the different phenotypes of dominant corneal stromal dystrophies caused by mutations in the TGFB1/BIGH3.27 The phenotypic expression of a mutation may depend upon its molecular site within a particular gene. Such variable expressivity based on the location of the mutation is exemplified by mutations in the rds gene, which may cause typical autosomal dominant retinitis pigmentosa or macular dystrophy depending on the position of the genetic defect.28 As embryonic cells multiply and differentiate in a particular tissue, only a subset of genes becomes active. Consequently, the expression of specific genes becomes limited to precise tissues. Tissue-specific genes explain why certain inherited diseases are restricted to particular parts of the body. However, although the clinical expression of some inherited disorders seems to be localized to special tissues, such as the eye, a number of ocular disorders are caused by genes that are expressed in tissues throughout the body.

PATTERNS OF HUMAN INHERITANCE The most common patterns of human inheritance are autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial. Figure 1-1-8 shows examples of these four inheritance patterns. Other inheritance patterns less commonly encountered in human disease include X-linked dominant, digenic inheritance (polygenic), pseudo­ dominance, and imprinting. Figure 1-1-9 defines the notation and symbols used in pedigree construction.

Autosomal Dominant

A disease-causing mutation that is present in only one of the two gene copies at an autosomal locus (heterozygous) is a dominant mutation. For example, a patient with dominant retinitis pigmentosa will have a defect in one copy of one retinitis pigmentosa gene inherited from one parent who, in most cases, is also affected by retinitis pigmentosa. The other copy of that gene, the one inherited from the unaffected parent, is normal (wild type). Affected individuals have a 50% chance of having affected siblings and a 50% chance of passing the abnormal gene to their offspring. Fifty percent of children of an affected individual will be affected. For a dominant disease, males and females transmit the disease equally and are affected equally. True dominant alleles produce the same phenotype in the heterozygous and homozygous states. In humans, most individuals affected by a disease caused by a dominant allele are heterozygous; however, occasionally homozygous mutations have been described. In cases where the homozygous individual is more severely affected than the heterozygous individual, the disease is more appropriately noted to be inherited as a semidominant trait. For example, alleles in the PAX3

PATTERNS OF INHERITANCE Pedigrees with an autosomal dominant trait

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1.1 Fundamentals of Human Genetics

Generation I

Fig. 1-1-8  Patterns of inheritance. For pedigrees with an autosomal dominant trait, panel 1 shows inheritance that originates from a previous generation, panel   2 shows segregation that originates in the second generation of this pedigree, and panel 3 shows an apparent ‘sporadic’ case, which is actually a new mutation that arises in the most recent generation.   This mutation has a 50% chance of being passed to offspring of the affected individual. For pedigrees with an autosomal recessive trait, panel 1 shows an isolated affected individual in the most recent generation (whose parents are obligatory carriers of the mutant gene responsible for the condition), panel 2 shows a pair of affected siblings whose father is also affected (for the siblings to be affected, the mother must be an obligate carrier of the mutant gene), and panel 3 shows an isolated affected individual in the most recent generation who is a product of a consanguineous marriage between two obligate carriers of the mutant gene. For pedigrees with an X-chromosomal trait, panel 1 shows an isolated affected individual whose disease is caused by a new mutation in the gene responsible for this condition, panel 2 shows an isolated individual   who inherited a mutant copy of the gene from the mother (who is an obligate carrier), and panel 3   shows segregation of an X-linked trait through a multigeneration pedigree (50% of the male offspring are affected, and their mothers are obligate carriers of the disease). For pedigrees with a mitochondrial trait, the panel shows a large, multigeneration pedigree – men and woman are affected, but only women have affected offspring.

V Pedigrees with a mitochondrial trait I II III IV affected male

affected female

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gene, causing Waardenburg’s syndrome, are semidominant, because a homozygote with more severe disease compared with their heterozygote relatives has been described.29 In some pedigrees with an autosomal dominant disease, some individuals who carry the defective gene do not have the affected phenotype. However, these individuals can still transmit the disease gene to offspring and have affected children. This phenomenon is called reduced penetrance and is disease-gene-specific. The gene responsible for retinoblastoma (RB1) is only 90% penetrant, which means that 10% of the individuals who inherit a mutant copy of the gene do not develop the tumor.30

Autosomal Recessive

Diseases that require both copies of a gene to be abnormal for development are inherited as recessive traits. Heterozygous carriers of mutant genes are usually clinically normal. The same recessive defect might affect both gene copies, in which case the patient is said to be a homozygote. Different recessive defects might affect the two gene copies, in which case the patient is a compound heterozygote. In a family with recessive disease, both parents are unaffected carriers, each having one wild-type gene (allele) and one mutant gene (allele). Each parent has a 50% chance of transmitting the defective allele to a child. Since a child must receive a defective allele from both parents to be affected, each child has a 25% chance of being affected (50% × 50% = 25%), while 50% of the offspring will be carriers of the disease. If the parents are related they may be carriers of the same rare mutations and there is a

unaffected female, gene carrier (heterozygous)

greater chance that a recessive disease can be transmitted to offspring. Males and females have an equal chance of transmitting and inheriting the disease alleles.

X-Linked Recessive

Mutations of the X chromosome produce distinctive inheritance patterns, because males have only one copy of the X chromosome whereas females have two. Most X-linked gene defects are inherited as X-linked recessive traits. Carrier females are typically unaffected because they have both a normal copy and a defective copy of the disease-associated gene. Carrier males are affected because they only have one defective X chromosome and they do not have a normal gene copy to compensate for the defective copy. All of the daughters of an affected male will be carriers of the disease gene because they will inherit the defective X chromosome. None of the sons of an affected male will be affected or be carriers because they will inherit the Y chromosome. Each child of a carrier female has a 50% chance of inheriting the disease gene. If a son inherits the defective gene he will be affected. If a daughter inherits the defective gene she will be a carrier. An important characteristic of X-linked recessive disorders is that males never transmit the disease to sons directly (male-to-male transmission). Usually female carriers of an X-linked disease gene do not have any clinical evidence of the disease. However, for some X-linked diseases, mild clinical features can be found in female carriers. For example, in X-linked retinoschisis, affected males are severely affected while carrier females have a visually insignificant but clinically detectable retinal

5

1

BASIC PEDIGREE NOTATION

Genetics

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Fig. 1-1-9  Basic pedigree notation. Typical symbols used in pedigree construction are defined.

abnormality.31 Mild phenotypic expression of the disease gene can be caused by the process of lyonization. In order for males (with one X chromosome) and females (with two X chromosomes) to have equal levels of expression of X-linked genes, female cells express genes from only one of their two X chromosomes. The decision as to which X chromosome is expressed is made early in embryogenesis, and the line of descending cells faithfully adheres to the early choice. As a result, females are mosaics, with some of the cells in each tissue expressing the maternally derived X chromosome and the remainder expressing the paternally derived X chromosome. When one of the X chromosomes carries an abnormal gene, the proportion of cells that express the mutant versus the normal gene in each tissue can vary. By chance a susceptible tissue might have a preponderance of cells expressing the mutant X chromosome, causing the disease to become manifest. Most females affected with X-linked conditions because of lyonization have milder disease than that found in their male relatives. Females can also be affected by an X-linked recessive disease if the father is affected and the mother coincidentally is a carrier of a mutation in the disease gene. In this case, 50% of daughters would be affected, because 50% would inherit the X chromosome from the mother carrying the disease gene and all the daughters would inherit the X chromosome from the father carrying the disease gene. Because most X-linked disorders are rare, the carrier frequency of disease genes in the general population is low, and the chance that a carrier female would mate with a male affected by the same disease is quite low.

Mitochondrial Inheritance

6

Mitochondria are small organelles located in the cytoplasm of cells. They function to generate ATP for the cell and are most abundant in cells that have high energy requirements such as muscle and nerve cells. Mitochondria have their own small chromosome – 16 569 bp of DNA encoding for 13 mitochondrial proteins, 2 ribosomal RNAs, and 22 tRNAs. Mutations occurring in genes located on the mitochondrial chromosome cause a number of diseases including Leber’s hereditary optic atrophy32 and Kearns–Sayre syndrome.33 Mutations occurring on the mitochondrial chromosome are inherited only from the mother because virtually all human mitochondria are derived from the maternal egg. Fathers do not transmit mitochondria to their offspring. Cells vary in the number of mitochondria they contain, and when cells divide the mitochondria are divided randomly. As a result, different cells can have varying numbers of mitochondria and if a fraction of

the mitochondria contain a mutated gene, different cells will have a varying proportion of healthy versus mutant mitochondria. The distribution of mutant mitochondria is called heteroplasmy and the proportion of mutant mitochondria can vary from cell to cell and can also change with age. Differences in the relative proportions of mutant mitochondria can partly explain the observed variable severity of mitochondrial diseases, and also the variable age of onset of mitochondrial diseases.

Pseudodominance

This is the term given to an apparent dominant inheritance pattern due to recessive defects in a disease gene. This situation arises when a parent affected by a recessive disease (two abnormal copies of the disease gene) has a spouse who is a carrier of one abnormal copy of the disease gene. Children from this couple will always inherit a defective gene copy from the affected parent and will have a 50% chance of inheriting the defective gene copy from the unaffected carrier parent. On average, half of the children will inherit two defective gene copies and will be affected. The pedigree would mimic a dominant pedigree because of apparent direct transmission of the disease from the affected parent to affected children and because approximately 50% of the children will be affected. Pseudodominant transmission is uncommon, because few people are asymptomatic carriers for any particular recessive gene.

X-Linked Dominant Inheritance

This inheritance pattern is similar to X-linked recessive inheritance, except that all females who are carriers of an abnormal gene on the X chromosome are affected rather than unaffected. All of the male offspring are also affected. Incontinentia pigmenti is probably inherited as an X-linked dominant trait. Affected females have irregularly pigmented atrophic scars on the trunk and the extremities, and congenital avascularity in the peripheral retina with secondary retinal neovascularization.34 This and other X-linked dominant disorders occur almost always in females, and it is likely that the X chromosome gene defects causing these diseases are embryonic lethals when present in males.

Digenic Inheritance and Polygenic Inheritance

Digenic inheritance occurs when a patient has heterozygous defects in two different genes, and the combination of the two gene defects causes disease. Individuals who have a mutation in only one of the genes are normal. Digenic inheritance is different from recessive inheritance, because the two mutations involve different disease genes. In some retinitis pigmentosa families, mutation analysis of the peripherin gene and the ROM1 gene showed that the affected individuals harbor specific mutations in both genes. Individuals with a mutation in only one copy of either gene were unaffected by the disease.35 Triallelic inheritance has been described in some families affected by Bardet–Biedl syndrome (BBS). In these pedigrees, affected individuals carry three mutations in one or two BBS genes (12 BBS genes have been identified),36 and unaffected individuals have only two abnormal alleles. In some families, it has been proposed that BBS may not be a single-gene recessive disease but a complex trait requiring at least three mutant alleles to manifest the phenotype. This would be an example of triallelic inheritance.37 If the expression of a heritable trait or predisposition is influenced by the combination of alleles at three or more loci, it is polygenic. Because of the complex inheritance, conditions caused by multiple alleles do not demonstrate a simple inheritance pattern. These complex traits may also be influenced by environmental conditions. Examples of phenotypes in ophthalmology that exhibit complex inheritance because of contributions of multiple genes and environmental factors are myopia,38 age-related macular degeneration,39 and adult-onset open-angle glaucoma.40

Imprinting

Some mutations give rise to autosomal dominant traits that are transmitted by parents of either sex, but they are expressed only when inherited from a parent of one particular sex. In families affected with these disorders, they would appear to be transmitted in an autosomal dominant pattern from one parent (either the mother or the father) and would not be transmitted from the other parent. Occasionally, the same mutation gives rise to a different disorder depending on the sex of the parent transmitting the trait. These parental sex effects are evidence of a phenomenon called imprinting. Although the molecular mechanisms

responsible for imprinting are not completely understood, it appears to be associated with DNA methylation patterns that can mark certain genes with their parental origin.41

retrovirus

Autosomal Dominant

Disorders inherited as autosomal dominant traits result from mutations that occur in only one copy of a gene (i.e., in heterozygous individuals). Usually, the parental origin of the mutation does not matter. However, if the gene is subject to imprinting (see below), then mutations in the maternal or paternal copy of the gene may give rise to different phenotypes.

therapeutic human gene Recombinant virus replicates in a packaging cell replace retroviral genes with therapeutic human gene

Haploinsufficiency

Under normal circumstances, each copy of a gene produces a protein product. If a mutation occurs such that one copy of a gene no longer produces a protein product then the amount of that protein in the cell has been reduced by half. Mutations that cause a reduction in the amount of protein or lead to inactivation of the protein are called lossof-function mutations. For many cellular processes, this reduction in protein quantity does not have consequences, i.e., the heterozygous state is normal, and these mutations may be inherited as recessive traits (see below). However, for some cellular processes there is an absolute requirement for the full dosage of protein product, which can only be furnished if both copies of a particular gene are active. Diseases that are caused by inheritance of a single mutation reducing the protein level by half are inherited as dominant traits.

1.1

Therapeutic gene engineered into retrovirus DNA

packaging cell

Fundamentals of Human Genetics

MOLECULAR MECHANISMS OF DISEASE

GENE THERAPY USING A RETROVIRUS VECTOR

virions

unpackagable helper provirus

Replicated recombinant virus infects the target cell and inserts copies of the therapeutic gene

Gain-of-function dominant negative effect

Autosomal dominant disorders can be caused by mutant proteins that have a detrimental effect on the normal tissue. Mutations in one copy of a gene may produce a mutant protein that can accumulate as a toxic product or in some other way interfere with the normal function of the cell. The mutant protein may also interfere with the function of the normal protein expressed by the remaining normal copy of the gene thus eliminating any normal protein activity.20 It is possible to have gain-of-function mutations that can also be dominant negative because the new function of the protein also interferes with the function of the remaining normal copy of the gene.

Autosomal and X-Linked Recessive

Recessive disorders result from mutations present on both the maternal and paternal copies of a gene. Mutations responsible for recessive disease typically cause a loss of biologic activity, either because they create a defective protein product that has little or no biologic activity or because they interfere with the normal expression of the gene (regulatory mutations). Most individuals heterozygous for recessive disorders, both autosomal and X-linked, are clinically normal.

GENE THERAPY Mutations in the DNA sequence of a particular gene can result in a protein product that is not produced, works poorly, or has adopted a novel function that is detrimental to the cell. Gene therapy involves the delivery of a normal gene to the tissue that contains the flawed gene. In some cases, the new gene may code for an entirely different protein whose function compensates for the protein encoded by the flawed gene. A common approach to delivering therapeutic genes to specific tissues is to use modified viruses as vectors.42 Normally, certain viruses invade a host cell, get incorporated into the host genome, then express the viral genes required for replication of the invading virus. The mature virus eventually takes over the cell, with the result that the cell dies, and releases new, infectious viral products that can infect adjacent cells. A general approach to gene therapy is to use an altered (recombinant) viral vector to carry the gene of interest to the desired tissue. Using genetic engineering techniques, the viral DNA is modified so that the viral genes required for virus proliferation are removed and the therapeutic gene is put in their place. Such a virus may invade the diseased tissue, become incorporated into the host DNA, and express the desired gene. Because the modified virus does not have the viral genes required for viral replication, the virus cannot proliferate, and the host cell does not die (Fig. 1-1-10). A successful example of this approach has recently been demonstrated by the restoration of vision in a canine

RNA

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Fig. 1-1-10  Gene therapy using a retrovirus vector. A therapeutic gene is engineered genetically into the retrovirus DNA and replaces most of the viral DNA sequences. The ‘recombinant virus’ that carries the therapeutic gene is allowed to replicate in a special ‘packaging cell,’ which also contains normal virus that carries the genes required for viral replication. The replicated recombinant virus is allowed to infect the human diseased tissue, or ‘target cell.’ The recombinant virus may invade the diseased tissue but cannot replicate or destroy the cell. The recombinant virus inserts copies of the normal therapeutic gene into the host genome and produces the normal protein product.

model of Leber’s congenital amaurosis using a recombinant adenoassociated virus carrying the normal gene (RPE65).43 Human trials using a similar approach also successfully restored vision in patients with RPE65 mutations.44 Diseases caused by mutations that create a gene product that is destructive to the cell need to be treated using a different approach. In these cases, genes or oligonucleotides that may inactivate the mutated gene are introduced into the cell. This is called ‘antisense therapy,’ and it is proving to be a useful approach for diseases caused by the gain-offunction mutations.45 A number of different viral vectors likely to be useful for gene therapy are currently under investigation. In addition, development of nonviral mechanisms, based on the emerging methodology of nanotechnology, to introduce therapeutic genes into diseased tissue is ongoing.46 In general, most of the current approaches to gene therapy are aimed at repairing the somatic cells of the particular tissue affected by the disease gene. Gene delivery may be tailored to the somatic cells affected by the disorder. Gene therapy of ocular disorders benefits from the

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accessibility of the eye, the ability to visualize the diseased tissue, and the large number of specific gene defects known to be responsible for many inherited eye disorders.47 Specific treatment of the diseased cells does not affect the other cells of the body, which include the germline cells. Because the germline cells continue to carry flawed copies of the gene, the disease may still be passed to offspring of the affected patient. Gene therapy targeted to germline cells as well as the diseased somatic cells results in successful treatment of the disease in the affected individual and prevents transfer of the disease to any offspring.

KEY REFERENCES 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 2010;467:1061–73. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010;363(11):1016–24.

Access the complete reference list online at

8

Burdon KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 2011;43:574–8. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of   age-related macular degeneration. Science 2005;308:419–21. Han J, Thompson-Lowrey AJ, Reiss A, et al. OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy. Genet Med 2006;8:217–25. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s con­ genital amaurosis. N Engl J Med 2008;358:2240–8. Schmedt T, Silva MM, Ziaei A, Jurkunas U. Molecular bases of corneal endothelial dystrophies.   Exp Eye Res 2012;95:24–34. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 2012;8(4):e1002654.

REFERENCES 1. Watson JD, Crick FHC. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 1953;171:737–8. 3. Wolfsberg TG, McEntyre J, Schuler GD. Guide to the draft human genome. Nature 2001;409:824–6. 4. Murray JC, Buetow KH, Weber JL, et al. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science 1994;265:  2049–54. 5. The International HapMap Consortium. The International HapMap Project. Nature 2003;426:789–96. 6. 1000 Genomes Project Consortium. A map of human genome variation from populationscale sequencing. Nature 2010;28;467:1061–73. 7. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–9. 8. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–21. 9. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and   age-related macular degeneration. Science 2005;308:421–4. 10. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5. 11. Solouki AM, Verhoeven VJ, van Duijn CM, et al. A genome-wide association study identifies   a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet 2010;42:897–901. 12. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9. 13. Burdon KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 2011;43:574–8. 14. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 2012;8(4):e1002654. 15. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010;363:1016–24. 16. Lindblad K, Schalling M. Expanded repeat sequences and disease. Semin Neurol 1999;19:289–99. 17. Lee JM, Ramos EM, Lee JH, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 2012;78:690–5. 18. Kato T, Kurahashi H, Emanuel BS. Chromosomal translocations and palindromic AT-rich repeats. Curr Opin Genet Dev 2012. [Epub ahead of print] doi: 10.1016/j.gde.2012.02.004. 19. Vladareanu AM, Müller-Tidow C, Bumbea H, et al. Molecular markers guide diagnosis and treatment in Philadelphia chromosome-negative myeloproliferative disorders (Review). Oncol Rep 2010;23:595–604.

25. Hjalt TA, Semina EV Current molecular understanding of Axenfeld–Rieger syndrome. Expert Rev Mol Med 2005;7:1–17. 26. Vincent MC, Gallai R, Olivier D, et al. Variable phenotype related to a novel PAX 6 mutation (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia. Am J Ophthalmol 2004;138:1016–21. 27. Schmedt T, Silva MM, Ziaei A, Jurkunas U. Molecular bases of corneal endothelial dystrophies. Exp Eye Res 2012;95:24–34. 28. Kim RY, Dollfus H, Keen TJ, et al. Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene.   Arch Ophthalmol 1995;113:451–5. 29. Wollnik B, Tukel T, Uyguner O, et al. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A 2003;122:42–5. 30. Harbour JW Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol 2001;119:1699–704. 31. Sikkink SK, Biswas S, Parry NR, et al. X-linked retinoschisis: an update. J Med Genet 2007;44:225–32. 32. Newman NJ Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol 2005;140:517–23. 33. Schmiedel J, Jackson S, Schafer J, et al. Mitochondrial cytopathies. J Neurol 2003;250:267–77.

1.1 Fundamentals of Human Genetics

2. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12(12):861–74.

24. Han J, Thompson-Lowrey AJ, Reiss A, et al. OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy. Genet Med 2006;8:217–25.

34. Shields CL, Eagle RC Jr, Shah RM, et al. Multifocal hypopigmented retinal pigment epithelial lesions in incontinentia pigmenti. Retina 2006;26:328–33. 35. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 1994;264:1604–8. 36. Sheffield VC. The blind leading the obese: the molecular pathophysiology of a human obesity syndrome. Trans Am Clin Climatol Assoc 2010;121:172–81. 37. Eichers ER, Lewis RA, Katsanis N, Lupski JR. Triallelic inheritance: a bridge between Mendelian and multifactorial traits. Ann Med 2004;36:262–72. 38. Hornbeak DM, Young TL. Myopia genetics: a review of current research and emerging trends. Curr Opin Ophthalmol 2009;20:356–62. 39. Deangelis MM, Silveira AC, Carr EA, et al. Genetics of age-related macular degeneration: current concepts, future directions. Semin Ophthalmol 2011;26:77–93. 40. Fan BJ, Wiggs JL. Glaucoma: genes, phenotypes, and new directions for therapy. J Clin Invest 2010;120:3064–72. 41. Lewis A, Reik W. How imprinting centres work. Cytogenet Genome Res 2006;113:81–9. 42. Bennett J, Chung DC, Maguire A. Gene delivery to the retina: from mouse to man. Methods Enzymol 2012;507:255–74. 43. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001;28:92–5. 44. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240–8.

20. Roubertoux PL, Kerdelhue B. Trisomy 21: from chromosomes to mental retardation. Behav Genet 2006;36:346–54.

45. Pelletier R, Caron SO, Puymirat J. RNA based gene therapy for dominantly inherited diseases. Curr Gene Ther 2006;6:131–46.

21. Soltanzadeh P, Friez MJ, Dunn D, et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord 2010;20:499–504.

46. Vasir JK, Labhasetwar V. Polymeric nanoparticles for gene delivery. Expert Opin Drug Deliv 2006;3:325–44.

22. Little PF. Structure and function of the human genome. Genome Res 2005;15:1759–66.

47. Bennett J, Maguire AM Gene therapy for ocular disease. Mol Ther 2000;1:501–5.

23. Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 2010;29:335–75.

8.e1

PART 1 GENETICS

1.2

Molecular Genetics of Selected Ocular Disorders Janey L. Wiggs

INTRODUCTION Tremendous advances in the molecular genetics of human disease have been made in the past 10 years. Many genes responsible for inherited eye disease have been isolated and characterized, and the chromosomal location of a number of additional genes has been determined. Identifying and characterizing genes responsible for human disease has led to DNA-based methods of diagnosis, novel therapeutic approaches, including gene therapy, and improved knowledge about the molecular events that underlie the disease processes. The disorders discussed in this chapter represent important examples of major advances in human ocular molecular genetics. Mutations may result in the formation of a defective gene product. If the normal protein product of a mutated gene is necessary for a critical biological function, an alteration of the normal phenotype may occur. Many changes in phenotype are normal variations of human traits (for example, brown hair instead of blond hair). However, some changes cause severe cellular dysfunction, which may be the cause of a disease. Although all inherited disorders are the result of gene mutations, the molecular consequences of a mutation are quite variable. The type of mutation responsible for a disease usually defines the inheritance pattern. For example, mutations that create an abnormal protein detrimental to the cell are typically autosomal dominant, because only one mutant gene is required to disrupt the normal functions of the cell. Mutations that result in proteins that have reduced biological activity (loss of function) may be inherited as autosomal dominant or autosomal recessive conditions, depending on the number of copies of normal genes (and the amount of normal protein) required. Disorders may be caused by mutations in mitochondrial DNA that result in a characteristic inheritance pattern. Also, mutations in genes carried on the X chromosome result in characteristic inheritance patterns.

DOMINANT CORNEAL DYSTROPHIES The autosomal dominant corneal dystrophies are an excellent example of dominant negative mutations that result in the formation of a toxic protein. Four types of autosomal dominant dystrophies that affect the stroma of the cornea have been described (reviewed in reference [1]):  Groenouw (granular) type I  lattice type I  Avellino (combined granular-lattice)  Reis–Bücklers. Although all four corneal dystrophies affect the anterior stroma, the clinical and pathological features differ. The granular dystrophies typically form discrete, white, localized deposits that may obscure vision progressively. Histopathologically, these deposits stain bright red with Masson trichrome and have been termed ‘hyalin.’ In lattice dystrophy, branching amyloid deposits gradually opacify the visual axis. These deposits exhibit a characteristic birefringence under polarized light after staining with Congo red. Avellino dystrophy includes features of both granular and lattice dystrophies. Reis–Bücklers dystrophy appears to involve primarily Bowman’s layer and the superficial stroma. All four dystrophies were mapped genetically to a common interval on chromosome 5q31, and mutations in a single gene, TGFB1 (also known as BIGH3), located in this region were found in affected individuals.2 The product of this gene, keratoepithelin, is probably an extracellular matrix protein that modulates cell adhesion. Four

KERATOEPITHEILIN GENE

secretory signal

recognition sequence for integrins

homologous domains D1

Arg124 Cys (lattice type 1) Arg 124 His (Avellino)

D2

D3

D4

Arg 555 Trp (Groenouw 2) Arg 555 Glu (Reis—Bücklers dystrophy)

Fig. 1-2-1  Keratoepithelin gene. Arrows point to the location of the reported mutations.

different missense mutations, which occur at two arginine codons in the gene, have been found (Fig. 1-2-1). Interestingly, mutations at one of these arginine codons cause lattice dystrophy type I or Avellino dystrophy, the two dystrophies characterized by amyloid deposits. Mutations at the other arginine codon appear to result in either granular dystrophy or Reis–Bücklers dystrophy. The mutation analysis of this gene demonstrates that different mutations within a single gene can result in different phenotypes. The mutation that causes Avellino and lattice dystrophies abolishes a putative phosphorylation site, which probably is required for the normal structure of keratoepithelin. Destruction of this aspect of the protein structure leads to formation of the amyloid deposits that are responsible for opacification of the cornea. Consequently, the mutant protein is destructive to the normal tissue. Mutations at the R555 (arginine at amino acid position 555) appear to result in either granular dystrophy or Reis–Bücklers dystrophy. These phenotype–genotype correlations demonstrate the variable expressivity of mutations in this gene and the significance of alteration of the arginine residues 124 and 555.

ANIRIDIA, PETER’S ANOMALY, AUTOSOMAL DOMINANT KERATITIS Some cellular processes require a level of protein production that results from the expression of both copies of a particular gene. Such proteins may be involved in a variety of biological processes. Certain disorders are caused by the disruption of one copy of a gene that reduces the protein level by half. Such a reduction is also called ‘haploinsufficiency.’ Mutations in the PAX6 gene are responsible for aniridia, Peter’s anomaly, and autosomal dominant keratitis.3 Most of the mutations responsible for these disorders alter the paired-box sequence within the gene (Fig. 1-2-2) and result in inactivation of one copy of the PAX6 gene. The paired-box sequence is an important element that is necessary for the regulatory function of the protein. Losing half the normal paired-box sequence, and probably other regulatory elements within the gene, appears to be the critical event that results in the associated ocular disorders. The protein plays an important role in ocular development, presumably by regulating the expression of genes that are

9

1

MYOCILIN/TIGR PROTEIN GENE

PAX6 GENE

Schematic gene structure

Genetics

ATG 5a

TAA 1 32

1

2

200 bp

3 4 5

6

7

paired box

8

9

10 11

homeobox

12

117

13

PST domain

RIEGER’S SYNDROME Rieger’s syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye. Typical clinical findings may include posterior embryotoxon, iris hypoplasia, iridocorneal adhesions, and corectopia. Approximately 50% of affected individuals develop a high-pressure glaucoma associated with severe optic nerve disease. The cause of the glaucoma associated with this syndrome is not known, although anomalous development of the anterior chamber angle structures is usually found. Genetic heterogeneity of Rieger’s syndrome is indicated by the variety of chromosomal abnormalities that have been associated with the condition including deletions of chromosome 4 and chromosome 13. Genes for Rieger’s syndrome have been located on chromosomes 4q25, 13q14, and 6p25. Iris hypoplasia is the dominant clinical feature of pedigrees linked to the 6p25 locus, whereas pedigrees linked to 4q25 and 13q14 demonstrate the full range of ocular and systemic abnormalities found in these patients. The genes located on chromosomes 4q25 and 6p25 have been identified.4 The chromosome 4q25 gene (PITX2) codes for a bicoid homeo­ box transcription factor. Like PAX6, this gene is expressed during eye development and is probably involved in the ocular developmental processes. The chromosome 6p25 gene, FOXC1 (also called FKHL7), is a member of a forkhead family of regulatory proteins. FOXC1 is expressed during ocular development, and mutations alter the dosage of the gene product. There is some indication that the FOXC1 protein and the PITX2 protein interact during ocular development. The identification of other genes responsible for Rieger’s syndrome and anterior segment dysgenesis is necessary to determine whether these genes are part of a common developmental pathway or represent redundant functions necessary for eye development.

JUVENILE GLAUCOMA

10

Primary juvenile open-angle glaucoma is a rare disorder that develops during the first two decades of life. Affected patients typically present with a high intraocular pressure, which ultimately requires surgical therapy. Juvenile glaucoma may be inherited as an autosomal dominant trait, and large pedigrees have been identified and used for genetic linkage analysis. One gene responsible for this condition, MYOC (also known at TIGR, trabecular meshwork glucocorticoid response protein),

169

72 signal peptide

179

437

259

504aa

501

myosin (25%)

olfactomedin (40%)

Proposed protein structure

Fig. 1-2-2  The PAX6 gene. (Data with permission from Glaser T, et al. PAX6 gene mutations in aniridia. In: Wiggs JL, editor. Molecular genetics of ocular disease. New York: Wiley–Liss; 1995. p. 51–82.)

involved in embryogenesis of the eye. A reduction in the amount of active gene product alters the expression of these genes, which results in abnormal development. The genes that code for the lens crystallin proteins are one class of genes developmentally regulated by the PAX6 protein. The clinical disorders caused by mutations in PAX6 exhibit extensive phenotypic variability. Similar mutations may give rise to aniridia, Peter’s anomaly, or autosomal dominant keratitis. Variation in the phenotype associated with a mutation is termed ‘variable expressivity’ and is a common feature of disorders that arise from haploinsufficiency. Possibly, the variability of the mutant phenotype results from the random activation of downstream genes that occurs when only half the required gene product is available.

368 364 347

leucine zipper

119 126

130

123

133 122

166

118

152

169

158

129

134

159

145

147

138

136

132

leucine

120

131

125

arginine

127

124 121

128

117

Fig. 1-2-3  Myocilin/trabecular meshwork glucocorticoid response (TIGR) protein gene. The myosin-like domain, the olfactomedin-like domain, and the leucine zipper are indicated. Amino acids altered in patients with juvenile- or adult-onset glaucoma are shown. (Reprinted by permission of Federation of the European Biochemical Societies from Orteto J, Escribano J, Coca-Prados M. Cloning and characterization of subtracted cDNAs from a human ciliary body library encoding TIGR, a protein involved in juvenile open angle glaucoma with homology to myosin and olfactomedin. FEBS Lett 1997;413:349–53.)

codes for the myocilin protein and is located on chromosome 1q23 (GLC1A). Myocilin has been shown to be expressed in the human retina, ciliary body, and trabecular meshwork. The protein has several functional domains, including a region homologous to a family of proteins called olfactomedins. Although the function of the protein and the olfactomedin domain is not known, nearly all the mutations associated with glaucoma have been found in the olfactomedin portion of the protein (Fig. 1-2-3).5 Mutations in myocilin also have been associated with some cases of adult-onset primary open-angle glaucoma. Patients with only one copy of the myocilin gene (because of chromosomal deletion removing the second copy of the gene) or without any functional myocilin (caused by homozygosity of a stop-codon polymorphism in the first part of the gene) do not develop glaucoma. These results suggest that mutations in myocilin cause a gain-of-function or dominant negative effect rather than a loss-of-function or haploinsufficiency. The role of myocilin in IOP elevation is not completely known, however, in vitro studies show that myocilin mutants are misfolded and detergent resistant. Myocilin mutations may be secretion incompetent and accumulate in the endoplasmic reticulum (ER) inducing ER stress. Recent studies using a transgenic mouse model indicate that compounds that relieve ER stress can also reduce the mutation-associated elevation of IOP.6

CONGENITAL GLAUCOMA

mutations and phenotypes can be found at the OMIM website (see Table 1-2-1).

Congenital glaucoma is a genetically heterogeneous condition, with both autosomal recessive and autosomal dominant forms reported. Two genes responsible for autosomal recessive congenital glaucoma have been identified, CYP1B1, a member of the cytochrome P-450 family of proteins (cytochrome P-4501B1)7 and LTBP2 (latent transforming growth factor beta binding protein 2).8 Mutations in CYP1B1 have been identified in patients with autosomal recessive congenital glaucoma from all over the world, but especially in areas where consanguinity is a custom.9 Responsible mutations disrupt the function of the protein, implying that a loss of function of the protein results in the phenotype.9 Recurrent mutations are likely to be the result of founder chromosomes that have been distributed to populations throughout the world.10,11 Because the defects responsible for congenital glaucoma are predominantly developmental, cytochrome P-4501B1 and latent transforming growth factor beta binding protein 2 must play a direct or indirect role in the development of the anterior segment of the eye.

1.2

RETINITIS PIGMENTOSA

NONSYNDROMIC CONGENITAL CATARACT At least one-third of all congenital cataracts are familial and are not associated with other abnormalities of the eye or with systemic abnormalities. A number of different genes can contribute to congenital cataract including some that code for the crystallin proteins.12 The human γ-crystallin genes constitute a multigene family that contains at least seven highly related members. All seven of the γ-crystallin genes have been assigned to chromosome 2q34-q35. Of the genes mapped to this region, only two of them, γ-C and γ-D, encode abundant proteins. Two of the genes, γ-E and γ-F, are pseudogenes, which means they are not expressed in the normal lens. A pedigree affected by the Coppock cataract, a congenital cataract that involves primarily the embryonic lens, was shown to be linked genetically to the region that contains the γ-crystallin genes. In individuals affected by the Coppock cataract, additional regulatory sequences have been found in the promoter region of the γ-E pseudogene.13 This result implies that the γ-E pseudogene is expressed in affected individuals and that expression of the pseudogene is the event that leads to cataract formation. A number of other genes have been associated with hereditary cataract. A useful collection of

Molecular Genetics of Selected Ocular Disorders

The molecular genetics of retinitis pigmentosa (RP) is exceedingly complex. The disease can exhibit sporadic, autosomal dominant, autosomal recessive, X-linked, or digenic inheritance. At least 165 genes are known to be associated with RP, and a number of genes have been mapped but not yet found. Most of these genes are expressed preferentially in the retina, but some are expressed systemically. A useful resource listing genes responsible for various forms of retinal diseases, including retinitis pigmentosa, can be found at the RetNet website (http://www.sph.uth.tmc.edu/Retnet/). Mutations in rhodopsin can cause an autosomal dominant form of RP that provides an interesting example of how mutant proteins can interfere with normal cellular processes. Initially, one form of autosomal dominant RP was mapped to chromosome 3q24. Using a candidate gene approach, the rhodopsin gene was identified as the cause of the disease in affected families14. Many of the first mutations detected in the rhodopsin protein were missense mutations located in the C-terminus of the gene (Fig. 1-2-4). To explore the pathogenic mechanisms of these mutations, transgenic mice were created that carried mutant copies of the gene.15 Histopathological studies of these mice showed an accumulation of vesicles that contained rhodopsin at the junction between the inner and outer segments of the photoreceptors. The vesicles probably interfere with the normal regeneration of the photoreceptors, thus causing photoreceptor degeneration. Because the C-terminus of the nascent polypeptide is involved in the transport of the maturing protein, the accumulation of rhodopsin-filled vesicles is likely to result from abnormal transport of the mutant rhodopsin to the membranes of the outer segments. Null mutations (mutations that cause a prematurely shortened or truncated protein) also have been found in the rhodopsin gene in patients who have autosomal recessive retinitis pigmentosa (see Fig. 1-2-4).16 Mutations responsible for recessive disease typically cause a loss of biological activity, either because they create a defective protein product that has little or no biological activity or because they interfere with the normal expression of the gene (regulatory mutations). Most individuals heterozygous for autosomal recessive disorders are

TABLE 1-2-1  WEB-BASED RESOURCES FOR INHERITED HUMAN OCULAR DISORDERS NCBI OMIM NEIBank RetNet Genes and Disease (NCBI Bookshelf) Center for Medical Genetics UCSC

National Center for Biotechnology Information Online Mendelian Inheritance in Man Expression databases Retinal disease genes Systemic inherited disorders Gene and genetic marker maps Human Genome Sequence

HUMAN RHODOPSIN MUTATIONS Autosomal dominant

Autosomal recessive C

C

Fig. 1-2-4  Human rhodopsin mutations. The red circles indicate the amino acids altered by mutations in the gene in patients who have autosomal dominant retinitis pigmentosa. The translational stop site that results from a nonsense mutation is indicated as a red circle in a patient who has autosomal recessive retinitis pigmentosa.

N

N G90D

http://www.ncbi.nlm.nih.gov/ http://www.ncbi.nlm.nih.gov/omim http://neibank.nei.nih.gov http://www.sph.uth.tmc.edu/Retnet/ http://www.ncbi.nlm.nih.gov/books/NBK22183/ http://www.marshfieldclinic.org/chg http://www.genome.ucsc.edu

P23H

K296E K296M

A292E

11

1 Genetics

clinically normal. Unlike the missense mutations responsible for the dominant form of the disease, the null mutations in rhodopsin produce an inactive protein that is not destructive to the cell. Null mutations result in retinitis pigmentosa only when they are present in both copies of the gene. Mutations in just one copy of the gene (heterozygous individuals) do not have a clinically detectable phenotype.

STARGARDT’S DISEASE Stargardt’s disease is characterized by progressive bilateral atrophy of the macular retinal pigment epithelium (RPE) and neuroepithelium, with the frequent appearance of orange-yellow flecks distributed around the macula. The choroid is characteristically dark on fluorescein angio­ graphy. The disease results in a loss of central acuity that may have a juvenile to adult onset and is inherited as an autosomal recessive trait. Inactivation of both copies of the responsible gene is necessary to cause the disease. Mutations in a photoreceptor cell-specific ATP-binding transporter gene (ABCR) have been found in affected patients.17,18 Most of the mutations reported to date are missense mutations in conserved amino acid positions. The retina-specific ABC transporter responsible for Stargardt’s disease is a member of a family of transporter proteins and is expressed in rod photoreceptors, which indicates that this protein mediates the transport of an essential molecule either into or out of photoreceptor cells. Accumulation of a lipofuscin-like substance in Stargardt’s disease may result from inactivation of this transporter protein.

X-LINKED JUVENILE RETINOSCHISIS Retinoschisis is a maculopathy caused by intraretinal splitting; the defect most likely involves retinal Müller cells. Retinoschisis is inherited as an X-linked recessive trait. X-linked recessive disorders, like autosomal recessive disorders, are caused by inactivating mutations. Because men have only one X chromosome, one mutant copy of a gene responsible for an X-linked trait results in the disease. Usually, women are heterozygous carriers of recessive X-linked traits and do not demonstrate any clinical abnormalities. Mutations in the gene coding for retinoschisin have been shown to be the cause of the disease.19 The protein is involved in cell–cell interaction and may be active in cell adhesion processes during retinal development. Most retinoschisis gene (XLRS1) mutations cause a loss of protein function.

NORRIE’S DISEASE Norrie’s disease is an X-linked disorder characterized by progressive, bilateral, congenital blindness associated with retinal dysplasia that has been referred to as a ‘pseudoglioma.’ The disease can include mental retardation and hearing defects. Norrie’s disease is inherited as an X-linked recessive trait, and a causative gene has been identified on the X chromosome that has a tertiary structure similar to transforming growth factor-β.20 Norrie’s disease is a member of the familial exudative vitreoretinopathy (FEVR) syndromes, which are genetically heterogeneous inherited blinding disorders of the retinal vascular system, and to date three other loci have been mapped.21 Mutations in the Norrie’s disease gene have been found in a small subset of patients with severe retinopathy of prematurity (ROP), although defects in this gene do not appear to be a major factor in ROP.22

SORSBY’S MACULAR DYSTROPHY Sorsby’s macular dystrophy is an autosomal dominant disorder characterized by early onset bilateral and multifocal choroidal neovascularization resulting in macular edema, hemorrhage and exudation. The disease typically begins at about 40 years of age. Missense mutations in the gene that codes for tissue inhibitor metalloproteinase-3 (TIMP-3) have been found in affected individuals.23 This protein is involved in remodeling of the extracellular matrix. Inactivation of the protein may lead to an increase in activity of the metalloproteinase, which may contribute to the pathogenesis of the disease.23

GYRATE ATROPHY 12

Hyperornithinemia results from deficiency of the enzyme ornithine ketoacid aminotransferase and has been shown to be the cause of gyrate

atrophy, an autosomal recessive condition characterized by circular areas of chorioretinal atrophy. Mutations in the gene for ornithine ketoacid aminotransferase mapped to chromosome 10q26 have been associated with the disease in affected individuals.24 Most of the responsible mutations are missense mutations, which presumably result in an inactive enzyme. One mutation has been found in homozygous form in the vast majority of apparently unrelated cases of gyrate atrophy in Finland, an example of a founder effect that produces a common mutation in an isolated population. Identification of the enzyme defect responsible for this disease makes it an interesting candidate for gene therapy. Previous studies indicated that a lower ornithine level, achieved through a strict lowarginine diet, may retard the progression of the disease.25 Replacement of the abnormal gene, or genetic engineering to produce a supply of normal enzyme, may result in a reduction of ornithine levels without dietary restrictions.

COLOR VISION Defective red–green color vision affects 2–6% of men and results from a variety of defects that involve the color vision genes. In humans, the three cone pigments – blue, green, and red – mediate color vision. Each visual pigment consists of an integral membrane apoprotein bound to the chromophore 11-cis retinal. The genes for the red and green pigments are located on the X chromosome, and the gene for the blue pigment is located on chromosome 7. The X chromosome location of the red and green pigment genes accounts for the X-linked inheritance pattern observed in red or green color vision defects. The common variations in red or green color vision are caused by the loss of either the red or the green cone pigment (dichromasy) or by the production of a visual pigment with a shifted absorption spectrum (anomalous trichromasy). A single amino acid change (serine to alanine) in the red photopigment gene is the most common color vision variation. Among Caucasian men, 62% have serine at position 180 in the red pigment protein, and 38% have alanine in this position. Men who carry the red pigment with serine at position 180 have a greater sensitivity to long-wavelength radiation than do men who carry alanine at this position.26 Recent work suggests that gene therapy could correct color vision defects.27

RETINOBLASTOMA A gene responsible for the childhood eye tumor retinoblastoma was identified in 1986 on chromosome 13q14.28 The gene product is involved in regulation of the cell cycle. Absence of this protein in an embryonic retinal cell results in the uncontrolled cell growth that eventually produces a tumor.29 Susceptibility to hereditary retinoblastoma is inherited as an autosomal dominant trait. Mutations in the retinoblastoma gene result in underproduction of the protein product or production of an inactive protein product. A retinal cell that has only one mutant copy of the retinoblastoma gene does not become a tumor. However, inactivation of the remaining normal copy of the retinoblastoma gene is very likely in at least one retinal cell out of the millions present in each retina. Among individuals who inherit a mutant copy of the retinoblastoma gene, 90% sustain a second hit to the remaining normal copy of the gene and develop a tumor (Fig. 1-2-5).30 Fifty percent of the offspring of individuals affected by hereditary retinoblastoma will inherit the mutant copy of the gene and are predisposed to develop the tumor. Approximately 10% of individuals who inherit a mutation do not sustain a second mutation and do not develop a tumor. The offspring of these ‘carrier’ individuals also have a 50% chance of inheriting the mutant copy of the retinoblastoma gene (see Fig. 1-2-5).

ALBINISM Autosomal recessive diseases often result from defects in enzymatic proteins. Albinism is the result of a series of defects in the synthesis of melanin pigment.31 Melanin is synthesized from the amino acid tyrosine, which is first converted into dihydroxyphenylalanine through the action of the copper-containing enzyme tyrosinase. An absence of tyrosinase results in one form of albinism. Mutations in the gene that codes for tyrosinase are responsible for tyrosinase-negative ocular cutaneous albinism. Most of the mutations responsible for this disease cluster in the binding sites for copper and disrupt the metal ion–protein

LEBER’S OPTIC NEUROPATHY Mutations in mitochondrial DNA are an important cause of human disease. Disorders that result from mutations in mitochondrial DNA demonstrate a maternal inheritance pattern. Maternal inheritance differs from Mendelian inheritance, in that men and women are affected equally, but only affected females transmit the disease to their offspring. The characteristic segregation and assortment of Mendelian disorders depend on the meiotic division of maternal and paternal chromosomes found in the nucleus of cells. In contrast, mitochondrial DNA is derived from the maternal egg and replicates and divides with the cell cytoplasm by simple fission. A mutation that occurs in mitochondrial DNA is present in all cells of the organism, which includes

INHERITANCE OF RETINOBLASTOMA

retina

tumor

gametes

50% retina

Congenital fibrosis of the extraocular muscles and Duane’s syndrome are inherited forms of congenital fibrosis and strabismus. At least twenty genes contribute to these conditions and other disorders of axon guidance,35 with the ARIX/PHOX2A genes causing congenital fibrosis of extraocular muscles type 236 and the SALL4 gene causing Duane’s radial ray syndrome.37

gametes

90% second hit

AUTOSOMAL DOMINANT OPTIC ATROPHY

normal retina

affected

tumor

Fig. 1-2-5  Inheritance of retinoblastoma. Individuals who inherit a mutation in the retinoblastoma gene are heterozygous for the mutation in all cells of the body. The ‘second hit’ to the remaining normal copy of the gene occurs in a developing retinal cell and leads to tumor formation (see text for explanation).

Of the inherited optic atrophies, autosomal dominant optic atrophy of the Kjer type is the most common. This disease results in a progressive loss of visual acuity, centrocecal scotoma, and bilateral temporal atrophy of the optic nerve. The onset is typically in the first two decades of life. The condition is inherited as an autosomal dominant trait with variable expressivity, and mutations in OPA1 have been found in a number of affected families.38,39 OPA1 codes for a dynamin-related GTPase that is targeted to mitochondria and may function to stabilize mitochondrial membrane integrity. It is

Fig. 1-2-6  Metabolism of tyrosine to produce melanin. In the final step, dopamine is converted into an indole derivative that condenses to form the highmolecular-weight pigment melanin.

METABOLISM OF TYROSINE TO PRODUCE MELANIN H 2O

O2

NH3

NH3

CH2CHCOO

CO2

CH2CHCOO



1.2

CONGENITAL FIBROSIS SYNDROMES AND DISORDERS OF AXON GUIDANCE

50%

10% no second hit

the gametes. Female eggs have abnormal mitochondria that may be passed to offspring. Sperm contain mitochondria but do not transmit mitochondria to the fertilized egg. A man who carries a mitochondrial DNA mutation may be affected by the disease, but he cannot transmit the disease to his offspring. Leber’s hereditary optic neuropathy (LHON) was one of the first diseases to be recognized as a mitochondrial DNA disorder.33 In familial cases of the disease, all affected individuals were related through the maternal lineage, consistent with inheritance of human mitochondrial DNA. Patients affected by LHON typically present in midlife with acute or subacute, painless, central vision loss that results in a permanent central scotoma and loss of sight. The manifestation of the disease varies tremendously, especially with respect to onset of visual loss and severity of the outcome. The eyes may be affected simultaneously or sequentially; the disease may progress rapidly, over a period of weeks to months, or slowly over several years; within a family, the disease may also vary among affected members. Several factors contribute to the variable phenotype of this condition. Certain mutations are associated with more severe disease, and some mitochondrial DNA haplotypes appear to be associated with more severe disease.34. Another important factor that affects the severity of the disease is the heteroplasmic distribution of mutant and normal mitochondria. Not all mitochondria present in diseased tissue carry DNA mutations. During cell division, mitochondria and other cytoplasmic organelles are distributed arbitrarily to the daughter cells. Consequently, the daughter cells are likely to have unequal numbers of mutant and normal mitochondria (Fig. 1-2-7). Because the diseased mitochondria are distributed to developing tissues, some tissues accumulate more abnormal mitochondria than others. Hence, some individuals have more abnormal mitochondria in the optic nerve and develop a more severe optic neuropathy.

Molecular Genetics of Selected Ocular Disorders

interaction necessary for enzyme function.32 Both copies of the gene for tyrosinase must be mutated before a significant interruption of melanin production occurs. Heterozygous individuals do not have a clinically apparent phenotype, which suggests that one functional copy of the gene produces sufficient active enzyme for the melanin level to be phenotypically normal (Fig. 1-2-6).



CH2CH2NH3 melanin OH

OH

dihydrobiopterin

OH

OH

dihydroxyphenylalanine

dopamine

tetrahydrobiopterin tyrosine

tyrosine hydroxylase

13

1

HETEROPLASMY IN MITOCHONDRIA

Genetics

nucleus normal mitochondrion

TABLE 1-2-2  GENES ASSOCIATED WITH COMMON COMPLEX OCULAR DISORDERS AND TRAITS Disease or trait

Genea

Reference

Macular degeneration

CFH HTRA1/ARMS2 C3 TIMP3 CFB,C2 CFI LIPC RREB1 SKIV2L, BF CAV1/CAV2 TMCO1 CDKN2BAS CDKN2BAS LRP12, ZFPM2 LOXL1 GJD2, ACTC1 RASGRF1 MYP11 MIPEP PDGFRA COL8A1 ZNF469 FOXO1 COL5A1 AVGR8 AKAP13 PDE8A ATOH7 PBLD CDC7,TGFBR3 SALL1 CARD10 CDKN2B SIX1,SIX6 SCYL1 DCLK1 CHEK2 ATOH7 BCAS3 TCF4

41, 42, 43 44 49, 50 51 49 49

mutant mitochondrion

cell division Glaucoma-POAG (primary openangle glaucoma) Glaucoma-NTG (normal-tension glaucoma) Glaucoma-ES (exfoliation syndrome) Myopia

replication and cell division

Astigmatism Central corneal thickness (CCT)

Optic nerve size

Fig. 1-2-7  Heteroplasmy in mitochondria. Daughter cells that result from the division of a cell that contains mitochondria with mutant DNA may contain unequal numbers of mutant mitochondria. Subsequent divisions lead to a population of cells with different numbers of normal and abnormal mitochondria.

interesting that this gene and the gene responsible for another optic atrophy, Leber’s hereditary optic atrophy (see earlier), both function in the mitochondria, emphasizing the critical role of mitochondria in optic nerve function.

Optic nerve vertical cup-to-disc ratio

Fuch’s corneal dystrophy

50 46 47 47, 48 48 52 53 54 55 56 57 58 59, 60 59 60

61, 62, 63 61, 62 62, 63 62 63 62

64

a

For associations that are located in intragenic regions, the nearest gene(s) are listed.

COMPLEX TRAITS Human phenotypes inherited as polygenic or ‘complex’ traits do not follow the typical patterns of Mendelian inheritance. Complex traits are not rare but widespread in the human population. Multiple genes are likely to contribute to the expression of the disease phenotype. Some genes render an individual susceptible to the disease phenotype, whereas other genes or environmental conditions may influence the full expression of the disease phenotype. Secondary genes responsible for modulation of the expression of a specific genetic mutation may be referred to as ‘modifier genes’; these modifier genes may be inherited completely independently from the gene directly responsible for the disease trait. Not every individual who inherits the mutation responsible for the disease trait also inherits a form of the modifier gene that is required for full expression of the disease. The digenic inheritance of retinitis pigmentosa that occurs via certain mutant alleles of peripherin and ROM1 is an example of the simplest form of polygenic inheritance (see previous chapter). Some patients with Bardet–Biedl syndrome demonstrate triallelic inheritance, indicating that three mutant alleles are required for disease expression.40 Certain conditions may require multiple genes or a combination of different genes and environmental conditions to be manifest. For example, single nucleotide polymorphism (SNP) in the complement factor H gene and sequence variants in the LOC37718 gene are known to be major genetic risk factors for age-related macular degeneration,41–44 and combined with smoking the risk is increased.45 Primary open-angle glaucoma is another disease with complex inheritance, and recently genome-wide association studies (GWAS) using large case–control cohorts have identified genes

14

Access the complete reference list online at

that contribute to this disease.46–48 The GWAS approach has also successfully identified genes contributing to other common complex ocular conditions and traits (Table 1-2-2).

KEY REFERENCES Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000;26:211–15. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010;363:1016–24. Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol 2010;2:a001784. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–9. Macgregor S, Hewitt AW, Hysi PG, et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 2010;19:2716–24. Neitz J, Neitz M. The genetics of normal and defective color vision. Vision Res 2011;51:633–51. Ramdas WD, van Koolwijk LM, Ikram MK, et al. A genome-wide association study of optic disc parameters. PLoS Genet 2010;6:e1000978. Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605. Stefansdottir G, Masson G, Hardarson GA, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400. Zode GS, Bugge KE, Mohan K, et al. Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2012;53:1557–65.

REFERENCES 1. Musch DC, Niziol LM, Stein JD, et al. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest Ophthalmol Vis Sci 2011;52:6959–63.

3. Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet 2010;77:  409–20. 4. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome. Expert Rev Mol Med 2005;7:1–17. 5. Hewitt AW, Mackey DA, Craig JE. Myocilin allele-specific glaucoma phenotype database. Hum Mutat 2008;29:207–11. 6. Zode GS, Bugge KE, Mohan K, et al. Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2012;53:1557–65. 7. Bejjani BA, Stockton DW, Lewis RA, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 2000;9:367–74. 8. Narooie-Nejad M, Paylakhi SH, Shojaee S, et al. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet 2009; 18:3969–77. 9. Li N, Zhou Y, Du L, et al. Overview of cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. Exp Eye Res 2011;93:572–9. 10. Chakrabarti S, Kaur K, Kaur I, et al. Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds. Invest Ophthalmol Vis Sci 2006;47:43–7. 11. Sena DF, Finzi S, Rodgers K, et al. Founder mutations of CYP1B1 gene in patients with congenital glaucoma from the United States and Brazil. J Med Genet 2004;41:e6. 12. Hejtmancik JF. Congenital cataracts and their molecular genetics. Semin Cell Dev Biol 2008;19:134–49. 13. Héon E, Priston M, Schorderet DF, et al. The gamma-crystallins and human cataracts: a puzzle made clearer. Am J Hum Genet 1999;65:1261–7. 14. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343:364–6. 15. Li T, Snyder WK, Olsson JE, et al. Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments. Proc Natl Acad Sci U S A 1996;93:14176–81. 16. Rosenfeld PJ, Cowley GS, McGee TL, et al. A null mutation in the rhodopsin gene caused rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat Genet 1992;1:209–13. 17. Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997;  15:236–46. 18. Vasireddy V, Wong P, Ayyagari R. Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 2010;29:191–207. 19. Vijayasarathy C, Ziccardi L, Sieving PA. Biology of retinoschisin. Adv Exp Med Biol 2012;723:513–18. 20. Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat 2010;31:656–66. 21. Toomes C, Downey LM, Bottomley HM, et al. Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy: exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. Br J Ophthalmol 2005;89:194–7. 22. Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis 2005;11:501–8. 23. Li Z, Clarke MP, Barker MD, et al. TIMP3 mutation in Sorsby’s fundus dystrophy: molecular insights. Expert Rev Mol Med 2005;7:1–15. 24. Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605. 25. Caruso RC, Nussenblatt RB, Csaky KG, et al. Assessment of visual function in patients with gyrate atrophy who are considered candidates for gene replacement. Arch Ophthalmol 2001;119:667–9. 26. Neitz J, Neitz M. The genetics of normal and defective color vision. Vision Res 2011;  51:633–51. 27. Mancuso K, Hauswirth WW, Li Q, et al. Gene therapy for red-green colour blindness in adult primates. Nature 2009;461:784–7. 28. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;643–6. 29. Manning AL, Dyson NJ. RB: mitotic implications of a tumour suppressor. Nat Rev Cancer 2012;12:220–6. 30. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet 2012;379:1436–46. 31. Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med Genet 2004;131C(1):75–81. 32. Ray K, Chaki M, Sengupta M. Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. Prog Retin Eye Res 2007;26:323–58.

34. Ji Y, Zhang AM, Jia X, et al. Mitochondrial DNA haplogroups M7b1’2 and M8a affect clinical expression of Leber hereditary optic neuropathy in Chinese families with the m.11778G→ a mutation. Am J Hum Genet 2008;83:760–8. 35. Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol 2010;2:a001784. 36. Nakano M, Yamada K, Fain J, et al. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001;29:315–20. 37. Al-Baradie R, Yamada K, St Hilaire C, et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 2002;71:1195–19. 38. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000;26:211–15. 39. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res 2011;30:81–114. 40. Badano JL, Leitch CC, Ansley SJ, et al. Dissection of epistasis in oligogenic Bardet–Biedl syndrome. Nature 2006;439:326–30. 41. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–9. 42. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and agerelated macular degeneration. Science 2005;308:421–4. 43. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–21. 44. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227–36. 45. Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 2006;78:852–64.

1.2 Molecular Genetics of Selected Ocular Disorders

2. Kannabiran C, Klintworth GK. TGFBI gene mutations in corneal dystrophies. Hum Mutat 2006;27:615–25.

33. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427–30.

46. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9. 47. Burdon KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 2011;43:574–8. 48. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 2012;8:e1002654. 49. Geno Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A 2010;107:7395–400. 50. Kopplin LJ, Igo RP Jr, Wang Y, et al. Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration. Genes Immun 2010;11:609–21. 51. Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 2010;107:7401–6. 52. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400. 53. Solouki AM, Verhoeven VJ, van Duijn CM, et al. A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet 2010;42:897–901. 54. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5. 55. Li Z, Qu J, Xu X, et al. A genome-wide association study reveals association between common variants in an intergenic region of 4q25 and high-grade myopia in the Chinese Han population. Hum Mol Genet 2011;20:2861–8. 56. Shi Y, Qu J, Zhang D, et al. Genetic variants at 13q12.12 are associated with high myopia in the Han Chinese population. Am J Hum Genet 2011;88:805–13. 57. Fan Q, Zhou X, Khor CC, et al. Genome-wide meta-analysis of five Asian cohorts identifies PDGFRA as a susceptibility locus for corneal astigmatism. PLoS Genet 2011;7:e1002402. 58. Vithana EN, Aung T, Khor CC, et al. Collagen-related genes influence the glaucoma risk factor, central corneal thickness. Hum Mol Genet 2011;20:649–58. 59. Lu Y, Dimasi DP, Hysi PG, et al. Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet 2010;6:e1000947. 60. Vitart V, Bencić G, Hayward C, et al. New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. Hum Mol Genet 2010;19:4304–11. 61. Macgregor S, Hewitt AW, Hysi PG, et al. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 2010;19:2716–24. 62. Ramdas WD, van Koolwijk LM, Ikram MK, et al. A genome-wide association study of optic disc parameters. PLoS Genet 2010;6:e1000978. 63. Khor CC, Ramdas WD, Vithana EN, et al. Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. Hum Mol Genet 2011;20:1864–72. 64. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010;363:1016–24.

14.e1

PART 1 GENETICS

1.3

Genetic Testing and Genetic Counseling

Janey L. Wiggs

Definition: A genetic test is any clinical or laboratory investigation that

SPECIFICITY AND SENSITIVITY

provides information about the likelihood that an individual is affected with a heritable disease. The majority of genetic tests are based on molecular evaluations of genomic DNA designed to identify the DNA mutations responsible for the disease.

GENETIC TESTING Role of Genetic Testing in the Clinic

DNA-based genetic tests can identify individuals at risk for disease before any clinical evidence is present (presymptomatic testing).1 This information coupled with effective genetic counseling and clinical screening can be useful. An effective presymptomatic test needs to meet the specificity and sensitivity expectations for any clinical test. Sensitivity is the number of affected individuals that are positive for a test compared with the total number of affected individuals (including those that tested negative for the test). Specificity is the number of unaffected individuals that are negative for the test compared with the total number of unaffected individuals tested (including those that tested positive for the test) (Fig. 1-3-1). The identification of a mutation responsible for a disease through DNA-based genetic testing can establish a molecular diagnosis. For some disorders, such as juvenile open-angle glaucoma caused by mutations in MYOC,2 specific mutations have been correlated with severity of disease or other clinical features that are useful prognostically. A molecular diagnosis may also help guide therapy and is required before gene-based therapies can be utilized. For example, mutations in a number of different genes can cause Leber’s hereditary amaurosis, but only those patients with disease due to mutations in RPE65 will benefit from novel RPE65-based therapies using gene replacement.3

Methods for DNA-based Genetic Testing

Although genetic testing can be performed using DNA, RNA, or protein, DNA is the easiest to work with and most genetic tests use this as the starting material. A biological sample from the patient is needed before genetic testing can be performed. The inclusion of family members may help the evaluation, but they are not absolutely required. DNA for testing can be obtained from a number of sources, including blood samples, mouthwash samples or buccal swabs, archived pathology specimens, or from hair.4–6 Genomic DNA sequencing is the most commonly used method to detect mutations. For many disorders sequencing the entire responsible gene is necessary, including all exons, immediate flanking intron sequences with splice signals and 5’ and 3’ flanking regulatory regions. Some disorders are caused by a specific mutation in a gene, and genetic testing can be limited to an evaluation of a single gene, while for other diseases, such as retinitis pigmentosa, sequencing multiple genes may be required before a causative mutation is identified. Genomic DNA sequencing will not usually identify large chromosomal abnormalities, including large copy number variations (deletions or insertions) or chromosomal translocations. Other techniques are necessary to detect

Affected individuals

Unaffected individuals

Individuals positive for test

A

B

Individuals negative for test

C

D

A A+C

Sensitivity

Specificity

D B+D

Fig. 1-3-1  Definition of sensitivity and specificity for a laboratory test. Sensitivity is defined as the number of affected individuals positive for the test (A) divided by the total number of affected individuals tested (A+C). Specificity is defined as the number of unaffected individuals negative for the test (D) divided by the total number of unaffected individuals tested (B+D).

TABLE 1-3-1  COMMON TYPES OF GENETIC TESTS Method

Indication

Example

Single gene DNA sequencing

Different mutations distributed throughout a single gene are known to cause the inherited condition Mutations in multiple genes are known to cause the condition Detects deletions and duplications in genes known to cause the condition and that may be missed by sequencebased approaches Detects a single DNA base pair change and is used if a small set of mutations are primarily the cause of the condition Detects large chromosomal rearrangements including deletions, duplications and translocations

Sequencing OPA1 in patients with autosomal dominant optic neuropathy

Multiple gene DNA sequencing MLPA (Multiplex Ligationdependent Probe Amplification)

TaqMan Assay or allelespecific assay

Karyotype

Autosomal recessive retinitis pigmentosa MLPA testing for PAX6 deletions in patients with aniridia

Three mutations commonly cause Leber’s hereditary optic neuropathy (LHON) Down syndrome

large chromosomal abnormalities, including karyotyping and MLPA (Multiplex Ligation-dependent Probe Amplification).7,8 For diseases that are caused primarily by a limited set of mutations (for example, the three mutations that commonly cause Leber’s hereditary optic neuropathy (LHON), 9 specific tests such as allele-specific PCR amplification or TaqMan assays can be used and can be more efficient than sequencing the entire gene (Table 1-3-1).

15

1

Current Recommendations for Genetic Testing for Ophthalmic Diseases

Genetics

Currently, genetic testing is indicated for patients with clinical evidence of a disorder whose causative gene(s) have been identified and for which the identification of the genetic mutation contributing to the disease has sufficient specificity and sensitivity that testing will be clinically useful. Serious failures of a diagnostic test are false-positives (individuals without the disease who test positively) and false-negatives (individuals with the disease who test negatively). Although genes have been identified for some common complex disorders such as age-related macular degeneration, primary open-angle glaucoma and exfoliation syndrome, in general, testing for these mutations is not sufficiently sensitive and specific that the test results are clinically meaningful. For example, over 90% of patients with exfoliation syndrome carry one of two missense changes in LOXL1; however, up to 80% of normal individuals also carry these same DNA sequence variants.10 Clearly the identification of these missense mutations alone is not clinically useful. Examples of genetic tests that are useful include: RPE65 for Leber’s hereditary amaurosis,11 PAX6 for aniridia,12 MYOC for earlyonset primary open-angle glaucoma,13 and OPA1 for optic neuropathy,14 as well as many other genes that are known to cause inherited ocular conditions.

CLIA Laboratories

Laboratories in the United States offering genetic testing must comply with regulations under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The Centers for Medicare and Medicaid Services administers CLIA, and requires that laboratories meet certain standards related to personnel qualifications, quality control procedures, and proficiency testing programs in order to receive certification. This regulatory system was put in place to encourage safe, accurate, and accessible genetic tests. In addition to ensuring that consumers have access to genetic tests that are safe, accurate, and informative, these policies encourage the development of genetic tests, genetic technologies, and the industry that produces these products. A number of CLIA-certified laboratories performing genetic testing for eye diseases exist in the United States. For a list of CLIA-certified laboratories participating in the National Eye Institute (NEI)-sponsored eyeGENE network, see the NEI website at: http://www.nei.nih.gov.

Genetic Reports

A genetic test report is a sensitive document that is the main form of communication between the CLIA laboratory and the physician requesting the genetic test. Genetic test reports may be shared with the patient and with genetic counselors. The report should include the following information: (1) the type of genetic test performed (i.e., sequencing or other methodology); (2) the gene or genes that were evaluated; (3) the results of the testing; (4) information about the pathogenicity of the sequence variants; (5) recommendations for clinical follow-up based on the results of testing; and (6) literature references providing additional information about the genes and mutations responsible for the disease. The report should be written clearly and have appropriate contact information. Novel DNA sequence changes are frequently found as a result of genomic DNA sequencing. New DNA sequence changes (variants) may be benign polymorphisms or causative mutations. Additional studies must be done before the sequence change can be designated as diseasecausing. While demonstrating that the mutant protein has an abnormal function or evaluation of the mutant gene in an animal model would be an ideal test of pathogenicity, these approaches are timeconsuming and may not be possible. Current approaches to evaluate the pathogenicity of a novel DNA sequence variant is to: (1) evaluate the change in a panel of control individuals; (2) investigate segregation of the change in other affected family members (if possible); (3) determine the evolutionary conservation of the DNA base pair that is mutated or the amino acid that is altered; and (4) utilize existing webbased software programs that asses DNA sequence variants for pathogenicity such as SIFT 15 and Polyphen2.16

GENETIC COUNSELING 16

Genetic counseling has become an important part of any clinical medicine practice. In 1975 the American Society of Human Genetics adopted the following descriptive definition of genetic counseling:17

Genetic counseling is a communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to: (1) comprehend the medical facts including the diagnosis, probable course of the disorder, and the available management, (2) appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives, (3) understand the alternatives for dealing with the risk of recurrence, (4) choose a course of action that seems to them appropriate in their view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision, and (5) to make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.

Clinical Evaluation and Family History

An accurate diagnosis is the first step in productive genetic counseling. The patient−physician discussion of the natural history of the disease and of its prognosis and management is entirely dependent on the correct identification of the disorder that affects the patient. Risk assessment for other family members and options for prenatal diagnosis also depend on an accurate diagnosis. In some cases, appropriate genetic testing may help establish the diagnosis. Examination of other family members may be indicated to determine if a particular finding is hereditary. A complete family history of the incidence of the disorder is necessary to determine the pattern of inheritance of the condition. The mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, or maternal) must be known to calculate the recurrence risk to additional family members, and it helps confirm the original diagnosis. For the record of family information, the gender and birth date of each individual and his or her relationship to other family members are indicated using the standard pedigree symbols. It is also helpful to record the age of onset of the disorder in question (as accurately as this can be determined). The pedigree diagram must include as many family members as possible. Miscarriages, stillbirths, and consanguineous parents are indicated. Occasionally a patient may appear to be affected by a condition that is known to be inherited, but the patient is unable to provide a family history of the disease. Several important explanations for a negative family history must be considered before the conclusion is made that the patient does not have a heritable condition. First, the patient may not be aware that other family members are affected by the disease. Individuals frequently are reluctant to share information about medical problems, even with close family members. Second, many disorders exhibit variable expressivity or reduced penetrance, which means that other family members may carry a defective gene that is not expressed or results in only a mild form of the disease that is not readily observed. Third, false paternity may produce an individual affected by a disease that is not found in anyone else belonging to the acknowledged pedigree. Genetic testing can easily determine the paternity (and maternity) of any individual if blood samples are obtained from relevant family members. Fourth, a new mutation may arise that affects an individual and may be passed to offspring, even though existing family members show no evidence of the disease.

Risk Prediction Based on Inheritance

Once the diagnosis and family history of the disorder are established, risk prediction in other family members (existing and unborn) may be calculated. The chance that an individual known to be affected by an autosomal dominant disorder will transmit the disease to his or her offspring is 50%. This figure may be modified, depending on the penetrance of the condition. For example, retinoblastoma is inherited as an autosomal dominant trait, and 50% of the children of an affected parent should be affected. However, usually only 40–45% of the children at risk are affected, because the penetrance of the retinoblastoma trait is only 80–90%, which means that 5–10% of children who have inherited an abnormal copy of the retinoblastoma gene do not develop ocular tumors. An individual affected by an autosomal recessive trait will have unaffected children unless he or she partners with another individual affected by the disease or with an individual who is a carrier of the disease. Two individuals affected by an autosomal recessive disease produce only affected offspring. (There are some rare exceptions to this

BOX 1-3-1  TYPES OF CLINICAL GENETICS SERVICES AND PROGRAMS

Specialty Clinics  Metabolic clinic  Spina bifida clinic  Hemophilia clinic  Craniofacial clinic  Other single-disorder clinics (e.g., neurofibromatosis type 1 clinic)

Known inherited condition

Genetic counseling can be useful for a family with a member affected by an established diagnosis. In this case, the goal of the counseling is to describe recurrence risks for other family members. For example, if a child has retinoblastoma and a positive family history, the family may be referred for genetic counseling to review recurrence risks. If diagnostic testing has been performed, that can also be discussed and will aid in the presentation of the recurrence risks, especially if other family members have been tested.

Ocular and systemic congenital anomalies

Prenatal Diagnosis Program: Perinatal Genetics  Amniocentesis/chorionic villus sampling clinics  Ultrasound program  Maternal serum α-fetoprotein program

Individuals with multiple ocular and systemic anomalies may or may not fit into a particular syndrome. In these situations, the experience of a geneticist in recognizing malformation patterns and understanding the variability of genetic conditions can aid diagnosis. If an underlying cause is identified, relatives can then undergo genetic counseling.

Genetic Screening  Newborn screening program/follow-up clinic  Other population-screening programs (e.g., for Tay–Sachs disease)

Specific eye diseases

Education/Training  Healthcare professional  General public  School system  Teratology information services

A genetic evaluation is important for families with inherited eye diseases. Many ophthalmologic diseases have a well-documented inheritance pattern, and describing the inheritance to family members may help identify affected relatives who could be diagnosed and treated early in the course of the disease. This is especially important in families with conditions such as dominantly inherited juvenile glaucoma.

1.3 Genetic Testing and Genetic Counseling

Center-Based Genetics Clinic  Outreach clinics  Inpatient consultations

Indications to Refer for Genetic Counseling

Ocular defects associated with genetic diseases

rule. If the disease is the result of mutations in two different genes, it is possible for two individuals affected by an autosomal recessive trait to produce normal children. Also, in rare cases, different mutations in the same gene may compensate for each other, and the resultant offspring will be normal.) If an individual affected by an autosomal recessive disease partners with a heterozygous carrier of a gene defect responsible for that disorder, the chance of producing an affected child is 50%. Among the offspring of an individual affected by an autosomal recessive disease, 50% will be carriers of the disorder. If one of these offspring partners with another carrier of the disease, the chance of producing an affected child is 25%. X-linked disorders are always passed from a female carrier who has inherited a copy of an abnormal gene on the X chromosome received from either her mother (who was a carrier) or her father (who was affected by the disease). Man-to-man transmission is not seen in diseases caused by defects in genes located on the X chromosome. Among sons born to female carriers of X-linked disorders, 50% are affected by the disease, and 50% of daughters born to female carriers of X-linked disorders are carriers of the disease. All the daughters of men affected by X-linked disorders are carriers of the disease. Mitochondrial disorders are inherited by sons and daughters from the mother. The frequency of affected offspring and the severity of the disease in affected offspring depend on the number of abnormal mitochondria present in the egg that gives rise to the affected child. Diseased and normal mitochondria are distributed randomly in all cells of the body, including the female gametes. As a result, not all the eggs present in a woman affected by a mitochondrial disorder have the same number of affected mitochondria (heteroplasmy). Men affected by mitochondrial disorders only rarely have affected children, because very few mitochondria in the developing embryo are derived from the sperm used to fertilize the egg.18 With careful diagnosis and family history assessment, even sporadic cases of heritable disorders are identifiable. In such cases, an estimate of recurrence risk can be calculated using the available pedigree and clinical information and the statistical principle called Bayes’ theorem. These individuals should be referred to clinical genetics services, such as those commonly found in hospital settings (Box 1-3-1).

Many genetic diseases have associated ocular defects. For example, a diagnosis of neurofibromatosis type 1 may be made in a child because Lisch nodules were detected on a clinical exam.19 The child and family should be referred for genetic counseling to help define the recurrence risks for other family members.

Confidentiality

Confidentiality is an important issue in genetic testing and genetic counseling. Insurance companies or employers may discriminate on the basis of genetic information, especially if genetic testing has indicated an increased risk of a disease. Insurance companies may use test results to deny coverage, claiming that a genetic disease is a pre-existing condition. Employers may try to use genetic information to make hiring decisions, basing their assessment on risk for medical complications or disability. These issues may cause families or individuals to decline genetic testing even if a positive test result could alter medical management. Others choose to pay for testing themselves to prevent the insurance company from having access to this information. Still others request that test results not be put in their medical record. Families may wish to have total control over the information. It is important that genetic professionals support the patients’ right to privacy. Confidentiality issues should be discussed prior to the initiation of testing so there is consensus on how results are reported, who receives results, and where the information is documented.

KEY REFERENCES Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. N Engl J Med 2010;362:2001–11. Kwon YH, Fingert JH, Kuehn MH, et al. Primary open-angle glaucoma. N Engl J Med 2009;360:1113–24. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240–8. Muto R, Yamamori S, Ohashi H, et al. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 2002;108:285–9. Sim NL, Kumar P, Hu J, et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012. [Epub] Web Server issue: W452-7. Thusberg J, Olatubosun A, Vihinen M. Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 2011;32:358–68. Yu-Wai-Man P, Shankar SP, Biousse V, et al. Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies. Ophthalmology 2011;118:558–63.

Access the complete reference list online at 17

REFERENCES 1. Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. N Engl J Med 2010;362:2001–11.

3. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358:2240–8. 4. Mulot C, Stucker I, Clavel J, et al. Collection of human genomic DNA from buccal cells for genetics studies: comparison between cytobrush, mouthwash, and treated card. J Biomed Biotechnol 2005;3:291–6. 5. Nussenzveig RH, Burjanivova T, Salama ME, et al. Detection of JAK2 mutations in paraffin marrow biopsies by high resolution melting analysis: identification of L611S alone and in cis with V617F in polycythemia vera. Leuk Lymphoma 2012;53:2479–86. 6. Suenaga E, Nakamura H. Evaluation of three methods for effective extraction of DNA from human hair. J Chromatogr B Analyt Technol Biomed Life Sci 2005;820:137–41. 7. Muto R, Yamamori S, Ohashi H, et al. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 2002;108:285–9. 8. Wawrocka A, Budny B, Debicki S, et al. PAX6 3’ deletion in a family with aniridia. Ophthalmic Genet 2012;33:44–8. 9. Tang S, Halberg MC, Floyd KC, et al. Analysis of common mitochondrial DNA mutations by allele-specific oligonucleotide and Southern blot hybridization. Methods Mol Biol 2012;837:259–79.

11. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol 2012;130:9–24. 12. Zhang X, Wang P, Li S, et al. Mutation spectrum of PAX6 in Chinese patients with aniridia. Mol Vis 2011;17:2139–47. 13. Alward WL, Kwon YH, Khanna CL, et al. Variations in the myocilin gene in patients with openangle glaucoma. Arch Ophthalmol 2002;120:1189–97. 14. Yu-Wai-Man P, Shankar SP, Biousse V, et al. Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies. Ophthalmology 2011;118:558–63. 15. Sim NL, Kumar P, Hu J, et al. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012. [Epub] Web Server issue: W452-7. 16. Thusberg J, Olatubosun A, Vihinen M. Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 2011;32:358–68. 17. Epstein CJ, Erickson RP, Hall BD, et al. The center-satellite system for the wide-scale distribution of genetic counseling services. Am J Hum Genet 1975;27:322–32. 18. Wallace DC. Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci U S A 1994;91:8739–46. 19. Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol 2004;88:1429–33.

1.3 Genetic Testing and Genetic Counseling

2. Kwon YH, Fingert JH, Kuehn MH, et al. Primary open-angle glaucoma. N Engl J Med 2009;360:1113–24.

10. Fan BJ, Pasquale LR, Rhee D, et al. LOXL1 promoter haplotypes are associated with exfoliation syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci 2011;52:2372–8.

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PART 2 OPTICS AND REFRACTION

2.1

Visible Light David Miller, Stephen K. Burns

Definition: Visible light is a small portion of the electromagnetic spectrum with a wavelength range between 400 and 700 nm.

Key features ■

The main source of visible light is the Sun. ■ The Earth’s atmosphere absorbs most of the light below 400 nm. ■ Visible light sensing by the eye depends upon: ■ The parameters of the light receptors – Unique size – Unique shape – Spectrum of sensitivity – Orientation as light guides ■ The characteristics of the dioptric media.

Effect of Earth’s Atmosphere

The Earth’s atmosphere is held in position by the gravitational pull of the mass of the Earth. The potentially harmful ultraviolet and infrared radiation released from the Sun’s surface is absorbed by ozone, carbon dioxide, and water vapor in the Earth’s atmosphere (Fig. 2-1-2).1 The Earth’s temperature, which is a result of the temperature of the Sun’s surface (6000 K) and its distance from Earth (almost 100 ×106 miles [160 ×106 km]), is responsible for the volume of atmospheric water vaporized from the oceans. Ozone and carbon dioxide result from photosynthesis and respiration. The core-produced X-rays are filtered first by the outer layers of the Sun’s matter. The Earth is 1/100th the diameter of the Sun and almost 100 ×106 miles (160 ×106 km) away, and it receives only a tiny fraction of the radiation (about a billionth of the total).2 The radiation that travels toward Earth is further filtered by the particles of the solar wind. In turn, this deadly solar wind is repelled by the Earth’s magnetic field. Finally, the size and temperature of the Earth, as well as life on Earth, combine to produce an atmosphere that allows little more than visible light to pass through.

Associated features ■

Understanding the transformation of an optical image composed of visible light into an electronic image composed of visible light ■ Processing of a 2D optical image into an electronic image ■ Processing of a 3D optical image into an electronic image

ORIGIN OF VISIBLE LIGHT Source

In general, clinical optics concerns the focusing or processing of visible light. Visible light comes primarily from suns (stars). Children are taught that this visible light also generates the energy necessary for life. The wavelengths of visible light (4 ×10−6−7 ×10−6 m) represent a minute fraction, about 1%, of the electromagnetic spectrum, which ranges from the shortest ionizing radiation (1 ×10−16 m) to the longest radiowaves (1 ×106 m; Fig. 2-1-1).1 Visible light does not start out as such in the core of the Sun. The Sun’s core may be considered a furnace in which thermonuclear fusion takes place. Here, because of the crush of gravity, temperatures close to 16 ×106 K are generated. In such a hot environment the elemental hydrogen protons fuse to produce helium nuclei and energy in the form of gamma rays. (The Sun converts 4 ×106 tons of matter into energy every second.) This resultant short-wavelength energy passes through about half a million miles (8 ×105 km) of dense solar matter before reaching the Sun’s surface. During this long and slow journey the photons lose energy and hence increase in wavelength. The radiation that leaves the Sun’s surface primarily represents a spectrum of radiation between ultraviolet and infrared, with a small fraction of ionizing radiation in the form of X-rays with wavelengths of 10−10  m and γ-rays with wavelengths of 10−14  m. This ionizing radiation (part of the entire cosmic radiation) can destroy life. However, the Sun also ejects huge amounts of matter (one million tons of hot electrons and protons every second), called the solar wind, which produces a vast shell around the Sun and prevents ionizing radiation from reaching the Earth. The fast-moving ions of the hot plasma of the solar wind are repulsed by the Earth’s magnetic field.

VISIBLE LIGHT SENSING We have traced the origins of visible light from the Sun to the Earth’s surface. Equally instructive are the mechanisms by which the biological molecule absorbs visible light and then informs the animal of that event. In a sense this represents the equivalent of Einstein’s photoelectric effect. Rhodopsin is the biological molecule typically used for this purpose. Perhaps the earliest form of sensory rhodopsin, bacteriorhodopsin, is found in a primitive purple-colored bacterium, Halobacterium halobium.3 It is not known how long this organism has inhabited the Earth. However, its preference for anaerobic conditions and a very salty environment may mean it developed at a time when little or no oxygen existed in the atmosphere and the sea contained high salt concentrations. Bacteriorhodopsin is a complicated molecule that contains 248 amino acids in the opsin portions, which are linked to one retinal chromophore. Time-resolved spectroscopic measurements have determined that a cis/trans isomerization in the retinal portion of the molecule begins about 10−12 seconds after light stimulation. This is followed by deprotonation in the opsin portion at 10−5 seconds after stimulation.4 This early rhodopsin absorbed light maximally at 495 nm but responded to almost all visible light. Estimates suggest that the ancestor of human color pigment genes diverged from the rhodopsin gene about 800 million years ago and eventually resulted in a series of pigments with maximal absorption peaks in the blue, green, and red areas of the spectrum.5 These specially adapted molecules are needed for accurate color vision. Thus, early animals used something akin to the original rhodopsin and a very simple optical system to see. For example, early worms and shellfish had light-sensing cells that lined a small cup-like structure. Such a system gives a sense of directionality, because each cell is shielded from light that approaches the cup from the non-seeing side. If the cup is made deeper and the sides are turned over, a lensless pinhole system is produced. Such a system is used by a very primitive swimming mollusk called Nautilus.6 Thus, with visible light falling on the Earth, and rhodopsin already present, the stage was set for the development from simple lightsensing to natural or living optics.

19

2 Optics and Refraction

Fig. 2-1-1  The electromagnetic spectrum. The pictures of mountains, people, buttons, viruses, etc., are used to produce a real (i.e., visceral) feeling of the size of some of the wavelengths. (Adapted from Zeilik M. Astronomy: the evolving universe. 3rd ed. New York: Harper & Row; 1982.)

THE ELECTROMAGNETIC SPECTRUM visible spectrum nm radio

700 1 GHz

600

500

400

100 GHz infrared

AM 540–1650 kHz

m

FM 88–108 MHz

ultraviolet soft

x-rays

hard -rays

frequency (Hz) 3 102

3 104

106 104 wavelength (m)

mountains

3 106 102

factory

3 108 3 1010 3 1012 3 1014 3 1016 3 1018 31020 3 1022 3 1024 1

people

10–2

button

10–4

point

10–6

dust

10–8

bacteria

10–10

virus

10–12

10–14

atom

10–16

atomic nucleus

size

atmospheric transparency

ABSORPTION OF THE SUN’S RADIATION BY THE EARTH’S ATMOSPHERE relative 22 energy curve for black body at 6000 K intensity 20 solar energy curve outside atmosphere 18 16 solar energy curve at sea level 14 ultraviolet visible infrared 12 10 8 6 4 2 0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 wavelength (m) Fig. 2-1-2  Absorption of the Sun’s radiation by the Earth’s atmosphere. The white areas show the actual measured spectrum at sea level. Note the white areas of absorption are produced by ozone, water, and carbon dioxide. (Adapted from Zeilik M. Astronomy: the evolving universe. 3rd ed. New York: Harper & Row; 1982.)

VISIBLE LIGHT RECEPTORS AND THE OCULAR MEDIA Life has existed on Earth for about 4 billion years. Primitive fish that had eyes somewhat like human eyes first appeared about 400 million years ago, so it might be said that ophthalmic optics originated at this time.7–9 The living form of optics operates under the same rules and regulations as mechanical glass optics. Obviously, the various aspects of natural optics are linked closely to the dimensions of the wavelengths of visible light. Some of the basic elements of optics, using living optics examples, are introduced below.

Receptors 20

Receptor size and shape

The essential job of an optical system is to convert information about an object into an image. In natural optics, the image is formed on the

retina and, therefore, it usually is much smaller than the object. Classically, the object has been considered as made up of a series of luminous points. For example, an object such as a tree does not contain points of light but can be thought of as reflecting points of light. The optical system converts the object points of light into image points. Because the image is smaller, the image points may be considered more densely packed. Thus, an image of high quality − also called an image of high resolution − demonstrates much detail. The finer and more tightly packed the receptors, the more detail is registered. The retinal receptor size and shape is influenced by a number of factors. Because smaller receptors are better for resolution than larger receptors, what factor actually limits the smallness of a photoreceptor such as a retinal cone? The answer is diffraction. The smallest point focus of light is surrounded by a diffraction pattern. Thus, very narrow receptors that receive a large diffraction pattern are wasteful. The size of the diffraction pattern, on the retina or on a screen, is known as an Airy disc. The diameter of this disc determines the distance between two resolvable points. That is to say, the diameter of the Airy disc, Dλ, or the width of the central maxima, also is equal to the just-resolvable distance between two intensity peaks when the minima of the interference patterns overlap (equation 2-1-1;10 Fig. 2-1-3).11,12 Equation 2-1-1

Dλ =

1.22 fλ κp

where 1.22 = constant for round pupil, λ = 550 nm (average for visible light), f = focal length of system, and p = pupillary diameter. For example, the size of the Airy disc image of a point of light for the human eye under photopic conditions may be determined as follows. If f = 17 mm (focal length of eye), p = 4 mm (average photopic pupil), l = 0.00055 mm (median wavelength in visible spectrum of 0.0004–0.0007 mm), then the diameter of the Airy disc, Dλ is given by equation 2-1-2. Equation 2-1-2

Dλ =

(1.22)(17)(0.00055) 4

= 2.8 µm

TABLE 2-1-1  F-NUMBERS FOR SEVERAL ANIMAL SPECIES

RESOLUTION OF DIFFRACTION PATTERNS OF TWO OBJECT SOURCES OF LIGHT

S2

Light intensity distribution

S1

Appearance of light distribution

central maxima + second minima

Pupil width (mm)

F-number

Net-casting spider Cat Flour moth Tawny owl Housefly Human Pigeon

1.325 14 0.02 13.3 0.0025 7–8 0.2

0.08 0.89 1.2 1.3 2.0 2.1–2.4 4.0

2.1 Visible Light

Production of diffraction patterns

Animal

(Modified from Lythgoe JN. The ecology of vision. Oxford: Clarendon Press; 1979.)

central maxima + first minima



(angle of separation)

merge to one image

Mosaic of retinal cones



Equation 2-1-4

(angle of resolution) intensity

S1

AS =

(1.22)(0.00055)

8 = 0.000084 radians = 2.5 minutes

For example, if it is assumed that the human separation criterion is one half the width of the Airy disc, then the angle of resolution is close to 1 minute of the arc. If the contrast enhancement known to be built into the neural processing of the human visual system is considered, it becomes apparent how some subjects have a resolution angle of less than 1 minute of arc.10,14 In conclusion, the resolution limit of natural optics is related to the size of the wavelengths within the spectrum of visible light.

S2

Fig. 2-1-3  Two object sources of light (S1 and S2) cannot be resolved if their diffraction patterns (Airy discs) overlap substantially. Two refraction patterns are produced by a circular aperture placed between two lenses, and resultant patterns of the light intensity distribution and appearance are shown: the central maxima of one diffraction pattern falls on the second minima of the diffraction pattern from the second source; the central maxima of one diffraction pattern falls on the first minima of the diffraction pattern from the second source, and the two images can just be resolved (Rayleigh’s criterion); the two images merge as one. Bottom right, mosaic of retinal cones with the diffraction pattern superimposed. (Adapted from Jenkins FA, White HE. Fundamentals of optics. New York: McGraw–Hill; 1950. p. 290–3; and Emsley HH. Visual optics. London: Hatton Press; 1950. p. 47.)

Note that the size of the Airy disc can vary with the focal length of the eye, the wavelength of light, and the pupil size. Also note that 2.8 µm is close to the size of the average foveal cone (1.5–2.0 µm). In comparison, the eagle has a large photopic pupil (about 6 mm); its foveal cones are thinner than those of the human and the eagle eye’s resolution is finer. Two other important optical concepts are buried in equation 2-1-1. First, note that f/p may be a key factor in determining the size of the Airy disc. The f/p ratio is called the f-number of the system. As p, the pupil diameter, decreases, the diameter of the diffraction pattern increases, and the resolution power lessens. The same occurs if the focal length increases, because this tends to widen the projection of the diffraction pattern. Thus, a larger f-number suggests a degradation in resolution. The second concept, the angle of resolution, is related closely to the Airy disc. The Airy disc is the physical distance, on the retina or a screen, between two points that are just-resolvable. The angle of resolution, AS, is another way to describe just-resolvable points in physical space (equation 2-1-3; see Fig. 2-1-3). Equation 2-1-3

The angle of resolution, AS, for two distant stars viewed by a healthy, average human eye with a pupil of 8 mm in diameter is given by equation 2-1-4. However, it is known that the human eye can resolve two separate points in 1 minute or even less.11 This discrepancy is explained as follows. The Raleigh criterion for resolution demands that the maxima of one point source must intersect the minima of the second point source (see Fig. 2-1-3),13 which allows a patch of no light (high-contrast image) between the two maxima. However, in the case of the healthy young human eye, contrast determinations can be made for targets of lower contrast. Thus, many human eyes are able to distinguish two point sources or two black bars when the diffraction patterns overlap (see Fig. 2-1-3).

AS =

1.22λ p

where 1.22 = constant for a circular pupil, p = pupil diameter, and λ = 0.000550 mm. The focal length of the system, f, is not used in equation 2-1-3.

Light sensitivity

When a firefly is seen in the distance, the number of photons collected by the eye from the firefly (per unit time) is distributed over the retinal image. Each image point is an Airy pattern. Thus, the smaller the patterns, the more concentrated the pattern and the brighter is the image. It may be wondered whether animals that have small eyes, with a small focal length, or insects that have even smaller eye facets can collect light as well as the human eye does. From equation 2-1-1, if the light-catching ability of an optical system depends primarily on the f-number (f/p), the small eyes of spiders and each facet of the housefly eye, theoretically, are even more sensitive than the human eye. Table 2-1-1 gives the f-number for some animal species;12 the tiny eye of the net-casting spider sees dim objects better than eyes of the other animals. In conclusion, we can make the following observations:  Small eyes may have low f-numbers and consequently have very sensitive light-catching abilities  The Airy disc or diffraction pattern from any point on the object is important in determining the density of photons that fall on a retinal area Thus, we can appreciate that the level of sensitivity of the receptor is tied ultimately to the wavelength within the spectrum of visible light.

Receptor shape

The shape of the photoreceptor plays an important role in resolution of light and sensitivity. For example, the tighter the packing of receptors, the closer the focused points on the retina may be placed (actually, these are Airy patterns). Theoretical analysis shows that hexagonal cross-sections of close elements allow the tightest packing and, in fact, photoreceptors have such hexagonal cross-sections.13,14 Of course, the tightness of the packing is related to the angle of resolution.

Receptor as a light guide

A light guide (fiberoptic element) receives light at its entrance. Because the core of the guide has a higher index of refraction than the outer

21

Fig. 2-1-4  Scanning electron micrograph of photoreceptors that can be considered a light guide. C, cone; R, rod. (From Prause JU, Jensen OA. Scanning electron micrograph of frozen-crack, dry cracked and enzyme digested retinal tissue of a monkey and man. Graefes Arch Klin Exp Ophthalmol 1980;212:261–70.)

2 Optics and Refraction

coating, or cladding, light that enters beyond the critical angle is not refracted but forced to reflect continually off the walls of the guide until it reaches the other end. (Critical angle refers to a refracting system, in which the incident ray is reflected instead of refracted.) As might be expected, at angles of entry close to the critical angle, a small amount of light may leak between closely packed light guides. The retinal cone acts as a light guide (Fig. 2-1-4).15 The body of the cone has one index of refraction and the surrounding interstitium, although narrow, has a lower index of refraction. Recall that the index of refraction varies with wavelength. A second point to note is that as the diameter of the guide gets smaller, the wave nature of light plays a more important role in the functioning of the guide. For example, as the diameter of the guide approaches the light’s wavelength, the waves of light that enter interfere more destructively with each other, which reduces the amount of light that reaches the other end. The interference pattern is known as a modal pattern. Because diffraction is ultimately dependent on the wavelength, the limiting diameters of a light-guiding cone are related to the wavelength.16–18 The second limiting factor is light crossover between receptors, which is related to the indices of refraction of the receptor and its surround, as well as to the closeness between receptors.19,20 Both of these properties may be thought of as related to the wavelength of light. In summary, the dimensions of receptors of about 2 µm in diameter and the separation between receptors of about 0.33 µm are related to the wavelength of visible light.

Dioptric Media

It seems obvious that dioptric media, or the optical elements of the eye, must be transparent. A perfectly transparent medium does not absorb or scatter light. Classically, pigments are described as absorbing visible light. The characteristic feature of a pigment molecule is a series of single and double bonds formed by the carbon atoms. The pi electrons of the double bond may be thought of as ‘free to wander’ across the carbon backbone structure of the molecule, which increases their combined probability distribution over the entire molecule. This condition makes it easier to excite the pi electrons with the less-energetic visible wavelengths. Ultraviolet, X-ray, and ionizing radiation have more energy than visible light. Transparent media have few or no pigment molecules. A good example of a medium transparent to visible light is the human ocular media,21 which consists primarily of water. When a beam of visible light passes through pure water, the water appears transparent because it contains no pigments and because the light waves scattered from each of the water molecules interfere destructively with one another in all directions except the forward direction. No light appears to have been scattered, because the scattered waves mutually cancel to give zero net scatter to the side. Water and glass interact with light in this way because their components are all of the same index of refraction and uniformly distributed. The transparent cornea may be thought of as made up of collagen fibers of one index of refraction embedded in a mucopolysaccharide (high water content) of a second index of refraction. However, because the distribution of the

22

Access the complete reference list online at

elements is in a uniform pattern, and because the collagen fibers are never more than the distance of one-half a wavelength of visible light apart, the number of scattered waves is small. In reality the cornea is only 90% transparent (10% of the incident light is scattered). It is functionally transparent,22 although not perfectly transparent. Once again, an important optical property (transparency) may be thought of as dependent on the wavelength of the incident light.

Photonics

Photonics is a field that started in the 1960s and started applying light in nontraditional ways, i.e., lasers and optical fibers. In this section we will describe some new ways that light is being used in ophthalmology. For example, adaptive optics is a high-resolution, aberration-corrected optical system capable of resolving in vivo micro-structural details of retinal photoreceptors.23,24 In treatment for keratoconus and corneal ectasia, the use of the photosensitizer riboflavin combined with ultraviolet illumination has been shown to cross-link corneal collagen fibers and thus strengthen the cornea.25,26 Recent results in the use of femtosecond lasers as a tool to penetrate cell walls demonstrate that the manipulation of light can be used as a tool for the study of the processes in individual cells.27 Early results demonstrate that the glucose level in the anterior chamber can be determined by using noninvasive polarimetric techniques, similar to those used in measuring sweetener levels in sodas.28 Quantum dots imbedded in retinal tissue show promise as a treatment for retinitis pigmentosa. These dots absorb light and generate nerve signals in the retina.29 High-resolution optical coherent topography has now been shown to detect faint structures such as Schwalbe’s line.30 Polarimetry is currently being used to accurately measure, in vivo, nerve fiber loss in glaucoma.31 An early study suggests that analyzing the interference pattern of polarized light reflected from the cornea correlates with intraocular pressure measurements.32 Studies demonstrate that analyzing the birefringence of the surgical area following filtering surgery measurements offers a new parameter for following post-op healing.33

SUMMARY In conclusion, in this chapter a perspective for optics as well as a focus on an important common denominator in optics is given. The common theme is related to the properties of the tiny portion of the electromagnetic spectrum known as visible light. The wavelength of visible light is critical in understanding the structural dimensions of the optical systems of animal and human eyes. Electronic images are increasingly common and have unique characteristics and possibilities, which should be included whenever considering vision and visible light.

KEY REFERENCES Hwang H, Kim M, Park C. A new noncontact tonometer using corneal photoelasticity: porcine eye study. Ophthalmic Res 2011;45:169–73. Jing T, Marziliano P, Wong HT. Automatic detection of Schwalbe’s line in the anterior chamber angle of the eye using HD-OCT images. Conf Proc IEEE Eng Med Biol Soc 2010;2010: 3013–16. Malik BH, Coté GL. Modeling the corneal birefringence of the eye toward the development of a polarimetric glucose sensor. J Biomed Opt 2010;15:037012. Medeiros FA, Alencar LM, Zangwill LM, et al. Detection of progressive retinal nerve fiber layer loss in glaucoma using scanning laser polarimetry with variable corneal compensation. Invest Ophthalmol Vis Sci 2009;50:1675–81. Miller DT, Kocaoglu OP, Wang Q, et al. Adaptive optics and the eye (super resolution OCT). Eye (Lond) 2011;25:321–30. Rossi EA, Chung M, Dubra A, et al. Imaging retinal mosaics in the living eye. Eye (Lond) 2011;25:301–8. Sehi M, Grewal, DS Zhu H, et al. Quantification of change in axonal birefringence following surgical reduction in intraocular pressure. Ophthalmic Surg Lasers Imaging 2011;42:45–52. Stevenson DJ, Gunn-Moore F, Dholakia K. Light forces the pace: optical manipulation for biopho­ tonics. J Biomed Opt 2010;15:041503. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17:356–60. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620–7. Yong KT, Law WC, Roy I, et al. Aqueous phase synthesis of CdTe quantum dots for biophotonics. J Biophotonics 2011;4:9–20.

REFERENCES 1. Zeilik M. Astronomy: the evolving universe. 3rd ed. New York: Harper & Row; 1982. 2. Kippenhahn R. Light from the depths of time. New York: Springer-Verlag; 1986.

4. Atkinson GH, Blanchard D, Lemaire H, et al. Picosecond time resolved fluorescence spectroscopy of K-590 in the bacteriorhodopsin photocycle. Biophys J 1989;55:263–74. 5. Yokoyama S, Yokoyama R. Molecular evolution of human visual pigment genes. Mol Biol Evol 1989;6:186–97. 6. Dawkins R. The blind watchmaker. New York: WW Norton; 1986. p. 85–6. 7. Calder N. The life game. New York: Viking Press; 1974. 8. Burton VL. Life story. Boston, MA: Houghton Mifflin; 1962. 9. Marshall K. The story of life. New York: Holt, Rinehart, and Winston; 1980. 10. Jenkins FA, White HE. Fundamentals of optics. New York: McGraw–Hill; 1950. p. 290–3. 11. Emsley HH. Visual optics. London: Hatton Press; 1950. p. 47. 12. Blatt FJ. Principles of physics. Boston MA: Allyn and Bacon; 1987. 13. Lythgoe JN. The ecology of vision. Oxford: Clarendon Press; 1979. 14. Snyder AW, Bossomaier JR, Huges A. Optical image quality and the cone mosaic. Science 1986;231:499–501. 15. Prause JU, Jensen OA. Scanning electron micrograph of frozen-crack, dry cracked and enzyme digested retinal tissue of a monkey and man. Graefes Arch Klin Exp Ophthalmol 1980;212:261–70. 16. Enoch JM. Retinal receptor orientation and the role of fiber optics in vision. Am J Optom Arch Am Acad Optom 1972;49:455–70. 17. Snyder AW, Menzal R. Photoreceptor optics. Berlin: Springer-Verlag; 1975. 18. Snyder AW, Miller WH. Photoreceptor diameter and spacing for highest resolving power. J Opt Soc Am 1977;67:696–8.

20. Barlow HB. Critical limiting factors in the design of the eye and visual cortex: The Ferrier Lecture 1980. Proc R Soc Lond B Biol Sci 1981;212:1–34.

2.1

21. Boettner EA, Wolter JR. Transmission of the ocular media. Invest Ophthalmol 1962;1:776–83. 22. Miller D, Benedek G. Intraocular light scattering. Springfield: CC Thomas; 1973. 23. Miller DT, Kocaoglu OP, Wang Q, et al. Adaptive optics and the eye (super resolution OCT). Eye (Lond) 2011;25:321–30. 24. Rossi EA, Chung M, Dubra A, et al. Imaging retinal mosaics in the living eye. Eye (Lond) 2011;25:301–8. 25. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620–7.

Visible Light

3. Oesterhelt D, Stoekenius W. Rhodopsin-like protein from the membrane of Halobacterium halobium. Nature New Biol 1971;233:149–52.

19. Snyder AW. Coupled mode theory for optical fibers. J Opt Soc Am 1972;62:1267–77.

26. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17:356–60. 27. Stevenson DJ, Gunn-Moore F, Dholakia K. Light forces the pace: optical manipulation for biophotonics. J Biomed Opt 2010;15:041503. 28. Malik BH, Coté GL. Modeling the corneal birefringence of the eye toward the development of a polarimetric glucose sensor. J Biomed Opt 2010;15:037012. 29. Yong KT, Law, WC, Roy I, et al. Aqueous phase synthesis of CdTe quantum dots for biophotonics. J Biophotonics 2011;4:9–20. 30. Jing T, Marziliano P, Wong HT. Automatic detection of Schwalbe’s line in the anterior chamber angle of the eye using HD-OCT images. Conf Proc IEEE Eng Med Biol Soc 2010;2010:3013–6. 31. Medeiros FA, Alencar LM, Zangwill LM, et al. Detection of progressive retinal nerve fiber layer loss in glaucoma using scanning laser polarimetry with variable corneal compensation. Invest Ophthalmol Vis Sci 2009;50:1675–81. 32. Hwang H, Kim M, Park C. A new noncontact tonometer using corneal photoelasticity: porcine eye study: Ophthalmic Res 2011;45:169–73. 33. Sehi M, Grewal DS, Zhu H, et al. Quantification of change in axonal birefringence following surgical reduction in intraocular pressure. Ophthalmic Surg Lasers Imaging 2011;42:45–52.

22.e1

PART 2 OPTICS AND REFRACTION

Physical Optics for Clinicians Edmond H. Thall

A lot of good physics is based on bad models.

Roger Herman

Definition: Physical optics is the branch of physics dealing with the

fundamental nature of light and its interaction with matter.

Key features ■ ■ ■ ■ ■

2.2

Interference of light waves. Polarization of light waves. Diffraction effects of light waves. Scattering of light waves (effects on glare and contrast sensitivity). Understanding the quantum model of light waves.

Associated features ■

Lasers and light waves. ■ Interaction of tissue and light waves (i.e., laser light).

OVERVIEW Leucippus and Democritus (c.450 BC) suggested light is a flow of tiny, indivisible particles (Aristotle, Metaphysics Book 1, Part 4). In 280 BC Euclid concluded the particles move at infinite speed in perfectly straight lines unless reflected or refracted (Euclid, Catoptrics, Introduction). This ‘corpuscular’ theory as it later became known lends itself especially well to expression in geometrical terms with lines or rays representing the actual paths followed by particles of light. The corpuscular theory successfully explains many common optical phenomena and was accepted for two thousand years. However, diffraction was described in 1665 AD.1 Known to be a property of waves not particles, the observation cast serious doubt on the corpuscular theory. In 1801, Thomas Young, a London physician, showed that under the appropriate conditions light can interfere destructively,2 which is impossible for particles. Only waves can demonstrate destructive interference. At this point the corpuscular theory had to be rejected but not abandoned, since its geometrical principles serve so well, especially in the design of imaging instruments (e.g., telescopes, microscopes, etc.). Today’s geometrical optics is based largely on the corpuscular theory with some important modifications such as a finite speed of light. Wave theory is more inclusive than geometrical optics because every phenomenon explicable by geometrical optics can also be explained by wave optics. Moreover, the wave model can explain many phenomena that geometrical optics cannot. Nevertheless, if the same observation can be explained by both theories, the geometrical explanation is usually much simpler. While more limited than wave theory, when applied appropriately geometrical optics offers simplicity and sufficient accuracy even though it is not strictly ‘true.’ However, geometrical optics will produce unreliable, perhaps even misleading, results when applied to situations where interference, diffraction, or other wave or quantum effects play a significant role. Of course, investigating the basic nature of light continued, and if light is a wave, then what sort of wave? In the early 1800s Young and

others thought light was a longitudinal wave but in 1818 Augustin Fresnel showed light was a transverse wave.3 For about the next 30 years light was considered a mechanical wave vibrating in a single transverse plane in some sort of material (called the ether). In 1862 James Clerk Maxwell discovered that oscillating electric and magnetic fields propagated at the speed of light and concluded that light was an electromagnetic (EM) wave with electric and magnetic fields oscillating in two perpendicular transverse planes.4 Again the mechanical wave theory was disproved but not discarded. With the important modification that light is an oscillating field, not a mechanical vibration, the scalar wave theory is the simplest way to explain many phenomena. Of course, EM wave theory explained more phenomena but is more complicated. At the close of the nineteenth century it seemed the nature of light was finally established. However, as understanding of atoms and molecules advanced in the early twentieth century, problems arose. According to EM theory, electrons orbiting a nucleus should constantly lose energy by radiating EM waves. The electrons should spiral into the nucleus and the atom collapse, which of course does not happen. Again, another theory was required involving a radical departure from previous thinking. As in the past, EM wave theory is still useful for explaining many phenomena. In quantum mechanics, electrons exist in stable non-radiating states and radiate energy only when transitioning from a higher to lower energy state. The energy is radiated in a ‘package’ called a photon with a frequency proportional to its energy.5 To date, quantum theory has been able to explain all observed phenomena but because of its complexity, it is used mainly at the atomic and molecular level. There are unresolved issues in quantum mechanics,6 and perhaps another theory looms just over the horizon. This chapter discusses those aspects of wave and quantum theory applicable to ophthalmology. Geometrical optics is discussed in other chapters.

ELECTROMAGNETIC AND SCALAR WAVES EM waves consist of an oscillating electric field perpendicular to an oscillating magnetic field, with both fields perpendicular to the direction of propagation (Fig. 2-2-1). The simpler model of a single oscillating field can explain many phenomena. This discussion is limited to the simpler ‘scalar’ wave approximation that suffices for clinical purposes.

POLARIZATION In general, there are two types of waves, longitudinal and transverse, both of which exhibit diffraction and interference. Longitudinal waves oscillate in the direction of propagation (e.g., sound waves). In transverse waves the direction of oscillation is perpendicular to the direction of propagation, and these two directions define a unique plane of polarization. Longitudinal waves cannot be polarized whereas transverse waves are always polarized. Typically, the plane of polarization changes randomly as light propagates; some refer to this as unpolarized light, but a better term is randomly polarized, because at any instant there is always a well-defined plane of polarization.7 If instead of changing randomly the plane of polarization is constant, then the wave is linearly polarized (Fig. 2-2-2). In elliptical and circular polarization the plane of polarization rotates at a constant angular rate. In circular polarization the amplitude

23

2

Fig. 2-2-1  Electromagnetic wave. An electromagnetic wave consists of an oscillating electric field perpendicular to an oscillating magnetic field. Both fields are perpendicular to the direction of propagation.

ELECTROMAGNETIC WAVE

Optics and Refraction POLARIZATION Horizontally polarized

Vertically polarized

polarizers also oriented in perpendicular meridians so each eye sees only one of the two displaced objects producing a sense of depth. Modern 3D movies also present different images to each eye but for technical reasons use circular polarizers. Devices for rapid vision screening also incorporate linear polarizers. The optotypes on any line are linearly polarized in orthogonal directions and the subject looks through linear polarizers so each eye sees only some of the letters on each line. The patient can keep both eyes open, shortening testing time. These tests can also be used to identify malingerers feigning monocular vision deficits; unaware that each eye is seeing different letters, malingerers correctly read the entire line. The cornea and retinal nerve fiber layer (NFL) are birefringent.8 The GDx™ system measures NFL birefringence using elliptically polarized light and relates it to NFL thickness.9 When the retina is illuminated with elliptically polarized light, the nerve fiber layer rotates the ellipse axis that is an indirect measure of NFL thickness.10 However, the cornea is also birefringent. Keratorefractive surgery alters the cornea’s birefringence characteristics, which can cause a fictitious change in NFL thickness measured by the GDx™.11 The addition of a variable corneal compensator (VCC) to later generations of the GDx™ may mitigate this problem. Linear polarization can be achieved simply by reflection. When light strikes the interface between two dielectric materials (e.g., air, glass, plastic, water) some light is reflected and the rest transmitted (refracted). Fresnel showed the reflected light exhibits at least partial linear polarization parallel to the reflecting surface. At the Brewster angle all the reflected light is polarized.12 Most reflecting surfaces in the environment are horizontal (e.g., water, snow, etc.). Midday sunlight strikes these surfaces at near normal incidence and relatively little light is reflected, and at angles that generally do not reach the eye. However, in morning and late afternoon more sunlight is reflected, it is more likely to cause glare, and it is also mostly polarized horizontally. Polaroid sunglasses have polarizers that markedly reduce reflected glare. Photographers sometimes mount a polarizer on the lens to reduce glare. Some direct ophthalmoscopes incorporate a circular polarizer to reduce annoying corneal reflections. Right circularly polarized light becomes left polarized on reflection from the cornea and is blocked by the right circular polarizer when it reflects back to the ophthalmoscope. Since the reflected polarization depends on the corneal curvature, a Maltese-style cross pattern and colored fringe artifacts are also observed.

DIFFRACTION AND INTERFERENCE

Fig. 2-2-2  Polarization. Both transverse waves propagate in the same direction but oscillate in different planes. Here, only the scalar wave approximation is adopted, and only the electric field is shown.

24

is constant as the wave propagates. In elliptical polarization the amplitude varies as the wave propagates with the maximum and minimum amplitudes in perpendicular meridians. There are simple practical ways to achieve each type of polarization. The term dichroic has several meanings, but in this context it refers to materials that absorb light polarized in one direction while transmitting light polarized in the perpendicular direction. If randomly polarized light passes through a dichroic filter about half the light is absorbed and the transmitted light is linearly polarized. A birefringent material has two different refractive indices depending on polarization. Randomly polarized light traversing a birefringent material is split into two beams each linearly polarized at right angles to each other. Clinically, linear polarization is mainly used to present each eye with a different image. No light passes through a pair of linear polarizers oriented at right angles to each other, but light is maximally transmitted when the polarizers are parallel and less light is transmitted when the orientations are at oblique angles. Most tests of stereopsis use slightly displaced objects that linearly polarize light in perpendicular meridians. The patient wears spectacles incorporating linear

According to the law of rectilinear propagation, a collimated pencil of light should remain collimated after traversing an aperture that limits its extent (Fig. 2-2-3). In fact, Francesco Grimaldi discovered that light changes direction upon traversing an aperture. Diffraction occurs whenever a light wave is partially broken by an edge or aperture. Grimaldi coined the word ‘diffraction’ from the Latin diffringere, meaning to fracture or break into pieces. Just why diffraction occurs is difficult to say. There are various ways to treat diffraction. The mathematics is too complicated to warrant inclusion here, but as a rule, the smaller the aperture relative to wavelength the more pronounced the diffraction effects. Once a wave changes direction it usually interferes with other parts of the diffracted wavefront. According to the principle of superposition, whenever two or more waves overlap, their amplitudes add. If the waves overlap peak to trough they cancel, producing little or no light at a given position (and time). Of course, if the waves align peak to peak they reinforce each other, producing more light (Fig. 2-2-4). One of the most important consequences of diffraction is that it places an absolute limit on the amount of detail in an image. Consider a single axial object point. Applying only geometrical optics (Snell’s law), it is possible to eliminate all aberrations and create a lens that converges all rays to a perfect point focus. However, geometrical optics ignores diffraction. Even an optical system entirely free of aberrations never produces a perfect point focus. In 1834 the astronomer George Airy showed that an aberration-free optical system images an axial object point as a central disc surrounded by rings (see Fig. 2-1-3). The pattern is the result of both diffraction and interference effects. The interference is apparent by the alternating light and dark rings surrounding the central disc that are analogous to

DIFFRACTION NO

Fig. 2-2-3  Diffraction by an aperture. According to the law of rectilinear propagation, light should not change direction after traversing an aperture (top left). Grimaldi discovered that light changes direction after traversing an aperture (top right). Diffraction occurs at all apertures, large (bottom left) and small (bottom right). However, the smaller the aperture the more pronounced the effect.

Fig. 2-2-4  Constructive and destructive interference. When two or more light waves are superimposed, the amplitudes sum. If two identical waves are in phase, the resulting amplitude doubles (bottom). If the waves are perfectly out of phase, the waves cancel out (top).

CONSTRUCTIVE AND DESTRUCTIVE INTERFERENCE

=

THE SPEED OF LIGHT AND DISPERSION

=

the fringes observed in Young’s two-slit experiment. Airy’s calculation is premised on the assumption that the source is monochromatic.13 A broadband (e.g., white light source) would produce a broader pattern possibly with colors at the edges of the ring fringes. Strictly speaking, the concentric ring pattern spreads out to infinity, but most of the energy is concentrated in the center. It is customary to disregard everything but the central ‘Airy’ disc, which has a radius dependent on the focal length, diameter of the exit (or entrance) pupil, and wavelength of incident light.

2.2 Physical Optics for Clinicians

YES

about 7.4 µm enveloping about 11 photoreceptor outer segments. The next question is what is the smallest detail a person can resolve when the central disc is a given size? Lord Rayleigh suggested the smallest resolvable detail equals the radius of the Airy disc. An Airy disc of 3.7 µm radius corresponds roughly to 20/15 visual acuity. In the early days of excimer laser keratorefractive surgery, some claimed that by eliminating all aberrations, acuity could be improved to 20/6.14 These overly optimistic claims were based on geometrical optics ignoring diffraction, which imposes the absolute limit on image quality. Instead of a smooth curve, the back surface of a diffractive intraocular lens (IOL) consists of discrete circular steps that each produces diffraction. Subsequent interference produces two axial foci, one for near and one for distance. Under ideal conditions diffractive multifocals probably produce the best images of any multifocal IOL, unfortunately circumstances are rarely ideal. Interference effects are sensitive to a fraction of a micron and diffractive IOLs also rely on symmetry. If a diffractive IOL is tilted, decentered, or if the pupil is not circular, image quality rapidly degrades. Although some multifocal IOLs claim to be refractive and not diffractive (e.g., ReZoom™), any lens with abruptly changing zones produces significant diffraction and suffers image degradation with tilt, decentration, etc. Thin films exemplify interference without diffraction. As noted above, some light is reflected at the interface between two media. At normal incidence an air–glass interface reflects about 4% of incident light. Magnesium fluoride (MgF2) has a refractive index between air and glass. In quality optical systems, lenses are coated with a thin (quarter of a wavelength) layer of MgF2. The front and back surfaces of the thin film each reflect about 2% of incident light but destructive interference reduces the reflected light to 0.4% of the incident light.15 Thin film interference is widely used in ophthalmology but mostly ‘behind the scenes.’ In fluorescein angiography, colored filters are used to restrict the wavelengths in the illumination and imaging paths of a fundus camera. In the past the filters consisted of chemical dyes that degrade over time. Chemical filters have been replaced by interference filters consisting of many thin film layers that do not age and provide superior wavelength separation, reducing pseudofluorescence. One important clinical finding is the presence of colored swirls on the tear film surface, resulting from thin film interference produced by the oil layer of the tear film.16 Slit-lamp observation of colored swirls in the tear film may indicate meibomian gland dysfunction. Thin film coatings are generally delicate and care should be taken when cleaning lenses with thin film coatings. Thin film anti-reflection coatings are also available for spectacle lenses. The additional transmitted light is probably not much of an advantage, but the coatings reduce stray reflections that some patients find annoying.

Radius = 1.22λ

f D

For instance, an eye with a 3 mm pupil has an f-number about 5. Setting λ at the peak of photopic sensitivity (0.55 µm) gives a diameter of

In the past, the meter was defined as the length of a platinum iridium bar, and the speed of light was measured in terms of meters (and seconds). Since 1983, the meter has been defined as 1/299 792 458 of the distance light travels in vacuum in one second.17 We can therefore say the speed of light in vacuum is exactly 299 792 458 meters per second. Light travels fastest in vacuum and slower in any other material. Refractive index is the ratio of the speed of light in vacuum divided by the speed of light in a material and is a number always greater than one. In general, every material has a different refractive index so refractive index is a fundamental characteristic of a material. A vacuum is a non-dispersive medium, meaning the speed of light in vacuum is the same for all frequencies.18 All other mediums are dispersive so the speed of light in a material and, therefore, the refractive index differs for every frequency.19 The rainbow observed when white light traverses a prism is produced by dispersion. Although there are exceptions, as a rule higher frequencies have higher refractive indices than lower frequencies. The Abbe number, V, is a measure of dispersion defined by:

V=

nd − 1 nF − nC

In this equation nd, nF, and nC are the refractive indices for wavelengths 587.6, 486.1, and 656.3 nm respectively. High Abbe numbers indicate

25

2 Optics and Refraction

low dispersion. There are several other measures of dispersion that use slightly different wavelengths but follow the same basic formula. As a general rule, the higher the refractive index the lower the Abbe number, which is a bit of a problem. All other things being equal, the higher the refractive index the thinner the spectacle lens. However, higher index materials typically have more dispersion which may produce undesirable color effects. Polycarbonate for instance has an index of 1.58 which is relatively high, but a fairly low Abbe number of 34. As a spectacle material, polycarbonate is fairly dispersive. The choice of material for spectacles depends on several factors, including density, scratch resistance, strength, cost, etc. Even a dispersive material may, on balance, be a good choice of spectacle material.

QUANTUM MODEL OF LIGHT The following is a highly simplified view of quantum mechanics but sufficient for clinical purposes. An atom consists of a positively charged nucleus surrounded by negatively charged electrons. Unlike earlier models, in quantum mechanics the electrons are not viewed as orbiting the nucleus but simply as occupying a state.20 Each state is associated with a specific energy.21 Electrons can move or transition between states by absorbing or emitting an amount of energy equal to the energy difference between the two states. The energy required to raise an electron from a lower to higher state may come from many sources, e.g., heat, electric current, or by absorbing a ‘packet’ of light called a photon. Similarly, an electron can drop to a lower state by releasing energy by nonradiative mechanisms or by a photon. The energy of a photon is directly proportional to its frequency according to the equation:22 E = hν



FLUORESCENCE AND PHOSPHORESCENCE The principles of quantum mechanics are illustrated by fluorescence. Like individual atoms, the electrons in molecules also exist in discrete states. The distribution of states in a fluorescein molecule is such that fluorescein can absorb photons corresponding to blue light. Absorbing a blue photon raises an electron to a higher state. The electron then quickly drops to a slightly lower energy state losing some energy by nonradiative means. The electron then drops to the original low energy state by radiating a photon, but one of slightly less energy, corresponding to yellow.23 In fluorescence the emitted photon is usually a longer wavelength than the absorbed photon (Fig. 2-2-5) and the difference is exploited clinically in fluorescein angiography, Goldman applanation tonometry, and the Seidel test. When the concentration of fluorescein exceeds 2%, fluorescein molecules form a non-fluorescent dimer, a phenomenon exploited in the Seidel test.24 Concentrated fluorescein is applied to an area suspected of leaking. Concentrated fluorescein is practically invisible under cobalt

FLUORESCENCE energy nonradiative transition

stimulating photon

26

emitted “fluorescent” photon

Fig. 2-2-5  Energy levels in a hypothetical fluorescent molecule. A relatively high energy photon raises an electron to the highest level. The electron drops to a nearby level by nonradiative means and then drops to its original low level emitting a lower energy photon than the one originally absorbed.

blue light, but if diluted by a wound leak it fluoresces making the leak apparent. Phosphorescence is similar to fluorescence except that the higher energy state is metastable. Instead of dropping to a lower state immediately, the electron remains in the elevated state for a long period of time, seconds to days depending on the material. Eventually, the electron drops to a nearby energy state nonradiatively and then to the ground state. The essential difference between fluorescence and phosphorescence is the amount of time an electron remains in a high energy state before dropping down.25

LASER FUNDAMENTALS Lasers are based on the phenomenon of stimulated emission.26 If an electron is in an elevated energy state, a passing photon can stimulate the electron to drop to a lower state and emit another photon of identical phase and frequency. For stimulated emission to occur the passing photon’s energy must exactly equal the energy difference between the two states. The stimulating and emitted photons are coherent, so stimulated emission could be the basis of a light source with uniquely useful properties, but to make it work requires overcoming some practical difficulties. Consider a glass tube containing a small amount of pure gas. Most of the electrons in the gas atoms will occupy the lower energy states, but because of thermal energy, some electrons will occupy higher energy states. The situation is a dynamic equilibrium with thermal energy constantly causing electrons to jump to higher levels and other electrons dropping to lower levels, but on average most electrons are in low energy states with relatively few in high energy states. When an electron drops to a lower state it generates a photon that might cause stimulated emission but probably will not. More likely, since there are so few other electrons in elevated states, the photon will leave the tube before encountering another electron in a high energy state. The odds can be improved by using a gas with a metastable state. Electrons remain in metastable states longer and increase the likelihood of encountering a passing photon stimulating emission. The odds can be further improved by pumping energy into the tube. Instead of relying on just thermal energy, ‘pumping’ more energy into the gas raises more electrons into high energy states. One way to pump energy into a laser is optically, by surrounding the gas-filled tube with a strong light source such as xenon. No matter how it is accomplished, pumping produces a population inversion – more electrons in elevated states than in lower states, the opposite of the normal situation. As stimulated emission causes electrons to drop to lower states, pumping quickly restores those electrons to higher states. To increase stimulated emission even further, the gas tube is placed in a resonator consisting of a fully reflecting mirror on one side and a partially reflecting mirror on the other, so each photon makes several passes through the tube producing more stimulated emission with each transit. Compared to the energy input, the energy output of a laser is modest, so lasers are not very efficient. However lasers produce a unique type of light, highly coherent, with unique applications. Lasers may operate either continuously or in pulsed mode. There are various ways to pulse a laser. No matter how it is accomplished, pulsing allows the energy output to be delivered in a very short time, increasing the instantaneous power to high levels.

LIGHT–TISSUE INTERACTIONS In ocular tissues a variety of pigments (e.g., melanin, xanthophyll, hemoglobin) absorb light and convert it to heat. A modest temperature rise of 10–20 °C can coagulate proteins.27 Light of sufficient irradiance causes coagulation in both pigmented and contiguous transparent tissues. The first therapeutic photocoagulation utilized sunlight delivered through a heliostat, which was replaced by a xenon flash light. In both cases it was difficult to direct light into the eye precisely and the broad spectrum could damage other tissues. Laser photocoagulation allows far more precise delivery of energy both anatomically and spectrally. Clinical use of laser photocoagulation is reviewed elsewhere in this text (see Chapter 6.4). Photovaporization occurs when tissue temperature is raised enough to boil water. Photovaporization is an undesirable complication of retinal photocoagulation. Higher power, smaller spot size and shorter duration increases the risk of photovaporization. The femtosecond laser operates in the near infrared and utilizes photovaporization

to ‘cut’ corneal flaps and recently has been applied to cataract surgery. Photodisruption produces a miniature lightning bolt inside the eye.28 A pulsed Nd : YAG laser operating at 1.06 µm is focused to a very small point producing an extremely high power density that literally rips electrons away from their nuclei, creating a plasma. When the electrons recombine, they create an audible spark that is a miniature lightning bolt and the sound is a clap of thunder. The acoustic vibration creates the capsulectomy. Photoablation does not strip electrons from their nuclei, but does break covalent bonds. Excimer laser photoablation breaks corneal collagen bonds thinning the cornea. The excimer laser is unusual in that the active medium is a gas dimer that has high energy transition that produces ultraviolet light. The propagation of ultraviolet light through air varies significantly with barometric pressure, humidity, and the presence of aromatic compounds. Reproducibility is a challenge in keratorefractive surgery. Vision itself relies on photochemical reactions in photoreceptor outer segments. A photon ‘flips’ a rhodopsin molecule from the cis to trans isomer, initiating a series of electrochemical events ultimately producing a visual perception. Photoactivation is also used to activate photosensitizing agents such as verteporfin.

GLARE

2.2

No light scattering

Physical Optics for Clinicians

Light scatter

LIGHT SCATTERING Light scattering is another violation of the law of rectilinear propagation. Rayleigh scattering is produced by particles of 0.1–50 nm (molecules to one-tenth of a wavelength of light). Rayleigh scattering varies inversely with the fourth power of wavelength, so 400 nm (blue) light is scattered 16 times more than 800 nm (near infrared) light. Rayleigh scattering by molecules in the atmosphere accounts for the color of the sun and sky. Viewed above the atmosphere the sun appears white. At midday sunlight traverses a small amount of atmosphere. Rayleigh scattering disperses blue wavelengths giving the sky its light blue color and the sun a yellow hue. At sunrise or sunset sunlight traverses more atmosphere and additional scattering gives sunlight a red color and the sky becomes a deeper blue. Iris color is determined by the amount of melanin in the anterior stroma and Rayleigh light scattering by stromal collagen. Mie scattering is produced by particles around 400 nm and larger.29 Unlike Rayleigh scattering, Mie scattering is only weakly dependent on wavelength. Mie scattering accounts for the white color of clouds and sclera. The Tyndall effect is produced by relatively large particles in suspension. Dust in a beam of sunlight, headlights in the fog, and anterior chamber cells are examples of the Tyndall effect. As a general rule, scattering has a more profound effect on acuity than aberrations. A small corneal abrasion or slight vitreous hemorrhage scatters a lot of light and markedly decreases acuity. Early keratoconus has much less effect on acuity. The direction of scattering must also be considered. Forward scattering in the ocular media decreases retinal image contrast, but backscattering has little effect. A mild vitreous hemorrhage forward scatters light and can markedly diminish acuity. Asteroid hyalosis only backscatters light, which makes it difficult to examine a patient’s retina but does not decrease the contrast of the patient’s retinal image. Glare is a decrease in the contrast of the retinal image due to increased light scattering, perhaps by a cataract. In general, intraocular light scattering increases with age (Fig. 2-2-6).

Fig. 2-2-6  Glare. Without light scatter, light from an off-axis glare source does not overlap with the central retinal image. Light scatter by the ocular media, such as an early cataract, may decrease contrast in the central retinal image.

KEY REFERENCES Airy GB. On the diffraction of an object-glass with circular aperture. Trans Camb Philos Soc 1836:5:283–92. Ditchburn RW. Light. Mineola: Dover; 1991. p. 1–17. Fahim MM, Haji S, Koonapareddy CV, et al. Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease. BNC Ophthalmol 2006;6:20. Fariza E, O’Day T, Jalkh AE, Medina A. Use of cross-polarized light in anterior segment photography. Arch Ophthalmol 1989;107;608–10. Hecht E. Optics. 3rd ed. Reading: Addison Wesley; 1997. p. 111–21. Hecht J. Understanding lasers: an entry-level guide. 2nd ed. New York: Wiley–IEEE Press; 1994. Jenkins FA, White EW. Fundamentals of optics. 3rd ed. New York: McGraw–Hill; 1990. Lipshitz I. Thirty-four challenges to meet before excimer laser technology can achieve super vision. J Refractive Surg 2002;18:740–3. O’Shea DC. Elements of modern optical design. New York: John Wiley & Sons; 1985. p. 34. Smith G, Atchison DA. The eye and visual optical instruments. New York: Cambridge University Press; 1997. p. 656.

Access the complete reference list online at

27

REFERENCES 1. Grimaldi FM. Physico mathesis de lumine, coloribus, et iride, aliisque annexis libri duo. Bologna: Vittorio Bonati; 1665.

3. Fresnel AJ. Mémoire sur la diffraction de la lumière. Paris: L’Académie des Sciences (Paris) 1826;28:33–475.

16. Hosaka E, Kawamorita T, Ogasawara Y, et al. Interferometry in the evaluation of precorneal tear film thickness in dry eye. Am J Ophthalmol 2011;151:18–23. 17. Penrose R. The road to reality: a complete guide to the laws of the universe. New York: Vintage Books; 2004. p. 410–11. 18. Hecht E. Optics. 3rd ed. Reading: Addison Wesley; 1997. p. 111–21. 19. Ditchburn RW. Light. Mineola: Dover; 1991. p. 1–17.

4. Maxwell JC. A treatise on electricity and magnetism. Oxford: Clarendon Press; 1873.

20. Born M, Wolf E. Principles of optics. 6th ed. New York: Pergamon; 1980. p. 10–32.

5. Eisberg R, Resnick R. Quantum physics of atoms, molecules, solids, nuclei, and particles. New York: Wiley; 1974.

21. Jenkins FA, White EW. Fundamentals of optics. 3rd ed. New York: McGraw–Hill; 1990.

6. Moyer M. Is space digital? Sci Am 2012;306:30–7. 7. Wood RW. Physical optics. 3rd ed. New York: Optical Society of America; 1988. 8. Fariza E, O’Day T, Jalkh AE, et al. Use of cross-polarized light in anterior segment photography. Arch Ophthalmol 1989;107;608–10. 9. Morgan JE, Waldock A, Jefferey G, Cowey A. Retinal nerve fiber layer polarimetry: histological and clinical comparison. Br J Ophthalmol 1998;82:684–90. 10. Colen TP, Tjon-Fo-sang MJ, Mulder PG, et al. Reproducibility of measurements with the nerve fiber analyzer (NfA/GDx). J Glaucoma 2000;9:363–70. 11. Nevyas JY, Nevyas HJ, Nevyas-Wallace A. Change in retinal nerve fiber layer thickness after laser in situ keratomileusis. J Cataract Refract Surg 2002;28:2123–8. 12. O’Shea DC. Elements of modern optical design. New York: John Wiley & Sons; 1985. p. 34. 13. Airy GB. On the diffraction of an object-glass with circular aperture. Trans Camb Philos Soc 1836;5:283–92. 14. Lipshitz I. Thirty-four challenges to meet before excimer laser technology can achieve super vision. J Refractive Surg 2002;18:740–3.

22. Eisberg R, Resnick R. Quantum physics of atoms, molecules, solids, nuclei, and particles. New York: Wiley; 1974. 23. Lakowicz JR, Geddes CD. Principles of fluorescence spectroscopy. 3rd ed. New York: Springer-Verlag; 2006. 24. Fahim MM, Haji S, Koonapareddy CV, et al. Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease. BNC Ophthalmol 2006;6:20. 25. Smith G, Atchison DA. The eye and visual optical instruments. New York: Cambridge University Press; 1997. p. 656.

2.2 Physical Optics for Clinicians

2. Young T. Experimental demonstration of the general law of the interference of light. Phil Trans R Soc Lond 1804:94.

15. Macleod HA, Macleod A. Thin-film optical filters. 3rd ed. Bristol: Institute of Physics Publishing; 2001.

26. Hecht J. Understanding lasers: an entry-level guide. 2nd ed. New York: Wiley-IEEE Press; 1994. 27. Mainster MA, Ho PC, Mainster KJ. Nd:YAG laser photocoagulators. Ophthalmology 1983;90(Suppl):48–54. 28. Mainster MA, Ho PC, Mainster KJ. Nd:YAG laser photodisrupters. Ophthalmology 1983;90(Suppl):45–7. 29. van de Hulst HC. Light scattering by small particles. New York: Wiley; 1957.

27.e1

PART 2 OPTICS AND REFRACTION

2.3

Light Damage to the Eye David Miller, Clifford A. Scott

Definition: Structural or functional damage to the external or internal eye from thermal or photochemical effects of the absorption of light.

Key features ■

With age, many of the photoprotective mechanisms of the eye degrade. ■ Cataract development and the risk of macular degeneration are accelerated by cumulative or excessive exposure to UV radiation.

SPECTRAL COMPOSITION OF SUNLIGHT solar flux 0.7 (103W/ m2/m) 0.6

top of atmosphere

a

0.5 0.4

Earth's surface

b

0.3 0.2

Associated features ■

Reduction of environmental exposure and the use of absorptive lenses diminish the risk of light damage to the eye. ■ Intake of antioxidant foods or dietary supplements may slow the development of cataracts and macular degeneration.

0.1 0 250 260

270

280

deoxyribonucleic acid

290

300

proteins

310

b 320

330 340 350 wavelength (nm)

a spectral composition of sunlight before reaching the ozone layer

ULTRAVIOLET FILTRATION The oxygen holocaust, a term invented by Margulis and Sagan,1 describes that period in the evolution of life on Earth when the atmospheric oxygen content rose from 0.0001% to 21%. The source of such an atmospheric change was the evolution of photosynthesis by ancient green and purple bacteria, which seems to have started about 2 billion years ago. The change in environment destroyed most of the anaerobic microbes on Earth. Newly evolved resistant bacteria multiplied and ultimately developed the reactions of aerobic metabolism that prevail in life today. A secondary effect of this ‘newly formed oxygen’ was that as it rose into the upper reaches of the Earth’s atmosphere it reacted with incoming ultraviolet (UV) light from the Sun and formed the ozone layer near the top of the atmosphere, about 30 miles (48.3 km) up. The ozone layer is important in two ways2 (Fig. 2-3-1). First, it helps to stabilize the atmospheric oxygen level at 21% (excess oxygen is used to make more ozone); it has been suggested that many living organisms would not tolerate levels of atmospheric oxygen a few percent higher than 21%. However, it is the second effect of the ozone layer that is discussed in this chapter. The ozone layer, only about 2−3 mm in thickness, is produced in the stratosphere by a photochemical reaction fueled by UV-C radiation and/or lightning and spread by the stratospheric winds. This is ironic, because the ozone layer then filters out most of the potentially destructive UV light that arrives from the Sun. Research that started in 1980 noted a 3–6% per decade decay in the ozone layer, notably in the northern hemisphere. This depletion of the ozone layer, thought to be caused by chlorine from industrial pollutants, leads to an approximate 1% increase in UV-B radiation that reaches the Earth’s surface for every 1% reduction in ozone.3

Ultraviolet Profile

28

Of all the light energy that rains down on Earth, 4 D.29–31 The image-enhancing mechanism in the retina and brain may have helped to increase the subjects’ perceived depth of focus in the clinical studies cited when compared with our calculated results found in Box 2-5-1. The example in Box 2-5-2 shows that, even without a mammalian accommodation system, the fly theoretically can see objects from infinity to within 1 D to 2 D) occurred in 4.3% of patients; 0.2% of patients had a cylinder increase exceeding 2 D. Compared by thickness of Intacs, patients who had 0.25 and 0.30  mm rings had higher predictability as compared to the 0.35  mm ring. Postoperative mean refractive spherical error within 0.5  D was 69.6% and 78.3% in patients with the 0.25 and 0.3  mm ring, respectively, as compared to 59.9% in patients with the 0.35  mm ring. The adverse event rate was 1.1% including infectious keratitis (0.2%), shallow placement (0.2%), loss of 2 lines of best spectacle-corrected visual acuity (BSCVA) (0.2%), and anterior chamber perforation during initial and exchange procedures (0.4%).17,18 Nine percent of patients had a reduced central corneal sensation of less than 20  mm 6 months after surgery, and 5.5% showed a reduction in corneal sensitivity at 12 months after surgery. At 12 months, 4.4% of patients reported difficulty with night vision, 2.9% reported blurry vision, 1.6% diplopia, 1.3% glare, and 1.3% halos. The explantation rate of Intacs was 8.7%, with 19 out of 39 (49%) due to dissatisfaction with visual symptoms such as glare, halos, and night vision problems; 15 out of 39 (38%) were due to dissatisfaction with the correction achieved. There were no clinically significant complications related to explantation. After explantation, all patients returned to BSCVA of 20/20 or better, a clear central cornea with remaining stromal haze, and deposits within the peripheral tunnels. Burris et al.3 analyzed corneal topography in 74 phase II participants and found that corneal flattening increased with ring thickness. Most other laser refractive surgeries convert corneal asphericity from a prolate shape with negative asphericity, which is steeper centrally than

A histopathological study using a rabbit model showed that the tissue adjacent to the ring had activated keratocyte, intracellular lipid accumulation, and new formation of collagen.25 The evaluation of wound healing after Intacs implantation was done by Ruckhofer et al. using confocal microscopy.26 In the central cornea, all layers of corneas had normal morphologic features. At the peripheral area, epithelial cells had high-density nuclei, especially in the basal cell layer (35% of eyes). The nerve plexus and corneal endothelium underneath the ring was intact, and the tissue adjunct to the ring segment showed moderate fibrosis.

3.9 Intrastromal Corneal Ring Segments and Collagen Crosslinking

Fig. 3-9-4  Corneal collagen crosslinking. After debriding the corneal epithelium and applying riboflavin solution, 370 nm wavelength ultraviolet is irradiated for 30 minutes to create photobonding between corneal collagen fibrils.

peripherally, to an oblate shape with positive asphericity, which is flatter centrally than peripherally. Holmes–Higgin et al.19 reported topographic corneal flattening with Intacs prolately aspheric in the patients of a FDA phase III clinical trial, with relatively greater flattening induced pericentrally than centrally. This property is thought to be more beneficial to maintain the corneal optical quality compared to laser refractive surgery, such as photorefractive keratectomy (PRK) and LASIK, which usually lose corneal prolate asphericity. Incisions more centrally placed caused more induced astigmatism, whereas more peripherally placed incisions caused vascularization.15 Transient loss of corneal sensation was noted 2 months postoperatively but returned to normal by 6 months. Asbell et al.20 reported the potential reversibility in the refractive effect of the ICR. They showed that ICR explantation resulted in return of corneal curvature and refractive error to preimplant values. Similar results were reported by Davis et al.21 and Twa et al.22 ICRSs, as opposed to LASIK, do not remove corneal tissue, but induce corneal curvature change. In addition, intraocular pressure may be reduced after Intacs implants as shown by Ruckhofer et al.23 (significant decrease at 6 months). Another advantage of Intacs compared to laser refractive surgery is that the duration of dry eye symptoms after surgery is quite short, resolving within 1 week.24 Undisturbed corneal nerve plexus is thought to be attributed to this feature.

POSTOPERATIVE CARE AND MANAGEMENT Immediately following surgery, an antibiotic–corticosteroid combination ointment or solution (0.1% dexamethasone plus 9.3% tobramycin or equivalent) is applied to the operative eye. Small epithelial defects are treated with lubricating drops, and bandage contact lenses are used for large defects. The segment placement and incision closure should be observed using slit-lamp examination. The operative eye is protected with a clear shield, and the patient should be given appropriate postoperative instructions.14,27 Foreign body sensation or ‘scratchiness’ is common during the immediate postoperative recovery period. Symptoms of infection include dull, aching pain or discomfort, with or without photophobia, any time in the postoperative period. During recovery, eyes may feel dry for the first 2–3 months. Vision is expected to fluctuate during the first month.14,27

ICRS FOR KERATOCONUS AND AFTER LASIK Intacs have been used to treat patients with keratoconus. The results are encouraging, especially in decreasing astigmatism, increasing topographical abnormalities, and minimizing the risk of further progression of corneal ectasia. Khan et al. reported that Intacs SK are effective for the correction of refractive error in eyes with advanced keratoconus.28 They showed that the mean spherical equivalent was −6.57 D preoperatively and −2.84 D at 12 months. The mean UCVA was significantly improved 12 months postoperatively (logMAR, 0.88) than preoperatively. Shabayek and Alió reported that Kera Ring ICRSs achieved a mean uncorrected visual acuity of 0.06 preoperatively and a mean uncorrected visual acuity of 0.03 (decimal scale) in the 6-month postoperative period, and corrected distance visual acuity of 0.54 and 0.71, respectively.29 Similarly, ICRSs have been used as an adjunct to LASIK surgery. LASIK and Intacs differ in several respects. LASIK is a more versatile technique that corrects low to moderately high levels of myopia ( 20%, and the prevalence of chronic glaucoma is about 4.5% in people

over 70 years old.1,2 The 5-year incidence of nuclear cataract in people with open-angle glaucoma and aged > 50 is estimated to be 20%.2 Surgi­ cal trabeculectomy results in a 78% increase in the risk of cataract formation.3 For these reasons, combining cataract surgery and glaucoma surgery in a single operation appears to be a valid management option. How­ ever, an important consideration is that cataract surgery alone results in an IOP drop of up to 5 mmHg in patients with glaucoma.4

SPECIFIC TECHNIQUES Phaco combined with glaucoma surgery probably produces better IOP control with fewer complications than manual extraction plus glauco­ ma surgery, although there are no large well-controlled, randomized studies on this.4–6 However, the IOP reduction and subsequent control seem to be less effective with combined surgery than with trabeculec­ tomy alone – possibly due to more prolonged breakdown of the blood– aqueous barrier associated with cataract surgery.7 If surgeons consider combined surgery, a single-site approach may be less time consuming, but a two-site approach allows the surgeon to use the familiar temporal clear corneal approach to the cataract. Debate continues on whether a single-site or two-site approach gives better control: several studies report no significant difference in pressure-lowering effect. In a single-site approach a standard trabeculectomy flap is fashioned, and phaco and implant insertion is performed through what would become the site of the penetrating sclerectomy. The sclerectomy is then completed with a blade or by using a punch, and this may be followed by peripheral iridectomy (although this is now less common). The scle­ ral flap then is resutured in the normal way for a trabeculectomy (see Chapter 10-30). Non-penetrating glaucoma surgery (deep sclerectomy +/− visco­ canaloplasty) can be combined with phaco. There are reports that these techniques are as effective as trabeculectomy when combined with phaco,8–10 but more longer-term studies are required before their true place in treatment of coexisting cataract and glaucoma can be determined.

COMPLICATIONS The surgical approaches described above demand careful resuture of the conjunctival flap to minimize the possibility of hypotony, and to minimize the risk of intraocular infection. Postoperatively, a visible bleb often is thought to be a sign of successful drainage, but in practice there seems to be little correlation between bleb presence and contin­ ued IOP control.11 Non-penetrating glaucoma surgery avoids the risks of hypotony and long-term bleb complications. The incidence of inflammatory response in anterior chamber, fibrinous uveitis, and other complications is reported to be higher with combined surgery than with single operations.12,13

OUTCOMES IOP reduction following combined surgery is greater than that follow­ ing cataract surgery alone, although not as great as following trab­ eculectomy alone.14 The addition of mitomycin C may result in a greater reduction in IOP (although possibly only in those at high risk of surgical failure).15

LENS SURGERY COMBINED WITH KERATOPLASTY

DSEK however is reasonably consistent, with a hyperopic shift of 0.75–1.5 D although this may be less with the use of Descemet mem­ brane epithelial keratoplasty (DMEK) where little or no stroma is transplanted.23

SPECIFIC TECHNIQUES

Anterior or posterior lamellar corneal surgery is now much more com­ mon than penetrating keratoplasty (PK). Eyes that require keratoplasty often have an associated increased risk of cataract due to the underlying pathology (Fig. 5-11-1); this includes corneal perforation as a result of trauma or infection. Also, age-related corneal degeneration, such as Fuchs’ corneal degeneration often coexists with age-related cataract. These factors resulted in the development of a variety of techniques for combined primary cataract surgery and keratoplasty (the ‘triple’ proce­ dure), or IOL exchange combined with keratoplasty. Combined cataract surgery and lamellar corneal surgery is often referred to as the ‘new triple procedure’.

The techniques of keratoplasty are dealt with elsewhere (Chapters 4-27 and 4-30). A significant recent trend is towards either anterior or pos­ terior lamellar keratoplasty, and there is significant benefit to the cata­ ract surgeon in these closed chamber techniques. The ongoing audit of keratoplasty conducted by the Corneal Graft Registry of NHS Blood and Tissue in the UK has shown that during 2010, 26% were deep posterior lamellar keratoplasties, 15% were deep anterior lamellar keratoplasty (DALK), and 56% were DSEK. Phaco surgery can be difficult because of the poor visibility as a result of the corneal disease. Selected cases with stromal opacity (Fig. 5-11-1) may be suitable for a routine phaco procedure after DALK and use of an ophthalmic viscosurgical device in the bed to restore anterior chamber and capsule visibility.24 In cases of endothelial disease where the stromal clarity is reasonable, a combined phaco with DSEK/DMEK is now the preferred technique (Fig. 5-11-2, Video 5-11-1). This offers much quicker visual rehabilitation and more predictable refractive out­ come than combined PK and phaco.25 Such an approach is not always possible, and ‘open-sky’ removal of the lens may be required. The altered anterior chamber and lens–iris diaphragm dynamics, abnormal light reflexes present in the open-sky situation (Fig. 5-11-3),26 and difficulty in controlling the anterior and posterior capsule results in an increased risk of surgical complications. Capsulorrhexis can be difficult because of decreased anterior pressure

SURGICAL OPTIONS A retrospective analysis of eyes that underwent PK for Fuchs’ endothe­ lial dystrophy, with an average follow-up period of 6 years,16 showed an incidence of significant cataract in 75% of patients over 60 years of age. In those who subsequently required lens surgery, 13% lost transplant clarity post-operatively. Two recent reports following Descemet strip­ ping endothelial keratoplasty (DSEK) showed the presence of cataract in 40% at 1 year in one study, and cataract extraction rate of 31% and 55% at years 1 and 3, respectively, in patients > 50 years old.17,18 Follow­ ing DSEK the endothelial cell loss rate can be as high as 56% in the first year,19 and there is, therefore, an argument for not subjecting such a cornea to further surgery when lens removal could be done as part of a combined procedure. There are some compelling arguments, therefore, for simultaneous lens and corneal surgery. Weighed against these are the problems associated with a combined approach, such as delayed visual rehabilitation especially after P-K; however, this is much less of a problem with DSEK. The decision in individual cases depends on the balance of the risks and benefits. One key decision for the clinician is whether it is possible to determine if the main barrier to good vision is cornea or lens. Another is the likelihood of development of frank decompensation if keratoplasty is not carried out. A combined approach may be the best choice in either circumstance. Choice of IOL depends on the individual circumstances. In the event that cataract surgery is part of the primary procedure, a standard IOL can be placed in the capsular bag. If an IOL is already present, and is considered either to be the cause of or to be exacerbating the corneal decompensation, then it should be replaced. If sufficient capsular and/ or zonular support exists, then the best option is a capsule or sulcusplaced posterior chamber IOL. If adequate support is not available, then the choice is a posterior chamber IOL, either transclerally sutured or iris sutured.20,21 Biometry and IOL power calculation is problematic if P-K or lamellar keratoplasty is combined with cataract surgery. The refractive impact of

Fig. 5-11-1  Patient with combined corneal and lens opacities. This degree of corneal opacity demands an open-sky approach to cataract removal.

Combined Procedures

HISTORICAL REVIEW

5.11

See clip: 5.11.01

Fig. 5-11-2  Appearance of an eye with previous Fuchs endothelial dystrophy and cataract several months after combined cataract surgery and DSEK. (Photograph courtesy of Mr Stephen Morgan FRCOphth)

Fig. 5-11-3  Abnormal reflexes make visualization of the posterior capsule difficult.

383

5 The Lens

caused by the open sky. Careful use of scissors can be of help. The nucleus is expressed manually after thorough hydrodissection. Manual irrigation–aspiration of the cortex is carried out using a cannula such as the Simcoe cannula. For surgery on an aphakic or pseudophakic patient, complete clear­ ance of any vitreous from the anterior chamber is mandatory. If a scleral-sutured IOL is to be fixed, then clearance of vitreous from the posterior chamber and from the region of the pars plana-vitreous base is required. As well as the problems of surgical visibility, an open-sky approach to vitrectomy leads to instability of the whole anterior seg­ ment, and use of a scleral support ring is helpful.

COMPLICATIONS Apart from the possible inherent complications of keratoplasty, the combined procedure offers an additional elevated risk of cystoid macu­ lar edema. Other complications of combined procedures are the variability of refractive outcome and the delayed visual rehabilitation compared to straightforward cataract surgery. Weighed against this, however, is the additional risk of graft failure inherent in the alternative of a two-stage procedure.

OUTCOMES The respective theoretical risks and benefits of a combined approach, a planned staged approach, and a keratoplasty wait-and-see approach have been discussed already. No definitive studies presently exist that provide hard evidence of the benefit of one approach over another.

COMBINED PHACOVITRECTOMY INTRODUCTION Cataract, both age-related and secondary, is present in many patients with vitreoretinal disorders. Cataract removal may be necessary to complete posterior segment surgery where cataract is obscuring the fundal view or it may be an integral part of a vitrectomy procedure, for example, in the case of a patient with a ruptured lens and a posterior segment intraocular foreign body (IOFB). Combined phaco with IOL implant and vitrectomy (phacovitrectomy) is now an estab­ lished technique to deal with concomitant cataract when vitrectomy is performed.

HISTORICAL REVIEW When pars plana vitrectomy was first introduced in the 1970s, the optimum way to remove associated cataracts was uncertain. However, it was the widespread acceptance of phaco in the late 1980s and 1990s that offered the possibility of efficient combined vitrectomy and cata­ ract surgery, with secure wound construction and stable intracapsular IOL fixation. Studies have shown that combined phacovitrectomy can be carried out with low morbidity and good results.27 As confidence with the technique has grown, indications for combined surgery have expanded.

INDICATIONS AND ADVANTAGES OVER NONCOMBINED SURGERY

384

When first introduced, phacovitrectomy was reserved for cases where cataract precluded an adequate fundal view during vitrectomy surgery. However, it is now being considered when lens opacities are mild or even nonexistent, particularly in patients over 50 years old.28 In these cases, cataract surgery is not necessary to successfully complete the vitrectomy but is done to avoid the need for subsequent cataract sur­ gery and hasten visual recovery. Vitrectomy surgery, particularly in the 50+ year age group, often results in the development of significant lens opacities, especially if long-acting gases are used, as in macular nuclear sclerotic hole surgery.29,30 The practice of what could be called optional phacovitrectomy in these situations offers a number of advantages over vitrectomy followed by subsequent cataract surgery in two steps. Only one operation is needed, and the surgical difficulties and morbidity associated with

cataract extraction following vitrectomy are avoided. These include small pupil size, deep anterior chamber with reverse pupil block, and increased mobility of the lens–iris diaphragm with an increased risk of posterior capsule tears. Combining phaco and vitrectomy also improves postoperative reti­ nal visualization, allowing accurate retinal assessment and treatment, and visual recovery is not delayed by subsequent cataract development. Phacovitrectomy allows more complete anterior vitrectomy and access to the anterior retina and vitreous base.

DISADVANTAGES The presence of macular hole and macular pucker are the commonest clinical scenarios where optional phacovitrectomy is considered, because of the high frequency of cataract formation after surgery for these conditions in the age group affected. However, not all patients are ideal candidates for phacovitrectomy in this situation. In some patients vitrectomy followed by sequential cataract surgery, if needed, is a better option. In diabetic patients, lens opacities following vitrectomy are paradoxically less common than in nondiabetic patients.31 Diabetic patients appear to have a higher incidence of posterior synechiae, pos­ terior capsule opacity, and inflammatory anterior uveitis following phacovitrectomy, especially if retinopathy is very active, a large amount of intraoperative laser is needed, or gas tamponade is used.32 Therefore, although phacovitrectomy is frequently carried out successfully in dia­ betic patients with significant lens opacities,33 such patients do not always form ideal optional phacovitrectomy candidates. The absence of accurate preoperative biometry secondary to vitreo­ retinal pathology with variable axial length measurements and fixation could also be regarded as a relative contraindication to optional nones­ sential phacovitrectomy. Fellow-eye measurements can be used but incorrect axial length estimations will result in IOL choice errors and potentially significant unplanned ametropia. Similarly, scleral buckling and silicone oil use alter the final refractive outcome in an unpredict­ able way. Phacovitrectomy in eyes with elevated maculae, such as occurs with epiretinal membrane and macular holes, has been reported to be associated with a myopic shift in the planned refraction. This is most likely to be related to measuring a short axial length preopera­ tively using ultrasound, but may also be related to gas-induced anterior chamber depth changes.34 The use of partial coherence interferometry (PCI) to measure axial length (which uses the retinal pigment epithe­ lium (RPE) reflection rather than the inner retinal surface) can over­ come some of these errors.35 However, if PCI is used in eyes with thickened maculas, the graph display should be inspected in certain situations. Because PCI uses the reflection from the RPE to assess axial length, a fixed constant is added to compensate for the normal inner retinal location. If the inner retinal reflectivity is high (e.g., with a dense epiretinal membrane) the device can occasionally inappropri­ ately interpret this reflective peak as the RPE. In this situation the graph cursor can be adjusted to the lower RPE peak manually. Details on adjustment and other potential errors in measurement can be found in manufacturers’ device manuals. If axial length is measured using ultrasound, aiming approximately 0.5  D hypermetropic or correcting for the preoperative macular thickening based on optical coherence tomography (OCT) measurements, can also reduce the effect.34,36

SPECIFIC TECHNIQUES Lens surgery can be carried out successfully via either a clear corneal or scleral tunnel incision. If a corneal incision is used, then the tun­ nel should be kept relatively short to avoid interference with the posterior segment view. Similarly, temporal incisions are less axial and less likely to interfere with the fundal view than superior ones. A suture can be used to secure the wound to avoid wound leak during scleral indentation. Posterior segment intraocular gas pressure can cause significant problems with phacovitrectomies. Anterior displacement of the optic of the IOL by posterior gas pressure can lead to optic capture by the iris. Similarly, displacement of the anterior capsule onto the iris can lead to postoperative posterior synechiae formation. There are a number of possible strategies to reduce the incidence of these problems. Sustained postoperative dilatation should be avoided, but some clinicians use short-acting mydriatics to discourage synechiae formation. Capsulor­ rhexis size should be large enough to avoid problems with rhexis

See clip: 5.11.02

CONCLUSION Phacovitrectomy is an effective technique to allow combined cataract extraction and vitrectomy. Its use is now being extended to patients with minimal lens opacities preoperatively undergoing, for example, macular hole surgery, to avoid delaying visual recovery secondary to postoperative cataract.

KEY REFERENCES Chaudhry NA, Cohen KA, Flynn Jr HW, et al. Combined pars plana vitrectomy and lens management in complex vitreoretinal disease. Semin Ophthalmol 2003;18:132–41. Cherfan GM, Michels RG, de Bustros S, et al. Nuclear sclerotic cataract after vitrectomy for idiopathic epiretinal membranes causing macular pucker. Am J Ophthalmol 1991;111:434–8. Friedman DS, Jampel HD, Lubomski LH, et al. Surgical strategies for coexisting glaucoma and cataract: an evidence-based update. Ophthalmology 2002;109:1902–13. Kovács I, Ferencz M, Nemes J, et al. Intraocular lens power calculation for combined cataract surgery, vitrectomy and peeling of epiretinal membranes for macular oedema. Acta Ophthalmol Scand 2007;85:88–91. Ling R, Simcock P, McCoombes J, et al. Presbyopic phacovitrectomy. Br J Ophthalmol 2003;87:1333–5. Lochhead J, Casson RJ, Salmon JF. Long term effect on intraocular pressure of phacotrabeculectomy compared to trabeculectomy. Br J Ophthalmol 2003;87:850–2. Manvikar SR, Allen D, Steel DH. Optical biometry in combined phacovitrectomy. J Cataract Refract Surg 2009;35:64–9.

5.11 Combined Procedures

phimosis, but should aim to just overlap the optic edges by 0.5 mm to hold the optic posteriorly. Capsulorrhexis can occasionally be difficult in eyes with vitreous hemorrhage and no red reflex. In these cases, capsule staining and use of the endoilluminator in the anterior cham­ ber can assist visualization. IOL optic diameter should be large to reduce the risk of optic capture. Lenses with broad haptic fixation offer advantages in avoiding optic capture and superior IOL centration. Intraocular lens insertion can be performed either before or after vitrectomy is completed. Peripheral vitreous base view can be impaired in pseudophakic eyes, and there is an argument for leaving IOL inser­ tion until after the posterior segment surgery is complete. Lenses with rounded, tapering, IOL edges and a gradual reduction in optic power offer advantages for ‘trans IOL’ vitrectomy by avoiding the occurrence of ‘jack-in-the-box’ prismatic effects when viewing the posterior seg­ ment through the edge of the IOL. Posterior capsule opacity appears to be more common after phacovitrectomy, and primary capsulectomy with the vitrectomy cutter can be performed avoiding another threat to delayed visual recovery.37 Acrylic folding IOLs have several advan­ tages over silicone with less IOL condensation during fluid–air exchange and also a reduced possibility of silicone oil adherence if oil is subsequently used.

Patel D, Rahman R, Kumarasamy M. Accuracy of intraocular lens power estimation in eyes having phacovitrectomy for macular holes. J Cataract Refract Surg 2007;33:1760–2. Payant JA, Gordon LW, VanderZwaag TO. Cataract formation following corneal transplantation in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9. Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology 2009;116:2361–8. Price MO, Price DA, Fairchild KM, et al. Rate and risk factors for cataract formation and extraction after Descemet stripping endothelial keratoplasty. Br J Ophthalmol 2010;94:1468–71. Siriwardena D, Kotecha A, Minassian D, et al. Anterior chamber flare after trabeculectomy and after phacoemulsification. Br J Ophthalmol 2000;84:1056–7. The AGIS Investigators. The Advanced Glaucoma Intervention Study, 8: Risk of cataract formation after trabeculectomy. Arch Ophthalmol 2001;119:1771–9.

Access the complete reference list online at

385

REFERENCES 1. Mitchell P, Cumming RG, Attebo K, et al. Prevalence of cataract in Australia: the Blue Mountains Eye Study. Ophthalmology 1997;104:581–8.

3. The AGIS Investigators. The Advanced Glaucoma Intervention Study, 8: Risk of cataract formation after trabeculectomy. Arch Ophthalmol 2001;119:1771–9. 4. Friedman DS, Jampel HD, Lubomski LH, et al. Surgical strategies for coexisting glaucoma and cataract: an evidence-based update. Ophthalmology 2002;109:1902–13. 5. Shingleton BJ, Jacobson LM, Kuperwaser MC. Comparison of combined cataract and glaucoma surgery using planned extracapsular and phacoemulsification techniques. Ophthalmic Surg Lasers 1995;26:414–9. 6. Wishart PK, Austin MW. Combined cataract extraction and trabeculectomy: phacoemulsification compared with extracapsular technique. Ophthalmic Surg 1993;24:814–21. 7. Siriwardena D, Kotecha A, Minassian D, et al. Anterior chamber flare after trabeculectomy and after phacoemulsification. Br J Ophthalmol 2000;84:1056–7. 8. Gimbel HV, Anderson Penno EE, Ferensowicz M. Combined cataract surgery, intraocular lens implantation and viscocanalostomy. J Cataract Refractive Surg 1999;25:1370–5. 9. Gianoli F, Schnyder CC, Bovey E, et al. Combined surgery for cataract and glaucoma: phacoemulsification and deep sclerectomy compared with phacoemulsification and trabeculectomy. J Cataract Refractive Surg 1999;25:340–6. 10. Carassa RG, Bettin P, Fiori M, et al. Viscocanalostomy versus trabeculectomy in white adults affected by open-angle glaucoma: a 2-year randomized, controlled trial. Ophthalmology 2003;110:882–7. 11. Simmons ST, Litoff D, Nichols DA, et al. Extracapsular cataract extraction and posterior chamber intraocular lens implantation combined with trabeculectomy in patients with glaucoma. Am J Ophthalmol 1987;104:465–70. 12. Naveh N, Kottass R, Glovinsky J, et al. Long term effects on intraocular pressure of a procedure combining trabeculectomy and cataract surgery as compared with trabeculectomy alone. Ophthalmic Surg 1990;21:339–45. 13. Siriwardena D, Kotecha A, Minassian D, et al. Anterior chamber flare after trabeculectomy and after phacoemulsification. Br J Ophthalmol 2000;84:1056–7. 14. Lochhead J, Casson RJ, Salmon JF. Long term effect on intraocular pressure of phacotrabeculectomy compared to trabeculectomy. Br J Ophthalmol 2003;87:850–2. 15. Shin DH, Ren J, Juzych MS, et al. Primary glaucoma triple procedure in patients with primary open-angle glaucoma: the effect of mitomycin C in patients with and without prognostic factors for filtration failure. Am J Ophthalmol 1998;125:346–52. 16. Payant JA, Gordon LW, VanderZwaag TO. Cataract formation following corneal transplantation in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9. 17. Tsui JY, Goins KM, Sutphin JE, et al. Phakic descemet stripping automated endothelial keratoplasty: prevalence and prognostic impact of postoperative cataracts. Cornea 2011;30:291–5. 18. Price MO, Price DA, Fairchild KM, et al. Rate and risk factors for cataract formation and extraction after Descemet stripping endothelial keratoplasty. Br J Ophthalmol 2010;94:1468–71.

20. Hardten DR, Holland EJ, Doughman DJ, et al. Early postkeratoplasty astigmatism following placement of anterior chamber lenses and transclerally sutured posterior chamber lenses. CLAO J 1992;18:108–11. 21. Michaeli A, Assia EI. Scleral and iris fixation of posterior chamber lenses in the absence of capsular support. Curr Opin Ophthalmol 2005;16:57–60. 22. Koenig SB, Covert DJ, Dupps Jr WJ, et al. Visual acuity, refractive error, and endothelial cell density six months after Descemet stripping and automated endothelial keratoplasty (DSAEK). Cornea 2007;26:670–4. 23. Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival Ophthalmology 2009;116:2361–8. 24. Ardjomand N, Fellner P, Moray M, et al. Lamellar corneal dissection for visualization of the anterior chamber before triple procedure. Eye 2007; 21: 1151-4. 25. Covert DJ, Koenig SB. New triple procedure: Descemet’s stripping and automated endothelial keratoplasty combined with phacoemulsification and intraocular lens implantation. Ophthalmology 2007;114:1272–7.

5.11 Combined Procedures

2. Chandrasekaran S, Cumming RG, Rochtchina E, et al. Associations between elevated intraocular pressure and glaucoma, use of glaucoma medications, and 5-year incident cataract: the Blue Mountains Eye Study. Ophthalmology 2006;113:417–24.

19. Dooren BT, Saelens IE, Bleyen I, et al. Endothelial cell decay after descemet’s stripping automated endothelial keratoplasty and top hat penetrating keratoplasty. Invest Ophthalmol Vis Sci 2011; 52:9226–31.

26. Groden LC. Continuous tear capsulotomy and phacoemulsification cataract extraction with penetrating keratoplasty. Refractive Corneal Surg 1990;6:458–9. 27. Chaudhry NA, Cohen KA, Flynn Jr HW, et al. Combined pars plana vitrectomy and lens management in complex vitreoretinal disease. Semin Ophthalmol 2003;18:132–41. 28. Ling R, Simcock P, McCoombes J, et al. Presbyopic phacovitrectomy. Br J Ophthalmol 2003;87:1333–5. 29. Cherfan GM, Michels RG, de Bustros S, et al. Nuclear sclerotic cataract after vitrectomy for idiopathic epiretinal membranes causing macular pucker. Am J Ophthalmol 1991;111:434–8. 30. Thompson JT. The role of patient age and intraocular gas use in cataract progression after vitrectomy for macular holes and epiretinal membranes. Am J Ophthalmol 2004;137:250–7. 31. Smiddy WE, Feuer W. Incidence of cataract extraction after diabetic vitrectomy. Retina 2004;24:574–81. 32. Shinoda K, O’Hira A, Ishida S, et al. Posterior synechia of the iris after combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation. Jpn J Ophthalmol 2001;45:276–80. 33. Lahey JM, Francis RR, Kearney JJ. Combining phacoemulsification with pars plana vitrectomy in patients with proliferative diabetic retinopathy: a series of 223 cases. Ophthalmology 2003;110:1335–9. 34. Patel D, Rahman R, Kumarasamy M. Accuracy of intraocular lens power estimation in eyes having phacovitrectomy for macular holes. J Cataract Refract Surg 2007;33:1760–2. 35. Manvikar SR, Allen D, Steel DH. Optical biometry in combined phacovitrectomy. J Cataract Refract Surg 2009;35:64–9. 36. Kovács I, Ferencz M, Nemes J, et al. Intraocular lens power calculation for combined cataract surgery, vitrectomy and peeling of epiretinal membranes for macular oedema. Acta Ophthalmol Scand 2007;85:88–91. 37. Jun Z, Pavlovic S, Jacobi KW. Results of combined vitreoretinal surgery and phacoemulsification with intraocular lens implantation. Clin Exp Ophthalmol 2001;29: 307–11.

385.e1

PART 5 THE LENS

Cataract Surgery in Complicated Eyes

5.12

Gary S. Schwartz, Stephen S. Lane

Key features ■ ■ ■

■

■

■

Pre-operatively, zonular integrity evaluated at the slit lamp by looking for the presence of phacodonesis or iridodonesis. Intraoperatively, a capsulorrhexis technique results in stronger capsular support during both nucleus and cortex removal. Intraoperatively, in the face of zonular laxity, a large capsulorrhexis (at least 5.5 mm in diameter) facilitates removal of nuclear fragments by minimizing zonular stress. Intraoperatively, the use of iris fixation hooks can stablilize areas of weakened zonules allowing for successful completion of the capsulorhexis. Intraoperative, zonular dehiscence may be managed by a polymethyl methacrylate capsular fixation segment or ring during cataract extraction alone or in combination with iris fixation hooks to stabilize the weakened areas. An intact anterior capsulorrhexis may provide adequate support for a posterior chamber intraocular lens even if there is some zonular laxity by prolapsing the optic through the anterior capsulorrhexis, capturing it in the capsular bed while the haptics are placed in the ciliary sulcus. ■ Pachymetry and specular microscopy should be performed as part of the pre-operative assessment on any patients with suspect cornea; a history of morning corneal edema predicts a poor prognosis for corneal clarity following even the most atraumatic cataract extraction procedure.

INTRODUCTION Modern cataract surgery can normally be performed with minimal anesthesia, manipulation of ocular tissue, and post-operative morbidity. Although most surgeons perform routine surgery using the same basic techniques from patient to patient, there are circumstances where the surgical technique must be altered because of a specific preoperative condition in that particular patient.

ZONULAR INSTABILITY

386

When cataract surgery and IOL placement are planned for a patient with a prior history of ocular trauma, surgery, pseudoexfoliation syndrome, or crystalline lens subluxation (e.g., Marfan’s syndrome), it is important for the surgeon to evaluate the status of the zonules. Zonular instability can not only make removal of the cataract more difficult, but it also increases the likelihood of IOL dislocation or decentration post-operatively.1,2 In these patients, zonular integrity should be evaluated preoperatively at the slit lamp by looking for the presence of phacodonesis or iridodonesis. If any question of loss of zonular integrity exists on the basis of slit-lamp evaluation, the zonules must be evaluated gonioscopically. If a patient has a history of ocular trauma, the eye should also be

examined for iridodialysis and vitreous in the anterior chamber, either of which makes zonular dehiscence more likely. During surgery, care must be taken to preserve as much of the remaining supporting zonules as possible. A large capsulorrhexis (at least 5.5 mm in diameter) is made to facilitate removal of nuclear fragments with minimal zonular stress. Careful and complete hydrodissection is carried out so that the nucleus rotates easily within the capsular bag, which decreases stress on the zonules during removal. If phacoemulsification (phaco) is to be carried out within the capsular bag, the main incision should be created in a position so that the phaco needle carves toward the area of the dehiscence whenever possible. In this way the lens nucleus is pushed toward the weakened area, which preserves the zonules, rather than pushed away from it, which may cause extension of the area of zonular dehiscence. If the surgeon feels that zonular support is not adequate for intracapsular manipulation, the nucleus may be subluxed from the capsular bag, and phaco can be performed within the anterior chamber. The surgeon may experience difficulty in performing capsulorrhexis in patients with significant zonular dehiscence because there are no zonules to offer resistance to the tearing forces applied by the surgeon’s instrument.3 A simple technique one can use to stabilize the capsular bag and facilitate completion of the capsulorrhexis utilizes capsular fixation hooks.4 If these are not available, nylon iris fixation hooks can be used in a similar manner. After starting the capsulorrhexis, the surgeon gently retracts the capsular edge with hooks in the direction of the area of dehiscence. After the capsulorrhexis is completed, the hooks can be left in place while hydrodissection and phaco are performed. Performing cataract extraction with a femtosecond laser may have considerable advantages in these patients. First, creation of the capsulorrhexis is not done by tearing, and, therefore, is not dependent upon counter-traction from healthy zonules. Second, much of the nuclear-fractis technique is made atraumatically by the laser, and therefore further zonular loss from the mechanical action of the phaco tip is avoided. Once the nucleus and epinucleus have been removed, cortical cleanup must be performed both delicately and completely. With the nucleus removed, the capsular bag is floppier in nature, and the area of the dehiscence may be drawn toward the aspiration tip. In such cases, it may give the surgeon more control to separate the irrigation and aspiration ports and perform bimanual irrigation-aspiration. In this way, the irrigation tip can be used to hold back the capsular fornix of the area of dehiscence while the aspiration tip safely removes cortex. After complete removal of the cataract, an appropriate IOL must be selected. Whenever possible, the IOL is placed within the capsular bag for reasons described above. Intracapsular IOL placement without a capsular tension segment or ring may be appropriate for patients who have up to 6 clock hours of zonular dehiscence. In such cases, a PCL with PMMA haptics should be placed so that one of the haptics is aimed toward the area of dehiscence, thus spreading the bag out in that direction (Fig. 5-12-1). If the haptics are rotated so that they are 90° away from the dehiscence, the optic is more likely to decenter in a direction away from the area of dehiscence. Zonular dehiscence can also be managed by a PMMA capsular fixation segment or ring during cataract extraction. Fixation segments and some fixation rings, such as the Cionni ring, have eyelets on them to allow fixation to the scleral wall with a prolene suture.5 These

INTRACAPSULAR POSTERIOR CHAMBER INTRAOCULAR LENS IMPLANT PLACEMENT WITH ZONULAR DEHISCENCE Correct placement

Incorrect placement

oval-shaped capsulorrhexis

equator of capsular bag

haptic posterior chamber intraocular lens

posterior chamber intraocular lens

zonules

equator of capsular bag

area of zonular dehiscence

haptic points away from area of zonular dehiscence area of zonular dehiscence

Cataract Surgery in Complicated Eyes

direction of decentering of posterior chamber intraocular lens

iris

zonules

5.12

capsulorrhexis

Fig. 5-12-1  Intracapsular posterior chamber intraocular lens implant placement with zonular dehiscence. The intraocular lens is first shown placed properly in the capsular bag with the haptics positioned toward the area of dehiscence. In this way, the bag is stretched toward the dehiscence and the optic does not decenter. Note that the capsulorrhexis is oval in shape because it has been pulled by the haptic in the direction of the dehiscence. The intraocular lens is then shown placed incorrectly in the bag with the haptics oriented 90° away from the dehiscence. A posterior chamber intraocular lens implant placed thus decenters away from the area of dehiscence in the direction of the arrow.

segments and rings are left in place after surgery and have been shown to help both expand and center the capsular bag post-operatively, thus keeping the lens implant from migrating away from areas of zonular dehiscence. If the capsular support is felt to be inadequate for intracapsular lens placement, an alternate technique should be performed (see Table 5-121). A sulcus-supported PCL can be placed so that the haptics are 90° away from the area of dehiscence (Fig. 5-12-2). This orientation prevents the haptic from slipping posteriorly into the vitreous chamber. If a continuous curvilinear capsulorrhexis has been performed, it may be advantageous to prolapse the optic into the capsular bag while the haptics are kept in the surgical sulcus. This technique often results in more stable optic centration in the presence of zonular dehiscence. If not enough capsule is present to support both haptics, a PCL may be sutured to the iris or held in place with a trans-scleral suture (Fig. 5-12-3).6 Since trans-scleral and iris fixation procedures are technically difficult to perform, the surgeon may opt for placement of an anterior chamber lens instead. Today’s anterior chamber lenses, with their onepiece, PMMA, flexible, open-loop configuration, have proved to be a safe alternative.

UVEITIS Cataract extraction with IOL insertion in uveitic patients is often made more difficult because of small pupils, posterior synechiae, and postoperative inflammation. If possible, a patient should not be operated upon until the uveitis has been quiescent for a number of months, or even a year. Even so, patients with a significant history of uveitis should receive oral prednisone 10 mg/kg daily for up to 1 week prior to surgery followed by a 2–3-week taper. In addition, select patients may benefit from intravenous methylprednisolone sodium succinate 125–250 mg during the surgery. Patients with chronic uveitis secondary to herpes simplex virus should be treated with peri-operative oral antivirals. Small incision phaco is the procedure of choice for patients who have a history of uveitis.7 The smaller incision results in less iris manipulation than does large-incision nuclear expression, and, therefore, usually results in less post-operative inflammation and faster healing. In addition, creating the wound in the avascular clear cornea

TABLE 5-12-1  OPTIONS FOR INTRAOCULAR LENS PLACEMENT AFTER CATARACT EXTRACTION Procedure

Position of optic

Position of haptics

Haptic fixation

Intracapsular posterior chamber intraocular lens implant Forward-prolapsed optic Sulcus-supported posterior chamber intraocular lens implant Optic bag–haptic sulcus Trans-sclerally sutured posterior chamber intraocular lens implant Iris-sutured posterior chamber intraocular lens implant Anterior chamber lens

Capsular bag

Capsular bag

Capsular bag fornices

Posterior chamber

Capsular bag

Posterior chamber

Ciliary sulcus

Capsular bag fornices Ciliary sulcus

Capsular bag

Ciliary sulcus

Ciliary sulcus

Posterior chamber

Ciliary sulcus

Trans-scleral sutures

Posterior chamber

Ciliary sulcus

Iris sutures

Anterior chamber

Anterior chamber

Aphakia

None

None

Anterior chamber angle None

The ‘forward-prolapsed optic’ and ‘optic bag–haptic sulcus’ techniques depend on an intact continuous curvilinear capsulorrhexis.

results in less inflammation than that through a scleral pocket incision because the limbal and conjunctival blood vessels are spared. Often, posterior synechialysis must be performed, which can be done with a cyclodialysis spatula or with viscodissection. The pupil may need to be enlarged by stretching it. The surgeon has the choice of stretching the pupil with two instruments usually found on the surgical tray (e.g., Beckert and chopper) or may use an instrument specifically designed for pupillary dilation (e.g., Beehler pupil dilator or Malyugin ring). After the cataract has been removed, the surgeon must address the question of which IOL to implant. Some forms of uveitis, such as pars

387

5

SULCUS PCL WITH ZONULAR DEHISCENCE

The Lens

capsulorrhexis is posterior to PCL optic equator of capsular bag posterior chamber intraocular lens haptic actually lies on top of the zonular ligaments

area of zonular dehiscence

zonules

Fig. 5-12-2  Sulcus PCL with zonular dehiscence. The IOL is properly placed in the ciliary sulcus. The haptics lie away from the area of the dehiscence and therefore are in the areas of greatest support. Placement here will decrease the likelihood that the haptics will prolapse backward into the vitreous cavity.

TRANS-SCLERALLY SUTURED POSTERIOR CHAMBER INTRAOCULAR LENS IMPLANT WITH NO ZONULAR SUPPORT

buried knot

eyelet on haptic

posterior chamber intraocular lens haptic with eyelet

peripheral iridectomy iris

iris with peripheral iridectomy

trans-scleral suture posterior chamber intraocular lens haptic with eyelet

posterior chamber intraocular lens

Fig. 5-12-3  Trans-sclerally sutured posterior chamber intraocular lens implant with no zonular support. The intraocular lens has no natural support from the lens capsule and zonules. This implant is a one-piece, polymethyl methacrylate intraocular lens held in place by two trans-scleral 10-0 prolene sutures tied to eyelets on the haptics. The knots are rotated to decrease the risk of long-term complications from knot erosion through the conjunctiva.

388

planitis, Fuchs’ heterochromic iridocyclitis, and human leukocyte antigen B27 (HLA-B27)-associated uveitis, tend to heal well with IOL placement after cataract extraction.8 In others, such as uveitis of VogtKoyanagi-Harada syndrome, sympathetic ophthalmia, and juvenile rheumatoid arthritis, the IOL may contribute to intraocular inflammation, and, therefore, it may be prudent to leave these patients aphakic.9,10 However, recent studies present the successful implantation of PCLs in patients who have cataract and a history of juvenile rheumatoid arthritis.11,12 In uveitic patients, it is best to avoid anterior chamber lenses, irissupported PCLs, and sulcus-supported PCLs, as they have a tendency to cause post-operative inflammation as a result of contact with the iris

and ciliary body. Whenever possible, a capsule-supported PCL is used. If capsular support is not present at the time of IOL implantation, a trans-sclerally sutured PCL may be used, or the patient may be left aphakic. In vitro and in vivo studies have demonstrated an advantage of heparin surface-modified polymethyl methacrylate (PMMA) lenses compared with regular PMMA lenses when looking at the adhesion of inflammatory cells.13 For this reason, heparin surface-modified PMMA lenses probably have an advantage over regular PMMA lenses in patients with a history of uveitis. However, because of the necessity for a larger incision when using PMMA lenses, it remains to be seen whether heparin surface-modified lenses have an advantage over

foldable silicone or acrylic IOLs when otherwise small-incision phaco is performed. If an IOL is to be placed in a patient who has a history of uveitis, an anterior chamber lens or a sulcus-supported posterior chamber lens should be avoided whenever possible, as increased contact with the iris and ciliary body may result in increased post-operative inflammation.

consent (including a discussion of the possibility of post cataract surgery corneal transplantation) is obtained prior to the procedure.

COMPROMISED ENDOTHELIUM

Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses. A historical and histopathological review. Surv Ophthalmol 1984;29:1–54.

KEY REFERENCES Ahmed IIK, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular tension ring. J Cataract Refract Surg 2001;27:977–81.

Fox GM, Flynn Jr HW, Davis JL, et al. Causes of reduced visual acuity on long-term follow-up after cataract extraction in patients with uveitis and juvenile rheumatoid arthritis. Am J Ophthalmol 1992;114:708–14. Hasanee K, Butler M, Ahmed IIK. Capsular tension rings and related devices. Curr Opin Ophthalmol 2006;17:31–41. Hooper PL, Rao NA, Smith RE. Cataract extraction in uveitis patients. Surv Ophthalmol 1990;35:120–44. Lane SS, Agapitos PJ, Lindquist TD. Secondary intraocular lens implantation. In: Lindquist TD, Lindstrom RL, editors. Ophthalmic surgery. St Louis, MI: Mosby; 1993. p. IG1–118. MacKool RL. Capsule stabilization for phacoemulsification. J Cataract Refract Surg 2000;26:629. Probst LE, Holland EJ. Intraocular lens implantation in patients with juvenile rheumatoid arthritis. Am J Ophthalmol 1996;122:161–70. Raizman MB. Cataract surgery in uveitis patients. In: Steinert RF, editor. Cataract surgery: technique, complications, and management. Philadelphia, PA: WB Saunders; 1995:243–6.

Cataract Surgery in Complicated Eyes

Some patients, specifically those with Fuchs’ endothelial dystrophy, have a compromised corneal endothelium at the time of cataract surgery. They may or may not have symptomatic corneal edema prior to surgery. Regardless, the trauma of intraocular surgery will lead to further endothelial cell loss, and can potentially cause prolonged, and even irreversible, corneal edema. Pachymetry and specular microscopy should be performed as part of the pre-operative assessment on any patients with suspected corneal edema. The surgeon should consider altering the surgical technique to diminish damage to the corneal endothelial cells. Rather than making the incision through temporal clear cornea, the surgeon may wish for a more posterior, scleral tunnel approach. A dispersive ophthalmic viscosurgical device (OVD) will be more protective to the corneal endothelium than a cohesive one, and the surgeon may wish to periodically refill the anterior chamber with OVD during the procedure. Phaco energy and time should be kept to a minimum, and nuclear fragments should be emulsified as posteriorly as possible with the tip of the phaco handpiece aimed away from the cornea. Post-operatively, patients with corneal edema may benefit from topical hyperosmotic agents. Despite all these steps, however, corneal decompensation may occur. It is critical that adequate informed

5.12

Smith SG, Lindstrom RL. Report and management of the sunrise syndrome. J Am Intraocul Implant Soc 1984;10:218–20. Terrada C, Julian K, Cassoux N, et al. Cataract surgery with primary intraocular lens implantation in children with uveitis: Long term outcomes. J Cataract Refract Surg 2011;37:1977–83. Tessler HH, Farber MD. Intraocular lens implantation versus no intraocular lens implantation in patients with chronic iridocyclitis and pars planitis. Ophthalmology 1993;110:1206–9. Ygge J, Wenzel M, Philipson B, et al. Cellular reactions on heparin surface-modified versus regular PMMA lenses during the first postoperative month. Ophthalmology 1990;97:1216–23.

Access the complete reference list online at

389

REFERENCES 1. Smith SG, Lindstrom RL. Report and management of the sunrise syndrome. J Am Intraocul Implant Soc 1984;10:218–20.

3. Ahmed IIK, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular tension ring. J Cataract Refract Surg 2001;27:977–81. 4. MacKool RL. Capsule stabilization for phacoemulsification. J Cataract Refract Surg 2000;26:629. 5. Hasanee K, Butler M, Ahmed IIK. Capsular tension rings and related devices. Curr Opin Ophthalmol 2006;17:31–41. 6. Lane SS, Agapitos PJ, Lindquist TD. Secondary intraocular lens implantation. In: Lindquist TD, Lindstrom RL, editors. Ophthalmic surgery. St Louis, MI: Mosby; 1993. p. IG1–118. 7. Raizman MB. Cataract surgery in uveitis patients. In: Steinert RF, editor. Cataract surgery: technique, complications, and management. Philadelphia, PA: WB Saunders; 1995. p. 243–6.

9. Hooper PL, Rao NA, Smith RE. Cataract extraction in uveitis patients. Surv Ophthalmol 1990;35:120–44. 10. Fox GM, Flynn Jr HW, Davis JL, et al. Causes of reduced visual acuity on long-term follow-up after cataract extraction in patients with uveitis and juvenile rheumatoid arthritis. Am J Ophthalmol 1992;114:708–14. 11. Probst LE, Holland EJ. Intraocular lens implantation in patients with juvenile rheumatoid arthritis. Am J Ophthalmol 1996;122:161–70. 12. Terrada C, Julian K, Cassoux N, et al. Cataract surgery with primary intraocular lens implantation in children with uveitis: Long term outcomes. J Cataract Refract Surg 2011;37:1977–83. 13. Ygge J, Wenzel M, Philipson B, et al. Cellular reactions on heparin surface-modified versus regular PMMA lenses during the first postoperative month. Ophthalmology 1990;97: 1216–23.

5.12 Cataract Surgery in Complicated Eyes

2. Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses. A historical and histopathological review. Surv Ophthalmol 1984;29:1–54.

8. Tessler HH. Farber MD. Intraocular lens implantation versus no intraocular lens implantation in patients with chronic iridocyclitis and pars planitis. Ophthalmology 1993;110:1206–9.

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PART 5 THE LENS

IN THIS CHAPTER Additional content available online at

Pediatric Cataract Surgery Elie Dahan†

Definition: Cataracts occurring in the pediatric age group, arbitrarily

defined as birth to adolescence.

Key features ■

Two main approaches are used to remove cataracts in children: pars plana and limbal. ■ Intraocular lenses, contact lenses, and spectacles, are the most readily available means to correct aphakia in children. ■ Posterior chamber intraocular lenses supplemented by spectacles are the best option for correction of aphakia in children, because most of the correction is permanently situated inside the eye globe.

INTRODUCTION Cataracts in childhood not only reduce vision but also interfere with normal visual development.1–3 The management of pediatric cataracts is far more complex than the management of cataracts in adults. The timing of surgery, the surgical technique, the choice of the aphakic correction, and the amblyopia management are of utmost importance in achieving good and long-lasting results in children.4–10 Children’s eyes are not only smaller than adults’ eyes, but their tissues are also much softer. The inflammatory response to surgical insult seems more pronounced in children, often because of iatrogenic damage to the iris.11 During the past two decades, the refinements that have occurred in adult cataract surgery have contributed to the further development of pediatric cataract surgery (PCS).2,4–8 Certain adaptations and modifications in surgical technique are required to achieve results similar to those achieved in adults.2–8 Furthermore, postoperative amblyopia management forms an integral part of visual rehabilitation in children.1–10

HISTORICAL REVIEW Discission of soft cataracts was first described by Aurelius Cornelius Celsius, a Roman physician who lived 2000 years ago. Because of its simplicity, discission remained the method of choice until the middle of the twentieth century. The technique consisted of lacerating the anterior capsule and exposing the lens material to the aqueous humor for resorption and/or secondary washout. Repeated discissions were often required to manage the inevitable secondary cataracts.2,11 Many early complications, e.g., plastic iritis, glaucoma, and retinal detachments were associated with these early techniques.2,11 With the advent of vitrectomy machines and viscoelastic substances, as well as the refinements in cataract surgery, these complications have been reduced markedly over the past two decades.2–11

PREOPERATIVE EVALUATION AND DIAGNOSTIC APPROACH 390

A careful history assists the clinician in selecting the investigations needed for determining the cataract’s etiology.2 Problems during

5.13

pregnancy (e.g., infections, rashes or febrile illnesses, exposures to drugs, toxins, or ionizing radiation) should be elicited. Family history of cataracts in childhood or other ocular abnormalities can be relevant. Both parents and all siblings should be examined with a slit lamp to determine any lens abnormalities. When family history is positive, consultation with a geneticist is recommended. A thorough examination by a pediatrician to assess the child’s general health and elicit information about other congenital abnormalities is mandatory. Laboratory tests in children who have bilateral cataracts in non­ hereditary cases are listed in Box 5-13-1. Most unilateral pediatric cataracts are idiopathic and do not warrant exhaustive laboratory tests. The ophthalmologic part of the evaluation starts with a complete ocular examination, which includes an assessment of visual acuity, pupillary response, and ocular motility. Biomicroscopy follows and might necessitate sedation or even general anesthesia in very young patients. Indirect fundus examination with dilated pupils is made unless the cataract is complete. A- and B-scan ultrasonography is carried out in both eyes to compare axial lengths and to discover any posterior segment abnormalities. Earlier photographs should be examined for the quality of the pupil’s red reflexes. This might help to date the onset of the cataracts.

ALTERNATIVES TO SURGERY The development of metabolic cataracts, such as those found in galactosemia, can be reversed if they are discovered in the early phases. With the elimination of galactose from the diet, the early changes in the lens, which resemble an oil droplet in the center of the lens, can be reversed.12 Later on, lamellar or total cataracts develop, which require surgery. When lens opacities are confined to the center of the anterior capsule or the anterior cortex, mild dilatation of the pupils with homatropine 2% twice daily can improve vision and postpone the need for surgery. Photophobia and partial loss of accommodation are side-effects of this measure. This temporary management should be implemented only in bilateral cataracts in which vision is equal in both eyes and better than 20/60.

ANESTHESIA General anesthesia is presently the only anesthetic option in PCS. It is extremely important to request deep anesthesia throughout the procedure in order to minimize iatrogenic damage to iris and cornea.5,7,8

BOX 5-13-1 LABORATORY TESTS FOR BILATERAL NONHEREDITARY PEDIATRIC CATARACTS Full blood count Random blood sugar Plasma calcium and phosphorus Urine assay for reducing substances after milk feeding Red blood cell transferase and galactokinase levels If Lowe’s syndrome is suspected, screening for amino acids in urine Toxoplasmosis titer Rubella titer Cytomegalovirus titer Herpes simplex titer

Children’s scleras and corneas are particularly soft, therefore, any tension on the extraocular muscles results in loss of anterior chamber depth and increased intraocular pressure. A useful marker for anesthesia depth is the position of the eye during surgery. If the cornea moves upwards, the anesthesia is too light and should be deepened. When this advice is followed, surgery is easier to perform and iatrogenic damage to the iris and cornea is diminished.

5.13 Pediatric Cataract Surgery

GENERAL TECHNIQUES Unlike in adults, pediatric cataracts are soft. Their lens material can be aspirated through incisions that are 1–1.5 mm long at the limbus or can be subjected to lensectomy through pars plana. When intraocular lens (IOL) implantation is intended, a larger limbal wound is needed to introduce the IOL. A scleral tunnel is safer than a clear corneal incision. Unlike in adults, the wound should be securely sutured to prevent wound dehiscence with iris incarceration – a common complication in children.2,4,5,7,8,10

SPECIFIC TECHNIQUES See clip: 5.13.01

Two main approaches exist for the removal of cataracts in children: the pars plana approach and the limbal approach. Both techniques have advantages and disadvantages. The pars plana approach was developed with the advent of vitrectomy machines in the late 1970s;13,14 it was intended to deal mainly with very young infants in whom surgery is more difficult. With the continuing refinements in cataract and implant surgery in adults, the pars plana approach is being abandoned gradually in favor of the limbal approach, because the latter allows better preservation of the capsular bag for in-the-bag IOL placement.2,5,7,8

Pars Plana Approach

The pars plana approach is indicated mainly for neonates and infants under 2 years of age, particularly for those who have bilateral congenital cataracts for whom immediate IOL implantation is not intended.2 The technique requires a guillotine-type vitrectome and balanced salt solution containing epinephrine (adrenaline) 1 : 500 000. The location of the pars plana in infants can be 1.5–3.5 mm from the limbus. In the last decade surgeons have largely abandoned the 20G vitrectomy apparatus in favor of the 23G or the 25G version. A lensectomy-anterior vitrectomy is completed, sparing a 2–3 mm peripheral rim of anterior and posterior capsule. These capsule remnants are used to create a shelf to support a posterior chamber IOL that may be implanted later on in life.15 It is important to avoid vitreous incarceration in the wounds by turning off the infusion before withdrawing the vitrectomy cutter from the eye. This precaution reduces the chances of suffering retinal traction and detachment later in life. This technique is rapid and allows a permanently clear visual axis. The postoperative course is normally less complicated than that after the limbal approach, because fewer maneuvers occur in the anterior chamber. Consequently, the iris and the corneal endothelium suffer less iatrogenic damage. In neonates who have bilateral cataracts, for whom the anesthetic risk is great, the two eyes can be operated on at the same sitting using different sets of instruments.2,6 Simultaneous surgery also reduces the risk of relative amblyopia, which can occur when two operations are undertaken a few days apart.2,6 A possible occurrence of the pars plana approach is the incarceration of vitreous in the scleral incisions. Subsequent vitreous traction may lead to retinal breaks and/or detachments.2,16 Another hindrance with the pars plana approach arises when the pupil is dilated insufficiently; the lensectomy has to be performed under partially ‘blind’ conditions, which means either leaving too much lens material in the periphery or too little peripheral capsular support for future posterior chamber IOL implantation.15

Limbal Approach

With the proper precautions, the limbal approach is the most versatile technique for PCS.2,4,5,7,8 Many surgeons have not yet recognized the importance of the anterior chamber maintainer (ACM) when operating on eyes in young patients. Although it is possible to use an aspirationirrigation device or a vitrectome with an irrigation sleeve in order to remove a soft cataract, the use of an ACM makes the surgery safer. Moreover, although viscoelastic materials maintain space, the ACM

Fig. 5-13-1  Anterior capsulectomy performed using a vitrectomy probe in a congenital cataract. Note the use of the anterior chamber maintainer for a deep anterior chamber and a well-dilated pupil.

provides, in addition, a steady intraoperative intraocular pressure (IOP) with continuous washout of blood, pigment, and prostaglandins that may be released during surgery. The ACM also helps to keep the pupil well dilated throughout the procedure because of the positive hydrostatic pressure. It prevents collapse of the globe when the instruments are withdrawn from the eye and thus helps to reduce damage to the iris and corneal endothelium. This feature of the ACM allows leaving a clear and ‘clean’ media with minimal occurrence of postoperative anterior chamber (A/C) fibrinous reaction. Two limbal incisions are made with a 20G stiletto knife; one for the ACM (connected to a balanced salt solution with epinephrine 1 : 500 000) and the other one for the aspiration cannula according to the surgeon’s preference positions. Various techniques have been described by which to open the anterior capsule.2,4,13,14 Capsulorrhexis can be carried out with the help of high-viscosity viscoelastics; however, the younger the child is, the more difficult it is to perform a capsulorrhexis. Infants have a very elastic anterior capsule, which easily tears toward the periphery. A practical alternative to manual capsulorrhexis is to use a vitrectomy probe to create a small central opening in the anterior capsule (Fig. 5-13-1). This initial hole can be enlarged gradually by ‘biting’ into the anterior capsule with the vitrectome until the desired 4–5 mm opening is achieved. The lens material can be aspirated manually or with an automatic aspiration device. Once the capsular bag is empty, the decision has to be made as to the management of the posterior capsule. Most surgeons agree that infants under 2 years of age should receive an elective posterior capsulectomy-anterior vitrectomy.2,4–8,13,14 Posterior capsulorrhexis can be carried out either manually or with the vitrectome, as described for the anterior capsule.2,4–8,13,14,17 The posterior capsulorrhexis diameter must be at least 4 mm. One third of the anterior vitreous must be removed to ensure a permanently clear visual axis (Fig. 5-13-2). Smaller posterior capsulectomies with shallow anterior vitrectomies tend to close down, especially in neonates.18 Posterior capsulectomy, either alone or when combined with a shallow anterior vitrectomy, does not guarantee a permanently clear visual axis, because vitreous remnants serve as a scaffold for the lens epithelium to grow on, which results in the formation of new opaque membranes. Furthermore, the immediate postoperative iritis seems markedly reduced when a generous anterior vitrectomy has been performed.2,4,5,7,8,14 Management

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5

BOX 5-13-2 GUIDELINES FOR THE CHOICE OF INTRAOCULAR LENS DIOPTRIC POWER

The Lens

Children Less Than 2 Years Old  Do biometry and undercorrect by 20%, or  Use axial length measurements only:  Axial length IOL dioptic power  17 mm, 25 D  18 mm, 24 D  19 mm, 23 D  20 mm, 21 D  21 mm, 19 D Children between 2 and 8 Years Old  Do biometry and undercorrect by 10%

to correct most, but not all, of the aphakia; the residual refractive error has to be corrected using spectacles, which can be adjusted throughout life. The implantation of anterior chamber IOLs in children was discontinued in the mid-1980s. Devastating complications, such as secondary glaucoma and corneal decompensation, were attributed to anterior chamber IOLs, especially in younger patients.19 Posterior chamber IOL implantation represents by far the better method for the correction of aphakia in adults, and the same applies in children. Fig. 5-13-2  Elective posterior capsulectomy and a deep anterior vitrectomy. This is performed using a vitrectomy probe, after all the lens material has been aspirated within the capsular bag.

of the posterior capsule in children older than 2 years remains controversial. Some authors prefer to leave it intact until opacification occurs; others perform an yttrium–aluminum–garnet (YAG) laser capsulectomy immediately after surgery. Experienced pediatric cataract surgeons choose to perform an elective posterior capsulectomy–anterior vitrectomy, routinely, in every child under 8 years of age in order to provide a one-stop treatment in this age group wherein amblyopia is still a risk. This alternative is logical when attentive follow-up is uncertain.4–10,13,14

CHOICE OF APHAKIC CORRECTION IN CHILDREN Spectacles, contact lenses, and IOLs are the most readily available means to correct aphakia in children.

Spectacles

Aphakic spectacles provide a satisfactory correction only in cases of bilateral aphakia in which anisometropia does not represent a problem.2 Most of these patients develop good visual acuity with spectacles, provided the eyes are not excessively microphthalmic.2 The disadvantages of spectacles are cosmetic blemish and the poor optical quality of high-plus lenses.

Contact Lenses

During the 1970s and 1980s, contact lenses were described as the method of choice to correct unilateral and bilateral aphakia in childhood.2,9,10 Contact lenses provide a better optical correction than spectacles, and their dioptric power can be adjusted throughout life. However, the management of contact lenses in children can be very difficult and costly. Frequent loss of lenses, recurrent infections, and poor follow-up turn this theoretically ideal choice into the most impractical option. Most ophthalmologists, therefore, now recommend the use of IOLs supplemented by spectacles in children rather than contact lenses.2,4,5,7,8,10,13

Intraocular Lenses

392

The IOL option was originally advocated in cases of unilateral pediatric cataracts because it facilitates amblyopia management by providing a more permanent correction.2,4,5,7,8,10,13 Implanting an IOL in a growing eye is not an ideal solution, but it is currently the most practical one. The aim in the IOL option, unlike in the contact lens alternative, is

Selection of intraocular lenses

The choice of the dioptric power of IOL to implant in young children is the main difficulty that faces the ophthalmologist.2 Pediatric IOLs are not yet readily available,20,21 and the rapid growth of the eye during the first 2 years of life makes an effective choice difficult.2,4,7,8,22–25 Nevertheless, in the 1990s increasingly positive reports were published on the use of posterior chamber IOLs in children and even in neonates. The material from which the IOL is made must have a long track record of safety. Polymethyl methacrylate (PMMA) IOLs have been in use for more than 50 years; PMMA is probably the safest material to be used for children, until a similar follow-up is obtained for other biomaterials.20 Nevertheless, during the last decade many surgeons have switched to the use of foldable hydrophilic and hydrophobic IOLs in children. The actual size of the capsular bag and the ciliary sulcus in children has been ascertained by the work of Bluestein and coworkers.21 Posterior chamber IOLs, which were originally oversized, have been reduced from 13–14 mm to 12–12.5 mm in diameter in most modern models. In children it is even more important to implant an IOL of the correct size.21 Oversized IOLs act like loaded springs in the eye and can dislocate, especially when a child rubs the pseudophakic eye causing damage to intraocular structures. Pediatric IOLs should not exceed 12 mm overall diameter because the average adult ciliary sulcus diameter rarely exceeds 11.5 mm. Ideally, the pediatric IOL should be available in diameters of the range 10.5–12 mm.21 The choice of IOL size is determined mainly by the site of implantation (i.e., in-the-bag or ciliary sulcus). Both the biometry and the age of the child determine the choice of the IOL dioptric power. Two main age groups exist in PCS: patients younger than 2 years and patients between 2 and 8 years. In the first group, the axial length and the keratometric (K) readings change rapidly, whereas in the second group the changes are slower and more moderate.22–25 In order to minimize the need to exchange IOLs later in life, when a large myopic shift occurs, it is advisable to undercorrect children with IOLs so that they can grow into emmetropia or mild myopia in adult life.22–25 Those who are under 2 years of age should receive 80% of the power needed for emmetropia at the time of surgery. Since the K readings also change rapidly during the first 18 months of life, it is practical to rely on the axial length only when the IOL dioptric power is chosen for infants (Box 5-13-2). The postoperative residual refractive error is corrected by spectacles, which can be adjusted at will as the child grows. Infants and toddlers can tolerate up to 6 D of anisometropia, which gradually disappears within 2–3 years.24 Most of the infants who have unilateral pseudophakia need a patch over the sound eye for half their waking hours until 4–5 years of age. Patches alleviate the symptoms of anisometropia but at the same time affect the chances for good binocularity to develop.26

LENS IMPLANTATION

5.13

The lens-in-the-bag implantation

Pediatric Cataract Surgery

A The bag-in-the-lens implantation

B Fig. 5-13-3  Schematic drawing of the lens-in-the-bag implantation (A) and the bag-in-the-lens implantation (B).

For the age range 2–8 years, the IOL dioptric power should be 90% of that needed for emmetropia at the time of surgery (see Box 5-13-2). The induced anisometropia is moderate and lessens with the expected myopic shift that occurs in adolescence.22–25 The need for spectacles after IOL implantation in PCS has some positive aspects:  More dependency on the ophthalmologist is needed because spectacles have to be taken care of, adjusted, and repaired periodically; this increases the chances of attentive follow-up.  The pseudophakic eye is protected from direct trauma by the spectacles.  Spectacles can be used as an adjunct to amblyopia therapy by atropine penalization of the sound eye and alteration of the dioptric power of its lens.

Implantation in children under 2 years of age

In unilateral cases, primary implantation is indicated as soon as the patient is fit for anesthesia, ideally between 2 and 3 months of age. The earlier the surgery is done, the better the chance that deep amblyopia can be overcome. After the cataract has been aspirated, an elective posterior capsulectomy–anterior vitrectomy is performed. The posterior chamber IOL is inserted through a scleral tunnel, which is prepared in advance. The surgeon has to choose between ciliary sulcus and the bag implantation according to his/her surgical experience. Sulcus implantation is easier and also allows an easier explantation in cases where IOL exchange will be needed later in life.24 This option is indicated in neonates and infants less than 1 year of age. The in-the-bag placement is more physiological, but more difficult technically. An in-the-bag IOL is more difficult to explant; this option should be chosen for infants above 1 year of age because they are less likely to need an IOL exchange, provided they are undercorrected by 20%.27

Implantation in children above 2 years of age

For children older than 2 years, the IOL should be inserted in the bag because the eye has reached nearly the adult size, although its sclera is much softer. Gimbel17 has described a special IOL implantation for this group of patients. The technique requires extreme dexterity as both anterior and posterior capsulorrhexises are performed. The IOL haptics are placed in the bag fornices, while the optic is protruded through both capsulorrhexises to be captured beneath the posterior capsule remnants. Tassignon has recently developed a new technique for a special IOL called bag-in-the-lens.20 The technique consists of creating an anterior and posterior capsulorrhexis. The specially designed IOL has, at its periphery, a groove that contains both anterior and posterior capsule rims (Fig. 5-13-3). Although technically demanding, promising early results indicate that this technique might do away with the need for elective anterior vitrectomy (Fig. 5-13-4).19

Postoperative treatment

Topical medications are sufficient when surgery has not been excessively traumatic. A combination of antibiotic–corticosteroid drops every 2 hours with a mild mydriatic agent twice daily is given for the first week. Thereafter, the medications are tapered off during the next

Fig. 5-13-4  Bag-in-the-lens IOL implanted in a 5-year-old child at 41 months follow-up. Note the perfectly clear visual axis and the capsular rims contained in the IOL peripheral groove. (Reproduced with permission of MJ Tassignon.)

3 weeks. Some authors have used systemic corticosteroids to overcome the intense inflammatory response in young children’s eyes.

COMPLICATIONS Intraoperative complications are usually related to the surgeon’s un­ familiarity with the child’s soft ocular tissues. The anterior chamber tends to collapse, the iris can protrude through the surgical wounds, and the pupil constricts on injury to the iris. These events can be avoided by operating under deep anesthesia and by using an ACM. Immediate postoperative complications include anterior plastic uveitis, high IOP, incarceration of iris tissue in the wound, and endophthalmitis. Atraumatic surgery, use of an ACM during surgery, thorough removal of viscoelastics at completion of surgery, and meticulous closure of the wound reduce the occurrence of these complications. Late complications include dislocation of the IOL, chronic iritis, glaucoma, and retinal detachment. Close follow-up enables detection of these complications at an early stage. Their treatment is similar to that for the same occurrences in adults.

Amblyopia Management

The child’s parents must understand that visual rehabilitation only starts with surgery and must be continued throughout childhood. The unilateral cases are the most difficult to manage.2,4,5,7–10 Amblyopia treatment starts soon after surgery, after postoperative inflammation subsides and the media becomes clear. The initial treatment must be aggressive in order to boost vision in the deprived eye. Full-time occlusion of the sound eye is carried out for a few days – 1 day per month of age. For example, a 3-month-old neonate should be subjected to occlusion for 3 consecutive days, a 4-month-old infant for 4 days, etc. Thereafter, occlusion is reduced to half the waking hours. The younger the infant, the easier it is to comply with the patch regimen. Autorefractometers, especially portable ones, help to determine the residual refractive error; retinoscopy is often difficult in pseudophakic children. Spectacles are prescribed from the age of 4 months onward. A bifocal lens with an add of +3.00 is prescribed in the pseudophakic eye from the age of 3 years, when the child becomes verbal. Unilateral pseudophakes should continue with half-day patches until 4–5 years of age. Thereafter, the patch time can be reduced gradually, but should not be abandoned until 10–12 years of age. After that age, amblyopia management is practically superfluous. Cases of bilateral pseudophakia should be followed closely to detect and treat relative amblyopia.

Intraocular Lens Exchange and Alternative Options

Exchange of IOLs should be considered when a great myopic shift has occurred.22–25 When the pseudophakic eye becomes 7 D more myopic

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5 The Lens

than the sound eye, the IOL should be exchanged, unless contact lens wear is a viable option. Refractive surgery in children is not yet an acceptable option. An experienced anterior segment surgeon who is familiar with IOL exchange should perform the procedure. An alternative to IOL exchange is to implant, preferably in the posterior chamber, an additional negative dioptric power IOL to correct the myopia. This procedure is easily performed when the primary IOL was inserted in the bag.

OUTCOME The visual outcome depends largely on the type of cataract the laterality of the pathology, the timing of intervention, the quality of surgery, and, above all, the amblyopia management. It is possible to achieve nearly normal vision even in unilateral congenital cataracts, provided amblyopia management is aggressive.2–10,24 Binocularity is usually poor in these cases, but some gross stereopsis can be expected.26 Aphakic and pseudophakic children certainly should be followed-up throughout childhood and preferably throughout life.28

KEY REFERENCES Ahmadieh H, Javadi MA, Ahmadi M, et al. Primary capsulectomy, anterior vitrectomy, lensectomy, and posterior chamber lens implantation in children: limbal versus pars plana. J Cataract Refract Surg 1999;25:768–75. Asrani S, Freedman S, Hasselblad V, et al. Does primary intraocular lens implantation prevent ‘aphakic’ glaucoma in children? J AAPOS 2000;4:33–9. Review.

Access the complete reference list online at

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BenEzra D, Cohen E, Rose L. Traumatic cataract in children: correction of aphakia by contact lens or by intraocular lens. Am J Ophthalmol 1997;123:773–82. Dahan E. Lens implantation in microphthalmic eyes of infants. Eur J Implant Refract Surg 1989;1:1–9. Dahan E, Drusedau MUH. Choice of lens and dioptric power in pediatric pseudophakia. J Cataract Refract Surg 1997;23:1–6. Dahan E, Salmenson BD. Pseudophakia in children: precautions, techniques and feasibility. J Cataract Refract Surg 1990;16:75–82. Dahan E, Salmenson BD, Levin J. Ciliary sulcus reconstruction for posterior implantation in the absence of an intact posterior capsule. Ophthalmic Surg 1989;20:776–80. Dahan E, Welsh NH, Salmenson BD. Posterior chamber implants in unilateral congenital and developmental cataracts. Eur J Implant Refract Surg 1990;2:295–302. Gimbel HV, Debroff BM. Posterior capsulorrhexis with optic capture: maintaining a clear visual axis after pediatric cataract surgery. J Cataract Refractive Surg 1994;20:658–64. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol 1985;103:785–9. Koch DD, Kohnen T. Retrospective comparison of techniques to prevent secondary cataract formation after posterior chamber intraocular lens implantation in infants and children. J Cataract Refract Surg 1997;23:657–63. Lambert SR, Drake AV. Infantile cataracts. Surv Ophthalmol 1996;40:427–58. Rabin J, Van Sluyters RC, Malach R. Emmetropization: A vision dependent phenomenon. Invest Ophthalmol Vis Sci 1981;20:561–4. Tassignon MJ, De Veuster I, Godts D, et al. Bag-in-the-lens intraocular lens implantation in the pediatric eye. J Cataract Refract Surg 2007;33:611–7. Wilson ME, Apple DJ, Bluestein EC, et al. Intraocular lenses for pediatric implantation: biomaterials, designs and sizing. J Cataract Refract Surg 1994;20:584–91.

REFERENCES 1. Elston JS, Timms C. Clinical evidence for the onset of the sensitive period in infancy. Br J Ophthalmol 1992;76:327–8. 3. Birch EE, Stager DR, Leffler J, et al. Early treatment of congenital cataract minimizes unequal competition. Invest Ophthalmol Vis Sci 1998;39:1560–6. 4. Ben-Ezra D, Paez JH. Congenital cataract and intraocular lenses. Am J Ophthalmol 1983;96:311–4. 5. Dahan E. Lens implantation in microphthalmic eyes of infants. Eur J Implant Refract Surg 1989;1:1–9. 6. Guo S, Nelson LB, Calhoun J, et al. Simultaneous surgery for bilateral congenital cataracts. J Pediatr Ophthalmol Strabismus 1990;27:23–5. 7. Dahan E, Salmenson BD. Pseudophakia in children: Precautions, techniques and feasibility. J Cataract Refract Surg 1990;16:75–82. 8. Dahan E, Welsh NH, Salmenson BD. Posterior chamber implants in unilateral congenital and developmental cataracts. Eur J Implant Refract Surg 1990;2:295–302. 9. Neumman D, Weissman BA, Isenberg SJ, et al. The effectiveness of daily wear contact lenses for the correction of infantile aphakia. Arch Ophthalmol 1993;111:927–30. 10. BenEzra D, Cohen E, Rose L. Traumatic cataract in children: correction of aphakia by contact lens or by intraocular lens. Am J Ophthalmol 1997;123:773–82. 11. Asrani S, Freedman S, Hasselblad V, et al. Does primary intraocular lens implantation prevent ‘aphakic’ glaucoma in children? J AAPOS 2000;4:33–9. Review. 12. Burke JP, O’Keefe M, Bowell R, et al. Ophthalmic findings in classical galactosemia – a screened population. J Pediatr Opthalmol Strabismus 1989;26:165–8. 13. Ahmadieh H, Javadi MA, Ahmadi M, et al. Primary capsulectomy, anterior vitrectomy, lensectomy, and posterior chamber lens implantation in children: limbal versus pars plana. J Cataract Refract Surg 1999;25:768–75. 14. Koch DD, Kohnen T. Retrospective comparison of techniques to prevent secondary cataract formation after posterior chamber intraocular lens implantation in infants and children. J Cataract Refract Surg 1997;23:657–63.

16. McLeod D. Congenital cataract surgeries: A retinal surgeon’s viewpoint. Aust NZ J Ophthalmol 1986;14:79–84. 17. Gimbel HV, Debroff BM. Posterior capsulorrhexis with optic capture: Maintaining a clear visual axis after pediatric cataract surgery. J Cataract Refractive Surg 1994;20:658–64. 18. Morgan KS, Karcioglu ZA. Secondary cataracts in infants after lensectomies. J Pediatr Ophthalmol Strabismus 1987;24:45–8. 19. Tassignon MJ, De Veuster I, Godts D, et al. Bag-in-the-lens intraocular lens implantation in the pediatric eye. J Cataract Refract Surg 2007;33(4):611–7. 20. Wilson ME, Apple DJ, Bluestein EC, et al. Intraocular lenses for pediatric implantation: Biomaterials, designs and sizing. J Cataract Refract Surg 1994;20:584–91. 21. Bluestein EC, Wilson ME, Wang XH, et al. Dimensions of the pediatric crystalline lens: implications for intraocular lenses in children. J Pediatr Ophthalmol Strabismus 1996;33: 18–20. 22. McClatchey SK, Dahan E, Maselli E, et al. A comparison of the rate of refractive growth in pediatric aphakia and psudophakia eys. Ophthalmology 2000;107:118–22. 23. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol 1985;103:785–9.

5.13 Pediatric Cataract Surgery

2. Lambert SR, Drake AV. Infantile cataracts. Surv Ophthalmol 1996;40:427–58.

15. Dahan E, Salmenson BD, Levin J. Ciliary sulcus reconstruction for posterior implantation in the absence of an intact posterior capsule. Ophthalmic Surg 1989;20:776–80.

24. Dahan E, Drusedau MUH. Choice of lens and dioptric power in pediatric pseudophakia. J Cataract Refract Surg 1997;23:1–6. 25. Flitcroft DI, Knight-Nanan D, Bowell R, et al. Intraocular lenses in children: changes in axial length, corneal curvature, and refraction. Br J Ophthalmol 1999;83:265–9. 26. Tytla ME, Lewis TL, Maurer D, et al. Stereopsis after congenital cataract. Invest Ophthalmol Vis Sci 1993;34:1767–72. 27. Dahan E. Insertion of intraocular lenses in the capsular bag. Metab Pediatr Syst Ophthalmol 1987;10:87–8. 28. Rabin J, Van Sluyters RC, Malach R. Emmetropization: A vision dependent phenomenon. Invest Ophthalmol Vis Sci 1981;20:561–4.

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IN THIS CHAPTER Additional content available online at

Complications of Cataract Surgery Thomas Kohnen, Marko Ostovic, Li Wang, Neil J. Friedman, Douglas D. Koch

Definition: All unwanted events during or after cataract surgery with

potential threat to the normal structure and/or function of the eye.

5.14

operative inflammation and pain, increased post-operative watertightness, and reduced surgically induced astigmatism.2

Tunnel Perforation Key features ■

Intra-operative complications depending on incision, perforation, detachment of structures, burns, anterior capsule, posterior capsule, zonulae, capsulorrhexis, iris problems, subluxation, sulcus structure, hemorrhage ■ Post-operative complications depending on wound characteristics, epithelial characteristics, corneal irregularities and problems, intraocular hemorrhage, glaucoma, problems with architecture of the implanted IOL, problems with the retina, dislocation of the lens

Associated feature ■

Understanding the mechanism of several complications in cataract surgery and performing the correct steps to minimize further unwanted negative results.

INTRODUCTION Phacoemulsification (phaco), sutureless, self-sealing tunnel incisions, and foldable intraocular lenses (IOLs) have changed cataract surgery dramatically over the past two decades. Post-operative astigmatism and inflammation are typically minimal; visual recovery and patients’ rehabilitation are accelerated. The published literature indicates that modern cataract surgery, though certainly not free of complications, is a remarkably safe procedure, regardless of which extraction technique is used.1 Using rigid criteria for scientific validity, Powe and colleagues1 analyzed 90 studies published between 1979 and 1991 that addressed visual acuity (n = 17 390 eyes) or complications (n = 68 316 eyes) following standard nuclear expression cataract extraction with posterior chamber IOL implantation, phaco with posterior chamber IOL implantation, or intracapsular cataract extraction with anterior chamber IOL implantation. Strikingly, the percentage of eyes with post-operative visual acuity of 20/40 or better was 89.7% for all eyes and 95.5% for eyes with no pre-existing ocular comorbidity. The incidence of sightthreatening complications was less than 2%. In this chapter, the key elements in the prevention, recognition, and management of the major intra-operative and post-operative complications of cataract surgery are discussed.

INTRA-OPERATIVE COMPLICATIONS Cataract Incision

The cataract incision serves as more than just the port of access to the anterior segment; it is a critical step of the operation that affects ocular integrity and corneal stability. The traditional limbal or posterior limbal incision has been largely replaced by tunnel constructions, which can be located in the sclera, limbus, or cornea and are characterized by their greater radial length and an anterior entry into the anterior chamber to create the self-sealing internal corneal valve. Advantages of tunnel incisions are increased intra-operative safety, decreased post-

Tearing of the roof of the tunnel predisposes to excessive intra-operative leakage, which compromises anterior chamber stability, and to postoperative wound leakage. If the tear occurs at either edge of the roof, surgery usually can be completed using the initial incision, proceeding slowly and observing the wound carefully as instruments are introduced or manipulated in the eye. It usually is preferable to suture the incision at the conclusion of surgery, even if the wound is watertight, to restore a more normal architecture and prevent external wound gape. If, however, the roof is perforated in the center of the flap and this is noted before the anterior chamber is entered, creation of a new incision should be considered. If the cut is extremely small (e.g.,  85 years) also benefit from cataract surgery.38,39 The positive impact of cataract surgery on patients’ self-assessed visual function seems to be long lasting, provided that no other ocular disease appears in the operated eye.40 Poor self-assessed visual function after cataract surgery may be caused by an ocular comorbidity, a disturbing cataract in the fellow eye, or anisometropia.41 Several factors are related to better subjective visual outcome. These include younger age, low pre-operative visual acuity, high post-operative visual acuity, secondeye surgery and no ocular comorbidity.42

CATARACT SURGERY OF ONE OR BOTH EYES Patients with bilateral cataract benefit from bilateral cataract extraction. Studies have shown that second-eye cataract surgery adds

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health-related quality of life for such patients.43,44 A remaining cataract in the fellow eye after first-eye surgery may have a poor effect on binocular vision.30,41 A bilateral cataract extraction can be performed sequentially with a varying interval between the two surgeries, so that some patients receive immediately sequential cataract surgery (ISCS), while others have delayed sequential cataract surgery (DSCS) with an interval between the surgeries of weeks or months. However, same-day bilateral cataract surgery requires a strict set of operating rules whereby each eye is treated as an entirely new operative procedure to avoid any possibility of cross contamination. Rapid rehabilitation of the patient is a worthy goal and a more economic process for all concerned.45

CATARACT SURGERY IN EYES WITH OCULAR COMORBIDITY In routine cataract surgery, a substantial number of patients have coexisting eye diseases. A sight-threatening ocular comorbidity is the most frequent reason for a poor outcome after cataract surgery.21,41,46–49 However, this does not mean that cataract extraction is unnecessary when there is an ocular comorbidity. Studies have shown that many patients with age-related macular degeneration and cataract benefit from cataract extraction.50,51

SUMMARY All clinicians realize that good history taking, a thorough examination, and quantification of the five areas that describe functional vision are all important in the determination of indications for surgery and outcome of surgery. Furthermore, it is extremely important to evaluate the indications for, and outcomes of, cataract surgery with respect to health-related quality of life. This is in the interests of patients, but it should also be done because of the significant costs to health-care linked to this procedure.

Access the complete reference list online at

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KEY REFERENCES Behndig A, Montan P, Stenevi U, et al. One million cataract surgeries. The Swedish National Cataract Register 1992–2009. J Cataract Refract Surg 2011;37:1539–45. Cataract Management Guideline Panel. Cataract in adults: management of functional impairment. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1993 (AHCPR pub. No. 93–0542; Clinical practice guideline No. 4). Hahn U, Krummenauer F, Kölbl B, et al. Determination of valid benchmarks for outcome indicators in cataract surgery. A multicenter, prospective cohort trial. Ophthalmology 2011;118:2105–12. Hard AL, Beckman C, Sjostrand J. Glare measurements before and after cataract surgery. Acta Ophthalmol Scand 1993;71:471–6. Holladay JT, Prager TC, Ruiz RS, et al. Improving the predictability of intraocular lens calculations. Arch Ophthalmol 1986;104:539–41. Koch DD. Glare and contrast sensitivity testing in cataract patients. J Cataract Refract Surg 1989;15:158–64. Laidlaw DA, Harrad RA, Hopper CD, et al. Randomised trial of effectiveness of second eye cataract surgery. Lancet 1998;352:925–9. Leivo T, Sarikkola AU, Uusitalo RJ, et al. Simultaneous bilateral cataract surgery: economic analysis; Helsinki Simultaneous Bilateral Cataract Surgery Study Report 2. J Cataract Refract Surg 2011;37:1003–8. Lundström M, Wendel E. Duration of self-assessed benefit of cataract extraction – a long-term study. Br J Ophthalmol 2005;89:1017–20. Lundström M, Barry P, Henry Y, et al. Evidence-based guidelines for cataract surgery: Guidelines based on data in the European Registry of Quality Outcomes for Cataract and Refractive Surgery database. J Cataract Refract Surg 2012;38:1086–93. Masket S. Reversal of glare disability after cataract surgery. J Cataract Refract Surg 1989;15:165–8. McAlinden C, Gothwal VK, Khadka J, et al. Head-to-Head comparison of 16 cataract surgery outcome questionnaires. Ophthalmology 2011;118:2374–81. National Research Council Committee on Vision. Recommended standards for the clinical measurement and specification of visual acuity. Adv Ophthalmol 1980;41:103–48. Osher RH, Barros MG, Marques DMV, et al. Early uncorrected visual acuity as a measurement of the visual outcomes of contemporary cataract surgery. J Cataract Refract Surg 2004;30:1917–20. Rönbeck M, Lundström M, Kugelberg M. Study of possible predictors associated with selfassessed visual function after cataract surgery: a Swedish National Cataract Register Study. Ophthalmology 2011;118:1732–8.

REFERENCES

2. National Research Council Committee on Vision. Recommended standards for the clinical measurement and specification of visual acuity. Adv Ophthalmol 1980;41:103–48. 3. Lundström M, Barry P, Leite H, et al. The 1998 European Cataract Outcome Study. Report from the European Cataract Outcome Study. J Cataract Refract Surg 2001;27:1176–8118884. 4. Lundström M, Barry P, Henry Y, et al. Evidence-based guidelines for cataract surgery: Guidelines based on data in the European Registry of Quality Outcomes for Cataract and Refractive Surgery database. J Cataract Refract Surg 2012;38:1086–93.

28. Pfoff DS, Werner JS. Effect of cataract surgery on contrast sensitivity and glare in patients with 20/50 or better Snellen acuity. J Cataract Refract Surg 1994;20:620–5. 29. Hard AL, Beckman C, Sjostrand J. Glare measurements before and after cataract surgery. Acta Ophthalmol Scand 1993;71:471–6. 30. Lundström M, Albrecht S, Nilsson M, et al. Patients benefit from bilateral same-day cataract extraction – a randomized clinical study. J Cataract Refract Surg 2006;32:826–30. 31. Sunderraj P, Villada JR, Joyce PW, et al. Glare testing in pseudophakes with posterior capsule opacification. Eye 1992;6:411–3.

5. Williamson TH, Strong NP, Sparrow J, et al. Contrast sensitivity and glare in cataract using the Pelli-Robson chart. Br J Ophthalmol 1992;76:719–22.

32. Masket S. Relationship between post-operative pupil size and disability glare. J Cataract Refract Surg 1992;18:506–7.

6. Levin ML. Opalescent nuclear cataract. J Cataract Refract Surg 1989;15:576–9.

33. Masket S. Reversal of glare disability after cataract surgery. J Cataract Refract Surg 1989;15:165–8.

7. Koch DD. Glare and contrast sensitivity testing in cataract patients. J Cataract Refract Surg 1989;15:158–64. 8. Barrett BT, Davison PA, Eustace PE. Effects of posterior segment disorders on oscillatory displacement thresholds, and on acuities as measured using the potential acuity meter and laser interferometer. Ophthalmic Physiol Opt 1994;14:132–8. 9. Alio JL, Artola A, Ruiz-Moreno JM, et al. Accuracy of the potential acuity meter in predicting the visual outcome in cases of cataract associated with macular degeneration. Eur J Ophthalmol 1993;3:189–92.

34. Hirsch RP, Nadler MP, Miller D. Clinical performance of a disability glare tester. Arch Ophthalmol 1984;102:1633–6. 35. McAlinden C, Gothwal VK, Khadka J, et al. A Head-to-Head comparison of 16 cataract surgery outcome questionnaires. Ophthalmology 2011;118:2374–81. 36. Lundström M, Pesudovs K. Catquest-9SF patient outcomes questionnaire. Nine item shortform Rasch-scaled revision of the Catquest questionnaire. J Cataract Refract Surg 2009;35:504–13.

10. Frisen L. High-pass resolution perimetry and age-related loss of visual pathway neurons. Acta Ophthalmol 1991;69:511–5.

37. Lundström M, Behndig A, Kugelberg M, et al. The outcome of cataract surgery measured with the Catquest-9SF. Acta Ophthalmol 2011;89:718–23.

11. Ball KK, Beard BL, Roenker DL, et al. Age and visual research: expanding the useful field of view. J Optom Soc Am Assoc 1988;5:2210–9.

38. Lundström M, Stenevi U, Thorburn W. Cataract surgery in the very elderly. J Cataract Refractive Surg 2000;26:408–14.

12. Cooper BA, Ward M, Gowland CA, et al. The use of the Lanthony New Color Test in determining the effects of aging on color vision. J Gerontol 1991;46:320–4.

39. Mönestam E, Wachmeister L. Impact of cataract surgery on the visual ability of the very old. Am J Ophthalmol 2004;137:145–55.

13. Hahn U, Krummenauer F, Kölbl B, et al. Determination of valid benchmarks for outcome indicators in cataract surgery. A multicenter, prospective cohort trial. Ophthalmology 2011;118:2105–12.

40. Lundström M, Wendel E. Duration of self-assessed benefit of cataract extraction – a longterm study. Br J Ophthalmol 2005;89:1017–20.

14. Holladay JT. A prospective, randomized, double-masked comparison of a zonal-progressive multifocal IOL. A discussion. Ophthalmology 1992;99:860.

41. Lundström M, Brege KG, Florén I, et al. Impaired visual function following cataract surgery. An analysis of poor outcomes as defined by the Catquest questionnaire. J Cataract Refractive Surg 2000;26:101–8.

15. Steinert RF, Post CT Jr, Brint SF, et al. A prospective, randomized, double-masked comparison of a zonal-progressive multifocal intraocular lens and a monofocal intraocular lens. Ophthalmology 1992;99:853–60.

42. Rönbeck M, Lundström M, Kugelberg M. Study of possible predictors associated with selfassessed visual function after cataract surgery: A Swedish National Cataract Register Study. Ophthalmology 2011;118:1732–8.

16. Lindstrom RL. Food and Drug Administration update. One-year results from 671 patients with the 3M multifocal intraocular lens. Ophthalmology 1993;100:91–7.

43. Laidlaw DA, Harrad RA, Hopper CD, et al. Randomised trial of effectiveness of second eye cataract surgery. Lancet 1998;352:925–9.

17. Javitt JC, Steinert RF. Cataract extraction with multifocal intraocular lens implantation: a multinational clinical trial evaluating clinical, functional, and quality of life outcomes. Ophthalmology 2000;107:2040–8.

44. Lundström M, Stenevi U, Thorburn W. Quality of life after first- and second-eye cataract surgery. Five-year data collected by the Swedish National Cataract Register. J Cataract Refract Surg 2001;27:1553–9.

18. Osher RH, Barros MG, Marques DMV, et al. Early uncorrected visual acuity as a measurement of the visual outcomes of contemporary cataract surgery. J Cataract Refract Surg 2004;30:1917–20.

45. Leivo T, Sarikkola AU, Uusitalo RJ, et al. Simultaneous bilateral cataract surgery: economic analysis; Helsinki Simultaneous Bilateral Cataract Surgery Study Report 2. J Cataract Refract Surg 2011;37:1003–8.

19. Holladay JT, Prager TC, Ruiz RS, et al. Improving the predictability of intraocular lens calculations. Arch Ophthalmol 1986;104:539–41.

46. Desai P, Minassian DC, Reidy A. National cataract surgery survey 1997–8: a report of the results of the clinical outcomes. Br J Ophthalmol 1999;83:1336–40.

20. Naeser K, Knudsen EB, Hansen MK. Bivariate polar value analysis of surgically induced astigmatism. J Cataract Refract Surg 2002;18:72–8.

47. Mangione CM, Orav EJ, Lawrence MG, et al. Prediction of visual function after cataract surgery: a prospectively validated model. Arch Ophthalmol 1995;113:1305–11.

21. Lundström M, Stenevi U, Thorburn W. The Swedish National Cataract Register: a 9-year review. Acta Ophthalmol Scand 2002;80:248–57.

48. Schein OD, Steinberg EP, Cassard SD, et al. Predictors of outcome in patients who underwent cataract surgery. Ophthalmology 1995;102:817–23.

22. Behndig A, Montan P, Stenevi U, et al. One million cataract surgeries. The Swedish National Cataract Register 1992–2009. J Cataract Refract Surg 2011;37:1539–45.

49. Lundström M, Stenevi U, Thorburn W. Outcome of cataract surgery considering the preoperative situation: a study of possible predictors of the functional outcome. Br J Ophthalmol 1999;83:1272–6.

23. Kohnen S, Neuber R, Kohnen T. Effect of temporal and nasal unsutured limbal tunnel incisions on induced astigmatism after phacoemulsification. J Cataract Refract Surg 2002;28:821–5. 24. Alio J, Rodriguez-Prats JL, Galal A, et al. Outcomes of microincision cataract surgery versus coaxial phacoemulsification. Ophthalmology 2005;112:1997–2003.

5.15

27. Qammar A, Mullaney P. Paired opposite clear corneal incisions to correct pre-existing astigmatism in cataract patients. J Cataract Refract Surg 2005;31:1167–70.

Outcomes of Cataract Surgery

1. Cataract Management Guideline Panel. Cataract in adults: management of functional impairment. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1993 (AHCPR pub. No. 93–0542; Clinical practice guideline No. 4).

26. Ben Simon GJ, Desatnik H. Correction of pre-existing astigmatism during cataract surgery: comparison between the effects of opposite clear corneal incisions and a single clear corneal incision. Craefes Arch Clin Exp Ophthalmol 2005;243:321–6.

50. Lundström M, Brege KG, Florén I, et al. Cataract surgery and quality of life in patients with age-related macular degeneration. Br J Ophthalmol 2002;86:1330–5. 51. Armbrecht AM, Findlay C, Aspinall PA, et al. Cataract surgery in patients with age-related macular degeneration: one-year outcomes. J Cataract Refract Surg 2003;29:686–93.

25. Borasio E, Mehta JS, Maurino V. Surgically induced astigmatism after phacoemulsification in eyes with mild to moderate corneal astigmatism: temporal versus on-axis clear corneal incisions. J Cataract Refract Surg 2006;32:565–72.

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5.16

Secondary Cataract Liliana Werner

Definition: Secondary cataract, also known as posterior capsule

opacification (PCO), is the most common complication after cataract surgery, resulting from migration and proliferation of residual lens epithelial cells (LECs) onto the central posterior capsule, leading to decrease in visual function, and ultimately in visual acuity. Opacification within the capsular bag may also present as anterior capsule opacification (ACO) or interlenticular opacification (ILO).

Key features ■

Caused by migration and proliferation of residual lens epithelial cells ■ Treatment is most commonly Nd:YAG laser ■ May be exacerbated or ameliorated via surgical technques and specific lens design

INTRODUCTION Secondary cataract or posterior capsule opacification (PCO) is the most common post-operative complication of cataract surgery. Its incidence has decreased over the past few decades as the understanding of its pathogenesis has evolved. Advances in surgical technique, intraocular lens (IOL) design and materials have all contributed to the gradual decline in PCO incidence. However it remains a major cause of decreased visual acuity after cataract surgery, occurring at a rate of between 3–50% in the first five post-operative years.1

PATHOGENESIS PCO results from migration and proliferation of residual lens epithelial cells (LECs) onto the central posterior capsule. When the cells invade the visual axis as pearls, fibrotic plaques, or wrinkles, the patient experiences a decrease in visual function, and ultimately in visual acuity.2 The epithelium of the crystalline lens consists of a sheet of anterior epithelial cells (‘A’ cells) that are in continuity with the cells of the equatorial lens bow (‘E’ cells). The latter cells comprise the germinal cells that undergo mitosis as they peel off from the equator. They constantly form new lens fibers during normal lens growth. Although both the anterior and equatorial LECs stem from a continuous cell line and remain in continuity, it is useful to divide these into two functional groups. They differ in terms of function, growth patterns, and pathologic processes. The anterior or ‘A’ cells, when disturbed, tend to remain in place and not migrate. They are prone to a transformation into fibrous-like tissue (pseudo-fibrous metaplasia). In contrast, in pathologic states, the ‘E’ cells of the equatorial lens bow tend to migrate posteriorly along the posterior capsule; e.g., in posterior subcapsular cataracts, and the pearl form of PCO. In general, instead of undergoing a fibrotic transformation, they tend to form large, balloon-like bladder cells (the cells of Wedl). These are the cells that are clinically visible as ‘pearls’ (Elschnig pearls). These equatorial cells are the primary source of classic secondary cataract, especially the pearl form of PCO. In a clinical study by Neumayer and coworkers, significant changes in the morphology of Elschnig pearls were observed within time intervals of only 24 hours. Appearance and disappearance of pearls, as well as progression and regression of pearls within these short intervals illustrate the dynamic behavior of regeneratory PCO.3 The ‘E’ cells are also those responsible for formation of a Soemmerring’s ring, which is a doughnut-shaped lesion composed of

retained/regenerated cortex and cells that may form following any type of disruption of the anterior lens capsule. This lesion was initially described in connection with ocular trauma. The basic pathogenic factor of the Soemmerring’s ring is the anterior capsular break, which may then allow exit of central nuclear and cortical material out of the lens, with subsequent Elschnig pearl formation. A Soemmerring’s ring forms every time any form of extracapsular cataract extraction (ECCE) is done, whether manually, automated, or with phacoemulsification (phaco). For practical purposes it is useful to consider this lesion as the basic precursor of classic PCO, especially the ‘pearl’ form. The LECs have higher proliferative capacity in the young compared with the old, therefore, the incidence of PCO formation is higher in younger patients. The same cell types mentioned above are also involved in other processes of opacification within the capsular bag (Fig. 5-16-1). These include anterior capsule opacification (ACO),4,5 and interlenticular opacification (ILO).6,7 This latter is the opacification of the space between two or more IOLs implanted in the bag (piggyback implantation).

Treatment and Prevention

The treatment of PCO is typically neodymium : YAG (Nd : YAG) laser posterior capsulectomy. This is a simple procedure in most cases, but is not without risks. Complications include IOL damage, IOL subluxation or dislocation, retinal detachment, and secondary glaucoma.8 Therefore, prevention of this complication is important, not only because of the risks associated with its treatment, but also because of the costs involved in the procedure. Extensive research has been performed on the inhibition of LEC proliferation and migration by pharmacologic agents through various delivery systems, or IOL coatings, in vitro and in vivo animal studies.9–11 Use of pharmacological and nonpharmacological agents for this purpose in an unsealed system may increase the risk of toxicity to surrounding intraocular structures, especially corneal endothelial cells. The PerfectCapsule™, a silicone device that reseals the capsular bag allowing isolated safe delivery of irrigating solutions into its inner compartment, was therefore developed.12 Immunotherapy and gene therapy, as well as physical techniques to kill/remove LECs have also been investigated.13,14 We have evaluated in our laboratory the efficacy of a Nd : YAG laser photolysis system in removing LECs using human cadaver eyes. Light microscopy and immunohistochemistry revealed that the laser photolysis system removed LECs from the anterior lens capsule and capsule fornix. Along with the cells, laminin, fibronectin, and cell debris remained in the untreated areas but were removed by the treatment, which may be useful for PCO prevention.14 While basic research on an effective mechanism for PCO eradication evolves, the practical surgeon can already apply some principles to prevent it.15 Studies done in our laboratory, as well as clinical studies done in other centers, have helped in the definition of three surgery-related factors that help in the prevention of PCO:  Hydrodissection-enhanced cortical clean-up,  In-the-bag IOL fixation, and  Performance of a capsulorrhexis slightly smaller than the diameter of the IOL optic (Fig. 5-16-2). The same studies helped in the definition of three IOL-related factors for PCO prevention:  Use of a biocompatible IOL to reduce stimulation of cellular proliferation,  Enhancement of the contact between the IOL optic and the posterior capsule, and  An IOL with a square, truncated optic edge.

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5 The Lens A

B

C

D

Fig. 5-16-1  Different forms of opacification within the capsular bag. A: Human eye obtained postmortem (posterior or Miyake-Apple view) implanted with a rigid lens, showing asymmetric fixation, and decentration. A doughnut-shaped, white lesion can be seen for 360° in the equatorial region of the capsular bag (Soemmerring’s ring), and the posterior capsule is fibrotic. B: Human eye obtained postmortem (posterior view) implanted with a rigid lens. Soemmerring’s ring is also present. A posterior capsulotomy had been performed for posterior capsule opacification, and proliferation of Elschnig pearls can be seen at the edges of the capsulotomy (arrow). C: Human eye obtained postmortem (posterior view) implanted with a foldable, plate silicone lens. The anterior capsule is fibrotic (arrow). Although Soemmerring’s ring formation can be seen, the posterior capsule is not opacified. D: Pair of foldable, hydrophobic acrylic lenses explanted because of interlenticular opacification. The lenses are fused together through the material within the interlenticular space.

Hydrodissection-enhanced cortical clean-up

Howard Fine introduced this technique and coined the term cortical cleaving hydrodissection. The edge of the anterior capsule is slightly tented up by the tip of the cannula, while injecting the fluid. The technique is used by many surgeons to facilitate cortex and equatorial LEC (‘E’ cell) removal, also enhancing the safety of the operation. Experimental studies used different solutions during the hydrodissection step of the phacoprocedure, e.g., preservative-free lidocaine 1%, antimitotics, etc.18 Further studies are necessary to establish the safety and utility of these solutions in terms of PCO prevention. While a careful cortical clean up and elimination of as many ‘E’ cells as possible is fundamental in reducing the incidence of PCO, the role of anterior capsule polishing and elimination of ‘A’ cells remains to be demonstrated. Indeed, Sacu and colleagues have performed a randomized, prospective study to evaluate the effect of anterior capsule polishing on PCO.16 The anterior capsule was extensively polished in one eye and was left unpolished in the other eye. Digital slit-lamp photographs taken one year post-operatively using a standardized photographic technique showed that anterior capsule polishing caused no significant difference in the outcome of PCO. Some authors actually believe that the post-operative fibrous metaplasia of remaining ‘A’ cells would push the IOL against the posterior capsule, and that would explain the relatively low PCO rates of eyes implanted with silicone lenses having rounded optic edges.17

In-the-bag IOL fixation 408

The hallmark of modern cataract surgery is the achievement of consistent and secure in-the-bag or endocapsular IOL fixation. The most obvious advantage of in-the-bag fixation is the accomplishment of good lens

centration. However, endocapsular fixation functions primarily to enhance the IOL-optic barrier effect, as will be discussed later. In a series of human cadaver eyes implanted with different IOLs and analyzed in our laboratory, central PCO and Nd : YAG rates were both influenced by IOL fixation; i.e., less PCO and Nd : YAG capsulotomies in eyes where the IOLs were in the bag.15 Marie-José Tassignon proposed a variation of the in-the-bag IOL fixation concept for PCO prevention, named ‘bag-in-the-lens’ implantation.18 This involves the use of a twin-capsulorrhexis IOL design, and performance of anterior and posterior capsulorrhexis of the same size. The biconvex lens has a circular equatorial groove in the surrounding haptic, for placement of both capsules after capsulorrhexis. If the capsules are well stretched around the optic of this lens, the LECs will be captured within the remaining space of the capsular bag and their proliferation will be limited to this space, so the visual axis will remain clear (Fig. 5-16-3). Experimental and clinical studies showed that bag-in-thelens implantation was highly effective in preventing PCO when the anterior and posterior capsules were properly secured in the IOL groove.

Capsulorrhexis size

There is evidence that PCO is reduced if the capsulorrhexis diameter is slightly smaller than that of the lens optic, so that the anterior edge rests on the optic. This helps provide a tight fit of the capsule around the optic analogous to ‘shrink-wrap’, which has beneficial effects in maximizing the contact between the lens optic and the posterior capsule. In a retrospective clinical study performed at the John A. Moran Eye Center, University of Utah, on patients implanted with different IOLs, including lenses with round or square optic edges, the degree of post-operative PCO was correlated with the degree of anterior capsule

Fig. 5-16-3  Clinical photograph taken 6 months after cataract surgery with ‘bagin-the-lens’ implantation in a 64-year-old patient. The area corresponding to the optic of the lens is completely free of opacities. Courtesy of Dr. Marie-José Tassignon, Belgium.

overlap.19 Considering all patients, but also considering the patients distributed in different IOL groups, there was always a significant negative, linear correlation between the degree of overlap and PCO.

Biocompatible IOL

There are many definitions for the term ‘biocompatibility’. With regards to PCO, materials with the ability to inhibit stimulation of cell proliferation are more ‘biocompatible’. The ‘Sandwich’ theory states that a hydrophobic acrylic IOL with bioadhesive surface would allow only a monolayer of LECs to attach to the capsule and the lens, preventing further cell proliferation and capsular bag opacification. We performed two immunohistochemical studies on the adhesion of proteins to different IOLs that had been implanted in human eyes obtained postmortem.20,21 Analyses of histological sections have demonstrated

5.16 Secondary Cataract

Fig. 5-16-2  Human eye obtained postmortem (posterior view) 19 months after implantation of a single-piece hydrophobic acrylic lens. This is an example of application of the three surgery-related factors for prevention of posterior capsule opacification. The lens was symmetrically implanted in the bag, via capsulorrhexis smaller than the optic diameter of the lenses (ideally, the capsulorrhexis margin should cover the edge of the lens for 360°). No significant Soemmerring’s ring formation is present.

that fibronectin mediates the adhesion of this hydrophobic acrylic lens to the anterior and posterior capsules. Analyses of explanted lenses have confirmed the presence of greater amounts of fibronectin on the surfaces of the same lens. However, even though differences among materials exist, in terms of PCO prevention it appears that the geometry of the lens, with a square posterior optic edge is the most important factor (see IOL optic geometry below). The adhesiveness of the material may have a more direct impact on the development of ACO. This generally occurs much earlier in comparison to PCO, sometimes within one month post-operatively. When the continuous curvilinear capsulorrhexis (CCC) is smaller than the IOL optic, the anterior surface of the optic’s biomaterial maintains contact with the adjacent posterior aspect of the anterior capsule. Any remaining anterior LECs (A cells) in contact with the IOL have the potential to undergo fibrous proliferation; thus ACO is essentially a fibrotic entity. Studies in our laboratory using pseudophakic human eyes obtained postmortem showed that ACO is more common with silicone IOLs, especially the plate designs, because of the larger area of contact between these lenses and the anterior capsule (Fig. 5-16-1C).4 However, the same studies showed that the plate design resists contraction forces within the capsular bag better than three-piece silicone lenses with flexible haptics (polypropylene).5 These latter showed the higher rates of capsulorrhexis phimosis and IOL decentration as a result of excessive capsular bag fibrosis. There is, therefore, a tendency in IOL manufacture favoring haptic materials with higher rigidity, such as poly(methyl methacrylate) (PMMA), polyimide (Elastimide), and poly(vinylidene) fluoride (PVDF). In the same studies, ACO was less significant with hydrophobic acrylic lenses having an adhesive surface. ACO has been considered a clinical problem when anterior capsular shrinkage associated with constriction of the anterior capsulectomy opening (capsulorrhexis contraction syndrome or capsular phimosis) accompanies excessive anterior capsule fibrosis. This has been especially observed in conditions associated with zonular weakness, e.g., pseudoexfoliation and advanced age, and with chronic intraocular inflammation. Besides phimosis of the CCC opening, excessive zonular traction and its sequelae, IOL dislocation and retinal detachment can also occur because of excessive capsular fibrosis. Excessive opacification of the anterior capsule is problematic in that it hinders visualization of the peripheral fundus during retinal examination. Otherwise, a certain degree of ACO is sometimes considered an advantage, as it can prevent potential dysphotopsia phenomena caused by the square edge of some IOL optic designs. Also, anterior capsule fibrosis with contraction of the capsular bag will push the IOL optic against the posterior capsule, helping in the prevention of PCO according to the ‘no space, no cells‘ theory. This mechanism would explain the relatively low PCO rates with some silicone lenses, in the absence of a square optic edge profile, as noted above (Hydrodissection-enhanced cortical clean-up).17 The adhesiveness of the IOL material may also have an influence on ILO formation. To date, all cases of ILO we analyzed in our laboratory seemed to be related to two hydrophobic acrylic IOLs being implanted in the capsular bag through a small capsulorrhexis, with its margins overlapping the optic edge of the anterior IOL for 360°.6 When these lenses are implanted in the capsular bag through a small capsulorrhexis, the bio-adhesion of the anterior surface of the front lens to the anterior capsule edge and of the posterior surface of the back lens to the posterior capsule prevents the migration of the cells from the equatorial bow onto the posterior capsule. This migration may be directed towards the inter-lenticular space. In this scenario, the two IOLs are sequestered together with aqueous and LECs in a hermetically closed microenvironment. In addition, the adhesive nature of the material seems to render the opacifying material very difficult to remove by any surgical means (Fig. 5-16-1D). Based on the common features of different cases of ILO, some surgical methods were proposed for its prevention. The first option would be to implant both IOLs in the capsular bag but with a relatively largediameter capsulorrhexis. The other possibility is to implant the anterior IOL in the sulcus and the posterior IOL in the bag with a small rhexis. These should help sequester the retained/proliferated equatorial LECs within the equatorial fornix. Re-assessment of factors leading to ILO formation is important because of the development of dual-optic accommodating IOLs to be implanted in the capsular bag.7 Also, piggyback implantation for correction of residual refractive errors appears to be increasing in popularity, including implantation of a multifocal IOL in pseudophakic patients. However, in these cases the second (anterior) IOL is generally fixated in the ciliary sulcus.

409

5 The Lens A

B

C

D

Fig. 5-16-4  Foldable, hydrophilic acrylic lenses with square optic and haptic edges. The lens in B was modified to incorporate an extra ridge all around the optic (enhanced square edge; arrow). C and D are photographs obtained from rabbit eyes (posterior view), experimentally implanted with the lenses in A and B, respectively. Soemmerring’s ring formation is observed in both eyes. The arrow in C shows the opacification of the posterior capsule, which started at the level of the optic-haptic junction. From: Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cataract Refract Surg 2004; 30:2403–2409.

Contact between the IOL optic and the posterior capsule

410

Different factors can help maximize the contact between the IOL and the posterior capsule, contributing to the so-called ‘no space, no cells’ concept. Optic/haptic angulation displacing the optic posteriorly, and stickiness of the IOL optic material are the most important lens features for obtaining a tight fit between lens and capsule. Three-piece lenses manufactured from the different haptic materials currently available today have in general a posterior optic/haptic angulation ranging from 5 to 10°. To keep the advantages of the two above-mentioned factors, it is important to achieve endocapsular lens fixation and to create a capsulorrhexis smaller than the diameter of the lens optic. Capsular tension rings may also have a role in the prevention of PCO. Equatorial capsular tension rings have the ability to maintain the contour of the capsular bag and to stretch the posterior capsule. They have thus primarily been used in cases of zonular rupture or dehiscence, secondary to trauma, or when inherent zonular weakness is present, such as in pseudo-exfoliation syndrome. It has been demonstrated by high-resolution laser interferometric studies that there is a space between the IOL and the posterior capsule with different lens

designs. With a capsular tension ring in place, this space was found to be smaller or non-existent. Thus, LECs would not find a space to migrate and proliferate onto the posterior capsule. Capsular tension rings also produce a circumferential stretch on the capsular bag, with the radial distention forces equally distributed. Formation of traction folds in the posterior capsule, which may be used as an avenue for cell ingrowth is thus avoided. Capsular tension rings may also have a role in the prevention of opacification of the anterior capsule. The presence of a broad, bandshaped, capsular ring would keep the anterior capsule leaf away from the anterior optic surface and the posterior capsule. This would ultimately lead to less metaplasia of LECs on the inner surface of the anterior capsule with less fibrous tissue formation, and thus less opacification and contraction of this structure. IOLs with design features that also help maintaining the anterior capsule away from the anterior surface of the lens have also been evaluated in our laboratory.7 A capsular tension ring designed to prevent opacification within the capsular bag was evaluated in two centers, one in Japan (Nishi O) and the other in Austria (Menapace R).22 Both centers reported a significant reduction

in PCO and ACO with the rings, in comparison to the contralateral eyes implanted with the same lens design.22

5.16

IOL optic geometry

IOLS MAINTAINING THE CAPSULAR BAG OPEN OR EXPANDED We have recently evaluated the outcome of capsular bag opacification with a new single-piece, disk-shaped hydrophilic acrylic IOL as compared to a commercially available single-piece, hydrophobic acrylic IOL in the rabbit eye for 5 weeks (Fig. 5-16-5).26 The peripheral rings of the disk-shaped lens, by expanding the capsular bag and preventing IOL surface contact with the anterior capsule, prevented ACO and PCO. We hypothesized that IOL designs maintaining an open or expanded capsular bag are associated with bag clarity. Mechanical compression of the inner bag surface (and residual LECs) by a relatively bulky device/IOL has been one of the possible mechanisms advanced to explain this finding. Another factor may be mechanical stretch of the bag at the level of the equatorial region (maintaining the overall bag contour), by devices such as the capsular bending ring of Nishi and Menapace,22 and Hara’s equator ring.27 Constant irrigation of the capsular bag’s inner compartment by the aqueous humor may also have an influence on the prevention of proliferation of residual LECs. Equatorial stretch and aqueous humor irrigation would help explain the PCO preventative effect, even in eyes where there was no contact between the IOL optic and the posterior capsule. Previous reports indicated that TGF-β2 in the normal aqueous humor inhibits proliferation of LECs and corneal endothelial cells.28 According to Nishi, constant irrigation by the aqueous humor may prevent certain cytokines that are involved in stimulating LEC proliferation from reaching a threshold concentration level within the bag compartment; one of these cytokines would be represented by interleukin-1.29 In summary, development of PCO is multifactorial, and its eradication depends on the quality of the surgery, as well as on the quality of the IOL implanted. Each factor described here does not act in isolation, and it is their interaction that produces the best results. Research on the prevention of any form of opacification/fibrosis within the capsular bag is increasing in importance, especially with the advent of specialized IOLs such as accommodative lenses, which are designed to enable a forward movement of the optic upon efforts of accommodation. The functionality of such lenses will likely require the long-term transparency and elasticity of the capsular bag. Further research to investigate new proposed mechanisms for capsular bag

Secondary Cataract

The square, truncated lens optic edge acts as a barrier, preventing migration of proliferative material from the equatorial region onto the posterior capsule.15 The barrier effect is absent in lenses having rounded edges, and proliferative material from the equatorial region has greater free access to the posterior capsule, opacifying the visual axis. The barrier effect of the square optic edge is functional when the lens optic is fully in the bag, in contact with the posterior capsule. When one or both haptics are out of the bag, a potential space exists that allows an avenue for cellular ingrowth towards the visual axis. Different modern lenses manufactured from different materials currently on the market present this important design feature. Some of them have a square edge on the posterior optic surface, while the anterior optic edge remains round in order to prevent disphotopsia. Findings from experimental studies which demonstrate that the square edges of different lenses on the market are not equally ‘sharp’, even when the same class of materials is considered, are however noteworthy.23,24 The optic–haptic junctions of square-edged single-piece lenses may represent a site for cell ingrowth and PCO formation.25 At the level of those junctions, the barrier effect of the square edge appears to be less effective. We obtained better results regarding PCO formation with a hydrophilic acrylic single-piece lens having an ‘enhanced’ square edge, than with the standard model of the same design.25 The enhanced edge provided the lens with a peripheral ridge around the lens optic for 360°. In the standard model, the square edge profile appeared to be absent at the level of the optic–haptic junctions (Fig. 5-16-4). Therefore, the square optic edge is probably the most important IOL design feature for PCO prevention. It appears however that it should be present for 360° around the IOL optic in order to provide an effective barrier effect.

Fig. 5-16-5  Gross photograph (Miyake-Apple view) of the anterior segment of a rabbit eye implanted with a new disk-shaped IOL, taken 5 weeks post-operatively. The lens is a single-piece, hydrophilic acrylic, monofocal lens suspended between two complete haptic rings that are connected by a pillar of the haptic material. This design maintains the capsular bag expanded, with the anterior capsule separated from the anterior optic surface Anterior and posterior capsules are overall clear. Minimal proliferation is limited to the space between the peripheral rings.

opacification prevention, such as with IOLs/devices maintaining an open capsular bag is warranted.

KEY REFERENCES Apple DJ, Werner L. Complications of cataract and refractive surgery: A clinicopathological documentation. Trans Am Ophthalmol Soc 2001;99:95–109. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsular opacification. Major review. Surv Ophthalmol 1992;37:73–116. Charles S. Vitreoretinal complications of YAG laser capsulotomy. Ophthalmol Clin North Am 2001;14:705–10. Kavoussi SC, Werner L, Fuller SR, et al. Prevention of capsular bag opacification with a new hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2011;37:2194–200. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and collagen type IV to intraocular lens materials in human autopsy eyes. Part I: histological sections. J Cataract Refract Surg 2000;26:1792–806. Mamalis N, Grossniklaus HE, Waring GO 3rd, et al. Ablation of lens epithelial cells with a laser photolysis system: histopathology, ultrastructure, and immunochemistry. J Cataract Refract Surg 2010;36:1003–10. Meacock WR, Spalton DJ, Boyce J, et al. The effect of posterior capsule opacification on visual function. Invest Ophthalmol Vis Sci 2003;44:4665–9. Neumayer T, Findl O, Buehl W, et al. Daily changes in the morphology of Elschnig pearls. Am J Ophthalmol 2006;141:517–23. Werner L, Pandey SK, Escobar-Gomez M, et al. Anterior capsule opacification: a histopathological study comparing different IOL styles. Ophthalmology 2000;107:463–71. Werner L, Pandey SK, Apple DJ, et al. Anterior capsule opacification: correlation of pathological findings with clinical sequelae. Ophthalmology 2001;108:1675–81. Werner L, Apple DJ, Pandey SK, et al. Analysis of elements of interlenticular opacification. Am J Ophthalmol 2002;133:320–6. Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cataract Refract Surg 2004;30:2403–9. Werner L, Müller M, Tetz M. Evaluating and defining the sharpness of intraocular lenses. Microedge structure of commercially available square-edged hydrophobic lenses. J Cataract Refract Surg 2008;34:310–7. Werner L, Tetz M, Feldmann I, et al. Evaluating and defining the sharpness of intraocular lenses: microedge structure of commercially available square-edged hydrophilic intraocular lenses. J Cataract Refract Surg 2009;35:556–66. Werner L, Tassignon MJ, Zaugg BE, et al. Clinical and histopathologic evaluation of six human eyes implanted with the bag-in-the-lens. Ophthalmology 2010;117:55–62.

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Access the complete reference list online at

REFERENCES 1. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsular opacification. Major review. Surv Ophthalmol 1992;37:73–116.

3. Neumayer T, Findl O, Buehl W, et al. Daily changes in the morphology of Elschnig pearls. Am J Ophthalmol 2006;141:517–23. 4. Werner L, Pandey SK, Escobar-Gomez M, et al. Anterior capsule opacification: a histopathological study comparing different IOL styles. Ophthalmology 2000;107:463–71. 5. Werner L, Pandey SK, Apple DJ, et al. Anterior capsule opacification: correlation of pathological findings with clinical sequelae. Ophthalmology 2001;108:1675–81. 6. Werner L, Apple DJ, Pandey SK, et al. Analysis of elements of interlenticular opacification. Am J Ophthalmol 2002;133:320–6. 7. Werner L, Mamalis N, Stevens S, et al. Interlenticular opacification: dual-optic versus piggyback intraocular lenses. J Cataract Refract Surg 2006;32:656–62. 8. Charles S. Vitreoretinal complications of YAG laser capsulotomy. Ophthalmol Clin North Am 2001;14:705–10. 9. Fernandez V, Fragoso MA, Billote C, et al. Efficacy of various drugs in the prevention of posterior capsule opacification: experimental study of rabbit eyes. J Cataract Refract Surg 2004;30:2598–605. 10. Werner L, Legeais JM, Nagel MD, et al. Evaluation of Teflon-coated intraocular lenses in an organ culture method. J Biomed Mater Res 1999;46:347–54. 11. Okajima Y, Saika S, Sawa M. Effect of surface coating an acrylic intraocular lens with poly(2methacryloyloxyethyl phosphorylcholine) polymer on lens epithelial cell line behavior. J Cataract Refract Surg 2006;32:666–71. 12. Maloof A, Pandey SK, Neilson G, et al. Selective death of lens epithelial cells using demineralized water and Triton X-100 with PerfectCapsule sealed capsule irrigation: a histological study in rabbit eyes. Arch Ophthalmol 2005;123:1378–84. 13. Meacock WR, Spalton DJ, Hollick EJ, et al. Double-masked prospective ocular safety study of a lens epithelial cell antibody to prevent posterior capsule opacification. J Cataract Refract Surg 2000;26:716–21. 14. Mamalis N, Grossniklaus HE, Waring GO 3rd, et al. Ablation of lens epithelial cells with a laser photolysis system: histopathology, ultrastructure, and immunochemistry. J Cataract Refract Surg 2010;36:1003–10.

17. Spalton DJ. In reply to: Nishi O. Effect of a discontinuous capsule bend. J Cataract Refract Surg 2003;29:1051–2. 18. Werner L, Tassignon MJ, Zaugg BE, et al. Clinical and histopathologic evaluation of six human eyes implanted with the bag-in-the-lens. Ophthalmology 2010;117:55–62. 19. Smith SR, Daynes T, Hinckley M, et al. The effect of lens edge design versus anterior capsule overlap on posterior capsule opacification. Am J Ophthalmol 2004;138:521–6. 20. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and collagen type IV to intraocular lens materials in human autopsy eyes. Part I: histological sections. J Cataract Refract Surg 2000;26:1792–806. 21. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and collagen type IV to intraocular lens materials in human autopsy eyes. Part II: explanted IOLs. J Cataract Refract Surg 2000;26:1807–18. 22. Menapace R, Sacu S, Georgopoulos M, et al. Efficacy and safety of capsular bending ring implantation to prevent posterior capsule opacification: three year results of a randomized clinical trial. J Cataract Refract Surg 2008;34:1318–28.

5.16 Secondary Cataract

2. Meacock WR, Spalton DJ, Boyce J, et al. The effect of posterior capsule opacification on visual function. Invest Ophthalmol Vis Sci 2003;44:4665–9.

16. Sacu S, Menapace R, Findl O, et al. Influence of optic edge design and anterior capsule polishing on posterior capsule fibrosis. J Cataract Refract Surg 2004;30:658–62.

23. Werner L, Müller M, Tetz M. Evaluating and defining the sharpness of intraocular lenses. Microedge structure of commercially available square-edged hydrophobic lenses. J Cataract Refract Surg 2008;34:310–7. 24. Werner L, Tetz M, Feldmann I, et al. Evaluating and defining the sharpness of intraocular lenses: microedge structure of commercially available square-edged hydrophilic intraocular lenses. J Cataract Refract Surg 2009;35:556–66. 25. Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cataract Refract Surg 2004;30:2403–9. 26. Kavoussi SC, Werner L, Fuller SR, et al. Prevention of capsular bag opacification with a new hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg 2011;37:2194–200. 27. Hara T, Hara T, Narita M, et al. Long-term study of posterior capsular opacification prevention with endocapsular equator rings in humans. Arch Ophthalmol 2011;129:855–63. 28. Nagamoto T, Tanaka N, Fujiwara T. Inhibition of posterior capsule opacification by a capsular adhesion-preventing ring. Arch Ophthalmol 2009;127:471–4. 29. Nishi O, Nishi K, Ohmoto Y. Effect of interleukin 1 receptor antagonist on the blood-aqueous barrier after intraocular lens implantation. Br J Ophthalmol 1994;78:917–20.

15. Apple DJ, Werner L. Complications of cataract and refractive surgery: A clinicopathological documentation. Trans Am Ophthalmol Soc 2001;99:95–109.

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PART 5 THE LENS

Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

5.17

Mark Wevill

Key features ■

■

■

■ ■

Cataract visual morbidity will double in the next 20 years and developing countries will share the burden disproportionately because they have a higher incidence of cataract and fewer resources. Factors in cataract pathogenesis include lens protein oxidation, mitochondrial function, failure of protective mechanisms, protein modification, and abnormalities of calcium metabolism, cellular proliferation and differentiation. An accumulation of environmental insults (e.g., ultraviolet light, toxins, drugs, and systemic diseases) results in age-related cataracts. Minor risk factors such as UV-B exposure and smoking can be modified. Nutritional, pharmacological, and genetic interventions are being investigated. Anomalies of lens growth are usually associated with other ocular or systemic disorders.

EPIDEMIOLOGY OF CATARACTS

412

The World Health Organization calculated that there were 161 million visually impaired people worldwide in 2002, of which cataract accounts for 47.8%.1 The estimated global costs of blindness and low vision in 2000 was estimated at US$42 billion,2 and this does not account for the reduced economic activity of each blind person’s caregiver.3 Over the next 20 years there will be an approximate doubling in the incidence of cataract, visual morbidity, and need for cataract surgery, as the world’s population will increase by about one third (predominantly in developing countries) and people will live to greater ages. But how much cataract is enough to warrant surgery, how should it be performed and delivered, and how should it be paid for? In the developed world, the threshold for cataract surgery is now 20/30 (6/9) or less, which has resulted in a three- to fourfold increase in patients receiving surgery, with an associated increased need for resources and funding. At what visual acuity level will governments and insurers pay for surgery in future?4 Developing countries will bear an increasing burden for cataract blindness, because cataracts occur earlier in life in such places, and the incidence is higher. In India, visually significant cataract occurs 14 years earlier than in the United States, and the age-adjusted prevalence of cataract is three times that of the United States.5,6 In addition there are fewer surgeons to carry out the surgery. The prevalence of blindness can be reduced, as illustrated by the Gambian Eye Care program, which reduced the prevalence of blindness from 0.7% to 0.42% between 1986 and 1996.3 However, in the developing world, the shift from intracapsular to extracapsular cataract surgery has resulted in a lower visual threshold for surgery, increasing the number of operations

that need to be done. In developing countries there are other challen­ ges, such as a poor uptake of services because of a lack of patient information, misinformation from traditional healers, superstition, poor quality of services, monetary costs, distance to services, and the need for an escort. Even where facilities are available, there is often a lack of surgeons, instruments, and other equipment (exacerbated by poor maintenance), and a shortage of consumables and medications. Developing intraocular lens-manufacturing facilities in these countries (such as the Fred Hollows Foundation in Eritrea and Nepal), will reduce costs and improve access to surgery.4

Genetics

Congenital or early-onset cataracts are usually inherited as a classic Mendelian disorder. Age-related cataracts are inherited as a multifactorial or complex trait. Many genes and mutations responsible for inherited forms of cataract have been identified. Only a small proportion of the genes currently implicated in age-related cataract have been identified. Also, mutations in the same gene may result in different cataract types. In the lens epithelial cells, increased gene expression of ionic transport (e.g. calcium-ATPase which controls calcium channels) and extracellular matrix proteins can cause cataracts.7 But most genes involved in cataract formation show decreased expression. These genes function in diverse processes, including protein synthesis, oxidative stress (e.g., glutathione peroxidases), structural proteins, chaperones, and cell cycle control proteins, many of which preserve lens clarity. Decreased expression reduces cell tolerance to stress. Future family and case control studies and next-generation sequencing techniques will identify more genetic determinants of inherited and age-related cataracts and gene–gene and gene–environment interactions. This may result in nonsurgical treatments for cataract or lifestyle interventions (e.g., diet) that help to prevent cataract.8, 9

Nutrition, Health, and Diabetes

A number of health-related factors – diabetes, hypertension, and body mass index – are associated with various forms of lens opacity, and they may be interrelated. A high body mass index increases the risk of developing posterior subcapsular, nuclear, and cortical cataracts.10 Diabetes and hypertension are associated with cortical cataracts.8 Severe diarrhea and dehydration was shown to increase the risks of developing cataracts in some studies,11 but not in others,12 and severe protein-calorie malnutrition is more common in people with cataract.5 Therefore, a moderate calorie intake may be optimal to reduce the risk of developing cataracts.

Antioxidants

The roles and mechanisms of action of dietary antioxidant vitamins and minerals in the biochemistry and metabolism of the lens are not clear. Ascorbate, a water-soluble antioxidant, has not been shown to reduce the incidence of cataract in most studies. Vitamin E is a lipidsoluble antioxidant, which inhibits lipid peroxidation, stabilizes cell membranes and enhances glutathione recycling, but had no effect on

Sunlight and Irradiation

Ultraviolet (UV) B light causes oxidative damage which is cataractogenic. The level of free UV filters in the lens decreases with age, and the breakdown products of the filters act as photosensitizers which promote the production of reactive oxygen species and oxidation of proteins in the aging lens. The risk of cortical and nuclear cataract is highest in those with high sun exposure at a younger age. Exposure later in life was more weakly associated with these cataracts. Wearing sunglasses, especially when younger, has some protective effect.14 Unfortunately, the risk attributable to sunlight exposure is small,15 and cortical cataracts are less debilitating than nuclear or posterior subcapsular cataracts. Therefore, reducing sunlight exposure may have a limited benefit in delaying the onset of cataracts. Exposure to high levels of X-rays and whole-body irradiation also causes cataracts.

Smoking and Alcohol

Smoking causes a threefold increase in the risk of developing nuclear cataracts, and cessation of smoking reduces this risk. Smoking may also be associated with posterior subcapsular cataracts. Smokers are also more likely to have a poor diet and high alcohol consumption, which are also risk factors for cataract. Smoking causes a reduction in endogenous antioxidants, and tobacco smoke contains heavy metals such as cadmium, lead, and copper, which accumulate in the lens and cause toxicity. No association between passive smoking and cataract has been demonstrated.16 Chronic alcoholism is associated with a significantly increased risk of cataract.17 Consumption of alcohol, particularly hard liquor and wine, is associated with nuclear opacities. Wine drinking was inversely related to cortical opacity.18 Some studies have not shown an association between alcohol consumption and cataracts.19

Age, Education, and Other Factors

Age is the greatest risk factor for cataract. There is a cumulative exposure to toxins (e.g. steroids) and other risk factors, an age-related decline in antioxidants and antioxidant enzymes20 and an increased incidence of diseases such as diabetes.21 A higher level of education is associated with a lower risk of age-related cataract; however, this may be related to smoking, alcohol intake, and increased sun exposure in people with less education.

Myopia

After controlling for age, gender, and other cataract risk factors (diabetes, smoking, and education), posterior subcapsular cataracts were found to be associated with myopia, deeper anterior chambers, and longer vitreous chambers.

Pharmacological Prevention of Cataracts

Potential anti-cataract compounds include aldose reductase inhibitors, pantethine, and aspirin-like drugs such as ibuprofen. Population studies have also revealed a decreased risk of nuclear sclerosis with estrogen replacement therapy. However, none of these agents has been shown to prevent cataracts in a trial setting. New drugs are under investigation.22–25 Anti-cataract agents would need to be safe for long-term use and sufficiently inexpensive to compete with increasingly cost-effective cataract surgery.8 Understanding the causes of age-related cataract will be helpful in preventing or delaying cataract formation but our knowledge is incomplete. Minor risk factors such as UV-B exposure and smoking can be modified but are not likely to result in large reductions in visual disability. Aging, the most important risk factor, cannot be modified. Other strategies such as nutritional, pharmacological, and specific medical and genetic interventions may be helpful in future, but are of unproved benefit at present. Integrated and innovative approaches to the provision of surgery, resource management, training, start-up capital equipment and consumables, and cost recovery mechanisms are required.4

PATHOPHYSIOLOGY OF CATARACTS The lens transmits, filters, and focuses light onto the retina. The high refractive index and transparency of the lens is due to the high concentration and orientation of intracellular structural proteins: α, β, and γ crystallins. The anterior subcapsular layer of cuboidal lens epithelial cells is nucleated, actively dividing, and accounts for almost all the metabolic activity of the lens. Cuboidal cells in the equatorial zone of the lens differentiate and elongate their cytoplasm into lens fiber cells, lose their intracellular organelles and ability to perform metabolic functions, and form mature lens fibers. As the lens fibers age, other biochemical, physiological, and structural changes occur. Aging changes share some similarities with age-related cataract changes, however, there are also unique cataract changes.26,27 The transparency of the lens is dependent on the regular organization of the lens cells and intracellular lens proteins. Genetic, metabolic, nutritional, and environmental insults and ocular and systemic diseases disrupt cellular organization and intracellular homeostasis, eventually causing light scattering and absorption, which compromise vision. Once damaged, the lens has limited means of repair and regeneration, and may lose its transparency by the formation of opaque lens fibers, fibrous metaplasia, epithelial opacification, accumulation of pigment, or formation of extracellular materials. Several interlinked mechanisms for cataract formation have been proposed, and no single theory completely explains age-related cataract (the commonest form).27 Much is still unknown about cataractogenesis, but many of the important components are becoming clearer.

Cell Proliferation and Differentiation

Aqueous growth factors control the proliferation, differentiation and maturation of the lens epithelial cells. Fibroblast growth factor (FGF), produced in the ciliary epithelium stimulates epithelial proliferation in low concentrations near the central anterior lens surface but induces lens fiber differentiation in higher concentrations near the lens equator. Other growth factors, such as epidermal growth factor (EGF), insulinlike growth factor (IGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF-β) are also involved in these processes. Differentiation of the epithelial cells will not occur if growth factor or cytokine concentrations are incorrect, then undifferentiated cells migrate to the posterior pole causing posterior subcapsular cataracts.26

5.17 Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

cataract incidence in most studies. Beta-carotene, the best-known carotenoid, is a lipid-soluble antioxidant, a vitamin A precursor and is one of 400 naturally occurring carotenoids. There are mixed reports in the literature, with some studies showing no benefit and others showing some benefit with vitamin A, carotenoids, and combinations of vitamins C and E and beta-carotene supplements.13

Metabolic Disturbance and Osmotic Regulation Failure

Altered gene expression changes enzyme, growth factor, membrane protein, and other protein levels, which reduces energy production, changes ion transport, calcium metabolism and antioxidant pathways, and breaks down protective mechanisms.26 For example the lens maintains high intracellular potassium and low sodium levels with the opposite extracellular concentrations via the action of the sodium-potassium ATPase pump. Pump inactivation causes increased intracellular osmolality, which results in water accumulation and light scatter.26 The aqueous humor is a source of nutrients and mineral ions including calcium (Ca2+). Ca2+ is an intracellular signal that regulates many functions including the permeability of the cell membranes. The extracellular Ca2+ concentration is 10 times the intracellular Ca2+ concentration which drives Ca2+ into the epithelial cell. Low intracellular Ca2+ levels are also maintained by intracellular organelle membrane pumps (on the endoplasmic reticulum, golgi apparatus, and mitochondria) and by binding to complex proteins (e.g., crystallins). Extracellular Ca2+ can also be bound to the outer layer of the cell membrane. Reduced binding of Ca2+ by membrane proteins increases cell membrane permeability and causes a rise in intracellular Ca2+ levels, the formation of calcium oxylate crystals, binding of Ca2+ to insoluble lens proteins, increased light scattering, and nuclear cataract formation. Increased intracellular Ca2+ levels also affect lens epithelial cell differentiation causing posterior subcapsular cataracts. Steroids have been shown to mobilize intracellular Ca2+ in other tissues which can increase Ca2+ levels. In the future Ca2+ regulating drugs may be developed to prevent cataracts.28

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5

Fig. 5-17-1  Conformational changes in lens proteins (unfolding) exposes thiol groups (-SH). Oxidization to disulfides (–S–S–) causes protein aggregation and scatters light.

CONFORMATIONAL CHANGES IN LENS PROTEINS

The Lens

unfolding

oxidation protein thiol groups (–SH) disulfide bonds (–S–S–)

Calpains

The roles of calpains in the lens are poorly understood, but they may degrade accumulated, damaged lens proteins. A lack of calpains can lead to elevated levels of damaged proteins, reduce optical performance, and cause cataract. Also, excessive stimulation of calpain activity by raised Ca2+ levels can increase proteolysis and cause cataracts. Calpain inhibitors, therefore, could be useful in the nonsurgical treatment of cataract. However, calpain inhibitors of high molecular weight are unable to cross membranes so have been of no therapeutic use, while others are poorly water-soluble or are toxic to lenses.29

Protein Modification

Additive modifications of lens proteins (e.g., crystallins) include methylation, acetylation, carbamylation, glycation in diabetics, and binding of ascorbate, which may be the cause of lens discoloration. These additions occur especially in disease and can alter the function or properties of a protein. Diabetes (reducing sugars), renal failure (cyanate generated from urea), aging (photo-oxidation products), and steroid use (ketoamines) have been linked to cataracts. Additive modifications can also make proteins more susceptible to photo-oxidation by UV light.26,27 Subtractive modifications include cleavage by enzymes (such as calpains) of crystallin which causes precipitation of lens proteins. Cleavage of channel proteins can affect intercellular communication. Neutral modifications such as isomerization can denature proteins, affecting their function. Deamidation changes the charge and affects protein– protein interactions. Proteins in the center of the lens are as old as the individual and are very stable, but over several decades they can undergo conformational changes (unfolding) that expose thiol groups, which are usually ‘hidden’ in the folds of the protein (Fig. 5-17-1). The exposed glutathione groups can be oxidized to form disulfide bonds (GSSG) causing aggregation of proteins. The conformation changes and aggregation result in scattering and absorption of light. 27

Oxidation

414

Oxidation is a key feature in the pathogenesis of most cataracts. Low oxygen levels (O2) are important for maintaining a clear lens. There is a steep oxygen gradient from the outer part of the lens to the center. Mitochondria in the lens cortex remove most of the oxygen, thus keeping nuclear O2 levels low. However, in older people mitochondrial function diminishes and superoxide production by the mitochondria increases, resulting in increased nuclear oxygen and superoxide levels. As the lens ages, a lens barrier develops at approximately the cortex– nuclear interface, which impedes the flow of molecules such as antioxidants (including glutathione) into the nucleus. Unstable nuclear molecules such as peroxide (H2O2), which are generated in the nucleus or which penetrate the barrier, therefore cause protein oxidation. Also, there is a lower concentration of antioxidants. Decomposition of UV

filters in the nucleus also produces unstable, reactive molecules that bind to proteins, especially if antioxidant glutathione (GSH) levels are low. Ascorbate also becomes reactive with proteins in the absence of GSH. These oxidative changes can be detected even in the earliest cataracts and are progressive. Elevated levels of superoxide H2O2 in the aqueous may also cause cortical cataracts since the cortex is closest to the aqueous. Copper and iron are present in higher concentrations in cataract lenses, and are also involved in redox reactions, which produce hydroxyl radicals.27

Defensive Mechanisms

Antioxidant enzymes and antioxidants such as ascorbate, glutathione, tocopherols, and carotenoids maintain lens proteins in the reduced state and are the primary defense mechanisms. In advanced, agerelated, nuclear cataracts more than 90% of protein sulfhydryl groups and almost half of all methionine residues in the nuclear proteins become oxidized. Secondary defenses include proteolytic and repair processes, which degrade and eliminate damaged proteins, UV filters, and other molecules such as glutathione reductase and free radical scavenging systems. Failure of these protective mechanisms, a shortage of antioxidants, and increased free radicals result in cell membrane and protein damage.26,27

Other Factors

Crystallins may have a number of functions. For example α-crystallin may be a chaperone that binds to other lens proteins to prevent precipitation. Decreased crystallin levels cause proteins to precipitate, which leads to cataract formation. Phase separation of proteins refers to the hydrophobic aggregation of lens proteins causing protein-rich and-poor regions in the lens fibers, which results in light scatter. The lipid composition of the cell membranes also changes with age, which may have functional consequences.

CAUSES OF CATARACT Age

The cumulative effect of many environmental factors (UV light, X-irradiation, toxins, metals, steroids, drugs, and diseases including diabetes) causes age-related cataracts. Gene expression changes result in altered enzyme, growth factor, and other protein levels. Protein modification, oxidation, conformational changes, aggregation and phase separation, formation of the nuclear barrier, increased proteolysis, defective calcium metabolism, and defense mechanisms are also important factors. Compromised ion transport leads to osmotic imbalances and intercellular vacuolation. Abnormal cellular proliferation and differentiation also produces opacities (Fig. 5-17-2).

Systemic Disorders

Fig. 5-17-2  Age-related cataract. Nuclear sclerosis and cortical lens opacities are present.

A

B Fig. 5-17-3  Traumatic cataract. (A) Typical flower-shaped pattern with coronary lens opacities. (B) Seen in retroillumination in anterior subcapsular region.

Trauma

Blunt trauma that does not result in rupture of the capsule may allow fluid influx and swelling of the lens fibers. The anterior subcapsular region whitens and may develop a characteristic flower-shaped pattern (Fig. 5-17-3), or a punctate opacity. A small capsular-penetrating injury results in rapid fiber hydration and a localized lens opacity; a larger rupture results in complete lens opacification. Penetrating injuries can be caused by accidental or surgical trauma such as a peripheral iridectomy or during a vitrectomy. Electric shocks as a result of lightning or industrial accident cause coagulation of proteins, osmotic changes and fern-like, grayish white

In uncontrolled type 1 diabetes mellitus in young people, hypergly­ cemia causes glucose to diffuse into the lens fiber, where aldose reductase converts it to sorbitol. The cell membrane is impermeable to sorbitol, therefore it accumulates and the osmotic effect draws water into the lens fibers which swell, and then rupture. The cataract progresses rapidly with the development of white, anterior and posterior subcapsular and cortical opacities. In type 2 diabetic adults, an early-onset age-related type of cataract occurs and is more prevalent with longer duration of the diabetes. Many mechanisms are involved and include sorbitol accumulation, protein glycosylation, increased superoxide production in the mitochondria, and phase separation. During hyperglycemia, glucose is reduced to sorbitol, depleting antioxidant reserves and less glutathione is maintained in the reduced form, which causes other oxidative damage. Levels of lens Ca2+ are also elevated, which activates calpains causing unregulated proteolysis of crystallins. The cataracts are usually cortical or posterior subcapsular, or less frequently nuclear, and progress more rapidly than age-related cataract.31,32 Galactosemia is an autosomal recessive disorder where a lack of one of the three enzymes involved in the conversion of galactose into glucose causes a rise in serum galactose levels. There is an accumulation of galactitol within the lens fibers, and water inflow. Anterior and posterior subcapsular opacities occur during infancy, which later become nuclear. Galactose-1-phosphate uridyltransferase galactosemia is also associated with failure to thrive, mental retardation, and hepato­ splenomegaly. Progression of the cataract can be prevented if galactose is removed from the diet. Galactokinase deficiency is associated with galactosemia and cataract but without the systemic manifestations.33 Fabry’s disease is an X-linked lysosomal storage disorder that results in accumulation of the glycolipid ceramide trihexoside. The patient suffers from episodic fever, pains, hypertension, renal disease, and a characteristic rash. In the affected man and the carrier woman, a typical mild, ‘spoke-like’, visually insignificant cataract develops. Lowe’s or oculocerebrorenal syndrome is a severe X-linked disorder that results in mental retardation, renal tubular acidosis, aminoacidosis, and renal rickets. Associated congenital glaucoma, congenital cataracts, and corneal keloids can all lead to blindness. The lens is small, discoid and with a total cataract. Female carriers may show focal dot opacities in the cortex. Alport’s syndrome is a dominant, recessive, or X-linked trait disease causing hemorrhagic nephropathy and sensorineural deafness. Ocular features include congenital or postnatal cortical cataract, anterior or posterior lenticonus, and microspherophakia. Dystrophia myotonica is a dominantly inherited disorder and results in muscle wasting and tonic relaxation of skeletal muscles. Other features include premature baldness, gonadal atrophy, cardiac defects, and mental retardation. Cataract is a key diagnostic criterion and may develop early, but usually occurs after 20 years of age and progresses slowly, eventually becoming opaque. Early cataract consists of polychromatic dots and flakes in the superficial cortex. As the opacities mature, a characteristic stellate opacity appears at the posterior pole. Other ocular features include hypotony, blepharitis, abnormal pupil responses, and pigmentary retinopathy. Rothmund-Thompson syndrome is an autosomal recessive disorder characterized by poikiloderma, hypogonadism, saddle-shaped nose, abnormal hair growth, and cataracts, which develop between the second and fourth decades of life and progress rapidly. Werner’s syndrome is an autosomal recessive disorder with features that include premature senility, diabetes, hypogonadism, and arrested growth. Juvenile cataracts are common. The condition usually leads to death at about 40 years of age. Cockayne’s syndrome causes dwarfism, but with disproportionately long limbs with large hands and feet, deafness, and visual loss from retinal degeneration, optic atrophy, and cataracts.

5.17 Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

anterior and posterior subcapsular opacities.30 Ionizing radiation, such as from X-rays, damages the capsular epithelial cell DNA, affecting protein and enzyme transcription and cell mitosis. An enlarging posterior pole plaque develops. Non-ionizing radiation, such as infrared, is the cause of cataract in glassblowers and furnace workers working without protective lenses. A localized rise in the temperature of the iris pigment epithelium causes a characteristic posterior subcapsular cataract, which may be associated with exfoliation of the anterior capsule.

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5

Dermatological Disorders

The Lens

The skin and the lens are of ectodermal origin embryologically. Therefore, skin disorders may be associated with cataract formation. Atopic dermatitis and eczema may affect any part of the body, especially the limb flexures. Localized proliferation of lens epithelium occurs in some atopic adults, usually as a bilateral, rapidly progressive ‘shield cataract’ (a dense, anterior subcapsular plaque with radiating cortical opacities, and wrinkling of the anterior capsule). Posterior subcapsular opacities may also occur. Ichthyosis is an autosomal recessive disorder that features hypertrophic nails, atrophic sweat glands, cuneiform cataracts, and nuclear lens opacities. Incontinentia pigmenti is an X-linked dominant disorder that affects skin, eyes, teeth, hair, nails, and the skeletal, cardiac, and central nervous systems. Blistering skin lesions occur soon after birth, followed by warty outgrowths. Ocular pathology includes leukokoria, cataract, chorioretinal changes, and optic atrophy.

Central Nervous System Disorders

Neurofibromatosis type II is an autosomal dominant disorder causing numerous intracranial and intraspinal tumors and acoustic neuromata. Ocular features include combined hamartoma of the retina and retinal pigment epithelium, epiretinal membranes, iris Lisch nodules (a diagnostic sign), and posterior subcapsular, or cortical cataracts that develop in the second or third decade of life. Zellweger syndrome, also known as hepatocerebrorenal syndrome, is an autosomal recessive disorder, characterized by renal cysts, hepato­ splenomegaly, and neurological abnormalities. Ocular features include corneal clouding, retinal degeneration, and cataracts. Norrie’s disease is an X-linked recessive disorder that causes leuko­ ria, congenital infantile blindness, and is associated with mental retardation and cochlear deafness. In the eye, vitreoretinal dysplasia, retinal detachment, vitreous hemorrhage, and formation of a white retrolental mass occur. Eventually, a cataract forms.

Ocular Disease and Cataracts

Inflammatory uveitis (e.g., Fuchs’ heterochromic cyclitis and juvenile idiopathic arthritis) usually results in posterior subcapsular or posterior cortical lens opacities. Infective uveitis (e.g., ocular herpes zoster and toxoplasmosis, syphilis, and tuberculosis) can cause cataracts, but the organism does not penetrate the lens. In maternal rubella infection, after 6 weeks of gestation, the virus can penetrate the lens capsule causing unilateral or bilateral, dense, nuclear opacities at birth, or they may develop several weeks or months later. Corticosteroid treatment can also cause cataracts, usually posterior subcapsular. Retinal pigment degenerations such as retinitis pigmentosa, Usher’s syndrome, and gyrate atrophy are associated with cataracts, which are usually posterior subcapsular opacities. Retinal detachment and retinal surgery may cause a posterior subcapsular cataract particularly in association with vitrectomy, silicone oil injection and tamponade, or an anterior subcapsular form may develop because of metaplasia of the lens epithelium after vitreoretinal surgery. High myopia is associated with posterior cortical, subcapsular, and nuclear cataracts. Ciliary body tumors may be associated with cortical or lamellar cataract in the affected quadrant. Anterior segment ischemia may cause a subcapsular or nuclear cataract, which progresses rapidly.

Toxic Causes

416

Topical, inhaled, and systemically administered steroids can cause posterior subcapsular cataracts. Direct mechanisms included interaction of steroids with enzymes which affects their function, e.g., steroid modulation of Na+,K+-ATPase may cause sodium-potassium pump inhibition affecting osmotic regulation. Steroids also induce crystallin conformational changes, causing aggregation and affecting intracellular Ca2+ homeostasis, which causes protein bonding. Indirectly, steroids affect DNA/RNA synthesis of proteins and enzymes causing metabolic changes, and may also affect ciliary body growth hormone levels responsible for lens cellular differentiation, which cause posterior subcapsular opacities.26 Chronic use of long-acting anticholinesterases previously used in the treatment of chronic open-angle glaucoma may cause anterior subcapsular vacuoles and posterior subcapsular and nuclear cataracts. Pilocarpine, a shorter-acting agent, causes less marked changes. The

mechanism of action is unknown. Phenothiazines, such as chlorpromazine, may cause deposition of fine, yellow-brown granules under the anterior capsule in the pupillary zone and may develop into large stellate opacities but are not usually visually significant. The development of the opacities may be related to the cumulative dose of the medication; photosensitization of the lens may play a role. Allopurinol used in the treatment of gout is associated with cataracts.34 Psoralen-UV-A therapy for psoriasis and vitilligo has been shown to cause cataracts in very high doses in animal studies, but is rare in humans; concomitant UV exposure may be a risk factor. Antimitotic drugs, such as busulfan, used in the treatment of chronic myeloid leukemia, may cause posterior subcapsular cataract. The antimalarial chloroquine (but not hydroxychloroquine), which is also used in the treatment of arthritis, may cause white, flake-like posterior subcapsular lens opacities. Amiodarone is used to treat cardiac arrhythmias and causes insignificant anterior subcapsular opacities and corneal deposits.35 Siderosis, from a ferrous intraocular foreign body, causes iron deposits in the lens epithelium and iris, and results in a brown discoloration of the iris and a flower-shaped cataract. Wilson’s disease, an autosomal recessive disorder of copper metabolism, causes a brown ring of copper deposition in Descemet’s membrane and the lens capsule, resulting in a sunflower cataract – an anterior and posterior capsular disc-shaped polychromatic opacity in the pupillary zone with petal-like spokes that is not usually visually significant.36 Hypocalcemia in hypoparathyroidism is associated with cataracts. In children, the cataract is lamellar; in adults it produces an anterior or posterior punctate subcapsular opacity.

Congenital and Juvenile Cataracts

Congenital cataracts are noted at birth, infantile cataracts occur in the first year, and juvenile cataracts develop during the first 12 years of life. Hereditary cataracts may be associated with other systemic syndromes, such as dystrophia myotonica. About one third of all congenital cataracts are hereditary and unassociated with any other metabolic or systemic disorders. Trisomy 21, or Down’s syndrome, is the most common autosomal trisomy, with an incidence of 1 per 800 births. Systemic features include mental retardation, stunted growth, mongoloid facies, and congenital heart defects. Ocular features include visually disabling lens opacities in 15% of cases, narrow and slanted palpebral fissures, blepharitis, strabismus, nystagmus, light-colored and spotted irises (Brushfield spots), keratoconus, and myopia.37 Cataract is also associated with trisomy 13 (Patau’s syndrome), trisomy 18 (Edwards’ syndrome), Cri du chat syndrome (deletion of short arm of chromosome 5), and Turner’s syndrome (X chromosome deletion). A total cataract is a complete opacity present at birth. It may be hereditary (autosomal dominant or recessive) or associated with systemic disorders such as galactosemia, rubella, or Lowe’s syndrome. Infantile cataracts cause amblyopia if unilateral and may cause strabismus and nystagmus if bilateral. The incidence is about 0.4% of newborns, but the majority of cases are not associated with poor vision. Amblyopia depends on the size, location, and density of the cataract. The causes of infantile cataracts are many and include maternal infections (such as rubella), systemic diseases, hereditary disorders, and ocular disease.

MORPHOLOGY Age-related changes in the lens affect the lens power and light transmissibility, causing fluctuations in vision and scattering of light. Slitlamp biomicroscopy can be used to grade and differentiate lens opacities. Each type of opacity has different clinical effects, and combinations of the different types occur. Nuclear opacities are caused by a gradual increase in the optical density of the deepest layers of the nucleus, progressing slowly to involve more superficial layers (see Fig. 5-3-1). The nucleus may also change color from clear to yellow to brown (catataracta brunescence) and sometimes to black (catataracta nigra). Patients may experience increased myopia (because of the increased refractive index of the lens) and a progressive, slow reduction in visual acuity and loss of contrast sensitivity. Cortical opacities cause few symptoms initially as the visual axis remains clear, but later the opacities may involve most of the cortex of the lens (Fig. 5-3-2).

ASSESSMENT AND GRADING OF CATARACTS Grading and classifications of cataracts (Box 5-17-1) are useful in cataract research, in studies to explore causation, and in trials of anticataract drugs. Direct ophthalmoscopy with retroillumination can be used to assess and grade cataracts.38 The Lens Opacification Classification System II (LOCS-II) slit-lamp grading system is reproducible and has been validated. Using slit-lamp direct and retroillumination, nuclear, cortical, and posterior subcapsular cataracts are graded by comparison with a set of standard photographs.39 Devices for quantifying lens opacification have also been developed (such as the Kowa Early Cataract Detector and the Scheimpflug Photo slit lamp).

BOX 5-17-1  INFANTILE CATARACTS Anterior Polar Cataract  Dominantly inherited, well-defined opacities of the anterior capsule may affect the vision  Caused by imperfect separation of lens from surface ectoderm, by epithelial damage, or by incomplete reabsorption of the vascular tunic of the lens  May have anterior or posterior conical projections; if it extends into the cortex in a rod shape, it is called a ‘fusiform’ cataract Spear Cataract  Dominantly inherited, polymorphic cataract with needle-like clusters of opacities in the axial region, which may not affect vision Coralliform Cataract  Dominantly inherited cataract, which consists of round and oblong opacities, grouped toward the center of the lens; they resemble coral Floriform Cataract  A rare, ring-shaped, bluish white, flower-shaped cataract in the axial region Lamellar Cataract  A common, bilateral and symmetrical, round, gray shell of opacity that surrounds a clear nucleus; usually dominantly inherited cataract, which may have a metabolic or inflammatory cause  Fibers become opacifed in response to a specific insult during their most active metabolic stage and are pushed deeper into the cortex as normal lens fibers are laid down around it

VISUAL EFFECTS OF CATARACTS The effect of cataract on vision varies according to the degree of the cataract and the cataract morphology.

Visual Acuity

Visual acuity is reduced, and this has been the standard measure of the visual effect of cataracts. However, visual acuity can remain good despite other lens opacity-related effects on vision, which compromise the patient’s ability to function.

Contrast Sensitivity, Glare, and Wavefront Aberrometry

Cataract-related reduction in contrast sensitivity causes reduced acuity at low ambient light levels. Contrast sensitivity measurements based on linear sine-wave gratings have resulted in improved understanding and quantifying of visual quality and function. Wavefront aberrometry measures the optical quality in terms of spatial distortion. Both measurements are useful for understanding the effects of cataracts on vision.40 Glare, which occurs as a result of forward scatter of light, may be produced by opacities that do not lie within the pupil diameter and, therefore, also affects visual function.41

Other Effects

The natural aging of the human lens produces a progressive hyperopic shift. Nuclear changes induce a modification of the refractive index of the lens and produce a myopic shift. Cortical opacities may cause localized changes in the refractive index of the lens, which may result in monocular diplopia or even polyopia. As the lens nucleus becomes more yellow, it absorbs blue light. The slow change is not apparent to the patient until after cataract surgery. The morphology, density, and location of lens opacities may cause changes in the visual field. These changes may be progressive and may obscure the disk; therefore, diagnosis and monitoring of glaucoma may be compromised.

ANOMALIES OF LENS GROWTH The lens is ectodermal and the vascular capsule is mesodermal in origin. A number of exogenous or endogenous influences can affect ectodermal or mesodermal development and can have multiple manifestations in the eye.

5.17 Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

Posterior subcapsular opacities begin at the posterior polar region, then spread toward the periphery. Patients have significant glare dis­ ability because of light scattering at the nodal point of the eye. Complete opacification of the lens eventually occurs. The crystalline lens may then swell (intumescent cataract; see Fig. 5-3-3). The cortical material may liquefy (Morgagnian cataract; see Fig. 5-3-4) and then re-absorbed causing the solid nucleus to ‘sink’ to the bottom of the capsular bag.

Aphakia

Aphakia is the absence of the lens. Primary aphakia is rare and is associated with a primary defect in the surface ectoderm. It is associated with other abnormalities of the anterior segment, such as microphthalmos, microcornea, and nystagmus. Secondary aphakia is more common and is characterized by the presence of lens remnants. The cause is unknown. It may be associated with the same malformations, or may be found in an otherwise normal eye.42

Cataracta Centralis Pulverulenta  Dominantly inherited, nonprogressive cataract consisting of fine, white, powdery dots within the embryonic or fetal nucleus (Fig. 5-17-4) Congenital Punctate Cerulean Cataract  Bilateral, nonprogressive, small, bluish dots scattered throughout the lens with little effect on vision Congenital Suture (Stellate) Cataract  Dominantly inherited bluish dots or a dense, chalky band around the sutures affecting one or both fetal sutures, especially posteriorly and may interfere with vision Mittendorf’s Dot  A small (about 1 mm diameter), nonprogressive, white condensation occurs on the posterior pole of the lens capsule; it may be decentered slightly inferonasally and may be attached to a free-floating thread in the vitreous gel, which represents the anterior part of the hyaloid artery remnant Congenital Disciform Cataract  Central thinning creates a doughnut shape, which may arise from failure of development of the embryonic nucleus

Fig. 5-17-4  Cataracta centralis pulverulenta. Opacification of fetal nucleus.

417

may be associated with coloboma of the iris, ciliary body, or choroid, or with ectopia lentis, sperophakia, or localized lens opacities. It may occur because persistence of mesodermal vascular capsules remnants prevents the development of zonules in that area.

5 The Lens

Ectopia Lentis

Fig. 5-17-5  Marfan syndrome. A retroillumination slit-lamp photograph of ectopia lentis associated with Marfan syndrome.

Microspherophakia

Microspherophakia is the presence of a small, usually spherical crystalline lens with an increased anteroposterior thickness and steeper than normal anterior and posterior lens curvatures. Hypoplastic zonules may cause the lens to be small and spherical, or the hypoplastic zonules may develop as a consequence of the lens changes. It is bilateral and may be familial, may occur as an isolated defect, or may be associated with other mesodermal defects, such as the Weill-Marchesani and Marfan syndromes. The condition causes lenticular myopia and may be associated with lens dislocation (usually downward) and pupil block.42,43

Lenticonus and Lentiglobus

Abnormalities of the central lens curvature include lenticonus (conical) and lentiglobus (spherical), and may be anterior or posterior. They may be associated with abnormalities of the lens epithelium, by traction from hyaloid remnants or by localized areas of capsule weakness, which causes bulging. They may be inherited as an autosomal recessive trait or be associated with other abnormalities, such as Alport’s syndrome (familial hemorrhagic nephritis) or Lowe’s oculocerebral syndrome (associated with posterior lenticonus). They can cause lenticular myopia with irregular astigmatism. Lens umbilication is a depression in the lens surface (usually posteriorly).42,44

Lens Coloboma

Lens coloboma is a unilateral, congenital indentation of the lens periphery, which occurs as a result of a localized absence of zonules. It

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418

Ectopia lentis, or displaced lens, is usually a bilateral condition caused by extensive zonular malformation. The lens is displaced in the opposite direction to the weak zonules (usually superomedially) and usually presents in childhood or young adulthood. The lens may sublux out of the central posterior chamber or may dislocate completely into the anterior chamber or vitreous or become cataractous. It may be an autosomal dominant or recessive trait or may be associated with other developmental abnormalities of the eyes, such as iris coloboma, microspherophakia, aniridia, or ectopia pupillae congenita. It may also be associated with systemic disorders such as Marfan syndrome (Fig. 5-17-5), Weill-Marchesani syndrome, homocystinuria, sulfite oxidase deficiency, and hyperlysinemia. The clinical features of a subluxed lens include iridodinesis (tremulous iris), fluctuating anterior chamber depth and vision, and phacodinesis (a visibly mobile lens). Vitreous may herniate into the anterior chamber. Pupil block may occur with iris apposition to the vitreous face or an anterior dislocated lens (into the anterior chamber).

KEY REFERENCES Chylack LT, Leske MC, McCarthy D. Lens Opacities Classification System II (LOCS). Arch Ophthalmol 1989;107:991–7. Blswas S, Harris F, Dennison S, et al. Calpains: enzymes of vision? Med Sci Monit 2005;11:301–10. Brian G, Taylor H. Cataract blindness – challenges for the 21st century. Bull World Health Org. 2001;79:249–56. Ederer F, Hiller R, Taylor HR. Senile lens changes and diabetes in two population studies. Am J Ophthalmol 1981;91:381–95. Frick KD, Foster A. The magnitude and cost of global blindness: an increasing problem that can be alleviated. Am J Ophthalmol 2003;135:471–6. Hawse JR, Hejtmancik JF, Horwitz J, et al. Identification and functional clustering of global gene expression differences between age-related cataract and clear human lenses and aged human lenses. Exp Eye Res 2004;79:935–40. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid induced posterior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75. Kelly SP, Thornton J, Edwards R, et al. Smoking and cataract: review of causal association. J Cataract Refract Surg 2005;31:2395–404. Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Org 2004;82:844–51. Shiels A, Bennett TM, Hejtmancik JF. Cat-Map: putting cataract on the map. Molecular Vision 2010;16:2007–15. Tang D, Borchman D, Yappert M, et al. Influence of age, diabetes, and cataract on calcium, lipidcalcium, and protein-calcium relationships in human lenses. Invest Ophthalmol Vis Sci 2003;44:2059–66. Truscott RJ. Age-related nuclear cataract – oxidation is the key. Exp Eye Res 2005;80:709–5. West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol 2006;141:157–66.

REFERENCES 1. Resnikoff S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Org 2004;82:844–51.

24. Drel V, Pacher P, Ali T, et al. Aldose reductase inhibitor fidarestat counteracts diabetesassociated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. International Journal of Molecular Medicine 2008;21(6):667–76.

3. Frick KD, Foster A, Bah M, et al. Analysis of costs and benefits of the Gambian Eye Care program. Arch Ophthalmol 2005;123:239–43.

25. Matsumoto T, Ono Y, Kuromiya A, et al. Long-term treatment with ranirestat (AS-3201), a potent aldose reductase inhibitor, suppresses diabetic neuropathy and cataract formation in rats. Journal of Pharmacological Sciences 2008;107(3):340–8.

4. Brian G, Taylor H. Cataract blindness – challenges for the 21st century. Bull World Health Org 2001;79:249–56.

26. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid-induced posterior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75.

5. Chaterjee A, Milton RC, Thyle S. Cataract prevalence and aetiology in Punjab. Br J Ophthalmology 1982;66:35–42.

27. Truscott RJ. Age-related nuclear cataract – oxidation is the key. Exp Eye Res 2005;80:709–25.

6. Khan HA, Leibowitz HM, Ganley JP, et al. The Framingham eye study: 1. Am J Epidemiol 1977;1206:17–32.

28. Tang D, Borchman D, Yappert M, et al. Influence of age, diabetes, and cataract on calcium, lipid-calcium, and protein-calcium relationships in human lenses. Invest Ophthalmol Vis Sci 2003;44:2059–066.

7. Hawse JR, Hejtmancik JF, Horwitz J, et al. Identification and functional clustering of global gene expression differences between age-related cataract and clear human lenses and aged human lenses. Exp Eye Res 2004;79:935–40.

29. Blswas S, Harris F, Dennison S, et al. Calpains: enzymes of vision? Med Sci Monit 2005;11:301–10.

8. Congdon NG. Prevention strategies for age related cataract: present limitations and future possibilities. Br J Ophthalmol 2001;85;516–20. 9. Shiels A, Bennett TM, Hejtmancik JF. Cat-Map: putting cataract on the map. Molecular Vision 2010;16:2007–15. 10. Hiller R, Podgor MJ, Sperduto RD, et al. The Framingham Eye Studies Group: a longitudinal study of body mass index and lens opacities. Ophthalmology 1998;105:1244–50. 11. Minassian DC, Mehra V, Verry J-D. Dehydrational crisis: a major risk factor in blinding cataract. Br J Ophthalmol 1989;73:100–05. 12. Mohan M, Sperduto RD, Angra SK, et al. The India Case-Control Study Group: India-US casecontrol study of age-related cataracts. Arch Ophthalmol 1989;107:670–6. 13. West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol 2006;141:157–66. 14. Neale RE, Purdie JL, Hirst LW, et al. Sun exposure as a risk factor for nuclear cataract. Epidemiology 2003;14:707–12. 15. McCarty CA, Nanjan MB, Taylor HR. Attributable risk estimates for cataract to prioritize medical and public health action. Invest Ophthalmol Vis Sci 1999;41:3720–5. 16. Kelly SP, Thornton J, Edwards R, et al. Smoking and cataract: review of causal association. J Cataract Refract Surg 2005;31:2395–404. 17. Hiratsuka Y, Li G. Alcohol and eye diseases: a review of epidemiologic studies. J Stud Alcohol 2001;62:397–402. 18. Morris MS, Jacques PF, Hankinson SE, et al. Moderate alcoholic beverage intake and early nuclear and cortical lens opacities. Ophthalmic Epidemiol 2004;11:53–65. 19. Klein BE, Klein R, Lee KE, et al. Socioeconomic and lifestyle factors and the 10-year incidence of age-related cataracts. Am J Ophthalmol 2003;136:506–12. 20. Taylor A. Nutritional and environmental influences on risk for cataract. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology, vol. 1. Ch 72. Philadelphia, PA: Lippincott Williams and Wilkins; 2002. 21. Ederer F, Hiller R, Taylor HR. Senile lens changes and diabetes in two population studies. Am J Ophthalmol 1981;91:381–95.

30. Fraunfelder FT, Hanna C. Electric cataracts. 1: Sequential changes, unusual and prognostic findings. Arch Ophthalmol 1972;87:179–83. 31. Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 2005;26:380–92. 32. Biswas S, Harris F, Singh J, et al. Role of calpains in diabetes mellitus-induced cataractogenesis: a mini review. Mol Cell Biochem 2004;261:151–59. 33. Elman MJ, Miller MT, Matalon R. Galactokinase activity in patients with idiopathic cataracts. Ophthalmology 1986;93:210–25. 34. Garbe E, Suissa S, LeLorier J. Exposure to allopurinol and the risk of cataract extraction in elderly patients. Arch Ophthalmol 1998;116:1652–6. 35. Flach AJ, Dolan BJ, Sudduth B, et al. Amiodarone induced lens opacities. Arch Ophthalmol 1983;101:1554–6. 36. Walshe JM. The eye in Wilson’s disease. Birth Defects Orig Artic Ser 1976;3:187–94. 37. Shaprito MB, France TD. The ocular features of Down’s syndrome. Am J Ophthalmol 1985;99:659–63. 38. Mehra V, Minassian DC. A rapid method of grading cataract in epidemiological studies and eye surveys. Br J Ophthalmol 1988;72:801–3. 39. Chylack LT, Leske MC, McCarthy D. Lens Opacities Classification System II (LOCS). Arch Ophthalmol 1989;107:991–7. 40. Ginsburg AP. Contrast sensitivity: determining the visual quality and function of cataract, intraocular lenses and refractive surgery. Curr Opin Ophthalmol 2006;17:19–26. 41. Lasa MS, Podgor MJ, Datiles MB, et al. Glare sensitivity in early cataracts. Br J Ophthalmol 1993;77:489–91. 42. Wong PC, Dickens CJ, Hoskins Jr D. The developmental glaucomas. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology, vol. 3, Ch 51. Philadelphia, PA: Lippincott Williams and Wilkins, 2002. 43. Chan RT, Collin HB. Microspherophakia. Clin Exp Optom 2002;85:294–9. 44. Gibbs ML, Jacobs M, Wilkie AO, et al. Posterior lenticonus: clinical patterns and genetics. J Pediatr Ophthalmol Strabismus 1993;30:171–5.

5.17 Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

2. Frick KD, Foster A. The magnitude and cost of global blindness: an increasing problem that can be alleviated. Am J Ophthalmol 2003;135:471–76.

23. 8b Kador P, Betts D, Wyman M, et al. Effects of topical administration of an aldose reductase inhibitor on cataract formation in dogs fed a diet high in galactose. American Journal of Veterinary Research 2006;67(10):1783–7.

22. Kojima M, Sun L, Hata I, et al. Efficacy of α-lipoic acid against diabetic cataract in rat. Japanese Journal of Ophthalmology 2007;51(1):10–3.

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PART 6 RETINA AND VITREOUS SECTION 1 Anatomy

6.1

Structure of the Neural Retina Hermann D. Schubert

Definition: The structure of the neural retina reflects its embryologic

development and its ultimate purpose: the absorption and processing of photons of visible light.

INTRODUCTION The primary purpose of the corneoscleral and uveal coats of the eye is to focus light on the retina; they also provide protection and nourishment and enable ocular movement. The retina is derived embryologically from the optic vesicle, an outpouching of the embryonic forebrain.1 The bilayered neuroepithelial structure of the mature retina reflects the apex-to-apex arrangement of the original optic cup. It also forms the wall of a cavity, the vitreous cavity, which is filled with glycosaminoglycans and collagen. The ocular cavity is homologous to a leptomeningeal cistern,2 in that both vitreous and choroid are derived from mesenchyme that sandwiches the neuroepithelium on its path away from the brain. The ocular neuroepithelial cyst has two openings. Anteriorly lies the pupil, which is a full-thickness aperture, and posteriorly lies the optic nerve in which, similar to a coloboma, only derivatives of the inner retinal layers are found. Since the cell apices are oriented inwardly, the two layers of the optic cup and their derivatives are enveloped externally by basement membrane (Fig. 6-1-1). The relationship of the epithelial layers to each other is modified from anterior to posterior. Anterior to the ora serrata, the pigmented and nonpigmented epithelia of the iris and ciliary body are joined at their apices by a system of intercellular junctions (Fig. 6-1-2), which is continuous with the external limiting layer of the neural retina and the

ARRANGEMENT OF MÜLLERIAN GLIA AND RETINAL PIGMENT EPITHELIAL CELLS

apical junctional girdles of the retinal pigment epithelium (RPE; Fig. 6-1-3). At the ora serrata, the pigmented epithelium is continued as RPE; its basement membrane becomes Bruch’s membrane. The nonpigmented epithelium of the ciliary body and pars plana is continued posteriorly as the neural retina; its basement membrane becomes the internal limiting membrane. The union of the epithelial layers delimits the anterior cul-de-sac of the subretinal space.3

ARRANGEMENT OF RETINA AND PIGMENT EPITHELIUM apical junctions

Fig. 6-1-2  Apex-to-apex arrangement of retina and pigment epithelium. Apical attachments connect the iris and ciliary body epithelia (red dotted line).

TRANSITION OF RETINA TO NONPIGMENTED EPITHELIUM AT THE ORA SERRATA internal limiting membrane Müller cells base

ora serrata vitreous attachments basement membrane

apex RPE cells Bruch’s membrane

internal limiting membrane

Müller cells

Fig. 6-1-1  Apex-to-apex arrangement of müllerian glia and retinal pigment epithelial cells. Because the cell apices face each other, the neuroepithelia are enveloped externally by a basement membrane. Note that this basement membrane is elaborated by a single-layer neuroepithelium, with the exception of the internal limiting membrane, which is formed by Müller cells.

apex base external limiting membrane

nonpigmented epithelium pigmented epithelium Bruch's (basement) membrane

Fig. 6-1-3  Transition of neural retina to nonpigmented epithelium at the ora serrata. The external limiting membrane, which consists of the attachment sites of photoreceptors and Müller cells, transforms into the apical junctional system of the pars plana epithelia. The internal limiting membrane becomes the basement membrane of the nonpigmented epithelium.

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6

STRUCTURES OF THE RETINA THAT BORDER THE OPTIC NERVE HEAD

FOVEAL MARGIN, FOVEAL DECLIVITY, FOVEOLA, AND UMBO

Retina and Vitreous

foveal diameter 1500 m

vitreous attachments

margin

foveola 350 m

Müller cells

internal limiting membrane Müller cells in inner nuclear layer

internal limiting membrane

central tissue meniscus of Kuhnt

external limiting membrane retinal pigment epithelium capillary arcade

external limiting membrane retinal pigment epithelium Bruch's (basement) membrane

intermediary border tissue of Kuhnt nerve axons

Fig. 6-1-4  Structures of the retina that border the optic nerve head. The junctional system of the external limiting membrane connects with the apical junctional system of the retinal pigment epithelium and is supported by the intermediary border tissue of Kuhnt.

declivity

umbo

fovea externa

Fig. 6-1-5  Foveal margin, foveal declivity, foveola, and umbo. The foveal diameter (from margin to margin) measures 1500 µm, and the foveola is 350 µm in diameter. The foveal avascular zone is slightly larger (500 µm) and is delimited by the capillary arcades at the level of the inner nuclear layer. The foveal excavation represents the fovea interna, which is lined by the internal limiting membrane. The fovea externa is represented by the junctional system of the external limiting membrane. Both Henle’s fibers and the accompanying glia assume a horizontal and radial arrangement in the fovea.

UMBO AND FOVEOLA The apex-to-apex arrangement between the epithelia that clearly exists anterior to the ora is continued posteriorly by Müller cells that face and intermittently contact the RPE (see Fig. 6-1-1). Here, the contact is maintained not by apical junctions (even though an interreceptor matrix exists) but by the pressure of the vitreous and by suction forces of the RPE. Müllerian glia are the main structural cells of the neural retina and are found throughout the retina from the ora to the optic nerve head. At the optic nerve head, the internal limiting membrane continues as the basement membrane of Elschnig, supported by the glial meniscus of Kuhnt (Fig. 6-1-4). The (glial) external limiting membrane joins the apices of the RPE to form the posterior cul-de-sac of the subretinal space,3 which is supported by a glial border tissue, the intermediary border tissue of Kuhnt. This border tissue continues posteriorly at the choroidal level as the border tissue of Elschnig; both tissues separate the outer retina and choroid from the axons of the inner retina. The axons in turn fixate the posterior retina to the scleral lamina cribrosa and its glial system. The retina, therefore, is fixed to the choroid directly by the apical junctional system at the ora serrata (anterior culde-sac of the subretinal space) and indirectly, via the choroid and ciliary body, to its attachments at the scleral spur and sclera. At the nerve head, all neuroepithelial and choroidal layers are fixed by both the junctional tissues and the exiting axons. The corneoscleral coat protects, moves, and holds the retina in the appropriate position and allows the object of regard to be focused on the center of the retina.

CENTER OF THE MACULA: UMBO

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The fovea represents an excavation in the retinal center and consists of a margin, a declivity, and a bottom (Fig. 6-1-5). The bottom corresponds to the foveola, the center of which is called the umbo. The umbo represents the precise center of the macula, the area of retina that results in the highest visual acuity. Usually, it is referred to as the center of the fovea or macula. Although both terms are commonly used clinically, neither is a precise anatomical designation. The predominant photoreceptor of the foveola and umbo is the cone. The foveal ‘nuclear cake’ results from the centripetal migration of the photoreceptors and the centrifugal lateral displacement of the bipolars and ganglion cells during foveal maturation, which occurs 3 months before and 3 months after term.4,5 Although their individual diameters are narrowed because of extreme crowding, central cones maintain their volume through elongation, up to a length of 70 µm.5 The central migration takes place in an area of 1500 µm diameter.4 The greatest concentration of cones is found in the umbo, an area of

fovea interna clear tissue

umbo

capillary

internal limiting membrane inner nuclear layer

nuclear cake

Henle's fibers outer nuclear layer external limiting membrane fovea externa umbo 150–200 m

Fig. 6-1-6  Umbo (center) and foveola. The outer nuclear layer is separated from the inner nuclear layer by the horizontal-oblique fibers of Henle. Umbo and foveola between few nuclei feature clear Müllerian fibers (clear tissue), delimited by Henle’s fibers externally and by the internal limiting membrane internally. The central 150–200 µm represents the umbo, where cone concentration is maximal.

150–200 µm diameter, referred to as the central bouquet of cones.5 Estimates of central cone density are 113 000 and 230 000 cones/mm2 in baboons and cynomolgus monkeys, respectively. For the central bouquet, the density of cones may be as high as 385 000 cones/mm2.6 The inner cone segments are connected laterally by a junctional system, the external limiting membrane. Their inner fibers (axons) travel radially and peripherally as fibers of Henle in the outer plexiform layer (Fig. 6-1-6). As a result of their high concentration and crowding, the central cones have their nuclei arranged in multiple layers in a circular shape, which resembles a cake (gateau nucleaire).5 Cones, including their inner and outer segments, are surrounded and enveloped by the processes of Müllerian glia, which concentrate on the vitreal side (tissu clair),5 just underneath the internal limiting membrane.7 Some glial cell nuclei are found in this inner layer, but most form part of the laterally displaced inner nuclear layer. Foveal development, therefore, involves the migration, elongation, concentration, and displacement of both neuronal cells and, most importantly, glial cells, the main structural element of the retina. Radiating striae found in the foveal internal limiting membrane are related to Henle’s fibers but are probably mediated by glia that elaborate and are connected to the internal limiting membrane. The density of the foveal glia has been measured as 16 600–20 000 cells/mm2.6

FOVEOLA

6.1 Structure of the Neural Retina

The bouquet of central cones is surrounded by the foveal bottom, or foveola, which measures 350 µm in diameter and 150 µm in thickness (see Fig. 6-1-5). This avascular area consists of densely packed cones that are elongated and connected by the external limiting membrane. As a result of the elongation of the outer segments, the external limiting membrane is bowed vitreally, a phenomenon that has been termed fovea externa. Both umbo and foveola represent the most visible part of the outer retina; however, to the level of the external limiting membrane, all cones and their axons are enveloped by the processes of Müller cells, which form the vitreal inner layer and elaborate and support the internal limiting membrane. Thus, the apex-to-apex arrangement of the optic cup is maintained by the processes of Müllerian glia that face the apices of the pigment epithelial cells in the foveola. The high metabolic demands of central cones are met by direct contact with the pigment epithelium, as well as through the processes of glia whose nuclei lie more peripheral in the inner nuclear layer and closer to the perifoveal vascular arcades (see Fig. 6-1-6). In pathologic conditions, loss of the normal foveolar reflex may indicate a glial disturbance (acute nerve cell damage, cloudy swelling) either primarily or mediated by the vitreous, which is tightly adherent to the thin internal limiting membrane. Loss of the foveal reflex may thus indicate traction or edema of glial cells and, secondarily, of cones. The inner glial layer may separate from the nuclear layer, which results in cyst-like schisis.

A

REGIONS OF THE MACULA (AREA CENTRALIS)

FOVEA The fovea consists of the thin bottom, a 22° declivity (the clivus),3 and a thick margin (see Figs 6-1-5 to 6-1-7). The bottom, or foveola, was described earlier. The declivity of 22° denotes the lateral displacement of the bipolars, horizontal and amacrine cells in the inner nuclear layer, which also includes the nuclei of its Müllerian glia. The avascular foveola is surrounded by the vascular arcades, a circular system of capillaries. These vessels are located at the level of the internal nuclear layer and leave an avascular zone of 250–600 µm between them. The declivity also is associated with an increase in basement membrane thickness, which reaches a maximum at the foveal margin. Internal limiting membrane thickness and strength of vitreal attachment are inversely proportional; that is, adhesions are strongest in the foveola.3 Not surprisingly, the foveal center is most affected in traumatic macular holes in which glial opercula suggest anterior-posterior traction as the cause. The margin of the fovea (margo foveae) is often seen biomicroscopically as a ring-like reflection of the internal limiting membrane, which measures 1500 µm (disc size) in diameter and 0.55 mm in thickness (see Fig. 6-1-7).

PARAFOVEA The parafovea is a belt that measures 0.5 mm in width and surrounds the foveal margin (see Fig. 6-1-7). At this distance from the center, the retina features a regular architecture of layers, which includes 4–6 layers of ganglion cells and 7–11 layers of bipolar cells.8

PERIFOVEA The perifovea surrounds the parafovea as a belt that measures 1.5 mm wide (see Fig. 6-1-7). The region is characterized by several layers of ganglion cells and six layers of bipolar cells.8

MACULA, OR CENTRAL AREA The umbo, foveola, fovea, parafovea, and perifovea together constitute the macula, or central area.9 The central area can be differentiated from the extra-areal periphery by the ganglion cell layer. In the macula, the ganglion cell layer is several cells thick; however, in the extra-areal periphery, it is only one cell thick. The macular border coincides with the course of the major temporal arcades and has an approximate diameter of 5.5 mm (see Fig. 6-1-7), which comprises the diameter of the fovea (1.5 mm), twice the width of the parafovea (2 × 0.5 = 1 mm), and twice the width of the perifovea (2 × 1.5 = 3 mm).10

perifoveal area parafoveal area fovea foveola umbo 1.5 mm

B

0.5 0.5 mm 0.35 mm mm 1.5 mm

1.5 mm

Fig. 6-1-7  Normal fundus with macula encompassed by major vascular arcades. The macula, or central area, has the following components from center to periphery: umbo, foveola, fovea, parafovea, and perifovea.

EXTRA-AREAL PERIPHERY The peripheral retina is divided arbitrarily into belts of near, middle, far, and extreme periphery.9 The belt of the near periphery is 1.5 mm wide, and the belt of the middle periphery, or equator, is 3 mm wide. The far periphery extends from the equator to the ora serrata. The width of this belt varies, depending on ocular size and refractive error. The average circumference of the eye is 72 mm at the equator and 60 mm at the ora serrata, and the average width of this belt is 6 mm. Since peripheral retinal pathology is usually charted in clock hours, 1 clock hour corresponds to 5–6 mm of far peripheral circumference. Therefore, the far periphery of the retina may be divided into 12 squares that measure approximately 6 × 6 mm. As a result of the insertion of the posterior vitreous base, most peripheral pathology falls into these squares. The ora serrata and pars plana are referred to as the extreme periphery.9

LAYERS OF THE NEURAL RETINA With the exception of the fovea, ora serrata, and optic disc, the neural retina is organized in layers, dictated by the direction of the müllerian glia, its organizational backbone. Essentially, there is the photoreceptor layer plus the bipolar and ganglion cell layer, which represent the outer first neuron and inner second neuron of the visual pathway. The müllerian glia elaborate the internal limiting membrane as its basement

421

6

NEURONAL CONNECTIONS IN THE RETINA AND PARTICIPATING CELLS

Retina and Vitreous

internal limiting membrane ganglion cell

amacrine cell

bipolar cell

horizontal cell

inner nuclear layer

middle limiting membrane external limiting membrane

membrane and extend to the external limiting membrane, where it communicates with the apices of the RPE (Fig. 6-1-8). The inner nuclear layer is home to the nuclei of the müllerian glia, the bipolar cells, and the horizontal and amacrine cells. The amacrine cells lie on the inside of the inner nuclear layer, and the horizontal cells lie on the outside (see Fig. 6-1-8). The inner nuclear layer has plexiform layers on either side, which connect it to the outer photoreceptor layer and the (inner) ganglion cell layer. From this simple anatomical consideration, it follows that rods and cones synapse with bipolar and horizontal cells in the outer plexiform layer. As a result of the increased length of Henle’s fibers, the junctional system (the middle limiting ‘membrane’) is found in the inner third of the outer plexiform layer, which is the only truly plexiform portion of this layer. The bipolar cells and amacrine cells of the inner nuclear layer synapse with the dendrites of the ganglion cells in the inner plexiform layer. In embryogenesis, müllerian glia, along with their internal limiting membrane and orientation, antedate photoreceptor differentiation; this is analogous to the rest of the central nervous system, in which structural development precedes individual cell differentiation.

KEY REFERENCES Fine BS, Yanoff M. Ocular histology. A text and atlas. New York: Harper & Row; 1979. p. 111–24. Gaertner I. The vitreous, an intraocular compartment of the leptomeninx. Doc Ophthalmol 1986;62:205–22.

Müller's fiber (glia)

Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Arch Ophthalmol 1969;82:151–9. Hogan MJ, Alvarado JA, Wedell JE. Histology of the human eye. Philadelphia: WB Saunders; 1971. p. 491−8.

cone

Krebs W, Krebs I. Quantitative morphology of the central fovea in the primate retina. Am J Anat 1989;184:225–36.

rod

Mann I. The development of the human eye. New York: Grune & Stratton; 1950. Polyak SL. The retina. Chicago: University of Chicago Press; 1941. Rochon-Duvigneaud A. Recherches sur la fovea de la retine humaine et particulierement sur le bouquet des cones centraux. Arch Anat Microsc 1907;9:315–42.

Fig. 6-1-8  Neuronal connections in the retina and participating cells. The inner nuclear layer contains the nuclei of the bipolar cells (second neuron) and Müllerian glia. The amacrine cells are found on the inside and the horizontal cells on the outside of this layer, next to their respective plexiform connections.

Access the complete reference list online at

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Spitznas M. Anatomical features of the human macula. In: l’Esperance FA, editor. Current diagnosis and management of retinal disorders. St Louis: CV Mosby; 1977. Yamada E. Some structural features of the fovea central in the human retina. Arch Ophthalmol 1969;82:151–9.

REFERENCES 1. Mann I. The development of the human eye. New York: Grune & Stratton; 1950.

3. Fine BS, Yanoff M. Ocular histology. A text and atlas. New York: Harper & Row; 1979. p. 111–24. 4. Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Arch Ophthalmol 1969;82:151–9. 5. Rochon-Duvigneaud A. Recherches sur la fovea de la retine humaine et particulierement sur le bouquet des cones centraux. Arch Anat Microsc 1907;9:315–42.

7. Yamada E. Some structural features of the fovea central in the human retina. Arch Ophthalmol 1969;82:151–9. 8. Spitznas M. Anatomical features of the human macula. In: l’Esperance FA, editor. Current diagnosis and management of retinal disorders. St Louis: CV Mosby; 1977. 9. Polyak SL. The retina. Chicago: University of Chicago Press; 1941. 10. Hogan MJ, Alvarado JA, Wedell JE. Histology of the human eye. Philadelphia: WB Saunders; 1971. p. 491−8.

6.1 Structure of the Neural Retina

2. Gaertner I. The vitreous, an intraocular compartment of the leptomeninx. Doc Ophthalmol 1986;62:205–22.

6. Krebs W, Krebs I. Quantitative morphology of the central fovea in the primate retina. Am J Anat 1989;184:225–36.

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PART 6 RETINA AND VITREOUS SECTION 1 Anatomy

Retinal Pigment Epithelium Michael F. Marmor

6.2

Definition: A melanin-containing epithelial layer that lies between the neural retina and choroid.

Key features ■ ■ ■ ■ ■ ■ ■ ■

Absorption of scattered light. Control of fluid and nutrients in the subretinal space (blood-retinal barrier function). Visual pigment regeneration and synthesis. Synthesis of growth factors to modulate adjacent structures. Maintenance of retinal adhesion. Phagocytosis and digestion of photoreceptor wastes. Electrical homeostasis. Regeneration and repair after injury or surgery.

INTRODUCTION The retinal pigment epithelium (RPE) is a vital tissue for the maintenance of photoreceptor function.1,2 It is also affected by many diseases of the retina and choroid. Embryologically, the RPE is derived from the same neural tube tissue that forms the neural retina, but the cells differentiate into a transporting epithelium, the main functions of which are to metabolically insulate and support the overlying neural retina.

STRUCTURE Cellular Architecture and Blood-Retinal Barrier

The RPE is a monolayer of interlocking hexagonal cells that are joined by tight junctions (zonulae occludens), which block the free passage of water and ions. This junctional barrier is the equivalent of the bloodretinal barrier of the neuroretina. In the macular region, RPE cells are small (roughly 10–14 µm in diameter), whereas toward the periphery, they become flatter and broader (diameter up to 60 µm). The density of photoreceptors also varies across the retina, but the number of photoreceptors that overlie each RPE cell remains roughly constant (about 45 photoreceptors per RPE cell). In cross section, the RPE cell is differentiated into apical and basal configurations. On the apical side (facing the photoreceptors), long microvilli reach up between (and envelop) the outer segments of the photoreceptors (Fig. 6-2-1). Melanin granules are concentrated in the apical end of the cell. The basal membrane has convoluted infolds to increase the surface area for the absorption and secretion of material.

Pigments

The pigment that gives the RPE its name is melanin, found in cytoplasmic granules called melanosomes. In older age, melanin granules often fuse with lysosomes and break down, so the elderly fundus typically appears less pigmented. The role of melanin in the eye remains somewhat speculative. The pigment serves to absorb stray light and minimize scatter within the eye, which has theoretical optical benefits. However, visual acuity is not degraded in very blond fundi. Further, the

Fig. 6-2-1  Apical surface of human retinal pigment epithelium as seen through a scanning electron microscope. Fine microvilli cover the surface and reach up between the photoreceptor outer segments (which have been peeled away in this view).

appearance of the fundus can be misleading with respect to the RPE, since the greatest racial differences are a result of choroidal pigmentation. Melanin also serves as a free radical stabilizer, and can bind toxins and retinotoxic drugs such as chloroquine and thioridazine, although it is unclear whether this effect is beneficial or harmful. The other major RPE pigment is lipofuscin, which accumulates gradually with age. It is thought that lipofuscin in the RPE is derived from aged or damaged outer segment lipids that have been ingested and then digested by the RPE. It is not clear to what degree excess lipofuscin damages the RPE directly or is a marker for cellular damage as it is a component of both normal and pathologic aging.

Metabolism and Growth Factors

A number of growth factors are elaborated by RPE cells and serve to modulate not only the behavior of the RPE but also the behavior of surrounding tissues. Knowledge of these interactions is growing rapidly, and it is now recognized that the RPE is a critical part of a complex system of cellular cross-talk that controls vascular supply, permeability, growth, immunologic responses, repair, and other processes vital to retinal function.1,3 Factors produced by the RPE include, among others, platelet-derived growth factor (PDGF), which modulates cell growth and healing; pigment epithelium-derived factor (PEDF), which acts as a neuroprotectant and vascular inhibitor; vascular endothelial growth factor (VEGF), which can stimulate normal or pathologic neovascular growth; fibroblast growth factor (FGF), which can be neurotropic; transforming growth factor (TGF), which moderates inflammation, and other immune regulating components such as toll-like receptors and complement factors.

MEMBRANE PROPERTIES AND FLUID TRANSPORT The RPE membrane contains selective ion channels, and active or facilitative transport systems for ions and for metabolites such as glucose and amino acids. Different channels and transporters are present on the apical and basal membranes. The net effects of the

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MECHANISM OF SEROUS DETACHMENTS

RPE PHAGOCYTOSIS OF PHOTORECEPTOR OUTER SEGMENTS

Normal RPE

Retina and Vitreous

vitreous retina normal RPE choroid

leak Damaged RPE/choroid complex

vitreous Fig. 6-2-3  Retinal pigment epithelium (RPE) phagocytosis of photoreceptor outer segments. The phagosome, containing the ingested material, enters the RPE cytoplasm, where it merges with lysosomes to facilitate digestion of the outdated membranes. (Adapted from Steinberg H, Wood I, Hogan MJ. Pigment epithelial ensheathment and phagocytosis of extrafoveal cones in human retina. Philos Trans R Soc Lond. 1977;277:459–74.)

retina compromised RPE choroid

leak

Fig. 6-2-2  Mechanism of serous detachment. When the retinal pigment epithelium (RPE) is normal, no serous detachment occurs beyond a focal site of leakage. When the RPE is compromised by choroidal or RPE disease that impairs outward fluid transport, a serous detachment forms until absorption across the exposed RPE balances the inward leak.

asymmetrical transport systems are a movement of water across the RPE in the apical-to-basal direction and the generation of voltage across the RPE. Water transport can be diminished either by blocking a transporter that moves ions in the basal direction or by stimulating a transporter that moves ions in the apical direction. The ability of the RPE to transport water actively is very powerful, but water also moves out if the RPE barrier function is broken because of intraocular pressure and osmotic suction from the choroid.4 Because tight junctions are required to protect the neural environment active transport by the RPE is required to keep the subretinal space dry. These physiological observations have relevance for clinical disorders such as serous detachments. The unusual thing about a serous detachment is not that fluid gets in (given that a break is present in the RPE barrier) but that fluid accumulates and persists (since the RPE would be expected to pump it right back out). Disorders such as central serous chorioretinopathy probably involve diffuse pathological changes of the RPE-choroid complex that impair fluid absorption5 (Fig. 6-2-2).

Electrical Activity

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The RPE generates no direct response to light. However, the asymmetrical transport properties of the apical and basal membranes generate a transepithelial voltage (called the standing potential), which can be modified secondarily by photoreceptor activity or by endogenously supplied substances.6 When the photoreceptors respond to light, the potassium concentration falls in the subneural retinal space, causing the apical membranes of the RPE to hyperpolarize, and produce the c wave of the electroretinogram. This potassium change is transmitted slowly through the RPE cell, and roughly 1 minute later, a hyperpolarization appears at the basal membrane, which accounts for the ‘fast oscillation’ of the electrooculogram (EOG). Light activation of photoreceptors also causes the release of an unknown messenger substance that induces a basal RPE depolarization 5–10 minutes later. This late basal depolarization is recorded clinically as the ‘light response’ of the clinical EOG. The light response is probably mediated through calcium-dependent chloride channels controlled in part by the bestrophin gene, which is altered in Best’s vitelliform dystrophy.7 The EOG is very subnormal in Best’s disease, but is not severely altered in most RPE disorders.6

PHOTORECEPTOR-RETINAL PIGMENT EPITHELIUM INTERACTIONS Visual Pigment Regeneration

Absorption of light in the photoreceptors converts 11-cis vitamin A to the all-trans form, which initiates the process of transduction and begins a series of regenerative chemical changes that are independent of vision. Vitamin A is split off from the opsin molecule and carried by a transport protein to the RPE. In the RPE, vitamin A may be stored in an ester form, but eventually it is isomerized back to the 11-cis form and recombined with opsin. The RPE is vital for this process and for the capture of vitamin A from the bloodstream to maintain its concentration within the eye. Defects in several genes that control this regenerative cycle in the RPE can cause Leber amaurosis or retinitis pigmentosa, such as RPE65, LRAT, RLPB (CRALBP), and RDH.A

Photoreceptor Renewal and Phagocytosis

Photoreceptors are continually exposed to radiant energy (light) and oxygen (from the choroid), which facilitates the production of free radicals that can damage membranes. Thus, a process of cellular renewal is needed. Every day, upward of 100 discs at the distal end of the photoreceptors are phagocytosed by the RPE (Fig. 6-2-3), while new discs are synthesized.8 The cellular renewal process has a circadian rhythm. The rods shed discs most vigorously in the morning at the onset of light, whereas cones shed more vigorously at the onset of darkness. The complete outer segments are renewed roughly every 2 weeks. Within the RPE, the phagocytosed discs become encapsulated in vesicles called phagosomes,9 which merge with lysosomes so that the material can be digested. Necessary fatty acids are recycled, while waste products are egested across the basal RPE membrane. Residual debris may contribute to the formation of lipofuscin and aging damage to the RPE.

Interphotoreceptor Matrix and Retinal Adhesion

The interphotoreceptor matrix (IPM) has an elaborate structure in which domains of distinct chemical characteristics surround the rods and cones (Fig. 6-2-4A).10 It provides physical support of the photo­ receptors, transfer of nutrients and visual pigments, and an adhesive bond between the retina and RPE. These functions are controlled actively by the RPE, through the transport of ions and water. Retinal adhesion is in fact a complex process involving several interactive mechanisms. The neural retina is pressed in place by the vitreous gel, intraocular fluid pressure, and RPE water transport, which drive or pull water through the semipermeable tissue. There is some physical resistance to separation of outer segments from enveloping RPE microvilli. The strongest mechanism for bonding the retina to the

REPAIR AND REGENERATION Although of neural origin, the RPE is capable of local repair (unlike the neural retina), and cells may migrate and take on altered characteristics. After a focal laser burn, for example, the RPE cells that surround the burn begin to divide, and cells fill the defect to form a new bloodretinal barrier within 1–2 weeks.12 Unfortunately, large RPE defects do not heal. In degenerative disease, such as retinitis pigmentosa, RPE cells can migrate into the injured neural retina. Growth factors from the RPE ordinarily contain unwanted proliferation, but under pathologic conditions may stimulate vascular or fibrous growth.

6.2 Retinal Pigment Epithelium

A

RPE space appears to be the IPM. When neural retina is freshly peeled from the RPE, the IPM material stretches dramatically before it breaks, which shows that it is firmly attached to both neural retinal and RPE surfaces (see Fig. 6-2-4B). However, the strength of the IPM adhesive system is constantly and acutely dependent on RPE metabolism.11 Retinal adhesive force drops to near zero within minutes after death, and adhesive strength can be reversibly restored or enhanced by tissue oxygenation. After a retinal detachment, full recovery of IPM morphology, RPE/photoreceptor intercalation, and normal adhesisve strength may require several weeks.

KEY REFERENCES Detrick B, Hooks JJ. Immune regulation in the retina. Immunol Res 2010;47:153–61. Marmor M. On the cause of serous detachments and acute central serous chorioretinopathy. Br J Ophthalmol 1997;81:812–13. Marmor MF, Wolfensberger TW, editors. The retinal pigment epithelium. Current aspects of function and disease. New York: Oxford University Press; 1998. Marmor MF. Clinical electrophysiology of the retinal pigment epithelium. Doc Ophthalmol 1991;76:301–13. Marmorstein AD, Cross HE, Peachey NS. Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res 2009;28:206–26. Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease. Curr Molecular Med 2010;10:802–23.

B Fig. 6-2-4  Cone sheaths of the interphotoreceptor matrix, shown by fluorescent staining with peanut agglutinin. Cone tips indent the sheaths from above; the retinal pigment epithelium (RPE) is on the bottom. (A) The matrix sheaths are short in a normal eye. (B) They stretch dramatically before breaking as the retina is peeled from the RPE. This shows that matrix material bonds across the subretinal space. (Reproduced with permission from Hageman GS, Marmor MF, Yao X-Y, Johnson LV. The interphotoreceptor matrix mediates primate retinal adhesion. Arch Ophthalmol. 1995;113:655–60.)

Access the complete reference list online at

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REFERENCES 1. Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease. Curr Molecular Med 2010;10:802–23.

3. Detrick B, Hooks JJ. Immune regulation in the retina. Immunol Res 2010;47:153–61. 4. Negi A, Marmor MF. The resorption of subretinal fluid after diffuse damage to the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1983;24:1475–9. 5. Marmor M. On the cause of serous detachments and acute central serous chorioretinopathy. Br J Ophthalmol 1997;81:812–13. 6. Marmor MF. Clinical electrophysiology of the retinal pigment epithelium. Doc Ophthalmol 1991;76:301–13.

8. Young RW. Visual cells and the concept of renewal. Invest Ophthalmol 1976;15:700–25. 9. Steinberg RH, Wood I, Hogan MJ. Pigment epithelial ensheathment and phagocytosis of extrafoveal cones in human retina. Philos Trans R Soc Lond 1977;277:459–74. 10. Hageman GS, Marmor MF, Yao X-Y, et al. The interphotoreceptor matrix mediates primate retinal adhesion. Arch Ophthalmol 1995;113:655–60. 11. Marmor MF, Yao X-Y. The metabolic dependency of retinal adhesion in rabbit and primate. Arch Ophthalmol 1995;113:232–8. 12. Negi A, Marmor MF. Healing of photocoagulation lesions affects the rate of subretinal fluid resorption. Ophthalmology 1984;91:1678–83.

6.2 Retinal Pigment Epithelium

2. Marmor MF, Wolfensberger TW, editors. The retinal pigment epithelium. Current aspects of function and disease. New York: Oxford University Press; 1998.

7. Marmorstein AD, Cross HE, Peachey NS. Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res 2009;28:206–26.

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PART 6 RETINA AND VITREOUS

IN THIS CHAPTER

SECTION 1 Anatomy

Additional content available online at

Retinal and Choroidal Circulation Caio Vinícius Saito Regatieri, Shiyoung Roh, John J. Weiter

INTRODUCTION Because many of the important diseases of the posterior segment are caused by changes in the vasculature of the retina and choroid, it is important to understand the circulatory systems involved in order to better recognize and treat disease states of the posterior segment. In this chapter, the anatomy and physiology of these circulatory systems are discussed.

POSTERIOR SEGMENT VASCULAR ANATOMY Retinal Vascular Anatomy

The retinal blood vessels provide nourishment for the inner two-thirds of the retina. The central retinal artery, which is the first branch of the ophthalmic artery, is an end artery that has no significant anastomoses.1 In the area of the lamina cribrosa, its lumen measures about 170 µm in diameter. Typically, just before its exit from the optic nerve, the central retinal artery divides into the superior and inferior papillary arteries, which in turn divide into nasal and temporal quadratic branches (Fig. 6-3-1A). The anatomic division of the retinal arteries into superior and inferior halves is usually maintained throughout the retina, because normal retinal vessels rarely cross the horizontal raphe (Fig. 6-3-1A). Cilioretinal arteries, derived from the posterior cilliary arteries, are variably present and emanate from the temporal rim of the optic nerve head toward the macula (Fig. 6-3-1A). Arteries and veins remain in the nerve fiber layer. Throughout the retina, the capillaries are arranged in laminar meshworks.2 Depending on the thickness of the retina, the capillary meshwork can vary from three layers at the posterior pole to one layer in the periphery. The arterial intraretinal branches supply three layers of capillary networks:  The radial peripapillary capillaries;  Superficial capillaries in the ganglion cell and nerve fiber layers; and  Deep, denser, capillaries in the inner nuclear layer. Like capillary networks elsewhere in the body, the retinal capillaries assume a meshwork configuration to ensure adequate perfusion to all inner retinal cells (Fig. 6-3-1C). A capillary-free zone is present around each of the larger retinal arteries and veins, but it is more prominent around arteries, where it measures up to 100 µm in diameter. In the fovea and the far retinal periphery, retinal capillaries are absent. The foveal avascular zone is 400–500 µm in diameter. The venous drainage of the retina generally follows the arterial supply. The retinal veins (mainly venules) are present in the inner retina, where they occasionally interdigitate with their associated arteries. When two vessels cross, the artery usually lies anterior to the vein, and the two vessels share a common adventitial coat. Many more arterio­ venous crossings occur temporally than nasally because the nasal vessels assume a much straighter course. The crossings are important because they represent the most common site of branch retinal vein obstructions. The retinal veins drain into the central retinal vein, which also acts as the major efferent channel for the vessels of the optic nerve (Fig. 6-3-1A).2

Choroidal Vascular Anatomy 426

The choroid is by far the most vascular portion of the eye and by weight one of the most vascular tissues in the body. The choroid is responsible for the vascular support of the outer retina (Fig. 6-3-1B). A structurally and functionally normal choroidal vasculature is essential for retinal

6.3

function: abnormal choroidal blood volume and/or compromised flow can result in photoreceptor and retinal pigment epithelium (RPE) dysfunction and death.3 Other likely functions include light absorption, thermoregulation via heat dissipation, and modulation of intraocular pressure via vasomotor control of blood flow. The choroid also plays an important role in the drainage of the aqueous humor from the anterior chamber, via the uveoscleral pathway. The blood supply to the choroid is from branches of the anterior and posterior ciliary arteries, branches of the ophthalmic artery. The overall structure of the choroid is segmental; this segmental distribution of blood begins at the level of the posterior ciliary branches and is mirrored in the vortex drainage system. As a result of the segmental distribution, the large and medium-sized choroidal arteries act as end arteries. Histologically, the choroid is divided in five layers: starting from the retinal (inner) side, these are:  Bruch’s membrane,  Choriocapillaris (layer of capillaries),  Sattler’s layer (layer of medium diameter blood vessels),  Haller’s layer (layer of large diameter blood vessels), and  Suprachoroidea (transitional zone between choroid and sclera).4 The choriocapillaris is a highly anastomosed network of capillaries, forming a thin sheet apposed to Bruch’s membrane. The fibrous basement membrane of the capillary endothelial cells forms the outermost layer of Bruch’s membrane in humans. The choriocapillaris is about 10 µm thick at the fovea, where there is the greatest density of capillaries, thinning to about 7 µm in the periphery. The capillaries arise from the arterioles in Sattler’s layer, each of which gives rise to a hexagonal (or lobular) shaped domain of a single layer of capillaries, giving a patch-like structure to the choriocapillaris (Fig. 6-3-2). The choriocapillaris has large diameter capillaries of 20–25 µm, which allow the passage of multiple red blood cells at any moment in time. Unlike the retinal capillaries, the choriocapillaris has fenestrations of 700–800 nm diameter, which allows more rapid transport of molecules (leakage).4 Besides the choriocapillaris, the choroid presents two other vascular regions: the outer Haller’s layer of large blood vessels and the inner Sattler’s layer of medium and small arteries and arterioles that feed the capillary network, and veins. The stroma (extravascular tissue) contains collagen and elastic fibers, fibroblasts, non-vascular smoothmuscle cells and numerous very large melanocytes that are closely apposed to the blood vessels. As in other types of connective tissue, there are numerous mast cells, macrophages, and lymphocytes.

BLOOD-RETINAL BARRIER The blood-retinal barrier (BRB) controls the exchange of metabolites and waste products between the vascular lumen and the neural retina, and is formed by the interaction of retinal glia and pericytes with the retinal vascular endothelium cells. In addition to the vascular contribution, the retina also possesses an epithelial barrier, the RPE, which controls the flow of fluid and nutrients from the highly vascularized choroid into the outer retina. Together the vascular and epithelial components of the BRB maintain the specialized environment of the neural retina. Both the vascular endothelium (inner barrier) and the RPE (outer barrier) possess well-developed junctional complexes that include adherens and tight junctions. The inner BRB controls permeability from the retinal blood vessels and consists of a well-developed junctional complex (adherens and tight junctions) in the vascular endothelial cells as well as

6.3 Retinal and Choroidal Circulation

A

B

C

D

Fig. 6-3-1  Angiogram using scanning laser ophthalmoscopy. (A) Normal fluorescein angiogram shows the normal filling of retinal arteries and veins, note the cilioretinal artery (green arrow); (B) Normal indocyanine green angiogram shows the normal filling of choroidal vessels; (C) Magnified area from image A shows the retinal capillaries (green arrows) close to the foveal avascular zone; (D) Indocyanine green angiogram shows a choroidal neovascularization (green arrow) secondary to AMD.

no fenestration. The tight junctions restrict flux of a wide variety of substances such as lipids and protein. The retinal capillaries are relatively impermeable, even to particles as small as sodium ions. The adherens junctions are essential to development of the barrier and influence the formation of the tight junction. Together the adherens junctions and tight junctions create the resistance barrier to the neural parenchyma. Although the endothelium of the retinal capillaries is where the barrier resides, the glial cells may play a role as metabolic intermediaries between the retinal capillaries and retinal neurons.5 Thus, macromolecules and ions do not passively diffuse into the retina from the circulation but are associated with selective active transport into the retina. The outer BRB is formed by tight junctions between cells of the RPE. The RPE resting upon the underlying Bruch’s membrane separates the neural retina from the fenestrated choriocapillaris and plays an

important role in transporting nutrients from the blood to the outer retina. While inter-RPE cell tight junctions are important in the control of paracellular movement of fluids and molecules between the choroid and retina, the polarized distribution of membrane proteins in the RPE is also important. The RPE plays an active role in supplying glucose to the photoreceptors and also retinol that is required for visual pigment synthesis.6 There are receptors on the basal and lateral cell membranes of the RPE for nutriments that have to be transported to the outer retina. Although the retina is protected by the inner (retinal vascular endothelium cells) and outer (RPE) blood-retinal barriers, in vivo, some leakage probably occurs. Most likely this protein leakage is actively transported across the RPE into the choroid and/or removed through Schlemm’s canal. Choroidal proteins exit the eye through emissary canals (openings in the sclera for vessels and nerves) or through the

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Fig. 6-3-2  The lobular architecture of the choroidal circulatory system. (Adapted with permission from Duker J, Weiter JJ. Ocular circulation. In: Tasman W, Jaeger EA, eds. Duane’s foundations of clinical ophthalmology. New York: JB Lippincott; 1991:1−34.)

LOBULAR ARCHITECTURE OF THE CHOROIDAL CIRCULATORY SYSTEM

Retina and Vitreous

choroidal arteriole

choroidal venule

sclera, probably facilitated by the relatively high tissue pressure of the eye (the intraocular pressure).6 In many clinically important pathological conditions including diabetic retinopathy, retinal vein occlusion, and some inflammatory diseases, there is a breakdown of the inner BRB, leading to leakage of blood components to the neural retina. In addition, outer BRB breakdown can occur in conditions such as age-related macular degeneration (AMD) (Fig. 6-3-1D), central serous chorioretinopathy, accelerated hypertension, and toxemia of pregnancy. Breakdown of the outer BRB results in serous retinal detachment or RPE detachment.

RETINAL AND CHOROIDAL BLOOD FLOW

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There are several techniques to analyze both qualitatively and quantitatively the retinal and choroidal blood flow, such as:  Fluorescein angiogram with dye dilution,  Indocyanine green with dye dilution,  Laser Doppler velocimetry,  Laser Doppler flowmetry,  Scanning laser flowmetry, and  Color Doppler ultrasound imaging (Fig. 6-3-3). These techniques have greatly enhanced the ability to quantify ocular perfusion defects in many disorders, including glaucoma, AMD, diabetic retinopathy and vascular occlusions, which are major causes of blindness in the industrialized world. However, methods for accurate, reproducible measurement of retinal and choroidal blood flow are still being perfected because of the difficult access to the retinal and choroidal circulation. Quantitative retinal blood flow is studied mainly by the use of laser Doppler flowmetry and laser Doppler velocimetry, which are noninvasive techniques which permit the assessment of relative blood velocity, volume and flow within a sampled volume of tissue. Using these techniques, it has been shown that the total retinal blood flow in healthy subjects is 44.0 ± 13.3 µL/min. The blood flow is highest in the temporal inferior quadrant, followed by the temporal superior quadrant, the nasal inferior quadrant, and the nasal superior quadrant. In all quadrants retinal blood velocities are linearly correlated to vessel diameters.7 Scanning laser ophthalmoscopic fluorescein angiography has also provided important information on retinal hemodynamics in normal and glaucoma subjects. In healthy subjects, arteriovenous passage times measured by scanning laser ophthalmoscopic angiography has been reported as averaging 1.58 ± 0.4 seconds and mean dye velocity

Fig. 6-3-3  Color Doppler image of the ophthalmic artery. The Doppler shifted spectrum (time velocity curve) is displayed at the bottom of the image. Red pixels represent blood movement toward to the transducer.

averaging 6.67 ± 1.59 mm/sec in a large study of 221 individuals. In the same study, capillary flow velocity averaged 2.89 ± 0.41 mm/sec in healthy subjects.8 On patients with primary open-angle glaucoma there is an 11% reduction in the mean dye velocity within major retinal arteries. It is also noted that arteriovenous passage time within retina was 41% slower in primary open-angle glaucoma.9 Several studies showed that glaucoma patients suffer from inadequate ocular blood flow and there is a relationship between ocular hemodynamic and progression of the disease. Unlike the retinal arteries, the retinal veins show no pulsations in blood velocity except at the point of exit from the globe.10 The venous pressure of the intraocular veins exiting the eye depends upon intraocular pressure (IOP) and coincides with the pulse, which results in a pulsating venous perfusion pressure. The retinal venous outflow resistance is located mainly at the lamina cribrosa. The closed nature of the eye means that the pulsatile choroidal arterial inflow results in a

TABLE 6-3-1  MAJOR DIFFERENCES BETWEEN THE RETINAL AND CHOROIDAL CIRCULATORY SYSTEM Retinal circulation

Choroidal circulation

Supply Blood Flow Tissue nourishment

Central Retinal Artery Normal for tissue Inner two-thirds of retina

Cellular junctions Nature of vasculature

Tight junctions between endothelial cells End artery system

Ciliary Arteries Highest in body Outer one-third of retina (photoreceptor and RPE complex) Fenestrations in choriocapillaris

Blood flow regulation

Autoregulation

Functionally end artery system (Lobular shaped domain) Controlled by the autonomic nervous system

pulse-related change in IOP, which causes a venous pulse. Depending upon the relationship between IOP and venous pressure, this may result in a clinically visible pulse of the veins at their point of exit from the globe. The choroid is primarily a vascular structure supplying the outer retina. The choroid circulation exhibits one of the highest rates of blood flow in the body. In fact, per tissue gram, the choroid has four times more blood flowing through it than does the cortex of the kidney. Several studies showed that the choroid receives 65–85% and the retina 5% or less of the ocular blood flow. Using laser Doppler velocimetry, the choroidal blood flow is documented to be 800 µL/min, 18 times higher than retinal blood flow. With advancing age the choroidal blood velocity and choroidal thickness decrease significantly which might be related with the pathogenesis of AMD. Interestingly mean blood pressure, smoking, and gender have no influence on the choroidal blood flow parameters. Studies assessing the choroidal circulation indicate a significant reduction of choroidal blood flow and volume in patients with glaucoma, AMD, non-proliferative and proliferative diabetic retinopathy. The major differences of the retinal and choroidal circulatory systems are shown in Table 6-3-1.

FUTURE PERSPECTIVES FOR RETINAL AND CHOROIDAL ASSESSMENT Similar to other medical imaging techniques such as ultrasound imaging, optical coherence tomography (OCT) can also provide velocity information by exploiting the Doppler effect and related mechanisms.11 An important application of Doppler OCT could be to use blood velocity as a contrast agent for visualization of the vasculature in the ocular fundus and quantify the blood flow in specific vessels of the retina and choroid.12 This technology holds promise in aiding the monitoring of vascular occlusions and neovascular AMD, specifically in evaluating an ischemic area or in determining if a neovascular lesion is active or inactive.

REGULATION OF RETINAL AND CHOROIDAL BLOOD FLOWS

6.3 Retinal and Choroidal Circulation

Property

the cervical sympathetic chain decreases choroidal flow, and sympathectomy increases it.13 The choroid does not show evidence of autoregulation, the lack of which may have serious consequences. Changes in IOP are not reflected by compensatory changes in the choroidal vascular pressure,13 and sudden changes in IOP, such as occur in the opening of the eye during surgery, can induce uveal effusion. Because the autonomic tonus probably protects the eye from transient elevations in the systemic blood pressure under normal circumstances, if the nervous regulation breaks down in the presence of systemic hypertension, fluid may be forced through the retinal pigment epithelial barrier into the retina.14 Such changes hypothetically could contribute to the pathology of central serous chorioretinopathy, cystoid macular edema, and hypotony maculopathy. The ophthalmic artery and its branches are innervated richly with adrenergic fibers until the lamina cribrosa is reached. From that point on, no nervous system control of the retinal circulation occurs.15 Thus, the retinal circulation must depend upon local autoregulation to maintain a constant metabolic environment. The process of autoregulation in a vascular bed maintains constant or nearly constant blood flow through a wide range of perfusion pressures. Autoregulation of the retina is commonly used today in a much broader sense, to encompass the local homeostatic blood flow mechanisms that provide a constant metabolic environment in the retina despite various conditions that tend to upset this equilibrium. Blood flow in the retina appears to be primarily controlled by metabolic needs, especially the need for oxygen16 and the accumulation of metabolic byproducts such as carbon dioxide and changes in pH. It is necessary to understand the factors that can influence autoregulation of the retinal circulation as these may have important clinical implications.17

KEY REFERENCES Feke GT, Zuckerman R, Green GJ, et al. Response of human retinal blood flow to light and dark. Invest Ophthalmol Vis Sci 1983;24(1):136–41. Epub 1983/01/01. Geitzenauer W, Hitzenberger CK, Schmidt-Erfurth UM. Retinal optical coherence tomography: past, present and future perspectives. Br J Ophthalmol 2011;95(2):171–7. Epub 2010/08/03. Harris A, Chung HS, Ciulla TA, et al. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration. Prog Retin Eye Res 1999;18(5):669–87. Epub 1999/08/07. J D, J WJ. Ocular circulation. In: W T, A JE, editors. Duane’s foundations of clinical ophthalmology. New York: JB Lippincott; 1991. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008;27(6):622–47. Epub 2008/10/23. Laties AM, Jacobowitz D. A comparative study of the autonomic innervation of the eye in monkey, cat, and rabbit. Anat Rec 1966;156(4):383–95. Epub 1966/12/01. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29(2):144–68. Epub 2010/01/02. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32(3):563–8. Epub 2012/03/01. Weiter JJ, Zuckerman R. The influence of the photoreceptor-RPE complex on the inner retina. An explanation for the beneficial effects of photocoagulation. Ophthalmology 1980;87(11):1133–9. Epub 1980/11/01. Wolf S, Arend O, Sponsel WE, et al. Retinal hemodynamics using scanning laser ophthalmoscopy and hemorheology in chronic open-angle glaucoma. Ophthalmology 1993;100(10):1561–6. Epub 1993/10/01.

Regulation of blood flow through the choroid, as in the body in general, is under the control of the autonomic nervous system. Stimulation of

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REFERENCES 1. Hayreh SS. The Ophthalmic Artery: Iii. Branches. Br J Ophthalmol 1962;46(4):212–47. Epub 1962/04/01.

3. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32(3):563–8. Epub 2012/03/01. 4. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29(2):144–68. Epub 2010/01/02. 5. Runkle EA, Antonetti DA. The blood-retinal barrier: structure and functional significance. Methods Mol Biol 2011;686:133–48. Epub 2010/11/18. 6. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008;27(6):622–47. Epub 2008/10/23. 7. Garhofer G, Werkmeister R, Dragostinoff N, et al. Retinal blood flow in healthy young subjects. Invest Ophthalmol Vis Sci 2012;53(2):698–703. Epub 2012/01/17. 8. Harris A, Chung HS, Ciulla TA, et al. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration. Prog Retin Eye Res 1999;18(5):669–87. Epub 1999/08/07.

6.3

10. Michelson G, Harazny J. Relationship between ocular pulse pressures and retinal vessel velocities. Ophthalmology 1997;104(4):664–71. Epub 1997/04/01. 11. Geitzenauer W, Hitzenberger CK, Schmidt-Erfurth UM. Retinal optical coherence tomography: past, present and future perspectives. Br J Ophthalmol 2011;95(2):171–7. Epub 2010/08/03. 12. Baumann B, Potsaid B, Kraus MF, et al. Total retinal blood flow measurement with ultrahigh speed swept source/Fourier domain OCT. Biomed Opt Express 2011;2(6):1539–52. Epub 2011/06/24. 13. Weiter JJ, Schachar RA, Ernest JT. Control of intraocular blood flow. II. Effects of sympathetic tone. Invest Ophthalmol 1973;12(5):332–4. Epub 1973/05/01. 14. Ernest JT. The effect of systolic hypertension on rhesus monkey eyes after ocular sympathectomy. Am J Ophthalmol 1977;84(3):341–4. Epub 1977/09/01. 15. Laties AM, Jacobowitz D. A comparative study of the autonomic innervation of the eye in monkey, cat, and rabbit. Anat Rec 1966;156(4):383–95. Epub 1966/12/01. 16. Feke GT, Zuckerman R, Green GJ, et al. Response of human retinal blood flow to light and dark. Invest Ophthalmol Vis Sci 1983;24(1):136–41. Epub 1983/01/01. 17. Weiter JJ, Zuckerman R. The influence of the photoreceptor-RPE complex on the inner retina. An explanation for the beneficial effects of photocoagulation. Ophthalmology 1980;87(11):1133–9. Epub 1980/11/01.

Retinal and Choroidal Circulation

2. J D, J WJ. Ocular circulation. In: W T, A JE, editors. Duane’s foundations of clinical ophthalmology. New York: JB Lippincott; 1991.

9. Wolf S, Arend O, Sponsel WE, et al. Retinal hemodynamics using scanning laser ophthalmoscopy and hemorheology in chronic open-angle glaucoma. Ophthalmology 1993;100(10):1561–6. Epub 1993/10/01.

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PART 6 RETINA AND VITREOUS SECTION 1 Anatomy

Vitreous Anatomy and Pathology J. Sebag

Definition: Vitreous is an extended extracellular matrix situated

between the lens and retina of approximately 4.0 mL in volume and 16.5 mm in emmetropic axial length.

Key features ■ ■ ■ ■ ■ ■

Optically clear Modulates growth of the eye Maintains media transparency Serves as a reservoir for anti-oxidants Plays a role in ocular physiology During aging, separate from the retina, in most cases innocuously

Associated features ■

Posterior vitreous detachment (PVD) a common cause of floaters PVD and vitrectomy increase oxygen levels contributing to cataractogenesis and glaucoma ■ Anomalous PVD is the inciting event in diseases of the vitreomacular interface, via ■ vitreo-macular adhesion; ■ vitreoschisis; ■ rhegmatogenous retinal detachment; ■ and may contribute to exudative age-related macular degeneration, proliferative diabetic vitreo-retinopathy, and macular edema. ■

6.4

MOLECULAR MORPHOLOGY Supramolecular Organization

Vitreous is composed of a dilute meshwork of collagen fibrils (Fig. 6-4-2) interspersed with extensive arrays of hyaluronan molecules.8–10 The collagen fibrils provide a solid structure that is ‘inflated’ by the hydrophilic hyaluronan.11 Rheological observations also suggest the existence of an important interaction between hyaluronan and collagen.12 Balazs hypothesized that the hydroxylysine amino acids of collagen mediate polysaccharide binding to the collagen chain through O-glycosidic linkages.11 These polar amino acids are present in clusters along the collagen molecule, consistent with proteoglycans attachment to collagen in a periodic pattern.13 Hyaluronan-collagen interaction in the vitreous may be mediated by a third molecule. In cartilage, ‘link glycoproteins’ have been identified that interact with proteoglycans and hyaluronan.14 Supramolecular complexes of these glycoproteins are believed to occupy interfibrillar spaces. Bishop9 has elegantly described the potential roles of type IX collagen chondroitin sulfate chains, hyaluronan, and opticin in the short-range spacing of collagen fibrils and how these mechanisms might break down in aging and disease. Many investigators believed that hyaluronan-collagen interaction occurs on a ‘physicochemical’ rather than a ‘chemical’ level.15 Reversible complexes of an electrostatic nature between solubilized collagen and various glycosaminoglycans could indeed form, since electrostatic binding between negatively charged hyaluronan and positively charged collagen likely occur in vitreous.

INTRODUCTION Although vitreous is the largest structure within the eye, constituting 80% of the ocular volume, investigators of vitreous anatomy are hampered by two fundamental difficulties: Attempts to characterize vitreous morphology are efforts to visualize a tissue that is invisible ‘by design’ (Fig. 6-4-1). The various techniques that were previously employed to study vitreous structure were flawed by artifacts induced by tissue fixatives, which caused precipitation of hyaluronan, formerly called hyaluronic acid. The development of slit-lamp biomicroscopy by Gullstrand in 1912 was expected to enable clinical investigation of vitreous structure without the introduction of these artifacts. Nonetheless a widely-varied set of descriptions resulted because vitreous is largely invisible. This problem even persists in more modern investigations. Consider, for example, that in the 1970s Eisner1 described ‘membranelles’ and Worst2 ‘cisterns’, in the 1980s Sebag and Balazs3,4 identified ‘fibers’, and in the 1990s Kishi and Shimizu5 found ‘pockets’ in the vitreous. The discrepant observations of the last-mentioned group have been explained as an age-related phenomenon with no relevance to the inherent macro­ molecular structure or anatomy.6,7

• •

430

Fig. 6-4-1  Vitreous obtained at autopsy from a 9-month-old child. The sclera, choroid, and retina were dissected off the transparent vitreous, which remains attached to the anterior segment. A band of gray tissue can be seen posterior to the ora serrata. This is neural retina that was firmly adherent to the vitreous base and could not be dissected. The vitreous is almost entirely gel (because of the young age of the donor) and thus is solid and maintains its shape, although situated on a surgical towel exposed to room air. (Courtesy of the New England Eye Bank, Boston, MA.)

STRUCTURE OF HUMAN VITREOUS COLLAGEN FIBRIL

Type V/XI collagen

Egger's line forming Wieger's ligament (hyaloideocapsular ligament)

N-propeptide of type V/XI collagen

Berger's space (retrolental space of Erggelet)

canal of Hannover pars plicata pars plana

ora serrata N - propeptide of type II collagen

Type IX collagen

Type II collagen Fig. 6-4-2  Structure of human vitreous collagen fibril. Schematic diagram of the major heterotypic collagen fibrils of vitreous based upon the current knowledge of the structure and biophysical attributes of the constituent molecules. (with permission from Bishop P: The biochemical structure of mammalian vitreous. Eye 10:64, 1996.)

VITREOUS ANATOMY

sclera choroid

canal of anterior vitreous Petit vitreous base cortex

Vitreous Anatomy and Pathology

Chondroitin sulphate glycosaminoglycan chain of type IX collagen

6.4

VITREOUS ANATOMY

retina

Cloquet's canal

area of Martegiani

secondary vitreous

Macroscopic Morphology

In an emmetropic adult human eye vitreous is approximately 16.5 mm in axial length with a depression anteriorly just behind the lens (patellar fossa). The hyloideo-capsular ligament of Weiger is the annular region (1–2 mm in width and 8–9 mm in diameter) where vitreous is attached to the posterior aspect of the lens. Erggelet’s or Berger’s space is at the center of the hyaloideocapsular ligament. The canal of Cloquet arises from this space and courses posteriorly through the central vitreous (Fig. 6-4-3), which is the former site of the hyaloid artery in the embryonic vitreous.16 The former lumen of the artery is an area devoid of collagen fibrils and surrounded by multifenestrated sheaths that were previously the basal laminae of the hyaloid artery wall.4 Posteriorly, Cloquet’s canal opens into a funnel-shaped region anterior to the optic disc, known as the area of Martegiani. Within the adult human vitreous parallel non-branching fibers course in an antero-posterior direction (Fig. 6-4-4) arising from the vitreous base, where they insert anterior and posterior to the ora serrata. The connections between the peripheral anterior vitreous fibers and the retina underlie the pathophysiology of retinal tears owing to strong adhesion in this location.4 The peripheral fibers near the vitreous cortex are circumferential with the vitreous cortex, while central fibers ‘undulate’ parallel to Cloquet’s canal. Ultrastructural studies demonstrated that collagen, organized in bundles of parallel fibrils, is the only microscopic structure corresponding to these fibers.3 It is hypothesized that visible vitreous fibers form when hyaluronan molecules no longer separate the microscopic collagen fibrils, which results in the aggregation of collagen fibrils into bundles from which hyaluronan molecules are excluded.3,4,17 The areas adjacent to these large fibers have a low density of collagen fibrils and a relatively high concentration of hyaluronan molecules. Composed primarily of ‘liquid vitreous’, these areas scatter very little incident light and, when prominent, constitute ‘lacunae’ seen in aging (Fig. 6-4-5).

Microscopic Morphology

The vitreous cortex is the peripheral ‘shell’ of vitreous that courses forward and inward from the anterior vitreous base (anterior vitreous cortex) and posteriorly from the posterior border of the vitreous base, (posterior vitreous cortex). The posterior vitreous cortex is 100– 110 mm thick and consists of densely packed collagen fibrils.4,18 Although no direct connections exist between the posterior vitreous and the retina, the posterior vitreous cortex is adherent to the internal limiting lamina (ILL) of the retina, which is in part the basal lamina of retinal Müller cells. Adhesion between the posterior vitreous cortex and

Fig. 6-4-3  Vitreous anatomy according to classical anatomic and histological studies. (Reprinted with permission from Schepens CL, Neetens A, eds. The vitreous and vitreo-retinal interface. New York: Springer-Verlag; 1987:20.)

Fig. 6-4-4  The eye of a 57-year-old man after dissection of the sclera, choroid, and retina, with the vitreous still attached to the anterior segment. The specimen was illuminated with a slit-lamp beam shone from the side and the view here is at a 90° angle to this plane to maximize the Tyndall effect. The anterior segment is below and the posterior pole is at the top of the photograph. A large bundle of prominent fibers courses anteroposteriorly to exit via the premacular dehiscence in the vitreous cortex.

the ILL probably results from the action of various extracellular matrix molecules.19 A hole in the prepapillary vitreous cortex can sometimes be visualized clinically when the posterior vitreous is detached from the retina (Fig. 6-4-6). If peripapillary glial tissue is torn away during PVD and remains attached to the vitreous cortex about the prepapillary hole, it is referred to as Vogt’s or Weiss’ ring. Vitreous can extrude through the

431

6

MI

Retina and Vitreous

CF

N

C

Fig. 6-4-5  Human vitreous in old age. The central vitreous has thickened, tortuous fibers. The peripheral vitreous has regions devoid of any structure, which contain liquid vitreous. These regions correspond to ‘lacunae,’ as seen clinically using biomicroscopy (arrows).

M V

Fig. 6-4-7  Ultrastructure of human hyalocyte. A mononuclear cell is embedded within the dense collagen fibril (CF) network of the vitreous cortex. There is a lobulated nucleus (N) with a dense marginal chromatin (C). In the cytoplasm there are mitochondria (M), dense granules (arrows), vacuoles (V), and microvilli (MI). (Courtesy of Joe Craft and DM Albert, MD.)

A

B

432

Fig. 6-4-6  Fundus view of posterior vitreous detachment. (A) The posterior vitreous in the left eye of this patient is detached and the prepapillary hole in the posterior vitreous cortex is anterior to the optic disc (arrows, slightly below and to the left of the optic disc here). (B) A slit beam illuminates the retina and optical disc (at bottom) in the center. To the right is the detached vitreous. The posterior vitreous cortex is the dense, whitish gray, vertically oriented linear structure to the right of the slit beam. (Courtesy of CL Trempe, MD.)

prepapillary hole in the vitreous cortex but does so to a lesser extent than through the premacular vitreous cortex where vitreo-macular adhesion and axial traction can cause vitreo-maculopathies.20 Tangential vitreo-macular traction21 is implicated in the pathogenesis of macular holes and macular pucker.22 Embedded within the posterior vitreous cortex are hyalocytes. These mononuclear cells are spread widely apart in a single layer situated 20–50 µm from the ILL of the retina. The highest density of hyalocytes is in the vitreous base, followed next by the posterior pole, with the lowest density at the equator. Hyalocytes are oval or spindle shaped, 10–15 µm in diameter, and contain a lobulated nucleus, a welldeveloped Golgi complex, smooth and rough endoplasmic reticula, many large lysosomal granules (periodic acid-Schiff positive), and phagosomes (Fig. 6-4-7). Balazs11 pointed out that hyalocytes are located in the region of highest hyaluronan concentration and suggested that these cells are responsible for hyaluronan synthesis. Hyalocyte capacity to synthesize collagen was first demonstrated by Newsome et al.23 Similar to chondrocyte metabolism in the joint, hyalocytes may synthesize vitreous collagen at some point(s) during life. The phagocytic capacity of hyalocytes is consistent with the presence of pinocytic vesicles and phagosomes and the presence of surface receptors that bind immunoglobulin G and complement.18 It is intriguing to consider that hyalocytes are among the first cells to be exposed to any migratory or mitogenic stimuli during various disease states, particularly proliferative vitreoretinopathy. Therefore, these cells may be important in the pathophysiology of proliferative disorders at the vitreo-retinal interface, including macular pucker.24 The basal laminae surrounding vitreous are composed of type IV collagen closely associated with glycoproteins.18 At the pars plana, the

AGE-RELATED CHANGES Embryology and Postnatal Development

Early in embryogenesis, the vitreous is filled with blood vessels, the vasa hyaloidea propria. It is not known what stimulates regression of this hyaloid vascular system, but studies have identified a protein native to vitreous that inhibits angiogenesis in experimental models.26 Teleologically, this seems necessary not only to induce regression of the vascular primary vitreous but also to inhibit subsequent cell migration and proliferation and thereby minimize light scatter and achieve transparency. Identifying the phenomena inherent in this transformation may reveal how to control pathologic neovascularization in the eye and elsewhere. Recent studies27–31 have characterized the proteomic profile of embryonic human vitreous during hyaloid vessel regression in an attempt to identify the factors that create and maintain a clear vitreous. These studies found that there is upregulation of certain pathways with concurrent downregulation of others. The findings may also have relevance to developing new ways to induce the regression of pathologic neovascularization in ocular and systemic diseases, such as metastatic carcinoma.

Developmental Anomalies

Persistent fetal vascular (PFV) syndrome is an uncommon developmental anomaly in which the hyaloid vasculature of the primary vitreous fails to involute. Initially described in detail by Reese32 in his 1955 Jackson Memorial Lecture as persistent hyperplastic primary vitreous (PHPV), this condition was revisited by Goldberg33 in his 1997 Jackson Memorial Lecture who coined the term PFV. There is a spectrum of PFV severity, ranging from pupillary strands and a Mittendorf ’s dot to a dense retrolenticular membrane and/or retinal detachment. Anterior PFV consists of retrolenticular fibrovascular tissue that attaches to the ciliary processes and draws them centrally, inducing cataract formation, shallowing of the anterior chamber, and angle-closure glaucoma. Iris vessel engorgement and recurrent intraocular hemorrhage can

result in phthisis bulbi, although the prognosis with surgery is often fair. In a series34 of operated eyes (both anterior and posterior PFV, n = 83), all of the successful cases (visual acuity of 20/70 or better, n = 12/83) were in anterior PFV. Posterior PFV consists of a prominent vitreous fibrovascular stalk that emanates from the optic nerve and courses anteriorly. Preretinal membranes at the base of the stalk are common, often with tractional retinal folds and traction retinal detachment. The prognosis for posterior PFV is poor, suggesting that pharmacotherapy may be the only solution for this form of PFV. In this regard, it has recently been proposed that insufficient levels of vitreous endostatin may be important in the pathogenesis of PFV,35 consistent with the aforementioned proteomic studies.27,30 Improper vitreous biosynthesis during embryogenesis underlies a variety of developmental abnormalities.36 Proper vitreous biosynthesis requires normal retinal development because at least some of the vitreous structural components are synthesized by retinal Müller cells.23 A clear gel, typical of normal ‘secondary vitreous’, appears only over developed retina. Thus, in various developmental anomalies, such as retinopathy of prematurity (ROP), familial exudative vitreoretinopathy, and related entities, vitreous that overlies undeveloped retina in the peripheral fundus is a viscous liquid but not a gel.37 The extent of this finding depends, at least in ROP, upon the gestational age at birth, because the younger the individual the more undeveloped retina is present in the periphery, especially temporally. In other, truly congenital conditions, there are inborn errors of collagen metabolism that have now been elucidated. In Stickler syndrome, defects in specific genes have been associated with particular phenotypes,38 thus enabling the classification of patients with Stickler syndrome into four subgroups. Patients in the subgroups with vitreous abnormalities are found to have defects in the genes coding for type II procollagen and type V/XI procollagen. Ongoing synthesis of both collagen and hyaluronan occurs during development to the adult39, the latter to stabilize the collagen network.17,19

6.4 Vitreous Anatomy and Pathology

basal lamina has a true lamina densa. The basal lamina posterior to the ora serrata is the ILL of the retina. The layer immediately adjacent to the Müller cell is a lamina rara, which is 0.03–0.06 mm thick. The lamina densa is thinnest at the fovea (0.01–0.02 mm) and disc (0.07– 0.1 mm). It is thicker elsewhere in the posterior pole (0.5–3.2 mm) than at the equator or vitreous base.4,18 The anterior surface (vitreous side) of the ILL is normally smooth, whereas the posterior aspect is irregular, filling the spaces created by the irregular subjacent nerve fiber layer. This feature is most marked at the posterior pole, whereas in the periphery both the anterior and posterior aspects of the ILL are smooth. The significance of this topographic variation is not known. At the rim of the optic disc the ILL ceases, although the basal lamina continues as the ‘inner limiting membrane of Elschnig’.25 This membrane is 50 microns thick and is believed to be the basal lamina of the astroglia in the papilla. At the central-most portion of the optic disc the membrane thins to 20 microns, follows the irregularities of the underlying cells of the optic nerve head, and is composed only of glycosaminoglycans with no collagen.25 This structure is known as the ‘central meniscus of Kuhnt.’ The thinness and chemical composition of these membranes may account for, among other phenomena, the frequency with which abnormal cell proliferation arises from or near the optic disc in proliferative diabetic retinopathy and macular pucker. The vitreous is most firmly attached at the vitreous base, disc, macula, and over retinal blood vessels. The posterior aspect (retinal side) of the ILL demonstrates irregular thickening farther posteriorly from the ora serrata.4,18 So-called attachment plaques between the Müller cells and the ILL have been described in the basal and equatorial regions of the fundus but not in the posterior pole, except for the fovea.4,18 It has been hypothesized that these develop in response to vitreous traction upon the retina. The thick ILL in the posterior pole dampens the effects of this traction, except at the fovea, where the ILL is thin. The thinness of the ILL and the purported presence of attachment plaques at the central macula could explain the predisposition of this region to changes induced by traction. An unusual vitreo-retinal interface overlies retinal blood vessels. Physiologically, this may provide a shock-absorbing function to dampen arteriolar pulsations. However, pathologically, this arrangement could also account for the proliferative and hemorrhagic events that are associated with vitreous traction upon retinal blood vessels.

Aging of the Vitreous

Substantial rheological, biochemical, and structural alterations occur in vitreous during aging.40,41 After 45–50 years of age there is a significant decrease in the gel volume and an increase in the liquid volume of human vitreous. These findings were confirmed qualitatively in postmortem studies of dissected human vitreous, and liquefaction was observed to begin in the central vitreous.1,4–6 Vitreous liquefaction actually begins much earlier than detectable by clinical examination or ultrasonography. Postmortem studies found evidence of liquid vitreous at 4 years of age and observed that by the time the human eye reaches its adult size (age 14–18 years) approximately 20% of the total vitreous volume consists of liquid vitreous.40 In these postmortem studies of fresh, unfixed human eyes it was observed that after the age of 40 years there is a steady increase in liquid vitreous simultaneous with a decrease in gel volume. By 80–90 years of age more than half the vitreous is liquid. The finding that the central vitreous is where fibers are first observed is consistent with the concept that breakdown of the normal hyaluronan-collagen association results in simultaneous vitreous liquefaction and aggregation of collagen fibrils into bundles of parallel fibrils, seen as large fibers (see Fig. 6-4-4).1,4–6 In the posterior vitreous such age-related changes often form large pockets of liquid vitreous, recognized clinically as lacunae,4–6 and mistakenly described as anatomic structures.5–7 The mechanism of vitreous liquefaction is not well understood. Gel vitreous can be liquefied in vivo through the removal of collagen by enzymatic destruction of the collagen network.42 Endogenous liquefaction may be the result of changes in the minor glycosaminoglycans and chondroitin sulfate profile of vitreous. It has been shown that the injection of chondroitinase can induce liquefaction and ‘disinsertion’ of the vitreous.43 Ocriplasmin is another agent that can induce liquefaction.45 Because of its ability to also induce dehiscence at the vitreo-retinal interface, this agent was FDA-approved in the United States in 2012 for pharmacologic vitreolysis.44,46 Another possible mechanism of endogenous vitreous liquefaction is a change in the conformation of hyaluronan molecules with aggregation or crosslinking of collagen molecules. Singlet oxygen can induce conformational changes in the tertiary structure of hyaluronan molecules. Free radicals generated by metabolic and photosensitized reactions could alter hyaluronan and/or collagen structure and trigger a

433

6 Retina and Vitreous

dissociation of collagen and hyaluronan molecules, which ultimately results in liquefaction.47 This is plausible because the cumulative effects of a lifetime of daily exposure to light may influence the structure and interaction of collagen and hyaluronan molecules by the proposed free radical mechanism(s). Biochemical studies support the rheologic observations. Total vitreous collagen content does not change after 20–30 years of age. However, in studies of a large series of normal human eyes obtained at autopsy, the collagen concentration in the gel vitreous at 70–90 years of age (approximately 0.1 mg/mL) was greater than at 15–20 years of age (approximately 0.05 mg/mL).40 Because the total collagen content does not change, this finding most likely reflects the decrease in the volume of gel vitreous that occurs with aging and consequent increase in the concentration of the collagen that remains in the gel. The collagen fibrils in this gel become packed into bundles of parallel fibrils,3,4,17,41 likely with crosslinks between them. Abnormal collagen crosslinks have, in fact, been identified in the vitreous of humans who have diabetes, and the findings are consistent with the existence of diabetic vitreopathy48 (see below), a phenomenon that has been described for other extracellular matrices in patients with diabetes. The structural changes that derive from the aforementioned biochemical and rheologic changes consist of a transition from a clear vitreous in youth (Fig. 6-4-8), to a fibrous structure in the adult (see Fig. 6-4-4), which results from aggregation of collagen fibrils. In old age advanced liquefaction (synchisis; see Fig. 6-4-5) occurs with ultimate collapse (syneresis) of the vitreous and PVD. The vitreous base posterior to the ora increases in size with increasing age to nearly 3 mm, to bring the posterior border of the vitreous base closer to the equator.49 This widening of the vitreous base was found to be most prominent in the temporal portion of the globe. The posterior migration of the vitreous base probably plays an important role in the pathogenesis of peripheral retinal breaks and

rhegmatogenous retinal detachment. Within the vitreous base, a ‘lateral aggregation’ of the collagen fibrils is present in older individuals,50 similar to aging changes within the central vitreous.17,41 Recent studies39 have confirmed posterior migration of the posterior border of the vitreous base during aging and also demonstrated intraretinal synthesis of collagen fibrils that penetrate the ILL of the retina and ‘splice’ with vitreous collagen fibrils. These aging changes at the vitreous base could contribute to increased traction on the peripheral retina and to the development of retinal tears and detachment.

Posterior Vitreous Detachment

The most common age-related event in the vitreous is PVD.51 True PVD is a separation between the posterior vitreous cortex and the ILL of the retina; PVD can be localized, partial, or total (up to the posterior border of the vitreous base). Autopsy studies reveal that the incidence of PVD is 63% by the eighth decade,52 and it is more common in myopic eyes, in which it occurs on average 10 years earlier than in emmetropic and hyperopic eyes. Cataract extraction in myopic patients introduces additional effects, which caused PVD to develop in all but 1 of 103 myopic (greater than −6 D) eyes.4 Vitreous liquefaction in conjunction with weakening of the vitreous cortex-ILL adhesion, results in PVD. It is likely that dissolution of the posterior vitreous cotex-ILL adhesion at the posterior pole allows liquid vitreous to enter the retrocortical space via the prepapillary hole and perhaps also the premacular vitreous cortex. With rotational eye movements, liquid vitreous can dissect a plane between the vitreous cortex and the ILL, which results in true PVD. This volume displacement from the central vitreous to the preretinal space causes vitreous syneresis (collapse). ‘Floaters’ are the most common symptom of patients with PVD. These usually result from entopic phenomena caused by condensed vitreous fibers, glial tissue of epipapillary origin (which adheres to the posterior vitreous cortex), and/or intravitreal blood. Floaters move with vitreous displacement during eye movement and scatter incident light, which casts a shadow on the retina that is perceived as a gray, ‘hair-like’ or ‘fly-like’ structure. Studies53 have determined that floaters are a clinically significant problem for some patients that can be treated by vitrectomy.54 In 1935, Moore55 described ‘light flashes’ as a common complaint that results from PVD. Wise56 noted that light flashes occurred in 50% of cases at the time of PVD; they were usually vertical and temporally located. Voerhoeff57 suggested that the light flashes result from the impact of the detached posterior vitreous cortex upon the retina during eye movement. Vitreous liquefaction58 and PVD59 increase intravitreal oxygen levels and may contribute to cataractogenesis. Vitrectomy has similarly been implicated in post-operative cataract formation60 as well as glaucoma.61

A

Anomalous Posterior Vitreous Detachment

B

434

Fig. 6-4-8  Vitreous structure in childhood. (A) The posterior and central vitreous in a 4-year-old child has a dense vitreous cortex with hyalocytes. A substantial amount of vitreous extrudes into the retrocortical (preretinal) space through the premacular vitreous cortex. However, no fibers are present in the vitreous. (B) Central vitreous structure in an 11-year-old child has hyalocytes in a dense vitreous cortex (arrows). No fibers are seen within the vitreous.

Anomalous posterior vitreous detachment (APVD)39 occurs when there is extensive vitreous liquefaction without concurrent weakening of vitreo-retinal adhesion, resulting in traction at the vitreo-retinal interface. There are various causes for an imbalance between the degree of gel liquefaction and weakening of vitreo-retinal adhesion. As described above, inborn errors of collagen metabolism, such as those present in Marfan’s, Ehlers-Danlos, and Stickler’s syndromes,38 result in extensive gel liquefaction at an early age when there is still considerable vitreo-retinal adherence. The result is a high incidence of large posterior retinal tears and detachments. Systemic conditions such as diabetes induce biochemical62 and structural63 alterations in vitreous, known as as diabetic vitreopathy,48 which are important in the pathobiology of proliferative diabetic vitreoretinopathy and diabetic macular edema. However, the overwhelming majority of cases are likely due to an as yet unidentified genetic predisposition for firm vitreo-retinal adhesion, probably related to the extracellular matrix between vitreous and the retina. Fig. 6-4-9 delineates the various deleterious effects of anomalous PVD. When the entire (full-thickness) posterior vitreous cortex separates from the macula but is still attached peripherally, there can be vitreoretinal traction causing peripheral retinal tears and detachments. Autopsy studies found that PVD is associated with retinal breaks in 14.3% of all cases. Non-diabetic patients with non-traumatic vitreous hemorrhage have retinal tears in 25%64 to 67%65 and retinal detachments in 8%64 to 39%65 of cases.

HEADING

anomalous PVD partial thickness = vitreoschisis

full-thickness but only partial PVD

premacular membrane

peripheral separation posterior traction

VPA & centrifugal (outward) contraction

no VPA & centripetal (inward) contraction

macular hole

macular pucker

posterior separation peripheral traction macular traction

optic disc traction

VMTS exud AMD

vitreo-papillary traction

retinal tears and detachment

VPA = Vitreo-Papillary Adhesion

Posterior full-thickness vitreo-macular adhesion with peripheral vitreo-retinal separation can pull on the macula and induce vitreomacular traction syndrome. Persistent vitreo-macular adhesion may exacerbate age-related macular degeneration. It is not clear by what mechanism this occurs, but patients with dry age-related macular degeneration (AMD) have a two- to three-fold higher prevalence of total PVD, while patients with wet AMD have a three to four-fold higher prevalence of vitreo-macular adhesion,66,67,68 observations that were not influenced by genetic or environmental factors. It is hypothesized that vitreo-macular traction could induce low grade inflammation and/or that the adherent posterior vitreous cortex could alter macular oxygenation from ciliary body and the egress of pro-angiogenic cytokines from the macula. Similarly, traction upon the optic disc can induce vitreopapillary traction syndromes69 or exacerbate neovascularization with vitreous hemorrhage in proliferative diabetic retinopathy. Moreover, persistent vitreo-papillary adhesion may promote macular hole formation as opposed to macular pucker.70,71 Anomlaous PVD can be associated with splitting of the posterior vitreous cortex, called vitreoschisis.55,72 This may be the first event in macular pucker and macular hole pathogenesis73,74 and may also play a role in diabetic macular edema.75 Autopsy studies76 reported that PVD was associated with vitreous cortex remnants at the fovea in 26 of 59 (44%) human eyes. Ulltrasonography studies56 detected vitreoschisis by ultrasound in 20% of eyes with proliferative diabetic retinopathy. Recent studies73,74 employing combined OCT/SLO detected vitreoschisis in about half of patients with macular pucker and macular holes.

Epiretinal membrane/macular pucker

Following anomalous PVD with vitreoschisis, premacular membranes can contract and cause significant visual impairment and metamorphopsia, sometimes necessitating surgical intervention. Studies of excised tissue have demonstrated the presence of astrocytes and retinal pigment epithelial (RPE) cells77,78 but there are likely to be other cells that can have similar appearances, such as hyalocytes. It has been hypothesized73 that macular pucker results when vitreoschisis splits the posterior vitreous cortex anterior to hyalocytes leaving a cellular membrane attached to the macula. These cells then elicit migration of monocytes from the circulation and contraction of vitreous via the action of Connective Tissue Growth Factor79 and other growth factors.24 Recent studies80 have also identified that nearly half of all eyes with macular pucker have more than one site of retinal contraction.

6.4 Vitreous Anatomy and Pathology

liquefaction without vitreo-retinal dehiscence

Fig. 6-4-9  Schematic of anomalous posterior vitreous detachment. Vitreous gel liquefaction without concurrent dehiscence at the vitreo-retinal interface causes various anomalies. If separation of vitreous from retina is full-thickness in the axial plane but incomplete in the coronal plane, there can be different forms of partial PVD (right side of diagram). Posterior separation with persistent peripheral attachment can induce retinal breaks and detachments. Peripheral vitreoretinal separation with persistent full-thickness vitreomacular adhesion (VMA) can induce vitreo-macular traction syndrome (VMTS). VMA is associated with exudative age-related macular degeneration (Exud AMD) and diabetic macular edema. Persistent attachment to the optic disc can induce vitreopapillopathies and also contribute to neovascularization and vitreous hemorrhage in ischemic retinopathies as well as macular holes. If during PVD, the posterior vitreous cortex splits (vitreoschisis) anterior to the level of the hyalocytes, a relatively thick, cellular membrane remains attached to the macula. If there is also separation from the optic disc, inward (centripetal) contraction induces macular pucker. If the split is posterior to the hyalocytes, the remaining premacular membrane is relatively thin and hypocellular. Persistent vitreo-papillary adhesion (present in 87.5% of cases) results in outward (centrifugal) tangential traction (especially nasally), inducing a macular hole. [From Sebag J: Anomalous PVD – a unifying concept in vitreo-retinal diseases. Graefes Arch Clin Exp Ophthalmol 242:690–698, 2004; Sebag J, Green WR: Vitreous and the Vitreo-Retinal Interface In: Retina (Ryan, ed) Elsevier, 2012 (in press).]

These studies found a higher incidence of intraretinal cysts and significantly more macular thickening with increasing foci of retinal contraction.

Macular holes

The precise pathogenesis of macular holes is unknown, although several hypotheses have been presented over the years. Initial theories cited antero-posterior traction by vitreous fibers, while more recent hypotheses implicate tangential traction upon the macula. If vitreoschisis plays a pathogenic role, the split likely occurs posterior to the level of hyalocytes leaving a thin, hypocellular membrane attached to the macula.73,74 If there is also persistent vitreo-papillary adhesion, the vector of tangential traction will be outward from the fovea opening a central dehiscence with surrounding cystoid spaces in the central macula.73,74

METABOLIC DISORDERS OF VITREOUS Diabetic Vitreopathy

In diabetes, there is an increase in vitreous glucose levels81 associated with increased advanced glycation endproducts.62 In poorly-controlled diabetes fluctuations in systemic glucose levels alter the ionic milieu influencing vitreous osmolarity and hydration. This could result in swelling and contraction of the entire vitreous via effects on hyaluronan, with consequent traction upon structures attached to the posterior vitreous cortex, such as new blood vessels from the optic disc and/or retina.82 These events could promote the proliferation of neovascular fronds and perhaps even induce rupture of these new vessels with vitreous hemorrhage. Molecular effects of diabetes result in morphological changes within the vitreous47 (Fig. 6-4-10). The roles of these and other pathological changes, such as posterior vitreoschisis55,72 may lead to therapy designed to inhibit diabetic vitreopathy. Alternatively, the induction of innocuous PVD early in the course of diabetic retinopathy may have long-term salubrious effects in patients at great risk.44

Synchysis Scintillans

This cause of vitreous opacification is a consequence of chronic vitreous hemorrhage when frank hemorrhage is no longer present. The opacities are flat, refractile bodies, golden brown in color, and freely mobile. Associated with liquid vitreous, they settle to the most

435

6 Retina and Vitreous

A

matrix.88 In these investigations, energy-dispersive X-ray analysis showed calcium and phosphorus to be the main elements in asteroid bodies. Electron diffraction structural analysis demonstrated calcium hydroxyapatite and possibly other forms of calcium phosphate crystals. Some reports suggest an association between asteroid hyalosis and diabetes mellitus,89,90 while other investigations found no such association.63,91 Asteroid hyalosis appears to be associated with certain pigmentary retinal degenerations,92 although it is not known whether this is related to the presence of diabetes in these patients. Yu and Blumenthal93 proposed that asteroid hyalosis results from aging collagen, whereas other studies94 suggested that asteroid formation is preceded by depolymerization of hyaluronan.

Amyloidosis

B Fig. 6-4-10  Diabetic vitreopathy. (A) Right eye of a 9-year-old girl who has a 5-year history of type 1 diabetes shows extrusion of central vitreous through the posterior vitreous cortex into the retrocortical (preretinal) space. The subcortical vitreous appears very dense and scatters light intensely. Centrally, there are vitreous fibers (arrows) with an antero-posterior orientation and adjacent areas of liquefaction. (B) Central vitreous in the left eye of the same patient shows prominent fibers that resemble those seen in non-diabetic adults (see Fig. 6-4-5). (Reprinted with permission from Sebag J. Abnormalities of human vitreous structure in diabetes. Graefes Arch Clin Exp Ophthalmol. 1993;231:257–60.)

Amyloidosis can result in the deposition of opacities in the vitreous of one or both eyes. Bilateral involvement can be an early manifestation of the dominant form of familial amyloidosis, although rare cases of vitreous involvement in non-familial forms have been reported. The opacities first appear in the vitreous adjacent to retinal blood vessels and later appear in the anterior vitreous. Initially, the opacities are granular with wispy fringes and later take on a ‘glass wool’ appearance. When the opacities form strands, they appear to attach to the retina and the posterior aspect of the lens by thick footplates.87 Following PVD, the posterior vitreous cortex is observed to have thick, linear opacities that follow the course of the retinal vessels. The opacities seem to aggregate by ‘seeding’ on vitreous fibrils and along the posterior vitreous cortex.88 Histopathological studies found that asteroid bodies contain starlike structures with dense, fibrillar centers. The amyloid fibrils are 5–10 nm in diameter and are differentiated from the 10–15 nm vitreous fibrils by stains for amyloid and by the fact that the vitreous fibrils are very straight and long.88 Electron microscopy can confirm the presence of amyloid, and immunocytochemical studies identified the major amyloid constituent as a protein that resembles prealbumin.95 Streeten88 proposed that hyalocytes could perform the role of macrophage processing of the amyloid protein before its polymerization. This may further explain why the opacities initially appear at the posterior vitreous cortex where hyalocytes reside.

KEY REFERENCES dependent portion of the vitreous when eye movement stops. The vitreous about these opacities is degenerated so that collagen is displaced peripherally. Chemical studies83 demonstrated the presence of cholesterol crystals in these opacities, thus the condition is sometimes referred to as ‘cholesterolosis bulbi’. Free hemoglobin spherules can also be present within the vitreous.84

Asteroid Hyalosis

This generally benign condition is characterized by small, yellow-white, spherical opacities throughout the vitreous. A study85 of 10,801 autopsy eyes found an incidence of 1.96%; with a male to female ratio of 2 : 1. Asteroid hyalosis is unilateral in over 75% of cases. Asteroid bodies are associated intimately with the vitreous gel and move with vitreous displacement during eye movement, suggesting a relationship with agerelated collagen fibril degeneration.86 However, PVD, either complete or partial, occurs less frequently in individuals with asteroid hyalosis than in age-matched controls,87 which does not support age-related degeneration as a cause. Histological studies demonstrate a crystalline ap­ pearance and a pattern of positive staining to fat and acid mucopolysaccharide stains that is not affected by hyaluronidase pretreatment.88 Electron diffraction studies showed the presence of calcium oxalate monohydrate and calcium hydroxyphosphate. Ultra­ structural studies reveal intertwined ribbons of multilaminar membranes (with a 6 nm periodicity) that are characteristic of complex lipids, especially phospholipids, that lie in a homogeneous background

Access the complete reference list online at 436

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PART 6 RETINA AND VITREOUS

IN THIS CHAPTER

SECTION 2 Ancillary Tests

Additional content available online at

Contact B-Scan Ultrasonography Yale L. Fisher, James M. Klancnik Jr, Hanna Rodriguez-Coleman, Antonio P. Ciardella, Nicole E. Gross, David Y. Kim

Definition: Diagnostic technique which is useful in the evaluation of

intraocular and orbital contents.

Key features

6.5

examination of posterior portions of the globe and orbit. Most contact B-scan machines are freestanding and relatively mobile; they consist of a detachable transducer probe, a signal processing box, and a display screen.

TECHNIQUE OF EXAMINATION

High-frequency sound waves are emitted and received by a handheld transducer probe ■ Images are processed and displayed on a video monitor

The handheld ultrasonic probe is placed gently against the eyelid or sclera using a sound-coupling agent such as methylcellulose. The ultrasonographer can move the probe systematically to scan the globe and orbit. Lateral or medial displacement of the probe can be used to avoid the lens system and thus prevent image artifacts (Fig. 6-5-1).

Associated features

CONCEPTS OF B-SCAN INTERPRETATION

■

■

Adequate interpretation for diagnosis of posterior segment disease depends on three concepts: ■ Real time ■ Gray scale ■ Three-dimensional analysis

Interpretation of a B-scan ultrasonograph depends on three concepts: Real time Gray scale Three-dimensional analysis

• • •

Real Time INTRODUCTION Ophthalmic ultrasonography is one of the most useful diagnostic techniques for intraocular and orbital evaluation, especially in the setting of opaque media. It involves pulse-echo technology in which high frequency sound waves are emitted from a handheld transducer probe. Returning echoes are processed and displayed on video monitors or oscilloscopes. In ophthalmology, two modes of display are common: A-scan mode (time-amplitude), used predominantly for interpretation of tissue reflectivity – the returning echoes form a graph-like image seen as vertical deflections from a baseline. B-scan mode (intensity modulation), used predominantly for anatomical information – it shows cross-sectional images of the globe and orbit. Both types of sonographic display are complementary. This chapter focuses on B-scan information. Developed in the mid-1950s with water immersion techniques, B-scan ultrasonography initially required a laboratory setting. In the early 1970s, contact devices were introduced utilizing methylcellulose, or a similar sound-coupling agent, and this rapidly increased B-scan availability and popularity. Subsequent improvements in image quality and scanning rates made interpretation easier for the examiner.1–8

• •

DEVICES See clip: 6.05.01

Commercially available instruments for ocular and orbital contact B-scan ultrasonography usually employ 10 MHz (megacycles/second) transducer probes enclosed in a handheld container. A motor within the handpiece moves the ultrasonic probe in a rapid sector scan to create cross-sectional B-scan images. In general, these devices have resolution capacities of approximately 0.4 mm axially and 1 mm laterally. Higher resolution ophthalmic instruments are available (20–50 MHz), but limited signal penetration renders them less effective in the

Ultrasound B-scan images can be visualized at approximately 32 frames/ second, allowing motion of the globe and vitreous to be easily detected. Characteristic real time movements can identify tissues such as detached retina or mobile vitreous, thus increasing diagnostic capability. Real time ultrasonic information frequently aids in vitreoretinal surgery.

Gray Scale

A variable gray scale format displays the returning echoes as a twodimensional image. Strong echoes, such as those seen from sclera or detached retina, are displayed brightly at high instrument gain and remain visible even when the gain is reduced. Weaker echoes, such as those from vitreous hemorrhage, are seen as lighter shades of gray that disappear when the gain is reduced. Comparing echo strengths during examination is the basis for qualitative tissue analysis. Diagnostic accuracy is enhanced if the strongest possible echoes from each tissue type are being evaluated by ensuring that the probe remains perpendicular to the tissues of interest at all times.

Three-Dimensional Analysis

Developing a mental three-dimensional image or anatomical map from multiple two-dimensional B-scan images is the most difficult concept to master. This is essential, because it provides the vital architectural information that is the basis for B-scan diagnosis. Three-dimensional understanding of ultrasound images is especially critical in the pre­ operative evaluation of complex retinal detachments and intraocular or orbital tumors.

DISPLAY PRESENTATION AND DOCUMENTATION B-scan images displayed on a screen are presented horizontally. Areas closest to the probe are imaged to the left of the screen and those farthest away are imaged to the right. The top of the screen correlates with a mark located on the examining probe that represents the initial transducer position for each sector scan.

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Fig. 6-5-1  Illustration demonstrating placement of handheld ultrasonic probe and corresponding B-scan image with optic nerve (arrow) as reference point. Additional material for ultrasound education available at www.OphthalmicEdge.org.

6 Retina and Vitreous See clip: 5.06.01

Contact B-scan ultrasonography necessitates a dynamic examination and individual ‘frozen’ cross-sectional images used for documentation should not alone be used for interpretation.

Normal Vitreous Cavity

The normal vitreous space is almost clear echogenically. Occasional small dots or linear echoes can be seen at the highest gain settings (90 dB), but they fade rapidly as the gain is reduced. Real time scanning during eye movement usually shows some motion of these fine echoes.

Vitreous Hemorrhage

Intravitreal hemorrhage produces easily detectable diffuse dots and blob-like vitreal echoes that correlate with the amount of blood present. Reduction of gain to 70 dB results in rapid fading of all but the densest areas of reflectivity. Real time evaluation usually shows a characteristic rapid, staccato motion with eye movement. This occurs because vitreous hemorrhage induces a general vitreous gel liquefaction and separation from the retina.

Retinal Detachment

Detached retina appears as a highly reflective sheet-like tissue within the vitreous space (Fig. 6-5-2). Small detachments often appear domelike on imaging. The appearance of total retinal detachment, which anatomically is cone shaped, varies depending upon the position of the examining probe. Axial images are funnel shaped with attachment to the optic nerve head. Coronal images show a circular cross section of the cone. Real time evaluation varies; recent detachments have a characteristic undulating movement slower than that of the vitreous gel. Longstanding detachments appear stiff due to proliferation of scar tissue on the retinal surface.

Choroidal Detachment

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Detached choroid appears smooth and convex on imaging. An elevated dome can be seen between the pars plana, vortex veins, and optic nerve where the choroid is most firmly attached. In serous choroidal detachments, the subchoroidal space is echolucent whereas in hemorrhagic choroidal detachments the subchoroidal space appears homogeneous initially and then, with liquefaction, develops fluid levels. When severe, the detached choroid can meet at the center of the globe and is termed ‘kissing’. A choroidal detachment can be differentiated from a retinal detachment by its shape, thickness being greater than retina alone, and insertion at the ciliary body as opposed to the ora serata. On dynamic imaging, choroidal detachments are virtually immobile in contrast to detached retina.

Fig. 6-5-2  Contact B-scan image of a retinal detachment. This axial section of a total retinal detachment reveals a highly reflective sheet-like membrane (arrows) in the vitreous space, detached from the posterior eye wall and attached only to the optic nerve head.

TUMORS Evaluation of intraocular tumors requires not only topographic localization but also interpretation of gray scale characteristics. Malignant choroidal melanomas, for example, have the most characteristic appearance. They are mostly dome or mushroom shaped and, on gray scale, their anterior borders are strongly reflective whereas the progressively deeper portions of the tumor are less reflective. This is due to cellular homogeneity that provides a false hollowing appearance. Tissues, such as orbital fat, localized behind these tumors are often shadowed and appear less reflective due to absorption of sound by the tumor.

DIGITAL CONTACT ULTRASOUND A series of advances in electronics, such as digital techniques and the development of high capacity storage devices, allow documentation of contact ultrasonography beyond static photographs. Real time kinetic movie recordings and playback of a B-scan examination with simultaneous amplitude information have made possible the recall of complete examinations. This is invaluable when comparison at a later date is of the essence, for example, in tumor evaluation.

SUMMARY

KEY REFERENCES Bronson NR, Fisher YL, Pickering NC, et al. Ophthalmic contact B-scan ultrasonography for the clinician. Baltimore: Williams & Wilkins; 1980.

Access the complete reference list online at

Coleman DJ, Lizzi FL, Jack RL. Ultrasonography of the eye and orbit. Philadelphia: Lea & Febiger; 1977. Coleman DJ, Silverman RH, Lizzi FL, et al. Ultrasonography of the eye and orbit. Philadelphia: Lippincott Williams & Wilkins; 2006. Coleman DJ. Reliability of ocular and orbital diagnosis with B-scan ultrasound. 1. Ocular diagnosis. Am J Ophthalmol 1972;73:501–16. Fisher YL. Contact B-scan ultrasonography: a practical approach. Int Ophthalmol Clin 1979;19:103–25. Fisher YL. Examination Techniques for the Beginner [Internet]. New York: Ophthalmic Edge LLC; 2012 [updated 2009 Sept 22]. Available from: http://www.OphthalmicEdge.org. Purnell EW. Intensity modulated (B-scan) ultrasonography. In: Goldberg RE, Sarin LK, editors. Ultrasonics in ophthalmology: diagnostic and therapeutic applications. Philadelphia: WB Saunders; 1967. p. 102–23.

6.5 Contact B-Scan Ultrasonography

Contact B-scan ultrasound provides a convenient, noninvasive means for the evaluation of intraocular structures in situations where clinical examination is not possible because of opaque ocular media; it also allows a dynamic examination of the vitreoretinal relationship. Threedimensional and digital technology expand teaching capability and bring the clinical availability of contact ultrasonography to a larger audience. Ultrasound studies should be used in conjunction with detailed clinical examination and other investigational modalities.

Bronson NR. Quantitative ultrasonography. Arch Ophthalmol 1969;81:400–72.

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REFERENCES

5. Bronson NR, Fisher YL, Pickering NC, et al. Ophthalmic contact B-scan ultrasonography for the clinician. Baltimore: Williams & Wilkins; 1980. 6. Fisher YL. Contact B-scan ultrasonography: a practical approach. Int Ophthalmol Clin 1979;19:103–25.

2. Coleman DJ. Reliability of ocular and orbital diagnosis with B-scan ultrasound. 1. Ocular diagnosis. Am J Ophthalmol 1972;73:501–16.

7. Coleman DJ, Silverman RH, Lizzi FL, et al. Ultrasonography of the eye and orbit. Philadelphia: Lippincott Williams & Wilkins; 2006.

3. Coleman DJ, Lizzi FL, Jack RL. Ultrasonography of the eye and orbit. Philadelphia: Lea & Febiger; 1977.

8. Fisher YL. Examination Techniques for the Beginner [Internet]. New York: Ophthalmic Edge LLC; 2012 [updated 2009 Sept 22]. Available from: http://www.OphthalmicEdge.org.

6.5 Contact B-Scan Ultrasonography

1. Purnell EW. Intensity modulated (B-scan) ultrasonography. In: Goldberg RE, Sarin LK, editors. Ultrasonics in ophthalmology: diagnostic and therapeutic applications. Philadelphia: WB Saunders; 1967. p. 102–23.

4. Bronson NR. Quantitative ultrasonography. Arch Ophthalmol 1969;81:400–72.

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PART 6 RETINA AND VITREOUS SECTION 2 Ancillary Tests

Fluorescein Angiography and Indocyanine Green Angiography

6.6

Raul Velez-Montoya, Jeffrey L. Olson, Naresh Mandava

FLUORESCEIN ANGIOGRAPHY Definition: Fluorescein angiography (FA) is a diagnostic technique that uses intravenous fluorescein dye to allow the sequential visualization of the blood flow simultaneously through retinal, choroidal and iris tissue.1 Since its introduction it has been an invaluable aid in the assessment of chorioretinal diseases and in the indication and outcome assessment of treatment methods.1,2

Key features ■

Intravenous or oral dose of fluorescein sodium dye administered Sequential fundus photographs obtained with camera equipped with appropriate exciting and absorbing filters or light sources taking advantage of the inherent fluorescent properties of the dye ■ Reflected light captured on either film or as digital images ■ Interpretation of images critically dependent on an understanding of ocular anatomy in both health and disease ■ Indocyanine green dye, administered intravenously , can be an important adjunct to the diagnosis of chorioretinal disease ■

INDOCYANINE GREEN ANGIOGRAPHY Definition: Indocyanine green angiography (ICGA) is a diagnostic technique that exploits indocyanine green (ICG) dye’s infrared fluorescence and biochemical properties, to adequately portray the characteristics of the choroidal circulation, aiding in the diagnosis of diseases in which choroidal circulation is affected; such as idiopathic polypoidal choroidal vasculopathy, exudative age-related macular degeneration, and inflammatory diseases – among others.5,7,20

Key features ■

Intravenous injection of indocyanine green dye ■ Serial photographs taken with digital imaging system to capture emission for dye ■ Interpretation of resultant images critically dependent on understanding of retinal and choroidal anatomy in health and disease

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FLUORESCEIN ANGIOGRAPHY INTRODUCTION Fluorescein angiography relies on the special fluorescent property of sodium fluorescein (SF) – defined as the ability of certain molecules to emit light of longer wavelength when stimulated by light of shorter wavelength. After stimulation, electrons return to the base energy level, emitting energy in the form of electromagnetic waves, which produces visible light.3–5 The dye has a narrow spectrum of light absorption with a maximum peak at 490 nm (485–500 nm, blue visible spectrum). The emitted light (fluorescence) occurs in the yellow-green spectrum with a wavelength of 530 nm (520–535 nm).5 A stimulation source transmits light energy to the patient’s retina using either a flash/filter or a laser in the 485–500 nm range. The energy is then either reflected back by the retina as blue light, or absorbed by the SF and emitted back as green light. Then a capturing device (camera) uses a green filter (520–535 nm) to selectively capture the fluorescent image onto film or a digital surface.

PURPOSE OF THE TEST In normal individuals, the SF molecule freely crosses the wall of highly permeable capillaries (choriocapillaris) but remains within the lumen of vessels with lower permeability (retinal and large choroidal vessels) since a good percentage circulates through the blood unbound to plasma proteins. This makes FA the ideal study for evaluating retinal circulation, its vascular architecture, and the status of the blood-retinal barrier; however, some information can be obtained regarding choroidal circulation and retinal pigment epithelium (RPE) as well.8,11 Vascular diseases, such as in diabetic retinopathy, central serous chorioretinopathy, venous occlusive disease, and choroidal neovascularization secondary to age-related macular degeneration (CNV-AMD) can be clearly demonstrated with FA and the images can be used to select the appropriate therapeutic approach, guide treatment, and assess therapeutic results.12

PROPERTIES OF SODIUM FLUORESCEIN DYE Sodium fluorescein (sodium resorcinolphathalein) is a yellow-red, synthetic salt dye that is most commonly used to evaluate flow patterns of subterranean waters, as a cosmetic and pharmacologic color, and as a labeling agent in protein research.6 It has a molecular weight of 376.7  kDa.13 Once injected to the bloodstream, approximately 80% of the dye becomes bound to plasma proteins (particularly albumin) while the rest remains unbound.13 The dye is metabolized by both the liver and kidneys and is eliminated in the urine within 24–36 hours of injection. Its most important property for ophthalmological purposes is its fluorescence. It has a narrow spectrum of absorption and excitation that makes the FA technique feasible (see introduction). Sodium fluorescein dye is generally available commercially in aliquots of 2–3  mL of 25% or 5  mL of 10% sterile aqueous solution.

PROCEDURE

COMPLICATIONS Fluorescein angiography is an invasive test and despite being deemed generally safe, it is not free of adverse reaction. These reactions range from mild to severe. Mild reactions are defined as transient and resolve spontaneously without treatment; most commonly these are nausea (approximately 3–15%), vomiting (up to 7%), sneezing, inadvertent arterial injection and pruritus.1,15 Moderate adverse reactions resolve with medical intervention; these include urticaria, angioedema, syncope, thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy.1,15 Severe reactions are those that require intensive intervention and the patients may have poor recovery; these include laryngeal edema, bronchospasm, anaphylaxis, hypotension, shock, myocardial infarction, pulmonary edema, hemolytic anemia, cardiac arrest, tonicclonic seizures, and death.1,15 The incidence of adverse reactions has been reported in a multicenter, collaborative study (Table 6-6-1). The overall incidence is estimated to be between 3% and 20%. While not considered a complication, the yellowing of the skin most commonly seen in fair-skinned individuals may lead to photosensitivity and patients should be cautioned about ultraviolet exposure. Patients should also be advised of possible darkening of the urine for 24–48 hours after the study. Previous efforts to try to relate the procedure technique, dye concentrations, rate of infusion and volume with the incidence of adverse reactions have not been conclusive.11 Although in vivo skin test remains the most reliable diagnostic tool for the diagnosis of IgEmediated allergy to SF, it is not particularly effective in predicting mild adverse reactions (AR), since they are not attributable to

Mild Moderate

Severe

Reaction

Incidence

Nausea, vomiting sneezing Urticaria Syncope Other Overall Respiratory Cardiac Seizures Death Overall

0–5% (based on 87% of respondents) 1 : 82 1 : 337 1 : 769 1 : 63 1 : 3800 1 : 5300 1 : 13900 1 : 221781 1 : 1900

From the survey conducted by Yannuzzi et al. Ophthalmology 1986;93:611–7.

immunological mechanisms.4 However it can be useful in predicting severe cases of anaphylaxis. Special attention should be paid to patients who have reported previous mild or moderate AR during the study because the rate of recurrence is high (48 to 68%) and the study should be avoided if possible.1 The American Academy of Ophthalmology Preferred Practice Patterns states that each angiographic facility should have in place an emergency protocol to minimize risk and manage complications.16 Regular stocking and updating of medications is needed, as well as regular training of photographers and supporting staff to recognize signs and symptoms of anaphylaxis. An emergency kit should be available on site which includes an airway bag, IV equipment, automated external defibrillator, oral or intramuscular antihistamines and auto­ injectors of epinephrine. The protocol should be posted in order to be visible for everybody.16 Although package inserts from most brands of SF dye state that injection should be avoided during pregnancy, especially during the first trimester, data existing from several series and animal studies have not been able to identify a higher rate of birth abnormalities or complications when performed on pregnant patients (regardless of SF concentration: 10 or 25%).14,17,18 Therefore it is reasonable to perform FA on pregnant patients when vision is threatened by potentially blinding diseases. Nonetheless, most of the clinicians prefer to wait until delivery. Nursing mothers are discouraged from breastfeeding for at least 24 to 48 hours after FA.19 Several technological advances have taken place since the introduction of film angiography:  Confocal Scanning Laser Ophthalmoscope (CSLO) as the energy source: The main benefit of switching to CSLO instead of a traditional cobalt blue flash bulb is that the exact laser wave length can be selected to generate the peak emission of light of the SF dye.2,6 This means a significant increase of the signal-to-noise ratio in each examination. Despite the fact that the retina receives a higher emission of light energy with this modality, the toxic threshold is not exceeded because the energy is emitted only for 0.1–0.7 microseconds.3 This enables high-speed acquisition of images and short movies allowing a dynamic evaluation of the blood flow through the retinal and choroidal vessels. The wavelength of the laser can be tuned or combined in order to acquire images with different dyes simultaneously (SF and Indocyanine green). The procedure is more comfortable for the patient since there is no bright flash (Fig. 6-6-1).3,6  The change of film to digital images: The development of highresolution (HD) cameras along with computers with higher storage capacity has allowed digital equipment to almost entirely supplant traditional film equipment.5,7,8 Digital images can have a similar or greater resolution than that of a traditional film-based one (4096 × 2736 pixels).8 The coupling of CSLO with pinhole cameras effectively blocks scattered light, as well as details outside the optical focus. As a result, greater detail in the capillary network becomes visible. And finally, a digital image enables real-time correction of gain, exposure, focus as well as instant visualization which means better image quality.7 It also makes the examination and manipulation of the images easier, allows for the rapid transmission of data by electronic means, and eliminates the need for physical storage space.7  Wide and ultra-wide angle of view: Traditionally, the standard angle of view was between 30–50° with a 2.5 magnification,5 making the evaluation of peripheral retinal pathology difficult. The introduction

6.6 Fluorescein Angiography and Indocyanine Green Angiography

A good quality FA is highly dependent on a high-resolution fundus camera, a skilled photographer and a clear view of the retina. The spherical refractive error of the patient is corrected by simultaneously focusing the cross hairs in the eye pieces reticule and the fundus. The focusing wheel is used only for fine focus. Most cameras are equipped with a joystick which is used to align the camera to the patients’ eye. Proper alignment results in even illumination of the fundus. Misalignment results in peripheral and central artifacts in the images. This can be ameliorated with careful lateral movements of the joystick. Variable amounts of magnification can usually be selected depending on the system and this should be tailored to the pathology being examined. Pharmacological mydriasis is usually required for most commercially available equipment but there are a few that do not require it. Before starting the infusion of the dye, a set of baseline red-free images are taken using a green filter. Green light provides excellent contrast and enhances the visibility of the retinal vasculature and vitreousretinal interface. It is particularly useful in assessing retinal hemorrhages, drusen, epiretinal membranes and exudates. The dye is typically injected in the antecubital vein with a 21 gauge butterfly needle in a rapid but controlled infusion (≈ 1 mL/second) to maximize the contrast of the early filling phase of the angiography.4,11 Although there is no evidence of increased side-effects when using higher concentrations of the dye, many practitioners prefer to use a smaller volume of a more concentrated solution. The two preferred doses are 2.5 mL of a 20% solution or 5.0 mL of a 10% solution. If the patient is a newborn or premature baby, a 10% solution at a dose of 0.1 mL/kg is recommended followed by an isotonic saline flush.14 Even though the infusion of the dye can be done from the left or right antecubital vein without changing the times or image qualities, if the patient has undergone mastectomy with lymph node dissection, the dye should probably not be injected in the ipsilateral arm due to potentially altered lymphatic flow.6 Extravasation of the dye should be avoided, as infiltration is painful and may rarely lead to tissue necrosis. A timer is started and image acquisition should begin immediately so initial choroidal and retinal filling can be captured. Photographs are usually taken at 4 second intervals, beginning 15 seconds before injection and continuing with a tapered frequency for 10 to 20 minutes. However, the timing and the interval between exposures should be adjusted based on the pathology that is being studied. For instance, a choroidal neovascular membrane leaks profusely early in the study, therefore the photographs should be taken with more frequency at the beginning of the study to capture the details of the membrane.

TABLE 6-6-1  INCIDENCE OF ADVERSE REACTIONS TO INTRAVENOUS FLUORESCEIN ANGIOGRAPHY

441

6 Retina and Vitreous A Fig. 6-6-2  Examples of ultra-wide field FAs (200° angle view). The figure shows a diabetic patient during the peak phase in which severe capillary dropout is evident up to the retinal periphery and involving the macula. (Courtesy of Valentina Franco-Cardenas, MD: International Retina Fellow, University of California Los Angeles (UCLA).)

B Fig. 6-6-1  FA and ICG taken simultaneously in the same patient. (A) shows the FA. (B) is the ICGA in which, in addition to the normal fluorescence of the retinal vessels, the deep choroidal vessels are visualized. (Courtesy of Jans Fromow-Guerra, MD: Associate Professor. Asociación para Evitar la Ceguera en México, IAP. México DF.)

of contact lens systems has increased the angle of view to up to 160°.2 In recent years a company has introduced a new system that uses an ellipsoidal mirror with two conjugate focus points combined with a scanning laser ophthalmoscope. By rotating the ellipse, the system is able to create an ellipsoidal surface capable of focusing light rays emanating from the peripheral retina, achieving an angle of view of up to 200° (Fig. 6-6-2).2,9,10

INTERPRETATION OF RESULTS Normal Fluorescein Angiogram

442

After injection, dye first enters the short posterior ciliary arteries, and, in most normal individuals, is then visualized in the choroid and optic nerve head 10–15 seconds later. This initial filling is dependent on the cardiovascular condition and age of the patient as well as the speed of injection. The choroidal circulation is seen initially as the choroidal flush – a mottled and patchy fluorescence created as dye fills the choriocapillaris. The patchy appearance is created as separate lobules of the choriocapillaris fill sequentially. As dye leaks from the choriocapillaris during the early phases of the angiogram, Bruch’s membrane is stained and choroidal vasculature detail is obscured. A cilioretinal artery is seen simultaneously with the fluorescence of the choroidal circulation in 10–15% of patients. The retinal circulation begins to fluoresce at 11–18 seconds, 1–3 seconds after the onset of choroidal filling. The retinal arterial system should fill completely in about 1 second. The early arteriovenous phase

Fig. 6-6-3  Peak phase angiogram. Approximately 25 seconds after injection, maximal fluorescence of the retinal circulation is evident. Note the intricate detail of the perifoveal capillary network.

is characterized by the passage of fluorescein dye through the central retinal arteries, the precapillary arterioles, and the capillaries, while the late arteriovenous phase is characterized by the passage of dye through the veins in a laminar pattern. During the late arteriovenous phase maximal fluorescence of the arteries occurs, with early laminar filling of the veins. Laminar filling of veins is caused by the preferential concentration of unbound fluorescein along the vessel walls. Several factors are responsible for the laminar pattern of venous filling; these include the more rapid flow of plasma along the vessel wall, as well as the higher concentration of erythrocytes in the central vascular lumen. Maximal fluorescence is achieved in the juxtafoveal or perifoveal capillary network after 20–25 seconds. The normal capillary-free zone, or foveal avascular zone, is approximately 300–500 µm in diameter. A dark background to this capillary-free zone in the macula is created through blockage of choroidal fluorescence by both xanthophyll pigment and a high density of RPE cells in the central macula. This phase of the angiogram has been termed the peak phase as maximal fluorescence of the capillaries and enhanced resolution of capillary detail occurs (Fig. 6-6-3). The management of microvascular diseases of the

BOX 6-6-2 CAUSES OF HYPERFLUORESCENCE

Blocked Retinal Fluorescence: Media opacity Vitreous opacification (hemorrhage, asteroids hyalosis, vitritis) Subhyaloid hemorrhage. Intraretinal pathology (hemorrhage [vein oclussion], edema)

Pseudofluorescence

•• •• •• • ••

Blocked Choroidal Fluorescence: All entities that cause blockade retinal fluorescence. Outer retinal pathology (lipid, hemorrhage, xanthophyll). Subretinal pathology (hemorrhage, lipid, melanin, lipofuscin, fibrin, inflammatory material) Subretinal pigment epithelium pathology (hemorrhage). Choroidal pathology (nevus, melanoma) Vascular Filling Defects: Retina: Occlusion or delayed perfusion. Central or branch artery occlusion Capillary nonperfusion (diabetes, vein oclusion, radiation, etc.) Atrophy or absence of retinal vessels

•• •• • • ••

Choroid: Occlusion of large choroidal vessels or choriocapillaris (sectoral infarct, malignant hypertension, toxemia, lupus, choroidopathy, renal disease) Atrophy or absence of choroidal vessels or choriocapillaris (choroideremia, acute multifocal placoid pigment epitheliopathy) Optic nerve: Oclusion (ischemic optic neuropathy) Atrophy or absence of tissue (coloboma, optic nerve pit, optic nerve hypoplasia, optic atrophy)

retinal capillaries, such as diabetic macular edema, requires excellent peak phase imaging. The first pass of fluorescein through the retinal and choroidal vasculature is complete after 30 seconds. The recirculation phases, characterized by intermittent mild fluorescence, follow. After approximately 10 minutes, both the retinal and choroidal circulations generally are devoid of fluorescein. Many normal anatomical structures continue to fluoresce during the late angiogram, such as the disc margin and optic nerve head. The staining of Bruch’s membrane, choroid, and sclera is more visible in patients who have lightly pigmented RPE.

Autofluorescence Transmitted Fluorescence Geographic atrophy Bull’s eye maculopathy Macular hole Atrophic chorioretinal scar Drusen

•• •• •

Abnormal vessels RETINA: Angioma; Wyburn-Mason syndrome Cavernous hemangioma Vascular tumor Retinoblastoma CHOROID: Melanoma Choroidal neovascularization Choroidal hemangioma OPTIC NERVE: Peripapillary vascular loops

• •• • •• • •

Pooling: Neurorensory detachment Central serous chorioretinopathy Optic nerve pit Best’s disease Subretinal neovascularization Retinal pigment epithelium detachment Serous Fibrovascular

• ••

•• •• ••

Staining Staphyloma Disc Sclera Chorioretinal scar

Leakage RETINAL VESSELS: Venous occlusive disease Frosted angitis Phebitis NEOVASCULARIZATION Diabetes retinopathy Radiation retinopathy Sickle cells retinopathy

•• • •• •

6.6 Fluorescein Angiography and Indocyanine Green Angiography

BOX 6-6-1 CAUSES OF HYPOFLUORESCENCE

Abnormal Fluorescein Angiography

The terms hypofluorescence and hyperfluorescence are used routinely in the interpretation of fluorescein angiograms. Hypofluorescence is a reduction or absence of normal fluorescence (Box 6-6-1), while hyperfluorescence is increased or abnormal fluorescence (Box 6-6-2).  Hypofluorescence: Hypofluorescence can be categorized into blockage (masking of fluorescence) or vascular filling defects. Blocked fluorescence can provide clues as to the level of the blocking material, such as vitreal, retinal, or subretinal. Only structures or material anterior to the area of fluorescence can block fluorescence. Blocked retinal fluorescence may be caused by any element that diminishes the visualization of the retina and its circulation (Fig. 6-6-4). Blockage of retinal fluorescence also may localize the pathology to the inner retina. The retinal circulation is unique in that the large retinal vessels and precapillary, first-order arterioles lie in the nerve fiber layer, while the capillaries and postcapillary venules are located in the inner nuclear layer. Flame-shaped hemorrhages are superficial and block all retinal vascular fluorescence, while deeper dot or blot hemorrhages (or intraretinal lipid) block capillary fluorescence but do not block larger superficial vessels. Fluorescence may also be blocked by melanin (scars, melanoma, nevus), lipofuscin deposits (Stargardt’s disease and Best disease), hemorrhage (diabetic retinopathy) and serosanguineous fluid beneath the RPE (CNV-AMD). Vascular filling defects produce hypofluorescence because of the reduced or absent perfusion of tissues. Retinal vascular filling defects can involve large-, medium-, or small-caliber vessels. Capillary nonperfusion manifests as vascular filling defects and is typically seen in common ischemic disease processes such as diabetic retinopathy (Fig. 6-6-5). Choroidal vascular filling defects are more difficult to

Fig. 6-6-4  Blockage. In this early phase angiogram, preretinal blood inferiorly (arrow) blocks both retinal and choroidal circulation. Superior to the fovea, subretinal blood (arrowhead) blocks choroidal fluorescence, but the retinal circulation is clearly seen.

visualize, because the native RPE prevents adequate visualization of the choroidal circulation. In general, occlusive diseases that involve isolated, larger choroidal vessels manifest as sectoral, wedge-shaped areas of hypofluorescence. Systemic diseases, including malignant hypertension, toxemia of pregnancy, and lupus choroidopathy, produce zones of hypofluorescence secondary to focal choroidal nonperfusion. Vascular filling defects of the optic nerve head may be noted by fluorescein angiography. Ischemic optic neuropathy manifests as sectoral or complete optic disc hypofluorescence, while other atrophic or hereditary anomalies of the optic nerve head have diffuse hypofluorescence.

443

6 Retina and Vitreous Fig. 6-6-5  Vascular filling defect. FA of a patient with diabetic retinopathy. Widespread nonperfusion is evident in the retinal periphery by capillary dropout (arrowheads) and arteriovenous collateral formation. Large arrows show areas of leakage due to retinal neovascularization.

 Hyperfluorescence: Hyperfluorescence is defined as an abnormal presence of fluorescence or an increase in normal fluorescence in the FA. It can be secondary to increased transmission of choroidal fluorescence due to a window defect created by an area with a decreased or absent RPE that allows a view of the underlying choroid (Fig. 6-66). The most frequent cause of hyperfluorescence is leakage of dye from the intravascular space into the extravascular space. In this case a localized, diffuse hyperfluorescent spot increases in both size and intensity as the study progresses (Fig. 6-6-7). When the dye leaks into an anatomical space (cysts, subretinal space, sub-RPE space) it is called pooling. In this case the boundaries of the hyperfluorescence are more defined and the speed of appearance depends mostly on the cause (Fig. 6-6-8). Finally staining refers to the deposition of dye within involved tissue and occurs in both normal (optic nerve and sclera) and pathological states (disciform scars and damage RPE tissue).

INDOCYANINE GREEN ANGIOGRAPHY INTRODUCTION Currently there are two commercially available types of imaging systems for ICG: modified fundus cameras (which utilize continuous illumination from a halogen bulb and periodic xenon lamp flashes), and SLO-based systems which use a focused laser beam to sweep the retina, allowing continuous image acquisition (20 to 30 images per second).21 While ICG dye gives off 4% of the fluorescence of SF, its maximal peak of absorption is at 790 to 805 nm and has a peak emission of 835 nm.3,19 Because both exciting and emitted light are in the nearinfrared spectrum, it allows deeper penetration through the retina and the emitted light passes more easily through the RPE, blood, lipids deposits, pigment and mild opacities (cataracts) to form images.21 Moreover, because the dye has a significantly greater molecular weight, and a greater proportion of molecules remain bound to proteins in the bloodstream than with SF, the dye normally remains within the fenestrated walls of the choriocapillaris, unlike SF which leaks freely from these vessels. This property makes ICGA an ideal technique for portraying the anatomy and hemodynamics of the choroid (Fig. 6-6-9).5

PROPERTIES OF INDOCYANINE GREEN 444

Indocyanine green (benzoindotricarbocyanin) is an amphiphilic tricarbocyanine dye with a molecular weight of 775 kDa.22 Due to its ability to form aggregates, the ICG lyophilisate has to be dissolved in water for

Fig. 6-6-6  Window defect. FA of a patient with an advanced case of Stargardt disease. The picture shows increasing fluorescence due to atrophy, noted since the early phases of the angiogram. (Courtesy of Valentina Franco-Cardenas, MD: International Retina Fellow, University of California Los Angeles (UCLA).)

injection. In the bloodstream, the dye is rapidly bound to proteins (98%), especially to albumin, globulins and lipoproteins, thus remaining longer in large blood vessels and having a lesser tendency to diffuse into the interstitial space.13 The dye is approved by the US Food and Drug Administration (FDA) for use in cardiac, hepatic and ophthalmic studies.6 ICG is solely metabolized by the liver through a specific carrier-mediated transport system and excreted in the biliary system. This explains the rapid elimination of the dye from the circulation after an intravenous injection.22 The dye has a plasma half-life of 2 to 4 minutes.

PROCEDURE Pharmacological mydriasis is usually required with most systems. The infusion technique is similar to FA. The dosage of ICG can vary between 20 to 50 mg of dye dissolved in 2 to 4 mL of aqueous solvent. The preferred technique is to inject 25 mg of ICG dye in 5 mL of water slowly. Higher dosages typically result in a larger degree of hyperfluorescence and thereby changes excitation. If both FA and ICGA are performed sequentially, an intravenous catheter may be placed to save the patient from multiple needle sticks.19 Excitation illumination should be at a maximum, with a video gain of +6 db. Approximately 10 images are acquired over the initial 30 seconds, starting immediately after injection. The video gain and excitation illumination levels should not be changed during the transit phase unless image bloom occurs (an increased fluorescence that obscures images). If this happens, the excitation level is reduced. The best images are retained and, ideally, the transit of ICG through the choroidal vasculature is captured again every 15 seconds. Late images at 5, 10, 15, 20 and 40 minutes after injection also are obtained. Alteration of the excitation level can be increased during the late phase of ICGA if signal intensity is reduced. During the very late stages, both excitation and video gain can be increased; however, a concomitant reduction in detail results.

COMPLICATIONS Mild adverse reactions such as nausea, vomiting, sneezing and transient itching occur in 0.15% of cases.20 Moderate adverse reactions,

6.6

C

Fluorescein Angiography and Indocyanine Green Angiography

A

B

Fig. 6-6-7  Leakage. FA of a patient with branch retinal vein occlusion. Angiogram demonstrates progressive leakage of dye indicating vascular incompetence and macular edema. Note the blocking effect of the intraretinal hemorrhage (A–C).

such as urticarial, syncope, fainting and pyrexia may also occur. Severe adverse reactions such as hypotension, shock, anaphylaxis and death have also been reported and occur in equal incidence following ICG and FA (1 : 1900).20 ICG is currently available in several pharmaceutical preparations. Because some of the manufacturing process adds iodine to allow crystallization of the molecule (≈ 5% of commercial ICG dyes), crossover allergy to iodine can occur in patients with seafood allergies (shellfish).6,22 Current contraindications to ICGA include prior anaphylactic reaction to ICG dye or contrast agents that contain iodine, hepatic insufficiency, uremia and pregnancy. Those patients undergoing hemodialysis are also at increased risk of complications from ICG.6,19 In cases in which local extravasation of the ICG occurs, minimal damage is observed; conversely, extravasation of SF may lead to more severe tissue necrosis.

INTERPRETATION OF RESULTS In the early phase of the test, 2 seconds after ICG injection filling of both the choroidal arteries and choriocapillaris, with early filling of the choroidal veins occurs. The retinal blood vessels are still dark along with the choroidal ‘water-shed zone’ around the optic nerve head. Then, 3 to 5 seconds after ICG injection, the larger choroidal veins begin to fill and fluoresce along with the retinal arteries as the dye flows. Later, at 6 seconds to 3 minutes, the outer-shed zone is now filled, but the choroidal arteries and large choroidal veins begin to fade (Fig. 6-6-10).19

The middle phase occurs between 3 to 15 minutes after ICG injection. It is marked by continuous fading of the choroidal and retinal vessels. The late phase occurs between 15 to 60 minutes after ICG injections. It demonstrates staining of the extrachoroidal tissue, giving the choroidal vasculature the illusion of hypocyanescence, as compared to the background tissue. No retinal vessels are seen during this phase.19 Abnormal areas on an ICGA are interpreted in a similar way to the FA. There can be either hypo- or hypercyanescence. Hypocyanescence can be attributed to blockage (by blood, serous fluid, pigment or exudates) or by impaired choroidal perfusion; either by blocked blood flows on a given area, or by loss of choroidal vasculature tissue (acute posterior multifocal placoid pigment epitheliopathy). Hypercyanescence can be caused by a lack of overlying tissue (RPE dropout, lacquer cracks), leakage from retinal or choroidal blood vessels (producing subsequent staining of surrounding tissue) or leakage from abnormal blood vessels (CNV, polypoidal vasculopathy). The terms ‘hot spots’ and ‘plaques’ are used to define areas of intense hyperfluorescence during the middle to late phases of the ICG angiogram. They are differentiated by size. Hot spots are defined as less than one disc diameter (DD) in size. Hot spots have been attributed to one of three etiologies: polypoidal choroidal neovascularization, retinal angiomatous proliferation, or occult choroidal neovascularization (Fig. 6-6-11). Plaques, which are more common, differ from hot spots in that they are larger (greater than 1 DD), more amorphous, and reveal less obvious leakage. Combined lesions, which have characteristics of both hot spots and plaques, can also occur.19,23,24

445

6 Retina and Vitreous A

C

446

Fig. 6-6-9  ICGA of a patient with severe RPE atrophy in which the choriocapillaris, as well as medium and large choroidal vessels can be observed. (Courtesy of Jans FromowGuerra, MD: Associate Professor. Asociación para Evitar la Ceguera en México, IAP. México DF.)

B

Fig. 6-6-8  Pooling. Color picture and FA sequence of a patient with central serous chorioretinopathy. (A) & (C), small arrowheads delineate an area of neurosensory detachment of the macula with pooling of the dye in the late phase of the study. (B) & (C) Large white arrows indicate areas of retinal pigment epithelium leakage of fluorescein. (Courtesy of Valentina Franco-Cardenas, MD: International Retina Fellow, University of California Los Angeles (UCLA).)

Fig. 6-6-10  Final stage of the early phase of a normal ICGA (at 90 seconds of the study), in where the retinal and large choroidal vessels are clearly visible. (Courtesy of Jans Fromow-Guerra, MD: Associate Professor. Asociación para Evitar la Ceguera en México, IAP. México DF.)

ACKNOWLEDGMENTS The authors thank Valentina Franco-Cardenas, MD from University of California Los Angeles (UCLA), and Jans Fromow-Guerra, MD from APEC for their assistance with the images in the chapter.

KEY REFERENCES Bernardes R, Serranho P, Lobo C. Digital ocular fundus imaging: a review. Ophthalmologica 2011;226:161–81. Halperin LS, Olk RJ, Soubrane G, et al. Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 1990;109:563–6.

A

Indocyanine green angiography. American Academy of Ophthalmology. Ophthalmology 1998;105:1564–9. Yannuzzi LA, Ober MD, Slakter JS, et al. Ophthalmic fundus imaging: today and beyond. Am J Ophthalmol 2004;137:511–24. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986;93:611–17. Yannuzzi LA. Indocyanine green angiography: a perspective on use in the clinical setting. Am J Ophthalmol 2011;151:745–51.e1.

6.6 Fluorescein Angiography and Indocyanine Green Angiography

Software available with the ICG system enables the user to manipulate the angiographic images. For example, the ‘trace’ function allows areas to be copied from the ICG angiogram and placed at the precise location on a red-free photograph. This is helpful when ICG angiography is used as a guide for laser photocoagulation.19

B Fig. 6-6-11  Hot Spot. FA and ICGA of a patient with idiopathic polypoidal choroidal vasculopathy and hemorrhagic pigment epithelial detachment. (A) shows the FA of a patient with idiopathic polypoidal choroidal vasculopathy with a hemorrhagic pigment epithelial detachment. (B) shows that the ICGA demonstrates a choroidal neovascular membrane (arrow) and characteristic saccular dilations of the choroidal vasculature (arrowhead).

Access the complete reference list online at

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REFERENCES 1. Lira RP, Oliveira CL, Marques MV, et al. Adverse reactions of fluorescein angiography: a prospective study. Arq Bras Oftalmol 2007;70:615–18.

3. Hassenstein A, Meyer CH. Clinical use and research applications of Heidelberg retinal angiography and spectral-domain optical coherence tomography – a review. Clin Experiment Ophthalmol 2009;37:130–43. 4. Kalogeromitros DC, Makris MP, Aggelides XS, et al. Allergy skin testing in predicting adverse reactions to fluorescein: a prospective clinical study. Acta Ophthalmol 2011;89:480–3. 5. Bennett TJ, Barry CJ. Ophthalmic imaging today: an ophthalmic photographer’s viewpoint – a review. Clin Experiment Ophthalmol 2009;37:2–13. 6. Gess AJ, Fung AE, Rodriguez JG. Imaging in neovascular age-related macular degeneration. Semin Ophthalmol 2011;26:225–33. 7. Yannuzzi LA, Ober MD, Slakter JS, et al. Ophthalmic fundus imaging: today and beyond. Am J Ophthalmol 2004;137:511–24. 8. Bernardes R, Serranho P, Lobo C. Digital ocular fundus imaging: a review. Ophthalmologica 2011;226:161–81. 9. Spaide RF. Peripheral areas of nonperfusion in treated central retinal vein occlusion as imaged by wide-field fluorescein angiography. Retina 2011;31:829–37. 10. Wessel MM, Aaker GD, Parlitsis G, et al. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina 2012;32:785–91. 11. Moosbrugger KA, Sheidow TG. Evaluation of the side-effects and image quality during fluorescein angiography comparing 2 mL and 5 mL sodium fluorescein. Can J Ophthalmol 2008;43:571–5. 12. Sulzbacher F, Kiss C, Munk M, et al. Diagnostic evaluation of type 2 (classic) choroidal neovascularization: optical coherence tomography, indocyanine green angiography, and fluorescein angiography. Am J Ophthalmol 2011;152:799–806.e1.

14. Lepore D, Molle F, Pagliara MM, et al. Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. Ophthalmology 2011;118:168–75. 15. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986;93:611–17. 16. Bearelly S, Rao S, Fekrat S. Anaphylaxis following intravenous fluorescein angiography in a vitreoretinal clinic: report of 4 cases. Can J Ophthalmol 2009;44:444–5. 17. Halperin LS, Olk RJ, Soubrane G, et al. Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 1990;109:563–6. 18. Olk RJ, Halperin LS, Soubrane G, et al. Fluorescein angiography – is it safe to use in a pregnant patient? Eur J Ophthalmol 1991;1:103–6. 19. Dzurinko VL, Gurwood AS, Price JR. Intravenous and indocyanine green angiography. Optometry 2004;75:743–55. 20. Yannuzzi LA. Indocyanine green angiography: a perspective on use in the clinical setting. Am J Ophthalmol 2011;151:745–51.e1. 21. Indocyanine green angiography. American Academy of Ophthalmology. Ophthalmology 1998;105:1564–9. 22. Desmettre T, Devoisselle JM, Mordon S. Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol 2000;45:15–27. 23. Regillo CD, Benson WE, Maguire JI, et al. Indocyanine green angiography and occult choroidal neovascularization. Ophthalmology 1994;101:280–8. 24. Lim JI, Sternberg P Jr, Capone Jr A, et al. Selective use of indocyanine green angiography for occult choroidal neovascularization. Am J Ophthalmol 1995;120:75–82.

6.6 Fluorescein Angiography and Indocyanine Green Angiography

2. Kaines A, Oliver S, Reddy S, et al. Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthalmol Clin 2009;49:53–9.

13. Ciardella AP, Prall FR, Borodoker N, et al. Imaging techniques for posterior uveitis. Curr Opin Ophthalmol 2004;15:519–30.

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PART 6 RETINA AND VITREOUS SECTION 2 Ancillary Tests

Optical Coherence Tomography Miriam Englander, David Xu, Peter K. Kaiser

Definition: Optical coherence tomography (OCT) is a non-invasive

imaging technique based on the priniciple of optical reflectometry light, which enables precise anatomic examination of ocular structures.

Key features ■

High-resolution evaluation of tissue pathology at the cellular level, achieving axial resolution of 2–3 µm ■ Direct correspondence to the histologic appearance of the retina, cornea and optic nerve in health and disease ■ Critical tool in the diagnosis and monitoring of ocular disease involving the retina, choroid, optic nerve and anterior segment

Associated features ■

Easy to use, non-invasive, reproducible, safe Obtainable through most media opacities including vitreous hemorrhage, cataract, and silicone oil ■ Recent advances allow for a dramatic improvement in the crosssectional image resolution with improved acquisition speed ■ Helpful in the interpretation of pathologies in all layers of the retina as well as the vitreoretinal interface ■ Also used for the detection and monitoring of optic nerve, glaucoma and anterior chamber pathology ■

INTRODUCTION Optical coherence tomography (OCT) is a non-invasive imaging technique that allows for the examination of ocular structures. This technique utilizes light waves to create the image. This imaging technique is similar to an ultrasound, except that the reflected and backscattered light is used to create the image. Infrared light at approximately 830 nm is scanned across the tissue and focused with an internal lens. A second beam internal to the OCT unit is used as a reference and a signal is formed by measuring the amount the reference beam is altered to match the reflected beam from the retina. The interface between different ocular tissues can be determined by changes in reflective properties between the tissues. Detection of these beams is based on time domain or spectral domain protocols.1 The use of light allows for high resolution. OCT permits evaluation of tissue pathology at the cellular level, achieving resolution of 2–3 µm. Other advantages include its ease of use, reproducibility, noninvasiveness, safety and repeatability. In addition, OCT can image through most media opacities including vitreous hemorrhage, cataract, and silicone oil.

OCT TECHNOLOGY PLATFORMS Time Domain OCT 448

In time domain (TD) OCT the path length of the reference arm is translated longitudinally in time. In TD OCT, an individual A-scan is acquired by varying the length of the reference arm in

6.7

an interferometer, such that the scanned length of the reference arm corresponds to the A-scan length. The image is then constructed using a false color scale that represents the amount of light backscattering. In the false color scale, bright colors such as red to white represent high reflectivity and dark colors such as blue to black represent minimal or no reflectivity. The main limitations in the clinical use of TD OCT are the limited resolution and slow acquisition.2

Spectral Domain OCT

In Spectral (SD) or Fourier domain OCT, the light composing the interference spectrum of echo time delays is measured simultaneously by a spectrometer and a high speed charge-coupled device, thereby the information of the full depth scan can be acquired within a single exposure. The interference spectrum is made up of oscillations whose frequencies are proportional to the echo time delay. By calculating the Fourier transform, the machine calculates the axial scan measurements without adjusting the reference mirror. This results in improved sensitivity and image acquisition speed compared to TD OCT. As a result, SD OCT is several orders of magnitude more sensitive than TD OCT.2 Spectral domain optical coherence tomography’s higher acquisition speeds allow for a shift from two-dimensional to three-dimensional (3D) images of ocular anatomy.

Multifunctional OCT

Functional extensions to OCT add to the clinical potential of this technology. For example, in Polarization-Sensitive OCT (PS-OCT) the tissue is illuminated either with circularly polarized light or with different polarization. PS-OCT provides intrinsic, tissue-specific contrast of birefringent (e.g., retinal nerve fiber layer [RNFL]) and depolarizing (e.g., retinal pigment epithelium [RPE]) tissue, which may be used for glaucoma diagnosis and for the diagnosis of RPE disturbances associated with diseases such as age-related macular degeneration (AMD).3,4 Doppler tomography enables depth-resolved imaging of flow by observing differences in phase between successive depth scans. This technology provides valuable information about blood flow patterns in the retina and choroid. This technology allows absolute quantification of flow within retinal vessels and thus has the potential to reduce the number of fluorescein angiographies which need to be performed.5

Time Encoded Frequency Domain OCT (Swept Source OCT)

Another way to perform Fourier domain OCT is to sweep the frequency of a narrow band, continuous wave light source and collect the time dependent interference signal. Here the advantage lies in high signal to noise ratio detection technology, achieving very small instantaneous bandwidths at very high frequencies (20–200 kHz). Drawbacks are the nonlinearities in the wavelength, especially at high scanning frequencies, and a high sensitivity to movements of the scanning target.2

High Speed, Ultra-high Resolution OCT (hsUHR-OCT)

This system uses spectral or Fourier domain detection, allowing for a dramatic improvement in the cross-sectional image resolution and acquisition speed. The system allows for axial resolution of approximately 3.5 µm compared with the 10 µm resolution in standard OCT, and it also allows for imaging speeds that are approximately 75 times

faster than standard OCT. Ultra-high-resolution OCT enables superior visualization of retinal morphology in a number of retinal abnormalities. High speed UHR OCT further improves visualization by acquiring high-transverse-pixel-density, high-definition images.6–8

The resolution of OCT systems in the axial dimension is set by the coherence properties of the light source. Current light sources can provide axial resolution below 3 µm, which is more than sufficient to resolve the axial dimensions of most retinal cells. However, the lateral resolution is substantially degraded from the diffraction limit by the optical aberrations present in the eye. Consequently, most ophthalmic OCT systems are designed to be operated with a lateral resolution in the range of 15–20 µm. Adaptive optics work by measuring aberrations using a wavefront sensor and apply this information to compensate the measured aberrations using a wavefront corrector. The ability to correct for the ocular imperfections allows for very high resolution (2–3 µm), sufficient for resolving individual cells6 (Table 6-7-1).

ANATOMIC RESULTS The OCT images correspond to the histologic appearance of the retina. In TD OCT the superior reflection on the OCT scan corresponds to the nerve fiber layer (NFL). It is red, representing a highly reflective layer. The external red line on the bottom of the OCT scan represents the RPE layer, Bruch’s membrane and the choriocapillaris. Between these, a red line represents the junction of the inner and outer segments. Inner cellular layers have lower reflectivity, represented by yellow, green and blue colors. The vitreous is not reflective and is therefore black, however, the posterior hyaloid face can occasionally be seen as an additional reflective layer anterior to the NFL (Fig. 6-7-1). The choroid is a highly vascular structure with blood flow and thickness varying in relation to the intraocular pressure, perfusion pressure, and age. It is possible to image the choroid with conventional OCT imaging (Fig. 6-7-2). Histologic studies have shown that glaucomatous damage is confined to the retinal ganglion cell layer (GCL) and NFL. Measurements of NFL and GCL on OCT improve our ability to detect glaucomatous damage (Fig. 6-7-3).

IMAGE OPTIMIZATION OCT measures the intensity of a backscattered optical signal, which represents the optical properties or reflectivity of the target tissue. The tissue reflectivity varies among different structures, allowing for measurements that can be displayed as false colors or gray scale images. The gray scale runs continuously from high signal (white) to no signal (black), and images can contain up to 256 shades of gray corresponding

OCT IMAGE INTERPRETATION Preretinal

6.7 Optical Coherence Tomography

Adaptive Optics OCT (AO-OCT)

to the optical reflectivity of the various tissue interfaces. The standard color scale uses a modified continuous rainbow spectrum in which darker colors such as blue and black represent regions of minimal or no optical reflectivity, and lighter colors such as red and white represent a relatively high reflectivity.9 Studies have shown that the gray scale images are easier to interpret and are more informative than the color ones due to their improved ability to visualize subtle retinal structures such as photoreceptor inner and outer segment junction (IS/OS) and subtle pathologies such as thin epiretinal membranes.10 Another method to improve image quality is to average multiple OCT scans. Frames with the least amount of motion artifacts are chosen. These frames are then averaged. Each pixel value is calculated as an average intensity from all frames, to create one frame. On average, 50 frames are used to create one image.11

The use of OCT has facilitated the diagnosis and description of diseases involving the vitreoretinal interface, including vitreomacular traction syndrome, epiretinal membranes, macular holes, and schisis.

Posterior vitreous detachment

The vitreous in a healthy eye is optically clear. In cases that the vitreous is completely attached, the vitreouretinal interfaces can be detected by the marked change in reflectivity between the vitreous and the internal limiting membrane. Posterior vitreous detachment (PVD) is believed to develop after liquefied vitreous passes abruptly into the subhyaloid space and separates the posterior hyaloid from the retina. OCT images of PVD reveal a surface of reflectance above the level of the retina. This additional surface depicts the posterior surface of the vitreous body. Based on OCT observations, a classification of normal PVD was developed; Stage 0: no PVD. Stage 1: incomplete PVD in the temporal perifovea, with a definite discrete linear signal with attachment to the fovea, optic nerve head, and midperipheral retina. Stage 2: incomplete PVD in the temporal and nasal perifovea, with convex retrovitreous spaces associated with attachment of the posterior vitreous face to the fovea and midperipheral retina. Stage 3: incomplete PVD over the posterior pole, with persistent attachment to the optic nerve head. Stage 4: complete PVD identified biomicroscopically12 (Fig. 6-7-4).

Vitreomacular traction

The vitreomacular traction (VMT) is a complication of anomalous partial PVD where the vitreous is separated from the retina throughout

TABLE 6-7-1  COMMERCIALLY AVAILABLE OCT SYSTEMS. System (company)

Axial resolution (µm)

A-scans per second

Advanced featuresa

Cirrus HD-OCT (Carl Zeiss Meditec)

5

27 000

Spectralis (Heidelberg Engineering)

7

40 000

RTVue-100 (Optovue)

5

26 000

3D-OCT 1000 3D-OCT 2000b (Topcon)

6

18 000

Spectral OCT/SLO (OPKO/OTI)

5

27 000

SOCT Copernicus (Optopol)

6

25 000

SOCT Copernicus HRb (Canon/Optopol, Inc)

3

50 000

SDOCT (Bioptigen)

4

20 000

7

53 000

Fixation-independent scan adjustment; multilayer en face C-scan visualization; high-resolution anterior segment imaging Point-to-point registration with eye tracking; up to six diagnostic methods in one platform; digital resolution to 3.5 µm; improved choroidal visualization 12 mm long macular scans can be overlapped; point-to-point registration with eye tracking; drusen analysis and Doppler blood flow characterization; high-resolution anterior segment imaging Nonmydriatic camera provides color fundus photographs Capable of exportation to common multimedia devices; able to import time domain Stratus OCT images Point-to-point registration with eye tracking; microperimetric macular analysis; high-resolution anterior segment imaging Point-to-point registration with eye tracking; high-resolution anterior segment imaging; can separate and view all retinal layers; software allows intraretinal cyst volumetric analysis Highest resolution and fastest speed of available devices; multilingual interface; Doppler retinal blood flow analysis Handheld head for pediatric patients or animal research; portability facilitates use in an operating room; Doppler retinal blood flow analysis Segmentation analysis of six distinct retinal layers

b

Retinascan RS-3000 (Nidek)

OCT = Optical Coherence Tomography SOCT = Spectral OCT SDOCT = Spectral domain OCT a Based on a review of available data at the time this manuscript was prepared. b Not yet approved by the Food and Drug Administration. (From Kiernan DF, Mieler WF, Hariprasad SM. Spectral domain optical coherence tomography: a comparison of modern high-resolution retinal imaging systems. Am J Ophthalmol. Jan 2010;149(1):18–31)

449

6

A

NFL

INL

ONL

IS/OS

Retina and Vitreous

Nasal B

Nasal

200 µm OPL

Temporal

RPE/BM NFL

ONL

ELM

INL IPL

IS/OS

OPL

Temporal

RPE/BM

C

Nasal

200 µm

Fig. 6-7-1  Optical coherence tomography (OCT) images of a normal retina. (A) Conventional OCT. (B) Spectral domain (SD) OCT. (C) Average of 12 SD OCT images (SD OCT with multiple B-scan averaging). Retinal structures visible include the hyper-reflective retinal nerve fiber layer (NFL),hyporeflective inner nuclear layer (INL), hyper-reflective outer plexiform layer (OPL), hyporeflective outer nuclear layer (ONL), hyper-reflective lines that correspond to the junction of the inner and outer photoreceptor segment layers (IS/OS), retinal pigment epithelium (RPE)/Bruch’s membrane (BM) complex (RPE/BM), external limiting membrane (ELM), inner plexiform layer (IPL), ganglion cell layer (GCL), and choroidal vessels (Ch). Red arrows indicate structures delineated only by single-scan SD OCT or SD OCT with multiple B-scan averaging. (From Sakamoto A, Hangai M, Yoshimura N. Spectral-domain optical coherence tomography with multiple B-scan averaging for enhanced imaging of retinal diseases. Ophthalmology. Jun 2008;115(6):1071–1078 e1077.)

GCL

Ch

200 µm

Temporal

Fig. 6-7-2  Comparative choroidal imaging with optical coherence tomography (OCT) sections through the fovea obtained with various OCT instruments. (Top) Heidelberg Spectralis SD OCT using enhanced depth imaging to obtain more choroidal details, including better visualization of the hyporeflective line indicating the edge of the choroid (Bottom) Cirrus SD OCT image in which choroidal details are visible with over sampling.

the peripheral fundus, but remains adherent in a broad region encompassing the macula and/or optic nerve. A subtle variant demonstrates a localized perifoveal vitreous detachment with a small, focal vitreofoveolar adhesion resulting in an anterior-posterior tractional force that may lead to cystic maculas edema (CME). Several OCT studies have documented that surgical separation of the vitreofoveal adhesion promotes the resolution of macular thickening, usually with improvement in visual acuity in patients with vision loss due to vitreomacular traction13 (Fig. 6-7-5).

Epiretinal membrane

450

An epiretinal membrane (ERM) is a result of proliferation of abnormal tissue on the surface of the retina. It is semi-translucent and proliferates on the surface of the internal limiting membrane. ERM has been found to consist of glial cells, RPE cells, macrophages, fibrocytes, and collagen fibers.14

On OCT, ERM appear as a highly reflective thick membrane on the surface of the retina. The strength of the reflection can differentiate it from the posterior hyaloid, which appears as a minimally reflective signal13 (Fig. 6-7-6).

Macular holes

OCT has become the gold standard in diagnosing and monitoring macular holes. OCT technology has been instrumental in the classification of macular hole development, following the sequence of events from antero-posterior vitreofoveal traction to full-thickness macular hole (FTMH).15–17 Stage I: OCT shows reduced or absent foveal pit secondary to a split in the inner retina at the level of the Müller cell processes caused by the anterior-posterior or oblique traction exerted by the perifoveal vitreous detachment

6.7 Optical Coherence Tomography

Fig. 6-7-3  Stratus TD OCT (A) and prototype, ultrahigh-resolution optical coherence tomography (B) scans of a normal subject. I, Macular linear scans, whose orientations are depicted in the upper image. II, Peripapillary circular scans. III, Optic nerve head (ONH) linear scans. Inf = inferior; INL = internal nuclear layer; IS/OS = inner segment/outer segment; NFL = nerve fiber layer; ONL = outer nuclear layer; OPL = outer plexiform layer; RPE – retinal pigment epithelium; Sup = superior; Temp = temporal. (From Wollstein G, Paunescu LA, Ko TH, et al. Ultrahigh-resolution optical coherence tomography in glaucoma. Ophthalmology. Feb 2005;112(2):229–237.)

Fig. 6-7-4  Stage 2 PVD. Persistent foveal attachment with perifoveal detachment.

Fig. 6-7-5  Vitreomacular traction (VMT). Vitreofoveolar traction resulting in an anterior-posterior tractional force leading to cystic macular edema.

451

6

ERM

Temporal

ERM

Nasal

Retina and Vitreous

Fig. 6-7-6  (Left) Fundus photograph showing an ERM on the macula. (Middle) Reconstructed fundus image corresponding to black box on fundus photograph. (Right) Spectral domain optical coherence tomography image showing the ERM. (From Legarreta JE, Gregori G, Knighton RW, Punjabi OS, Lalwani GA, Puliafito CA. Three-dimensional spectral domain optical coherence tomography images of the retina in the presence of epiretinal membranes. Am J Ophthalmol. Jun 2008;145(6):1023–1030.)

Pseudoholes usually are minimally symptomatic and have normal or near-normal visual acuities. It is sometimes a challenge to differentiate a macular pseudohole from a true macular hole clinically. There are a few biomicroscopic signs that may aid in the diagnosis, including wrinkling of the inner retinal surface surrounding the hole, apparent retinal tissue in the base of the pseudohole, absence of yellow RPE deposits, and an overlying operculum or pseudo-operculum. OCT images can also readily distinguish between macular pseudohole and a FTMH.18 Similarly to lamellar holes, OCT shows an intact photoreceptors layer. Foveal pseudocyst has also been described as an early stage in the development of macular holes. In these cases the posterior hyaloid is partially detached over the posterior pole, but still adherent to the fovea causing a biconvex appearance20 (Fig. 6-7-9).

Intraretinal

Macular edema

Fig. 6-7-7  (Top) Optical coherence tomography (OCT) shows a stage 2 hole. (Bottom) OCT shows a stage 3 hole. (From Smiddy WE, Flynn HW, Jr. Pathogenesis of macular holes and therapeutic implications. Am J Ophthalmol. Mar 2004;137(3):525–537.)

Stage II: Partial break in the retinal surface with small full-thickness loss of retinal tissue with cystic spaces in the retina Stage IIA:  30 genes causing autosomal recessive retinitis pigmentosa, and > 2 genes causing X-linked retinitis pigmentosa have been identified. More have been located but not identified, and these numbers are expected to increase in the future (see Table 6-13-1). The RetNet retinal information network database (http://www.sph.uth. tmc.edu/Retnet) provides an updated catalog of genes associated with retinitis pigmentosa and other inherited retinal diseases. The identified RP-associated genes may be grouped into mainly five categories: Phototransduction, Retinal metabolism, Tissue development and maintenance, Cellular structure, and Splicing.25 Rhodopsin was the first major retinitis pigmentosa gene to be identified.26 As with rhodopsin, the majority of the retinitis pigmentosa genes identified thus far involve components of the phototransduction cascade within the rod photoreceptor, which include transducin, phosphodiesterase (a- and b-subunits of PDE), arrestin, recoverin, and the G protein-coupled Na+/K+ light-activated channel on the rod membrane. Another set of genes code for structural proteins in rod cells and include RDS/peripherin27 and ROM1.28 Developmental genes are also implicated, such as the homeobox gene CRX in the development of a cone-rod degeneration.29 More recently, genes involved in the spliceosomal protein complex which catalyzes the removal of intronic sequences such as PRPF3, PRPF8, PRPF31 have been identified and found to comprise ~10% of the RP-associated genes.25 The molecular mechanisms by which these genetic mutations eventually cause rod-cell death are unclear, although ample evidence indicates that apoptosis is involved in the final pathway of cell death.30 That the cone photoreceptors ultimately die from a disease that begins with rod-cell disease remains a puzzle. One hypothesis invokes common elements of the RPE that are involved intimately in the diurnal cycle of phagocytosis of the outer-segment discs shed daily by both rods and cones. In the case of rhodopsin mutation retinitis pigmentosa, rhodopsin is the major protein in the rod outer segments and the diurnal process of phagocytosis of the shed rod-disc membrane by the RPE

• • • • •

TABLE 6-13-1  RETINAL DEGENERATION/RETINITIS PIGMENTOSA: DIFFERENTIAL DIAGNOSIS Autosomal Recessive (AR) Conditions

X-linked (XL) Conditions

Systemic Diseases with Retinal Degeneration Component

Acquired Conditions

AD Retinitis Pigmentosa -rod-cone dystrophy -causative genes: 23 identified genes; most common are RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1

AR Retinitis Pigmentosa (RP) -rod-cone dystrophy -causative genes: 36 known genes

XL Retinitis Pigmentosa -rod-cone dystrophy (usually early onset and severe disease) -causative genes: RPGR and RP2 cause the majority of cases

Toxic Retinopathy -pigmentary retinopathy can be secondary to a variety of medications (thioridazine, clofazimine, hydroxychloroquine [Fig 6-13-9], chloroquine) or toxic agents

AD Cone-Rod dystrophy -cone or cone-rod dystrophy -causative genes: at least 10 identified genes including CRX, GUCY2D, PROM1, and PRPH2

AR Cone-Rod dystrophy -cone or cone-rod dystrophy -causative genes: at least 13 identified genes including ABCA4, CERKL, KCNV2, RDH5, and RPGRIP1

XL Cone-Rod dystrophy -cone or cone-rod dystrophy -causative genes: RPGR, CACNA1F

AD Leber Congenital Amaurosis -causative genes : CRX, IMPDH1, OTX2

AR Leber Congenital Amaurosis -early-onset rod-cone dystrophy, nystagmus, flat electroretinography responses -at least 16 genes identified including CEP290, CRB1, AIPL1, CRX, RPE65, LRAT, RDH12, RPGRIP1

Choroideremia -early-onset night vision difficulties, progressive visual field defects, central vision maintained till later in disease -carriers usually show fundus changes -causative gene: CHM

AD Congenital Stationary Night Blindness -nyctalopia and nonprogressive retinal dysfunction -causative genes: GNAT1, PDE6B, RHO

Achromatopsia -reduced central vision, light aversion, nystagmus, color vision defects, severely reduced cone electroretinography responses -causative genes: CNGB3, CNGA3, GNAT2, PDE6C AR Congenital Stationary Night Blindness -nyctalopia and nonprogressive retinal dysfunction -electronegative electroretinography responses -causative genes: 9 genes including GNAT1, TRPM1, RDH5

Juvenile Retinoschisis -characteristic spoke-wheel pattern, foveal and/or peripheral schisis, electronegative electroretinography pattern -causative genes: RS1 / XLRS1

Usher’s Syndrome - AR inheritance - RP-like retinal degeneration in association with: sensorineural hearing loss, ± hearing loss -causative genes: 5 genes known to cause type I (best known MYO7A), 3 genes known to cause type II (best known USH2A), one gene known to cause type III: CLRN1 Bardet-Biedl Syndrome - AR inheritance - RP-like retinal degeneration (Fig. 6-13-10) in association with: polydactyly, obesity, mental retardation, and hypogenitalism. - 17 identified genes including BBS1, 2, 6, 9, 10 and MKS1, CEP290 Refsum Disease - AR inheritance - RP-like retinal degeneration in association with: hearing loss, anosmia, ataxia, ichthyosis, peripheral neuropathy, cataract -elevated serum phytanic acid -improved prognosis with early dietary intervention -causative gene: PEX7 Kearns Sayre Syndrome - mitochondrial disease - RP-like retinal degeneration in association with: progressive external ophthalmoplegia and complete heart block -causative genes: KSS Joubert / Senior-Loken Syndrome -AR inheritance - RP-like retinal degeneration in association with: nephronophthisis (SeniorLoken) -multisystem findings sometimes including retinal degeneration (Joubert) -causative genes: more than 15 identified genes including AHI1, NPHP1 and NPHP2, CEP290, RPGRIP1L and KIF7

Cancer-Associated Retinopathy -symptoms include photopsias and flickering lights, reduced acuity and visual field defects -electroretinography typically shows electronegative response

Best Disease -reduction of central vision with typical fundus changes (differ according to stage of disease), vitelliform lesions, abnormal electro-oculography with reduced Arden ratio -causative gene: Best1 (also known as VMD2 / RP50)

XL Congenital Stationary Night Blindness -nyctalopia and nonprogressive retinal dysfunction -electronegative electroretinography responses -causative genes: CACNA1F, NYX

XL Blue Cone Monochromatism -reduced central vision, light aversion, nystagmus, color vision defects, severely reduced cone electroretinography responses -causative genes: OPN1LW, OPN1MW

may eventually result in secondary RPE pathology. With time, the RPE cannot properly service the cone photoreceptors, which subsequently die as ‘innocent bystanders’. Alternative explanations include postulating that cone viability depends on the existence of a rod-derived factor,31 and hypothesizing that the mechanical scaffold provided by rods is required for cone survival. Clinical examination of the retina from a 73-year-old woman who had autosomal dominant retinitis pigmentosa from a pro-23-his rhodopsin mutation revealed that she had 20/50 (6/15) visual acuity several months before death, and her fields were only 17°. Her fundus had typical retinitis pigmentosa changes of heavy bone-spicule pigmentation across the entire 360° periphery, and the underlying RPE was atrophic (Fig. 6-13-2). After her death, histologic examination of her eye showed major loss of the photoreceptors (Fig. 6-13-4). Tissue from the parafoveal region of the left eye in the region of relative preserved retina showed:

Postinfectious Retinopathy -pigmentary retinopathy can be secondary to a number of infectious agents (syphillis, rubella, parasitic agents)

Pigmentary retinopathy secondary to trauma

Melanoma-Associated Retinopathy -symptoms include photopsias and flickering lights, reduced acuity and visual field defects -electroretinography typically shows electronegative response

6.13 Progressive and ‘Stationary’ Inherited Retinal Degenerations

Autosomal Dominant (AD) Conditions

hotoreceptor outer segments shortened greatly, such that they are • Pnearly absent, and the inner segments shortened. umber of photoreceptor nuclei (outer nuclear layer) decreased • Ngreatly, the majority of those left being cone nuclei – virtually no rod photoreceptors remain in this end-stage retinitis pigmentosa retina. RPE swollen grossly by intraretinal debris, with loss of melanosomes and dispersion of pigment granules.

•

SYSTEMIC ASSOCIATIONS AND DIFFERENTIAL OF PIGMENTARY RETINOPATHY Retinitis pigmentosa is associated with many systemic conditions, of which the following warrant particular attention either because of their incidence (e.g., the Usher syndromes, in which early-onset hearing loss is associated with retinitis pigmentosa) or because the diagnosis, which

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pro-23-his RP

Control

Retina and Vitreous

INL INL

ONL

IS

ONL OS/IS

OS RPE RPE

Fig. 6-13-4  Histology of the parafoveal retina of a 73-year-old woman who had a pro-23-his rhodopsin mutation (same patient and eye as in Fig. 6-13-2). Only the macula retained any photoreceptors. The eyes were fixed about 1 hour postmortem. INL, inner nuclear layer; IS, inner segments; ONL, outer nuclear layer; OS, outer segments; RPE, retinal pigment epithelium.

may be recognized by the ophthalmologist first, has major medical implications. At other times diagnosis can be important for early treatment with subsequent long-term positive health and vision effects (e.g., Refsum disease, abetalipoproteinemia). Secondary causes of RP-like disease should be entertained in the absence of family history of the disease; the differential diagnosis of pigmentary retinopathy includes multiple nonhereditary conditions. Table 6-13-1 lists the main features of many retinal degenerations and associated systemic conditions, with a brief updated list of associated genes as well as acquired conditions that are part of the differential diagnosis.

COURSE AND OUTCOMES Projections about future vision are always difficult in degenerative disease, particularly because the retinitis pigmentosa subtypes do not have a single clinical course. XLRP typically affects visual acuity by young adulthood, and visual acuity of some XLRP female carriers also becomes severely impaired. Thus, a simple summary of vision loss in the various forms of retinal degeneration is not possible, particularly for visual acuity. In all cases, functional tests using ERG and visual thresholds best establish the current stage of retinal cell function in aggregate and thus provide an initial basis for any prognostic statement. Prognostic statements depend upon careful disease subtyping. When subtyping is elusive, analysis of whether the patient has rod-cone disease or conerod disease provides vision estimates that may be used for general prognosis.

‘STATIONARY’ RETINAL DISORDERS

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The generalized main feature of rod-cone or cone-rod degenerations described above, is their progressive nature. In contrast, some inherited retinal disorders are less progressive, and, even though there is often some change over the lifetime, are relatively stable by comparison to most forms of RP.32 Historically they have carried the name ‘stationary’.

Congenital Stationary Night Blindness

Congenital Stationary Night Blindness (CSNB) comprises a heterogeneous group of disorders that have a common history but differ considerably in terms of clinical pictures and visual function studies. The main symptom of patients with CSNB is one of night blindness, which is often severe from birth, but color discrimination is unaffected and visual acuity is usually mildly affected. Refractive changes vary but high myopia can be seen and nystagmus may be present. There are many forms of CSNB that have been classified based on inheritance pattern (all types seen), ERG findings (electronegative most common), and fundus appearance (normal most common).33 X-linked CSNB is most common and may be confused with XLRP at first presentation, as both occur in young boys and cause complaints of difficult vision at night and show alterations in the fundus pigmentation. Differentiation between these two forms is critical because in CSNB vision remains ‘stationary’ in contrast to the progressive nature of XLRP.34

Congenital Stationary Night Blindness with Normal Fundus

Both ERG and visual field tests are critical in the diagnosis of CSNB. The scotopic ERG is the most significant finding and most commonly demonstrates an electronegative ERG in which the dark-adapted response b-wave amplitude is considerably more reduced than the a-wave amplitude. The photopic ERG is also abnormal with a characteristically wide cone a-wave trough. Visual fields are full for CSNB, whereas they are constricted to the Goldmann I4e target even in early XLRP and choroideremia. A classification of ‘complete’ and ‘incomplete’ CSNB is suggested on the basis of visual function studies performed on patients with autosomal recessive and X-linked recessive CSNB who manifested the most commonly seen Schubert-Bornschein electronegative ERG findings.35 The complete type of CSNB (also known as type 1, CSNB1) manifests no detectable rod function, with only a slight reduction in cone function in association with diminished vision and myopia. The incomplete type of disease manifests some remaining rod function, more severe cone dysfunction, visual acuity loss, and no specific refractive error. There are now identified genetic bases for these differences. Mutations in genes involved in the phototransduction cascade (GNAT1, PDE6B, RHO, RHOK, and SAG) underlie autosomal dominant CSNB. Complete CSNB has been found to be associated with defects in the ON bipolar pathway (GRM6 and NYX).36 Incomplete CSNB (also known as type 2, CSNB2) is associated with defects in the ON/OFF pathway (CACNA1F, CABP4, and CACNA2D4). Ultimately, it has been found that mutations in CACNA1F and NYX account for 80% of all mutations in CSNB.36 CSNB most often have a normal fundus, however, other less common diseases have an abnormal fundus. A fundus of abnormal appearance in association with CSNB includes Oguchi’s disease and fundus albipunctatus. These two diseases have very little in common, except early-onset nonprogressive night blindness.

Oguchi’s Disease

Named by the Japanese ophthalmologist C. Oguchi, the characteristic fundus findings in this disease is the yellowish metallic sheen of the posterior pole makes for a clinical diagnosis37 (Fig. 6-13-5A). After prolonged dark adaptation the yellowish fundus appearance reverts to normal, a phenomenon described by and named after Mizuo38 (see Fig. 6-13-5B) Re-exposure to light results in the return of the metallic sheen. Cone function appears normal. Rod function is abnormal, with normal rod thresholds reached only after 4 hours or longer (30 minutes is normal) and scotopic ERG showing only a small electronegative response, even when the rod thresholds have reached normal values. Oguchi’s disease is inherited in an autosomal recessive pattern. Mutations in RHOK (rhodopskin kinase) and SAG (arrestin) which are involved with terminating the phototransduction cascade lead to the disease.36,39,40

Fundus Albipunctatus

Like Oguchi’s disease, fundus albipunctatus has a distinctive fundus appearance, which again leads to a clinical diagnosis. There are multiple tiny white dots that are very regularly spaced, involve the posterior pole, spare the macula, and extend into the mid-periphery (Fig. 6-13-6).

6.13

Fig. 6-13-6  Fundus Albipunctatus. Numerous small round yellow-white lesions throughout the retina but excluding the central macula where atrophy and hyperpigmentation is observed.

Progressive and ‘Stationary’ Inherited Retinal Degenerations

A

Congenital Red-Green Color Deficiency

The genes encoding the three main photopigments give rise to the three classes of cone photoreceptors that underlie normal color vision. The genes encoding the red or long-wave sensitive (L) photopigment and the green or middle-wave-sensitive (M) photopigment are arranged in a head-to-tail tandem array on the X-chromosome (Xq28).42 Their close proximity and high sequence homology makes this area prone to recombinations during gamete formation in females, giving rise to X-linked color deficiencies. Total ‘red-green’ color vision deficiency caused by lack of red-sensitive cones (protanopia) or green-sensitive cones (deuteranopia) affects 2–3% of men. Partial forms are termed anomalous color perception (e.g., protanomaly or deuteranomaly). Tritanopia (total blue blindness) is exceedingly rare. For all forms together, 4–7% of men manifest some type of congenital color deficiency. Given this frequency, some men who are affected by other retinal degenerations are also ‘color blind’, and the congenital condition must be differentiated from the acquired disease. Progressive cone dystrophy also impairs color discrimination but is differentiated by abnormal visual acuity and/or peripheral fields, both of which are usually normal in the congenital color deficiencies. Female carriers manifest no clinical signs.

Blue Cone Monochromacy

B Fig. 6-13-5  Oguchi’s disease. (A) The yellowish metallic sheen is apparent nasal to the optic disc. (B) After 3 hours of dark adaptation the fundus reverts to the normal coloration (Mizuo phenomenon).

Fundus albipunctatus is inherited in an autosomal recessive manner and the main symptoms are delayed dark adaptation and night blindness. This should be distinguished from retinitis punctata albescens which can also have the appearance of a flecked retina but, unlike fundus albipunctatus, behaves clinically like retinitis pigmentosa. However, while amplitudes of the ERG a-wave and b-wave of the photopic and scotopic responses are diminished under normal test conditions, the scotopic response slowly returns to normal after a few hours in the dark, distinguishing it from retinitis punctata albescens. Mutations in retinol dehydrogenase (RDH5) are associated with this disease.41

Blue Cone Monochromatism (BCM) is a rare ( 80–95%. Only 1% of cones are blue-sensitive cones, and no blue-sensitive cones are found

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within the human fovea, which accounts for the poor acuity in BCM patients. Female carriers show no changes. An X-linked family history helps differentiate BCM from autosomal dominant or autosomal recessive, early age, progressive cone dystrophy.

Retina and Vitreous

Achromatopsia

Achromatopsia or ‘total color blindness’ is monogenic congenital retinal dystrophy that causes reduced visual acuity, extremely limited color vision discrimination, nystagmus and photophobia. It is inherited as an autosomal recessive trait and thus both sexes are affected. Both BCM patients and achromats fail the Ishihara and American Optical Hardy-Rand-Rittler (HRR) color plate tests and the Farnsworth D-15 and 100 Hue tests. Differentiation between achromats and BCM patients is aided by specially designed ‘blue arrow’ color plate tests, which boys and men affected by BCM pass but achromats fail.44 Achromatopsia was traditionally regarded as a stationary disease but more recent evidence points to slow progression over time.45

Ocular Albinism

Ocular albinism occurs in several forms and follows all the inheritance patterns. When restricted to the eyes (‘ocular albinism’, OA) it is inherited most frequently as an X-linked recessive trait. When the skin is also involved (‘oculo-cutaneous albinism’, OCA) inheritance is usually autosomal recessive. All forms are evident from birth and cause moderate-amplitude nystagmus, which the parents notice quite early. The fundus is hypopigmented and the iris may transilluminate. Acuity is between 20/70 and 20/200 but is difficult to test precisely during infancy. Color vision remains normal and nyctalopia does not occur. The foveal reflex may be muted and the fovea may be hypoplastic. The electroretinogram is normal or even supranormal because of enhanced intraocular light reflection. OCA with systemic manifestations include with Hermansky-Pudlak syndrome (platelet dysfunction) and ChediakHigashi syndrome (white blood cell lysosomal dysfunction). Diagnosis is made by clinical examination. Vision remains stable. Confusion arises in the differentiation of ocular albinism from the ‘blond fundus’ of patients who have pale skin and hair tones but normal acuity. The pattern-onset visual evoked potential is useful for this differential diagnosis.46

Fig. 6-13-7  X-linked female retinitis pigmentosa carrier affected by lacunae of disease. Atrophy of retinal pigment epithelium and intraneural retinal bone-spicule pigment result. Acuity is 20/200 (6/60) because of macular atrophy.

FEMALE CARRIERS OF X-LINKED RETINAL DEGENERATIONS

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Female carriers of X-chromosomal retinal dystrophies may manifest retinal pigmentary changes and have functional vision impairment that present special difficulty in diagnosis. Recognition of the carrier state is important to establish the correct inheritance pattern for family genetic counseling. Some carriers have a severe vision abnormality, which may lead to a misdiagnosis of autosomal dominant disease. In female carriers, one of the two X chromosomes has a mutant gene. As a result of random X-chromosome inactivation, only one gene is active in each cell (the Lyon hypothesis). Because the mutant gene is retained in some retinal cells during early development, clusters of neighboring cells have the disease, and patches of clinical disease occur that mimic a mild form of the fully expressed male condition in choroideremia, XLRP, and X-linked ocular albinism. Carriers of juvenile retinoschisis, blue cone monochromacy, CSNB, and color vision dichromacy show no fundus changes and experience no functional vision abnormality. Carriers of autosomal recessive disease rarely show retinal changes or have visual symptoms. Female carriers of XLRP (Fig. 6-13-7) show one or more small or large retinal patches of typical, intraneural retinal bone-spicule pigmentation and atrophy of the underlying RPE and choriocapillaris in more than 50% of cases. Many carriers have myopic astigmatism at an oblique axis. Although vision is involved minimally in the majority, some are functionally blind by late middle age or older. Changes progress with time but generally do so much more slowly than those in XLRP-affected men. An ERG is very helpful, as amplitudes of one or more ERG components are reduced in 80–95% of XLRP carriers.47 Further, the ERG amplitudes generally correlate with the expected severity of overall vision loss in later years. Choroideremia carrier females also show widespread retinal pigmentary disturbance of the RPE in the periphery and into the macula in 90% of cases. However, very few carriers have any visual symptoms

Fig. 6-13-8  Punctate granularity and attenuation of the normally uniform pigmentation of the retinal pigment epithelium in an X-linked female carrier of ocular albinism. This can often be associated with iris transillumination defects.

beyond mild glare sensitivity in later age, and visual acuity remains normal. Electroretinograms are affected far less frequently than those of XLRP carriers; fundus examination is the most sensitive means of detection. Most choroideremia carriers are emmetropic or hyperopic, in contrast to the myopia typical of XLRP carriers. Progression has been observed in some choroideremia carriers.47,48 X-linked ocular albinism female carriers (Fig. 6-13-8) show punctate RPE pigmentation across the entire fundus and RPE thinning in the periphery (a mild version of changes found in the affected men), which may mimic the ‘salt-andpepper’ appearance of congenital rubella retinopathy. Visual acuity is not affected, and ERG is normal. Symptoms do not extend beyond mild glare sensitivity to bright light. Carriers of non-X-linked albinism rarely show fundus changes.

TREATMENT OF RETINAL DEGENERATIONS No FDA-approved treatments currently exist for retinal degenerations. Treatment trials to date have spanned vitamin supplementation, medical therapy, gene transfer based therapy, stem-cell based therapy and retinal implants with many of them currently ongoing and many more will likely start in the next few years.

Vitamin A

A long-term study of oral vitamin A palmitate supplementation (15 000 IU daily) administered to 600 patients who had typical retinitis

vitamin A and as such it should not be recommended for women who are pregnant or planning to become pregnant.50

6.13

Docosahexaenoic Acid

Acetazolamide for Cystoid Macular Edema Fig. 6-13-9  Hydroxychloroquine bull’s-eye parafoveal atrophy. This clinical sign is often a late indicator of retinal toxicity. Other testing such as Humphrey visual field testing and OCT especially can detect signs of toxicity prior to any clinically observable retinal abnormalities.

Some patients with retinitis pigmentosa have cystoid macular edema (CME), possibly because the efficiency with which fluid is pumped across the RPE is compromised or because of slow retinal vascular leakage. Some studies show that treatment with acetazolamide may be of benefit,57 with an initial dose of 250 mg daily, increased to 500 mg daily if no effect is apparent. A trial of several weeks is warranted, with successful outcome judged by improved visual acuity on careful repeated measurements or by decreased CME on fluorescein angiography or OCT. If decreased CME is observed by fluorescein angiography after several weeks of use, the continuation of acetazolamide may be considered even if visual acuity has not improved, provided the patient is able to tolerate the drug.

Progressive and ‘Stationary’ Inherited Retinal Degenerations

Docosahexaenoic acid (DHA), a 22 : 6 fatty acid, is the major lipid component of rod photoreceptor membranes and is important for the maintenance of membrane fluidity required for rods to function. Abnormal cholesterol and serum lipid levels have been reported in some retinitis pigmentosa patients,51 and DHA levels are particularly and somewhat consistently low in XLRP patients.52 On the basis that insufficient DHA may affect photoreceptor survival, two randomized clinical trials designed to determine whether DHA dietary supplementation slows progression in retinal degeneration have been completed. The first one included only male patients with X-linked retinitis pigmentosa,53 while the second one recruited patients regardless of inheritance mode.54 Unfortunately, these studies did not show a statistically significant effect of DHA on the course of visual loss. A recent study did report that a diet high in long chain omega-3 fatty acids could slow the rate of visual acuity of patients with RP who were taking vitamin A.55 Lutein has also been investigated as a potential therapy for RP in addition to vitamin A, with some reported positive effects.56

Gene Therapy

Fig. 6-13-10  Clinical appearance of retina in a patient with Bardet-Biedl syndrome. Retina demonstrates extensive peripheral retinal pigment epithelium thinning and parafoveal retinal pigment epithelium atrophy.

pigmentosa showed a modest but positive slowing of vision loss.49 For all cases in aggregate, vision loss slowed to a decline of 8.3% per year compared with 10% per year in controls. Such a slight slowing of degeneration is rarely noticeable to an individual patient over a short period, but it may provide additional years of vision when spread over a lifetime. The rescue mechanism is unknown, but vitamin A is essential for the formation of light-sensitive rhodopsin. Opsin alone, in the absence of vitamin A, may exhibit a small degree of toxicity and possibly cause photoreceptor demise over a lifetime. In the same study,49 the administration of vitamin E (400 IU daily) without vitamin A speeded the degeneration by a small but statistically significant amount. However, when combined with vitamin A, low doses of vitamin E did not substantially alter the slowing of progression afforded by vitamin A palmitate alone, and thus the modest amount of vitamin E in multivitamin formulations may not be detrimental when taken along with vitamin A. If this treatment is suggested, the patient is advised to use vitamin A for the long-term and to expect no immediate benefit in vision. Yearly checks of serum liver enzymes and/or vitamin A levels are advisable while vitamin A is taken at high dosage, and discontinuation is necessary if pregnancy is expected. The main caution is to the female patient who must be counseled on the risk of teratogenicity of high-doses of

Since retinitis pigmentosa arises as a consequence of mutations in many genes, one rational approach to therapy relies on correcting the genetic defect. Two approaches have been proposed. The first involves delivering a normal copy of the specific affected gene to the retina with a virus vector or other delivery method. An example is gene transfer therapy as treatment for autosomal recessive Leber Congenital Amaurosis (LCA) from mutations in the RPE65 gene. After successful gene therapy in an RPE65 dog LCA model,58 this was extended to a human RPE65 trial, with preliminary evidence of benefit to visual function.59–61 This method would be applicable when both copies of the gene harbor mutations, as in recessive retinitis pigmentosa. More long-term study of participants in this study indicate that the effects of treatment are long lasting.62 The second relies on inactivating a mutated gene whose gene product has a deleterious effect, a situation usually associated with dominant retinitis pigmentosa. Currently clinical trials involving gene therapy for a number of retinal degenerations including Stargardt and Usher’s are currently underway (www. clinicaltrials.gov).

Neurotrophic Factors

A report in 1990 showed that intraocular injection of basic fibroblast growth factor effectively slowed photoreceptor degeneration in the RCS rat model of retinal degeneration.63 These and other results implied that effective therapies may be developed to slow the rate of degeneration radically in these diseases.64 Ciliary neurotrophic factor (CNTF), delivered intravitreally has been effective to rescue photoreceptors in multiple animal models of retinal degeneration.65,66 Small clinical trials in humans have now been done with CNTF delivered by encapsulated cell technology in patients with advanced retinitis pigmentosa67 and in age-related macular degeneration (AMD) patients with geographic atrophy.68 In these small studies the implants were well tolerated and each reported some positive effects. Future studies using CNTF in the treatment of retinal degenerations are underway (www.clinicaltrials.gov).

Stem Cell Based Therapies

The previous mentioned therapies address the function and longevity of existing retinal cells. However, as the name implies, patients with

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retinal degenerations lose certain cells with time. The two main approaches involving stem cells involve either a regenerative approach, which involves the generation of more differentiated cells to replace a specific cell type that has been lost, and the other is to harness the trophic factors generated by relatively undifferentiated stem cells to provide the molecular boost to fortify existing cells (similar to the previous section). Recently, a recent report on the short-term use of transplanted human-derived retinal pigment epithelial cells demonstrated short-term safety.69 Research is progressing quickly in this area and future studies are underway.

Retinal Prostheses/Implants

Another method to address the loss of retinal cells seen in a range of retinal degenerations has been to use an artificial implant that would detect light, convert light energy into an electrical signal, and then pass on that electrical signal to other cells in the visual system that would get the electoral signal to the brain where it could be interpreted as vision.70 A commercial implant prototype is available in Europe and one is currently FDA-approved for use in the United States. The concept has been around longer than that of stem cell based therapies and several clinical trials have been conducted using various versions of these implants. Progress continues to evolve especially as technology evolves.

Berson EL, Rosner B, Sandberg MA, et al. Vitamin A supplementation for retinitis pigmentosa. Arch Ophthalmol 1993;111(11):1456–9. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol 2007;125(2):151–8. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343(6256):364–6. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008;19(10):979–90. Hoffman DR, Locke KG, Wheaton DH, et al. A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. Am J Ophthalmol 2004;137(4):704–18. Holopigian K, Greenstein VC, Seiple W, et al. Rod and cone photoreceptor function in patients with cone dystrophy. Invest Ophthalmol Vis Sci 2004;45(1):275–81. Khan NW, Wissinger B, Kohl S, et al. CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci 2007;48(8):3864– 71. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358(21):2240–8. Marmor MF, Holder GE, Seeliger MW, et al. Standard for clinical electroretinography (2004 update). Doc Ophthalmol 2004;108(2):107–14. Noble KG, Carr RE, Siegel IM. Autosomal dominant congenital stationary night blindness and normal fundus with an electronegative electroretinogram. Am J Ophthalmol 1990;109(1):44–8.

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Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008;358(21):2231–9.

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9. Zeng Y, Takada Y, Kjellstrom S, et al. RS-1 Gene Delivery to an Adult Rs1h knockout mouse model restores ERG b-Wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci 2004;45(9):3279–85.

46. Apkarian P. A practical approach to albino diagnosis. VEP misrouting across the age span. Ophthalmic Paediatr Genet 1992;13(2):77–88.

10. Schmitz-Valckenberg S, Holz FG, et al. Fundus autofluorescence imaging: review and perspectives. Retina 2008;28(3):385–409. 11. Lima LH, Burke T, Greenstein VC, et al. Progressive constriction of the hyperautofluorescent ring in retinitis pigmentosa. Am J Ophthalmol 2012;153(4):718–27, 27 e1–2. 12. Wen Y, Klein M, Hood DC, et al. Relationships among multifocal electroretinogram amplitude, visual field sensitivity, and SD-OCT receptor layer thicknesses in patients with retinitis pigmentosa. Invest Ophthalmol Vis Sci 2012;53(2):833–40. 13. Holopigian K, Greenstein VC, Seiple W, et al. Rod and cone photoreceptor function in patients with cone dystrophy. Invest Ophthalmol Vis Sci 2004;45(1):275–81. 14. Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143(5):801–9. 15. Song J, Smaoui N, Ayyagari R, et al. High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci 2011;52(12):9053–60.

47. Berson EL, Rosen JB, Simonoff EA. Electroretinographic testing as an aid in detection of carriers of X-chromosome-linked retinitis pigmentosa. Am J Ophthalmol 1979;87(4):460–8. 48. Sieving PA, Niffenegger JH, Berson EL. Electroretinographic findings in selected pedigrees with choroideremia. Am J Ophthalmol 1986;101(3):361–7. 49. Berson EL, Rosner B, Sandberg MA, et al. Vitamin A supplementation for retinitis pigmentosa. Arch Ophthalmol 1993;111(11):1456–9. 50. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985;313(14): 837–41. 51. Converse CA, McLachlan T., Hammer HM. Hyperlipidemia in retinitis pigmentosa. In: LaVail MM, Anderson R.E., Hollyfield J.G., editors. Retinal degenerations. New York: Alan R Liss; 1985. p. 63–74. 52. Hoffman DR, Birch DG. Docosahexaenoic acid in red blood cells of patients with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci 1995;36(6):1009–18.

16. Massof RW, Finkelstein D, Starr SJ et al. Bilateral symmetry of vision disorders in typical retinitis pigmentosa. Br J Ophthalmol 1979;63(2):90–6.

53. Hoffman DR, Locke KG, Wheaton DH, et al. A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. Am J Ophthalmol 2004;137(4):704–18.

17. Henkes HE. Does unilateral retinitis pigmentosa really exist? An ERG and EOG study of the fellow eye. In: Burian HM, Jacobson JH, editor. Clinical electroretinography Proceedings 3rd ISCERG Symposium. London: Pergamon Press; 1966. p. 327–50.

54. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol 2004;122(9):1297–305.

18. Cogan DG. Pseudoretinitis pigmentosa. Report of two traumatic cases of recent origin. Arch Ophthalmol 1969;81(1):45–53.

55. Berson EL, Rosner B, Sandberg MA, et al. Omega-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol 2012.

19. Weleber RG, Carr RE, Murphey WH, et al. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol 1993;111(11):1531–42.

56. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol 2010;128(4):403–11.

20. Richards JE, Scott KM, Sieving PA. Disruption of conserved rhodopsin disulfide bond by Cys187Tyr mutation causes early and severe autosomal dominant retinitis pigmentosa. Ophthalmology 1995;102(4):669–77. 21. Kranich H, Bartkowski S, Denton MJ, et al. Autosomal dominant ‘sector’ retinitis pigmentosa due to a point mutation predicting an Asn-15-Ser substitution of rhodopsin. Hum Mol Genet 1993;2(6):813–14. 22. Humphries P, Farrar GJ, Kenna P, et al. Retinitis pigmentosa: genetic mapping in X-linked and autosomal forms of the disease. Clin Genet 1990;38(1):1–13. 23. Galvin JA, Fishman GA, Stone EM, et al. Evaluation of genotype-phenotype associations in leber congenital amaurosis. Retina 2005;25(7):919–29. 24. Simunovic MP, Moore AT. The cone dystrophies. Eye (Lond) 1998;12(Pt 3b):553–65. 25. Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 2010;29(5):335–75. 26. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 1990;343(6256):364–6. 27. Farrar GJ, Kenna P, Jordan SA, et al. A three-base pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature 1991;354(6353):478–80. 28. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 1994;264(5165):1604–8. 29. Swain PK, Chen S, Wang QL, et al. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 1997;19(6):1329–36. 30. Chang GQ, Hao Y, Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 1993;11(4):595–605. 31. Leveillard T, Mohand-Said S, Lorentz O, et al. Identification and characterization of rodderived cone viability factor. Nat Genet 2004;36(7):755–9. 32. Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol 2004;88(2):291–7. 33. Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol 2008;19(3):255–62. 34. Carr RE. Congenital stationary night blindness. Trans Am Ophthalmol Soc 1974;72:448–87. 35. Miyake Y, Yagasaki K, Horiguchi M, et al. Congenital stationary night blindness with negative electroretinogram. A new classification. Arch Ophthalmol 1986;104(7):1013–20.

6.13 Progressive and ‘Stationary’ Inherited Retinal Degenerations

2. Nettleship E. On retinitis pigmentosa and allied diseases. R Lond Ophthalmol Hosp Rep 1907;(17):1–56.

36. Zeitz C, Labs S, Lorenz B, et al. Genotyping microarray for CSNB-associated genes. Invest Ophthalmol Vis Sci 2009;50(12):5919–26.

57. Steinmetz RL, Fitzke FW, Bird AC. Treatment of cystoid macular edema with acetazolamide in a patient with serpiginous choroidopathy. Retina 1991;11(4):412–15. 58. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001;28(1):92–5. 59. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008;358(21):2231–9. 60. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008;358(21):2240–8. 61. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: shortterm results of a phase I trial. Hum Gene Ther 2008;19(10):979–90. 62. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010;18(3):643–50. 63. Faktorovich EG, Steinberg RH, Yasumura D, et al. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 1990;347(6288):83–6. 64. Steinberg RH. Survival factors in retinal degenerations. Curr Opin Neurobiol 1994;4(4): 515–24. 65. LaVail MM, Yasumura D, Matthes MT, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 1998;39(3):592–602. 66. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci 2002;43(10):3292–8. 67. Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A 2006;103(10):3896–901. 68. Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 2011;108(15):6241–5. 69. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012;379(9817):713–20. 70. Weiland JD, Cho AK, Humayun MS. Retinal prostheses: current clinical results and future needs. Ophthalmology 2011;118(11):2227–37.

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PART 6 RETINA AND VITREOUS SECTION 4 Dystrophies

6.14

Macular Dystrophies David G. Telander, Kent W. Small

Definition: The process of premature retinal cell aging and cell death,

generally confined to the macula, in which no clear demonstrable extrinsic cause is evident, and a heritable genetically determined enzymatic defect is confirmed or implicated.

Key features ■

Yellowish material within or beneath the retinal pigment epithelium ■ Loss of macular photoreceptors and retinal pigment epithelial cells ■ Loss of central vision

Associated features ■

Neural retinal, retinal pigment epithelial, and choroidal atrophy commonly limited to the macula ■ Bull’s-eye appearance seen rarely ■ Pigment clumps in the posterior pole, midperiphery, or far periphery seen rarely ■ Optic atrophy, retinal vascular attenuation, macular edema, and choroidal neovascularization seen rarely

INTRODUCTION The macula is the center of all human vision and is critically unique to our visual function. Its irreducibly complex design requires many unique proteins that allow light to be converted to neuronal impulses (phototransduction). These disorders, while rare, are important not only for the individuals affected, but also because they allow a window into a better understanding of macular function in general. Macular dystrophies allow us to see the clinical abnormalities of specific gene defects in complex systems involved in macular function. Molecular genetics has been instrumental in unlocking the secrets of these mechanisms and has allowed us to peer through the keyhole for a better understanding of the macula. The first retinal degeneration mapped by genetic linkage was one type of X-linked retinitis pigmentosa (XLRP) in 1984. Subsequently linkage of autosomal dominant retinitis pigmentosa (ADRP) to chromosome 3 was achieved by Humphries et al. This allowed Dryja and colleagues in 1992 to discover the first rhodopsin mutant associated with the disease. The first macular dystrophy to be

genetically linked was North Carolina macular dystrophy in 1990 by Small et al. Since then there have been so many important contributions by many groups around the world that even cataloging them is a formidable task. Fortunately, we can refer the reader to the online version of McKusick’s classic, ‘Mendelian Inheritance of Man’ which is now available only online (OMIM, www.omim.com; accessed July 2013). Other helpful online resources include RetNet (sph.uth.tmc.edu/ Retnet/; accessed July 2013) and Retina International (www.retinainternational.org; accessed July 2013). From a clinical perspective, significant phenotypic variations associated with any inherited disease are the rule. For example, differences in phenotype can represent mutations in different genes, different mutations in the same gene, and/or variability in the genetic background in which a gene is expressed. The clinical phenotype can be further modulated by the environment. Collectively, these factors may make it difficult for even the skilled clinician to make the correct diagnosis via ophthalmoscopy alone. Interestingly, many of the most common macular dystrophies are marked by the deposition of yellow subretinal deposits leading to cellular dysfunction and death; however the pathogenesis of each disease is unique. Table 6-14-1 demonstrates how identification of genetic phenotypes has given us insights into macular dystrophies. Table 6-14-2 categorizes the macular dystrophies by the location of the defective cell. The purpose of this chapter is to highlight the clinical features of some of these macular dystrophies, discuss the pertinent molecular genetics and molecular biology of these diseases and correlate the functional consequences of the mutant gene products in the framework of the known anatomy and physiology of the retina and retinal pigment epithelium (RPE). Obviously, every disease cannot be reviewed. However the intention is to convey certain underlying biological principles that can be extended to understand the molecular pathogenesis of other disease processes. With the advent of gene therapy, stem cell therapy, artificial vision, and a plethora of new retinal pharmacologics, proven therapy for these disorders is in the near future. In addition, therapies to halt the progression of choroidal neovascularization have progressed and can benefit some who develop this complication.

STARGARDT DISEASE AND FUNDUS FLAVIMACULATIS EPIDEMIOLOGY AND PATHOGENESIS Stargardt disease is the most common macular dystrophy with an estimated incidence of 1 : 10,000, which accounts for approximately 7% of

TABLE 6-14-1  EXAMPLES OF CELLULAR SPECIFICITY OF MACULAR DYSTROPHY CANDIDATE GENES Cellular location

Retinal dystrophy

Chromosome

Gene

RPE specific

AD Best’s AD Sorsby’s macular dystrophy Malattia leventinese (Doyne honeycomb macular dystrophy) AD Stargardt’s macular dystrophy AD Cone dystrophy AR Stargardt’s AD adult foveal macular dystrophy

11q12.3 22q12.3 2p16

VMD2, Bestrophin (chloride channel) TIMP-3 (tissue inhibitor of metalloproteinase) EFEMP1 (EGF-containing fibrillin-like extracellular matrix protein 1)

6q14 6p21.1 1p22.1 6p21.2

ELOVL4 (photoreceptor-specific elongation of very long chain fatty acids) GUCA1A (guanylate cyclase activator 1A) ABC4 (ATP binding cassette protein found in rods and foveal cones) RDS/peripherin (cone and rod outer segment glyco-protein in disc membranes for structural integrity)

Rod specific Cone specific Cone-rod specific

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6

TABLE 6-14-2  MACULAR DYSTROPHIES AND EXAMPLE GENES

Retina and Vitreous

Dystrophy

Inheritance

Chromosome

Gene

Stargardt’s disease

AR

1p22.1

Stargardt’s disease (butterfly pattern dystrophy) Best’s disease Adult vitelliform outer dystrophy

AD

6q14 (STGD3)

AD AD

11q12.3 (VMD2) 6p

Sorsby mascular dystrophy Malattia leventinese (Doyne’s dystrophy) North Carolina mascular dystrophy Cone dystrophy

AD AD AD AD, AR, mitochondrial, X

22q12.3 2p16 6q (MCDR1) Multiple genes (CORD1–8), multiple chromosomes

ABCR or ABCR4 (ATP binding cassette transporter in rod and cone outer segments) ELOVL4 (photoreceptor-specific membrane-bound protein for elongation of very long chain fatty acid) Bestrophin (chloride channel) Peripherin/RDS (cone and rod segment glycoprotein in disc membranes for structural integrity) TIMP-3 (tissue inhibitor of metalloproteinases) EFEMP1 (EGF-containing fibrillin-like extracellular matrix protein 1) Not identified

(Modified from Voo & Small. Retina. 2004.)

all retinal dystrophies. Stargardt disease is also known as Stargardt macular dystrophy or fundus flavimaculatus. Stargardt disease most commonly is inherited in an autosomal recessive manner caused by a mutation on an adenosine triphosphatebinding cassette (ABCA4) gene, which has been localized to chromosome 1p21–22.1–4 Only 60% of these patients have a detectable mutation in the ABCA4 gene. ABCA4 normally encodes for a protein involved in the visual cycle. Lipofuscin buildup in the subretinal space appears to be related to a mutation in ABCA4 and the resulting production of a dysfunctional protein. Lipofuscin is a complex mixture of bisretinoid fluorophores that are amassed by RPE cells. In the RPE, lipofuscin does not form as a result of oxidative stress unlike in other cell-types. Instead it forms because of a non-enzymatic reaction of vitamin A aldehyde in photoreceptor cells; which is transferred to the RPE by the phagocytosis of the photoreceptor outer segments. In recessive Stargardt and ELOV4-related retinal dystrophies, the formation of this lipofuscin is accelerated leading to cell death.5 Carrier parents are unaffected. Interestingly, mutations in this gene may play a role in other retinal diseases including age-related macular degeneration, autosomal recessive retinitis pigmentosa and autosomal recessive cone-rod dystrophy.5,6 These ABCA4-related dystrophies likely represent a spectrum of phenotypes with overlapping retinal changes, just as Stargardt disease itself exhibits great variability in clinical expression.7–9 In addition to recessive Stargardt disease, there are other rarer forms inherited as dominant rather than recessive traits. Autosomal dominant Stargardt disease is rarely due to different mutations of the ELOVL4 gene, which codes for a photoreceptor-specific membrane-bound protein that plays a role in long chain fatty acid biosynthesis.10 Several other retinal diseases mapped near to ELOVL4 including recessive retinitis pigmentosa, Leber congenital amaurosis, dominant cone-rod dystrophy, North Carolina macular dystrophy, early onset dominant drusen, and progressive bifocal chorioretinal atrophy.11–13

Ocular Manifestations and Diagnosis

492

The phenotypic variation of mutations in the ABCA4 gene presents in many forms as described above. Stargardt disease is the term to describe the macular dystrophy characterized by macular flecks that accumulate at the level of the RPE sometimes resulting in central macular atrophy early in life. Fundus flavimaculatus is caused by mutations in the same gene; however the phenotype was historically considered different as these patients have the characteristic flecks distributed throughout the fundus and onset is in adulthood. Stargardt disease classically is marked by the accumulation of discrete ‘pisciform’ flecks at the level of the RPE (Fig. 6-14-1).14,15 Early in the disease, patients may have few flecks, but they often will develop more macular flecks, along with patches of characteristic central atrophy. Patients with fundus flavimaculatus have pisiform flecks more in the peripheral retina sparing the macula. Therefore fundus flavimaculatus patients tend to retain their central vision. Stargardt patients, on the other hand, develop a macula with a ‘beaten bronze’ appearance caused by atrophic changes in the RPE. In addition, they also often have a ‘dark’ or ‘silent’ choroid on fluorescein angiography, which appears as a prominent retinal circulation against hypofluorescent choroid. While this finding can be helpful in making the diagnosis only up to one fourth of patients have a dark choroid.16 On angiography the pisciform flecks do not stain. Autofluorescence can be helpful in showing the lipofuscin in flecks and atrophic areas, which will show

Fig. 6-14-1  Stargardt’s disease.

photoreceptor dysfunction17 (Fig. 6-14-2). The electroretinogram (ERG) is normal early in the disease but may be reduced in more advanced cases. Of note, the ERG findings do not directly correlate with clinical findings.18 Also, the electroculogram (EOG) Arden ratio may also be mildly reduced when there are diffuse RPE changes. High resolution optical coherence tomography (OCT) can shows atrophic changes in the photoreceptors and RPE, and lipofuscin deposits can be detected within the parafoveal RPE19–21 (Fig. 6-14-3). Interestingly, these changes usually precede the occurrence of fundus abnormalities. The OCT can also help with diagnosis and aid in determining the status of the photoreceptor layer in the macula, which is beneficial in the assessment of central vision.22

PATHOLOGY Histologic studies reveal that Stargardt patients have a buildup of a lipofuscin-like pigment in the RPE.23 The mouse model (a knockout abcr−/−) of Stargardt disease also has an accumulation of lipofuscin in the RPE. Specifically, the toxic bis-retinoid, N-retinylidene-N retinylethanolamine (A2E) protein builds up suggesting its role in causing the disease.1

TREATMENT, COURSE, AND OUTCOME To date there is known proven treatment for this disease. As ABCA4 plays a role in vitamin A processing in the visual cycle, additional vitamin A is suspected to make the disease worse. Therefore all forms of vitamin A supplements are discouraged for these patients.24 Polyunsaturated fatty acids such as decosahexanoid acid (DHA) have shown to reduce toxicity of A2E, and is therefore recommended especially for patients if they are autosomal dominant Stargardts.25

6.14 Macular Dystrophies

A

B

Fig. 6-14-2  Fundus autofluorescence clearly delineates areas of central macular atrophy in Stargardt disease allowing accurate measurements of atrophy. Color fundus of the right eye (A) can be compared to autofluorescence of the right (B).

Fig. 6-14-3  Fundus OCT findings showing central retinal thinning in Stargardt patient from photoreceptor and RPE cell loss.

493

6 Retina and Vitreous

Gene therapy has only recently been initiated for Stargardt and StarGen has sponsored a Phase I/IIa Dose Escalation Safety Study of Subretinally Injected gene therapy agent (http://clinicaltrials.gov/ct2/ show/NCT01367444; accessed July 2013). Another clinical trial has been launched using RPE precursor cells derived from embryonic stem cells injected subretinally for patients with Stargardt disease. Advanced Cell Technology used retinal pigment epithelial cells derived from human embryonic stem cells (hESC_RPE) surgically implanted into the submacular space. This study shows the first treated patient tolerated the treatment without adverse effects, and the patient with Stargardt disease reported improved best corrected visual acuity improved slightly from hand motions to 20/800.26 Saffron, MP-4, and DHA are all being studied in additional clinical trials for Stargardt disease (clinicaltrials.gov). Individual members of families with Stargardt disease often display tremendous variability in presentation, course, and outcome. The visual prognosis ranges from 20/50 to 20/200, as determined by the extent of macular atrophy depending mostly on the extent of macular atrophy for both Stargardt and fundus flavimaculatus.15,16,27 Choroidal neovascularization is rare but can worsen the prognosis if it occurs.28

VITELLIFORM MACULAR DYSTROPHY (BEST’S DISEASE) EPIDEMIOLOGY AND PATHOGENESIS Vitelliform macular dystrophy is an inherited macular dystrophy in which lipofuscin accumulates in the central macula causing progressive central vision loss. Vitelliform dystrophy can present early in life (described as Best’s disease); however the onset of symptoms can vary widely. The adult-onset form of vitelliform dystrophy (described below) usually presents in middle age. Best’s disease is an autosomal dominant macular dystrophy, and linked to mutation in the bestrophin (VMD2) gene. Like Stargardt, Best’s patients can be highly variable in clinical phenotype, and men and women appear to be equally affected. Best’s disease is quite rare compared to Stargardt disease, however its accurate incidence has not been determined. VMD2 encodes for a transmembrane protein, which acts as an ion exchanger.30–32 VMD2 is expressed in the RPE cell membrane and appears to be important in the formation of chloride channels.33 This leads to the accumulation of lipofuscin through mechanisms which are still unclear. Several mutations within the bestrophin gene have been identified and are associated with both classic Best’s and adult vitelliform-like presentation.34 Interestingly, some patients with the mutation can be completely free from any clinically observable retinal changes. Incomplete penetrance by clinical exam alone has been well documented although EOG generally does demonstrate abnormalities.29 In fact, Best’s disease expresses a great deal of phenotypic variability even among single family members all with the same mutation.

OCULAR MANIFESTATIONS AND DIAGNOSIS

494

Vitelliform dystrophies are characterized by bilateral yellow, yolk-like (vitelliform) macular lesions (Fig. 6-14-4). While Best’s presents during childhood, adult vitelliform typically presents later in life. In Best’s the diameter of the lesion is in the range 1–5  mm. For Best’s patients the lesion will change later in life resulting in macular scarring and atrophy. This may make it more difficult to diagnose later. The stages or evolution of the macular lesions are described as progressing from 1) previtelliform stage to 2) vitelliform stage to the 3) scrambled egg stage with or without hypopyon finally to 4) the atrophic stage. Rarely, the lesions may be multifocal.35 All Best’s patients have a light-todark (or Arden) ratio of less than 1.5 and often close to 1.1 when tested with the electro-oculogram (EOG). Electroretinograms (ERG) testing shows only occasionally a reduced C wave. Therefore this is the only disease with relatively normal ERG results associated with an abnormal EOG. Moreover OCT findings appear to be very specific (Fig. 6-14-5). In Best’s disease the OCT reveals that the vitelliform material appears as a dome-shaped, hyperreflective and homogenous lesion (Fig. 6-14-5), located below the hyperreflective photoreceptor layer.36

Fig. 6-14-4  Best’s disease. Typical vitelliform lesion from an 11-year-old girl. (Courtesy of Ola Sandgren, University Hospital of Umeå, Sweden.)

PATHOLOGY Best’s patients have an accumulation of lipofuscin-like material throughout the RPE.37–40 Unlike Stargardt disease, despite the accumulation of lipofuscin-like material in the RPE, these patients do not exhibit a dark choroid effect on fluorescein angiography. In addition, Best’s patients lose vision from atrophy and scarring in the macula, not from accumulated material in the RPE.

TREATMENT, COURSE, AND OUTCOME Even though the age of onset of Best’s disease is variable, most patients present in childhood. Rarely, onset is in adulthood. Best’s patients usually have good visual acuity when the ‘yolk’ remains intact; however the vision drops when macular atrophy begins.35 Visual acuity can decrease to the 20/200 range, but most patients will keep enough vision in at least one eye to read and drive. Rarely Best’s patients develop choroidal neovascular membranes (CNV), usually from an old scar.35

ADULT VITELLIFORM MACULAR DYSTROPHY/ ADULT-ONSET FOVEOMACULAR DYSTROPHY (PATTERN DYSTROPHY) EPIDEMIOLOGY AND PATHOGENESIS Unlike Best’s disease, the adult-onset form of vitelliform dystrophy usually presents in middle age and typically only causes mild, if any, central vision loss. While these two diseases can be phenotypically similar, the clinical course is highly divergent. While Best’s is caused by mutations in VMD2, adult vitelliform dystrophy has been associated with mutations of both VMD2 and retinal degeneration slow (RDS); however the causative gene cannot be found in most patients with adult vitelliform dystrophy.30,41 Interestingly, several mutations within the bestrophin gene have been identified and are associated with both classic Best’s and adult vitelliform-like presentation.34 RDS encodes a protein called peripherin. This protein is essential for the normal function of light-sensing (photoreceptor) cells in the retina. How a mutation in RDS only affects the macula and not the remainder of the retina is unclear.

OCULAR MANIFESTATIONS AND DIAGNOSIS

PATHOLOGY Adult vitelliform dystrophy patients have damage at the level of the RPE with focal loss of the photoreceptors in the areas of atrophic RPE

TREATMENT, COURSE, AND OUTCOME Adult vitelliform dystrophy usually presents during the fourth to sixth decade, and visual symptoms are usually metamorphopsia and mildly blurred vision. Rarely, these patients can also develop CNV.46 Interestingly, as in Best’s disease adult vitelliform dystrophy patients usually only lose significant vision when atrophy and scarring occur. Best’s disease should be distinguished from adult vitelliform dystrophy as there are potential genetic implications that require appropriate counseling.

6.14 Macular Dystrophies

Adult vitelliform (Figs. 6-14-6A and B) and Best’s disease can often appear very similar. While Best’s presents during childhood, adult vitelliform typically presents later in life. In Best’s the diameter of the lesion is in the range 1–5 mm; while in adult vitelliform the lesion tends to be smaller (Fig. 6-14-7). Adult vitelliform degenerations include foveomacular dystrophy of Gass, and adults who have coalescent, widespread, cuticular drusen that form vitelliform lesions in the macula.42 Adult vitelliform can be differentiated from Best’s disease by having a near normal EOG (Arden ratio  2 D was actually found to be more common among European-derived individuals than among Chinese in one study, even though PACG rates were much higher among the Chinese.97 In a South Indian population, axial length and refractive error were not risk factors for PACG when using a multiple regression analysis, suggesting that these factors may predispose to PACG because of their association with other ocular biometric features, such as anterior chamber depth.90 Indeed, strong correlations have been demonstrated between ACD and refractive errors.108

Lens thickness

Several studies confirm that eyes with PACG or AAC, as well as fellow eyes in patients with unilateral AAC, have lenses 0.2–0.6 mm thicker than controls,5,98–100 although work from South India showed very similar lens thickness in normal eyes, PACG eyes, and eyes with occludable angles.90 Groups that are more susceptible to angle closure tend to have thicker lenses. Mean lens thickness in Eskimos is 0.3–0.4 mm greater than that of whites and blacks, while mean lens thickness in Chinese is 0.1–0.2 mm thicker than in whites and blacks.102 Lens thickness increases with age, and may be an important explanation for the progressive shallowing of the anterior chamber and increased prevalence of PACG observed in older age groups.102

Radius of corneal curvature

A smaller radius of corneal curvature results in a more crowded anterior chamber, which is associated with a higher risk of angle closure. Most studies have found that eyes with PACG and fellow eyes of patients with unilateral AAC have a slightly smaller average corneal

Systemic Risk Factors for PACG

SECONDARY GLAUCOMAS Population-based studies with low rates of pseudoexfoliation report rates of secondary glaucoma (resulting from pseudoexfoliation, vein occlusions, diabetes, uveitis, trauma, and other causes) between 0.15% and 0.7%, with secondary glaucoma comprising 4–18% of all glaucoma cases.7,8,15,109,110 Whether or not pseudoexfoliation glaucoma is a primary or secondary form of glaucoma depends on definition, and researchers vary in how they present their data. Secondary glaucomas other than pseudoexfoliation occur infrequently. In populations where pseudoexfoliation is found, its prevalence varies substantially, with the highest rates found in Greek and Scandinavian populations (Table 10-1-4).7–11,15,111–113 People with pseudoexfoliation have substantially higher mean IOPs, and have a significantly higher risk of glaucoma.8,11,15,111

10.1 Epidemiology of Glaucoma

Using these techniques, several groups have been able to identify persons with occludable angles (defined by gonioscopy) with sensitivities and specificities exceeding 80%.91,103 An important recently identified risk factor is lens vault into the anterior chamber which is correlated with ACD but independently associated with angle closure.104 Anterior chamber width, area and volume are other risk factors for angle closure identified by anterior segment OCT.105

OCULAR HYPERTENSION Ocular hypertension is a condition where the IOP is higher than would be expected based on population statistics for ‘normal’ IOP. In European-derived populations the traditional cut-off has been 22 mmHg since this number is outside two standard deviations from the mean.114 However, some Asian populations have a lower mean IOP, and a pressure above 19 mmHg would be considered elevated in these individuals. Many now think of an IOP of 24 mmHg or higher as consistent with ocular hypertension, as was required for enrolment in the Ocular Hypertension Treatment Study (OHTS).39 The percentage of people with an IOP elevated to 22 mmHg or greater in the absence of glaucoma ranges from 1% to 4% in most population-based studies (see Table 10-1-1). In the OHTS trial, the rate of developing either disc or field loss was about 10% at 5 years,39 similar to the 5-year incidence of glaucoma noted in mostly untreated ocular hypertensives from a population-based study in Barbados.115 Persons with certain risk factors (large baseline cup-to-disc ratio, thin corneas, older age, higher IOP, and subtle decrements in the baseline visual field) have much higher rates of glaucoma development, whereas those lacking these risk factors are very unlikely to develop glaucoma even if untreated.39

GLAUCOMA SUSPECTS Some individuals present with concerning optic nerve appearances and either borderline visual field loss or normal visual fields. Physicians typically monitor these persons without treatment, although certain individuals with this presentation will be treated. Studies using a wide variety of definitions to identify angle closure suspects and open-angle glaucoma suspects, reporting a prevalence of 1–8% for open-angle glaucoma suspects8,18,24,29 and 6–7% for angle-closure suspects (Table 10-1-5).19,90,91 TABLE 10-1-4  PREVALENCE OF PSEUDOEXFOLIATION IN DIFFERENT POPULATION-BASED STUDIES Study

Country

Age group studied

Prevalence of pseudoexfoliation noted per 100 persons

Middle-Norway113 Thessaloniki112 Blue Mountains15 Roscommon8 Aravind11 Kongwa7 Proyecto Ver10 Chinese9

Norway Greece Australia Ireland India Tanzania US Hispanics Singapore

65+ 60+ 50+ 50+ 40+ 40+ 40+ 40−79

16.9 11.9% 2.2 1.3 0.4 23.00 to ≤ 25.00 mean = 24

≤ 23.00 mean = 21.5

19 of 113 16%

≤ 556 mean = 532.2

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33 of 124 27%

21 of 130 16%

14 of 128 11%

5 of 124 4%

14 of 132 11% >556 to ≤ 591 mean = 573.5

5 of 126 4%

4 of 126 3%

6 of 120 5% >591 mean = 614.2

baseline central corneal thickness ( m)

Fig. 10-9-1  Graph demonstrating the effect of central corneal thickness and baseline intraocular pressure on progression to glaucoma in ocular hypertension patients. These results were derived from analysis of pooled data from OHTS and EGPS. (Reproduced from data, Ocular Hypertension Treatment Study Group and European Glaucoma Prevention Study Group. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. 2007;114:10−19, Copyright 2007, with permission from American Academy of Ophthalmology. Copyright 2007, American Medical Association. All rights reserved.)

Pattern Standard Deviation

A greater baseline pattern standard deviation (PSD) on standard automated perimetry (SAP) correlated with increased risk of progression from OHT to POAG.

Even when OHT patients had no clinically apparent glaucomatous structural damage, a larger cup-to-disc ratio was a risk factor for progression.

Other Predictive Factors

There were several relevant risk factors confirmed by other studies that were found not to be significant in the OHTS trial. Race was found to be significant in the univariate analysis, but not in the multivariate analysis of the OHTS that included cup-to-disc ratio and CCT. However, many studies support the finding that POAG is 3–4 times more prevalent in black versus white populations.10–12 Though family history was not found to be a significant predictor for progression in the OHTS, other studies have shown it to play a key role in the susceptibility to POAG.13,14

DIAGNOSIS A thorough medical and ocular history must rule out any secondary causes of elevated IOP such as corticosteroid use or trauma. A complete ophthalmic exam with the following key components is necessary: Tonometry: IOP greater than 21 mmHg. Ophthalmoscopy: normal optic nerve with no evidence of glaucomatous cupping or nerve fiber layer (NFL) loss. Standard automated perimetry: no evidence of visual defects. Pachymetry: measurements should be performed over the central cornea in an area without pathology. Gonioscopy: open angles with no evidence of pathology. Other tests utilized for imaging of the optic nerve and/or the retina that may be beneficial include: Optical coherence tomography (OCT). Heidelberg Retina Tomography. GDX-scanning laser polarimetry, Laser Diagnostic Technologies, San Diego, CA.

• • • • • •

• • •

DIFFERENTIAL DIAGNOSIS The differential diagnosis for OHT includes undiagnosed POAG as well as secondary causes of OHT such as topical or systemic corticosteroid use, angle-recession, and angle-closure glaucoma.

TREATMENT The OHTS trial provided predictive factors (CCT, PSD, age, cup-to-disc ratio, and IOP) that should be considered when deciding whether to treat OHT and confirmed the safety and efficacy of treating OHT with topical medications. In general, treatment of OHT can be considered in high-risk patients after accounting for patient preference, age, and health status. Patients at low risk of conversion can be followed yearly, typically without treatment, as long as they are monitored for signs of early disease.15 Some physicians may prefer to follow all OHT patients, initiating medication only after early damage is detected. It is important to involve the patient in decision-making, in order to create an individualized treatment plan. Patients can be stratified by risk calculators derived from the OHTS and European Glaucoma Prevention Study (EHPS) data.16 Costeffectiveness analysis using OHTS data supports treating OHT patients

COURSE AND OUTCOME The majority of OHT patients do well over long periods of follow-up. The accepted rate for progression from OHT to POAG is 1–2% per year but higher risk subgroups can progress at faster rates. In eyes with OHT that did not reach an endpoint for POAG, the rate of change of mean deviation was slow (−0.05 dB/y) whereas eyes that converted to POAG progressed at a faster rate (−0.26 dB/y).20 While data from the OHTS also suggest that visual field change in early glaucoma is most commonly localized, a significant number of individuals will show diffuse changes that may go undetected if only pattern deviation analyses are used.20,21 The earliest changes of POAG, however, were most commonly structural, highlighting the importance of clinical examination, optic disc photographs, and imaging of the optic nerve and NFL. In general, high-risk patients who are treated are likely to have good outcomes. For the monitored patients who progress, early detection of damage and treatment may slow further progression. In addition to SAP, frequency doubling technology (FDT) may be beneficial in detecting early damage as it has been shown to detect glaucomatous progression up to 4 years before changes in white-on-white perimetry occur.22 Emerging imaging technologies such as OCT are being used to detect subclinical damage from glaucoma by analyzing not only the NFL around the optic nerve, but also by detecting loss of ganglion cells in the macula.23,24 High resolution imaging techniques show promise and their utility in the management of OHT will increase in the future.

10.9 Ocular Hypertension

Optic Nerve

if there is at least a 2% annual risk of developing POAG.17 While the calculator may help guide the clinician in determining patient management, it should not supersede clinical judgment.18,19

KEY REFERENCES Artes PH, Chauhan BC, Keltner JL, et al. Longitudinal and cross-sectional analyses of visual field progression in participants of the Ocular Hypertension Treatment Study. Arch Ophthalmol 2010;128:1528–32. Demirel S, De Moraes CG, Gardiner SK, et al. The rate of visual field change in the ocular hypertension treatment study. Invest Ophthalmol Vis Sci 2012;53:224–7. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714–20; discussion 829–30. Gordon MO, Gao F, Beiser JA, et al. The 10 year incidence of glaucoma among treated and untreated ocular hypertensive patients. Arch Ophthalmol 2011;129:1630–1. Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology 2007;114:10–19. Kass MA, Gordon MO, Gao F, et al. Delaying treatment of ocular hypertension: the ocular hypertension treatment study. Arch Ophthalmol 2010;128:276–87. Kymes SM, Kass MA, Anderson DR, et al. Management of ocular hypertension: a costeffectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141:997–1008. Kymes SM, Plotzke MR, Kass MA, et al. Effect of patient’s life expectancy on the cost-effectiveness of treatment for ocular hypertension. Arch Ophthalmol 2010;128:613–18. Leung CK, Liu S, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a prospective analysis with neuroretinal rim and visual field progression. Ophthalmology 2011;118:1551–7. Medeiros FA, Sample PA, Weinreb RN. Frequency doubling technology perimetry abnormalities as predictors of glaucomatous visual field loss. Am J Ophthalmol 2004;137:863–71. Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol 2005;123:1351–60. Miglior S, Pfeiffer N, Torri V, et al. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology 2007;114:3–9. Tan O, Chopra V, Lu AT, et al. Detection of macular ganglion cell loss in glaucoma by Fourierdomain optical coherence tomography. Ophthalmology 2009;116:2305–14 e1–2. Weinreb RN, Friedman DS, Fechtner RD, et al. Risk assessment in the management of patients with ocular hypertension. Am J Ophthalmol 2004;138:458–67.

Access the complete reference list online at

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REFERENCES

13. Hart WM Jr, Yablonski M, Kass MA, et al. Multivariate analysis of the risk of glaucomatous visual field loss. Arch Ophthalmol 1979;97:1455–8. 14. Armaly MF, Monstavicius BF, Sayegh RE. Ocular pressure and aqueous outflow facility in siblings. Arch Ophthalmol 1968;80:354–60.

2. Nemesure B, Wu SY, Hennis A, et al. Factors related to the 4-year risk of high intraocular pressure: the Barbados Eye Studies. Arch Ophthalmol 2003;121:856–62.

15. Kass MA, Gordon MO, Gao F, et al. Delaying treatment of ocular hypertension: the ocular hypertension treatment study. Arch Ophthalmol 2010;128:276–87.

3. Ramakrishnan R, Nirmalan PK, Krishnadas R, et al. Glaucoma in a rural population of southern India: the Aravind comprehensive eye survey. Ophthalmology 2003;110:1484–90.

16. Glaucoma Five Year Risk Estimator. Available from: http://ohts.wustl.edu/risk/calculator.html (last modified 5 December 2006; accessed 17 April 2013).

4. Iwase A, Suzuki Y, Araie M, et al. The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 2004;111:1641–8.

17. Kymes SM, Plotzke MR, Kass MA, et al. Effect of patient’s life expectancy on the costeffectiveness of treatment for ocular hypertension. Arch Ophthalmol 2010;128:613–18.

5. Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973–1975. Surv Ophthalmol 1980;24(Suppl):335–610.

18. Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol 2005;123: 1351–60.

6. Gordon MO, Gao F, Beiser JA, et al. The 10 year incidence of glaucoma among treated and untreated ocular hypertensive patients. Arch Ophthalmol 2011;129:1630–1. 7. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714–20; discussion 829–30. 8. Miglior S, Pfeiffer N, Torri V, et al. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology 2007;114:3–9. 9. Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology 2007;114:10–19. 10. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991;266:369–74. 11. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992;99:1499–504.

19. Weinreb RN, Friedman DS, Fechtner RD, et al. Risk assessment in the management of patients with ocular hypertension. Am J Ophthalmol 2004;138:458–67.

10.9 Ocular Hypertension

1. Kymes SM, Kass MA, Anderson DR, et al. Management of ocular hypertension: a costeffectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006;141:997–1008.

12. Hiller R, Kahn HA. Blindness from glaucoma. Am J Ophthalmol 1975;80:62–9.

20. Demirel S, De Moraes CG, Gardiner SK, et al. The rate of visual field change in the ocular hypertension treatment study. Invest Ophthalmol Vis Sci 2012;53:224–7. 21. Artes PH, Chauhan BC, Keltner JL, et al. Longitudinal and cross-sectional analyses of visual field progression in participants of the Ocular Hypertension Treatment Study. Arch Ophthalmol 2010;128:1528–32. 22. Medeiros FA, Sample PA, Weinreb RN. Frequency doubling technology perimetry abnormalities as predictors of glaucomatous visual field loss. Am J Ophthalmol 2004;137:863–71. 23. Tan O, Chopra V, Lu AT, et al. Detection of macular ganglion cell loss in glaucoma by Fourierdomain optical coherence tomography. Ophthalmology 2009;116:2305–14 e1–2. 24. Leung CK, Liu S, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a prospective analysis with neuroretinal rim and visual field progression. Ophthalmology 2011;118:1551–7.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Primary Open-Angle Glaucoma James C.H. Tan, Paul L. Kaufman

Definition: A progressive optic neuropathy characterized by cupping

of the optic nerve, intraocular pressure (IOP) exceeding normal limits without apparent cause, and gonioscopically open angles.

Key features ■ ■ ■ ■ ■

Intraocular pressure above normal limits Glaucomatous disc cupping and retinal nerve fiber loss Abnormal visual field testing Open angles on gonioscopy Progression

Associated features ■

Corneal thickness Chronic disease ■ Visual impairment ■

DEFINITION AND CLASSIFICATION Glaucoma describes a progressive optic neuropathy that is recognized by the appearance of characteristic cupping of the optic disc associated with corresponding visual deficit. The condition has as its basis gradual loss of retinal ganglion cells and their axons, and as a major risk factor, intraocular pressure (IOP). Glaucoma is progressive, and, if left unchecked, may cause blindness. Glaucoma is classified as primary if the cause of elevated IOP is unknown and secondary where a cause is known. Conventionally the term primary open-angle glaucoma (POAG) is applied to eyes with primary chronic glaucoma with open anterior chamber drainage angles and elevated IOP. Two other entities are closely considered with POAG. People with ocular hypertension have open angles and elevated IOP (above 21 mmHg) that has apparently not caused nerve damage. They are at risk of developing glaucoma. People with normal tension glaucoma (NTG) have primary chronic glaucoma and open anterior chamber drainage angles but IOP within normal statistical limits (less than 22 mmHg). Neither ocular hypertension nor NTG is rare:1,2 ocular hypertension is more prevalent than POAG, while at least a third of people with primary chronic glaucoma in Western countries have NTG. This chapter will discuss the risk factors for POAG, the nature of progressive visual loss in the disease, and broad principles of diagnosis and treatment.

INTRAOCULAR PRESSURE AND OTHER RISK FACTORS FOR POAG

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The cut-off for ‘normal’ IOP of 21 mmHg has its source in a German population survey in the 1950s in which 95% of normal people studied had IOP below this level.3 This analysis assumed that IOP is normally distributed but it is now known that the distribution of IOP in populations is skewed toward higher IOP.4 The right-skew increases with age

10.10

and varies with race. This statistical quirk means that the proportion of people with IOP exceeding 21 mmHg having glaucoma is less than initially predicted, and many will be diagnosed with ocular hypertension. It thus makes it difficult to define POAG by a simple cut-off IOP. Nevertheless it is clear from many epidemiological, clinical, histopathological, and experimental studies that IOP is a major and causal risk factor for glaucoma4,5 Eyes with ocular hypertension are at increased risk of POAG. The risk of developing POAG is up to six times higher in ocular hypertension than in those without any risk factors for glaucoma.6 The risk of developing POAG in ocular hypertension is 1–2% per year7,8 or about 10% per decade,9 and may be as high as 9.5% over 5 years based on Ocular Hypertension Treatment Study (OHTS) data.10 This risk rises with IOP, rising significantly at pressures over 24 mmHg, and especially over 30 mmHg.4,7,10–12 The entity NTG is prevalent in Japan and China, comprising over 80% of open-angle glaucoma.13,14 The matching prevalence in Western countries is about 30%.1,2,15 Because glaucoma cases in Western populations have traditionally been identified by elevated IOP and not by visual field or optic disc criteria, it is likely that NTG contributes to glaucoma under-diagnosis in these populations.1,2,16 Although NTG does not meet the cut-off criterion for ‘elevated IOP’, IOP is probably still too high in these eyes,13 for which reducing IOP can slow progression.17,18 Pathological IOP elevation in POAG is attributed to increased resistance to aqueous humor outflow.19 Cellular and molecular mechanisms influence the functioning of this pathway.20 An example is the mutated myocilin (or TIGR) gene found on chromosome 1 that is seen in some families with autosomal dominant juvenile-onset open-angle glaucoma and 3–4% of adult-onset POAG.21,22 Myocilin expression is induced by steroids21 and hydrostatic pressure,23 and mutation of the gene can affect myocilin expression in the trabecular meshwork.24 Other significant risk factors are age, genetic predisposition, positive family history, race and thin corneas, which can also cause IOP underestimation by Goldmann tonometry.10 IOP fluctuation itself is a risk factor for disease progression.25 IOP and aqueous outflow resistance increase with age.26 While the converse of an IOP decline with age is observed in the Japanese,27–29 their presentation with glaucoma is different as most develop NTG.13 IOP aside, the strongest independent risk factor for developing glaucoma is age, with subjects aged over 60 years seven times more likely to develop glaucoma than those aged less than 40 years.7 Glaucoma is more prevalent in those of Hispanic and African descent,16,30 with the latter typically younger and with higher IOP and more advanced optic neuropathy at initial diagnosis compared with whites. Their disease is also more refractory to treatment and has a worse prognosis.31 Myopia, diabetes, systemic hypertension, and vascular conditions such as migraine and vasospasm are also considered risk factors for POAG. Large epidemiological and randomized control studies from recent decades have yielded vital quantitative data on the link between risk factors and glaucoma.32 In the future such information may be useful for estimating the actuarial risk of glaucoma in individuals, providing an extra tool for case-finding, diagnosis, and treatment.33

DIAGNOSIS Diagnosing POAG requires evaluation of IOP, the anterior chamber angle (by gonioscopy), optic disc, and related structures such as the retinal nerve fiber layer and visual field.

A

NATURE OF PROGRESSIVE VISUAL LOSS Observing visual field change over time can inform on how POAG progresses. Progression may be considered in four phases: preperimetric (occult), threshold, critical,37 and compatible with blindness.

Pre-perimetric

Initially, disease is subclinical during a prolonged occult period in which white-on-white visual fields – the standard for diagnosis – remain normal. Any decreased visual sensitivity during this time is still too subtle to be detected by perimetry as for this to happen sensitivity must be decreased enough to consistently exceed the visual threshold of detection. Perimetric signs, if present, are non-specific and include blind spot change, isopter shrinkage on kinetic perimetry, and increased regional variability.38–40 However, other parameters of visual function such as sensitivity to contrast, colour (blue–yellow perimetry), motion and the spatial frequency doubling illusion (frequency doubling perimetry) may already be abnormal. Despite visual fields being well preserved, significant retinal ganglion cell loss, progressive disc cupping and retinal nerve fiber layer thinning may already be present.41–44

10.10 Primary Open-Angle Glaucoma

IOP has a normal diurnal variation that is more exaggerated with disease.34 IOP is usually measured by Goldmann applanation tonometry. In measuring IOP, clinicians should be aware of extremes of corneal thickness,35 wherein IOP is overestimated in thick corneas and underestimated in thin corneas, as Goldmann tonometry assumes a central corneal thickness of 550 µm. This is important to consider in individuals who have had laser refractive surgery, or carry a diagnosis of NTG or ocular hypertension.10 The optic disc is evaluated for glaucomatous cupping (see Figs 10-10-1–10-10-3). In practice, it can be difficult to separate normal from glaucomatous optic discs by appearance. This is because the range of normal disc morphology overlaps with that of glaucoma, especially with early disease.36 Optic disc stereophotography and retinal nerve fiber layer observation by red-free fundoscopy or photography are traditional methods for assessing structural abnormality or change, with disc photography still commonly used. Newer imaging technologies such as scanning laser tomography, scanning laser polarimetry and optical coherence tomography have special analytical algorithms to help identify glaucomatous morphology. How they should best be applied clinically is the subject of ongoing study. Evidence of reproducible visual field abnormality on standard ‘whiteon-white’ perimetry is enough to corroborate the suspicion of a glaucomatous-appearing optic disc. The visual field defect should correspond to the region of perceived optic disc abnormality. Although ‘white-on white’ visual field defects are not always the earliest sign of glaucoma, perimetry remains essential to diagnosing glaucoma.

Threshold and Conversion

‘Conversion’ refers to persistent visual field defects developing in previously normal visual fields. The term describes the appearance of visual

B

Fig. 10-10-1  Progressive glaucomatous optic neuropathy. (A) Glaucomatous optic disc; (B) the same optic disc 3 years later. There is increased cupping associated with localized rim thinning inferiorly and superiorly. Blood vessel deviation is present.

A

B

Fig. 10-10-2  Histopathologic correlation of glaucomatous optic disc cupping. (A) Normal human optic nerve with a small cup. Axons of the thick retinal nerve fiber layer turn posteriorly to form the neuroretinal rim of the optic disc. The lamina cribrosa of the anterior optic nerve lies horizontally in continuity with flanking sclera. (B) Glaucomatous optic nerve with a markedly thinned retinal nerve fiber layer and neuroretinal rim, large cup, and posteriorly bowed lamina cribrosa. (Photographs courtesy of Dr Morton E. Smith.)

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10 Glaucoma A

B

Fig. 10-10-3  Histopathology of human retina showing the effect of glaucoma. (A) Normal retina seen in cross-section. (B) Glaucomatous retina in which the retinal nerve fiber layer is thinned and ganglion cell bodies are more sparse. (Photographs courtesy of Dr Morton E. Smith.)

field abnormality over time in glaucoma suspects. Normal fields ‘convert’ when visual sensitivity in one or more regions decreases to persistently lie outside normal limits. This is often gradual, although these early visual field defects may appear transiently or abruptly because they are just at the threshold of detection.37 They may disappear after treatment, only to reappear later, and it could be years before they become consistently present. At conversion the earliest visual field defects involve small regions in the arcuate and central 30° of the visual field, and nasal steps.38,40 Inferior arcuate defects are mainly nasal, but superior arcuate defects are more central and nearer fixation. Conversion does not imply a sudden appearance of glaucoma but that previously pre-perimetric disease has worsened to become detectable.

Critical Phase

When the earliest consistent visual field defects appear, disease is no longer early as 30–50% of ganglion cells and axons may already be lost.37,41,42 Despite treatment many eyes may show visual deterioration. In unilateral glaucoma there is a 26% risk of visual field abnormality developing in the fellow eye within 5 years.45 Without adequate treatment the risk of vision deteriorating to cause functional impairment within a decade is significant.46,47 Scotomas frequently evolve by deepening, but enlarging arcuate defects and the appearance of new defects are also common.48 Change over time usually follows a linear or curvilinear course but it may also seem episodic and more step-wise. Bigger and denser scotomata tend to deteriorate faster.49 The upper and lower visual field hemispheres show differing susceptibilities to developing abnormality, but over a decade roughly a third of eyes with only one hemisphere affected initially will develop bi-hemispheric abnormality.37,48 Because upper hemispheric involvement tends to be more central,50 the visual impact of such abnormality is expected to be greater. Simultaneous bi-hemispheric involvement carries a poor prognosis; without adequate treatment up to half of these eyes will suffer absolute visual field loss over a decade.30

Blindness

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Blindness may occur despite treatment. Studies show the following: despite treatment the risk over 20 years of developing unilateral and bilateral blindness is 27% and 9% respectively;51 the cumulative rate of glaucoma blindness despite treatment is 19% over 22 years;52 despite IOP being controlled below 22 mmHg, the probability of retaining useful vision declined by 31% over 15 years, with half of visual disability attributable to glaucoma.47 This high incidence of blindness is seen in both developed and developing countries. Glaucoma affects between 60 and 70 million people worldwide and is the leading cause of irreversible blindness.53,54 Three-quarters of

people with glaucoma have the open-angle variant, of whom 10% are bilaterally blind.53 POAG is the most prevalent form of glaucoma in the United States, where glaucoma together with age-related macular degeneration and cataract are the leading causes of blindness. About 60% of blindness among African Americans is caused by glaucoma and cataracts.55 The prevalence of POAG in people in their 70s is about 5% in whites, 12% in African Americans, and 15% in Afro-Caribbeans and Latinos.1,2,16,30 This prevalence may even exceed 20% in those over 80 years of age.16,30 The prevalence of glaucoma blindness markedly increases with age. Glaucoma blindness is higher in African Americans than whites, with African Americans going blind 10 years earlier on average.56 In Stockholm, Sweden, glaucoma is at least partly responsible for 55% of bilateral blindness in low-vision clinics, with the prevalence of glaucoma-related blindness seven times higher in persons aged over 50 years than in all younger age groups combined.57 Sometimes severe visual impairment is already present at diagnosis. In the Olmstead County Community Study in Minnesota, over 10% of persons with POAG were already blind in both eyes at diagnosis with visual acuities worse than 20/200.46

TREATMENT AND MONITORING IOP is the only risk factor that can be manipulated to stop or slow glaucoma progression. Rigorous IOP-lowering can help control POAG.17,18,58–63 This is commonly achieved by medication, laser trabeculoplasty, surgery or, some combination thereof. Presently it is neither known how other risk factors influence the disease, nor how these risk factors may be altered. Ocular hypertensive patients at high risk of conversion may benefit from closer monitoring or treatment to modify risk.62 Clinicians are forced initially to guess a level of IOP – known as ‘target pressure’ – which will stop or slow further damage.61 Once target pressure is achieved, the level of IOP still needs to be monitored as it may change over time or not be low enough.63 Isolated clinic measurements do not necessarily predict the peak and range of IOP variation. The possibility of higher IOP may be verified by checking IOP at other times of the day, although this does not fully capture nocturnal variations, and there remains a need for new technologies to monitor IOP continuously. Treatment needs to be individualized as the IOP level needed to control disease varies widely between individuals. There is no universal formula to tell how much IOP needs to be reduced. Clinical judgment is needed, aided by reliable clinical measurements where available. Patients with moderate or advanced disease may benefit from earlier surgery and more aggressive IOP lowering.64 Lowering IOP has limits, however, as determined by treatment side-effects and possibility of hypotony, especially following surgery. The real guide for long-term clinical management is not IOP but the course taken by the optic neuropathy. It is standard practice to

that glaucoma treatments may cause symptoms whereas the disease may otherwise be asymptomatic. Older patients are especially susceptible to the systemic side-effects of glaucoma medications (e.g., betablockers). It is useful to involve patients’ families as supports where possible. Timely and effective treatment is critical to prevent visual disability from POAG. It is vital that the clinician develops some estimate of the rate of progression, its likely threat to central fixation, and lifetime risk of functional visual compromise. Factors that may influence prognosis such as race, age or family history ought to be taken into account, as should other issues common to chronic disease such as the co-existence Fig. 10-10-4  Longitudinal scanning laser tomography images of the optic nerve from an eye with moderately advanced progressive glaucoma. There is progressive neuroretinal rim loss over time in the superior and inferior poles of the disc so that the cup is enlarged vertically. Top row: topography images. Second row: the same images are color-coded to identify the neuroretinal rim (blue and green) and optic cup (red). Third and fourth rows: results of automated image analysis66 where only the parts of the rim (blue–green) and corresponding cup (red) with significant change are color-coded.

Fig. 10-10-5  Longitudinal scanning laser tomography images of the optic nerve from an eye with severe and progressive glaucoma. The neuroretinal rim, although already very thin, undergoes further detectable neural loss over time. Top row: topography images; middle row: the neuroretinal rim (blue–green) and cup (red); bottom row: regions of the superior rim (blue–green) and cup (red) with progressive change are color-coded following automated image analysis.66 Progressive rim loss is also seen inferiorly (analysis not shown).

10.10 Primary Open-Angle Glaucoma

sequentially examine the visual field and optic disc to ascertain progression. But reliably detecting progression using subjective and qualitative methods is not easy,65 especially when trying to identify smaller amounts of disease-induced change. It is important to determine if perceived change from testing is real and reproducible and not due to test variability. It is hoped that newer objective, quantitative, and potentially more reliable vision (e.g., multifocal VEP) and imaging tests (see examples in Figs 10-10-4, 10-10-5) will help in this regard. POAG is chronic, and patients are more likely to comply with treatments if they understand the nature of the disease and the need for ongoing treatment and monitoring. One reason for non-compliance is

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of other illness, life expectancy, quality of life, and the cost and sideeffects of long-term treatments.

Glaucoma

KEY REFERENCES AGIS Investigators AGIS 7: The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000;130:429–40. Drance SM. The early field defects in glaucoma. Invest Ophthalmol 1969;8:84–91. Gabelt BT, Kaufman PL. Changes in aqueous humor dynamics with age and glaucoma. Prog Retin Eye Res 2005;24:612–37. Hart WMJ, Becker B. The onset and evolution of glaucomatous visual field defects. Ophthalmology 1982;89:268–79. Heijl A, Leske MC, Bengtsson B, et al, Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268–79. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701–13.

Access the complete reference list online at

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Kerrigan-Baumrind LA, Quigley HA, Pease MM, et al. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 2000;41:741–8. Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma. Ophthalmology 1994;101:1651–7. Molteno AC, Bosma NJ, Kittleson JM. Otago glaucoma surgery outcome study: long-term results of trabeculectomy – 1976 to 1995. Ophthalmology 1999;106:1742–50. Pederson JE, Anderson DR. The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Ophthalmol 1980;98:490–5. Polansky JR, Fauss DJ, Chen P, et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica 1997;211:126–39. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262–7. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991;109:77–83. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090–5.

REFERENCES

2. Mitchell P, Smith W, Attebo K, et al. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:1661–9. 3. Leydhecker W, Al-Hamad A, Neuringer M. Der intraokulare Drucke gesunder menschicher Augen. Klin Monatsbl Augenheilkd 1958;133:662. 4. Wilson RM, Martone JF. Epidemiology of chronic open-angle glaucoma. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas. St Louis, MO: Mosby; 1996. p. 753–69. 5. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res 1999;18:39–57. 6. Leske MC, Connell AM, Wu SY, et al. Incidence of open-angle glaucoma: the Barbados Eye Studies. The Barbados Eye Studies Group. Arch Ophthalmol 2001;119:89–95. 7. Armaly MF, Krueger DE, Maunder L, et al. Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual-field defects. Arch Ophthalmol 1980;98:2163–71. 8. Kitazawa Y, Horie T, Aoki S, et al. Untreated ocular hypertension. A long-term prospective study. Arch Ophthalmol 1977;95:1180–4. 9. Quigley HA, Enger C, Katz J, et al. Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol 1994;112:644–9. 10. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714–20. 11. David R, Livingstone DG, Luntz MH. Ocular hypertension: a long-term follow-up of treated and untreated patients. Br J Ophthalmol 1977;61:668. 12. Hovding G, Aased H. Prognostic factors in the development of manifest open-angle glaucoma: a long-term follow-up study of hypertensive and normotensive eyes. Ophthalmologica 1986;64:601.

34. Liu JH, Kripke DF, Twa MD, et al. Twenty-four-hour pattern of intraocular pressure in the aging population. Invest Ophthalmol Vis Sci 1999;40:2912–17. 35. Shah S, Chatterjee A, Mathai M, et al. Relationship between corneal thickness and measured intraocular pressure in a general ophthalmology clinic. Ophthalmology 1999;106:2154–60. 36. Jonas JB, Budde WM, Panda-Jonas S. Ophthalmoscopic evaluation of the optic nerve head. Surv Ophthalmol 1999;43:293–320. 37. Hart WMJ, Becker B. The onset and evolution of glaucomatous visual field defects. Ophthalmology 1982;89:268–79. 38. Aulhorn E, Harms H. Early visual field defects in glaucoma. In: Glaucoma Symposium, Tutzing Castle, Basle, Switzerland. Basle: Karger; 1967. p. 151–86. 39. Werner EB, Drance SM. Increased scatter of responses as a precursor of visual field changes in glaucoma. Can J Ophthalmol 1977;12:140–2. 40. Drance SM. The early field defects in glaucoma. Invest Ophthalmol 1969;8:84–91. 41. Kerrigan-Baumrind LA, Quigley HA, Pease MM, et al. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci 2000;41:741–8. 42. Harweth RS, Carter-Dawson L, Shen F, et al. Ganglion cell losses underlying visual field defects from experimental glaucoma. Invest Ophthalmol Vis Sci 1999;40:2250. 43. Pederson JE, Anderson DR. The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Ophthalmol 1980;98:490–5. 44. Sommer A, Katz J, Quigley HA, et al. Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 1991;109:77–83. 45. Susanna R, Drance SM, Douglas GR. The visual prognosis of the fellow eye in uniocular chronic open-angle glaucoma. Br J Ophthalmol 1978;62:327–9.

13. Iwase A, Suzuki Y, Araie M, et al. The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 2004;111:1641–8.

46. Hattenhauer MG, Johnson DH, Ing HH, et al. The probability of blindness from open-angle glaucoma. Ophthalmology 1998;105:2099–104.

14. He M, Foster PJ, Ge J, et al. Prevalence and clinical characteristics of glaucoma in adult Chinese: a population-based study in Liwan district, Guangzhou. Invest Ophthalmol Vis Sci 2006;47:2782–8.

47. Molteno AC, Bosma NJ, Kittleson JM. Otago glaucoma surgery outcome study: long-term results of trabeculectomy – 1976 to 1995. Ophthalmology 1999;106:1742–50.

15. Hollows FC, Graham PA. Intraocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol 1966;50:570–86. 16. Varma R, Ying-Lai M, Francis BA, et al, Los Angeles Latino Eye Study Group. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology 2004;111:1439–48. 17. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 1998;126:487–97. 18. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998;126:498–505. 19. Gabelt BT, Kaufman PL. Production and flow of aqueous humor. In: Levin L, Nilsson SFE, Ver Hoeve J, et al, editors. Adler’s Physiology of the eye. London: Saunders; 2011. p. 274–307. 20. Tan JC, Peters DM, Kaufman PL. Recent developments in understanding the pathophysiology of elevated intraocular pressure. Curr Opin Ophthalmol 2006;17:168–74. 21. Polansky JR, Fauss DJ, Chen P, et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica 1997;211:126–39. 22. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science 1997;275:668–70. 23. Borrás T, Rowlette LL, Tamm ER, et al. Effects of elevated intraocular pressure on outflow facility and TIGR/MYOC expression in perfused human anterior segments. Invest Ophthalmol Vis Sci 2002;43:33–40. 24. Swiderski RE, Ross JL, Fingert JH, et al. Localization of MYOC transcripts in human eye and optic nerve by in situ hybridization. Invest Ophthalmol Vis Sci 2000;41:3420–8. 25. Karai A, Russell P, Stefani FH, et al. Localization of myocilin/trabecular meshwork-inducible glucocorticoid response protein in the human eye. Invest Ophthalmol Vis Sci 2000;41: 729–40. 26. Gabelt BT, Kaufman PL. Changes in aqueous humor dynamics with age and glaucoma. Progr Retin Eye Res 2005;24:612–37. 27. Nakano T, Tatemichi M, Miura Y, et al. Long-term physiologic changes of intraocular pressure: a 10-year longitudinal analysis in young and middle-aged Japanese men. Ophthalmology 2005;112:609–16. 28. Nomura H, Shimokata H, Ando F, et al. Age-related changes in intraocular pressure in a large Japanese population: a cross-sectional and longitudinal study. Ophthalmology 1999;106:2016–22. 29. Shiose Y. The aging effect on intraocular pressure in an apparently normal population. Arch Ophthalmol 1984;102:883–7. 30. Leske MC, Connell AM, Schachat AP, et al. The Barbados Eye Study. Prevalence of open angle glaucoma. Arch Ophthalmol 1994;112(6):821–9. 31. The Advanced Glaucoma Intervention Study (AGIS) 3. Baseline characteristics of black and white patients. Ophthalmology 1998;105:1137–45.

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33. Palmberg P. Answers from the ocular hypertension treatment study. Arch Ophthalmol 2002;120:829–30.

Primary Open-Angle Glaucoma

1. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991;109:1090–5.

32. Friedman DS, Wolfs RC, O’Colmain BJ, et al. Eye Diseases Prevalence Research Group. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 2004;122:532–8.

48. Mikelberg FS, Drance SM. The mode of progression of visual field defects in glaucoma. Am J Ophthalmol 1984;98:443–5. 49. Mikelberg FS, Schulzer M, Drance SM, et al. The rate of progression of scotomas in glaucoma. Am J Ophthalmol 1986;101:1–6. 50. Heijl A, Lundqvist L. The location of earliest glaucomatous visual field defects documented by automatic perimetry. In: Greve EL, Heijl EL, editors. Fifth International Visual Field Symposium. The Hague: Dr W Junk; 1983. p. 153–8. 51. Hattenhauer MG, Johnson DH, Ing HH, et al. The probability of blindness from open-angle glaucoma. Ophthalmology 1998;105:2099–104. 52. Kwon YH, Kim CS, Zimmerman MB, et al. Rate of visual field loss and long-term visual outcome in primary open-angle glaucoma. Am J Ophthalmol 2001;132:47–56. 53. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262–7. 54. Thylefors B, Negrel AD, Pararajasegaram R, et al. Global data on blindness. Bull World Health Org 1995;73:115–21. 55. The Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122:477–85. 56. Tielsch JM, Sommer A, Witt K, et al. Blindness and visual impairment in an American urban population. Arch Ophthalmol 1990;108:286–90. 57. Blomdahl S, Calissendorff BM, Tengroth B, et al. Blindness in glaucoma patients. Acta Ophthalmol Scand 1997;75:589–91. 58. AGIS Investigators AGIS 7: The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000;130:429–40. 59. Migdal C, Gregory W, Hitchings R. Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma. Ophthalmology 1994;101:1651–7. 60. Leske MC, Heijl A, Hyman L, et al. Factors for progression and glaucoma treatment: the Early Manifest Glaucoma Trial. Curr Opin Ophthalmol 2004;15:102–6. 61. Hitchings R, Tan J. Target pressure. J Glaucoma 2001;10:S68–70. 62. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701–13. 63. Heijl A, Leske MC, Bengtsson B; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268–79. 64. Musch DC, Gillespie BW, Niziol LM, et al, CIGTS Study Group. Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology 2011;118:1766–73. 65. Werner EB. In discussion of: Schulzer M, and the Normal Tension Glaucoma Study Group. Errors in the diagnosis of visual field progression in normal tension glaucoma. Ophthalmology 1994;101:1595. 66. Tan JC, Hitchings RA. Approach for identifying glaucomatous optic nerve progression by scanning laser tomography. Invest Ophthalmol Vis Sci 2003;44:2621–6.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Normal-Tension Glaucoma Deborah S. Kamal, Roger A. Hitchings

Definition: Variety of primary open-angle glaucoma that features an

intraocular pressure (IOP) within the normal range.

Key features ■ ■ ■ ■ ■

Intraocular pressure within the normal range Glaucomatous cupping Retinal nerve fiber type of visual field loss Open angles on gonioscopic examination No history of eye disease with raised intraocular pressure

Associated features ■

Peripheral vasospasm, as in Raynaud’s phenomenon Migraine ■ Optic disc hemorrhage ■

INTRODUCTION Chronic open-angle glaucoma typically is associated with an elevated intraocular pressure (IOP). Total population surveys show that 10−30% of patients newly diagnosed with glaucoma have IOPs that are and remain normal. The traditional therapy for primary open-angle glaucoma is to lower IOP to within the normal range, but this approach becomes more challenging when the initial IOP is within the normal range.

10.11

glaucoma (NTG). The appearance of the optic disc and the visual field defect can be identical. However, some differences can occur. Patients who have NTG are, on average, 10 years older than those who have high-tension glaucoma, and their optic discs are more likely to show focal notching and optic disc hemorrhages. The visual field is more likely to show defects close to fixation.7 Familial tendency occurs, and it has been reported that women are affected twice as frequently as men.8 The IOP may be slightly higher in the more severely affected eye, although the difference may only be 1–2 mmHg.9,10 In genetic studies, families with OPA-1 polymorphism and optineurin (OPTN) mutation have been reported.11–13 Long-term follow-up suggests that, although most patients maintain the same IOP over many years, approximately 8% show a trend toward higher IOPs.14 Two reviews of the untreated condition exist. Both suggest that over a period of 4–5 years, up to 50% of patients will not show demonstrable progression.15,16

DIAGNOSIS Confirmation of the diagnosis requires: Repetitive IOP measurements (diurnal phasing), to establish the height and range of the IOP and to establish a target range for IOP reduction. Confirmation of glaucomatous cupping, rather than a ‘suspicious’ appearance to the optic disc (Fig. 10-11-1). Objective optic disc analysis may also be helpful in this respect. Central corneal thickness may be an independent risk factor for severity of disease.17 Exclusion of other causes of optic disc changes and risk factors for previous ocular hypertension.

• • • •

EPIDEMIOLOGY AND PATHOGENESIS Total population surveys in Europe, North America, and Australia reveal open-angle glaucoma with normal IOPs in 10–30% of the population surveyed.1,2 Interestingly, in Japan, where the upper limit of normal IOP is approximately 18 mmHg (2.4k Pa), up to 90% of patients affected by open-angle glaucoma have baseline IOPs below this level.3 The pathogenesis of the condition remains unclear. Progressive optic neuropathy with a normal IOP suggests an underlying vascular insufficiency. The association with peripheral vasospasm, migraine, and recurrent optic disc hemorrhages supports this hypothesis. For some patients (and normal individuals) in whom ambulatory blood pressure has been monitored, the nocturnal blood pressure falls dramatically, 80/40 mmHg (10.6/5.3 kPa) being not uncommon.4,5 Such nocturnal ‘dips’ may lower pulse pressure at the optic disc if no commensurate fall in IOP occurs. Sleep apnoea has been found in a proportion of such patients and it may precipitate the condition. The most effective management has been to lower IOP. The mechanical support given by the lamina cribrosa may be insufficient, and the quality (type) of the collagen may be deficient with an increased vulnerability to IOPs even in the mid teens.6

H

OCULAR MANIFESTATIONS No characteristic features exist, other than level of IOP that consistently differentiates high-tension glaucoma from normal-tension

Fig. 10-11-1  Optic disc of a patient who has normal-tension glaucoma. Note disc hemorrhage (H).

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BOX 10-11-1 DIFFERENTIAL DIAGNOSIS OF NORMALTENSION GLAUCOMA

Glaucoma

• • ••

High-tension primary open-angle glaucoma with episodic ‘normal intraocular pressure’ Secondary open-angle glaucoma from previous elevated intraocular pressure Non-glaucomatous optic neuropathy Other lesions that affect the visual pathways

onfirmation that the visual field defect is of the retinal nerve fiber • Clayer type and corresponds with the location of changes at the neu-

roretinal rim. The identification of additional vascular factors may also be helpful: Ambulatory blood pressure monitoring to identify ‘nocturnal dips.’ Careful history-taking of vasospastic disorders and antihypertensive medications. The possibility of a retro-ocular lesion must be ruled out. A brain scan and other neurological investigations are indicated if any disparity arises between the optic disc appearance and the visual field defect. However, routine neurological investigation is not indicated on all NTG patients. In glaucoma, a close association is found between glaucomatous cupping and the visual field defect. Atrophy greater than the field loss suggests anterior ischemic optic neuropathy, or intracranial disease affecting the visual pathways.18 Visual field defects that respect a vertical meridian and central (rather than paracentral and arcuate) field defects indicate the need for neurological investigation.

• •

DIFFERENTIAL DIAGNOSIS The differential diagnosis of NTG is summarized in Box 10-11-1. High-tension, primary open-angle glaucoma that has episodic normal IOP is a theoretical concept in which wide diurnal fluctuations ‘hide’ elevated IOPs that induce damage. In secondary open-angle glaucoma, a normal IOP is present after a previous hypertensive episode sufficient to produce glaucomatous cupping (e.g., corticosteroid-induced glaucoma, hypertensive uveitis). Any young patient who has glaucoma and a history of external eye disease must be questioned closely about topical corticosteroid medication use. In non-glaucomatous optic neuropathy, the IOP, visual field, and the age of the patient are similar to those in the patient with glaucoma. The optic disc does not show glaucomatous cupping, but rather a flat optic atrophy in which the area of atrophy exceeds the extent of the visual field defect (disc-field disparity). When extensive neuronal loss has occurred, the optic disc may develop a massive enlargement of the optic cup with pallor of the remaining rim. The condition does not progress. Other lesions that affect the visual pathways include lesions of the optic chiasm and visual pathways, back to the occipital cortex, which produce visual field defects that respect the vertical meridian. In time, such lesions also produce optic atrophy without glaucomatous cupping.

SYSTEMIC ASSOCIATIONS No systemic diseases are directly associated with NTG. The association with peripheral and perhaps central (ocular) vasospasm, migraine, and Raynaud’s phenomenon suggests a vascular predisposition to the condition in some patients.19,20 MRI scans reveal the presence of white matter lesions (WMLs) in the deep cerebral cortex of patients with NTG, suggesting ‘small vessel disease.’ These were associated in a Japanese study with a tendency for more inferior visual field defects.21 There is no clear evidence as yet for any link between NTG and other neurodegenerative disease such as Alzheimer’s dementia.

TREATMENT 1058

Treatment is indicated for patients with progressive disease, although the rate of progression can be highly variable. Therefore,

many clinicians may wish to treat confirmed NTG before progression is confirmed, particularly in high-risk groups. However, many patients are elderly at diagnosis and have a sufficiently slow rate of change that, even without treatment, clinically significant loss of vision does not occur.15 Significant visual loss may cause social restriction, such as the loss of a driving license, and drivers should be aware of their responsibility to inform the licensing authorities of their diagnosis. Trend or event analysis that uses commercially available software will identify progression. Cluster or point-wise analysis is more likely to identify progression than analyses that rely on the identification of a global change. Care must be taken to differentiate between long-term fluctuations and true change before any therapeutic decisions are made. Management is largely directed toward the implementation of a lower IOP, with attention to the correction of reversible possible circulatory deficiencies at the optic nerve.

Lower Intraocular Pressure

Studies suggest that a reduction in IOP may exert a beneficial effect on the course of the disease.22–25 A 25–30% fall is required, best achieved by a combination of topical prostaglandins26 and adjunctive carbonic anhydrase inhibitors or beta-blockers. In a recent large randomized treatment trial for normal pressure glaucoma, patients treated with brimonidine showed less visual field progression than those on a twicedaily regime of timolol.27 The use of topical beta-blockers at night should be avoided, particularly in blood pressure dippers, but morningonly doses of low dose formulations may be effective in lowering IOP where the choice of therapeutic agents is limited. Potential neuroprotective effects of topical agents remain unproven. Filtration surgery is recommended if sufficient IOP reduction is not achieved medically. The success of surgery has been shown to be enhanced by the use of perioperative antimetabolites including 5-fluorouracil and more recently mitomycin C. If treatment does not achieve this 25–30% fall, the rate of change is likely to remain unaltered.28,29

Reversal of Circulatory Deficiencies at the Optic Nerve Head Vasospasm

The possible benefits of systemic calcium-channel blockers remain controversial but may be useful in those patients with continued progression despite adequate IOP lowering, particularly where a change in antihypertensives may be indicated.

Nocturnal hypotension

Patients who take drugs to lower blood pressure (especially betablockers) and some patients who have NTG exhibit an excessive fall in systolic and diastolic blood pressures while asleep (dips). Such changes may reduce ocular perfusion pressure unless the IOP also falls. A change to the antihypertensive medication or regime should be considered. Otherwise, IOP lowering, particularly during the early hours, may be beneficial in the ‘dipper’ group, either by bed-time administration of prostaglandin analogs or by filtration surgery.

Monitoring for Progression

The younger the patient at diagnosis, the greater is the possibility of clinically significant visual loss in their lifetime. It is important for these patients to be ‘trained’ early in the management of their disease to become reliable performers with threshold perimetry. All patients require repeat visual field testing to identify progression and, within reason, the more frequently the field test is repeated, the better. Perimetry 3–4 times a year gives a better chance of identifying change, and will do so considerably earlier than field testing once or twice a year. Longitudinal analysis of sequential Heidelberg Retina Tomograph images30 may also be helpful, usually using commercially available software.

Therapeutic Intervention

Medical management to lower IOP that fails to maintain a 25% reduction is unlikely to affect the course of the disease. A trial of medical management may be justified in patients with progressive disease, but failure to achieve this reduction should mean a recommendation for fistulizing surgery, rather than waiting for further progression to occur.

COURSE AND OUTCOME Many patients are in their seventh and eighth decade of life at diagnosis and, with slow disease progression, they do not notice any visual change. Progression for other patients is more rapid, and they can suffer severe visual loss. No progression has been seen in some patients monitored for 10 years or more by the authors, while other patients have demonstrated rates of loss at individual retinal locations of up to and exceeding 5 db per year. The identification of change, either by the patient’s symptoms or by visual performance, is an indication that IOP must be lowered by 25% or more. To maintain this reduction in IOP for the necessary decades may be difficult, but if this is not carried out the visual loss may be slowed only and not halted. To date, the only approach shown to significantly affect the course of the disease is lowering of IOP by at least 25–30% and this remains our major challenge.

KEY REFERENCES Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 1998;126:487–97. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998;126: 498–505. Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:699–708. Haefliger IO, Hitchings RA. Relationship between asymmetry of visual field defects and intraocular pressure difference in an untreated normal (low) tension glaucoma population. Acta Ophthalmol (Copenh) 1990;68:564–7. Iwase A, Suzuki Y, Araie M, et al, Tajimi Study Group, Japan Glaucoma Society. The prevalence of primary open angle glaucoma in Japanese: the Tajimi Study. Ophthalmolog 2004;111: 1641–8. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992;99:1499–504.

10.11 Normal-Tension Glaucoma

Glaucoma surgery designed to lower IOP safely by 30% from a starting level of, say, 17 mmHg can be challenging. The often asymptomatic patient may become one with symptoms of fluctuating and progressively deteriorating sight due to cataract or less commonly hypotonous sequelae.24,29 It is essential, therefore, to have identified progressive disease correctly and to have discussed with patients the effect of their rate of visual loss on their vision before asking them to undergo filtering surgery. The risk of loss of sight due to irreversible visual field damage must be balanced against the relatively lower risks of surgical complications.

Krupin T, Liebmann JM, Greenfield DS, et al. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. [Erratum appears in Am J Ophthalmol 2011;151:1108]. Am J Ophthalmol 2011;151: 671–81. Membrey WL, Poinoosawmy DP, Bunce C, et al. Comparison of visual field progression in patients with normal pressure glaucoma between eyes with and without visual field loss that threatens fixation. Br J Ophthalmol 2000;84:1154–8. Membrey WL, Poinoosawmy DP, Bunce C, et al. Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 Intraocular pressure control and complications. Br J Ophthalmol 2000;84:586–90. Rezai T, Aung T, Okada K, et al. The phenotype of normal tension glaucoma patients with and without OPA1 polymorphisms. Br J Ophthalmol 2003;87:145–52.

Access the complete reference list online at

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REFERENCES 1. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992;99:1499–504.

3. Iwase A, Suzuki Y, Araie M, et al, Tajimi Study Group, Japan Glaucoma Society. The prevalence of primary open angle glaucoma in Japanese: the Tajimi Study. Ophthalmolog 2004;111:1641–8. 4. Graham SL, Drance SM, Wijsman K, et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. Ophthalmology 1995;102:61–9. 5. Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117:603–24. 6. Dandona L, Quigley HA, Brown AE, et al. Quantitative regional structure of the normal human lamina cribrosa. A racial comparison. Arch Ophthalmol 1990;108:393–8. 7. Geijssen HC. Studies on normal pressure glaucoma. Amsterdam: Kugler Publications; 1991.

18. Ahmed II, Feldman F, Kucharczyk W, et al. Neuroradiologic screening in normal-pressure glaucoma: study results and literature review. J Glaucoma 2002;11:279–86. 19. Corbett JJ, Phelps CD, Eslinger P, et al. The neurologic evaluation of patients with lowtension glaucoma. Invest Ophthalmol Vis Sci 1985;26:1101–4. 20. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case–control study. Invest Ophthalmol Vis Sci 1985;26:1105–8. 21. Suzuki A, Tomidokoro J, Araie M, et al. Visual field damage in normal-tension glaucoma patients with or without ischemic changes in cerebral magnetic resonance imaging. Jpn J Ophthalmol 2004;48:340–4. 22. Bhandari A, Crabb DP, Poinoosawmy D, et al. Effect of surgery on visual field progression in normal-tension glaucoma. Ophthalmology 1997;104:1131–7. 23. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 1998;126:498–505.

8. Poinoosawmy D, Fontana L, Hitchings RA. Asymmetric field defects in normal tension glaucoma. Ophthalmology 1998;105:988–91.

24. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol 1998;126:487–97.

9. Haefliger IO, Hitchings RA. Relationship between asymmetry of visual field defects and intraocular pressure difference in an untreated normal (low) tension glaucoma population. Acta Ophthalmol (Copenh) 1990;68:564–7.

25. Koseki N, Araie M, Shirato S, et al. Effect of trabeculectomy on visual field performance in central 30 degrees field in progressive normal-tension glaucoma. Ophthalmology 1997;104:197–201.

10. Crichton A, Drance SM, Douglas GR, et al. Unequal intraocular pressure and its relation to asymmetric visual field defects in low-tension glaucoma. Ophthalmology 1989;96:1312–4. 11. Rezai T, Aung T, Okada K, et al. The phenotype of normal tension glaucoma patients with and without OPA1 polymorphisms. Br J Ophthalmol 2003;87:145–52.2. 12. Aung T, Rezai T, Okada M, et al. Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene. Invest Ophthalmol Vis Sci 2005;46:2816–22. 13. Rezai T, Child AH, Hitchings RA. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;295:1077–9. 14. Membrey WL, Poinoosawmy DP, Bunce C, et al. Comparison of visual field progression in patients with normal pressure glaucoma between eyes with and without visual field loss that threatens fixation. Br J Ophthalmol 2000;84:1154–8. 15. Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:699–708. 16. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003;121:48–56.

10.11 Normal-Tension Glaucoma

2. Mitchell P, Smith W, Attebo K, et al. Prevalence of open angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103:1661–9.

17. Kurtz S, Haber I, Kesler A. Corneal thickness measurements in normal-tension glaucoma workups: is it worth the effort? J Glaucoma 2010;19:58–60.

26. Greve EL, Rulo AH, Drance SM, et al. Reduced intraocular pressure and increased ocular perfusion pressure in normal tension glaucoma: a review of short-term studies with three dose regimens of latanoprost treatment. Surv Ophthalmol 1997;41(Suppl 2):S89–92. 27. Krupin T, Liebmann JM, Greenfield DS, et al. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. [Erratum appears in Am J Ophthalmol 2011;151:1108]. Am J Ophthalmol 2011;151:671–81. 28. Membrey WL, Poinoosawmy DP, Bunce C, et al. Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 Intraocular pressure control and complications. Br J Ophthalmol 2000;84:586–90. 29. Jongsareejit B, Tomidokoro A, Mimura T, et al. Efficacy and complications after trabeculectomy with mitomycin C in normal-tension glaucoma. Jpn J Ophthalmol 2005;49:223–7. 30. Chauhan BC, Nicolela MT, Artes PH. Incidence and rates of visual field progression after longitudinally measured optic disc change in glaucoma. Ophthalmology 2009;116:2110–8.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Angle-Closure Glaucoma Jovina L.S. See, Maria Cecilia D. Aquino, Paul T.K. Chew

Definition: A group of glaucomas characterized by elevated

intraocular pressure (IOP) as a result of mechanical obstruction of the trabecular meshwork by either apposition of the peripheral iris to the trabecular meshwork or by synechial angle closure.

Key features ■

May be acute, subacute, or chronic. Acute angle closure may result in sudden pain, blurred vision, photophobia, colored halos around lights, ocular injection, headache, nausea, and vomiting. ■ Subacute angle closure may be symptomatic with headaches, often mistaken for migraine by both patient and non-ophthalmic physician, or asymptomatic. ■ Chronic angle closure is generally asymptomatic and often misdiagnosed as primary open-angle glaucoma. ■

INTRODUCTION Angle-closure glaucoma (ACG) was probably the first glaucoma to be recognized, when St Yves, in 1722, described its symptoms, signs, and prognosis. It was not until 1923, however, when Raeder proposed that glaucoma be classified into two main types, one with a shallow anterior chamber and the other with a normal or deep chamber, that ACG was distinguished from open-angle glaucoma (OAG). Population-based surveys of the prevalence of eye diseases in Europe1 and the United States2–4 suggest a much greater rate of OAG compared to ACG. Hence, little was published about the epidemiology of ACG, until recent epidemiologic studies in Asia reported that Eskimos,5,6 Mongolians,7 and Chinese8,9 had significantly higher rates of ACG. It is now confirmed that not only is ACG more common than originally thought, but also it is associated with a much higher visual morbidity than OAG. ACG, if recognized and treated early, results in a good visual prognosis. Visual morbidity can be prevented if ACG is detected early; hence, early detection is key.

EPIDEMIOLOGY AND PATHOGENESIS Prevalence

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The prevalence of primary angle-closure glaucoma (PACG) in whites is reported to be 0.6% in Italy and 0.5% in Wales10 in the 40-plus age group, and 0.1% in the 55-plus age group in Sweden.11 The prevalence in Eskimos is some 20–40 times higher.5,6,12,13 The prevalence in East Asia and Southeast Asia has been reported to range from 1.4% to 4.3%, depending on the age group.7,9,14 Recent estimates based on various population-based studies of the prevalence of ACG suggest that in 2010 approximately 60.5 million people were affected by glaucoma (44.7 million with OAG and 15.7 million with ACG). This number is projected to increase to 79.6 million by 2020.15 Of these, 26% will have ACG. The prevalence of ACG in 2010 among those aged 40 years and older was estimated to be 1.26% in China and 1.20% in Southeast Asia, compared to 0.25% in Europe and 0.16% in Africa. Given the high prevalence of ACG in

10.12

Asia,16,17 Asians are predicted to represent 87% of those with ACG. Women will comprise 69.5% of cases of ACG, due to the higher prevalence of the disease in women,18 as well as their greater longevity. The World Health Organization currently ranks glaucoma as the second most common cause of blindness.19 By 2010, bilateral blindness was estimated to be present in 3.9 million people with ACG. This is estimated to rise to 5.3 million people in 2020. The number of people blinded by ACG is nearly equal to the number blinded by OAG because of the higher morbidity of the former disease.

Incidence

The incidence of acute PACG varies widely among different ethnic groups, from 4.7 (per 100 000 per year in the population aged 30 years and older) in Finland20 to 11.4 in Japan21 and 12.2 in Singapore.18

Risk Factors

1. Demographic factors: a. Age (> 60 years old) b. Female sex c. Chinese ethnic origin22 d. Family history (especially first-degree relatives, because ocular anatomic features are inherited) 2. Anatomic factors:23–27 a. Shallow anterior chamber depth, especially peripherally b. Thick/anteriorly positioned/increased anterior curvature of lens c. Short axial length d. Small diameter/increased curvature of cornea e. Plateau iris configuration/thick peripheral iris roll 3. Precipitating factors: a. Dim illumination (including extremes of temperature causing people to stay indoors)18,28–30 b. Drugs i. Anticholinergic agents [topical, e.g., atropine, cyclopentolate, and tropicamide; or systemic, e.g., antihistamine, antipsychotic (especially antidepressants), anti-parkinsonian, atropine, and gastrointestinal spasmolytic drugs] ii. Adrenergic agents (topical, e.g., epinephrine and pheny­ lephrine, or systemic, e.g., vasoconstrictors, central nervous system stimulants, bronchodilators, appetite depressants, and hallucinogenic agents) c. Emotional stress, excruciating pain (possibly due to mydriasis secondary to increased sympathetic tone) ACG may be broadly subdivided into: 1. Primary ACG: no cause other than anatomic predisposition is identified. 2. Secondary ACG: angle closure is the result of a specific pathologic condition that may arise in any part of the eye, e.g., neovascular glaucoma and anterior uveitis. The traditional classification of ACG (Box 10-12-1) evolved from clinical observations and is based on symptoms that are subjective and may be highly variable. The lack of standardization and the frequent overlap in clinical presentation make it difficult for comparison in epidemiologic studies. Furthermore, this form of classification does not offer any insight as to the natural history of the disease, or the presence or absence of glaucomatous optic neuropathy and is therefore not useful for visual prognostication. Hence, the International Society of Ophthalmic Epidemiology developed a classification that is based on the natural history of the disease (Box 10-12-2).31

BOX 10-12-3 CLASSIFICATION BASED ON ANATOMIC LEVELS OF OBSTRUCTION TO AQUEOUS FLOW (PATHOPHYSIOLOGY OF ANGLE-CLOSURE GLAUCOMA)

Acute Sudden onset of IOP elevation resulting from total angle closure, accompanied by symptoms of severe, usually unilateral, ocular pain, red eye, blurred vision, halos, headache (ipsilateral frontal), nausea, and vomiting

Apposition of the iris to the trabecular meshwork in angle-closure glaucoma may be due to forces acting at four anatomic levels:

•

Subacute/Intermittent An episode of sudden IOP elevation that is spontaneously aborted, so that symptoms are mild or even absent. Such subacute IOP elevations may be recurrent and therefore termed ‘intermittent angle closure.’ Intermittent episodes can result in progressive PAS formation.

•

Chronic Chronic IOP elevation due to the presence of PAS that permanently close the anterior chamber angle. Symptoms are usually absent. Creeping angle closure refers to chronic closure of angle where the root of the iris slowly creeps, or is pushed, into the depths of the narrow angle until it gradually smothers the outflow channels.23

•

Latent Evidence that an open but narrow angle can and does close under certain circumstances. Asymptomatic, but PAS is often found on gonioscopy.

•

IOP, intraocular pressure; PAS, peripheral anterior synechiae.

BOX 10-12-2 CLASSIFICATION BASED ON NATURAL HISTORY Primary Angle-Closure Suspect (PACS) An eye in which appositional contact between the peripheral iris and posterior trabecular meshwork is present or considered possible, in the absence of elevated IOP, PAS, disc, or VF changes. Epidemiologically, this has been defined as an angle in which 180−270° of the posterior trabecular meshwork cannot be seen gonioscopically.

•

Primary Angle Closure (PAC) PACS with statistically raised IOP and/or primary PAS, without disc or VF changes.

•

Primary Angle-Closure Glaucoma (PACG) PAC with glaucomatous optic neuropathy and corresponding VF loss.

•

IOP, intraocular pressure; PAS, peripheral anterior synechiae; VF, visual field.

Adapted from Foster PJ, Buhrmann RR, Quigley HA, et al. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002;86:238–42.

This classification is evidence-based and is therefore more objective. These definitions have been widely used in the classification of subjects in research, and have been adopted in the Asia Pacific Glaucoma Guidelines. However, it does not identify the pathophysiologic mechanism that is responsible for angle closure, and hence does not facilitate the clinician in choosing an appropriate treatment. A classification devised by Ritch and colleagues32 is useful for this purpose and should be used in parallel (Box 10-12-3; Figs 10-12-1–10-12-7).

Pupillary Block

Pupillary block represents the most common mechanism underlying angle closure. In pupillary block, iridolenticular contact at the pupil limits the flow of aqueous from its site of production at the nonpigmented ciliary epithelium to the anterior chamber, resulting in a pressure gradient between the posterior and anterior chambers that further pushes the iris anteriorly. Anterior bowing of the peripheral iris narrows the angle and may then cause iridotrabecular apposition and angle closure. Laser iridectomy re-establishes aqueous flow from the posterior to the anterior chamber and relieves the pressure gradient, thereby allowing the iris to flatten and the angle to widen.

Iris Pupillary block (Fig. 10-12-1) *Non-pupillary block/angle crowding mechanisms, e.g., thick peripheral iris roll (see Fig. 10-12-2) Contraction of fibrovascular membrane in neovascular glaucoma Contraction of fibrin in angle secondary to anterior uveitis or hyphema Endothelial proliferation (iridocorneoendothelial syndromes) Epithelial downgrowth

•• •• •• • •

Ciliary Body Plateau iris configuration (forward rotation of the ciliary body or anterior position of ciliary processes) (see Fig. 10-12-3) Iridociliary cysts (pseudoplateau iris) (see Fig. 10-12-4)

10.12 Angle-Closure Glaucoma

BOX 10-12-1 TRADITIONAL CLASSIFICATION OF ANGLECLOSURE GLAUCOMA (BASED ON CLINICAL PRESENTATION AND SYMPTOMATOLOGY)

Lens Phacomorphic glaucoma (thick lens) (see Fig. 10-12-5) Phakotopic glaucoma (anteriorly positioned lens) Subluxed lens (e.g., pseudoexfoliation syndrome, traumatic) (see Fig. 10-12-6) Vectors Posterior to Lens Aqueous misdirection (malignant glaucoma) (see Fig. 10-12-7) Serous or hemorrhagic choroidal detachment or effusion Space-occupying lesion (gas bubble, vitreous substitutes, tumor) Retrolenticular tissue contracture (retinopathy of prematurity, persistent hyperplastic primary vitreous)

•• ••

Secondary causes of angle closure are shown in italics. *Non-pupillary block/angle crowding mechanisms have been included here as an addition to Ritch’s classification.

Non-Pupillary Block Mechanisms

The variable efficacy of laser iridectomy in many cases of angle closure as well as ultrasound biomicroscopy imaging suggests that pupillary block may not be the only mechanism responsible. The role of angle crowding, for example that caused by a thick peripheral iris roll, has been increasingly recognized in many cases of angle closure. This has been added to Ritch’s classification, for the sake of completeness. In many such cases, the peripheral iris stroma is thick. Upon pupil dilatation, the peripheral iris bunches up. If the angle is already narrow, this thick peripheral iris roll may become apposed to the trabecular meshwork and result in angle closure.

Plateau Iris Configuration

On gonioscopy, the iris assumes a steep approach at its insertion before flattening centrally. The peripheral iris is forced into the angle by anterior rotation of the ciliary body or anteriorly positioned ciliary processes. The development of angle closure either spontaneously or after pupil dilatation in an eye with plateau iris configuration, in the presence of a patent laser iridectomy, is termed ‘plateau iris syndrome.’ Disorders of the ciliary body, such as iridociliary cysts or tumors, may result in a similar plateau iris configuration. This is termed ‘pseudoplateau iris.’

Aqueous Misdirection

This condition, also called malignant glaucoma or ciliary block glaucoma, is characterized by shallowing or flattening of the anterior chamber, accompanied by a rise in intraocular pressure (IOP). It is typically seen in the postoperative period, but can arise spontaneously. It is believed that aqueous passes posteriorly to the posterior segment instead of anteriorly to the posterior chamber, due to obstruction to flow caused by the anterior rotation of ciliary processes resulting in their apposition to the lens equator in the phakic eye, or against the anterior hyaloid in the aphakic eye. The accumulation of aqueous in the posterior segment causes an anterior displacement of the lens−iris diaphragm. Laxity of the lens zonules allowing this forward movement has also been suggested to play a role in the development of this condition.

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10 Glaucoma A

B

C Fig. 10-12-1  Pupillary block. (A) Photograph of eye with pupillary block. (B) Anterior segment optical coherence tomography image. (C) Ultrasound biomicroscopy image.

A

B Fig. 10-12-2  Peripheral iris roll. Anterior segment optical coherence tomography images of the same eye taken in (A) light and (B) dark conditions.

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Fig. 10-12-3  Plateau iris configuration. Ultrasound biomicroscopy image.

10.12 Angle-Closure Glaucoma

A A

B B Fig. 10-12-4  Iridociliary cysts. (A) Ultrasound biomicroscopy image. (B) Anterior segment optical coherence tomography image (arrowhead).

Fig. 10-12-5  Phacomorphic glaucoma.

Fig. 10-12-7  Malignant glaucoma. (A) Ultrasound biomicroscopy image. (B) Anterior segment optical coherence tomography image.

The term ‘malignant’ was used originally to describe its poor response to conventional miotic treatment. Early recognition of aqueous misdirection is important in reducing its morbidity. Management involves prompt medical treatment with topical cycloplegic agents such as atropine, which increases zonular tension and pulls the lens posteriorly. Atropine 1% may be given 2–4 times a day for weeks to months or even years. Topical beta-blockers, alpha-2-agonists, and carbonic anhydrase inhibitors may be used to decrease aqueous production and lower the IOP. Hyperosmotic agents may also be used to decrease the vitreous volume. If the condition persists beyond 5 days despite adequate medical therapy, laser or surgical intervention must be considered. Neodymium : yttrium−aluminum−garnet (Nd : YAG) laser has been demonstrated to be effective in the pseudophakic and aphakic eye by disrupting the anterior hyaloid face, especially peripherally. Aspiration of the anterior vitreous, anterior pars plana vitrectomy, or lens extraction with a posterior capsulotomy may be performed; however, disruption of the hyaloid face is key to the success of this procedure. A prophylactic laser iridectomy should also be considered for the fellow eye, as there is a significant risk that aqueous misdirection may occur following intraocular surgery in that eye.

DIAGNOSIS External Examination

The majority of people with PACG do not experience any symptoms.3,7 Characteristic findings in a patient presenting during an acute angleclosure attack include conjunctival hyperemia, a hazy cornea with corresponding decreased visual acuity (Fig. 10-12-8), and a mid-dilated nonreactive or sluggish pupil. The pupil is mid-dilated due to ischemic paralysis of the iris sphincter muscles as a result of the greatly elevated IOP. If these muscles infarct, the pupil does not return to its normal appearance even when the IOP has been lowered, and iris whorling may become evident. Digital palpation of the eye through a closed eyelid reveals a firm (often rock-hard) eye. The patient may also experience bradycardia or arrhythmia.

Penlight Examination Fig. 10-12-6  Anteriorly subluxed lens.

When a slit lamp or goniolens is unavailable, a penlight may be used to estimate the anterior chamber depth. This test is performed by shining the penlight from the temporal side of the eye. A flat iris with a deep anterior chamber would allow the nasal iris to be illuminated,

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10 Glaucoma Fig. 10-12-8  Acute angle-closure glaucoma.

Fig. 10-12-10  Glaucomflecken.

Fig. 10-12-9  Iris whorling and atrophy.

while an iris that is convex with a correspondingly shallow anterior chamber would block the illumination, causing the nasal iris to be in shadow.

Slit-Lamp Examination

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In acute angle closure, the cornea usually appears hazy due to epithelial and stromal edema secondary to the acute rise in IOP with mid-dilated pupil and peripherally shallow anterior chamber. Iris bombé is usually present due to pupillary block. Iris whorling (sectoral infarction of the iris sphincter leading to torsion of the iris), patchy iris stromal atrophy (Fig. 10-12-9), and lens glaucomflecken (Fig. 10-12-10) (small gray−white anterior subcapsular or capsular opacities in the pupillary zone, due to infarction of lens fibers) may also be evident if the patient has had an acute rise in IOP previously. Both central and peripheral anterior chamber depth (ACD) may be assessed at the slit lamp. While the central ACD only weakly correlates with the angle width,33 peripheral ACD estimation appears to perform well in the detection of occludable angles.34 The van Herick technique35 (Fig. 10-12-11) is useful for estimating the peripheral ACD. In this technique, the illumination column is offset from the axis of the microscope by 60°. The brightest, narrowest possible vertical beam of light is directed at the temporal limbus, perpendicular to the ocular surface. Viewed from the nasal aspect, the peripheral ACD is compared to the adjacent corneal thickness that is illuminated by the light beam. The angle may be occludable if the peripheral ACD is less than one-fourth of the corneal thickness. The limbal chamber depth method of grading the peripheral anterior chamber is a recent modification of the van Herick test.36 Instead of the four grades used in the van Herick method, it has seven grades that are expressed as a percentage fraction of the thickness of the adjacent cornea: 0%, 5%, 15%, 25%, 40%, 75%, and

Fig. 10-12-11  Van Herick technique.

100%. The limbal chamber depth method has been demonstrated to perform better in the detection of established PACG and is now widely used in epidemiologic research. Slit-lamp examination should also include a thorough check for the presence of any inflammation, hyphema, and cataract or subluxed lens. IOP is often severely elevated (often > 40 mmHg). Careful examination of the optic disc should also be performed in order to detect any evidence of glaucomatous optic neuropathy.

Gonioscopy

Careful gonioscopic examination of the angle is vital to make the diagnosis of angle closure. This is best performed using first a two-mirror goniolens (e.g., Goldmann) to avoid artifactual distortion of the angle caused by inadvertent pressure on the cornea, followed by a four-mirror goniolens (e.g., Sussman, Zeiss) that allows indentation gonioscopy to reveal whether any closure is due to peripheral anterior synechiae (PAS) or is merely appositional. Gonioscopy should be performed in a dark room using a 1 mm light beam reduced to a very narrow slit, and care should be taken to avoid any light falling on the pupil, which might otherwise cause pupil constriction and angle widening. The vertical light beam should be offset horizontally for the assessment of the superior and inferior angles, while the horizontal beam should be offset vertically for the nasal and temporal angles. Assessment of the angles should be carried out at ×25 magnification. Although currently the reference standard for angle assessment, gonioscopy remains a subjective technique that depends on the experience of the clinician as well as conditions of illumination.

Other Imaging Techniques Scheimpflug photography

Scheimpflug photography (Fig. 10-12-12) has been used to assess angle width. However, its relatively low resolution limits its usefulness in the evaluation of angle closure.

Ultrasound biomicroscopy (UBM)

Ultrasound biomicroscopy (UBM) (Fig. 10-12-13) allows dynamic highresolution imaging of the anterior segment structures, including the

anterior chamber angle, the iris, iris−lens interaction, and ciliary body. Thus, it can help to elucidate the underlying mechanism of angle closure in most cases, including plateau iris syndrome and iridociliary cysts, thereby allowing the appropriate treatment to be given. It is also useful in demonstrating angle occludability when performed in a dark room. The major disadvantages of UBM are that it is a time-consuming procedure that requires a skilled operator and contact with the patient’s eye. Its high cost also limits its availability.

Anterior segment optical coherence tomography (AS-OCT)

More recently, anterior segment optical coherence tomography (AS-OCT) (Fig. 10-12-14) using light of wavelength 1310 nm has enabled high-speed imaging of the anterior segment structures. It is an easy technique to master and does not require contact with the patient’s eye. A comparison with gonioscopy has found that it may be superior in its ability to detect angle occludability.38 It suggests that gonioscopy (which uses visible light) may be underestimating angle occludability, even when performed in ideal darkroom conditions. AS-OCT has also been reported to be similar to ultrasound biomicroscopy in quantitative anterior chamber angle measurement and detection of narrow angles.39

10.12 Angle-Closure Glaucoma

Various grading systems, including Scheie, Shaffer, and Spaeth, have been proposed for the recording of gonioscopic findings (see Chapter 10-27). These gonioscopic grades provide an index of the likelihood of angle closure.37 With the Scheie grading system, there is a high risk of angle closure in eyes that are graded III (only anterior TM and Schwalbe’s line visible) or IV (only Schwalbe’s line visible). Shaffer grades I (angle width 0–10°) and II (10–20°) are associated with risk of angle closure, while an angle with a Spaeth grade of B20s (iris insertion behind Schwalbe’s line, angle width 20°, steep peripheral iris contour) may be potentially occludable. ‘Biometry gonioscopy,’ where a reticule in the eyepiece of the slit lamp is used to measure the distance from the iris insertion to Schwalbe’s line, has also been suggested as a more reproducible and objective method of gonioscopy.

Scanning peripheral anterior chamber depth analyzer (SPAC)

Evaluation of the peripheral anterior chamber is also possible with the newly developed SPAC,40 for which early results are encouraging.

Provocative tests

Historically, provocative tests were used to attempt to trigger angle closure in primary angle-closure suspects (PACS), in order to identify patients for whom treatment is then recommended. These included the darkroom prone test and pharmacologic pupil dilatation. However, these tests may not be easily reversible and are associated with high false-positive and false-negative rates. They are therefore seldom practiced now.

DIFFERENTIAL DIAGNOSIS 1. Secondary ACG (shown in italics in Box 10-12-3). 2. Other causes of headache (e.g., migraine or cluster headache).

MANAGEMENT OF ACUTE ANGLE CLOSURE Acute angle closure is an ophthalmologic emergency. Measures should be taken within minutes to hours to lower the IOP and break the

Fig. 10-12-12  Scheimpflug photography.

A

B

Fig. 10-12-13  Ultrasound biomicroscopy. (A) UBM device. (B) UBM image of the anterior chamber angle.

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fellow eye should be evaluated by gonioscopy for risk of angle occludability and treated with prophylactic laser iridectomy (Box 10-12-4) if necessary. Topical steroids should be continued four times a day for about 5–7 days post-laser iridectomy, and antiglaucoma medications discontinued when IOP returns to normal.

10 Glaucoma

Even Later

A repeat gonioscopic examination should be carried out after laser iridectomy has been successfully performed, in order to assess if the eye is still at risk of angle closure as well as to document the presence and extent of PAS. Once it is deemed safe to dilate the pupil, a dilated ocular examination should also be performed in order to assess the optic nerve status, as well as to exclude any secondary causes of angle closure that may need further treatment. The IOP should be monitored closely in the first 12 months after the attack to detect any asymptomatic rise in IOP early.

MANAGEMENT OF CHRONIC ACG A

In the case of a patient presenting with elevated IOP, in the presence of partially or totally occluded angles with PAS and glaucomatous optic neuropathy, medical treatment (see below) to lower IOP should be commenced. Laser iridectomy and laser iridoplasty should be considered. Gonioscopy should be repeated to assess angle width and the extent of PAS. If IOP continues to be inadequately controlled, or if there is any evidence of progression in optic nerve or visual field damage, then the decision to go on to surgical treatment (see below) should be taken.

MANAGEMENT OF ANGLE-CLOSURE GLAUCOMA Medical Treatment

B Fig. 10-12-14  Anterior segment optical coherence tomography. (A) AS-OCT device (Carl Zeiss Meditec). (B) AS-OCT image of anterior chamber.

attack, followed by identifying the mechanism of angle closure and treating appropriately in an attempt to widen the angle. Corneal indentation with a four-mirror goniolens or cotton-tipped applicator may be attempted at 30-second intervals in order to force open an area of appositionally closed trabecular meshwork that will allow some aqueous to exit the eye.41 However, this technique may cause pain and momentary further increases in IOP. Hence, it may not be suitable in all cases. Recent studies suggest that laser iridoplasty may be a useful alternative to conventional systemic medication as a first-line treatment in the management of acute angle closure, especially when certain medications are contraindicated, for example, in patients with pre-existing asthma, or cardiac or renal disease.42,43

After 1–2 Hours

f the attack is broken and corneal edema resolves, perform laser • Iiridectomy. Laser iridoplasty should be performed in addition in

cases of plateau iris syndrome, and can also be considered where the angle remains narrow despite a patent laser iridectomy. If the attack is not broken but the cornea is clear, perform laser iridectomy. If the attack is not broken and the cornea is still hazy, perform laser iridoplasty first, followed by laser iridectomy later when corneal edema resolves.44–46 Laser iridectomy is the definitive treatment in ACG and results in significant angle opening in the majority of cases.47 Anterior chamber paracentesis has also been suggested as an alternative to break the attack if all else fails, especially if laser is unavailable.48

• •

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Later

If the attack is still not broken, consider surgery (lens extraction if the lens is the causative factor, or surgical peripheral iridectomy). The

In acute angle closure, topical beta-blockers, alpha-2-agonists, and carbonic anhydrase inhibitors may be used to lower the IOP to a level where corneal edema resolves, allowing laser iridectomy to be performed. Topical pilocarpine (2 or 4%) can also be used in the acute setting to constrict the pupil in an attempt to pull the peripheral iris away from the trabecular meshwork, thus helping to re-establish aqueous outflow. Pupil constriction also helps to stretch the iris, so that laser iridectomy may be performed more easily through a thinner iris. Pilocarpine is effective in inducing miosis only when iris ischemia is relieved (i.e., when IOP falls to  50% of patients, but electron microscopy evidence has shown PEX debris in the clinically unaffected fellow eye4,5 Approximately 25% of patients with clinically unilateral disease will develop PEX signs in the fellow eye within 10 years PEX syndrome accounts for 15−20% of open-angle glaucoma in general but an even higher percentage in some populations 20% of PEX patients have glaucoma and elevated IOP at the time of diagnosis The annual incidence of PEX syndrome is 26 per 100 000 and of PEX glaucoma is 10 per 100 0006

and was equally present in PEX syndrome. Actual PEX glaucoma was associated with haplotypes formed by two nonsynonymous SNPs in the first exon of LOXL1. Association studies of these two SNPs showed that the highest risk haplotype conferred a 700-fold greater risk of PEX glaucoma than the lowest risk haplotype. The two higher-risk haplotypes explained over 99 percent of PEX glaucoma cases in this population. The product of LOXL1 is a protein involved in cross-linking of elastin fibers in the extracellular matrix. Other studies have confirmed the importance of LOXL1 sequence variants, although differences may exist based on geography and ethnic background.8,9

SYSTEMIC MANIFESTATIONS PEX syndrome is associated with deposition of abnormal fibrillary material on both ocular and nonocular tissues. PEX syndrome has been associated with cardiovascular disease, including hypertension, angina, coronary artery disease, retinal vascular disease, and peripheral vascular disease.10–13 Sensorineural hearing loss may be an additional extraocular manifestation of PEX syndrome.14,15

CLINICAL PRESENTATION AND OCULAR MANIFESTATIONS PEX syndrome is usually asymptomatic and diagnosed incidentally on examination. Although the PEX material may be seen bilaterally, it is more often noted to be unilateral. However, in most ‘unilateral’ cases the apparently uninvolved eye has subclinical PEX syndrome, as multiple electron microscopy studies demonstrate. Therefore, asymmetrical may be a better term to use than unilateral when describing this entity. Patients with PEX syndrome occasionally present in dramatic fashion with a sudden awareness of unilateral vision loss, markedly elevated IOP, and an open angle. Far advanced visual field damage and optic neuropathy are common in this clinical scenario. The IOP may be

10.13

50–60 mmHg or higher on presentation, yet most patients have no pain, indicating the chronicity of the IOP elevation. Patients also may have narrow angles, and some of these may present with a clinical picture similar to angle-closure glaucoma (corneal edema, pain, and elevated IOP).16 Narrow angles may result from zonular instability with resulting anterior displacement of the lens–iris diaphragm. Moreover, posterior synechiae and iris rigidity may increase pupillary block. Miotic medications should be used with caution in these patients, as they may also exacerbate papillary block.1,17 Conversely, if the angle is shallow due to zonular laxity, anticholinergic agents often paradoxically deepen the angle in PEX patients by tightening the cilio-zonular complex. The clinical hallmark of PEX syndrome is the deposition of whitish PEX material on the anterior lens capsule (Fig. 10-13-1). Three zones of PEX material deposition are classically seen on the anterior capsule: a central zone of a disc-shaped homogenous material, a relatively clear intermediate zone, and an outer peripheral zone of material. The intermediate clear zone results from the physiologic movement of the iris, which clears away the PEX material, and can be difficult to identify until the pupil has been dilated. The peripheral zone is always present but may vary in its appearance. The central zone may be absent in 10–20% of cases, thereby necessitating the dilation of the pupil to identify the disease in some cases. An early sign of PEX syndrome is the development of radial, nongranular striae in the middle third of the lens capsule behind the iris.18 Sometimes, PEX material can be identified on the ciliary body, zonules, corneal endothelium, anterior vitreous face, and the angle. In pseudophakic or aphakic patients, PEX material on these structures often helps confirm the diagnosis. Because of the zonular fragmentation and instability inherent in this syndrome, patients occasionally demonstrate phacodonesis or frank subluxation or dislocation of the natural or implant lens (Fig. 10-13-2). Capsular phimosis may be a precursor to impending IOL subluxation. Patients with PEX syndrome often display an increased amount of pigmentation in the angle and on the corneal endothelium. PEX syndrome has been associated with nonguttate endothelial loss and subsequent corneal decompensation.19,20 Peripupillary iris transillumination defects (TIDs) are common yet distinctly different from the midstromal and peripheral radially oriented TIDs of pigment dispersion syndrome (PDS). The angle deposition of pigment is often patchy and unevenly distributed in PEX, contrasting with the homogeneous dense angle pigment seen in PDS. A Sampaolesi’s line, most often in the inferior angle, will occasionally be noted. Dilation may liberate pigment in PEX syndrome, leading to an open-angle postdilation IOP spike. A postdilation IOP check should be considered in these patients. Other suggestive signs are atrophy of the iris sphincter, poor dilation of the iris, anisocoria, a ground-glass appearance of the lens capsule, and heterochromia in which the more involved side is lighter. PEX syndrome eyes may also have important biomechanical differences, including decreased corneal hysteresis and corneal resistance factor to

the ocular response analyzer.21 However, studies are inconsistent as to whether PEX syndrome and glaucoma eyes have thinner corneas.22–24 PEX glaucoma is defined as glaucomatous optic neuropathy in the face of clinical PEX syndrome. Patients with PEX syndrome should be considered glaucoma suspects and monitored periodically with a complete ophthalmic examination, IOP, visual field testing, and nerve fiber layer quantification. All patients with PEX should be examined at least yearly, more frequently if there is concern for or evidence of significant disease.

Glaucoma Associated with Pseudoexfoliation Syndrome

Fig. 10-13-1  PEX material deposition on the anterior lens capsule. A central disc of PEX material is seen with a relatively clear intermediate zone due to iris chaffing and a peripheral zone of PEX deposits. (Reproduced with permission from Wallace Alward, MD, Copyright University of Iowa.)

Fig. 10-13-2  Subluxed crystalline lens. Exfoliation material can be seen along the equator of the subluxed lens and within the zonules. In addition, peripupillary atrophy is evident. (Reproduced with permission from Samuelson TW. Management of coincident glaucoma and cataract. Curr Opin Ophthalmol. 1995;1:14–21.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis for PEX syndrome includes: Pigment dispersion syndrome Capsular delamination (true exfoliation) Primary amyloidosis PDS is more often clinically bilateral, more common in young myopic males than females, and displays characteristic TIDs and angle pigmentation findings noted in the previous section. Capsular delamination, or true exfoliation, is a splitting of the anterior lens capsule without deposition of PEX material. It can occur secondary to heat, trauma, irradiation, or inflammation and is rare. Another rare condition that may produce fibrillar material deposition on the lens surface is primary familial amyloidosis. Evaluation of this material has shown it to be distinctly different from PEX material. Most commonly, PEX glaucoma is misdiagnosed as POAG or primary angle-closure glaucoma because of failure to recognize the characteristic PEX material and clinical signs. PEX may also be confused with iritis if the PEX material deposited on the corneal endothelium is confused with keratic precipitates.

• • •

TREATMENT AND OUTCOME As many as 40% of patients with PEX syndrome eventually develop glaucoma. Despite medical or surgical treatment, one study noted that 25% of patients affected by PEX glaucoma are blind in at least one eye and 7% are blind in both eyes.25 Although this study may have been biased by the referral-based nature of the practice and the fact that modern pharmaceuticals and mitomycin C were not available at the time of its publication, these statistics underscore the aggressive nature of PEX glaucoma. Medical management of PEX glaucoma is similar to that of POAG and consists of the use of all current classes of IOP-lowering pharmaceuticals. PEX glaucoma is frequently more resistant to medical management, and such management carries a higher failure rate compared with POAG.26,27 Although miotic agents may be beneficial because they decrease the liberation of pigment and PEX material by limiting pupil movement, they also can induce angle closure and the formation of posterior synechiae. Most glaucoma specialists begin medical treatment for PEX glaucoma with a prostaglandin analog or standard aqueous suppressants but advance quickly to other treatment modalities if medical IOP control is unsatisfactory.

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10 Glaucoma

Argon or selective laser trabeculoplasty can be performed in PEX patients if the angle is open enough to allow laser application. Laser trabeculoplasty is reported to have a higher success rate in PEX glaucoma patients than in POAG and therefore is often used earlier in the management of PEX cases. If IOP is not adequately controlled with medical or laser treatment, trabeculectomy should be considered. The results of trabeculectomy are favorable, with no significant difference in the postoperative complication rate compared with the same surgery for POAG28 even though PEX patients are more prone to an increased postoperative inflammatory response because of the alteration of the blood−aqueous barrier.29 Trabecular aspiration has been used with success as another surgical alternative; however, long-term follow-up is lacking.30 Many times, trabeculectomy is combined with cataract surgery in PEX glaucoma patients, and several important considerations must be made in these cases. First, the zonular attachments in PEX syndrome may be weakened by the accumulation of the PEX material.17 This results in a 5–10 times higher incidence of lens subluxation, zonular dialysis, and vitreous loss in these patients compared with non-PEX patients.31 Another potentially complicating factor is the reduced response to pharmacologic pupil dilation in PEX patients.32 Poor dilation is the single most important predictor for vitreous loss in cataract surgery among these patients. The use of iris retractors, pupillary stretching techniques, viscoadaptive agents, and pupillary-dilation devices has greatly enhanced the safety of cataract surgery in PEX syndrome. Capsular tension rings (CTR) may be useful in decreasing zonular and capsular instability, as well as improving IOL centration and decreasing capsular phimosis. While some advocate the use of CTR in all patients with PEX, others do not see the validity of their use in patients with clinically stable capsules. Spontaneous dislocation of the capsular bag and its IOL has been reported with increasing frequency, and it is not yet known whether a CTR will prevent this late postoperative complication seen in PEX patients.33,34 In some cases, it may be necessary to place the IOL into the ciliary sulcus, preferably with optic capture within the capsule. Profound capsular instability may necessitate suture fixation of the lens to the iris or sclera. Other observations made in eyes with PEX syndrome include a greater risk for perioperative IOP spikes, posterior synechiae formation, and cellular precipitates on the IOL. Before surgery, all patients should be carefully examined both preand postdilation for signs of iridodonesis or phacodonesis. Instability of the lens can often best be seen by using the gonioscope, but it is possible to find instability of the lens in the operating room that was not observable in the clinic setting. If the lens is unstable, it may be best to perform supracapsular phacoemulsification by aggressive hydrodissection of the lens from the capsular bag. Consideration of a pars plana

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approach should be made if the lens appears to be very unstable. Nonetheless, with a gentle and methodical surgical technique, the results of cataract surgery in patients with PEX can be quite good. If PEX glaucoma is well controlled and there is no evidence of advanced visual field or nerve damage, clear cornea cataract surgery alone can produce improved IOP control.35 Cataract surgery alone avoids the inherent risks of trabeculectomy and may improve IOP control in appropriate patients. A trabeculectomy can then be offered as a second procedure if necessary. With the use of modern surgical equipment and techniques, successful outcomes for the management of cataract and glaucoma in PEX patients are increasing. PEX is common and deserves special attention in terms of the aggressive nature of the condition and its associated glaucoma. Future research will pave the way for a better understanding of the pathogenesis and management of this disease.

KEY REFERENCES Cahill M, Earla A, Stack S, et al. Pseudoexfoliation and sensorineural hearing loss. Eye 2002;16:261–6. Carpel EF. Pupillary dilation in eyes with pseudoexfoliation syndrome. Am J Ophthalmol 1988;105:692–3. Forsius H. Exfoliation syndrome in various ethnic populations. Acta Ophthalmol 1988;66:71–85. Gross FJ, Tingey D, Epstein DL. Increased prevalence of occludable angles and angle closure glaucoma in patients with pseudoexfoliation. Am J Ophthalmol 1994;117:333–6. Hammer T, Schlotzer-Schrehardt U, Naumann GO. Unilateral or asymmetric pseudoexfoliation syndrome? An ultrastructural study. Arch Ophthalmol 2001;119:1023–31. Henry CJ, Krupin T, Schmitt M, et al. Long-term follow-up of pseudoexfoliation and the development of elevated intraocular pressure. Ophthalmology 1987;94:545–52. Jehan FS, Mamalis N, Crandall AS. Spontaneous late dislocation of intraocular lens within the capsular bag in pseudoexfoliation patients. Ophthalmology 2001;108:1727–31. Konstas AG, Jay JL, Marshall GE, et al. Prevalence, diagnostic features, and response to trabeculectomy in exfoliation glaucoma. Ophthalmology 1993;100:619–27. Lumme P, Laatikainen L. Exfoliation syndrome and cataract extraction. Am J Ophthalmol 1993;116:51–5. Merkur A, Damji KF, Mintsioulis G, et al. Intraocular pressure decrease after phacoemulsification in patients with pseudoexfoliation syndrome. J Cataract Refract Surg 2001;27:528–32. Mitchell P, Wang JJ, Smith W. Association of pseudoexfoliation syndrome with increased vascular risk. Am J Ophthalmol 1997;124:685–7. Naumann GO, Schlotzer-Schrehardt U. Keratopathy in pseudoexfoliation syndrome as a cause of corneal endothelial decompensation: a clinicopathologic study. Ophthalmology 2000;107:1111–24. Ritch R. Exfoliation syndrome: clinical findings and occurrence in patients with occludable angles. Trans Am Ophthalmol Soc 1994;92:845–944. Thorburn W. The outcome of visual function in capsular glaucoma. Acta Ophthalmol 1988;66:132–8. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400.

REFERENCES 1. Ritch R. Exfoliation syndrome: clinical findings and occurrence in patients with occludable angles. Trans Am Ophthalmol Soc 1994;92:845–944.

3. Liebowitz HM, Krueger DE, Maunder LR. The Framingham Eye Study Monograph. Surv Ophthalmol 1980;24(Suppl):335–610. 4. Prince AM, Streeten BW, Ritch R, et al. Preclinical diagnosis of pseudoexfoliation syndrome. Arch Ophthalmol 1987;105:1076–82. 5. Hammer T, Schlotzer-Schrehardt U, Naumann GO. Unilateral or asymmetric pseudoexfoliation syndrome? An ultrastructural study. Arch Ophthalmol 2001;119:1023–31. 6. Krager RA, Jeng SM, Johnson DO, et al. Estimated incidence of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in Olmsted County, Minnesota. J Glaucoma 2003;12:193–7. 7. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400. 8. Pasutto F, Krumbiegel M, Mardin CY, et al. Association of LOXL1 common sequence variants in German and Italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci 2008;49:1459–63. 9. Fan BJ, Pasquale L, Grosskreutz CL, et al. DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a US clinic-based population with broad ethnic diversity. BMC Medical Genetics 2008;9:5–11. 10. Mitchell P, Wang JJ, Smith W. Association of pseudoexfoliation syndrome with increased vascular risk. Am J Ophthalmol 1997;124:685–7. 11. Citrik M, Acaroglu G, Batman C, et al. A possible link between the pseudoexfoliation syndrome and coronary artery disease. Eye 2007;21:11–15. 12. Schumacher S, Schlotzer-Schredhardt U, Martus P, et al. Pseudoexfoliation syndrome and aneurysms of the abdominal aorta. Lancet 2001;357:359–60. 13. Praveen MR, Shah SK, Vasaveda AR, et al. Pseudoexfoliation as a risk factor for peripheral vascular disease: a case–control study. Eye 2011;25:174–9. 14. Cahill M, Earla A, Stack S, et al. Pseudoexfoliation and sensorineural hearing loss. Eye 2002; 16:261–6. 15. Yazdani S, Tousi A, Pakravan M, et al. Sensorineural hearing loss in pseudoexfoliation syndrome. Ophthalmology 2008;115:425–9. 16. Gross FJ, Tingey D, Epstein DL. Increased prevalence of occludable angles and angle closure glaucoma in patients with pseudoexfoliation. Am J Ophthalmol 1994;117:333–6. 17. Schrehardt US, Naumann GO. A histopathologic study of zonular instability in pseudoexfoliation syndrome. Am J Ophthalmol 1994;118:730–43.

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20. Wirbelauer C, Anders N, Pham DT, et al. Corneal endothelial cell changes in pseudoexfoliation syndrome after cataract surgery. Arch Ophthalmol 1998;116:145–9. 21. Yenerel NM, Gorgun E, Kucumen RB, et al. Corneal biomechanical properties of patients with pseudoexfoliation syndrome. Cornea 2011;30:983–6. 22. Bechmann M, Thiel MJ, Roesen B, et al. Central corneal thickness determined with optical coherence tomography in various types of glaucoma. Br J Ophthalmol 2000;84:1233–7. 23. Ventura AC, Bohnke M, Mojon DS. Central corneal thickness measurements in patients with normal tension glaucoma, primary open angle glaucoma, pseudoexfoliation glaucoma, or ocular hypertension. Br J Ophthalmol 2001;85:792–5. 24. Ozcura F, Aydin S, Dayanir V. Central corneal thickness and corneal curvature in pseudoexfoliation syndrome with and without glaucoma. J Glaucoma 2011;20:410–13. 25. Thorburn W. The outcome of visual function in capsular glaucoma. Acta Ophthalmol 1988; 66:132–8. 26. Henry CJ, Krupin T, Schmitt M, et al. Long-term follow-up of pseudoexfoliation and the development of elevated intraocular pressure. Ophthalmology 1987;94:545–52. 27. Brooks AV, Gilles WE. The presentation and prognosis of glaucoma in pseudoexfoliation of the lens capsule. Ophthalmology 1988;95:271–6. 28. Konstas AG, Jay JL, Marshall GE, et al. Prevalence, diagnostic features, and response to trabeculectomy in exfoliation glaucoma. Ophthalmology 1993;100:619–27. 29. Nguyen NX, Kuchle M, Martus P, et al. Quantification of blood–aqueous barrier breakdown after trabeculectomy: pseudoexfoliation versus primary open-angle glaucoma. J Glaucoma 1999;8:18–23. 30. Jacobi PC, Dietlein TS, Krieglstein GK. Comparative study of trabecular aspiration vs trabeculectomy in glaucoma triple procedure to treat pseudoexfoliation glaucoma. Arch Ophthalmol 1999;117:1311–18. 31. Lumme P, Laatikainen L. Exfoliation syndrome and cataract extraction. Am J Ophthalmol 1993;116:51–5. 32. Carpel EF. Pupillary dilation in eyes with pseudoexfoliation syndrome. Am J Ophthalmol 1988;105:692–3. 33. Jehan FS, Mamalis N, Crandall AS. Spontaneous late dislocation of intraocular lens within the capsular bag in pseudoexfoliation patients. Ophthalmology 2001;108:1727–31.

Glaucoma Associated with Pseudoexfoliation Syndrome

2. Forsius H. Exfoliation syndrome in various ethnic populations. Acta Ophthalmol 1988;66: 71–85.

19. Naumann GO, Schlotzer-Schrehardt U. Keratopathy in pseudoexfoliation syndrome as a cause of corneal endothelial decompensation: a clinicopathologic study. Ophthalmology 2000;107:1111–24.

34. Gimbel HV, Condon GP, Olson RJ, et al. Late in-the-bag intraocular lens dislocation: incidence, prevention, and management. J Cataract Refract Surg 2005;31:2193–204. 35. Merkur A, Damji KF, Mintsioulis G, et al. Intraocular pressure decrease after phacoemulsification in patients with pseudoexfoliation syndrome. J Cataract Refract Surg 2001;27:528–32.

18. Konstas AGP, Marshall GE, Cameron SA, et al. Morphology of iris vasculopathy in exfoliation glaucoma. Acta Ophthalmol (Copenh) 1993;71:751–9.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Pigmentary Glaucoma M. Bruce Shields

Definition: A form of open-angle glaucoma characterized by

dispersion of pigment granules from the iris pigment epithelium, with deposition throughout the anterior segment, including the trabecular meshwork.

Key features ■

Mid-peripheral, spoke-like iris transillumination defects, with pigment deposition on the corneal endothelium (Krukenberg’s spindle) and heavy, homogeneous pigmentation of the trabecular meshwork leading to glaucoma in some patients

Associated features ■ ■ ■ ■ ■ ■

Presence of key features without glaucoma is called pigment dispersion syndrome 15% of patients with pigment dispersion syndrome may convert to pigmentary glaucoma during 15 years of observation Typical patient is a young, myopic male Predominantly in whites ‘Reverse’ pupillary block mechanism Autosomal dominant inheritance

INTRODUCTION In 1949 Sugar and Barbour described a patient with pigment dispersion in the anterior chamber and glaucoma and coined the term pigmentary glaucoma.1 Although once thought to be a rare form of open-angle glaucoma, it has been estimated to account for 0.5–5% of the glaucoma population in the United States.2 A severalfold larger number of individuals have the typical pigment dispersion without glaucoma, which is referred to as pigment dispersion syndrome. The mechanism of the pigment dispersion was suggested by Campbell in 1979 to be a rubbing of iris pigment epithelium against packets of lens zonules, which results from a posterior bowing of the peripheral iris.3 This iris configuration is seen most commonly in young, myopic men, and is felt to result from a reverse pupillary block.4 In a study of 113 patients with pigment dispersion syndrome, the probability of converting to pigmentary glaucoma was 10% at 5 years and 15% at 15 years.5

EPIDEMIOLOGY AND PATHOGENESIS The prevalence of pigment dispersion syndrome is unclear, since phenotypic expressions may be mild, leading to underdiagnosis in some cases, while other patients may have pigment on the corneal endothelium and increased trabecular meshwork pigmentation from a different etiology, leading to an overdiagnosis. Although the pigment dispersion syndrome is found in roughly equal numbers of men and women, pigmentary glaucoma is more common in men, who have a 3 : 1 predominance. The glaucoma also tends to occur earlier in men (35 years) than women (46 years), with a tendency in both genders for the condition to

10.14

decrease in severity or disappear by the sixth to seventh decade of life.6,7 Patients are usually myopic, and there is a strong preponderance of whites. Pigment dispersion syndrome has an autosomal dominant inheritance, and one study of four families linked the condition to the long arm of chromosome 7 (7q35–q36).8 The configuration of the eye is believed to be responsible for the forces that lead to the iris-zonular rubbing and pigment dispersion. The eyes are larger than average, explaining the preponderance of men and myopes, and the anterior chamber is deep, which may explain the spontaneous improvement in older patients, as lens changes lead to a shallowing of the chamber. Other anatomic features that may predispose to the mechanism of pigment dispersion are a flatter corneal curvature than in age-matched myopic controls,9 a more posterior insertion of the iris into the ciliary body,10 and a relatively larger iris.11 In addition to the above-noted anatomic features, which favor iriszonular rubbing, it has been reported that histopathologic observations of the iris of patients with pigment dispersion syndrome and pigmentary glaucoma have revealed focal atrophy, hypopigmentation, and apparent delayed melanogenesis of the iris pigment epithelium.12 It may be, therefore, that both the mechanical iris-zonular rubbing and a developmental abnormality of the iris pigment epithelium are necessary to produce the liberation of pigment granules in these patients. The concept of reverse pupillary block is critical to an understanding of the mechanisms that lead to pigmentary glaucoma The configuration of the eye in these patients, as described above, appears to favor a ‘pumping’ action of the iris, in which eye movement, as with blinking, causes the peripheral iris to act as a bellows in forcing aqueous from the posterior to the anterior chamber. This results in a reverse pressure gradient, i.e., higher in the anterior than posterior chamber. The iris then acts as a one-way valve against the lens, preventing aqueous from returning to the posterior chamber. The increased pressure in the anterior chamber leads to posterior bowing of the mid-peripheral iris and consequently to the rubbing of the iris pigment epithelium against packets of lens zonules, with liberation of pigment granules into the aqueous. Support for the concept of reverse pupillary block is seen in ultrasound biomicroscopic studies, in which prevention of blinking eliminates the posterior bowing.13 The most compelling support, however, is the response to peripheral iridectomy, in which pigment-laden aqueous is noted to be sucked back from the anterior to the posterior chamber, and the plane of the peripheral iris shifts forward. Once the pigment granules are released from the iris pigment epithelium into the aqueous, some of them lodge in the trabecular meshwork, where they obstruct aqueous outflow resulting in elevated intraocular pressure (IOP).14 Histopathological examinations show that the trabecular endothelial cells engulf the pigment, which results in cell injury and death from phagocytic overload.15 Macrophages carry off the pigment and debris, leaving the denuded collagen beams to collapse and fuse, with obliteration of the outflow channels. This may explain why treatments directed at increasing trabecular outflow, such as laser trabeculoplasty, are more effective in the earlier stages of pigmentary glaucoma.

OCULAR MANIFESTATIONS As in most eyes with axial myopia, a deep anterior chamber is the rule, but with the additional finding of posterior bowing of the peripheral iris. The resulting contact between the iris and packets of lens zonules leads to characteristic mid-peripheral, spoke-like iris transillumination

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10 Glaucoma Fig. 10-14-1  Transillumination defects. The radial, mid-peripheral, spoke-like iris transillumination defects, typical of patients with pigmentary glaucoma, correspond anatomically to packets of lens zonules.

Fig. 10-14-3  Gonioscopic appearance in pigmentary glaucoma. A wide, open angle with heavy, homogeneous trabecular meshwork pigmentation is a consistent feature of pigmentary glaucoma.

BOX 10-14-1 THEORETICAL EFFECT OF PERIPHERAL IRIDECTOMY ON LONG-TERM COURSE IN PIGMENTARY GLAUCOMA

• •• •• • • Fig. 10-14-2  Krukenberg’s spindle. Vertical, spindle-shaped deposition on central corneal endothelium in patient with pigmentary glaucoma.

defects. This typically appears first in the inferior quadrant, but may be seen for 360° in advanced cases (Fig. 10-14-1). With elimination of the iris-zonule rubbing, as a result of either treatment or age, the transillumination defects gradually fill in and disappear. The dispersed pigment granules may deposit on many ocular structures in the anterior segment. One of the most common is a vertical, spindle-shaped deposition on the central corneal epithelium, referred to as Krukenberg’s spindle (Fig. 10-14-2). Another common location is on the iris stroma, where the pigment granules may accumulate in both the radial and circumferential iris ridges. But the most classic finding, and indeed that associated with the final mechanism of IOP elevation in pigmentary glaucoma, is the dense, homogeneous pigmentation of the trabecular meshwork (Fig. 10-14-3).

DIFFERENTIAL DIAGNOSIS 1074

There are several additional forms of glaucoma that may have variable amounts of pigment dispersion in the anterior chamber and which must be distinguished from pigmentary glaucoma, including pseudoexfoliation syndrome, glaucoma in pseudophakia, in which the iris rubs

Relieves the reverse pressure gradient between anterior and posterior chamber Relieves posterior bowing of peripheral iris Relieves rubbing between iris pigment epithelium and packets of lens zonules Reduces liberation of pigment granules into the aqueous humor Reduces the continual bombardment of the trabecular meshwork with pigment granules Allows the meshwork to clear the pigment and recover normal outflow function (if changes not already irreversible) Over time (months to years), allows normalization or easier control of intraocular pressure (although studies have failed to support this clinical benefit)

against the optic or haptic of a posterior chamber intraocular lens, some forms of uveitis, trauma, ocular melanosis and melanoma, and chronic open-angle glaucoma with increased pigment dispersion.

TREATMENT Initial treatment is typically medical therapy, and all classes of ocular hypotensive medications for open-angle glaucoma are effective in these patients. Laser trabeculoplasty is effective in pigmentary glaucoma, especially in the early stages of the disease. With selective laser trabeculoplasty, however, patients with heavily pigmented trabecular meshwork may have significant post-laser IOP elevations.16 Trabeculectomy is also effective, when other measures are inadequate. A controversial option in the treatment of pigmentary glaucoma is the use of laser peripheral iridectomy. In theory, the elimination of posterior iris bowing by peripheral iridectomy should have a beneficial effect on the long-term course of pigmentary glaucoma (Box 10-14-1). In fact, however, studies have failed to prove this theory. In small, prospective studies, iridectomy was shown to reduce IOP rise over time17 or to reduce aqueous pigment,18 although another study showed no long-term IOP reduction.19 In a retrospective study of 46 pigmentary glaucoma patients, treated with uniocular iridectomy and followed for an average of 70 months, the treated eyes had significantly lower pressures.20 However, analysis by linear regression models indicated that a higher mean

COURSE AND OUTCOME Despite the relatively low conversion rate from pigment dispersion syndrome to pigmentary glaucoma, individuals with the former condition must be followed closely as glaucoma suspects, since the glaucoma has a relatively aggressive nature, once it does become manifest. And, although it does have a tendency to ‘burn out’ in later life, the stakes are high in the patient with pigmentary glaucoma, considering their long life expectancy. Therefore, aggressive treatment is often required in order to ensure that these individuals will get through the active decades of the glaucoma with their sight intact.

Campbell DG. Pigmentary dispersion and glaucoma: a new theory. Arch Ophthalmol 1979;97:1667–72. Grant WM. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 1963;69:783–801. Harasymowycz PJ, Papamatheakis DG, Latina M, et al. Selective laser trabeculoplasty (SLT) complicated by intraocular pressure elevation in eyes with heavily pigmented trabecular meshwork. Am J Ophthalmol 2005;139:1110–13. Kupfer C, Kuwabara T, Kaiser-Kupfer M. The histopathology of pigmentary dispersion syndrome with glaucoma. Am J Ophthalmol 1975;80:857. Liebmann JM, Tello C, Chew SJ, et al. Prevention of blinking alters iris configuration in pigment dispersion syndrome and in normal eyes. Ophthalmology 1995;102:446–55. Reistad CE, Shields MB, Campbell DG, et al. The influence of peripheral iridectomy on the intraocular pressure course in patients with pigmentary glaucoma. J Glaucoma 2005;14:255–9. Richardson TM, Hutchinson BT, Grant WM. The outflow tract in pigmentary glaucoma; a light and electron microscopic study. Arch Ophthalmol 1977;95:1015–25.

10.14 Pigmentary Glaucoma

baseline IOP in the treated eyes accounted for the apparent benefit of the iridectomy. Most recently, in a study of 116 patients with pigment dispersion syndrome and ocular hypotension, who were randomized to Nd : YAG peripheral iridectomy in one eye or no laser treatment and followed for an average of three years, there was not statistically significant difference in conversion to pigmentary glaucoma, as determined by visual field progression, or initiation of glaucoma medication.21

Scott A, Kotecha A, Bunce C, et al. YAG laser peripheral iridectomy for the prevention of pigment dispersion glaucoma: A retrospective, randomized, controlled trial. Ophthalmology 2011;118:468–73. Siddiqui Y, Hulzen RDT, Cameron JD, et al. What is the risk of developing pigmentary glaucoma from pigment dispersion syndrome? Am J Ophthalmol 2003;135:794–9.

KEY REFERENCES Andersen JS, Pralea AM, DelBono EA, et al. A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36. Arch Ophthalmol 1997;115:384–8.

Access the complete reference list online at

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REFERENCES 1. Sugar HS, Barbour FA. Pigmentary glaucoma: a rare clinical entity. Am J Ophthalmol 1949;32:90–2. 3. Campbell DG. Pigmentary dispersion and glaucoma: a new theory. Arch Ophthalmol 1979;97:1667–72. 4. Karickhoff JR. Reverse pupillary block in pigmentary glaucoma: follow-up and new developments. Ophthalmic Surg 1993;24:562–3. 5. Siddiqui Y, Hulzen RDT, Cameron JD, et al. What is the risk of developing pigmentary glaucoma from pigment dispersion syndrome? Am J Ophthalmol 2003;135:794–9.

13. Liebmann JM, Tello C, Chew SJ, et al. Prevention of blinking alters iris configuration in pigment dispersion syndrome and in normal eyes. Ophthalmology 1995;102:446–55. 14. Grant WM. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 1963;69:783–801. 15. Richardson TM, Hutchinson BT, Grant WM. The outflow tract in pigmentary glaucoma; a light and electron microscopic study. Arch Ophthalmol 1977;95:1015–25. 16. Harasymowycz PJ, Papamatheakis DG, Latina M, et al. Selective laser trabeculoplasty (SLT) complicated by intraocular pressure elevation in eyes with heavily pigmented trabecular meshwork. Am J Ophthalmol 2005;139:1110–13.

6. Sugar HS. Pigmentary glaucoma: a 25-year review. Am J Ophthalmol 1966;62:499–507.

17. Gandolfi SA, Vecchi M. Effect of a YAG laser iridectomy on intraocular pressure in pigment dispersion syndrome. Ophthalmology 1996;103:1693–5.

7. Richter CU, Richardson TM, Grant WM. Pigmentary dispersion syndrome and pigmentary glaucoma: a prospective study of the natural history. Arch Ophthalmol 1986;104: 211–15.

18. Kuchle M, Nguyen NX, Mardin CY, et al. Effect of neodymium:YAG laser iridectomy on number of aqueous melanin granules in primary pigment dispersion syndrome. Graefes Arch Clin Exp Ophthalmol 2001;239:411–15.

8. Andersen JS, Pralea AM, DelBono EA, et al. A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36. Arch Ophthalmol 1997;115:384–8.

19. Wang JC, Liebmann JM, Ritch R. Long-term outcome of argon laser iridectomy in pigment dispersion. Invest Ophthalmol Vis Sci (Suppl) 2001;42:s560.

9. Lord FD, Pathanapitoon K, Mikelberg FS. Keratometry and axial length in pigment dispersion syndrome: a descriptive case–control study. J Glaucoma 2001;10:383–5.

20. Reistad CE, Shields MB, Campbell DG, et al. The influence of peripheral iridectomy on the intraocular pressure course in patients with pigmentary glaucoma. J Glaucoma 2005;14:255–9.

10. Sokol J, Stegman Z, Liebmann JM, et al. Location of the iris insertion in pigment dispersion syndrome. Ophthalmology 1996;103:289–93. 11. Potash SD, Tello C, Liebmann J, et al. Ultrasound biomicroscopy in pigment dispersion syndrome. Ophthalmology 1994;101:332–9.

10.14 Pigmentary Glaucoma

2. Ritch R. Going forward to work backward. Arch Ophthalmol 1997;115:404–6.

12. Kupfer C, Kuwabara T, Kaiser-Kupfer M. The histopathology of pigmentary dispersion syndrome with glaucoma. Am J Ophthalmol 1975;80:857.

21. Scott A, Kotecha A, Bunce C, et al. YAG laser peripheral iridectomy for the prevention of pigment dispersion glaucoma: A retrospective, randomized, controlled trial. Ophthalmology 2011;118:468–73.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

10.15

Neovascular Glaucoma Malik Y. Kahook

Definition: A secondary glaucoma resulting from neovascularization of the anterior segment, including the iris and angle, often associated with retinal ischemia.

Key features ■

Neovascularization of the iris, angle, and anterior chamber ■ Elevated intraocular pressure ■ Peripheral anterior synechiae

Associated features ■ ■ ■ ■ ■ ■ ■

Decreased vision Ectropion uveae Anterior chamber inflammation Cupping of the optic nerve Corneal edema, depending on acuteness Conjunctival congestion Retinal disease with ischemia, inflammation, or tumor

INTRODUCTION Neovascular glaucoma (NVG) occurs when new vessels proliferate onto the iris surface and over the anterior chamber angle structures, namely the trabecular meshwork. Retinal ischemia with retinal capillary nonperfusion and subsequent secretion of vaso-proliferative factors are the events that lead to neovascularization and glaucoma in most cases. The evolution of NVG usually follows an ordered sequence beginning with new vessel formation and ending with fibrovascular membranes migrating over the drainage angle, potentially leading to endstage glaucoma. There is a high likelihood of profound vision loss once intraocular pressure (IOP) increases, making early diagnosis key to preserving ocular function. Medications, laser treatment, and incisional surgery have been the mainstay of treatment. Recently, treatment modalities targeting the vasoproliferative factors directly have emerged, potentially improving outcomes.

EPIDEMIOLOGY AND PATHOGENESIS

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Coats described the occurrence of iris neovascularization in connection with central retinal vein obstruction (CRVO) in 1906.1 Weiss and colleagues coined the term neovascular glaucoma in 1963 basing the diagnosis on the presence of new vessels on the iris leading to increased IOP.2 Diabetic retinopathy and CRVO are the most common pathologic processes involved in the development of ocular neovascularization (Box 10-15-1). Thirty-six percent of all cases of NVG arise from CRVO, 32% from proliferative diabetic retinopathy, and 13% from carotid artery occlusive disease.3 The common denominator in all of these diseases is ocular tissue hypoxia.

BOX 10-15-1  CAUSES OF IRIS NEOVASCULARIZATION Retinal Ischemia Diabetic retinopathy Central retinal vein occlusion Central retinal artery occlusion Retinal detachment Sickle cell retinopathy Retinoschisis Carotid artery occlusion

•• •• •• • •• ••

Inflammatory Chronic uveitis Endophthalmitis Vogt–Koyanagi–Harada syndrome Sympathetic ophthalmia

Tumors Choroidal/iris melanoma Ocular lymphoma Retinoblastoma

•• • •• •

Irradiation External beam radiation Charged particle therapy Plaque therapy

The concept of an angiogenic factor stimulating new vessel proliferation as a consequence of hypoxia has long been theorized. Recent advances in molecular biology identified vascular endothelial growth factor (VEGF) as a leading protein involved in the neovascular cascade. Tolentino et al. showed that injection of recombinant human VEGF is sufficient to produce neovascularization in a nonhuman primate model.4 Tripathi and colleagues found elevated VEGF levels in the aqueous humor of neovascular glaucoma patients.5 Sample analysis detected VEGF in 12 of 12 samples from patients with NVG, 15 of 28 of primary open-angle glaucoma patients, and 4 of 20 aqueous humor samples from patients with cataract. Mean VEGF concentration in the aqueous humor of patients with NVG was 40 and 113 times higher than that of POAG and cataract patients, respectively. Recently, antiVEGF medications have been shown to dramatically reduce ocular neovascularization when injected in the vitreous of patients with macular degeneration and NVG.6,7 Although ischemia is believed to be a primary instigator of angiogenesis, other factors play a role in abnormal vessel formation. Inflammation and hypoxia often coexist in the microenvironment leading to new vessel formation. These links remain incompletely understood and only recently have they been partially elucidated. Inflammatory mediators such as angiopoietin-1 and angiopoietin-2 are now known to play a role in new vessel formation and remodeling, along with their role in inflammation.8 Furthermore, intravitreal triamcinolone, a potent antiinflammatory agent, has shown modest efficacy in decreasing iris neovascularization.9 Theoretically, corticosteroids decrease neovascularization by interrupting the inflammatory cascade that contributes to the neovascular drive.

OCULAR MANIFESTATIONS Neovascular glaucoma can be divided into three stages (Box 10-15-2). Stage 1 consists of vascular proliferation at the pupillary margin. Neovascularization of the iris may be difficult to detect at this point. Slitlamp biomicroscopy reveals fine, tortuous, randomly oriented tufts of vessels on the surface of the iris, near the pupillary margin. These tufts may be obscured in dark irides and more obvious in lighter irides. Neovascularization characteristically progresses from the pupillary margin toward the angle (Fig. 10-15-1) of undilated pupils, but angle

BOX 10-15-2  STAGES OF NEOVASCULAR GLAUCOMA

•• • •• • •• ••

Stage II: Open-Angle Glaucoma Elevated IOP Increased NVI and NVA No synechial angle closure Stage III: Angle-Closure Glaucoma Elevated IOP Reduced visual acuity Synechial angle closure IOP, intraocular pressure; NVI, neovascularization of the iris; NVA, neovascularization of the angle

•• •• •



Uveitic glaucoma Acute angle-closure glaucoma Chronic angle-closure glaucoma Iridocorneal endothelial (ICE) syndrome Fuchs’ heterochromic iridocyclitis

representing the second stage of NVG. Stage II of NVG is characterized by contraction of the fibrovascular membrane, which pulls the peripheral iris over the trabecular meshwork and results in variable degrees of synechial angle closure. Ectropion uveae and hyphema occur frequently. Ectropion uveae results from radial traction along the surface of the iris, which pulls the posterior pigmented layer of the iris around the pupillary margin onto the anterior iris surface. It is at this stage that patients may present with the dramatic onset of pain secondary to elevated IOP. Patients typically experience severely reduced visual acuity accompanied by corneal edema and anterior chamber inflammation. Stage III findings are similar to Stage II, with the exception that synechial angle closure is present.

10.15 Neovascular Glaucoma

Stage I: Rubeosis Iridis Normal IOP NVI with or without NVA Vascular tufts at pupillary margin

BOX 10-15-3  DIFFERENTIAL DIAGNOSIS OF NEOVASCULAR GLAUCOMA

DIAGNOSIS

Fig. 10-15-1  Neovascularization of the iris. Note the florid neovascular proliferation at the pupillary margin, which grows in random orientation on the iris surface.

Fig. 10-15-2  Neovascularization of the angle. Gonioscopic view of new vessels that cover the trabecular meshwork and impart a characteristic red flush.

neovascularization in the absence of pupillary involvement may occur. Repeated gonioscopy is indicated in eyes at high risk for the development of NVG. As vascular proliferation develops, biomicroscopy of the anterior chamber shows cells and flare. Gonioscopy reveals new vessels that grow from the circumferential artery of the ciliary body onto the surface of the iris and onto the surface of the wall of the angle. The vessels cross the angle recess and grow forward over the ciliary body band and scleral spur onto the trabecular meshwork, which imparts a characteristic red flush (Fig. 10-15-2). Early in the course of anterior segment neovascularization the IOP often is normal. The new blood vessels arborize to form a fibrovascular membrane (invisible on gonioscopy) that gives rise to a secondary open-angle glaucoma

The medical history is crucial in evaluating patients for the development of NVG. Diabetes mellitus, hypertension, arteriosclerosis, and a previous history of vision loss indicative of CRVO, central retinal artery obstruction (CRAO), or retinal detachment are important. Recent ocular surgery may increase the risk in predisposed individuals. It is imperative that a posterior segment examination be performed in all patients to identify concomitant retinal disease. The diagnosis of NVG is made based on the clinical examination. Careful slit-lamp and gonioscopic examinations are usually sufficient to make the diagnosis. An undilated pupil is helpful. The goal is to establish the diagnosis well before angle structures become involved and elevated IOP or synechial angle closure occurs. Involvement of the anterior chamber angle sometimes occurs before the appearance of neovascularization of the iris. These vessels typically run on the iris surface, follow a nonradial course, and may cross the scleral spur. Thus, gonioscopy must be performed on every patient at risk for the development of NVG. In most instances, however, small tufts of neovascularization are noted first at the pupillary margin. This tendency for initial involvement of the pupillary margin appears to result from aqueous flow dynamics, whereby angiogenic factors produced in the posterior segment have the most contact with the pupillary margin. Occasionally, early neovascularization may be missed when the new vessels are fine and thin, the iris is darkly pigmented, or pressure from the gonioscopy lens reduces the caliber of the new vessels and renders them clinically unapparent. Frequent follow-up of patients at high risk for NVG enables early detection of new vessels in difficult cases. Fluorescein angiography of the iris may be used to demonstrate the presence of new vessels before they become visible clinically with slit-lamp biomicroscopy. Fluorescein angiography of the retinal circulation, if corneal clarity and pupillary dilation allows is an important adjunct. Peripheral sweeps or wide field angiograms are especially helpful in detecting peripheral retinal capillary nonperfusion as well as detecting posterior segment neovascularization. The b-wave to a-wave amplitude ratio of the bright-flash, darkadapted electroretinogram may help predict which eyes will develop NVG following CRVO.10 This ratio was found to be less than 1.0 (average 0.84) in eyes that developed NVG after ischemic CRVO. In contrast, the b-wave to a-wave amplitude ratio was always greater than 1.0 in eyes that did not develop NVG following CRVO.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of NVG is summarized in Box 10-15-3. The diagnosis of NVG is often made easy by the appearance of iris neovascularization in the presence of retinal pathology. However, occasional cases are less obvious with subtle neovascularization and little or no visible retinal pathology. In these cases, the treating physician should

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10 Glaucoma 1078

be familiar with other disease processes infrequently linked to rubeosis iridis and high IOP. Uveitic glaucoma can mimic NVG with high pressure and dilated iris vessels. Fuchs’ heterochromic iridocyclitis can present with high IOP and abnormal vessels in the anterior chamber angle. Finally, endstage NVG can look identical to chronic angleclosure glaucoma with angle closure due to diffuse anterior synechiae.

TREATMENT The key to successful management of NVG is early diagnosis. Recognition of neovascularization of the iris is crucial so that preventive treatment can be initiated before the anterior chamber angle is closed by peripheral anterior synechiae. Once the florid, intractable final stage is established, the eye is likely blind, with very high IOP and painful bullous keratopathy. If the NVG is secondary to carotid artery or other systemic disease, it is important to evaluate and treat the primary systemic condition. Panretinal photocoagulation (PRP) remains the first line of therapy in almost all cases of NVG. Prompt application of PRP has been shown to effect regression of anterior and posterior segment neovascularization and to reduce the risk of developing neovascularization of the iris in eyes that have retinal vascular disease.11 In the open-angle glaucoma stage and early angle-closure glaucoma stage, PRP may reverse or mitigate IOP elevation. For eyes that have advanced synechial angle closure of the anterior chamber with some potentially useful vision, PRP may eliminate the stimulus for neovascularization, which prepares the eye for filtering surgery and the prevention of further visual loss. Panretinal cryotherapy is an alternative to PRP in eyes that have cloudy media and in eyes for which complete PRP fails to halt the progression of neovascularization.12 It is rarely employed given its high rate of complications. Goniophotocoagulation may be used as an adjunct to PRP to reduce neovascularization in the angle before it is closed by synechiae, but generally the effects are only temporary.13 The treatment of NVG is directed by the visual potential. Any usable vision, even 20/400 (6/120) or less in a monocular patient, is worth preserving. The role of glaucoma filtering surgery in NVG is to prevent pressureinduced injury to the optic nerve and, theoretically, to improve vascular perfusion. Before glaucoma surgery, every attempt is made to reduce or eliminate the stimulus for angiogenesis using PRP. By allowing the maximal amount of time between PRP and glaucoma surgery the risk of intraoperative and postoperative bleeding and severe intraocular inflammation is reduced. The importance of complete preoperative PRP to the success of glaucoma filtering surgery in patients who have NVG cannot be overstressed. Of special importance is the use of intraoperative cautery to achieve hemostasis and avoid bleeding. Direct cauterization of the peripheral iris before iridectomy may reduce the risk of bleeding. Variable success rates have been reported after conventional filtering surgery in patients who have NVG. Allen et al.14 reported IOP control in 67% of patients who had NVG and underwent trabeculectomy or posterior lip sclerectomy after PRP. Tsai et al.15 reported a high risk of long-term failure with 5-fluorouracil filtering surgery; 12 of 34 NVG patients (35%) lost light perception vision, and 8 patients (24%) developed phthisis bulbi over a 5-year follow-up period. Younger age (= 50 years) and type I diabetes mellitus are significant risk factors for early surgical failure. Skuta et al.16 described the use of mitomycin C with trabeculectomy in patients who had NVG. Glaucoma drainage implants are also used for the primary surgical treatment of NVG. Seton procedures place the effective sclerostomy inside the anterior chamber away from the angle, which maintains a patent fistula between the anterior chamber and an equatorial bleb. Sidoti et al.17 cited life-table success rates of 79% and 56% at 12 and 18 months, respectively, following Baerveldt glaucoma implantation surgery for NVG. Success was defined as a final IOP of 6−21 mmHg (0.8–2.8 kPa) without additional glaucoma surgery or devastating complication. Loss of light perception occurred in 31% of patients. Cox model regression survival analysis demonstrated young patient age and poorer preoperative visual acuity as significant predictors of surgical failure. Another study that evaluated the use of the single-plate Molteno implant for NVG reported success rates of 62% at 1 year, 52.9% at 2 years, 43.1% at 3 years, 30.8% at 4 years, and 10.3% at 5 years; loss of light perception was seen in 29 of 60 eyes (48%), and phthisis bulbi developed in 11 eyes (18%).18 Noninvasive techniques are employed to achieve patient comfort if the eye has no visual potential. Topically administered corticosteroids

and cycloplegics may relieve ocular discomfort. Topical beta-adrenergic blockers, alpha-adrenergic agonists, and carbonic anhydrase inhibitors may be used to reduce aqueous production. Miotic therapy is avoided, as it may aggravate intraocular inflammation and pain. Once the anterior chamber angle is closed, medical therapy alone may not provide long-term IOP control, and surgical intervention becomes necessary. Cyclocryotherapy had been advocated in the treatment of elevated IOP in NVG. Although the IOP can be controlled in a high percentage of patients who undergo the procedure, the long-term visual outcome is dismal; loss of light perception occurs in 58.5% of patients. In addition, the high incidence of major complications, which include anterior segment necrosis and phthisis bulbi (34%), means that its use in eyes that have visual potential is limited.19 Other modalities of therapy to control IOP include diode and neodymium : yttrium−aluminum−garnet transscleral cyclophotocoagulation. Schuman et al.20 reported a 39% success rate using the latter in patients who had advanced NVG. As laser treatment has evolved, the standard cyclodestructive modality has become diode laser cyclophotocoagulation of the ciliary body. This technique is typically performed transsclerally with an 810 nm diode laser equipped with a semi-disposable G-probe. The pain and inflammation of this procedure is typically less than that seen with prior, more destructive versions. More targeted techniques using an endoscope in the operating room setting have also been used to adequately lower IOP.21 In painful eyes that have poor visual potential, cycloablation, retrobulbar alcohol injection, and enucleation may help achieve comfort.

COURSE AND OUTCOME The natural course of NVG is uniformly one of complete loss of vision and the development of intractable, severe pain. The high degree of ocular morbidity and mortality in patients who have NVG emphasizes the severity of the underlying systemic conditions associated with diabetic retinopathy and CRVO, the main causes of this disorder. Usually, NVG occurs in patients burdened with serious systemic disease. Krupin et al.22 and Mermoud et al.18 cited mortality rates of 22% and 15% in patients who have NVG. Diabetes mellitus was the underlying cause of NVG in the majority of patients reported by the Diabetes Control and Complication Research Group,23 which highlights the importance of effective blood-sugar control in patients who have diabetic retinopathy. The risk of progression of mild diabetic retinopathy and the development of proliferative diabetic retinopathy is reduced to half in patients using effective blood-sugar control. NVG does not invariably follow the development of neovascularization of the iris. When such neovascularization is detected, it behoves the clinician to follow patients carefully with repeated slit-lamp examinations and undilated gonioscopy. Neovascularization of the iris has been reported to develop in 50% of patients who have proliferative diabetic retinopathy and in 60% of those who have the ischemic type of CRVO. It is imperative that PRP be applied promptly to ischemic retina to eliminate the stimulus for further neovascularization. Visual loss in NVG is common and may be attributed to a combination of causes, including severe ocular ischemia with progression of the underlying retinal disease, glaucomatous optic nerve damage, cataract formation, corneal decompensation, and phthisis bulbi. The most common cause of surgical failure in patients who have NVG is related to progression of the underlying retinal disease, not to uncontrolled IOP.15,17,22 The ultimate solution for patients who have NVG lies in the development of new modalities of treatment designed to prevent the initiation of neovascularization. Murata et al.24 recently showed that thiazolidinediones, a novel class of drugs that can be used to improve insulin resistance in type II diabetes, inhibit angiogenic responses to VEGF in vitro. Current research to develop pharmacologic therapies targeted at the inhibition of angiogenic factors offers hope for the preservation of vision in patients at risk.

EMERGING TREATMENTS It is clear that the best way to treat NVG is to prevent it from occurring in the first place. Having failed to prevent its occurrence, NVG is best dealt with when diagnosed early and treated aggressively. Current therapeutic options such as laser and incisional surgery carry with them the high risk of loss of visual field or visual acuity and, in the case of drainage devices and trabeculectomy, a high risk of infection. Newer treatment modalities should offer more precise targeting of the angiogenic mediators.

synechiae and they also highlighted the need for continued monitoring of patients due to the long-term recurrence of neovascularization seen in some patients. It should be noted that Bakri et al.35 found the vitreous half-life of 1.25 mg IVB is 4.32 days in a rabbit eye. Recurrence of neovascularization is to be expected if the hypoxic drive remains in place from an ischemic retina. It is clear within our university based practice that anti-VEGF injections are becoming a standard of care for patients presenting with NVG and have improved comfort and visual outcomes when combined with PRP, CPC, and/or prior to performing incisional surgeries like trabeculectomy and glaucoma drainage device implantation.

KEY REFERENCES Cashwell LF, Marks WP. Panretinal photocoagulation in the management of neovascular glaucoma. South Med J 1988;81:1364–8.

10.15 Neovascular Glaucoma

Anti-angiogenic medications are promising as new devices for treating NVG. Bevacizumab (Avastin, Genentech) has been investigated as a potential adjunct in the treatment of NVG.7 Vascular endothelial growth factor (VEGF) is a potent mitogen specific for vascular endothelial cells and is upregulated under conditions of retinal ischemia and NVG.25,26 A downregulation in the production of VEGF through the use of inhibitors should limit neovascularization in diseases that lead to retinal ischemia.27 Multiple case series publications have highlighted the regression of neovascularization of both the iris and angle after injections of VEGF inhibitors.7,26–33 Kahook et al.7 reported a patient who was treated with the anti-VEGF bevacizumab after having failed IOP control with transscleral CPC and PRP. A rapid decrease in IOP was noted and the patient was symptomatically improved within 48 hours. Other similar case reports found matching results after use of bevacizumab for NVG.29,30 Iliev et al.31 described the use of intravitreal bevacizumab (IVB, 1.25 mg/0.05 ml) in a series of six consecutive patients with NVI and refractory NVG. They noted marked regression of anterior segment neovascularization and rapid relief of symptoms. IOP was significantly reduced in three patients and the remaining three patients were controlled after the addition of CPC and PRP. Oshima et al.32 reported on the IVB treatment of seven eyes with NVI due to PDR in which NVI regressed within one week. With the use of iris fluorescein angiography Grisanti et al.33 studied the effects of IVB on NVI and noted a decrease in iris fluorescein angiography leakage as early as one day after injection. Gheith et al.34 presented a case series of six patients with NVG each of whom received 1.25 mg/0.05 ml IVB followed by PRP one week later. All patients had a complete regression of iris and angle neovascularization. The authors noted that topical medications failed to control IOP in the patients who developed peripheral anterior

Kahook MY, Schuman JS, Noecker RJ. Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2006;37:144–6. Krupin T, Kaufman P, Mandell AI, et al. Long-term results of valve implants in filtering surgery for eyes with neovascular glaucoma. Am J Ophthalmol 1983;95:775–82. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331–5. Schuman JS, Bellows AR, Shingleton BJ, et al. Contact transscleral Nd:YAG laser cyclophotocoagulation: midterm results. Ophthalmology 1992;99:1089–95. Skuta GL, Beeson CC, Higginbotham EJ, et al. Intraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery. Ophthalmology 1992;99:438–44. Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114:964–70. Vernon SA, Cheng H. Panretinal cryotherapy in neovascular disease. Br J Ophthalmol 1988; 72:401–5.

Access the complete reference list online at

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REFERENCES 1. Coats G. Further cases of thrombosis of the central vein. R Lond Ophthalmol Hosp Rep 1906;16:516–64.

3. Brown GC, Magargal LE, Schachat A, Shah H. Neovascular glaucoma. Etiologic considerations. Ophthalmology 1984;91:315–20. 4. Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114:964–70. 5. Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 1998;105:232–7. 6. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331–5. 7. Kahook MY, Schuman JS, Noecker RJ. Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2006;37:144–6. 8. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNFalpha and has a crucial role in the induction of inflammation. Nat Med 2006;12:235–9. 9. Jonas JB, Kreissig I, Degenring RF. Neovascular glaucoma treated by intravitreal triamcinolone acetonide. Acta Ophthalmol Scand 2003;81:540–1. 10. Sabates R, Hirose T, McNeel JW. Electroretinography in the prognosis and classification of central retinal vein occlusion. Arch Ophthalmol 1983;101:232–5. 11. Cashwell LF, Marks WP. Panretinal photocoagulation in the management of neovascular glaucoma. South Med J 1988;81:1364–8. 12. Vernon SA, Cheng H. Panretinal cryotherapy in neovascular disease. Br J Ophthalmol 1988; 72:401–5. 13. Simmons RJ, Deppermann SR, Dueker DK. The role of gonio-photocoagulation in neovascularization of the anterior chamber angle. Ophthalmology 1980;87:79–82. 14. Allen RC, Bellows AR, Hutchinson BT, et al. Filtration surgery in the treatment of neovascular glaucoma. Ophthalmology 1982;89:1181–7. 15. Tsai JC, Feuer WJ, Parrish RK II, et al. 5-Fluorouracil filtering surgery and neovascular glaucoma. Long-term follow-up of the original study. Ophthalmology 1995;102:887–93. 16. Skuta GL, Beeson CC, Higginbotham EJ, et al. Intraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery. Ophthalmology 1992;99:438–44. 17. Sidoti PA, Dunphy TR, Baerveldt G, et al. Experience with the Baerveldt glaucoma implant in treating neovascular glaucoma. Ophthalmology 1995;102:1107–18.

20. Schuman JS, Bellows AR, Shingleton BJ, et al. Contact transscleral Nd:YAG laser cyclophotocoagulation: midterm results. Ophthalmology 1992;99:1089–95. 21. Lima FE, Magacho L, Carvalho DM, et al. A prospective, comparative study between endoscopic cyclophotocoagulation and the Ahmed drainage implant in refractory glaucoma. J Glaucoma 2004;13:233–7. 22. Krupin T, Kaufman P, Mandell AI, et al. Long-term results of valve implants in filtering surgery for eyes with neovascular glaucoma. Am J Ophthalmol 1983;95:775–82. 23. Diabetes Control and Complications Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993;329:977–86. 24. Murata T, Hata Y, Ishibashi T, et al. Response of experimental retinal neovascularization to thiazolidinediones. Arch Ophthalmol 2001;119:709–17. 25. Horsley MB, Kahook MY. Anti-VEGF therapy for glaucoma. Curr Opin Ophthalmol 2010;21:112–17. 26. Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 1998;105:232–7.

10.15 Neovascular Glaucoma

2. Weiss DI, Shaffner RN, Nehrenberg TR. Neovascular glaucoma complicating carotidcavernous fistula. Arch Ophthalmol 1963;69:304–7.

19. Krupin T, Mitchell KB, Becker B. Cyclocryotherapy in neovascular glaucoma. Am J Ophthalmol 1978;86:24–6.

27. Grover S, Gupta S, Sharma R, et al. Intracameral bevacizumab effectively reduces aqueous vascular endothelial growth factor concentrations in neovascular glaucoma. Br J Ophthalmol 2009;93:273–4. 28. Sivak-Callcott JA, O’Day DM, Gass JD, et al. Evidence-based recommendations for the diagnosis and treatment of neovascular glaucoma. Ophthalmology 2001;108:1767–76. 29. Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 2006:26:352–4. 30. Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina 2006;26:354–6. 31. Iliev ME, Domig D, Wolf-Schnurrbursch U, et al. Intravitreal bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 2006;142:1054–6. 32. Oshima Y, Sakaguchi H, Gomi F, et al. Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol 2006;142:155–8. 33. Grisanti S, Biester S, Peters S, et al, for the Tuebingen Bevacizumab Study Group. Intracameral bevacizumab for iris rubeosis. Am J Ophthalmol 2006;142:158–60. 34. Gheith ME, Siam GA, de Barros DS, et al. Role of intravitreal bevacizumab in neovascular glaucoma. J Ocul Pharmacol Ther 2007;23:487–91. 35. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855–9.

18. Mermoud A, Salmon JF, Alexander P, et al. Molteno tube implantation for neovascular glaucoma. Long-term results and factors influencing the outcome. Ophthalmology 1993; 100:897–902.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Inflammatory and CorticosteroidInduced Glaucoma

10.16

Ridia Lim, Ivan Goldberg

Definition: Characteristic glaucomatous optic neuropathy associated

with ocular inflammation and/or exposure to corticosteroids.

Key features ■

Optic disc pallor and cupping and nerve fiber bundle perimetric defect(s) with evidence of inflammation involving one or more ocular tissues and/or past or continuing exposure to corticosteroids. ■ Pre-existing glaucoma or a tendency to angle-closure may preexist and may contribute to pathophysiology.

(trabecular and uveoscleral). All these as well as aqueous circulation can be altered by inflammation, its effects on the ocular tissues involved, and by treatment, particularly corticosteroids. To identify the different processes over time, repeated careful history and examination are required. Development of glaucomatous optic neuropathy depends on disease chronicity, susceptibility to corticosteroid and dose and duration, patient age and optic nerve susceptibility to damage. Some eyes have multi-mechanism glaucoma. While elevated IOP is a risk factor for uveitic glaucoma; IOP may not be elevated, and raised IOP (uveitic ‘ocular hypertension’) does not universally lead to glaucoma.

MECHANISMS OF ELEVATED IOP See Box 10-16-1.

Associated features ■

Variably raised and/or fluctuating intraocular pressure. ■ Mechanisms for IOP rise may vary over time and require continuous reassessment to focus treatment effectively. ■ Use of corticosteroids may lead to IOP rise; avoid treatments that exacerbate inflammation (miotics). ■ Specific treatment for the cause of any uveitis is important. Nonspecific treatments of uveitis include corticosteroids, NSAIDS, immunosuppressives and newer biological agents. ■ Treat inflammatory glaucomas with ocular hypotensive medications (primarily aqueous suppressants), laser therapies, and augmented filtering surgery. ■ Hypotony is a risk with drainage surgery, especially if there has been previous cyclodestruction.

INTRODUCTION Ocular inflammation and/or corticosteroid use can cause glaucomatous damage by elevating intraocular pressure (IOP) and/or by ischemia or infiltration of the optic nerve head. To be effective, management requires precise detection of inflammation, treatment of the inflammation and its underlying cause (if possible), elucidation of the mechanism(s) of any IOP elevation, and its effective control. Symptoms and signs may vary from marked to none; clinical course may be acute, subacute, unpredictably relapsing, or chronic. Management of the inflammation and any glaucoma is often challenging, especially as the mechanism(s) for raised IOP may change. This demands ongoing re-evaluation of mechanism(s) raising IOP and changes to treatment. Raised IOP complicates about 20% of clinic-based uveitis cases; about 40% of these later have abnormal perimetry.1 It is more common with anterior than with intermediate or posterior uveitides.

PATHOPHYSIOLOGY 1080

The relationship between IOP and inflammation is complex. IOP depends on the comparative rates of aqueous production and outflow

Secondary Open-Angle Glaucoma

Trabecular meshwork obstruction is the most common mechanism2 and may follow: White blood cell accumulation (macrophages and activated T lymphocytes) or their aggregations. Seen gonioscopically as small pale yellow or gray precipitates, or later fine peripheral anterior synechiae and angle-closure glaucoma. Inflammatory debris such as proteins, fibrin or even normal serum components following blood−aqueous barrier (BAB) breakdown. IOP may rise from increased aqueous viscosity. Altered vascular permeability may persist indefinitely with a subtle aqueous flare the clinical clue. This may predispose to recurrent inflammations, by increasing intraocular concentrations of substances like prostaglandins (PGs). Rarely, other solid components contribute to the blockage, for example, in Schwartz’s syndrome (rhegmatogenous retinal detachment, uveitis and glaucoma, rod outer segments can block trabeculum).3

• •

•

BOX 10-16-1 POSSIBLE CAUSES OF RAISED INTRAOCULAR PRESSURE Secondary Open-Angle Glaucoma Trabecular meshwork obstruction Canal of Schlemm and episcleral venous outflow obstruction Corticosteroid-induced elevation of intraocular pressure Permanent, direct trabecular meshwork tissue damage Post-trabecular outflow damage Hypersecretion

•• •• ••

Pre-Existing Primary Open-Angle Glaucoma Secondary Angle-Closure Glaucoma Peripheral anterior synechiae Posterior synechiae

••

Pre-Existing Disposition to Primary Angle-Closure Glaucoma Combined Mechanism Glaucoma

IOP. These various mechanisms may potentiate one another. Canal of Schlemm and episcleral venous outflow obstruction can be caused by similar physical and chemical means, or by raised episcleral venous pressure − particularly with scleritis, episcleritis and keratitis. Corticosteroids induce IOP elevation in susceptible patients by reducing trabecular outflow facility through changes to the mechanical structure of the trabecular meshwork, extracellular matrix trabecular deposits and reduction of trabecular endothelial functional and phagocytic activity.4 It is possible with topical, other local (dermal or inhalational), depot (subconjunctival, sub-Tenon’s, intravitreal), or systemic corticosteroids. Following 4−6 weeks of topical corticosteroids, in about 5% of patients IOP will rise by more than 16 mmHg and 30%, by 6−15 mmHg.5,6 In a minority, the IOP rise can be faster and greater; risk factors for this include primary open-angle glaucoma (POAG), family history of glaucoma, very young and older ages, diabetes, connective tissue disease, and myopia.7 Ninety-two percent of POAG patients are high steroid responders; among their children, 19%.6 Intravitreal triamcinolone acetonide (IVTA) can increase IOP for months. A 20 mg dose increased IOP above 21 mmHg in 40% of people for up to 9 months: 1% required trabeculectomy.8 More than 50% of children less than 10 years old respond to dexamethasone.9 Within two years of implanting the intravitreal Retisert implant (0.59 mg fluocinolone acetonide; Bausch & Lomb), which acts for more than 30 months, 60% required IOP-lowering medications and 32% needed filtering surgery. Topical corticosteroids vary in their IOP elevation effect (from the strongest effect to the least: dexamethasone 0.1%, prednisolone 1%, fluorometholone 0.1%, medrysone 1%);7 to reduce steroid response, minimize the strength, frequency and duration of corticosteroids. If possible, elucidate an individual’s IOP steroid response before using depot corticosteroids. Monitoring IOP is essential in all patients receiving corticosteroids. Once topical corticosteroids have ceased, IOP almost always returns to baseline within 4 weeks.10 In uveitis treatment, steroids show variable effects on IOP, depending on their influence at that time on rates of aqueous inflow, outflow, viscosity, and the BAB (Table 10-16-1). Permanent direct trabecular meshwork tissue damage can result from: Anterior and/or limbal scleritis. Destructive or degenerative connective tissue diseases. Chemical injuries including caustic soda, ammonia, formalin, nitrogen mustards, and chloroform. Post-trabecular outflow damage from scleritis with vasculitis: lymphocytes surround intrascleral outflow channels, with an anterior uveal perivasculitis. Hypersecretion may occur in uveitis but is difficult to quantify: the BAB breakdown renders fluorophotometry inaccurate. It may contribute to glaucomatocyclitic crises, but flow is probably normal.11

Pre-Existing Open-Angle Glaucoma

An elevated IOP in an eye with uveitis does not mean inflammation is the cause. Other primary or secondary forms of open-angle glaucoma, such as post-traumatic (particularly if unilateral) or pseudoexfoliative (may be uni- or bilateral) glaucoma must be ruled out. An acute onset and unilaterality suggest uveitis as the cause, whereas an afferent pupil defect with asymmetric disc cupping and perimetric loss in a patient with a short symptomatic (uveitic) history suggests a chronic underlying glaucomatous process.

Secondary Angle-Closure Glaucoma

Peripheral anterior synechiae (PAS) commonly complicate uveitis and if allowed to progress, may seal the angle partly or completely, raising IOP. PAS may follow organization of inflammatory debris or protracted irido-trabecular contact from an acute secondary angle-closure attack, a flat or shallow anterior chamber after incisional surgery, or an exudative retinal detachment with anterior displacement of the lens−iris diaphragm. Ciliary body rotation anteriorly from uveitis-induced swelling or suprachoroidal exudation can produce the same result. Swelling of the peripheral iris and exudation of proteins and other inflammatory products such as fibrin into the chamber angle enhance PAS formation. Neovascularization of the anterior chamber angle with subsequent fibrovascular closure may follow chronic uveitis. Posterior synechiae (PS) form with fibrin, with later fibrovascular organization. Involvement of the entire pupil margin results in a secluded pupil: iris bombé produces a shallow or closed peripheral anterior chamber with normal central depth. PAS follow if this acute secondary angle-closure is not treated promptly with one or more adequate peripheral iridectomies. With widespread adhesion of iris to anterior lens surface, bombé may not occur evenly or at all. Lens−iris diaphragm forward movement may be the only sign of pupillary block and can be confused with an underlying tendency to primary angle closure. Compare the anterior chamber configuration with that of the fellow eye to differentiate these mechanisms. Laser peripheral iridectomy placement can be crucial. Drainage surgery may be indicated. With uveitis, iris bombé and a closed angle, a low or normal IOP signals possible profound aqueous hyposecretion. Successful drainage surgery may precipitate the eye into phthisis bulbi, an increased risk anyway with uveitis.

Pre-existing Disposition to Primary Angle Closure

• • • •

With pre-existing shallow anterior chamber and relative pupillary block, an acute angle-closure crisis may be precipitated by anterior segment edema and inflammation, increased aqueous viscosity, swelling and forward rotation of the ciliary body and anterior shift of the lens−iris diaphragm. All or some of these factors may accompany uveitis. The depth of the contralateral anterior chamber will inform this diagnosis.

•

Combined-Mechanism Glaucoma

TABLE 10-16-1  EFFECTS OF CORTICOSTEROID THERAPY ON INTRAOCULAR PRESSURE IN OCULAR INFLAMMATION Action

Result

Effect on IOP

Decrease trabecular meshwork inflammation Increase blood–aqueous barrier

Increase trabecular meshwork outflow Decrease aqueous viscosity Increase trabecular meshwork outflow Return aqueous inflow to normal

Decrease

Decrease trabecular meshwork outflow

Increase

Decrease ciliary body inflammation Alter trabecular meshwork endothelial cells in corticosteroid responders IOP, intraocular pressure.

Decrease Increase

10.16 Inflammatory and Corticosteroid-Induced Glaucoma

of trabecular lamellae and endothelial cells with narrowing • Sofwelling trabecular pores and dysfunction. verwhelming the trabecular endothelial phagocytic and pathway• Oclearing processes by a severe inflammation. I f trabecular endothelial cell loss or damage becomes irreversible, • permanent reduction in conventional outflow follows. D irect trabecular damage keratitis, or the toxic effects of cor• neal stromal destruction. from Keratitis without uveitis rarely elevates

Usually the raised IOP associated with uveitis results from more than one of these mechanisms. The mix may change as the disease and its treatment proceed. Recognizing the responsible mechanism(s) at any time point enables effective antiglaucoma therapy.

PRINCIPLES OF MANAGEMENT Both the underlying inflammation and the glaucoma require assessment, diagnosis, and directed treatment. Management demands flexibility as the disease(s), the effects on the eye(s), and the treatment itself may change significantly over time. An open mind and careful examination and re-examination are vital for therapeutic success.

UVEITIS Diagnosis

A careful history with a review of systems and a complete ocular examination followed by targeted investigations should allow the majority of

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BOX 10-16-2 INFLAMMATORY CONDITIONS COMMONLY ASSOCIATED WITH RAISED INTRAOCULAR PRESSURE

Glaucoma

Anterior Uveitis HLA-B27-related acute anterior uveitis 20% (0%) Glaucomatocyclitic crisis (Posner–Schlossman syndrome) 100% (0%) Phacolytic glaucoma Herpes virus-associated uveitis 30% (29%) Fuchs’ heterochromic iridocyclitis Juvenile idiopathic arthritis-associated uveitis Chronic anterior uveitis

•• •• •• •

Intermediate Uveitis (Pars Planitis) Posterior Uveitis Peripheral anterior synechiae Sarcoidosis 34% (39%) Behçet’s disease 21% (50%) Toxoplasmosis 12% (36%) Vogt–Koyanagi–Harada syndrome 16% (34%) Sympathetic ophthalmia Acute retinal necrosis Masquerade syndromes Retinal detachment, uveitis, and glaucoma (Schwartz’s syndrome)

•• •• •• •• •

Percentages are cases with raised intraocular pressure (% with abnormal perimetry)

(From Takahashi T., Ohtani S., Miyata K., et al. A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol. 2002;46:556–562, and P McCluskey, personal communication.)

TABLE 10-16-2  TREATMENT GUIDELINES FOR INFLAMMATORY GLAUCOMA 1.  Treat underlying systemic disease (if present) Specific Non specific

e.g., Anti-infectives for toxoplasmosis, toxocariasis, Lyme disease, syphilis, TB Anti-inflammatory Immunosuppression

Steroids, NSAIDs Steroid-sparing agents: methotrexate, cyclosporine, mycophenolate, mofetil, azathioprine, cyclophosphamide

2.  Treat ocular inflammation Specific Non-specific

e.g., Intravitreal antibiotics for bacterial endophthalmitis Anti-inflammatory Pupillary dilation

Topical, depot, intravitreal or systemic steroids, NSAIDs Cycloplegic, sympathomimetic agents

3.  Treat elevated IOP Medical

Surgical

Reduce aqueous production Increase uveoscleral outflow Peripheral iridectomy Augmented trabeculectomy Glaucoma drainage devices Cyclodestruction: transscleral or endoscopic laser, cryotherapy

Beta-blockers, alpha-2-adrenergic agonists, carbonic anhydrase inhibitors Prostaglandin analogs For pupillary block, if present If medications are insufficient If augmented trabeculectomy fails For eyes with little visual potential

TB, tuberculosis; NSAIDs, nonsteroidal anti-inflammatory drugs.

ocular inflammations to be diagnosed. Please refer to sections on uveitis, keratitis, and scleritis. Box 10-16-2 lists conditions that commonly raise IOP.

Management

Detected ocular and any associated systemic diseases are treated on their merits: control active inflammation, prevent its damaging effects on aqueous circulation and drainage, and control elevated IOP (Table 10-16-2). Corticosteroids inhibit non-selectively most inflammatory reactions irrespective of cause; they do not treat the cause. Corticosteroids aid IOP control by treating trabeculitis, restoring the BAB; the balance can shift to higher IOP with steroid responsiveness and recovery of aqueous production with resolution of iridocyclitis. Corticosteroids remain firstline treatment for inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive drugs (methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, cyclophosphamide) are indicated alone, in combination with one another, or together with corticosteroids where steroids alone have failed to control inflammation or are contraindicated. These steroid-sparing agents are particularly useful in chronic uveitides in steroid-responsive patients. But given the potential for significant systemic side-effects, monitor these patients carefully. Biologic agents, particularly anti-tumor necrosis factor (TNF) blockers, are increasingly being incorporated into uveitis treatment. Antibiotics and antifungal agents are necessary when inflammation is secondary to a specific infection (e.g. toxoplasmosis) in addition to anti-inflammatory measures.

Mydriasis and Cycloplegia

Pupillary dilation with cycloplegics (atropine, homatropine) and sympathomimetics (phenylephrine) helps to prevent posterior synechiae forming or to break them, thereby avoiding a secluded pupil. These drugs help to control IOP by increasing uveoscleral outflow and by stabilizing the BAB. By decreasing ciliary muscle spasm, they may relieve discomfort.

GLAUCOMA

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In most eyes with acute inflammation, the optic disc is healthy and can withstand elevated IOP levels even into the thirties for weeks or months. Controlling inflammation and protecting the eye from damage to aqueous circulation and drainage mechanisms will normalize IOP. IOP reduction per se may not be required unless levels are thought unsafe, disc decompensation appears, other risk factors predispose

additionally to retinal vein occlusion, corneal endothelial disease contributes to edema, or recurrent or chronic inflammation provokes longstanding ocular hypertension.

Medical Management

Reduction of aqueous production is the cornerstone of medical management of raised IOP with inflammation: beta-blockers (timolol, betaxolol, carteolol, bunolol), alpha-2-adrenergic agonists (apraclonidine, brimonidine), and topical or systemic carbonic anhydrase inhibitors (dorzolamide, brinzolamide, acetazolamide, dichlorphenamide, methazolamide). Latanoprost, travoprost, and bimatoprost in uveitis are now accepted and have been used effectively in many uveitic eyes without sequelae.4 Exacerbation of uveitis and cystoid macular edema were concerns; use these agents cautiously. NSAIDs reduce the ocular hypotensive effect of brimonidine and possibly, latanoprost.12,13 Because they enhance posterior synechiae formation by aggravating BAB breakdown, by producing miosis and by contributing to anterior chamber shallowing, miotics (pilocarpine, carbachol) should be avoided.14 They may exaggerate discomfort with ciliary muscle spasm, and may raise IOP paradoxically by failing to improve trabecular outflow while blocking uveoscleral outflow.

Surgical Management

Laser peripheral iridectomy (LPI) is indicated if posterior synechiae precipitate a secluded pupil with iris bombé and medical mydriatic measures fail to break them. To eliminate pupillary block, the iridectomy(ies) must be adequate in size and position. LPI can raise IOP and exaggerate anterior uveitis; it can be difficult technically because of iris congestion. Gentle argon laser flattening (settings: 200–500 mW, 0.2–0.5 s, 200–500 µm spot) or ‘chipping’ pretreatment (settings: 800–1000 mW, 0.02 s, 50 µm spot) may facilitate neodymiu m:yttrium−aluminum−garnet (Nd-YAG) laser penetration of the iris. Laser openings may close with active inflammation: monitor carefully and maybe retreat or consider surgical peripheral iridectomy. In eyes with severe uveitis, particularly children, a larger surgical iridectomy may be preferable to YAG iridectomy as it minimizes inflammation and is less likely to close. Argon laser trabeculoplasty (LT) can exacerbate anterior uveitis and promote PAS formation; it has a poor chance of reducing IOP significantly.15 It is contraindicated in inflammatory glaucoma. Selective laser trabeculoplasty has not yet been evaluated adequately in these eyes. In corticosteroid-induced glaucoma, it may be effective.

SPECIFIC ENTITIES Table 10-16-2 highlights conditions associated with ocular inflam­ mation and glaucoma etiologically. Refer to other chapters for more detail.

Glaucomatocyclitic Crisis (Posner–Schlossman Syndrome)

Posner and Schlossman described nine patients with this entity in 1948.21 Clinical features include episodic, unilateral markedly elevated IOP (usually 40–60 mmHg), associated with a mild anterior uveitis. Recurrences are always in the same eye. Posterior synechiae and PAS are absent and the drainage angle remains open. Each attack lasts from a few hours to a month, but usually between 1 and 3 weeks. Antiglaucoma treatment does not abbreviate the attack and iridectomy or filtering surgery do not prevent recurrences. Glaucomatous optic neuropathy may occur. Between attacks there are generally no signs or symptoms of inflammation or glaucoma and the contralateral eye remains normal. Of unknown etiology, although infection (CMV, herpes, Helicobacter pylori) has been implicated, this condition has a complex relationship with primary open-angle glaucoma.22–27 Management comprises: Hypotensive measures. Apraclonidine or brimonidine seem particularly effective during attacks, with supplementation as required with other aqueous suppressants. The role for PG derivatives is yet to be established. Rarely hyperosmotic agents may be needed. Anti-inflammatory measures. Although there is no evidence that they shorten the attack, or prevent recurrences, many clinicians consider corticosteroids and/or topical NSAIDs ‘useful.’ Cycloplegics are not needed. Intervals between attacks vary from a few days to several years. Some are seasonal. Attacks are rare in the elderly, suggesting a self-

• •

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resolving course. Thus prevention of irreversible disc and field damage is all the more important. An anterior chamber paracentesis may reveal an infectious etiology for Posner–Schlossman syndrome, which in turn may guide specific therapy directed against that agent, rather than treatment of elevated IOP. Should aqueous PCR reveal CMV, for example, treatment with ganciclovir may be curative of the IOP elevation. Topical ganciclovir ointment in addition to oral valganciclovir can be of benefit; however, systemic treatment is necessary in the case of CMV.25 Valganciclovir is not benign and the patient must be followed closely to treatment toxicity.

Fuchs’ Uveitis Syndrome (Fuchs’ Heterochromic Iridocyclitis)

More expansive than its 1906 description by Fuchs,28 this condition encompasses a chronic, usually unilateral (90%), low-grade panuveitis with rapid cataract formation (commencing as posterior subcapsular) and a high risk of secondary open-angle glaucoma. This entity is differentiated from other inflammatory glaucomas by the lack of posterior synechiae and the rarely more than ‘moderate’ anterior chamber cells and flare; it is asymptomatic. Vitreous cells are common. Pathognomonically, keratic precipitates are small, round or stellate, and discrete; they cover the entire corneal endothelial surface and fine filaments are often seen between them. Their presence and extent greatly exceeds the inflammation. Rubella has been implicated as the inciting event,29 as has CMV.25–27 Anterior chamber paracentesis with aqueous PCR is recommended in Fuchs’ heterochromic iridocyclitis, as for Posner– Schlossman syndrome. Should an infectious etiology be present, treatment is as described above for Posner–Schlossman syndrome, specific to the infectious agent. This may completely eliminate the need for ocular antihypertensive treatment, with IOP normalization. Fuchs’ uveitis syndrome (FUS) and Posner–Schlossman syndrome may be thought of as part of a spectrum of uveitic glaucomas, and may share the same infectious etiology. Unless an infectious etiology for the FUS is found, therapy of the uveitis is unnecessary, although a short intensive trial of steroids may help to confirm the diagnosis (by lack of response). When the eye is symptomatic, short bursts of topical steroids may restore comfort, but steroids do not normalize the BAB or achieve total quiescence. The glaucoma is more difficult to control.30 Initially a raised IOP may respond to anti-inflammatory treatment, but in two-thirds of patients, a chronic IOP rise often resists medications. Argon LTP is ‘underwhelming’ in its effect, and is contraindicated by angle changes. Selective laser trabeculoplasty has not been evaluated. Should even augmented trabeculectomy fail, GDDs may prove helpful. Patients require ongoing monitoring, especially for glaucoma damage and for progressive iris atrophy, which hint at a poor prognosis. Recognition is important; it renders unnecessary anti-inflammatory therapy.

10.16 Inflammatory and Corticosteroid-Induced Glaucoma

Filtration surgery becomes necessary when medical and laser management, along with treatment of both inflammation and its cause, cannot reduce the IOP below levels that are causing or likely to cause optic disc decompensation and functional damage. Because of increased postoperative inflammation and a greater risk of profound hypotony leading to bleb failure, filtering surgery is less likely to succeed in inflamed eyes than in those with primary open-angle glaucoma.16 Trabeculodialysis (modified goniotomy) has been tried with some success. One of the keys to success in all drainage surgery is to control inflammation maximally both pre- and post-surgery with, for example, intensive topical, local, or even systemic steroids. Adjunctive antifibrotic agents (intraoperative 5-fluorouracil (5FU), mitomycin C17, postoperative 5FU18) have improved trabeculectomy success rates appreciably − in both the short and long term. Complication rates increase, however, with these agents, most seriously, hypotonous maculopathy and late endophthalmitis from leaks through thin-walled blebs. Glaucoma drainage devices (GDDs), both valved (Ahmed) and nonvalved (Molteno and Baerveldt) have had more success than unaugmented trabeculectomies. GDDs do not achieve the low levels of IOP (7–11 mmHg) that augmented trabeculectomies often can. In eyes with extensive optic disc damage, a GDD-attained IOP of 14–18 mmHg may not be sufficiently protective. In eyes with visual potential, a GDD is indicated where augmented trabeculectomies have failed.19 GDD tubes must be patched with donor sclera or equivalent to prevent erosion, especially in uveitic glaucoma. In chronic glaucoma where aqueous production is borderline and hypotony risk is high, a smaller GDD (single plate Molteno or 250 mm2 Baerveldt or Ahmed) is preferable to larger devices. Reducing aqueous production by damaging ciliary epithelium (cyclodestruction) by Diode, Nd-YAG or ultrasound energy has been used to lower IOP. Because they may aggravate ocular inflammation and lower IOP unpredictably (with significant risk of secondary phthisis bulbi or failure to control IOP), as well as the albeit small risk of sympathetic ophthalmia, cyclodestruction is recommended where all else has failed and with little visual potential.20 Lower laser power settings are prudent and lasers delivering lower doses such as the micropulse and endoscopic laser show promise. Drainage surgery after ciliary body destruction in an inflamed eye is a likely setting for hypotony and phthisis bulbi.

KEY REFERENCES Chee SP, Bacsal K, Ja A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol 2008;145:834–40. Goldberg I. Management of uncontrolled glaucoma with the Molteno system. Aust NZ J Ophthalmol 1987;15:97–107. Kass MA, Becker B, Kolker AE. Glaucomatocyclitic crisis and primary open-angle glaucoma. Am J Ophthalmol 1973;75:668–73. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of the literature. Eye 2006;20:407–16. Krupin T, Dorfman NH, Spector SM, et al. Secondary glaucoma associated with uveitis. Glaucoma 1988;10:85–90. Kwok AK, Lam DS, Ng JS, et al. Ocular-hypertensive response to topical steroids in children. Ophthalmology 1997;104:2112–16. Liu Y, Takusagawa HL, Chen TC, et al. Fuchs heterochromic iridocyclitis and the rubella virus. Int Ophthalmol Clin 2011;51:1–12. Posner A, Schlossman A. Syndrome of unilateral recurrent attacks of glaucoma with cyclitic symptoms. Arch Ophthalmol 1948;39:517–35. Sallam A, Sheth HG, Habot-Wilner Z, et al. Outcome of raised intraocular pressure in uveitic eyes with and without a corticosteroid-induced hypertensive response. Am J Ophthalmol 2009;148:207–13. Takahashi T, Ohtani S, Miyata K, et al. A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol 2002;46:556–62. Weinreb RN. Intraocular pressure. Consensus series-4. The Hague: Kugler Publications; 2007.

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REFERENCES 1. Takahashi T, Ohtani S, Miyata K, et al. A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol 2002;46:556–62.

3. Schwartz A. Chronic open-angle glaucoma secondary to rhegmatogenous retinal detachment. Am J Ophthalmol 1973;75:205–11. 4. Sallam A, Sheth HG, Habot-Wilner Z, et al. Outcome of raised intraocular pressure in uveitic eyes with and without a corticosteroid-induced hypertensive response. Am J Ophthalmol 2009;148:207–13. 5. Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal eye. Invest Ophthalmol 1965;4:187–97. 6. Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 1965;4:198–205. 7. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review if the literature. Eye 2006;20:407–16. 8. Jonas JB, Degenring RF, Kreissig I, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology 2005;112:593–8. 9. Kwok AK, Lam DS, Ng JS, et al. Ocular-hypertensive response to topical steroids in children. Ophthalmology 1997;104:2112–16. 10. Becker B, Mills DW. Corticosteroids and intraocular pressure. Arch Ophthalmol 1963;70: 500–7. 11. Weinreb RN. Intraocular pressure. Consensus series-4. The Hague: Kugler Publications; 2007. 12. Sponsel WE, Paris G, Trigo Y, et al. Latanoprost and brimonidine: therapeutic and physiologic assessment before and after oral nonsteroidal anti-inflammatory therapy. Am J Ophthalmol 2002;133:11–18.

16. Hoskins HD Jr, Hetherington J Jr, Shaffer RN. Surgical management of the inflammatory glaucomas. Perspect Ophthalmol 1977;1:173–81. 17. Kitazawa Y, Kawase K, Matsushita H, et al. Trabeculectomy with mitomycin. A comparative study with fluorouracil. Arch Ophthalmol 1991;109:1693–8. 18. The Fluorouracil Filtering Surgery Study Group. Fluorouracil Filtering Surgery Study one-year follow-up. Am J Ophthalmol 1989;108:625–35. 19. Goldberg I. Management of uncontrolled glaucoma with the Molteno system. Aust NZ J Ophthalmol 1987;15:97–107. 20. McAllister J, O’Brien C. Neodymium: YAG transscleral cyclocoagulation: a clinical study. Eye 1990;4(Pt 5):651–6. 21. Posner A, Schlossman A. Syndrome of unilateral recurrent attacks of glaucoma with cyclitic symptoms. Arch Ophthalmol 1948;39:517–35. 22. Kass MA, Becker B, Kolker AE. Glaucomatocyclitic crisis and primary open-angle glaucoma. Am J Ophthalmol 1973;75:668–73. 23. Teoh SB, Thean L, Koay E. Cytomegalovirus in aetiology of Posner–Schlossman syndrome: evidence from quantitative polymerase chain reaction. Eye 2005;19:1338–40. 24. Bloch-Michel E, Dussaix E, Cerqueti P, et al. Possible role of cytomegalovirus infection in the etiology of the Posner–Schlossman syndrome. Int Ophthalmol 1987;11:95–6. 25. Chee SP, Bacsal K, Ja A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol 2008;145:834–40. 26. Van Gelder RN. Idiopathic no more: clues to the pathogenesis of Fuchs’ heterochromic iridocyclitis and glaucomatocyclitic crisis. Am J Ophthalmol 2008;145:769–71. 27. Van Boxtel LA, Van der Lelij A, Van der Meer J, et al. Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology 2007;114:1358–62. 28. Fuchs E. Uber Komplicationen der Heterochromic. Z Augenheilkd 1906;15:191–212.

13. Kashiwagi K, Tsukahara S. Effect of non-steroidal anti-inflammatory ophthalmic solution on intraocular pressure reduction by latanoprost. Br J Ophthalmol 2003;87:297–301.

29. Liu Y, Takusagawa HL, Chen TC, et al. Fuchs’ heterochromic iridocyclitis and the rubella virus. Int Ophthalmol Clin 2011;51:1–12.

14. Ignarro LJ, Colombo C. Enzyme release from polymorphonuclear leukocyte lysosomes: regulation by autonomic drugs and cyclic nucleotides. Science 1973;180:1181–3.

30. Jones NP. Glaucoma in Fuchs’ heterochromic uveitis: aetiology, management and outcome. Eye 1991;5(Pt 6):662–7.

10.16 Inflammatory and Corticosteroid-Induced Glaucoma

2. Krupin T, Dorfman NH, Spector SM, et al. Secondary glaucoma associated with uveitis. Glaucoma 1988;10:85–90.

15. Robin AL, Pollack IP. Argon laser trabeculoplasty in secondary forms of open-angle glaucoma. Arch Ophthalmol 1983;101:382–4.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

10.17

Glaucoma Associated with Ocular Trauma David P. Tingey, Bradford J. Shingleton

Definition: Glaucomatous damage to the optic nerve related to

elevated intraocular pressure associated with acute or prior ocular trauma.

Key features Previous blunt or penetrating ocular trauma − glaucoma is more likely to follow blunt trauma. ■ Angle recession − the greater the number of clock hours recessed, the more likely glaucoma is to occur, even months, years, or decades after the injury. ■ Hyphema − often accompanies angle recession, and may be an acute cause of elevated intraocular pressure, especially in the presence of hemoglobinopathies (e.g., sickle-cell disease or trait). ■

Associated features ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Trabecular tears/trabeculitis Angle recession Iridodialysis Pupillary sphincter tears Cyclodialysis Zonular dehiscence Lens damage, subluxation, or dislocation Vitreous hemorrhage May lead to ghost cell glaucoma Retinal dialysis/retinal tear

INTRODUCTION

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Glaucoma may represent a problem in traumatized eyes in the period immediately following injury or years or decades later. There exist a plethora of potential causes of glaucoma following ocular trauma. It is important for the evaluating ophthalmologist to be familiar with the various types of glaucoma in this setting as well as their pathogenesis. Recent cohort studies have examined the relationship of glaucoma following ocular injury to several baseline structural and functional ocular characteristics. The risk of developing glaucoma in 3627 patients in the United States Eye Injury Registry with penetrating ocular injury was 2.67%. The development of glaucoma in these patients was independently associated with advancing age, lens injury, poor baseline acuity, and inflammation.1 In a similar study, 6021 patients in the registry who experience ocular contusion injury were found to have a risk of developing glaucoma of 3.39% at 6 months after their injury. The development of glaucoma was independently associated with: advancing age visual acuity worse than 20/200

• •

ris injury • ilens • angleinjury recession. • Ultrasound biomicroscopy was used in conjunction with clinical 2

features to determine early predictors of traumatic glaucoma after closed-globe injury prospectively in 40 consecutive eyes.3 This study found that the best clinical indicators of the development of chronic glaucoma included degree of trabecular pigmentation, angle recession more than 180°, hyphema, lens displacement, and higher baseline intraocular pressure (IOP). Ultrasound biomicroscopic findings that were significant predictors of chronic glaucoma included a wider angle and the absence of cyclodialysis.3. In the initial period following an ocular injury, the IOP may be normal, high or low. Several mechanisms exist to explain a low pressure. These mechanisms include aqueous hyposecretion based on ciliary contusion and inflammation, increased egress of aqueous through a cyclodialysis cleft, or loss of integrity of the wall of the globe. The presence of ocular hypotension or normal IOP does not preclude the development of glaucoma at a later date. Whether glaucoma is present initially or at a later date, it is generally a reflection of reduced facility of outflow of aqueous humor. One may categorize the existence of traumatic glaucoma relative to the time of onset of the glaucoma (immediate or delayed) and the type of trauma that caused the injury. The type of trauma may be divided into blunt-force trauma or penetrating trauma. A broader classification would include chemicals, electromagnetic radiation and surgery as additional causes of trauma that might induce glaucoma. Glaucoma may also occur as a result of the therapeutic modalities employed to treat the initial injury.

IMMEDIATE OR EARLY-ONSET GLAUCOMA AFTER OCULAR TRAUMA Contusion

IOP elevation in the setting of blunt trauma with a notable absence of clinical evidence of tissue damage may be noted on occasion. Gonioscopy is entirely normal with no evidence of angle recession and there is no evidence of blood or abnormal pigment in the angle. Flare and cells may be evident at the slit lamp. The presumed mechanism of this type of glaucoma is reduced outflow facility as a result of trabecular inflammation. The course of this glaucoma is usually brief and self-limited although a trial of topical anti-inflammatory drops in addition to any IOP-lowering agents may hasten improvement and shorten the clinical course.

Trabecular Disruption

Evidence of trauma-related changes to the trabecular meshwork has been documented in a study utilizing gonioscopy performed within the first 48 hours following injury. Documented abnormalities ranged from sharply demarcated hemorrhage into Schlemm’s canal and possibly the outer trabecular sheets to full-thickness rupture of the trabecular meshwork for part of its circumference. A trabecular flap may be created with a point of rupture at or just below the insertion of the trabecular sheets at Schwalbe’s line. This flap is typically hinged in the region of the scleral spur. Lesions such as these at the trabecular meshwork may or

may not be associated with elevated IOP at the time of injury. Trabecular lesions may scar with time and become increasingly difficult to recognize over time. Although angle recession is associated with the late development of glaucoma, the occurrence of late glaucoma may correlate better with the amount of trabecular disruption observed acutely.4

Hyphema

The presence of hyphema (Figure 10-17-1) following ocular trauma is an indicator of significant intraocular injury. Cho et al. compared the clinical characteristics of 18 patients with very poor visual outcome after nonperforating hyphema to 166 patients with better visual outcome after nonperforating hyphema. The presence of posterior segment injuries, anterior segment injuries, poor initial visual acuity, glaucoma, vitreous hemorrhage, and eyelid laceration were all associated with long-term poor visual outcome.5 Hyphema may produce glaucoma via several mechanisms including contusion/inflammation of the trabecular meshwork, physical disruption of the meshwork, and plugging of the meshwork with red blood cells. In addition, a large clot in the anterior chamber may even produce pupillary block by entirely occluding the pupillary aperture. Elevation of IOP in association with hyphema may threaten vision as a result of optic nerve damage, compromised blood flow to the posterior segment, or corneal blood staining. IOP elevation occurs in up to 27% of patients acutely; however, this elevation is often mild and self-limited.4 The duration and level of IOP required to damage the optic nerve for a given individual is difficult to determine. Read and Goldberg6 studied 137 hyphema patients prospectively and determined that optic atrophy tended to occur with IOPs at or greater than 35 mmHg with durations varying from 5 to 14 days. Optic atrophy as a direct result of the trauma itself may be a confounding factor in such studies. Corneal blood staining occurs more readily in the presence of an IOP greater than 25 mmHg which has persisted for at least 6 days.6 If the corneal endothelial cells are already compromised as a result of the trauma itself or preexisting disease, the risk of staining with only marginal pressure elevation is even greater. Sickle-cell disease represents a unique challenge in the hyphema patient. Even small amounts of blood in the anterior chamber of such patients may result in severe IOP elevation.7 Sickled erythrocytes presumably obstruct the outflow apparatus. Optic atrophy has also been reported in such patients with only mild pressure elevation.7,8 Compromised blood flow to the optic nerve as a result of sickling has been proposed as a mechanism for this. These complications may be seen in patients with either sickle-cell disease or trait. In addition, several of the conventional IOP-lowering pharmacological agents may be harmful to patients with sickle-cell hemoglobinopathy. Carbonic anhydrase inhibitors may produce systemic acidosis which enhances sickling. Methazolamide may be a safer choice than acetazolamide in

10.17 Glaucoma Associated with Ocular Trauma

Fig. 10-17-1  Blood layering (arrow) in the anterior chamber (hyphema). (From Schuman JS, Christopoulos V, Dhaliwal D, et al. Rapid diagnosis in ophthalmology series: Lens and glaucoma. Elsevier; 2007.)

this setting because it causes less systemic acidosis. Both carbonic anhydrase inhibitors and osmotic agents increase hemoconcentration and viscosity because of their diuretic effect. This may in turn compromise blood flow in a system already at risk from sickled erythrocytes. Acetazolamide can increase ascorbate in the aqueous humor and this may worsen the sickling process as well. Epinephrine agents and less specific alpha agonists such as apraclonidine may cause vasoconstriction which may also compromise ocular blood flow in sickle cell patients. The presence of hyphema in the sickling patient calls for the judicious use of pharmacologic agents to control even mild pressure elevation and a lower threshold on the part of the clinician for performing a washout of erythrocytes from the anterior chamber. The successful use of intracameral tissue plasminogen activator in a sickle cell patient with traumatic hyphema and acute glaucoma has been reported.9 Rebleeding into the anterior chamber can be a devastating complication which typically occurs between days 2 and 6 following the initial injury. The reported incidence of rebleeding is somewhere between 6 and 33% based on several studies.6,8,10,11 Markedly elevated IOP and its attendant complications are a particular concern with rebleeding. Aminocaproic acid decreases the rate of rebleeding in some patients.8,11 Systemic corticosteroids have been recommended by some to reduce the incidence of rebleeding.12,13 However, Spoor and associates14 showed no benefit from oral corticosteroids in a prospective study. Although aminocaproic acid may reduce the incidence of rebleeding in some patients, exaggerated clot lysis in patients with larger hyphemas may develop 1–2 days following therapy discontinuation with associated acute IOP elevation as a result of lysed cells and debris obstructing outflow.15 This and the fact that aminocaproic acid may have systemic side-effects including nausea and vomiting as well as the relatively low incidence of rebleeds overall may account for why some clinicians choose not to employ this drug. Acute IOP elevation in the setting of hyphema may be treated with conventional pharmacologic agents, with the exception of miotic agents and prostaglandin agents. Both of these agents may exacerbate any pre-existing inflammation and so they are not generally used as first line agents. Cycloplegic agents and topical corticosteroids are often employed in the treatment of any associated inflammation following hyphema. The potential for either topical or systemic steroids to produce IOP elevation with more chronic use must be kept in mind. If the IOP remains elevated at a level that threatens the optic nerve or the cornea in spite of medical therapy, then surgical intervention may be necessary. Many surgical procedures have been reported in the literature including anterior chamber washout,16 mechanical clot expression,17 delivery of the clot with a cryoprobe,18 automated hyphemectomy,19 and ultrasonic emulsification and aspiration of the clot.20 Trabecular gonioaspiration has been reported as a successful way of managing pressure elevation resulting from blood obstructing the trabecular meshwork in patients with sickle cell trait.21 Adjunctive procedures may include peripheral iridectomy to relieve clot-induced papillary block.22 Trabeculectomy has been used to achieve pressure normalization.23,24 Cyclodiathermy to control recurrent bleeding has also been described.25 Paracentesis and anterior chamber washout is the simplest and safest procedure for clot evacuation. This can be performed by simple irrigation or by manual coaxial irrigation and aspiration. Removal of the entire clot may not be necessary. This technique also spares the conjunctiva for future filtration surgery if it becomes required.

Massive Choroidal Hemorrhage

This is a rare cause of acute IOP elevation following ocular trauma. A shallow anterior chamber both axially and peripherally in association with a reduced red reflex or a frank retrolenticular mass at the slit lamp will be seen. Indirect ophthalmoscopy reveals choroidal elevation. Obstruction of the trabecular meshwork from secondary angle closure is the most common reason for IOP elevation in this setting although other mechanisms from associated other effects of the trauma such as hyphema, inflammation etc. may also play a role. Initial treatment consists of topical IOP-lowering agents as well as oral carbonic anhydrase inhibitors and a systemic hyperosmotic agent if needed. Miotics should be avoided as they will further shallow the anterior chamber. Cycloplegics may be effective in deepening the anterior chamber. Oral corticosteroids may be helpful in reducing inflammation and stabilizing compromised choroidal vasculature.

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10 Glaucoma

Certain situations, such as persistent angle closure with IOP elevation, lens–cornea apposition, and kissing choroidals with retinal apposition may warrant surgical drainage of the blood in the suprachoroidal space. It is advisable to wait several days if possible for the blood clot to become liquefied in the suprachoroidal space before intervening. Chronic synechial closure of the angle may be a sequela of massive suprachoroidal hemorrhage. This may require intervention in the form of chronic medical therapy, laser iridoplasty, surgical goniosynecholysis, conventional filtration surgery, or cycloablation depending on circumstances. Massive choroidal detachment with intraretinal dissection is a rarely seen occurrence following trauma in the setting of age-related macular degeneration. This results in a ‘Y-suture’ apposition of posterior segment tissues pushing the lens-iris diaphragm forward and leading to angle closure.26 IOP rises dramatically, and vision is often reduced to no light perception. Medical or surgical therapy rarely restores vision.

Chemical Trauma

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Alkali burns produce tissue saponification, resulting in severe damage to the ocular structures. Acid burns are often more self-limited as a result of tissue coagulation. Glaucoma is more often associated with alkali burns. Glaucoma as a result of alkali burns may be immediate or delayed. In 1946, Hughes27 documented several cases of elevated IOP with delayed onset following an alkali burn. Several papers in the 1960s documented acute pressure elevation following alkali burn.28,29 The angle was gonioscopically open in these cases. The nature of the acute IOP rise has been studied in rabbits by Chiang and associates.30 They demonstrated a dicrotic rise in IOP following the application of sodium hydroxide. In the rabbit model there was an immediate rise in IOP of 40 mmHg, followed by a gradual decline in pressure to 20 mmHg above normal in 10 minutes. The IOP again rose gradually reaching 40 mmHg above normal at 1 hour. The IOP was 20 mmHg above normal at 3 hours following the alkali application. The mechanism of IOP rise in rabbits following alkali application was elucidated by Paterson and Pfister.31 They implicated tissue shrinkage involving the outer coats of the eye in the initial pressure spike. Lid contraction and extraocular muscle spasm were not felt to play an important role in pathogenesis. Prostaglandin release as part of the inflammatory cascade was felt to be the greatest contributor to the second hypertensive phase. The authors also postulated that blockage of the trabecular meshwork with inflammatory debris might also play a later role in the rise of IOP. The potential for acute IOP elevation in the setting of alkali burn as documented in the animal model points to the importance of attempting to document IOP as early as possible following the injury. In addition to the conventional therapies directed at the anterior segment consequences of an alkali burn, treatment of any IOP elevation is important. Arguably, treatment with IOP-lowering agents on a prophylactic basis is a reasonable consideration, particularly in severe burns given the propensity for these burns to produce a rapid and severe IOP elevation. When the decision to treat with IOP-lowering agents is made, treatment with topical beta-blockers, alpha-agonists and carbonic anhydrase inhibitors are all appropriate as well as systemic treatment with carbonic anhydrase inhibitors and hyperosmotic agents as needed. Miotics and topical prostaglandin analogs are generally avoided because of the inflammatory nature of this condition. Anti-inflammatory medications and adequate cycloplegia are also important. Anterior chamber paracentesis with aspiration of aqueous humor may be required if the IOP is extremely high during the initial hypertensive phase. This reduces the IOP and removes inflammatory mediators, debris, and alkali directly from the anterior chamber. After the initial alkali burn, glaucoma may appear or reappear. Ongoing inflammation with secondary peripheral anterior synechiae and angle closure is the most common mechanism. In one study looking at the incidence of glaucoma in eyes with severe chemical burn, before and after keratoprosthesis, Cade et al. found that 21 of 28 eyes in this group had preoperative evidence of glaucoma, 9 of these eyes developed glaucoma progression after keratoprosthesis implantation and 2 more eyes developed glaucoma postoperatively.32 The treatment of this late-onset glaucoma includes conventional medical and surgical therapies.

LATE-ONSET GLAUCOMA AFTER OCULAR TRAUMA Angle Recession

The first pathological description of angle recession resulting from blunt trauma was described by Collins33 in 1892. In 1949, D’Ombrain34 described a chronic post-traumatic glaucoma which he attributed to a proliferative lesion scarring the trabecular meshwork. No observation of pathologic deepening of the anterior chamber angle was made. The pathological entity of angle recession and the clinical phenomenon of unilateral chronic glaucoma were linked by Wolff and Zimmerman in 1962.35 Anatomical recession of the anterior chamber angle (Figure 10-17-2) is common following blunt trauma. The incidence of angle recession following traumatic hyphema ranges from 71 to 100% based on several reports.36–39 Glaucoma is relatively uncommon following angle recession, being found in 7–9% of eyes.36,38,40 Attempts have been made to correlate the degree of angle recession with the likelihood of developing glaucoma. Alper41 believed that the risk of glaucoma developing was highest if more than 240° of the angle appeared recessed. In a population-based survey Salmon et al. performed gonioscopy on 987 inhabitants of a small South African village. They found a cumulative lifetime prevalence of angle recession in the community of 14.6%. The prevalence of glaucoma in people with angle recession was 5.5% (8/146). Of 87 eyes with 360° of angle recession, only 7 (8.0%) had glaucoma.42 The elevation of IOP from angle recession demonstrates a bimodal pattern with glaucoma occurring either within the first year or after 10 years as described by Blanton.36 This author found that the earlieronset group often had less angle recession, and the IOP rise was transient in some patients. Other authors have found recession greater than 270° more common in the early-onset group.4 Angle recession is defined pathologically as a separation between the longitudinal and circular fibers of the ciliary body muscle.35 The longitudinal muscles remain attached to the scleral spur and there is a posterior displacement of the iris root. Iridodialysis (Figure 10-17-3) and cyclodialysis may also be observed. Lenticular changes including subluxation, dislocation or cataract may occur. Late evaluation of the angle may show a broad ciliary band with a fusiform appearance attributed to atrophy of the inner circular portion of the ciliary muscle. Variable degrees of fibrosis and hyalinization of the trabecular meshwork may occur. Peripheral synechiae may also be present. Elevated IOP immediately after injury may be due to extensive angle recession, although it may also be due to other causes, as cited earlier in this chapter. The clinical presentation of glaucoma secondary to

Fig. 10-17-2  Tear between the longitudinal and circular muscles of the ciliary body presenting as a widening (arrow) of the ciliary band (angle recession). (From Schuman JS, Christopoulos V, Dhaliwal D, et al. Rapid diagnosis in ophthalmology series: Lens and glaucoma. Elsevier; 2007.)

angle recession is variable and depends somewhat on the time of presentation relative to the initial injury. Often, angle-recession glaucoma presents years after the initial event as a chronic unilateral glaucoma. In a pathologic review of 100 eyes enucleated for unilateral glaucoma, Miles and Boniuk43 found 11 eyes with angle deformity as the principal cause for the glaucoma. None of these deformities had been recognized clinically. Eight of these 11 patients gave a history of previous trauma to the eye ranging from 6 months to 24 years before the onset of glaucoma. Unilateral glaucoma is typically secondary, and a history of previous trauma should always be sought. Examination will often reveal clues including a deeper anterior chamber on the affected side, tears of the iris sphincter or root, thinning of the iris stroma, or abnormal clumps of pigmentation on the iris. As a result of pigmentary changes, the iris color may differ between the two eyes. Tonjum44 has demonstrated a paralyzed or paretic pupillary sphincter in the same sector as the chamber angle deformity in acutely injured eyes. This pupillary change may recover over time. The lens may be abnormally mobile or frankly dislocated. There may be clues to previous injury in the posterior segment including pigment in the vitreous, macular edema, retinal pigment epithelial hyperplasia, choroidal or retinal scars or frank retinal detachment. Gonioscopy is key in establishing a diagnosis of angle recession. The cardinal features of angle recession on gonioscopy include an exposed ciliary body face which appears wider than usual and an iris root that appears to be posteriorly displaced. Uveal processes are disrupted and the scleral spur may appear abnormally pale or white. Comparison of the angle appearance between contralateral eyes is helpful in detecting more subtle degrees of angle recession. The technique of bilateral simultaneous Koeppe gonioscopy is most helpful in this regard. An additional gonioscopic finding is the presence of a gray–white membrane covering the angle recess which may be observed even years after the initial injury.41 Elevated IOP in angle recession is a result of significant injury to the trabecular meshwork as opposed to the more evident tear into the ciliary body. The facility of outflow, as measured by tonography, is reduced and correlates with the degree of angle recession and glaucoma.37 Herschler4 was able to document a high incidence of visible damage to the trabecular meshwork and Schlemm’s canal in eyes undergoing gonioscopy within 48 hours of injury. These trabecular lesions decreased over time while the ciliary body tears persisted. An underlying predisposition to the development of glaucoma in some injured patients may exist. Spaeth45 studied 13 patients in whom unilateral angle-recession glaucoma had developed and found that approximately 50% of these patients had evidence of frank or probable glaucoma in their fellow eye. Angle-recession glaucoma is a secondary chronic open-angle glaucoma that is generally amenable to standard topical medications used to treat the glaucomas. Laser trabeculoplasty may be attempted provided the initial IOP is not too high.46,47 Neodymium:yttrium– aluminum–garnet (Nd:YAG) laser trabeculopuncture met with some success in a small series of 11 Japanese patients with angle-recession glaucoma.48 Filtration surgery is certainly an option in these patients provided the conjunctiva is not extensively scarred from the injury

Peripheral Anterior Synechiae

10.17 Glaucoma Associated with Ocular Trauma

Fig. 10-17-3  Tear in the root of the iris (iridodialysis). (From Schuman JS, Christopoulos V, Dhaliwal D, et al. Rapid diagnosis in ophthalmology series: Lens and glaucoma. Elsevier; 2007.)

itself or related ocular surgeries such as retinal detachment repair. Trabeculectomy may be less successful in post-traumatic angle-recession glaucoma. Mermoud et al. found the success rate of trabeculectomy for angle-recession glaucoma to be 43% in 35 consecutive patients compared to a success rate of 74% in 35 consecutive matched primary open-angle glaucoma patients. These authors advocated the routine use of antimetabolites in such cases.49 These results were also supported by a retrospective analysis of 87 drainage procedures performed over an 8-year period in which trabeculectomy with antimetabolite outperformed trabeculectomy without antimetabolite and Molteno implantation.50 The effectiveness of using mitomycin C in filtering surgery for angle-recession glaucoma was demonstrated in a retrospective review of 43 consecutive procedures. Cumulative probability of success was 85% at 1 year and 81% at 2 years.51 Additionally, tube shunt surgery or cyclodestruction represent additional available therapeutic modalities as indicated. A prospective case series examined 38 patients who received a Molteno implant with a mean follow-up of 10.9 years. IOP of 21 mmHg or less (with or without hypotensive medication) occurred with a probability of 0.80 at five years and 0.72 at 10 years.52 More recently, de Kierk and Au reported successful treatment of angle-recession glaucoma with the i-Stent in two patients.53

Peripheral anterior synechiae (PAS) are a product of apposition of iris to the angle structures or peripheral cornea in the setting of inflammation. Ocular trauma can provide these conditions on occasion. Organization of blood and inflammatory debris in the angle can occur following hyphema. Penetrating trauma may shallow the chamber for extended periods, resulting in extensive synechial closure of the angle. Endothelization of the angle has been observed following blunt trauma, and this can pull the angle closed. Epithelial or fibrous downgrowth following penetrating trauma will produce angle closure. Massive choroidal hemorrhage after trauma will push the angle closed and sets up an inflammatory cascade, often leaving the angle closed after the hemorrhage has resolved. The potential for synechial closure necessitates careful and repeated gonioscopy after a traumatic event. Treatment of synechial closure can often be directed at attempting to reopen the angle, particularly if the intervention occurs early rather than late. Iridogonioplasty with the argon laser may be sufficient to pull the iris away from the angle. Failing this, surgical goniosynechialysis may be effective in reopening the angle for filtration. If the angle is permanently closed, with ensuing high IOP, therapy is directed at lowering the pressure with more conventional medical and surgical methods.

Ghost Cell (Hemolytic) Glaucoma

Campbell and colleagues initially described ghost cell glaucoma by demonstrating that after vitreous hemorrhage, fresh red blood cells degenerated into ghost cells in the vitreous usually within 1 or 2 weeks.54 If there is hyaloid face disruption, the ghost cells gain access to the anterior chamber. Ghost cells differ from normal red blood cells in that they are rigid and do not pass through the meshwork easily. These cells obstruct outflow and produce an elevation of IOP. An early review of ghost cell glaucoma by Campbell examined the clinical characteristics of 14 patients, all of whom had a traumatic ghost cell glaucoma.55 A common clinical course of severe trauma resulting in anterior chamber and vitreous hemorrhage was followed by clearing of the anterior chamber blood; however the fresh red blood cells in the vitreous gradually converted to ghost cells. These cells had a characteristic ochre color and were found both in the posterior and anterior segment. Occasionally, ghost cells would layer out in the anterior chamber creating a ‘pseudohypopyon’. Ghost cell glaucoma occurred anywhere from 2 weeks to 3 months after the trauma but was most common 1 month after the injury. The IOP was usually very elevated, ranging from 30 to 50 mmHg. Histopathological examination of one eye demonstrated ghost cells in the anterior chamber with a relatively normal-looking angle. Macrophages laden with red blood cell debris were evident in the vitreous cavity as well as free ghost cells in the vitreous cavity. The anterior hyaloid face was disrupted, allowing passage of the ghost cells into the anterior chamber. Phase contrast microscopy demonstrated a crenated shrunken appearance of the ghost cells with Heinz bodies demonstrating denatured hemoglobin present in the cytoplasm of some of the ghost cells.55

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Standard glaucoma medical therapy is initially employed to treat ghost cell glaucoma although Campbell found that less than half of patients are controlled by medical therapy alone.55 Initial surgical intervention involves washing the ghost cells out of the anterior chamber. If this is unsuccessful, a pars plana vitrectomy may be necessary to ensure complete removal of the cellular load from the eye.

Lens-Induced Glaucoma

Lens dislocation, lens swelling, phacolytic glaucoma, and lens particle glaucoma can all account for elevated IOP following ocular trauma.56 These are a group of glaucomas that share the lens as a common pathway in their pathogenesis.

Lens dislocation

Trauma of a sufficient magnitude may disrupt the zonules resulting in subluxation or dislocation of the lens. Pupillary block with angle closure may result from forward advancement of the lens. Pupillary block may also be the result of vitreous blocking the papillary aperture if the lens has dislocated posteriorly. The onset of angle-closure glaucoma with pupillary block may present acutely with a painful red eye, corneal edema, and severely elevated IOP, mimicking acute angle-closure glaucoma with primary papillary block. The chamber will appear shallow both axially and peripherally with iris convexity. The angle will appear closed on gonioscopy. A previous history of trauma and an axially deep chamber in the fellow eye with a wide open angle on gonioscopy all point to traumatic lens subluxation. In a study from China of 526 cases presenting as primary acute-angle closure, 5.89% of cases were found to be secondary to lens subluxation. Previous history or signs of trauma were often neglected.57 Phacodonesis may be appreciated at the slit lamp. With lens dislocation vitreous blocking the pupil may be appreciated at the slit lamp. Evident lens dislocation may also be seen on ophthalmoscopy. Secondary glaucoma as a result of traumatic lens dislocation was found to occur in 88% of 106 patients in a review from China.58 Treatment of this form of glaucoma is directed at relieving the pupillary block with laser iridectomy or surgical iridectomy. Lensectomy may be required for reasons of visual rehabilitation or if the lens continues to compromise the angle or cornea following iridectomy/iridectomy because of persistent extreme anterior displacement.

Lens swelling

An intumescent cataractous lens resulting from trauma can cause angle closure either as a result of pupillary block or direct angle compromise from mass effect. A previous history of trauma and presence of unilateral cataract with chamber depth asymmetry will help to establish etiology. Pupillary block may be relieved by laser iridectomy or surgical iridectomy. Cataract surgery is indicated to remove the underlying cause of this problem and restore vision. If chronic angle closure exists laser iridoplasty or surgical goniosynecholysis at the time of cataract surgery may be beneficial.

Phacolytic glaucoma

Phacolytic glaucoma is seen in the setting of a hypermature cataract. Leakage of high molecular weight proteins through an intact lens capsule compromises outflow facility. This is a rare secondary lens-induced glaucoma related to glaucoma that can conceivably be related to previous trauma. Treatment is directed at surgical removal of the lens.

Lens particle glaucoma

Lens particle glaucoma is a result of obstruction of the trabecular meshwork from lens fragments that have been liberated from the lens as a result of traumatic disruption of the lens capsule. These lens fragments are evident on slit-lamp examination. Treatment is directed as removal of the lens and any associated free fragments.

Delayed Closure of a Cyclodialysis Cleft

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Cyclodialysis cleft represents a separation between scleral spur and ciliary muscle. These can occur as a result of trauma or surgical intervention. A cyclodialysis cleft is associated with hypotony as a result of increased egress of aqueous humor through this alternative pathway as well as decreased aqueous production. A cyclodialysis cleft can close spontaneously or as a result of intentional intervention. When closure

of the cleft occurs the IOP may rise dramatically. Goldmann59 postulated that the reduction in flow of aqueous humor across the conventional trabecular pathway during a cyclodialysis cleft results in a reduced permeability of the trabecular meshwork which is manifest as dramatically elevated IOP following closure of the cleft. Closure of a cyclodialysis cleft will often produce acutely elevated IOP with associated subjective symptoms including decreased vision, ocular discomfort, and even systemic effects including nausea and vomiting. Corneal edema, a formed anterior chamber, and an open angle will be present. A previous history of trauma or a previously documented cleft with associated signs and symptoms of hypotony may be elicited. When closure of the cleft is a concern, reopening the cleft with miotics and phenylephrine may be effective in reopening the cleft and lowering the IOP. Repeating gonioscopy following this maneuver will assist in confirming the diagnosis.

Epithelial Downgrowth

Epithelial cells may proliferate abnormally in the anterior chamber of the eye either as a result of their introduction into the eye following penetrating trauma or they may grow into the anterior chamber as a result of a patent fistula allowing communication between the external surface of the eye and the anterior chamber. Subsequent proliferation of these abnormally located epithelial cells can produce glaucoma as either a result of an epithelial sheet-like proliferation over the meshwork or subsequent angle closure from PAS as the epithelial sheets contract and pull peripheral iris into the angle. This rare occurrence has a poor prognosis and is difficult to treat.

Retained Intraocular Foreign Body

A retained foreign body may be associated with several types of glaucoma. Loss of integrity of the globe as a result of penetration may produce a shallow or flat anterior chamber. This, in association with attendant inflammation, can result in secondary angle-closure glaucoma with extensive peripheral anterior synechiae. As discussed in our previous section, penetration may introduce epithelial cells or create a fistula resulting in epithelial downgrowth and associated glaucoma. Frank disruption of the lens capsule may produce a lens particle glaucoma. Cataract formation may produce a phacomorphic glaucoma or a phacolytic glaucoma if the cataract becomes hypermature. Siderotic glaucoma may occur as a late manifestation of a retained iron-containing foreign body. This can present long after the initial trauma with associated heterochromia, mydriasis, and a rust-like discoloration of the anterior subcapsular surface of the lens and the posterior corneal surface. The existence of an occult foreign body should be suspected in this setting. A distant history of a foreign body striking the eye may be elicited. There may be hints on examination pointing to an occult foreign body including unilateral cataract or a small lenticular capsular rupture, chronic inflammation, unilateral glaucoma, discrete areas of iris transillumination, or a corneal or scleral wound. Dilated fundus exam may allow easy visualization of the retained foreign body. Occasionally, a foreign body is located in the anterior chamber and is found on gonioscopy. Some patients may have signs of chalcosis or siderosis, as outlined previously. If the media are not clear enough to allow funduscopic examination, additional studies including plain films, computed tomography, and ultrasonography are helpful in confirming the diagnosis. Reduced retinal function may also be evident with a reduction electroretinogram activity.

Rhegmatogenous Retinal Detachment

The presence of rhegmatogenous retinal detachment often increases uvealscleral outflow via the retinal tear resulting in a reduction in IOP relative to the fellow eye.60 Ocular hypertension may occur in 5–10% of patients with rhegmatogenous retinal detachment.61 Possible reasons for this include preexisting primary open-angle glaucoma, associated inflammation, or Schwartz’s syndrome.62 Schwartz’s syndrome was initially described in 11 cases of rhegmatogenous retinal detachment associated with glaucoma. Five of these 11 cases were associated with previous ocular trauma.63 Matsuo and associates64 elucidated the pathogenesis of this glaucoma after demonstrating photoreceptors in the aqueous humor by performing transmission electron microscopy on the aqueous humor of 7 patients with this syndrome.

KEY REFERENCES Belcher CD, Brown SVL, Simmons RJ. Anterior chamber washout for traumatic hyphema. Ophthalmic Surg 1985;16:475.

Girkin CA, McGwin G Jr, Morris R, et al. Glaucoma following penetrating ocular trauma: a cohort study of the United States Eye Injury Registry. Am J Ophthalmol 2005;139:100–5. Kaufman JH, Tolpin DW. Glaucoma after traumatic angle recession: A ten year prospective study. Am J Ophthalmol 1974;78:648. Matsuo N, Takabatake M, Ueno H, et al. Photoreceptor outer segments in the aqueous humor in rhegmatogenous retinal detachment. Am J Ophthalmol 1986;101:673. Paterson CA, Pfister RR. Intraocular pressure changes after alkali burns. Arch Ophthalmol 1974;91:211. Schwartz A. Chronic open angle glaucoma secondary to rhegmatogenous retinal detachment. Am J Ophthalmol 1973;75:205. Sihota R, Kumar S, Gupta V, et al. Early predictors of traumatic glaucoma after closed globe injury: trabecular pigmentation, widened angle recess and higher baseline intraocular pressure. Arch Ophthalmol 2008;126:921.

Campbell DG. Ghost cell glaucoma following trauma. Ophthalmology 1981;88:1151.

Tesluk GC, Spaeth GL. The occurrence of primary open angle glaucoma in the fellow eye of patients with unilateral angle cleavage glaucoma. Ophthalmology 1985;92:904.

Canavan YM, Archer DB. Anterior segment consequences of blunt ocular injury. Br J Ophthalmol 1982;66:549.

Weiss JS, Parrish RK, Anderson DR. Surgical therapy of traumatic hyphema. Ophthalmic Surg 1983;14:343.

Edwards WC, Layden WE. Traumatic hyphema: A report of 184 consecutive cases. Am J Ophthalmol 1973;75:110.

Wolff SM, Zimmerman LE. Chronic secondary glaucoma: Associated with retrodisplacement of iris root and deepening of the anterior chamber angle secondary to contusion. Am J Ophthalmol 1962;54:547.

Epstein DL. Diagnosis and management of lens-induced glaucoma. Ophthalmology 1982;89:227. Girkin CA, McGwin G Jr, Long C, et al. Glaucoma after ocular contusion: a cohort study of the United States Eye Injury Registry. J Glaucoma 2005;14:470–3.

Access the complete reference list online at

10.17 Glaucoma Associated with Ocular Trauma

Unilateral glaucoma in the presence of rhegmatogenous retinal detachment is an unusual presentation and emphasizes the importance of careful funduscopic examination in all cases of unilateral glaucoma. Repair of the retinal detachment promptly returns the intraocular pressure to normal provided there are no associated ocular abnormalities, such as angle recession, that could contribute to chronic elevation of intraocular pressure.

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REFERENCES 1. Girkin CA, McGwin G Jr, Morris R, et al. Glaucoma following penetrating ocular trauma: a cohort study of the United States Eye Injury Registry. Am J Ophthalmol 2005;139:100–5.

3. Sihota R, Kumar S, Gupta V, et al. Early predictors of traumatic glaucoma after closed globe injury: trabecular pigmentation, widened angle recess and higher baseline intraocular pressure. Arch Ophthalmol 2008;126:921. 4. Herschler J. Trabecular damage due to blunt anterior segment injury and its relationship to traumatic glaucoma. Trans Am Acad Ophthalmol Otolaryngol 1977;83:239. 5. Cho J, Jun BK, Lee YJ, et al. Factors associated with the poor final visual outcome after traumatic hyphema. Korean J Ophthalmol 1998;12:122–9. 6. Read J, Goldberg MF. Comparison of medical treatment for traumatic hyphema. Trans Am Acad Ophthalmol Otolaryngol 1974;78:799. 7. Goldberg MF. The diagnosis and treatment of sickled erythrocytes in human hyphemas. Trans Am Ophthalmol Soc 1978;76:481. 8. Crouch ER, Frenkel M. Aminocaproic acid in the treatment of traumatic hyphema. Am J Ophthalmol 1976;81:355. 9. Karaman K, Culic S, Erceg I, et al. Treatment of post-traumatic trabecular meshwork thrombosis and secondary glaucoma with intracameral tissue plasminogen activator in previously unrecognized sickle cell anemia. Coll Antropol 2005;29(Suppl. 1):123–6.

33. Collins ET. On the pathological examination of three eyes lost from concussion. Trans Ophthalmol Soc UK 1892;12:180. 34. D'Ombrain A. Traumatic monocular chronic glaucoma. Trans Ophthalmol Soc Aust 1986;5:116. 35. Wolff SM, Zimmerman LE. Chronic secondary glaucoma: Associated with retrodisplacement of iris root and deepening of the anterior chamber angle secondary to contusion. Am J Ophthalmol 1962;54:547. 36. Blanton FM. Anterior chamber angle recession and secondary glaucoma: A study of the aftereffects of traumatic hyphemas. Arch Ophthalmol 1964;72:39. 37. Tonjum AM. Intraocular pressure and facility of outflow late after ocular contusion. Acta Ophthalmol 1968;46:886. 38. Monney D. Angle recession and secondary glaucoma. Br J Ophthalmol 1973;57:608. 39. Canavan YM, Archer DB. Anterior segment consequences of blunt ocular injury. Br J Ophthalmol 1982;66:549. 40. Kaufman JH, Tolpin DW. Glaucoma after traumatic angle recession: A ten year prospective study. Am J Ophthalmol 1974;78:648. 41. Alper MG. Contusion angle deformity and glaucoma: Gonioscopic observations and clinical course. Arch Ophthalmol 1963;69:455. 42. Salmon JF, Mermoud A, Ivey A, et al. The detection of post-traumatic angle recession by gonioscopy in a population-based glaucoma survey. Ophthalmology 1994;101:1844.

10. Edwards WC, Layden WE. Traumatic hyphema: a report of 184 consecutive cases. Am J Ophthalmol 1973;75:110.

43. Miles DR, Boniuk M. Pathogenesis of unilateral glaucoma: A review of 100 cases. Am J Ophthalmol 1962;62:493.

11. McGetrick JJ, Jampol LM, Goldberg MF, et al. Aminocaproic acid decreases secondary hemorrhage after traumatic hyphema. Arch Ophthalmol 1983;101:1031.

44. Tonjum AM. Gonioscopy in traumatic hyphema. Acta Ophthalmol 1968;44:650.

12. Yasuna E. Management of traumatic hyphema. Arch Ophthalmol 1974;91:190.

45. Tesluk GC, Spaeth GL. The occurrence of primary open angle glaucoma in the fellow eye of patients with unilateral angle cleavage glaucoma. Ophthalmology 1985;92:904.

13. Rynne MV, Romano PE. Systemic corticosteroids in the treatment of traumatic hyphema. J Pediatr Ophthalmol Strabismus 1980;17:141.

46. Robin AL, Pollack IP. Argon laser trabeculoplasty in secondary forms of open angle glaucoma. Arch Ophthalmol 1983;101:382.

14. Spoor TC, Hammer M, Belloso H. Traumatic hyphema: Failure of steroids to alter its course: A double-blind prospective study. Arch Ophthalmol 1980;98:116.

47. Thomas JV, Simmons RJ, Belcher CD. Argon laser trabeculoplasty in the pre-surgical glaucoma patient. Ophthalmology 1982;89:187.

15. Dieste MC, Hersh PS, Kylstra JA, et al. Intraocular pressure increase associated with epsilonaminocaproic acid therapy for traumatic hyphema. Am J Ophthalmol 1988;106:383.

48. Fukuchi T, Iwata K, Schoichi S, et al. Nd:YAG laser trabeculopuncture (YLT) for glaucoma with traumatic angle recession. Graefes Arch Clin Exp Ophthalmol 1993;231:571.

16. Belcher CD, Brown SVL, Simmons RJ. Anterior chamber washout for traumatic hyphema. Ophthalmic Surg 1985;16:475.

49. Mermoud A, Salmon JF, Straker C, et al. Post-traumatic angle recession glaucoma: a risk factor for bleb failure after trabeculectomy. Br J Ophthalmol 1993;77:631–4.

17. Sears ML. Surgical management of black ball hyphema. Trans Acad Ophthalmol Otolaryngol 1970;74:820.

50. Mermoud A, Salmon JF, Barron A, et al. Surgical management of post-traumatic angle recession glaucoma. Ophthalmology 1993;100:634–42.

18. Hill K. Cryoextraction of total hyphema. Arch Ophthalmol 1968;80:368.

51. Manners T, Salmon JF, Barron A, et al. Trabeculectomy with mitomycin C in the treatment of post-traumatic angle recession glaucoma. Br J Ophthalmol 2001;85:159–63.

19. McCuen BW, Fung WE. The role of vitrectomy instrumentation in the treatment of severe traumatic hyphema. Am J Ophthalmol 1979;88:930. 20. Kelman CD, Brooks DL. Ultrasonic emulsification and aspiration of traumatic hyphema: a preliminary report. Am J Ophthalmol 1971;71:1289. 21. Pandey P, Sung VC. Gonioaspiration for refractory glaucoma secondary to traumatic hyphema in patients with sickle cell trait. Ophthalmic Surg Lasers Imaging 2010;41:386. 22. Parrish RK, Bernardino V. Iridectomy in the surgical management of eight ball hyphema. Arch Ophthalmol 1982;100:435.

52. Fuller JR, Bevin TH, Molteno AC. Long-term follow-up of traumatic glaucoma treated with Molteno implants. Ophthalmology 2001;108:1796–800. 53. De Kierk TA, Au L. I-stent for the treatment of angle recession with raised intraocular pressure. Clin Experiment Ophthalmol 2011;1442. 54. Campbell DG, Simmons RJ, Grant WM. Ghost cells as a cause of glaucoma. Am J Ophthalmol 1973;97:2141. 55. Campbell DG. Ghost cell glaucoma following trauma. Ophthalmology 1981;88:1151.

23. Weiss JS, Parrish RK, Anderson DR. Surgical therapy of traumatic hyphema. Ophthalmic Surg 1983;14:343.

56. Epstein DL. Diagnosis and management of lens-induced glaucoma. Ophthalmology 1982;89:227.

24. Baig MS, Ahmed J, Ali MA. Role of trabeculectomy in the management of hypertensive traumatic total hyphema. J Coll Phys Surg Pak 2009;19:496.

57. Luo L, Li M, Zhong Y, et al. Evaluation of secondary glaucoma associated with subluxated lens misdiagnosed as acute primary angle-closure glaucoma. J Glaucoma 2013;22:307–10.

25. Gilbert HD, Smith RE. Traumatic hyphema: Treatment of secondary hemorrhage with cyclodiathermy. Ophthalmic Surg 1975;7:31.

58. Peng SX, Zhou WB. Traumatic lens dislocation-related glaucoma. Zhonghua Yan Ke Za Zhi 1993;29:332–5.

26. Pesin SR, Katz LJ, Augsburger JJ, et al. Acute angle closure glaucoma from spontaneous massive hemorrhagic retinal or choroidal detachment. Ophthalmology 1990;97:76.

59. Goldmann H. Klinische Studien zum Glaucomproblem. Ophthalmologica 1953;125:16.

27. Hughes WF. Alkali burns of the eye. 1: Review of the literature and summary of present knowledge. Arch Ophthalmol 1946;35:423. 28. Grant WM. Toxicology of the eye. Springfield, IL: Charles C Thomas; 1965. p. 35.

10.17 Glaucoma Associated with Ocular Trauma

2. Girkin CA, McGwin G Jr, Long C, et al. Glaucoma after ocular contusion: a cohort study of the United States Eye Injury Registry. J Glaucoma 2005;14:470–3.

32. Cade F, Grosskreutz CL, Tauber A, et al. Glaucoma in eyes with severe chemical burn, before and after keratoprosthesis. Cornea 2011;30:1322.

60. Dobbie JG. A study of the intraocular fluid dynamics in retinal detachment. Arch Ophthalmol 1963;69:159. 61. Linner E. Intraocular pressure in retinal detachment. Acta Ophthalmol 1966;84:101.

29. Highman VN. Early rise in intraocular pressure after ammonia burns. Br Med J 1969;1:359.

62. Schwartz A. Chronic open angle glaucoma secondary to rhegmatogenous retinal detachment. Am J Ophthalmol 1973;75:205.

30. Chiang TS, Moorman LR, Thomas RP. Ocular hypertensive response following acid and alkali burns in rabbits. Invest Ophthalmol Vis Sci 1971;10:270.

63. Baruch E, Bracha R, Godel V, et al. Glaucoma due to rhegmatogenous retinal detachment; Schwartz’s syndrome. Glaucoma 1981;3:229.

31. Paterson CA, Pfister RR. Intraocular pressure changes after alkali burns. Arch Ophthalmol 1974;91:211.

64. Matsuo N, Takabatake M, Ueno H, et al. Photoreceptor outer segments in the aqueous humor in rhegmatogenous retinal detachment. Am J Ophthalmol 1986;101:673.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

10.18

Glaucoma with Raised Episcleral Venous Pressure E. Randy Craven

Definition: Glaucoma with elevated intraocular pressure (IOP) caused by a decrease in aqueous outflow secondary to increased episcleral venous pressure (ESVP).

Venous obstruction Superior vena cava syndrome

Key features ■

TABLE 10-18-1  VENOUS AND ARTERIAL ABNORMALITIES LEADING TO ELEVATED EPISCLERAL VENOUS PRESSURE

Unilateral elevation of intraocular pressure in an eye with prominent episcleral veins

Associated features ■

Blood in Schlemm’s canal ■ Either venous obstruction or arterial-venous abnormalities

Thyroid ophthalmopathy Sturge–Weber syndrome Jugular vein obstruction Cavernous sinus thrombosis

Arterial–venous abnormality

Dural-cavernous fistula Orbital varix

Tests to consider

Other findings

Chest X-ray

Cyanosis

MRI MRI

Proptosis Skin/retina Cyanosis

Carotid-cavernous fistula

MRI

Pain

MRI, magnetic resonance imaging.

INTRODUCTION Raised episcleral venous pressure can cause open-angle glaucoma by obstructing the outflow of aqueous into the venous drainage system. Raised episcleral venous pressure can come from systemic abnormalities that can be ultimately fatal; therefore, due to the morbidity associated with these problems, one needs to be keyed into looking beyond the eye when a patient presents with a red eye and glaucoma.

EPIDEMIOLOGY AND PATHOGENESIS When the episcleral venous pressure (ESVP) rises, there is a similar direct rise in the intraocular pressure (IOP).1 The ultimate IOP is influenced by the production/secretion (F) and facility of outflow (C) of aqueous humor but is balanced by the ESVP (the Goldmann equation):

IOP = F / C + ESVP

The ESVP is increased at times by the body position2 and venous drainage pressure in the superior/inferior ophthalmic veins, cavernous sinus, petrosal sinuses, and internal and external jugular veins. Thus, any abnormality, including hereditary, leading to increased venous pressure in the venous drainage system downstream from the eye can lead to elevated IOP.3 Idiopathic raised ESVP and glaucoma can occur.4 This syndrome does not appear to feature any extra-ocular venous abnormalities; color Doppler imaging has not helped to reveal any specific retro-orbital etiology to the cause of this syndrome. These patients tend to be older, without a family history of glaucoma. Unilateral presentation is common and the right eye is more commonly involved with this syndrome. Venous and arterial abnormalities leading to elevated ESVP are summarized in Table 10-18-1.

OCULAR MANIFESTATIONS 1090

Raised episcleral venous pressure leads to engorged episcleral veins (Fig. 10-18-1), and blood in Schlemm’s canal best seen via gonioscopy

Fig. 10-18-1  Prominent episcleral veins. The episcleral vessels are tortuous and appear succulent. The eye lacks the classic ciliary flush seen with iritis or infections.

(Fig. 10-18-2). If there is associated anterior segment or retinal ischemia, neovascularization of the iris can occur.5 Hemorrhagic choroidal detachments with secondary angle closure may develop.6 When the venous pressure approaches arterial pressure in patients with arterial-venous abnormalities, the subsequent IOP elevation can be quite high. Venous obstruction or arterial-venous abnormalities can lead to raised episcleral venous pressure (Table 10-18-1). Proptosis can occur with thyroid eye disease, carotid-cavernous fistulae, or an orbital varix. An orbital varix can have positional proptosis. Carotid-cavernous fistulae can cause pulsatile proptosis. Hemangiomas associated with Sturge–Weber syndrome can involve the skin and retina (‘tomato catsup’ fundus). Chemosis is common with carotid cavernous fistulae and can be seen with Sturge–Weber or thyroid ophthalmopathy. Glaucomatous optic atrophy and visual field loss from raised ESVP can take longer than other forms of acute glaucoma and may not occur despite very high intraocular pressures. This is especially true in the more acute problems that present with raised ESVP, such as carotidcavernous fistulae.

TREATMENT

Fig. 10-18-2  Blood in Schlemm’s canal. Gonioscopy reveals prominent red hue over the trabecular meshwork zone of the angle.

DIAGNOSIS The appearance of the episcleral veins in problems with raised episcleral venous pressure is quite characteristic. The appearance of the vessels (Fig. 10-18-1) is unique enough for the diagnosis; it is possible, however, to measure the venous pressure to confirm or determine the level of the raised venous pressure. Five methods for determining the episcleral venous pressure have been used. The direct method for measuring the episcleral venous pressure can be done by cannulation; this is the most accurate method and reveals the episcleral venous pressure to be 5–12 mmHg. Non-invasive methods look for a collapse in the vein (partially or totally) while a force is applied to the vein. The remaining four methods use an indirect method where the pressure required for venous collapse can be determined by a pressure chamber (of Seidel), an air jet, a torsion balance, or an indirect method.7–8 The pressure chamber or indirect (venometer) methods probably provide the most accurate readings apart from direct cannulation.

When elevated IOP occurs because of the elevated ESVP, it is possible to lower the IOP to the level of the ESVP but not much lower. Aggressive filtering surgery with an avascular bleb can work; however, it can, therefore, be very difficult to drop the IOP satisfactorily without treating the primary cause of the raised ESVP. Treatment for the fistulae can involve neuroradiologic intervention or neurosurgical intervention. Dural-cavernous are low-flow fistulae and can spontaneously close, whereas the carotid-cavernous fistulae tend to need intervention. Dural-cavernous fistulae are usually watched and can resolve by the patient sleeping with the head elevated or sitting for a period of time. Treatment of other medical problems leading to raised ESVP should be attempted if possible. Medications that suppress the aqueous production are good first-line medication choices. Beta-blockers and carbonic anhydrase inhibitors are commonly used agents. Alpha-agonists, because of their vasoconstrictive effects on the arteries leading into the eye, are also a good first choice for medications. Laser trabeculoplasty provides little help in most cases. Some surgeons feel nonpenetrating procedures may be a safer form of filtration surgery and some surgeons prefer valves.9 Preoperative mannitol and other pressure-lowering medications should be given. Because of the prominent vessels, a releasable suture should be considered with trabeculectomy.

COURSE AND OUTCOME Once the problem that caused the raised episcleral venous pressure is treated, the IOP is easier to control. If it is not possible to lower the episcleral venous pressure, such as in Sturge–Weber syndrome, the glaucoma is chronic and progressive until the IOP is controlled.

DIFFERENTIAL DIAGNOSIS

KEY REFERENCES

Prominent ocular vessels can occur without glaucoma. The pattern of vessels and involved vessels with infections, inflammation, or allergies can cause significant injection, but usually the vessels are finer with a more diffuse hue to the tissue. Ataxia telangiectasia can cause abnormal vessels on the ocular surface but tend to be more localized to a quadrant and smaller vessels. Scleritis and episcleritis tend to have smaller caliber vessels than with raised ESVP. Additionally, the vessels are more of a criss-cross pattern with a network of deep vessels along with radial vessels and overall more diffuse involvement of the vessels. Intraocular tumors can cause prominent scleral vessels (Reese’s sign). Conditions with scleral thinning, such as that seen after repeated ciliary body destructive procedures, can lead to a more prominent view of the normal veins.

Brubaker RF. Determination of episcleral venous pressure in the eye. Arch Ophthalmol 1967;77:110.

SYSTEMIC ASSOCIATIONS Carotid-cavernous fistulae commonly occur after significant trauma. Pulsating exophthalmos, blurred vision, pain, chemosis, and audible

10.18 Glaucoma with Raised Episcleral Venous Pressure

shunts can be heard with a stethoscope. These tend to develop rather suddenly. Dural-cavernous fistulae occur commonly in mid-aged females with a more gradual onset. Superior vena cava syndrome occurs in the presence of bronchogenic carcinomas. Cavernous sinus thrombosis occurs from infections spreading from the middle ear, sinuses, or the face. Significant congestive heart failure can lead to elevated venous pressure; many findings are present, including peripheral edema and pulmonary congestion.

Budenz DL. Nonpenetrating deep sclerectomy for Sturge–Weber syndrome: author reply. Ophthalmol 2001;108:2153. Buus DR, Tse DT, Parrish RK. Spontaneous carotid cavernous fistula presenting with acute angle closure glaucoma. Arch Ophthalmol 1989;107:596–7. Friberg TR, Sandborn G, Weinreb RN. Intraocular and episcleral venous pressure increases during inverted posture. Am J Ophthalmol 1987;103:523–6. Harris MJ, Fine SL, Miller NR. Photocoagulation treatment of proliferative retinopathy secondary to carotid-cavernous fistula. Am J Ophthalmol 1980;90:515. Lanzl IM, Welge-Luessen U, Spaeth GL. Unilateral open-angle glaucoma secondary to idiopathic dilated episcleral veins. Am J Ophthalmol 1996;121:587–9. Minas TF, Podos SM. Familial glaucoma associated with elevated episcleral venous pressure. Arch Ophthalmol 1968;80:202–8. Moses RA, Grodzki WJ. Mechanism of glaucoma secondary to increased venous pressure. Arch Ophthalmol, 1985;103:1653–8. Zeimer RC, Gieser DK, Wilensky JT. A practical venomanometer. Arch Ophthalmol 1983;101:1447.

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REFERENCES 1. Moses RA, Grodzki WJ. Mechanism of glaucoma secondary to increased venous pressure. Arch Ophthalmol 1985;103:1653–8.

3. Minas TF, Podos SM. Familial glaucoma associated with elevated episcleral venous pressure. Arch Ophthalmol 1968;80:202–8. 4. Lanzl IM, Welge-Luessen U, Spaeth GL. Unilateral open-angle glaucoma secondary to idiopathic dilated episcleral veins. Am J Ophthalmol 1996;121:587–9.

6. Buus DR, Tse DT, Parrish RK. Spontaneous carotid cavernous fistula presenting with acute angle closure glaucoma. Arch Ophthalmol 1989;107:596–7. 7. Brubaker RF. Determination of episcleral venous pressure in the eye. Arch Ophthalmol 1967;77:110. 8. Zeimer RC, Gieser DK, Wilensky JT. A practical venomanometer. Arch Ophthalmol 1983;101:1447. 9. Budenz DL. Nonpenetrating deep sclerectomy for Sturge–Weber syndrome: author reply. Ophthalmol 2001;108:2153.

10.18 Glaucoma with Raised Episcleral Venous Pressure

2. Friberg TR, Sandborn G, Weinreb RN. Intraocular and episcleral venous pressure increases during inverted posture. Am J Ophthalmol 1987;103:523–6.

5. Harris MJ, Fine SL, Miller NR. Photocoagulation treatment of proliferative retinopathy secondary to carotid-cavernous fistula. Am J Ophthalmol 1980;90:515.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Aqueous Misdirection Syndrome Nishat P. Alvi, Louis B. Cantor

Definition: A rare form of glaucoma, also known as ‘malignant glaucoma’, that develops primarily in patients with primary angle closure and is characterized by elevated intraocular pressure (IOP) with a shallow or flat anterior chamber despite a patent iridectomy.

Key features ■ ■ ■ ■ ■ ■ ■

Shallowing or flattening of both the central and peripheral anterior chamber despite patent iridectomy. Almost always associated with markedly elevated intraocular pressure. Chronic angle-closure glaucoma. Worsened by miotics and relieved by cycloplegics and mydriatics. Usually occurs after intraocular surgery. Involves some degree of aqueous misdirection into the vitreous cavity. Supraciliary or suprachoroidal effusion, if present, is very small.

Associated features ■ ■

May occur after laser or medical therapy of glaucoma. Intraocular pressure may be within the normal range.

INTRODUCTION

10.19

intraocular pressure (IOP).4 Quigley and colleagues suggested that choroidal thickening may predispose to angle-closure glaucoma. These changes in the choroid may result in forward rotation of the ciliary body and choroid that predisposes to aqueous misdirection.5 Events that incite aqueous misdirection include a small, crowded anterior segment, angle closure, swelling and inflammation of the ciliary processes, and anterior rotation of the ciliary body and movement of the lens–iris diaphragm forward as a result of the use of miotics. It is notable that the vast majority of reported cases of aqueous misdirection occur in the white populations rather than the Asian population even though primary angle-closure glaucoma is more prevalent in South-East Asia and China. This may potentially indicate a different etiology of angle closure in white verses Asian populations.6–8

OCULAR MANIFESTATIONS A red, painful eye develops immediately, or days or even months, after intraocular surgery, typically for acute angle-closure glaucoma. Its development often corresponds to the cessation of cycloplegic therapy or the institution of miotic drops. Slit-lamp examination (Fig. 10-19-1) characteristically reveals a shallow or flat anterior chamber, both centrally and peripherally (with asymmetry with respect to the fellow eye), and no iris bombé. A high index of suspicion is necessary to make the appropriate diagnosis, since initially the IOP may not be elevated much. The key is that the IOP is elevated and the anterior chamber is axially shallow. Furthermore, if an attempt is made to reform the anterior chamber postoperatively through the paracentesis site using a viscoelastic substance, a great deal of posterior resistance may be noted, the anterior chamber may not deepen as much as in a hypotonic eye that does not have aqueous misdirection, and the IOP may rise substantially.

Aqueous misdirection glaucoma, also known as malignant glaucoma, is a rare form of glaucoma that typically follows intraocular surgery in patients with primary angle closure and primary angle-closure glaucoma. It occurs after routine cataract surgery, after the administration of miotics in eyes with or without a prior surgical history, after ciliary body swelling, or less commonly spontaneously.1 It may be difficult to make an accurate diagnosis, particularly in the early stages.

EPIDEMIOLOGY AND PATHOGENESIS

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Aqueous misdirection occurs in approximately 2–4% of patients who undergo surgery for angle-closure glaucoma, especially if some of the angle is closed preoperatively. If the angle is open or has been opened prophylactically via a laser iridectomy before the development of an angle-closure attack, aqueous misdirection seems less likely to occur after subsequent surgery.1 This condition also may occur after the cessation of topical cycloplegic therapy, the initiation of topical miotic therapy, laser iridectomy, laser capsulectomy, laser cyclophotocoagulation, cataract extraction, pars plana vitrectomy, seton implantation, central retinal vein occlusion, or argon laser suture lysis, or in eyes that have hyperopia, short axial lengths, or nanophthalmos.2,3 The pathogenesis of aqueous misdirection is thought to be multifactorial. Shaffer and Hoskins suggested that there is posterior misdirection of aqueous flow by a relatively impermeable hyaloid membrane into or behind the vitreous body; the subsequent increase in vitreous volume results in a shallower anterior chamber and an increase in

Fig. 10-19-1  Aqueous misdirection. Note the flat anterior chamber despite a patent iridectomy.

TABLE 10-19-1  DIFFERENTIAL DIAGNOSIS OF AQUEOUS MISDIRECTION Aqueous misdirection

Pupillary block

Suprachoroidal hemorrhage

Serous choroidal effusions

Intraocular pressure Anterior chamber depth

Normal or elevated Shallow; flat centrally and peripherally No Choroid and retina flat

Elevated Shallow; flat peripherally, but deeper centrally Yes Choroid and retina flat

Low Shallow; flat centrally and peripherally

Anterior rotation of ciliary body and lens −

Iris bombé with lens in normal position −

Normal or elevated Shallow; flat centrally and peripherally No Bullous dark brown or dark red choroidal elevations −

Intraoperative or early postoperative period. Occasionally months to years later

Early postoperative period

Relief by iridectomy Ophthalmoscopy Ultrasound biomicroscopy B-scan ultrasound

Onset

DIAGNOSIS The diagnosis of aqueous misdirection is based clinically on the previously mentioned ocular manifestations, and it is made only after ruling out pupillary block, suprachoroidal hemorrhage, serous choroidal effusions, or other causes of a flat anterior chamber. High-resolution ultrasound biomicroscopy can be useful to confirm the diagnosis.9 It reveals anterior rotation of the ciliary body against the peripheral iris and forward displacement of the posterior chamber intraocular lens, as well as a shallow central anterior chamber, all of which are reversible.

DIFFERENTIAL DIAGNOSIS The most difficult entity to distinguish from aqueous misdirection is pupillary block. Pupillary block should be suspected if iris bombé is present and if the anterior chamber is relatively deeper centrally and shallow to flat peripherally. In contrast, with aqueous misdirection, the anterior chamber is uniformly shallow or flat both centrally and peripherally. Next, the presence or absence of a patent iridectomy must be established. If an iridectomy is not present or not patent, a peripheral iridectomy should be performed. Pupillary block is confirmed if the anterior chamber deepens with an iridectomy. If no relief occurs with iridectomy and ophthalmoscopy or B-scan ultrasonography rules out suprachoroidal hemorrhage or serous choroidal effusion, a diagnosis of aqueous misdirection is made. The distinguishing features of these entities are summarized in Table 10-19-1.

TREATMENT Medical

The first line of therapy is medical and involves the use of cycloplegics and mydriatics, such as atropine 1% four times a day and phenylephrine 2.5% four times a day to move the lens–iris diaphragm back and relax the ciliary muscle. To decrease aqueous production, topical betablockers, oral or topical carbonic anhydrase inhibitors, and α-agonists are used. Osmotic agents such as isosorbide 1.5 mg/kg orally or mannitol 2 g/kg intravenously over a 45-minute period can be used to shrink the vitreous volume. No oral foods or liquids should be given 2 hours before and after the administration of a hyperosmotic agent to avoid reduction in the osmotic effect. The patient is maintained on atropine for a prolonged period with a very slow taper because of the high risk of recurrence. Miotic agents are contraindicated, as they may cause or contribute to aqueous misdirection. Medical therapy is successful in approximately 50% of cases within 4–5 days.3,6

Laser

The second line of treatment is laser therapy. Neodymium : yttrium– aluminum–garnet (Nd : YAG) laser may be used in aphakic and pseudophakic patients to create a large peripheral iridectomy and anterior

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Smooth, thick, dome-shaped movement with little aftermovement Heterogeneous low-medium reflective echoes Intraoperative or early postoperative period associated with pain, nausea/vomiting

No Bullous light brown choroidal elevations − Smooth, thick, dome-shaped membrane with little aftermovement Echolucent suprachoroidal space, high reflective choroidal thickening Intraoperative or early postoperative period

10.19 Aqueous Misdirection Syndrome

Criterion

capsulectomy with hyaloid rupture to release the trapped aqueous from the vitreous and re-establish normal aqueous flow.3,10 Several openings are made peripherally − that is, not directly behind the optic.3,12 The placement of the iridectomies should be peripheral since the underlying etiology is an abnormal relationship between the hyaloid and the ciliary processes.3,10 Peripheral placement will enable anterior migration of the aqueous and maximize the likelihood of resolution of the malignant glaucoma. In addition, transscleral cyclodiode laser photocoagulation can be used to coagulatively shrink the ciliary processes and lead to posterior rotation of the ciliary processes.11 Alternatively, direct argon laser treatment can be applied to the ciliary processes through a laser peripheral iridectomy.12 If there is corneal-lenticular contact there is the risk of corneal decompensation; therefore, the chamber should be reformed by the injection of a viscoelastic substance via a 30-gauge cannula through the original paracentesis at the slit lamp following Nd : YAG laser hyaloidectomy.1

Surgery

When medical or laser therapy fails, surgery must be performed. In pseudophakic eyes, vitrectomy surgery is successful in resolving malignant glaucoma in 65–90% of patients compared to only 25–50% of phakic patients.13,14 In phakic eyes, definitive management usually requires phacoemulsification with IOL combined with pars plana vitrectomy. The key is to open the posterior capsule and debulk the vitreous sufficiently to disrupt the vicious cycle of malignant glaucoma.13,15–17

Fellow Eye

There is a high risk of malignant glaucoma in the fellow eye. If a narrow angle is present in the fellow eye, a laser peripheral iridectomy is performed before any other surgical procedures. The risk of aqueous misdirection may be reduced in the fellow eye after iridectomy if the angle remains open and the IOP is normal; failure to provide prompt therapy to the fellow eye has been reported to result in bilateral blindness. Lens extraction can be considered as a primary procedure prior to glaucoma surgery.3 In fact, combined vitrectomy and phacoemulsification with IOL is advocated in high-risk cases.18

KEY REFERENCES Brown RH, Lynch MG, Tearse JE, et al. Neodymium-YAG vitreous surgery for phakic and pseudophakic malignant glaucoma. Arch Ophthalmol 1986;104:1464–6. Byrnes GA, Leen MM, Wong TP, et al. Vitrectomy for ciliary block (malignant) glaucoma. Ophthalmology 1995;102:1308–11. Epstein DL. The malignant glaucoma syndromes. In: Epstein DL, editor, with Allingham RR, Schuman JS. Chandler and Grant’s Glaucoma. 4th ed. Baltimore, MD: Williams & Wilkins; 1997. p. 285–303. Shahid H, Salmon JF. Malignant glaucoma: a review of the modern literature. J Ophthalmol 2012; vol. 2012, article ID 852659. doi:10.1155/2012/852659.

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REFERENCES 1. Simmons RJ, Maestre FA. Malignant glaucoma. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas, vol. 2. 2nd ed. St Louis, MO: Mosby-Yearbook; 1996. p. 841–55.

3. Epstein DL. The malignant glaucoma syndromes. In: Epstein DL, editor, with Allingham RR, Schuman JS, Chandler and Grant’s Glaucoma. 4th ed. Baltimore, MD: Williams & Wilkins; 1997. p. 285–303. 4. Shaffer RN, Hoskins HD. The role of vitreous detachment in aphakic and malignant glaucoma. Trans Am Acad Otolaryngol 1954;58:217–28. 5. Quigley HA. Angle-closure glaucoma: simpler answers to complex mechanisms: LXVI Edward Jackson Memorial Lecture. Am J Ophthalmol 2009;148:657–69. 6. Shahid H, Salmon JF. Malignant glaucoma: a review of the modern literature. J Ophthalmol 2012; vol. 2012, article ID 852659. doi:10.1155/2012/852659. 7. Tham CCY, Kwong YYY, Leung DYL, et al. Phacoemulsification versus combined phacotrabeculectomy in medically uncontrolled chronic angle closure glaucoma with cataract. Ophthalmology 2009;116:725–31. 8. He M, Foster PJ, Johnson GJ, et al. Angle-closure glaucoma in East Asian and European people. Different diseases? Eye 2006;20:3–12. 9. Trope GE, Pavlin CJ, Bau A, et al. Malignant glaucoma: clinical and ultrasound biomicroscopic features. Ophthalmology 1994;101:1030–5.

11. Carassa RG, Bettin P, Fiori M, et al. Treatment of malignant glaucoma with contact transscleral cyclophotocoagulation. Arch Ophthalmol 1999;117:688–90. 12. Herschler J. Laser shrinkage of the ciliary processes. A treatment for malignant (ciliary block) glaucoma. Ophthalmology 1980;87:1155–9. 13. Byrnes GA, Leen MM, Wong TP, et al. Vitrectomy for ciliary block (malignant) glaucoma. Ophthalmology 1995;102:1308–11. 14. Tsai JC, Barton KA, Miller MH, et al. Surgical results in malignant glaucoma refractory to medical or laser therapy. Eye 1997;11:677–81. 15. Sharma A, Sii F, Shah P, et al. Vitrectomy-phacoemulsification-vitrectomy for the management of aqueous misdirection syndromes in phakic eyes. Ophthalmology 2006; 113:1968–73. 16. Bitrian E, Caprioli J. Pars plana anterior vitrectomy, hyaloido-zonulectomy and iridectomy for aqueous humour misdirection. Am J Ophthalmol 2010;150:82–7. 17. Azuara-Blanco A, Katz LJ, Gandham SB, et al. Pars plana tube insertion of aqueous shunt with vitrectomy in malignant glaucoma. Arch Ophthalmol 1998;116:808–10. 18. Chaudhry NA, Flynn HW, Murray TG, et al. Pars plana vitrectomy during cataract surgery for prevention of aqueous misdirection in high-risk fellow eyes. Am J Ophthalmol 2000;129: 387–8.

10.19 Aqueous Misdirection Syndrome

2. Disclanfani M, Liebmen JM, Ritch R. Malignant glaucoma following argon laser release of scleral flap sutures after trabeculectomy. Am J Ophthalmol 1989;108:597–600.

10. Brown RH, Lynch MG, Tearse JE, et al. Neodymium–YAG vitreous surgery for phakic and pseudophakic malignant glaucoma. Arch Ophthalmol 1986;104:1464–6.

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PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors

10.20

Elliott M. Kanner, James C. Tsai

Definition: A group of secondary glaucomas, either open- or closedangle, that are caused by specific abnormalities of the anterior and posterior segment. The open-angle varieties include ghost cell hemolytic glaucoma and Schwartz’s syndrome. The closed-angle glaucomas include the iridocorneal endothelial (ICE) syndromes, Axenfeld–Rieger syndrome, epithelial downgrowth and fibrous ingrowth (proliferation), aniridia, and intraocular tumors. Other conditions feature either mixed or nonspecific mechanisms of elevated intraocular pressure, such as the postcorneal transplant and postalkali injury glaucomas.

Key features ■

Iris abnormalities Previous intraocular surgery ■ Rhegmatogenous retinal detachment ■ Elevated intraocular pressure ■ Ocular tumors ■

GHOST CELL HEMOLYTIC GLAUCOMA INTRODUCTION Lysed red blood cells (RBCs) from vitreous hemorrhage can accumulate in the eye if not properly cleared. Remnants of these partially degraded cells contain very little hemoglobin and are referred to as ghost cells, which can cause blockage of the trabecular meshwork. These denatured erythrocytes develop within 2–4 weeks of a vitreous hemorrhage. Any traumatic event that leads to hemorrhage in the vitreous cavity1 or, rarely, in the anterior chamber, may result in the formation of ghost cell glaucoma.

EPIDEMIOLOGY AND PATHOGENESIS The membrane remnants (ghost cells) have lost their intracellular hemoglobin and appear as khaki-colored cells that are less flexible than normal red blood cells. This loss of pliability results in obstruction of the normal trabecular meshwork pathways and subsequent development of secondary glaucoma. In order for the remnant RBCs to gain access to the anterior chamber, the hyaloid face or posterior lens capsule must be disrupted (which may occur after surgery).

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The usual history is a chronic vitreous hemorrhage resulting in a sudden onset of elevated intraocular pressure (IOP). The IOP level may be

Fig. 10-20-1  Ghost cell glaucoma. Layered ghost cells in the inferior anterior chamber angle.

sufficient to cause corneal edema. The anterior chamber is filled with circulating, small, tan-colored cells that layer in the inferior anterior chamber angle (Fig. 10-20-1). The cellular reaction appears out of proportion to the aqueous flare, and the conjunctiva tends not to be inflamed unless the IOP is elevated markedly. On gonioscopy, the angle appears normal except for the presence of ghost cells layered over the inferior trabecular meshwork.

PATHOLOGY Ghost cells lose their hemoglobin through permeable cell membranes. The cells are nonpliable, having lost their natural biconcavity, and are unable to exit through the trabecular meshwork efficiently. Heinz bodies (denatured hemoglobin) can be found in the cytoplasm.1

TREATMENT The initial treatment is antiglaucoma medical therapy, followed by intraocular surgery in eyes that are nonresponsive to medical treatment. Irrigation of the anterior chamber and pars plana vitrectomy are the initial surgeries of choice to eliminate the source of degenerative red blood cells. If this proves unsuccessful, glaucoma filtration surgery may be required.

SCHWARTZ’S SYNDROME The first description of chronic open-angle glaucoma secondary to rhegmatogenous retinal detachment was presented in 1973 by Schwartz.2 These patients presented with retinal detachments and increased IOP.

Progressive (Essential) Iris Atrophy

This variation is characterized by severe iris atrophy that results in heterochromia, marked corectopia, ectropion uveae, and pseudopolycoria (hole formation). Iridal hole formation is the hallmark finding of progressive iris atrophy (Fig. 10-20-2).

Chandler’s Syndrome

This variation shows minimal or no iris stromal atrophy, but mild corectopia may be present. The corneal edema and angle findings are the predominant and typical features (Fig. 10-20-3).

Iris–Nevus Syndrome (Cogan–Reese Syndrome)

The extent of iris atrophy tends to be variable and less severe. Tan, pedunculated nodules may appear on the anterior iris surface. The entire spectrum of corneal and other iris defects may occur in this variant.

PATHOLOGY The common pathologic feature is the appearance of the corneal endothelium, which appears as a fine, hammered silver material, similar to the guttae seen in Fuchs’ corneal endothelial dystrophy.11 Descemet’s membrane is normal, but the endothelial cells are abnormal. These endothelial cells take on characteristics of epithelial cells. With electron microscopy, this endothelial layer varies in thickness

IRIDOCORNEAL ENDOTHELIAL SYNDROME INTRODUCTION Since the initials ‘ICE’ fit both the term iridocorneal endothelial syndrome and the first letter of each of the three component entities, Yanoff8 suggested the term ICE syndrome in 1979 for this spectrum of clinical and histopathologic abnormalities. That term is now the one most commonly used. Historically, the component entities were classified as the iris nevus (Cogan–Reese), Chandler’s, and essential (progressive) iris atrophy syndromes. Collectively, the ICE syndrome describes a group of disorders characterized by abnormal corneal endothelium that is responsible for variable degrees of iris atrophy, secondary angle-closure glaucoma in association with characteristic peripheral anterior synechiae (PAS), and corneal edema.

10.20 Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors

The elevated IOP resolved following repair of the retinal detachment. All patients had an apparent anterior chamber inflammatory response. In 1977 Phelps and Burton3 surveyed 817 patients who underwent retinal detachment repair. They found 18 patients (2.2%) who fitted the criteria for Schwartz’s syndrome. At that time, several mechanistic theories were proposed. Schwartz2 postulated that the associated iridocyclitis causes a trabeculitis that decreases aqueous outflow. Matsuo et al.4 detected photoreceptor outer segments in the anterior chambers of seven patients who had retinal detachments, a discovery that suggested a connection between the subretinal space and the anterior chamber in this condition. In 1989, Lambrou et al.5 injected rod outer segments into the anterior chambers of cats in vivo, which resulted in an average rise in IOP of 10 mmHg (1.33 kPa). Electron microscopy revealed occlusion of the intratrabecular spaces by the rod outer segments, with little evidence of inflammatory activity. An interesting observation was that the injected rod outer segments mimicked cells in the anterior chamber,6 which may represent what Schwartz described as iridocyclitis in his original article.7 Davidorf7 described four cases of retinal detachment with elevated IOP and heavy pigmentation of the trabecular meshwork. The IOP decreased after successful reattachment of the retina in these cases. Regardless of the presumed pathophysiology of Schwartz’s syndrome, treatment consists of repair of the retinal detachment. The blocked trabecular meshwork causes an increase in IOP that is resistant to medical therapy. The anterior chamber ‘inflammation’ does not typically respond to conventional medical treatment.

EPIDEMIOLOGY AND PATHOGENESIS The condition is sporadic and unilateral, but with subclinical irregularities of the corneal endothelium commonly noted in the fellow eye. The syndrome affects individuals between 20 and 50 years of age and occurs more often in women. Glaucoma is present in approximately half of all cases.9 In a study of 37 cases of ICE syndrome, approximately half (21 cases) were Chandler’s syndrome; the other two clinical variations each accounted for about one-fourth of all cases.10 Gonioscopic examination of the angle may not reveal anatomic closure, though the ‘open appearing angle’ may still be functionally closed by the endothelial membrane.

Fig. 10-20-2  Hole formation in progressive iris atrophy.

OCULAR MANIFESTATIONS Patients present with differing degrees of pain, decreased vision, and abnormal iris appearance. The vision may be decreased from corneal edema, which may be worse in the morning and becomes improved later in the day. Microcystic corneal edema may be present without elevated IOP, especially in the case of Chandler’s syndrome. In the advanced stages of the syndrome, symptoms of blurred vision and pain may persist throughout the day. Patients also may present with a chief complaint of an irregular shape or position of the pupil (corectopia), or they may describe a dark spot in the eye, which may represent hole formation (pseudopolycoria) or stromal atrophy of the iris. Various degrees of iris atrophy characterize each of the specific clinical entities.

Fig. 10-20-3  Corneal edema and iris findings are typical of Chandler’s syndrome.

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from a single layer to multiple layers (while normal endothelial cells are invariably a monolayer).12,13 The endothelial cell layer can vary in thickness in different areas. The cells appear to have the potential to move, as demonstrated by filopodial cytoplasmic processes and cytoplasmic actin. The morphology of the endothelium suggests a widespread state of high metabolic activity.14,15 These changes and endothelial dysfunction result directly in the corneal edema. The anterior chamber angle may also show high PAS that extend beyond Schwalbe’s line. The high PAS are caused by contraction of the endothelial cell layer and surrounding tissues, which extend from the peripheral cornea over the trabecular meshwork and iris. These membranes can contract and cause progressive angle closure. As noted earlier, secondary glaucoma with an open angle may also occur when the endothelial membrane covers the trabecular meshwork without observable evidence of synechiae formation. The extent of iris abnormalities differentiates the specific clinical variations. When the endothelial cell layer contracts over the iris, this distorts the iris directly, causing holes (Fig. 10-20-4).16 Hole formation may be associated with ischemia of the iris, as suggested by fluorescein angiography. In Cogan–Reese syndrome, the pigmented, pedunculated nodules seen are composed of underlying iris stroma pinched off by abnormal cellular membrane.17 A viral cause has been postulated for the pathophysiologic mechanism of ICE syndrome. Epstein–Barr and herpes simplex viruses have been found serologically in ICE patients.12,18 Lymphocytes were found on a sample of the corneal endothelium of an ICE patient, suggesting chronic inflammation.

TREATMENT A diagnosis of ICE syndrome must be considered in younger patients who have unilateral angle-closure glaucoma; and can be confirmed by specular or confocal microscopy. Aqueous suppressant medications tend to be effective in controlling the IOP, while prostaglandin analogs and other outflow-associated medications are less effective. Corneal edema may often be controlled using hypertonic saline solutions. Reduction of the elevated IOP may lessen the degree of corneal edema. If the IOP level remains uncontrolled despite medical treatment, filtration surgery may be indicated, though late surgical failures have been reported secondary to endothelization of the fistular opening.19,20 These endothelial obstructions of the fistula may be reopened successfully using the neodymium : yttrium–aluminum–garnet (Nd : YAG) laser. In a study of 83 patients who had ICE syndrome, the success rates of initial trabeculectomy operations at 1 and 3 years were both 58%20 and those of second and third operations at 1-year intervals were both 58%.13 Glaucoma tube shunt procedures are indicated for cases refractory to the previously mentioned treatments and, more recently, have been used as the primary procedure.21

AXENFELD–RIEGER SYNDROME Axenfeld–Rieger (A–R) syndrome represents a rare spectrum of developmental disorders involving abnormalities of both ocular and

extraocular structures derived from the neural crest.22 The term anterior cleavage syndrome was used in the past,23 but it incorrectly reflects the development in this syndrome. All clinical variations of this syndrome are now referred to as Axenfeld–Rieger syndrome (rather than the individual component syndromes).

EPIDEMIOLOGY AND PATHOGENESIS A–R syndrome involves the anterior segment bilaterally and is associated with secondary glaucoma due to arrested angle development in about 50% of cases. A–R syndrome is a rare, autosomal dominant inherited disorder. Shields24 postulated that the developmental arrest late in gestation results in primordial endothelium being retained over parts of the iris and anterior chamber angle. Contraction of this layer causes iris stromal thinning, corectopia, and hole formation. With contraction, the anterior uvea is hindered from posterior migration, which results in a high insertion of the iris into the anterior chamber angle.22 Several mutations are associated with A–R, including PITX2, FOXC1, and PAX6.25 The affected anterior segment structures are primarily of neural crest derivation. The most common extraocular defects involve dentition and facial bones.

OCULAR MANIFESTATIONS The typical abnormality of the cornea is an anteriorly displaced Schwalbe’s line (posterior embryotoxon), which appears as a white ring on the posterior cornea near the limbus. The ring tends to be more common temporally and rarely involves all 360°. An anteriorly displaced Schwalbe’s line occurs in 8–15%26,27 of the general population and may not always be present with A–R syndrome. On gonioscopy, thread-like PAS extending to the posterior embryotoxon may obscure the angle. Iris defects, ranging from stromal thinning to actual hole formation, corectopia, and ectropion uveae, may occur.

SYSTEMIC ASSOCIATIONS Developmental defects associated with A–R syndrome most commonly involve dentition and facial bones. Microdontia (peglike incisors), hypodontia (decreased number of evenly spaced teeth), and anodontia (focal absence of teeth) are noted most commonly.23,27 The facial abnormalities include maxillary hypoplasia and a protruding lower lid. Telecanthus, hypertelorism, and primary empty-sella syndrome have also been documented with A–R syndrome.22,28,29

PATHOLOGY The peripheral cornea characteristically exhibits an anteriorly displaced Schwalbe’s line. This posterior embryotoxon shows a cellular monolayer with basement membrane that covers dense collagen.22,27 The iridocorneal strands tend to be iris stroma mixed with the above-mentioned cellular monolayer. This cellular membrane also may extend over the iris surface, which distorts the iris, creates iris stromal thinning, and results in actual hole formation and corectopia as it contracts.

TREATMENT Topical medications that decrease aqueous flow (beta-blockers, carbonic anhydrase inhibitors, and short-term use of α-agonists) are more effective than outflow facilitators (prostaglandin analogs, pilocarpine). Surgical intervention may be goniotomy or trabeculectomy.30,31 The procedure of choice in A–R syndrome is usually trabeculectomy with the adjunctive use of antimetabolites.32,33 If the initial surgical treatment fails, glaucoma tube shunt procedures may be utilized.34

C

IP

P IR

L

EPITHELIAL DOWNGROWTH AND FIBROUS INGROWTH (PROLIFERATION)

CB

INTRODUCTION 1096

Fig. 10-20-4  Iridocorneal endothelial syndrome. Histological section of an eye that had essential (progressive) iris atrophy shows a peripheral synechia (P), various degrees of degeneration and loss of the central iris stroma, and total loss of the central iris pigment epithelium (IP). (C, cornea; CB, ciliary body; IR, iris root; L, lens.) (With permission from Yanoff M, Fine BS. Ocular pathology. London: Mosby; 1996.)

Unlike the ICE syndrome, epithelial downgrowth/fibrous ingrowth results from the access of epithelial/fibrous cells into the anterior chamber. Epithelial/fibrous cells entering through an insufficiently closed wound usually cause these conditions.35 Fortunately, with

resultant secondary angle-closure glaucoma is a frequent complication and is often difficult to control medically.

EPIDEMIOLOGY AND PATHOGENESIS

PATHOLOGY

The incidence of epithelial downgrowth and fibrous ingrowth has declined greatly over the years with the advent of small-incision surgery. The prevalence of epithelial downgrowth occurred in the range of 0.12–0.6% following intracapsular cataract surgery.36–38 While previously more common after cataract surgery, epithelial downgrowth is now more commonly seen after penetrating keratoplasty,39–41 ocular trauma, and glaucoma filtration surgery.42,43 Fibrous ingrowth is more prevalent than epithelial downgrowth, progresses more slowly, and is often self-limited. Epithelial downgrowth and fibrous ingrowth can occur simultaneously.36 Prolonged ocular inflammation is a major risk factor for epithelial and fibrous proliferation.44 Other risk factors appear to be wound dehiscence, delayed closure of the wound postoperatively, and stripping of Descemet’s layer.45,46 Normal postoperative healing of the corneal scleral wound requires invasion of connective tissue to the inner margin of the wound and formation of a fibrous plug. By the second week the inner wound is usually covered by endothelium. Contact inhibition stops the movement of endothelium.47,48 When the endothelium fails to close this defect, epithelial and fibrous proliferation can occur; thus, an abnormality in the corneal endothelium is also a risk factor. Posterior limbal incisions may be more commonly associated with fibrous ingrowth, while anterior limbal incisions may be associated with epithelial downgrowth.44 Small incisional cataract surgery has minimized the importance of such distinctions. Other proposed risk factors for fibrous and epithelial proliferation are fornix-based conjunctival flaps, intraocular use of surgical instruments on the conjunctiva,49 and use of intracameral anticoagulant therapy.50

Epithelial downgrowth consists of a multilayered membrane composed of nonkeratinized, stratified, squamous epithelium that has surface microvilli; wide intercellular borders, with occasional hemidesmosomes attached to a subepithelial connective tissue layer; and epithelial cells of uneven sizes and shapes.55,56 This epithelial sheet lacks blood vessels and shows multiple tonofilaments at its leading edge (Fig. 10-20-7).57 The underlying structures in contact with the epithelial sheet undergo disorganization and destruction.

OCULAR MANIFESTATIONS

TREATMENT Management of epithelial cysts includes observation until complications are observed. Numerous approaches have been used to excise epithelial cysts, but currently a wide excision of the intact cyst is preferred. If the cyst is adherent to any intraocular structures, it may be collapsed by aspiration before excision.58 Photocoagulation of epithelial cysts, a less invasive procedure than surgical removal, has been performed successfully.59 Photocoagulation is less effective when the cyst is nonpigmented or adherent to underlying structures. Management options for epithelial proliferation include: ● Freezing the involved corneal surface to close the wound gape or fistula. ● Swabbing the involved corneal surface with absolute alcohol. ● Resecting the posterior membrane.60 ● Intracameral injection of 5-fluorouracil.61 Management of glaucoma is a difficult challenge and has a high failure rate using traditional filtration surgery techniques. Glaucoma drainage tube implants have been shown to be the most effective procedure, with both fibrous and epithelial ingrowth.34,62 Cycloablation is used only when other treatment modalities fail.

Epithelial proliferation may be present in three forms: ‘pearl’ tumors of the iris, epithelial cysts, and epithelial ingrowth. Epithelial cysts and epithelial ingrowth often cause secondary glaucoma. Epithelial cysts appear as translucent, nonvascular anterior chamber cysts that originate from surgical or traumatic wounds (Fig. 10-20-5). Epithelial ingrowth presents as a grayish, sheet-like growth with rolled edges on the posterior surface of the cornea (Fig. 10-20-6), trabecular meshwork, iris, and ciliary body; it is often associated with wound incarceration, wound gape, ocular inflammation, band keratopathy,41,51 and corneal edema. The degree of ingrowth can be very specifically detected by the characteristic whitening on application of the argon laser (Fig. 10-20-7).52 Specular and confocal microscopy provides another means of diagnosis by direct visualization of epithelial cells.53 Unlike epithelial proliferation, fibrous ingrowth is slow to progress and may be self-limited. A common cause of corneal graft failure, fibrous ingrowth appears as a thick, gray-white, vascular, retrocorneal membrane with an irregular, scalloped border reminiscent of woven cloth.54 The ingrowth often involves the angle, which results in the formation of PAS and the destruction of the trabecular meshwork. The

Aniridia is seen in approximately 1.8/100 000 live births.63 Three phenotypes are recognized, of which autosomal dominant aniridia is the most common; it is present in approximately 85% of all cases and is not associated with any other systemic manifestations. The second type is congenital sporadic aniridia, found in association with Wilms’ tumor (nephroblastoma), genitourinary anomalies, and mental

Fig. 10-20-5  Translucent, nonvascular, anterior chamber epithelial cyst.

Fig. 10-20-6  Grayish, sheet-like epithelial ingrowth with rolled edges.

ANIRIDIA INTRODUCTION Aniridia is a rare, bilateral, hereditary absence of the iris. The condition rarely occurs in its pure form and usually presents with a rudimentary stump of iris.

10.20 Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors

advancements in microsurgical techniques (e.g., improved wound closure), the incidence of these entities has been reduced greatly.

EPIDEMIOLOGY AND PATHOGENESIS

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C

B Fig. 10-20-7  Epithelial iris cyst and downgrowth. (A) Scanning electron microscopy shows a sheet of epithelium that covers the trabecular meshwork, anterior face of the ciliary body, anterior iris, and pupillary margin. (B) Epithelium lines the posterior cornea, anterior chamber angle, and peripheral iris and extends onto the vitreous posteriorly in a surgically aphakic eye. (With permission from Yanoff M, Fine BS. Ocular pathology. London: Mosby; 1996.) (C) Detection of epithelial downgrowth by application of argon laser to the iris.

retardation (Miller’s syndrome). The second type has been labeled the WAGR syndrome (for Wilms’ tumor, aniridia, genitourinary anomalies, retardation), is linked with partial deletions of the short arm of chromosome 11 (11p13), and accounts for approximately 13% of all aniridias. Autosomal recessive aniridia is the third genetic type; it is seen in approximately 2% of all cases and is associated with cerebellar ataxia and mental retardation (Gillespie syndrome).64 Hereditary aniridia is associated with the PAX6 gene.65 Different theories have been developed to explain the pathogenesis of aniridia. Some researchers consider it a subtype of coloboma. In addition, some aniridias are associated with hypoplastic discs and the absence of iris musculature, on the basis of which investigators have proposed mesodermal and neuroectodermal theories, respectively. Glaucoma develops in about 50% of patients who have aniridia.66 Glaucoma is rare in newborns; it is usually seen after the second decade of life, as anatomic changes occur in the angle secondary to contracture of peripheral iris strands.67 These iris strands bridge the space between the iris stump and trabecular meshwork, resulting in angle-closure glaucoma. In addition, goniodysgenesis is noted in some cases.

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The clinical manifestations of aniridia include photophobia related to the extent of iris involvement. Pendular nystagmus, decreased vision, amblyopia, and strabismus are seen secondary to foveal and optic nerve head hypoplasia. Bilateral ptosis also may occur in aniridia. With gonioscopy, the iris appears as a rudimentary stump with fibers that bridge the angle. This rudimentary iris leaflet appears to be pulled forward by iris strands, which results in posterior synechiae formation and subsequent angle-closure glaucoma. In addition to the anterior segment changes, findings in the posterior segment may include foveal and optic nerve head hypoplasia and choroidal coloboma. Lenticular changes include cataract, ectopia lentis, microphakia, and persistent pupillary membranes. Microcornea68 and corneal opacifications also have been observed in aniridic patients. The corneal opacification is often associated with a fine, vascular network and pannus formation.69

SYSTEMIC ASSOCIATIONS Wilms’ tumor (nephroblastoma) is found in association with aniridia in Miller’s syndrome; 25–33% of patients who have sporadic aniridia develop Wilms’ tumor. In addition to Wilms’ tumor, severe mental retardation, genitourinary anomalies, craniofacial dysmorphism, and hemihypertrophy can occur.62 In Gillespie’s syndrome, mental retardation and cerebellar ataxia are seen.

PATHOLOGY Arrestment of the neuroectodermal tissue is the most striking histopathological feature of this condition. With histological examination, a small stump of iris that lacks iris musculature may be observed. The iris remnant appears continuous with the trabecular meshwork. Glaucoma in Miller’s syndrome may develop secondary to angle anomalies, which include dysgenesis of the trabecular meshwork and Schlemm’s canal.63

TREATMENT Glaucoma and its surgical complications are the main causes of blindness in patients with aniridia. Surgery is often required by age 20 for IOP control.63,70,71 A prophylactic modified goniotomy has been advocated to prevent this secondary glaucoma in certain young patients with aniridia.72,73

TUMORS AND GLAUCOMA INTRODUCTION A variety of intratumors may cause unilateral glaucoma; the most common ones associated with glaucoma include primary melanomas, metastases, and retinoblastomas. The mechanism of glaucoma

EPIDEMIOLOGY AND PATHOGENESIS In 1987, Shields et al.74 studied 2704 eyes that had intraocular tumors, of which 5% were found to have IOP elevation secondary to the tumor. The most common tumor in adults to result in glaucoma was malignant uveal melanoma.75–79 Direct infiltration of the angle was the most common cause of increased IOP. The trabecular meshwork can also be obstructed by pigment, tumor or inflammatory cells. Shields et al.74 found glaucoma in 7 of 102 eyes that had iris melanoma. Iris melanocytomas are rare and have a predisposition to release pigment into the anterior chamber, which causes a secondary open-angle glaucoma.80 Ciliary body melanomas may present with increased IOP secondary to a variety of mechanisms.76 Shields et al.74 reported that 16 of 96 eyes that had ciliary body melanomas also had associated glaucoma. Medulloepithelioma (diktyoma) is a tumor of the nonpigmented ciliary epithelium and usually presents in childhood as a cystic or solid tumor, and in one study, about 50% of these eyes presented with glaucoma, with neovascularization as the most common cause of glaucoma.76 Mechanical displacement of the angle, direct invasion of the angle, and one case of recurrent hyphema also caused glaucoma.77 Retinoblastoma is the most common malignant intraocular tumor of childhood. Approximately 1 in 14 000–20 000 newborns have retinoblastoma, and 30–35% of cases occur bilaterally, with no sex or race predisposition. Glaucoma secondary to retinoblastoma has an incidence of 2–22%.74,81 Neovascular glaucoma secondary to retinal ischemia is the most common mechanism (73%).74 The second most common cause of glaucoma in these eyes is anterior displacement of the lens–iris diaphragm. Metastatic tumors in the uvea are usually posterior. The most common sites of origin are breasts in women and lungs in men.80 In contrast to iris and ciliary body metastases, metastatic tumors to the choroid show only about a 2% incidence of glaucoma. The main presentation of glaucoma results from a forward shift of the lens–iris diaphragm secondary to nonrhegmatogenous retinal detachment.81 Glaucoma is associated with 64% of iris metastases and 67% of ciliary body metastases.74 Elevated IOP is seen in patients with these tumors, usually from localized blockage of the trabecular meshwork by released tumor cells.81

OCULAR MANIFESTATIONS The clinical presentation of glaucoma that arises from intraocular tumors is dependent on the mechanism of inducement. Glaucoma secondary to tumors may present as a secondary angle-closure glaucoma by a posterior-push mechanism or an anterior-pull mechanism. Other mechanisms include those of secondary open-angle glaucoma.

PATHOLOGY Iris melanoma usually appears as a well-circumscribed, variably pigmented, fixed, or slow-growing tumor that may eventually invade the trabecular meshwork. The tumor is composed of spindle-shaped cells with occasional epithelioid cells.81 Ciliary body melanoma appears as a circumscribed mass that replaces the ciliary body. Choroidal melanoma appears as a variably pigmented mass that may result in a secondary nonrhegmatogenous retinal detachment. As the tumor breaches Bruch’s membrane it can form the characteristic ‘mushroom’ shape. Melanocytoma appears as a brown or black mass that may be well circumscribed80 and usually occurs at the optic disc but may arise anywhere in the uvea. Necrotic areas are present within the mass, which may result in fragmentation and liberation of tumor cells into the angle.81 Iris and ciliary body metastases usually have poor differentiation, which makes determination of the primary site difficult. Choroidal metastases are ill-defined, relatively elevated, or diffuse lesions, often associated with serous or choroidal retinal detachment. The lesions

may present with a brown discoloration secondary to overlying pigment or with a gray to yellow-cream color. Retinoblastoma appears as a chalky white mass within the globe and is composed of neuroblastic cells; areas of calcification and necrosis are common findings. The differentiated tumors are characterized by highly organized Flexner– Wintersteiner rosettes.80 Medulloepithelioma is an embryonic tumor that usually occurs in the ciliary body. The tumor appears as a yellowpink solid or cystic mass and may contain rosettes. Medulloepithelioma has two types of presentation: the nonteratoid type is composed of nonpigmented epithelium and the teratoid type shows two different germ layers (i.e., cartilage and skeletal muscle).81

TREATMENT Malignant ocular tumors are often enucleated as the definitive management. Traditional filtration techniques run the risk that tumor cells may be seeded to extraocular areas, even after treatment with radiation. Secondary glaucoma from benign tumors can be managed medically and with traditional filtration surgeries. Proper diagnosis of tumors usually is made clinically. Fluorescein angiography and ultrasonography [e.g., A-scan, B-scan, ultrasound microscopy (UBM)] help in the detection and diagnosis of intraocular tumors. In some patients, a fineneedle biopsy, aqueous aspiration, or biopsy is needed for diagnosis.

PENETRATING KERATOPLASTY INTRODUCTION Secondary glaucoma is a common complication of penetrating keratoplasty and occurs with increased frequency in aphakic and pseudophakic patients81 and in repeat corneal grafts. The different mechanisms of secondary glaucoma formation are listed in Box 10-20-1. Distortion of the angle, chronic angle closure, and a predisposition prior to surgery are the most common causes.

EPIDEMIOLOGY AND PATHOGENESIS Improved surgical and storage techniques have resulted in a large increase in the number of corneal transplants being done. Penetrating keratoplasty is one of the most successful of all transplants, with a 1-year survival rate of 80–90%.82 Postkeratoplasty glaucoma occurs more frequently in patients affected by pre-existing glaucoma. Aphakic and pseudophakic bullous keratopathies are the most common indications for penetrating keratoplasty, at rates of 20–70% and 18–53%, respectively.83 One study indicated no early or late glaucoma in patients who had penetrating keratoplasty for keratoconus, and a less than 2% incidence in patients who had Fuchs’ corneal endothelial dystrophy treated with penetrating keratoplasty.84

10.20 Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors

development varies with the location, type, and size of the tumor. Choroidal melanomas and other choroidal and retinal tumors close the angle by a mass effect, by shifting the lens–iris diaphragm forwards, with angle closure. Inflammation caused by necrotic tumors can cause posterior synechiae, which can exacerbate this angle closure through a pupillary block mechanism. Neovascularization can be caused by choroidal melanomas, medulloepitheliomas, and retinoblastomas. Liberated tumor cells can also obstruct aqueous outflow.

OCULAR MANIFESTATIONS Graft clarity is reduced significantly when postkeratoplasty glaucoma is present.85,86 Glaucoma affects the cornea directly and the visual potential by causing optic neuropathy. In early postkeratoplasty glaucoma, epithelial edema is found along with stromal thinning and compression. Such findings are noted before endothelial damage occurs.87 Progressive angle closure from peripheral synechiae formation is an early sign of impending glaucoma in postkeratoplasty patients. Some studies have demonstrated the presence of PAS in all eyes with elevated IOP after keratoplasty.88 A major study in which routine gonioscopy was

BOX 10-20-1 MECHANISMS OF SECONDARY GLAUCOMA FORMATION

•• •• •• •



Wound distortion of trabecular meshwork Fibrous ingrowth Postoperative inflammation Chronic angle closure Viscoelastic Corticosteroid induced Pre-existing conditions

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conducted, however, concluded that progressive synechial closure was a plausible explanation for only 14% of eyes that had elevated IOP.89 As topical corticosteroids are the mainstay of rejection treatment in corneal transplants, this can also be a cause of increased IOP in susceptible individuals. The use of potent corticosteroids at frequent intervals was reported to reduce the rates of early IOP elevation.87 In contrast, certain cases of IOP elevation may be related to corticosteroid responders. Following corticosteroid use, reported rates of secondary IOP are increased from 5% to 60%.88–92 This fact outlines the double-edged sword of corticosteroids: (1) the necessity for postkeratoplasty inflammation and (2) potential for postkeratoplasty glaucoma. As we gain experience with other immunosuppressants and their effects on the eye in uveitis, these agents may play a role as steroid-sparing agents in corneal transplants.

TREATMENT Treatment modalities for postkeratoplasty glaucoma include medical therapy, trabeculectomy, glaucoma tube shunt procedures, and cyclodestructive procedures. The initial treatment of choice is medical therapy. However, in the presence of significant synechial closure, drugs that influence outflow facility (i.e., miotics) may have limited action. Similarly, the role of prostaglandin analogs in this type of glaucoma and their influence on graft survival and graft clarity remain uncertain. Dorzolamide has been shown to decrease corneal endothelial function and to increase corneal thickness, and reported cases of graft failure have been attributed to its use.93 Glaucoma drainage implants (e.g., Ahmed, Krupin, Molteno, Baerveldt, Schocket) have been useful in controlling IOP among patients who have had difficult previous surgeries.94 In one study, 29% of patients progressed to failure after Molteno implantation, and 20% after insertion of Schocket’s tube.95 Long-term studies of glaucoma implants have shown that even in cases with well-controlled glaucoma there is an increase in the failure rate of the corneal graft (75% failure at 2 years, with more than 63% having well-controlled glaucoma).96 Placement of the shunt implant through the pars plana may also improve graft survival. Filtration surgery shows success rates of 27–80%.89,95,97–99 Aphakic eyes have a lower success rate than do pseudophakic or phakic eyes. Graft failure at 3 years after trabeculectomy is in the range of 11–20%.89,98 Cyclodestructive procedures can lower IOP effectively after penetrating keratoplasty. Laser cyclophotoablation is used in preference to cyclocryotherapy because of its reduced side-effects and improved visual result. The reported success rate for laser cyclophotoablation is 50–100%. Graft failure has been reported with laser cyclophotoablation.98,100,101

ALKALI CHEMICAL TRAUMA INTRODUCTION In the acute setting of a patient who has an alkali burn, glaucoma may be overlooked as a complication. It occurs in the acute and late settings, with a possible intermediate period of hypotony secondary to ciliary body damage. Secondary glaucoma occurs more often in association with alkali burns than with acidic burns.

EPIDEMIOLOGY AND PATHOGENESIS Alkali can cause severe damage to ocular tissues as a result of the saponification of fatty acids in tissue, which allows deep penetration and damage. In contrast, acidic chemicals have a tendency to coagulate tissue proteins, and the layer of precipitated protein helps buffer and limit the acid’s penetration through the cornea. Different mechanisms for each phase of IOP elevation have been postulated. The initial

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pressure elevation may be secondary to tissue shrinkage of the outer coats of the eye102 or to prostaglandin release that increases uveal blood flow.103 The intermediate and late phases show changes in the eye as part of the body’s response. In these phases, trabecular damage, PAS, and secondary pupillary block are possible mechanisms for the development of glaucoma.

OCULAR MANIFESTATIONS Damage to the cornea may be widespread and progressive. Epithelial disintegration may be followed by stromal ulcerations and perforation. Measurement of IOP in eyes that have extensive corneal damage may be difficult using Goldmann applanation tonometry. A Tonopen or pneumotonometer may be more accurate. Gonioscopy may be difficult in these patients because of corneal opacification, in which case ultrasound examination may be necessary to visualize the extent of optic nerve cupping and retinal damage. Later in the disease process, symblepharon formation of the palpebral conjunctiva may obliterate the fornices.

PATHOLOGY After exposure to an alkaline chemical, the corneal keratocytes rapidly coagulate to leave devitalized corneal stroma. The bulk of the corneal mucopolysaccharide ground substance also is destroyed, which is followed by collagen fiber swelling. Anterior segment shrinkage or prostaglandin-mediated inflammation may contribute to the IOP elevation. Inflammation will cause PAS, which also contributes. Intraocular lens damage may result in cataract formation, and the associated lens swelling may result in a secondary phacomorphic glaucoma.

TREATMENT Immediate ocular irrigation is needed to remove the chemical from the corneal surface and fornices. Neutralization of an acid with a base causes thermal reaction, which will worsen injury. The management of increased IOP in the early phase is pharmacological. Miotics and prostaglandin analogs should be used cautiously since they may increase intraocular inflammation. Anti-inflammatory medications and cycloplegics are important during the first week; topical corticosteroids are administered with caution because of their potential effect on corneal stromal melting.104 Conventional medical and surgical therapies are used for the later phases of IOP elevation associated with chemical trauma.

KEY REFERENCES Alvarenga LS, Mannis MJ, Brandt JD, et al. The long-term results of keratoplasty in eyes with a glaucoma drainage device. Am J Ophthalmol 2004;138:200–5. Cohen EJ, Schwartz LW, Luskind RD, et al. Neodymium:YAG laser transscleral cyclophotocoagulation for glaucoma after penetrating keratoplasty. Ophthalmic Surg 1989;20:713–16. Green K, Paterson CA, Siddiqui A. Ocular blood flow after experimental alkali burns and prostaglandin administration. Arch Ophthalmol 1985;103:569–71. Matsuo N, Takabatake M, Ueno H, et al. Photoreceptor outer segments in the aqueous humor in rhegmatogenous retinal detachment. Am J Ophthalmol 1986;101:673–9. Nelson LB, Spaeth GL, Nowinski TS, et al. Aniridia: a review. Surv Ophthalmol 1984;28:621–42. Ozment R. Ocular tumors and glaucoma. In: Albert D, Jakobiec F, editors. Principles and practices of ophthalmology. Philadelphia, PA: W.B. Saunders; 1994. p. 128–456. Polack FM. Glaucoma in keratoplasty. Cornea 1988;7:67. Shields J, Shields C, Shields MB. Glaucoma associated with intraocular tumors. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas. St Louis, MO: CV Mosby; 1996. p. 1131–8. Shields MB. Axenfeld–Rieger syndrome. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas. St Louis, MO: CV Mosby; 1996. p. 875–84. Weiner MJ, Trentacoste J, Pon DM, et al. Epithelial downgrowth: a 30-year clinicopathological review. Br J Ophthalmol 1989;73:6. Wilson MC, Shields MB. A comparison of the clinical variations of the iridocorneal endothelial syndrome. Arch Ophthalmol 1989;107:1465–9.

REFERENCES 1. Campbell DG, Simmons RJ, Grant WM. Ghost cells as a cause of glaucoma. Am J Ophthalmol 1976;81:441–3750.

3. Phelps CD, Burton TC. Glaucoma and retinal detachment. Arch Ophthalmol 1975;95: 418–22. 4. Matsuo N, Takabatake M, Ueno H, et al. Photoreceptor outer segments in the aqueous humor in rhegmatogenous retinal detachment. Am J Ophthalmol 1986;101:673–9. 5. Lambrou FH, Vela A, Woods W. Obstruction of the trabecular meshwork by retinal rod outer segments. Arch Ophthalmol 1989;107:742–5. 6. Matsuo T. Photoreceptor outer segments in aqueous humor: key to understanding a new syndrome. Surv Ophthalmol 1994;39:211–30. 7. Davidorf FH. Retinal pigment epithelial glaucoma. Ophthalmol Diagn 1976;38:11. 8. Yanoff M. In discussion of Shields MB, McCracken JS, Klintworth GK, et al. Corneal edema in essential iris atrophy. Ophthalmology 1979;86:1549–55. 9. Laganowski HC, Kerr Muir MG, Hitchings RA. Glaucoma and the iridocorneal endothelial syndrome. Arch Ophthalmol 1992;110:346–50. 10. Wilson MC, Shields MB. A comparison of the clinical variations of the iridocorneal endothelial syndrome. Arch Ophthalmol 1989;107:1465–9. 11. Hirst LW, Quigley HA, Stark WJ, et al. Specular microscopy of iridocorneal endothelial syndrome. Am J Ophthalmol 1980;89:11–21. 12. Campbell DG, Shields MB, Smith TR. The corneal endothelium and spectrum of essential iris atrophy. Am J Ophthalmol 1978;86:317–24. 13. Alvarado JA, Murphy CG, Maglio M, et al. Pathogenesis of Chandler’s syndrome, essential iris atrophy, and Cogan–Reese syndrome. I. Alterations of the corneal endothelium. Invest Ophthalmol Vis Sci 1986;27:853–82. 14. Rodrigues MM, Stutling RD, Waring 3rd GO. Clinical, electron microscopic, and immunohistochemical study of the corneal endothelium and Descemet’s membrane in the iridocorneal endothelial syndrome. Am J Ophthalmol 1986;101:16–27.

39. Feder RS, Krachmer JH. The diagnosis of epithelial downgrowth after keratoplasty. Am J Ophthalmol 1985;99:697. 40. Sugar A, Meyer RF, Hood I. Epithelial downgrowth following penetrating keratoplasty in the aphake. Arch Ophthalmol 1977;95:464–7. 41. Leibowitz JM, Elliott JH, Boruchoff SA. Epithelialization of the anterior chamber following penetrating keratoplasty. Arch Ophthalmol 1967;78:613–17. 42. Costa VP, Katz LJ, Cohen EJ, et al. Glaucoma associated with epithelial downgrowth controlled with Molteno implant. Ophthalmol Surg 1992;23:797–800. 43. Loane MF, Weinreb RN. Glaucoma secondary to epithelial downgrowth and 5-fluorouracil. Ophthalmol Surg 1990;21:704–6. 44. Henderson T. A histological study of normal healing of wounds after cataract extraction. Ophthalmol Rev 1907;26:127–9. 45. Dunnington JH. Healing of incisions for cataract extraction. Am J Ophthalmol 1951;34:36. 46. Anseth A, Dohlman CH, Albert DM. Epithelial downgrowth-fistula repair and keratoplasty. Refract Corneal Surg 1991;7:23–7. 47. Terry TL, Chisholm Jr JF, Schonberg AL. Studies on surface epithelium invasion of the anterior segment of the eye. Am J Ophthalmol 1939;22:1083. 48. Cameron JD, Flaxman BA, Yanoff M. In vitro studies of corneal wound healing. Invest Ophthalmol 1974;12:575–9. 49. Ferry AP. The possible role of epithelium-bearing in surgical instruments in pathogenesis of epithelialization of the anterior chamber. Ann Ophthalmol 1971;3:1089. 50. Weiner MJ, Trentacoste J, Pon DM, et al. Epithelial downgrowth: a 30-year clinicopathological review. Br J Ophthalmol 1989;73:6. 51. Swan KC, Campbell L. Unintentional filtration following cataract surgery. Arch Ophthalmol 1964;71:43–9. 52. Maumenee AE. Treatment of epithelial downgrowth and intraocular fistula following cataract extraction. Trans Am Ophthalmol Soc 1964;62:153. 53. Smith RE, Parrett C. Specular microscopy of epithelial downgrowth. Arch Ophthalmol 1978;96:1222–4.

15. Eagle Jr RC, Font RL, Yanoff M, et al. Proliferative endotheliopathy with iris abnormalities: the iridocorneal endothelial syndrome. Arch Ophthalmol 1979;97:2104–11.

54. Swan KC. Fibroblastic ingrowth following cataract extraction. Arch Ophthalmol 1973;89:445–9.

16. Yanoff M, Fine BS. Ocular pathology. London: Mosby; 1996.

55. Spencer WH, Font RL, Green WR, et al. Ophthalmic pathology: an atlas and textbook. 3rd ed. Philadelphia, PA: W.B. Saunders; 1985. p. 511–14.

17. Shields MB, Campbell DG, Simmons RJ. The essential iris atrophies. Am J Ophthalmol 1978;85:749–59. 18. Alvarado JA, Underwood JL, Green WR, et al. Detection of herpes simplex viral DNA in the iridocorneal endothelial syndrome. Arch Ophthalmol 1994;112:1601–9. 19. Daicker B, Sturrock G, Guggenheim R. Clinicopathological correlation in Cogan–Reese syndrome. Klin Monatsbl Augenheilkd 1982;180:531–8. 20. Kidd M, Hetherington Jr J, Magee S. Surgical results in iridocorneal endothelial syndrome. Arch Ophthalmol 1988;106:199–201. 21. Assaad MH, Baerveldt G, Rockwood ET. Glaucoma drainage devices: pros and cons. Curr Opin Ophthalmol 1999;10:147–53. 22. Shields MB. Axenfeld–Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983;81:736–84. 23. Reese AB, Ellsworth RM. The anterior chamber cleavage syndrome. Arch Ophthalmol 1966;75:307. 24. Shields MB. Axenfeld–Rieger syndrome. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas. St Louis, MO: CV Mosby; 1996. p. 875–84. 25. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome. Expert Rev Mol Med 2005;7:1–17. 26. Alkemade PPH. Dysgenesis mesodermalis of the iris and the cornea. Asses: Van Gorcum; 1969. 27. Burian HM, Braley AE, Allen L. External and gonioscopic visibility of the ring of Schwalbe and the trabecular one: an interpretation of the posterior corneal surface. Trans Am Ophthalmol Soc 1955;51:389–94. 28. Wesley RK, Baker JD, Golnick AL. Rieger’s syndrome (oligodontia and primary mesodermal dysgenesis of the iris): clinical features and report of an isolated case. J Pediatr Ophthalmol Strabismus 1978;15:67. 29. Kleinman RE, Kazarian EL, Raptopoupos LE, et al. Primary empty sella and Rieger’s anomaly of anterior chamber of the eye. N Engl J Med 1981;304:90–3. 30. Wallace DK, Plager DA, Snyder SK, et al. Surgical results of secondary glaucomas in childhood. Ophthalmology 1998;105:101–10. 31. Mullaney PB, Selleck C, Al-Awad A, et al. Combined trabeculotomy and trabeculectomy as an initial procedure in uncomplicated congenital glaucoma. Arch Ophthalmol 1999;117:457–60.

56. Zavala EY, Binder PS. The pathologic findings of epithelial ingrowth. Arch Ophthalmol 1980;98:2007–14. 57. Iwamoto T, Srinivasan BD, DeVoe AG. Electron microscopy of epithelial downgrowth. Ann Ophthalmol 1977;9:1095–110. 58. Tsai JC, Arrindell EL, O’Day DM. Needle aspiration and endodiathermy treatment of epithelial inclusion cyst of the iris. Am J Ophthalmol 2001;131:263–5. 59. Schoiz RT, Kelley JS. Argon laser photocoagulation treatment of iris cysts following penetrating keratoplasty. Arch Ophthalmol 1982;100:926–7. 60. Peyman GA, Peralta F, Ganiban GJ, et al. Endoresection of the iris and ciliary body in epithelial downgrowth. J Cataract Refract Surg 1998;24:130–3. 61. Lai MM, Haller JA. Resolution of epithelial downgrowth in a patient treated with 5-fluorouracil. Am J Ophthalmol 2002:133:562–4. 62. Sidoti PA, Baerveldt G. Glaucoma drainage implants. Curr Opin Ophthalmol 1994;5: 85–98. 63. Berlin HS, Ritch R. The treatment of glaucoma secondary to aniridia. Mt Sinai J Med 1981;48:111. 64. Mintz-Hittner HA. Aniridia. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas. St Louis. MO: CV Mosby; 1996. 65. Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993;2:2093–7. 66. Francois J, Lentini F. Gillespie syndrome (inkomplette Aniridie, zerebellare Ataxie and Oligophrenie). Klin Monatsbl Augenheilkd 1984;184:313. 67. Nelson LB, Spaeth GL, Nowinski TS, et al. Aniridia: a review. Surv Ophthalmol 1984;28: 621–42. 68. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Am J Ophthalmol 1974;78:842–7. 69. David R, MacBeath L, Jenkins T. Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 1978;62:118. 70. Wiggins RE, Tomey KF. The results of glaucoma surgery in aniridia. Arch Ophthalmol 1992;110:503–85. 71. Misato A, Dickens CJ, Hetherington J, et al. Clinical experience of trabeculectomy for the surgical treatment of aniridic glaucoma. Ophthalmology 1997;104:2121–5.

32. Mandal AK, Walton DS, John T, et al. Mitomycin C-augmented trabeculectomy in refractory congenital glaucoma. Ophthalmology 1997;104:996–1003.

72. Chen TC, Walton PS. Goniosurgery for prevention of aniridic glaucoma. Trans Am Ophthalmol Soc 1998;96:155–69.

33. Mandal AK, Prasad K, Nadurilath TJ. Surgical results and complications of mitomycin C-augmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Lasers 1999;30:473–9.

73. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol 1999;117:1144–8.

34. Burgoyne JK, WuDunn D, Lakhani V, et al. Outcomes of sequential tube shunts in complicated glaucoma. Ophthalmology 2000;107:309–14. 35. Smith MF, Doyle JW. Glaucoma secondary to epithelial and fibrous downgrowth. Semin Ophthalmol 1994;9:248–53. 36. Theobald GD, Haas JS. Epithelial invasion of the anterior chamber following cataract extraction. Trans Am Acad Ophthalmol Otolaryngol 1948;52:470. 37. Payne BF. Epithelialization of the anterior segment after cataract extractions. Am J Ophthalmol 1958;45:182.

10.20 Glaucomas Secondary to Abnormalities of the Cornea, Iris, Retina, and Intraocular Tumors

2. Schwartz A. Chronic open angle glaucoma secondary to rhegmatogenous retinal detachment. Am J Ophthalmol 1973;73:205–11.

38. Rummelt V, Lang GK, Yanoff M, et al. A 32-year follow-up of the rigid Schreck anterior camber lens. A clinicopathological correlation. Arch Ophthalmol 1990;108:401–4.

74. Shields CL, Shields JA, Shields MB. Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors. Ophthalmology 1987;94:839–41. 75. Geisse LJ, Robertson DM. Iris melanomas. Am J Ophthalmol 1978;85:407. 76. Ozment R. Ocular tumors and glaucoma. In: Albert D, Jakobiec F, editors. Principles and practices of ophthalmology. Philadelphia, PA: W.B. Saunders; 1994. p. 128–456. 77. Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Am J Ophthalmol 1978;85:407. 78. Reese AB, Cleasby GW. The treatment of iris melanoma. Am J Ophthalmol 1959;47:118.

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79. Kersten RC, Tse DT, Anderson R. Iris melanoma-nevus or malignancy? Surv Ophthalmol 1985;29:423–33.

93. Konowal A, Morrison JC, Brown SV, et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. Am J Ophthalmol 1999;127:403–6.

80. Shields JA, Annesley WH, Spaeth GL. Necrotic melanocytoma of iris with secondary glaucoma. Am J Ophthalmol 1977;84:826–9.

94. McDonnell PJ, Robin JB, Schanzlin DJ, et al. Molteno implant for control of glaucoma in eyes after penetrating keratoplasty. Ophthalmology 1988;95:364–9.

81. Shields J, Shields C, Shields MB. Glaucoma associated with intraocular tumors. In: Ritch R, Shields MB, Krupin T, editors. The glaucomas, St Louis, MO: CV Mosby; 1996. p. 1131–8.

95. Kirkness CM. Penetrating keratoplasty, glaucoma and silicone drainage tubing. Dev Ophthalmol 1987;14:161.

82. Council on Scientific Affairs. Report of the organ transplant council: corneal transplantation. JAMA 1988;259:719–22.

96. Alvarenga LS, et al. The long-term results of keratoplasty in eyes with a glaucoma drainage device. Am J Ophthalmol 2004;138:200–5.

83. Schanzlin DJ, Robin JB, Gomez DS, et al. Results of penetrating keratoplasty for aphakic and pseudophakic bullous keratopathy. Am J Ophthalmol 1984;98:302.

97. Gilvarry AME, Kirkness CM, Steele AD, et al. The management of post-keratoplasty glaucoma by trabeculectomy. Eye 1989;3:713–18.

84. Polack FM. Glaucoma in keratoplasty. Cornea 1988;7:67.

98. Gross RL, Feldman RM, Spaeth GL, et al. Surgical therapy of chronic glaucoma in aphakia and pseudoaphakia. Ophthalmology 1988;95:1195–201.

85. Paton D. The prognosis of penetrating keratoplasty based upon corneal morphology. Ophthalmic Surg 1976;7:36–45. 86. Polack FM. Corneal transplantation. New York: Grune & Stratton; 1977. 87. Olson RJ, Kaufman HE. A mathematical description of causative factors and prevention of elevated intraocular pressure after keratoplasty. Invest Ophthalmol Vis Sci 1977;16: 1085–92. 88. Thoft RA, Gordon JM, Dohlman CH. Glaucoma following keratoplasty. Trans Am Acad Ophthalmol Otolaryngol 1974;78:OP-352–64. 89. Foulks GN. Glaucoma associated with penetrating keratoplasty. Ophthalmology 1987;94:871–4. 90. Kirkness CM, Moshegov C. Post-keratoplasty glaucoma. Eye 1988;2(Suppl):919. 91. Goldberg DB, Schanzlin DJ, Brown SI. Incidence of increased intraocular pressure after keratoplasty. Am J Ophthalmol 1981;92:372–7. 92. Krontz DP, Wood TO. Corneal decompensation following acute angle-closure glaucoma. Ophthalmic Surg 1988;19:334–8.

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99. Kushwaha DC, Pual AK. Incidence and management of glaucoma in postoperative cases of penetrating keratoplasty. Indian J Ophthalmol 1981;29:167–70. 100. Cohen EJ, Schwartz LW, Luskind RD, et al. Neodymium:YAG laser transscleral cyclophotocoagulation for glaucoma after penetrating keratoplasty. Ophthalmic Surg 1989;20:713–16. 101. Levy NS, Bonney RC. Transscleral YAG cyclophotocoagulation of the ciliary body for high intraocular pressure following penetrating keratoplasty. Cornea 1989;8:178–81. 102. Paterson CA, Pfister PR. Intraocular pressure changes after alkali burns. Arch Ophthalmol 1974;91:211. 103. Green K, Paterson CA, Siddiqui A. Ocular blood flow after experimental alkali burns and prostaglandin administration. Arch Ophthalmol 1985;103:569–71. 104. Donshik PC, Berman MB, Dohlman CH, et al. Effect of topical corticosteroids on ulceration in alkali-burned corneas. Arch Ophthalmol 1978;96:2117–20.

PART 10 GLAUCOMA SECTION 3 Specific Types of Glaucoma

Congenital Glaucoma James D. Brandt

Definition: Glaucoma in children less than 2 years of age that can be

subdivided into: primary infantile glaucoma, which is the result of isolated abnormal development of the anterior chamber angle structures, and secondary infantile glaucomas, associated with ocular or systemic syndromes and with surgical aphakia.

Key features ■

Elevated intraocular pressure Glaucomatous optic atrophy ■ Ocular enlargement (‘buphthalmos’) ■

Associated features ■ ■ ■ ■ ■

Corneal edema Haab’s striae Photophobia Tearing Amblyopia

INTRODUCTION While clinicians commonly group all the various forms of glaucoma in children as ‘congenital,’ in reality, primary infantile glaucoma that represents a specific developmental defect of the anterior chamber angle structures is exceedingly rare. Nonetheless, most ophthalmologists will encounter the wide variety of secondary glaucomas seen in this age group. In this chapter, the reader is provided with a basic understanding of how the various forms of glaucoma can present in infants and young children, along with their differential diagnosis and the options available for treatment.

EPIDEMIOLOGY AND PATHOGENESIS The incidence of primary infantile glaucoma is between 1 : 10 000 and 1 : 15 000 live births in the heterogeneous population of the United States. In other countries, the published series range from a low of 1 : 30 000 in Northern Ireland1 to a high of 1 : 2500 in Saudi Arabia2 and 1 : 1250 among gypsies in Romania.3 Primary infantile glaucoma is bilateral in up to 80% of larger case series; in North America and Europe it is more common in boys, whereas in Japan it is more common in girls.4,5 The varied incidence among different populations suggests a strong genetic component to the disease. Most (about 90%) new cases of primary infantile glaucoma are sporadic. However, in the remaining 10% there appears to be a strong familial component; penetrance of the defect varies in the range 40–100%. Taken as a group, the secondary glaucomas of childhood are far more commonly encountered than primary infantile glaucoma. Perhaps the most common of these are the early- and later-onset forms of glaucoma associated with cataract extraction during infancy. More than half of children who have undergone lens extraction eventually develop ocular

10.21 hypertension or glaucoma.6 After one year of follow-up, the Infant Aphakia Treatment Study reported a 12% incidence of glaucomarelated adverse events; younger age at cataract surgery and the presence of persistent fetal vasculature were significant risk factors for glaucoma.7 The exact cause and pathophysiology that underlies primary infantile glaucoma remains unknown. Genetic loci with the prefix ‘GLC3’ represent genetic regions strongly associated with primary infantile glaucoma; four loci (A through D) have been identified through linkage analysis in affected families, with mutations in the GLC3A region the most common identifiable cause of primary infantile glaucoma worldwide.8 These are autosomal recessive mutations in the gene that encodes cytochrome P450 (specifically cytochrome P450, family 1, subfamily b, polypeptide 1 – CYP1B1). The specific mutations in this gene vary around the world9 and the phenotype (e.g., clinical presentation, anterior chamber angle appearance, disease severity) are correlated with specific mutations.10 Why a mutation in a ubiquitous protein like cytochrome P450 should be expressed so focally in the anterior chamber angle remains a mystery. Mutations in the promoter region of CYP1B1 appear to have a strong independent effect on phenotype.11 Studies of a CYP1B1 knockout mouse recently suggested that concurrent mutations in the tyrosinase (Tyr) gene were necessary for phenotypic expression.12 However, molecular studies of large Saudi Arabian families with confirmed CYP1B1 mutations and congenital glaucoma failed to implicate Tyr as a modifying gene necessary for the disease.13 CYP1B1 mutations appear to play a role in the glaucoma associated with the systemic disorder, Sturge–Weber syndrome14 and the panocular disorder Peters anomaly,15 strongly implicating the gene in normal anterior segment development. As the gene(s) associated with primary infantile glaucoma are characterized further and the physiologic or developmental role of the proteins they encode become better understood, the molecular, cellular, and embryologic pathophysiology of this rare disorder will become clear. In an attempt to explain why the operation he developed – goniotomy – was so successful in cases of infantile glaucoma, Barkan postulated that a thin, imperforate membrane covered the anterior chamber angle structures and impeded aqueous humor outflow.16 This Barkan’s membrane, as the structure became known, has never been confirmed on light or electron microscopy, despite numerous attempts to do so. Some observers have described a compaction of trabecular meshwork that might appear clinically as a continuous membrane.17 That the anterior chamber ‘cleavage’ disorders,18 despite their broad spectrum, often are associated with infantile glaucoma suggests that the principal defect in primary infantile glaucoma is a failure of one or more steps in the normal development of the anterior chamber angle. Among the secondary glaucomas of childhood, the underlying pathophysiology is as varied as that in adults. Presentation at or shortly after birth indicates a profound developmental abnormality of the anterior chamber angle, whereas presentation later in life usually suggests a different process. For example, patients who have aniridia who present with obvious glaucoma at birth or early childhood have visibly abnormal anterior chamber angle structures; when glaucoma presents later in life in patients who have aniridia, the previously functional trabecular meshwork is occluded by an anterior migration and rotation of the rudimentary iris stump.19 In patients who suffer from Sturge– Weber syndrome or its variants, presentation at birth is associated with a gonioscopic appearance that cannot be differentiated from that of primary infantile glaucoma, whereas later presentation is thought to be related to elevated episcleral venous pressure.

1101

10 Glaucoma Fig. 10-21-1  Clinical appearance of primary infantile glaucoma. This 8-month-old boy presented with an acute (3-day) history of corneal edema in the left eye. Note the enlarged corneas in both eyes and the epiphora. Intraocular pressure at examination under anesthetic was > 35 mmHg (> 4.7 kPa) in the right eye. Trabeculotomy ab externo was carried out bilaterally.

Angle closure may be caused by forward pressure from a process that occurs in the vitreous cavity, as in persistent hyperplastic primary vitreous, retinopathy of prematurity, or retinoblastoma. Synechial angle closure, caused by chronic inflammation or neovascularization, is seen in a variety of settings. Primary angle closure that results from iris bombé generally is not seen in children, except in cases of spherophakia, but when the pupil becomes secluded by an inflammatory or neovascular membrane, iris bombé and subsequent angle closure may occur. Secondary open-angle glaucomas also occur in young children. Both corticosteroid-induced and chronic uveitic glaucomas are described clearly.20 Open-angle glaucoma may develop long after blunt trauma to the eye has occurred,21 and may also follow the spontaneous bleeding of juvenile xanthogranuloma.22 It is difficult to classify the underlying cause of glaucoma that frequently follows pediatric cataract extraction. Rabiah reported that in a case series of 570 eyes with a minimum of 5 years of follow-up, patients who underwent cataract surgery earlier in life had a much higher risk of glaucoma than those who underwent the surgery later in life.23 Haargaard and colleagues performed a retrospective review of a surgical registry in Denmark and found similar prevalence and risk factors24 which mirror the one-year results of the Infant Aphakia Treatment Study mentioned earlier.7 Walton examined 65 children, most of whom presented with glaucoma two or more years after lensectomy.25 Preoperative gonioscopy revealed no consistent angle defect, but postoperative gonioscopy revealed a near constant (96%) filtration-angle deformity he characterized as blockage of the posterior trabecular meshwork with pigment and synechiae. Many clinicians familiar with this scenario believe that retained lens material is one risk factor for glaucoma that follows pediatric cataract extraction; another may be the presence of a small cornea. Parks and colleagues described a secondary glaucoma risk of 15% in their cohort of 174 eyes;26 only 2.9% of eyes that had normal corneal diameters developed glaucoma, whereas 32% of eyes that had corneal diameters 12 mm gives a high index of suspicion for the disease. As the cornea stretches and distends, Descemet’s membrane and the overlying corneal endothelium may fracture and rip, which results in breaks in these structures that are evident clinically as profound corneal edema (see Fig. 10-21-1) and in severe cases, acute hydrops (see Fig. 10-21-2). As the endothelial cells migrate over the breaks and lay down new basement membrane, ridges develop along the separated edges of Descemet’s membrane, which results in the formation of the double striae first recognized by Haab31 in 1899 (Fig. 10-21-3).

10.21 Congenital Glaucoma

A

B Fig. 10-21-4  Reversal of optic disc cupping after successful treatment of infantile glaucoma. (A) Significant cupping in a 1-year-old child at the initial examination under anesthesia; (B) The same optic nerves 6 months after uncomplicated 360° trabeculotomy; note the dramatic reversal of optic disc cupping.

In children above 2 years of age, corneal enlargement usually is not the predominant sign that glaucoma is present. In these children, decreased visual acuity or strabismus noted at the pediatrician’s office or progressive unilateral myopia noted in an optometrist’s office prompts a referral and the correct diagnosis. The hallmark of all forms of glaucoma, and the principal cause of irreversible visual loss, is damage to the optic nerve. Early descriptions of infantile glaucoma stated that optic nerve cupping occurred late in the disease process.32 It is now apparent not only that cupping may occur rapidly in infants, but also that with surgical treatment and normalization of IOP, this cupping is reversible.33 Mochizuki and coworkers recently described a series of patients in whom optic disc cupping reversal was documented with digital photography; planimetry revealed that the scleral canal shrinks in size as the entire globe shrinks circumferentially.34 Reversibility of optic nerve cupping is one of the hallmarks of successful treatment of glaucoma in infants and young children (Fig. 10-21-4). The resilience of the infant optic nerve should be taken into account by the surgeon who contemplates incisional surgery based only on borderline anterior segment findings; if the optic nerve is normal, a repeat examination under anesthetic in a few weeks may spare the child an unnecessary intraocular procedure.

DIAGNOSIS AND ANCILLARY TESTING The diagnosis of glaucoma in infants is clinical. In the majority of cases, particularly when the disease presents unilaterally or

asymmetrically, the diagnosis is made in the office using a penlight (see Figs 10-21-1, 10-21-2). With some practice, IOP can be measured in the office in a conscious, swaddled infant using a Tonopen or hand-held Goldmann (Perkins) tonometer. Usually, the IOP in normal infants is in the range of 11–14 mmHg (1.5–1.9 kPa) using these devices. The office measurement of an IOP greater than 20 mmHg (2.7 kPa) in a calm, resting infant is suspicious for glaucoma when other signs and symptoms suggest the disease, as is an asymmetry of more than 5 mmHg (6.7 kPa) in suspected unilateral or asymmetric cases. Measurements of IOP undertaken while a child cries and resists efforts to hold the eye open are highly unreliable, since the Valsalva maneuver and lid squeezing can result in IOP readings of 30–40 mmHg (4.0– 5.3 kPa), even in normal infants. In toddlers and older children, the iCare Rebound tonometer can be helpful in evaluating IOP and avoiding general anesthesia, but the device is less accurate than Goldmann tonometry.35 The recent recognition that central corneal thickness (CCT) can be an important confounder of accurate tonometry has led to investigations of CCT in children.36–38 Variations in CCT may actually represent additional aspects of certain pediatric glaucoma syndromes such as aniridia.39 The growing realization that tonometry is far less accurate in adults and children than previously appreciated should drive home the fact that the diagnosis of glaucoma in children should not be made solely on the basis of IOP measurement but rather on a constellation of findings. Examination of the optic nerve is attempted whenever possible, as the presence of obvious glaucomatous cupping confirms the diagnosis.

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10

BOX 10-21-1 DIFFERENTIAL DIAGNOSIS OF OCULAR SIGNS AND SYMPTOMS IN CONGENITAL GLAUCOMA

Glaucoma

Corneal Edema or Clouding Congenital hereditary endothelial dystrophy Mucopolysaccharidoses I, IS, II, III Cystinosis Sclerocornea Rubella keratitis Obstetric birth trauma (‘forceps injury’) Chemical injury

•• •• •• • •• • •• • •• •

Epiphora and/or Red Eye Nasolacrimal duct obstruction Conjunctivitis (viral, chlamydial, bacterial) Corneal epithelial defect, abrasion Photophobia Conjunctivitis Iritis Trauma (especially hyphema) Fig. 10-21-5  Gonioscopic appearance of the anterior chamber angle in primary infantile glaucoma. When viewed through a Koeppe diagnostic lens, the iris is seen to insert anteriorly, and the peripheral iris is hypoplastic and unpigmented and has a scalloped appearance. A sheen occurs over the angle structures (which is difficult to photograph) and gives the impression that a membrane coats the surface of the angle; however, Barkan’s membrane has not been identified histologically.

Corneal Enlargement Axial myopia Megalocornea (X-linked or sporadic) Microphthalmic fellow eye

DIFFERENTIAL DIAGNOSIS

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Shaffer and colleagues noted a cup-to-disc (C/D) ratio >0.3 in 68% of 126 eyes affected by primary infantile glaucoma, whereas a C/D ratio >0.3 was found in  21 mmHg (investigator discretion if EUA data alone) Optic disc cupping: a progressive increase in cup-to-disc ratio, cup-disc asymmetry of ≥0.2, or focal rim thinning Corneal findings: Haab striae or diameter: ≥11 mm in newborn, >12 mm in child 13 mm any age Progressive myopia or myopic shift coupled with an increase in ocular dimensions out of keeping with normal growth A reproducible visual field defect that is consistent with glaucomatous optic neuropathy with no other observable reason for the visual field defect.

•• • • •

Definition of Glaucoma Suspect – at Least 1 required IOP > 21 mmHg on two separate occasions, or Suspicious optic disc appearance for glaucoma, i.e. increased cup-to-disc ratio for size of optic disc, or Suspicious visual field for glaucoma, or Increased corneal diameter or axial length in setting of normal IOP

•• ••

Primary Childhood Glaucoma Primary congenital glaucoma (PCG) Juvenile open-angle glaucoma (JOAG)

•• •• •• •• •• ••

Secondary Childhood Glaucoma Glaucoma associated with ocular anomalies Glaucoma associated with systemic disease or syndrome Glaucoma associated with acquired condition Glaucoma following congenital cataract surgery Primary Congenital Glaucoma (PCG) Isolated angle anomalies (± mild congenital iris anomalies) Meets glaucoma definition (usually with ocular enlargement) Subcategories based on age of onset Neonatal or newborn onset (0–1 month) Infantile onset (>1–24 months) Juvenile onset or late-recognized (>2 years)

•

Spontaneously arrested cases with normal IOP but typical signs of PCG may be classified as PCG.

Juvenile Open-Angle Glaucoma (JOAG) No ocular enlargement No congenital ocular anomalies or syndromes Open angle (normal appearance) Meets glaucoma definition

•• •• ••

Glaucoma Associated with Non-acquired Ocular Anomalies Meets glaucoma definition List ocular anomalies (i.e. aniridia, iris hypoplasia, etc) Glaucoma Associated with Non-acquired Systemid Disease or syndrome Meets glaucoma definition List systemic syndrome or disease (i.e. trisomy 13, Marfan, NF-1, etc.)

•• • • ••

10.21 Congenital Glaucoma

Definition of Childhood Based on national criteria: / = 50% open) or (2)  Angle closure glaucoma ( 4.0 kPa).8 However, since the population with lower IOP is vastly greater than that with higher IOP, the majority of patients with glaucoma will not have highly elevated IOP. Asymmetric or unilateral glaucoma, including secondary glaucoma or angle-closure glaucoma, typically results in worse damage in the eye affected by the higher IOP. Numerous animal models of glaucoma have shown that chronically raised IOP induces glaucomatous optic neuropathy in both primate and nonprimate species. Multicentered clinical trials have definitively proven that lowering IOP is beneficial in preventing ongoing glaucoma progression in eyes

PREVALENCE OF PRIMARY OPEN-ANGLE GLAUCOMA prevalence 20 %

Black American White American

15 10 5 0

10

14

18

22

26

30

34

intraocular pressure (mmHg) Fig. 10-22-1  Prevalence of primary open-angle glaucoma in relation to screening intraocular pressure. The curves are smoothed using a running mean with window width of 7 mmHg. For white American subjects, n = 5604 eyes, and for black American subjects, n = 4464 eyes. (Data from Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991;266:369–74.)

1107

10 Glaucoma

with manifest glaucoma damage. In the Advanced Glaucoma Intervention Study (AGIS), when IOP was below 18 mmHg on all visits over 6 years (average IOP of 12 mmHg), almost no visual field progression ensued; for eyes with IOP 8Δ horizontally or 4Δ vertically usually have ARC and suppression, although these may be difficult to demonstrate. Asymptomatic binocular patients who have smaller tropias, or a smaller tropia with superimposed phoria, usually have MFS. Many sensory tests are available to the busy clinician, but access to and understanding of just a few enable evaluation of the patient’s sensory status. It is important to perform sensory testing at the beginning of the examination; prolonged monocular occlusion to evaluate visual acuity may dissociate the eyes and confound determination of the patient’s ambient sensory status.

Fig. 11-5-4  Near Worth four-dot target and anaglyph glasses. The near target is brought to the face to elicit a binocular response in patients who have strabismus and large scotomas.

Testing for Binocularity (Simultaneous Perception)

Many tests require simple tools to demonstrate binocularity. Holding a red lens before one eye and presenting a white light detects perception of two lights, red and white, in patients who have NRC and diplopia. Prisms may be used to project one light beyond the bounds of a suppression scotoma in patients who have ARC and suppression or NRC– MFS. Commercially available Polaroid projection slides, when viewed through polarized lenses, present one-half of an optotype line to each eye; binocular patients view the entire line, whereas nonbinocular patients view the half perceived by the foveating eye only. Prismatically, overcorrection of a strabismic patient elicits diplopic symptoms, which proves the presence of binocular vision. The Worth four-dot test uses a fixed wall target for distance fixation (Fig. 11-5-3) and a handheld wand for testing at variable near-fixation distances (Fig. 11-5-4). The stimulus is an array of four round targets (‘dots’), usually presented with the red dot above two green dots that in

POSSIBLE WORTH FOUR-DOT PERCEPTS IN BINOCULAR PATIENTS

distant target

near target right eye

left eye

perceived image

Esotropic right eye with ARC and suppression or with monofixation syndrome, fixing with left eye distant target

near target right eye

left eye

perceived image

POSSIBLE WORTH FOUR-DOT RESPONSES IN NONBINOCULAR PATIENTS Any strabismus in patient fixing right eye all target distances right eye

left eye

Fig. 11-5-6  Possible Worth four-dot responses in patients who do not have binocularity. The red lens is over the right eye and the green lens over the left eye.

perceived image

Any strabismus in patient fixing left eye all target distances right eye

left eye

perceived image

turn are above one white dot. The diameter of the target array subtends 1.25° at 20 ft (6 m) and 6° at 1 ft (33 cm). The targets are viewed through red–green (anaglyph) glasses, and the patient describes the percept to the examiner or simply counts the lights viewed. Binocular patients perceive red and green lights simultaneously, but the near wand must be held very close to a patient with a large strabismic deviation to project the target beyond the bounds of a suppression scotoma (Fig. 11-5-5). Nonbinocular patients see two red or three green lights at all testing distances (Fig. 11-5-6). Bagolini lenses are finely ruled plano lenses that give a streak appearance to a point light source perpendicular to the ruled direction. The lenses are placed in orthogonal orientation (traditionally at 135° right eye and 45° left eye; Fig. 11-5-7) in a trial frame and the patient views a light at distance fixation. Binocular patients perceive an ‘X’ figure or, if a suppression scotoma exists, one complete line and the peripheral elements of the second. Nonbinocular patients see only one entire line. Haploscopes, for example, the major amblyoscope, may present slightly different but fusible images to each eye; if portions of each image are perceived, the patient is binocular. The viewing tubes may be displaced to the strabismic angle if such exists, or the tubes may be kept in the straight position and targets used that are large enough to project beyond the suppression scotoma.

11.5 

Fig. 11-5-7  Bagolini lenses. Placed at 135° orientation in the trial frame before the patient’s right eye and at 45° before the patient’s left eye.

Sensory Status in Strabismus

Esotropic left eye with ARC and suppression or with monofixation syndrome, fixing with right eye

Fig. 11-5-5  Possible Worth four-dot percepts in binocular patients. Note the similar distant responses in patients who have esotropia with abnormal retinal correspondence (ARC) and suppression and in those who have monofixation syndrome. Patients who have exotropia with ARC and suppression give the same responses, but the suppression scotoma is larger and shaped somewhat differently (see Fig. 11-4-2). The red lens is over the right eye and the green lens over the left eye.

BOX 11-5-2 RETINAL CORRESPONDENCE TESTING Bagolini striated lenses; Aulhorn phase-difference haploscope Synoptophore (major amblyoscope) Red glass test Worth four-dot test; Polaroid lens and mirror test Afterimage test Dazzle test The lower the listing of an abnormal retinal correspondence response, the more the depth of the abnormal correspondence. After successful treatment, a normal retinal correspondence response develops with time, initially shown by the bottom tests and then through to the top. Not all listed tests are described in the test.

Tests of Retinal Correspondence

Many of the preceding tests may be used in binocular patients to diagnose ARC and suppression, NRC bifoveality, or NRC–MFS at a given testing distance at a given moment. As ARC exists only under binocular testing conditions, some tests may yield an ARC response at a given moment whereas other tests yield an NRC response, depending on the room illumination and the length of time ARC has been present. Tests that confound correctable single binocular vision and that poorly reproduce ordinary binocular viewing conditions demonstrate ARC later than tests that closely simulate typical binocular viewing conditions. Retinal correspondence tests are listed by depth of abnormal correspondence in Box 11-5-2. The Worth four-dot test demonstrates suppression of one eye when presented with a distant viewing target and fusion of lights of the near viewing target in patients who have ARC and suppression and NRC– MFS (Fig. 11-5-5); thus, it cannot be used to differentiate ARC from NRC easily.11 The Bagolini lens test most closely simulates ordinary viewing and is the least dissociating of all retinal correspondence tests.12 Central (foveal) fixation must be assumed and the alignment of the eyes known; possible outcomes are given in Fig. 11-5-8. The afterimage test is most removed from ordinary binocular viewing and the most dissociating of all commonly performed retinal correspondence tests; an ARC response on this test declares the ARC to be deep-seated. An afterimage (positive in dim illumination, negative in bright) is imprinted on each retina in turn with a photographic flash device. The fellow eye is covered during the flash. Usually a vertical flash is presented to one eye and a horizontal flash to the other. The fovea is protected by a central mask with fixation target and thus ‘labeled’ as the center of an afterimage line. An NRC response yields a cross pattern (see Fig. 11-5-9), as the fovea in each eye retains the straight-ahead directional value. A crossed heteronymous localization occurs in ARC with esotropia, as the straight-ahead directional value lies in the nasal retina of the strabismic eye; the fovea has a temporal directional value.13 In patients who have ARC and exotropia, the afterimage percept is an uncrossed homonymous localization. Clinicians who have access to a major amblyoscope may set the tubes at the objective angle of strabismus; if the targets are superimposed, NRC exists. Crossed diplopia occurs in patients who have ARC

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POSSIBLE BAGOLINI LENS PERCEPTS, CENTRAL FIXATION Test

Pediatric and Adult Strabismus

Right eye lens at 135 in trial frame, left eye lens at 45. Fixate on distant light in semidarkened room. Closest sensory test to normal viewing, first to exhibit abnormal retinal correspondence (ARC) strabismus, first to revert to normal retinal correspondence (NRC) when eyes aligned. Results Cover–uncover test irrelevant

No binocularity, right eye fixing

No binocularity, left eye fixing

No shift on cover–uncover testing (no tropia)

NRC bifoveal

NRC monofixation, left eye fixing

Shift on cover–uncover testing (tropia)

8∆ NRC monofixation, left eye fixing 8∆ ARC, left eye fixing esotropia Fig. 11-5-10  Titmus stereotest.

8∆ ARC, left eye fixing exotropia

8∆ NRC,

NRC, exotropic diplopia

esotropic diplopia

Fig. 11-5-8  Possible Bagolini lens percepts, central fixation.

AFTERIMAGE TEST PERCEPTS, CENTRAL FIXATION Test Horizontal flash before fixing eye, vertical flash before nonfixing eye. Flash one eye at a time. After both eyes flashed, ask patient to close eyes; positive afterimage is seen. When eyes open, negative afterimage noted. Results Normal retinal correspondence

Abnormal retinal correspondence (assume right strabismus, vertical flash before right eye)

Fig. 11-5-11  Randot stereotest with Polaroid glasses. esotropia

exotropia

Fig. 11-5-9  Afterimage test percepts, central fixation. Shown are those possible in patients who have central fixation and binocular vision.

and esotropia and uncrossed diplopia in patients who have ARC and exotropia. An ‘angle of anomaly’ is defined when the patient moves the tubes until the targets are superimposed; this subjective angle equals the objective angle in ‘harmonious’ ARC and is less or greater in ‘unharmonious’ ARC.

Stereopsis Tests

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Clinically useful stereopsis tests provide slightly different views of the same target to each eye; each unique view is maintained by either Polaroid filters (Titmus, Wirt, Randot, Lang) or anaglyph glasses (TNO). The Titmus stereotest (Fig. 11-5-10) provides disparity in the range 3000 seconds of arc at 40 cm testing distance (fly wings above background) to 40 seconds of arc (ninth circle). Younger children may respond to the depth illusion of three sets of five animals, one of which appears to float above the background (400, 200, 100 sec of arc). The older Wirt stereotest provided circles with disparity as fine as 14

seconds of arc. The first few circles may be identified accurately by nonstereoptic patients because the circles possess monocular clues;14 the Randot test (Fig. 11-5-11) avoids this problem because it provides similar targets as random dots with no monocular clues. Children who reject the Polaroid glasses may be tested using the similarly targeted Lang test,15 in which random-dot stereograms are presented through a cylinder grating that overlies the target. The TNO stereotest uses random-dot stereograms viewed through anaglyph glasses and contains disparities in the range 480–15 seconds of arc.

Test for Monofixation Syndrome

One feature of this syndrome (see Chapter 11.4) is a small, round scotoma that surrounds the fovea of one eye under binocular viewing conditions. As the patient views a distant target, a 4Δ prism, usually held base-out, is introduced before one eye. If held before the fixing eye, it will saccade to the new target position toward the prism’s apex, as does the fellow eye. A slower fusional vergence movement in the fellow eye in the opposite direction follows. When the prism is held before a nonfixing eye there is no saccade, as the image displacement falls within a scotoma and is therefore not perceived.16 The test must be performed with the prism before each eye. Some patients switch fixation to the fellow eye when a prism is introduced before either and no saccadic shift is generated.

TABLE 11-5-1  SYNOPSIS OF SENSORY TESTING IN STRABISMUS NRC–Bifoveal

NRC–Monofixation

Abnormal Retinal Correspondence

Diplopia

No Binocularity

Worth four-dot, distance (6 m) Worth four-dot, near (40 cm) Stereo

4 4 None to 14 sec arc

2 or 3 4 None to 67 sec arc

2 or 3 4 None

5 5 None

2 or 3 2 or 3 None

The Worth four-dot test and Titmus stereotest are used to define a patient’s sensory status. Appreciation of four distant lights demands normal retinal correspondence (NRC) and bifoveality, as does recognition of seven or more circles on the stereotest. Any level of stereoptic appreciation on this test signifies NRC at that moment at that testing distance. Appreciation of four lights on the Worth test at any testing distance signifies binocular vision.

The busy clinician may determine the sensory status of most patients by using two straightforward and easily available tests – the Worth four-dot test and the Titmus stereotest. A summary of sensory testing interpretation using these commonly available testing devices is given in Table 11-5-1.

KEY REFERENCES Abrams MS, Duncan CL, McMurtrey R. Development of motor fusion in patients with a history of strabismic amblyopia who are treated part-time with Bangerter foils. J AAPOS 2011;15:127–30.

Bielschowsky A. Application of the after image test in the investigation of squint. Am J Ophthalmol 1937;20:408–13. Fray KJ. Functional benefits of sensory and motor evaluation before strabismus surgery. Review. Am Orthopt J 2010;60:33–42. Julesz B. Binocular depth perception of computer-generated patterns. Bell Syst Technol J 1967;46:1203–21. Kassem RR, Elhilali HM. Factors affecting sensory functions after successful postoperative ocular alignment of acquired esotropia. J AAPOS 2006;10:112–16.

11.5  Sensory Status in Strabismus

Test

Morrison D, McSwain W, Donahue S. Comparison of sensory outcomes in patients with monofixation versus bifoveal fusion after surgery for intermittent exotropia. J AAPOS 2010;14:47–51.

Amigo G. A vertical horopter. Optica Acta 1974;21:277–92.

Schor LE, Tyler CW. Spatio-temporal properties of Panum’s fusional area. Vision Res 1981;21: 683–92.

Bagolini B. Anomalous correspondence: definition and diagnostic methods. Doc Ophthalmol 1967;23:638–51.

Wang J, Hatt SR, O’Connor AR, et al. Final version of the Distance Randot Stereotest: normative data, reliability, and validity. J AAPOS 2010;14:142–6.

Access the complete reference list online at

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REFERENCES 1. Schor LE, Tyler CW. Spatio-temporal properties of Panum’s fusional area. Vision Res 1981;21:683–92.

3. Kassem RR, Elhilali HM. Factors affecting sensory functions after successful postoperative ocular alignment of acquired esotropia. J AAPOS 2006;10:112–16. 4. Amigo G. A vertical horopter. Optica Acta 1974;21:277–92. 5. Abrams MS, Duncan CL, McMurtrey R. Development of motor fusion in patients with a history of strabismic amblyopia who are treated part-time with Bangerter foils. J AAPOS 2011;15:127–30. 6. Julesz B. Binocular depth perception of computer-generated patterns. Bell Syst Technol J 1967;46:1203–21. 7. Julesz B. Foundations of cyclopean perception. Chicago: University of Chicago Press; 1971. 8. Blakemore C. The range and scope of binocular depth discrimination in man. J Physiol (Lond) 1970;211:599–622.

11. Roundtable discussion. In: Gregerson E, editor. Transactions of the European Strabismological Association. Copenhagen: Jencodan Tryk; 1984. p. 215–24. 12. Bagolini B. Anomalous correspondence: definition and diagnostic methods. Doc Ophthalmol 1967;23:638–51. 13. Bielschowsky A. Application of the after image test in the investigation of squint. Am J Ophthalmol 1937;20:408–13. 14. Kohler L, Stigmar G. Vision screening in four-year-old children. Acta Paediatr Scand 1973;63:17–25. 15. Lang J. A new stereotest. J Pediatr Ophthalmol Strabismus 1983;20:72–4. 16. Morrison D, McSwain W, Donahue S. Comparison of sensory outcomes in patients with monofixation versus bifoveal fusion after surgery for intermittent exotropia. J AAPOS 2010;14:47–51.

11.5  Sensory Status in Strabismus

2. Wang J, Hatt SR, O’Connor AR, et al. Final version of the Distance Randot Stereotest: normative data, reliability, and validity. J AAPOS 2010;14:142–6.

9. Richards W. Stereopsis and stereoblindness. Exp Brain Res 1970;10:380–8. 10. Fray KJ. Functional benefits of sensory and motor evaluation before strabismus surgery. Review. Am Orthopt J 2010;60:33–42.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

11.6 

Esotropia

Gary R. Diamond, Raza M. Shah

CONGENITAL ESOTROPIA Definition: Inward deviation of the visual axes, with an onset before 6 months of age.

Key features Esotropia greater than 30Δ Cross-fixation ■ No binocular vision ■ Typical refractive error (between +1.50 and +3.00) ■ Initially, similar deviation at distance and near fixation

Associated features ■

Ptosis on attempted adduction Elevation or depression of the globe on attempted adduction ■ Limitation of abduction, adduction, or both ■ Esotropia or exotropia in some patients, usually acquired and rarely larger than 30° ■

■

■

Associated features ■

Inferior oblique overaction ■ Dissociated vertical deviation ■ Latent horizontal and manifest rotary nystagmus ■ Amblyopia in about one-third of patients

ACCOMMODATIVE ESOTROPIA Definition: Inward deviation of the visual axes caused by high hyperopia or a high accommodative convergence-to-accommodation ratio, or both.

Key features ■

Initially intermittent acquired esotropia ■ Esotropia larger at near than distance fixation

Associated features ■

Patients who have a high accommodative convergence-toaccommodation ratio may have any refractive error ■ Age of onset usually between 18 months and 3 years

INTRODUCTION Esotropias represent the most common form of strabismus and include congenital, accommodative, cyclic, and nonaccommodative forms. They also are seen in some patients who have Duane’s and Möbius’ syndromes.

CONGENITAL ESOTROPIA INTRODUCTION The most common form of esotropia is ‘congenital’ esotropia, somewhat arbitrarily defined as esotropia that presents before 6 months of age (Fig. 11-6-1). Recent work has demonstrated that many infants begin life with a moderate exodeviation that disappears between 2 and 4 months of age; prospective studies have determined that this is the age at which congenital esotropia is first noted. For younger children, it cannot be predicted which ones will develop congenital esotropia by age 2–4 months.1 These important observations suggest that the causes of congenital strabismus are neither purely motor nor purely sensory in most cases; rather, there is a difficulty in coupling the two systems.

EPIDEMIOLOGY AND PATHOGENESIS The incidence of congenital esotropia is roughly 1% in most series and may be more common in children who have neurological disorders.2 The term congenital esotropia is so widely used that it should be retained despite evidence that few, if any, children are truly esotropic from birth. Sex and racial distributions are equal. Concordance in one series was 81% in monozygous twins and 9% in dizygous twins.3 It is common to find accommodative esotropia or other cases of congenital esotropia in other members of the proband’s family.

DUANE’S SYNDROME Definition: Congenital miswiring of the medial or lateral rectus muscles, or both, often associated with strabismus.

Key features 1206

■

Retraction of the affected globe(s) on attempted adduction

Fig. 11-6-1  Congenital esotropia. The child is fixing with her left eye; note the decentered light reflex in the right eye.

CONGENITAL ESOTROPIA AND CROSS-FIXATION

BOX 11-6-1 DISSOCIATED VERTICAL DEVIATION COMPARED WITH INFERIOR OBLIQUE OVERACTION Inferior Oblique Overaction Present in adduction only Obeys the Hering law Rapid elevation, abduction movement Often associated with V pattern Not proportional to illumination in fixing eye Objective fundus excyclotorsion

Esotropia

Dissociated Vertical Deviation Present in all gaze positions Does not obey the Hering law Slow floating abduction, elevation, excyclotorsion movement Not associated with A or V pattern Proportional to ambient illumination in fixing eye No objective fundus torsion

11.6 

Fig. 11-6-2  Congenital esotropia and cross-fixation. The infant uses the right eye to view left, and vice versa. Doll’s head maneuver shows full abduction.

Fig. 11-6-3  Overelevation in adduction of the left eye. This arose from inferior oblique overaction and must be differentiated from dissociated vertical deviation, which also may cause overelevation in adduction.

Fig. 11-6-4  Dissociated vertical deviation in the right eye. If the patient fixes with the right eye, no hypodeviation is seen in the left. Therefore, dissociated vertical deviation does not obey the Hering law. (Reproduced with permission from Cheng KP, Biglan AW, Hiles DA. Pediatric ophthalmology. In: Zitelli BJ, Davis HW, editors. Atlas of pediatric physical diagnosis. 2nd ed. New York: Gower Medical Publishing; 1992. p. 19.1.)

OCULAR MANIFESTATIONS Amblyopia occurs in 25–40% of patients, but the majority ‘cross-fixate,’ i.e., use the right eye to fix across the nose to view objects to the left of the patient, and vice versa4 (Fig. 11-6-2). A child who does not have amblyopia switches fixation at the midline as an object is brought from one side to the other and does not maintain fixation and adopt a progressive head turn. As a rule, the deviation is >35Δ and comitant, measuring roughly the same in all gaze positions, distance and near. Inferior oblique overaction is noted in up to 75% of patients, with an onset most frequently during the second year of life; it may be unilateral or bilateral (Fig. 11-6-3).5 Early surgical correction of the esotropia does not prevent the later development of inferior oblique overaction. This must be differentiated from dissociated vertical deviation (DVD), which also occurs in roughly 75% of these patients and has similar onset patterns (Fig. 11-6-4);6,7 DVD may be manifest or latent, is very asymmetrical, and may present as any combination of elevation, abduction, and excyclotorsion (Box 11-6-1). Although its cause is unknown, DVD may represent a primitive eye movement pattern uncovered by deficient fusion. Brodsky8 concluded that DVD is a dorsal light reflex in which asymmetrical input evokes a vertical divergence, serving in lower lateral-eyed animals as a righting response by

Fig. 11-6-5  Pseudostrabismus. This results from a flat nasal bridge, wide epicanthal folds, and small interpupillary distance. (Reproduced with permission from Cheng KP, Biglan AW, Hiles DA. Pediatric ophthalmology. In: Zitelli BJ, Davis HW, editors. Atlas of pediatric physical diagnosis. 2nd ed. New York: Gower Medical Publishing; 1992. p. 19.1.)

equalizing visual input to each eye. Nystagmus may be present in both manifest rotary and latent horizontal forms. The former is uncommon and tends to diminish during the first decade of life. Latent nystagmus with fast phase toward the unoccluded eye is found in approximately 50% of patients. Asymmetrical monocular pursuit is a feature of congenital esotropia, as measured by opticokinetic nystagmus (OKN). Temporal-to-nasal pursuit is favored; patients who have congenital esotropia show poor nasal-to-temporal OKN regardless of the degree of stereopsis or the timing of surgery.9 Roughly half of young children sent to ophthalmologists by pediatricians for esotropia have pseudostrabismus, an illusion caused by a wide and flat nasal bridge, wide epicanthal folds, and the ability of young children to converge accommodatively to very close distances (Fig. 11-6-5).10

DIAGNOSIS Cover test measurements to detect amblyopia may be difficult in very young children, and a variation of the light reflex test in which the deviation is neutralized by prisms held apex-to-apex before both eyes may be required. The deviation tends to be constant but may vary; rarely, spontaneous resolution may occur during a 3–4-year period. Refractive errors tend to be similar to those of normal children of the same age. Nystagmus may confound attempts at monocular acuity measurement; fogging one eye with plus lenses or the use of anaglyph (red– green) lenses may provide a more accurate acuity measurement in the face of latent nystagmus. Side-gaze observations by non-ophthalmologists may be particularly deceptive in the case of pseudostrabismus, as the adducted eye is buried easily under the skin fold. Hirschberg’s light reflexes may demonstrate alignment to parents, as can elevation of the nasal bridge skin away from the face to alter the facial appearance temporarily.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of congenital esotropia (Box 11-6-2) includes the entities discussed in detail later. The nystagmus blockage (compensation) syndrome, in the opinion of some investigators, accounts for a significant segment of the young population with large-angle, earlyonset esotropia.11 These patients have a large esotropia and nystagmus

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11

BOX 11-6-2 DIFFERENTIAL DIAGNOSIS OF CONGENITAL ESOTROPIA

Pediatric and Adult Strabismus

Early-onset accommodative esotropia Nystagmus blockage (compensation) syndrome Möbius’ syndrome Duane’s syndrome Cyclic esotropia Esotropia associated with visual loss in one eye, neurologic impairment, or increased intracranial pressure Strabismus fixus and other fibrosis syndromes

at a young age; the nystagmus is of minimal amplitude in adduction and maximal in abduction.12 Therefore, the patient makes a continuous effort to maintain both eyes in adduction through the use of convergence, and it may be impossible to neutralize the esodeviation using prisms held before one or both eyes. Although nystagmus may occur in patients who have the common form of congenital esotropia, it is present in equal degrees in all gaze positions. Various series imply that nystagmus blockage syndrome affects 10–12% of esotropic patients, but many investigators believe that it is much less common.

TREATMENT

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The theoretical goals of treatment include:  excellent visual acuity in each eye;  perfect single binocular vision in all gaze positions at distance and near; and  a normal esthetic appearance. All are obtainable except for perfect single binocular vision, because (with rare exceptions)13 these patients, even with early treatment, do not view with both foveae simultaneously. However, as discussed later, most obtain peripheral fusion and the monofixation syndrome and generally stable alignment. Other reported benefits of successful surgical alignment include improvement in fine motor skills, heightened bonding of parents and child, and enlarged binocular visual field. Amblyopia traditionally is treated preoperatively, because compliance is usually better, acuity may be evaluated more easily (the eye moves to take up fixation in the presence of a large strabismus), and amblyopia responds more quickly in a younger child. A common approach is to occlude the better-sighted eye for all waking hours and evaluate the child at intervals related to age. For example, a 1-year-old child is evaluated 1 week after the onset of occlusion, a 2-year-old at 2 weeks, and a 6-month-old at 3 days. After acuity has equalized, the duration of patching may be decreased to approximately 2 hours per day, with good assurance that amblyopia will not return; in compliant children, patching may be discontinued, with a 50% or better assurance that amblyopia will not return. Some investigators have induced cycloplegia in the better-sighted eye, if hyperopic, using atropine or via occlusion with an opaque contact lens, with success. The impact of treatment of refractive errors of less than +2.00 D usually is variable and minimal. Larger refractive errors are corrected, and the deviation is remeasured, because postoperative exotropia may occur if surgery is performed on uncorrected, highly hyperopic eyes. An occasional patient responds to miotic treatment, but such patients usually have an intermittent deviation and probably have an early-onset accommodative esotropia. When congenital esotropia is left untreated, patients do not display binocular vision of any variety when they become old enough to cooperate for testing of their visual sensory status; the primary goal of surgical treatment at this age is to align the eyes sufficiently to stimulate the development of binocularity. This binocularity usually fulfills the criteria for monofixation syndrome as defined by Parks14 and is generally a stable alignment.15 The mainstay of therapy for this form of strabismus is surgery. Ing found that surgical alignment before the age of 24 months resulted in peripheral fusion in 93% of patients; surgery after 24 months resulted in similar results in only 31% of patients.2 Few available data suggest that surgery at 6 months of age is more effective than that performed 1 year later. One report that provides such data describes seven patients who underwent surgery between 13 and 19 months of age; three developed stereopsis on random dot stereograms and fused with Worth

four-dot test at distance, and two of the three achieved stereoacuity of 40 seconds of arc by Titmus testing, which suggests bifoveality.16 Advocates of surgery after 2 years of age are concerned about the later development of inferior oblique overaction and DVD, which require separate surgical procedures, and the difficulty of measuring acuity in children who have aligned visual axes; they are unconvinced of the benefits of the monofixation syndrome (peripheral fusion without central fusion). Given reproducible strabismus measurements, informed and supportive parents, the availability of safe pediatric anesthetic, and the absence of amblyopia, most strabismus surgeons in the United States opt for attainment of horizontal alignment by age 2 years. The two major surgical options for correction are symmetrical medial rectus recessions on both eyes (possibly adding a monocular or binocular lateral rectus resection) and a recession of one medial rectus combined with resection of the opponent lateral rectus on the same eye. Some surgeons prefer a limbal incision because of the ease of access and orientation, as well as the ability to recede contracted conjunctiva and thus augment the effect of the medial rectus recession. Many prefer the fornix approach popularized by Parks because it often does not require suture closure and avoids proximity to the cornea, which enables rapid patient mobilization. A novel approach to congenital esotropia is the use of botulinum toxin, originally popularized by Scott and studied further by Magoon.17 He injected one medial rectus in 15 children and obtained excellent results, the children remaining stable for at least 1 year. Most children required ketamine sedation, and many required more than one injection. Because patients with DVD usually exhibit no binocularity when DVD is present, they are asymptomatic. The major reason for treatment of DVD is esthetic. If DVD is monocular or highly asymmetrical, optical means may enable fixation to be switched to the eye that has DVD and thus render it entirely latent. Usually, however, surgical treatment is necessary. This can be symmetrical or asymmetrical and may involve significant recessions of the superior rectus muscles or resection of the inferior rectus muscles. Some surgeons combine the former with a posterior fixation suture, which alone is ineffective. It is crucial to dissect the intermuscular septum from the vertical recti so that lid position is not affected. Treatment of inferior oblique overaction is often undertaken primarily for esthetic reasons, but the condition may interfere with binocular function if elevation of the adducted eye occurs close to fixation and if it is bilateral. Because of the frequency of increased overaction in an unoperated, overactive oblique muscle after the other is weakened, unilateral surgery is reserved for those cases that are clearly unilateral. Traditional weakening procedures include disinsertion, myectomy, denervation and extirpation, and measured recession. Anteriorization of the oblique insertion to the margin of the inferior rectus significantly weakens the muscle and may be effective treatment for simultaneous DVD. Clear separation between DVD and inferior oblique overaction is necessary, however, because weakening of a normally functioning inferior oblique muscle may cause limitation of elevation in adduction, compensatory head postures, and all the signs and symptoms of cyclovertical muscle palsy.

COURSE AND OUTCOME Whatever the approach, a recent tendency toward larger medial rectus recessions has improved the surgical success rates significantly. Recent series quote rates as high as 90% for alignment to within 10Δ of perfect alignment.18 Some surgeons prefer to perform recessions measured from the limbus rather than the original muscle insertion, because of increased uniformity and better results. A common protocol for surgical treatment is given in Table 11-6-1. As a result of the instability of postoperative alignment, children who have surgery for congenital esotropia require long-term follow-up. Residual esotropia of >10Δ found 4–6 weeks after initial surgery may respond to antiaccommodative measures if the patient is significantly hyperopic, but it probably requires a second surgical procedure. This might consist of bilateral lateral rectus resection for those who initially underwent bilateral medial rectus recessions, and a recess–resect procedure on the unoperated eye for those who underwent a unilateral procedure. A significant fraction of patients who initially achieve alignment later develop accommodative esotropia and require treatment with glasses or miotics.19 Asymmetrical monocular pursuit as

TABLE 11-6-1  SURGERY FOR CONGENITAL ESOTROPIA Deviation (Δ)

Asymmetric (one eye)

Recede Medial Rectus, Both Eyes (mm)

Resect Lateral Rectus (mm)

Recede Medial Rectus (mm)

5.0 5.5 6.0 6.5 7.0

5.0 5.5 6.0 6.5 7.0

8.0 9.0 10.0 10.0 10.0

measured by OKN testing persists indefinitely and may be a perpetual marker for congenital esotropia.

ACCOMMODATIVE ESOTROPIA INTRODUCTION Accommodative esotropia is characterized by two mechanisms that may occur in variable proportions in the same individual. The first cause is high hyperopia, with an average of +4.50 D, and the second is a larger eso tendency at near fixation than can be controlled comfortably by fusional divergence. A third cause may be anisometropia greater than or equal to 1 D, especially in patients who have lower overall hyperopia (less than +3.00 D).20

EPIDEMIOLOGY AND PATHOGENESIS The typical history is of intermittent esotropia that appears between 6 months and 7 years of age (average 30 months) toward the end of the day or when the child is very tired, ill, or daydreaming (especially at near fixation distances, such as across the dinner table). At onset, the child may experience asthenopia as fusional divergence amplitudes are stressed and may rub the eyes or squint; an older child may complain of headaches or diplopia. As the esotropia becomes more frequent, abnormal retinal correspondence and suppression, when extant, relieve asthenopic symptoms at the possible expense of fusional divergence amplitudes. Some children maintain intermittent esotropia for long periods, whereas others progress quickly to constant esotropia, especially at near fixation.

OCULAR MANIFESTATIONS Patients who have high hyperopia must generate large, accommodative input to see clearly at near fixation and thus stress fusional divergence amplitudes. They may choose blurred vision and maintain comfortable single binocular vision, or they may choose clear vision and risk asthenopia or esotropia. Those patients who have high hyperopia but do not develop esotropia, yet who maintain excellent acuity, often have low ratios of accommodative convergence to accommodation (AC/A). Patients who have typical hyperopia (average +2.25 D) or myopia and who develop an esodeviation greater at distance than near have an overactive convergence response to a given accommodation requirement – a high AC/A ratio. This ratio can be calculated by two methods, the heterophoria method and the gradient method, as described in Box 11-6-3. Some patients have mildly high hyperopia and mildly high AC/A ratios and therefore have a mixed mechanism of accommodative esotropia. In all cases, however, the patient’s fusional divergence amplitudes are insufficient to control the eso tendency.

DIAGNOSIS AND ANCILLARY TESTING The ophthalmologist must be alert to historical clues, evaluate the AC/A ratio, and, if possible, measure fusional divergence amplitudes at distance and near fixation. Historically, atropine has been considered essential to obtain the maximal hyperopic refractive error; however, its use requires a return visit, and its cycloplegic effect is prolonged. The outpatient use of cyclopentolate and tropicamide permits immediate treatment and, in most patients, provides results within +0.50 D of the refractive error obtained using atropine, although a few patients have greater uncovered hyperopia.

Heterophoria Method Determine phoria by prism and alternate cover test at optical infinity and 0.33 m distances. Control accommodation and correct acuity to 20/30 (6/9) using least plus lens. ( ∆2 − ∆1) AC /A = IPD(cm) + F where AC/A = accommodative convergence to accommodation IPD = interpupillary distance Δ1 = distance phoria Δ2 = near phoria (eso is +, exo is – ) F = near fixation distance in diopters of vergence Example: IPD = 60 mm or 6 cm Δ1 = 4 eso Δ2 = 30 eso F = 1/33 cm = 3 D 30 − 4 AC/A = 6 + 3 = about 15/1

11.6  Esotropia

35 40 or 45 50 or 55 60 or 65 ≥ 70

Symmetric

BOX 11-6-3 ACCOMMODATIVE CONVERGENCE-TOACCOMMODATION RATIO CALCULATIONS

Gradient Method Determine phoria by prism and alternate cover test at a fixed distance, generally 0.33 m. Control accommodation and correct acuity to 20/30 (6/9) with least plus lens. Vary lens power held before eyes and remeasure alignment. ∆1 − ∆ 2 AC/A = D Δ1 = original phoria in diopters Δ2 = new phoria with new lens D = power of lens Example: Δ2 = 2 eso Δ1 = 6 eso D = +1.00 6−2 AC/A = 1 = 4 /1

It is important to recognize that most individuals without strabismus have flexible AC/A ratios that adjust to changes in refractive error over the person’s lifetime; however, patients who have accommodative esotropia often have rigid AC/A ratios that respond inflexibly to changes in refractive correction. This fact may be used to the patient’s benefit through the prescription of a hyperopic correction. In older patients, the fusional divergence amplitudes may be measured and prove to be deficient. As successful treatment proceeds, normal fusional measurements are obtained. If the esodeviation cannot be found on initial attempts, occlusion of one eye for 45 minutes to 3 hours may be carried out, or cycloplegia can be induced and cover testing performed using suitably large targets. An esodeviation after cycloplegia provides strong confirmation of parental observations and may be sufficient to warrant initiation of treatment.

DIFFERENTIAL DIAGNOSIS Differential diagnosis includes variable esotropia accompanied by normal AC/A ratios and refractive errors; these (uncommon) patients exhibit fusional divergence amplitudes equally deficient at distance and near. Some of these patients respond to antiaccommodative measures, and others do not. Another group of patients have a V-pattern esotropia with greater deviation in downgaze. It is important to measure near deviations in primary position to avoid confusion with V-pattern esotropes.

TREATMENT, COURSE, AND OUTCOME Treatment consists of antiaccommodative measures, primarily the prescription of much or all of the patient’s hyperopic refractive error (to do

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11 Pediatric and Adult Strabismus 1210

the focusing for the child, so as not to stimulate accommodation and thus convergence). In very young children or myopes, the uncoupling of accommodation from convergence using miotics may be considered. Glasses are a problem in children younger than approximately 1 year of age because of their weight, flat nasal bridge, lack of cooperation, and small face, which makes fitting difficult. Treatment of accommodative esotropia in this group is often better initiated with miotics such as ecothiopate iodide 0.125% used every evening for 2 weeks. If this is successful, less frequent administration may be attempted. To decrease the risk of pupillary margin cysts, phenylephrine 2.5% may be added 2 weeks after miotic initiation to maintain pupillary dilatation. Because ecothiopate is a true cholinesterase inhibitor with a potential systemic effect, parents must be warned to alert all physicians to the child’s use of this drug, especially if general anesthesia is indicated; nondepolarizing agents may be used to avoid prolonged anesthesia reversal. Despite years of experience using this drug in the treatment of accommodative esotropia, when it is used at this frequency and strength in children, no cases of cataract or retinal detachment have been described. Older children may complain of brow ache and miotic spasm, so an attempt is made to switch patients to glasses at age 1 year when possible; however, many parents prefer to continue using the miotic because it has no esthetic disadvantages, works consistently well, and does not demand the child’s cooperation. At present, ecothiopate iodide is difficult to obtain in the United States. In children 1–4 years of age, the full cycloplegic refraction is given, and the child is re-evaluated after a month’s full-time wear of the prescription. If the distance and near esodeviations are reduced to within the monofixational range (≤8Δ of esotropia) and the child has a comfortably controlled phoria and no asthenopic signs or symptoms, the treatment is considered initially successful and the patient is re-evaluated 3–6 months later, depending on age. At every visit, assessment of visual acuity at distance and near, assessment of alignment at distance and near, and sensory testing are performed. Cycloplegic refractions are repeated every 6 months. If the distance tropia is greater than the above limit, the cycloplegic refraction is repeated; if it is still so with the new refraction or no change has occurred in the refraction, the patient becomes a candidate for surgery. If the distance deviation is controlled but an esotropia greater than the above limit is present at near fixation, or if a symptomatic phoria at near fixation persists, the patient is given bifocal glasses (Fig. 11-6-6). Parents must be warned that a newly fitted child exhibits larger and more frequent esodeviations when glasses are removed. The bifocals are prescribed high enough to split the pupil in primary position; strengths above +1.00 D may be prescribed as executive style, but lower strengths often can be ground only as a large flat-top style. The initial bifocal strength may be estimated from measurement of the near esodeviation using various strengths of trial frame lenses or arbitrarily given as +2.50–3.00 D. The patient is asked to wear the bifocals for 1 month and then return for re-evaluation; rarely, except for V-pattern esotropia, does the near deviation not respond to bifocal prescription if the distance deviation is controlled using full cycloplegic refraction. Patients who have V-pattern accommodative esotropia may require miotics alone or in addition to single-vision glasses, as bifocals require downgaze fixation and the deviation is largest in downgaze in such patients. As a rule, glasses and miotics are equally effective treatments, and it is rare for a patient to respond to one but not the other; conversely, use of both together rarely salvages a patient who does not respond to one or the other. An intellectual preference exists for refractive treatment for the highly hyperopic ‘refractive’ accommodative esotrope and miotic treatment for the patient who has a high AC/A ratio. When the successfully treated child is about 5 years of age, the parents note less esodeviation without glasses; at about 6 years of age, the glasses may be weakened progressively, roughly 0.50–0.75 D every 6 months, beginning with the bifocals. A common practice is to place the weaker correction in a trial frame and perform cover testing; occasionally, a patient appears aligned during this office evaluation but develops a significant esodeviation, asthenopic symptoms, or both when the weaker correction is worn. In such cases, the patient must return to the previous stronger prescription. It is often possible to rid children of their bifocals by 8 or 9 years of age and of their mild to moderate hyperopic correction by the early teens. Patients who have high hyperopia, significant astigmatism, or anisometropia may require optical correction for acuity purposes after their accommodative

A

B

C Fig. 11-6-6  Hyperopic child with right esotropia. (A) Esotropia controlled at distance fixation through distance (top) segment of bifocals. (B) Esotropia near fixation through distance segment of bifocals. (C) Aligned eyes at near fixation through near (bottom) segment of bifocals.

esotropia has resolved; for some, treatment may consist of wearing contact lenses. Patients whose treatment is initiated at 4–8 years of age may not accept their full hyperopic correction without a period of cycloplegia. Ideally, the minimal correction necessary to provide and maintain comfortable single binocular vision and (in the case of high hyperopia) good visual acuity is prescribed. After 6 years of age the AC/A ratio tends to normalize, but the hyperopia may increase. Initiation of treatment in children older than 9 years of age is difficult but is similar to that described earlier; some of these older patients may respond to miotics. At any time after a period of successful antiaccommodative treatment a patient may develop an esotropia that is not controlled with glasses or miotics.21 Repeat refraction is carried out, and if greater hyperopia is found, it is prescribed. It is difficult to predict the effect of even as little as +0.50 D additional correction on a decompensated accommodative esotrope. If no effect is obtained after a few weeks’ trial, the patient should undergo strabismus surgery. The contribution of high hyperopia, a high AC/A ratio, progressively increasing hyperopia, undercorrection of hyperopia, and overactive inferior oblique muscles to decompensation of accommodative esotropia is still somewhat unclear. The clinical experience of one author (G.D.) is that significant inferior oblique overaction implies less likelihood that weaning from glasses can be achieved and a greater incidence of decompensation; the same is true of increased interpupillary distance. Strabismus surgery classically is directed toward only the nonaccommodative component of the distance esodeviation, with an arbitrary

CYCLIC ESOTROPIA First reported by Burian24 in 1958, this curious condition of cyclic esotropia most commonly presents as alternating 24-hour periods of perfect alignment followed by constant, usually large-angled (30–40Δ) esotropia. The age of onset is generally 3–4 years. Other cycles of alternation, often 12 or 36 hours, have been described.25 When the eyes are aligned, excellent fusional abilities and stereopsis are found; when esotropia is present, patients exhibit abnormal retinal correspondence and suppression. Some patients who have cyclic esotropia display irritability and emotional withdrawal during the periods of strabismus. The incidence has been estimated as 1 in 5000 cases of strabismus (roughly 150 cases appear in the literature). Aids to diagnosis include a strong suspicion and a log of the strabismus periods kept by the parents. This condition differs from intermittent esotropia because, during the aligned periods, little or no strabismus may be elicited despite prolonged occlusion. The cause is unknown but may be related to the ‘biological clock’ phenomenon popularized by Richter.26 Some patients develop a cyclic esotropia after head trauma, neurosurgical procedure, strabismus surgery, or infection. The course is usually stable, but some patients decompensate to a persistent strabismus. Antiaccommodative measures usually have little effect during the periods of strabismus and are not needed during the aligned periods. Surgical treatment is typically successful in 75–90% of cases in attaining alignment with one operation, whether performed during aligned or strabismic periods.

of the sixth nerve fascicles and nuclei and aberrant medial rectus insertion, as some patients have medial recti that insert quite close to the limbus. No treatment is necessary or successful in patients who have gaze palsies alone; those who are esotropic and unable to abduct to the midline require medial rectus recessions. These recessions may be technically quite challenging because the muscles are very tight and difficult to hook, suture, and safely detach from the globe; doubleoverlapping marginal myotomies may be safer in some situations. Resections of the nonfunctioning lateral recti are avoided, as they are fruitless. Systemic associations include mental retardation, polydactyly, syndactyly, brachydactyly, clubbed feet, peroneal muscular atrophy, and a peculiar gait.29 Brainstem auditory evoked responses often are abnormal.

11.6  Esotropia

addition (1 mm additional recession per medial rectus) for a high AC/A ratio. Some investigators believe that posterior fixation sutures combined with medial rectus recessions benefit patients with high AC/A ratios.22 Some surgeons favor directing surgery toward the near esodeviation; others operate for the average deviation between distance and near fixation. Parents must be warned of the continual need for antiaccommodative treatment even after strabismus surgery. Hyperopic laser in situ keratomileusis (LASIK) has been effective in patients aged 10 to 52 years.23 A difficult group of patients consists of teenagers who are well controlled in bifocals or high hyperopic correction but who have esthetic concerns. A switch to contact lenses places less accommodative demand on the patient and may enable comfortable single binocular vision at near fixation without the need for separate reading glasses. Bifocal contact lenses may be tolerable to some patients; few are satisfied with ‘monovision’ fitting of one lens for distance needs and another for near. Blended bifocals may be tolerated by some teenagers and permit persistent bifocal treatment without the dysesthetic impact of a bifocal line. Some teenagers accept miotics in addition to single-vision glasses to avoid bifocal lenses. Finally, cautious single medial rectus recession, or small bimedial rectus recession, may be performed in those patients who fuse at distance when wearing single-vision lenses and who wish to be rid of their bifocals. The effective management of accommodative esotropia demands a long period of cooperation among patient, physician, and parents and is as much art as science. Nowhere else in strabismus management are communication skills so important.

DUANE’S SYNDROME EPIDEMIOLOGY AND PATHOGENESIS Duane’s syndrome, which accounts for 1% of all strabismus, is a congenital miswiring of the medial and lateral rectus muscles, such that globe retraction on attempted adduction occurs, as well as limitation of adduction, abduction, or both. Its most common variant (type I; 85% of cases) presents in the left eye (60%) (Fig. 11-6-7),30 predominantly in girls (60%), as severely limited or absent abduction (Fig. 11-6-8).

OCULAR MANIFESTATIONS Neuropathologically, this disorder has been shown to be caused by an absent sixth nerve nucleus and nerve and innervation of the lateral rectus by a branch from the inferior division of the third nerve.31 Thus, classic electromyographical findings of absent lateral rectus firing upon attempted abduction, and firing of both horizontal recti upon attempted adduction, are explained.32 No mechanism exists to improve the abduction limitation. About 40% of patients who develop esotropia and tight medial rectus muscles adopt a head turn toward the affected eye to maintain single binocular vision, or they maintain a straight head but accept esotropia, abnormal retinal correspondence, and suppression, if extant. Duane’s syndrome is bilateral in roughly 20% of cases; the sex and eye predominance pertain only to type I. Less common forms include type II (14%), with limitation of adduction and a tendency toward exotropia, and type III (1%), with limitation of both abduction and adduction and any form of horizontal strabismus. Often associated is a ‘tether’ phenomenon, which consists of overelevation, overdepression, or both in adduction as the retracted globe escapes from its horizontal rectus restrictions.

TREATMENT The amount of esotropia in monocular Duane’s syndrome type I is rarely greater than 30Δ. Recession of the medial rectus muscle in the involved eye aligns the eye but does not improve abduction beyond

MÖBIUS’ SYNDROME Möbius’ syndrome, in its full presentation, consists of bilateral abduction limitation with or without esotropia, upper motor neuron seventh nerve palsies, and twelfth nerve palsy with atrophy of the tongue.27 Some patients have difficulty suckling as young infants, as well as abnormal phonation. Close inspection of the tongue reveals atrophy of its terminal third. The upper motor neuron seventh nerve palsies cause smooth facies, absent nasolabial folds, round mouth, and decreased facial emotional responses. Lid closure is variable. Patients who have esotropia (38%) generally have tight medial recti on forced duction testing;28 those who have gaze palsy and straight eyes do not. Esotropia, when present, is quite large, and the patients cross-fixate in a manner similar to congenital esotropes; as a rule, however, abduction to the midline cannot be performed.19 The syndrome is not defined strictly; some patients are included who also have vertical gaze palsies and lower motor neuron seventh nerve palsies. The cause of the esotropia may include both involvement

Fig. 11-6-7  Head posture in left Duane’s syndrome type I. This child shows a face turn to the left to compensate for deficient abduction in the left eye. (Reproduced with permission from Fells P, Lee JP. Strabismus. In: Spalton DJ, Hitchings RA, Hunter PA, editors. Atlas of clinical ophthalmology. London, New York: Gower Medical Publishing; 1984. p. 6.7.)

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11 Pediatric and Adult Strabismus

A

B

C

D

E Fig. 11-6-8  Versions in Duane’s syndrome type I. This child has normal versions in her right eye and no abduction of the left eye beyond the midline. The lid fissure narrows on adduction of the left eye and widens on attempted abduction. The exotropia in upgaze is common in patients with Duane’s syndrome.

primary position. Rarely, very large weakening procedures on the medial rectus result in consecutive exotropia, but the mechanisms are unclear. A small medial rectus recession in the opposite eye helps stabilize the pathologic eye in primary position by application of the Hering law;33,34 resection of the lateral rectus generally is avoided, as it increases retraction and may not improve abduction. However, Morad et al.35 showed improved abduction with no worsening of globe retraction after modest unilateral medial rectus recession and lateral rectus resection in carefully selected patients with mild globe retraction and good preoperative adduction. Lateral transposition of the vertical rectus muscles has been shown to improve abduction of the affected eye, but almost half the patients required additional medial rectus recession, and 15% developed vertical strabismus.36 The tether phenomenon may be improved surgically using horizontal rectus posterior fixation sutures or by horizontal splitting of the lateral rectus into a ‘Y’ structure, with resuturing of the muscle above and below the axis of the lateral rectus. If extreme retraction with pseudoptosis is dysesthetic, both horizontal recti may be receded to relieve the retraction.

SYSTEMATIC ASSOCIATIONS Systemic associations in 30% of cases include: Goldenhar’s syndrome; Klippel–Feil syndrome; a rare autosomal dominant form; and the Wildervanck association of Duane’s syndrome, Klippel–Feil syndrome, and congenital labyrinthine deafness. Pairs of identical twins who have mirror-image Duane’s syndrome have been described. Brainstem auditory evoked responses occasionally are abnormal, which suggests widespread neurological abnormalities.

STRABISMUS FIXUS 1212

This rare, congenital, stationary, very large-angle esotropia of unknown cause may represent a form of congenital fibrosis of the medial rectus muscles. Usually no abduction is possible, and strabismus surgery on these very tight muscles is often of little benefit.

ESOTROPIA IN THE NEUROLOGICALLY IMPAIRED The incidence of strabismus is higher in the population of neurologically impaired children than in the general population. In addition to the previously mentioned categories, children with neurological impairment may have a variable intermittent esotropia that is unresponsive to antiaccommodative measures; it may be stable, worsen to a constant tropia, or disappear with maturity. Surgery is avoided unless measurements of the deviation are reproducible; the patient is intellectually capable of benefiting from improved binocular function; and the effects of any neurotropic medications, especially sedatives, are considered. Surgical outcome may be less successful in these patients, but antiaccommodative measures may be helpful.37 In addition, a patient under significant emotional stress occasionally presents with a temporary esotropia, sometimes related to accommodative spasm.

ESOTROPIA ASSOCIATED WITH VISUAL DEFICIT Children who have impaired vision in one or both eyes are at risk for the development of strabismus. Esotropia develops in a high proportion of infants younger than 2 years of age who have decreased acuity secondary to congenital cataract, corneal opacity, retinal pathology, or other devastating media-clarity impairment. The prognosis for the development of stable single binocular vision with early treatment of the media pathology and surgical alignment is poor; therefore, in most cases, surgical treatment is performed primarily for esthetic improvement.

HEAD-TILT DEPENDENT ESOTROPIA ASSOCIATED WITH TRISOMY 21 Abnormal head tilt may be used to control purely horizontal strabismus. Six of seven children who adopted a compensatory head tilt to decrease esotropia had trisomy 21.38

ESOTROPIA CAUSED BY HIGH MYOPIA AND GLOBE PROLAPSE FROM THE MUSCLE CONE

Costenbader F. Infantile esotropia. Trans Ophthalmol Soc UK 1970;59:397–429. Hiles DA, Watson A, Biglan AW. Characteristics of infantile esotropia following early bimedial rectus recession. Arch Ophthalmol 1980;98:697–703. Ing MR. Early surgical alignment for congenital esotropia. Trans Am Ophthalmol Soc 1981;79:625–33. Louwagie CR, Diehl NN, Greenberg AE, et al. Long-term follow-up of congenital esotropia in a population-based cohort. J AAPOS 2009;13:8–12.

KEY REFERENCES Archer SM, Sondhy N, Helveston EM. Strabismus in infancy. Ophthalmology 1989;96:133–8. Baker JD, Parks MM. Early-onset accommodative esotropia. Am J Ophthalmol 1980;90:11–18.

Pediatric Eye Disease Investigator Group. Interobserver reliability of the prism and alternate cover test in children with esotropia. Arch Ophthalmol 2009;127:59–65.

11.6  Esotropia

In some patients who have acquired esotropia with high myopia, the lateral rectus muscle shifts inferiorly and the superior rectus muscle shifts nasally, leading to esotropia and hypotropia.39

Birch EE, Wang J. Stereoacuity outcomes after treatment of infantile and accommodative esotropia. Optom Vis Sci 2009;86:647–52.

Waardenburg PJ. Squint and heredity. Doc Ophthalmol 1954;7:422–94. Weakley DR, Birch E, Kip K. The role of anisometropia in the development of accommodative esotropia. J AAPOS 2001;5:153–7.

Access the complete reference list online at

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REFERENCES 1. Archer SM, Sondhy N, Helveston EM. Strabismus in infancy. Ophthalmology 1989;96:133–8.

21. Baker JD, Parks MM. Early-onset accommodative esotropia. Am J Ophthalmol 1980;90:11–8. 22. Elsas FJ, Mays A. Augmenting surgery for sensory esotropia with near/distance disparity with a medial rectus posterior fixation suture. J Pediatr Ophthalmol Strabismus 1996;3:28–30.

4. Costenbader F. Infantile esotropia. Trans Ophthalmol Soc UK 1970;59:397–429.

23. Stidham DB, Borissova O, Borissov V, et al. Effect of hyperopic laser in situ keratomileusis on ocular alignment and stereopsis in patients with accommodative esotropia. Ophthalmology 2002;1009:1148–53.

5. Hiles DA, Watson A, Biglan AW. Characteristics of infantile esotropia following early bimedial rectus recession. Arch Ophthalmol 1980;98:697–703.

24. Burian M. Cyclic esotropia. In: Allen H, editor. Strabismus ophthalmic symposium II. St Louis, MO: CV Mosby; 1958.

6. Birch EE, Wang J. Stereoacuity outcomes after treatment of infantile and accommodative esotropia. Optom Vis Sci 2009;86:647–52.

25. Costenbader F, Manuel D. Cyclic esotropia. Arch Ophthalmol 1964;71:150–4.

7. Helveston EM. Dissociated vertical deviation, a clinical and laboratory study. Trans Am Ophthalmol Soc 1981;78:734–79.

27. Henderson JC. The congenital facial diplegia syndrome: clinical features, pathology and aetiology. A review of 61 cases. Brain 1939;62:381–403.

3. Waardenburg PJ. Squint and heredity. Doc Ophthalmol 1954;7:422–94.

8. Brodsky MC. Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol 1999;117:1216–22.

26. Richter C. Biologic clocks in medicine and psychiatry. Springfield, IL: CC Thomas; 1965.

28. Parks MM. Ophthalmoplegic syndromes and trauma. In: Duane TD, Jaeger E, editors. Clinical ophthalmology. Philadelphia, PA: JB Lippincott; 1985.

9. Aiello A, Wright KW, Borchert M. Independence of opticokinetic nystagmus asymmetry and binocularity in infantile esotropia. Arch Ophthalmol 1994;112:1580–3.

29. Gadoth N, Bioedner B, Torde G. Möbius’ syndrome and Poland anomaly: case report and review of the literature. J Pediatr Ophthalmol Strabismus 1978;16:374–6.

10. Cheng KP, Biglan AW, Hiles DA. Pediatric ophthalmology. In: Zitelli BJ, Davis HW, editors. Atlas of pediatric physical diagnosis. 2nd ed. New York: Gower Medical Publishing; 1992.

30. Fells P, Lee JP. Strabismus. In: Spalton DJ, Hitchings RA, Hunter PA, editors. Atlas of clinical ophthalmology. London/New York: Gower Medical Publishing; 1984. p. 6.7.

11. Van Noorden GK. The nystagmus blockage syndrome. Trans Am Ophthalmol Soc 1976;74:220–36.

31. Hotchkiss MG, Miller NR, Clark AW, et al. Bilateral Duane’s retraction. A clinical-pathologic report. Arch Ophthalmol 1980;98:870–4.

12. Ciancia AO. On infantile esotropia with nystagmus in abduction. J Pediatr Ophthalmol Strabismus 1995;32:280–8.

32. Huber A. Electrophysiology of the retraction syndrome. Br J Ophthalmol 1974;58:293–300.

13. Wright KW, Edelman PM, McVey JH, et al. High-grade stereoacuity after early surgery for congenital esotropia. Arch Ophthalmol 1994;112:913–19. 14. Parks MM. The monofixation syndrome. In: Dabezies O, editor. Strabismus. Transactions New Orleans Academy of Ophthalmology. St Louis, MO: CV Mosby; 1971. 15. Pediatric Eye Disease Investigator Group. Interobserver reliability of the prism and alternate cover test in children with esotropia. Arch Ophthalmol 2009;127:59–65. 16. Louwagie CR, Diehl NN, Greenberg AE, et al. Long-term follow-up of congenital esotropia in a population-based cohort. J AAPOS 2009;13:8–12. 17. Magoon EH. Infantile esotropes treated under age one with botulinum chemodenervation routinely show motor fusion. Invest Ophthalmol Vis Sci 1984;25:74–8. 18. Repka ML. Esotropia. In: Plager D, editor. Strabismus surgery. Oxford: Oxford University Press; 2004. ch. 1. 19. Carta A, Mora P, Neri A, et al. Ophthalmic and systemic features in Möbius syndrome: an Italian case series. Ophthlmol 2011;118: 1518–23.

11.6  Esotropia

2. Ing MR. Early surgical alignment for congenital esotropia. Trans Am Ophthalmol Soc 1981;79:625–33.

20. Weakley DR, Birch E, Kip K. The role of anisometropia in the development of accommodative esotropia. J AAPOS 2001;5:153–7.

33. Pressman SH, Scott WE. Surgical treatment of Duane’s syndrome. Ophthalmology 1986;93:29–38. 34. Saunders RA, Wilson MF, Bluestein EC, et al. Surgery on the normal eye in Duane’s retraction syndrome. J Pediatr Ophthalmol Strabismus 1994;31:162–9. 35. Morad Y, Kraft SP, Mims JL. Unilateral recession and resection in Duane syndrome. J AAPOS 2001;5:158–63. 36. Molarte AB, Rosenbaum AL. Vertical rectus muscle transposition surgery for Duane’s syndrome. J Pediatr Ophthalmol Strabismus 1990;27:171–7. 37. Pickering JB, Simon JW, Ratliff CD, et al. Alignment success following medial rectus recessions in normal and delayed children. J Pediatr Ophthalmol Strabismus 1995;32:225–7. 38. Leuder GT, Arthur B, Garibaldi D, et al. Head-tilt dependent esotropia associated with trisomy 21. Ophthalmology 2004;111:596–9. 39. Aoki Y, Nishida Y, Hayashi O, et al. Magnetic resonance imaging measurements of extraocular muscle path shift and posterior eyeball prolapse from the muscle cone in acquired esotropia with high myopia. Am J Ophthalmol 2003;136:482–9.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

11.7 

Exotropia

Gary R. Diamond, Raza M. Shah

Definition: An acquired or, rarely, congenital, outward deviation of the visual axis of one or both eyes, which may be constant, intermittent, or latent.

Key feature ■

An intermittent exotropia that measures greater at distance than at near fixation A

Associated features ■

History of squinting one eye in bright sunlight Amblyopia, if present, usually mild unless exotropia constant ■ Common inferior or superior oblique muscle overaction ■ Common A, V, or other “alphabet” patterns ■

INTRODUCTION Exotropia is a manifest outward deviation of the visual axes of one or both eyes which is either constantly or intermittently present. The term is also used loosely to describe a latent outward deviation that, more accurately, is termed exophoria. Patients who have intermittent exotropia compose a spectrum that extends from those that are easy to dissociate to those that are very difficult to dissociate; thus, there is a continuum of patients who have a form of exodeviation. Intermittent exotropia (Fig. 11-7-1) is by far the most frequent cause of exodeviation and is often a progressive disease; an exophoria decompensates to an intermittent exotropia and finally to a constant exotropia. The angle of deviation usually does not increase until secondary contracture of the lateral recti ensues, but the deviation at near often increases to approach that at distance. Von Noorden1 reported that 75% of 51 patients progressed, 9% did not, and 16% improved with time.

EPIDEMIOLOGY AND PATHOGENESIS

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Exotropia is about one-third as common as esotropia and may be more prevalent in the Middle East, Asia, and Africa; Nepal appears to have the highest incidence of exotropia compared with esotropia, at 76%.2 Some patients who have exotropia also have orbital anomalies (craniosynostosis syndromes), mechanical restrictions (Duane’s syndrome type II), or neurological pathologies (third nerve palsy) that account for the strabismus; some develop exotropia after strabismus surgery for esotropia. These causative disorders are not present in most patients; the majority are believed to have a primary deficiency of fusional convergence. Evidence exists that when an exotropia starts to manifest, neurons of the lateral rectus muscle of the deviating eye begin to fire, which suggests an active divergence contribution to the final deviation; secondary contracture also may intervene.3 A tendency toward exotropia may be inherited.4,5 Chavasse6 noted that the visual axes migrate from a lateral to a frontal position as phylogeny progresses, while oculomotor control migrates from the midbrain to the cerebral cortex. He speculated that exotropia represents an atavistic loss of cortical control. Exotropia provides an enlarged visual field and may

B Fig. 11-7-1  Intermittent exotropia. (A) Eyes straight. (B) A few moments later, the exotropia has become manifest. (Courtesy of Howard Eggers.)

have had a protective function at one time; aligned eyes provide better binocular vision, with heightened stereopsis, and are more suited to effective hunting and manipulation for tool making. Patients who have intermittent exotropia tend to have excellent alignment at near with superb stereopsis; at distance, where stereopsis is less effective, they have the benefit of an enlarged visual field. These patients, according to this theory, have developed an alignment strategy that provides an ideal system for those who are sometimes hunters and sometimes hunted.

OCULAR MANIFESTATIONS Ocular manifestations, in addition to the outward deviation of the eye, are squinting in bright sunlight, contracture of lateral recti in longstanding cases, true overaction of oblique muscles, lateral gaze incomitance, alphabet patterns, and accommodative spasm. Most patients who have intermittent exotropia possess normal retinal correspondence when their eyes are aligned and anomalous retinal correspondence when deviated.7 Contracture of the lateral recti may occur in patients who have longstanding intermittent exotropia and those who have constant exotropia. Adduction may be limited, and the tight lateral recti may act as tethering cords; on attempted elevation and depression in adduction, the globe may overelevate or overdepress, and oblique muscle dysfunction may be erroneously diagnosed. Confusingly, both the inferior oblique and superior oblique muscles may become truly overactive in patients with intermittent exotropia. Forced duction testing of the

DIAGNOSIS AND ANCILLARY TESTING Intermittent exotropia typically presents between the ages of 2 and 4 years with a gradual, but more frequently noted, exodeviation when the child fixes on a distant target. Squinting of the deviating eye and eye rubbing in bright sunlight are noted so frequently as to be volunteered by parents and may be the presenting complaint. A family history of strabismus should be sought, as well as an estimation of age of onset, progression in frequency and severity, and recognition by family, friends, and teachers. Previous treatment for this or other strabismus should be noted. The ophthalmologist should study the alignment of the eyes as the child enters the room and during the medical history to gain insight into the alignment under ordinary viewing conditions. Cover testing is the initial diagnostic test during the examination, using an accommodation-controlling target in primary position at distance (ideally 20 ft [6 m]) and near (1 ft [0.3 m]) fixation and in gazes right, left, up, and down at distance fixation. Near measurements used to calculate the accommodative convergence-to-accommodation (AC/A) ratio should be made after 1 hour of monocular occlusion to eliminate those who have pseudo-high AC/A ratios. Those rare patients who have intermittent exotropia and true high AC/A ratios often have an esophoria at 6 inches (0.15 m) or 3 inches (0.07 m) testing distance.11 Ductions and versions are then evaluated to search for oblique muscle dysfunction or contracture of the lateral recti with adduction limitation. Evaluation of alignment at far distance fixation (horizon seen through a window or at the end of a long hallway) is attempted, because accommodative convergence may be generated even in an examination lane 20 ft (6 m) long, and the deviation decreased accordingly. Many also add tests at near fixation with the patient wearing +3.00 D lenses before each eye to relax accommodative convergence. Sensory tests in a cooperative child for the presence of anomalous retinal correspondence, suppression, and stereopsis are performed and evaluated, as discussed in Chapters 11.4 and 11.5. Frequently, the parents note strabismus at home, but the physician cannot detect misalignment with typical cover tests. Occlusion of one eye to disrupt fusion may be performed for periods from 30 minutes to 2 hours, and the eye uncovered at the moment of alternate cover testing.

DIFFERENTIAL DIAGNOSIS Only rarely is intermittent exotropia confused with another form of strabismus; should it decompensate to constant exotropia, it must be differentiated from congenital exotropia and exotropia associated with Duane’s syndrome (see Chapter 11.6), convergence paralysis, third nerve palsy (see Chapter 11.10), and orbital anomalies (Box 11-7-1). Constant, large-angle exotropia can occur before 1 year of age (“infantile” or “congenital” exotropia) and is about 3% as common as infantile

BOX 11-7-1 DIFFERENTIAL DIAGNOSIS OF EXOTROPIA Pseudoexotropia from large, positive angle κ or hypertelorism Third nerve palsy with medial rectus weakness Duane’s syndrome type II Synergistic divergence “Congenital” exotropia Exotropia consecutive to surgery for esotropia

or congenital esotropia. Inferior oblique muscle overaction and dissociated vertical deviation are common, but latent nystagmus is rare. Sometimes spontaneous alignment occurs by 1 year of age; surgical correction by 2 years of age provides alignment with monofixation syndrome in most cases.12

TREATMENT Nonsurgical Treatment

11.7  Exotropia

oblique muscles differentiates those with true oblique muscle overaction from those with merely tight lateral recti.8 Some patients who have intermittent exotropia have less misalignment on side-gaze than in the primary position and historically have been considered at greater risk for surgical overcorrection.9 This phenomenon was challenged as the result of an artifact of faulty prism technique when deviations are measured with the head turned to the side.10 Many patients have greater deviations in upgaze or downgaze, or both, than in primary position; some have oblique overactions, which may explain the incomitance. All so-called alphabet patterns may be found, from the common A (greatest deviation in downgaze) and V (greatest deviation in upgaze) patterns to the X, Y, and lambda patterns.

Successful treatment of intermittent exotropia is enhanced by correction of significant refractive errors and amblyopia. Undercorrected myopia is corrected fully not only to improve visual acuity at distance but also to stimulate accommodative convergence at near fixation. Significant amounts of uncorrected hyperopia (greater than +3.00 D) are corrected as well, because uncorrected high hyperopia may be associated with hypoaccommodation.13 Correction of amblyopia alone rarely improves alignment, but treatment compliance is often better before surgery, and it is easier to follow visual acuity levels in each eye in nonverbal children before the eyes are aligned. Active orthoptic training is based on the concept of deficient motor fusion and has been performed in some fashion for more than 80 years. Fusional vergence amplitudes are enhanced, when deficient, by using a major amblyoscope or fusional training exercises in free space. Other techniques utilize monocular targets that are progressively more difficult to fuse, beginning with large, detailed stereoscopic targets at near. Eventually, simple targets at distance are presented. Results vary depending on the success criteria, but most practitioners agree that intermittent, comitant deviations that measure less than 25Δ have a better prognosis than large, incomitant, constant exotropias. Monocular occlusion has been used by some authors, initially continuously and more recently for specific periods (3–8 hours per day).14 A decrease in frequency of exotropic alignment and improvement from intermittent exotropia to exophoria have been noted.15 Those for whom monocular occlusion therapy failed and who subsequently underwent surgery showed postoperative alignment equal to that of those who had not undergone occlusion. Overcorrecting minus lenses (–2.00 to –4.00 D over the habitual distance prescription) have been prescribed to stimulate accommodative convergence, with some success. After improved alignment, the patients were weaned slowly from the overcorrected lenses.16 Use of therapeutic (base-in) prisms has been attempted in some patients who have intermittent exotropia, with questionable long-term efficacy; typically, about 50% of the maximal distance deviation is corrected with prisms. Most younger patients relax fusional convergence in response to the prism (“eat” the prism), and the physician may have to increase the prism strength progressively; older patients who have more constant exotropia and limited fusional amplitudes may respond more positively. Intermittent exotropia may become more constant when the prism glasses are removed.17 Prisms greater than 5 D are difficult to incorporate into lenses; thus, Fresnel membrane prisms are more useful for larger deviations (see Chapter 11.13).18

Surgical Treatment

Surgical treatment of strabismus is appropriate only after nonsurgical approaches have been attempted and the results found to be unsatisfactory to the patient or physician. Patients who have intermittent exotropia become reasonable surgical candidates when many of the features listed in Box 11-7-2 are present. Usually, tropias under 10Δ are associated with the monofixation syndrome and do not require, nor is the patient’s sensory status benefited by, surgery unless a symptomatic, superimposed phoria is present.

BOX 11-7-2 FEATURES CONSIDERED IN THE DECISION ON SURGICAL TREATMENT Increasing frequency of strabismus, more than once a day Increasing amplitude of strabismus Decompensation to constant exotropia Increasing symptoms of squinting and rubbing of eye(s), asthenopia, myopic spasm Strabismus noted by childhood friends, teachers, strangers Cosmetic deformity

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11

TABLE 11-7-1  ADVANTAGES AND DISADVANTAGES OF SYMMETRICAL AND ASYMMETRICAL SURGERY

Pediatric and Adult Strabismus

Symmetrical surgery (recession of both lateral recti or resection of both medial recti) Asymmetrical surgery (recession of one lateral rectus and resection of one medial rectus)

Advantages

Disadvantages

Recessions technically easier than resections Does not create lid fissure anomalies on side-gaze Recessions do not sacrifice muscle tissue Does not alter refractive error Preferred if one eye deeply amblyopic Preferred if patient demands surgery on one eye Monocular surgery lends itself more easily to local anesthetic techniques

Bilateral surgery may be difficult to explain to patients who note monocular strabismus Monocular surgery lends itself more readily to local anesthetic techniques Resections involve disposal of muscle tissue Induces plus cylinder axis 90° for 6 weeks postoperatively Often leads to subtle lid tissue anomalies on side-gaze (wider in abduction than adduction)

TABLE 11-7-2  SUGGESTED EXTENT OF SURGERY FOR PATIENTS WITH EXOTROPIA Deviation (Δ)

Recede lateral rectus by (mm)

Resect medial rectus by (mm)

12 15 20 25 30 35 40 45 50 60 70

3.5 4.0 5.0 6.0 7.0 7.5 8.0 8.5 9.0 10.0 11.0

2.5 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Adapted from data from Marshall M. Parks, MD.

The surgeon must then decide between symmetrical surgery (recession of both lateral recti or resection of both medial recti) and asymmetrical surgery (recession of one lateral rectus combined with resection of its antagonist medial rectus). The historical approach was to reserve recession of both lateral recti for patients with “true divergence excess” intermittent exotropia, in whom the deviation remained larger at distance fixation than at near fixation after a trial of +3.00 D lenses at near. Patients with a greater intermittent exotropia at near fixation than at distance fixation (“convergence insufficiency”) received resection of both medial recti, and all others received asymmetrical surgery. Some reports suggest that, except for those with convergence insufficiency, all patients may be given bilateral lateral rectus recessions, because the results are equivalent to those obtained with asymmetrical procedures. One prospective study found that patients with “basictype” intermittent exotropia (near deviation equal to distance deviation) had better outcomes after unilateral recess–resect procedures.19 The advantages and disadvantages of symmetrical and asymmetrical surgery are listed in Table 11-7-1. Most published series show that symmetrical and asymmetrical surgery give equivalent results. Patients who receive the former are often esotropic for a few weeks after surgery. However, in a recent study, after 3.8 years from surgery, the symmetric surgery group showed better results than the asymmetric group.20 The amounts of recession and resection for intermittent exotropia or exotropia for given deviations are suggested in Table 11-7-2; these figures provide a roughly 5% ultimate overcorrection rate and a 15% ultimate undercorrection rate. These amounts are modified from data of Dr Marshall M. Parks and require the suture to be placed 1.0– 1.5 mm from the lateral rectus insertion. If symmetrical surgery is chosen, each muscle is receded by the amount shown in the

Access the complete reference list online at

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appropriate column. If asymmetrical surgery is chosen, the appropriate amount of surgery shown is performed on each muscle. Most surgeons operate for the maximal deviation uncovered at far distance fixation, except in patients with convergence insufficiency; in those patients, surgeons operate for the maximal deviation at near fixation distance. Those who have lateral gaze incomitance of more than 10Δ less than the primary position measurement should have 1.0 mm less lateral rectus recession performed on the eye on the side of the lesser deviation. All patients who have binocular vision should be warned of the possibility of postoperative diplopia.

COURSE AND OUTCOME Published surgical results vary, depending on criteria for success and length of follow-up. Cosmetic success is often defined as an esotropia or exotropia of less than 15Δ, and functional success is often defined as a small asymptomatic phoria or constant tropia less than 10Δ with peripheral fusion, or small residual intermittent exotropia, which rarely occurs. Typical published success rates after one operation are in the range 60–90% for functional success and 70–95% for cosmetic success. Patients should be warned of the smaller lateral visual field expanse that occurs after successful surgery.

KEY REFERENCES Blodi FC, Van Allen M. Electromyography in intermittent exotropia; recordings before, during, and after corrective operation. Doc Ophthalmol 1962;26:21–34. Buck D, Powell CJ, Rahi J, et al. The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort. BMC Ophthalmol 2012;12:1. Choi J, Chang JW, Kim S-J, et al. The long-term survival analysis of bilateral lateral rectus recession versus unilateral recession–resection for intermittent exotropia. Am J Ophthalmol 2012;153:343–51. Friedman DS, Repka MX, Katz J, et al. Prevalence of amblyopia and strabismus in white and African American children aged 6 through 71 months: the Baltimore Pediatric Eye Disease Study. Ophthalmology 2009;116:2128–34. Lim SH, Hong JS, Kim MM. Prognostic factors for recurrence with unilateral recess–resect procedure in patients with intermittent exotropia. Eye (Lond) 2011;25:449–54. Erratum in: Eye (Lond) 2011;25:1104. Moore S. The prognostic value of lateral gaze incomitance in intermittent exotropia. Am Orthoptic J 1969;19:69–74. Scheiman M. Treatment of symptomatic convergence insufficiency in children with a home-based computer orthoptic training program. J Pediatr Ophthalmol Strabismus 2011;15:123–4. Serrano-Pedraza I, Manjunath V, Osunkunle O, et al. Visual suppression in intermittent exotropia during binocular alignment. Invest Ophthalmol Vis Sci 2011;52:2352–64. Struck MC, Hariharan L, Kushner BJ, et al. Surgical management of clinically significant hypertropia associated with exotropia. J AAPOS 2010;14:216–20. Von Noorden GK. Some aspects of exotropia. In: Binocular vision and ocular motility: theory and management of strabismus. St Louis, MO: CV Mosby; 1990. p. 236

REFERENCES 1. Von Noorden GK. Some aspects of exotropia. In: Binocular vision and ocular motility. Theory and management of strabismus. St Louis, MO: CV Mosby; 1990. p. 236.

3. Blodi FC, Van Allen M. Electromyography in intermittent exotropia; recordings before, during, and after corrective operation. Doc Ophthalmol 1962;26:21–34. 4. Buck D, Powell CJ, Rahi J, et al. The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort. BMC Ophthalmol 2012;12:1. 5. Struck MC, Hariharan L, Kushner BJ, et al. Surgical management of clinically significant hypertropia associated with exotropia. J AAPOS 2010;14:216–20. 6. Chavasse BF. Worth’s squint or the binocular reflex and the treatment of strabismus. 7th ed. Philadelphia, PA: Blakiston & Son; 1939. p. 107–8. 7. Jampolsky A. Physiology of intermittent exotropia. Symposium: intermittent exotropia. Am Orthoptic J 1952;2:5–14. 8. Capo H, Mallotte R, Guyton D. Overacting obliques in exotropia: a mechanical explanation. Presented at the American Association for Pediatric Ophthalmology and Strabismus Meeting; 1988. 9. Moore S. The prognostic value of lateral gaze incomitance in intermittent exotropia. Am Orthoptic J 1969;19:69–74. 10. Serrano-Pedraza I, Manjunath V, Osunkunle O, et al. Visual suppression in intermittent exotropia during binocular alignment. Invest Ophthalmol Vis Sci 2011;52:2352–64.

12. Biglan AW, Davis JS, Cheng KP, et al. Infantile exotropia. J Pediatr Ophthalmol Strabismus 1996;33:79–84. 13. Iacobucci I, Archer S, Giles C. Children with exotropia respond to spectacle correction of hyperopia. Am J Ophthalmol 1993;116:79–83. 14. Lim SH, Hong JS, Kim MM. Prognostic factors for recurrence with unilateral recess–resect procedure in patients with intermittent exotropia. Eye (Lond) 2011;25:449–54. Erratum in: Eye (Lond) 2011;25:1104. 15. Iacobucci I, Henderson SW. Occlusion in the preoperative management of exotropia. Am Orthoptic J 1965;15:42–7.

11.7  Exotropia

2. Friedman DS, Repka MX, Katz J, et al. Prevalence of amblyopia and strabismus in white and African American children aged 6 through 71 months: the Baltimore Pediatric Eye Disease Study. Ophthalmology 2009;116:2128–34.

11. Kushner B. Diagnosis and treatment of exotropia with a high accommodation convergence– accommodation ratio. Arch Ophthalmol 1999;117:221–4.

16. Cattrider N, Jampolsky A. Overcorrecting minus lens therapy for treatment of intermittent exotropia. Ophthalmology 1983;96:1160–5. 17. Kuklanis K, Georgievski Z, Zhang K. The use of distance stereoacuity measurement in determining the effectiveness of minus lenses in intermittent exotropia. J Pediatr Ophthalmol Strabismus 2010;14:488–93. 18. Goldrich SG. Oculomotor biofeedback therapy for exotropia. Am J Optom Physiol Opt 1982;59:306. 19. Scheiman M. Treatment of symptomatic convergence insufficiency in children with a homebased computer orthoptic training program. J Pediatr Ophthalmol Strabismus 2011;15: 123–4. 20. Choi J, Chang JW, Kim S-J, et al. The long-term survival analysis of bilateral lateral rectus recession versus unilateral recession–resection for intermittent exotropia. Am J Ophthalmol 2012;153:343–51.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

11.8 

Oblique Muscle Dysfunctions Gary R. Diamond, Raza M. Shah

POSTERIOR DISPLACEMENT OF LEFT TROCHLEA

Definition: Dysfunction of inferior or superior oblique muscle enough to cause measurable deviation.

Key features ■

Hyperdeviation ■ A- and V-pattern deviations

Associated features ■ ■ ■ ■ ■ ■

Primary inferior oblique overaction Secondary inferior oblique overaction Inferior oblique underaction Primary superior oblique overaction Secondary superior oblique overaction Superior oblique underaction

right eye

left eye

inferior oblique

superior oblique

inferior oblique

Fig. 11-8-1  Posterior displacement of the left trochlea. This may give mechanical advantage to the left inferior oblique muscle.

INTRODUCTION Overactions and underactions of both oblique muscles are well recognized. Often, the term “primary” is used to indicate ignorance of the cause of the dysfunction, and “secondary” is appended when the dysfunction is caused by known pathology of another cyclovertical muscle. Gobin1 suggested that many oblique dysfunctions are caused by a mismatch between the course of the inferior oblique muscle and that of the superior oblique tendon. If the trochlea is positioned anterior to the bony origin of the inferior oblique when viewed coronally, a mechanical advantage accrues to the superior oblique; conversely, if the trochlea is positioned behind the inferior oblique origin, the inferior oblique obtains a mechanical advantage (Fig. 11-8-1). The former situation occurs in some patients who have midface retrusion or hydrocephalus (Fig. 11-8-2), and the latter occurs in some patients who have orbital roof retrusion. However, many patients with oblique muscle dysfunction have normal orbital anatomy and unknown reasons for the dysfunction.

PRIMARY INFERIOR OBLIQUE OVERACTION EPIDEMIOLOGY AND PATHOGENESIS Overelevation in adduction caused by inferior oblique overaction develops in about 72% of congenital esotropes, 34% of accommodative esotropes, and 32% of intermittent exotropes who are followed for longer than 5 years.2 In a study by Wilson and Parks,2 the incidence of inferior oblique overaction in patients with congenital esotropia was not related to age at strabismus onset, time from onset to surgery for the esotropia, age at first surgery, or decompensation of horizontal alignment; it was, however, related to the number of surgeries necessary to align the eyes horizontally. The mean age of onset was 3.6 years. The presence of fundus excyclotorsion in children with congenital esotropia may predict the later development of inferior oblique overaction.

Fig. 11-8-2  Hydrocephalus and frontal bossing. As the frontal floor advances, it pulls the trochlea forward. This trochlear advance is postulated to give mechanical advantage to the superior oblique muscles, with resultant overdepression in adduction and an A-pattern strabismus.

Primary inferior oblique overaction is usually asymmetrical and may be unilateral at onset (23%). Frequently, the second eye becomes involved soon after unilateral surgery for inferior oblique weakening.

OCULAR MANIFESTATIONS The hyperdeviation in the affected eye may present a few degrees in adduction, in full adduction only, or only in the field of action of the inferior oblique (Fig. 11-8-3). Several grading systems have been devised for this overaction, but none is ideal (Table 11-8-1). If extreme bilateral overaction is present, the patient has only a narrow range of comfortable single binocular vision to either side of primary position. A V-pattern strabismus is often associated with inferior oblique overaction and yields greater exodeviation in upgaze than in downgaze. This is explained easily by the tertiary abduction ability of the inferior

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REATTACHMENT OF INFERIOR OBLIQUE MUSCLE

Pediatric and Adult Strabismus

14-mm recession location original insertion of inferior oblique muscle 10-mm recession location anterior transposition to inferior rectus insertion Fig. 11-8-3  Right eye inferior oblique overaction and overelevation in adduction.

TABLE 11-8-1  GRADING OF HYPERDEVIATION Grade

Elevation or Depression in Adduction (D)

Trace 1+ 2+ 3+ 4+

5 10 20 30 45

BOX 11-8-1 DIFFERENTIAL DIAGNOSIS OF OVERELEVATION IN ADDUCTION Inferior oblique overaction Dissociated vertical deviation Aberrant regeneration of third cranial nerve Rectus rotation in patients who have craniosynostosis Tether effect in patients who have Duane’s syndrome Tight lateral rectus muscle syndrome

oblique muscles in upgaze, but it is unclear why all patients with inferior oblique overaction do not develop a V-pattern strabismus. Vertical strabismus in primary position is quite uncommon, despite asymmetry of overaction.

DIAGNOSIS Patients who have primary inferior oblique overaction exhibit no subjective symptoms of ocular torsion, but they do have objective evidence of excyclotorsion of the involved globes. The Parks–Bielschowsky threestep test (see Chapter 11.10) is negative, and no torsion is admitted by the patient on Maddox rod, Bagolini lens, or Lancaster red–green testing. However, examination of the fundus by camera shows the fovea to be positioned below its normal position of 0.3 disc diameters below a horizontal line that extends from the center of the disc (inverted, of course, by indirect ophthalmoscopy). Forced duction testing shows the inferior oblique muscles to be tighter than normal.3 Presumably, for patients with primary inferior oblique overaction, sensory adaptations are available to reconcile globe excyclotorsion and thus maintain comfortable single binocular vision.

DIFFERENTIAL DIAGNOSIS

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The differential diagnosis of primary inferior oblique overaction is listed in Box 11-8-1. Dissociated vertical deviation often coexists with inferior oblique overaction, especially in patients who have congenital esotropia. Capo et al.4 presented a form of pseudo-inferior oblique overaction that may explain normalization of function after exotropia surgery. Semantically, the situation is clouded between primary and secondary inferior oblique overaction in some patients who have longstanding exotropia, in whom all obliques contract and overact.

origin of inferior oblique muscle

anterior transposition anterior to inferior rectus insertion

Fig. 11-8-4  Reattachment of inferior oblique muscle after disinsertion.

TREATMENT Although treatment of primary inferior oblique overaction is usually performed for esthetic purposes, it often provides a functional benefit as well, because duction normalization permits a wider range of single binocular vision. The only effective treatment is surgery on the overacting muscle. Care must be taken to include the entire muscle in the procedure; in addition, direct visualization of the muscle should prevent rupture of a vortex vein or violation of Tenon’s capsule. The latter may lead to fibrofatty proliferation of orbital fat on the sclera or contracture of radial fibrous tissue orbital septae, which results in an “adherence syndrome” of progressive hypotropia, excyclotropia, and elevation limitation. Excessive traction on the inferior oblique muscle may traumatize parasympathetic fibers of the ciliary ganglion and result in a (usually) transient pupillary dilatation and decreased accommodative tone. Postoperatively, patients with primary inferior oblique overaction do not usually complain of torsional diplopia, and primary position horizontal or vertical alignment is not affected. Patients who have trace or 1+ overaction usually do not require treatment unless the inferior oblique muscle in the other eye is being weakened. In such cases, a 10 mm recession is performed (Fig. 11-8-4), which requires that the muscle be disinserted and reattached to a point 3 mm posterior and 2 mm temporal to the temporal border of the inferior rectus insertion. Patients who have 2+ overaction usually receive a 10 mm recession. Patients who have 3+ or more overaction may be offered a number of powerful weakening procedures. The 14 mm recession places the new muscle insertion on the sclera that straddles the inferotemporal vortex vein ampulla. The irreversible myectomy removes as much inferior oblique muscle as the surgeon can harness, extending from Tenon’s capsule to the muscle’s insertion; this may be combined with denervation.5 Anteriorization places the insertion at or anterior to the temporal border of the lateral rectus insertion and cripples the elevating action of the muscle, transforming it into a supplementary depressor;6,7 unilateral procedures are restricted to placement of the insertion at the level of the inferior rectus so as not to create a postoperative hypotropia.

SECONDARY INFERIOR OBLIQUE OVERACTION Secondary inferior oblique overaction is usually caused by paresis of the antagonist superior oblique muscle with contracture, but occasionally it may be associated with superior rectus palsy in the opposite eye. Patients who have secondary overaction often have a vertical strabismus in primary position. Adult patients with a recent onset of palsy may complain of vertical and torsional diplopia and may also have a positive Parks–Bielschowsky three-step test. Of course, these patients also have the objective signs of oblique dysfunction mentioned earlier

INFERIOR OBLIQUE UNDERACTION Many patients who have limitation of elevation in adduction have Brown’s syndrome, associated with V-pattern exotropia in upgaze, duction and version limitations of elevation of similar degree (worse in adduction than abduction), and tight forced duction testing. A few have true inferior oblique palsy, a difficult entity to reconcile neuroanatomically, but one that is analogous to superior oblique palsy.8–10 These patients may have a hypodeviation in primary position if fixing with the nonparetic eye (Fig. 11-8-5), secondary overaction of the antagonist superior oblique muscle, and an A-pattern exotropia with better elevation in abduction than adduction. Elevation is better on duction than version testing, and forced duction testing is unrestricted unless the superior oblique is contracted. Some patients respond well to vertical prisms, but many require surgery; recession of the contralateral superior rectus or weakening of the ipsilateral superior oblique is the usual procedure.11 Secondary inferior oblique underaction caused by inhibitional palsy of the yoke of the antagonist to a paretic inferior rectus is seen occasionally. If the patient chooses to fixate with the paretic eye, a hypo­ deviation in the other eye in primary position is present.

negative Parks–Bielschowsky three-step test. However, some patients affected by primary superior oblique overaction have a vertical strabismus in primary position. As a result of the tertiary abduction effect of the superior oblique in downgaze, some have an A-pattern strabismus as well (see Fig. 11-8-6). Superior oblique overactions may be seen in esotropia and exotropia and occasionally without any horizontal strabismus. Antagonist inferior oblique function often is normal, but occasional underactions may be demonstrated. Children who have neurologic dysfunction have been found to have increased incidence of superior oblique muscle overaction.12 Prism therapy for a vertical strabismus benefits some patients. If the condition is esthetically significant, the superior oblique may be weakened by tenotomy, tenectomy, graded recession, or lengthening with biological plastic (Silastic) bands. If the tenotomy spares the intermuscular septum, contractile force is transmitted around the tenotomy to the distal tendon and thus prevents superior oblique palsy; some investigators advocate simultaneous inferior oblique weakening to delay or prevent the onset of superior oblique palsy.

11.8  Oblique Muscle Dysfunctions

− excyclotorsion of the fovea around the optic nerve and positive forced duction testing. Head tilts and turns to avoid diplopia are common in this group. Therapy is indicated not only for esthetic reasons and to increase the range of comfortable single binocular vision but also to obviate the need for changes in head posture to avoid visual confusion and diplopia. Some patients respond positively to vertical prisms, but many require surgery. Older patients must be warned of the possibility of temporary postoperative diplopia.

PRIMARY SUPERIOR OBLIQUE OVERACTION Superior oblique overactions (overdepression in adduction) without known cause are similar to primary inferior oblique overactions, in that they are usually asymptomatic and exhibit evidence of torsion (here incyclotorsion) of the fundus, positive forced duction testing, and a

Fig. 11-8-5  Left eye inferior oblique underaction and underelevation in adduction. This must be differentiated from the more common Brown’s vertical retraction syndrome.

Fig. 11-8-6  Child who has bilateral superior oblique overaction, overdepression in adduction, and an A-pattern exotropia.

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11 Pediatric and Adult Strabismus

Tenectomy is more associated with palsy than is tenotomy.13 Measured recessions, although more technically challenging, offer reproducibility and less likelihood of palsy.14,15 Lengthening by the interposition of Silastic material appears to be a promising method of superior oblique weakening.16 Many are cautious about weakening overacting superior obliques in patients who show fusion in the primary position and choose to treat A-pattern strabismus with horizontal or vertical rectus translations. Reports describe little if any eso shift in primary position after bilateral superior oblique weakening procedures.17

SECONDARY SUPERIOR OBLIQUE OVERACTION Secondary superior oblique overactions are usually caused by ipsilateral inferior oblique palsy or contralateral inferior rectus palsy (if the patient fixes with the paretic eye). In the latter case, the patient may exhibit a hypodeviation in the nonparetic eye. Patients who have secondary superior oblique overaction may have a vertical deviation in primary position and a compensatory head posture, and they are expected to show a positive Parks–Bielschowsky three-step test. They also have objective evidence of globe torsion, as mentioned earlier. Some patients can be treated using vertical prisms, but many require strabismus surgery.

SUPERIOR OBLIQUE UNDERACTION Superior oblique palsy is the most common form of cyclovertical muscle weakness. Its diagnosis and treatment are described in Chapter 11.10. Before spread of comitance to other cyclovertical muscles, underdepression in adduction, excyclotorsion of the fundus of the paretic eye, and a compensatory head posture occur. The Parks– Bielschowsky three-step test is positive. Adults with recent-onset

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superior oblique palsy show torsion on Maddox rod, Bagolini lens, or Lancaster red–green testing; children or adults with chronic palsy often do not. Some patients respond well to vertical prisms, but many require surgery. Occasionally, a patient with superior rectus palsy in the contralateral eye presents with a secondary superior oblique underaction if he or she chooses to fix with the paretic eye.

KEY REFERENCES Caldeira JAF. Graduated recession of the superior oblique muscle. Br J Ophthalmol 1975;59: 513–59. Capo H, Mallette RA, Guyton DL. Overacting oblique muscles in exotropia: a mechanical explanation. J Pediatr Ophthalmol Strabismus 1988;25:281–5. Del Monte AA, Parks MM. Denervation and extirpation of the inferior oblique. Ophthalmology 1983;90:1178–83. Demer JL, Kung J, Clark RA. Functional imaging of human extraocular muscles in head tilt dependent hypertropia. Invest Ophthalmol Vis Sci 2011;52(6):3023–31. Diamond GR, Parks MM. The effect of superior oblique weakening procedures on primary position horizontal alignment. J Pediatr Ophthalmol Strabismus 1981;18:1–3. Donohue S, Ithanarat P. A-pattern strabismus and overdepression in adduction: a special type of bilateral skew deviation. J Pediatr Ophthalmol Strabismus 2010;14:42–26. Gobin MH. Sagittalization of the oblique muscles as a possible cause for the “A,” “V,” and “X” phenomena. Br J Ophthalmol 1968;52:13–21. Guyton DL. Exaggerated traction test for the oblique muscles. Ophthalmology 1981;88:1035–40. Hamasaki I, Hasebe S, Furuse T, et al. Relationship between static ocular counterroll and Bielschowsky head tilt phenomenon. Invest Ophthalmol Vis Sci 2010;51(1):201–6. Lambert SR. Late spontaneous resolution of congenital Brown syndrome. J AAPOS 2010;14(4):373–5. Pineles SL, Rosenbaum AL, Demer JL. Changes in binocular alignment after surgery for concomitant and pattern intermittent exotropia. Strabismus 2008;16(2):57–63. Wilson ME, Parks MM. Primary inferior oblique overaction in congenital esotropia, accommodative esotropia, and intermittent exotropia. Ophthalmology 1989;96:7–11.

REFERENCES 1. Gobin MH. Sagittalization of the oblique muscles as a possible cause for the “A,” “V,” and “X” phenomena. Br J Ophthalmol 1968;52:13–21.

3. Guyton DL. Exaggerated traction test for the oblique muscles. Ophthalmology 1981;88:1035–40. 4. Capo H, Mallette RA, Guyton DL. Overacting oblique muscles in exotropia: a mechanical explanation. J Pediatr Ophthalmol Strabismus 1988;25:281–5. 5. Del Monte AA, Parks MM. Denervation and extirpation of the inferior oblique. Ophthalmology 1983;90:1178–83. 6. Hamasaki I, Hasebe S, Furuse T, et al. Relationship between static ocular counterroll and Bielschowsky head tilt phenomenon. Invest Ophthalmol Vis Sci 2010;51(1):201–6. 7. Parvataneni M, Olitsky SE. Unilateral anterior transposition and resection of the inferior oblique muscle for the treatment of hypertropia. J Pediatr Ophthalmol Strabismus 2005;42:163–5. 8. Scott WE, Nankin SJ. Isolated inferior oblique paresis. Arch Ophthalmol 1977;95:1586–93.

10. Hunter DG, Lam GC, Guyton DL. Inferior oblique muscle injury from local anesthesia for cataract surgery. Ophthalmology 1995;102(3):501–9. 11. Pineles SL, Rosenbaum AL, Demer JL. Changes in binocular alignment after surgery for concomitant and pattern intermittent exotropia. Strabismus 2008;16:57–63. 12. Hamed LM, Fang EN, Fanous MM, et al. The prevalence of neurologic dysfunction in children with strabismus who have superior oblique overaction. Ophthalmology 1993;100:1483–7. 13. Donohue S, Ithanarat P. A-pattern strabismus and overdepression in adduction: a special type of bilateral skew deviation. J Pediatr Ophthalmol Strabismus 2010;4:42–26. 14. Demer JL, Kung J, Clark RA. Functional imaging of human extraocular muscles in head tilt dependent hypertropia. Invest Ophthalmol Vis Sci 2011;52:3023–31. 15. Caldeira JAF. Graduated recession of the superior oblique muscle. Br J Ophthalmol 1975;59:513–59. 16. Lambert SR. Late spontaneous resolution of congenital Brown syndrome. J AAPOS 2010;14:373–5. 17. Diamond GR, Parks MM. The effect of superior oblique weakening procedures on primary position horizontal alignment. J Pediatr Ophthalmol Strabismus 1981;18:1–3.

11.8  Oblique Muscle Dysfunctions

2. Wilson ME, Parks MM. Primary inferior oblique overaction in congenital esotropia, accommodative esotropia, and intermittent exotropia. Ophthalmology 1989;96:7–11.

9. Pollard ZF. Diagnosis and treatment of inferior oblique palsy. J Pediatr Ophthalmol Strabismus 1993;30:936–9.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

Alphabet-Pattern Strabismus Gary R. Diamond, Raza M. Shah

Definition: The presence of significant incomitance from upgaze to

downgaze in patients who have esotropia, exotropia, or no horizontal misalignment in primary position.

11.9 

elastin surround each rectus muscle at the eye’s equator and serve as the functional origin of the muscles; pulley ectopia could cause alphabet-pattern strabismus in some cases.

V-PATTERN ESOTROPIA Key features ■

V pattern – at least 15 D greater exodeviation or lesser esodeviation in gaze up 30° than gaze down 30° when the patient is fixing on an accommodation-control distance target ■ A pattern – at least 10 D lesser exodeviation or greater esodeviation in gaze up 30° than gaze down 30° when the patient is fixing on an accommodation-control distance target

Associated features ■

Inferior oblique overaction in some patients who have V patterns and Y patterns ■ Superior oblique overaction in some patients who have A patterns and lambda patterns ■ Both superior and inferior oblique overactions in some patients who have X patterns

INTRODUCTION

The cause of the V pattern is obscure in patients who have normally functioning oblique muscles. Some authorities have postulated the existence of anatomical variations in the horizontal rectus muscles that permit greater effect of the lateral rectus muscles in upgaze and the medial rectus muscles in downgaze.6 Other investigators have incriminated the vertical rectus muscles and claim that the superior rectus muscles are translated temporally and the inferior rectus muscles are translated nasally, which permits the former to act as abductors in upgaze and the latter to act as adductors in downgaze.7

OCULAR MANIFESTATIONS This common pattern presents with esotropia greatest in downgaze and often with a chin-down posture to maintain comfortable single binocular vision. The cause of the V pattern in some patients is inferior oblique overaction, as the abductive effect of the inferior obliques in upgaze produces an exo shift in horizontal alignment. The ultimate deviation in upgaze represents a sum of the underlying esodeviation and the abductive pull of the inferior obliques in upgaze (Fig. 11-9-1).

DIAGNOSIS

This diverse group of ocular misalignments has incomitance from upgaze to downgaze as its unifying theme. It should be suspected in any patient who has a history or presentation of chin-up or chin-down posture, and it can be associated with eso, exo, or no deviation in primary position. Every patient must be evaluated for alphabet-pattern strabismus using prism and alternate-cover test measurements at distance fixation with the chin elevated 30°, depressed 30°, and in primary position. The relative incidence of alphabet-pattern strabismus is given in Table 11-9-1.1 Every muscle group has been incriminated as causative in these patients. Patients who do not have oblique overaction have been postulated to have anatomical alterations in their rectus positions on the globe.2 Those who have A-pattern esotropia tend to have lateral canthi higher than medial (“mongoloid” facies), and those who have V-pattern esotropia tend to have lateral canthi lower than medial (“antimongoloid” facies), but no predilection can be determined for exotropes.3,4 Demer et al.5 demonstrated that compliant pulleys of collagen and

TABLE 11-9-1  RELATIVE INCIDENCE OF ALPHABET-PATTERN STRABISMUS

Esotropia Exotropia Total

INTRODUCTION

V (%)

A (%)

Total (%)

41 23 64

25 11 36

66 34 100

Data from Costenbader FD. Trans Am Acad Ophthalmol Otolaryngol 1964;68:354–5.

A three-step head-tilt test is performed in all patients with V-pattern esotropia to investigate the presence of bilateral superior oblique palsy, which may accompany this picture. A left hyperdeviation on left head tilt and a right hyperdeviation on right head tilt with bilateral fundus extorsion confirm the diagnosis.

TREATMENT Mild amounts of incomitance (less than 15Δ difference from upgaze to downgaze) may be ignored unless a compensatory chin posture results. Antiaccommodative measures (plus lenses or miotics) are effective for some patients, but the progressively increasing esotropia in downgaze confounds the use of bifocals in most patients who have V-pattern esotropia and a high accommodative convergence-to-accommodation ratio. If surgery is indicated, inferior oblique overaction is reduced, together with the horizontal misalignment; inferior oblique weakening procedures do not affect horizontal ocular alignment in the primary position. If the oblique muscles function normally, the lateral recti may be translated upward and the medial recti downward to a variable degree, up to perhaps one half the tendon width.8 Likewise, the superior rectus muscles may be translated nasally and the inferior rectus muscles temporally to a similar degree. Translations larger than one-half the tendon width tend to be unpredictable. In children, the resultant globe torsion is well tolerated; adults may complain postoperatively of torsional diplopia. To avoid overcorrection in patients who have great incomitance between upgaze and primary position, horizontal surgery for the least esodeviation (upgaze) is performed when combined with horizontal tendon translations.

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V-PATTERN ESOTROPIA

Pediatric and Adult Strabismus Fig. 11-9-1  V-pattern esotropia, increasing from upgaze to downgaze. The eyes of a child who has bilateral inferior oblique overaction; a chin-down head posture is common.

Fig. 11-9-2  V-pattern exotropia, increasing from downgaze to upgaze. The child has bilateral inferior oblique overaction; a chin-up head posture is common.

V-PATTERN EXOTROPIA OCULAR MANIFESTATIONS

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Patients who have V-pattern exotropia commonly present with a chinup head posture to place the eyes in a position of least horizontal strabismus (Fig. 11-9-2). Mild incomitance (less than 15Δ difference from upgaze to downgaze) may be ignored unless it results in a compensatory chin posture.

TREATMENT Evidence of overaction of the inferior oblique muscles must be sought, and if surgery is undertaken, the inferior oblique muscles should be weakened. If the oblique muscles function normally, the lateral rectus muscles may be translated upward and the medial recti downward, as discussed earlier. To avoid overcorrection in patients who have great incomitance between downgaze and primary position, horizontal surgery for the least exodeviation (downgaze) is performed in combination with horizontal tendon translations.

11.9  Alphabet-Pattern Strabismus

Fig. 11-9-3  A-pattern esotropia, increasing from downgaze to upgaze. The child has bilateral superior oblique overaction; a chin-up head posture is common.

The occasional patient with a Y-pattern strabismus that consists only of exotropia in upgaze can be treated with inferior oblique weakening alone if the oblique muscles overact, or with a pure upward translation of the lateral rectus muscles if the oblique muscles do not overact.

A-PATTERN ESOTROPIA OCULAR MANIFESTATIONS This common pattern is suspected in patients who maintain a chin-up posture and have esotropia in upgaze. Some patients have overaction of the superior oblique muscles and harness the abduction effect of the superior obliques in downgaze to overcome the esotropia partially or totally. Other patients have oblique muscles that act normally, and in these cases, the reason for the A pattern is less clear (Fig. 11-9-3). Mild amounts of incomitance (less than 10Δ difference from upgaze to downgaze) may be ignored unless a compensatory chin posture results.

TREATMENT Traditionally, caution was recommended when superior oblique weakening procedures were considered for patients in whom fusion in primary position occurred, because postoperative primary position hyperdeviations and excyclotorsional diplopia were feared. Modern, graded superior oblique recession procedures and silicone tendon expander techniques6 have become available and provide symmetrical superior oblique weakening in such patients with less risk than in previous techniques. Superior oblique weakening procedures do not affect primary position horizontal alignment. Those patients whose superior oblique muscles act normally benefit from downward translation of the lateral rectus muscles, upward translation of the medial rectus muscles,9 or both, combined with the necessary surgery to reduce horizontal strabismus. To avoid overcorrection in patients who have great incomitance between downgaze and primary position, horizontal surgery for the least esodeviation (downgaze) is performed, along with horizontal tendon translation. An approach for patients who have little horizontal misalignment is temporal translation of the superior rectus muscles, nasal translation of the inferior rectus muscles, or both.10

A-PATTERN EXOTROPIA OCULAR MANIFESTATIONS Patients with this pattern have a chin-down posture to move the eyes away from the position of maximal exotropia (see Fig. 11-8-6). Mild amounts of incomitance (less than 10 D from upgaze to downgaze) may be ignored unless a compensatory chin position results.

TREATMENT Patients who do not have superior oblique overaction should undergo translation of the lateral rectus muscles downward, translation of the medial rectus muscles upward, or both, together with surgery for the exotropia.11 To avoid overcorrection in patients who have great incomitance between upgaze and primary position, horizontal surgery for the least exodeviation (upgaze) is performed in combination with horizontal tendon translations. Graded recessions of the superior oblique muscles12 or silicone tendon expander techniques,13 if the muscles are overactive, prevent asymmetrical weakening by tenotomy or tenectomy14 and creation of a vertical strabismus and excyclodiplopia in primary position. Patients who have little exodeviation in primary position (lambda, or λ, pattern) may benefit from pure translation of the lateral rectus muscles downward or the inferior rectus muscles nasally.15

X-PATTERN STRABISMUS Patients who have long-standing exotropia may develop secondary contracture of all four oblique muscles and an X-pattern strabismus (Fig. 11-9-4). Alternatively, the lateral rectus muscles may contract, which results in a “tether” effect on upgaze and downgaze and creates an X pattern. Because each of these visual axis deviations is approached by a different surgical technique, evidence of true oblique overaction must be sought by forced duction testing and observation of fundus torsion in upgaze and downgaze, and staged surgery should be considered. Lateral rectus recessions alone alleviate the X pattern if it is caused by a tether effect alone.

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X-PATTERN STRABISMUS

Pediatric and Adult Strabismus Fig. 11-9-4  X-pattern strabismus with straight eyes in primary position. Both overelevation and overdepression in adduction in each eye.

KEY REFERENCES

Pineles SL, Rosenbaum AL, Demer JL. Decreased postoperative drift in intermittent exotropia associated with A and V patterns. J AAPOS 2009;13:127–31.

Biedner B, Rothkoff L. Treatment for ‘A’ or ‘V’ pattern esotropia by slanting muscle insertion. Br J Ophthalmol 1995;79:807–8.

Pott JW, Godts D, Kerkhof DB, et al. Cyclic esotropia and the treatment of over-elevation in adduction and V-pattern. Br J Ophthalmol 2004;88:66–8.

Costenbader FD. Introduction on symposium: the “A” and “V” patterns in strabismus. Trans Am Acad Ophthalmol Otolaryngol 1964;68:354–5.

Ribeiro G de B, Brooks SE, Archer SM, et al. Vertical shift of the medial rectus muscles in the treatment of A-pattern esotropia: analysis of outcome. J Pediatr Ophthalmol Strabismus 1995;32:167–71.

Das VE, Mustari MJ. Correlation of cross-axis eye movements and motoneuron activity in nonhuman primates with “A” pattern strabismus. Invest Ophthalmol Vis Sci 2007;48:665–74. Demer JL. Should we require evidence about the etiology of A-pattern strabismus? J AAPOS 2010;14:4–5. Demer JL, Miller JM, Poukens V. Surgical implications of the rectus extraocular muscle pulleys. J Pediatr Ophthalmol Strabismus 1996;33:208–18. Helveston EM. An atlas of strabismus surgery. St Louis, MO: CV Mosby; 1993. p. 381. Knapp P. Vertically incomitant horizontal strabismus: the so-called “A” and “V” syndromes. Trans Am Ophthalmol Soc 1969;67:304–10. Pineles SL, Rosenbaum AL, Demer JL. Changes in binocular alignment after surgery for concomitant and pattern intermittent exotropia. Strabismus 2008;16:57–63.

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1224

Romano P, Roholt P. Measured graduated recessions of the superior oblique muscles. J Pediatr Ophthalmol Strabismus 1983;20:134–9. Shin GS, Elliott RL, Rosenbaum AL. Posterior superior oblique tenectomy at the scleral insertion for collapse of A-pattern strabismus. J Pediatr Ophthalmol Strabismus 1996;33:211–18. Urrets-Zavalia A, Solares-Zamora J, Olmos H. Anthropological studies on the nature of cyclovertical squint. Br J Ophthalmol 1961;45:578–96. Wright KW. Superior oblique silicone expander for Brown syndrome and superior oblique overaction. J Pediatr Ophthalmol Strabismus 1991;28:101–7.

REFERENCES 1. Costenbader FD. Introduction on symposium: the “A” and “V” patterns in strabismus. Trans Am Acad Ophthalmol Otolaryngol 1964;68:354–5.

3. Urrets-Zavalia A, Solares-Zamora J, Olmos H. Anthropological studies on the nature of cyclovertical squint. Br J Ophthalmol 1961;45:578–96. 4. Helveston EM. An atlas of strabismus surgery. St Louis, MO: CV Mosby; 1993. p. 381. 5. Demer JL, Miller JM, Poukens V. Surgical implications of the rectus extraocular muscle pulleys. J Pediatr Ophthalmol Strabismus 1996;33:208–18.

11. Pineles SL, Rosenbaum AL, Demer JL. Decreased postoperative drift in intermittent exotropia associated with A and V patterns. J AAPOS 2009;13:127–31. 12. Romano P, Roholt P. Measured graduated recessions of the superior oblique muscles. J Pediatr Ophthalmol Strabismus 1983;20:134–9. 13. Wright KW. Superior oblique silicone expander for Brown syndrome and superior oblique overaction. J Pediatr Ophthalmol Strabismus 1991;28:101–7.

6. Knapp P. Vertically incomitant horizontal strabismus: the so-called “A” and “V” syndromes. Trans Am Ophthalmol Soc 1969;67:304–10.

14. Shin GS, Elliott RL, Rosenbaum AL. Posterior superior oblique tenectomy at the scleral insertion for collapse of A-pattern strabismus. J Pediatr Ophthalmol Strabismus 1996;33:211–18.

7. Pott JW, Godts D, Kerkhof DB, et al. Cyclic esotropia and the treatment of over-elevation in adduction and V-pattern. Br J Ophthalmol 2004;88:66–8.

15. Pineles SL, Rosenbaum AL, Demer JL. Changes in binocular alignment after surgery for concomitant and pattern intermittent exotropia. Strabismus 2008;16:57–63.

8. Biedner B, Rothkoff L. Treatment for “A” or “V” pattern esotropia by slanting muscle insertion. Br J Ophthalmol 1995;79:807–8.

11.9 

10. Das VE, Mustari MJ. Correlation of cross-axis eye movements and motoneuron activity in non-human primates with “A” pattern strabismus. Invest Ophthalmol Vis Sci 2007;48:665–74.

Alphabet-Pattern Strabismus

2. Demer JL. Should we require evidence about the etiology of A-pattern strabismus? J AAPOS 2010;14:4–5.

9. Ribeiro G de B, Brooks SE, Archer SM, et al. Vertical shift of the medial rectus muscles in the treatment of A-pattern esotropia: analysis of outcome. J Pediatr Ophthalmol Strabismus 1995;32:167–71.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

11.10 

Paralytic Strabismus Steven E. Rubin, Raza M. Shah

Definition: Strabismus resulting from partial or complete paralysis of

the third, fourth, or sixth cranial nerve.

Key features ■ ■

Incomitancy – deviation’s magnitude is gaze dependent. In each gaze, magnitude is larger when paretic eye fixing (secondary deviation).

Associated features ■

In third nerve palsy – ipsilateral exotropia and hypotropia; ptosis and pupillary findings possible ■ In fourth nerve palsy – ipsilateral hypertropia with a head tilt to the opposite side ■ In sixth nerve palsy – ipsilateral esotropia with head turn to the affected side

INTRODUCTION The most common type of strabismus, by far, is the comitant variety – the angle of deviation varies little with gaze direction. Less commonly, muscle overactions or underactions cause a vertical gazedependent variation in a regular fashion to give an ‘alphabet-pattern’ strabismus, discussed in Chapter 11.9. Least common are the disorders that result from paresis (or restriction) of one or more extraocular muscles. This chapter discusses only paralytic strabismus. In contrast to the straightforward evaluation of comitant strabismus, an expanded array of diagnostic techniques must be employed in patients who have paralytic strabismus. Accurate classification of strabismus requires measurement in the cardinal fields (as discussed in Chapter 11.3) to detect the characteristic incomitance of paretic or restrictive disorders. In general, the measured deviation is greatest in the field of action of the paretic muscle(s). In some cases, the measured deviation may be ‘infinite’ if the affected muscle is completely unable to move the affected eye into the field of gaze that is being measured. With nonrestrictive and nonparetic strabismus syndromes, prism measurements are independent of the fixing eye, even in patients who have a fixation preference for one eye (suggesting amblyopia). If the measurements change when the fellow eye takes up fixation, a paretic or restrictive etiology is usually the cause. The deviation is larger when the affected eye is used for fixation, termed secondary deviation. Restriction can be confirmed by forced duction testing, whereby the anesthetized perilimbal conjunctiva of the affected eye of a very cooperative patient is grasped with a forceps and manually ‘forced’ into the affected field; resistance indicates mechanical restriction rather than muscle weakness as the cause of the strabismus. The reverse technique, force generation testing, is sometimes useful to confirm a paretic rather than a restrictive problem involving a rectus muscle. The anesthetized perilimbal conjunctiva of an even more cooperative patient is grasped with a forceps and the patient instructed to look in the affected field;1 little experience is necessary to distinguish between the pull of a normal versus a paretic one. Similar information can be gained from

careful observation of saccades into the paretic or restricted field. A steady but slow movement into the gaze direction in question suggests a paretic cause, in contrast to an initially rapid and abruptly ending movement, which suggests a restrictive cause. A Tensilon test should also be considered, as myasthenia gravis can mimic any isolated or combined extraocular muscle palsy. Diplopia in adults and cooperative children can be assessed with binocular visual fields. A slight modification can incorporate the effect of torsion. This technique utilizes a standard Goldmann perimeter to identify and quantify the extent of the diplopic and nondiplopic areas of gaze.2 Patients who have extraocular muscle palsies also require consideration for more extensive evaluation. Whereas comitant strabismus is only rarely secondary to a neurological or other systemic disease, paralytic strabismus can be secondary to other causes, many of which are amenable to treatment, sometimes life-saving. The lists of possible causes of a muscle palsy differ for children and adults; this is discussed with individual disorders subsequently. Although congenital palsies are the main cause in children, they can also be the cause of fourth nerve palsies in adults, who can keep their deviation latent for many years or even decades. Management of paralytic strabismus follows the same general guidelines as for any difficult condition – less invasive and less risky remedies are tried or considered before those that involve greater risk. Hence, patients with a small or slowly improving paresis can be offered occlusion or prism therapy before surgery is considered. Because the goal of management for these conditions is treatment and not cure, the precise goals must be made exceedingly clear to the patient and family beforehand. Ocular alignment in primary position and downgaze (for reading) has priority over achieving alignment in all fields; the latter is almost always unattainable in these incomitant deviations. Appropriate informed consent for surgery requires discussion of all the alternative treatments, including the option of no treatment. If and when surgery is planned, the muscle(s) at work in the field(s) of greatest deviation must be targeted. Details of surgical strategies are discussed in the following with the individual muscle palsies.

THIRD NERVE PALSY INTRODUCTION Because the third nerve innervates the inferior oblique, inferior rectus, and medial rectus muscles (by its inferior division) and the superior rectus and levator muscles (by its superior division), weakness of this nerve can have a comprehensive effect upon ocular motility; this nerve innervates extraocular muscles responsible for motility in all three planes (horizontal, vertical, and torsional) and is also the major innervator of the levator muscle. In affected young children who develop a significant ptosis, the visual axis obstruction is cumulative to an already calamitous effect on their immature visual system.

OCULAR MANIFESTATIONS Third nerve palsies can be congenital or acquired; each can be partial, affecting one or more muscles (Fig. 11-10-1), or complete (Fig. 11-10-2). Possible causes, manifestation, associated features, and treatment vary according to the type of palsy. Cyclic palsies have also been reported.3

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11 Pediatric and Adult Strabismus

A

A

B

B Fig. 11-10-2  Elderly woman with complete left third nerve palsy. (A) Complete ptosis, left eye. (B) Left exotropia and (small) left hypotropia.

may now produce, instead of or in addition to adduction, depression, retraction (from simultaneous vertical rectus muscle contraction), globe elevation, lid elevation, or pupillary constriction. The two most common manifestations are lid elevation (pseudo-Graefe sign) and pupillary constriction, each of which occurs on adduction, downgaze, or both. C

D

Congenital third nerve palsies (generally idiopathic) are quite rare – reports from large institutions consist of few cases, yet they span decades. Affected children most often have unilateral involvement and no other neurological abnormalities.4 Some of the latter have been reported5 but are thought to represent concurrent injury rather than a cause of the palsy. These cases cannot be considered traumatic in origin as excessive birth trauma is not consistently found. Most often, all of the extraocular muscles innervated by the third nerve are affected in some way, resulting in exotropia (compromised medial rectus muscle function), hypotropia (paretic superior rectus and/ or inferior oblique muscle[s]), and ptosis (due to levator involvement) of varying amounts. The measured deviation is largest in the field of action of the affected muscle(s). Pupillary involvement in congenital palsies can result from either a primary manifestation of the palsy (a larger pupil from deficient sphincter innervation) or aberrant regeneration (pupillary constriction with adduction or downgaze). Pupillary sparing is not a reliable indicator of congenital origin as its presence in congenital cases is inconsistent.4,6,7 When ptosis is either absent or incomplete, to optimize their binocularity affected children may develop an abnormal head posture (torticollis) consisting of chin elevation or a contralateral face turn to neutralize the hypotropia, ptosis, or exotropia. Most such children suffer loss of binocular function from ptosis or constant exotropia in addition to amblyopia.

E

Acquired Third Nerve Palsies

Fig. 11-10-1  Adult with a partial left third nerve palsy. (A) Primary gaze showing slightly larger pupil, mild ptosis, left exotropia, and left hypotropia. (B) Normal left gaze. (C) No adduction of the left eye on right gaze. (D) Poor elevation. (E) Poor depression.

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Congenital Third Nerve Palsies

Among conditions that affect ocular motility, aberrant regeneration is a phenomenon peculiar to third nerve palsies, hence the alternative term oculomotor synkinesis. After a paretic event, the extramedullary axons can heal and regenerate, but not necessarily to their original locations.4 Hence, action potentials that previously resulted in adduction

Acquired third nerve palsies, although more common than their congenital counterpart, are still unusual, so any incidence data are imprecise. They also are rarely bilateral. Possible causes are age dependent (Table 11-10-1). Acquired palsies of the oculomotor nerve produce findings similar to those of a congenital palsy (exotropia and/or hypotropia and/or ptosis) along with the characteristic incomitant deviation largest in the field of action of the affected muscle(s). In addition, visually mature adults report diplopia and visual confusion unless they also have significant ptosis. Torticollis (contralateral face turn and/or chin-up posture) also develops if the posture neutralizes the diplopia.

TABLE 11-10-1  CAUSES OF ACQUIRED THIRD NERVE PALSY BY AGE GROUP Children (%)

Adults (%)

Trauma Neoplasm Aneurysm Vascular/diabetic Other Undetermined

40 14 0 0 29 17

14 11 12 23 16 24

Reproduced with permission from Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:568–74.

Patients who have an acquired third nerve palsy require further neurological evaluation as the palsy is often an ominous sign, especially in younger patients,8,9 although exceptions occur.10 Once thought indicative of benign and non-life-threatening vascular disease, pupillary sparing can occur even in cases caused by aneurysm11–13 (see Part 9, Neuro-ophthalmology, for specific details and recommendations for evaluating these patients). Isolated pareses of individual muscles innervated by either branch of the third nerve have been described14 and generally defy neuroanatomic localization. They are almost never indicative of serious pathology elsewhere, and manifestations depend upon the affected muscle. Brown’s syndrome must also be considered in a patient with an apparent isolated inferior oblique muscle palsy; the three-step test (discussed later) and forced duction testing can usually distinguish between these two conditions. In patients who have craniofacial disease, isolated pareses may be due to congenital absence of a rectus or oblique muscle.15 Abnormal horizontal insertions also have been reported.16

TREATMENT Third nerve palsy is the most difficult and challenging of the paralytic strabismus syndromes because of the number of muscles and different motility planes involved and the significant risk of amblyopia in young children from both strabismus and ptosis. Definitive treatment is almost never immediately required as many cases exhibit at least some degree of improvement, either spontaneously or when an underlying cause is removed or otherwise dwindles in significance. The therapeutic goals are elimination of diplopia and optimization of binocularity in as many gaze positions as possible. Restoration of normal motility is generally not attainable except in the mildest of cases, so realistic goals should be made clear to the patient and family in the early stages of treatment.

Nonsurgical Treatment

The period of possible improvement can extend up to 3 years in some patients. In visually immature children, careful attention must be paid to both monocular and binocular visual development during this period. Amblyopia can develop rapidly from the constant exotropia– hypotropia and/or occlusion by the lid, requiring aggressive patching. When the horizontal or vertical deviation is small, prisms may be beneficial to keep binocular development on track. In visually mature individuals without a complete ptosis, diplopia may be alleviated with occlusion during the period of expectant observation. Even incomplete occlusion, accomplished by applying translucent tape to a spectacle lens, may be sufficient. In visually immature children, in addition to their temporary use during the recovery phase to maintain binocular development, prisms may be a permanent solution when the residual deviation is small. Although prisms work best in small comitant deviations, success in incomitant strabismus is possible if the prism’s magnitude is chosen to match the functionally important primary position and downgaze. Botulinum toxin therapy can be a useful adjunct to treatment in the acute phase. Injecting the antagonist muscle(s), either by direct surgical visualization or transconjunctivally under audible electromyographic control, can prevent permanent contracture, which would otherwise interfere with recovery or complicate subsequent surgical treatment, or both.17–19

Surgical Treatment

Surgical treatment should be undertaken when little if any expectation of additional subsequent recovery exists. When some medial rectus muscle function is present, a large recess–resect procedure may produce

11.10  Paralytic Strabismus

Cause

acceptable results for the horizontal deviation;20,21 this has been advocated in some patients with complete paralysis if combined with a traction suture.22,23 Generally, in a complete palsy or when no demonstrable medial rectus function exists, some other method to generate adducting force is necessary in addition to functional crippling of the lateral rectus muscle; the latter requires recession of at least 16 mm from the original insertion.24 This can be accomplished by transposition of the superior oblique tendon25 insertion to a position adjacent to the medial rectus insertion, either with26 or without27 its removal from the trochlea. Resections of completely nonfunctional muscles have little long-term effect as the nonfunctioning muscle stretches with time. Although advocated by some for routine use in all cooperative strabismus surgical patients, adjustable sutures have an even greater indication in surgery for paralytic strabismus. The great variability in the degree of weakness of affected muscles makes published tables of graded recessions and resections somewhat less reliable in third, fourth, and sixth nerve palsies. This suggests a greater potential role for an adjustable suture technique. An accompanying ptosis is generally addressed after ocular alignment has been optimized. If done in reverse order, raising the lid of a hypotropic eye unable to utilize Bell’s phenomenon to protect the cornea may produce significant exposure keratitis. However, this strategy may have to be followed in visually immature children to prevent the development or worsening of amblyopia. With isolated muscle palsies, the prognosis for an acceptable outcome is much greater because only one muscle is affected, producing a deviation in only one direction and without lid involvement. Such pareses are generally treated by weakening the antagonist muscle along with strengthening (resection) of the affected muscle, provided some of its function remains. In the case of isolated inferior oblique muscle paresis, antagonist weakening (of the superior oblique muscle) must be done with caution because of the resulting effects on ocular torsion. In such cases, vertical rectus muscle weakening can also be effective.28 Whenever performing surgery on multiple rectus muscles on the same eye, anterior segment ischemia (ASI) is a possible complication. This condition may result when perfusion of the anterior segment is abruptly compromised by sudden loss of the contribution made from the anterior ciliary arteries that normally accompany the rectus muscles and penetrate the sclera at the muscle insertions. The vertical rectus muscles generally contribute more than the horizontal rectus muscles. With time, lost contribution to the anterior segment can be replaced, at least in part, by augmented circulation from another source (the posterior ciliary circulation). Although this lends support to the strategy of staging surgery by waiting several months to operate on additional muscles when multiple rectus muscles need surgery, ASI can occur many years after the initial extraocular surgery29 or even after surgery on only two muscles.30 Acute manifestations of ASI include pain, corneal edema, Descemet’s membrane folds, and anterior chamber inflammation. Late effects include iris atrophy, an eccentric pupil, and infrequent visual loss.31 Although ASI usually arises only with surgery on three or four rectus muscles, circumstances such as circulatory disorders or advanced age can increase the risk with surgery on fewer muscles. Preservation of the anterior ciliary circulation during rectus muscle surgery, either with32 or without33 use of the operating microscope, has been proposed to reduce if not eliminate the risk of this complication.

FOURTH NERVE PALSY INTRODUCTION Palsies of the fourth (and sixth) nerves are generally much less complicated clinical pictures because these two cranial nerves each innervate only one extraocular muscle. The fourth (trochlear) nerve controls the superior oblique muscle, and the sixth (abducens) nerve innervates the lateral rectus muscle. As the superior oblique muscle acts as a depressor and is the major intorter of the eye, manifestations of its weakness or paralysis are more complicated than those of the sixth nerve, which has no torsional or vertical effects. Although incidence data are age dependent, large series generally indicate that palsies of the fourth nerve occur somewhat less often than those of the third cranial nerve;20,34–36 pediatric studies show that order reversed.37 Data from a practice based on strabismus surgery, however,

1227

11

might indicate that they are the most common palsy.14 The much greater ability of patients to keep a fourth nerve palsy latent (with the development of large vertical fusional vergence amplitudes) probably influences the reported statistics.

Pediatric and Adult Strabismus

EPIDEMIOLOGY AND PATHOGENESIS Fourth nerve palsies rarely have a neurological etiology. When a history of recent major trauma is lacking, a neurological work-up may be considered but is usually unproductive. Most cases are congenital (idiopathic) or post-traumatically acquired in origin.4,38 The fourth cranial nerve is uniquely susceptible to trauma39 as it is the only one with a dorsal exit from the brainstem, which results in the longest intracranial course of any cranial nerve. A patient who has a ‘unilateral’ palsy, especially in traumatic cases, should be very carefully and meticulously examined for evidence of bilateral involvement, which may not become evident until after surgery.14 Congenital fourth nerve palsy is almost always sporadic; there are only rare reports of familial occurrence.40,41 Although the diagnosis in many patients is not made in childhood or youth, inspection of old photographs often reveals a consistent characteristic head tilt. Patients also commonly exhibit facial asymmetry discussed below. Amblyopia is almost never a complication in congenital or early acquired cases.42 In rare cases, a fourth nerve ‘palsy’ is due to congenital absence of the superior oblique tendon or muscle,43 especially in patients who have craniofacial disorders.15 This can be suspected preoperatively on finding an associated horizontal deviation, amblyopia, a large primary-position hypertropia, spread of comitance, and/or pseudo-overaction of the contralateral superior oblique muscle.44

OCULAR MANIFESTATIONS Weakness of the superior oblique muscle allows unopposed action of its direct antagonist, which results in an ipsilateral hypertropia and

excyclotorsion. Vertical diplopia or vague reports of ‘eyestrain’ or other difficulty reading in downgaze are the most common complaints vocalized in fourth nerve palsy. Some of the more observant and articulate patients also report excyclotorsion; affected engineers even draw the equivalent of Lancaster screen findings, including the effect on torsion. The classical sign of unilateral fourth nerve palsy is a contralateral head tilt (an ‘ocular’ torticollis). It is exhibited by most patients and is usually the sole presenting sign in children, although nonophthalmological causes must also be considered.45 In this tilted position, reflex compensatory ocular countertorsion (to counteract the head tilt in direction but not degree for degree in magnitude) of the affected eye recruits the inferior oblique and inferior rectus muscles to produce compensatory excyclotorsion of the affected eye and avoids stimulation of the paretic superior oblique. When those normally acting cyclovertical muscles produce this reflex countertorsion, their opposite vertical effects are mutually neutralized and no vertical deviation results, allowing the patient to maintain fusion. However, with a tilt to the ipsilateral side (the side of the paretic eye), the countertorsion of the affected eye recruits the incyclotorters, the superior rectus and paretic superior oblique muscles. The vertical effect of the normal superior rectus muscle, which produces elevation, is unopposed or insufficiently neutralized by the weakened superior oblique muscle, resulting in an ipsilateral hypertropia46 (Fig. 11-10-3). Paradoxically, some patients maintain a head tilt to the ipsilateral side, presumably to increase the vertical separation between the images and make it easier simply to ignore one of them.47 The Bielschowsky three-step head-tilt test48 can be used to confirm the presence of a fourth nerve palsy or of any isolated cyclovertical muscle palsy if vision in each eye is adequate for fixation and there are no restrictions on either globe. It must be performed while the patient is erect or else the vestibular input, upon which this test is heavily dependent, will be eliminated. The test was modified by Parks;49 it is now often termed the three-step test and is summarized in

A

D

B

C

1228

E

Fig. 11-10-3  Young woman with idiopathic (presumed congenital) left fourth nerve palsy. (A) Primary position left hypertropia from loss of the depressor effect of the paretic left superior oblique muscle. (B) Normal motility in left gaze, away from the fields of action of the paretic left superior oblique muscle. (C) Compensatory overaction of the antagonist left inferior oblique muscle in its field of action in right gaze. (D) No vertical deviation on contralateral head tilt, when reflex excyclotorsion of the affected left eye is accomplished by the unaffected inferior rectus and inferior oblique muscles. (E) Large left hypertropia on ipsilateral head tilt, when reflex incyclotorsion recruits the superior rectus muscle and the paretic superior oblique muscle, and the vertical effect of the unaffected superior rectus muscle cannot be neutralized by the paretic superior oblique muscle.

BOX 11-10-1 KNAPP CLASSIFICATION OF SUPERIOR OBLIQUE PARESIS

Step

Test

1 2 3

Determine whether there is a right or left hypertropia in or near primary gaze Determine the lateral gaze direction that worsens the hypertropia Determine the side to which tilting the head increases the hypertropia

Class 1. Greatest deviation is with the affected eye elevated in adduction, the field of the ipsilateral (antagonist) inferior oblique muscle 2. Greatest deviation is with the affected eye depressed in adduction, the field of the affected paretic superior oblique muscle 3. Greatest deviation is in all contralateral gazes (down, level, and up) 4. Greatest deviations are in all contralateral gaze and in all downgaze positions (contralateral, straight, and ipsilateral) 5. Greatest deviations are in all downgaze positions 6. V-pattern esotropia, cyclotropia, and bilaterally positive three-step test indicates a bilateral palsy 7. Poor elevation and depression in adduction of the affected eye, resulting from direct injury to the superior oblique muscle, causing its restriction and paresis

TABLE 11-10-3  CHARACTERISTIC THREE-STEP TEST PATTERNS AND THEIR INTERPRETATION Test outcome (Step 1–Step 2–Step 3)

Affected cyclovertical muscle

R–L–R L–R–L L–L–L R–R–R L–L–R R–R–L L–R–R R–L–L

Right superior oblique muscle Left superior oblique muscle Right inferior oblique muscle Left inferior oblique muscle Left inferior rectus muscle Right inferior rectus muscle Right superior rectus muscle Left superior rectus muscle

This test requires each eye to have vision sufficient for fixation and no restrictions. The test is not helpful in patients who have more than one weak cyclovertical muscle in each eye and may be positive in patients with Brown’s syndrome, muscle entrapment, or other causes of restricted eye movement.

Table 11-10-2. Each of the three steps consists of an alternate cover test measurement of the deviation in the indicated gaze position(s): primary position for step one, right and left gaze for step two, and 45° head tilt to each side for step three. Table 11-10-3 summarizes the eight possible outcomes of the three-step test as well as which of the eight cyclovertical muscles is the culprit in each condition. It is important to remember that a positive three-step test does not prove the existence of an isolated muscle paresis50 – it may be positive due to other causes, such as Brown’s syndrome. Patients with bilateral palsy often have ‘reversing’ hypertropias (e.g., a right hypertropia on left gaze and a left hypertropia on right gaze) and a bilaterally positive third step of the three-step test (right hypertropia on right head tilt and left hypertropia on left head tilt). A bilateral palsy often causes a chin-down head position in response to a V-pattern esotropia, resulting from the loss of the superior oblique muscle’s tertiary abducting action in downgaze and large degrees of cyclotorsion, as discussed subsequently. Although symptoms of cyclotropia should be evident in any acquired fourth nerve palsy, it is often not a significant problem except in acquired bilateral cases, which typically result from closed head trauma. In congenital or very early acquired cases, sensory reorientation of the retinal meridians develops to eliminate subjective cyclotropia.51,52 When both superior oblique muscles are weak or completely paralyzed, their opposing hypertropias can neutralize each other, but their cyclodeviations are additive; the paresis on each side produces an ipsilateral excyclotropia that worsens the effect of the contralateral excyclotropia. This effect is maximized in downgaze, the field of greatest action of both superior oblique muscles. When the excyclotorsion (as measured by double Maddox rod) exceeds 10°53 or 15°,54,55 a bilateral fourth nerve palsy is strongly suggested, although smaller amounts of torsion do not rule out a bilateral palsy.38 Such affected patients, having no hypertropia to cause them to develop a compensatory head tilt, may adopt a chin-down head position to keep their eyes in the upgaze position where the paretic superior oblique muscles contribute least to ocular alignment, minimizing the cyclotropia and V-pattern esotropia. Observation of the relative positions of the disc and fovea with indirect ophthalmoscopy can be used to assess torsion in preverbal children or otherwise uncooperative patients.56,57 Congenital or long-standing fourth nerve paresis can cause physiological and anatomic changes that may be helpful in suggesting the time of onset. These patients are constantly challenged to maintain fusion despite a slowly increasing vertical deviation, allowing very large vertical vergence amplitudes to develop; 15–20 prism diopters are not unusual in these patients, a normal value being 3–4 prism diopters.58 In addition, the constant head tilt is strongly associated with facial asymmetry; the ipsilateral side is vertically shortened and hypoplastic. In such patients, a line drawn through both pupils and another line drawn through the corners of the mouth intersect near the face on the

11.10  Paralytic Strabismus

TABLE 11-10-2  THE THREE-STEP TEST FOR DIAGNOSIS OF AN ISOLATED SINGLE CYCLOVERTICAL MUSCLE PALSY

Adapted from Knapp P. Classification and treatment of superior oblique palsy. Am Orthopt J. 1974;24:18–22.

side of the tilt instead of running parallel as in patients with symmetrical facies. The asymmetry was once thought to be due to ipsilateral carotid artery compression, but more recent work suggests that it is due to deformational molding from monotonous ipsilateral positioning during sleep.59 Early surgery in congenital cases is thought to prevent this asymmetry.59,60

TREATMENT General principles of treatment apply in fourth nerve palsies – small, asymptomatic deviations can usually be ignored until they produce a bothersome head tilt or other discomfort. In children, a persistent head tilt can even induce scoliosis.61 Small, symptomatic deviations may, in some cases, be successfully treated using prisms. Even though incomitant deviations such as fourth nerve palsies are not ideal indications for prism treatment, some palsies exhibit spread of comitance (a ‘smoothing out’ of the deviation) that makes these palsies more amenable to prism therapy. In cases without spread of comitance, prisms may still be successfully used by addressing primary position and downgaze deviations and by taking advantage of the patient’s large vertical vergence amplitudes. As with third nerve palsies, acquired fourth nerve palsies, usually traumatic, should initially be nonsurgically treated during a period of observation lasting at least 6 months; improvement or even complete resolution frequently occurs. However, unlike their third nerve counterparts, congenital fourth nerve palsies almost always progress to the point at which surgery is required.

Surgical Treatment

Surgical treatment of fourth nerve palsies follows the general principles of treatment for any incomitant deviation in that the muscle(s) selected for manipulation must be the one(s) active in the field of largest deviation, especially when primary position and downgaze (reading position) are concerned. One approach is to assume that the antagonist inferior oblique muscle always overacts to some degree and that weakening the inferior oblique muscle (recession, myectomy) resolves up to approximately 15 PD of primary position hypertropia. Patients who have larger primary position hypertropias require additional muscle surgery to address the additional deviation, usually with recession of the contra­ lateral inferior rectus muscle (the yoke of the paretic superior oblique muscle) with or without an adjustable suture technique. A comprehensive surgical management plan for this difficult problem was codified by Knapp62 in 1974 and is summarized in Box 11-10-1; it accounts for the observed spread of comitance and follows the general principles already outlined. In class 1 and 2, where only one gaze field has a large deviation, the muscle whose field of greatest action lies within that gaze field is operated on. The overacting inferior oblique muscle is weakened in class 1 cases, and the paretic superior oblique muscle is strengthened with a tendon tuck or plication in class 2 cases. A small Brown’s syndrome (inability to elevate the eye in adduction) is a desirable result following this surgery for class 2 cases.

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11 Pediatric and Adult Strabismus

In class 3, where all contralateral fields are affected, inferior oblique weakening (or superior oblique strengthening, as originally recommended) can be performed alone for vertical deviations below 20 D; larger deviations require a graded recession of the contralateral inferior rectus muscle. Class 4 cases evolve from class 3 cases – the deviation extends from the lateral gaze positions to affect all three downgaze positions as well. Knapp62 recommended the same treatment as in class 3 cases, then to wait for the downgaze deviation to resolve after the lateral gaze deviation had been treated, presuming that it is due to temporary underaction of the ipsilateral inferior rectus muscle. If it did not resolve, he advocated resection of the inferior rectus muscle. More recent analysis attributes this development to contracture of the ipsilateral superior rectus muscle from constant hypertropia;38 this muscle may be receded for treatment if it is thought that oblique surgery alone will be insufficient. Class 5 pareses have maximum deviations in the downgaze fields and are unusual. Although Knapp’s original recommendation was to tuck the affected superior oblique muscle in combination with tenotomy of the contralateral superior oblique muscle, this strategy may convert a unilateral palsy into a bilateral one. Bilateral superior oblique palsies constitute Knapp’s class 6; he recommended a bilateral tuck of the superior oblique tendon. Successful treatment has been accomplished more recently by the Fells modification53,63 – bilateral transposition of the anterior half of the superior oblique tendon as originally described by Harada and Ito.64 Combined paresis and restriction of the superior oblique muscle constitute class 7 cases; these are usually due to trauma, especially dog bites,62 directly to the trochlear region. Surgery on the frontal sinus can also be responsible.14 Knapp offered no solution for this difficult situation; initial alleviation of the restriction with subsequent treatment of the paretic component has since been recommended. The vast majority of congenital cases have a demonstrable laxity or other abnormality of the tendon, which is infrequently found in acquired cases.65,66 This can be assessed, and when present, this finding strongly suggests treatment with a tendon-strengthening procedure, perhaps combined with weakening of the antagonist inferior oblique muscle.67

SIXTH NERVE PALSY INTRODUCTION Because only the lateral rectus muscle is affected, palsies of the sixth cranial nerve have presentations that are much less complex than those of the third or fourth nerves. A deviation in the horizontal plane alone is produced, with no torsion or lid involvement, thus reducing the amblyogenic causes in susceptible children. Sixth nerve palsies are more common than either third or fourth nerve palsies in most age groups.20,34–37

EPIDEMIOLOGY AND PATHOGENESIS

1230

Congenital sixth nerve palsy is unusual and in many cases resolves rapidly.68 If improvement is not forthcoming after serial observation, a neurological evaluation should be considered. More often, an esotropia with poor abduction of one or both eyes dating from birth represents another condition (Box 11-10-2), most commonly congenital esotropia. These children, who have a large, constant esotropia, often exhibit cross-fixation, looking to the right with their left eye and vice versa, thus never having to abduct either eye. A sixth nerve palsy can be ruled out by provoking abduction, either by unilateral occlusion for a few days (risking an occlusion amblyopia in a young infant) or preferably by utilizing the vestibulo-ocular reflex. The examiner holds the baby faceto-face at a close distance while they both spin, first to one side and then the other. An examination chair that swivels facilitates this maneuver; caution should be observed when using this procedure on a postprandial baby! If the reflex saccades in the opposite direction are brisk and abduction full, a sixth nerve palsy can be discounted. Möbius’ syndrome69 should be considered, although children with this disorder have other obvious problems (mask-like facies, poor feeding, hypoglossal atrophy, skeletal abnormalities) related to the other elements of this syndrome, which include palsies of the seventh and twelfth nerves in addition to the sixth. Also, Duane’s syndrome should be considered in

BOX 11-10-2 POSSIBLE CAUSES OF ABDUCTION DEFICITS Congenital  Congenital esotropia  Möbius’ syndrome69  Duane’s syndrome  Congenital horizontal gaze palsy Acquired  Trauma  Neoplasm  Meningitis  Hydrocephalus  Benign recurrent sixth nerve palsy74–77  Pseudotumor cerebri  Gradenigo’s syndrome  Demyelinating disease  Vascular disease  Aneurysm  Postmyelography  Postimmunization  Postviral

the differential diagnosis of congenital sixth nerve palsy, and congenital gaze palsy has been reported70 as a cause of an abduction deficit. As it has a long intracranial course and the longest subarachnoid course of any cranial nerve, the sixth nerve is prone to both injuries from trauma and an extensive array of nontraumatic diseases of contiguous and nearby structures, summarized in Box 11-10-2. A benign ipsilateral recurrent palsy that follows a viral illness or immunization can affect children;71,72 the adult counterpart has no known cause.73 Studies indicate that in children, trauma is a more common cause of an acquired sixth nerve palsy than neoplasm.20,34 Earlier studies indicated the reverse, perhaps because of the delayed diagnosis of tumors prior to the advent of computed tomography and magnetic resonance imaging, a delay that allowed a paralytic strabismus to develop.34 Acquired, bilateral palsies are more ominous than their unilateral counterpart. Despite the lengthy list of possible causes, acquired unilateral sixth nerve weakness (Fig. 11-10-4) is often benign even if recurrent.74 However, careful examination must be performed to make sure the palsy is truly isolated and not accompanied by any other neurological findings suggesting a serious cause. Patients who have a truly isolated paresis may be observed with serial examination for up to 6 months before any further investigation is indicated.75 Prompt, spontaneous resolution of a sixth nerve palsy, however, does not rule out neoplasm as a cause in children or adults.76 The appearance of new indicative findings or progression of the paresis demands immediate investigation. Although rare since the advent of antibiotics, children should be evaluated for otitis media as the cause; Gradenigo’s syndrome occurs if contiguous inflammation of the petroclinoid ligament affects the adjacent sixth nerve as it passes through Dorello’s canal.77

OCULAR MANIFESTATIONS The only manifestation of a sixth nerve palsy is an esotropia, which almost always affects primary position. In congenital palsies that result from Möbius’ syndrome an esotropia may be lacking, which raises the question of whether this syndrome (discussed later) produces a true sixth nerve palsy or, more accurately, a gaze palsy because the horizontal gaze center is very close to or even coincides with, the sixth nerve nucleus.78,79 When present, the esotropia of a sixth nerve palsy initially exhibits the typical findings of a paralytic strabismus; the deviation is maximized in ipsilateral horizontal gaze and smallest in gaze to the opposite side (incomitancy). In addition, in a given gaze position the deviation is larger when the paretic eye is fixing (secondary deviation). However, contracture of its antagonist and yoke muscles (the ipsilateral medial rectus and the contralateral medial rectus muscles, respectively) can rapidly convert the deviation into a comitant esotropia.80 In unilateral cases that have not yet developed comitancy, an ipsilateral face turn may be adopted to maintain binocularity.

11.10  Paralytic Strabismus

A

Fig. 11-10-5  Full-tendon ‘transposition’ of the superior and inferior rectus muscles to the insertion of the left lateral rectus muscle. (Courtesy of R. Scott Foster, MD.)

B

surgical management and sometimes essential to prevent or minimize the risk of postoperative ASI.

Surgical Treatment

C Fig. 11-10-4  A 33-year-old man with a right sixth nerve palsy. (A) Right esotropia in primary position. (B) No deviation in contralateral (left) gaze. (C) Large esotropia in ipsilateral (right) gaze – the affected right eye cannot even get to midline position.

TREATMENT As with palsies of the third and fourth cranial nerves, surgical treatment of sixth nerve palsy should be deferred whenever a chance for improvement exists and at least for the first 6 months after onset.

Nonsurgical Treatment

During this period of expectant observation, young children who do not adopt the characteristic ipsilateral face turn to maintain binocularity should undergo unilateral occlusion to avoid the development of sensory adaptations to binocularity; to minimize the possibility of amblyopia the occlusion should alternate between the eyes. To minimize accommodation (which can worsen their esotropia) spectacles with full hypermetropic correction should also be given. Adults may also appreciate unilateral occlusion to eliminate their uncrossed diplopia. Small deviations may be amenable to treatment using prisms, especially because the originally incomitant deviation can rapidly become comitant due to contracture of both medial rectus muscles, as discussed earlier. To nurture continued improvement, the minimum amount of horizontal prism that allows fusion should be prescribed. Chemodenervation with botulinum toxin can be used during the acute phase of a sixth nerve palsy to prevent contracture of the antagonist medial rectus muscle while the lateral rectus muscle recovers function.17,18,81 Despite its frequent lack of lasting benefit as a sole remedy for chronic palsy,17,18,81 some patients may require or even prefer its repeated use as their treatment.82 It is very useful as an adjunct to

Surgical treatment should be considered when more than 6 months have passed after onset, serial examinations are stable (which indicates that subsequent improvement is unlikely), and the deviation is too large for reasonable consideration of prisms. The goals of treatment are primary position alignment and expansion of the diplopia-free field, visible prior to treatment only with a face turn. The surgical plan is largely determined by the depth of the palsy and the quantity of medial rectus muscle contracture. Remaining lateral rectus muscle function can be assessed directly by a force generation test,1 discussed earlier. Careful observation of ipsilateral saccades and modified electrooculography can provide similar information.83 Traditional forced duction testing estimates the degree of medial rectus contracture. When the preceding tests reveal that at least some lateral rectus muscle function remains (usually with an esotropia of less than 30 D), a graded recess–resect procedure based on published tables often succeeds. Effective treatment when little or no abducting force remains generally requires a new source of abducting force provided by a muscle transposition procedure, together with weakening the antagonist medial rectus muscle, which is usually contracted. Abducting force can be supplied by moving the adjacent vertical rectus muscles to the lateral rectus muscle insertion or by nonsurgical union of the adjacent halves of the lateral and vertical rectus muscles. The many variations of these techniques are reviewed elsewhere.84 The original Hummelsheim procedure85 involves longitudinally splitting the superior and inferior rectus muscles and transposing each lateral half to the insertion of the paretic lateral rectus muscle. Full-tendon ‘transpositions,’ more accurately termed ‘translations’ (Fig. 11-10-5), can transfer more force and are equally effective; a proposed modification utilizes a posterior fixation suture to better direct the transferred force as horizontally as possible.86,87 The Jensen procedure88 entails longitudinal splitting of the lateral rectus and the vertical rectus muscles. The adjacent halves are then joined with an unabsorbable suture, usually in conjunction with medial rectus recession. Because only one rectus muscle is actually severed from the globe, interrupting its anterior ciliary artery circulation, it was originally thought that this procedure would eliminate the risk of ASI, a theory that has since been disproved.89 To minimize this risk and at the same time preserve the effectiveness of full-tendon transposition, adjunctive chemodenervation of the medial rectus muscle with botulinum toxin (instead of surgical recession) has been advocated.90

SUMMARY In summary, paralytic strabismus is a difficult challenge in both diagnosis and management. Patterns of incomitant strabismus must be analyzed using the strabismologist’s full range of tests and maneuvers to arrive at the correct diagnosis. Other findings, both historical and

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11 Pediatric and Adult Strabismus 1232

physical, must be sought to determine whether systemic evaluation or consultations are necessary. The management of paralytic strabismus, especially with surgery, challenges us to maximize alignment and motility with fewer normally functioning muscles than in the original complex design.

Knapp P. Classification and treatment of superior oblique palsy. Am Orthopt J 1974;24:18–22.

KEY REFERENCES

von Noorden GK, Murray E, Wong SY. Superior oblique paralysis. A review of 270 cases. Arch Ophthalmol 1986;104:1771–6.

Foster RS. Vertical muscle transposition augmented with lateral fixation. J Am Assoc Pediatr Ophthalmol Strabismus 1997;1:20–30.

Parks MM. Isolated cyclovertical muscle palsy. Arch Ophthalmol 1958;60:1027–35.

Harley RD. Paralytic strabismus in children. Etiologic incidence and management of the third, fourth, and sixth nerve palsies. Ophthalmology 1980;87:24–43.

Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:568–74. Kushner BJ. Errors in the three-step test in the diagnosis of vertical strabismus. Ophthalmology 1989;96:127–32. Mottier ME, Mets MB. Vertical fusional vergences in patients with superior oblique palsies. Am Orthopt J 1990;100:88–93.

Robb RM. Idiopathic superior oblique palsies in children. J Pediatr Ophthalmol Strabismus 1990;27:66–9. Rubin SE, Wagner RS. Ocular torticollis. Surv Ophthalmol 1986;30:366–76.

Helveston EM, Krach D, Plager DA, et al. A new classification of superior oblique palsy based on congenital variations in the tendon. Ophthalmology 1992;99:1609–15.

Saunders RA, Sandall GS. Anterior segment ischemia syndrome following rectus muscle transposition. Am J Ophthalmol 1982;93:34–8.

Holmes JM, Mutyala S, Maus TL, et al. Pediatric third, fourth, and sixth nerve palsies: a populationbased study. Am J Ophthalmol 1999;127:388–92.

Scott AB, Kraft SP. Botulinum toxin injection in the management of lateral rectus paresis. Ophthalmology 1985;92:676–83.

Ing EB, Sullivan TJ, Clarke MP, et al. Oculomotor nerve palsies in children. J Pediatr Ophthalmol Strabismus 1992;29:331–6.

Trobe JD. Third nerve palsy and the pupil: footnotes to the rule. Arch Ophthalmol 1988;106: 601–2.

Access the complete reference list online at

REFERENCES 1. Scott AB. Active force tests in lateral rectus paralysis. Arch Ophthalmol 1971;85:397–404.

3. Bateman DE, Saunders M. Cyclic oculomotor palsy: description of a case and hypothesis of the mechanism. J Neurol Neurosurg Psychiatry 1983;46:451–3. 4. Miller NR. Walsh and Hoyt’s clinical neuro-ophthalmology, vol. 2. 6th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2004. 5. Balkan R, Hoyt CS. Associated neurologic abnormalities in congenital third nerve palsies. Am J Ophthalmol 1984;97:315–19. 6. Ing EB, Sullivan TJ, Clarke MP, et al. Oculomotor nerve palsies in children. J Pediatr Ophthalmol Strabismus 1992;29:331–6. 7. Ng YS, Lyons CJ. Oculomotor nerve palsy in childhood. Can J Ophthalmol 2005;40:645–53. 8. Abdul-Rahim AS, Savino PJ, Zimmerman RA, et al. Cryptogenic oculomotor nerve palsy: the need for repeated neuroimaging studies. Arch Ophthalmol 1987;107:387–90. 9. Schultz KL, Lee AG. Diagnostic yield of the evaluation of isolated third nerve palsy in adults Can J Ophthalmol 2007;42:110–15. 10. Mizen TR, Burde RM, Klingele TG. Cryptogenic oculomotor nerve palsies in children. Am J Ophthalmol 1985;100:65–7. 11. Trobe JD. Third nerve palsy and the pupil: footnotes to the rule. Arch Ophthalmol 1988;106:601–2. 12. Lustbader JM, Miller NR. Painless, pupil-sparing but otherwise complete oculomotor nerve paresis caused by basilar artery aneurysm. Arch Ophthalmol 1988;106:583–4. 13. Ikeda K, Tamura M, Iwasaki Y, et al. Relative pupil-sparing third nerve palsy: etiology and clinical variables predictive of a mass. Neurology 2001;13;57:1741–2. 14. von Noorden GK. Binocular vision and ocular motility. St Louis, MO: Mosby–Year Book; 1996. p. 392–429. 15. Diamond GR, Katowitz JA, Whitaker LA, et al. Variations in extraocular muscle number and structure in craniofacial dysostosis. Am J Ophthalmol 1980;90:416–18. 16. Coats DK, Ou R. Anomalous medial rectus muscle insertion in a child with craniosynostosis. Binocul Vis Strabismus Q 2001;16:119–20. 17. Kim EJ, Hong S, Lee JB, et al. Recession–resection surgery augmented with botulinum toxin a chemodenervation for paralytic horizontal strabismus. Korean J Ophthalmol 2012;26: 69–71. 18. Holmes JM, Beck RW, Kip KE, et al. Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis. J AAPOS 2000;4:145–9. 19. Talebnejad MR, Sharifi M, Nowroozzadeh MH. The role of botulinum toxin in management of acute traumatic third-nerve palsy J AAPOS 2008;12:510–13. 20. Harley RD. Paralytic strabismus in children. Etiologic incidence and management of the third, fourth, and sixth nerve palsies. Ophthalmology 1980;87:24–43. 21. Schumacher-Feero LA, Yoo KW, Solari FM, et al. Results following treatment of third cranial nerve palsy in children. Trans Am Ophthalmol Soc 1998;96:455–72.

41. Harris Jr DJ, Memmen JE, Katz NNK, et al. Familial congenital superior oblique palsy. Ophthalmology 1986;93:88–90. 42. Robb RM. Idiopathic superior oblique palsies in children. J Pediatr Ophthalmol Strabismus 1990;27:66–9. 43. Helveston EM, Giangiacomo JD, Ellis FD. Congenital absence of the superior oblique tendon. Trans Am Ophthalmol Soc 1981;79:123–35. 44. Wallace DK, von Noorden GK. Clinical characteristics and surgical management of congenital absence of the superior oblique tendon. Am J Ophthalmol 1994;118:63–9. 45. Nucci P, Kushner BJ, Serafino M, et al. A multi-disciplinary study of the ocular, orthopedic, and neurologic causes of abnormal head postures in children. Am J Ophthalmol 2005;140:65–8. 46. Rubin SE, Wagner RS. Ocular torticollis. Surv Ophthalmol 1986;30:366–76. 47. Gobin MH. The diagnosis and treatment of IVth cranial nerve paralysis. Ophthalmologica 1976;173:292–5. 48. Hofmann FB, Bielschowsky A. Die Verwertung der Knipfneigung zur Diagnose der Augenmuskellahmungen. Graefes Arch Ophthalmol 1900;51:174. 49. Parks MM. Isolated cyclovertical muscle palsy. Arch Ophthalmol 1958;60:1027–35. 50. Kushner BJ. Errors in the three-step test in the diagnosis of vertical strabismus. Ophthalmology 1989;96:127–32. 51. von Noorden GK. Clinical and theoretical aspects of cyclotropia. J Pediatr Ophthalmol Strabismus 1984;21:126–32. 52. Ruttum M, von Noorden GK. Adaptation to tilting of the visual environment in cyclotropia. Am J Ophthalmol 1983;96:229–37. 53. Mitchell PR, Parks MM. Surgery for bilateral superior oblique palsy. Ophthalmology 1982;89:484–8. 54. Ellis FD, Helveston EM. Superior oblique palsy: diagnosis and classification. Int Ophthalmol Clin 1976;16:127–35. 55. Kraft SP, O’Reilly C, Quigley PL, et al. Cyclotorsion in unilateral and bilateral superior oblique paresis. J Pediatr Ophthalmol Strabismus 1993;30:361–7. 56. Guyton DL. Clinical assessment of ocular torsion. Am Orthopt J 1983;33:7–15. 57. Bixenman WW, von Noorden GK. Apparent foveal displacement in normal subjects and in cyclotropia. Ophthalmology 1982;89:58–62. 58. Mottier ME, Mets MB. Vertical fusional vergences in patients with superior oblique palsies. Am Orthopt J 1990;100:88–93. 59. Goodman CR, Chabner E, Guyton DL. Should early strabismus surgery be performed for ocular torticollis to prevent facial asymmetry? J Pediatr Ophthalmol Strabismus 1995;32:162–6. 60. Wilson ME, Hoxie J. Facial asymmetry in superior oblique muscle palsy. J Pediatr Ophthalmol Strabismus 1993;30:315–18. 61. Ruedemann AD. Scoliosis and vertical ocular muscle imbalance. Arch Ophthalmol 1956;56:389–414.

22. Helveston EM. Surgical management of strabismus. 4th ed. St Louis, MO: Mosby–Year Book; 1993. p. 302.

62. Knapp P. Classification and treatment of superior oblique palsy. Am Orthopt J 1974;24:18– 22.

23. Khaier A, Dawson E, Lee J. Traction sutures in the management of long-standing third nerve palsy. Strabismus 2008;16:77–83.

63. Fells P. Management of paralytic strabismus. Br J Ophthalmol 1974;58:255–65. 64. Harada M, Ito Y. Surgical correction of cyclotropia. Jpn J Ophthalmol 1964;8:88–96.

24. Nelson LB. Strabismus disorders. In: Nelson LB, Calhoun JH, Harley RB, editors. Pediatric ophthalmology. 3rd ed. Philadelphia: WB Saunders; 1991. p. 128–75.

65. Helveston EM, Krach D, Plager DA, et al. A new classification of superior oblique palsy based on congenital variations in the tendon. Ophthalmology 1992;99:1609–15.

25. Yonghong J, Kanxing Z, Wei L, et al. Surgical management of large-angle incomitant strabismus in patients with oculomotor nerve palsy. J AAPOS 2008;12:49–53.

66. Guyton DL. Exaggerated traction test for the oblique muscles. Ophthalmology 1981;88:1035–40.

26. Reinecke RD. Surgical management of third and sixth cranial nerve palsies. In: Nelson LB, Wagner RS, editors. Strabismus surgery. [International ophthalmology clinics.] Boston, MA: Little Brown; 1985. p. 139–48.

67. Reynolds JD, Biglan AW, Hiles DA. Congenital superior oblique palsy in infants. Arch Ophthalmol 1984;102:1503–5.

27. Scott AB. Transposition of the superior oblique. Am Orthopt J 1977;27:11–14.

68. Reisner SH, Perlman M, Ben-Tovim N, et al. Transient lateral rectus muscle paresis in the newborn infant. J Pediatr 1971;78:461–5.

28. Pollard ZF. Diagnosis and treatment of inferior oblique palsy. J Pediatr Ophthalmol Strabismus 1993;30:15–18.

69. Miller MT, Ray V, Owens P, et al. Möbius’ and Möbius-like syndromes (TTV–OFM, OMLH). J Pediatr Ophthalmol Strabismus 1989;26:176–88.

29. Saunders RA, Sandall GS. Anterior segment ischemia syndrome following rectus muscle transposition. Am J Ophthalmol 1982;93:34–8.

70. Hoyt CS, Billson FA, Taylor H. Isolated unilateral gaze palsy. J Pediatr Ophthalmol Strabismus 1977;14:343–5.

30. Murdock TJ, Kushner BJ. Anterior segment ischemia after surgery on 2 vertical rectus muscles augmented with lateral fixation sutures. J AAPOS 2001;5:323–4.

71. Bixenman WW, von Noorden GK. Benign recurrent VI nerve palsy in childhood. J Pediatr Ophthalmol Strabismus 1981;18:29–34.

31. France TD, Simon JW. Anterior segment ischemia syndrome following muscle surgery: the AAPO&S experience. J Pediatr Ophthalmol Strabismus 1986;23:87–91.

72. Werner DB, Savino PJ, Schatz NJ. Benign recurrent sixth nerve palsies in childhood. Secondary to immunization or viral illness. Arch Ophthalmol 1983;101:607–8.

32. McKeown CA, Lambert HM, Shore JW. Preservation of the anterior ciliary vessels during extraocular muscle surgery. Ophthalmology 1989;96:498–507.

73. Hamilton SR, Lessell S. Recurrent idiopathic lateral rectus muscle palsy in adults. Am J Ophthalmol 1991;112:540–2.

33. Freedman HL, Waltman DD, Patterson JH. Preservation of anterior ciliary vessels during strabismus surgery: a nonmicroscopic technique. J Pediatr Ophthalmol Strabismus 1992;29:38–43.

74. Okutan V, Yavuz ST, Mutlu FM, et al. Benign recurrent abducens (sixth) nerve palsy. J Pediatr Ophthalmol Strabismus 2009;46:47–9.

34. Kodsi SR, Younge BR. Acquired oculomotor, trochlear, and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol 1992;114:568–74. 35. Rucker CW. Paralysis of the third, fourth and sixth cranial nerves. Am J Ophthalmol 1958;46:787–94. 36. Rucker CW. The causes of paralysis of the third, fourth, and sixth cranial nerves. Am J Ophthalmol 1966;61:1293–8. 37. Holmes JM, Mutyala S, Maus TL, et al. Pediatric third, fourth, and sixth nerve palsies: a population-based study. Am J Ophthalmol 1999;127:388–92. 38. von Noorden GK, Murray E, Wong SY. Superior oblique paralysis. A review of 270 cases. Arch Ophthalmol 1986;104:1771–6. 39. Mansour AM, Reinecke RD. Central trochlear palsy. Surv Ophthalmol 1986;30:279–97.

11.10  Paralytic Strabismus

2. Woodruff G, O’Reilly C, Kraft SP. Functional scoring of the field of binocular single vision in patients with diplopia. Ophthalmology 1987; 94:1554–61.

40. Astle WF, Rosenbaum AL. Familial congenital fourth nerve palsy. Arch Ophthalmol 1985;103:532–5.

75. Savino PJ, Hilliker JK, Cassell GH, et al. Chronic sixth nerve palsies. Are they really harbingers of serious intracranial disease? Arch Ophthalmol 1982;100:1442–4. 76. Volpe NJ, Lessell S. Remitting sixth nerve palsy in skull base tumors. Arch Ophthalmol 1993;111:1391–5. 77. Gradenigo G. A special syndrome of endocranial otitic complications (paralysis of the motor oculi externus of otitic origin). Ann Otol Rhinol Laryngol 1904;13:637. 78. Brodsky MC, Baker RS, Hamed LM. Pediatric neuro-ophthalmology. New York: SpringerVerlag; 1996. p. 201–50. 79. Glaser JS. Infranuclear disorders of eye movement. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology. vol. 2. Philadelphia: Lippincott–Raven; 1995. p. 1–56. 80. Parks MM, Mitchell PR. Cranial nerve palsies. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology. vol. 1. Philadelphia: Lippincott–Raven; 1995. p. 1–112.

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11 Pediatric and Adult Strabismus 1232.e2

81. Scott AB, Kraft SP. Botulinum toxin injection in the management of lateral rectus paresis. Ophthalmology 1985;92:676–83.

87. Struck MC. Augmented vertical rectus transposition surgery with single posterior fixation suture: modification of Foster technique. J AAPOS 2009;13:343–9.

82. Lee J. Modern management of sixth nerve palsy. Aust NZ J Ophthalmol 1992;20:41–6.

88. Jensen CDF. Rectus muscle union: a new operation for paralysis of the rectus muscles. Trans Pacific Coast Ophthalmol Soc 1964;45:359–87.

83. Metz HS, Scott AB, O’Meara D, Stewart HL. Ocular saccades in lateral rectus palsy. Arch Ophthalmol 1970;84:453–60. 84. Helveston EM. Surgical management of strabismus. 4th ed. St Louis. MO: Mosby–Year Book; 1993. p. 292–3. 85. Hummelsheim E Weitere Erfahtungen mit partieller Sehnenuberpflanzung an den Augenmuskeln. Arch Augenheilkd 1908–1909;62:71–4. 86. Foster RS. Vertical muscle transposition augmented with lateral fixation. J Am Assoc Pediatr Ophthalmol Strabismus 1997;1:20–30.

89. von Noorden GK. Anterior segment ischemia following the Jensen procedure. Arch Ophthalmol 1976;94:845–7. 90. Rosenbaum AL, Kushner BJ, Kirschen D. Vertical rectus muscle transposition and botulinum toxin (Oculinum) to medial rectus for abducens palsy. Arch Ophthalmol 1989;107:820–3.

PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

Other Vertical Strabismus Forms Mitchell B. Strominger, Howard M. Eggers

Definition: Vertical strabismus not paretic in origin.

Key features ■ ■

Incomitance Supranuclear or mechanical causation

INTRODUCTION The various findings in nonparetic vertical strabismus group into several clinical entities. All share incomitance as a feature. The cause is frequently unknown, although the phenomenology of the deviation is descriptively either supranuclear, a mechanical restriction to rotation, or a local orbital cause of poor muscle contraction.

DISSOCIATED VERTICAL DIVERGENCE INTRODUCTION Dissociated vertical divergence (or dissociated vertical deviation; DVD) is characterized by a spontaneous upward deviation of either eye (dissociation) while the other eye fixates a target (Fig. 11-11-1).1 The deviation is variable within an episode and from one dissociated episode to another. After a period of usually no more than a few tenths of seconds or on a shift of gaze, the eye returns down and may even become mildly

11.11 

hypotropic. The amplitude of the deviation and the frequency of spontaneous dissociation are usually not equal in the two eyes. The spontaneous deviation may occur with or without daydreaming or fatigue, although these states make the deviation worse or the spontaneous dissociation more common.

EPIDEMIOLOGY AND PATHOGENESIS Although DVD is most common with congenital esotropia, it can occur with any horizontal strabismus and sometimes as an isolated defect. Seldom present at birth, DVD is frequently a new finding after the age of 2–3 years and is thought to be associated with the early disruption of binocular development. Elevation in adduction, which produces an apparent inferior oblique overaction, can be the initial presentation. Fusion maldevelopment syndrome (FMS, latent or manifest latent nystagmus) commonly occurs with DVD in congenital esotropia.

OCULAR MANIFESTATIONS In cover testing, the eye drifts upward, outward and excyclorotates behind the occluder. The eye then returns downward when the occluder is removed and vision restored. The uncovered eye typically remains stationary. Binocular visual input thus plays a role in stabilization of the eyes in primary position, although the deviation can occur with inattention or be manifest. Since the deviated eye is usually suppressed, diplopic symptoms seldom occur.2 Rarely, the suppression is not deep enough and vertical diplopia occurs. Occasionally, a patient may find it physically uncomfortable for the eye to turn upward. The spontaneous deviation may also disturb psychosocial function. Because each eye drifts upward under cover and moves downward on removal of the cover, it is difficult to measure accurately the vertical deviation of DVD. Thus the prism power that makes the residual vertical drift symmetrical can be used as an estimate. Occasionally, the drift movement is chiefly horizontal and the term dissociated horizontal deviation is used.3 If it is primarily torsional, the term dissociated torsional deviation is used.

DIAGNOSIS A

B Fig. 11-11-1  Dissociated vertical divergence. (A) The eyes are approximately straight in primary position. (B) Occlusion of an eye leads to an upward drift of the covered eye. Dissociated vertical divergence is usually bilateral, although it may show asymmetrical amounts of drift. On cover testing, each eye drifts up when under cover. A measure of a simultaneous vertical deviation is the prism power that equalizes the amplitude of the vertical drift in the two eyes.

The cause of DVD is the subject of much speculation. The normal versions and ductions imply a defect in supranuclear control of eye position. Eye movement studies implicate an abnormal vertical vergence system.4 The Bielschowsky phenomenon is a curious characteristic of DVD that must be related to the abnormal supranuclear control of vertical eye position. It is demonstrated by occlusion of one eye to make it deviate upward. Then, a neutral density wedge is placed before the opposite, unoccluded eye. The eye behind the cover makes a gradual downward movement in proportion to the attenuation of light that reaches the open eye. This phenomenon sometimes becomes manifest in a blind or significantly visually impaired eye.

DIFFERENTIAL DIAGNOSIS The characteristic findings in DVD eliminate the need for any differential diagnosis except in cases that have minimal involvement, concurrent vertical deviation, or difficulty in examination because of young age. Overaction of the inferior oblique (primary or secondary) and superior oblique paresis must be ruled out. In cases of vertical strabismus, a coexisting DVD may be difficult to diagnose.

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TREATMENT

Pediatric and Adult Strabismus

Although binocular sensory and motor fusions are poor in DVD, the aim of nonsurgical therapy for DVD is to strengthen the patient’s fusional mechanisms. This is done by elimination of any concurrent strabismus and optimization of vision through accurate refractive prescription and treatment of amblyopia. Indications for surgery are visual symptoms, physical discomfort from a large deviation, or disfigurement produced by the updrift. A variety of surgical procedures have been advocated for DVD. These include resection of the inferior recti, recession of the superior recti with or without a Faden procedure, and anterior transposition of the inferior oblique.5–8 If one eye is used habitually for fixation, surgery needs to be performed only on the opposite eye. If either eye is used at times for fixation, both eyes need to be operated on, but asymmetrically, each eye in proportion to its drift. Dissociated horizontal deviation can be helped by a lateral rectus recession on the involved side.

PRIMARY INFERIOR OBLIQUE OVERACTION

A

B

EPIDEMIOLOGY AND PATHOGENESIS Overelevation in adduction may be the result of primary overaction of the inferior obliques. The cause is unknown although it is associated with horizontal strabismus. An anatomic variation plays a role since it can be seen in the craniosynostosis. A difference in the plane of action of the superior and inferior obliques, referred to as desagittalization, may leave the inferior oblique with a stronger vertical action in adduction than the superior oblique.9 Excyclorotation of the globe or orbit may also raise the insertion of the medial rectus above the horizontal midline to give it a vertical action that assists elevation in adduction and simulates inferior oblique overaction.

OCULAR MANIFESTATIONS Primary inferior oblique overaction refers to a marked elevation of an eye when in the adducted position under binocular viewing conditions (Fig. 11-11-2). Usually no vertical deviation occurs in primary position. When bilateral, a right hypertropia is seen in left gaze and a left hypertropia in right gaze. The elevation in adduction may be bilaterally symmetrical or asymmetrical. The head-tilt test result is negative and depression on adduction is normal. It is typically associated with a horizontal strabismus, either an esotropia or exotropia, and produces a V pattern.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes secondary inferior oblique overaction (from a paretic ipsilateral superior oblique or contralateral superior rectus), Duane’s syndrome, and DVD. Overaction secondary to superior oblique paresis shows a positive head-tilt test. The differentiation of DVD from inferior oblique overaction is important because different surgical procedures are used, depending on the diagnosis. Primary inferior oblique overaction commonly occurs in congenital esotropia and is frequently confused with DVD. Genuine inferior oblique overaction should produce a V pattern and show measurable vertical deviations in lateral gaze. The abducted eye becomes lower as the high, adducted eye takes up fixation. The deviation is the same regardless of which eye fixates. In DVD, dissociation of the eyes occurs by occlusion of much of the visual field of the adducted eye by the nose and eyebrow, which results in elevation of the occluded eye. If the adducted eye is the fixating eye, much less or no elevation occurs in adduction. Occlusion of the abducted eye may make that eye elevate and thus reverse the hypertropia findings. The updrift and recovery movements are slower than in a true tropia of inferior oblique overaction and are frequently accompanied by torsional movements, extorsion as the eye rises, and intorsion during recovery.

TREATMENT 1234

When elevation in adduction genuinely results from inferior oblique overaction, a weakening procedure is required for these muscles.10

C Fig. 11-11-2  Elevation in adduction. The apparent overaction of the inferior oblique must be confirmed with cover testing. A dissociated vertical divergence frequently gives the same appearance on testing versions. True inferior oblique overaction gives a measurable deviation in lateral gaze and may produce a V pattern. In dissociated vertical divergence, the abducted eye may circumduct under occlusion. (A) Right gaze. (B) Gaze in primary position. (C) Left gaze. Note elevation of adducted eye in lateral gaze to either side.

Surgical options include inferior oblique recession or myectomy. If a concurrent DVD is present inferior oblique anterior transposition may reduce the upward drift. Apparent overaction of the inferior obliques may also disappear after surgery for esotropia.

DOUBLE ELEVATOR PALSY INTRODUCTION Double elevator palsy is an apparent paralysis of both elevators (superior rectus and inferior oblique) of one eye that results in a hypotropia on the affected side that increases on upgaze. The levator palpebrae may or may not be involved. A subtype with inferior rectus restriction may also occur. Bell’s phenomenon is usually absent, but if present, implies a supranuclear lesion. The pupil is normal, as are horizontal rotations.

EPIDEMIOLOGY AND PATHOGENESIS Double elevator palsy may be congenital or acquired. The cause of the congenital form is not known. Acquired cases have all been adults who have small lesions in the pretectum thus necessitating neuroimaging.11

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes mechanical restriction of elevation (orbital floor fracture, thyroid orbitopathy, congenital fibrosis of the extraocular muscles) and Brown’s syndrome (which can sometimes affect primary position).

TREATMENT, COURSE, AND OUTCOME

11.11 

A

BROWN’S SYNDROME INTRODUCTION

Other Vertical Strabismus Forms

Forced ductions should be carried out to confirm any mechanical restriction of movement. Surgical treatment consists of transferring the entire tendon of both the medial and lateral rectus muscles to the ends of the superior rectus insertion (Knapp’s procedure).12,13 Horizontal rotations are impaired only slightly, and vertical rotations are improved remarkably. If the inferior rectus is restricted, it has to be recessed, either before or after the muscle transposition. Because four anterior ciliary arteries are sacrificed for the transposition, it is best to allow 6 months for adaptation of the blood supply before operation on a third rectus muscle. Alternatively, dissection and preservation of the anterior ciliary arteries from the muscle may enable the third muscle to be included at the initial operation. If the lid height does not improve with the raising of eye position, lid surgery may also be needed.

B

The motility features of the superior oblique tendon sheath syndrome are the result of a short anterior sheath of the superior oblique tendon (Fig. 11-11-3).14 Brown14 differentiated true from simulated sheath syndrome on the basis of whether the causative defect was a short anterior sheath or some other anomaly. This differentiation cannot be based on clinical features but can be made only at the time of surgery.

EPIDEMIOLOGY AND PATHOGENESIS In Brown’s original series there was a 3 : 2 predominance of women to men and nearly twice as many cases involved the right eye as the left; 10% of cases showed bilaterality. Familial occurrence of Brown’s syndrome has been reported.15

C

OCULAR MANIFESTATIONS The most striking clinical feature is restriction of elevation in adduction, which is limited to the horizontal plane. The lid fissure may widen when the eye is adducted. Because the limitation arises from mechanical factors, it is the same on version, duction, and forced duction testing. The maximal elevation possibly increases as the eye moves from adduction to abduction, in which it is normal. Divergence in gaze up from primary position is seen, but there is normal elevation into the ipsilateral upper corner field (normal superior rectus function). The ipsilateral superior oblique usually does not overact. Variable features are head tilt and tropia in all fields. The simulated sheath syndrome can be congenital or acquired. The congenital simulated sheath syndrome results from structural anomalies other than a short sheath. Other fibrous adhesions may be present around the trochlear area. Adhesions around the inferior oblique have also been reported. Acquired cases arise from orbital trauma,16 direct trochlear trauma, orbit or muscle surgery, scleral buckling, frontal sinusitis or sinus surgery, Molteno valve implantation, and inflammation of the superior oblique tendon or sheath. Orbital floor fractures may trap the orbital tissue in such a way as to simulate Brown’s syndrome. Brown’s syndrome is produced easily during surgery to tuck the superior oblique if the tendon sheath is not stripped away adequately or if the surgery is carried out too close to the trochlea. Inflammation of the superior oblique tendon has occurred in rheumatoid arthritis and juvenile rheumatoid arthritis.17–19 Intermittent forms of vertical retraction syndrome have been associated with a click, which occurs as the restriction is released (superior oblique click syndrome).20,21

TREATMENT If binocular vision is present and the head position is correct, treatment is not obligatory but may be carried out electively. Treatment is required for visual symptoms, strabismus, or incorrect head position. Acquired cases that have active inflammation of the superior oblique tendon may benefit from local corticosteroid injections in the region of the trochlea.17 Prisms may provide some relief from diplopia in acquired forms.

D

E Fig. 11-11-3  Brown’s syndrome. Elevation of the left eye is impaired most in right gaze. The differential diagnosis is one of inferior rectus paresis. Brown’s syndrome is characterized by a positive traction test for elevation in adduction, but muscle paresis is not. (A) Gaze to right and up. Note limitation of elevation of adducted left eye. (B) Gazing upward shows mild limitation of elevation of left eye. (C) Gazing left and up shows no restrictions. (D) Gazing to the right shows no vertical deviation in this case, but one may be present. (E) Primary position shows no deviation.

The goal of surgery is to restore free ocular rotations. Brown advocated that the superior oblique tendon be stripped. The results of such a procedure are frequently unsatisfactory because of reformation of scar tissue. A procedure of luxation of the whole trochlea, with the superior oblique tendon and orbital structures left intact, appears promising.22 Tenotomy of the superior oblique tendon has also been advocated.23 This has the disadvantage that it frequently produces a superior oblique paresis.24 Furthermore, if the tendon is not tight, the tenotomy may not improve the restricted movement. Surgery without any preconception

1235

11 Pediatric and Adult Strabismus

about the site of restriction may be preferable. During surgery, a traction test is repeated frequently until the globe rotations are free. Recession of the conjunctiva in the inferotemporal quadrant may help to free rotations. If the restrictive adhesions are not found near the trochlea, they must be sought elsewhere around the globe. After the rotations are as free as possible, the eye is anchored in an elevated, adducted position for up to 2 weeks. This maneuver is intended to prevent the reformation of scar tissue in the same places. In healing, the eye position shifts for several months after surgery, and a second procedure is frequently required. If a vertical strabismus is present, satisfactory mechanical freeing needs to be followed by treatment of the strabismus.

CONGENITAL FIBROSIS Congenital fibrosis of the extraocular muscles (CFEOM) is a group of conditions within the general category of the congenital cranial disinnervation disorders25 (CFEOM1, CFEOM2, CFEOM3, and Tukel syndrome). It manifests as a variable degree of fibrosis and atropy of the extraocular muscles innervated by cranial nerves III and IV. This leads to a restrictive orbitopathy. Blepharoptosis and a compensatory elevated chin position occur. Attempts at upward eye movements may result in convergence. The overall prevalence is 1 : 230 000 and has been identified throughout the world. Tukel syndrome is associated with hand anomalies. The differential diagnosis includes Graves’ disease, Brown’s syndrome, orbital floor fracture, double elevator palsy, and chronic progressive external ophthalmoplegia. Surgical treatment can relieve only the extreme downward tethering of the eyes. The head position improves as a result. The lids may need to be raised, but caution is necessary because the upward rotation of the eyes is limited and the normal Bell’s phenomenon does not occur with blinking. It is, therefore, easy to produce corneal exposure.

FRACTURES OF THE ORBITAL FLOOR OCULAR MANIFESTATIONS Ocular motility may be impaired in orbital floor fractures as a result of proptosis and edema from the original trauma, muscle contusion, intraorbital hemorrhage, herniation of the orbital fascia, and muscle entrapment.26 Eye movements in general, but particularly elevation and depression, may be limited. The inferior rectus is the muscle most commonly affected.

DIAGNOSIS The diagnosis of inferior rectus entrapment is made on the basis of the presence of limited elevation on the affected side, which results in hypotropia, and a positive forced duction testing. Mild cases show hypotropia only in upgaze. Depression may also be limited by entrapment or by damage to the nerve to the inferior rectus. Diplopia may persist after the inferior rectus has been freed. The pathophysiology of any resultant strabismus is the herniation of the orbital contents – fat, connective tissue septa, and muscle – into the fracture and consequent tethering of the eye. If the entrapment is old, the muscle can become permanently fibrotic and inelastic, which results in a reduced range of rotation. A paresis of the inferior rectus may also occur, which presumably arises from trauma to the nerve that supplies the inferior rectus. On occasion, the inferior rectus may be devitalized by compromise of its blood supply. The muscle is then found to be quite friable at the time of surgery.

TREATMENT

1236

A floor fracture does not require repair if no disturbance of motility exists.26 Large fractures, however, should be repaired to prevent enophthalmos. Some clinicians treat immediately while others wait for up to 2 weeks for regression of the edema, which may result in significantly improved motility. To repair the fracture the lid is incised just below the lash line and the periosteum at the orbital edge. A silicone plate is placed under the periosteum of the orbital floor to extend as far back as the fracture site and hold in the herniated orbital contents. This

procedure may still not free the inferior rectus adequately. Ocular muscle surgery is carried out for the hypotropia that remains with restriction to elevation with or without floor fracture repair.

GRAVES’ OPHTHALMOPATHY (DYSTHYROID ORBITOPATHY) INTRODUCTION Dysthyroid orbitopathy is an autoimmune inflammatory condition that involves the orbital tissues, primarily the muscles and fat, but spares the muscle tendons. The muscles are affected by an autoimmue inflammatory process of interstitial edema and round cell infiltration. The muscles enlarge and then become fibrotic and inelastic. Other findings are lid edema, proptosis, lid retraction, and compressive optic neuropathy. Proptosis results from edema and enlargement of the muscles and orbital fat.

OCULAR MANIFESTATIONS The usual motility findings are caused by a restrictive myopathy. In addition orbital inflammation can result in diffuse adhesions of Tenon’s capsule and orbital tissues to the globe. The inferior rectus is the muscle most commonly affected, which results in a limitation of elevation. When the condition is more severe, the eye may be tethered down by the inferior rectus leading to a hypotropia in primary position. The medial rectus is the next most commonly involved muscle, followed by the superior and lateral recti. The inferior oblique may also be involved. The orbitopathy is frequently asymmetrical between the two eyes.

DIAGNOSIS The diagnosis is primarily clinical, since the patient may have any level of thyroid activity. Also, thyroid ophthalmopathy may recur after many quiescent years. Orbital computed tomography, magnetic resonance imaging, or B-scan ultrasonography shows enlargement of the muscles with tendon sparing. Forced duction testing demonstrates restriction. Intraocular pressure becomes elevated as the eye attempts to rotate against the restriction. Usually lid edema, proptosis or lid retraction is present in addition to any motility disturbance.

TREATMENT Treatment of dysthyroid orbitopathy begins with correcting the thyroid state by an endocrinologist. The goal from the ophthalmic standpoint is single vision in primary position and downgaze. Fresnel press-on prisms may provide some relief of diplopia until the deviation has stabilized. Because more than one muscle is usually involved, horizontal, vertical and occasionally oblique deviations are present. The patient should be observed until the deviation has stabilized and the orbital inflammation has subsided, which often may take 6 months or longer. Although some improvement in motility may occur as a result of subsidence of orbital edema, the fibrotic changes in the muscles prevent resolution of the portion of the deviation that arises from restrictive muscle changes. Surgically, tight muscles are recessed to enable better movement and reduce the deviation. A secondary goal is to improve the incomitance. An untoward effect of recessing a restrictive muscle, however, is to produce an underaction in its field of action thus potentially producing diplopia in an area not seen previously. Resection of a fibrosed muscle may worsen the deviation and is reserved for special circumstances. If the eye is hypotropic a tight inferior rectus is recessed sufficiently to allow fusion in primary position. Upgaze is the least useful of the gaze positions, and diplopia may be allowed to exist if it allows better alignment in the more useful positions of primary gaze and downgaze. It may not be possible to achieve vertical alignment with the eyes lowered for reading. The reading material then must be held higher, or the head lowered for reading, or prism reading glasses prescribed. Recession of the medial rectus may be necessary for single vision in primary position but tends to produce a convergence insufficiency.

HEAVY EYE SYNDROME Convergent strabismus fixus (heavy eye syndrome) is an ocular motor abnormality where the eye is fixed in adduction. It is usually also hypotropic with limitation of elevation. Typically associated with moderate to high myopia, it is a progressive disorder that can initially mimic a paralytic strabismus but then becomes restrictive. Orbital imaging studies demonstrate a slippage or displacement of the extraocular muscle path and pulley, with the lateral rectus displaced inferiorly and the superior rectus displaced medially. Loop myopexy has become the treatment of choice for this disorder.27

KEY REFERENCES Bielschowsky A. Die einseitigen und gegensinnigen (‘dissoziierten’) Vertikalbewegungen der Augen. Graefes Arch Ophthalmol 1930;25:493–553. Boylan C, Clement RA, Howrie A. Normal visual pathway routing in dissociated vertical deviation. Invest Ophthalmol Vis Sci 1988;29:1165–7. Burke JP, Ruben JB, Scott WE. Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long-term stability. Br J Ophthalmol 1992;76:734–7. Guyton DL, Cheeseman Jr EW, Ellis FJ, et al. Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc 1998;96:389–424; discussion 424-9. Heidary G, Engle EC, Hunter DG. Congenital fibrosis of the extraocular muscles. Semin Ophthalmol 2008;23:3–8. Hermann JS. Acquired Brown’s syndrome of inflammatory origin. Arch Ophthalmol 1978;96:1228–32. MacDonald AI, Pratt-Johnson A. The suppression patterns and sensory adaptations to dissociated vertical divergent strabismus. Can J Ophthalmol 1974;9:113–19. Wilson ME, McClatchey SK. Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus 1991;28:90–5. Wong I, Seo-Wei L, Boo-Kian K. Loop myopexy for treatment of myopic strabismus fixus. JAAPOS 2005:9:589–91.

11.11  Other Vertical Strabismus Forms

Convergence is also compromised by recession of the inferior recti, which then have less secondary convergence action in lowered gaze for reading. Recession of both superior and inferior recti may be indicated. Recession of the superior rectus may improve downgaze through release of restriction. Frequently, a prism is required to achieve single vision in primary position or in an area of interest despite eye muscle surgery.

Access the complete reference list online at

1237

REFERENCES 1. Bielschowsky A. Die einseitigen und gegensinnigen (‘dissoziierten’) Vertikalbewegungen der Augen. Graefes Arch Ophthalmol 1930;25:493–553.

3. Wilson ME, McClatchey SK. Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus 1991;28:90–5. 4. Zubcov AA, Goldstein HP, Reinecke RD. Dissociated vertical deviation (DVD). The saccadic eye movements. Strabismus 1994;2:1–111. 5. Sprague JB, Moore S, Eggers HM, Knapp P. Dissociated vertical deviation. Treatment with the Faden operation of Cüppers. Arch Ophthalmol 1980;98:465–8. 6. Guyton DL, Cheeseman Jr EW, Ellis FJ, et al. Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc 1998;96:389–424; discussion 424-9. 7. Magoon E, Cruciger M, Jampolsky A. Dissociated vertical deviation: an asymmetric condition treated with large bilateral superior rectus recession. J Pediatr Ophthalmol Strabismus 1982;19:152–6. 8. Burke JP, Scott WE, Kutschke PJ. Anterior transposition of the inferior oblique muscle for dissociated vertical deviation. Ophthalmology 1993;100:245–50. 9. Boylan C, Clement RA, Howrie A. Normal visual pathway routing in dissociated vertical deviation. Invest Ophthalmol Vis Sci 1988;29:1165–7. 10. Parks MM. The weakening surgical procedures for eliminating overaction of the inferior oblique muscle. Am J Ophthalmol 1972;73:102–22. 11. Jampel RS, Fells P. Monocular elevation paresis caused by a central nervous system lesion. Arch Ophthalmol 1968;80:45–55. 12. Burke JP, Ruben JB, Scott WE. Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long-term stability. Br J Ophthalmol 1992;76:734–7.

15. Moore AT, Walker J, Taylor D. Familial Brown’s syndrome. J Pediatr Ophthalmol Strabismus 1988;25:202–4. 16. Zipf RF, Trokel SL. Simulated superior oblique tendon sheath syndrome following orbital floor fracture. Am J Ophthalmol 1973;75:700–5. 17. Hermann JS. Acquired Brown’s syndrome of inflammatory origin. Arch Ophthalmol 1978;96:1228–32. 18. Killian PJ, McClain B, Lawless OJ. Brown’s syndrome. An unusual manifestation of rheumatoid arthritis. Arthritis Rheum 1977;20:1080–4. 19. Wang FM, Wertenbaker C, Behrens MM, et al. Acquired Brown’s syndrome in children with juvenile rheumatoid arthritis. Ophthalmology 1984;91:23–6. 20. Roper Hall MJ. The superior oblique click syndrome. In: Mein J, Bierlaagh JJM, Brummel Kamp-Dons TE, editors. Orthoptics, Proceedings of the Second International Orthoptic Congress. Amsterdam: Excerpta Medica Foundation; 1972. 21. Girard LJ. Pseudoparalysis of the inferior oblique muscle. South Med J 1956;49:342–6. 22. Mombaerts I, Koornneef L, Everhard-Halm YS, et al. Superior oblique luxation and trochlear luxation as new concepts in superior oblique muscle weakening surgery. Am J Ophthalmol 1995;120:83–91. 23. Crawford JS, Orton R, Labow-Daily L. Late results of superior oblique muscle tenotomy in true Brown’s syndrome. Am J Ophthalmol 1980;89:824–9.

11.11  Other Vertical Strabismus Forms

2. MacDonald AI, Pratt-Johnson A. The suppression patterns and sensory adaptations to dissociated vertical divergent strabismus. Can J Ophthalmol 1974;9:113–19.

14. Brown HW. True and simulated superior oblique tendon sheath syndromes. Doc Ophthalmol 1973;34:123–36.

24. Eustis HS, O’Reilly C, Crawford JS. Management of superior oblique palsy after surgery for true Brown’s syndrome. J Pediatr Ophthalmol Strabismus 1987;24:10–16. 25. Heidary G, Engle EC, Hunter DG. Congenital fibrosis of the extraocular muscles. Semin Ophthalmol 2008;23:3–8. 26. Bonsagi ZC, Meyer DR. Internal orbital fractures in the pediatric age group – characterization and management. Ophthalmology 2000;107:829–36. 27. Wong I, Seo-Wei L, Boo-Kian K. Loop myopexy for treatment of myopic strabismus fixus. JAAPOS 2005;9:589–91.

13. Burke JP, Ruben JB, Scott WE. Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long term stability. Br J Ophthalmol 1992;76:734–7.

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PART 11 PEDIATRIC AND ADULT STRABISMUS SECTION 3 Ocular Manifestations

11.12 

Amblyopia

Gary R. Diamond, Raza M. Shah

Definition: Amblyopia is a developmental defect of spatial visual processing that occurs in the central visual pathways of the eye.

TESTS OF VERNIER ACUITY

Key features ■ ■

Decreased recognition and vernier and grating acuity Decreased contrast sensitivity and spatial localization

Associated features ■

Accentuation of the ‘crowding’ phenomenon Stable acuity behind neutral density filters ■ Mild afferent pupillary defect in severely amblyopic eyes ■ Decreased saccadic amplitudes and impaired pursuit movements ■

INTRODUCTION Amblyopia is a ‘developmental defect of spatial visual processing that occurs in the central visual pathways of the brain.’1 It presents most dramatically as loss of visual acuity in one or, rarely, both eyes, but amblyopia is more than this; certain forms of amblyopia also present with diminished contrast sensitivity, vernier acuity, grating acuity, and spatial localization of objects. These defects may be explained by the mechanism of lack of use of an eye because of media opacity or extreme refractive errors that cause a chronically blurred image to form on the fovea of that eye; however, the cause of amblyopia in an eye that has strabismus is not as straightforward and is the result of abnormal binocular interaction.

Anisometropic Amblyopia

Patients who have anisometropia and decreased visual acuity in the more ametropic eye and who possess the sensory characteristics of monofixation syndrome (Chapter 11.4) are almost always amblyopic; the decreased acuity does not improve totally with corrective lenses alone. These patients have decreased acuity, as measured using graded optotypes (Chapter 11.2), gratings, and vernier testing (Fig. 11-12-1) in the same proportion. This acuity loss extends to the peripheral visual field equally nasally and temporally, which implies uniform degradation of the visual system by an amount proportional to the anisometropia.2 As monocular visual function in the far temporal periphery of the visual field is spared, the acuity defect found in the more central field must result from, in some part, binocular interaction.3 The contrast sensitivity curve shows substantial losses at high spatial frequencies only (Fig. 11-12-2).3 Spatial localization as measured by Hess and Holliday4 is decreased in proportion to contrast sensitivity loss (see Fig. 11-12-3).

Stimulus-Deprivation Amblyopia 1238

Amblyopia that results from a media opacity of early onset in one or both eyes may be devastating visually and sometimes irreversible. Common causes include congenital or early-onset cataract, corneal

Fig. 11-12-1  Tests of vernier acuity. The vernier resolution task is to detect the offset in the grating (left) or line (right). The smallest detectable offset (threshold) is expressed as an angle at the viewing distance used. Under optimal conditions, vernier acuity may be as good as 3–6 arc seconds.

opacity from glaucoma or dystrophy, lid masses (Fig. 11-12-4), and persistent hypertrophic primary vitreous.

Strabismic Amblyopia

Amblyopia in patients who have strabismus occurs only if one eye is preferred for fixation; free alternation of fixation between the eyes is incompatible with the development of strabismic amblyopia. The fovea of the eye that is used less loses acuity in proportion to the amount of fixational preference shown to the other eye and the age of the child at onset of the preference.

EPIDEMIOLOGY AND PATHOGENESIS Anisometropic Amblyopia

The initial development of amblyopia from any cause rarely occurs in children older than about 5.5 years, but once it has developed and been reversed by therapy, it may reappear until about 9 or 10 years of age. Anisometropic amblyopia rarely occurs unless the anisometropia has been present for more than 2 years.5 Children at birth frequently have modest amounts of astigmatism equal in each eye, which disappears without permanent effect by the age of 6 months. The critical period for the development of anisometropic amblyopia in humans is not known with any precision (see later in this chapter).

Stimulus-Deprivation Amblyopia

Constant monocular occlusion of the visual axis for more than 1 week per year of life places a child at significant risk for the development of stimulus-deprivation amblyopia until about 5.5 years of age. Significant monocular congenital lens opacities (axial diameter = 3.0 mm) must be removed and the eye optically corrected at as young an age as feasible, certainly during the first few weeks of life; binocular similarly significant opacities should be removed before about 6 weeks of age.

Strabismic Amblyopia

Strabismic amblyopia may occur initially from birth to about 5.5 years of age, but even if successfully treated it may recur until about 9 or 10 years of age. The peak age for development of fixation preference in strabismic children is about 1 year of age (range 9 months to 2 years),6 but fixation preference can occur until about 8–9 years of age. Numerous publications describe successful improvement of visual acuity in

CONTRAST SENSITIVITY FOR HYPEROPTIC AND MYOPIC ANISOMETROPES Central visual field

Monocular visual field

hyperopic anisometrope

10

11.12  Amblyopia

contrast 300 sensitivity 100 (threshold–1) 30

Peripheral binocular visual field

Fig. 11-12-2  Contrast sensitivity for hyperopic and myopic anisometropes in binocular and monocular visual field. Red lines represent the amblyopic eye, blue lines the sound eye, and mauve the monocular visual field. (Data from Hess RF, Pointer JS. Differences in the neural basis of human amblyopia: the distribution of the anomaly across the visual field. Vision Res. 1985;25:1577–94.)

3 1 300

myopic anisometrope

100 30 10 3 1 0.1 0.2 0.4 0.8 1.6 3.2 6.4 10 0.1 0.2 0.4 0.8 1.6 3.2 6.4 10 0.1 0.2 0.4 0.8 1.6 3.2 6.4 10 spatial frequency (cycle/degree)

SPATIAL LOCALIZATION TEST

Fig. 11-12-3  Spatial localization test. The goal of this test is to align the middle grating between the upper and lower gratings.

OCULAR MANIFESTATIONS Anisometropic Amblyopia

The two most common forms of anisometropic amblyopia occur in anisometropic hyperopes and unilaterally high myopes. Patients who have anisometropic hyperopia exert sufficient accommodation to provide clear visual acuity in the less hyperopic eye and leave the other blurred; these patients may have better distance than near acuity in the amblyopic eye. Patients who have unilaterally high myopia often have better near than distance visual acuity. Anisometropic amblyopia may occur in patients who have monocular astigmatism alone but may be confined to a meridian in which maximal unfocusing occurs; detection of this type of ‘meridional’ amblyopia often requires special testing.

Stimulus-Deprivation Amblyopia

All forms of visual acuity (optotype, vernier, grating) are affected equally, as are spatial localization (Fig. 11-12-5) and contrast sensitivity.

Strabismic Amblyopia

Optotype visual acuity is usually worse than grating acuity,9 probably because the gratings are larger than the area suppressed under binocular viewing conditions, and distortion renders optotypes (letters, numbers, pictures) more difficult to identify than grating orientations (Fig. 11-12-6). Vernier acuity, about six times more precise than grating or optotype acuity in normal individuals and patients who have anisometropic amblyopia, is less precise in patients who have strabismic amblyopia.10 This degradation of vernier acuity occurs at both fine and coarse levels. Contrast sensitivity in strabismic amblyopes may be normal or abnormal at high spatial frequencies.4

DIAGNOSIS AND ANCILLARY TESTING

Fig. 11-12-4  Stimulus-deprivation amblyopia. A 6-month-old infant with infantile hemangioma of the right upper lid, completely covering the visual axis.

strabismic or anisometropic amblyopia in older teenagers;7 the loss of the better-sighted eye has led to spontaneous improvement in visual acuity in the remaining amblyopic eye of middle-aged adults! Perhaps the critical period for reversal of strabismic and anisometropic amblyopia really has no end.8

Amblyopia should be suspected in any strabismic child who has a preference for fixation with one eye, but it is important to recognize that many patients who have amblyopia have aligned eyes (monofixation syndrome with amblyopia). Amblyopia should also be suspected as a contributor to decreased visual acuity when the hyperopic refractive errors between the two eyes differ by more than about 2.00 D, when the myopic refractive errors differ by more than about 4.00 D, and when astigmatic errors differ by more than about 1.25 D.11 A deeply amblyopic eye ( 50 years

Bilateral

No

No

Isolated spasms of the orbicularis oculi

None in typical cases

Meige’s syndrome

F > M, 2–3 : 1

> 50 years

Bilateral

No

No

Hemifacial spasm

F > M, 3 : 2

> 45 years

Unilateral, L > R

No

Yes

Apraxia of eyelid opening; involuntary levator inhibition

—

—

—

No

—

F=M

Any

Unilateral

No

Yes

Facial tic

F=M

Childhood

Unilateral or bilateral

Yes

Yes

Usually a vascular compression of the seventh cranial nerve root Unknown; seen in extra­ pyramidal disease such as Parkinson’s, Huntington’s, Wilson’s disease, or with supranuclear palsy, and Shy–Drager syndrome 1. Uncertain 2. Multiple sclerosis, intramedullary tumor 3. Caffeine, stress Tourette syndrome

CT or MRI; must rule out a posterior fossa tumor Orbicularis oculi muscle EMG inactive; total inhibition of levator muscle

Facial myokymia

Blepharospasm plus midfacial spasm Tonic–clonic spasms in distribution of the seventh cranial nerve 1. Passive involuntary closure of eyelids; raised eyebrows; relaxed eyelids 2. Occasionally seen with essential blepharospasm Rapid undulating flicking muscles

1. Uncertain 2. Basal group ganglia 3. Brainstem Same as for BEB

Facial seizure

F=M

Any age

Unilateral

No

—

Focal cortical lesion

CT, MRI

Facial synkinesis

Equally affected

Any

Unilateral

No

Yes

Prior history of facial paralysis

EMG evidence of synkinesis, fibrillation potential, reduced motor units

BEB, benign essential blepharospasm; CT, computed tomography; EMG, electromyogram; MRI, magnetic resonance imaging.

Stereotypic movements, brief repetitive, suppressible Movements occurring with head; questionable eye deviation 1. Unilateral contracture with weakness 2. Gustatory lacrimation

Same as for BEB

EMG

None

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1 Orbit and Oculoplastics

in the lower lid alone have a pronounced effect on spasms in the lower face, thus eliminating or decreasing the dosage required in the lower face for Meige’s syndrome and hemifacial spasm. The recommended starting dosage for botulinum toxin type A is 1.25–5 units per injection site.18 If a suboptimal response occurs, the dosage should be doubled.19 More recently botulinum toxin type B (Myobloc) has been shown to be useful in cases of secondary treatment failure with toxin type A.20 Recovery of function following toxin injection results from axonal sprouting and formation of new neuromuscular junctions.17 The reported response rate to botulinum toxin is 95–98%. Antibody formation to previous or current toxin exposure may be responsible for the 2–5% failure rate with this modality and has been reported most often when high doses of toxin are used at frequent intervals.16 In cases in which antibodies are demonstrated and no response occurs to botu­ linum toxin type A, other antigenically distinct serotypes, such as type B, may be of help. The major adverse reactions to botulinum toxin include ptosis, epi­ phora, keratitis, dry eyes, and diplopia. These effects are usually tran­ sient and resolve long before the beneficial effects of the drug are exhausted. Rare complications such as transient increase in intraocular pressure and secondary biliary colic have been reported.

KEY REFERENCES Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin 2005;45:49–75. Dutton JJ. Acute and chronic, local and distant effects of botulinum toxin. Surv Ophthalmol 1996;40:51–65. Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to Botox. Ophthal Plast Reconstr Surg 2006;22:173–7. Holds JB, Anderson RL, Fogg SG, et al. Motor nerve sprouting in human orbicularis muscle after botulinum A injection. Invest Ophthalmol Vis Sci 1990;31:964–7. Jankovic J, Orman J. Blepharospasm: demographic and clinical survey of 250 patients. Ann Ophthalmol 1984;16:371–6.

COURSE AND OUTCOME

Patil B, Foss AJ. Upper lid orbicularis oculi muscle strip and sequential brow suspension with autologous fascia lata is beneficial for selected patients with essential blepharospasm. Eye 2009;23:1549–53.

As noted above, botulinum toxin currently is the initial treatment of choice for BEB. Oral pharmacological agents often are helpful as

Wilkins RH. Hemifacial spasm: a review. Surg Neurol 1991;36:251–577.

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1294

adjunctive therapy, for patients with incomplete response. Myectomy usually is reserved for individuals who respond poorly to more con­ servative therapy. Application of these various treatment modalities based on individual assessment and response characteristics usually results in a favorable prognosis for the vast majority of patients. In hemifacial spasm, in which the pathology is an abnormal com­ pression of the seventh cranial nerve root by a blood vessel, botulinum toxin is the initial treatment of choice. However, in the proper hands, neurosurgical decompression of the seventh nerve has a high success rate.21

Peckham EL, Lopez G, Shamin EA, et al. Clinical features of patients with blepharospasm: a report of 240 patients. Eur J Neurol 2011;18:382–6.

REFERENCES 1. Peckham EL, Lopez G, Shamin EA, et al. Clinical features of patients with blepharospasm: a report of 240 patients. Eur J Neurol 2011;18:382–6.

3. Jankovic J, Orman J. Blepharospasm: demographic and clinical survey of 250 patients. Ann Ophthalmol 1984;16:371–6. 4. Patrinely JR, Anderson RL. Essential blepharospasm: a review. Geriatr Ophthalmol 1986; Jul/Aug:27–33. 5. Jankovic J, Hallett M. Therapy with botulinum toxin. New York: Marcel Dekker; 1994. p. 191–7. 6. Price J, O’Day J. A comparative study of tear secretion in blepharospasm and hemifacial spasm patients treated with botulinum toxin. J Clin Neuroophthalmol 1993;13:67–71. 7. Adams WH, Digre KB, Patel BC, et al. The evaluation of light sensitivity in benign essential blepharospasm. Am J Ophthalmol 2006;142:82–7. 8. Paulson GW, Gill W. Oral and facial movements of blepharospasm. Arch Neurol 1993;25: 380–2. 9. Dutton JJ, Buckley EG. Botulinum toxin in the management of blepharospasm. Arch Neurol 1986;43:380–2. 10. Creel DJ, Holds JB, Anderson RL. Auditory brain-stem responses in blepharospasm. Electroencephalogr Clin Neurophysiol 1993;86:138–40.

12.8

13. Kerty E, Eidal K. Apraxia of eyelid opening: clinical features and therapy. Eur J Ophthalmol 2006;16:204–8. 14. Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin therapy for blepharospasm. Cochrane Database Syst Rev 2005;1:CD004900. 15. Cerinkaya A, Brannon PA. What is new in the era of focal dystonia treatment? Botulinum injections and more. Curr Opin Ophthalmol 2007;18:424–9. 16. Dutton JJ. Acute and chronic, local and distant effects of botulinum toxin. Surv Ophthalmol 1996;40:51–65. 17. Holds JB, Anderson RL, Fogg SG, et al. Motor nerve sprouting in human orbicularis muscle after botulinum A injection. Invest Ophthalmol Vis Sci 1990;31:964–7. 18. Ortisi E, Henderson HW, Bunce C, et al. Blepharospasm and hemifacial spasm: a protocol for titration of botulinum toxin dose to the individual patient and for the management of refractory cases. Eye 2006;20:916–22. 19. Pang A, O’Day J. Use of high-dose botulinum A toxin in benign essential blepharospasm: is too high too much? Clin Exp Ophthalmol 2006;34:441–4.

Essential Blepharospasm

2. Ben Simon GJ, McCann JD. Benign essential blepharospasm. Int Ophthalmol Clin 2005;45:49–75.

12. Patil B, Foss AJ. Upper lid orbicularis oculi muscle strip and sequential brow suspension with autologous fascia lata is beneficial for selected patients with essential blepharospasm. Eye 2009;23:1549–53.

20. Dutton JJ, White JJ, Richard MJ. Myobloc for the treatment of benign essential blepharospasm in patients refractory to Botox. Ophthal Plast Reconstr Surg 2006;22: 173–7. 21. Wilkins RH. Hemifacial spasm: a review. Surg Neurol 1991;36:251–577.

11. Hurwitz JJ, Kazdan M, Codere F, et al. The orbicularis stripping operation for intractable blepharospasm: surgical results in eighteen patients. Can J Ophthalmol 1986;21:167–9.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 2 Eyelids

12.9

Benign Eyelid Lesions Ann G. Neff, Keith D. Carter

Definition: Benign eyelid lesions can arise from epithelial or dermal

adnexal elements. These include epithelium, hair follicles, apocrine and eccrine glands, blood vessels and nerves. Some may appear aggressive and must be differentiated from malignancies.

Key features ■

Three times more common than malignant neoplasms. Can occur on any skin surface, some occur most often or exclusively on the eyelids. ■ May reflect local pathology or be manifestations of systemic disease. ■ Many lesions appear similar and present a diagnostic challenge. ■

Squamous Papilloma

The most common benign lesion of the eyelid is the squamous papilloma, also known as a fibroepithelial polyp, acrochordon, or skin tag. These lesions may be single or multiple and commonly involve the eyelid margin. Squamous papillomas characteristically are flesh colored and may be sessile or pedunculated (Fig. 12-9-1). Diagnosis is made by the typical clinical appearance and histological characteristics. The differential diagnosis includes seborrheic keratosis, verruca vulgaris, and intradermal nevus. Microscopically, the lesion has finger-like projections (fronds) with a fibrovascular core, and the overlying epidermis demonstrates acanthosis and hyperkeratosis. Treatment is simple excision at the base of the lesion.

Cutaneous Horn

A cutaneous horn is a projection of packed keratin (Fig. 12-9-2). This is a clinically descriptive term, not a diagnostic one. Cutaneous horn is not a distinct pathological entity, but may develop from a variety of

Associated features ■

Solid or cystic

■

Epithelial or subepithelial Often multiple ■ Confused with malignant neoplasms. ■

INTRODUCTION The eyelids may be affected by a wide spectrum of benign lesions. In studies that analyzed all eyelid lesions submitted for histopathological examination, benign lesions were 3–6 times more frequent than malignant neoplasms.1,2 Many lesions that affect the eyelids may occur on any skin surface, but some occur exclusively or more frequently on the eyelids. The more common benign eyelid lesions are presented here, classified by origin, with each discussion highlighting the important clinical features, differential diagnosis, pertinent systemic associations, histopathology, and treatment.

A

EPITHELIAL TUMORS A variety of histopathological changes that affect these layers of the epidermis may be observed within lesions affecting the eyelids. Hyperkeratosis, or thickening of the keratin layer, is seen clinically as an adherent scale. Parakeratosis is a form of hyperkeratosis characterized by incomplete keratinization, with retention of nuclei within the keratin layer. Dyskeratosis is abnormal keratinization of cells within the squamous layer. Acanthosis, or thickening of the squamous layer, is seen commonly in proliferative epithelial lesions. Acantholysis refers to separation of epithelial cells. Each type of epithelial tumor may exhibit some variability in its clinical picture and morphological features. In addition, different types of tumors may share similar clinical and morphological features, which results in clinical diagnostic confusion. A definitive diagnosis of these various lesions depends upon histopathological examination.3,4

B Fig. 12-9-1  Squamous papilloma. (A) Typical flesh-colored, pedunculated skin tag involving the left upper eyelid. (B) Fibroepithelial papilloma consists of a narrowbased (to the right) papilloma with fibrovascular core and finger-like projections covered by acanthotic, hyperkeratotic epithelium.

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12 Orbit and Oculoplastics Fig. 12-9-2  Cutaneous horn. Note the projection of packed keratin that arises from the skin in the region of the left lateral canthus. Fig. 12-9-4  Dermatosis papulosa nigra. Multiple pigmented papules involving the malar region. Fig. 12-9-3  Seborrheic keratosis. Brown, stuckon plaque, typical of seborrheic keratosis.

papillomatosis.6 Most lesions contain horn cysts, which are keratinfilled inclusions within the acanthotic epidermis, and pseudohorn cysts, which represent invaginations of surface keratin.7 Simple excision may be performed for biopsy or cosmesis, or to prevent irritation.

Inverted Follicular Keratosis

Inverted follicular keratosis, also known as basosquamous cell acanthoma, usually appears as a small, solitary, papillomatous lesion on the face. It is a well-demarcated, keratotic mass, which may appear as a cutaneous horn. The lesion may resemble verruca vulgaris and seborrheic keratosis – many consider it an irritated seborrheic keratosis.8 Histopathology reveals hyperkeratosis and lobular acanthosis. Proliferation of basaloid cells occurs with areas of acantholysis and zones of squamous cells, often arranged in whorls called squamous eddies. Treatment is complete excision, because recurrence is common after incomplete removal.

Keratoacanthoma underlying lesions, including seborrheic keratosis, actinic keratosis, inverted follicular keratosis, verruca vulgaris, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and other epidermal tumors. Because definitive therapy is dependent on the underlying cause, biopsy of the cutaneous horn (including the underlying epidermis) is required to obtain a histological diagnosis.5

Seborrheic Keratosis

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Seborrheic keratosis, also known as senile verruca, is a common benign epithelial neoplasm that may occur on the face, trunk, and extremities. These lesions usually affect middle-aged and older adults, occurring as single or multiple, greasy, stuck-on plaques (Fig. 12-9-3). Color varies from tan to brown, and the surface is frequently papillomatous. The differential diagnosis includes skin tag, nevus, verruca vulgaris, actinic keratosis, and pigmented BCC. Seborrheic keratoses are not considered premalignant lesions. A systemic association, however, known as the sign of Leser-Trélat, denotes a rapid increase in the size and number of seborrheic keratoses, which may occur in patients with occult malignancy. A variant of seborrheic keratosis, which shares a similar histopathological appearance, is dermatosis papulosa nigra, which occurs primarily in dark-skinned individuals. These lesions usually appear on the cheeks and periorbital region as multiple pigmented papules (Fig. 12-9-4). Although different histopathological types of seborrheic keratoses exist, all lesions share features of hyperkeratosis, acanthosis, and

Keratoacanthoma most commonly appears as a solitary, rapidly growing nodule on sun-exposed areas of middle-aged and older individuals. The nodule is usually umbilicated, with a distinctive central crater filled with a keratin plug (Fig. 12-9-5). The lesion develops rapidly over weeks and typically undergoes spontaneous involution within 6 months to leave an atrophic scar. Lesions that occur on the eyelids may produce mechanical abnormalities, such as ectropion or ptosis, and occasionally may cause destructive changes. The differential diagnosis includes SCC, BCC, verruca vulgaris, and molluscum contagiosum (MC). Patients with Muir–Torre syndrome may develop, in association with internal malignancy, multiple keratoacanthomas, and sebaceous neoplasms. Microscopically, there is cup-shaped elevation of acanthotic squamous epithelium that surrounds a central mass of keratin. Microabscesses, which contain necrotic keratinocytes and neutrophils, may be found within the proliferative epithelium. Cellular atypia may be present, making differentiation from SCC difficult. Many pathologists consider keratoacanthoma a type of low-grade SCC. Complete excision is recommended because an invasive variant exists, with the potential for perineural and intramuscular spread.9 Both radiotherapy and intra­ lesional fluorouracil have been advocated.10

Actinic Keratosis

Actinic keratosis, also known as solar or senile keratosis, is the most common premalignant skin lesion. The lesions develop on sun-exposed areas and commonly affect the face, hands, and scalp and, less commonly, the eyelid. They usually appear as multiple, flat-topped papules

12.9 Benign Eyelid Lesions

A

Fig. 12-9-6  Epidermal inclusion cyst. This lesion appeared as a slow-growing, cystic lesion in a region of previous penetrating trauma.

B Fig. 12-9-5  Keratoacanthoma. (A) Lesion shows typical clinical appearance; history was also typical. (A) The lesion that can be seen above the surface epithelium has a cup-shaped configuration, and a central keratin core. The base of the acanthotic epithelium is blunted (rather than invasive) at the junction of the dermis.

with an adherent white scale. The development of SCC in untreated lesions reportedly ranges as high as 20% (see Chapter 12.10).11 Microscopically, actinic keratoses display hyperkeratosis, parakeratosis, and dyskeratosis. Atypical keratinocytes in the deep epidermal layers often form buds that extend into the papillary dermis. Management is surgical excision or cryotherapy (following biopsy).

Epidermal Inclusion Cyst

Epidermal inclusion cysts appear as slow-growing, round, firm lesions of the dermis or subcutaneous tissue. Eyelid lesions are usually solitary, mobile, and less than 1 cm in diameter. These cysts usually arise from traumatic implantation of surface epidermis (Fig. 12-9-6). Cysts may become inflamed with a foreign body granulomatous reaction. Diagnosis is based on the clinical appearance and histopathology. Differential diagnosis includes dermoid cyst, pilar cyst, and neurofibroma. Microscopically, the cyst is filled with keratin and is lined by a keratinizing, stratified squamous epithelium. Adnexal structures are not present in the cyst wall.12 Treatment is complete excision, preferably of the entire cyst wall, to prevent recurrence.

Pilar Cyst

Pilar cysts, formerly known as sebaceous cysts, are smooth, round, movable dermal or subcutaneous masses, clinically identical to epidermal inclusion cysts. The differentiation within these cysts is thought to be toward hair keratin.13 These cysts tend to occur in areas with large numbers of hair follicles and are found most commonly on the scalp. They may occur occasionally in the periocular region, particularly in the brow or along the eyelid margin. Histopathology reveals an epithelium-lined cyst, with palisading of the basal layer. The lining lacks a granular layer, unlike that of epidermal cysts. Eosinophilic

Fig. 12-9-7  Dermoid cyst. Cystic, subcutaneous lesion in the right upper lid and brow region, attached to the underlying frontozygomatic suture.

material within the cyst comprises desquamated cells and keratin, and commonly calcifies. Cyst rupture may occur and incite a foreign body granulomatous response. Treatment is complete surgical excision – incomplete excision may result in recurrence.

Epidermoid and Dermoid Cysts

Although generally considered in discussions of orbital lesions (see Chapter 12.12), epidermoid and dermoid cysts are included here because they may appear as an eyelid mass. These cysts can occur as superficial, subcutaneous, or deep orbital lesions. Both are choristomas that are firm, slowly enlarging, nontender masses, most commonly in the lateral upper eyelid and brow region (Fig. 12-9-7). Superficial lesions usually are recognized during early childhood.14 These cysts presumably occur secondary to entrapment of skin along embryonic closure lines. Attachment to underlying bony sutures often is present (see Chapter 12.1). Lesions may extend posteriorly into the orbit. Microscopically, both dermoid and epidermoid cysts are lined by a stratified squamous keratinizing epithelium. Dermoid cysts also contain adnexal elements in the cyst wall, including hair follicles and sebaceous and eccrine glands. Treatment is complete surgical excision. Preoperative orbital imaging is indicated if the entire cyst cannot be palpated or if orbital extension is suspected. Complete excision eliminates the potential for cyst rupture, which can produce secondary foreign body granulomatous inflammation.

ADNEXAL TUMORS Lesions of adnexal origin arise from the epidermal appendages, which include the sebaceous glands of Zeis, meibomian glands, pilosebaceous units (consisting of hair follicles and associated sebaceous glands), eccrine sweat glands, and apocrine sweat glands of Moll.

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12 Orbit and Oculoplastics

Fig. 12-9-8  Milia. Multiple, small, white lesions that affect the upper and lower eyelids.

Fig. 12-9-9  Eccrine hidrocystoma. Cystic lesion involving the left lower eyelid margin. The lesion was filled with translucent fluid.

Benign Lesions of Sebaceous Origin

Sebaceous lesions of the eyelid may arise from several sources: the glands of Zeis, found in association with the eyelashes; the meibomian glands, located within the fibrous tarsal plates; and sebaceous glands, associated with hair follicles of the eyebrows and on the cutaneous surfaces of the eyelids. The sebaceous glands create their secretions by a holocrine mechanism, in which the central cells undergo disintegration and subsequent extrusion into a common excretory duct.

primarily in young women, occurring as multiple, small (1–3 mm diameter), skin-color to yellowish papules distributed symmetrically on the lower eyelids and cheeks. Microscopically, syringomas contain ducts lined by double-layered cuboidal epithelium, embedded in a dense fibrous stroma. The ducts may taper to a solid core of cells, to produce a comma-shaped or ‘tadpole’ configuration.16 Rarely, syringomas can undergo malignant transformation. Treatment modalities include surgical excision, electrodesiccation, and carbon dioxide laser.17

Milia

Chondroid syringoma

Milia form as multiple, firm, white lesions, which range from 1 to 4 mm in diameter. They usually appear on the face and commonly affect the eyelids, nose, and malar region (Fig. 12-9-8). Lesions may occur spontaneously or secondarily due to trauma, radiotherapy, skin infection, or bullous diseases. Occlusion of pilosebaceous units with retention of keratin is thought to be the causative mechanism. Histopathology reveals a dilated, keratin-filled hair follicle, with compression and atrophy of the adjacent sebaceous glands. Treatment includes simple incision, electrodesiccation of the surface, or puncture and expression of the contents.

Sebaceous adenoma

This uncommon lesion usually appears in the elderly as a solitary, yellow papule, with a predilection for the eyelid and brow. The importance of this and other benign sebaceous neoplasms is the association with internal malignancy, known as the Muir–Torre syndrome. Even a single cutaneous sebaceous neoplasm may be significant, so patients should be evaluated accordingly.15 Patients with this syndrome also may develop multiple keratoacanthomas. Microscopically, the sebaceous adenoma is a well-circumscribed lesion, with lobules containing an outer layer of basal germinal cells, which become lipidized centrally. Treatment is complete surgical excision, because incompletely excised lesions commonly recur.

Benign Lesions of Eccrine Origin

The eccrine sweat glands are found throughout the cutaneous surface of the eyelids. They are composed of three segments, including an intradermal secretory coil, an intradermal duct, and an intraepidermal duct.

Eccrine hidrocystoma

Eccrine hidrocystomas, also known as sudoriferous or sweat gland cysts, appear as solitary or multiple, small nodules on the eyelids. The overlying skin is shiny and smooth, and the cyst usually is translucent and fluid filled (Fig. 12-9-9). Eccrine hidrocystomas are thought to be ductal retention cysts, which tend to increase in size in hot, humid weather. The differential diagnosis includes apocrine hidrocystoma and epidermal inclusion cyst. Histopathology reveals a dermal cyst lined by a double-layered cuboidal epithelium without papillary infoldings. Treatment is complete excision.

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Syringoma

The syringoma is a common adnexal tumor arising from adenomatous proliferation of the intraepidermal duct of eccrine glands. They occur

Chondroid syringoma, also known as a pleomorphic adenoma or mixed tumor of the skin, most commonly occurs in the head and neck region and, rarely, may involve the eyelid.18 It appears as a 0.5–3 cm in diameter, asymptomatic, dermal nodule. The lesions are thought to arise from eccrine sweat glands and owe their name to the mixture of sweat gland and cartilaginous elements. Differential diagnosis includes epidermal inclusion cyst, pilar cyst, neurofibroma, and pilomatrixoma. Microscopically, it is identical to pleomorphic adenoma (mixed tumor) of the lacrimal gland. Ducts lined with an inner secretory layer and an outer myoepithelial layer are embedded in a stroma with areas of chondroid metaplasia. Treatment is surgical excision. Malignant variants have been reported.

Benign Lesions of Apocrine Origin

The apocrine glands of Moll are found along the eyelid margin in association with the eyelash follicles. They are modified sweat glands that contain a secretory coil, an intradermal duct, and an intraepithelial duct. Their secretions are produced by decapitation of the secretory cells.

Apocrine hidrocystoma

Apocrine hidrocystoma, also known as cystadenoma, usually appears as a solitary, translucent cyst on the face, sometimes at the eyelid margin. The cyst is usually small (less than 1 cm in diameter) and filled with clear or milky fluid, with shiny, smooth overlying skin (Fig. 12-910). Lesions may display a bluish coloration, attributed to the Tyndall effect. Unlike the eccrine variety, these lesions are thought to be proliferative in origin and do not increase in size in hot weather. The differential diagnosis includes eccrine hidrocystoma and cystic BCC. An association has been reported, thought to represent an ectodermal dysplasia, in which patients display multiple apocrine hidrocystomas, hypodontia, palmar-plantar hyperkeratosis, and onychodystrophy.19 Histopathology reveals a dermal cyst with papillary infoldings, lined by an inner secretory layer with eosinophilic columnar cells and an outer myoepithelial layer. Treatment is usually by complete excision. Larger or multiple lesions may be treated by chemical ablation with trichloroacetic acid.20

Cylindroma

Cylindroma, presumably of apocrine origin, may occur on the eyelid or brow. It usually appears as a dome-shaped, skin-colored, or pinkish-red, dermal nodule (Fig. 12-9-11). Solitary lesions usually occur in adulthood in the head and neck region and may appear similar to a pilar or epidermal inclusion cyst. Multiple lesions are inherited in an

12.9 Benign Eyelid Lesions

Fig. 12-9-10  Apocrine hidrocystoma. Cystic lesion, filled with milky fluid, involving the right lower eyelid margin. Fig. 12-9-12  Pilomatrixoma. Reddish nodule arising from the left lower eyelid.

transformation to BCC exist.22 Treatment includes surgical excision of solitary lesions and cryosurgery or laser for multiple lesions.

Trichofolliculoma

Trichofolliculoma is a fairly well differentiated hamartomatous lesion, usually appearing as an asymptomatic, solitary, flesh-colored nodule during adulthood on the face or scalp. A central umbilication usually is present, which is the opening of a keratin-filled follicle. Small white hairs may protrude from the central pore and are suggestive of the diagnosis. The lesion may be confused clinically with a pilar cyst, nevus, or BCC. Histopathology reveals a dilated follicle, filled with keratin and hair shafts, and lined by stratified squamous epithelium continuous with the epidermis. Surgical excision is curative.

Trichilemmoma

Fig. 12-9-11  Cylindroma. Multiple, pinkish-red dermal nodules involving the eyelids, forehead, nose, and malar region.

autosomal dominant fashion and usually appear on the scalp, where extensive involvement is referred to as a turban tumor. Multiple lesions have been associated with trichoepitheliomas. Microscopically, the cylindroma consists of islands with large, pale-staining cells centrally and small, cuboidal cells peripherally, surrounded by an eosinophilic basement membrane. Treatment is surgical excision.

Benign Lesions of Hair Follicle Origin

Benign lesions of hair follicle origin are rather rare tumors, often confused clinically with BCC, the most common malignant eyelid lesion. Confirmation of diagnosis by incisional biopsy is helpful for suspiciouslooking lesions, which allows less extensive resection of lesions confirmed as benign.21

Trichoepithelioma

Trichoepithelioma is a tumor of hair follicle origin with a predilection for the face. The solitary lesion tends to occur in older individuals as an asymptomatic, flesh-colored to yellowish, firm papule that rarely ulcerates. Multiple lesions, also known as multiple benign cystic epithelioma or Brooke’s tumor, are inherited in an autosomal dominant pattern with variable penetrance. Lesions appear during adolescence as multiple firm nodules involving the face, and also the scalp, neck, and trunk. They may increase in size and number, but rarely ulcerate. Diagnosis is made by the clinical appearance, family history, and histopathology. Differential diagnosis includes basal cell nevus syndrome, in which lesions tend to ulcerate more frequently (see Chapter 12.10). Histopathology reveals multiple, keratin-filled horn cysts surrounded by islands of basaloid cells that display peripheral palisading. The abundant fibrous stroma is well demarcated from the surrounding dermis. Lesions may histologically resemble BCC, and rare reports of

Trichilemmoma is a tumor that arises from the outer hair sheath. A solitary lesion generally appears during adulthood as an asymptomatic, flesh-colored, nodular, or papillomatous lesion. The nose is the most common site of occurrence, followed by the eyelid and the brow. The lesion may appear as a cutaneous horn or may resemble verruca vulgaris or BCC. Multiple trichilemmomas are a marker for Cowden’s disease, or multiple hamartoma syndrome, a rare genodermatosis inherited in an autosomal dominant fashion. In addition to the facial trichilemmomas, patients may develop acral keratoses and oral papillomas. Patients are at increased risk of developing breast and thyroid carcinoma, as well as multiple hamartomas. The mucocutaneous lesions usually precede the onset of malignancy. Microscopically, glycogen-rich cells with clear cytoplasm proliferate in lobules, with peripheral palisading and a distinct basement membrane. Hair follicles may be present. Treatment is surgical excision, cryosurgery, or laser.

Pilomatrixoma

The pilomatrixoma, also known as the calcifying epithelioma of Malherbe, is a benign tumor of hair matrix origin.23 The lesion tends to occur in children and young adults on the head and upper extremities. Lesions may occur in the periorbital region, particularly the upper eyelid and brow.24 Usually a solitary lesion, it appears as a solid or cystic, mobile, subcutaneous nodule with normal overlying skin. It is firm, irregular, often reddish blue, and may contain chalky white nodules (Fig. 12-9-12). Histopathology reveals islands of basophilic epithelial cells, which transform into shadow cells located more centrally. Most tumors contain masses of calcified shadow cells, which may incite a giant cell granulomatous response. Rare cases of malignant transformation have been reported. Treatment is surgical excision.

VASCULAR TUMORS Capillary Hemangioma

The capillary hemangioma, also known as a benign hemangioendothelioma, is a common vascular lesion of childhood. It occurs in 1–2% of infants and is the most common orbital tumor found in children. Girls

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12 Orbit and Oculoplastics

A

endothelial cells diminished in number. As regression takes place, progressive fibrosis occurs, with thickening of the fibrous septa and replacement of endothelial lobules by adipose tissue. Atrophy of the vascular component of the lesion eventuates. Because most capillary hemangiomas undergo spontaneous regression to some extent, treatment generally is reserved for patients who have specific ocular, dermatologic, or systemic indications for intervention. Various management modalities have been advocated, each with potential significant risks, which are beyond the scope of this discussion. Ocular indications include amblyopia, compressive optic neuropathy, and proptosis with globe exposure. Treatment modalities include intralesional corticosteroid injection,26 systemic corticosteroids, radiotherapy, laser therapy, systemic interferon, and surgery. More recently, systemic propranolol has been shown to induce significant regression of lesions in the proliferative phase.27,28 Surgery should be considered for localized, noninfiltrative lesions, or for those that fail to respond medically.29 Amblyopia should be treated with appropriate patching and spectacle correction, as indicated.

Cavernous Hemangioma

Cavernous hemangioma is the most common benign orbital tumor of adults (only occasionally occurring as a primary eyelid lesion); the lesions usually appear during adulthood and normally do not undergo spontaneous regression. Superficial skin lesions are dark blue, compressible and, unlike the orbital variety, not encapsulated. The differential diagnosis includes lymphangioma, with associated hemorrhage, and varices. A rare syndrome exists, termed the blue rubber bleb nevus syndrome, which is characterized by multiple cutaneous lesions consistent with cavernous hemangiomas, associated with gastrointestinal hemangiomas that often bleed. Histologically, cavernous hemangiomas contain dilated, endothelium-lined vascular spaces, often with thrombosis and phlebolith formation. Treatment is surgical excision.

Lymphangioma

B Fig. 12-9-13  Capillary hemangioma. (A) Superficial, raised, red mass involving the right upper eyelid and medial canthal region. (B) High magnification of endothelial cells.

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are more commonly affected than boys, with a 3 : 2 ratio. A periorbital hemangioma may appear as a superficial cutaneous lesion, subcutaneous lesion, deep orbital tumor, or combination of these types. Approximately one-third of lesions are visible at birth, with the remainder manifest by 6 months of age. There is typically an initial rapid growth phase within 6 months of diagnosis, followed by a period of stabilization and subsequent involution over several years. It is estimated that approximately 75% regress to some extent by the time the child reaches 7 years of age. The classic superficial lesion, the strawberry nevus, appears as a red, raised, nodular mass that blanches with pressure (Fig. 12-9-13). It may first be seen as a flat lesion with telangiectatic surface vessels. A subcutaneous lesion appears as a bluish-purple, spongy mass. Deep orbital lesions may cause proptosis and globe displacement, with no associated cutaneous findings. The most common ocular complication is amblyopia, which may result from occlusion of the visual axis, or from anisometropia due to induced astigmatism. Strabismus may occur secondary to the amblyopia or be caused by orbital involvement with restriction of ocular motility.25 Lesions that involve the eyelid and anterior orbit usually can be diagnosed by clinical findings. The differential diagnosis of orbital lesions includes rhabdomyosarcoma, neuroblastoma, encephalocele, lymphangioma, and inflammatory masses (see Chapter 12.12). Ultrasonography, computed tomography, and magnetic resonance imaging may aid in diagnosis and in determining the extent of involvement (see Chapter 12.3). Microscopically, the early proliferative phase of the lesion contains lobules of plump endothelial cells separated by fibrous septa, with frequent mitotic figures and small, irregular vascular lumina. Mature lesions contain more prominent vascular structures and flatter

Lymphangiomas may involve the eyelid, conjunctiva, or orbit.30 Lesions often appear at birth or early in childhood, and only occasionally in adulthood. They often are poorly circumscribed, with an infiltrative growth pattern. Eyelid involvement may occur as a superficial lesion with multiple cyst-like excrescences, or as a complex of channels that cause lid thickening and distortion. Hemorrhage into the lesion may occur, to produce a hematoma when the eyelid is involved or proptosis when orbital lesions are present (see Chapter 12.12). Biopsy may be needed for definitive diagnosis. Microscopically, dilated, thin-walled vascular spaces lined by endothelial cells are present. Surgical excision is indicated for cosmesis, or eyelid malposition. Large lesions may be difficult to manage due to extensive infiltration. Carbon dioxide laser is a useful modality when excision is required.

Nevus Flammeus

Nevus flammeus, also known as a port-wine stain, presents as a flat, purple, vascular lesion, usually unilateral and in the distribution of a branch of the trigeminal nerve (Fig. 12-9-14). It is congenital and does not undergo spontaneous regression. If associated with ocular and leptomeningeal vascular hamartomas, it represents the Sturge–Weber syndrome. Ocular manifestations of this syndrome include diffuse choroidal hemangioma, ipsilateral glaucoma, and serous retinal detachment. Histopathology of the skin lesion reveals dilated, telangiectatic capillaries within the dermis. Management is primarily with cosmetics. Tunable dye laser therapy also may be used to improve the appearance of the lesion.31

Pyogenic Granuloma

Pyogenic granuloma is the most common acquired vascular lesion to involve the eyelids. It usually occurs after trauma or surgery as a fastgrowing, fleshy, red-to-pink mass, which readily bleeds with minor contact (Fig. 12-9-15). Lesions also may develop in association with inflammatory processes, including chalazia. The differential diagnosis includes Kaposi’s sarcoma and intravascular papillary endothelial hyperplasia, a rare endothelial proliferation. Microscopically, there is granulation tissue consisting of fibroblasts and blood vessels, with acute and chronic nongranulomatous inflammatory cells. Notably, a pyogenic granuloma is neither pyogenic nor granulomatous. Treatment is by surgical excision at the base of the lesion.

Fig. 12-9-14  Nevus flammeus. Flat, purple, vascular lesion involving the skin of the face.

12.9 Benign Eyelid Lesions

Fig. 12-9-16  Neurofibroma. Note the fleshy mass on the eyelid of this patient with disseminated cutaneous neurofibromas.

Fig. 12-9-17  Plexiform neurofibroma. Note the ptosis and typical S-shaped curvature of the upper lid.

TUMORS OF NEURAL ORIGIN A

B Fig. 12-9-15  Pyogenic granuloma. (A) Red mass arising from the palpebral conjunctiva and protruding over the eyelid margin. This lesion developed in association with a chalazion. (B) Vascularized tissue (granulation tissue) that consists of inflammatory cells (polymorphonuclear lymphocytes and fibroblasts) and the endothelial cells of budding capillaries.

Neurofibroma

Neurofibromas most commonly are considered in the context of neurofibromatosis, in which patients often develop multiple cutaneous lesions in association with other stigmata of the disease, usually apparent by adolescence.32 The neurofibromas may occur on any cutaneous surface, including the eyelid, and typically enlarge slowly over many years. They appear as soft, fleshy, often pedunculated masses (Fig. 12-9-16). Isolated cutaneous neurofibromas, often resembling intradermal nevi, also may occur in individuals with no other associated abnormality. The plexiform neurofibroma, characteristic of type 1 neurofibromatosis, often occurs as a diffuse infiltration of the eyelid and orbit. The upper eyelid is usually ptotic, with an S-shaped curvature (Fig. 12-917). On palpation, the lesion feels like a ‘bag of worms.’ Histopathology reveals units of proliferating axons, Schwann cells, and fibroblasts, with each unit surrounded by a perineural sheath. Management depends on the site and extent of disease. Isolated cutaneous lesions, unrelated to neurofibromatosis, may be excised surgically. Surgical debulking may be performed for plexiform neurofibromas that produce mechanical ptosis or cosmetic deformity. However, due to the infiltrative nature of these lesions, complete excision is usually impossible and recurrence is common.

XANTHOMATOUS LESIONS Xanthomatous lesions are characterized by the presence of histiocytes that have accumulated lipid, resulting in a foamy appearance of the cytoplasm histologically.

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12 Orbit and Oculoplastics Fig. 12-9-19  Freckles. Multiple, tan-brown, small macules, involving the skin of sunexposed areas. Fig. 12-9-18  Xanthelasma. Multiple, soft, yellow plaques involving the lower eyelid. Lipid-laden foam cells seen in dermis and tend to cluster around blood vessels.

Xanthelasma

Xanthelasma palpebrarum is the most common cutaneous xanthoma, typically occurring in middle-aged and older adults as soft, yellow plaques on the medial aspect of the eyelids (Fig. 12-9-18). The diagnosis often can be made clinically. Hyperlipidemia is reported to occur in approximately 50% of patients with xanthelasma,33 therefore lipid serum screening is recommended. Type IIa is the most commonly associated hyperlipidemia. The differential diagnosis of atypical lesions includes Erdheim–Chester disease, a systemic xanthogranulomatous disorder, which has lesions that typically appear more indurated. Microscopically, xanthelasmas are composed of foamy, lipid-laden histiocytes (xanthoma cells) clustered around blood vessels and adnexal structures within the superficial dermis. Surrounding fibrosis and inflammation may be observed. Treatment modalities include surgical excision, carbon dioxide laser ablation, and topical trichloroacetic acid. Recurrence is common.

Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG), also known as nevoxanthoendothelioma, is a benign histiocytic proliferation that most commonly affects the skin. It occurs mainly in children less than 2 years of age and usually appears within the first year of life. The skin lesions mostly appear in the head and neck region as elevated orange, red, or brown nodules. They typically increase in size and number initially, but subsequently regress spontaneously into an atrophic scar over months to years. Lesions that appear in adulthood are more likely to persist and often require treatment to induce regression. The most common site of extracutaneous involvement is the eye, with a predilection for the iris.34 The iris may contain localized vascular nodules or diffuse infiltration of tumor. Complications include hyphema, uveitis, and glaucoma, with resulting visual loss and phthisis. Treatment, which includes topical and subconjunctival corticosteroids, is recommended for intraocular lesions,35 because they rarely regress spontaneously and complications are common. Biopsy of skin lesions helps to confirm the clinical diagnosis in patients who have cutaneous disease alone and in patients who have suspicious eye findings associated with skin lesions. Microscopically, lesions contain an infiltrate of lipid-laden histiocytes, lymphocytes, eosinophils, and Touton giant cells. Fibrosis appears in older lesions. Skin lesions may be treated by excision or, if necessary, corticosteroid injection.

PIGMENTED LESIONS OF MELANOCYTIC ORIGIN 1302

Skin lesions of melanocytic origin arise from one of three cell types:  Epidermal, or dendritic, melanocytes, which lie between the basal cells of the epidermis.

 Nevus cells, or nevocytes, which usually form nests of cells within the epidermis.  Dermal, or fusiform, melanocytes, which lie in the subepithelial tissues. Melanocytes are derived from neural crest cells. Epidermal melanocytes produce melanin, which is transferred to surrounding epidermal cells, with tanning and racial pigmentation resulting from this process.

Freckles

Freckles, also known as ephelides, arise from epidermal melanocytes. They appear as small (1–3 mm in diameter), tan-to-brown macules in sun-exposed areas, including the eyelids (Fig. 12-9-19). Freckles occur more commonly in light-complected individuals and darken with sun exposure. These lesions reflect melanocytic overactivity, not proliferation. Microscopically, hyperpigmentation occurs within the basal layer of the epidermis. No treatment is necessary, but sunscreen may help prevent further darkening of lesions.

Lentigo Simplex

Lentigo simplex is another epidermal melanocytic lesion that may appear on skin and mucous membranes as small, brown macules. They usually appear during childhood and are unaffected by sun exposure. Lesions may be solitary and have an appearance similar to that of junctional nevi. Multiple lesions may be a manifestation of a systemic syndrome, such as Peutz–Jeghers syndrome. Patients who have this syndrome develop multiple lesions, often periocular and perioral in distribution, in association with gastrointestinal polyps, which may undergo malignant transformation. Multiple lesions may resemble freckles, but do not change in pigmentation with sun exposure as freckles often do. Microscopically, lentigo simplex has hyperpigmentation along the basal layer of the epidermis, with an increased number of melanocytes. Elongation of the rete ridges occurs along with mild lymphocytic infiltration of the superficial dermis. Intervention is not required, because these lesions are thought to have no malignant potential.

Solar Lentigo

Lesions of solar lentigo, also of epidermal melanocytic origin, are tanto-brown macules found commonly in sun-exposed areas of older individuals. They also are known as senile lentigines, but may occur in younger individuals after prolonged sun exposure. These lesions also are found commonly in patients who have xeroderma pigmentosum, often appearing during the first decade of life. Lesions usually have slightly irregular borders, but are evenly pigmented. Initially, lesions are a few millimeters in diameter, but slowly increase in size. They may resemble junctional nevi and seborrheic keratoses. Lesions should be differentiated from lentigo maligna, a premalignant condition, which usually has variable pigmentation and more prominent border

Melanocytic Nevi

Melanocytic nevi, also known as nevocellular nevi, are derived from nevocytes. They are extremely common lesions, especially in faircomplected individuals.36,37These lesions frequently occur on the eyelid skin and eyelid margin. The clinical appearance often is predictive of the histological type, which may be junctional, compound, or intradermal. Lesions typically occur during childhood as small, flat, tan macules that gradually increase in size radially. Nests of nevus cells are found within the epidermis, at the dermal–epidermal junction, representing a junctional nevus. As the lesion ceases to increase in diameter in older children and young adults, nests of cells ‘drop off ’ into the dermis, forming a compound nevus. Clinically, compound nevi are slightly elevated and pigmented. Lesions further evolve as the remaining epidermal nests migrate into the dermis, to produce an intradermal nevus. This lesion, most common in adults, may be dome-shaped, pedunculated, or papillomatous, and usually is less pigmented or amelanotic (Fig. 12-9-20). Later in life, as the nevus cells induce fibroplasia within the dermis, the cells decrease in number and are replaced by normal dermal tissue. Diagnosis usually is based on the typical clinical appearance. Malignant transformation may occur rarely, generally in the junctional or

compound stages. Thus, suspicious-looking lesions that demonstrate irregular growth or appearance should be excised. Otherwise, removal of common nevi is not required, unless desired for cosmesis or relief of mechanical irritation.

Congenital Melanocytic Nevus

These lesions are derived from nevocytes and occur in approximately 1% of newborns. Lesions may be single or multiple, and usually are deeply pigmented. The border often is irregular and the surface may be covered with hair. Congenital nevi that appear in a symmetrical fashion on adjacent portions of the upper and lower eyelids are referred to as kissing nevi and are formed as a result of melanocytic migration to the lids prior to separation of the embryonic eyelids (Fig. 12-9-21). The size of congenital nevi is critical in management, because large lesions are associated with a higher risk of malignant transformation. Controversy exists regarding the definition of ‘large’ and ‘small’ congenital nevi. Large lesions in the head and neck region commonly are defined as those greater than or equal to the area of the patient’s palm. The risk of malignant transformation is estimated at 5%. Histologically, congenital nevi display a variety of patterns. Many lesions contain features of compound nevi, with nevus cells in the dermis and the dermal–epidermal junction. Nevus cells often extend into the deep dermis and subcutaneous tissue. Malignant melanoma usually develops within the deep dermis, which makes early diagnosis difficult. Thus, any suspicious-looking lesion should be sampled for biopsy. Large lesions should be excised, but complete excision is impossible in some patients due to the size and extent of the lesion. The management of small lesions is controversial – some advocate excision of all congenital nevi.38

12.9 Benign Eyelid Lesions

irregularity and notching. Biopsy should be performed on suspiciouslooking lesions. Histologically, solar lentigo lesions display hyperpigmentation of the basal layer of the epidermis, with proliferation of melanocytes. More extensive elongation of the rete ridges is found in comparison with lentigo simplex. Treatment is not required, unless desired for cosmetic reasons.36

Nevus of Ota

Nevus of Ota, or oculodermal melanocytosis, arises from dermal melanocytes. The lesion appears as a blue-to-purple, mottled discoloration of the skin in the distribution of the ophthalmic and maxillary divisions of the trigeminal nerve. It is usually congenital and unilateral and frequently is associated with ipsilateral ocular melanocytosis involving the conjunctiva, sclera, and uveal tract. Diagnosis is based on the typical clinical appearance.39 Histopathology reveals pigmented, dendritic melanocytes throughout the dermis. Malignant degeneration may occur, particularly in whites, with the choroid the most common site of involvement.40 Periodic dilated fundus examination, thus, is recommended.

Blue Nevus

A

The blue nevus appears as a solitary blue nodule, usually less than 1 cm in diameter. The differential diagnosis includes melanoma, pigmented BCC, and vascular lesions. Microscopically, the lesion is composed of pigmented dendritic melanocytes and melanophages scattered throughout the dermis, often with fibrosis of adjacent tissue. The cellular blue nevus is a lesion that also arises from dermal melanocytes. It is less common and usually larger than the blue nevus,

B Fig. 12-9-20  Intradermal nevus. (A) Elevated, papillomatous lesion, amelanotic in color, involving the eyelid margin. (B) Nests of nevus cells fill the dermis except for a narrow area just under the epithelium. The nuclei of the nevus cells become smaller, thinner or spindle-shaped, and darker as they go deeper into the dermis (i.e., they show normal polarity).

Fig. 12-9-21  Kissing nevus. Congenital melanocytic nevus in a symmetrical fashion on adjacent portions of the upper and lower eyelids.

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12 Orbit and Oculoplastics

and appears as a solitary blue papule. Histologically, the lesion contains pigmented dendritic melanocytes interspersed with pale spindle cells. This lesion occasionally may become malignant and metastasize to regional lymph nodes. Excision of these lesions may be performed for definitive diagnosis or cosmesis.

INFLAMMATORY LESIONS Chalazion

A chalazion is a focal inflammatory lesion of the eyelid that results from the obstruction of a sebaceous gland, either meibomian or Zeis. Extravasated lipid material produces a surrounding chronic lipogranulomatous inflammation. A chalazion may occur acutely with eyelid edema and erythema and evolve into a nodule, which may point anteriorly to the skin surface or, more commonly, towards the posterior surface of the lid. The lesion may drain spontaneously or persist as a chronic nodule, usually a few millimeters from the eyelid margin. Lesions also may appear insidiously as firm, painless nodules (Fig. 12-9-22). Chalazia often occur in patients with blepharitis and rosacea. These lesions may be mistaken for other more serious lesions such as malignancies.41 Diagnosis is based on the typical clinical features. Acute lesions appear similar to hordeola in appearance – differentiation is nearly

impossible to make clinically. In recurrent or atypical lesions, a sebaceous gland carcinoma needs to be excluded; thus, histopathological examination is important. Histopathology reveals lipogranulomatous inflammation, with clear spaces corresponding to lipid, surrounded by foreign body giant cells, epithelioid cells, neutrophils, lymphocytes, plasma cells, and eosinophils. A fibrous pseudocapsule may form around a lesion. Treatment varies according to the stage of a lesion. Acute lesions are treated with hot compresses to encourage localization and drainage. Chronic chalazia may be treated using intralesional corticosteroid injection or surgical drainage. Vertical transconjunctival incisions allow adequate exposure of lesions and limit damage to surrounding meibomian glands. Small chalazia, which may resolve spontaneously, can be removed with incision and curettage.

Hordeolum

A hordeolum is an acute purulent inflammation of the eyelid. An external hordeolum, or stye, results from inflammation of the follicle of a cilium and the adjacent glands of Zeis or Moll. The lesion typically causes pain, edema, and erythema of the eyelid, which becomes localized and often drains anteriorly through the skin near the lash line (see Fig. 12-9-22). An internal hordeolum occurs due to obstruction and infection of a meibomian gland. Initially, a painful edema and erythema localizes as an inflammatory abscess on the posterior conjunctival surface of the tarsus. In both external and internal lesions, cellulitis of the surrounding soft tissue may develop. Diagnosis is based on the clinical appearance and culture, with Staphylococcus aureus most frequently isolated. Hordeola frequently occur in association with blepharitis. Histopathology reveals an abscess or a focal collection of polymorphonuclear leukocytes and necrotic tissue. Although the inflammatory process usually is self-limited, with drainage and resolution occurring within 5–7 days, hot compresses and topical antibiotics help confine the spread of the lesion. Rarely, incision and drainage are necessary. Systemic antibiotics are used only if significant cellulitis exists. Treatment of accompanying blepharitis is helpful to prevent the formation of new lesions.

INFECTIOUS LESIONS Molluscum Contagiosum

A

B

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Fig. 12-9-22  Chalazion and external hordeolum. (A) The medial lesion of the upper eyelid appeared as a firm, painless nodule, consistent with a chalazion. The lateral lesion caused pain and eyelid erythema, subsequently becoming more localized, with drainage of purulent material through the skin surface. (B) A clear, circular area surrounded by epithelioid cells and multinucleated giant cells can be seen. In processing the tissue, lipid is dissolved out, leaving a clear space.

A common viral skin disease, molluscum contagiosum (MC) is caused by a large DNA pox virus. Infection usually arises from direct contact or fomites in children and by a sexually transmitted route in adults. The typical lesion appears as a raised, shiny, white-to-pink nodule with a central umbilication filled with cheesy material. Lesions may be single or multiple, but usually fewer than 20 are present. Eyelid margin lesions may produce a secondary follicular conjunctival reaction. Other ocular manifestations include epithelial keratitis, pannus formation, conjunctival scarring, and punctal occlusion. Primary conjunctival or limbal lesions occur rarely. Diagnosis of MC usually is based on the clinical appearance of the lesion. Biopsy rarely is required in an otherwise healthy individual. The differential diagnosis includes keratoacanthoma, verruca vulgaris, squamous papilloma, milia, and SCC or BCC (see Chapter 12.10). Patients who have acquired immunodeficiency syndrome (AIDS) often have an atypical clinical picture of MC. Disseminated disease may be present and lesions often are more confluent. Patients may have 30–40 lesions on each eyelid, or a confluent mass (Fig. 12-9-23). Secondary keratoconjunctivitis develops less frequently. Histopathology of MC shows invasive acanthosis, with lobules of epithelial hyperplasia invaginating into the dermis. The epithelium at the surface degenerates and sloughs into a central cavity, which opens through a pore to the epidermal surface. Intracytoplasmic inclusions containing virions, referred to as molluscum bodies, are round and eosinophilic in the lower layers of the epidermis. These inclusions increase in size and are more basophilic in the granular and horny layers. Usually, MC spontaneously resolves within 3–12 months, but the patient may be treated to prevent corneal complications, reduce transmission, and speed recovery. Various treatment options exist, including simple incision or excision, incision and curettage, cryosurgery, and electrodesiccation. Management is more difficult in patients with AIDS because of extensive involvement and recurrences. Hyperfocal cryotherapy has been effective in these patients.42

12.9 Benign Eyelid Lesions

A

Fig. 12-9-24  Verruca vulgaris. Skin-colored, irregular lesion with a papillomatous surface appearing on the upper eyelid.

CONCLUSION

B Fig. 12-9-23  Molluscum contagiosum. (A) Multiple raised nodules, with areas of confluent lesions, affecting the eyelids of a patient with AIDS. (B) Intracytoplasmic, small, eosinophilic molluscum bodies occur in the deep layers of epidermis. The bodies become enormous and basophilic near the surface. The bodies may be shed into the tear film where they cause a secondary, irritative, follicular conjunctivitis.

The eyelids may be affected by a variety of benign lesions, some indicative of local pathology, others associated with or resulting from systemic pathology. Some lesions may be identified readily by the clinical appearance and behavior. However, many pose a diagnostic challenge. Most important is the differentiation of benign from malignant lesions, because management often differs. Biopsy with ocular pathology consultation is, thus, warranted for any suspicious-looking lesion.3 Epithelial lesions that display painless growth, irregular or pearly borders, ulceration, induration, or telangiectasis should raise concern for malignancy. Signs that herald malignant change in pigmented lesions include irregular borders, asymmetrical shape, color change or presence of multiple colors, recent changes, or diameter greater than 5 mm. In general, biopsy should precede all extensive tumor resections, even if the clinical diagnosis seems apparent. An incisional biopsy should be performed for the diagnosis of large lesions prior to definitive therapy. Small lesions may be excised for both diagnosis and treatment.

OUTCOMES Most benign eyelid lesions have an excellent prognosis. The treatment varies according to site, diagnosis, concurrent systemic involvement, and other factors.

KEY REFERENCES Verruca Vulgaris

Verruca vulgaris, or the common cutaneous wart, is caused by epidermal infection with the human papillomavirus, which is spread by direct contact and fomites. Verruca vulgaris is more common in children and young adults and may occur anywhere on the skin, occasionally on the eyelid. Lesions appear elevated with an irregular, hyperkeratotic, papillomatous surface (Fig. 12-9-24). Lesions along the lid margin may induce mild papillary conjunctivitis due to shedding of virus particles into the tear film. Patients also may develop a superficial punctate keratitis and may have pannus formation. Primary conjunctival lesions also may occur.43 Diagnosis is based on the typical appearance and is confirmed by biopsy. Histologically, papillomatosis is present, with hyperkeratosis, acanthosis, and parakeratosis. Large, vacuolated keratinocytes are seen, with deeply basophilic nuclei surrounded by a clear halo. Observation is recommended if no ocular complications occur, because most lesions are self-limiting. Treatment, if necessary, is either cryotherapy or complete surgical excision. Incomplete excision may cause multiple recurrences.

Access the complete reference list online at

Aurora AL, Blodi FC. Lesions of the eyelids: a clinicopathological study. Surv Ophthalmol 1970;15:94–104. Bardenstein DS, Elmets C. Hyperfocal cryotherapy of multiple molluscum contagiosum lesions in patients with the acquired immune deficiency syndrome. Ophthalmology 1995;102:1031–4. Dutton JJ, Gayre GS, Proia AD. Diagnostic atlas of common eyelid diseases. New York: Informa Healthcare; 2007. El-Essaw R, Galal R, Abdelbaki S. Nonselective β-blocker propranolol for orbital and periorbital hemangiomas in infants: a new first-line treatment? Clin Ophthalmol 2011;5:1639–44. Fridman G, Grieser E, Hill R, et al. Propranolol for the treatment of orbital infantile hemangiomas. Ophthal Plast Reconstr Surg 2011;27:190–4. Grossniklaus HE, Wojno TH, Yanoff M, et al. Invasive keratoacanthoma of the eyelid and ocular adnexa. Ophthalmology 1996;103:937–41. Margulis A, Adler N, Bauer BS. Congenital melanocytic nevi of the eyelids and periorbital region. Plast Reconstr Surg 2009;124:1273–83. Mencia-Guterrez E, Gutierrez-Diaz E, Redondon-Marcos I, et al. Cutaneous horns of the eyelid: a clinicopathological study of 48 cases. J Cutan Pathol 2004;31:539–43. Ozdal PC, Codere F, Callejo S, et al. Accuracy of the clinical diagnosis of chalazion. Eye 2004;18:135–8. Scharf BH. Viral eyelid infections. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea. Vol. II: Cornea and external disease: clinical diagnosis and management. St Louis, MO: Mosby–Year Book; 1997. p. 641–51.

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3. Deokule S, Child V, Tarin S, et al. S. Diagnostic accuracy of benign eyelid skin lesions in the minor operation theater. Orbit 2003;22:235–8. 4. Dutton JJ, Gayre GS, Proia AD. Diagnostic atlas of common eyelid diseases. New York: Informa Healthcare; 2007. 5. Mencia-Guterrez E, Gutierrez-Diaz E, Redondon-Marcos I, et al. Cutaneous horns of the eyelid: a clinicopathological study of 48 cases. J Cutan Pathol 2004;31:539–43. 6. Kobalter AS, Roth A. Benign epithelial neoplasms. In: Mannis MJ, Macsai MS, Huntley AC, editors. Eye and skin disease. Philadelphia: Lippincott–Raven; 1996. p. 345–55. 7. Cribier B. Seborrheic keratosis. Ann Dermatol Venerol 2005;132:292–5. 8. Lever WF. Inverted follicular keratosis is an irritated seborrheic keratosis. Am J Dermatopathol 1983;5:474. 9. Grossniklaus HE, Wojno TH, Yanoff M, et al. Invasive keratoacanthoma of the eyelid and ocular adnexa. Ophthalmology 1996;103:937–41. 10. Boynton JR, Searl SS, Caldwell EH. Large periocular keratoacanthoma: The case for definitive treatment. Ophthalmic Surg 1986;17:565–9. 11. Scott KR, Kronish JW. Premalignant lesions and squamous cell carcinoma. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Clinical practice, vol. 3. Philadelphia: WB Saunders; 1994. p. 1733–44. 12. Folberg R. Eyelids: study of specific conditions. In: Folberg R, editor. Pathology of the eye [CD-ROM]. St Louis, MO: Mosby–Year Book; 1996. 13. Campbell RJ. Tumors of the eyelids, conjunctiva. In: Garner A., Klintworth GK, editors. Pathobiology of ocular disease: a dynamic approach, Part B. 2nd ed. New York: Marcel Dekker; 1994. p. 1367–403. 14. Weiss RA. Orbital disease. In: McCord CD, Tanenbaum M., Nunery WR, editors. Oculoplastic surgery. 3rd ed. New York: Raven Press; 1995. p. 417–76. 15. Jakobiec FA, Zimmerman LE, La Piana F, et al. Unusual eyelid tumors with sebaceous differentiation in the Muir–Torre syndrome. Ophthalmology 1988;95:1543–8. 16. Ni C, Dryja TP, Albert DM. Sweat gland tumors in the eyelids: a clinicopathological analysis of 55 cases. Int Ophthalmol Clin 1982;22:1–22. 17. Nerad JA, Anderson RL. CO2 laser treatment of eyelid syringomas. Ophthal Plast Reconstr Surg 1988;4:91–4. 18. Mandeville JT, Roh JH, Woog JJ, et al. Cutaneous benign mixed tumor (chondroid syringoma) of the eyelid: clinical presentation and management. Ophthal Plast Reconstr Surg 2004;20:110–16. 19. Alessi E, Gianotti R, Coggi A. Multiple apocrine hidrocystomas of the eyelids. Br J Ophthalmol 1997;137:642–5. 20. Dailey RA, Saunlay SM, Tower RN. Treatment of multiple apocrine hidrocystomas with trichloroacetic acid. Ophthal Plast Reconstr Surg 2005;21:148–50. 21. Simpson W, Garner A, Collin JRO. Benign hair-follicle derived tumours in the differential diagnosis of basal-cell carcinoma of the eyelids: a clinicopathological comparison. Br J Ophthalmol 1989;73:347–53.

23. Yap EY, Hoberger GG, Bartley GB. Pilomatrixoma of the eyelids and eyebrows in children and adolescents. Ophthal Plast Reconstr Surg 1999;15:185–9. 24. Orlando RG, Rogers GL, Bremer DL. Pilomatrixoma in a pediatric hospital. Arch Ophthalmol 1983;101:1209–10. 25. Haik BG, Karcioglu ZA, Gordon RA, et al. Capillary hemangioma (infantile periocular hemangioma). Surv Ophthalmol 1994;38:399–426. 26. Kushner B. Intralesional corticosteroid injection for infantile adnexal hemangioma. Am J Ophthalmol 1982;93:496–506. 27. Fridman G, Grieser E, Hill R, et al. Propranolol for the treatment of orbital infantile hemangiomas. Ophthal Plast Reconstr Surg 2011;27:190–4. 28. El-Essaw R, Galal R, Abdelbaki S. Nonselective β-blocker propranolol for orbital and periorbital hemangiomas in infants: a new first-line treatment? Clin Ophthalmol 2011;5:1639–44. 29. Walker RS, Custer PL, Nerad JA. Surgical excision of periorbital capillary hemangiomas. Ophthalmology 1994;101:1333–40.

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2. Deprez M, Uffer S. Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature. Am J Dermatopathol 2009;31:256–62.

22. Sternberg I, Buckman G, Levine MR, et al. W. Trichoepithelioma. Ophthalmology 1986;93:531–3.

30. Pang P, Jakobiec FA, Iwamoto T, et al. Small lymphangiomas of the eyelids. Ophthalmology 1984;91:1278–84. 31. Tan OT, Gilchrest BA. Laser therapy for selected cutaneous vascular lesions in the pediatric population: a review. Pediatrics 1988;82:652–62. 32. Woog JJ, Albert DM, Solt LC, et al. Neurofibromatosis of the eyelid and orbit. Int Ophthalmol Clin 1982;22:157–87. 33. Rohrich RJ, Janis JE, Pownell PH. Xanthalasma palpebrarum: a review and current management principles. Plast Reconstr Surg 2002;110:1310–14. 34. Kuruvilla R, Escaravage GK, Dinn AJ, et al. Infiltrative subcutaneous xanthogranuloma of the eyelid in a neonate. Ophthal Plast Reconstr Surg 2009;25:330–2. 35. Casteels I, Olver J, Malone M, et al. Early treatment of juvenile xanthogranuloma of the iris with subconjunctival steroids. Br J Ophthalmol 1993;77:57–60. 36. Desjardins L. Benign pigmented lesions of the eyelids. J Fr Ophthalmol 2005;28:889–95. 37. Margulis A, Adler N, Bauer BS. Congenital melanocytic nevi of the eyelids and periorbital region. Plast Reconstr Surg 2009;124:1273–83. 38. Ritz M, Corrigan B. Congenital melanocytic nevis of the eyelids and periorbital region. Plast Reconstr Surg 2010;125:1568–9. 39. Swann PG, Kwong E. The naevus of Ota. Clin Exp Optom 2010;93:264–7. 40. Dutton JJ, Anderson RL, Schelper RL, et al. Orbital malignant melanoma and oculodermal melanocytosis: report of two cases and review of the literature. Ophthalmology 1984;91:497–507. 41. Ozdal PC, Codere F, Callejo S, et al. Accuracy of the clinical diagnosis of chalazion. Eye 2004;18:135–8. 42. Bardenstein DS, Elmets C. Hyperfocal cryotherapy of multiple molluscum contagiosum lesions in patients with the acquired immune deficiency syndrome. Ophthalmology 1995;102:1031–4. 43. Scharf BH. Viral eyelid infections. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea. Vol. II: Cornea and external disease: clinical diagnosis and management. St Louis, MO: Mosby–Year Book; 1997. p. 641–51.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 2 Eyelids

12.10 

Eyelid Malignancies

Gregory J. Vaughn, Richard K. Dortzbach, Gregg S. Gayre

Definition: Cutaneous cancers that arise from the epidermis, dermis,

or adnexal structures of the eyelid. Rarely they may be metastatic from distant sites. They include a number of histologically distinct tumors from diverse skin cell types.

Key features ■

Flat, eroded, or elevated lesion on the eyelid margin, eyelid skin, or brow ■ Nodular and well circumscribed or irregular with indistinct borders ■ Ulcerated with a central crater or benign in appearance with some telangiectatic vessels ■ Slow, generally painless, growth

Associated features ■ ■ ■ ■ ■ ■ ■ ■ ■

Dilated blood vessels Ectropion from skin contracture Firm induration Loss of eyelashes Palpable preauricular nodes Proptosis Ptosis Restricted ocular motility Thickened eyelid margin

EPIDEMIOLOGY AND PATHOGENESIS BCC is the most common malignant tumor of the eyelids and constitutes 85–90% of all malignant epithelial eyelid tumors at this site.1,2 Over 99% of BCCs occur in whites; about 95% of these lesions occur between the ages of 40 and 79 years, with an average age at diagnosis of 60 years.3 Rarely, they also may be seen in children.4 BCC arises from a pleuripotential stem cell in the epidermis that proliferates, amplifies, and eventually terminally differentiates.5 Proposed mechanisms for BCC invasion include enhanced tumor cell motility and collagenase content.1 Having had one BCC is a prognostic factor for the development of additional lesions.

OCULAR MANIFESTATIONS Up to 50–60% of BCCs affect the lower eyelid. The medial canthus is involved 25–30% of the time. The upper eyelid is involved nearly 15% of the time and the lateral canthus is only rarely involved (5%). On the basis of their histopathological presentation, BCCs may be classified into five basic types:  Nodular-ulcerative  Pigmented  Morphea or sclerosing  Superficial  Fibroepithelioma. Two additional, although very rare, types are the linear basal cell nevus and generalized follicular basal cell nevus.6 The nodular type of BCC, the most common lesion, has the classical appearance of a pink or pearly papule or nodule with overlying telangiectatic vessels. As the nodule grows in size, central ulceration may occur surrounded by a rolled border (Fig. 12-10-1). This appearance is often described as a ‘rodent ulcer.’ The pigmented BCC is similar to the noduloulcerative type in morphology but with brown or black pigmentation. These lesions represent

INTRODUCTION Malignant lesions are common around the eyes, partly because many are induced by sun exposure or develop from sun-related benign lesions. Typically, most of these are small and grow slowly, which results in minimal concern for the patient and a low index of suspicion for the physician. Although the most common malignancies rarely metastasize, they can all be very destructive locally. Any periocular lesion that shows some growth, especially when associated with chronic irritation or bleeding, should undergo biopsy for diagnosis. Confirmation of histopathology is also mandatory before committing the patient to a major resection or reconstructive procedure.

BASAL CELL CARCINOMA

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Basal cell carcinoma (BCC) is a malignant tumor derived from cells of the basal layer of the epidermis. The etiology is linked to excessive ultraviolet light exposure in fair-skinned individuals. Other predisposing factors include ionizing radiation, arsenic exposure, and scars. Although metastases are rare, local invasion is common and can be very destructive.

Fig. 12-10-1  Nodular basal cell carcinoma of the eyelid. A firm, pink-colored left upper eyelid BCC is seen with raised border, superficial telangiectatic vessels, and characteristic central ulceration. These lesions are more commonly seen on the lower eyelid. (Courtesy of Dr Morton Smith.)

DIAGNOSIS The diagnosis of BCC is initially made from its clinical appearance, especially with the noduloulcerative type with its raised pearly borders and central ulcerated crater. Definitive diagnosis, however, can be made only on histopathological examination of biopsy specimens.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of BCC and of other periocular malignant lesions may be divided into several categories: other malignant lesions, premalignant lesions, benign adnexal tumors and cysts, and inflammatory and infectious conditions (Table 12-10-1; see Chapter 12.9).8 In many cases the diagnosis depends upon histopathology.

Palmar and plantar pits also develop in young adulthood. The BCCs in this syndrome typically develop at puberty and have a predilection for the periorbital region and face.3 Multiple lesions occur with a high rate of recurrence. Other rare BCC syndromes include Bazex’s syndrome, linear unilateral basal cell nevus, and Rombo syndrome. Also, BCC may be associated with albinism, xeroderma pigmentosum, and nevus sebaceus.

PATHOLOGY The BCCs may be grouped as either undifferentiated or differentiated by their histopathological appearance.6 The typical histopathology of an undifferentiated BCC consists of nests, lobules, and cords of tumor cells with peripheral palisading of cells and stromal retraction (Fig. 12-10-2). Undifferentiated BCCs include the solid noduloulcerative, morphea or sclerosing, pigmented, superficial, and fibroepithelioma forms. The morphea or sclerosing form is characterized by strands of proliferating, malignant basal cells in a fibrous stroma (Fig. 12-10-3). The adenoid and metatypical or basosquamous are the most common differentiated forms. These tumors differentiate toward glandular structures with mucinous stroma. They exhibit morphological features between those of basal cell and squamous cell carcinoma. The metatypical BCCs are more aggressive and invasive with a higher recurrence rate and potential for metastasis.11

12.10  Eyelid Malignancies

the most common pigmented malignancy on the eyelids and may resemble malignant melanoma. The morphea or sclerosing type of BCC appears as a flat, indurated, yellow–pink plaque with ill-defined borders. It may simulate a blepharitis or dermatitis. As it has a flat appearance, it may not be as clinically noticeable as others. However, this form of BCC is aggressive and may invade the dermis deeply. It characteristically occurs in the medial canthal region and may invade into the paranasal sinuses and orbit. Superficial BCC appears as an erythematous, scaling patch with a raised pearly border. Fibroepithelioma BCC presents as a pedunculated or sessile smooth, pink nodule. Both the superficial and fibroepithelioma types typically arise on the trunk rather than the eyelid.7

SYSTEMIC ASSOCIATIONS Basal cell nevus syndrome (Gorlin–Goltz syndrome) is inherited as an autosomal dominant disorder with high penetrance and variable expressivity. Basal cell nevus syndrome is rare, occurring in less than 1% of individuals with BCC.9 The group of clinical findings described in 1960 as a syndrome by Gorlin and Goltz10 includes:  Multiple BCCs affecting the face, trunk, and extremities  Cysts of the jaw (odontogenic keratocysts)  Skeletal abnormalities (e.g., bifid ribs)  Neurological abnormalities (e.g., mental retardation, ectopic calcification, cerebellar medulloblastoma)  Endocrine disorders (e.g., ovarian cysts and testicular disorders).7

TABLE 12-10-1  DIFFERENTIAL DIAGNOSIS OF PERIOCULAR MALIGNANCIES Simulating Lesion Basal cell carcinoma Malignant melanoma Sebaceous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma in situ Actinic keratosis Radiation dermatitis Keratoacanthoma Cavernous hemangioma Cutaneous horns Dermoid and sebaceous cysts Eccrine and apocrine cysts Inverted follicular keratosis Nevus cell and nevocellular nevi, pigmented lesions of epidermal and dermal melanocyte origin Papillomatous lesions Pseudoepitheliomatous hyperplasia Seborrheic keratosis nevus Trichilemmoma Blepharitis Chalazion Eczema Fungal infections Hordeolum Psoriasis Seborrheic dermatitis Superior limbic keratoconjunctivitis Verruca vulgaris Conjunctival hemorrhage

BCC X X X X X X X X X X

X X X X X X X X

SCC

SGC

X

X

X X X

Fig. 12-10-2  Nodular basal cell carcinoma of the eyelid. Basophilic nests of proliferating epithelial tumor cells are shown with characteristic peripheral, palisading nuclei and stromal reaction. (Courtesy of Dr Morton Smith.)

X

X

X

X X X X X

MM

X X

X X

X

X

X

BCC, basal cell carcinoma; MM, malignant melanoma; SCC, squamous cell carcinoma; SGC, sebaceous gland carcinoma.

X

Fig. 12-10-3  Morphea or sclerosing type of basal cell carcinoma of the eyelid. Strands and islands of basaloid cells are shown within a dense connective tissue matrix. (Courtesy of Dr Morton Smith.)

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TREATMENT

Orbit and Oculoplastics

The goal of therapy is the complete removal of tumor cells with preservation of unaffected eyelid and periorbital tissues. Although nonsurgical treatments such as cryotherapy, electrodesiccation, and laser ablation are advocated by some,12 surgical therapy is generally accepted as the treatment of choice for removal of BCCs.13 Some BCCs, especially the morphea and multicentric types, may extend far beyond the area that is apparent clinically. Recurrences are generally more aggressive, infiltrative, and destructive than the primary tumor.2 Therefore, histological monitoring of tumor margins is essential. Mohs’ micrographic surgery and excisional biopsy with frozen section control are the two basic techniques available. An incisional biopsy may be performed prior to definitive treatment to confirm the clinical suspicion of BCC.14

Surgery

Mohs’ micrographic surgery provides the highest cure rate with the most effective preservation of normal tissue.15,16 Tissue is excised in layers that provide a three-dimensional mapping of the excised tumor. These layers are processed as frozen sections and viewed under the microscope. Any areas of residual tumor are identified, and the map is used to direct additional tumor excision.17,18 This technique is particularly useful for morphea and multicentric-type BCCs in the medial canthal region, which may exhibit subclinical extension to orbital bone or sinuses. Mohs’ micrographic surgery technique is somewhat limited if the tumor has extended to the plane of orbital fat. In addition, it requires the collaboration of a trained Mohs’ surgeon and a dermatopathologist. Excisional biopsy with frozen section control is also an effective way to remove BCCs and can be performed by the ophthalmologist. Several studies have reported no recurrences after excision of BCCs with frozen section monitoring.19,20 However, following simple excisional biopsy without frozen section control, recurrence rates up to 50% have been reported.21 Eyelid reconstruction should be performed within 2–3 days after tumor excision. Various reconstructive surgical techniques may be used depending upon the location and size of the residual defect (see Chapter 12.11).

Radiation Therapy

Radiation therapy is generally not recommended in the initial treatment of periocular BCCs.22 However, it may be useful in the treatment of advanced or recurrent lesions in the medial canthal region or elsewhere. Doses are in the range 4000–7000 cGy.23 Radiation therapy is less effective in treating morphea BCCs, with the likelihood of BCC recurrence following radiotherapy being higher than that for previously described surgical techniques. A recurrence rate of 12% was noted in one series following radiation therapy.24 Surgical management is very difficult after radiation treatment of an affected area. Radiotherapy complications include skin atrophy and necrosis, madarosis, cicatricial entropion and ectropion, dry eye syndrome, cataract, and corneal ulceration.25 Radiation therapy is contraindicated in basal cell nevus syndrome and is associated with significant complications in patients who have scleroderma or acquired immunodeficiency syndrome (AIDS).

Cryotherapy

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syndrome). However, long-term follow-up of patients treated with this modality is not yet available.27

COURSE AND OUTCOME Complete surgical excision of BCCs is almost always curative, because these lesions rarely metastasize. Incomplete primary resection is the main risk factor for recurrence of tumor, and is especially more common with a medial canthal location or morpheaform histology.28 The incidence of metastasis ranges from 0.028 to 0.55%.7 Tumor-related death is exceedingly rare, but when it does occur, it is usually caused by direct orbital and intracranial extension.

SQUAMOUS CELL CARCINOMA Squamous cell carcinoma (SCC) is a malignant tumor of the squamous layer of cells of the epidermis. It is much less common than BCC on the eyelids and carries a greater potential for metastatic spread.29,30

EPIDEMIOLOGY AND PATHOGENESIS Typically, SCC affects elderly, fair-skinned individuals. In the region of the eye it is usually found on the lower eyelid. Although SCC is 40 times less common than BCC of the eyelid, it is more common than BCC on the upper eyelid and lateral canthus.31 The exact mechanism of the pathogenesis of SCC is not known. However, environmental and intrinsic stimuli initiate a process in which cell growth and regulation are lost. Most periorbital SCCs arise from actinic lesions, but they may also arise de novo. Environmental factors may contribute to the development of SCC, including cumulative ultraviolet radiation (sun exposure), ionizing radiation, arsenic ingestion, psoralen plus ultraviolet A (PUVA) therapy for psoriasis, and the human papilloma virus.32 Intrinsic factors that contribute to the development of SCC include the autosomal recessive conditions xeroderma pigmentosum and oculocutaneous albinism. Chronic skin dermatoses, ulceration, and scarring are also associated with the development of this tumor. In fact, scarring of the skin is the most common intrinsic factor leading to SCC in black patients.33

OCULAR MANIFESTATIONS Typically, SCC presents as an erythematous, indurated, hyperkeratotic plaque or nodule with irregular margins. These lesions have a high tendency toward ulceration and tend to affect the eyelid margin and medial canthus. Lymphatic spread and perineural invasion are possible.

DIAGNOSIS The diagnosis of SCC is often suspected from the clinical appearance. However, because so many other malignant and benign processes can be confused with SCC, the diagnosis requires biopsy for histological confirmation.

PATHOLOGY

Cryotherapy is often used to treat BCCs outside the periorbital area. Around the eyelids it may be used to treat eyelid notching and malpositions, symblepharon formation with fornix foreshortening, and pigmentary changes. It is associated with a higher recurrence rate than the surgical approaches. Cryotherapy is contraindicated in lesions greater than 1 cm in diameter, medial canthal lesions, morphea-like lesions, and recurrent BCC.26

Well-differentiated SCC exhibits polygonal cells with abundant eosinophilic cytoplasm and hyperchromatic nuclei (Fig. 12-10-4). Dyskeratosis, keratin pearls, intercellular bridges, and abnormal mitotic figures are prominent. Poorly differentiated lesions show little keratinization and fewer intercellular bridges.7

Chemotherapy and Photodynamic Therapy

TREATMENT

Topical, intralesional, and systemic chemotherapeutic agents, including 5-fluorouracil, cisplatinum, doxorubicin, bleomycin, and interferon, have been used to treat BCCs. However, these agents are generally not recommended for tumors in the periorbital region.3 Photodynamic therapy may be considered as an alternative treatment for large numbers of cutaneous BCCs (e.g., basal cell nevus

Before planning any therapy, the clinical diagnosis of SCC should be confirmed by incisional biopsy.34 Compared with BCC, SCC is a more aggressive and invasive tumor, but early SCC lesions of the eyelid rarely metastasize. Surgery, irradiation, and cryotherapy management options are similar to those described previously for BCC.

12.10  Eyelid Malignancies

Fig. 12-10-4  Squamous cell carcinoma of the eyelid. Anaplastic squamous cells with hyperchromatic nuclei, abundant eosinophilic cytoplasm, and intercellular bridges. (Courtesy of Dr Morton Smith.)

Fig. 12-10-5  Sebaceous cell carcinoma of the eyelid. A large, firm, irregular nodule with yellowish coloration of the left upper eyelid is shown. Associated inflammation, telangiectatic vessels, and loss of cilia are observed. (Courtesy of Dr Morton Smith.)

COURSE AND OUTCOME Wide local surgical excision, either with the Mohs’ technique or under frozen section control, is usually curative. Advanced cases may be associated with metastasis to the preauricular and submandibular lymph nodes, which heralds a more guarded prognosis. Invasion of the deep orbital tissues may sometimes be seen and frequently requires orbital exenteration for cure.

SEBACEOUS GLAND CARCINOMA Sebaceous gland carcinoma (SGC) is a highly malignant neoplasm that arises from the meibomian glands, the glands of Zeis, and the sebaceous glands of the caruncle and eyebrow. It is an aggressive tumor with a high recurrence rate, a significant metastatic potential, and a notable mortality rate.35–37

EPIDEMIOLOGY AND PATHOGENESIS Although it is relatively rare, SGC is the third most common eyelid malignancy, accounting for 1–5.5% of all eyelid cancers. It affects all races, occurs in women more often than men, and usually presents in the sixth to seventh decades, but cases in younger patients have been reported.38 The cause of SGC is unclear. However, there are reported associations that link SGC with prior radiation therapy39 and with the production of nitrosamines and photosensitization from prior diuretic use.40

OCULAR MANIFESTATIONS The upper eyelid is the site of origin in about two-thirds of all cases, but SGC may arise from any of the periocular structures previously mentioned7 and may have a variety of clinical appearances. It often presents as a firm, yellow nodule that resembles a chalazion. It may present as a plaque-like thickening of the tarsal plate with destruction of meibomian gland orifices and tumor invasion of eyelash follicles leading to madarosis, or loss of lashes (Fig. 12-10-5). Also, SGC may mimic a chronic blepharoconjunctivitis, meibomianitis, or chalazion that does not respond to standard therapies, thus the term ‘masquerade syndrome.’ SGC tends to invade overlying epithelium, which may form nests of malignant cells (pagetoid spread), or it may result in diffuse spread that replaces the entire thickness of the conjunctiva (intraepithelial carcinoma). The carcinoma may exhibit multicentric spread to the other eyelid, conjunctiva, or corneal epithelium.7 This neoplasm may spread through the canaliculus to the lacrimal excretory system and even to the nasal cavity.40

Fig. 12-10-6  Sebaceous cell carcinoma of the eyelid. Large, hyperchromatic neoplastic cells with vacuolated (frothy), basophilic cytoplasm are observed. (Courtesy of Dr Morton Smith.)

DIAGNOSIS The clinical appearance of SGC must be confirmed by a full-thickness wedge biopsy of the affected eyelid. Because of potential multicentric spread, multiple biopsy specimens should also be taken from the adjacent bulbar and palpebral conjunctiva and the other ipsilateral eyelid. The pathologist should be alerted to the clinical suspicion of SGC, and fresh tissue should be submitted to pathology so that special lipid stains may be performed on the specimen to confirm the diagnosis.41

PATHOLOGY Dysplasia and anaplasia of the sebaceous lobules in the meibomian glands are exhibited by SGC, with associated destruction of tarsal and adnexal tissues. Intraepithelial (pagetoid) spread to conjunctiva distant from the primary tumor may be observed. The intraepithelial spread may resemble SCC in situ. Typically, SGC shows highly pleomorphic cells arranged in lobules or nests with hyperchromatic nuclei and vacuolated (foamy or frothy) cytoplasm due to a high lipid content (Fig. 12-10-6). Histologically, SGC may resemble the appearance of SCC. However, the cytoplasm in SGC tends to be more basophilic compared with the eosinophilic appearance of SCC. Also, SCC cells tend not to exhibit a regular, lobular arrangement. Four histological patterns have been described: lobular, comedocarcinoma, papillary, and mixed. Special stains for lipid (e.g., oil red O) on fresh tissue may assist in the histopathological diagnosis of SGC (Fig. 12-10-7).7

TREATMENT Successful treatment of SGC depends largely upon heightened clinical suspicion and awareness of the possible masquerade syndrome

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12 Orbit and Oculoplastics

Fig. 12-10-7  Lipid stain (oil red O) of sebaceous gland carcinoma. Tumor cells stain strongly positive (red) for lipid. (Courtesy of Dr Morton Smith.)

followed by early confirmatory biopsy. Wide surgical excision with microscopic monitoring of the margins is the procedure of choice.42 Mohs’ micrographic surgical excision may be used, but it may not be as successful as in BCC or SCC because of the possibility of multicentric and pagetoid spread. If the tumor is very large or recurrent with demonstrated spread to bulbar conjunctiva, to the other eyelid, or to orbital tissues, a subtotal or complete exenteration may be necessary.3,40 If evidence of spread to regional lymph nodes is present, the patient should be referred to a head and neck surgeon for possible lymph node or radical neck dissection. Radiation therapy may be considered as an adjunct to local surgery. However, primary treatment of the tumor with irradiation alone is inadequate. Recurrence of tumor usually occurs within 3 years following radiotherapy alone.43

COURSE AND OUTCOME An invasive, potentially lethal tumor, SGC may cause extensive local destruction of eyelid tissues. It carries a risk of metastasis to preauricular and submandibular lymph nodes or may spread hematogenously to distant sites. It may invade locally into the globe, the orbit, the sinuses, or the brain. Early reports demonstrated a high (30%) tumor-related mortality rate.39 More recent reviews show a much lower mortality rate, attributed to heightened clinical suspicion and early diagnosis of the tumor. Histologic confirmation of complete excision with clear margins confers a better prognosis.44 Nonmetastatic disease has a 0–15% mortality rate. However, the presence of distant metastases carries a very poor prognosis with a 50–67% 5-year mortality.38,39

MALIGNANT MELANOMA Cutaneous malignant melanoma is an invasive proliferation of malignant melanocytes. Melanoma may also arise from the conjunctiva, where it constitutes a distinct entity (see Chapter 4.8). Cutaneous malignant melanoma may be classified into four different types:7  Lentigo maligna melanoma (5%)  Superficial spreading melanoma (70%)  Nodular melanoma (16%)  ‘Other,’ including acral lentiginous melanoma (9%) Nodular melanoma is the most common type to affect the eyelids.45

EPIDEMIOLOGY AND PATHOGENESIS

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Cutaneous malignant melanoma of the eyelid accounts for about 1% of all eyelid malignancies.46 The incidence of malignant melanoma has been increasing, and it causes about two-thirds of all tumor-related deaths from cutaneous cancers. The incidence increases with age but remains relatively stable from the fifth to the seventh decades.47 Risk factors for the development of malignant melanoma include congenital and dysplastic nevi, changing cutaneous moles, excessive sun exposure and sun sensitivity, family history (genetic factors), age greater than 20 years, and white race. Malignant melanoma is 12 times

Fig. 12-10-8  Lentigo maligna melanoma (Hutchinson freckle). Clinical appearance of acquired pigmented lesion of the left lower lid.

more common in whites than in blacks and 7 times more common in whites than in Hispanics. In contrast to BCC, a history of severe sunburns rather than cumulative actinic exposure is thought to be a major risk factor for developing malignant melanoma.47 Cutaneous malignant melanoma arises from the neoplastic transformation of intraepidermal melanocytes derived from the neural crest. Initially, a noninvasive horizontal growth phase occurs, which is followed by an invasive vertical growth phase.

OCULAR MANIFESTATIONS Lentigo maligna melanoma and its precursor lentigo maligna (melanotic freckle of Hutchinson) present as a flat macule with irregular borders and variable pigmentation. It may have a long in situ (horizontal growth) phase, in which the pigmentation extends for up to several centimeters in diameter and lasts many years. This phase is associated with variable growth and spontaneous regression of the lesion with alteration in pigmentation. It typically occurs in sun-exposed areas and commonly involves the lower eyelid and canthi (Fig. 12-10-8). Superficial spreading melanoma is typically a smaller pigmented lesion with mild elevation and irregular borders. It tends to have a more rapid progression to the invasive phase, characterized by development of nodules and induration. Nodular melanoma may present as a markedly pigmented or amelanotic nodule that rapidly increases in size with associated ulceration and bleeding. Acral lentiginous melanoma occurs on the palms, soles, and distal phalanges as well as on the mucous membranes.7,47

DIAGNOSIS The diagnosis of cutaneous malignant melanoma is made by clinical suspicion and confirmed with excisional biopsy and histopathological examination.

SYSTEMIC ASSOCIATIONS The dysplastic nevus syndrome (also known as B–K mole syndrome) is an autosomal dominantly inherited condition characterized by multiple, large, atypical cutaneous nevi.48 The moles appear in childhood and continue to grow through adulthood. Patients with this syndrome have a high risk of developing malignant melanoma.49

PATHOLOGY Lentigo maligna is hyperpigmentation in the epidermis characterized by a diffuse hyperplasia of atypical melanocytes throughout the basal cell layer. The entity is regarded as lentigo malignant melanoma when dermal invasion occurs during the transition to the vertical growth phase (Fig. 12-10-9). Superficial spreading melanoma is typified by atypical melanocytes that occur in nests or singly throughout all levels of the epidermis. Pagetoid spread into the epidermis is characteristic. A

mixture of epithelioid, spindle, and nevus-like cells may be present. In nodular melanoma, dermal invasion is always present; it exhibits large, anaplastic epithelioid cells.

TREATMENT Wide surgical excision, with 1 cm of skin margins (when possible) confirmed by histological monitoring, is the procedure of choice for treatment of cutaneous malignant melanoma of the eyelid. Regional lymph node dissection should be performed for tumors greater than 1.5 mm in depth and/or for tumors that show evidence of vascular or lymphatic spread. A metastatic evaluation is also recommended for patients who have such tumors. Cryotherapy may be useful in treating some conjunctival malignant melanomas, but it is not an effective treatment option for cutaneous malignant melanoma of the eyelid.45 More recently, topical 5% imiquimod has shown some encouraging results for periocular lentigo maligna.50

COURSE AND OUTCOME Prognosis and metastatic potential are linked to the depth of invasion and thickness of the tumor. Clark and associates51 correlated prognosis with depth of invasion, characterized at five levels:

12.10  Eyelid Malignancies

Fig. 12-10-9  Malignant melanoma. Subepithelial pigmented, spindle-shaped melanoma cells invade the dermis. (Courtesy of Dr Morton Smith.)

 Level 1: tumor confined to the epidermis with an intact basement membrane  Level 2: tumor extension beyond the basement membrane with early invasion of the papillary dermis  Level 3: tumor fills the papillary dermis and reaches the interface between the papillary and reticular dermis  Level 4: tumor penetrates the reticular dermis  Level 5: tumor invasion of the subcutaneous tissues For lentigo maligna melanoma in levels 1 and 2 there is a 100% survival rate after therapy, whereas for nodular melanoma extending to level 4 there is a 65% survival rate following treatment. The survival drops dramatically to only 15% with extension of any type to level 5.52 Breslow53 related prognosis to tumor thickness − malignant melanomas less than 0.76 mm thick are associated with a 100% 5-year survival rate after excision; tumors greater than 1.5 mm in thickness are associated with a less than 50% 5-year survival rate. Therefore, nodular melanoma has the worst prognosis and lentigo maligna melanoma has the most favorable prognosis of all tumor types. The Clark and Breslow systems may be used in conjunction to predict the prognosis for patients with malignant melanoma. In a review by Tahery et al.,54 malignant melanoma involving the eyelid margin was found to have a poorer prognosis than eyelid malignant melanoma that did not affect the margin. This worse prognosis was attributed to conjunctival involvement in the eyelid margin tumors.

KEY REFERENCES Barnes EA, Dickenson AJ, Langtry JA, et al. The role of Mohs excision in periocular basal cell carcinoma. Br J Ophthalmol 2005;89:992–4. Berman AT, Rengan R, Tripuraneni P. Radiotherapy for eyelid, periocular, and periorbital skin cancers. Int Ophthalmol Clin 2009;49:129–42. Boulos PR, Rubin PA. Cutaneous melanomas of the eyelid. Semin Ophthalmol 2006;21:195–206. Margo CE, Waltz K. Basal cell carcinoma of the eyelid and periocular skin. Surv Ophthalmol 1993;38:169–92. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol 2005;50:103–22. Song A, Carter KD, Syed NA, et al. Sebaceous cell carcinoma of the ocular adnexa: clinical presentations, histopathology, and outcomes. Ophthal Plast Reconstr Surg 2008;24:194–200. Sullivan TJ. Squamous cell carcinoma of eyelid, periocular, and periorbital skin. Int Ophthalmol Clin 2009;49:17–24. Tahery DP, Goldberg R, Moy RL. Malignant melanoma of the eyelid: a report of eight cases and a review of the literature. J Am Acad Dermatol 1992;27:17–21. Thosani MK, Schneck G, Jones EC. Periocular squamous cell carcinoma. Dermatol Surg 2008;34:585–99. Tildsley J, Diaper C, Herd R. Mohs surgery vs primary excision for eyelid BCCs. Orbit 2010;29: 140–5.

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3. Haas AF, Kielty DW. Basal cell carcinoma. In: Mannis MJ, Macsai MS, Huntley AC, editors. Eye and skin disease. Philadelphia, PA: Lippincott–Raven; 1996. p. 395–403. 4. Al-Buloushi A, Filho JP, Cassie A, et al. Basal cell carcinoma of the eyelids in children: a report of three cases. Eye 2005;19:1313–14. 5. Cotsarelis G, Cheng S, Dong D. Existence of slow cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 1989;57:201–9. 6. Lever WF, Schaumburg-Lever G. Tumors of the epidermal appendages. In: Histopathology of the skin. 7th ed. Philadelphia, PA: JB Lippincott; 1990. p. 578–650. 7. Font RL. Eyelids and lacrimal drainage system. In: Spencer WH, editor. Ophthalmic pathology: an atlas and textbook. 4th ed. Vol. 4. Philadelphia, PA: WB Saunders; 1996. p. 2218–433. 8. Yanoff M, Fine BS. Skin and lacrimal drainage system. In: Yanoff M, Fine BS, editors. Ocular pathology. Hagerstown: Harper & Row; 1975:177–232. 9. Kahn LB, Gordon W. Nevoid basal cell carcinoma syndrome. S Afr Med J 1967;41:832–5. 10. Gorlin RJ, Goltz RW. Multiple nevoid basal cell epithelioma, jaw cysts and bifid rib, a syndrome. N Engl J Med 1960;262:908–12. 11. Borel DM. Cutaneous basosquamous carcinoma. Review of the literature and report of 35 cases. Arch Pathol 1973;95:293–7. 12. Murchison AP, Walrath JD, Washigton CV. Non-surgical treatments of primary, nonmelanoma eyelid malignancies: a review. Clin Exp Ophthalmol 2011;30:65–83. 13. Mannor GE, Chern PL, Barnette D. Eyelid and periorbital skin basal cell carcinoma: oculoplastic management and surgery. Int Ophthalmol Clin 2009;49:1–16. 14. Warren RC, Nerad JA, Carter KD. Punch biopsy technique for the ophthalmologist. Arch Ophthalmol 1990;108:778–9. 15. Barnes EA, Dickenson AJ, Langtry JA, et al. The role of Mohs excision in periocular basal cell carcinoma. Br J Ophthalmol 2005;89:992–4. 16. Tildsley J, Diaper C, Herd R. Mohs surgery vs primary excision for eyelid BCCs. Orbit 2010;29:140–5. 17. Waltz K, Margo CE. Mohs’ micrographic surgery. Ophthalmol Clin North Am 1991;4:153–63. 18. Mohs FE. Micrographic surgery for microscopically controlled excision of eyelid tumors. Arch Ophthalmol 1986;104:901–9. 19. Glatt HJ, Olson JJ, Putterman AM. Conventional frozen sections in periocular basal cell carcinoma: a review of 236 cases. Ophthalmic Surg 1992;23:6–9. 20. Frank HJ. Frozen section control of excision of eyelid basal cell carcinoma: 8½ years’ experience. Br J Ophthalmol 1989;73:328–32. 21. Einaugler RB, Henkind P. Basal cell epithelioma of the eyelid: apparent incomplete removal. Am J Ophthalmol 1969;67:413–17. 22. Berman AT, Rengan R, Tripuraneni P. Radiotherapy for eyelid, periocular, and periorbital skin cancers. Int Ophthalmol Clin 2009;49:129–42.

28. Nemet AY, Deckel Y, Martin PA, et al. Management of periocular basal cell and squamous cell carcinoma: a series of 485 cases. Am J Ophthamol 2006;142:293–7. 29. Sullivan TJ. Squamous cell carcinoma of eyelid, periocular, and periorbital skin. Int Ophthalmol Clin 2009;49:17–24. 30. Thosani MK, Schneck G, Jones EC. Periocular squamous cell carcinoma. Dermatol Surg 2008;34:585–99. 31. Lederman M. Discussion of carcinomas of conjunctiva and eyelid. In: Boniuk M, editor. Ocular and adnexal tumors. St Louis, MO: CV Mosby; 1964. p. 104–9. 32. Haas AF, Tucker SM. Squamous cell carcinoma. In: Mannis MJ, Macsai MS, Huntley AC, editors. Eye and skin disease. Philadelphia, PA: Lippincott–Raven; 1996. p. 405–11. 33. Mora RG, Perniliaro C. Cancer of the skin in blacks. I. A review of 163 black patients with cutaneous squamous cell carcinoma. J Am Acad Dermatol 1981;5:535–43. 34. Donaldson MJ, Sullivan TJ, Whitehead KJ, et al. Squamous cell carcinoma of the eyelids. Br J Ophthalmol 2002;86:1161–5.

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27. Wilson BD, Mang TS, Stoll H, et al. Photodynamic therapy for the treatment of basal cell carcinoma. Arch Dermatol 1992;128:1597–601.

35. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol 2005;50:103–22. 36. Hornblass A, Lauer SA. Sebaceous carcinoma of the eyelids. Ophthalmology 2005;111:1641. 37. Song A, Carter KD, Syed NA, et al. Sebaceous cell carcinoma of the ocular adnexa: clinical presentations, histopathology, and outcomes. Ophthal Plast Reconstr Surg 2008;24:194–200. 38. Rao NA, Hidayat AA, McLean IW, et al. Sebaceous gland carcinomas of the ocular adnexa: a clinicopathologic study of 104 cases, with five-year follow-up data. Hum Pathol 1982;13:113–22. 39. Boniuk M, Zimmerman LE. Sebaceous carcinoma of the eyelid, eyebrow, caruncle, and orbit. Trans Am Acad Ophthalmol Otolaryngol 1968;72:619–41. 40. Khan JA, Grove AS, Joseph MP, et al. Sebaceous gland carcinoma: diuretic use, lacrimal system spread, and surgical margins. Ophthal Plast Reconstr Surg 1989;5:227–34. 41. Pereira PR, Odachiro AN, Rodrigues-Reyes AA, et al. Histopathological review of sebaceous carcinoma of the eyelid. J Cutan Pathol 2005;32:496–501. 42. Hamada S, Kersey T, Thaller VT. Eyelid basal cell carcinoma: non-Mohs excision, repair, and outcome. Br J Ophthalmol 2005;89:992–4. 43. Nunery WR, Welsh MG, McCord CD Jr. Recurrence of sebaceous carcinoma of the eyelid after radiation therapy. Am J Ophthalmol 1983;96:10–15. 44. Burns SJ, Foss AJ, Butler TK. Outcome of periocular sebaceous gland carcinoma. Ophthal Plast Reconstr Surg 2005;21:353–5. 45. Garner A, Koornneef L, Levene A, et al. Malignant melanoma of the eyelid skin: histopathology and behavior. Br J Ophthalmol 1985;69:180–6. 46. Boulos PR, Rubin PA. Cutaneous melanomas of the eyelid. Semin Ophthalmol 2006;21: 195–206. 47. McCormick SA, DeLuca RL. Tumors of melanocytic origin. In: Mannis MJ, Macsai MS, Huntley AC, editors. Eye and skin disease. Philadelphia, PA: Lippincott–Raven; 1996. p. 381–93. 48. Taylor SF, Cook AE, Leatherbarrow B. Review of patients with basal cell nevus syndrome. Ophthal Plast Reconstr Surg 2006;22:259–65. 49. Clark WH Jr, Reimer RR, Greene MH, et al. Origin of familial malignant melanoma from heritable melanocytic lesions. The B-K mole syndrome. Arch Dermatol 1978;114:732–8.

23. Westgate SJ. Radiation therapy for skin tumors. Otolaryngol Clin 1993;26:295–309.

50. Demirci H, Shields CL, Bianciotto CG, et al. Topical imiquimod for periocular lentigo maligna. Ophthalmology 2010;117:2424–9.

24. Payne JW, Duke JR, Buther R, et al. Basal cell carcinoma of the eyelids. A long-term follow-up study. Arch Ophthalmol 1969;81:553–8.

51. Clark WH Jr, Ainsworth AM, Bernardino EA, et al. Developmental biology of primary human malignant melanomas. Semin Oncol 1975;2:83–103.

25. Rodrequez-Sains RS, Robbins P, Smith B, et al. Radiotherapy of periocular basal cell carcinoma: recurrence rates and treatment with special attention to the medial canthus. Br J Ophthalmol 1988;72:134–8.

52. Kopf AW, Bart RS, Rodriguez-Sain RS, et al. Malignant melanoma. New York: Masson; 1979. 53. Breslow A. Thickness, cross-sectional areas and depths of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970;172:902–8.

26. Fraunfelder FT, Zacarian SA, Wingfield DL, et al. Results of cryotherapy for eyelid malignancies. Am J Ophthalmol 1985;97:184–8.

54. Tahery DP, Goldberg R, Moy RL. Malignant melanoma of the eyelid: a report of eight cases and a review of the literature. J Am Acad Dermatol 1992;27:17–21.

1311.e1

PART 12 ORBIT AND OCULOPLASTICS SECTION 2 Eyelids

Eyelid Trauma and Reconstruction Techniques

12.11 

Jeffrey P. Green, George C. Charonis, Robert A. Goldberg

Definition: Injuries varying from simple skin abrasions to more

complex cases with extensive tissue loss and underlying fractures of the facial skeleton.

Key features ■

Caused by blunt or penetrating facial trauma Partial-thickness eyelid injury ■ Eyelid margin lacerations ■ Eyelid injuries with tissue loss ■ Full-thickness eyelid injury ■

INTRODUCTION

Assessment of visual acuity is mandatory and made prior to any reconstructive efforts. The pupils are checked and if a relative afferent pupillary defect is found, the potential of poor visual outcome is discussed with the patient prior to surgical repair. The extraocular muscles are evaluated and any diplopia documented prior to surgery. The external examination includes a complete bone assessment of the facial skeleton, with particular emphasis on the periorbital region. A palpable step-off, crepitus, or unstable bone requires radiological evaluation. The baseline measurement of globe projection is documented with Hertel exophthalmometry because enophthalmos is a common late sequela of orbital trauma. Eyelid position, orbicularis muscle function, and any evidence of lagophthalmos are noted. Measurement of the intercanthal distance and evaluation of the integrity of the canthal tendons also are performed, because traumatic tendon dehiscence and telecanthus frequently are associated with periorbital injuries. The integrity of the lacrimal system is checked, with a high index of suspicion for canalicular lacerations (see Chapter 12.15).

Injuries that involve the eyelids and periorbital area are common after blunt or penetrating facial trauma. Such injuries can vary from simple skin abrasions to more complex cases that have extensive tissue loss and underlying fractures of the facial skeleton. Stabilization of vital systems should be the first priority in the management of these patients. Restoration of structure and function of the specific ocular adnexal injuries, along with adherence to basic esthetic principles, should be the primary concern of the reconstructive surgeon involved in the management of such injuries.

Medicolegal Documentation

PREOPERATIVE EVALUATION AND DIAGNOSTIC APPROACH

Usually, an appropriate laboratory evaluation is performed by the emergency room team. A complete blood count and serum chemistry analysis are often needed for anesthetic purposes. Coagulative studies may be helpful in selected cases; blood chemistry studies for alcohol and other toxic substances are necessary in others. When the clinical suspicion of orbital fractures is high, appropriate orbital imaging studies, mainly computed tomography, should be ordered (see Chapter 12.3). Ultrasonic examination of the globe contents, extraocular muscles, optic nerve, and orbit can sometimes be an important adjunctive study.

Systemic Stabilization

The evaluation of periorbital injuries begins after the traumatized patient has been stabilized and life-threatening injuries addressed. The role of the ophthalmologist in the evaluation and management is very important − good communication must exist between the trauma team and the ophthalmologist. The incidence of ocular injuries in craniofacial trauma is high, ranging between 15 and 60% in various studies.1

Medical History

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Ophthalmologic Examination

A complete history is obtained to determine the time course and circumstances of the injury. For children, consideration must be given to the possibility of child abuse as the cause of ocular and periorbital injury. A history consistent with injuries from high-speed projectile particles may require the appropriate imaging studies to determine the presence of intraocular or intraorbital foreign bodies. Animal and human bites deserve particular attention and are managed accordingly with the administration of appropriate antibiotics. The site of injury is inspected carefully for any missing tissue, and any amputated tissue found at the site of injury is preserved and placed on ice as soon as possible. In most cases this tissue can be sutured back to the proper anatomic location.

All injuries are documented precisely and completely with detailed drawings on the patient’s charts or, even better, with photographic documentation. Bullets and other projectiles must be retained and marked so that no break occurs in the chain of evidence. The medicolegal implications can be significant, so every effort must be made to complete the preoperative documentation of every injury.

Laboratory and Radiographic Evaluation

Infection Prophylaxis

Prevention of infection is a primary concern. A complete tetanus immunization history is obtained and the appropriate management followed if the patient is not up to date with immunizations (Table 12-11-1).2 If an animal bite is known or suspected, all information about the site of injury, the owner of the animal, and any abnormal animal behavior must be obtained and the local animal care department notified. The standard rabies protocol is followed. A section on dog bites is presented later and contains more detailed information on the evaluation and management of such injuries. Cat bites, and even wounds caused by cat claws, carry a high risk for infection, mainly with Pasteurella multocida (see the later section on dog bites). Appropriate prophylaxis includes penicillin VK (phenoxymethylpenicillin) 500 mg a day for 5–7 days. In allergic patients tetracycline may be given.3

Timing of Repair

The timing of the repair is governed by several factors. Every effort must be made to reconstruct the injured tissues as soon as possible after the patient has been thoroughly evaluated and appropriate ancillary studies have been obtained. However, waiting for 24–48 hours to assemble the most efficient and experienced reconstructive team is a viable alternative unless amputated tissue needs to be replaced. It must be emphasized here that the best chances for restoration of structure and function and for successful cosmesis exist in the initial surgery. To try to address complications or a poor outcome in secondary procedures can be difficult. Should a slight delay in treatment be deemed necessary, the wound should be kept moist with continuous application of soaked saline gauze pads to prevent wound drying and desiccation. Adequate eye protection with copious lubrication must be given or even a temporary tarsorrhaphy performed, if a significant threat of exposure keratopathy exists.

ANESTHESIA The choice of anesthetic for the repair of adnexal injuries depends on several factors. Obviously, the patient’s age is critical because almost all children require general anesthesia for the best reconstructive results to be achieved. Large injuries with extensive soft tissue and osseous involvement are best managed with general anesthesia. However, even with a general anesthetic, local infiltration of epinephrine (adrenaline) is essential for hemostasis. The majority of adult injuries can be

TABLE 12-11-1  GUIDELINES FOR TETANUS PROPHYLAXIS IN WOUND TREATMENT Immunization history

Clean, minor wound

Other type of wound

Uncertain history

Tetanus and diphtheria toxoids* Tetanus and diphtheria toxoids* Tetanus and diphtheria toxoids* None unless the last dose is more than 10 years previously

Tetanus and diphtheria toxoids + tetanus immune globulin Tetanus and diphtheria toxoids + tetanus immune globulin Tetanus and diphtheria toxoids† None unless the last dose is more than 10 years previously

None or one previous dose Two previous doses More than three previous doses

Adapted from Mustarde JC. Eyelid reconstruction. Orbit 1983;1:33–43. * Adult type; for children less than 7 years of age, DTP (diphtheria, tetanus, pertussis). † For wounds more than 24 hours old, add tetanus immune globulin.

repaired with local infiltrative or regional anesthetic of 1–2% lidocaine (lignocaine) with 1 : 100 000 epinephrine. Infiltrative anesthetic can cause significant tissue distortion; this can be minimized with the use of hyaluronic acid (hyaluronidase), which facilitates spreading of the anesthetic solution. Regional anesthesia of the infraorbital, supra­ orbital, infratrochlear, and supratrochlear nerves can be a very effective adjunct and causes no associated tissue distortion.

GENERAL TECHNIQUES The techniques of eyelid and orbital reconstruction after trauma are numerous and varied. Which technique is used largely depends upon the extent of the injury and the specific adnexal structures involved.4 The general approach is to address each anatomic structure independently and to respect appropriate priorities − eye protection first, then function, and finally cosmesis.5 In many cases, a number of reconstructive techniques are combined to achieve an acceptable result.6,7

SPECIFIC TECHNIQUES Partial-Thickness Eyelid Injuries

Small, superficial eyelid lacerations that do not involve the lid margin and that are parallel to the relaxed skin tension lines can be stabilized with skin tape. Larger lacerations and those that are perpendicular to the relaxed skin tension lines require careful approximation and eversion of the skin edge. This can be accomplished with simple interrupted 6-0 or 7-0 absorbable or nonabsorbable sutures. If the full thickness of the orbicularis muscle is involved, it should be repaired separately. Penetration of the orbital septum (see Chapter 12.1) with resultant levator aponeurosis injury must be ruled out in upper eyelid injuries; if present, such injuries must be repaired.

Eyelid Margin Lacerations

This type of adnexal trauma requires the most meticulous eyelid approximation, which must be precise to avoid eyelid notching and margin malposition.8 All tarsal irregularities at the wound edges are trimmed to allow good tarsal-to-tarsal approximation of the repaired edges. This is done along the entire vertical height of the tarsus to prevent tarsal buckling, even though the primary laceration may involve only the marginal tarsus.9 The repair begins with the placement of a 6-0 absorbable or nonabsorbable suture in the plane of the meibomian glands at the lid margin, approximately 2 mm from the wound edges and 2 mm deep (Fig. 12-11-1A). A good margin eversion should be the goal. This suture is left long and untied, and traction is applied to facilitate repair of the remaining lid segments. The tarsus is next closed with fine, interrupted, partial-thickness sutures, such as 6-0 or 7-0 Dexon, polyglactin (Vicryl), chromic, or 7-0 silk.10 The knots are tied on the anterior tarsal surface to avoid corneal irritation (see Fig. 12-11-1B). Additional margin sutures are then placed, usually in the eyelash line and in the gray line. These sutures are tied and left long. The anterior lamella of the eyelid is closed next, with fine interrupted sutures. The long margin sutures are tied through these skin sutures to prevent the suture ends from abrading the cornea (see Fig. 12-11-1 C). When nonabsorbable sutures are used, they are removed after approximately 2 weeks.

DIRECT CLOSURE OF A MARGINAL EYELID LACERATION Placement of initial margin suture

orbicularis muscle

tarsus skin

Partial-thickness lamellar sutures in the tarsus

eyelid retractors

tarsal sutures

12.11  Eyelid Trauma and Reconstruction Techniques

Human bite injuries require the administration of appropriate antibiotics, such as penicillin, Augmentin (amoxicillin and clavulanic acid), erythromycin, or dicloxacillin, as the potential exists to inoculate a large number of bacteria.3 Additional consideration should be given to human immunodeficiency virus and hepatitis and the appropriate testing administered. Following any type of bite injury, copious irrigation of all injured tissues and removal of superficial foreign bodies lodged in the conjunctival fornices are performed. Vigorous irrigation and removal of foreign bodies are generally sufficient to prevent wound infection in most bites.

Margin sutures tied through skin sutures

Fig. 12-11-1  Direct closure of a marginal eyelid laceration. The suture is placed precisely in the plane of the meibomian glands at the eyelid margin, approximately 2 mm from the wound edges and 2 mm deep. This placement should provide adequate margin eversion. Partial-thickness lamellar sutures are placed across the tarsus and tied anteriorly. The anterior skin and muscle lamella is closed with fine sutures, and these are tied over the long marginal sutures to prevent corneal touch.

skin sutures

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12

Eyelid Injuries with Tissue Loss

Orbit and Oculoplastics

Injuries of the eyelid that result in tissue loss provide a difficult reconstructive challenge. If a full-thickness loss of eyelid tissue leads to lagophthalmos and corneal exposure, aggressive lubrication with antibiotic ointments is instituted or a temporary tarsorrhaphy placed until definitive repair can be accomplished. Tissue loss that involves only the anterior skin-muscle lamella may be repaired, if the tissue loss is small and the defect lies anterior to the orbital septum, by allowing the defect to granulate. This method may obviate the need for skin grafts and myocutaneous flaps; however, the wound must be monitored carefully for infection and late contracture. The result of allowing the eyelid to granulate spontaneously can be equal to, or even surpass, the outcome of primary repair.11,12 If the loss of anterior lamella is more extensive, with exposure of the underlying fat and posterior lamellar tissue, local advancement flaps and skin grafts are required. Acute skin grafting may produce an excellent cosmetic result; also, it may reduce the possibility of a shrinkage phase, which can result in lagophthalmos, lid retraction, and the corneal exposure that is likely to occur if the eyelid is left to granulate spontaneously. Whether the surgeon chooses to employ acute skin grafting or other means of repair, it must be recognized that immediate repair is directed at protection of the integrity of the globe, with the recognition that further reconstructive surgery may be necessary to achieve the maximal functional and cosmetic result.13

Full-Thickness Eyelid Lacerations

Full-thickness lacerations that do not involve the eyelid margin may be associated with significant internal disarrangement of lid structures and perforation of the globe. These injuries require adequate layer-bylayer inspection of the wound to assess the integrity of the orbital septum, levator muscle and levator aponeurosis, conjunctiva, rectus muscles, and the globe. Meticulous layered closure is required, with the septum left unsutured. If the posterior lamella of the eyelid is involved in a full-thickness eyelid injury but can be reapproximated without undue tension, it is repaired directly. Tarsal alignment is achieved best through interrupted buried sutures. In the upper eyelid these sutures must be passed through the tarsus but remain subconjunctival because full-thickness sutures may result in corneal contact and irritation. When an injury is severe enough to result in full-thickness tissue loss that involves both the anterior and posterior lamellae of the eyelid, the technique of repair depends on the amount and location of tissue loss. Many of the repair techniques for such injuries are used in lid reconstructions implemented after eyelid skin cancer resections. The amount of tissue loss can usually be ascertained only after careful reapproximation of the wound. Fortunately, tissue loss is usually less significant than the initial presentation may suggest, as retraction of the tissue gives the appearance of greater tissue loss than actually has occurred. Every effort is made to preserve all tissue. The generous adnexal vascular supply usually preserves even narrow pedicles, and even largely avulsed tissue can be reattached with significant survival rates. If large defects persist, standard methods of eyelid reconstruction are employed to complete the anatomic repair.14,15

Tissue loss of 25−60%

Primary closure of upper or lower eyelid injuries with full-thickness tissue loss that includes the margin can be accomplished by release and advancement of lateral tissues. Some injuries that are at the upper limit of primary closure may have their closure facilitated by a lateral canthotomy, followed by cantholysis of the lateral canthal tendon of the involved upper or lower eyelid. If more tissue is required to reconstruct an upper or lower eyelid defect, the lateral canthotomy can be made in a semicircular fashion. The entire semicircular skin-muscle flap can be rotated into the lid defect area as described by Tenzel and Stewart17 (Fig. 12-11-2). A periosteal flap can be used to supplement the lateral posterior lamella when either the upper or lower eyelid is reconstructed2 (Fig. 12-11-3). Also, the lateral posterior lamella can be supplemented with hard palate or ear cartilage grafts.18 Initially, the eyelid may appear tense, but it gradually relaxes over time. Another technique for upper lid defects with tissue loss between 25 and 60% is the Mustarde lid-switch technique. This technique is useful in patients who have broad, shallow defects of the upper eyelid. It is a two-stage procedure in which the first stage involves the transfer of a pedicle flap from the lower eyelid to the upper eyelid (Fig. 12-11-4A). An advantage of this flap is that lashes are transferred to the upper eyelid. The amount of tissue that can be transferred without the need to reconstruct the lower eyelid with an advancement flap is 6 mm. The width of the flap is 7−8 mm, and it contains the marginal artery. As the middle portion of the lower eyelid has the longest eyelashes and is away from the canthal regions, it is often the best donor site. The second stage, in which the pedicle flap is separated, should be performed 2–3 weeks after the first stage (see Fig. 12-11-4B).

TENZEL MYOCUTANEOUS FLAP temporal incision line

traumatic and surgical defect

Fig. 12-11-2  Repair of a lower eyelid defect with the Tenzel myocutaneous flap.

Upper and Lower Full-Thickness Eyelid Injuries Tissue loss of 0−25%

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If either the upper or lower eyelid has sustained a full-thickness injury that results in less than 25% loss of tissue (including the eyelid margin), the repair can generally be closed primarily. However, it is often necessary to ‘freshen up’ the eyelid margins prior to reconstruction. This not only removes any necrotic, nonviable tissue but also allows the surgeon to create two perpendicular, tarsal-to-tarsal wound edges to prevent any postoperative abnormalities of the lid contour. Other than this minimal débridement required to square off the tarsal edges, no other eyelid tissue should be discarded. Closure of the resultant defect can be accomplished with the same technique as used for full-thickness marginal lid lacerations. In older patients, because of increased eyelid laxity, primary closure of both the upper and lower eyelid may be accomplished for injuries that have up to 40% tissue loss.16 Injuries with greater than 25% full-thickness tissue loss (40% in the elderly) require borrowing or advancing adjacent tissue for closure.

Fig. 12-11-3  A periosteal flap can be rotated to supplement the lateral posterior lamella in eyelid reconstruction. (Courtesy of Regents of the University of California, 1997; reprinted with permission.)

For deep medial canthal and lower eyelid defects, the medially based upper eyelid myocutaneous or median forehead transpositional flap gives good results, and heals with remarkably little scarring.23–25

A

When large, upper eyelid defects are reconstructed, the surgeon must appreciate the effects of both horizontal and vertical tension on the final result. Excessive horizontal tension on the upper lid causes tether ptosis, and excessive vertical tension causes lagophthalmos. Care must be taken to avoid these postoperative complications. Multiple surgical modalities exist to address full-thickness tissue loss greater than 60%, all of which share the principles of replacement of both posterior and anterior lamellar structures.26,27 A large, horizontal advancement of an upper eyelid tarsoconjunctival flap is useful for full-thickness defects of up to two-thirds the length of the upper lid margin. The anterior lamella can be replaced with a fullthickness skin graft. A Cutler–Beard bridge flap reconstruction is useful for upper eyelid defects covering up to 100% of the eyelid margin (Fig. 12-11-7).28 This technique, a two-stage procedure, takes tissue from the lower eyelid to reconstruct the upper eyelid. First, skin, muscle, and conjunctiva are advanced from the lower eyelid to replace the defect in the upper eyelid; the second stage can usually be performed 3–4 weeks after the initial reconstruction. This procedure does not replace lost eyelashes of the upper eyelid and is also fraught with the need for secondary corrective procedures. A tarsal substitute is usually placed within the reconstructed lid, either donor sclera or other material.29

Eyelid Trauma and Reconstruction Techniques

Upper eyelid

12.11 

Postoperative Care B Fig. 12-11-4  The Mustarde eyelid switch is a very helpful technique in patients who have broad, shallow defects of the upper eyelid. (A) A pedicle flap of marginal eyelid is cut from the central lower lid and rotated into the upper eyelid defect. (B) After 2–3 weeks the flap is separated and repaired to restore satisfactory upper and lower eyelid contours, with preservation of lashes. (Courtesy of Regents of the University of California, 1997; reprinted with permission.)

Full-Thickness Eyelid Injuries with Greater Than 60% Tissue Loss Lower eyelid

The repair of large tissue defects of the lower lid requires supplemental tissue from adjacent regions.19 The Hughes tarsoconjunctival flap is a two-stage procedure best suited to large, centrally located lower eyelid full-thickness defects that spare the eyelid margins medially and laterally20 (Fig. 12-11-5). Shallow, full-thickness, lateral lower eyelid defects may be addressed with the transposition tarsoconjunctival flap described by Hewes et al.21 This is a one-stage procedure in which the superolateral portion of the upper lid tarsus is used as a flap based at the lateral canthus. The flap is rotated down and sutured to the tarsus and conjunctiva in the lower lid, with the tarsal margin in the downmost position. This transposed tarsoconjunctival flap is then covered with a full-thickness skin graft from a suitable donor site. The Mustarde flap is a large, rotational, skin-muscle cheek flap that can, if necessary, be relied on to cover virtually any lower lid defect22 (Fig. 12-11-6). It may be considered a progression in size from the smaller Tenzel semicircular rotational flap. This flap is most useful for vertical, deep, medial, full-thickness lower lid defects. The advantage of this procedure is that it is a one-stage, complete lower lid reconstruction. The disadvantages of this procedure are the excessively long scar on the face and the adynamic nature of the reconstructed lower lid. A graft of either hard palate or ear cartilage is needed for posterior lamellar support. The authors have used an advancement of suborbital ocularis oculi fascia in lower lid defects that cannot be closed primarily. This myocutaneous advancement flap allows reconstruction of the lower lid posterior and anterior lamellar structures in a vertical direction, by directing cheek tissue superiorly. In conjunction with lifted suborbital ocularis oculi fascia, posterior lamellar and anterior lamellar grafts can be used as needed to complete the lower eyelid reconstruction.

For the first 2 days after any reconstructive surgery on the eye, the patient should be instructed to use ice compresses on the wound and to keep the head of the bed elevated. These steps help to reduce postoperative edema. The authors prefer not to bandage the patient’s eye unless skin grafts have been used. Antibiotic ointment placed on the wound two to three times a day not only helps to prevent infection but also assists in lubrication of the wound. The antibiotic ointment also helps to hasten reepithelialization of portions of the wound that may be left to granulate spontaneously. The authors generally remove skin sutures at 5–7 days and lid margin sutures at 10–14 days. Patients are instructed to stay out of direct sunlight and to use sun block on the maturing scar for at least 6 months postoperatively. This helps to avoid abnormal pigmentation of the scar. When the cicatricial phase of wound healing commences, at 3–4 weeks, the patient is instructed to massage the wound to prevent cicatricial changes such as ectropion, entropion, or lagophthalmos.

Late Repair of Eyelid Injuries

It is not uncommon for the patient who has undergone extensive traumatic eyelid repair to require secondary surgery. Skin grafts on the upper eyelid for lagophthalmos and on the lower eyelid for lower eyelid cicatricial ectropion are often necessary in the late postoperative period (Fig. 12-11-8). To improve the postoperative esthetic result, donor sites for skin grafts should be matched to the area of skin loss. The contra­ lateral upper eyelid, pre- or postauricular areas, and supraclavicular areas have been used with excellent results for skin grafts on eyelids and the periocular region. When skin grafts are used in either the acute setting of trauma or the late postoperative period, the involved upper or lower eyelid should be kept on stretch using a traction suture (Frost or reverse Frost suture). Alternatively, a vertical scar in the lower eyelid that causes vertical shortening can be corrected with Z-plasty techniques. If the patient has shortening of the posterior lamella in the late postoperative period, hard palate or mucous membrane grafts can be implemented to treat cicatricial entropion.

Dog Bites

Of the 44 000 facial dog bites that present to emergency rooms in the United States each year, orbital and periorbital injuries occur in 4–8% of cases.30 In a recent series in the ophthalmic literature, over half of these bites occurred in children younger than 5 years and two-thirds in children younger than 10 years. It is absolutely essential to ascertain information about the dog’s health and rabies vaccination status. Pasteurella multocida is identified in up to 50% of dog bite injury infections; Pa. multocida infections commonly occur within 48 hours of inoculation and are characterized

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12 Orbit and Oculoplastics

A

C

B

D

Fig. 12-11-5  The Hughes tarsoconjunctival flap procedure. (A) The lower eyelid defect is examined to estimate the width of the flap. (B) The flap is dissected from the posterior lamella of the upper eyelid. At least 4 mm of tarsus must remain along the upper eyelid margin to enable stabilization. (C) A skin graft can provide adequate anterior lamella of the lower eyelid. (D) After 4–6 weeks the flap is divided to restore the eyelid margins. (Courtesy of Regents of the University of California, 1997; reprinted with permission.)

MUSTARDE MYOCUTANEOUS FLAP temporal incision line

eyelid defect

Fig. 12-11-6  Repair of large, full-thickness lower eyelid defects with the Mustarde myocutaneous flap.

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by prominent wound inflammation and drainage. The organism is a small, gram-negative coccobacillus that grows in both aerobic and anaerobic environments. Gonnering,31 in a study of periorbital dog bites, found no penetration injuries of the globe and no tissue loss. Disruption of the lacrimal system was present in 14 of the 16 cases. All dog bite wounds are presumed to be contaminated and, therefore, must be decontaminated prior to surgical repair to limit infection. Forceful irrigation with at least 200 mL of normal saline using a 35 mL syringe and 18-gauge irrigating cannula is recommended while the cornea is protected with a scleral contact lens.32 Surgical repair is carried out as for any other eyelid reconstruction, with restoration of normal anatomic structure and function. Care should be taken to evaluate and repair medial canthal tendon avulsions as well as lacrimal system injuries.33

Fig. 12-11-7  The Cutler–Beard bridge flap. A full-thickness flap of lower eyelid tissue is advanced beneath a marginal bridge into the upper eyelid defect. After 3–4 weeks the flap is cut at the appropriate level and the lower lid is repaired. (Courtesy of Regents of the University of California, 1997; reprinted with permission.)

Adjunct medical therapy includes tetanus prophylaxis and rabies prophylaxis if the rabies status of the dog is unknown or positive. The need for prophylactic antibiotics in dog bites is controversial. Adequate wound decontamination is probably the single most important modality that prevents infection. Various studies have isolated many different pathogens as the cause of infections after dog bites. No single antimicrobial agent is optimal against these various pathogens, which may include Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa, and anaerobes in addition to Pa. multocida and Capnocytophaga canimorsus. Recommended choices of antibiotic prophylaxis include penicillin, Augmentin (amoxicillin and clavulanic acid), cefuroxime, and cephalexin.31 Alternatives for the penicillin-allergic patient include erythromycin and tetracycline. Decisions about tetanus prophylaxis

B Fig. 12-11-8  Patient with an obvious cicatricial left medial canthal dystopia as a result of trauma. (A) Primary repair did not address the reconstruction of the critical deep portion of the medial canthal tendon. (B) The same patient as in A after left medial canthoplasty and anterior lamella reconstruction with a skin graft. It is imperative to reconstruct all elements of the medial canthal complex to achieve satisfactory eyelid apposition to the globe. (Courtesy of Regents of the University of California, 1997; reprinted with permission.)

depend on the patient’s immunization history and the character of the wound (see Table 12-11-1). If rabies is suspected, health department officials should be notified. The health department can assist in quarantine of the animal as well as offer advice about current recommendations for rabies prophylaxis. The incubation period for rabies averages 30–50 days. Prophylactic treatment must be administered before the onset of clinical disease. The treatment consists of inactive rabies virus human diploid cell vaccine, which offers active immunity, and rabies immune globulin, which offers passive immunity.

Eyelid Burns

Severe burn injuries frequently involve the face, with the incidence of eyelid involvement being 20–30%.34 Fortunately, Bell’s phenomenon, the blink reflex, rapid reflex head movements, and shielding of the eyes with arms and hands often prevent conjunctival and corneal injury. The initial evaluation of an eyelid burn includes an assessment of the depth of the burn wound. First- and second-degree burns are partial-thickness skin injuries, and third-degree burns are full-thickness injuries. The mild swelling, erythema, and pain of first-degree burns (which involve only the epidermis) generally resolve within 5–10 days with no compromise of eyelid function and structure, as the damage is quite superficial. Second-degree burns, characterized by erythema, bulla formation, considerable edema, and pain, often heal uneventfully within 7–14 days without sequelae. A deep second-degree burn can result in cicatricial eyelid deformities, especially if superinfection occurs. Third-degree burns represent the most severe burn injuries. The burned lids may have a dark, leathery appearance or appear translucent

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12.11  Eyelid Trauma and Reconstruction Techniques

A

or waxy white. These burns are not very painful because the terminal nerve endings have been destroyed. A thick black eschar forms and then separates within 2–3 weeks. Granulation tissue then forms and the myofibroblasts produce contracture, with ensuing eyelid retraction, cicatricial ectropion, and lagophthalmos. Acute treatment of all eyelid burns requires frequent lubrication with artificial tear drops and lubricating ointment at bedtime.35 If associated corneal and conjunctival injuries exist, appropriate topical antibiotic ointment is used as well. The topical antibiotic is continued until the cornea has reepithelialized. Topical burn medications are placed on the periorbital skin in coordination with the burn-team care. In the intermediate phase (1–4 weeks) of eyelid burn healing, firstdegree burns generally do not undergo significant cicatricial changes and often heal without sequelae. Second- and third-degree burns are accompanied by cicatrization and shortage of skin surface area. This results in lagophthalmos secondary to lower eyelid ectropion and upper eyelid retraction. Corneal exposure may lead to epithelial compromise, and it may be followed by sterile or infectious corneal ulcers. In this intermediate period, prior to full cicatrization before the wounds are ready for skin grafts, it is best to perform temporizing measures. If heavy ocular lubrication is not sufficient, surgical scar release using Frost suture eyelid closure or non-margin-injuring tarsorrhaphy can be performed. When burn wounds are healed completely and the cicatricial phase of healing is over, definitive eyelid reconstruction may be undertaken. Usually, full-thickness skin grafts are used for eyelid reconstruction. Optimal donor sites for a full-thickness graft are the non-hair-bearing retroauricular, contralateral eyelid, and supraclavicular skin. In a severely burned patient, any available donor site may be used for fullthickness tissue, and split-thickness skin grafts may be used if necessary. The late phase of eyelid-burn healing may also lead to scar formation (webbing) of the lateral and medial canthi. Skin grafts and Z-plasty techniques can be employed to address this canthal webbing. In the treatment of the eyelid-burn patient, emphasis is placed on protection of the cornea and conjunctiva. Skin deformities can often be repaired in the late postoperative period, after temporizing measures to protect the cornea have been implemented. Corneal scarring may require limbal stem cell and amniotic membrane grafting.36

OUTCOME The expected goals of reconstructive surgery on the eyelids are:  Preservation of vision  Restoration of eyelid structure and function to as near normal as possible  Achievement of adequate cosmesis. Although all three objectives are important, esthetic concerns should not override functional considerations. In most cases, patients can expect good to excellent results for all three goals. In some cases, multiple repeated operations may be necessary to achieve these results.

KEY REFERENCES Bowman PH, Foski SW, Hartstein ME. Periocular reconstruction. Semin Cutan Med Surg 2003;22:263–72. Chandler DB, Gausas RE. Lower eyelid reconstruction. Otolaryngol Clin North Am 2005;38: 1033–42. Chang EL, Rubin PA. Management of complex eyelid lacerations. Int Ophthalmol Clin 2002;42:187–201. Codner MA, McCord CD, Mejia JD, et al. Upper and lower eyelid reconstruction. Plast Reconstr Surg 2010;126:231e–45e. Fish R, Davidson RS. Management of ocular thermal and chemical injuries, including amniotic membrane therapy. Curr Opin Ophthalmol 2010;21:317–21. Gossman MD, Roberts DM, Barr CC. Ophthalmic aspects of orbital injury: a comprehensive diagnostic and management approach. Clin Plast Surg 1992;19:71–85. McNab AA, Collin JRO. Eyelid and canthal lacerations. In: Linberg JV, editor. Oculoplastic and orbital emergencies. Norwalk, CT: Appleton & Lange; 1990. p. 1–13. Murchison AP, Bilyk JR. Management of eyelid injuries. Facial Plast Surg 2010;26:464–81. Price DL, Sherris DA, Bartley GB, et al. Forehead flap periorbital reconstruction. Arch Facial Plast Surg 2004;6:222–7. Verity DH, Collin JR. Eyelid reconstruction: the state of the art. Curr Opin Otolaryngol Head Neck Surg 2004;12:344–8.

1317

REFERENCES 1. Gossman MD, Roberts DM, Barr CC. Ophthalmic aspects of orbital injury: a comprehensive diagnostic and management approach. Clin Plast Surg 1992;19:71–85. 3. Walton RL, Matory WE Jr. Wound care. In: Ho MT, Saunders CE, editors. Current emergency diagnosis and treatment. 3rd ed. Norwalk, CT: Appleton & Lange; 1990. p. 756–80. 4. Murchison AP, Bilyk JR. Management of eyelid injuries. Facial Plast Surg 2010;26:464–81. 5. Hartstein ME, Fink S. Traumatic eyelid injuries. Intl Ophthalmol Clin 2002;42:123–34. 6. Sharma V, Benger R, Martin PA. Techniques of periocular reconstruction. Indian J Ophthalmol 2006;54:149–58. 7. Verity DH, Collin JR. Eyelid reconstruction: the state of the art. Curr Opin Otolaryngol Head Neck Surg 2004;12:344–8. 8. Chang EL, Rubin PA. Management of complex eyelid lacerations. Int Ophthalmol Clin 2002;42:187–201. 9. Gossman MD, Berlin AJ. Management of acute adnexal trauma. In: Stewart WB, editor. Surgery of the eyelid, orbit and lacrimal system, vol. 1. San Francisco, CA: American Academy of Ophthalmology; 1993. p. 170–85. 10. Custer PL, Vick V. Repair of marginal eyelid defects with 7-0 chromic sutures. Ophthal Plast Reconstr Surg 2006;22:256–8.

20. Hughes WL. Total lower lid reconstruction: technical details. Trans Am Ophthalmol Soc 1976;74:321–9. 21. Hewes EH, Sullivan JH, Beard C. Lower eyelid reconstruction by tarsal transposition. Am J Ophthalmol 1976;81:512–14. 22. Mustarde JC. Major reconstruction of the eyelids − functional and aesthetic considerations. Clin Plast Surg 1988;15:255–62. 23. Price DL, Sherris DA, Bartley GB, et al. Forehead flap periorbital reconstruction. Arch Facial Plast Surg 2004;6:222–7. 24. Schaudig U, Grundmann T, Ussmuller J. Transposition flaps for reconstruction of deep defects of the medial eyelids. Fasciocutaneous rotation and transposition flaps and modified pure fascial transposition flap. Ophthalmologe 2004;101:461–5. 25. Jelks GW, Glat PM, Jelks EB, et al. Medial canthal reconstruction using a medially based upper eyelid myocutaneous flap. Plast Reconstr Surg 2002;110:1636–43. 26. Pham RT. Reconstruction of the upper eyelid. Otolaryngol Clin North Am 2005;38:1023–32. 27. Codner MA, McCord CD, Mejia JD, et al. Upper and lower eyelid reconstruction. Plast Reconstr Surg 2010;126:231e–45e. 28. Cutler NL, Beard C. A method for partial and total upper lid reconstruction. Am J Ophthalmol 1955;39:1–7.

11. Mehta HK. Spontaneous reformation of upper eyelid. Br J Ophthalmol 1988;72:856–62.

29. Holloman EL, Carter KD. Modification of the Cutler–Beard procedure using donor Achilles tendon for upper eyelid reconstruction. Ophthal Plast Reconstr Surg 2005;21:267–70.

12. Bowman PH, Foski SW, Hartstein ME. Periocular reconstruction. Semin Cutan Med Surg 2003;22:263–72.

30. Palmer J, Rees M. Dog bites of the face; a 15 year review. Br J Plast Surg 1983;36:315–18.

13. Rubin PAD, Shore JW. Penetrating eyelid and orbital trauma. In: Albert DM, Jakobiec FA, editors. Principles and practices of ophthalmology: clinical practice. Philadelphia, PA: WB Saunders; 1994. p. 3426–40. 14. McNab AA, Collin JRO. Eyelid and canthal lacerations. In: Linberg JV, editor. Oculoplastic and orbital emergencies. Norwalk, CT: Appleton & Lange; 1990. p. 1–13. 15. Karim A, Schapiro D, Morax S. Reconstruction of full-thickness lower eyelid defects. J Fr Ophthalmol 2005;28:675–80. 16. McCord CD Jr. System of repair of full-thickness lid defects. In: McCord CD Jr, Tanenebaum M, Nunery WR, editors. Oculoplastic surgery. 3rd ed. New York: Raven Press; 1995. p. 85–97. 17. Tenzel RR, Stewart WB. Eyelid reconstruction by semi-circular flap technique. Trans Am Soc Ophthalmol Otolaryngol 1978;85:1164–9. 18. Hughes WL. Reconstruction of the lids. Am J Ophthalmol 1945;28:1203–11.

31. Gonnering RS. Ocular adnexal injury and complications in orbital dog bites. Ophthal Plast Reconstr Surg 1987;3:231–5. 32. Stevenson TR, Thacker JG, Rodenheaver GT, et al. Cleansing the traumatic wound by high pressure syringe irrigation. J Am Coll Emerg Physicians 1976;5:17–21.

12.11  Eyelid Trauma and Reconstruction Techniques

2. Mustarde JC. Eyelid reconstruction. Orbit 1983;1:33–43.

19. Chandler DB, Gausas RE. Lower eyelid reconstruction. Otolaryngol Clin North Am 2005;38:1033–42.

33. Fish R, Davidson RS. Management of ocular thermal and chemical injuries, including amniotic membrane therapy. Curr Opin Ophthalmol 2010;21:317–21. 34. Glover AT. Eyelid burns. In: Shingleton BJ, Hersh PS, Kenyon KR, editors. Eye trauma. St Louis, MO: Mosby–Year Book; 1991. p. 315–22. 35. Malhotra R, Sheikh I, Dheansa B. The management of eyelid burns. Surv Ophthalmol 2009;54:356–71. 36. Fish R, Davidson RS. Management of ocular thermal and chemical injuries, including amniotic membrane therapy. Curr Opin Ophthalmol 2010;21:317–21.

1317.e1

PART 12 ORBIT AND OCULOPLASTICS SECTION 3 Orbit and Lacrimal Gland

12.12 

Orbital Diseases Jonathan J. Dutton

Definition: The orbit is the bony cavity that contains the eye, eye

muscles, lacrimal gland, and neural and vascular structures that serve eye function. Numerous diseases occur in the orbit that can affect visual function.

Key features ■

A mass lesion of the orbit may cause proptosis or displacement of the eye. ■ Orbital lesions may be the presenting sign of systemic diseases, such as metastatic cancer. ■ Demographics such as age, sex, and location within the orbit may be helpful in making a specific diagnosis. ■ Treatment of orbital lesions may be medical, such as the use of steroids or radiotherapy for inflammatory disease, and does not always require surgery.

INTRODUCTION The orbit and ocular adnexa are important sites for primary and sec­ ondary diseases. Various tissue types, such as osseous, vascular, neural, muscular, and glandular, may be involved with specific pathologies.1–5 Tumors or inflammations can secondarily invade the orbit from peri­ orbital regions including the paranasal sinuses, eyelids, and intracranial compartment.

CLINICAL EVALUATION The initial step in the evaluation of orbital disease is a complete oph­ thalmic examination.5 A careful medical and ophthalmic history, including time course of the disease, past trauma, ocular surgery, and systemic illnesses, must be obtained. A complete clinical examination includes assessment of visual acuity and visual fields, anterior and posterior segment evaluation, optic nerve function, and external and periorbital inspection. The use of modern imaging techniques is almost always indicated − the choice depends on the disease processes suspected. In this chapter, the most common orbital lesions are categorized by diagnostic criteria, to enable the reader to evaluate patients more easily and establish a meaningful differential diagnosis (Tables 12-12-1– 12-12-3).5,6 In addition, the key points and diagnostic criteria for each lesion are given.

TABLE 12-12-1  FREQUENCY OF ORBITAL LESIONS BY MAJOR DIAGNOSTIC GROUP Diagnostic group

Frequency (%)

Thyroid orbitopathy Inflammatory lesions Cystic lesions Lymphoproliferative lesions Other and unclassified Vascular neoplasms Secondary tumors Mesenchymal lesions Optic nerve tumors Lacrimal gland lesions Metastatic tumors Vascular, structural

50 11 10 5 5 4 4 4 3 2 2 1

Data from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39; and Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315.

TABLE 12-12-2  AGE DISTRIBUTION OF COMMON ORBITAL DISEASES Diagnostic group

Frequency (%) Childhood and adolescence (0–20 years)

Adenoid cystic carcinoma of lacrimal gland Capillary hemangioma Cavernous hemangioma Cystic lesions Fibrous histiocytoma Infectious processes Inflammatory lesions Lymphangiomas Lymphoproliferative diseases Optic nerve glioma Optic nerve meningioma Pleomorphic adenoma of lacrimal gland Rhabdomyosarcoma Secondary and metastatic malignancies Thyroid orbitopathy Trauma

Middle age (21–60 years)

Later adult life (61+ years)

18

73

9

100 10 77 25 35 12 6 1 5 4 0

0 75 3 50 3 5 1 3 1 88 89

0 15 4 25 3 9 0 12 1 8 11

98 1

2 2

0 9

4 7

59 4

40 2

Data rounded to the nearest percentage point. Modified from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39.

METASTATIC TUMORS INTRODUCTION

1318

Metastatic tumors represent 2−3% of all orbital tumors.6 In 30–60% of patients, orbital metastases develop before the diagnosis of the primary tumor (Table 12-12-4). Metastases reach the orbit via hematogenous spread and occur less commonly than do uveal metastases. In adults, metastases are usually carcinomas. In children, metastases are more likely to be sarcomas and embryonal tumors of neural origin. Only 4% of orbital metastases are bilateral. Clinical symptoms include

TABLE 12-12-3  TEMPORAL ONSET OF COMMON ORBITAL DISEASES Hours

Days

Weeks

Months

Years

Traumatic Hemorrhagic Infectious

Inflammatory Infectious Traumatic Hemorrhagic Vascular

Inflammatory Neoplastic Traumatic Lymphoid Vascular

Neoplastic Lymphoid Vascular Inflammatory Degenerative

Neoplastic Degenerative Lymphoid Vascular Inflammatory

Modified from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39.

12.12  Orbital Diseases

Fig. 12-12-1  Metastatic breast carcinoma to the right orbit with ptosis, proptosis, and downward displacement of the globe.

TABLE 12-12-4  PRIMARY ORIGINS OF METASTATIC TUMORS OF THE ORBIT Origin

Per cent

Breast Prostate Gastrointestinal Lung Sarcomas and other

53 11 11 4 21

Modified from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott;1988. p. 119–39; and Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315.

proptosis, axial displacement of the globe, ptosis, diplopia, pain, and chemosis.7 (Fig. 12-12-1).

METASTATIC CARCINOMA Key Points

The most common primary sites of metastatic carcinoma to the orbit are the breast, lung, prostate, gastrointestinal tract, and kidney.8–10 Key features are:  For breast carcinoma, the interval from primary diagnosis to orbital metastasis is 3–5 years.  In scirrhous cell breast carcinoma and gastric carcinoma, enophthal­ mos may result from orbital fibrosis.  Metastatic lung cancer is seen most commonly in smoking males aged 45–60 years, and may present before the primary is discovered.  Prostatic metastases occur most commonly in elderly men, and pain is common because of bony involvement. Metastases are characterized by a rapid onset of orbital symptoms, which include exophthalmos and globe displacement.

Orbital Imaging

Metastatic carcinomas usually are poorly defined, non-encapsulated, diffuse masses that are somewhat infiltrative (Fig. 12-12-2). Extraocu­ lar muscles are often involved. Osteoblastic changes may be seen with prostatic carcinoma. On MRI, the T1-weighted image is usually isointense and the T2-weighted image hyperintense to muscle.

Treatment and Prognosis

Treatment requires chemotherapy combined with local radiotherapy. Orchiectomy may be indicated for prostate carcinoma, and hormonal therapy for breast carcinoma. Orbital metastases from carcinoma reflect more widespread sys­ temic disease, so the prognosis for survival is generally poor.

LACRIMAL GLAND LESIONS INTRODUCTION Lesions of the lacrimal gland include infiltrative processes such as inflammatory diseases and lymphoma,11 structural disorders (such as

Fig. 12-12-2  CT scan of a metastatic breast carcinoma with an irregular mass in the right retrobulbar orbit.

BOX 12-12-1 CAUSES OF ABAXIAL GLOBE DISPLACEMENT Downward Displacement  Fibrous dysplasia  Frontal mucocele  Lymphoma  Neuroblastoma  Neurofibroma  Schwannoma  Subperiosteal hematoma  Thyroid orbitopathy Upward Displacement  Lacrimal sac tumors  Lymphoma  Maxillary sinus tumor  Metastatic tumors Lateral Displacement  Ethmoid mucocele  Lacrimal sac tumors  Lethal midline granuloma  Metastatic tumors  Nasopharyngeal tumors  Rhabdomyosarcoma Medial Displacement  Lacrimal fossa tumors  Sphenoid wing meningioma The direction of ocular displacement may be helpful in narrowing the differential diagnosis.

cysts), and epithelial neoplasms.12–16 Epithelial tumors represent 20–25% of all lacrimal gland lesions. The appropriate management of lacrimal fossa lesions requires a thorough evaluation and determina­ tion of the cause. Almost all lacrimal gland lesions result in a mass effect, with swelling of the lateral eyelid and often with a downward and medial displacement of the globe (Box 12-12-1). Inflammatory processes are more commonly associated with pain, eyelid edema, and conjunctival chemosis and injection.

PLEOMORPHIC ADENOMA (BENIGN MIXED CELL TUMOR) Key Points

Pleomorphic adenomas occur mainly in the orbital lobe and rarely in the palpebral lobe of the lacrimal gland.17–20 They are composed of

1319

12 Orbit and Oculoplastics

epithelial and mesenchymal elements (thus the term benign ‘mixed’ cell tumor), but both elements are derived from epithelium. Key fea­ tures are:  They represent 3–5% of all orbital tumors, 25% of lacrimal mass lesions, and 50% of epithelial lacrimal gland tumors.  Most commonly they occur in the second to fifth decades of life (mean age, 39 years).  The male to female ratio is 1.5 : 1. Orbital symptoms are painless proptosis, downward displacement of the globe, diplopia, retinal striae, fullness of the upper eyelid, and a palpable eyelid mass. These tumors are slowly progressive over 12 or more months.

Orbital Imaging

Well-circumscribed, round-to-oval, encapsulated lesions are typical. Remolding of the bone may be seen with long-standing tumors, but no bone destruction occurs. The tumors may be cystic and may contain areas of calcification. On MRI the T1-weighted image is hypointense and the T2-weighted image hyperintense to muscle.

The prognosis is generally very good, despite the small possibility of malignant transformation.

ADENOID CYSTIC CARCINOMA Key Points

Adenoid cystic carcinoma accounts for 23% of all epithelial tumors of the lacrimal gland and is the most common epithelial malignancy of the lacrimal gland (Table 12-12-5).21 Key features are:  It occurs most commonly in the fourth decade of life but may be seen at any age.  It is slightly more common in women.  The duration of symptoms is generally short − often less than 6 months, and usually less than 12 months. Orbital symptoms include proptosis, downward globe displacement, ptosis, and diplopia. Orbital pain as a result of perineural spread is common, seen in 10–40% of cases.

Orbital Imaging

Pleomorphic adenomas are encapsulated tumors that demonstrate ducts, cords, and squamous pearls, with myxoid and chondroid tissue (Fig. 12-12-3).

Computed tomography and MRI usually show a poorly demarcated, irregular lesion that may extend along the lateral wall to the orbital apex. Bone destruction is common, and foci of calcification are seen frequently. On MRI the T1- and T2-weighted images are hyperintense to muscle, and the signal is heterogeneous.

Treatment and Prognosis

Pathology

Pathology

These adenomas must be excised completely with an intact capsule; biopsy may result in recurrence associated with infiltration. Malignant degeneration occurs at a rate of 10% in 10 years.

Solid cords of malignant epithelial cells are seen, with cystic spaces (‘Swiss cheese’ appearance) or hyalinization of cylinders of connective tissue (Fig. 12-12-4).

Treatment and Prognosis

Treatment consists of radical en bloc excision or exenteration, with wide margins including bone. A recent histologic study22 showed that 80% of these lesions involved adjacent bone. Adjunctive radiotherapy for incompletely excised lesions may be necessary. The prognosis is often poor, with relentless recurrences. The mortality rate is high.

MESENCHYMAL TUMORS INTRODUCTION Non-osseous mesenchymal tumors arise from fibroblasts, myoblasts, and lipoblasts. Classification of such lesions is difficult, as their fea­ tures overlap, so the terminology is confusing. Together, these orbital lesions form an important group that accounts for about 8% of all orbital lesions.23–33

A

S

FIBROUS HISTIOCYTOMA Key Points

Fibrous histiocytoma is a benign or malignant mesenchymal tumor that arises from fascia, muscle, or other soft tissues.34,35 In children, it may result from early orbital radiotherapy. In adults, it is the most common mesenchymal orbital tumor, usually seen in middle-aged patients (40–60 years).

M

C

TABLE 12-12-5  FREQUENCY OF LACRIMAL FOSSA LESIONS M C

B

1320

Fig. 12-12-3  Benign mixed tumor. (A) The patient had proptosis of the left eye for quite some time. It had gradually increased in severity. (B) The characteristic diphasic pattern is shown. It consists of a pale background that has a myxomatous stroma and a relatively amorphous appearance, contiguous with quite cellular areas that contain mainly epithelial cells. C, Cellular epithelial areas; M, myxomatous stroma; S, surface of tumor. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

Lesion

Frequency (%)

Dacryoadenitis Pleomorphic adenoma Reactive lymphoid hyperplasia Adenoid cystic carcinoma Dacryops (epithelial cyst) Lymphoma Mucoepidermoid carcinoma Pleomorphic adenocarcinoma Plasmacytoid lesions

51 18 9 7 5 4 3 2 1

Modified from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39; and Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315.

The upper nasal quadrant is the most common orbital site. Symp­ toms are proptosis, decreased vision, ptosis, motility restriction, and epiphora. The lesions may be circumscribed or infiltrative and can be locally aggressive.

Usually a well-defined, rounded mass is seen, as in other benign lesions, but the tumor can be more infiltrative. On MRI the signal is

Pathology

The tumor is a mixture of spindle-shaped fibroblasts and histiocytes arranged in a storiform pattern, twisted about a central focus (Fig. 12-12-5). The benign form (63% incidence) is a well-circumscribed, slow-growing lesion with a fine capsule. A small potential exists for malignant degeneration. The malignant form (37% incidence) is more infiltrative and rapidly growing and is often associated with pain and necrosis.

12.12  Orbital Diseases

Orbital Imaging

heterogeneous, with isointense T1 and variable T2 signals with respect to muscle. Enhancement with gadolinium is moderate.

Treatment and Prognosis

Local surgical excision for benign, or orbital exenteration for malignant lesions is required, with recurrences being common (in up to 30% of cases). Radiotherapy offers no benefit, and the effects of chemotherapy are unknown. For the benign form, the prognosis for life is excellent. With malig­ nant tumors, the overall mortality rate is more than 40%.

RHABDOMYOSARCOMA Key Points

A

C S

C

B Fig. 12-12-4  Adenoid cystic carcinoma. (A) The patient had a rapidly progressing proptosis of the left eye. (B) The characteristic ‘Swiss cheese’ pattern (S) of adenoid cystic carcinoma is shown. The ‘Swiss cheese’ tumor is also present in the perineural sheath around the ciliary nerve (C). Adenoid cystic carcinoma is noted for its rapid invasion of ciliary nerves. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

Rhabdomyosarcoma is the most common soft tissue mesenchymal tumor in children, accounting for 3.4% of all childhood malignancies.36–38 The tumors arise from pluripotential mesenchymal precursors that normally differentiate into striated muscle cells. About 70% occur dur­ ing the first decade of life (mean age, 7–8 years; range, 0–78 years), and boys are affected more commonly than girls, at a ratio of 5 : 3. In the orbit, the most common histological variant is the embryonal type, fol­ lowed by the alveolar type. Symptoms may be acute to subacute, with rapidly progressive prop­ tosis, eyelid edema, and ptosis. This rapidity may cause diagnostic confusion with an infectious process. The tumor is located in the retrobulbar muscle cone in 50% of cases, and in the superior orbit in 25% of cases.

Orbital Imaging

Typically, the tumor presents as an irregular but well-defined soft tissue mass (Fig. 12-12-6). Bony erosion may be seen but is uncommon. On MRI the T1 signal is isointense to hyperintense, and the T2 signal is hyperintense with respect to muscle.

Pathology

Cross-striations may be seen in 50–60% of embryonal-type tumors and in 30% of the alveolar type (Fig. 12-12-7). Myoglobulin is a specific immunohistochemical marker. Electron microscopy shows actin myo­ filaments and myosin filaments.

H

F

A

B

Fig. 12-12-5  Fibrous histiocytoma. (A) This is the fourth recurrence of an orbital tumor that was first excised 10 years previously. The histology of the primary lesion and of the four recurrences appear identical. (B) A histological section shows the diphasic pattern consisting of a histiocytic component (H), mainly on the far left, and a fibrous component (F). (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

1321

12 Orbit and Oculoplastics

A

B Fig. 12-12-6  Rhabdomyosarcoma of the lateral orbital wall in a 7-year-old girl.

Staging

There are four stages:  Localized tumor, completely resected  Regional spread, ± positive nodes, grossly resected  Gross residual tumor remaining after incomplete resection  Distant metastases.

B

Treatment and Prognosis

An immediate biopsy is required to confirm the diagnosis. Surgical excision is carried out only if the lesion is well circumscribed and the excision can be performed easily without excessive tissue damage. Local radiotherapy doses are 4000 cGy for stage II and 5000 cGy for stages III and IV. Adjuvant chemotherapy is given, using vincristine, actinomycin D, and cyclophosphamide. Some centers prefer only sur­ gery and chemotherapy, to avoid the potential for radiation-induced orbital malignancies in children.39 The 5-year survival rate is 90–95%. A more favorable prognosis exists for orbital tumors because of the near absence of orbital lymphat­ ics. For local treatment failures, orbital exenteration may be necessary.

C

A C B

NEUROGENIC TUMORS

C

INTRODUCTION Peripheral nerves in the orbit are subject to tumors that arise from vari­ ous cellular components, such as Schwann cells, axons, endoneural fibroblasts, and nerve sheaths (Table 12-12-6). In contrast, the optic nerve, which represents a white-matter tract of the central nervous system (CNS), may give rise to CNS tumors such as astrocytomas and meningiomas. TABLE 12-12-6  FREQUENCY OF THE MOST COMMON NEUROGENIC ORBITAL LESIONS Lesion

Frequency (%)

Sphenoid wing meningioma Optic nerve glioma Neurofibroma Schwannoma Optic sheath meningioma Other

30 22 19 14 11 4

Data from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39; Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315; and the author’s personal data.

PLEXIFORM NEUROFIBROMA 1322

Key Points

Plexiform neurofibroma is the most common benign peripheral nerve tumor in the eyelid and orbit and is considered characteristic of

C Fig. 12-12-7  Embryonal rhabdomyosarcoma. (A) The patient has a unilateral right ocular proptosis of very recent onset. Often, rhabdomyosarcoma presents rapidly, causes lid redness, and is mistaken for orbital inflammation. (B) A marked embryonic cellular pattern is shown, hence the term embryonal rhabdomyosarcoma (A, relatively acellular area; B, blood vessels; C, relatively cellular area). (C) A trichrome stain shows characteristic cross-striations in the cytoplasm of some of the rhabdomyoblasts. Cross-striations (C), although not abundant in embryonal rhabdomyosarcoma, can be seen in sections stained with hematoxylin and eosin but are easier to see with special stains. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

neurofibromatosis.40–43 The tumor grows along the nerve, is invasive, and is not encapsulated. Key features are:  A propensity for sensory nerves, but may also involve motor, para­ sympathetic, and sympathetic nerves  Children in the first decade of life are affected most commonly  31% of plexiform neurofibromas occur in the eyelids. Clinically, this tumor has been described as a palpable ‘bag of worms,’ with thickened overlying skin and an S-shaped eyelid (Fig. 12-12-8). It may be associated with uveal neurofibromas (50%), iris (Lisch) nodules (77%), prominent corneal nerves (25%), optic nerve gliomas

12.12  Orbital Diseases

A

Fig. 12-12-8  Plexiform neurofibroma of the right eyelid in a child with neurofibromatosis.

N

N B

Fig. 12-12-9  Plexiform neurofibroma. Diffuse proliferation of Schwann cells within the nerve sheath enlarges the nerve. N, Thickened abnormal nerves.

Fig. 12-12-10  Neurilemmoma. (A) Proptosis of the patient’s left eye had been present for many months and was increasing in size. An orbital tumor was removed. (B) Ribbons of spindle Schwann cell nuclei can be seen. This shows a tendency toward palisading. Areas of relative acellularity, mimicking tactile corpuscles, are called Verocay bodies. This pattern is called the Antoni type A pattern. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

(15%), and pulsatile proptosis from an absence of the greater sphenoid wing.

frequently cystic. Orbital symptoms may include exophthalmos, diplo­ pia, and visual loss from optic nerve compression.

Orbital Imaging

Orbital Imaging

N

A diffuse, irregular mass is seen with variable contrast enhancement. It may involve extraocular muscles, orbital fat, and the cavernous sinus. On MRI the T1 is hypointense and the T2 hyperintense to muscle.

Pathology

Interwoven bundles of axons, Schwann cells, and endoneural fibro­ blasts are seen in a mucoid matrix (Fig. 12-12-9). A characteristic cel­ lular perineural sheath defines the tumor cords. Immunohistochemistry is positive for S100 stain.

Treatment and Prognosis

Surgical excision is generally difficult and frustrating, with excessive bleeding and a poor cosmetic result. Repeated debulking may be neces­ sary for severe symptoms, and orbital exenteration for extensive cases. Radiotherapy offers no benefit. There is a small risk of malignant transformation. These tumors may occasionally erode into the anterior cranial fossa, which results in death.

SCHWANNOMA (NEURILEMMOMA) Key Points

Schwannoma is a Schwann cell tumor that arises as an outpouching from peripheral or cranial nerves (e.g., acoustic neuroma). It has a neural crest origin.44 Schwannomas represent 1% of all orbital tumors and 35% of peripheral nerve tumors, They are mostly benign but rarely may undergo malignant transformation in patients with neurofibromatosis. Schwannoma is seen most commonly in young adults to middleaged individuals (20–50 years). It presents as a slow-growing, painless, well-defined solitary mass, usually in the superior orbit, and is

The tumor is typically an extraconal, fusiform, well-defined, some­ times cystic mass that is aligned anteroposteriorly along the involved nerve. On MRI the signal is homogeneous to heterogeneous; T1 is hypointense and T2 isointense to muscle.

Pathology

The encapsulated mass has yellow areas and patterns of cells described as Antoni A (whorls) or Antoni B (no palisading) patterns (Fig. 12-1210). Spindle cells are seen with vesiculated nuclei in a palisading con­ figuration. The cells are negative for alcian blue and positive for S100 stain.

Treatment and Prognosis

Surgical excision is required. The prognosis for life is good, except fol­ lowing intracranial spread. Late orbital recurrences may be seen after partial excision.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MALIGNANT SCHWANNOMA) Key Points

Malignant peripheral nerve sheath tumors are rare malignant tumors of Schwann cells and perineural cells that arise de novo or in associa­ tion with neurofibromatosis.45,46 When associated with neurofibroma­ tosis, the onset is slow, characterized by proptosis, globe displacement, and occasionally pain, ptosis, visual loss, diplopia, and chemosis. The tumors generally occur in patients 20–50 years of age, or earlier in neurofibromatosis. The clinical course is characterized by relentless invasion along tis­ sue planes to the middle cranial fossa. Metastases to the lungs are common.

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12

Orbital Imaging

A poorly defined, irregular mass is seen. Bone destruction may occur when the lesion is large.

Orbit and Oculoplastics

Pathology

The tumor has plexiform, swollen nerve bundles and spindle-shaped cells in whorls of interlacing fascicles.

Treatment and Prognosis

Wide surgical resection is required. Ancillary chemotherapy and radio­ therapy may be palliative only. Prognosis is very poor, with death from metastases or intracranial spread.

NEUROBLASTOMA Key Points

Neuroblastoma is an undifferentiated malignant tumor of primitive neuroblasts, which may be metastatic to the orbit.47 It represents the second most common malignant orbital tumor in children, after rhab­ domyosarcoma. It arises from the sympathetic system and ganglia and represents the peripheral nervous system counterpart of retinoblasto­ ma. Rarely, neuroblastomas may be primary lesions in the orbit, where they may arise from the ciliary ganglion. Key features are:  60% of the primary tumors occur in the abdomen.  10–40% of systemic neuroblastomas result in orbital metastases, on average 3 months after diagnosis of the primary.  90% of orbital lesions originate from the abdomen.  Only 8% of cases first present with an orbital lesion; in 92% of cases the presence of an extraorbital primary tumor is already known.  40% of orbital lesions are bilateral.  The mean age at presentation is 2 years old.  75% of cases occur before the age of 4 years. Symptoms include rapid progression of proptosis over several weeks, lid ecchymosis from necrosis and hemorrhage, eyelid edema, ptosis, Horner’s syndrome (from mediastinal tumors), papilledema, retinal striae, and decreased vision. Systemic symptoms may involve fever, weakness, and an abdominal or thoracic mass.

P

P

P

Orbital Imaging

Fig. 12-12-12  Optic nerve ‘glioma.’ Well-differentiated astrocytes spread out the pial septa (P). (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

Pathology

enlargement of the lesion occurs from mucoid degeneration and arach­ noid hyperplasia.

An irregular, poorly circumscribed mass is seen, frequently associated with bone destruction and separation of sutures, especially at the zygoma. Metastases to the skull bones occur in 74% of cases.

The lesion is a soft, friable, bluish mass; small round cells that resem­ ble lymphocytes with specks of calcium and areas of necrosis are seen. Electron microscopy reveals neurosecretory tubules.

Treatment and Prognosis

If no systemic primary disease exists, the orbital tumor can be excised. With systemic primary disease, chemotherapy yields resolution in 60–70% of cases in 4–6 months. Radiotherapy (1500 cGy in children and 4000 cGy in patients older than 10 years) may be used for local orbital disease. Recurrences may be seen in 90% of cases over 1–2 years, and a 50–60% mortality rate occurs after 2 years. Bony and orbital metastases are associated with a poorer prognosis.

OPTIC NERVE GLIOMA (PILOCYTIC ASTROCYTOMA OF CHILDHOOD) Key Points

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Fig. 12-12-11  Optic nerve glioma in a child with neurofibromatosis type 1.

Optic nerve glioma is a neoplasm of astrocytes48 that affects primarily children (mean age, 8 years). No sex predilection exists. The optic nerve alone is affected in 28% of cases; 72% involve the optic chiasm, and of these, 43% involve the chiasm and midbrain. In 29% there is an association with type 1 neurofibromatosis. In neurofibromatosis, the lesion may be bilateral. Symptoms include slow loss of vision, optic atrophy or edema, and proptosis. After an initial decrease, vision remains stable in 80% of patients. Hypothalamic signs may be seen in 22% of cases. Rapid

Orbital Imaging

Typically, the lesion appears as an intraconal, fusiform enlargement of the optic nerve, with or without a chiasmal mass. The nerve may appear kinked with cystic spaces. On MRI the T1 signal is hypotense to isointense, and the T2 signal shows variable intensity compared to muscle (Fig. 12-12-11). Enhancement with gadolinium is variable.

Pathology

Optic nerve gliomas demonstrate cystic spaces that contain a mucoid material and pial septae that are separated by well-differentiated astro­ cytes (Fig. 12-12-12). Eosinophilic Rosenthal fibers may represent degenerated astrocytic processes. Immunohistochemistry is positive for neuron-specific enolase.

Treatment and Prognosis

Treatment consists of observation if the vision is good. The patient should be followed with serial MRI scans. Surgical excision is offered if a tumor approaches the chiasm. Surgery also is indicated for pain or disfiguring proptosis. The role of radiotherapy remains controversial; it may be associated with CNS complications. More recently, chemo­ therapy has shown promising results.49 Prognosis for vision is poor. For lesions confined initially to the optic nerve, prognosis for life is good. For those lesions that involve the chiasm, mortality approaches 20%. Once the midbrain and hypothala­ mus are involved, the overall prognosis is poor, with mortality exceed­ ing 55%.

OPTIC NERVE SHEATH MENINGIOMA Key Points

Orbital Imaging

The lesion is usually seen as a tubular enlargement of the optic nerve with a characteristic ‘tram-track’ pattern of an enhancing nerve sheath with a lucent central nerve. Small areas of calcification may be seen. Marked contrast enhancement on computed tomography is character­ istic. On MRI the T1 signal is hypointense, and the T2 signal is hyper­ intense. Heterogeneity results from low signal areas that represent calcium. Areas of subarachnoid fluid distention are hyperintense.

Pathology

There are several histological types. The meningothelial type of lesion shows syncytial lobules of meningothelial cells. The psammomatous type demonstrates calcified concretions or psammoma bodies (Box 12-12-2). A rare angioblastic type contains vascular elements that resemble a hemangiopericytoma.

BENIGN REACTIVE LYMPHOID HYPERPLASIA Key Points

This disease constitutes a benign proliferation of lymphoid follicles that contain polymorphic lymphocytes that are immunohistochemi­ cally polyclonal.54,55 Benign reactive lymphoid hyperplasia (BRLH) occurs most commonly in the anterior superior orbit, with a predilec­ tion for the lacrimal gland (15%). The clinical course is indolent, with painless exophthalmos, globe displacement, and typically normal vision. A firm, rubbery mass is often palpable beneath the orbital rim, and there may be a pink subconjunctival ‘salmon-patch’ infiltrate.

12.12  Orbital Diseases

Optic nerve sheath meningioma is a benign neoplasm of meningothe­ lial cells of arachnoid tissue50 that affects primarily middle-aged adults (20–60 years). Women are involved slightly more commonly than men, at a ratio of 3 : 2. In 4–9% of cases there is an association with type 1 neurofibromatosis, and in 6% of cases the lesion may be bilateral; 5% of meningiomas are confined to the optic canal, which makes diagnosis difficult. Symptoms and signs include slowly progressive proptosis over sev­ eral years, visual loss, optic disc edema, optic atrophy, development of opticociliary shunt vessels, and ocular motility restriction.

(pseudotumors), lymphoproliferative reactive and atypical diseases, and lymphomas. The relationships between the last two groups and their relationship to systemic disease are not always clear, and some confu­ sion still surrounds the diagnosis and prognosis of each.

Orbital Imaging

An infiltrative mass is seen in the eyelids or anterior orbit. It typically molds to the globe and other adjacent structures and may extend along the rectus muscles. On MRI the T1 signal is hypointense and the T2 signal hyperintense to muscle.

Pathology

Typically, the tumor is a polymorphous array of small lymphocytes and plasma cells, with mitotically active germinal centers (Fig. 12-12-13). Immunohistochemistry is positive for polyclonal T- and B-cell markers.

Treatment and Prognosis

Treatment involves systemic corticosteroids or local radiotherapy at 1500–2000 cGy. Some lesions may require cytotoxic agents (chloram­ bucil) for control. There is a 15–25% chance of developing systemic lymphoma within 5 years.

BOX 12-12-2 CALCIFIED ORBITAL LESIONS Phlebolith Orbital varix Lymphangioma Thrombosed atrioventricular shunt Chronic inflammation Malignant lacrimal gland tumors Optic nerve sheath meningioma Dermoid cyst Mucocele walls Fibro-osseous tumors

ATYPICAL LYMPHOID HYPERPLASIA Key Points

Atypical lymphoid hyperplasia (ALH) represents an intermediate between BRLH and malignant lymphoma and may be unilateral or bilateral. Presentation is as for BRLH, but ALH may involve other sys­ temic organs and more frequently does not respond to corticosteroids. There is a 15% incidence of extraorbital involvement. Systemic lym­ phoma may develop.

Treatment and Prognosis

Treatment consists of observation if the vision remains good. In patients with blindness and significant proptosis, or when the optic canal is threatened, surgical excision is indicated.51 Radiotherapy may slow progression.52,53 Prognosis for life is excellent, but visual outcome typically is poor.

LYMPHOPROLIFERATIVE DISEASES

Orbital Imaging and Echography

Computed tomography and MRI scans are similar to those for BRLH.

Pathology

Monomorphous sheets of lymphocytes that have larger nuclei than those of BRLH are seen. Some abortive follicles may be present.

Treatment and Prognosis

INTRODUCTION Lymphoid lesions are uncommon in the orbit and account for 6% of all orbital mass lesions (Table 12-12-7). This group includes lymphocytic, plasmacytic, and leukemic lesions. Among the lymphoid infiltrates, lesions are divided into three categories: idiopathic inflammations TABLE 12-12-7  FREQUENCY OF LYMPHOPROLIFERATIVE DISEASES OF THE ORBIT Disease

Frequency (%)

Lymphoma Reactive and atypical lymphoid hyperplasia Plasma cell dyscrasias Leukemia Histiocytoses

51 36 7 2 4

Modified from Dutton JJ, Frazier Byrne S, Proia A. Diagnostic atlas of orbital diseases. Philadelphia, PA: WB Saunders; 2000. p. 1–5.

If no systemic involvement exists, radiotherapy at 2500–3000 cGy is appropriate. There is a 40% chance of systemic lymphoma developing within 5 years.

MALIGNANT ORBITAL LYMPHOMA (LYMPHOSARCOMA) Key Points

Malignant orbital lymphoma is a low-grade malignancy characterized by a proliferation of monoclonal B cells (non-Hodgkin’s), which arise in lymph nodes or in an extranodal site such as the orbit.56–59 Most com­ monly affected is the older age group (50–70 years). Clinically, a palpa­ ble mass may be present in the anterior orbit. Symptoms include exophthalmos, occasional diplopia, lid edema, and ptosis (Fig. 12-12-14). In 75% of cases the process is unilateral, and in 25% it is bilateral; 40% of cases are associated with systemic disease at the time of diagnosis.

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12 Orbit and Oculoplastics

A

Fig. 12-12-15  Lymphoma infiltrating along the lateral orbital wall.

Orbital Imaging

A well-defined mass is seen that molds to encompass adjacent struc­ tures. Most lesions are located in the anterior, superior, and lateral orbit and frequently involve the lacrimal gland (Fig. 12-12-15).

Pathology

Infiltrative, anaplastic lymphocytes with large cleaved nuclei and fre­ quent nucleoli are seen. Follicles are absent. Immunohistochemistry reveals a monoclonal proliferation of B cells.

Treatment and Prognosis

B Fig. 12-12-13  Reactive lymphoid hyperplasia. (A) The patient noted a fullness of the lower right lid. Large, thickened, redundant folds of conjunctiva in the inferior cul-de-sac are seen. The characteristic ‘fish flesh’ appearance of the lesion suggests the clinical differential diagnosis of a lymphoid or leukemic infiltrate or amyloidosis. (B) Lymphocytes are mature, quite small, and uniform; occasional plasma cells are large monocytoid lymphocytes. The uniformity of the lymphocytes makes it difficult to differentiate this benign lesion from a well-differentiated lymphosarcoma. The very mature appearance of the cells and the absence of atypical cells, along with the presence of plasma cells, suggests the diagnosis of a benign lesion. In such cases, testing using monoclonal antibodies may be quite helpful. If the population is of mixed B and T cells, the chances are that the tumor is benign. If it is predominantly of one cell type or the other, usually B cells, it is probably malignant and may represent mucosal-associated lymphoid tissue of the conjunctiva. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

If no systemic involvement occurs, observation is warranted for lowgrade differentiated lesions. For less well-differentiated types, chemo­ therapy or radiotherapy at 2500–4000 cGy is recommended, with local control rates of 60–100%.60 When the disease is confined to the orbit, the visual prognosis is excellent, but the overall prognosis for life is variable. A 60% chance exists of developing systemic lymphoma within 5 years.

HISTIOCYTIC TUMORS INTRODUCTION Histiocytic tumors are rare proliferative disorders of histiocytes that range from solitary benign lesions to those that exhibit a more malignant course. A typical feature of all these lesions is the presence of Langerhans’ cells, a type of histiocyte normally found in the epidermis.

EOSINOPHILIC GRANULOMA (HISTIOCYTOSIS X) Key Points

Eosinophilic granuloma is the most common and benign form of the histiocytosis X group. The disease affects primarily children and teen­ agers (from birth to 20 years of age). It consists of a unifocal, granulo­ matous proliferation in bone. Orbital involvement occurs in up to 20% of cases, most commonly in the superotemporal orbit. Clinically, a rapid onset of abaxial displacement of the globe occurs and painful superolateral swelling. Erythema and inflammatory signs are seen in the overlying skin.

Orbital Imaging

Typically, an osteolytic lesion is seen near the superotemporal bony rim. Usually an irregular contour is noted, with marginal hyperostosis. Occasionally, the lesion may extend into the cranial fossa. Fig. 12-12-14  Subconjunctival anterior orbital lymphoma.

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Pathology

This is a soft, friable, tan–yellow tumor with sheets of binuclear histio­ cytes, eosinophils, and giant cells (Fig. 12-12-16). Characteristic Lang­ erhans’ granules are seen in the cytoplasm.

Orbital Imaging

Posterior Tenon’s capsule shows thickening and enhancement. A shaggy orbital infiltrate or discrete mass is present, which may mold to the globe or optic nerve sheath. The lacrimal gland may be enlarged. On MRI the T1 signal is hypointense and the T2 signal is hyperintense to muscle. Moderate enhancement occurs with gadolinium.

12.12  Orbital Diseases

teenagers to the elderly.61 Most commonly it occurs in the anterior or mid orbit, and it frequently involves the lacrimal gland. It is typically unilateral but rarely may be bilateral. Uveitis and retinal detachment may be associated with scleritis. Symptoms include abrupt pain, conjunctival injection, chemosis, lid edema, exophthalmos, and motility restriction. A palpable mass is detected in 50% of cases.

Pathology A

The pseudotumor is a gray rubbery mass composed of a polymorphic infiltrate of lymphocytes, eosinophils, plasma cells, and polymorpho­ nuclear leukocytes. In the sclerosing type, the dominant feature is scarification and collagen deposition.

Treatment and Prognosis

Systemic corticosteroids typically result in a dramatic improvement. Rarely, some lesions may require cytotoxic agents. The sclerosing type shows little or no response to treatment. Prognosis generally is excellent, with complete resolution of disease.

MYOSITIS Key Points

An acute to subacute idiopathic inflammation of the extraocular mus­ cles, myositis may affect teenagers to the elderly.62 Typically, the disease is unilateral and involves only one muscle, most commonly the supe­ rior or lateral rectus. Symptoms include pain, motility restriction, exophthalmos, and displacement of the globe. B Fig. 12-12-16  Eosinophilic granuloma. (A) A 4-year-old boy presented clinically with rapid onset of erythema and swelling over the lateral edge of the left orbit. Osteomyelitis versus rhabdomyosarcoma was diagnosed clinically; the area was explored surgically. (Courtesy of Dr D. B. Schaffer.) (B) Histological section shows large histiocytes (abnormal Langerhans’ cells) and numerous eosinophils characteristic of a solitary eosinophilic granuloma. (Courtesy of Dr D.B. Schaffer. In: Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

Treatment and Prognosis

Surgical curettage generally is curative, but radiotherapy at 900– 1500 cGy also may be used. The prognosis is very good.

INFLAMMATIONS AND INFECTIONS INTRODUCTION Inflammatory diseases are common orbital lesions that may simulate neoplasms. They include a variety of acute and subacute idiopathic processes, chronic inflammations, and specific inflammations of uncer­ tain etiology. Most notable among these lesions is Graves’ orbitopathy, which accounts for more than half of all such cases.

DIFFUSE IDIOPATHIC ORBITAL INFLAMMATION (PSEUDOTUMOR) Key Points

Diffuse orbital pseudotumor is a nongranulomatous acute to subacute inflammatory disease with no systemic manifestations that may affect

Orbital Imaging

Enlargement of an extraocular muscle is seen, with involvement of the entire muscle from origin to insertion.

Treatment and Prognosis

Systemic corticosteroids generally result in prompt resolution. The prognosis is excellent.

THYROID ORBITOPATHY (GRAVES’ DISEASE) Key Points

Thyroid orbitopathy is an immunological disorder that affects the orbital muscles and fat.63,64 Hyperthyroidism is seen with orbitopathy at some point in most patients, although the two are commonly asyn­ chronous. Key features are:  Middle-aged adults (30–50 years) are affected most frequently.  The disease is seen in women more commonly than in men, in a ratio of 3−4 : 1.  It is always a bilateral process but is often asymmetrical.  Multiple muscles are involved simultaneously, most commonly the inferior and medial rectus. Symptoms and signs include dry eyes, conjunctival injection, lid retraction, exophthalmos, diplopia, corneal exposure, and rarely optic nerve compression. Graves’ disease usually runs a progressive course for 3–5 years and then stabilizes.

Orbital Imaging

Increased fat lucency is seen, as well as extraocular muscle enlargement confined to the bellies, but with sparing of the insertions and origins. On MRI the T1 is isointense and the T2 isointense to slightly hyper­ intense to muscle.

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The orbital disease is usually progressive over 1–5 years, followed by stabilization. Eyelid recession, strabismus surgery, or orbital decom­ pression may be offered after stabilization, as needed, to improve func­ tion and cosmesis.

12 Orbit and Oculoplastics

ORBITAL CELLULITIS Key Points

A

The major causes of orbital cellulitis are sinusitis (58%), lid or face infection (28%), foreign body (11%), and hematogenous (4%).65 Staphylococcus and Streptococcus are the most common causative organisms in adults, Haemophilus influenzae in children. Less common organ­ isms are Pseudomonas and Escherichia coli. Orbital symptoms are pain, lid edema and erythema, chemosis, and axial proptosis if diffuse disease occurs or abaxial displacement if an abscess forms. Decreased ocular motility is common, and intraocular pressure may be elevated. A rapid loss of vision from optic nerve com­ pression, optic neuritis, or vasculitis may ensue. With posterior exten­ sion, cavernous sinus thrombosis, subdural empyema, and intracranial abscess may develop. Systemic symptoms may include malaise and fever. If the cavernous sinus is involved, headache, nausea, vomiting, and decreased con­ sciousness may supervene. The warning signs of orbital cellulitis are a dilated pupil, marked ophthalmoplegia, loss of vision, afferent pupillary defect, papilledema, perivasculitis, and violaceous lids.

Orbital Imaging

Diffuse orbital infiltrate is seen, often with opacification of adjacent sinuses.

Treatment and Prognosis B

In children, treatment is with systemic antibiotics; sinus drainage is needed in only 50% of cases. In adults, the drainage of sinuses and abscesses may be needed in 90% of cases. The prognosis is very good with prompt antibiotic therapy and surgi­ cal drainage when indicated.

WEGENER’S GRANULOMATOSIS Key Points

C Fig. 12-12-17  Graves’ disease. (A) In Graves’ disease, exophthalmos often looks more pronounced than it actually is because of the extreme lid retraction that may occur. This patient, for instance, had minimal proptosis of the left eye but marked lid retraction. (B) The orbital contents obtained post mortem from a patient with Graves’ disease. Note the enormously thickened extraocular muscle. (C) Both fluid and inflammatory cells separating the muscle bundles may be seen. The inflammatory cells are predominantly lymphocytes, plus plasma cells. (A, Courtesy Dr H.G. Scheie. In: Yanoff M, Fine BS. Ocular pathology. 5th ed. St. Louis, MO: Mosby; 2002. B−C, Courtesy Dr R.C. Eagle Jr. In: Hufnagle TJ, et al. Ophthalmology. 1984;91:1411.)

Wegener’s granulomatosis is a necrotizing granulomatosis of the upper respiratory tract, characterized by vasculitic pneumonitis, glomerulo­ nephritis, sinusitis, and mucosal ulcerations of the nasopharynx.66 A limited form does not involve the kidney. The cause is T-cell immune complex formation secondary to inhaled antigens. Key features are:  Peak incidence is in adults 40–50 years of age.  Men are more commonly affected than women, in a ratio of 2 : 1.  Classic antineutrophil cytoplasmic antibody is positive in 80% of cases.  40–50% of patients may have ocular involvement (mostly contigu­ ous from the sinus or pharynx, but it may be isolated).  18–22% of patients demonstrate orbital involvement, usually bilateral. Symptoms are chemosis, exophthalmos, motility restriction, papille­ dema, and decreased vision. Ocular tissue involvement may include scleritis and episcleritis (20–38%), uveitis (10–20%), peripheral corneal guttering (14–28%), and retinal vasculitis (7–18%).

Orbital Imaging

A diffuse orbital mass may be bilateral and may involve the adjacent nasopharynx.

Pathology

The enlarged, rubbery muscles show variable amounts of edema and infiltration with inflammatory round cells (Fig. 12-12-17). An increased amount of acid mucopolysaccharides infiltrates the orbital tissue.

Treatment and Prognosis 1328

Symptomatic therapy is given until the disease stabilizes. Systemic corticosteroids or radiotherapy may be indicated for acute orbital inflammation and congestion.

Pathology

The pathology is necrotizing granulomatous vasculitis with giant cells.

Treatment and Prognosis

Treatment consists of administration of systemic corticosteroids plus cyclophosphamide or azathioprine. Radiotherapy is of doubtful value Improvement with systemic therapy is usual, with up to 90% remission.

Patients who have the more limited form of the disease have a better prognosis.

INTRODUCTION Structural lesions of the orbit include choristomatous lesions such as dermoid cysts, which arise from errors in embryogenesis, and anatomi­ cal abnormalities such as mucoceles, which result from local disease processes (Box 12-12-3).

DERMOID CYST Key Points

A dermoid cyst is a developmental choristoma, lined with epithelium and filled with keratinized material.67,68 The majority of such cysts are located in the eyelids and orbit (Fig. 12-12-18). These cysts represent 24% of all orbital and lid masses, 6–8% of deep orbital masses, and 80% of cystic orbital lesions. Dermoid cysts may lie latent for many years before growth and may be located superficially in the eyelid and ante­ rior orbit or deep in the orbit. If ruptured, sudden growth may occur because of a secondary granulomatous inflammatory reaction.

Superficial Lesions

Superficial lesions arise from a sequestration of epithelium during embryogenesis along bony suture lines. They are present in early infancy, typically in the superotemporal or superonasal quadrants. Clinically, they present as a slowly enlarging, unilateral, painless, firm mass; they may be mobile or fixed to underlying structures and are free from overlying skin.

Orbital imaging

The round, well-defined lesions have an enhancing rim that may con­ tain calcium, and a lucent center. They may be associated with a wellcorticated bone defect.

BOX 12-12-3  COMMON CYSTIC LESIONS OF THE ORBIT  Dermoid cysts  Conjunctival cysts  Sweat gland cysts  Microphthalmos with cyst  Lacrimal gland cysts  Lymphangioma  Schwannoma  Infectious abscesses Modified from Rootman JL. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA:  JB Lippincott; 1988. p. 119–39.

Fig. 12-12-18  Right superomedial superficial orbital dermoid cyst in a young child.

The cyst usually has a thin, fibrous capsule and a central lumen lined with keratinized stratified squamous epithelium. If derived from con­ junctiva, the lining may be cuboidal with goblet cells. The cyst wall contains hair follicles and sweat and sebaceous glands. The cyst con­ tains keratin debris, hair shafts, and oily material. About 38% of cysts are associated with chronic granulomatous inflammation.

Treatment and prognosis

Complete surgical excision in one piece is required. The prognosis is excellent, but recurrences with infiltration may follow incomplete exci­ sion or rupture of the capsule.

12.12  Orbital Diseases

STURCTURAL LESIONS

Pathology

Deep Lesions

Deep lesions are seen in both children and adults. They are associated with any bony suture in the orbit and may extend across bones into the frontal sinus, temporal fossa, or cranium. Symptoms from the slow-growing mass include proptosis, occasion­ ally motility restriction, and decreased vision. Spontaneous rupture produces marked orbital inflammation.

Orbital imaging

The well-defined lesion has an enhancing rim that may contain areas of calcification. The central lumen is non-enhancing and of variable density, depending on its contents; it may show a fluid–fat interface. A bone defect may be seen.

Pathology

A smooth, thin rim of keratinized squamous epithelium, which may have goblet cells if derived from conjunctiva, lines the cyst. The cyst wall contains hair shafts, and sweat and sebaceous glands are characteristic.

Treatment and prognosis

Treatment consists of total excision without rupture of the capsule. The prognosis is excellent.

MUCOCELE Key Points

Mucoceles arise from a primary obstruction of a paranasal sinus follow­ ing trauma, sinusitis, or, rarely, a tumor.69 Frequently, they expand into the orbit by expansion of a bony wall. Mucoceles consist of a cystic mass filled with mucus and may be bounded by an eggshell layer of bone (when they become infected, mucoceles are referred to as pyo­ celes). The majority of mucoceles (70%) occur in adults (aged 40–70 years), and the frontal and ethmoid sinuses are most commonly involved − rarely the sphenoid sinus. Symptoms include headache, exophthalmos, and a palpable fluctu­ ant mass in the medial or superomedial orbit.

Orbital Imaging

An opacified frontal or ethmoid sinus, loss of ethmoid septae, and a bony dehiscence (Fig. 12-12-19) are observed. The cystic content shows variable density and is non-enhancing.

Fig. 12-12-19  Anterior ethmoid sinus mucocele eroding into the orbit.

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12

Pathology

Orbit and Oculoplastics

The lining is composed of pseudostratified, ciliated columnar epitheli­ um with goblet cells. The cyst content is mucoid with chronic inflam­ matory debris.

Treatment and Diagnosis

Treatment consists of surgical excision with restoration of sinus drain­ age. Obliteration of the sinus with fat or muscle may be necessary to treat recurrences. The prognosis is very good, but there is a significant rate of recurrence.

VASCULAR NEOPLASTIC LESIONS INTRODUCTION Neoplastic lesions that arise from the vascular system include both benign and malignant tumors (Table 12-12-8). Unlike non-neoplastic vascular lesions, which usually reflect the hemodynamic functions of the underlying vascular structures, neoplastic lesions typically manifest only a mass effect, occasionally modified by some hemodynamic char­ acteristics. They may be well circumscribed or infiltrative.

CAPILLARY HEMANGIOMA (HEMANGIOENDOTHELIOMA) Key Points

Capillary hemangioma is a congenital hamartoma of tightly packed capillaries that typically presents during the first 6 months of life.6,56,70,71 It is generally unilateral and usually visible on the surface, but it may lie deep in the orbit (Fig. 12-12-20). More common in the supero­ nasal quadrant of the upper lid, capillary hemangioma appears as a fluctuant mass that may involve the overlying skin as a reddish lesion.

TABLE 12-12-8  FREQUENCY OF THE MOST COMMON VASCULAR ORBITAL LESIONS Lesion

Frequency (%)

Cavernous hemangioma Capillary hemangioma Hemangiopericytoma Lymphangioma Orbital varices Other

50 18 13 10 5 5

Modified from Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315.

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Fig. 12-12-20  Capillary hemangioma of the lower eyelid in a young child.

Capillary hemangiomas show rapid growth over weeks to months, fol­ lowed by slow spontaneous involution over months to years.

Superficial Lesions

Also known as the ‘strawberry nevus,’ capillary hemangioma is con­ fined to the dermis. It may be single or multiple and is generally elevat­ ed. Symptoms include ptosis, sometimes associated with astigmatism and amblyopia.

Treatment and prognosis

Observation is warranted in most cases, since involution usually occurs. Recently, systemic propranolol for 8-12 months has been shown to achieve dramatic resolution for lesions in the proliferative phase.72 Intralesional steroids, radiotherapy, and, more recently, topical corticosteroids also have been advocated. Surgery is useful for small, circumscribed lesions, but for larger ones, this may result in cosmetic compromise. The prognosis is good; 30% of cases involute by 3 years of age, 60% by 4 years of age, and 75% by 7 years of age. Large lesions may not completely disappear.

Deep Lesions

Deep lesions occur most frequently in the lids or posterior to orbital septum and are more common in the superonasal quadrant. Symptoms are proptosis, displacement of the globe, subtle pulsa­ tions as a result of high vascular flow, and increasing size with the Valsalva maneuver or crying. Secondary amblyopia may result from distortion of the globe. Large lesions may sequester platelets.

Orbital imaging

A well-defined to infiltrating intraconal or extraconal lesion is observed, with moderate to intense enhancement. On MRI the signals are homo­ geneous to heterogeneous, being hypointense on T1 and hyperintense on T2 images. Flow voids appear as hypointense regions. Moderate enhancement is seen with gadolinium.

Pathology

A florid proliferation of capillary endothelial cells and small capillaries is seen, with few spaces (Fig. 12-12-21). Mitoses are common, but this is not a malignant tumor.

Treatment and prognosis

Treatment consists of observation, since many lesions will involute, although few orbital lesions completely disappear. If the lesion is large or amblyopia is present, local radiotherapy (500 cGy) or corticosteroids (systemic or local) may be indicated. If the lesion is small and welldefined, surgery may be attempted. Recently, propranolol has been shown to cause significant involution for tumors in the proliferative phase.73 The prognosis is excellent for vision and for life.

Fig. 12-12-21  Capillary hemangioma. The tumor is composed of blood vessels of predominantly capillary size. (From a presentation by Dr W.C. Frayer to the meeting of the Verhoeff Society, 1989.)

CAVERNOUS HEMANGIOMA

LYMPHANGIOMA

Key Points

Key Points

Orbital Imaging

A well-defined, oval to round, typically intraconal mass is seen with minimal enhancement. With large, long-standing lesions, molding of bone and internal calcification may occur. On MRI the lesion is iso­ intense on T1 and hyperintense on T2 with respect to muscle. Signal voids represent calcific phleboliths. Enhancement with gadolinium is moderate.

Pathology

The encapsulated nodular mass consists of dilated, vascular spaces lined by flattened endothelial cells (Fig. 12-12-22). Septae may contain lymphocytes and smooth muscles cells.

Treatment and Prognosis

Surgical excision is required if the lesion is symptomatic − typically, there is little or no bleeding. There is no role for radiotherapy. The prognosis is excellent for vision and life.

Lymphangioma is a rare vascular hamartoma of lymphatic channels that is hemodynamically isolated from the vascular system.74 It occurs in children and teenagers, but most frequently in the first decade of life. The size of the lesion fluctuates with posture and the Valsalva maneu­ ver, and with upper respiratory infections.

Superficial Lesions

Superficial lesions occur in the conjunctiva or lid and are visible as cystic spaces with clear fluid; they may be partially filled with blood.

Orbital Diseases

Cavernous hemangioma is a benign, noninfiltrative, slowly progressive tumor of large endothelial-lined channels.5,6 Although it is congenital, it typically becomes symptomatic in adults (aged 20–40 years). Cavern­ ous hemangioma is usually found in an intraconal location, more com­ monly in the temporal quadrant. Rarely, it may be intraosseous. Symptoms relate to its mass effect, which produces proptosis and late motility restriction. When cavernous hemangiomas are very large, choroidal folds and decreased vision may result. The lesions may enlarge during pregnancy.

12.12 

Deep Lesions

Symptoms with deep lesions are proptosis and diplopia. Spontaneous hemorrhage may lead to sudden enlargement and orbital pain and pos­ sible visual loss, with the formation of ‘chocolate cysts.’

Orbital Imaging

The orbital lesion is seen as a low-density cystic, intra- and extraconal mass, with variable enhancement. There is no vascular component on angiography. On MRI the lesion is hypointense on T1; on T2 the signal is hyperintense but may be variable, depending on the state of hemo­ globin degeneration.

Pathology

Lymphangiomas show infiltrative endothelium-lined channels, with a sparse cellular framework and lymphocytes. Lymphatic follicles often are seen in the walls of the tumor. Red blood cells are not present unless a secondary hemorrhage has occurred.

Treatment and Prognosis

Observation is justified in most cases. Surgery may be hazardous and lead to poor cosmetic results. If acute hemorrhage causes severe symp­ toms, the lymphangioma may be evacuated and partial resection or ligation attempted. Recurrences are common. The lesion shows limited radiosensitivity. The prognosis is variable. Amblyopia is common from globe compression and recurrent hemorrhage.

ARTERIOVENOUS FISTULA Key Points

Arteriovenous fistulas can be traumatic (more common in males than females, age range 15–30 years) or spontaneous (more common in females than males, age range 30–60 years).5,6 Symptoms depend on blood flow rate − most fistulas are associated with venous dilation, fluid transudation, sludging, and thrombosis.

A

Low-flow type

Low-flow fistulas usually result from dural artery-to-cavernous sinus shunts. Symptoms are chemosis, increased episcleral venous pressure, and venous dilatation.

High-flow type

High-flow fistulas usually result from carotid artery-to-cavernous sinus shunts. Symptoms are chemosis, orbital edema, proptosis, pulsatile exophthalmos, audible bruit, secondary glaucoma, retinal vascular dila­ tion, papilledema, afferent pupillary defect, decreased vision, and cra­ nial nerve palsies (third and sixth nerves most common).

Primary shunt

Primary shunts (mainly congenital malformations) are rare in the orbit and are usually associated with syndromes (e.g., Wyburn–Mason and Osler–Weber–Rendu). B Fig. 12-12-22  Cavernous hemangioma. (A) Clinical appearance of left exophthalmos. (From a presentation by Dr W.C. Frayer to the meeting of the Verhoeff Society, 1989.) (B) MRI shows optic nerve stretched over tumor that ‘lights up’ in the T2-weighted image, characteristic of a hemangioma. (Reproduced with permission from Yanoff M, Fine BS. Ocular pathology. 5th ed. St Louis, MO: Mosby; 2002.)

Secondary shunts

Secondary shunts are located outside the orbit, usually in the cavernous sinus. Retrograde blood flow is directed forward into the orbital veins. Secondary shunts may be spontaneous (from venous thrombosis or hypertension) or secondary (from trauma). The latter are usually of the high-flow type, 40–50% causing visual loss.

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12 Orbit and Oculoplastics 1332

Orbital Imaging

A dilated superior ophthalmic vein with enlargement of the superior orbital fissure is seen; erosion of the anterior clinoid processes occurs.

Treatment and Prognosis

Resolution of small, spontaneous low-flow shunts frequently occurs from thrombosis and is seen in up to 40% of cases. Embolization is not indicated unless visual loss, glaucoma, or severe pain is present. With traumatic, high-flow shunts, spontaneous resolution is less common. The rate of visual loss is 40–50%, and intervention is therefore required. Balloon or other embolization is the treatment of choice. With treatment, the prognosis is generally good for vision.

Access the complete reference list online at

KEY REFERENCES Ahmed SM, Esmaeli B. Metastatic tumors of the orbit and ocular adnexa. Curr Opin Ophthalmol 2007;18:405–13. Dutton JJ, Byrne SF, Proia A. Diagnostic atlas of orbital diseases. Philadelphia, PA: WB Saunders; 2000. Rootman J. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39. Shields CL, Shields JA, Peggs M. Metastatic tumors to the orbit. Ophthal Reconstr Plast Surg 1988;4:73–80. Shields JA, Shields CL. Eyelid, conjunctival, and orbital tumors. 2nd ed. Philadelphia, PA: Lippincott Williams & Williams; 2008. Shinder R, Al-Zubidi N, Esmaeli B. Survey of orbital tumors at a comprehensive cancer center in the United States. Head Neck 2011;33:610–14.

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3. Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with orbital tumors and simulating lesions: The 2002 Montgomery Lecture, part I. Ophthalmology 2004;111: 997–1008. 4. Shields JA, Shields CL. Eyelid, conjunctival, and orbital tumors. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008. 5. Rootman J. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. p. 119–39. 6. Shields JA. Metastatic cancer to the orbit. In: Shields JA, editor. Diagnosis and management of orbital tumors. Philadelphia, PA: WB Saunders; 1989. p. 291–315. 7. Ahmed SM, Esmaeli B. Metastatic tumors of the orbit and ocular adnexa. Curr Opin Ophthalmol 2007;18:405–13. 8. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974;92:276–86. 9. Hart WM. Metastatic carcinoma to the eye and orbit. In: Zimmerman LE, editor. Tumors of the eye and adnexa. Int Ophthalmol Clin 1962;2:465–82. 10. Shields CL, Shields JA, Peggs M. Metastatic tumors to the orbit. Ophthal Reconstr Plast Surg 1988;4:73–80. 11. Rasmussen P, Ralfkiaer E, Prause JU, et al. Malignant lymphoma of the lacrimal gland: a nation-based study. Arch Ophthalmol 2011;129:1275–80. 12. Font RL, Gamel JW. Epithelial tumors of the lacrimal gland: an analysis of 265 cases. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham: Aesculapius; 1978. p. 787.

38. Shields JA, Shields CL. Rhabdomyosarcoma: review for the ophthalmologist. Surv Ophthalmol 2003;48:39–57. 39. Franca CM, Caran EM, Alves MT, et al. Rhabdomyosarcoma of the oral tissues – two new cases and literature review. Med Oral Patol Oral Cir Bucal 2006;11:E136−40. 40. Gurland JE, Tenner M, Hornblass A, et al. Orbital neurofibromatosis. Arch Ophthalmol 1976;94:1723–5. 41. Korbin EA, Blodi FC, Weingeist TA. Ocular and orbital manifestations of neurofibromatosis. Surv Ophthalmol 1984;188:118–27. 42. Della Rocca RC, Roen J, Labay JR, et al. Isolated neurofibroma of the orbit. Ophthalmic Surg 1985;16:634–8. 43. Farris SR, Grove AS Jr. Orbital and eyelid manifestations of neurofibromatosis: a critical study and literature review. Ophthal Plast Reconstr Surg 1996;12:245–59. 44. Rootman J, Goldberg C, Robertson W. Primary orbital schwannomas. Br J Ophthalmol 1982;66:194–204. 45. Jakobiec FA, Font RL, Zimmerman LE. Malignant peripheral nerve sheath tumors of the orbit. A clinicopathologic study of eight cases. Trans Am Ophthalmol Soc 1985;83:332–66. 46. Dutton JJ, Tawfik HA, DeBacker CM, et al. Multiple recurrences in malignant peripheral nerve sheath tumor of the orbit: a case report and review of the literature. Ophthal Plast Reconstr Surg 2001;17:293–9. 47. Traboulsi EI, Shammas IV, Massad M, et al. Ophthalmological aspects of metastatic neuroblastoma. Report of 22 consecutive cases. Orbit 1984;3:247–54. 48. Dutton JJ. Gliomas of the anterior visual pathways. Surv Ophthalmol 1993;38:427–52. 49. Listernick R, Louis DN, Packer RJ, et al. Optic nerve gliomas in children with NF-1: consensus statement for the NF-1 Optic Pathway Glioma Task Force. Ann Neurol 1997;141:143–9. 50. Dutton JJ. Optic nerve sheath meningiomas. Surv Ophthalmol 1994;37:167–83.

13. Bernardini FP, Devoto MH, Croxatto JO. Epithelial tumors of the lacrimal gland: an update. Curr Opin Ophthalmol 2008;19:409–13.

51. Boulos PT, Dumont AS, Mandell JW, et al. Meningiomas of the orbit: contemporary considerations. Neurosurg Focus 2001;10(5):E5.

14. Goder GJ. Tumours of the lacrimal gland. Orbit 1982;1:91–6.

52. Carrasco JR, Penne RB. Optic nerve sheath meningiomas and advanced treatment options. Curr Opin Ophthalmol 2004;15:406–10.

15. Zimmerman LA, Sanders TE, Ackerman LV. Epithelial tumors of the lacrimal gland: prognostic and therapeutic significance of histologic types. Int Ophthalmol Clin 1962;2: 337–67.

53. Turbin RE, Pokorny K. Diagnosis and treatment of orbital optic nerve sheath meningioma. Cancer Control 2004;11:334–41.

16. Lemke AJ, Hosten N, Neumann K, et al. Space occupying lesions of the lacrimal gland in CT and MRI exemplified by four cases. Aktuelle Radiol 1995;5:363–6.

54. Knowles DM II, Jakobiec FA. Ocular adnexal lymphoid neoplasms: clinical, histopathologic, electron microscopic, and immunologic characteristics. Hum Pathol 1982;13:148–62.

17. Sanders TE, Ackerman LV, Zimmerman LE. Epithelial tumors of the lacrimal gland. A comparison of the pathologic and clinical behavior with those of the salivary glands. Am J Surg 1962;104:657–65.

55. Ellis JH, Banks PM, Campbell RJ, et al. Lymphoid tumors of the ocular adnexa. Clinical correlation with the working formulation, classification and immunoperoxidase staining of paraffin sections. Ophthalmology 1985;92:1311–24.

18. Mercado GJ, Grunduz K, Shields CL, et al. Pleomorphic adenoma of the lacrimal gland in a teenager. Arch Ophthalmol 1998;116:962–3.

56. Dutton JJ, Byrne SF, Proia A. Diagnostic atlas of orbital diseases. Philadelphia, PA: WB Saunders; 2000.

19. Rose GE, Wright JE. Pleomorphic adenoma of the lacrimal gland. Br J Ophthalmol 1992;76:395–400.

57. Arnow SJ, Notz RG Eosinophilic granuloma of the orbit. Trans Acad Ophthalmol Otolaryngol 1983;36:41–8.

20. Alyahya GA, Stenman G, Persson F, et al. Pleomorphic adenoma arising in an accessory lacrimal gland of Wolfring. Ophthalmology 2006;113:879.

58. Farmer JP, Lamba M, Lamba WR, et al. Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis. Can J Ophthalmol 2005;40:151–60.

21. Font RL, Gamel JW. Adenoid cystic carcinoma of the lacrimal gland. A clinicopathologic study of 79 cases. In: Nicholson DH, editor. Ocular pathology update. New York: Masson; 1980. p. 277–83.

59. Coupland SE, Hummel M, Stein H. Ocular adnexal lymphomas: five case presentations and a review of the literature. Surv Ophthalmol 2002;47:470–90.

22. Williams MD, Al-Zubidi N, Debnam JM, et al. Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations. Ophthal Plast Reconstr Surg 2010;26:403–8.

60. Yaday BS, Shema SC. Orbital lymphoma: role of radiation. Indian J Ophthalmol 2009;57:91–7.

23. Shields JA, Nelson LB, Brown JF, et al. Clinical, computed tomographic, and histopathologic characteristics of juvenile ossifying fibroma with orbital involvement. Am J Ophthalmol 1983;96:650–3.

62. Weinstein GS, Dresner SC, Slamovits TL, et al. Acute and subacute orbital myositis. Am J Ophthalmol 1983;96:209–17.

24. Jakobiec FA, Jones IS. Mesenchymal and fibro-osseous tumors. In: Jones IS, Jakobiec FA, editors. Diseases of the orbit. New York: Harper & Row; 1979. p. 461–502. 25. Liakos GM, Walker CB, Carruth JAS. Ocular complications in cranial fibrous dysplasia. Br J Ophthalmol 1979;63:611–16. 26. Moore RT. Fibrous dysplasia of the orbit. Review. Surv Ophthalmol 1969;13:321–34. 27. Dhir SP, Munjal VP, Jain IS, et al. Osteosarcoma of the orbit. J Pediatr Ophthalmol Strabismus 1980;17:312–4. 28. Mortada A. Fibroma of the orbit. Br J Ophthalmol 1971;55:350–2. 29. Stokes WH, Bowers WF. Pure fibroma of the orbit. Report of a case and review of the literature. Arch Ophthalmol 1934;11:279–82. 30. Eifrig DE, Foos RY. Fibrosarcoma of the orbit. Am J Ophthalmol 1969;67:244–8. 31. Yanoff M, Scheie HG. Fibrosarcoma of the orbit. Report of two patients. Cancer 1966;19:1711–16. 32. Kojima K, Kojima K, Sakai T. Leiomyosarcoma. Acta Soc Ophthalmol Jpn 1972;76:74–7. 33. Meekins B, Dutton JJ, Proia AD. Primary orbital leiomyosarcoma: a case report and review of the literature. Arch Ophthalmol 1988;106:82–6. 34. Font RL, Hidayat AA. Fibrous histiocytoma of the orbit. A clinicopathologic study of 150 cases. Hum Pathol 1982;13:199–209. 35. Ros PR, Kursunoglu S, Batle JF, et al. Malignant fibrous histiocytoma of the orbit. J Clin Neuro-Ophthalmol 1985;5:116–19. 36. Knowles DM II, Jakobiec FA. Rhabdomyosarcoma of the orbit. Am J Ophthalmol 1975;80:1011–18.

12.12  Orbital Diseases

2. Ohtsuka K, Hashimoto M, Suzuki Y. A review of 244 orbital tumors in Japanese patients during a 21-year period: origins and locations. Jpn J Ophthalmol 2005;49:49–55.

37. Abramson DH, Notis CM. Visual acuity after radiation for orbital rhabdomyosarcoma. Am J Ophthalmol 1994;118:808–9.

61. Kennerdell JS, Dresner SC. The nonspecific orbital inflammatory syndromes. Surv Ophthalmol 1984;29:93–103.

63. Sergott RC, Glaser JS. Graves’ ophthalmopathy. A clinical and immunological review. Surv Ophthalmol 1981;26:1–21. 64. Bahn RS. Graves’ orbitopathy. N Engl J Med 2010;362:726–38. 65. Bergin DJ, Wright JE. Orbital cellulitis. Br J Ophthalmol. 1986;70:174–8. 66. Koornneef L, Melief CJM, Peterse HL, et al. Wegener’s granulomatosis of the orbit. Orbit 1983;2:1–110. 67. Ahuja R, Azar NE. Orbital dermoids in children. Semin Ophthalmol 2006;21:207–11. 68. Avery G, Tang RA, Close LG. Ophthalmic manifestations of mucoceles. Ann Ophthalmol 1983;15:734–7. 69. Shields JA, Shields CL. Orbital cysts of childhood − classification, clinical features, and management. Surv Ophthalmol 2004;49:281–99. 70. Jakobiec FA, Jones IS. Vascular tumors, malformations and degenerations. In: Jones IS, Jakobiec FA, editors. Diseases of the orbit. Hagerstown: Harper & Row; 1979. p. 269–308. 71. Rootman J, Hay E, Graebo D, et al. Orbital-adnexal lymphangiomas: a spectrum of hemodynamically isolated vascular hamartomas. Ophthalmology 1986;93:1558–70. 72. Schupp CJ, Kleber JB, Gunther P, et al. Propranolol therapy in 55 infants with infantile hemangioma: dosage, duration, adverse effects, and outcome. Pediatr Dermaol 2011;28:640–4. 73. Fridman G, Grieser E, Hill R, et al. Propranolol for the treatment of orbital infantile hemangiomas. Ophthal Plast Reconstr Surg 2011;27:190–4. 74. O’Keefe M, Lanigan B, Byrne SA. Capillary haemangioma of the eyelids and orbit: a clinical review of the safety and efficacy of intralesional steroid. Acta Ophthalmol Scand 2003;81:294–8.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 3 Orbit and Lacrimal Gland

12.13

Orbital Surgery Jonathan J. Dutton

Definition: Orbital surgery involves tissues bounded by the bony

orbital walls posteriorly and by the orbital septum anteriorly.

Key features ■

Surgical approaches to the orbit may be anterior, lateral, medial, or superior, depending on the location of the lesion and the exposure needed. ■ Meticulous attention to anatomical detail, hemostasis, and gentle manipulation of tissues is mandatory to avoid devastating complications. ■ The most important complications are loss of vision, injury to extraocular muscles with diplopia, hemorrhage, and cerebrospinal fluid leak and possible meningitis.

INTRODUCTION Orbital and lacrimal gland surgery is indicated for the evaluation or treatment of orbital disease, restoration of anatomical relationships following trauma, or cosmetic improvement of congenital or acquired deformities. Biopsy of mass lesions is an important technique. Although some authors advocate fine-needle aspiration biopsy of orbital mass lesions under computed tomographic or echographic guidance,1–2 cytological evaluation on such specimens may be inaccurate.3 For most orbital lesions, an open biopsy is preferred. The removal of orbital masses may be indicated when these are well defined and cause either functional compromise or cosmetic deformity. Benign tumors, such as hemangiomas, and some malignant lesions usually can be dissected away from adjacent structures. More infiltrative lesions, such as lymphangiomas, usually are impossible to extirpate completely. When not amenable to medical therapy and when it is necessary to restore function, these tumors may be carefully debulked. Nonsurgical traumatic injury to the orbit frequently involves bony fracture or hemorrhage. Orbital rim fractures are easily accessible through anterior approaches; they may be repaired with miniplate fixation of the displaced fragments. Orbital wall fractures, often associated with soft tissue injury or incarceration, must be carefully explored and realigned when it is necessary to restore function or orbital volume. Diffuse orbital hemorrhage following trauma may produce massive proptosis and, occasionally, increased intraocular pressure or optic nerve compression. Orbital decompression with a lateral canthotomy is usually sufficient to manage the potential visual loss. If this fails, drainage of loculated pockets or bony decompression may be necessary. Massive proptosis associated with Graves’ orbitopathy may require orbital decompression for the treatment of threatened visual function or cosmetic disfigurement. This is achieved by removal of one or more orbital walls. Decompression also may be indicated for other expanding lesions of the orbit that cannot be surgically extirpated. Removal of the globe and part or all of the normal orbital contents may be necessary to manage neoplastic processes or to control chronic pain. It is also useful for the cosmetic improvement of congenital or traumatic ocular or orbital deformities. When only the globe is involved, enucleation or evisceration is indicated (see Chapter 12.14). Cure of neoplasms that extend into the orbit from the globe or eyelids may require more radical exenteration of all the orbital soft tissues.

PREOPERATIVE EVALUATION AND DIAGNOSTIC APPROACH Before a decision is made about the need for orbital or lacrimal gland surgery, a complete evaluation of the patient is mandatory.4 Measurement of visual acuity with current refraction and a visual field test is required on all patients who have suspected orbital disease, especially if visual loss occurs. The presence of periorbital edema or erythema, chemosis, ptosis, and decreased corneal or facial sensation is noted. The degree of proptosis, if any, and the direction of globe displacement are important to help localize orbital pathology (see Chapter 12.12). Ocular motility should be carefully measured and, if abnormal, a forced traction test performed to distinguish between paralytic and restrictive causes. The anterior orbit should be palpated for any abnormal masses behind the bony rim. Modern orbital imaging techniques provide critical information on the specific location of lesions, as well as their relationship to adjacent structures5 (see Chapter 12.3). Echography allows the determination not only of topographical contours and surface characteristics but also of the consistency, gross internal structure, and vascularity, which may be difficult to detect with other techniques.6,7 High-resolution orbital CT with contrast provides superb topographical data and structural details. It is essential if there is any suggestion of bony involvement.5 Orbital CT should be obtained in both axial and coronal orientations, with contrast enhancement and bone windows when indicated. Key information, not available with CT alone, may be provided by magnetic resonance imaging, including gadolinium enhancement and fat suppression techniques.

GENERAL TECHNIQUES General techniques in orbital and lacrimal gland surgery require a thorough understanding of orbital anatomy and the relationships with paraorbital structures.8 More than for other ophthalmic procedures, orbital and lacrimal gland surgery demands strict respect for fascial planes, adequate exposure and visualization, a planned approach appropriate to the expected pathology, and concern for postoperative cosmesis. The surgeon must be well versed in both gross and microsurgical techniques and must not hesitate to involve other surgical subspecialists when appropriate. Gentle dissection is essential to avoid injury to delicate neurovascular structures; meticulous hemostasis is critical to prevent complications and even potential blindness. The orbit may be approached through several surgical routes, all generally grouped under the term orbitotomy – literally, to cut into the orbit (Box 12-13-1). Since this term has no particular reference to bone, it may be applied to anterior incisions through the eyelid and lateral or other approaches through the orbital walls.9 Since the orbital septum represents the anatomically anteriormost layer of the orbital fascial

BOX 12-13-1 ORBITAL SURGERY: GENERAL TECHNIQUES Anterior Orbit  Anterior orbitotomy  Inferior orbitotomy Mid-Orbit  Lateral orbitotomy  Medial orbitotomy Orbital Apex  Superior orbitotomy-craniotomy

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12 Orbit and Oculoplastics

system, any transeyelid surgery that is carried through the septum represents orbital surgery. The major approaches to the orbit are:  Anterior transcutaneous orbitotomy  Lateral orbitotomy  Superior orbitotomy. The specific approach taken for each orbital procedure is determined primarily by:  The nature of the pathology  The ultimate goals of surgery – whether diagnostic biopsy, palliative debulking, or complete excision  The location and size of the lesion  The age or general medical condition of the patient. For biopsy alone, a palpable anterior lesion usually can be reached through a small transcutaneous or transconjunctival incision. Removal of such a lesion, however, may require a much broader exposure, which may necessitate removal of the lateral orbital wall. Posterior or apical lesions, even when small, usually can be safely reached only via a craniotomy approach. Medial lesions are best approached from the medial side so as not to risk injury to the optic nerve and muscle cone by instruments passed through a lateral orbitotomy incision. The approach to malignant tumors must be carefully planned to avoid contaminating adjacent tissue fields. The biopsy site must be placed so as not to transcend uninvolved closed compartments and must be located within the zone of subsequent excision. When complete excision is required, the surgeon must be prepared to remove a wide section of normal tissue, including adjacent bone.10

SPECIFIC TECHNIQUES The orbitotomy procedures include a number of operations for access into the various orbital soft tissue compartments. The specific approach selected depends on the following:11,12  The working diagnosis  The location of the pathology  Involvement of adjacent bone or paraorbital areas  The need for wide surgical margins  The requirements for adequate exposure. Three surgical spaces are of interest to the orbital surgeon, each of which requires specific consideration for appropriate visualization.8 The subperiosteal compartment lies between the orbital bony walls and periorbita. Access to this space is necessary to repair orbital wall fractures or to decompress expanding orbital volume, as in Graves’ orbitopathy. This is the location where subperiosteal hematomas, expanding mucoceles, and some intracranial lesions, such as sphenoid wing meningiomas, occur. Also, bone lesions, such as aneurysmal bone cysts, cholesterol granulomas, and eosinophilic granulomas, frequently are confined to the subperiosteal space. The extraconal or peripheral orbital space lies between the periorbita and the fascial septa that interconnect the extraocular muscles. This septal system is far more complex than once believed;13 it is unusual for lesions to be confined precisely to the extraconal space alone. Access to the peripheral space may be through a transcutaneous orbitotomy, if ANTERIOR ORBITOTOMY APPROACH, UPPER EYELID

orbital septum

preaponeurotic fat lesion

lesion preaponeurotic fat

1334

levator aponeurosis

in the anterior orbit, or though a lateral or medial orbitotomy, if deeper. The intraconal or central orbital space is delimited by the extraocular muscle cone from the annulus of Zinn to the posterior Tenon’s capsule (see Chapter 12.1). It is not a clearly defined compartment, however, since the intermuscular septum is largely incomplete posteriorly and poorly defined anteriorly. Lesions frequently extend between the extraconal and intraconal compartments without regard to these artificial boundaries.4 Optic nerve gliomas and sheath meningiomas are located primarily within the muscle cone. The surgical approach is via a lateral orbitotomy for deep lesions and via a transconjunctival medial or lateral orbitotomy for lesions immediately behind the globe. Other types of approaches have been introduced for access to the orbital apex and posterior orbit.14,15 The specific surgical procedures described here are designed to give direct access to certain structures and to minimize trauma to adjacent tissues. The anterior orbitotomy is used to reach lesions in the anterior orbit to the level of the posterior globe. Lateral orbitotomy involves removal of the lateral orbital rim and various amounts of the greater sphenoid wing. It allows wide access to the deep orbital contents and optic nerve; it is preferred for most retrobulbar lesions. Extension of the superior bony cut gives better exposure to the lacrimal gland for en bloc excision within its fossa. Meticulous attention to hemostasis must be ensured throughout any orbital surgery for visualization. After adequate exposure has been achieved, the dissection must proceed slowly and with great deliberation. Magnification and microdissection instruments are used to gently separate the lesion from adjacent normal structures. Light traction on the lesion usually is necessary to allow posterior dissection. This may be achieved with forceps, but for more vascular lesions, a cryoprobe allows traction without surface bleeding. Dissection around the optic nerve is particularly hazardous because of the delicate pial vessels that penetrate its surface and the close approximation of the posterior ciliary nerves.

Anterior Orbitotomy

Transcutaneous anterior orbitotomy is used to access the anterior extraconal and anteriormost intraconal orbital spaces (see Chapter 12.2) to biopsy or excise small lesions located beneath the orbital rims.16 With care and the use of retractors, deeper lesions to the level of the posterior globe are accessible. An incision line is marked in the upper eyelid crease to access the superior orbit, or 2 mm below the lower eyelid lash line to access the inferior orbit. The skin and orbicularis muscle are opened with scissors to enter the postorbicular fascial plane. A horizontal cut is made with a scalpel or scissors through the orbital septum to enter the extraconal orbital space. If the lesion is not visible immediately, careful palpation through the wound usually locates the structure. The fat lobules are gently separated with narrow malleable retractors and a Freer periosteal elevator, taking care not to injure vascular structures (Fig. 12-13-1). In the upper eyelid, the levator muscle lies toward the inferior side of the wound. In the lower eyelid, the inferior oblique and rectus muscles lie on the superior side of the wound. Fig. 12-13-1  Anterior orbitotomy approach, upper eyelid. A lid crease incision is cut, and the orbital septum is opened. Fat is then retracted, and the lesion is identified for biopsy or removal. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

LATERAL ORBITOTOMY APPROACH (1)

LATERAL ORBITOTOMY APPROACH (3)

Lateral Orbitotomy

12.13 Orbital Surgery

The lateral approach is used for deeper orbital lesions that cannot be reached through an anterior incision, procedures that require wider exposure, or where disruption of the lateral orbit requires extensive dissection.18 This gives excellent access to the mid-intraconal compartment, except for the extreme medial side and orbital apex. A variety of skin incisions can be used, including an S-shaped rim incision, a horizontal canthal crease incision, or an eyelid crease incision. We prefer an extended upper eyelid crease incision.19 The skin is cut with a scalpel blade, and the dissection is extended through orbicularis muscle and deep fascia to the periosteum of the orbital rim. Periosteum along the lateral orbital rim is cut and elevated from the lateral orbital wall for a distance of 3–4 cm (Fig. 12-13-2). Similarly, periosteum is elevated from the temporal fossa to expose the zygomatic bone

and greater wing of the sphenoid (see Chapter 12.2). Wide, malleable retractors are inserted on either side of the bony orbital rim at the level of the frontozygomatic suture line to protect the soft tissues. The bone is cut with an oscillating saw, angling the cut slightly inferiorly and parallel to the orbital roof. The cut is made about 1 cm deep, into the thin bone along the sphenozygomatic suture line. A second cut is made through the orbital rim just above the zygomatic arch (Fig. 12-13-3). Small holes can be drilled on either side of each cut near the rim to facilitate later replacement of the bone. The bony rim is grasped with a sturdy rongeur between the cuts and fractured outward. The thin bone of the greater sphenoid wing is removed with rongeurs to provide adequate retrobulbar exposure (Fig. 12-13-4). The lateral rectus muscle is identified by grasping its insertion at the globe and rotating the eye medially. The periorbita is then opened with scissors by making a vertical cut just inferior or superior to the muscle. The orbital fat is dissected gently by blunt separation of the interlobular capsules with a Freer elevator or dissectors. Once the lesion has been identified, it is dissected carefully from adjacent structures, with meticulous hemostasis maintained with gentle cautery. Traction on the lesion may be achieved with the use of a cryoprobe (Fig. 12-13-5). After biopsy or removal of the lesion, the periorbita is closed with interrupted

The lesion may then be biopsied or dissected carefully away from adherent tissues. All bleeding points are cauterized meticulously with bipolar electrode forceps. Care is taken to avoid excessive traction on the orbital fat. A cryo-probe may be helpful in providing traction on the lesion without injury to its surface.17 The cutaneous wound is closed with a running stitch of 6-0 absorbable or non-absorbable suture.

periorbita

periorbita

lateral orbital rim greater wing of sphenoid bone

periosteum

Fig. 12-13-2  Lateral orbitotomy approach. The lateral orbital rim is exposed, and the periorbita is elevated from the lateral orbital wall. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

LATERAL ORBITOTOMY APPROACH (2)

Fig. 12-13-4  Lateral orbitotomy approach. The greater sphenoid wing is removed to provide adequate exposure of the deep orbit. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

LATERAL ORBITOTOMY APPROACH (4) cryoprobe

periorbita

lesion lateral orbital rim temporalis fossa Fig. 12-13-3  Lateral orbitotomy approach. After periosteum has been elevated from the temporal fossa, the lateral rim is cut. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

Fig. 12-13-5  Lateral orbitotomy approach. The periorbita is opened, and the lesion is located using gentle dissection. A cryoprobe facilitates removal without surface bleeding. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

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12 Orbit and Oculoplastics

sutures of 4-0 Vicryl, with several gaps left in the closure for drainage. The lateral orbital rim is replaced and secured with microplate fixation or with 4-0 Prolene or nylon sutures passed through the predrilled holes. Periosteum is closed over the orbital rim with interrupted stitches of 4-0 Vicryl. The orbicularis muscle is approximated with 6-0 chromic gut and the skin with 6-0 nylon or silk vertical mattress sutures. A firm, but not tight, dressing is placed over the orbit for 24 hours. Systemic corticosteroids may be administered for several days, especially if any manipulation around the optic nerve was carried out. Antibiotic ointment is applied to the suture line four times daily for 1 week. The skin sutures are removed after 5–7 days.

Orbital Decompression: Inferior and Medial Walls

Orbital decompression is indicated to expand the bony walls when increased orbital soft tissue volume is present. The procedure is used most frequently for Graves’ orbitopathy associated with optic nerve compression or severe exophthalmos and lagophthalmos.20,21 The operation involves intentional outfracturing of selected orbital walls, usually into adjacent paranasal sinuses (Fig. 12-13-6). The procedure is usually performed through an anterior approach with removal of the orbital floor and medial wall.20 In some cases removal of orbital fat alone can give adequate results.22,23 In all operations for decompression, the periorbita must be opened widely to allow fat lobules to prolapse into the bony defects (see Fig. 12-13-6). Without this step, surgery is ineffective. In Graves’ orbitopathy, fibrosis of the interlobular fascial septa may prevent prolapse. Careful blunt dissection to separate these is needed, but in some cases, the effect of decompression is still disappointing.

The operation may be performed through a subciliary incision cut 2 mm below the lower eyelid lash line or through a transconjunctival fornix incision. Periosteum is incised 2 mm outside the orbital rim and dissected over the latter with a Freer elevator. Elevation of periorbita is continued along the orbital floor for a distance of 3.5–4 cm posterior to the rim (Fig. 12-13-7). The thinnest part of the floor is located medial to the infraorbital canal; a small hole is punched through this area with a hemostat. The orbital floor medial to the infraorbital canal is removed with rongeurs (Fig. 12-13-8). Additional bone is removed back to the posterior wall of the maxillary sinus, medially to the maxillary-ethmoid suture, and laterally to the edge of the infraorbital tissue. The author prefers to leave a narrow bridge of bone over the infraorbital nerve to prevent postoperative injury from displaced orbital contents. The periorbita is sutured to periosteum over the inferior orbital rim with interrupted sutures of 4-0 Vicryl. Skin or conjunctiva is closed with a running suture. A firm dressing is applied for 24 hours. Antibiotic ointment is placed on the suture line four times daily for 7 days. Systemic antibiotics and nasal decongestants are prescribed for 1 week. The skin sutures are removed after 5–7 days.

Repair of Orbital Floor Fractures

Blowout fractures of the orbital floor result from hydraulic compression of orbital contents24 and perhaps from deformation forces transmitted directly from the orbital rims. These occur most frequently just medial to the infraorbital canal, where the bone is thinnest.25,26 Paresthesias of the cheek and upper gum suggest a more central fracture with injury to the infraorbital nerve. Spontaneous recovery of sensation usually occurs after several months. Vertical diplopia and a positive forced Fig. 12-13-6  Orbital decompression. The orbital floor and medial wall are removed. The periorbita is then opened to allow fat to prolapse into the adjacent sinuses. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

ORBITAL DECOMPRESSION (1)

maxillary sinus periorbita

inferior neurovasular bundle prolapsing of orbital fat lacrimal gland

prolapsing orbital fat maxillary sinus

Fig. 12-13-7  Orbital decompression. A skin or conjunctival incision is used to expose the inferior orbital rim. The periorbita is elevated to expose the orbital floor. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

ORBITAL DECOMPRESSION (2) periosteum orbital floor

orbital septum

orbital fat periosteum orbital floor

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orbicularis muscle

and with bone window settings helps determine which cases require immediate repair and which are likely to improve using medical management alone.31 In many cases, orbital surgery can be avoided, with no compromise of long-term results.32 For the repair of orbital floor fractures, the operation is similar to that for orbital decompression described earlier, up to the stage of exposure of the floor (see Fig. 12-13-7). The anterior edge of the fracture site is then exposed, and the extent of incarceration of the periorbita and fascial tissues is evaluated (Fig. 12-13-9). Bony fragments are gently depressed or elevated while periorbita and fat lobules are teased free with a periosteal elevator or microdissector. Orbital tissues are carefully separated from the infraorbital nerve and vessels. The entire fracture site must be exposed to its posterior limit.33 A piece of Supramyd, Teflon, porous polyethylene, or other implant material is cut to a size large enough to overlap the defect by at least 5 mm on all sides.34,35 It is best to fix the implant into position to prevent later migration.36 If a full floor implant is used, one or two small holes are drilled through the orbital rim and through the front of the implant, and the latter is secured into position with 4-0 Prolene sutures to prevent forward displacement (Fig. 12-13-10). If a smaller implant is used, a small tongue flap can be cut and pushed beneath the anterior defect edge to prevent migration. Several small overlapping implants can be used through small lid incisions with good results.37 Periosteum is closed over the orbital rim with interrupted sutures of 4-0 Vicryl. The skin or conjunctival wound is repaired with a running stitch.

12.13 Orbital Surgery

traction test suggest mechanical restriction, with entrapment of the inferior rectus muscle or, more likely, of its fascial attachments in the inferior orbit.27 However, vertical diplopia and a positive forced traction test also may be seen with contusion injuries to the muscle, in which case motility function typically improves over several weeks as the hematoma resolves.28,29 Failure to improve over several weeks suggests mechanical restriction that requires surgical exploration. Orbital fractures may be associated with downward displacement of the globe when the fracture site involves primarily the orbital floor. Enophthalmos or hypo-ophthalmos alone usually does not cause diplopia, but it may be of cosmetic consequence. When significant, this is an indication for early surgical intervention.30 Associated orbital hemorrhage initially can mask enophthalmos, which may become manifest only after several weeks, when the hematoma resolves. Late enophthalmos, which may occur over several years or even over several decades, results from progressive fat atrophy. This is repaired using volume augmentation of the orbital contents. Medial wall fractures are sometimes associated with orbital emphysema. Medial rectus muscle entrapment is uncommon, but it may produce a horizontal diplopia. Enophthalmos may be significant even with pure ethmoid fractures. Injury to the lacrimal drainage system may be seen with more anterior medial rim or nasomaxillary fractures. Before contemplating any surgical intervention, radiographic imaging is essential. In most cases, CT in both the axial and coronal planes

Fig. 12-13-8  Orbital decompression. The floor is removed using rongeurs. The maxillary sinus is then exposed. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

ORBITAL DECOMPRESSION (3)

orbital floor orbital septum rongeur orbicularis muscle

rongeur

ORBITAL FLOOR FRACTURE REPAIR (1)

fractured orbital floor

Fig. 12-13-9  Orbital floor fracture repair. The floor is exposed as for orbital decompression. The fracture site is identified, and any soft tissue incarceration is freed. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

entrapped periorbita maxillary sinus fractured orbital floor

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12 Orbit and Oculoplastics

Supramyd floor implant

periorbita

COMPLICATIONS Orbital and lacrimal gland surgery is fraught with potential complications, even for experienced surgeons. The close approximation of numerous neurovascular structures means that complications may lead to disastrous consequences for visual function. With a comprehensive knowledge of anatomy, intense attention to surgical detail, and strict respect for tissue handling, these risks can be kept to a minimum. Visual loss is the most serious complication of orbital surgery. It may result from the following:  Optic nerve injury by malleable retractors  Excessive pressure on the globe  Cautery adjacent to the optic nerve  Vascular compromise. The surgeon must keep in mind the anatomical relationships in the orbital apex and the position of key landmarks. Constant monitoring of pupillary reactions during surgery is important. Postoperative orbital hemorrhage is a rare complication that largely can be avoided by meticulous attention to hemostasis during surgery. Excessive traction on orbital fat should be avoided, and bone wax must be applied to any vessels retracted into bony canals. An expanding postoperative hematoma is heralded by progressive proptosis, deep orbital pain, and decreasing vision. Treatment may require immediate surgical decompression, either through the original surgical wound or through an alternative, more direct route to the hematoma. A cerebrospinal fluid (CSF) leak may occur with any surgery on the medial orbital wall carried above the level of the frontoethmoid suture line and causing injury to the cribriform plate. If minimal, it may be treated conservatively, as for CSF rhinorrhea. Alternatively, the leakage site may be packed with fat or sealed with cyanoacrylate glue, and a lumbar drain may be placed. The patient should be covered with appropriate antibiotics. Diplopia is a constant risk with any surgery adjacent to extraocular muscles or their motor nerves. Muscle sheaths should be left intact whenever possible, and traction sutures across the muscle bellies must be avoided. The inferior oblique muscle is particularly vulnerable where it lies immediately behind the orbital septum, just inside the inferior orbital rim. It may not be recognized by an inattentive orbital surgeon. In the superior medial orbit, the superior oblique trochlea is injured easily by overly aggressive periorbital dissection. When extraocular muscle dysfunction fails to resolve over 3–4 months, strabismus surgery may be required. Upper eyelid ptosis occurs almost universally following most surgery on the orbit. In most cases, this is transient and usually resolves over days to weeks. Permanent ptosis may result from injury to the

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Fig. 12-13-10  Orbital floor fracture repair. A suitable floor implant is placed over the defect and fixed in position. The anterior view is the inverted image as seen by the surgeon. (Adapted with permission from Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991.)

ORBITAL FLOOR FRACTURE REPAIR (2)

Access the complete reference list online at

Supramyd floor implant

aponeurosis, Whitnall’s ligament, or the superior division of the oculomotor nerve. If the ptosis does not resolve within 3–4 months, surgical repair may be necessary. Lower eyelid ectropion, epiblepharon, and other eyelid malpositions may result from injury to the capsulopalpebral fascia or scarring of the orbital septum. These disorders are rarely seen in younger individuals but are more common in older patients who have preexisting eyelid laxity. The appropriate dissection planes should be maintained in all dissections carried through these structures; similar to the techniques applied in eyelid surgery.

OUTCOME With appropriate planning and surgical technique, orbital surgery yields a high degree of success and few permanent complications. Visual function usually is improved, cosmetic appearance is enhanced, and lifethreatening conditions can be eliminated. In some cases, however, vision or cosmesis must be compromised in favor of preservation of life. Such decisions should always be made with the complete understanding and participation of the patient. Occasionally, less radical surgery may be undertaken, even in the face of serious pathology, as dictated by the patient’s age, physical condition, and visual status of the contralateral eye.

KEY REFERENCES Abouchadi A, Capon-Degardin N, Martinot-Duquennoy V, et al. Eyelid crease incision for lateral orbitotomy. Ann Chir Plast Esthet 2005;50:221–7. Chang A, Carter KD, Nerad JA. Orbital floor fractures. In: Holck DEE, Ng JD, editors. Evaluation of treatment of orbital fractures. A multidisciplinary approach. London: Elsevier Saunders; 2006. p. 93–102. Cockerman KP, Bejjani GK, Kennerdell JS, et al. Surgery for orbital tumors. Part II: transorbital approaches. Neurosurg Focus 2001;10:E3. Dutton JJ. Atlas of ophthalmic surgery, vol. II. Oculoplastic, lacrimal, and orbital surgery. St Louis, MO: Mosby–Year Book; 1991. Dutton JJ. Atlas of clinical and surgical orbital anatomy. 2nd ed. London: Saunders; 2011. Goldberg RA, Shorr N, Arnold AC, et al. Deep transorbital approach to the apex and cavernous sinus. Ophthal Plast Reconstr Surg 1998;14:336–41. Khan AM, Varvares MA. Traditional approaches to the orbit. Otolaryngol Clin North Am 2006;39:895–909. Robert PY, Camezind P, Adenis JP. Orbital fat decompression techniques. J Fr Ophthalmol 2004;27:845–50. Rootman J. Diseases of the orbit. A multidisciplinary approach. Philadelphia, PA: JB Lippincott; 1988. Su GW, Harris GJ. Combined inferior and medial surgical approaches and overlapping thin implants for orbital floor and medial wall fractures. Ophthal Plast Reconstr Surg 2006;22:420–3.

REFERENCES 1. Kennerdell JS, Slamovitz TL, Dekker A, et al. Orbital fine needle aspiration biopsy. Am J Ophthalmol 1985;99:547–51.

3. Krohel GB, Tobin DR, Chavis RM. Inaccuracy of fine-needle aspiration biopsy (FNAB). Ophthalmology 1985;92:666–70. 4. Rootman J, Stewart B, Goldberg RA. Orbital surgery. A conceptual approach. Philadelphia, PA: Lippincott–Raven; 1995. 5. Dutton JJ. Radiology of the orbit and visual pathways. London: Saunders; 2010. 6. Byrne SF. Standardized echography in the differentiation of orbital lesions. Surv Ophthalmol 1984;29:226–8. 7. Levine RA. Orbital ultrasonography. Radiol Clin North Am 1987;25:447–69.

21. Kennerdell JS, Maroon JC. An orbital decompression for severe dysthyroid exophthalmos. Ophthalmology 1982;89:467–72. 22. Ettl A. Orbital decompression in Graves’ disease: indications, techniques, results and complications. Klin Monatsbl Augenheilkd 2004;221:922–6. 23. Robert PY, Camezind P., Adenis JP. Orbital fat decompression techniques. J Fr Ophthalmol 2004;27:845–50. 24. Smith B, Regan WFJ. Blow-out fracture of the orbit. Mechanism and correction of internal orbital fracture. Am J Ophthalmol 1957;44:733–8. 25. Gilbard SM, Mafee MF, Lagouros PA, et al. Orbital blowout fractures. The prognostic significance of computed tomography. Ophthalmology 1985;92:1523–8. 26. Greenwald HS, Keeney AR, Shannon GM. A review of 128 patients with orbital fractures. Am J Ophthalmol 1974;78:655–64.

8. Dutton JJ. Atlas of clinical and surgical orbital anatomy. 2nd ed. London: Saunders, 2011.

27. Koornneef L. Current concepts on the management of orbital blow-out fractures. Ann Plast Surg 1982;9:185–200.

9. Hayek G, Mercier P, Fournier HD. Anatomy of the orbit and its surgical approach. Adv Tech Stand Neurosurg 2006;31:35–71.

28. Putterman AM. Late management of blow-out fractures of the orbital floor. Trans Am Acad Ophthalmol Otolaryngol 1977;83:650–9.

10. Valenzuela AA, Selva D, McNab AA, et al. En bloc excision in malignant tumors of the lacrimal drainage apparatus. Ophthal Plast Reconstr Surg 2006;22:356–60.

29. Putterman AM. Management of blow-out fractures of the orbital floor. III. The conservative approach. Surv Ophthalmol 1991;35:292–5.

11. Khan AM, Varvares MA. Traditional approaches to the orbit. Otolaryngol Clin North Am 2006;39:895–909.

30. Manson PN, Iliff N. Management of blow-out fractures of the orbital floor. II. Early repair for selected injuries. Surv Ophthalmol 1991;35:280–92.

12. Cockerman KP, Bejjani GK, Kennerdell JS, et al. Surgery for orbital tumors. Part II: Transorbital approaches. Neurosurg Focus 2001;10:E3.

31. Dutton JJ. Management of blow-out fractures of the orbital floor. I. Editorial comment. Surv Ophthalmol 1991;35:279–80.

13. Koornneef L. Orbital septa: anatomy and function. Ophthalmology 1979;86:876–80.

32. Emery JM, von Noorden GK, Schlernitzauer DA. Orbital floor fractures: long-term follow-up of cases with and without surgical repair. Trans Am Acad Ophthalmol Otolaryngol 1971;75:802–12.

14. Goldberg RA, Shorr N, Arnold AC, et al. Deep transorbital approach to the apex and cavernous sinus. Ophthal Plast Reconstr Surg 1998;14:336–41. 15. Kennerdell JS, Maroon JC, Celin SF. The posterior inferior orbitotomy. Ophthal Plast Reconstr Surg 1998;14:277–80. 16. Dutton JJ. Atlas of oculoplastic and orbital surgery. Philadelphia, PA: Lippincott, Williams & Williams; 2012. 17. Rosen N, Priel A, Simon GJ, et al. Cryo-assisted anterior approach for surgery of retroocular orbital tumors avoids the need for lateral or transcranial orbitotomy in most cases. Acta Ophthalmol 2010;88:675–80. 18. Evans BT, Mourouzis C. Lateral orbitotomy: a useful technique in the management of severe traumatic disruption of the lateral orbital skeleton. Int J Oral Maxillofac Surg 2009;38:984–7. 19. Abouchadi A, Capon-Degardin N, Martinot-Duquennoy V, et al. Eyelid crease incision for lateral orbitotomy. Ann Chir Plast Esthet 2005;50:221–7.

12.13 Orbital Surgery

2. Dresner SC, Kennerdell JS, Dekker A. Fine needle aspiration biopsy of metastatic tumors. Surv Ophthalmol 1983;27:397–8.

20. Anderson RL, Linberg JV. Transorbital approach to decompression in Graves’ disease. Arch Ophthalmol 1981;99:120–4.

33. Chang A, Carter KD, Nerad JA. Orbital floor fractures. In: Holck DEE, Ng JD, editors. Evaluation of treatment of orbital fractures. A multidisciplinary approach. London: Elsevier Saunders; 2006. p. 93–102. 34. Lee S, Maronian N, Most SP, et al. Porous high-density polyethylene for orbital reconstruction. Arch Otolaryngol Head Neck Surg 2005;131:446–50. 35. Rinna C, Ungari C, Saltarel A, et al. Orbital floor restoration. J Craniofac Surg 2005;16:968–72. 36. Smith B, Putterman AM. Fixation of orbital floor implants: description of a simple technique. Arch Ophthalmol 1970;83:598. 37. Su GW, Harris GJ. Combined inferior and medial surgical approaches and overlapping thin implants for orbital floor and medial wall fractures. Ophthal Plast Reconstr Surg 2006;22:420–3.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 3 Orbit and Lacrimal Gland

Enucleation, Evisceration, and Exenteration

12.14 

Myron Tanenbaum

Definitions ■

Enucleation: surgical removal of the entire globe. ■ Evisceration: surgical removal of the entire contents of the globe leaving a scleral shell. ■ Exenteration: removal of the entire orbit including the globe, eyelid, and orbital contents – usually performed for malignant tumors.

INTRODUCTION Enucleation, evisceration, and exenteration surgery all involve the permanent removal of the patient’s eye. In this chapter the important aspects of each procedure are emphasized, including:  Indications for surgery  Preoperative patient counseling  Surgical techniques  Postoperative management  Complications of surgery.

PREOPERATIVE EVALUATION AND DIAGNOSTIC APPROACH Indications for Surgery

Enucleation or evisceration surgery may be indicated for a blind painful eye, endophthalmitis, or cosmetic improvement of a deformed eye. In cases of intraocular neoplasms or the treatment of severe ocular trauma with a ruptured globe, where sympathetic ophthalmia is a concern, enucleation is appropriate and evisceration is contraindicated. Other indications for enucleation may include progressive phthisis bulbi, severe microphthalmia, and biopsy in a bilateral process where one eye is blind and the other eye is not as involved. In the vast majority of situations, the indication for exenteration surgery is to eradicate life-threatening malignancy or life-threatening orbital infection. The extent of the procedure should be explained to the patient, especially which tissues are to be removed (this includes the eyeball, orbital soft tissues, and part or all of the eyelid structures). A summary of the indications for surgery is given in Box 12-14-1.

Preoperative Counseling

Faced with the permanent loss of an eye, a patient requires the physician’s reassurance, caring explanations, and psychological support. The patient (and family) should understand that evisceration and enucleation surgery involve the complete, permanent removal of the diseased or deformed eye. The indication for surgery should be clearly explained. The patient should be informed of the choices between enucleation and evisceration surgery and of the availability of a variety of orbital implants, including common alloplastic implants,1,2 newer implants designed to maximize ultimate ocular prosthesis motility,3,4 or autologous tissue orbital implants such a dermis-fat.5 The patient should understand the risks and benefits of wrapping orbital implants with either autologous tissues or preserved donor tissue and that donor tissues may carry the risks of communicable diseases, such as syphilis, hepatitis, and human immunodeficiency virus. A thorough explanation allows the patient and family to make a wellinformed decision regarding surgery.

BOX 12-14-1 INDICATIONS FOR SURGERY Enucleation  Blind painful eye  Intraocular tumor  Severe trauma with risk of sympathetic ophthalmia  Phthisis bulbi  Microphthalmia  Endophthalmitis/panophthalmitis  Cosmetic deformity Evisceration  As for enucleation, except for intraocular tumors or risk of sympathetic ophthalmia Exenteration  Cutaneous tumors with orbital invasion  Lacrimal gland malignancies  Extensive conjunctival malignancies  Other orbital malignancies  Mucormycosis  Chronic orbital pain  Orbital deformities

ANESTHESIA Enucleation surgery may be performed using local anesthesia. For psychological reasons, and occasionally for medical reasons, however, general anesthesia is usually employed. Under any circumstance, agents should be used that maximize intraoperative hemostasis, suppress the oculocardiac reflex,6 and minimize postoperative pain. The author’s choice is to instill 10% phenylephrine eye drops into the conjunctival cul-de-sac to achieve intense vasoconstriction, and to infiltrate extensive retrobulbar and peribulbar bupivacaine 0.5% with epinephrine (adrenaline) 1 : 100 000 and hyaluronidase. After adequate time, an excellent anesthetic and vasoconstrictive effect is achieved. Most evisceration surgeries are performed under local anesthesia with intravenous sedation. A mixture of lidocaine (lignocaine) 2% with epinephrine 1 : 100 000, bupivacaine 0.5% with 1 : 100 000 epinephrine, and hyaluronidase is injected in retrobulbar fashion into the muscle cone. The use of intravenous anesthetic sedatives prevents either the local anesthetic injection or the surgical procedure itself from being unpleasant or producing anxiety. Exenteration surgery is usually performed under general anesthesia, which may be combined with bupivacaine and epinephrine infiltration to aid hemostasis and provide postoperative analgesia.

SPECIFIC TECHNIQUES Enucleation

The indications for enucleation surgery and important aspects of preoperative counseling have already been discussed. Here two surgical techniques are described:  Enucleation with placement of a simple sphere implant  Enucleation with placement of a sclera-wrapped porous implant for improved motility.

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Enucleation with simple sphere implant

Orbit and Oculoplastics

A self-retaining lid speculum is placed to expose the entire epibulbar surface. A 360° conjunctival peritomy is performed (Fig. 12-14-1). Tenon’s fascia is bluntly dissected away from the sclera in all four quadrants. Each of the four rectus muscles is sequentially gathered on a muscle hook, secured with a double-armed 6-0 Vicryl suture, and detached from the globe. The superior oblique tendon is severed and detached from the globe. The inferior oblique muscle should be hooked and secured with a 6-0 Vicryl suture, detached, and saved for later attachment to the inferior border of the lateral rectus muscle. This use of the inferior oblique muscle is perhaps more important as an eventual ‘hammock’ for the orbital implant than to enhance meaningfully anophthalmic socket motility. After the extraocular muscles are detached, the surgeon is ready to sever the optic nerve. Anterior traction on the globe is useful when cutting the optic nerve and can be achieved with a curved hemostat applied to the medial rectus tendon. It is the author’s preference to clamp the optic nerve with a curved hemostat inserted behind the globe in the superonasal direction (Fig. 12-14-2). With the hemostat in place, a slender, curved pair of Metzenbaum scissors is used to transect the optic nerve, and the entire eyeball is removed. The surgeon should

ENUCLEATION PROCEDURE – CONJUNCTIVAL PERITOMY

conjunctiva

Tenon's capsule

inspect the entire globe for intactness and/or unusual findings before submitting the specimen for histopathologic examination. Malleable retractors are placed so as to visualize directly the still clamped cut edge of the optic nerve, and the central retinal vessels are cauterized to obtain meticulous hemostasis before removing the clamp (Fig. 12-14-3). If the optic nerve is not clamped, such as for intraocular tumors, orbital packing with direct pressure for 5–10 minutes can be applied to achieve adequate hemostasis. In select enucleations, as with tumors in contact with the optic disc or with retinoblastoma-containing eyes, it may be necessary to obtain a long segment of optic nerve.7 For the average-sized adult orbit a 20 mm polymethyl methacrylate orbital implant is usually adequate. The implant type and size can, of course, vary, and it may also be wrapped in either autologous fascia or donor sclera. The orbital implant is inserted behind posterior Tenon’s fascia, through the central rent left by cutting the optic nerve. Multiple interrupted 6-0 Vicryl sutures securely close posterior Tenon’s fascia that overlies the orbital implant. Each of the four rectus muscles is sutured to the adjacent fornix by passing the previously placed double-armed Vicryl sutures fullthickness through Tenon’s fascia and conjunctiva (see Fig. 12-14-4). This will provide motility to the ocular prosthesis. Care should be taken to avoid advancing the superior rectus suture too close to the midline to avoid inadvertent tension or traction on the superior rectus muscle, which could induce an upper lid ptosis. After anterior Tenon’s fascia is closed in the midline with 6-0 Vicryl sutures (Fig. 12-14-5),8 the conjunctival edges are loosely reapproximated with a 6-0 plain gut running suture. A broad-spectrum ophthalmic antibiotic ointment is applied to the conjunctiva. A medium-sized clear acrylic lid conformer is placed and a firm pressure bandage applied over the socket. The pressure bandage remains intact for 3–4 days postoperatively and, upon removal, the patient uses topical cool compresses with crushed ice. Pain medication is prescribed as appropriate. This perioperative and postoperative management regimen allows the large majority of enucleation procedures to be performed as outpatient procedures, with adequate control of postoperative pain.

Enucleation with porous implant

Fig. 12-14-1  Enucleation procedure. Following a 360° conjunctival peritomy, a small pair of tenotomy scissors is used to dissect bluntly Tenon’s fascia in all four quadrants.

The purpose of the porous implant, such as the hydroxyapatite, porous polyethylene, or aluminum oxide implant, is to allow the potential for maximum motility of the ocular prosthesis.9 The microstructure of these implants allows fibrovascular ingrowth of the host tissues into the implant.3,10 Once the implant is well vascularized, it can be secondarily fitted with a motility peg. This motility peg is then coupled to the ocular prosthesis to enhance maximally prosthesis motility. A standard enucleation technique is performed, as already described. The socket may be ‘sized’ using sterile trial spheres, but in most cases an 18 mm or 20 mm implant is appropriate. Keep in mind that

ENUCLEATION PROCEDURE – CUTTING OF THE OPTIC NERVE Frontal view

Cross-sectional view

hemostat clamps optic nerve

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hemostat inserted from a superonasal direction and clamped around the optic nerve

traction of 4–0 silk suture pulls globe laterally and outward

4–0 silk traction sutures

Fig. 12-14-2  Each of the four rectus muscles is tagged with a double-armed 6-0 Vicryl suture and detached from the globe. Some 4-0 silk sutures may be placed through the medial and lateral recti muscle stumps to provide anterior traction on the globe, as a slender, curved hemostat is used to clamp the optic nerve.

ENUCLEATION PROCEDURE – CAUTERY APPLIED TO THE OPTIC NERVE

ENUCLEATION PROCEDURE – FINAL CLOSURE

conjunctival closure

optic nerve surrounded by orbital fat

hemostat clamp on optic nerve

Fig. 12-14-3  The globe has been removed and cautery is applied to the optic nerve stump to maintain meticulous hemostasis.

ENUCLEATION PROCEDURE – PLACEMENT OF ORBITAL IMPLANT posterior Tenon's closed

lid conjunctiva and anterior Tenon's fascia

suture from muscle passed through Tenon's and conjunctiva to outside

extraocular muscles

buried spherical implant

Fig. 12-14-4  An orbital implant has been placed behind posterior Tenon’s fascia. This layer is then closed with multiple, interrupted 6-0 Vicryl sutures. The four rectus muscle stumps remain free with the 6-0 Vicryl sutures attached.

wrapping the implant with sclera or fascia adds approximately 1–1.5 mm to the overall diameter of the implant. If a wrapping material such as sclera is used, the scleral shell should be cut to the appropriate size and shape to enclose the implant securely. Multiple interrupted 6-0 Vicryl sutures are suitable for securely closing the sclera. The round opening where the cornea was removed should be positioned posteriorly. Rectangular windows, approximately 2–4 mm, are cut through the sclera located within 8–10 mm from the anteriormost apex of the implant for attachment of the extraocular muscles. To promote further fibrovascular ingrowth into a hydroxyapatite implant, a handheld 20-gauge needle is used to create drill holes at the site of each window and at the site of the posterior round corneal window.11

extraocular rectus muscles sewn into respective fornices

Fig. 12-14-5  Enucleation surgery – final closure. The 6-0 Vicryl rectus sutures are sewn onto their respective fornices by passing the sutures through Tenon’s fascia and conjunctiva. The anterior Tenon’s is closed with 6-0 Vicryl and the conjunctiva with a running 6-0 plain suture.

Enucleation, Evisceration, and Exenteration

unipolar cautery applied to optic nerve

12.14 

The wrapped or unwrapped implant is placed into the anophthalmic orbit and the four rectus muscles are secured to the anterior lip of the corresponding rectangular scleral window. Anterior Tenon’s fascia is sutured over the implant with multiple interrupted 6-0 Vicryl sutures. The conjunctiva can be closed with a loosely running 6-0 plain suture, which is tied and cut on each end. Implant exposure is a significant problem with porous implants12 compared with alloplastic sphere implants,13 thus emphasizing the need for meticulous closure of Tenon’s. As is the case with any enucleation procedure, a polymethyl methacrylate lid conformer is placed in the conjunctival cul-de-sac with broad-spectrum antibiotic ointment and a pressure bandage applied. The unique properties of porous implants allow fibrovascular ingrowth and integration of the implant with the ocular prosthesis. Without placement of the motility peg, no demonstrable motility difference exists between a porous implant and a polymethyl methacrylate implant.2,14 Thus porous implants are most appropriate for patients who express a strong interest in eventual second-stage procedure to maximize prosthesis motility. These titanium motility pegs are surgically inserted after adequate fibrovascular ingrowth into the hydroxy­ apatite implant has occurred.15–17 Surveys of oculoplastic surgeons in the USA and UK, show that less than 10% of porous implants are currently pegged because of excessive peg complications. If a peg is not placed, a simple and inexpensive silicone implant with muscles directly attached can provide equal motility with fewer potential complications.18

Evisceration Overview

Evisceration is the surgical technique that removes the entire intraocular contents of the eye while leaving the scleral shell and extraocular muscle attachments intact. Evisceration surgery is a simpler procedure than enucleation surgery and offers better preservation of the orbital anatomy19 and natural motility of the anophthalmic socket tissues. A combined enucleation and evisceration technique has been described as an alternative, particularly in patients with a phthisical eye.20 In cases of documented or suspected intraocular malignant tumors, evisceration is contraindicated. A preoperative ocular ultrasound is mandatory to rule out occult malignancy. Evisceration surgery may be more difficult in eyes with severe phthisis or scleral contracture or that are severely deformed. Finally, the issue of potential sympathetic ophthalmia should be considered.21–23 Evisceration surgery in a recently injured eye carries a definite small risk of sympathetic ophthalmia in the apposing eye, because some uveal tissue is always left behind in scleral canals.21 Except in these situations, evisceration can be considered as an alternative to enucleation.24,25

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12

Surgical technique

Orbit and Oculoplastics

The procedure begins with a 360° conjunctival peritomy (Fig. 12-14-6). Tenon’s fascia is bluntly separated from the underlying sclera in all four quadrants. A full-thickness incision around the corneal limbus is made with a sharp scalpel blade and the entire corneal button removed. The sclera is grasped with a forceps, and a cyclodialysis spatula is used to separate the iris root and ciliary body from the sclera. The remainder of the uveal tissue is dissected away from the scleral wall back to the attachment around the optic nerve with an evisceration spoon (Fig. 12-14-7). The intraocular contents are lifted from the scleral shell and submitted for histopathologic examination. All remaining uveal tissue is carefully removed from the scleral shell with a small curette or the sharp end of a caudal periosteal elevator. Cotton-tip applicators saturated with 70% ethanol may be used to cleanse the interior of the scleral shell and denature any remaining uveal pigmented tissue. Cautery is applied if needed to control the oozing of blood. A polymethyl methacrylate spherical implant is placed in the evisceration scleral shell (Fig. 12-14-8). When the cornea is removed, it is unusual to place an implant larger than 14–16 mm. The scleral edges are closed with multiple interrupted 6-0 Vicryl sutures, with the medial and lateral scleral edges cut to reduce any dog ears (Fig. 12-14-9). The

EVISCERATION PROCEDURE – PERITOMY

conjunctiva is gently closed with a running 6-0 plain gut suture. If a larger implant is desired, it is necessary to perform radial relaxing sclerotomy incisions posteriorly26 between the rectus muscles (Fig. 12-14-10). If a porous implant is used, such sclerotomy openings are necessary to enhance vascular ingrowth.27 Dressing and postoperative care are as for enucleation.

Exenteration Overview

Exenteration surgery involves complete removal of the eyeball, and a total or subtotal removal of the retrobulbar orbital soft tissues, and most or all of the eyelids.28,29 The most common indication for exenteration surgery is for the treatment of epithelial malignancy with orbital invasion.30,31 Since in many cases this procedure is done for recurrent tumor, the need for exenteration can be minimized by aggressive primary management of the initial lesion.32 When exenteration is performed for orbital malignancies, periorbita is usually excised to remove completely all potentially involved tissues. The bare orbital bone can slowly heal by secondary intent, but in most situations the exenterated orbit is covered with a split-thickness skin graft at the time of the procedure. As there is potential for recurrent tumor, reconstruction with thick, bulky tissue grafts or flaps, which could obscure recurrence, is avoided. In very select situations, however, a variety of ancillary reconstructive techniques may be of use, such as those involving ipsilateral temporalis muscle flaps,33 free dermis-fat grafts,34 latissimus dorsi myocutaneous free flaps,35 osseointegrated implant techniques,36 and other procedures.37–40

Surgical technique

conjunctival cut around corneal limbus

Fig. 12-14-6  Evisceration procedure. A 360° conjunctival peritomy is made, followed by complete excision of the corneal button.

The area of the proposed exenteration incision is marked with adequate wide margins where necessary for tumors, yet with preservation of as much normal periocular soft tissue as possible (Fig. 12-14-11). If necessary, adjacent areas of the medial canthus, temple, or forehead are included in the excision site. When surgery is necessary for a conjunctival or deep orbital tumor, a subciliary incision around the eyelid margins and wrapping around the inner canthus preserve the eyelid skin and orbicularis muscle, which can be used for reconstruction.40 The skin is incised along the mark and any orbicularis muscle to be spared dissected in a suborbicular plane. The dissection is carried down through periorbita to expose the orbital rim. A periosteal elevator is used to elevate periosteum over the orbital rim and periorbita from the orbital walls (Fig. 12-14-12). Firm attachments to bone are encountered at the lateral orbital tubercle, the superior oblique trochlea, the medial canthal tendon, the distal lacrimal sac as it enters the bony nasolacrimal canal, the inferior oblique origin near the posterior lacrimal crest, and the superior and inferior orbital fissure attachments (Fig. 12-14-13; see Chapter 12.2). Except for these sites of resistance, the periorbita can be elevated quite easily. Medially, the surgeon should use particular care when elevating periorbita so as to avoid inadvertent penetration of the Fig. 12-14-7  An evisceration spoon is used to detach the ciliary body and bluntly elevate the choroid from the scleral wall.

EVISCERATION PROCEDURE – DETACHMENT OF THE CILIARY BODY Frontal view

Cross-sectional view evisceration spoon

lens ciliary body choroid

choroid sclera

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sclera retina

EVISCERATION PROCEDURE – PLACEMENT OF THE ORBITAL IMPLANT

EVISCERATION PROCEDURE – RELAXING SCLEROTOMY

cutting cautery introducer

cuts in scleral shell

optic nerve eviscerated scleral shell

Enucleation, Evisceration, and Exenteration

plastic implant

12.14 

Fig. 12-14-8  A sphere introducer is used to place the orbital implant into the evisceration scleral shelf.

EVISCERATION PROCEDURE – CLOSURE OF THE SCLERAL SHELL

sclera conjunctiva

Fig. 12-14-9  The scleral opening is closed with multiple, interrupted 6-0 Vicryl sutures. Conjunctiva is subsequently closed over the scleral wound using running 6-0 plain gut sutures.

lamina papyracea into the ethmoid sinus air cells, which could result in a chronic sino-orbital fistula. Superiorly, the superior orbital bone may be quite attenuated in elderly patients and atrophic bony defects may be present. Monopolar cautery to the orbital roof should be avoided, as this may cause inadvertent cerebrospinal fluid leakage.41 It is generally safe to use bipolar cautery along the orbital roof and deep orbital tissues without the risk of cerebrospinal fluid leakage. The periorbital lining is mobilized along all orbital walls toward the orbital apex. The dissection and mobilization of soft tissues must extend posteriorly beyond the extent of tumor invasion. A thin, curved hemostat can be used to clamp the apical tissues while a slender pair of Metzenbaum scissors are used to excise the exenteration specimen anterior to the clamp (Fig. 12-14-14). An enucleation snare may also be used to incise the apical stump to complete the severing of the exenteration specimen.42 When necessary, frozen section pathology analysis of the apical stump tissues should be used to verify that the margins of resection are free and clear of neoplasm. The orbital bone should be

Fig. 12-14-10  A unipolar cautery is used to incise relaxing sclerotomy slits to expand the scleral shell. This sclerotomy technique to enlarge the scleral shell volume is ‘optional’ with polymethyl methacrylate sphere implants. Sclerotomy slits are ‘mandatory’ when using hydroxyapatite spheres in order to facilitate vascular ingrowth.

carefully inspected for subtle bone pitting or other signs of bone erosion or destruction. In patients who have very bulky or massive orbital neoplasms, exenteration may be difficult, with little space in which to separate periorbita from orbital bone. It may be helpful here first to enucleate the eyeball to make enough room for access to the deeper apical soft tissues under good visualization. In most patients, the orbit will be lined with a split-thickness skin graft harvested from the anterior surface of the thigh. It is usually preferable to expand the skin graft in a mesher. Multiple interrupted 6-0 Vicryl sutures secure all residual host skin edges to the meshed skin graft. The graft is tamponaded within the orbit with a Telfa dressing and Xeroform gauze packing under pressure. If the upper lid and lower eyelid skin and muscle are preserved, it may be possible in elderly patients with a lot of loose eyelid skin simply to suture the skin edges together and then place a pressure dressing to tamponade the myocutaneous edges against the bare bone. In selected cases, the socket can be allowed to heal by granulation.43

Postoperative management

The orbital pack and pressure dressing should remain in place for approximately 5–7 days. Following removal of the dressing, the patient can use gentle hydrogen peroxide rinses to cleanse the socket. Generally, these orbits heal best when left open to the air, so the patients should wear a patch only when going out in public. The surgeon should remain vigilant to the possibility of infection of the skin graft, especially by Pseudomonas, Staphylococcus, or Streptococcus. Systemic antibiotics may be necessary if these infections arise. In some patients, the exenterated orbit retains chronic, moist, ulcerated areas intermixed with areas of healthy keratinizing epidermis. The use of a gentle handheld hair dryer can help ‘cure’ these slower healing areas. A combined eyelid-ocular prosthesis can be made by an anaplastologist. Many exenteration patients prefer simply to wear a black patch.

COMPLICATIONS Evisceration

Postoperative infection is always of concern when evisceration surgery is performed in the setting of endophthalmitis or panophthalmitis. The use of broad-spectrum systemic antibiotics usually minimizes this risk,

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12

EXENTERATION – SURGICAL PLANES OF DISSECTION

Orbit and Oculoplastics

total exenteration subtotal exenteration with upper and lower myocutaneous lid tissue spared enucleation with socket ablation

Fig. 12-14-12  Exenteration procedure. A 360° skin incision is made down to the periosteum of the orbital rim. A periosteal elevator is used to begin reflecting the superior periorbita downward.

EXENTERATION PROCEDURE Frontal view

Cross-sectional view frontal bone

orbital bone

4-0 silk sutures

periosteal elevator

periorbita reflected downward

periosteal elevator

and the surgeon can generally use a primary orbital implant. Postoperative extrusion of the orbital implant is a complication of evisceration surgery that may be related to postoperative scleral shell shrinkage, to poor wound healing of the scleral edges, or to improper selection of the orbital implant size. Postoperative pain is more common when the cornea is retained.

Enucleation

1344

Orbital implant extrusion is also a complication of enucleation surgery.12,44 Meticulous attention to careful Tenon’s fascia wound closure and the proper selection of implant size are important principles in avoiding this outcome. Risk of implant extrusion is increased with prior irradiation treatment of the eye and orbit, severe traumatic injuries to the eye and orbit, and severe eye and orbital infections.

Fig. 12-14-11  Cross-sectional view of surgical planes of dissection for exenteration surgical techniques: total exenteration, subtotal exenteration with sparing of myocutaneous eyelid tissue, and enucleation with partial socket ablation.

levator muscle

extraocular muscles

Long-term complications of the anophthalmic socket are numerous, including generalized volume deficiency of the anophthalmic socket, lower eyelid laxity with poor prosthesis support, orbital implant migration, upper eyelid ptosis, and chronic conjunctivitis and mucoid discharge.

Exenteration

Exenteration surgery carries the risk of severe blood loss. It is important preoperatively to discontinue aspirin and all other medicines that could adversely affect blood clotting. Other complications unique to exenteration surgery include cerebrospinal fluid leakage via orbital roof transgression of the dura and chronic sino-orbital fistulas through the region of the lamina papyracea and ethmoid sinus air cells.32 During the first few weeks of healing, free skin grafts are susceptible to

Fig. 12-14-13  Bony orbit demonstrating the normal sites of increased resistance to dissection during orbital exenteration.

BONY LANDMARKS OF THE ORBIT

Enucleation, Evisceration, and Exenteration

optic foramen

attachment of trochea

superior orbital fissure

attachment of medial canthal tendon

attachment of lateral canthal tendon

lacrimal sac fossa

attachment of inferior inferior oblique muscle orbital fissure

Fig. 12-14-14  Periorbita has been elevated for 360°. Forward traction is applied to the orbital contents as a hemostat is used to clamp the apical orbital tissues.

REMOVAL OF ORBITAL CONTENTS Frontal view

12.14 

Cross-sectional view

hemostat clamp periorbita eyelids

hemostat clamp bony socket

infection. Patients may require treatment with broad-spectrum systemic antibiotics for coverage of Staphylococcus, Streptococcus, Pseudomonas, and other bacteria. The administration of systemic antibiotics is combined with maintenance of vigorous topical hygiene of the splitthickness skin graft using hydrogen peroxide rinses. Long term, the surgeon should always remain vigilant for the possible recurrence of tumor.

KEY REFERENCES Ben Simon GJ, Schwarcz RM, Douglas R, et al. Orbital exenteration: one size does not fit all. Am J Ophthalmol 2005;139:11–17. Chalasani R, Poole-Warren L, Conway RM, et al. Porous orbital implants in enucleation: a systematic review. Surv Ophthalmol 2007;52;145–55.

Access the complete reference list online at

Custer PL, McCaffery S. Complications of sclera-covered enucleation implants. Ophthalmic Plast Reconstr Surg 2006;22:269–73. Custer PL, Trinkaus KM. Porous implant exposure: incidence, management, and morbidity. Ophthal Plast Reconstr Surg 2007;213:1–7. Levin PS, Dutton JJ. A 20-year series of orbital exenteration. Am J Ophthalmol 1991;112:496–501. Migliori ME. Enucleation versus evisceration. Curr Opin Ophthalmol 2002;13:298–302. Migliori ME, Putterman AM. The doomed dermis-fat graft orbital implant. Ophthal Plast Reconstr Surg 1991;7:23–30. Shields JA, Shields CL, Suvarnamani C. Orbital exenteration with eyelid sparing: indications, techniques, and results. Ophthalmic Surg 1991;22:292–7. Shore JW, Burks R, Leone Jr CR, et al. Dermis-fat graft for orbital reconstruction after subtotal exenteration. Am J Ophthalmol 1986;102:228–36. Soares JP, França VP. Evisceration and enucleation. Semin Ophthalmol 2010;25:94–7. Wells TS, Harris GJ. Direct fixation of muscles to a silicone sphere: a cost sensitive, low-risk enucleation procedure. Ophthal Plast Reconstr Surg 2011;27:364–7.

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REFERENCES 1. Coston TO. The spherical implant. Trans Am Acad Ophthalmol Otolaryngol 1970;74:1284–6.

3. Perry AC. Integrated orbital implants. Adv Ophthal Plast Reconstr Surg 1990;8:75–81. 4. Dutton JJ. Coralline hydroxyapatite as an ocular implant. Ophthalmology 1991;98:370–7. 5. Migliori ME, Putterman AM. The doomed dermis-fat graft orbital implant. Ophthal Plast Reconstr Surg 1991;7:23–30. 6. Munden PM, Carter KD, Nerad JA. The oculocardiac reflex during enucleation. Am J Ophthalmol 1991;111:378–9. 7. Karcioglu ZA, Haik BG, Gordon RA. Frozen section of the optic nerve in retinoblastoma surgery. Ophthalmology 1988;95:674–6. 8. Nunery WR, Hetzler KJ. Improved prosthetic motility following enucleation. Ophthalmology 1983;90:1110–15. 9. Chalasani R, Poole-Warren L, Conway RM, et al. Porous orbital implants in enucleation: a systematic review. Surv Ophthalmol 2007;52;145–55. 10. Jordan DR, Klapper SR. Surgical techniques in enucleation: the role of various types of implants and the efficacy of pegged and nonpegged approaches. Int Ophthalmol Clin 2006;46:109–32. 11. Ferrone PJ, Dutton JJ. Rate of vascularization of coralline hydroxyapatite ocular implants. Ophthalmology 1992;99:375–9. 12. Custer PL, Trinkaus KM. Porous implant exposure: incidence, management, and morbidity. Ophthal Plast Reconstr Surg 2007;213:1–7. 13. Nunery WR, Cepela MA, Heinz GW, et al. Extrusion rate of silicone spherical anophthalmic socket implants. Ophthal Plast Reconstr Surg 1993;9:90–5. 14. Frueh BR, Felker GV. Baseball implant: a method of secondary insertion of an intraocular implant. Arch Ophthalmol 1979;94:429–30. 15. Shields CL, Shields JA, Eagle RC, et al. Histopathologic evidence of fibrovascular ingrowth four weeks after placement of the hydroxyapatite orbital implant. Am J Ophthalmol 1991;111:363–6. 16. DePotter P, Shields CL, Shields JA, et al. Role of magnetic resonance imaging in the evaluation of the hydroxyapatite orbital implant. Ophthalmology 1992;99:824–30. 17. Spirnak JP, Nieves N, Hollsten DA, et al. Gadolinium-enhanced magnetic resonance imaging assessment of hydroxyapatite orbital implants. Am J Ophthalmol 1995;119:431–40. 18. Wells TS, Harris GJ. Direct fixation of muscles to a silicone sphere: a cost sensitive, low-risk enucleation procedure. Ophthal Plast Reconstr Surg 2011;27:364–7. 19. Afran SI, Budenz DL, Albert DM. Does enucleation in the presence of endophthalmitis increase the risk of postoperative meningitis? Ophthalmology 1987;94:235–7. 20. Madill S, Maclean H. Enucleation with reverse replacement of sclera as an alternative to conventional evisceration. Orbit 2005;24:23–8. 21. Green WR, Maumenee AE, Sanders TE, et al. Sympathetic uveitis following evisceration. Trans Am Acad Ophthalmol Otolaryngol 1972;76:625–44.

12.14 

24. Migliori ME. Enucleation versus evisceration. Curr Opin Ophthalmol 2002;13:298–302. 25. Soares JP, França VP. Evisceration and enucleation. Semin Ophthalmol 2010;25:94–7. 26. Stephenson CM. Evisceration of the eye with expansion sclerotomies. Ophthal Plast Reconstr Surg 1987;3:249–51. 27. Kostick, DA, Linberg JV. Evisceration with hydroxyapatite implant. Surgical technique and review of 31 case reports. Ophthalmology 1995;102:1542–9. 28. Goldberg RA, Kim JW, Shorr N. Orbital exenteration: results of an individualized approach. Ophthal Plast Reconstr Surg 2003;19:229–36. 29. Ben Simon GJ, Schwarcz RM, Douglas R, et al. Orbital exenteration: one size does not fit all. Am J Ophthalmol 2005;139:11–17. 30. Bartley GB, Garrity JA, Waller RR, et al. Orbital exenteration at the Mayo Clinic. Ophthalmology 1989;96:468–73. 31. Levin PS, Dutton JJ. A 20-year series of orbital exenteration. Am J Ophthalmol 1991;112: 496–501. 32. Rahman I, Cook AE, Leatherbarrow B. Orbital exenteration: a 13 year Manchester experience. Br J Ophthalmol 2005;89:1335–40. 33. Naquin HA. Orbital reconstruction utilizing temporalis muscle. Am J Ophthalmol 1956;41:519–21. 34. Shore JW, Burks R, Leone Jr CR, et al. Dermis-fat graft for orbital reconstruction after subtotal exenteration. Am J Ophthalmol 1986;102:228–36. 35. Donahue PJ, Liston SL, Falconer DP, et al. Reconstruction of orbital exenteration cavities: the use of the latissimus dorsi myocutaneous free flap. Arch Ophthalmol 1989;107:1681–6. 36. Nerad JA, Carter KD, La Velle WE, et al. The osseointegration technique for the rehabilitation of the exenterated orbit. Arch Ophthalmol 1991;109:1032–8.

Enucleation, Evisceration, and Exenteration

2. Sami D, Young S, Petersen R. Perspective on orbital enucleation implants. Surv Ophthalmol 2007;52:244–65.

23. Croxatto JE, Galentine P, Cupples HP, et al. Sympathetic ophthalmia after pars plana vitrectomy–lensectomy for endogenous bacterial endophthalmitis. Am J Ophthalmol 1984;91:342–6.

37. Gass JDM. Technique of orbital exenteration utilizing methyl methacrylate implant. Arch Ophthalmol 1969;82:789–91. 38. Mauriello Jr JA, Han KH, Wolfe R. Use of autogenous split-thickness dermal graft for reconstruction of the lining of the exenterated orbit. Am J Ophthalmol 1985;100:465–7. 39. Yeatts RP, Marion JR, Weaver RG, et al. Removal of the eye with socket ablation. Arch Ophthalmol 1991;109:1306–9. 40. Shields JA, Shields CL, Suvarnamani C. Orbital exenteration with eyelid sparing: indications, techniques, and results. Ophthalmic Surg 1991;22:292–7. 41. Wulc AE, Adams JL, Dryden RM. Cerebrospinal fluid leakage complicating orbital exenteration. Arch Ophthalmol 1989;107:827–30. 42. Buus DR, Tse DT. The use of the enucleation snare for orbital exenteration. Arch Ophthalmol 1990;108:636–7. 43. Cooper J. Wound management following orbital exenteration surgery. Br J Nurs 2009;18: S4–14. 44. Custer PL, McCaffery S. Complications of sclera-covered enucleation implants. Ophthal Plast Reconstr Surg 2006;22:269–73.

22. Rubin JR, Albert DM, Weinstein M. Sixty-five years of sympathetic ophthalmia: a clinicopathologic review of 105 cases (1913–1978). Ophthalmology 1980; 87:109–21.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 3 Orbit and Lacrimal Gland

12.15 

The Lacrimal Drainage System Jeffrey J. Hurwitz

Definition: The tear disposal system of the eye that consists of the punctum, canaliculi, lacrimal sac, and nasolacrimal duct.

Key features ■

The orbicularis muscle and eyelids provide a lacrimal pump mechanism. ■ The drainage system is composed of the punctum, canaliculi, lacrimal sac, and lacrimal duct. ■ Stenosis or occlusion results in epiphora. ■ Testing procedures are designed to localize the site of obstruction.

Associated features ■

Congenital obstruction is usually caused by an imperforate membrane at the nasal end of the lacrimal duct. ■ Acquired obstruction may result from chronic fibrosis of the duct, trauma, or previous nasal or sinus surgery. ■ Correction of congenital obstruction is typically achieved with a simple probing procedure. ■ For acquired obstructions, a dacryocystorhinostomy is usually required for permanent resolution.

INTRODUCTION Under normal circumstances, the quantity of tears secreted should equal the quantity eliminated. In this way, neither a dry eye nor symptoms of a watery eye occur. Tearing (a watery eye) may be due to hypersecretion of tears or to decreased elimination (Table 12-15-1). Hypersecretion may result from an increased production of tears from any stimulation of the neurophysiological pathway, either centrally or locally. Decreased elimination is caused by reduced passage of tears into or through the lacrimal drainage system.

ANATOMY AND PHYSIOLOGY

1346

Tears are secreted by the lacrimal gland, with a 24-hour secretory volume of approximately 10 mL.1 With blinking, the palpebral aperture closes from lateral to medial, and tears are pumped along the marginal tear strips of the upper and lower lids toward the lacrimal lake at the inner canthus. In the normal resting state, most of the tears are lost by evaporation, and only a small percentage of the volume passes down through the nasolacrimal passageways. Tears pass from the lacrimal lake into the canaliculi through the puncta mainly by capillarity. It is important that the puncta of each lid contact the opposite lid on closure and thereby become physiologically occluded. When the lids separate, capillarity draws the tears into the empty canaliculi. Tears then flow to the common canaliculus and lacrimal sac due to a combination of factors:2–4  A change in the caliber of these passages  A change in pressure within the canalicular passages  A pumping function (lacrimal pump) of the orbicularis muscle that surrounds these passages.

TABLE 12-15-1  CAUSES OF TEARING Lacrimation (hypersecretion) Corneal foreign bodies Corneal irritation with dry spots Ocular surface inflammation Refractive errors Thyroid dysfunction Nasal irritation and inflammation

Epiphora (decreased tear elimination) Anatomic Factors Strictures Obstructions Foreign bodies (e.g., stones) Tumors

Physiological Dysfunction Orbicularis muscle weakness Punctal or eyelid malpositions Nasal obstruction with normal lacrimal pathway

Tears flow into the inferior meatus of the nose through the effect of the lacrimal pump, gravity, and, to a lesser extent, pressure changes within the nose due to respiration. Valves within the drainage system permit only one-way flow of tears.

EVALUATION OF EPIPHORA Clinical History

The history of symptoms associated with tearing is important. Pain at the side of the nose suggests dacryocystitis, but pain in the eye itself may be due to foreign bodies, keratitis, recurrent corneal erosion, iritis, or glaucoma. Itchiness is suggestive of an allergic problem rather than a lacrimal obstruction. Grittiness and burning of the eyes associated with tearing suggest a tear film problem, such as occurs in keratitis sicca, or dysthyroid eye disease. A history of medication such as echothiophate iodide (Phospholine Iodide), epinephrine (adrenaline), or pilocarpine is important, since all these drugs may produce lacrimal obstruction. Chemotherapy and radiotherapy also can cause obstruction in the canaliculi. Photo­ dynamic therapy has also been associated with canalicular stenosis.

Physical Examination Eyelids

Poor orbicularis muscle tone and lacrimal pump dysfunction may be presumed if the lid can be pulled more than 8 mm away from the globe, if there is decreased snap-back, or if there is frank ectropion. The puncta normally should be directed backward into the lacrimal lake. Lesions of the caruncle may interfere with the proper drainage of tears. Blepharitis may cause secondary oversecretion of tears. Any evidence of nasal conjuncticochalasis overhanging the punctum should be noted.

Lacrimal passages

Facial asymmetry suggests congenital or traumatic anatomical blockage of the nasolacrimal canal. Any mass at the inner canthus should be palpated to determine whether it is soft (indicating mucus) or firm (suggesting a possible tumor) and whether it is compressible or noncompressible. Orbital signs such as proptosis, displacement of the globe, diplopia, and ptosis could indicate that the lacrimal lesion involves the orbit, or vice versa.

Nose

The nasal examination is an essential part of every lacrimal evaluation. Nasal and sinus conditions, which range from infections and inflammations to tumors, may result in epiphora. Symptoms include anosmia

(loss of smell), epistaxis, anesthesia around the roof of the nose, and nasal obstruction.

Secretory tests Schirmer’s test

The amount of wetting on a strip of filter paper over 5 minutes helps assess tear production. In the normal nonanesthetized eye, 15 mm of wetting is expected in a patient younger than 40 years of age, and at least 10 mm of wetting is expected in a patient older than 40 years. If anesthetic is placed onto the eye, the basal secretion is expected to be 10 mm of wetting in a normal patient younger than 40 years and at least 5 mm in a patient older than 40 years.

Excretory tests

Lacrimal syringing

In syringing, a lacrimal irrigation cannula is passed into the punctum and advanced through the canaliculus to the medial wall of the lacrimal sac fossa (see Chapter 12.2). If the cannula hits bone (hard stop), the canaliculus is open, so the obstruction is probably in the sac or the duct. If it does not hit bone (soft stop), the obstruction is probably in the common canaliculus, especially if the medial angle of the palpebral aperture shifts medially as the cannula is advanced toward lacrimal bone. Clear water or saline is then gently irrigated through a cannula. If fluid passes into the nose without reflux out of the opposite canaliculus, the system is totally patent. If fluid passes into the nose with resistance and reflux occurs through the opposite canaliculus, the system is anatomically patent but physiologically stenotic (partially occluded). If no fluid passes into the nose but it all comes back through either punctum, complete nasolacrimal duct obstruction is present.

12.15  The Lacrimal Drainage System

Clinical Diagnostic Tests

Fig. 12-15-1  Dacryocystogram. Complete obstruction of the lacrimal drainage pathways at the medial common canalicular level on the right side.

Fig. 12-15-2  Dacryocystogram. Stenosis at the sac-duct junction is greater on the left side than on the right.

Jones fluorescein dye test

The Jones5 dye test is used to determine whether the lacrimal drainage system is fully patent or, if partially obstructed, whether the problem is in the upper system (lids, puncta, canaliculi, common canaliculus) or in the lower system (sac, duct, nose). A drop of fluorescein is placed into the conjunctival cul-de-sac. The nose is examined after 5 minutes to determine whether the dye has passed through the lacrimal system spontaneously, which indicates that it is functionally patent. This test may be facilitated by looking into the nose with a flashlight or an endoscope, or by having the patient blow their nose. In the second part of the test, the cannula is placed in the sac, and the system is irrigated. Any fluid that passes into the nose during irrigation must be recovered and examined. If no fluorescein is present in the recovered fluid, this suggests that it did not pass into the sac during the initial fluorescein test, so the problem is likely in the upper (canalicular) system. If fluorescein is present in the fluid, this indicates that it reached the sac during the initial test and that the upper system is probably normal, meaning that the problem is in the lower (sac, duct) system. Although many surgeons find these tests useful, other tests and radiological investigation may be necessary for diagnosis or surgical planning.

Fig. 12-15-3  Dacryocystogram. Medial deflection of contrast material within the right sac indicates sac stones.

Diagnostic Imaging Dacryocystography

Dacryocystography (DCG), an anatomical test, is extremely useful to determine the exact site of obstruction or stenosis within the system (Fig. 12-15-1, Fig. 12-15-2) and to visualize any deflection of the passages by diseases of the surrounding structures (Fig. 12-15-3; Box 12-15-1). Injection of either a viscous oil (conventional macrodacryocystography)6 or a water-soluble contrast material (digital subtraction dacryocystography)7 through a catheter demonstrates the lacrimal drainage pathways and outlines any anatomical abnormalities. This test does not evaluate physiological function.

Computed tomography

High-resolution computed tomography (CT) in the axial and coronal planes is a useful anatomical study to assess those patients who have diseases in the structures adjacent to the nasolacrimal drainage pathways (Fig. 12-15-4).8 Injection of the canaliculi with contrast provides simultaneous visualization of the lacrimal drainage system (CT-DCG).9

BOX 12-15-1 USES OF DACRYOCYSTOGRAPHY  Complete obstruction where the site of block (canalicular vs sac) cannot be determined clinically  Incomplete obstruction where the area of stenosis cannot be localized on clinical testing  In cases of suspected lacrimal sac tumors, to visualize a filling defect  In adnexal disease, to image compression or deflection of the sac or duct

1347

12 Orbit and Oculoplastics

T

A

S

T

Fig. 12-15-5  Endoscopy. Endoscopic view of the nose demonstrates the nasal septum (S), lateral wall, and turbinates (T).

B Fig. 12-15-4  Tearing secondary to neoplasm. (A) Patient with right-sided tearing and a mass at the inner canthus. The system was fully patent to syringing. (B) CT scan in this patient demonstrates an ethmoidal orbital plasmocytoma with compression of the lacrimal sac.

Endoscopy

Nasal endoscopy using a rigid telescope is useful to observe the anatomy of the opening of the nasal lacrimal duct in the inferior meatus and to diagnose any disease within the nose itself (Fig. 12-15-5). If a lacrimal drainage operation is contemplated, the endoscope is the best method to assess the future surgical site. Should tearing persist following lacrimal surgery, it is useful to view the size and location of the previous dacryocystorhinostomy (DCR) opening using an endoscope to determine whether the opening is obstructed by fibrous tissue, polyps, granuloma, or foreign bodies.

Sometimes, this may persist into adult life. If spontaneous resolution does not occur by 1 year of age, the patient may be treated by probing through the membrane. If a child has passed the age of 5 or 6 years, the success rate of probing decreases to such an extent that it is preferable to treat the obstruction with a DCR.

Nuclear lacrimal scan

Acquired obstructions of the sac and duct may be classified as nonspecific (idiopathic) obstructions and specific obstructions.

This is an adjunctive physiological test of lacrimal function; it does not demonstrate anatomical structures. A drop of technetium-99m pertechnetate is placed into the palpebral aperture, and a pinhole collimator of a gamma camera is used to record its transit to the nose. The lacrimal scan can help determine the extent of stenosis from a physiological point of view (Fig. 12-15-6). It also can help evaluate the flow of tears to determine whether lid or punctal malpositions contribute to drainage dysfunction.

OBSTRUCTIONS OF THE LACRIMAL SAC AND DUCT 1348

Fig. 12-15-6  Lacrimal scan. Complete obstruction on the left side and stenosis on the right side.

Congenital Obstruction

Congenital nasolacrimal obstruction is due to an imperforate membrane, which usually opens spontaneously at the time of birth.

Acquired Obstruction

Nonspecific acquired obstruction

The evolution of nonspecific lacrimal sac inflammation from an early inflammatory stage through an intermediate phase to a late fibrotic stage has been proposed by Linberg and McCormick.10 The early phase is characterized by vascular congestion, lymphocytic infiltration, and edema. These changes tend to occur at the superior aspect of the naso­ lacrimal canal just beneath the point where the sac passes into the nasolacrimal intraosseous duct. This seems to occur more commonly in older patients. It is more frequent in whites than in blacks and is more common in women than in men; it has also been suggested that it is more common in people from lower socioeconomic levels.11 Inflammatory conditions that affect the inferior meatus of the nose also may involve the respiratory-like mucosa of the inferior aspect of the nasolacrimal canal, thereby leading to obstruction.

BOX 12-15-2 SPECIFIC CAUSES OF ACQUIRED NASOLACRIMAL PATHWAY OBSTRUCTION

Infections  Staphylococcus  Actinomyces  Streptococcus  Pseudomonas  Infectious mononucleosis  Human papillomavirus  Ascaris  Leprosy  Tuberculosis

Trauma and Postsurgical  Nasoethmoid fractures  Nasal and endoscopic sinus surgery  Rhinoplasty  Orbital decompression

The Lacrimal Drainage System

Inflammatory Diseases Sarcoidosis Wegener’s granulomatosis

12.15 

Neoplasms  Primary lacrimal sac tumors  Benign papillomas  Squamous and basal cell carcinoma  Transitional cell carcinoma  Fibrous histiocytoma  Midline granuloma  Lymphoma Fig. 12-15-8  A patient who has dacryocystitis and orbital cellulitis. Ocular mobility is limited, indicating infection posterior to the orbital septum.

orbit and produce a tremendous amount of eyelid swelling (Fig. 12-158). If the infection proceeds posterior to the orbital septum a true orbital cellulitis may occur, resulting in globe proptosis or displacement, afferent pupillary defect, motility disturbance, optic neuropathy, and even blindness.

TREATMENT OF LACRIMAL SAC AND DUCT OBSTRUCTION Congenital Nasolacrimal Obstruction

Fig. 12-15-7  A patient who has dacryocystitis localized to the lacrimal sac.

Specific acquired obstruction

Specific causes of nasolacrimal drainage system obstruction include inflammatory diseases such as sarcoidosis and Wegener’s granulomatosis.12 The former is often treated with systemic corticosteroids before a DCR becomes necessary, and the latter is treated either with dacryo­ cystectomy and removal of all involved mucosa or with a full DCR. Infection, trauma, surgical injury, and foreign bodies, such as retained silicone or eyelashes, also may cause obstruction.12 Primary neoplasms of the lacrimal sac and duct or secondary tumors arising in the adjacent sinuses are rare causes of obstruction (Box 12-15-2).

Dacryocystitis

Dacryocystitis may be classified as acute, subacute, or chronic. It may be localized in the sac, extend to include a pericystitis, or progress to orbital cellulitis. When dacryocystitis is localized to the sac, a palpable painful swelling occurs at the inner canthus (Fig. 12-15-7), and obstruction is present at the junction of the nasolacrimal sac and duct. A preexisting dacryocystocele may or may not be present. When the infection develops, the lateral expansion of the nasolacrimal sac tends to push on the common canaliculus and produce a kink within it, with the result that the sac is no longer reducible. Approximately 40% of initial attacks do not recur, but in the other 60% of patients, repeated attacks occur. Chronic dacryocystitis may be the end stage of acute or subacute dacryocystitis, but it may present initially as a subclinically infectious cause of nasolacrimal duct obstruction. A common organism involved is Staphylococcus aureus. In some cases, especially in young women, stones may develop that lead to intermittent attacks of dacryocystitis; this has been termed acute dacryocystic retention syndrome. In dacryocystitis with pericystitis there is percolation of infected debris through the mucosal lining of the wall of the sac, and infection around the sac is present. The infection may spread to the anterior

More than 90% of patients with congenital nasolacrimal obstruction undergo spontaneous resolution by 1 year of age.13 Therefore, except under extreme circumstances, initial probing should be postponed until this age. Congenital amnioceles usually resolve on their own and rarely require probing. Probings are performed more easily with the patient under general anesthesia. The probe is passed into the lower canaliculus with the lid stretched laterally. The probe is advanced to the lacrimal bone. It is turned past the 90° angulation and advanced inferiorly until it perforates the membrane. Fluorescein-tinted irrigation saline is introduced to see whether it passes into the inferior meatus, or metal-to-metal contact may be obtained by inserting a probe into the nose. The success rate of probing is greater than 90%. If this fails, however, one should wait 3 months before doing another procedure, during which time most cases of seemingly failed probing resolve spontaneously. If the repeat probing does not proceed easily, Silastic tubes should be placed and left for at least 3 months (preferably 6 months). If these tubes fail and the child is still tearing, a DCR is performed at a later date. Complications of silicone include cheese-wiring, with destruction of the punctum and proximal canaliculus, and dislocation of the tubes laterally over the cornea. In this latter situation, it is better to reposition the tubes than to remove them.

Acquired Nasolacrimal Obstruction

After an attack of dacryocystitis or obstruction, a period of observation is useful. Occasionally, if a mucous plug was responsible, symptoms may resolve spontaneously. In the presence of frank dacryocystitis, the cardinal rule is to first treat the infection with an antistaphylococcal agent such as oral cloxacillin. If postseptal orbital cellulitis is present, a CT scan is obtained to rule out an abscess, and intravenous antibiotics are used. If the infection does not resolve and perforation is impending, a dacryocystotomy should be performed. After injecting lidocaine (lignocaine), an incision is made directly over the lacrimal sac, and the debris within the sac is curetted. Transcutaneous aspiration of sac contents for culture may be done with a No. 22 needle. If epiphora persists, probing and syringing may be attempted with or without insertion of silicone tubes but this technique is not very successful. More recently, balloon dacryoplasty has been reported to improve tear drainage.14,15

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12

Dacryocystorhinostomy

Orbit and Oculoplastics

DCR is an operation whereby the lacrimal sac is drained into the nose via a bypass conduit.16 The classic transcutaneous procedure of Toti17 has undergone many minor modifications, but the basic operation has withstood the test of time and has a high success rate of 93–95%.18 It may be performed with the patient under general or local anesthesia.19 In either case, the nose is premedicated with naphazoline nasal spray at 2 hours, 1 hour, and 30 minutes before surgery. The procedure is well described elsewhere.20,21 An incision as small as 8 mm is made on the side of the nose below the medial canthal tendon, and the dissection is carried down to bone. The periosteum is reflected from the anterior lacrimal crest to reveal the lacrimal sac fossa. The sac is then reflected laterally. The nose is entered by pushing a blunt instrument through the suture line between the lacrimal bone and the frontal process of the maxilla. Kerrison punches are used to remove bone between the sac fossa and the nose, to create an opening large enough to anastomose the sac and nasal mucosa. Flaps are created in the medial sac wall and in the adjacent nasal mucosa. The posterior flaps and then the anterior flaps of the sac and nasal mucosa are sutured together to form a mucosa-lined tunnel across the ostium (Fig. 12-15-9). Silicone tubes

EXTERNAL DACRYOCYSTORHINOSTOMY anterior lacrimal sac flap

are usually not necessary, but if desired, they can be placed at this time and left in for 6–12 weeks.22 However, recent studies have shown that silicone stents offer no significant increase in success rate.23 Nasal packing is not necessary unless profuse bleeding occurs at the end of the operation. Complications of hemorrhage within the first 24 hours should be controlled by lowering the blood pressure to normal values and by nasal packing. Delayed hemorrhage 4–7 days after surgery is due to clot retraction. Vaseline gauze packs soaked with thrombin are useful and should be left in place for 48 hours. A hypertrophic cutaneous scar is unusual, but if present, it usually settles quite well with massage. Triamcinolone also may be injected into the scar. Surgical failure may result from closure of the DCR anastomosis,24 or an obstruction may occur at the common canaliculus, either undiagnosed preoperatively or developing postoperatively. Initial treatment is conservative, consisting of decongestants or corticosteroid nasal sprays to shrink the inflammatory membrane or granulation tissue. A probe may be performed to perforate the inflammatory membrane, which often produces a permanent cure. In some situations, probing with placement of bicanalicular Silastic tubes may be useful to prevent granulation tissue from closing over the newly formed DCR opening.25 If these conservative measures fail, reoperation with revision of flaps may be performed, and a bicanalicular Silastic stent tube is left in place for a minimum of 3 months. The success rate of this last procedure is greater than 80%. If the obstruction is at the common canalicular level, a canaliculodacryocystorhinostomy (CDCR) may be useful. The scar tissue at the common canaliculus is excised; then the individual canaliculi or residual common canaliculus can be sutured into the nose.26

Endonasal Dacryocystorhinostomy

Silastic tubing

A anterior nasal mucosal flap

posterior nasal posterior mucosal flap lacrimal sac flap

TUMORS OF THE LACRIMAL SAC

suture

Primary lacrimal sac tumors present as masses at the medial canthus. Depending on the age of the patient, there may or may not be symptoms of tearing. These patients often exhibit patency to syringing because the tumor usually arises in the epithelium and only later grows toward the lumen. Bloody tears may be present. Lacrimal sac tumors may be benign or malignant, epithelial or nonepithelial.33 DCG and CT are useful to demonstrate the location of the mass and its extent, as well as associated involvement of the lacrimal drainage pathways. Bony erosion is often present in these cases. lacrimal sac anterior lacrimal sac mucosal flap

B

When the obstruction is in the lower drainage system and the canaliculi are anatomically normal, an endonasal approach may be attempted as an alternative to an external DCR.27,28 The advantage of this procedure is that it avoids any cutaneous incisions.23 This procedure has a success rate reported to be equal to or slightly lower than the external approach.29,30 After decongesting the nasal mucosa, a light pipe is passed through the canaliculus to the lacrimal bone and visualized in the nose. The nasal mucosa is incised, elevated, and removed around the light spot with the use of a scalpel or laser.31,32 The thin bone of the lacrimal bone is punctured and enlarged with Kerrison punches. The ostium should not extend behind the posterior lacrimal crest or above the lacrimal sac. The sac mucosa is opened with Vannas scissors, and a portion of the medial wall is excised. Silicone stents must be placed through the system and left for 3–4 months. This approach also allows the surgeon to deal with nasal adhesions, granulation tissue, and hypertrophic turbinates at the same time.

rhinostomy anterior nasal opening mucosal flap

DISEASES OF THE CANALICULI Canalicular obstruction may have inflammatory, traumatic, idiopathic, or suppurative (canaliculitis – usually actinomycotic) causes. Whereas some diseases certainly involve both the punctum and the canaliculus, many involve either one or the other and so should be considered separately.34

PUNCTAL STENOSIS 1350

Fig. 12-15-9  External dacryocystorhinostomy. (A) Posterior flaps of the sac and nasal mucosa being sutured. (B) Anterior flaps of the sac and nasal mucosa being anastomosed. (Adapted with permission from Hurwitz JJ. Diseases of the sac and duct. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. Artwork courtesy of Terry Tarrant, London.)

Punctal stenosis can be congenital or acquired.35 Congenital obstruction may be caused by a membrane overlying the punctal papilla. In such situations, the rest of the punctum and the canaliculus are patent, so merely perforating the membrane with a No. 25 needle may be

KEY REFERENCES Ansara SA, Pak J, Shields M. Pathology and imaging of the lacrimal drainage system. Neuroimaging Clin North Am 2005;15:221–37.

Ben Simon GJ, Joseph J, Lee S, et al. External versus endoscopic dacryocystorhinostomy for acquired nasolacrimal duct obstruction in a tertiary referral center. Ophthalmology 2005;112:1463–8.

12.15 

Dietrich C, Mewes T, Kuhnemund M, et al. Long-term follow-up of patients with microscopic endonasal dacryocystorhinostomy. Am J Rhinol 2003;17:57–61. Doucet TW, Hurwitz JJ. Canaliculodacryocystorhinostomy in the management of unsuccessful lacrimal surgery. Arch Ophthalmol 1982;100:619–24. Feng YF, Cai JQ, Zhang JY, et al. A meta-analysis of primary dacryocystorhinostomy with and without silicone intubation. Can J Opthalmol 2011;46:521–7. Hurwitz JJ. Diseases of the sac and duct. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia. PA: Lippincott–Raven; 1996. p. 117–48. Linberg JV, McCormick SA. Primary acquired nasolacrimal duct obstruction: a clinical pathological report and biopsy technique. Ophthalmology 1986;93:1055–62. Zaidi FH, Symanski S, Olver JM. A clinical trail of endoscopic vs. external dacryocystorhinostomy for partial nasolacrimal duct obstruction. Eye 2011;25:1219–24.

The Lacrimal Drainage System

sufficient to achieve permanent patency. If the papilla of the punctum is absent, the distal canaliculus often has not developed either, so affected patients usually require the placement of a Jones tube. Marsupialization of the remaining canaliculus into the lacrimal lake does not offer a good solution. Acquired obstructions may result from antiviral or antiglaucoma medications, cicatrizing diseases of the conjunctiva, various infections, radiation, and chemotherapeutic agents, which may also obstruct the canaliculi.36 Intrinsic tumors, such as papillomas and skin malignancies (e.g., basal cell and squamous carcinoma), also may obstruct the puncta. Most acquired punctal obstructions, however, are secondary to punctal eversion, which may be related to eyelid laxity or to cicatrizing diseases of the skin.

Access the complete reference list online at

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REFERENCES 1. Norn MS. Tear secretion in normal eyes. Acta Ophthalmol 1965;43:567–77.

3. Ahl NC, Hill JC. Horner’s muscle and the lacrimal system. Arch Ophthalmol 1982;100:488–93. 4. Becker BB. Tricompartment model of the lacrimal pump mechanism. Ophthalmology 1992;99:1139–45. 5. Jones LT. An anatomical approach to problems of the eyelids and lacrimal apparatus. Arch Ophthalmol 1961;66:111–20. 6. Lloyd GAS, Welham RAN. Subtraction macrodacryocystography. Br J Radiol 1974;47:379–91. 7. Galloway JE, Kavic TA, Raflo GT. Digital subtraction macrodacryocystography. Ophthalmology 1984;91:956–68. 8. Ansara SA, Pak J, Shields M. Pathology and imaging of the lacrimal drainage system. Neuroimaging Clin North Am 2005;15:221–37. 9. Ashenhurst ME, Hurwitz JJ. Combined computed tomography and dacryocystography for complex lacrimal obstruction. Can J Ophthalmol 1991;26:27–37. 10. Linberg JV, McCormick SA. Primary acquired nasolacrimal duct obstruction: a clinical pathological report and biopsy technique. Ophthalmology 1986;93:1055–62. 11. Hurwitz JJ. Diseases of the sac and duct. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 117–48. 12. Marthin JK, Lindegaard J, Prause JU, et al. Lesions of the lacrimal drainage system: a clinicopathologic study of 643 biopsy specimens of the lacrimal drainage system in Denmark 1910–1999. Acta Ophthalmol Scand 2005;83:94–9. 13. Welham RAN, Bergin DJ. Congenital lacrimal fistulas. Arch Ophthalmol 1985;103:545–8. 14. Perry JD. Balloon dacryoplasty. Ophthalmology 2004;111:1796–7. 15. Maheshwari R. Ballon catheter dilation for complex congenital nasolacrimal duct obstruction in older children. J Pediatr Ophthalmol Strabismus 2009;46:215–17. 16. Mandeville JT, Woog JJ. Obstruction of the lacrimal drainage system. Curr Opin Ophthalmol 2002;13:303–9. 17. Toti A. Nuovo metodo conservatore di cura radicale della suppurazioni croniche de sacco lacrimale (dacriocistornostomia). Clin Me 1904;10:385. 18. Hurwitz JJ, Rutherford S. Computerized survey of lacrimal surgery patients. Ophthalmology 1986;93:14–21. 19. Ananthanaryan CR, Hew EM, Hurwitz JJ. Anesthesia for lacrimal surgery. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 247–56.

21. Delaney YM, Khooshabeh R. External dacryocystorhinostomy for the treatment of acquired partial nasolacrimal obstruction in adults. Br J Ophthalmol 2002;86:533–5. 22. Archer K, Hurwitz JJ. An alternative method of canalicular stent tube placement in lacrimal drainage surgery. Ophthalmic Surg 1988;19:510–20. 23. Feng YF, Cai JQ, Zhang JY, et al. A meta-analysis of primary dacryocystorhinostomy with and without silicone intubation. Can J Opthalmol 2011;46:521–7. 24. Ben Simon GJ, Joseph J, Lee S, et al. External versus endoscopic dacryocystorhinostomy for acquired nasolacrimal duct obstruction in a tertiary referral center. Ophthalmology 2005;112:1463–8. 25. Hurwitz JJ. A new, wider-diameter Crawford tube for stenting in the lacrimal drainage system. Ophthal Plast Reconstr Surg 2004;20:40–3. 26. Doucet TW, Hurwitz JJ. Canaliculodacryocystorhinostomy in the management of unsuccessful lacrimal surgery. Arch Ophthalmol 1982;100:619–24. 27. Dietrich C, Mewes T, Kuhnemund M, et al. Long-term follow-up of patients with microscopic endonasal dacryocystorhinostomy. Am J Rhinol 2003;17:57–61. 28. Anijeet D, Dolan L, Macewwn CJ. Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction. Cochrane Database Syst Rev 2011;19:CD007097. 29. Zaidi FH, Symanski S, Olver JM. A clinical trial of endoscopic vs. external dacryocystorhinostomy for partial nasolacrimal duct obstruction. Eye 2011;25:1219–24.

12.15  The Lacrimal Drainage System

2. Jones LT, Wobig JL. Surgery of the eyelids and lacrimal system. Birmingham: Aesculapius; 1976.

20. Hurwitz JJ. Dacryocystorhinostomy. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 261–96.

30. Karim R, Ghabrial R, Lynch T, et al. A comparison of external and endoscopic endonasal dacryocystorhinostomy for acquired nasolacrimal duct obstruction. Clin Ophthalmol 2011;5:979–89. 31. Massaro EM, Gonnering RS, Harris GJ. Endonasal laser dacryocystorhinostomy: new approach to lacrimal duct obstruction. Arch Ophthalmol 1990;108:1172–8. 32. Lee DW, Chai CH, Loon SC. Primary external dacryocystorhinostomy versus primary endinasal dacryocystorhinostomy: a review. Clin Exp Ophthalmol 2010;38. 33. Howarth D, Hurwitz JJ. Lacrimal sac tumours. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 187–94. 34. Hurwitz JJ. Canalicular diseases. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 139–47. 35. Hurwitz. JJ. Diseases of the punctum. In: Hurwitz JJ, editor. The lacrimal system. Philadelphia, PA: Lippincott–Raven; 1996. p. 149–53. 36. Esmaeli B, Amin S, Valero V, et al. Prospective study of incidence and severity of epiphora and canalicular stenosis in patients with metastatic breast cancer receiving docetaxel. J Clin Oncol 2006;24:3619–22.

1351.e1

PART 12 ORBIT AND OCULOPLASTICS SECTION 4 Periorbital Aesthetic Procedures

Cosmetic Blepharoplasty and Browplasty

12.16 

François Codère, Nancy Tucker

Definition: Surgeries to correct changes in the eyelids and forehead area that are secondary to aging and manifest by redundancy and displacement of tissues.

ORBITAL SEPTUM INSERTS INTO THE LEVATOR APONEUROSIS

Key features ■ ■ ■ ■ ■

Brow position plays a key role in the appearance of the upper eyelid. Excessive skin removal is to be avoided in upper and lower eyelid surgery. Position of the fat pad determines the position of the lid crease. In the lower eyelid, repositioning the lid should precede any removal of skin. Eventual forehead surgery is considered when planning upper blepharoplasty.

preaponeurotic fat pads

Müller‘s muscle orbital septum eyelid crease

INTRODUCTION Aging changes in the eyelids and the face are related to loss of tone in the various layers underlying the skin. Changes that occur in the upper eyelid skin are usually due to passive stretching, loss of support, or redundancy of skin secondary to lowering of the brows. Most patients do not appreciate the extent to which brow malposition contributes to the overall appearance of the aging periorbital area. This needs to be pointed out specifically to help the patient understand why a blepharoplasty alone often will not fully correct the problem. If a manual lift of the brow to the desired position significantly improves the patient’s appearance, a browplasty, either alone or combined with blepharoplasty, should be considered. If a blepharoplasty is performed without recognizing any associated brow ptosis, the lateral eyebrow can appear pulled down, which produces an undesirable, sad appearance.

levator aponeurosis

tarsus

ANATOMIC CONSIDERATIONS Eyelids

Key anatomic features that cause excess upper eyelid skin include brow ptosis from the loss of forehead deep tissue support, loss of the deep invagination of the eyelid skin in the principal lid crease as a result of anterior displacement of the suborbicularis fat pads, and stretching of attachments between the levator aponeurosis and the skin. To understand the anatomy, the lid may be arbitrarily divided into two distinct portions (Fig. 12-16-1).

Fig. 12-16-1  The orbital septum inserts into the levator aponeurosis (arrows). The preaponeurotic fat pads are located posterior to the septum. In downgaze the lid crease becomes attenuated (weakened), and in a normal young eyelid the fold is absent. (Adapted with permission from Zide BW, Jelks BW. Surgical anatomy of the orbit. ch. 4. New York: Raven Press; 1985. p. 23.)

Upper eyelid

1352

Anatomy of the upper eyelid is discussed in Chapter 12.1. The eyelid crease is an important anatomic and aesthetic structure. If upper lid fat recedes, or the levator aponeurosis becomes stretched or disinserted, the crease assumes a higher position. In Asiatic eyelids, the crease (if present) is lower because of the low insertion of the septum into the aponeurosis.1

When the eyelid opens, the lid crease skin is pulled upward and backward by the aponeurosis as it retracts under the fat pad (Fig. 12-162).2 The portion of the lid above the crease bulges slightly as this fat pushes the skin forward. During downgaze, tension in the aponeurosis becomes lax, resulting in a weakened or absent lid crease.

INVAGINATION OF NORMAL EYELID

SURGICAL ANATOMY OF THE FOREHEAD MUSCLES AND FASCIA

orbital septum eyelid crease

levator aponeurosis

superior temporal line

deep division supraorbital nerve frontalis muscle

inferior temporal line

temporal fusion line

superficial temporal fascia

procerus muscle

seventh cranial nerve

corrugator supercilii muscle

Cosmetic Blepharoplasty and Browplasty

galea aponeurotica

12.16 

Fig. 12-16-3  Surgical anatomy of the forehead muscles and fascia.

Fig. 12-16-2  The invagination of the normal eyelid crease is created by the posterior pull on the septal insertion by the elevating levator aponeurosis. The preaponeurotic fat is also retracted by the septum. The flat portion of the lid under the crease slips inside the upper preseptal portion. (Adapted with permission from Zide BW, Jelks BW. Surgical anatomy of the orbit. ch 4. New York: Raven Press; 1985. p. 23.)

Lower eyelid

The lower eyelid has a similar, but simpler, anatomy and is reviewed in Chapter 12.1. Integrity of the medial and lateral canthal tendons (see Chapter 12.1) is very important to maintain a proper lid position, especially in the aging face.3 However, the bony configuration of the midface also plays a key role.

Brows

A thorough understanding of the forehead anatomy is essential to evaluate brow ptosis4 (Fig. 12-16-3). The layers in the midforehead are skin, dermis, superficial galea, frontalis muscle, deep galea, and peri­ osteum. The forehead skin is much thicker than the eyelid skin. The dermis and subcutaneous fat are connected to the underlying frontalis muscle by multiple fibrous septa. The paired frontalis muscles originate just anterior to the coronal suture line. A smooth fibrous sheath, the galea aponeurotica, envelops the frontalis to form both superficial and deep galeal layers. Laterally, the frontalis muscle ends and does not extend beneath the lateral third of the brow. Here, the superficial galea, the superficial temporalis fascia, and the periosteum of the frontal bone fuse. The confluence of these tissue planes is called the ‘zone of fixation.’ The eyebrow fat pad (subgaleal fad pad) is a transverse band of fibroadipose tissue 2–2.5 cm above the orbital rim. It allows movement of the frontalis muscle in the lower forehead. Centrally, the procerus muscle is continuous with the medial portion of the frontalis muscle and inserts into the nasal bone and glabellar subcutaneous tissue. It causes horizontal wrinkles of the glabella.5 The corrugator supercilii muscle is obliquely oriented, passing from the subcutaneous brow to the frontal bone medially. It causes vertical glabellar furrows.6,7 Several important neurovascular structures occur in the forehead. The frontal branch of the facial nerve lies within the superficial temporal fascia before entering the frontalis muscle. At the superior rim there

are the lacrimal nerve laterally, the supraorbital nerve with its deep and superficial division, and the supratrochlear nerve more nasally. Several factors contribute to the appearance of the aging forehead and brow. These include changes in the quality of the skin, loss of tissue support, and forehead and glabellar furrows related to action of the underlying facial muscles.8,9 The lateral eyebrow segment is more prone to become ptotic because of less structural support in this area. The final brow position depends on the dynamics between the frontalis muscle pulling the brow up and the descending temporal soft tissue dragging it down.7

BLEPHAROPLASTY Preoperative Evaluation and Diagnostic Approach History and psychological evaluation

When evaluating patients who seek cosmetic improvement of the periorbital area, the surgeon should understand the patients’ motives for undergoing surgery and the decision-making process they have undertaken. Asking patients what they expect the surgery will change for them can sometimes reveal unexpected motives or unrealistic expectations. The psychological screening should include a past medical and surgical history with specific questions about previous cosmetic surgery. Outcomes of previous surgeries might give a clue to unrealistic expectations, especially if the objective results of these previous surgeries are not in harmony with the patient’s perception. Previous mental illness should alert the surgeon – a psychiatric consultation is sometimes useful. In assessing expectations, the surgeon can help by carefully discussing the surgery and explaining the improvements to be expected. It is important to detail the cosmetic defects that cannot be changed by surgery and establish a realistic plan for facial rejuvenation.10 The patient is asked to consider carefully the decision to undergo surgery and, if one is sought, should be encouraged to obtain a second opinion. Establishing a relationship of trust is of paramount importance. If in any doubt, even for unclear objective reasons, a conservative attitude is recommended.

Physical examination

The position and shape of the different periorbital structures are evaluated along with the quality of the skin.5,11 In the forehead area, the level

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12 Orbit and Oculoplastics

and shape of the hairline, the quality of skin of the forehead, and the position and shape of the brows are evaluated with specific attention to detecting brow asymmetry. The muscular layer is judged by looking at the frown lines in the forehead and glabellar area and by asking the patient to relax the forehead. Concomitant treatment with paralyzing injection (Botox) can distort this assessment. The bony orbit is then evaluated, especially laterally at the orbital rim, where some prominence can mimic lacrimal gland prolapse. This is a good time to evaluate the position of the globe in relation to the bony orbit, as this is an important determinant of the type of lid fold to aim for. A fuller orbit with a large eye leads to a convex upper eyelid above the crease, whereas a large orbit with a small eye results in a more concave upper lid above the crease. A prominent globe with recessed zygoma often leads to lower lid malposition. The inferior periorbital area is evaluated in a similar fashion. The quality of the skin is important, and cicatricial changes from dermatologic conditions can make the lid more susceptible to malposition after surgery. The cheek is examined for the presence of festoons, noting whether they consist of only skin and orbicularis or also of suborbicularis fascia and/or orbital fat.12 Precise measurements of the eyelid aperture should be recorded, noting the high point of the upper lid and the general shape of the palpebral fissure. The position of the lid crease and fold should be documented. The amount of fat to be removed in all fat pad areas, both superiorly and inferiorly, is estimated. The position of the lacrimal glands is also noted. In the lower lids the fat pads are also carefully assessed. Laxity of the canthal tendons is noted and manually tightened with the finger before considering removal of any skin. The nasojugal area should be examined to detect tear trough deformities, which may need correction instead of fat pad removal.13 The use of a flow sheet to outline systematically the physical findings is an excellent way to plan present and future surgery. Surgery planning must take into account the patient’s desires, what he or she is willing to undergo, and what the surgeon thinks is reasonable and safe. Figure 12-16-4 gives an overview of the evaluation of the patient consulting for blepharoplasty and brow malposition. A good set of photographs should carefully document the changes noted and be kept as part of the patient’s chart.

Anesthesia

Local infiltrative anesthesia containing epinephrine for hemostasis is adequate for all blepharoplasty procedures.

General Techniques

Draping should be done carefully to avoid distortion of the brow and lateral canthi and to allow the patient to sit up, if necessary, during the operation. The amount of skin to be removed is marked before infiltration. In the upper eyelid, excessive removal of thin lid skin and dragging down of thick brow skin are a nonesthetic shortcut and should not be substituted for adequate repositioning of the brows. In the lower lids the same principle applies: the lid should be repositioned and the scleral show corrected before any skin is removed.

Specific Techniques

Upper lid blepharoplasty

The lid crease is first marked at 8–10 mm above the lash line, taking into account the racial background of the patient. The crease marking usually goes from a point above the superior punctum to, but not beyond, the lateral orbital rim. Skin excess should be evaluated so that in downgaze the crease is attenuated without lid retraction, and a gentle fold reforms over it in primary position. In general, 20–24 mm of skin should be left between the brow and the lid margin.14 Even if associated brow ptosis is not to be corrected at the same time, excessive skin removal should be avoided. The long-taught rule that the eyes should not close on the operating table has certainly become obsolete. Excessive skin removal medially may result in hood formation. If disproportionate tissue is still present in this region after surgery, a glabellar lift should be considered. An optional small triangular flap of skin can be added to the usual skin pattern medially to minimize folding of the skin at the time of closure in patients with excess of skin medially (Fig. 12-16-5). The lid is placed under traction. A Bard–Parker No. 15 blade is used to incise the skin. The skin flap is then removed with a blade or scissors, leaving the orbicularis intact at this stage.

WORKSHEET TO DOCUMENT PHYSICAL FINDINGS AND SURGICAL PLAN

Brow ptosis

Exophthalmos? Lid retraction?

Corrugator?

Surgical plan Coronal................................................

Type lift –

Procerus?

Skin resection

Fat

Upper– (right)

Fat

Hollow?

Transpose fat? Fat

Fat

Aperture deformities? Fat

Corrugator............................................

Retraction? Ptosis? R Skin (Left)

mm

L

mm

Type

Fat

e Ton Fat

Fat Fat

Fat

Skin

Festoons or Malar bags Thickness

Epicanthal folds? Tear troughs mm

Encroaching Anterolateral

Malar complex

Muscle

Type flap skin, skin and muscle, tarsus conjunctiva Orbital rims?

Incision location.................................... Orbital rims.......................................... Forehead excision.................................

Canthopexy resection

Tone

Procerus...............................................

Upper blepharoplasty............................ Medial epicanthoplasties........................ Transconjunctival fat.............................. Low skin excision................................... Canthoplexy.......................................... Tear trough implants.............................. Malar implants......................................

Corrugator insertion Hemiexophthalmos?

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Fig. 12-16-4  A sample worksheet to document the physical findings and surgical plan. (Adapted with permission from Flowers RS, Flowers SS. Precision planning in blepharoplasty. Clin Plast Surg 1993;20:303–10.)

Lower lid blepharoplasty

Two specific techniques are popular for lower lid blepharoplasty.15 The skin approach allows modification of the interaction between the muscle and the skin planes and makes lid tightening or canthal

SKIN INCISION LINE FOR UPPER EYELID BLEPHAROPLASTY

repositioning easier. When only fat prolapse is present, the transconjunctival approach allows surgical access without visible scar and avoids the risk of lid malposition.

Skin approach

In the skin approach, the skin is marked 3 mm below the lash line from the inferior punctum to the lateral canthal angle. If excess skin is to be removed or if the orbicularis muscle is to be tightened, the incision is extended laterally and downward toward the earlobe for a short distance. The skin is incised with a No. 15 blade. Scissor dissection exposes the suborbicularis plane and the anterior surface of the orbital septum. The septum is easily identified by pushing gently on the globe to prolapse the fat and opened with scissors. The temporal and central fat pads are one continuous pad separated by a vertical band of fascial connections between the capsulopalpebral fascia and the orbital septum.3 The capsule of each of the fat pads is opened. Care is taken to tease the fat out of the respective pockets without undue traction in order to avoid deep bleeding in the orbit. In the medial lid the fat capsule is opened separately, and care must be taken to protect the inferior oblique at the time of excision. The fat is carefully examined for bleeders before it is allowed to retract into the orbit. In some cases repositioning of the lower eyelid fat into the suborbicularis oculi fat (SOOF) plane is another useful procedure to fill-in a tear trough deformity.16 A canthopexy can be used to lift a sagging lateral angle by placing a suture through the lateral canthus and attaching it to periosteum.17 If horizontal lid laxity is present, a tarsal strip procedure can be performed (see Chapter 12.7).18 A small triangle of skin and orbicularis muscle may be excised laterally. Closure of the orbicularis as a sliding flap often helps to rejuvenate an older lid. Hemostasis is attained carefully before the skin is closed with a continuous suture of 6-0 nylon.

12.16  Cosmetic Blepharoplasty and Browplasty

Gentle pressure on the globe prolapses the orbital fat and helps identify the orbital septum. The fat is exposed by making a small buttonhole centrally through the orbicularis and the septum above its insertion on the aponeurosis. The septum is opened laterally and medially from this buttonhole (Fig. 12-16-6). Each fat pad capsule is opened. The fat is gently prolapsed and sectioned. The section line can be cauterized with a bipolar cautery (see Fig.12-16-6). The orbicularis muscle is thinned down. The aponeurosis is bared of orbicularis just above the tarsal border to encourage the formation of a good adherence between the aponeurosis and the skin where the lid crease is to be formed. Invagination of the skin by fixing the skin edge to the aponeurosis at the time of closure ensures a good position of the crease in fuller lids but is not always necessary. The orbicularis can be tacked down to the aponeurosis immediately under the upper skin edge using two or three 6-0 plain sutures. This defines the position of the eyelid crease and controls the position of the fat pad in the lid (Fig. 12-16-7). The skin is closed with a running 6-0 nylon suture. The area beyond the lateral canthal angle is closed with interrupted sutures to obtain an edge-to-edge closure without folds (Fig. 12-16-8).

Transconjunctival approach

With the transconjunctival approach, the lid is everted over a Desmarres retractor. The lateral fat pad is often the most difficult to expose – a buttonhole through the conjunctiva laterally about 4 mm from the inferior tarsal border can be helpful. The Desmarres retractor is used to pull the lid toward the cheek to expose the lateral fat pad. The fat is cauterized at the base and carefully cut with fine scissors. This approach allows early identification of the lateral fat pad before any bleeding occurs. The incision can then be extended medially to expose the central and medial pads, which are removed in the same way. Closure of the conjunctiva is completed with a few 6-0 plain catgut sutures. Fig. 12-16-5  Typical skin incision line used for upper eyelid blepharoplasty. A small additional medial flap is added (shaded area) if a dog-ear or fold develops because of excessive skin nasally.

Other Surgical Techniques

Specific techniques should be used when operating on Asian eyelids – the goals determine the technique to be used.19 In general, the skin

EXPOSURE AND CAUTERIZATION OF FAT PADS Septum opened and fat exposed orbital septum

preaponeurotic orbital fat

orbicularis

Fat pad is cauterized bipolar cautery

opened orbital septum

medial fat pad

orbicularis

Desmarres' retractor

Fig. 12-16-6  Exposure and cauterization of fat pads. Preaponeurotic fat pads are a key landmark just anterior to the aponeurosis. The orbital septum is opened to expose the fat, and each pad is carefully cauterized along its base before being cut with scissors.

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12

Orbital hemorrhage and blindness

EYELID FOLD REFORMED

Orbit and Oculoplastics

bone suture attaching orbicularis muscle to aponeurosis orbital septum lid fold suture levator aponeurosis

lid fold

orbicularis oculi muscle

tarsus

Orbital hemorrhage following blepharoplasty is an emergency. It has been associated with permanent loss of vision in some cases, especially if the lower eyelid is involved.14,21,22 Prevention involves careful preoperative screening for use of anticoagulants, including aspirin. Meticulous hemostasis, gentle manipulation of fat during surgery, and good control of blood pressure postoperatively are important. Early removal of patches and application of cold packs minimize swelling. Strenuous activities should be avoided for the first 3–4 days. Anticoagulants should not be administered for at least 5–6 days after surgery. The surgeon and medical staff should be alerted by unusual pain, swelling under tension, or double or blurred vision. If in doubt, the patient must be seen immediately for an assessment of visual acuity and pupillary response. In the presence of a deep hematoma the patient should be admitted for close monitoring of optic nerve function. If optic nerve dysfunction appears, the wounds are opened and the blood is evacuated. A lateral cantholysis helps decompress the soft tissues of the orbit, but with a deep hemorrhage an orbital exploration may be required.

Infections Fig. 12-16-7  The eyelid fold or crease is reformed by passing several sutures from the orbicularis muscle to the aponeurosis at the appropriate height.

SKIN CLOSURE TECHNIQUE interrupted sutures

Fortunately, the eyelids are well vascularized so that infections after blepharoplasty are rare. Patients should be aware that an increase in swelling with redness and pain may be the first sign of infection. If it is confirmed by examination, appropriate cultures and sensitivities should be obtained and the patient started immediately on widespectrum systemic antibiotics. Close follow-up to rule out abscess formation in the orbit is necessary in severe cases and proper orbital imaging should be obtained. Blindness is a rare complication of infection, but it has occurred following blepharoplasty.23

Ptosis

Ptosis may be present but unrecognized on initial preoperative examination in patients with severe skin excess. Palpebral fissures should be evaluated along with the levator action as if all patients were consulting for ptosis (see Chapter 12.5). If present, ptosis should be corrected by advancing the levator aponeurosis on the tarsal surface. Otherwise, at the time of blepharoplasty care should be taken not to damage the aponeurosis. If impending ptosis is present and the lid crease is reconstructed by supratarsal fixation, a slight tightening of the aponeurosis may be wise. When ptosis appears after surgery, conservative observation for 6 months is recommended. If it persists, surgical correction may be necessary. running stitch Fig. 12-16-8  The skin is closed with two to three interrupted sutures laterally, where the skin is thicker, and with a running suture along the remainder of the wound.

incision is made lower toward the lid margin, depending upon the desired position of the resulting crease.20 Some preaponeurotic fat should be left to act as a barrier between the levator and the skin if the Asian-type lid is to be preserved.

Postoperative Care

A medium-pressure bandage is applied to the lids with an appropriate antibiotic ointment. The patient can remove the patches soon after surgery and start applying cold packs to the surgical site for 10 minutes each hour during the first evening and then four or five times the next day. Light analgesia for blepharoplasty is usually sufficient. Severe pain is not expected and warrants immediate examination to rule out orbital hemorrhage, infection, or corneal abrasion. The sutures on the skin can be removed 5–7 days postoperatively if nylon 6-0 is used.

Complications

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Complications of blepharoplasty are of two orders. One group of complications can occur from events unrelated to the technique used; a second group can occur following improper surgery for a particular deformation. For example, infection, despite the best surgical techniques, will occur in a small number of patients; the same is true of milia formation along a scar line. Lower lid ectropion or canthal angle rounding in the lower eyelid is usually the result of improper surgical planning or techniques.

Lagophthalmos, lower lid retraction, ectropion, and lateral canthal deformities

If excessive skin has been removed in the upper lid, resulting in lagophthalmos, time is often of help; the brows continue their downward drift and the lagophthalmos often progressively decreases. Massage and ocular lubricants in the first few months after surgery may bring the patient out of this difficult phase. But if keratitis ensues and threatens the integrity of the eye, surgical correction should be done. In the lower lid, gravity works against spontaneous improvement. Frank ectropion might resolve with massage but almost invariably leaves lower scleral show. Using the transconjunctival approach when minimal or no skin excess is present, tightening the lateral canthal tendon if necessary, and avoiding excessive skin removal are the best ways to prevent this complication.24 Revision using a lateral tarsal strip procedure combined with a disinsertion of the lower eyelid retractors can give satisfactory results in mild cases. A midfacial lift or a skin graft may become necessary with more severe deformities.25–29

Other complications

Tearing after blepharoplasty can be a complex problem, especially if lagophthalmos is present. Investigation of this complication should include a full lacrimal work-up with assessment of the reflex component if keratitis is present. The integrity of the canaliculi and the position of the lid margin and puncta are all evaluated before planning correction (see Chapter 12.15). Injury to the extraocular muscles can occur, especially in the lower lid, where the inferior oblique and inferior rectus are prone to damage with exploration of the medial fat pad.30 The superior oblique tendon can also be damaged in upper lid surgery.31 In these instances, a follow-up of at least 6 months is necessary prior to considering surgical interventions, as spontaneous resolution is fortunately the rule.

Outcome

SURGICAL APPROACHES TO BROW PLASTY

bicoronal forehead lift

BROW MALPOSITION

midfrontal brow lift

Preoperative Evaluation and Diagnostic Approach

The ideal brow position and shape are subjective, but in general the brow is straighter and at the superior orbital rim in a man, and more curved and slightly above the rim in a woman. An evaluation of the most cosmetically pleasing brows in women suggests that the medial eyebrow should be positioned at or below the supraorbital rim, with the eyebrow shape having an apex lateral slant.32 The clinical evaluation should include brow position (estimated by the difference between the actual resting brow position and the desired position), the amount of excess forehead skin and degree of furrowing, the hairline position, and the length of the forehead. The length of the forehead can be determined by passing imaginary horizontal lines through the hairline, the upper border of the eyebrows, and directly below the nose. These lines divide the balanced face into three equal portions. An increase or reduction of the upper segment is an important factor when selecting the incision site using the coronal approach.33 The extent to which the procerus and corrugator muscles contribute to furrowing of the forehead should be determined. A family history of male pattern baldness should be sought. It is important to determine how extensive a surgery the patient is willing to undergo to achieve the best results; often the final surgical choice is a compromise between the most effective technique and the least invasive procedure.34

Anesthesia

Anesthesia is provided by supraorbital and supratrochlear regional blocks along with direct local infiltration, depending on the extent of anesthesia desired for each of the various techniques. In selected patients, general anesthesia may be considered. Gentle but constant pressure minimizes the formation of hematomas that can distort anatomy.

General Techniques

Surgical approaches to the correction of brow ptosis include direct, midfrontal, and bicoronal brow lifts (Fig. 12-16-9). More recently, endoscopic and small incision browplasties have been described. Minimal brow elevation can also be approached through an eyelid crease incision at the time of blepharoplasty. The choice of technique depends on the amount of correction required and on the patient’s expectations.35

Specific Techniques

The bicoronal forehead lift

The bicoronal forehead lift allows the maximal effect of brow elevation with a well-camouflaged incision site.36 It is ideally suited for patients with significant brow ptosis, without frontal baldness, and with a normal to low hairline. The incision is hidden posterior to the hairline (post-trichion). Alternatively, in patients who have a high forehead, the incision can be placed at the hairline (pretrichion) to avoid further elevating the hairline. There are two major choices for the surgical dissection plane: subcutaneous and subgaleal.33 Factors that influence the choice of dissection plane include the quality and elasticity of the skin, the amount of skin wrinkling, and the depth of the furrows, but surgeon preference is likely to be the most significant factor.8,33 A combined coronal brow lift and blepharoplasty can be used in patients with excessive eyelid fat and brow ptosis but little or no dermatochalasis.37 The major disadvantages of the bicoronal technique include its invasive surgical approach, which can be intimidating to the patient, and the increased risk of hematoma and nerve injury.

The midfrontal brow lift

The midfrontal approach provides less brow lift effect than does the bicoronal but more than the direct brow lift approach. Advantages

direct brow lift

12.16  Cosmetic Blepharoplasty and Browplasty

Most patients who seek cosmetic eyelid or brow surgery expect some improvement in their appearance and in their self-image and are usually happy with the result. Some, in whom the anatomic deformity interferes with visual function, as in severe overhanging dermatochalasis, can also notice improvement in their visual field. The patients who enter into surgery with unrealistic goals, either physical or social, are more at risk of not being satisfied with the results.

Fig. 12-16-9  Surgical incision sites for correction of brow ptosis.

include less risk of hematoma (because only moderate undermining is required and it is performed above the frontalis muscle) and less risk of nerve damage. The corrugator supercilii and procerus may be resected directly through this approach. It is ideally suited for patients who have deep horizontal furrows in the forehead (usually men), especially when frontal baldness prevents the use of a bicoronal incision. There are various types of incisions that can be used:  Along a furrow line the entire length of the forehead  Along a furrow line staggered centrally  Two separate fusiform excisions, each extending from the medial to lateral end of the brow. The major disadvantage of this technique is the resultant scar line.

The direct brow lift

The direct brow lift is the oldest and simplest surgical approach. Its advantages include a less invasive surgical dissection with less risk of damage to the facial nerve and minimal risk of hematoma. It is ideally suited for patients with bushy brows and mild brow ptosis. It can also be used in patients who have unilateral brow ptosis, which most commonly occurs following peripheral facial nerve palsy. It does not fully correct the medial brow ptosis, and it results in a visible scar even when placed directly above the eyebrow with often an unnaturally sharp border due to loss of the fine upper brow hairs. In patients who have large bushy brows, the incision tends to be less apparent. Modifications include a more temporal skin excision to correct isolated temporal brow ptosis.

Endoscopic brow lift

Recently, less invasive techniques have emerged in an attempt to reduce complications and achieve faster recovery. These techniques include endoscopic procedures, which involve small incisions placed temporally and/or centrally on the scalp, posterior to the hairline.38 A subperiosteal or subgaleal dissection is carried down to the level of the brow. The procerus and corrugator muscles are usually cut and excised, and the periosteum is transected at the superior orbital rim. The forehead is pulled upward and the periosteum fixed into position.

Transblepharoplasty brow fixation

For minimal brow ptosis, the brow can be elevated through a blepharoplasty incision by suturing the sub-brow dermis higher on to the frontalis muscle. This approach can help correct mild brow ptosis or small asymmetries.34,39

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12

Complications

Orbit and Oculoplastics

Complications of browplasty depend on the technique used. There are two major groups of complications: those related to the incision site and those related to the extent of dissection.

Excessive cutaneous scar and alopecia

The forehead skin is thicker and less vascular than the eyelid skin, so incisions in the forehead often heal with a visible scar. Meticulous closure with adequate subdermal tension-bearing sutures and careful approximation of the wound edges is important. However, placement of the incision is the main determinant of scar visibility. It is generally preferable to locate the incision site at or above the hairline. Alopecia can be secondary to tension of wound, ischemia, or superficial dissection.

Paresthesia and hematoma

Related to the extent of dissection are the potential associated nerve injuries, which can result in frontal paresis, numbness, and an increased risk of hematoma formation. Temporary paresthesia following browplasty is common but usually resolves within 6 months. Hematomas can occur after bicoronal brow lift. They can be prevented at the end of surgery by placement of suction drains under the flaps. Small hematomas often resolve spontaneously, but larger ones should be evacuated to avoid flap necrosis, especially with a subcutaneous dissection where necrosis is more likely.

Overcorrection and undercorrection

Overcorrection of brow position or loss of movement of the brow can result in a ‘look of perpetual surprise,’ particularly if the brow has been fixed to the underlying periosteum in an overzealous direct brow lift.

Access the complete reference list online at

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Undercorrection occurs when insufficient elevation is achieved; it is more common with the endoscopic technique and with posterior fixation of the brow through a blepharoplasty incision.

Outcome

Following brow elevation procedures, the patient should experience an improvement in appearance and a restoration of superior visual field. In order to achieve these results, the brow repair may have to be combined with a blepharoplasty.

KEY REFERENCES Angelos PC, Stallworth CL, Wang TD. Forehead lifting: state of the art. Facial Plast Surg 2011;27:50–7. Bosniak S. Reconstructive upper lid blepharoplasty. Ophthalmol Clin North Am 2005;18:279–89. Burroughs JR, Bearden WH, Anderson RL, et al. Internal brow elevation at blepharoplasty. Arch Facial Plast Surg 2006;8:36–41. Chee E, Choo CT. Asian blepharoplasty – an overview. Orbit 2011;30:58–61. Kim DW, Bhatki AM. Upper blepharoplasty in the Asian eyelid. Facial Plast Surg Clin North Am 2005;13:525–32. Lelli GL, Lisman RD. Blepharoplasty complications. Plast Reconstr Surg 2010;125:1007–17. McCord CD, Boswell CB, Hester TR. Lateral canthal anchoring. Plast Reconstr Surg 2003;112: 222–37. Mohadjer Y., Holds JB. Cosmetic lower eyelid blepharoplasty with fat repositioning via intraSOOF dissection: surgical technique and initial outcomes. Ophthal Plast Reconstr Surg 2006;22:409–13. Pak J, Putterman AM. Revisional eyelid surgery: treatment of severe postblepharoplasty lower eyelid retraction. Facial Plast Surg Clin North Am 2005;13:561–9. Ridgeway JM, Larrabee WF. Anatomy for blepharoplasty and brow-lift. Facial Plast Surg 2010;26:177–85.

REFERENCES 1. Chee E, Choo CT. Asian blepharoplasty – an overview. Orbit 2011;30:58–61. 2. Zide BW, Jelks BW. Surgical anatomy of the orbit. ch. 4. New York: Raven Press; 1985. p. 23.

20. Lam SM, Karam AM. Supratarsal crease creation in the Asian upper eyelid. Facial Plast Surg Clin North Am 2010;18:43–7. 21. McCord CD, Shore JW. Avoidance of complications in lower lid blepharoplasty. Ophthalmology 1983;90:1039–46. 22. Teng CC, Reddy S, Wong JJ, et al. Retrobulbar hemorrhage nine days after cosmetic blepharoplasty resulting in permanent visual loss. Ophthal Plast Reconstr Surg 2006;22: 388–9.

4. Angelos PC, Stallworth CL, Wang TD. Forehead lifting: state of the art. Facial Plast Surg 2011;27:50–7.

23. Morgan SC. Orbital cellulitis and blindness following a blepharoplasty. Plast Reconstr Surg 1979;64:823–6.

5. Lyon DB. Upper blepharoplasty and brow lift: state of the art. Mo Med 2010;107:383–90.

24. Zarem HA, Resnick JI. Minimizing deformities in lower blepharoplasty. Clin Plast Surg 1993;20:317–21.

6. Knize DM. Limited-incision forehead lift for eyebrow elevation to enhance upper blepharoplasty. Plast Reconstr Surg 1996;97:1334–42. 7. Ridgeway JM, Larrabee WF. Anatomy for blepharoplasty and brow-lift. Facial Plast Surg 2010;26:177–85. 8. Ortiz-Monasterio F, Barrera G, Olmedo A. The coronal incision in rhytidectomy – the brow lift. Clin Plast Surg 1978;5:167–79. 9. Connell BF. Eyebrow, face and neck lifts for males. Clin Plast Surg 1978;5:15–23.

25. Anderson RL, Gordy DD. The tarsal strip procedure. Arch Ophthalmol 1979;97:2192–7. 26. Morax S, Touitou V. Complications of blepharoplasty. Orbit 2006;25:303–18. 27. Lelli GL, Lisman RD. Blepharoplasty complications. Plast Reconstr Surg 2010;125: 1007–17. 28. Pak J, Putterman AM. Revisional eyelid surgery: treatment of severe postblepharoplasty lower eyelid retraction. Facial Plast Surg Clin North Am 2005;13:561–9.

10. Von Soest T, Kvalem IL, Skolleborg KC, et al. Psychosocial factors predicting the motivation to undergo cosmetic surgery. Plast Reconstr Surg 2006;117:51–62.

29. Ferri M, Oestreicher JH. Treatment of post-blepharoplasty lower lid retraction by free tarsoconjunctival grafting. Orbit 2002;21:281–8.

11. Bosniak S. Reconstructive upper lid blepharoplasty. Ophthalmol Clin North Am 2005;18: 279–89.

30. Harley RD, Nelson LB, Flannagan JC, et al. Ocular motility disturbances following cosmetic blepharoplasty. Ophthalmology 1980;89:517–21.

12. Furnas DW. Festoons of orbicularis muscle as a cause of baggy eyelids. Plast Reconstr Surg 1978;61:540–6.

31. Wesley RE, Pollard ZF, McCord CD Jr. Superior oblique paresis after blepharoplasty. Plast Reconstr Surg 1980;66:283–7.

13. Flowers RS. Tear trough implants for correction of tear trough deformities. Clin Plast Surg 1993;20:403–15.

32. Freund RM, Nolan WB. Correlation between brow lift outcomes and aesthetic ideals for eyebrow height and shape in females. Plast Reconstr Surg 1996;97:1343–8.

14. Kulwin DR, Kersten RC. Blepharoplasty and brow elevation. In: Dortzbach RK, editor. Ophthalmic plastic surgery: prevention and management of complications. New York: Raven Press; 1994. p. 91–111.

33. Guyuron B. Subcutaneous approach to forehead, brow, and modified temple incision. Clin Plast Surg 1992;19:461–76.

15. Perkins SW, Batniji RK. Rejuvenation of the lower eyelid complex. Facial Plast Surg 2005;21:279–85. 16. Mohadjer Y, Holds JB. Cosmetic lower eyelid blepharoplasty with fat repositioning via intra-SOOF dissection: surgical technique and initial outcomes. Ophthal Plast Reconstr Surg 2006;22:409–13. 17. Flowers RS. Canthopexy as a routine blepharoplasty component. Clin Plast Surg 1993;20:351–65. 18. McCord CD, Boswell CB, Hester TR. Lateral canthal anchoring. Plast Reconstr Surg 2003;112:222–37. 19. Kim DW, Bhatki AM. Upper blepharoplasty in the Asian eyelid. Facial Plast Surg Clin North Am 2005;13:525–32.

Cosmetic Blepharoplasty and Browplasty

3. Glassman ML, Hornblass A. The lateral canthus in cosmetic surgery. Facial Plast Surg Clin North Am 2002;10:29–35.

12.16 

34. Morgan JM, Gentile RD, Farrior E. Rejuvenation of the forehead and eyelid complex. Facial Plast Surg 2005;21:271–8. 35. Patrocinio LG, Patrocinio JA. Forehead-lift: a 10-year review. Arch Facial Plast Surg 2008;10:391–4. 36. Dingman DL. Transcoronal blepharoplasty. Plast Reconstr Surg 1992;90:815–9. 37. Ellenbogen R. Transcoronal eyebrow lift with concomitant upper blepharoplasty. Plast Reconstr Surg 1983;71:490–9. 38. Jones BM, Grover R. Endoscopic brow lift: a personal review of 538 patients and comparison of fixation techniques. Plast Reconstr Surg 2004;113:1242–50. 39. Burroughs JR, Bearden WH, Anderson RL, et al. Internal brow elevation at blepharoplasty. Arch Facial Plast Surg 2006;8:36–41.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 4 Periorbital Aesthetic Procedures

12.17 

Injectable Skin Fillers Gregg S. Gayre

Definition: Injectable fillers are used to treat superficial static or fixed wrinkles in the periocular and facial skin.

TABLE 12-17-1  SELECTION GUIDE FOR INJECTABLE FILLERS Site

Product Options

Nasolabial Folds

Restylane Perlane Juvederm Ultra Juvederm Ultra Plus Radiesse Restylane Juvederm Ultra Restylane Juvederm Ultra Restylane Juvederm Ultra* Restylane* Juvederm Ultra* Restylane* Juvederm Ultra* Juvederm* Restylane* Juvederm* Restylane*

Key features ■

Numerous skin fillers are now available with different clinical indications and physical characteristics. ■ Injection techniques are different for each type of filler and require some experience in order to avoid complications.

Marionette Lines Lipstick Lines Lip Augmentation Tear Trough Deformity

INTRODUCTION

Horizontal Forehead Lines†

With the increasing popularity of Botox comes a renewed interest in injectable fillers as either an adjuvant or alternative to botulinum toxin therapy for wrinkle reduction.1 There are two basic types of skin wrinkles: dynamic and static. Dynamic wrinkles appear within the skin due to repeated contracture by the underlying muscles of facial expression. Static wrinkles result from intrinsic changes in the components of the dermal ground substance of the skin and from exogenous changes brought about by such factors as smoking, gravity, and sun exposure. Generally, dynamic wrinkles are best treated by Botox injections. Filler agents are more suited to static wrinkles. For deeper wrinkles and furrows that do not resolve with Botox treatment alone, the addition of filler substance may enhance the overall treatment outcome. When considering fillers to augment botulinum toxin therapy, cost, duration of action, intended site of placement, and the potential for adverse reactions must be considered. No one filler type is ideal for all clinical applications so that several different fillers must often be available to the aesthetic surgeon to achieve desired results.2,3 However, regardless of the specific preparation, all must adhere to safety concerns by being non-allergenic, biocompatible, produce minimal inflammation, be associated with minimal migration, and cause little or no pain. In addition, costeffectiveness is a major consideration.

Glabellar Frown Lines†

COLLAGEN Collagen and collagen-based products were introduced as filler materials more than four decades ago. While they remain acceptable filler materials, their use is rapidly declining as newer products have become available.4–6 Collagen absorbs rapidly, and therefore requires repeat injections every 3–5 months.

HYALURONIC ACID Hyaluronic acid has surpassed collagen injections to become the most common injectable filler in the United States.7 Hyaluronic acid is a naturally occurring glycosaminoglycan that is a major component of all connective tissue. It is uniform throughout nature, exhibiting no species or tissue specificity. In the skin, hyaluronic acid molecules bind water and create volume. The amount of hyaluronic acid in the skin decreases with age, and its loss results in reduced dermal hydration and increased skin wrinkling and folding. While original sources of injectable hyaluronic acid were derived from animal sources, commercially available versions today are referred to as Non-Animal Stabilized Hyaluronic Acid (NASHA), which are bioengineered products of bacteria that are purified and then converted into a biodegradable gel. As a

Periocular Lines†

* Considered off-label † Considered an advanced technique

result, NASHAs, unlike collagen, has no potential for immunologic reactions, and skin testing prior to treatment is not required. NASHA is marketed in different brands that vary in the amount of cross-linked hyaluronic acid. Greater amounts of cross-linking results in increased viscosity. Because of cross-linking these products have longer lasting results than seen with collagen based fillers.8 Currently, there are two commercially available FDA-approved brands of NASHA in the United States: Restylane and Juvederm.

Restylane

The Restylane family of products (marketed by Medicis in the United States) was approved for soft tissue injection in the United States in 2003. Restylane remains the only NASHA approved for volume augmentation of the lips in the United States. The Restylane family includes Restylane and Perlane, each available with or without lidocaine. Restylane has 100 000 gel particles per ml and is intended for injection in the mid dermis to correct moderate to severe wrinkles.9 In addition, Restylane is FDA approved for volume augmentation of the lips in patients 21 years of age and older. Perlane has 8000 gel particles per mL and is used for deeper folds and volume augmentation by injection within the deeper dermis10 (Table 12-17-1). Results of augmentation have been reported to last between 9 and 12 months.11

Juvederm

Juvederm® was created by Allergan and was FDA-approved in 2006. Juvederm also uses a NASHA gel filler, that differs from Restylane in its greater degree of cross-linking. The increased cross-linking of this product results in a slightly smoother flowing gel when injected into the skin. Like Restylane, Juvederm is also available pre-mixed with lidocaine (marketed as Juvederm XC). Juvederm is intended for injection into the mid dermis for moderate to severe wrinkles. Juvederm Ultra Plus is a more highly cross-linked formulation and is touted to have a longer duration of action.12

CALCIUM HYDROXYAPATITE Radiesse is a calcium hydroxyapatite product that is FDA-approved as a dermal filler. It has a high density with low solubility, so that it

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12 Orbit and Oculoplastics

persists long term, and causes little immunoreactivity. Radiesse is injected as a viscous gel composed of carboxymethylcellulose, glycerine and water with 30% consisting of particles of synthetic hydroxyapatite measuring 25–45 µm in diameter. It is used for moderate to severe facial wrinkles and folds such as the nasolabial fold.13,14 The material is usually placed subdermally, and lasts for 9–18 months.

POLY-L-LACTIC ACID This is a synthetic material used in some absorbable sutures such as Vicryl. The filler preparation, Sculptra, consists of microspherules measuring 40–60 µm in diameter which are reconstituted prior to injection. This product is approved for correction of facial lipodystrophy associated with HIV. However, it has been used off-label for facial aesthetic improvement.15 It is usually placed into the deep dermis or subdermal space, and has a duration of 1–2 years. The safety profile in several clinical trials has been very good.16

TREATMENT TECHNIQUES Anesthesia

Even when the agent is premixed with lidocaine, injection of all fillers can be painful. The use of a local or regional anesthesia may improve patient comfort. Regional nerve blocks provide adequate anesthesia without distorting the tissues that are to be augmented. A mixture of lidocaine 1% with 1 : 100 000 dilution of epinephrine is usually adequate. Local injection of anesthetic is also helpful in achieving anesthesia, but infiltration of the anesthetic tends to distort the tissues. To minimize tissue distortion, a small bleb of anesthetic injected into the dermis at the point of needle insertion may be used when a threading technique is enlisted. EMLA (Astra Zeneca LP, Wilmington, Delaware) cream (2.5% lidocaine and 2.5% prilocaine) and similar topical anesthetic agents may also be used in some instances. Although such topical anesthetics do not produce sufficient numbness for deeper cutaneous needle penetrations, they do seem to diminish the perception of pain and discomfort. For maximum effectiveness, topical anesthetics must be applied at least 30 minutes to 1 hour before treatment. Application of a plastic wrap external dressing enhances their penetration and effectiveness significantly.17

Injection of Filler Substances

Injection technique is believed to be the single most important factor in the successful application of filler agents. The ability to properly implant the filler requires a learning curve, and proper placement of the implant within the tissue will improve with experience. Each type of filler should carefully be placed at a particular depth within the dermis to effect the best outcome (Fig. 12-17-1).

ZONES OF PLACEMENT Restylane Hylaform Zyderm 2 CosmoDerm 2

epidermis

dermis

subcutis

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Perlane Hylaform plus Zyplast CosmoPlast

Restylane and Juvederm are intended for injection in the mid dermis. In contrast, Perlane is formulated to be placed in the deeper dermis. When injecting hyaluronic acid fillers, a linear threading technique is used (Fig. 12-17-2). A standard 30-gauge needle permits smooth injection of the material. With the bevel of the needle just visible beneath the skin the needle is advanced along the line fold to be treated; the injection is made with constant pressure on the syringe plunger as the needle is withdrawn. The needle is then re-entered further down the line or fold in a similar fashion. When injecting, the resistance of the dermal matrix is felt against the injecting hand, and the plane of the injected site should elevate as the material is being placed. A second hand is useful to stretch the skin taught while injecting. During the injection, a ‘pop’ or sudden loss of resistance indicates that the needle has passed into the subdermal space. Should this occur the needle should be withdrawn and then re-injected into the dermis. Successive threads may be laid down above, below, and beside the previous injections until the entire wrinkle or fold has been treated. If there are small depressions between the linear threads, isolated serial puncture injections are used to fill in. The goal is to smooth the wrinkle out as much as possible but not to overcorrect the area. Once the products are injected, the material may be gently massaged along the line of injection to ensure that the material is smooth. Each patient should be checked in 2–4 weeks for the adequacy of volume replacement. Some will require additional tissue augmentation for the desired effect.11

CONTRAINDICATIONS AND ADVERSE REACTIONS Although generally considered safe, all dermal fillers may be associated with potential complications. Strategies for recognition and management of adverse results must be understood.18–20 Unlike with collagen products that may cause serious hypersensitive reactions, hyaluronic acid products are limited only to nonhypersensitive reactions. However, these non-animal stabilized hyaluronic acid products should not be used by people with previous allergies to hyaluronic acid products, or to gram-positive bacteria or their toxins. These products should not be used by people with bleeding disorders. NASHA should not be injected anywhere except the skin, or in the case of Perlane, just under the skin. Juvederm XC, Restylane-L and Perlane-L should not be used by anyone with a known allergy to lidocaine. Use at the site of skin sores, pimples, rashes, hives, cysts, or infection should be postponed until healing is complete. The products should not be used during pregnancy, when breastfeeding, or in patients under 18 years of age. Treatment volumes of NASHAs should be limited to 6.0 mL in wrinkles and folds, such as nasolabial folds, and limited to 1.5 mL per lip as greater amounts significantly increase moderate and severe injection site reactions. The safety or effectiveness of treatment in areas other than nasolabial folds and lips (in the case of Restylane) has not been established in controlled clinical studies. Fig. 12-17-1  Zones of placement of injectable collagen and hyaluronic acid derivatives.

12.17  Injectable Skin Fillers

A

B

C

D

Fig. 12-17-2  Injection technique for the treatment of lateral rhytids (crow’s-feet) with injectable filler (A and B). Crow’s-feet before (C) and after (D) filler injection.

Nonhypersensitive Reactions

Local injection-related reactions occurring with hyaluronic acid injections include transient bruising, swelling, erythema, pain, itching, and tenderness. Rarely, reactivation of herpetic eruptions and localized bacterial infection may occur. Occasionally, superficial injection of fillers will lead to unwanted visible blue or whitish lumps or beads within the skin that may persist for a few weeks up to several months, due to a Tyndall effect from light passing through the material. Some areas (such as compressed scars) resist precise placement of the material resulting in a slight elevation beside the actual defect. More serious nonhypersensitive reactions include vascular interruption at the treatment site with subsequent localized tissue necrosis, and intravascular injection of filler agents resulting in distal embolic events. Vascular interruption is much more likely to occur with more viscous agents because they are intended to be injected deeper, near the vascular supply of the dermis.5,21 The incidence of vascular occlusion by NASHA is unknown but the incidence with bovine derived collagen products is reported to be approximately 0.09% of all treated patients.22 Because 56% of all reported necrotic events occur in the glabellar area, practitioners are cautioned against using any filler at this site.23 The basis for increased incidence in the glabellar area has been shown to be caused by a lack of collateral circulation in this area when branches of the supratrochlear artery are temporarily occluded.24 Tissue necrosis results in scab formation followed by sloughing of the tissue at the treatment site, followed by formation of a shallow scar. If, upon injection, the practitioner notes severe blanching of the area and complaints of pain by the patient, the injection should immediately be stopped because local compromise of vascular supply has possibly occurred. The value of massage, warm compresses, or nitroglycerin gel in this situation is unsubstantiated, but any or all of these therapies

Access the complete reference list online at

may be utilized in an attempt to limit the loss of tissue.23 If tissue necrosis occurs, maintain good wound care as the tissue sloughs in order to prevent infection and to allow healing to occur.24 Embolic events may result from intravascular injection of filler agents. Two reports of partial vision loss have been reported after bovine collagen therapy.25,26 These are probably the result of an occlusive event involving the retinal artery caused by retrograde injection of the material directly into a distal branch of the ophthalmic artery.23

KEY REFERENCES Bailey SH, Cohen JL, Kenkel JM. Etiology, prevention, and treatment of dermal filler complications. Aesthetic Surg J 2011;31:110–21. Bass LS, Smith S, Busso M, et al. Calcium hydroxyapatite (Radiesse) for treatment of nasolabialfolds: long-term safety and efficacy results. Aesthet Surg J 2010;30:235–8. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers: a comprehensive review. Facial Plast Surg 2009;25:86–94. Brandt FS, Cazzaniga A. Hyaluronic acid fillers: Restylane and Perlane. Facial Plast Surg Clin North Am 2007;15:63–76. Carruthers J, Cohen SR, Joseph JH, et al. The science and art of dermal fillers for soft-tissue augmentation. J Drugs Derm 2009;8:335–50. Fagien, S. Facial soft tissue augmentation with autologous and homologous injectable collagen. In: Klein AW, editor. Tissue augmentation in clinical practice: procedures and techniques. New York: Marcel Dekker; 1998. p. 88–124. Jordan DR. Cosmetic dermal filler agents on the horizon. In: Lipham WJ, editor. Cosmetic and clinical applications of botulinum toxin. Thorofare, NJ: Slack Inc; 2004. p. 133–40. Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clin 2001;19:491–508. Rohrich RJ, Ghavami A, Crosby MA. The role of hyaluronic acid fillers (Restylane) in facial cosmetic surgery: review and technical considerations. Plast Reconstr Surg 2007;120:41S–54S. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008;10:35–42.

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REFERENCES 1. Berbos ZJ, Lipham WJ. Update on botulinum toxin and dermal fillers. Curr Opin Ophthalmol 2010;21:387–95.

3. Jones D. Volumizing the face with soft tissue fillers. Clin Plast Surg 2011;38:379–90. 4. Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clin 2001;19: 491–508. 5. Fagien, S. Facial soft tissue augmentation with autologus and homologous injectable collagen. In: Klein AW, editor. Tissue augmentation in clinical practice: procedures and techniques. New York: Marcel Dekker; 1998. p. 88–124. 6. Sclafani A, Romo T 3rd, Parker A, et al. Autologous collagen dispersion (Autologen) as a dermal filler: clinical observations and histologic findings. Arch Facial Plastic Surg 2000;2:48– 52.

14. Ahn MS. Calcium hydroxyapatite: Radiesse. Facial Plast Surg Clin North Am 2007;15:85–90. 15. Beer KR, Rendon MI. Use of Sculptra in esthetic rejuvenation. Semin Cutan Med Surg 2006;25:127–31. 16. Engelhaard P, Humble G, Mest D. Safety of Sculptra: a review of clinical trial data. J Cosmet Laser Ther 2005;7:201–5. 17. Jeter TS, Nishioka GJ. The lip lift: an alternative corrective procedure or iatrogenic vertical maxillary deficiency. Report of a case. J Oral Maxillofac Surg 1988;46:323–5. 18. Bailey SH, Cohen JL, Kenkel JM. Etiology, prevention, and treatment of dermal filler complications. Aesthetic Surg J 2011;31:110–21. 19. Sclafani AP, Fagein S. Treatment of injectable soft tissue filler complications. Dermatol Surg 2009;35(Suppl 2):1672–80. 20. Emer J, Waldorf H. Injectable neurotoxins and fillers: there is no free lunch. Clin Dermatol 2011;29:678–90.

7. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers: a comprehensive review. Facial Plast Surg 2009;25:86–94.

21. Stegman S, Chu S, Armstrong R. Adverse reactions to bovine collagen implant: clinical and histologic features. J Dermatol Surg Oncol 1988;14(Suppl):39–48.

8. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008;10:35–42.

22. Kraus MC. Recent advances in soft tissue augmentation. Semin Cutan Med Surg 1999;18:119–28.

9. Brandt FS, Cazzaniga A. Hyaluronic acid fillers: Restylane and Perlane. Facial Plast Surg Clin North Am 2007;15:63–76.

23. Klein AW. Collagen substances. Facial Plast Surg Clin North Am 2001;9:205–18.

12.17  Injectable Skin Fillers

2. Carruthers J, Cohen SR, Joseph JH, et al. The science and art of dermal fillers for soft-tissue augmentation. J Drugs Derm 2009;8:335–50.

13. Bass LS, Smith S, Busso M, et al. Calcium hydroxyapatite (Radiesse) for treatment of nasolabial folds: long-term safety and efficacy results. Aesthet Surg J 2010;30:235–8.

24. Elson ML. Soft tissue augmentation: A review. Dermatol Surg 1995;21:491–500.

10. Rohrich RJ, Ghavami A, Crosby MA. The role of hyaluronic acid fillers (Restylane) in facial cosmetic surgery: review and technical considerations. Plast Reconstr Surg 2007;120:41S–54.

25. DeLustro F, Smith ST, Sundsmo J, et al. Reaction to injectable collagen in human subjects. J Dermatol Surg Oncol 1988;14(Suppl 1):49.

11. Jordan DR. Cosmetic dermal filler agents on the horizon. In: Lipham WJ, editor. Cosmetic and clinical applications of botulinum toxin. Thorofare, NJ: Slack Inc.; 2004. p. 133–40.

26. McGrew R, Wilson RS, Havener W, et al. Sudden blindness secondary to injection of common drugs in the head and neck, Part 1: clinical experiences. Otolaryngology 1978;86:147–51.

12. Bogdan AI, Baumann L. Hyaluronic acid gel (Juvederm) preparations in the treatment of facial wrinkles. Clin Interv Aging 2006;3:628–34.

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PART 12 ORBIT AND OCULOPLASTICS SECTION 4 Periorbital Aesthetic Procedures

12.18 

Cosmetic Wrinkle Reduction with Botulinum Toxin William J. Lipham

Definition: Botulinum toxin has proven to be a useful modality for the reduction of facial wrinkles by relaxation of facial muscles.

BOTULINUM TOXIN MOLECULE NH2

COOH

Key features ■

Botulinum toxin for static wrinkles is a noninvasive, cost-effective technique. ■ Botulinum toxin can be used for the reduction of forehead frown lines, glabellar furrows, and lateral rhytids or crow’s-feet, as well as for exaggerated facial expression lines.

light chain

heavy chain S–S

NH2

S S

INTRODUCTION In most modern societies, facial wrinkles are perceived as signs of aging, weakness, or absence of general health. Much medical and personal effort is devoted to reversing the signs of aging in order to modify perception and thereby influence the attitudes of others toward us.1 Individuals are living longer and discretionary income has risen, both contributing to the growing demand for rejuvenation procedures. In recent years techniques for wrinkle reduction have gained in popularity because they are relatively noninvasive and cost effective compared to more radical surgical procedures. Botulinum toxin has become a major treatment modality, both as a safe and effective primary aesthetic procedure as well as an adjunct to other aesthetic therapies.2,3

COOH Fig. 12-18-1  The botulinum toxin molecule consists of a light chain and heavy chain joined by a single disulfide bond. While the heavy chain is responsible for binding to the nerve terminal receptors, the light chain exerts its effect by preventing the release of acetylcholine from the nerve terminal.

BOTULINUM TOXIN MOLECULE BINDING

BOTULINUM NEUROTOXIN There are seven distinct strains of Clostridium botulinum that have been identified. Each of these different strains is characterized by the type of botulinum neurotoxin they are capable of producing and have been classified as type A, B, C1, D, E, F, and G.4 Botulinum toxin type A is felt to exert the most powerful neuromuscular blockade and is also capable of exerting its effect for the longest duration of time.5 Botulinum toxin type A and type B are composed of a 150 kDA polypeptide consisting of a light chain and heavy chain joined by a disulfide bond (Fig. 12-18-1).6

BTX-A binding to neuron nerve ending

MECHANISM OF ACTION

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At the neuromuscular junction, the motor nerve terminal lies in close apposition with the adjacent muscle fiber. When botulinum toxin is administered the heavy chain binds selectively to cell membrane receptors on the outer surface of the presynaptic nerve terminal (Fig. 12-182). The entire neurotoxin complex (both light and heavy chains) is then internalized into the nerve terminal via receptor-mediated endocytosis (Fig. 12-18-3). The vesicles containing the botulinum toxin then fuse with digestive vacuoles that cleave the botulinum toxin molecule into separate light and heavy chains.7 The light chain exerts the paralytic effect of botulinum toxin by inactivating a group of proteins that are responsible for the fusion of

muscle acetylcholine release Fig. 12-18-2  The heavy chain of the botulinum toxin molecule binds selectively to cell membrane receptors on the outer surface of the nerve terminal. BTX-A, botulinum toxin type A.

ENDOCYTOSIS OF NEUROTOXIN COMPLEX

vesicle containing internalized BTX-A

Fig. 12-18-3  The entire neurotoxin complex is internalized into the motor nerve terminal through receptor-mediated endocytosis. BTX-A, botulinum toxin type A.

vesicles containing the neurotransmitter acetylcholine (ACh) with the nerve cell membrane and thereby blocking the release of ACh into the neuromuscular junction. This group of proteins is referred to as the SNARE complex (soluble N-ethylmalemide-sensitive factor attachment protein receptor), a neural exocytic complex that regulates the membrane docking wand fusion of synaptic vesicles and the release of ACh.8 The inhibition of ACh release results in localized muscle weakness that gradually reverses over time. Approximately 2 months after administration of botulinum toxin the axon begins to expand, new nerve terminal sprouts emerge, and these extend toward the muscle surface.9 Once one of the new sprouts forms a physical synaptic connection with the previous neuromuscular junction, the motor nerve unit is re-established. The clinical duration of effect corresponds to the time that is required for new sprouts to grow from the nerve root to re-establish the motor endplate.10 For aesthetic facial applications this may vary from 3 to as many as 5 months.11

CONTRAINDICATIONS AND PRECAUTIONS The only contraindications to the administration of botulinum toxin include neuromuscular disease, such as myasthenia gravis or Eaton– Lambert syndrome, as well as coadministration of aminoglycoside antibiotics, which can potentiate the effects of botulinum toxin.12 Since the effects of botulinum toxin on pregnancy in human subjects are unknown, administration during pregnancy or while breast-feeding is not recommended. Finally, since both compounds contain human albumin to stabilize the lyopholite, individuals with allergies to eggs should not receive botulinum toxin.

ADVERSE REACTIONS In clinical trials of Botox for wrinkle reduction, the most common adverse events included blepharoptosis, facial weakness, headache, respiratory infection, flu syndrome, and nausea. A thorough understanding of facial muscle anatomy and proper injection technique are the best way to avoid these problems. Transient upper eyelid ptosis is probably the most common adverse event caused by diffusion through or inadvertent administration of botulinum toxin behind the orbital septum. If eyelid ptosis occurs, one drop of apraclonidine 0.5% may be administered three times daily to temporarily stimulate Müller’s muscle, which elevates the eyelid, until the ptosis resolves.

At present there are four commercially available products containing botulinum toxin for medical use in various parts of the world. Botulinum toxin type A is commercially available as three preparations: Botox (Allergan Inc., Irvine, CA) and Dysport (Ipsen Pharmaceuticals, France). Xeomin is a newer formulation that is drug-free for proteins that can cause immunologic resistance.13 Botulinum toxin type B is currently approved for use in the United States and is commercially available as Myobloc (Élan Pharmaceuticals, South San Francisco, CA). While both Botox and Dysport are sold as a lyophilized powder that requires subsequent reconstitution with sterile saline, Myobloc is sold as an aqueous solution in a 3.5 mL vial at a pH of 5.6. It is felt that this relatively acidic pH can be attributed to the increased discomfort that patients subjectively experience with Myobloc injections.14 Dosing of botulinum toxin agents are described in units of biological activity (U). For all of these compounds 1 U is defined as the amount of neurotoxin complex that is lethal in 50% of female Swiss–Webster mice after a single intraperitoneal injection (mouse LD50). While the definition of a unit of toxin is similar for all four compounds, the formulation and methods of testing vary significantly, resulting in discrepancies with respect to the potency of a single unit of botulinum toxin between the three preparations.15 This results in a lack of uniformity between the products with respect to dosing.16 A review of the literature reveals that unit doses of Dysport range from 3 to 4 times higher than equivalent doses of Botox when used to treat similar conditions.6,17 In contrast, the unit doses of Myobloc are 50–100 times higher than those typically seen with Botox.18 It is, therefore, imperative that whenever dosing and administration are discussed, the agent utilized must be clearly described.19

12.18  Cosmetic Wrinkle Reduction with Botulinum Toxin

nerve cell membrane

COMMERCIALLY AVAILABLE BOTULINUM TOXIN AGENTS

SUGGESTED DILUTION PROTOCOLS Botox may be reconstituted with either 1 or 2 mL of sterile nonpreserved saline to yield a concentration of 10 units/0.1 mL or 5 units/0.1 mL, respectively. While the manufacturers of Dysport recommend diluting each vial with 2.5 mL of sterile nonpreserved saline, this provides a solution with a concentration of 20 U/0.1 mL, which yields a 4 : 1 ratio when compared to an equivalent volume of Botox. There are conflicting reports that describe the ratio of Dysport units to Botox units, ranging from 3 : 1 to 4 : 1.17,20,21 In the author’s experience, 3 Dysport units are clinically equivalent to 1 Botox unit for cosmetic purposes. We recommend diluting one 500 U vial of Dysport with 4 mL of saline to give a dose–volume equivalency of 3 : 1. Following dilution, studies have shown that the toxin can be used for up to 6 weeks without losing effectiveness.22

COSMETIC APPLICATIONS OF BOTULINUM TOXIN It is important for both physicians and patients to appreciate the difference between active, kinetic lines that occur during facial expression and passive or fixed lines that are present at rest. Kinetic lines develop in the skin during contraction of underlying facial muscles responsible for creating a variety of facial expressions. Examples include vertical glabellar folds or ‘frown lines,’ lateral orbicularis oculi rhytids or ‘smile lines,’ and transverse forehead lines that develop from contraction of the frontalis muscle in an effort to elevate the brows. Botulinum toxin exerts its wrinkle-reducing effect by weakening the muscles of facial expression that are responsible for the formation of these dynamic lines.23 Over many years, these repetitive facial expressions eventually result in the formation of lines that remain at rest due to the breakdown and remodeling of collagen in the deeper dermis. For these individuals, weakening of facial muscles with botulinum toxin will not yield as dramatic an effect as it will on the dynamic wrinkles, and these fixed lines will remain to some extent even when the muscles are relaxed. For this reason, botulinum toxin injections for cosmetic wrinkle reduction are best suited for younger individuals who have not yet developed deep static lines at rest. The typical age range for this subset of patients is between 30 and 50 years of age.

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For individuals who have static wrinkles, alternative treatments may be considered.24,25 If the lines are fine and result primarily from a loss of skin elasticity, chemical peels or laser skin resurfacing may be the best options, as these approaches promote epidermal turnover and tighten and smooth the underlying dermis.26,27 In contrast, dermal filler agents, which include collagen as well as hyaluronic acid derivatives, are the best options to reduce the appearance of deeper lines. These compounds exert their effect by filling in and ‘plumping up’ the underlying dermis to elevate the skin surface and reduce the depth of the wrinkle or line.28,29

TREATMENT OF GLABELLAR FURROWS As noted previously, the glabellar region was the first area to be successfully treated with botulinum toxin for cosmetic purposes with Food and Drug Administration (FDA) approval. The central brow depressors consist of the procerus muscle, depressor supercilli, and corrugator muscle complex.30 Contraction of the procerus muscle over time produces a transverse line that is located immediately below the glabellar region above the nasal bridge.31 In contrast, the corrugator muscle, along with the depressor supercilli muscle, is responsible for the development of vertical glabellar furrows or frown lines, which are located medial to the brow cilia. Inactivation of the central brow depressor muscles induces a smoothing or softening effect between the eyebrows and above the nasal bridge (Fig. 12-18-4).

The procerus muscle is located between the glabellar furrows and runs vertically between the two ‘frown’ lines. It may be inactivated with either 2–6 units of Botox or 6–12 units of Dysport as a single injection in the central body of the muscle. For most individuals, 4–6 units of Botox or 12 units of Dysport may be given to the medial aspect of the corrugator muscle complex.32 This injection site is located just medial to the medial aspect of the brow or approximately 3 mm lateral to the medial canthus of the eye. The lateral aspect of the corrugator muscle may be injected in a similar fashion depending on the strength and tone of the muscle. For most patients, 2–4 units of Botox or 6–12 units of Dysport may be administered to the lateral aspect of the corrugator muscle complex. The exact location of the injection is dependent on the area of muscle contraction, but usually corresponds to an area superior to the brow cilia and directly above the medial aspect of the pupil. Total injection doses for the central brow depressors, therefore, range from 14 to 30 units of Botox or 42–60 units of Dysport, depending on the patient’s muscle volume and strength of contraction (Fig. 12-18-5). In males, starting doses of at least 40 units of Botox give better results.33

TRANSVERSE FOREHEAD LINES When treating the frontalis muscle for cosmetic purposes it is important to avoid using large doses of botulinum toxin as this may result in generalized brow descent, giving the patient a tired or fatigued look.34 In female patients, it is desirable to maintain ability to elevate the lateral aspect of the brow because this will favor a cosmetically appealing brow contour. An aesthetically ‘ideal’ female brow contour rises upwards with its highest point positioned above the lateral canthus at the lateral third of the brow.

INJECTION PATTERN FOR GLABELLAR FURROWS

O

1364

Fig. 12-18-4  Inactivation of the central brow depressors induces a smoothing or softening effect between the eyebrows and above the nasal bridge. The effect is seen in this patient prior to botulinum toxin administration and again 2 weeks following injection.

X

O

X

O

Fig. 12-18-5  Injection pattern for reduction of glabellar furrows. Sites marked with ‘X’ typically require 5 Botox units or 15 Dysport units. Sites marked with ‘O’ may be given a variable amount of Botox depending on muscle strength using 2.5–5 Botox units or 7.5–15 Dysport units accordingly.

TREATMENT OF TRANSVERSE FOREHEAD LINES

X

X

Cosmetic Wrinkle Reduction with Botulinum Toxin

X

12.18 

X

O

Fig. 12-18-6  Treatment of transverse forehead lines. Injections are given midway between the brow and hairline. Typical doses are 5 Botox units or 15 Dysport units to each area marked with an ‘X.’ Centrally, the frontalis muscle contains fewer muscle fibers and may only require 2.5–5 Botox units or 7.5–15 Dysport units at sites marked with ‘O.’ Injections should be avoided in the lateral forehead to prevent brow ptosis.

Whereas the treatment of glabellar furrows and periocular ‘crow’sfeet’ consists of relatively uniform treatment patterns that can easily be modified, treatment of transverse forehead lines requires a more individualized approach. In the evaluation of transverse forehead lines, the patient is asked to elevate the brows; the strength of frontalis muscle contraction and the location of resulting skin creases are then noted. Most authorities agree that injection of botulinum toxin into the forehead region should be performed at least midway between the level of the brow cilia and hairline to reduce inadvertent diffusion into the central brow depressors.35 It is generally advisable to avoid injecting the lateral brow region in women to reduce the incidence of lateral brow ptosis, which is cosmetically undesirable.34,36 Typical injection doses are in the range of 4–5 units of Botox or 12–15 units of Dysport at each injection site (Fig. 12-18-6). Centrally, the frontalis muscle contains fewer muscle fibers and may only require 2–5 Botox units or 6–15 Dysport units. It is sometimes beneficial to place this injection slightly lower to facilitate diffusion into the medial portions of the frontalis muscle and obtain a more uniform distribution. Carruthers et al. have shown that higher total doses in the range of 48 units of Botox give greater efficacy and longer duration of effect.37 Since the frontalis muscle is located beneath the thick skin of the scalp, injections must be placed at least 4–5 mm below the skin surface to obtain a true intramuscular injection.

TREATMENT OF ORBICULARIS RHYTIDS OR ‘CROW’S-FEET’ Contraction of the lateral orbicularis muscle is responsible for the creation of active lines or wrinkles that radiate from the lateral canthal angle; these are commonly referred to as ‘smile lines’ or ‘crow’s-feet’ (Fig. 12-18-7). As the skin in this region is quite thin (60–80 µm), most

Fig. 12-18-7  Contraction of the lateral orbicularis oculi muscle is responsible for the creation of active lines or wrinkles that radiate from the lateral canthal angle, commonly referred to as ‘smile lines’ or ‘crow’s-feet.’ Injection of this area with botulinum toxin softens these lines as seen in this patient prior to and 1 month after botulinum toxin administration.

currently available dermal filler agents are incapable of reducing these lines effectively without inducing unwanted overcorrection. Since these dynamic lines are caused by active muscle contraction, they may be effectively treated with botulinum toxin. The injections may be distributed at either two or three locations around the lateral canthal angle. For most individuals, three injections per side is sufficient. The first injection is placed in the same horizontal plane as the lateral canthal angle at or just lateral to the lateral orbital rim. Additional injections are placed 5 mm superior and inferior to the initial injection to soften the appearance of lines in this area of muscle contraction. For most individuals, the superior and inferior injections are typically performed with 4 units of Botox or 12 units of Dysport per site, while the central injection in the lateral canthal angle may consist of 2–4 units of Botox or 6–12 units of Dysport, depending on the amount of muscular contraction and muscle volume (Fig. 12-18-8). A single injection technique has been used with similarly good results.38 Therefore, patients require repeat injections on average every 3–5 months.

1365

12

KEY REFERENCES

INJECTION PATTERN FOR CROW’S-FEET

Berbos ZJ, Lipham WJ. Update on botulinum toxin and dermal fillers. Curr Opin Ophthalmol 2010;21:387–95. Review.

Orbit and Oculoplastics

Carruthers A, Carruthers J. Patient-reported outcomes with botulinum neurotoxin type A. J Cosmet Laser Ther 2007;9(Suppl 1):32–7. Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic applications. J Cosmet Laser Ther 2007;9:186–92. Coleman KR, Carruthers J. Combination therapy with Botox and fillers: the new rejuvenation paradym. Dermatol Ther 2006;19:177–88. Flynn TC. Botulinum toxin: examining duration of effect in facial aesthetic applications. Am J Clin Dermatol 2010;11:183–99. Kane M, Donofrio L, Ascher B, et al. Expanding the use of neurotoxins in facial aesthetics: a consensus panel’s assessment and recommendations. J Drugs Dermatol 2010;9:s7–22.

X O X

X O X

Fig. 12-18-8  For individuals with greater orbicularis muscle volume or increased contraction strength three injections per side may be performed. The first injection is placed in line with the lateral canthal angle at or just lateral to the lateral orbital rim.

Access the complete reference list online at

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Said S, Meshkinpour A, Carruthers A, et al. Botulinun toxin A: Its expanding role in dermatology and esthetics. Am J Clin Dermatol 2003;4:609–16. Wise JB, Greco T. Botox and fillers for the aging face. Facial Plast Surg 2006;22:140–6.

REFERENCES 1. Carruthers A, Carruthers J. Patient-reported outcomes with botulinum neurotoxin type A. J Cosmet Laser Ther 2007;9(Suppl 1):32–7.

3. Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic applications. J Cosmet Laser Ther 2007;9:186–92. 4. Jankovic J. Botulinum A toxin in the treatment of blepharospasm. Adv Neurol 1988;49: 467–72. 5. Hankins CL, Strimling R, Rogers GS. Botulinum A toxin for glabellar wrinkles. Dose and response. Dermatol Surg 1998;24:1181–3. 6. Lew MF. Review of the FDA-approved uses of botulinum toxins, including data suggesting efficacy in pain reduction. Clin J Pain 2002;18(Suppl 6):S142–6. 7. Pearce LB, First ER, MacCallum RD, et al. Pharmacologic characterization of botulinum toxin for basic science and medicine. Toxicon 1997;35:1373–412. 8. Setler P. The biochemistry of botulinum toxin type B. Neurology 2000;55(Suppl 5):S22–218. 9. Angaut-Petit D, Molgo J, Comello JX, et al. Terminal sprouting in mouse neuromuscular junctions poisoned with botulinum type A toxin: morphological and electrophysiological features. Neuroscience 1990;37:799–808. 10. Edelstein C, Shorr N, Jacobs J, et al. Oculoplastic experience with the cosmetic use of botulinum A exotoxin. Dermatol Surg 1998;24:1208–12. 11. Flynn TC. Botulinum toxin: examining duration of effect in facial aesthetic applications. Am J Clin Dermatol 2010;11:183–99. 12. Niamtu J 3rd. Complications in fillers and Botox. Oral Maxillofac Surg Clin North Am 2009;21:13–21. 13. Park J, Lee MS, Harrison AR. Profile of Xeomin (incobotulinumtoxinA) for the treatment of blepharospasm. Clin Ophthalmol 2011;5:725–32. 14. Ramirez AL, Reeck J, Maas CS. Botulinum toxin type B (MyoBloc) in the management of hyperkinetic facial lines. Otolaryngol Head Neck Surg 2002;126:459–67. 15. Bakshi E, Hartstein ME. Compositional differences among commercially available botulinum toxin type A. Curr Opin Ophthalmol 2011;22:407–12. 16. Kane M, Donofrio L, Ascher B, et al. Expanding the use of neurotoxins in facial aesthetics: a consensus panel’s assessment and recommendations. J Drugs Dermatol 2010;9:s7–22. 17. Odergren T, Hjaltason S, Kaakkola S, et al. A double blind, randomized, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry 1998;64:6–12.

22. Hexsel DM, De Almeida AT, Rutowitsch M, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003;29:523–9. 23. Foster JA, Wulc AE, Holck DE. Cosmetic indications for botulinum A toxin. Semin Ophthalmol 1998;13:142–8. 24. Wise JB, Greco T. Botox and fillers for the aging face. Facial Plast Surg 2006;22:140–6. 25. Coleman KR, Carruthers J. Combination therapy with Botox and fillers: the new rejuvenation paradym. Dermatol Ther 2006;19:177–88. 26. Rohrer TE. Lasers and cosmetic dermatologic surgery for aging skin. Clin Geriatr Med 2001;17:769–94, vii. 27. Zimbler MS, Holds JB, Kokoska MS, et al. Effect of botulinum toxin pretreatment on laser resurfacing results: a prospective, randomized, blinded trial. Arch Facial Plast Surg 2001;3:165–9. 28. Klein AW. Skin filling. Collagen and other injectables of the skin. Dermatol Clin 2001;19: 491–508, ix. 29. Berbos ZJ, Lipham WJ. Update on botulinum toxin and dermal fillers. Curr Opin Ophthalmol 2010;21:387–95. 30. Cook BE Jr, Lucarelli MJ, Lemke BN. Depressor supercilii muscle: anatomy, histology, and cosmetic implications. Ophthalmic Plast Reconstr Surg 2001;17:404–11. 31. Pribitkin EA, Greco TM, Goode RL, et al. Patient selection in the treatment of glabellar wrinkles with botulinum toxin type A injection. Arch Otolaryngol Head Neck Surg 1997;123:321–6. 32. Rzany B, Ascher B, Fratila A, et al. Efficacy and safety of 3- and 5-injection patterns (30 and 50 U) of botulinum toxin A (Dysport) for the treatment of wrinkles in the glabella and central forehead region. Arch Dermatol 2006;142:320–6. 33. Carruthers A, Carruthers J. Prospective, double-blind, randomized, parallel-group, doseranging study of botulinum toxin type A in men with glabellar rhytids. Dermatol Surg 2005;31:1297–303.

12.18  Cosmetic Wrinkle Reduction with Botulinum Toxin

2. Said S, Meshkinpour A, Carruthers A, et al. Botulinun toxin A: its expanding role in dermatology and esthetics. Am J Clin Dermatol 2003;4:609–16.

21. Lowe NJ. Botulinum toxin type A for facial rejuvenation. United States and United Kingdom perspectives. Dermatol Surg 1998;24:1216–18.

34. Carucci JA, Zweibel SM. Botulinum A exotoxin for rejuvenation of the upper third of the face. Facial Plast Surg 2001;17:11–20. 35. Koch RJ, Troell RJ, Goode RL. Contemporary management of the aging brow and forehead. Laryngoscope 1997;107:710–5. 36. Wieder JM, Moy RL. Understanding botulinum toxin. Surgical anatomy of the frown, forehead, and periocular region. Dermatol Surg 1998;24:1172–4.

18. Klein AW. Dilution and storage of botulinum toxin. Dermatol Surg 1998;24:1179–80.

37. Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytids. Dermatol Surg 2003;29:461–7.

19. Garcia A, Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum toxin. A dose–response study. Dermatol Surg 1996;22:39–43.

38. Salti G. Botulinum toxin for periocular lines: the single-injection technique. J Cosmet Dermatol 2004;3:122–5.

20. Nussgens Z, Roggenkamper P. Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol 1997;235:197–9.

1366.e1

Index Indexer: Dr Laurence Errington Illustrations are comprehensively referred to from the text. Therefore, significant material in illustrations (figures and tables) have only been given a page reference in the absence of their concomitant mention in the text referring to that illustration. ‘vs.’ indicates the differential diagnosis of conditions.

A

aberrations, 76–80 clinical application of theory, 80 clinical measurement (aberrometry), 73–75, 79–80 corneal, 76–80 wavefront analysis see wavefront analysis high-order, 78 lens, 73 mathematical considerations, 79 Acanthamoeba keratitis, 228–230 contact lens-related, 289 acathoma, basosquamous cell, 1296 accommodation, 967–968 automated refractometry, 67 in binocular balance testing, effort of, 50 loss/degradation, 967–968 physiologic see presbyopia accommodative-convergence to accommodation ratio (AC/A), calculation, 1209 accommodative esotropia, 1209–1211 accommodative intraocular lenses presbyopia, 157, 160 acetazolamide in cystoid macular edema, 489, 631 acetylcholine (and its receptor), 937–938 botulinum toxin and, 1363 myasthenia gravis and, 938 acetylcholinesterase inhibitors see anticholinesterases achromatopsia, 485t, 488 cerebral, 912 aciclovir see acyclovir acid burns (corneal and ocular surfaces), 296–298, 1086 acne rosacea and blepharitis, 178–179 acquired (adaptive) immunity, 690 acquired immunodeficiency syndrome see HIV disease and AIDS Acri.LISA 366D, 158 clinical studies, 158–159 acrochordon, 1295 acromegaly, 906 AcrySof Cachet, 130f, 132–133 complications, 134–135 surgical procedures, 132–133 AcrySof ReSTOR SN6AD3, 157–158 clinical studies, 158–159 actinic keratosis, 1296–1297 Actinomyces causing keratitis, 219–220 active force generation test, 1196 active orthotopic training in exotropia, 1215 Acufocus KAMRA, 155–157 acute demyelinating optic neuritis, 879–883 acute macular neuroretinopathy, 786–787 acute phase of wound healing, 297–298 acute posterior multifocal placoid pigment epitheliopathy, 779–780 acute zonal occult outer retinopathy, 786

acyclovir (aciclovir) herpes simplex keratitis, 235–236 retinitis, 701 herpes zoster, 182 retinitis, 701 adalimumab in uveitis in juvenile idiopathic arthritis, 751 in sarcoidosis, 757 adaptive immunity, 690 adaptive optics optical coherence tomography, 449 add-on (piggy-back) IOLs in pseudophakic eyes, 89, 340–341, 370 adduction cyclovertical extraocular muscles in, 1183f overelevation in, 1207f, 1208, 1217, 1218f, 1234 differential diagnosis, 1218b adenohypophysitis, lymphocytic, 901 adenoid cystic carcinoma, 1320 adenoma eyelid pleomorphic adenoma, 1298 sebaceous adenoma, 1298 orbit, pleomorphic adenoma, 1319–1320 pituitary, 901, 906–907, 983 cranial neuropathies, 934 adenoma sebaceum, 846 adenomatous polyposis, colonic, and retinal pigment epithelium hypertrophy, 842–843 adenosine triphosphate-binding cassette-4 gene and Stargardt’s disease, 492 adenoviral conjunctivitis, 184–185 adherens junctions, 426–427 adhesion (surgically created), retinal pigment epithelium–retina, 468 adhesion molecules and uveitis, 691 adhesive(s) and glues corneal perforations, 325–327 post-pterygium excision, 314 adhesiveness of IOL materials interlenticular opacification and, 409 posterior capsule opacification and, 409 Adie’s syndrome, 964 tonic pupil, 963f, 964 adnexal tissue glaucoma, abnormalities, 1022t tumors, 1297–1299 adolescents (teenagers), bifocals for accommodative esotropia, 1211 adrenaline (epinephrine), peribulbar block, 358 adrenergic agonists in glaucoma non-selective glaucoma, 1112, 1118t α-selective, 1112, 1115, 1118t adverse effects, 1023t, 1115 adrenergic antagonists in glaucoma, beta-selective (beta-blockers), 1112, 1114–1115, 1118t adverse effects, 1023t, 1114, 1118t adrenergic mydriasis, 963f Advanced Glaucoma Intervention Study, 1107– 1108, 1112–1113, 1177b, 1178 aesthetic/cosmetic periorbital procedures, 1352–1358 afferent visual system, 866–868 anatomy and physiology, 866–868 pupillary defects and the, 958–960 glaucoma and, 1020 aflibercept age-related macular degeneration, 597 choroidal neovascularization, 732 diabetic retinopathy, 546–547

afterimage test, 1203 ‘against’ motion retinoscopy, 65–66 age aphakic correction in children related to, 392 astigmatic or radial keratotomy and, 143 cataract occurrence and, 413–414 pharmacological prevention of, 413 congenital optic disc anomalies and, 871 eyelid and face changes with, 1352–1353 glaucoma and, 1050, 1109 open-angle (primary) and, 1002 of headache onset, 969 lens changes with, 330 orbital diseases relating to, 1318t transient visual loss related to, 996 vitreous changes with, 433–435 age-related macular degeneration, 580–599 diagnosis and ancillary testing, 582–585 differential diagnosis, 585 epidemiology, 580 natural history and prognosis, 588–589 ocular manifestations, 581–582 cystoid macular edema, 630 pathogenesis, 580–581 light exposure in, 465, 581 pathology, 585–588 treatment and prevention, 589–598 Agency for Health Research and Quality (AHRQ), 1174 agonist(s), paired (extraocular muscles in separate eyes), 1186 agonist–antagonist pairs (extraocular muscles in same eye), 1186 agranulocytes, 690 agraphia, 912 Ahmed valve, 1083, 1159–1163 endoscopic cyclophotocoagulation vs., 1128 Aicardi syndrome, 873–874 AIDS see HIV disease and AIDS Airpuff, 1021t Airy disc, 20–21, 24–25, 40 Alagille syndrome, 294t albinism, 12–13 ocular, 12–13, 488 choroideremia vs., 504 alcohol cataracts and, 413 glaucoma and, 1003–1004 leakage during LASEK, 104 see also tobacco–alcohol amblyopia aldose reductase and diabetic retinopathy, 542 alexia, 912 alignment (ocular) evaluation, 917, 1192 foveal images, 1197f alkali burns (corneal and ocular surfaces), 296–298, 1086 glaucoma with, 1086, 1100 stem cell failure, 320f alkaptonuria, 291t alkylating agents scleritis, 216 uveitis, 698t allergic conjunctivitis, 192–195 contact lens-related, 284 allergic reactions see hypersensitivity reactions allografts keratolimbal, 322–323 rejection see rejection alopecia, brow lift, 1358

1367

Index

1368

alpha-2 adrenergic agonists see adrenergic agonists alpha-linolenic acid, 278 alphabet-pattern strabismus see strabismus AlphaCor, 305 Alport syndrome, 294t cataracts and, 415 alternate cover test, 1194 alternating nystagmus, periodic, 954, 957 Alzheimer’s disease, 861, 981 diagnosis and testing, 981 epidemiology and pathogenesis, 980 optical coherence tomography, 861 amacrine cells, 421, 422 amaurosis, Leber’s congenital/hereditary see Leber’s congenital/hereditary amaurosis amaurosis fugax, 972, 996, 996t amblyopia, 1238–1243 cover test, 1207 iatrogenic, 1242 management/treatment, 1208, 1215, 1242 after pediatric cataract surgery, 393 sector occluders, 1244f tobacco–alcohol, 890 amblyoscope, major, 1195, 1203–1204 amelanotic primary acquired melanosis, 198 American Academy of Ophthalmology (AAO) open-angle glaucoma definition, 1007 screening for chloroquine and hydroxychloroquine retinopathy, 683–684 amikacin, keratitis, 222 amino acid metabolism, inherited defects, 291, 291t aminoglycosides, keratitis, 222 amiodarone-related optic neuropathy, 891–892 amniotic membrane (transplantation), 321 chemical burns, 297–298 corneal perforations, 327 HSV keratitis, 236 pterygium, 314 amphotericin B, endophthalmitis, 736 Amsler chart testing stroke patients, 998 threshold, optic nerve vs. macular disorders, 869–870 amyloid P, serum, as antifibrotic agent, 1156 amyloid polyneuropathy type IV, familial (lattice dystrophy type II), 260 amyloidosis (amyloid deposition and degeneration) conjunctival, 204–205 corneal, 272–273 familial subepithelial, 260 extraocular muscle involvement, 948 pseudoexfoliation syndrome vs., 1071 vitreous, 436 anatomical disorders (ocular), 294 anatomical factors in angle-closure glaucoma, 1060 ANCHOR study, 590–592 anesthesia blepharoplasty, 1354 brow lift, 1357 cataract surgery, 352, 356–360 general, 360 local, 356–359 medical aspects, 356 pediatric, 390–391 conjunctival surgery, 312 corneal surgery endothelial keratoplasty, 316 keratoplasty, 299 superficial procedures, 306 cyclodestructive procedures, 1126 enucleation, 1339 evisceration, 1339 examination under see examination under anesthesia exenteration, 1339 eyelid conditions ectropion, 1286 entropion, 1280 ptosis, 1275 retraction, 1270 trauma repair, 1313 intravitreal injection, 477 retinal break surgery, 645 scleral buckling, 467 skin fillers, 1360

anesthesia (Continued) strabismus surgery, 1247–1248 vitrectomy, 471 aneurysm idiopathic retinal vasculitis and, and neuroretinitis (IRVAN syndrome), 578 intracranial, 992–993 course and outcome, 987 diagnosis and testing, 985 differential diagnosis, 985 epidemiology and pathogenesis, 983 ocular manifestations, 984, 992–993 pathology, 986 treatment, 987 see also macroaneurysms angiogenic (vasoproliferative) growth factors in neovascular glaucoma, 1076 in retinopathy of diabetes, 542 inhibitors, 546 in retinopathy of prematurity, 535 see also antiangiogenic agents; neovascularization angiography, 854 carotid, in ocular ischemic syndrome, 552–553 cerebral/intracranial, 854 parasellar/pituitary fossa lesions, 906 scanning laser ophthalmoscopic, choroidoretinal vessels, 428, 441 see also fluorescein angiography; indocyanine green angiography angioid streaks, 601–602 angiomatous proliferation, retinal (=choroidal neovascularization type 3), 454 angiotensin-converting enzyme (ACE), serum levels in sarcoidosis, 755 angiotensin-converting enzyme inhibitors, diabetic retinopathy, 546 angle, anterior chamber measurement, 1024–1026 surgery, 1134–1142 see also angle-closure glaucoma; open-angle glaucoma angle-closure acute, management, 1065–1066 primary (PAC), 1061 genetic factors, 1004, 1171 pre-existing disposition, 1081 suspect (PACS), 1061 secondary, children, 1102 angle-closure glaucoma, 1001, 1004–1005, 1060–1069 blindness, 1002t, 1060 chronic, 1066–1069 indication for lens surgery, 344 primary, 1060 epidemiology, 1004–1005 secondary, 1060, 1080b, 1081 neovascularization and, 1077 suspects (in population studies), 1006t angle recession (and angle-recession glaucoma), 1086–1087 angle-supported IOLs, 127, 131–135 advantages and disadvantages, 129t complications, 133–135, 137–138 history, 127 results, 131t sizing, 130 surgical procedures, 132–133 angular magnification, 71 aniridia, 9–10, 1097–1098 IOL, 344, 344f anisocoria, 960 in bright light, 963–964 in dim light, 960–963 physiologic, 961f structural, 961f anisometropic amblyopia, 1238 diagnosis/ancillary testing and experimental anatomic and physiological changes, 1240 epidemiology and pathogenesis, 1238–1239 ocular manifestations, 1239 anisometropic distance correction, 50 ankylosing spondylitis (AS) and HLA-B27associated uveitis, 748 annulus of Zinn, 1181–1183, 1260 anomalous retinal correspondence, 1197–1198

anterior chamber angle see angle blood in see hyphema collapse (in anterior capsulectomy), prevention, 396 depth, angle-closure glaucoma, 1004–1005, 1064–1065 epithelial cysts, 1097 epithelial downgrowth, 1088 and fibrous downgrowth, 1096–1097 flat, in penetrating keratoplasty, 301 glaucoma patients, examination, 1024 optical coherence tomography in angle-closure glaucoma, 1065 glaucoma patients, shallow (following trabeculectomy), 1165–1166 hydrodynamics in phacoemulsification, 362–363 IOLs, 398 early forms, 331 intermediate forms, 331 minus, for high/myopic/aphakic eyes, 341 modern forms, 332 see also angle-supported IOLs; iris-supported/ fixated IOLs IOLS from posterior chamber falling into, 402 maintainer in limbal approach in pediatric cataract surgery, 391 in mini-nuc extracapsular cataract extraction, 380 anterior embryotoxin, 174 anterior segment hemorrhage in cataract surgery, 399 ischemia see ischemia ischemic syndrome (ocular), 551 neovascularization, glaucoma resulting from, 530, 1076–1079 optical coherence tomography, 455–456 photography, iris melanoma, 802 sickle cell hemoglobinopathy, 555–556, 559 toxocariasis, 745 vitrectomy with complications of surgery of, 472 anterior uveitis, herpes zoster, 181 antiamebic agents in Acanthamoeba keratitis, 229, 230t antiangiogenic agents diabetic retinopathy, 546 neovascular glaucoma, 1079 antibiotics blepharitis, 179 cataract surgery intraoperative, 352–353, 353t postoperative, 354 preoperative, 351–352 conjunctivitis, 184 C. trachomatis, 186 neonatal gonococcal, 188 parinaud oculoglandular syndrome, 188 endophthalmitis, 725–727 in exenteration surgery, 1344–1345 with eyelid bite wounds, prophylactic, 1312– 1313, 1316–1317 keratitis, 222–223 meningitis, 977 in penetrating injury, prophylactic, 675 uveitis-causing infections, 1082 brucellosis, 719 cat scratch disease, 721 leprosy, 719 leptospirosis, 715 Lyme disease, 714t syphilis, 711 tuberculosis, 718 Whipple’s disease, 722 antibody (immunoglobulin), 691 see also autoimmune mechanisms and autoantibodies; fluorescent antibody testing; monoclonal antibody therapy; serological detection antibody-mediated hypersensitivity, 692 anticholinergic (incl. antimuscarinic) drugs, 967 dry eye syndrome relating to, 275t pupillary supersensitivity to, 964 anticholinesterases (cholinesterase inhibitors) accommodative esotropia, 1210 myasthenia gravis, 939–940

aqueous humor (Continued) secretion first step, 1014 second step, 1014 third step, 1015 aqueous tear deficiency, 274–278 arcuate lesions, superior epithelial (SEALs), with contact lenses, 285–286 arcuate resection, laser (gas), 143 arcuate visual field defects, 1030, 1031f arcus senilis, 269 AREDS (Age-Related Eye Disease Study), 588–589 arginine-restricted diet in gyrate atrophy, 507 argon laser iridectomy, 1122–1123, 1123t Nd-YAG laser iridectomy combined with, 1123 Nd-YAG laser iridectomy vs., 1123 argon laser trabeculoplasty (ALT), 1082, 1120– 1122, 1123t, 1173–1174 historical review, 1111, 1120 study, 1177b arterial supply episcleral venous pressure elevation related to abnormalities in, 1090t orbit extraocular muscles, 1184 eyelids, 1257 optic chiasm, 900–901 retina, 426 obstruction, 518–525 see also retinal arteries arteriovenous fistulas and shunts (orbital/ intracranial), 1331–1332 cavernous sinus thrombosis or orbital apex syndrome vs., 985 dural, 932, 936, 994 arteriovenous malformations (AVMs), 995 in Wyburn-Mason syndrome, 848–849 arteritic anterior ischemic optic neuropathy (AAION), 884–886 arthritis enthesitis-related, 750 juvenile idiopathic, 750–751 rheumatoid see rheumatoid arthritis arthro-ophthalmopathy, hereditary see Stickler’s syndrome arthropathy and HLA-B27-associated uveitis, 749 articaine, peribulbar block, 357–358 Artisan (Verisyse) iris-claw lens/ICL, 128, 131t, 133, 135 complications, 138 aseptic cavernous sinus thrombosis, treatment, 987 Asiatic eyelids, 1352 cosmetic surgery, 1355–1356 aspergillosis, endophthalmitis, 733–734 asphericity, contact lenses, 53 asphericity (Q/eccentric) factor, 38 in laser treatment, 83, 120 asteroid hyalosis, 436 astigmatic keratotomy, 87, 141–146 complications, 144–146 definition, 141 surgical technique, 142–144 astigmatism, 38 axis of, 143–144 cataract patients and intra-operative management of preoperative astigmatism in prevention of induction of astigmatism, 366–367 postoperative residual or induced astigmatism and its management, 368–369, 405 toric IOLs, 88, 368–369 treatment of preoperative astigmatism, 367–368 contact lenses, 53 definition/meaning, 77 direct ophthalmoscopy, 70 genes associated with, 14t LASIK, 107–108 results, 116–117 lens surgery in, 349–350 monocular subjective refraction testing, 47 of oblique incidence, 78 phakic IOLs, 129 photorefractive keratectomy, 95–96, 99–100

astigmatism (Continued) postoperative in astigmatic or radial incisional keratotomy, 145 in phototherapeutic keratectomy, irregular astigmatism, 310 in phototherapeutic keratectomy, myopic astigmatism, 310 in penetrating keratoplasty, 302 ptosis surgery-related changes in, 1277 regular, 77 retinoscopy, 66 astrocytes, retinal, 867 astrocytoma pilocytic (optic nerve) see glioma retinal, 833–835 ataxia (cerebellar) autosomal dominant, 980 Friedreich’s, 861, 980 spinocerebellar (SCA), 980 ataxia telangiectasia, 980 atherosclerotic cardiovascular disease central retinal artery obstruction and, 521 ocular ischemic syndrome and, 553 atmosphere UV light passing through, 28 visible light passing through, 19 atopic dermatitis and cataracts, 416 atopic keratoconjunctivitis, chronic, 192–194 ATP-binding cassette-4 gene and Stargardt’s disease, 492 atrophia areata, 500 atrophic holes, 642 auditory system visual system and, integration, 912 Vogt–Koyanagi–Harada disease and signs relating to, 762 aura migraine with, 971 structural lesions mimicking, 972 treatment, 971–972 migraine without, 970–971 treatment, 971–972 autofluorescence, fundus (FAF), 482 age-related macular degeneration, 582–584 central serous chorioretinopathy, 607 chloroquine and hydroxychloroquine retinotoxicity, 684 cystoid macular edema, 629 Stargardt’s disease, 492 autografts conjunctival, after pterygium excision, 314 keratolimbal stem cells see stem cells autoimmune disease (in general), serous retinal detachment, 655 autoimmune mechanisms and autoantibodies cicatricial pemphigoid, 206 glaucomatous optic neuropathy, 1017 Graves’ disease, 946 myasthenia gravis, 938 diagnostic detection, 939 peripheral ulcerative keratitis, 238–239 scleritis, 212 Sjögren’s syndrome, 276 uveitis, 691–692 infection and triggers of, 692 intermediate, 774 autoimmune optic neuritis, 881 autoimmune retinopathy, paraneoplastic, 792 automated keratometry before cataract surgery, 339–340 automated lensometer, 68 automated objective refracto(mete)rs, 47, 66–68 automated perimetry in glaucoma diagnosis, 1029–1034 autonomic nervous system and retinochoroidal blood flow, 429 see also parasympathetic innervation; sympathetic innervation autoregulation of retinal circulation, 429 autosomal dominant inheritance, 4–5 albinism, 12–13 cerebellar ataxia, 980 corneal dystrophies, 9 cystoid macular edema, 499

Index

anticoagulants and cataract surgery, 356 antifibrotic agents, 1083, 1152–1158 trials, 1178 antifungal agents endophthalmitis, 736 keratitis, 226–227, 230 uveitis, 1082 antigen presenting cells, 691 uveitis and, 692–693 antihelminthic drugs cysticercosis, 746 keratitis, 231 onchocerciasis, 231, 747 antihypertensives diabetic retinopathy, 546 hypertensive retinopathy, 517 anti-inflammatory agents in uveitis, 698t see also non-steroidal anti-inflammatory drugs antimetabolites in glaucoma surgery, 1152–1153, 1162 application techniques, 1154–1155 complications, 1157b, 1167–1168 improvement in use, 1154b indications for use, 1153–1154 pterygium excision, 314 uveitis, 697–699, 698t Behçet’s disease, 760 antimuscarinic drugs see anticholinergic drugs antioxidants and cataracts, 412–414 antiparasitic drugs see antihelminthic drugs; antiprotozoal drugs antiplatelet therapy, diabetic retinopathy, 546 antiprotozoal drugs Acanthamoeba keratitis, 229, 230t toxoplasmosis (and uveitis), 742 antiretroviral therapy (highly active – HAART) and CMV infection, 706–707 antisense therapy, 7 antisepsis, intravitreal injection, 477 antivirals cytomegalovirus retinitis, 706–707 intravitreal implants, 478 herpes simplex keratitis, 235–236 newer agents, 236–237 herpes simplex retinal disease, 701 herpes zoster disease, 182 corneal disease, 182 postherpetic neuralgia, 182 retinal disease, 701 aortic arch syndrome see Takayasu’s arteritis Apert syndrome, 290t aphakia, 417 lens surgery keratoplasty and, 384 secondary implant, 340 pediatric, treatment choices, 392–393 UV vulnerability, 29 aphakic IOLs, corneal refractive surgery combined with (=bioptics), 119 apocrine benign lesions of eyelids, 1298 aponeurosis, levator palpebrae see levator palpebrae aponeurosis apoptosis and glaucomatous optic neuropathy, 1017 applanation tonometer (Goldmann), 59–61, 1020 apraclonidine, 1115 Horner’s syndrome diagnosis, 962 apraxia, eyelid, 1293t aqueous humor in angle-closure glaucoma, anatomic levels of obstruction of flow, 1061b formation/production complexities, 1015 drugs decreasing, 1114–1116 functional overview, 1014 structural basis, 1013–1014 inflow, physiology, 1013–1016 misdirection (in trabeculectomy), 1165–1166 misdirection syndrome (=malignant glaucoma ), 1061, 1063, 1092–1093 outflow, drugs increasing, 1116–1118 outflow pathway in glaucoma damage, 1012–1013 episcleral venous pressure elevation causing obstruction to, 1090 reabsorption, 1015

1369

Index

autosomal dominant inheritance (Continued) glaucoma, 1170 juvenile, 10, 1171 primary open-angle, 1002, 1171 keratitis, 9–10 mechanisms of disease with, 7 optic atrophy, 13–14, 864, 891 retinal degenerations (incl. retinitis pigmentosa), 485t retinoblastoma, 12, 16, 793 Rieger’s syndrome, 10 risk prediction of disorders with, 16 Sorsby’s macular dystrophy, 12 vitreoretinochoroidopathy, 509, 511, 574 autosomal recessive inheritance, 5 mechanisms of disease with, 7 retinal degenerations (incl. retinitis pigmentosa), 485t risk prediction of disorders with, 16–17 Avellino corneal dystrophy, 9, 261 Axenfeld anomaly (Axenfeld–Rieger Syndrome), 175, 1096 glaucoma and, 1022t, 1024, 1096 axial globe-displacing lesions, 1319b axial length IOLs and calculation of, 337–340 primary angle-closure glaucoma and, 1005 in refractive surgery, modification procedures, 90 axial plane imaging of orbit, 1264–1265 axons (nerve fibers) birefringency, 24 guidance disorders, 13 retinal ganglion cell, 866–867 anatomy and physiology, 866–867 birefringency, 24 direct ophthalmoscopy of status, 70 optical coherence tomography of layers of see optical coherence tomography azole antimicrobials Acanthamoeba keratitis, 229 fungal keratitis, 226–227, 230t Azorean disease, 980

B

1370

B cells, 690 inhibitors, in uveitis, 698t B-scan mode ultrasonography see ultrasound imaging B-wave (electroretinogram), 458–460 bacilli causing keratitis, Gram-positive, 219 Bacillus cereus keratitis, 219 baclofen, periodic alternating nystagmus, 957 bacteria (including pathogenic forms) in pathogenesis blepharitis, 178 endophthalmitis, 402, 724 microbiallergic conjunctivitis, 194 bacterial biofilms, contact lenses, 281 bacterial infection in blepharitis, treatment, 179 conjunctivitis caused by, 183–184 acute, 183 chronic, 183t, 184 hyperacute, 183–184 neonatal, 187–188 cornea (keratitis), 217–224 contact lens-related, 288 photorefractive keratectomy-related, 310 uveitis caused by, 704–708 bacteriorhodopsin, 19 Baerveldt implant, 1083, 1159–1161, 1163, 1168– 1169, 1178b Bagolini lenses, 1203 Baikoff lenses ZB, 127 ZB5M, 127, 134–135 Bailey–Lovie chart, 43 balanced salt solution (BSS), 352–353, 353t balanced salt solution plus (BSS plus), 352–353, 353t Balint’s syndrome, 919 balloon nevus cells, 823 Baltimore Eye Survey, 1003, 1109 band (calcific) keratopathy, 270 juvenile idiopathic arthritis and, 751 Barbados Eye Study, 1050, 1109

Bardet–Biedl syndrome, 6, 14, 485t, 489f bare sclera technique, 313–314 Bartonella henselae see cat scratch disease basal cell carcinoma (BCC), 1306–1308 differential diagnosis, 1307, 1307t basal cell nevus syndrome, 294t, 1307 basement membrane corneal epithelium, 164 dystrophy, anterior, 256–257 retinal pigment epithelium, in age-related macular degeneration, 585–586 basilar meningitis, 977 basosquamous cell acanthoma, 1296 BAX and glaucomatous optic neuropathy, 1017 Bayes’ theorem and glaucoma screening, 1008– 1009, 1009t BCL-2 and glaucomatous optic neuropathy, 1017 BEAT-ROP study, 539 Behçet’s disease, 758–760 diagnosis and testing, 979 epidemiology and pathogenesis, 758, 977 ocular involvement, 758, 978 pathology, 979 Benedickt’s syndrome (red nucleus lesions), 924t, 955, 998–999 BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment), 882 benign essential blepharospasm (BEB), 1292–1294 benign paroxysmal positional nystagmus, 953, 953t benign paroxysmal tonic upward gaze, 920 benign tumors, 821–824 benzodiazepines, blepharospasm, 1293 Berlin’s edema, 671 Best disease, 485t, 494 BEST1-related dystrophies, 511 beta-blockers see adrenergic antagonists bevacizumab in age-related macular degeneration, 592 photodynamic therapy plus, 596–597 ranibizumab vs., 592–596 choroidal neovascularization, 732 Coats’ disease, 563–564 diabetic retinopathy, 546–547 neovascular glaucoma, 1079 radiation retinopathy, 568 retinal arterial macroaneurysms, 579 retinal vein occlusion-related macular edema branch, 533 central, 530 retinopathy of prematurity, 538–539 biaxial micro-incisional cataract surgery (B-MICS), 363, 374 vertical chop technique, 375 Biber–Haab–Dimmer corneal dystrophy (lattice dystrophy type I), 9, 259–260 bicoronal forehead lift, 1357 Bielschowsky (Parks–Bielschowsky) three-step test, 929, 1228–1229 bifocals accommodative esotropia, 1210 teenagers, 1211 dead zone, 50–51 bilateral diffuse uveal melanocytic proliferation, 792, 822–823 bimatoprost glaucoma, 1117 side-effects, 1118 systemic safety, 1118 binocular balance testing, 49–50 binocular indirect ophthalmoscope, 69 binocular vision loss (bilateral blindness), 996 children, 955 isolated, 997–998 sensory fusion, 1201 testing, 1202–1203 biochemical changes in aging vitreous, 434 biocompatible IOLs and posterior capsule opacification, 409 biofilms, contact lenses, 281 biological agents see immunomodulatory and biological agents biomarker testing, glaucoma screening, 1010

biomicroscope central serous chorioretinopathy, 606 epiretinal membrane, 615–616 slit lamp see slit-lamp (bio)microscope ultrasound see ultrasound biomicroscopy biopsies incl. fine-needle aspiration (and subsequent histopathology) choroidal or ciliary body melanoma, 805 cicatricial pemphigoid, 207–208 conjunctival melanocytic tumors, 199 corneal, 306–307 infectious keratitis see subheading below endophthalmitis, 735 Aspergillus, 734f eyelid lesions, 1305 excisional, for basal cell carcinoma, 1308 iris melanoma, 802 Acanthamoeba, 229 keratitis, bacterial, 221 metastases, 811 retinoblastoma, 795–796 sarcoidosis, 755 scleritis, 213 Sjögren’s syndrome, 276 temporal artery, 984–985 in anterior ischemic optic neuropathy, 886 bioptics, 119 phakic IOLs, 119, 140 bipolar cells, 420–422 birdshot chorioretinopathy, 573, 778–779 birefringency, 24 bite wounds to lids, 1312 dog, 1312, 1315–1317 B-K mole syndrome, 1310 black sunburst lesion (retina) in sickle cell hemoglobinopathy, 556 black widow spider bite, 937t blastoma, pleuropulmonary (family tumor and dysplasia syndrome), 820 bleb(s) with contact lenses, 55–56 in drainage implant surgery, deflation, 1162 filtering see filtration bleb; trabeculectomy blebitis, 1168 with antimetabolites, 1157b bleeding see hemorrhage blepharitis, 177–179 diagnosis and ancillary tests, 178 Meibomian gland dysfunction see Meibomian gland dysfunction ocular manifestations, 178 pathogenesis, 177–178 treatment, 178–179 blepharoconjunctivitis, HSV, 232 blepharophimosis syndrome, 1273 blepharoplasty, 1353–1357 horizontal eyelid shortening plus, 1288 lower lid, 1355 upper lid, 1354–1355 see also transblepharoplasty brow fixation blepharoptosis, 1272–1277 following blepharoplasty, 1356 following entropion surgery, 1283 following orbital surgery, 1338 blepharospasm, 1292–1294 essential, 1292–1294 in neurodegenerative disease, 980 secondary, 1292 blindness see visual deficits and loss blinking with contact lenses, incomplete, 282 blood anterior chamber see hyphema dyscrasia, carbonic anhydrase inhibitor-induced, 1116 viscosity in diabetic retinopathy, 542 see also hyperviscocity syndromes blood flow (circulation), optic nerve, 1047–1049 measurement, 1047–1049 reversal of deficiencies, 1058 blood flow (circulation), retinochoroidal, 428–429 assessment, 428–429 Doppler studies see Doppler studies regulation, 429 systemic disease-associated disruption, 655

C

Cachet see AcrySof Cachet caffeine and glaucoma, 1003–1004

calcarine cortex, 910 lesions, diagnostic features, 910–911 infarction, 998 calcific band keratopathy see band keratopathy calcific emboli, 522 calcium hydroxyapatite fillers, 1359–1360 calcium ions and cataract pathophysiology, 413 calpains and cataracts, 414 CAM vision stimulator, 1242 camera, fundus, 70–71 Campbell–Green relation, 44 can-opener capsulectomy, 379 canal of Schlemm see Schlemm’s canal canaliculi, lacrimal anatomy, 1346 diseases, 1350 injury, 1290–1291 canaloplasty (Schlemm’s canal) (SC), 1140–1142, 1145 cancer see malignant tumors candidiasis, endophthalmitis, 733 canthaxanthine retinotoxicity, 684–685 canthoplasty, medial, 1289–1290 canthus/canthal tendons, 1256 assessment, 1279 blepharoplasty complicated by deformities, 1356 laxity lateral, 1285 medial, 1285 surgery in ectropion, 1286 in entropion, 1280 cap (corneal), free, complicating LASIK, 114 capillaries choroidal (choriocapillaris), 426, 688–689 retinal, 426 macroaneurysms, 576–577 capillary hemangioma (benign hemangioendothelioma; strawberry nevus) eyelid, 1299–1300 orbital, 1330 retinal, 836–838 retinal arterial macroaneurysm vs., 577–578 in von Hippel–Lindau syndrome, 836–838, 847 capsular bag IOL complications, 398 decentration, 401 entrapment of OVD in capsular bag (=capsular block syndrome), 401 IOLs maintaining open or expanded bag, 411 see also endocapsular IOL fixation capsular tension rings, 410 capsule (lens) anterior opacification (ACO), 407, 409 in pseudoexfoliation syndrome, 1071 posterior IOL optic contact with, 410–411 opacification see cataracts, secondary ruptured (in cataract surgery), 397–398 surgery (in general), 346, 348, 375–376 tension rings in pseudoexfoliation glaucoma, 1072 see also intercapsular techniques; intracapsular cataract extraction capsulectomy/capsulotomy anterior, 346, 375–376, 379–380 complications, 396 posterior, children, 391–392 capsulopalpebral fascia, 1278–1279 anatomy, 1256 assessment, 1278–1279 surgery, 1280–1281 capsulorrhexis, continuous curvilinear (CCC), 348, 372 in extracapsular cataract extraction, 380 in mini-nuc technique, 380 in limbal approach to pediatric cataract surgery, 391 posterior capsular opacification and size of, 408–409 tears, management, 396 in zonular instability, 386 carbidopa, amblyopia, 1242 carbon monoxide poisoning, 990

carbonic anhydrase inhibitors in glaucoma, 1112, 1115–1116, 1118t adverse effects, 1023t, 1116, 1118t carcinoma eyelid, 1306–1310 lacrimal gland, 1320 metastatic intraocular, 791–792, 810–811, 814 conjunctiva, 202 indocyanine green angiography, 811 metastatic orbital, 1319 pituitary, 901 renal cell, in von Hippel–Lindau syndrome, 847 cardiovascular disease atherosclerotic see atherosclerotic cardiovascular disease see also heart carotid arteries central retinal artery obstruction in disease of, 520–521 in ocular ischemic syndrome arteriography, 552–553 endarterectomy, 554 carotid–cavernous sinus fistula, 993–995 cranial neuropathy, 932, 934 treatment, 936 glaucoma with raised episcleral venous pressure and, 1091 retinal neovascularization, 571 carotid–ophthalmic artery aneurysms, 992 carotid–ophthalmic artery ischemic attacks, 998 carotid vessels aneurysms, 992–993 intracavernous, 932, 992–993 extraocular muscle supply, 1184 occlusive disease non-arteritic anterior ischemic optic neuropathy and, 886 ocular manifestations, 998–999 case–control studies of glaucoma therapy, 1175 case reports and glaucoma therapy, 1174–1175 cat scratch disease (B. henselae infection), 188, 720–721, 881 neuroretinitis, 636, 720–721 cataracts (lens opacities), 330, 334–342 advanced, 336 assessment, 335–337, 417 causes, 414–416 classification, 335–336, 417 complicated eyes, 386–389 complications of surgery, 381–382, 393–403 cystoid macular edema (Irvine–Gass syndrome), 354–355, 402, 452, 627 rhegmatogenous retinal detachment, 648 congenital see congenital cataract in diabetic retinopathy, 545 diagnosis, 335 direct ophthalmoscopy through, 70 epidemiology, 412–413 in Fuchs’ heterochromic iridocyclitis, 772–773 grading, 336, 417 IOL-related AC angle-supported phakic IOLs, 135 iris-supported phakic IOLs, 138 PC phakic IOLs, 139 as laser iridectomy complication, 1124 morphology, 416–417 pathophysiology, 413–414 scleritis and development of, 216 secondary (=posterior capsule opacification), 402–403 pathogenesis, 402–403, 407–411 prevention, 407–411 treatment, 403 surgery (incl. extraction), 216, 334–342 anesthesia see anesthesia complications see subheading above diabetic retinopathy, 545 endophthalmitis following, 354, 402, 723–724 glaucoma and see glaucoma good clinical practice, 341–342 history, 346t indications, 343–344 in intermediate uveitis, 775 investigations for further refinements, 341 limbal relaxing incisions, 87 manual, 378–381

Index

blood pressure see antihypertensives; hypertension; hypotension blood-retinal barrier, 423, 426–428, 687 cystoid macular edema and, 625 blood vessels/supply see neovascularization; vascular supply blue cone monochromatism, 485t, 487–488 blue nevus, 1303–1304 blue rubber bleb syndrome, 1300 blunt (non-penetrating) injury to posterior segment, 670–674 glaucoma patient with history of, 1019 bobbing, ocular, 955 bones fractures see fractures orbital, 1258–1259 tumors, choroidal, 830–832 Borrelia burgdorferi and Lyme disease, 712–714, 881 Boston-K-Pro, 305 Botox, 1363 botulinum toxin (denervation), 1362–1366 adverse reactions, 1363 blepharospasm, 1293–1294 commercially available forms, 1363 contraindications and precautions, 1363 cosmetic applications, 1363 diluting protocols, 1363 entropion, 1280 mechanism of action, 1362–1363 nystagmus, 957 strabismus, 1245–1246 congenital esotropia, 1208 paralytic (IIIrd nerve), 1227 botulism, 937t, 940t, 941 Bowman’s membrane (BM), corneal dystrophy of type I (=Reis–Bücklers dystrophy), 9, 257–258 type II (=Thiel–Behnke dystrophy), 258 brain, 969–975 afferent pathways in, and their lesions, 909–914 atrophy in multiple sclerosis, 860 efferent pathways in, and their lesions, 915–921 imaging see neuroimaging infections, 976–977 inflammation, 977–979 trauma, 988–989 tumors see tumors see also retina–brain system and specific regions/ structures brainstem migraine pathogenesis, 972–973 ocular motor nerve fascicular disorders, 922–926 stroke signs and symptoms, 999 Branhamella catarrhalis keratitis, 220 Breslow thickness, 1311 brimonidine, 1115 Brodman’s area 17 (primary visual cortex; V1), 910, 912 bromocriptine, pituitary adenoma, 907 Brooke’s tumor, 1299 brow (forehead) anatomy, 1353 malposition, 1352 surgery (brow lift/browplasty), 1357–1358 wrinkles, botulinum toxin, 1364–1365 Brown’s syndrome, 935, 1235–1236 brucellosis, 719 Bruch’s membrane, 426, 688–689 in age-related macular degeneration, 585–588 rupture/breaks in choroidal neovascularization and, 600–604 traumatic, 600–601, 671 bruits, carotid–cavernous sinus fistulas and dural shunts, 994 bullous keratopathy after cataract surgery, 400 bull’s eye maculopathy chloroquine and hydroxychloroquine, 683 clofazimine, 686 burns chemical see chemical burns thermal eyelid, 1317 phaco tip-related, 396

1371

Index

1372

cataracts (lens opacities) (Continued) open-sky, 305, 383–384 outcome, 394 patient work up, 334–342 pediatric, 390–394 pharmacotherapy, 351–355 postoperative care see postoperative management pre-existing medical conditions and, 334, 356 triple procedure of keratoplasty and IOL implantation with, 305, 383–384 uni- vs. bilateral, results, 405–406 trabeculectomy and formation or worsening of, 1168 uveitis and, 695, 750–751 visual effects, 336–337, 417 CATT (Comparison of Age-Related Macular Degeneration Treatment Trial), 592–596 cavernous hemangioma eyelid, 1300 orbital, 1331 retinal, 838–839 cavernous sinuses, 900–901 carotid aneurysms within, 932, 992 cranial neuropathies relating to, 931–932 thrombosis course and outcome, 987 diagnosis and testing, 985 differential diagnosis, 985 epidemiology and diagnosis, 983 ocular manifestations, 984 pathology, 986 treatment, 987 tumors involving, 976 see also carotid–cavernous sinus fistula CDKN2B-AS gene and low-tension glaucoma, 1171 cell division meiosis, 2–3 mitosis, 2 cell-mediated (delayed) hypersensitivity, 692 cellulitis, orbital, 1328 dacryocystitis and, 1349 central areolar choroidal dystrophy, 500–501 central cloudy dystrophy, 262 central confusion, 1197 central diplopia, 1197, 1199 central disruption of fusion, 921 central nervous system cataracts and disorders of, 416 esotropia relating to (in neurologically-impaired child), 1212 malformations, optic disc anomalies and, 871 sarcoidosis involvement, 756 tuberous sclerosis-associated tumors of, 833– 834, 846 treatment, 834–835 Vogt–Koyanagi–Harada disease involvement, 762 see also brain; neuro-ophthalmology central neurone Horner’s syndrome, 961f central presby-LASIK, 152–153 central serous chorioretinopathy, 423–424, 605– 609, 653–654 central tolerance, 691–692 central vestibular nystagmus, 953, 953t cephalosporins, keratitis, 222 cerebellum hemangioblastoma in von Hippel–Lindau syndrome, 847 neurodegenerative disease, 980 ocular motility disorders, 920 cerebral achromatopsia, 912 see also brain cerebral angiography see angiography cerebral artery middle, ischemia and stroke, 998 posterior, occlusion/hypoperfusion, 998 cerebral vessels disease (ischemic or occlusive), 981 disorders, 992–999 cerebrospinal fluid (CSF) leak in orbital surgery, 1338 testing in syphilis, 711 chalazion, 1304 chalcosis with copper-containing foreign bodies, 675

CHAMPIONS (Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance), 882 CHAMPS (Controlled High-Risk Avonex MS Prevention Study), 882 Chandler’s syndrome, 1095 Charleaux’s sign, 252 Charles Bonnet syndrome, 981, 990 checkerboards pattern for evoked potential test, 1189, 1189f chemical burns (corneal and ocular surfaces), 296– 298, 1086, 1100 glaucoma with, 1086, 1100 stem cells in see stem cells chemodenervation see botulinum toxin chemokines/chemokine receptors and uveitis, 691 chemotherapy choroidal/ciliary body melanoma, 809 corneal tumors intraepithelial neoplasia, 197 lymphoma, 201 eyelid basal cell carcinoma, 1308 leukemia, 818 metastases, 813 retinoblastoma combined with other modalities, 799 intravenous, 796–797 intravitreal, 799 ophthalmic artery infusion, 797 periocular, 798–799 vitreoretinal lymphoma (primary), 788–789 cherry-red spot (macula) central retinal artery obstruction, 519 ocular ischemic syndrome, 552 other causes, 519b chiasma see optic chiasm Childhood Glaucoma Research Network (CGRN) classification of pediatric glaucoma, 1104 children accommodative dysfunction, 968 cataract surgery, 390–394 endophthalmitis, 724 fascicular VIth cranial nerve palsy, 926 glaucoma, 1101–1106 goniotomy, 1131–1132 secondary, 1101–1102 trials, 1179 Horner’s syndrome, 962–963 Leber’s hereditary optic neuropathy analysis in, 863 monocular visual loss see monocular visual loss pilocytic astrocytoma see glioma preverbal/preliterate children, evaluation of vision, 1188–1191 pupillary light reflex assessment, 960 retinal disorders, vitrectomy, 472 retinoblastoma see retinoblastoma sarcoid, 756 strabismus see strabismus see also infants; neonates and entries under congenital Chlamydia trachomatis, conjunctivitis (chronic), 186–187 neonatal, 187 chloride ions and aqueous inflow, 1014–1015 chloroquine retinotoxicity, 683–684 cholesterol emboli, 522 cholinergic agonists dry eye syndrome, 278 glaucoma, adverse effects, 1023t cholinergic antagonists see anticholinergic drugs cholinesterase inhibitors see anticholinesterases chondroid syringoma (mixed cell tumor; pleomorphic adenoma) eyelid, 1298 orbit, 1319–1320 chorea, 980–981 Huntington’s (Huntington’s disease), 980–982 choriocapillaris, 426, 688–689 chorioretinal (retinochoroidal) atrophy, Sveinsson, 500 chorioretinal (retinochoroidal) coloboma, 634–635 chorioretinal (retinochoroidal) degeneration, helicoid peripapillary see serpiginous choroiditis

chorioretinitis (posterior uveitis; retinochoroiditis), 694, 694t, 696t, 778–787, 1082b cat scratch disease involving, 721 EBV, 701 intravitreal implants in, 478 parasitic, 744–747 toxoplasmosis, 740f, 741–742, 741t, 742b sarcoidosis, treatment, 756–757 syphilitic, 709 tuberculous, 716–718 unknown causes, 778–787 chorioretinitis sclopetaria, 671 chorioretinopathy birdshot, 573, 778–779 central serous, 423–424, 605–609, 653–654 see also vitreoretinochoroidopathy choristomas, corneal or conjunctival, 174–175, 201 choroid anatomy, 688–689 vascular, 426 blood flow and its assessment see blood flow blood vessels see vascular supply degenerations/dystrophies (inherited), 502–507 central areolar, 500–501 helicoid peripapillary see serpiginous choroiditis detachment, 438 massive, 1086 serous, 660–662 ultrasound, 438 effusions complicating scleral buckling, 469 complicating trabeculectomy, 1167 serous, aqueous misdirection syndrome vs., 1093t fluid flow through, 653 alterations causing serous detachment of neural retina, 653–655 hemorrhage see hemorrhage melanoma, 573, 803–809, 1099 choroidal hemorrhage mistaken for, 664 serous retinal detachment with, 654–655 neovascularization/CNV, 600–604, 636 in age-related macular degeneration, 581–582, 585–589, 587b central serous chorioretinopathy vs, 607 in choroidal osteoma, 831 in histoplasmosis, 729–732 inflammatory causes, 603–604, 627b optic disc abnormalities associated with, 636 optical coherence tomography, 454 secondary causes (in general), 600–604 neovascularization/CNV, treatment with age-related macular degeneration, 589 with angioid streaks, 602 with choroidal nevus, 823 in histoplasmosis, 731–732 in inflammatory disorders, 603–604 as laser photocoagulation complication, 609 in pathologic myopia, 603 in traumatic rupture of Bruch’s membrane, 600–601 optical coherence tomography of, 449 various pathologies, 454 polypoid vasculopathy, vs. central serous chorioretinopathy, 607 sarcoidosis, 754 traumatic rupture, 671 tubercles and tuberculoma, 716–717 tumors, 654–655 hemangioma see hemangioma lymphoma (primary), 789 melanocytic nevus, 821–824 melanoma see subheading above metastatic, 655, 812, 1099 osteoma, 830–832 serous retinal detachment with, 654–655 choroideremia, 485t, 502–505 female carriers, 488, 503 choroiditis multifocal see multifocal choroiditis punctate inner see punctate inner choroidopathy serpiginous see serpiginous choroiditis see also chorioretinitis

cochlin and glaucoma, 1013 Cochrane Collaboration and glaucoma trials, 1174 Cockayne’s syndrome, 415 coenzyme Q10 treatment in mitochondrial disorders, 944–945 Cogan microcystic dystrophy, 256–257 Cogan–Reese syndrome, 1095 Cogan syndrome, 246–247 cohort study of glaucoma therapy, 1175 Collaborative Initial Glaucoma Treatment Study (CIGTS), 1008–1009, 1030, 1112–1113, 1133, 1173, 1177b, 1178 Collaborative Normal-Tension Glaucoma Study (CNTGS), 1107–1108 collagen, corneal cross-linking, 89–90, 147–150 in keratoconus and other ectasias, 116 intrastromal corneal ring segments combined with, 150 in laser photoablation, 34–35 technique, 148–149 type IIa mutations, Stickler’s syndrome, 508 type VIII mutations Fuchs’ dystrophy, 264 posterior polymorphous dystrophy, 267 collagen, vitreous, 430, 432–433 aging and, 434 collagen fillers, 1359 zones of placement, 1360f collagen vascular disease see connective tissue disease collagenase inhibitors, keratitis, 223 colliculus, superior, fascicular syndrome of IVth nerve involving, 925 coloboma lens, 418 optic disc, 634–635, 872 retinochoroidal, 634–635 colonic adenomatous polyposis–carcinoma syndrome, familial, and retinal pigment epithelium hypertrophy, 842–843 color, laser, 33 color Doppler central retinal artery obstruction, 520 ocular ischemic syndrome, 552 optic nerve blood flow, 1048 color temperature (bulb) in direct ophthalmoscopy, 70 color vision with cataracts color shift, 337 effects of surgery, 405 contrasts with spectacles/sunglasses, improving, 30 defects/deficits, 12 inherited retinal degenerations, 482, 487–488 perception of color, 912 colored contact lenses, 53 coma, 39, 78 comitant (deviation), 928 commotio retinae, 671 communicating artery, posterior, aneurysms, 983, 992 complement inhibitors, uveitis, 698t compliance problems, contact lens wearing, 282 compound nevus, 1303 compression oculomotor (IIIrd cranial) nerve palsy due to, 929 optic nerve (and associated neuropathies), 859, 877, 891 dysthyroid eye disease, 895, 946–948 non-tumor causes (in general), 897b tumors, 894–897 computed tomography, 851 axial (of orbit), 1264f–1265f clinical applications, 851 choroidal or ciliary body melanoma, 805 Coats’ disease, 562–563 metastases, 811 neurological studies see subheading below posterior segment trauma, 670–671 retinoblastoma, 795 scleritis, 212 serous retinal detachment, 658 lacrimal drainage system, 1347

computed tomography (Continued) MRI compared with, 851t, 856t neurological studies, 851, 856–857 optic chiasma/parasellar/pituitary fossa lesions, 905–906 optic nerve glioma, 895, 905–906 optic nerve sheath meningioma, 896 principles, 851 safety, 851 computed tomography angiography, 854 cranial nerve III palsies, 934 MRA vs., 854 computerized videokeratoscopy/videokeratography see videokeratoscopy cone(s) (photoreceptors), 21–22, 39, 420 see also blue cone monochromatism; rod–cone dystrophy cone dystrophy, 484, 500 cone-rod dystrophy, 481, 485t confidentiality, genetic counseling, 17 Confocal Scanning Laser Ophthalmoscopy Ancillary Study to Ocular Hypertension Treatment Study (OHTS), 1108 confocal scanning laser technology (tomography/ CSLT; microscopy; ophthalmoscopy/CSLO), 441, 1041–1043 in glaucoma, 1041–1043 optic nerve, 1003, 1041–1043 in screening, 1009–1010 congenital amaurosis, Leber’s see Leber’s congenital/hereditary amaurosis congenital anomalies (developmental anomalies) corneal see cornea lens, 417–418 optic disc see optic disc retinal vessels, causing serous retinal detachment, 656–658 systemic, genetic counseling, 17 vitreous, 433 congenital cataract, 416 nonsyndromic, 11 congenital cranial nerve palsies IIIrd nerve, 924, 1226 IVth nerve, 924, 1228–1229 VIth nerve, 929, 1230 congenital ectropion, 1284 congenital entropion, 1279 congenital esotropia, 1206–1209 congenital fibrosis of extraocular muscles, 13, 1236 congenital gaze palsies, 918 congenital glaucoma, 11, 1101–1106 genetic factors, 1101, 1170 goniotomy for, 1131–1132 congenital hereditary endothelial dystrophy, 266–267 congenital hereditary stromal dystrophy, 263 congenital hypertrophy of retinal pigmented epithelium, hypertrophy, 842–843 congenital melanocytic nevus, 1303 congenital monocular elevator deficiency (double elevator palsy), 920, 1234–1235 congenital nasolacrimal obstruction, 1348 treatment, 1349 congenital nystagmus, 951–952, 952t drug treatment, 957 surgery, 957 congenital ptosis, 1272–1273 congenital red–green color deficiency, 487 congenital stationary night blindness, 485t, 486 congenital toxoplasmosis, 738–740 conjunctiva, 180–182 anatomy, 1256 in blepharoplasty, approach via, 1355 contact lenses problems, 54–56, 283–284 degenerations, 203–205 flap see flap in glaucoma buttonholes complicating trabeculectomy, 1164 examination, 1022 peritomy in enucleation, 1340 in exenteration, 1342 in strabismus surgery, incisions, 1248 surgery see surgery syphilitic involvement, 710

Index

choroidopathy, traumatic, 674 see also birdshot chorioretinopathy; neovascular vitreoretinochoroidopathy; punctate inner choroidopathy; serpiginous choroiditis chromatic aberrations, 39, 73 chromosome(s), 1–2 abnormalities, corneal manifestations, 290t DNA packaging into, 1 in meiosis, 2–3 in mitosis, 1–2 rearrangements causing breaks, 4 chromosome 13q deletion syndrome, 290t, 795 chronic paroxysmal hemicrania, 975 chronic progressive external ophthalmoplegia see progressive external ophthalmoplegia cicatricial ectropion, 1284, 1285f, 1286, 1289, 1289f cicatricial entropion, 1279, 1282 cicatricial pemphigoid, 206–208 cicatricial skin changes, 1285 ciclosporin see cyclosporine cigarette smoking see smoking ciliary arteries, 1047–1048, 1184 ciliary block glaucoma (malignant glaucoma), 1061, 1063 ciliary body anatomy, 687–688 in angle-closure glaucoma pathophysiology, 1061b epithelium (pigmented/PE and non-pigmented/ NPE), and aqueous inflow, 1013–1016 in exenteration, detachment, 1342f inflammation (cyclitis) see uveitis, anterior medulloepithelioma, 819 melanoma, 803–809, 1099 metastases, 1099 nevus differential diagnosis, 822 pathology, 823 see also cyclodestructive procedures; cyclodialysis cleft; cycloplegic agents ciliary muscle-zonular complex, 90 ciliary sclerotomy, anterior, in presbyopia, 160 ciliary sulcus-supported IOLs see posterior chamber (sulcus-supported) IOLs cilioretinal arteries, 426 obstruction, 524 circle of Willis, 900–901 circular keratorrhaphy, 88 circulation see blood flow; vascular supply circumscribed choroidal hemangioma, 825–829 cleansing, blepharitis, 178–179 clear corneal incisions (in cataract patients) opposite, to treat preoperative astigmatism, 367–368 in prevention of induction of astigmatism, 366–367 CLEAR-IT 2 study, 597 climatic proteoglycan stromal keratopathy, 273 clinical decision support system (CDSS), 1179 clinical examination see examination Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories, 16 clock dial, refraction, 47 clofazimine retinotoxicity, 686 clonazepam, downbeat nystagmus, 957 Cloquet’s canal, 431 clostridial keratitis, 219 Clostridium botulinum, 1362 see also botulinum toxin; botulism cluster-type headache, 973–974 classification, 971b location of pain, 970f CMV see cytomegalovirus coagulation–compression (peripheral cornea), 87–88 coagulopathies, central retinal artery obstruction, 521 Coats disease, 560–564 cystoid macular edema, 625, 630 retinal arterial macroaneurysms vs., 577 serous retinal detachment, 656 Coat’s white ring, 271 cocaine, Horner’s syndrome diagnosis, 962 cocci causing keratitis, Gram-positive, 218–219 coccidioidomycosis, endophthalmitis, 734

1373

Index

1374

conjunctiva (Continued) in trabeculectomy, as preoperative factor, 1148t tumors, 196–202 see also peritomy; subconjunctival cysticercosis; tarsoconjunctiva conjunctivitis, 183–191 contact lens-related, 54–56, 283–284 follicular see follicular conjunctivitis giant papillary see giant papillary conjunctivitis infectious, 183–188 HSV see herpes simplex non-infectious, 188–191 allergic forms see allergic conjunctivitis see also blepharoconjunctivitis; keratoconjunctivitis conjunctivochalasis, 314 connective tissue, eyelid, 1259–1260 connective tissue disease (incl. collagen vascular disease) inherited, 291, 291t interstitial keratitis in, 246 peripheral ulcerative keratitis (and Mooren’s ulcer) in, 238–239, 245 consent (informed) cataract surgery, 342 trabeculectomy, 1148b contact lenses (in equipment) in gonioscopy, 1025 in lasers, 34 in slit-lamp microscope, 59 epiretinal membrane, 615 contact lenses (in eye), 52–56, 280–289 aphakic children, 392 care systems, 281 complications/problems, 54–56, 280–289 risk factors, 280–283 corneal physiology and, 280 damage, 281 deposits, 280–281 endothelial specular microscopy, 63 follow-up care, 54–56 in glaucoma laser iridectomy, 1123 laser trabeculoplasty, 1121 pediatric glaucoma diagnosis, 1104 initial fitting, 53–54 intolerance following astigmatic or radial incisional keratotomy complication, 145 non-compliance, 282 spoilage, 280–281 trial hard, before cataract surgery, 339 types and usage, 52 unsupervised wear, 282–283 warpage, 281 wearing and replacement schedules, 282 non-compliance, 282 contact ultrasonography see ultrasound imaging continuous curvilinear capsulectomy/ capsulorrhexis see capsulorrhexis continuous laser modalities, 33 contrast (tissue) binocular indirect ophthalmoscope, 69 slit lamp microscopy, 58 contrast-enhanced MRI, 853 optic nerve sheath meningioma, 896 contrast sensitivity with cataracts effects of surgery, 404–405 reduction, 405, 417 experimental studies, 1240 recording, 44 spectacles/sunglasses, improvement, 30 testing, 43–44 anisometropic amblyopia, 1238 optic nerve vs. macular disorders, 870 contusion glaucoma associated with, 1084 pigmented retinal epithelium, 674 convergence insufficiency, 921 head/brain injury, 989 see also accommodative-convergence to accommodation ratio convergence retraction nystagmus, 919, 956 stroke patients, 999 convergent strabismus fixus, 1237

conversion (visual field) in primary open-angle glaucoma, 1053–1054 conversion reaction, 912, 914 COPERNICUS study, central retinal vein occlusion, 530 copper-containing foreign bodies, 675 Coppock cataract, 11 cornea, 209–216 aberrations see aberrations absence, 174 arcus, 269 artificial, 305–306 in astigmatic or radial incisional keratotomy incision-related complications, 144 perforations, and their complications, 144–145 wound healing after incisional keratotomy, 141–142 biopsy see biopsies birefringency, 24 cap, free, complicating LASIK, 114 central islands in LASIK, 114–115 central thickness genes associated with, 14t LASIK and measurement of, 110, 118 central thickness in glaucoma, 1020–1021, 1050, 1108 pediatric, 1103 primary open-angle glaucoma, 1003, 1050 as risk factor, 1108 chemical burns, 296–298 collagen see collagen congenital anomalies, 173–176, 290 of clarity, 174–176 of size and shape, 173–174 contact lenses problems, 54–56 degenerations, 245, 269–273 pellucid, 254 in diabetic retinopathy, 545 dystrophies, 256–258, 308–310 anterior, 256–258, 308–310 endothelial, 264–268 Fuchs’ see Fuchs’ corneal dystrophy granular see granular corneal dystrophy inherited (and mutations), 9, 259t, 260–264, 266–267 phototherapeutic keratectomy, 257, 308–310 recurrence following penetrating keratoplasty, 302 recurrence following phototherapeutic keratoplasty, 310 stromal, 259–263 ectasia see keratectasia endothelium see endotheliitis; endothelium enlargement, pediatric, 1104 epithelium see epithelium excimer laser treatment of pathology see phototherapeutic keratectomy flap see flap in fundus photography, reducing, 71 furrow see furrow glaucoma patients abnormalities causing glaucoma, 1094–1100 examination, 1022–1024 indentation (therapeutic) in acute angleclosure, 1066 incisions for cataract surgery see incisions infections see keratitis intrastromal/intracorneal ring segments see intracorneal ring segments irrigation see irrigation–aspiration in laser iridectomy, injury, 1124 light reflex tests, 1193 light-scattering after phototherapeutic keratectomy, 310 melting inflammatory causes, 325 post-astigmatic or radial incisional keratotomy, 145–146 opacities see opacities optical coherence tomography, 455 optical properties, 38 perforation see perforation photoablation see photoablation physiology contact lenses and, 280

cornea (Continued) radius of curvature, and primary angle-closure glaucoma, 1005 sensory decrease, differential diagnosis, 247b silicone tube contact with (in drainage device surgery), management, 1162 stroma see stroma surface see surface surgery see surgery thinning inflammatory causes, 325 non-inflammatory causes, 325 topography see topography in trabeculectomy, as preoperative factor, 1148t tumors, 196–202 ulcer see ulcer wedge reflex, 1121 see also intracorneal inlay and entries under keratcornea farinata, 272 corneorenal syndromes, 294, 294t coronal plane imaging of orbit, 1265–1266 coronary (ischemic) heart disease and cataract surgery, 356 corrugator supercilii, 1353 glabellar furrows and botulinum toxin and the, 1364 cortex (brain) higher functions, 910 representation of vision, 911–914 cortex (lens) in extracapsular cataract extraction removal in mini-nuc technique, 381 washout, 380 hydrodissection-enhanced cleanup/cleaving, 408 irrigation see irrigation–aspiration opacities, 336 corticosteroids see steroids Corynebacteria causing keratitis, 219 cosmetic/aesthetic periorbital procedures, 1352–1358 cotton-wool spots diabetic retinopathy, 543 ocular ischemic syndrome, 552 counseling, preoperative globe removal, 1339 refractive surgery, 93 trabeculectomy, 1148 see also education counter-rolling, ocular, 916f, 920 cover test, 1193–1195 alternate, 1194 amblyopia, 1207 young children, 1207 cranial fracture (skull), 989 cranial nerves diabetic disease, 545 supplying extraocular muscles see ocular motor nerves craniofacial malformations, 290 craniopharyngiomas, 902–903, 907–908 CRB1 gene mutation and Coats’ disease, 560 critical phase of visual loss in primary open-angle glaucoma, 1054 crocodile shagreen, 271–272 Crohn’s disease and HLA-B27-associated uveitis, 749 cross-fixation and congenital esotropia, 1207 cross-sectional studies of glaucoma therapy, 1175 crossing-over in genetic recombination, 3f Crouzon syndrome, 290t crow’s-feet (orbicularis rhytids) botulinum toxin, 1365 filler, 1361f CRUISE study, central retinal vein occlusion, 530 crus cerebri syndromes, 924t, 999 cryotherapy choroidal or ciliary body melanoma, 808 ciliary body (in glaucoma) see cyclocryotherapy Coats’ disease, 563 cornea and conjunctiva tumors epithelial, 197 lymphoid, 201 eyelid basal cell carcinoma, 1308 retinal breaks (=cryopexy), 644–645 retinal neovascularization, 574

cystoid macular edema (CME) (Continued) branch, 533, 625 central, 530, 626 scleral buckling complicated by, 469 uveitis complicated by, 626–627, 630, 699 birdshot chorioretinopathy, 779 intermediate uveitis, 775 juvenile idiopathic arthritis-related, 751 cystoid vitreomacular traction, 622 cytochrome P450 CYP1B1 gene and congenital glaucoma, 1101, 1170 cytoid body branch retinal artery obstruction, 523 ocular ischemic syndrome, 553–554 cytokines (inflammatory) glaucomatous optic neuropathy and, 1017 uveitis and, 691 cytomegalovirus (CMV), 704–708 Posner–Schlossman syndrome and, 773 retinitis (CMVR), 704–706 clinical presentation, 704–706 diagnosis, 706 differential diagnosis, 701, 706 in HAART era, 706 treatment, 478 cytotoxic agents, uveitis in Behçet’s disease, 760 cytotoxic (antibody-mediated/type II) hypersensitivity, 692

D

dacryoadenopathy in sarcoidosis, 754–755 dacryocystitis, 1349 dacryocystography, 1347 dacryocystorhinostomy, 1350 endonasal, 1350 daily wear contact lenses, complications with, 280 dark (dim light), pupillary inequality increasing in, 960–963 dark adaptation, 45 in choroideremia, 503 in retinal inherited degenerations, 481f, 482 with spectacles/sunglasses, improving, 30 Daroff ’s rules, nuclear IIIrd cranial nerve palsies, 923 de Morsier syndrome, 871 dead zone, bifocals, 50–51 debridement with partial stem cell failure, 321 decentration IOLs, 401–402 PC phakic, 140 with lasers, 169f LASIK, 114 phototherapeutic keratectomy, 310 decision-making, clinical, 1179 decompression optic nerve sheath, 887 orbital, 1336 in dysthyroid optic neuropathy, 895, 948 deep anterior lamellar keratoplasty (DALK), 303, 383–384 keratoconus, 254 lattice dystrophy type I, 260 defensive mechanisms and cataract formations, 414 deferioxamine retinotoxicity, 685 defocus, 77 delayed hypersensitivity, 692 deletion mutations, 4 dementias, 981 see also Alzheimer’s disease Demodex and blepharitis, 178–179 demographic risk factors, glaucoma angle-closure, 1060 primary, 1004 open-angle, primary, 1001–1002 DENALI study, 596–597 dendritic ulcer, 234 deposition keratopathy, 164 depth perception, 1201–1202 dermatoconjunctivitis, allergic, 194 dermatological (cutaneous; skin) conditions in Behçet’s disease, 759 cataracts associated with, 416 in sarcoidosis, 756 in tuberous sclerosis, 846 in Vogt–Koyanagi–Harada disease, 762

dermato-ocular conditions (skin and ocular combined abnormalities), 294t inherited, 294t Mooren’s ulcer, 245 dermoids (dermoid cyst) corneal or conjunctival, 174–175, 201 eyelid, 1297 orbital, 1329 dermolipoma, conjunctival, 201 Descemet’s membrane, 164–165 circumferential breaks, 1023–1024 detachment complicating cataract surgery, 395 in Fuchs’ dystrophy, 264–266 treatment targeting, 264 in keratoconus, 252–255 Descemet’s (membrane) endothelial keratoplasty (DMEK), 303, 316–318 hybrid technique (DMEK-S), 316, 318 outcomes/complications, 318–319 technique, 317–318 in triple procedure, 305 Descemet’s (membrane) stripping automated endothelial keratoplasty (DSEK/DSAEK), 303, 316–317 congenital hereditary endothelial dystrophy, 266 Fuchs’ dystrophy, 266 lens surgery combined with, 383 outcomes/complications, 318–319 technique, 317 in triple procedure, 305 development anomalies see congenital anomalies embryological see embryo vitreous, 433 Devic’s disease see neuromyelitis optica dexmedetomidine, cataract surgery, 359 Diabetes Control and Complications Trial (DCCT), 541 diabetes mellitus, 541–550 cataracts and, 412, 415 surgery, 356 type 1 diabetes, 415 type 2 diabetes, 415 endophthalmitis and, 723 glaucoma and, 545, 1003 papillopathy, 877, 887–888 papillophlebitis, 985 retinopathy, 541–550, 571 cystoid macular edema, 489, 625, 629–630 neovascularization, 550, 571 ocular ischemic syndrome vs., 553 proliferative see proliferative retinopathies vitrectomy, 472, 548–550 vitreopathy, 435 Diabetic Retinopathy Study, 547–548, 550 Diabetic Retinopathy Vitrectomy Study (DRVS), 549 diagnostic testing in glaucoma, evaluation, 1175–1176 diamond burr superficial keratectomy in anterior basement membrane dystrophy, 257 diamond excision medial, plus horizontal lid shortening, 1287 tarsoconjunctiva, 1286–1287 diamond knife in astigmatic or radial keratotomy, 143 diathermy, ciliary body destruction via, 1125 dichroic, 24 didanosine retinotoxicity, 685–686 dietary management, gyrate atrophy, 507 dietary supplementation with essential fatty acids, 278 see also nutrition diffraction, 24–25, 40 historical description, 23 photoreceptors and, 20 diffuse choroidal hemangioma, 825–829, 828b diffuse endotheliitis, HSV, 234–235 diffuse idiopathic orbital inflammation, 1327 diffuse lamellar keratitis in LASIK, 115 diffuse uveal melanocytic proliferation, bilateral, 792, 822–823 diffusion-weighted MRI, 853 digenic inheritance, 6 digital contact ultrasound, 438

Index

cryotherapy (Continued) retinal tumors capillary hemangioma, 837 retinoblastoma, 798 retinopathy of diabetes, 548 retinopathy of prematurity, 538 trial (CRYO-ROP), 535–539 sickle cell hemoglobinopathy, 558 cryptococcal endophthalmitis, 734 Crystalens, 88, 160 crystallin(s), 330 cataract formation and, 414 γ-crystallin pseudogene, 11 crystalline dystrophy, Schnyder, 262 crystalline keratopathy, infectious, 218–219 crystalline lens, optical properties, 39 culture (and culture media) bacterial keratitis, 221 endophthalmitis, 725 fungal keratitis, 226 HSV keratitis, 235 cutaneous conditions see entries under dermatoCutler–Beard bridge flap, 1315 cyanoacrylate, corneal perforations, 325 CyberKnife radiotherapy, choroidal/ciliary body melanoma, 807 cyclic esotropia, 1211 cyclitis see uveitis, anterior cyclocryotherapy, 1125–1126 children, 1106 complications, 1128t outcome, 1128 cyclodestructive procedures, 1112, 1125–1128 alternatives to, 1126 angle-closure glaucoma, 1069 children, 1106 cyclodialysis cleft, delayed closure, 1088 cyclophosphamide peripheral ulcerative keratitis, 240 scleritis, 216 cyclophotocoagulation children (=cyclophotocoagulation), 1106 endoscopic (ECP), 1125–1128, 1126t transcleral (TCP), 1125–1128, 1126t cycloplegic agents, 967, 967t in accommodative esotropia, 1210 in angle-closure glaucoma, 1063 in cataract surgery, preoperative, 351 in refraction testing, 46 in uveitis, 697, 1082 HLA-B27-related uveitis, 749–750 of idiopathic or syndromic causation, 772 cyclosporine (ciclosporin) Behçet’s disease, 760 peripheral ulcerative keratitis, 240 scleritis, 216 cyclotropia in fourth nerve palsy, 1229 cyclovertical extraocular muscles major actions, 1183f third nerve lesions and, 1228–1229, 1229t cylindroma, 1298–1299 CyPass Micro-Stent, 1143–1144 cyst dermoid see dermoids epidermal inclusion, 1297 epidermoid, 1297 epithelial anterior chamber, 1097 conjunctival, complicating strabismus surgery, 1254 pars plana, 639 pilar, 1297 see also microcysts cystadenoma, 1298 cystic blebs, post-trabeculectomy, 1154 cystic carcinoma, adenoid, 1320 cystic epithelioma, multiple benign, 1299 cysticercosis, 745–746 cystinosis, 291t, 292f, 294t cystoid macular edema (CME), 625–631 acetazolamide therapy, 489, 631 autosomal dominant, 499 cataract surgery complicated by (Irvine–Gass syndrome), 354–355, 402, 452, 627 in diabetes, 542–543, 625, 629–630 retinal vein occlusion complicated by

1375

Index

1376

digital fundus imaging, 441 retinopathy of prematurity, 539 dilator muscle of pupil, 687 dim light see dark diode laser cyclophotocoagulation, 1125–1126 complications, 1127–1128 endoscopic, 1126–1127 outcome, 1128 dioptric media, 22 diplopia, 1197 brain trauma, 989 central, 1197, 1199 in Graves’ ophthalmopathy, 948 as laser iridectomy complication, 1124 monocular, cataracts, 337 orbital surgery complicated by, 1338 peripheral, 1197–1198 scleral buckling complicated by, 469 tests, 1195, 1225 in third nerve palsy, 1227 direct brow lift, 1357 direct gonioscopy, 1025 direct ophthalmoscope, 69 disciform keratitis, 234 DisCoVisc, 353–354 dispersion of light, 25–26 disposable contact lenses, 52–53 dissociated nystagmus, 952f, 955 dissociated vertical deviation/divergence (DVD), 920, 1207, 1207b, 1233–1234 differential diagnosis, 1233–1234 treatment, 1208, 1234 distance for visual acuity testing, 42–43 distortion, 78 divergence dissociated vertical see dissociated vertical deviation insufficiency, 921 divergence paralysis, 921 divide and conquer technique (nucleofractis phacoemulsification), 373 DNA, 1 in genetic disease testing, 15 HSV, testing for, 235 mitochondrial see mitochondrial DNA docosahexaenoic acid (DHA) dietary supplementation, 278 in retinal degenerations, administration, 489 dog bite wounds, 1312, 1315–1317 doll’s eye reflex, 917 dominance (ocular), development, 1241f dominant inheritance autosomal see autosomal dominant inheritance X-linked, 6 donor selection/preparation/insertion endothelial keratoplasty, 316–318 lamellar keratoplasty, 303–304 penetrating keratoplasty, 299–300 dopamine agonists, pituitary adenoma, 907 Doppler studies optic nerve blood flow, 1048 retinochoroidal blood flow, 428–429 central retinal artery obstruction, 520 ocular ischemic syndrome, 552 dorzolamide, 1116 double elevator deficiency or palsy, 920, 1234–1235 double helix (DNA), 1 double Maddox rod test, 929 double pass problem, 79 double-plate (dual-chamber) drainage implant, 1159–1161 downbeat nystagmus, 954–955, 957 downgaze A-pattern esotropia increasing to, from downgaze, 1223f abnormalities/palsies, 919–920 V-pattern esotropia increasing from upgaze to, 1222f V-pattern exotropia increasing from, to upgaze, 1222f Down’s syndrome (trisomy 21) cataract and, 416 head tilt-dependent esotropia associated with, 1212

Doyne honeycomb macular dystrophy (malattia leventinese), 491t–492t, 497, 499 drainage area under eyelid (in trabeculectomy), position, 1155 subretinal fluid see subretinal fluid drainage implants/devices (silicone tube shunts) in glaucoma, 1083, 1133, 1145, 1159–1163, 1168–1169 alternatives, 1160 angle-closure glaucoma, 1069 children, 1105–1106 complications, 1162, 1168–1169 historical review, 1159 in penetrating keratoplasty-related glaucoma, 1100 study (Tube Versus Trabulectomy – TVT), 1133, 1136, 1159–1160, 1162–1163, 1168–1169, 1178, 1178b suprachoroidal, 1142–1144 surgical technique, 1160–1162 drugs (medications; pharmacological agents) accommodative esotropia, 1210 adverse effects/toxicity/conditions caused by, 683–686 anterior uveitis, 773 antiglaucoma drugs, 1021–1022, 1023t, 1111, 1114–1118, 1118t central serous chorioretinopathy, 605, 608 contact lens wearers, 282 cystoid macular edema, 630 dry eye syndrome, 275t follicular conjunctivitis, 188–189 retinal toxicity, 683–686 specific agents, 683–686 visual pathways see visual pathway lesions allergic conjunctivitis, 193–194 giant papillary conjunctivitis, 195 amblyopia, 1242 arteritic anterior ischemic optic neuropathy, 887 blepharitis, 179 blepharospasm, 1293 in cataract prevention, 413 in cataract surgery, 351–355 cicatricial pemphigoid, 208 corneal thinning or melting from inflammatory disorders, 325 in diabetes treatment of retinopathy, 546–547 worsening of retinopathy, 542 dry eye syndrome, 278 episcleritis, 209–210 giant-cell arteritis, 986–987 in glaucoma (incl. IOP-lowering agents), 1058, 1082, 1111, 1113–1119 adverse effects, 1021–1022, 1023t, 1111, 1114–1118, 1118t in alkali burns, 1100 angle-closure glaucoma, 1063 malignant glaucoma, 1093 in massive choroidal hemorrhage, 1085 normal-tension glaucoma, 1058 ocular blood flow-improving agents, 1049 episcleral venous pressure elevation-related glaucoma, 1091 pseudoexfoliation glaucoma, 1071 trials, 1177–1178 Graves’ ophthalmopathy, 948 HLA-B27-related anterior uveitis, 749–750 juvenile idiopathic arthritis and, 751 in Horner’s syndrome diagnosis, 962 idiopathic juxtafoveal retinal telangiectasia, 562–563 inflammatory myopathies, 949 intravitreal implants containing, 478 keratitis bacterial, 222–223 fungal, 226–227 HSV, 235–236 peripheral ulcerative, 240–241, 243, 250 Lambert–Eaton myasthenic syndrome, 942 migraine, 971–972 myasthenia gravis, 939–940 nystagmus, 957 papilledema, 877 pituitary adenoma, 907

drugs (medications; pharmacological agents) (Continued) pseudophakic cystoid macular edema, 630 refractive surgery contraindicated with, 92b retinal degenerations, 488–489 retinal vein occlusion branch, 533 central, 530 scleritis, 213–216 sickle cell hemoglobinopathy, 558 uveitis, 697–699, 1081–1082 Behçet’s disease, 760 birdshot chorioretinopathy, 779 HLA-B27-related see subheading above of idiopathic or syndromic causation, 772 intermediate, 775 progressive subretinal fibrosis and uveitis syndrome, 778 relentless placoid chorioretinitis, 782 sarcoidosis, 756–757 serpiginous choroiditis, 781 sympathetic, 768 Vogt–Koyanagi–Harada disease, 763 see also pharmacology and specific (types of) drugs drusen age-related macular degeneration and, 580–582 familial, 497–498 optic nerve head, optical coherence tomography, 456 dry age-related macular degeneration differential diagnosis, 587b epidemiology, 580 ocular manifestations, 581–582 treatment and prevention, 589 dry eye (xerophthalmia/dry eye disease/DED), 274–279 blepharitis in, 177, 179 diagnosis and ancillary testing, 277 epidemiology, 274 ocular manifestations, 276 pathogenesis, 274–276 post-refractive surgery photorefractive keratectomy, 101 LASEK and epiLASIK, 104 treatment, 274 see also specific (types of) drugs dual-chamber (double-plate) drainage implant, 1159–1161 dual optic IOL, Synchrony, 88, 160 Duane’s (retraction) syndrome, 929, 935, 1186, 1211–1212 ductions, 1195, 1195t forced duction test, 1196 see also abduction; adduction duochrome test, 49 dural shunts, 993–995 arteriovenous, 932, 936, 994 glaucoma with raised episcleral venous pressure and, 1091 dynamic contour tonometry, 1021t dyslexia, 912 dyslipoproteinemias, 291, 293t dysplastic nevus syndrome, 1310 Dysport, 1363 dystonia, 980 dystrophia myotonica (myotonic dystrophy), 415 dystrophic myopathies, 943–945

E

E (equatorial lens bow) cells in secondary cataract pathogenesis, 407–411 Eales’ disease, 572 Early Manifest Glaucoma Trial, 1008, 1031, 1108, 1173, 1177–1178 Early Treatment Diabetic Retinopathy Study (ETDRS), 541, 544, 546–548 Early Treatment for Retinopathy of Prematurity (ETROP) study, 537 Eaton–Lambert (Lambert–Eaton) myasthenic syndrome, 937t, 940t, 941–942 EBV (Epstein-Barr virus), 701–702 eccentric factor see asphericity factor eccrine lesions of eyelids, benign, 1298 echo time (TE) time in MRI, 852 echography see ultrasound imaging

encephalocele, trans-sphenoidal, 871–872 encephalopathy, mitochondrial, with lactic acidosis and stroke-like episodes, 943–945, 944f encircling buckles, 468 endocapsular hematoma, 401 endocapsular (in-the-bag) IOL fixation, 393, 408 endonasal dacryocystorhinostomy, 1350 endophthalmitis (as complication), 723–728 antimetabolite-related, 1157 endogenous, 723t, 725 exogenous, 723–725, 723t fungal, 733–737 phacogenic glaucoma vs., 764–765 risk factors, 723–725 cataract surgery, 354, 402, 723–724 intravitreal injections, 478, 724–725 penetrating injury, 675–676 penetrating keratoplasty, 301, 724 toxocariasis, 744 endoresection of choroidal or ciliary body melanoma, 808–809 endoscopy brow lift via, 1357 cyclophotocoagulation via (ECP), 1125–1128, 1126t nasolacrimal dacryocystorhinostomy via, 1350 diagnostic, 1348 trabeculostomy via erbium:YAG laser, 1135 excimer laser, 1134 laser-assisted, 1134 see also minimally-invasive glaucoma surgery endotheliitis CMV, 707–708 HSV, 234–235 endothelium, corneal, 164–165, 264–268 anatomy/embryology/physiology, 164–165 cataract surgery with compromisation of, 389 complications/damage with AC angle-supported phakic IOLs, 134 with AC iris-supported phakic IOLs, 138 with PC phakic IOLs, 140 definition, 264 dystrophies, 264–268 Fuchs’ see Fuchs’ corneal dystrophy glaucoma patients abnormalities, 1095 examination, 1024 HSV keratitis involving, 234–235 injury responses (healing), 167 keratoplasty involving removal add replacement with donor tissue, 315–319 Melles modifications see Descemet’s (membrane) endothelial keratoplasty; Descemet’s (membrane) stripping automated endothelial keratoplasty key and associated features, 264b microscopy, 62–64 rejection in penetrating keratoplasty, 302 stress responses, 165–166 see also iridocorneal endothelial syndrome endovascular surgery, intracranial aneurysm, 987 enophthalmos, 1279 enthesitis-related arthritis, 750 entropion, 1278–1283 enucleation, 1339–1341 anesthesia, 1339 choroidal/ciliary body melanoma, 806–807 complications, 1344 conjunctiva/corneal tumors epithelial, 197 melanocytic, 200 corneal/conjunctival epithelial tumors, 197 indications, 1339 iris melanoma, 803 retinal astrocytoma, 834–835 retinoblastoma, 796 technique, 1339–1341 environmental risk factors in age-related macular degeneration, 581 enzyme-linked immunosorbent assay (ELISA), toxocariasis, 744 eosinophilic granuloma, 1326–1327 ephelides, 1302 epiblepharon vs. entropion, 1279

epibulbar injection of anesthetic agent in strabismus surgery, 1247–1248 epidemic keratoconjunctivitis, 184 epidermal inclusion cyst, 1297 epidermoid cyst, 1297 epidermolysis bullosa, 188–189 epikeratophakia/epikeratoplasty, 84 epiLASIK, 85, 102–106 advantages, 102 complications, 104 early, 104 late, 104 indications, 102 LASIK vs., 106, 111 outcomes, 105–106 postoperative management, 104 preoperative evaluation, 102 technique, 104 epinephrine, peribulbar block, 358 epiphora, 1346–1348 epiretinal membrane (ERM; macular pucker), 435 dissection, 473 optical coherence tomography, 450, 617–618 proliferative vitreoretinopathy and, 666 retinal breaks and, 645 scleral buckling complicated by, 469, 652 vitreomacular traction syndrome vs., 621 episclera in glaucoma examination, 1022 venous outflow obstruction, 1081 venous pressure elevation, 1081, 1090–1091 episcleral plate (of drainage implant), 1159 episcleritis, 209–210 epithelial cell (lens), 413 cataract (primary) occurrence, 413 residual, in secondary cataract pathogenesis, 402–403, 407–411 E cells, 407–411 preventive strategies, 410–411 surgery, 348, 349b epithelial keratitis, 234 treatment, 236 trial, 236 epithelial tumors eyelid benign, 1295–1297 malignant (=carcinoma) eyelid, 1306–1310 lacrimal gland, 1319–1320 epithelioid nevus cells, 823 epithelioma, multiple benign cystic, 1299 epithelium anterior chamber see anterior chamber antimetabolite-related erosions, 1157 ciliary (pigmented/PE and non-pigmented/NPE), and aqueous inflow, 1013–1016 conjunctival cysts, complicating strabismus surgery, 1254 tumors, 196–198 corneal, 163–164 anatomy/embryology/physiology, 163–164 basement membrane see basement membrane contact lens-related lesions, 285–286 epiLASIK, problems, 104 incisional keratotomy, wound healing, 141 ingrowth/downgrowth after surgery, 115, 400 injury responses (healing), 166 LASEK, problems, 104 LASIK, problems, 114–115 penetrating keratoplasty, persistent defect, 301 photorefractive keratectomy, problems, 100 in photorefractive keratectomy, removal, 97 as phototherapeutic keratectomy, delayed healing (epithelialization), 310 punctate erosion see punctate epithelial erosion tumors, 196–198 neural, 419 retinal pigment see pigment epitheliopathy; pigmented epithelium Epstein-Barr virus (EBV), 701–702 equatorial lens bow (E) cells in secondary cataract pathogenesis, 407–411 equipment see instrumentation and equipment erbium:YAG laser-assisted presbyopia reversal, 160–161 erbium:YAG laser trabeculostomy, 1135

Index

eclipse retinopathy, 463 ectopia lentis, 418 ectrodactyly–ectodermal dysplasia–clefting, 294t ectropion, 1284–1291 blepharoplasty complicated by, 1356 eczema, atopic, and cataracts, 416 edema Berlin’s, 671 corneal cataract surgery-related, 400 contact lens-related, 55, 286 macular in branch retinal vein occlusion, 533, 533b in central retinal vein occlusion, 529–530 cystoid see cystoid macular edema diabetic (DME), 542–543, 546–548, 629–630 optical coherence tomography, 452 optic disc see papilledema Edinger–Westphal nucleus/subnucleus, 961, 964– 965, 967, 1261 education cataract occurrence and levels of, 413 patient cataract surgery, 334 glaucoma therapy, 1114 see also counseling EFEMP1 mutations, 497, 499 effective lens position (ELP) with IOLs, 337–338 anterior capsulectomy and, 376 efferent pupillary defects, 960–964 efferent visual system, 915–921 Ehlers–Danlos syndrome type VI, 254–255, 291t eicosapentaenoic acid (EPA), dietary supplementation, 278 elderly see older people electrical activity of retinal pigmented epithelium, 424 electrocardiogram, mitochondrial disorders, 944 electromagnetic spectrum, 20f electromagnetic waves, 23 electromyogram, gyrate atrophy, 506 electronic IOLs, 89 electro-oculogram, inherited retinal degenerations, 483 electro-oculogram, 458, 460, 1192 electrophysiological tests neuromuscular Lambert-Eaton myasthenic syndrome, 942 myasthenia gravis, 939 retina, 458–460 historical review, 458 inherited retinal degenerations, 482–483 electroretinogram (ERG), 458–460 choroidal inherited dystrophies choroideremia, 503 gyrate atrophy, 506 diseases with selective loss of B-wave amplitude, 511b epiretinal membrane, 614–615 glaucoma screening, 1010 multifocal see multifocal electroretinogram ocular ischemic syndrome, 552 radiation retinopathy, 566 retinal inherited degenerations, 482 retinitis pigmentosa, 459 X-linked juvenile retinoschisis, 510 ELENZA Sapphire AutoFocal IOL, 89 elevator deficiency/palsy, monocular congenital, 920 long-standing, 920 supranuclear/prenuclear, 920 ELISA, toxocariasis, 744 Elschnig’s spots, 515–516 embolism fat, 681 retinal, 522, 996 talc, 573 embryology extraocular muscles, 1181 vitreous, 433 embryonal rhabdomyosarcoma, 1322f embryotoxon anterior, 174 posterior see Schwalbe’s line emergencies, neuro-ophthalmological, 983–987 EMLA with skin fillers, 1360

1377

Index

1378

Erdheim–Chester disease, 1302 erythema multiforme major, 189–190 erythrocyte (red blood cell) lysis leading glaucoma (ghost cell glaucoma), 1087–1088, 1094 Escherichia coli keratitis, 220 esotropia, 1198f, 1206–1213 A-pattern, 1221, 1223 accommodative, 1209–1211 congenital, 1206–1209 cover test, 1194f in cranial VIth nerve palsy, 934, 1230 cyclic, 1211 head tilt-dependent, in trisomy 21, 1212 high myopia-related, 1213 in neurological impairment, 1212 retinal correspondence and anomalous, 1198f normal, 1198f V-pattern, 1209, 1221 visual deficit-associated, 1212 essential blepharospasm, 1292–1294 essential fatty acids, dietary supplementation, 278 etanercept in sarcoidosis-related uveitis, 757 ethnicity see race ETROP (Early Treatment for Retinopathy of Prematurity) study, 537 European Glaucoma Prevention Study, 1021, 1051, 1107–1108 evaporative dry eye, 275–276, 278 evidence-based medicine in glaucoma, 1173–1179 evisceration, 1341–1342 anesthesia, 1339 complications, 1343–1344 indications, 1339 technique, 1341–1342 ex vivo expanded limbal stem cells, 322–323 examination, physical/ophthalmic for blepharoplasty, 1353–1354 for cataract surgery, 334–335 optic nerve vs. macular disorders, 869 epiphora, 1346–1347 eye movements/ocular motor system, 917–918 eyelid retraction, 1268 eyelid trauma, 1312 glaucoma, 1019–1028, 1041, 1051 angle-closure, 1063–1065 for refractive surgery, 92–93 uveitic eye, 695 examination under anesthesia in glaucoma, 1130 children, 1105 excimer laser, 27, 95 endoscopic trabeculostomy, 1134 history and fundamentals, 95 phototherapeutic keratectomy see phototherapeutic keratectomy refractive surgery, 81–83 epiLASIK and LASEK see epiLASIK; LASEK LASIK see LASIK photorefractive keratectomy see photorefractive keratectomy in presbyopia, 151–153 excisional biopsy, basal cell carcinoma, 1308 excitotoxicity and glaucomatous optic neuropathy, 1017 excretory tests in epiphora, 1347 excyclotorsion, double Maddox rod test, 929 exenteration, 1342–1343 anesthesia, 1339 choroidal/ciliary body melanoma, 809 complications, 1344–1345 conjunctiva/corneal tumors epithelial, 197 melanocytic, 200 indications, 1339 technique, 1342–1343 exophoria, cover test, 1194f exophthalmos carotid–cavernous sinus fistula, 994–995 Graves’ disease, 946–948 exotropia, 1198f, 1214–1216 A-pattern, 1223 cover test, 1194f V-pattern, 1222–1223 expansion bands, ciliary, in presbyopia, 160

exposure of ocular surface, excessive, 276 keratitis/keratopathy following entropion surgery, 1283 following ptosis surgery, 1277 Ex-Press, 1142 extended wear contact lenses, complications with, 280 external examination, glaucoma, 1021–1022 angle-closure, 1063 extra-areal periphery of retina, 421 extracapsular (partial) cataract extraction (ECCE), 347, 379–381 history, 331, 378 extracellular matrix metalloproteinases see metalloproteinases; tissue inhibitor of metalloproteinase in proliferative vitreoretinopathy, 667 extraocular muscles, 1181–1187 anatomy, 1181–1184, 1260 motor supply see ocular motor nerves; ocular motor system congenital fibrosis, 13, 1236 cyclovertical, major actions, 1183f embryology, 1181 esotropia relating to globe prolapse from cone of, 1213 lost or slipped, in strabismus surgery, 1254 paralysis see ophthalmoplegia physiology, 1186 surgery see surgery toxicity of local anesthetic in peribulbar block, 358 see also movement and specific muscles exudates, retinal, 452 macular, optic disc abnormalities associated with, 636 retinal detachment associated with, 649–651 exudative vitreoretinopathy, familial, 509, 511– 512, 573 eyeball (globe) perforation or penetration in peribulbar block, 358 eyebrow fat pads, 1353 eyelids, 1268–1271 age-related changes, 1352–1353 anatomy, 1255–1257, 1352–1353 apraxia, 1293t area under (in trabeculectomy), position, 1155 crease abnormalities following ptosis surgery, 1277 ectropion see ectropion entropion, 1278–1283 in epiphora, examination, 1346–1347 hemangioma see hemangioma infections, 1304–1305 laxity see laxity lesions and masses (in general), 1285 benign, 1295–1305 malignant see malignant tumors orbital surgery complications affecting, 1338 ptosis see blepharoptosis retraction, 1268–1271 complicating blepharoplasty, 1356 complicating entropion surgery, 1283 trauma, and reconstruction, 1312–1317 see also entries under blephar-

F

f-number, 21 Fabry’s disease, 164, 293t–294t cataracts, 415 face age-related changes, 1352–1353 movement disorders, 1293t pain, 969–975 differential diagnosis, 974–975 International Headache Society classification, 970 facial nerve branches supplying eyelids, 1256 famciclovir, herpes zoster, 182 postherpetic neuralgia, 182 familial amyloid polyneuropathy type IV (lattice dystrophy type II), 260 familial amyloidosis cornea, subepithelial, 260 pseudoexfoliation glaucoma vs., 1071

familial colonic adenomatous polyposis–carcinoma syndrome and retinal pigment epithelium hypertrophy, 842–843 familial drusen, 497–498 familial exudative vitreoretinopathy, 509, 511–512, 573 familial retinal degeneration, 480 family history of age-related macular degeneration, 581 genetic counseling and, 16 glaucoma, 1019 primary angle-closure, 1004 primary open-angle, 1002 far point, retinoscope, 65 fascia (orbital), 1259–1260 lower eyelid see capsulopalpebral fascia orbicularis oculi, in eyelid repair, 1315 fascicular disorders (ocular motor nerve), 922–926 fast eye movements see saccades fast-moving objects, 45 fat cushions/pad/pockets, 1184 in blepharoplasty, 1355 eyebrow/subgleal, 1353 preaponeurotic, 1256 fat embolism syndrome, 681 fat suppression MRI, 852 fatty acids, essential, dietary supplementation, 278 female carriers of X-linked retinal degenerations, 488, 503 femtosecond laser astigmatic keratotomy, 143 cataract surgery, 348, 375–377 in zonular instability, 386 with intrastromal corneal ring segments, channeling, 148 in intrastromal correction of presbyopia, 153–155 LASIK, 86, 111–112, 118 femtosecond laser-assisted lamellar keratoplasty (FALK), 304, 305f fentanyl, cataract surgery, 359 Ferrara, 147 fibrin glue corneal perforations, 326 post-pterygium excision, 314 fibroepithelial polyp, 1295 fibroepithelioma basal cell carcinoma, 1307 fibrosis agents preventing see antifibrotic agents congenital (of extraocular muscles), 13, 1236 progressive subretinal, and uveitis, 784 fibrous downgrowth and epithelial downgrowth, anterior chamber, 1096–1097 fibrous histiocytoma, 1320–1321 field of view fundus camera, 71 ophthalmoscope binocular indirect, 69 filamentous bacteria causing keratitis, 219–220 filarial parasites see loiasis; onchocerciasis filtration bleb (filtering bleb), 1022 cataract surgery complicated by, 399–400 surgical creation in glaucoma see trabeculectomy filtration surgery, 1112 bleb-forming see trabeculectomy complications, 1156 nonbleb-forming, 1146 trabeculectomy compared with, 1147t risk factors for scarring risk after, 1153t, 1173 studies and trials, 1175, 1177b, 1178 fine-needle aspiration biopsy see biopsies Fine technique (phacoemulsification), 373 secondary cataract, 408 fingolimod retinotoxicity, 685 Finnish type familial amyloid polyneuropathy (lattice dystrophy type II), 260 fish eye disease, 293t fixation examination/assessment, 917 preverbal/preliterate children, 1188 instabilities see nystagmus see also cross-fixation; monofixation syndrome FLAIR (fluid-attenuated inversion recovery), 852

focus length of (focal length), resolution and, 40 see also defocus FOCUS trial, 592, 596–597 focusing, automated refractometer, 67 follicular conjunctivitis, 184 HSV, 232 toxic, 188–189 follicular keratosis, inverted, 1296 forced-choice preferential looking, preverbal/ preliterate children, 1189–1190, 1191t forced downgaze see tonic downward deviation of gaze forced duction test, 1196 forced upgaze see tonic upward deviation of gaze foreign bodies, intraocular (IOFB) examination, 670 imaging, 670–671 retained, 1088 treatment, 675 fornix-based conjunctival flap drainage implant surgery, 1160 trabeculectomy, 1150 four-diopter prism test, 913 four-dot test, Worth, 1202–1203, 1205t Fourier transformation, 43–44 fovea, 420–421 alignment of foveal images, 1197f choroidal neovascularization in relation to, 731–732 foveal pit, 39–40 see also vitreofoveal traction syndrome foveola, 420–421 foveomacular dystrophy, adult-onset, 494–495 FOXC1 gene, 10, 1171 fractures orbit, 1336–1337 floor, 1236, 1336–1337 medial wall, 1337 rim, 1333 skull, 989 François’ central cloudy dystrophy, 262 François–Neeton’s dystrophy, 263 freckles, 1302 Hutchinson’s melanotic (=lentigo maligna melanoma), 1310–1311 free radicals (incl. reactive oxygen species/ROS), 30 damaging effects, 30 glaucomatous optic neuropathy and, 1017 lens, 330 UV-related generation, 30 see also oxidative stress/damage frequency-doubling technology (FDT) in glaucoma, 1036 for screening, 1009–1010 Fresnel membrane prisms, 1245 Friedreich’s ataxia, 861, 980 frizzled-4 and familial exudative vitreoretinopathy, 511 frontal nerve, 1261 frontalis muscle, 1353 botulinum toxin treatment and, 1363–1365 suspension, 1275–1276 Fuchs’ corneal dystrophy, 14t, 264–266 cataract surgery, 389 Fuchs’ heterochromic iridocyclitis (Fuchs’ uveitis syndrome), 772–773, 1083 Fukuhara’s syndrome (MERRF; myoclonic epilepsy with ragged red fibers), 943–946 full-thickness lid injuries, 1314–1315 full-thickness wedge resection/excision, horizontal eyelid shortening wedge by, 1287 functional imaging, 855–856 functional status assessment of glaucoma patient, 1019 functional visual loss, 912–914 fundoscopy see ophthalmoscope fundus anatomy, 638 autofluorescence see autofluorescence camera, 70–71 in choroidal dystrophies, 502–503 in congenital stationary night blindness, normal appearance, 486 digital imaging see digital fundus imaging

fundus (Continued) dilated examination (funduscopy), pre-refractive surgery, 93 in gyrate atrophy, 506 in optic nerve vs. macular disorders, 869 red reflex, 64, 70 special lenses in slit lamp microscopy, 58–59 toxoplasmosis, 740f–741f fundus albipunctatus, 486–487 fundus falvimaculatis, 491 fungal (mycotic) infections conjunctivitis, 188 keratitis, 225–227, 230–231 contact lens-related, 288–289 uveitis, 729–732 furrow (corneal), limbal/marginal, 249 Fusarium endophthalmitis, 734 keratitis, 225 contact lenses and, 288 Fused Cross-Cylinder test, 50 fusional vergence, 1195–1196 FZDD4 and familial exudative vitreoretinopathy, 511

Index

flap conjunctival, 312–313 drainage implant surgery, 1160 history, 312 in HSV keratitis, 236 in trabeculectomy, 1148, 1150, 1155 corneal, in LASIK complications, 113–115, 118 creation, 111–112, 118 eyelid for ectropion, 1288–1289 for trauma repair, 1314–1315 scleral, in trabeculectomy, 1148, 1150 Fleck dystrophy, 263 flicker, 45 floppy-iris syndrome, 379 floury cornea (cornea farinata), 272 flow-based phacoemulsification, 362 flucytosine in keratitis, 227 fluid-attenuated inversion recovery (MRI), 852 fluid flow/transport (posterior eye), 653 in aqueous humor formation, 1014–1015 choroid see choroid retinal pigment epithelium, 423–424 sclera, outflow deficits leading to serous retinal detachment, 655–656 fluidics, phacoemulsification, 362–363 FluidVision intraocular lens, 88 fluocinolone acetonide, diabetic retinopathy, 547 fluorescein angiography, 71, 440–444 age-related macular degeneration, 584–585 anterior ischemic optic neuropathy (ION) arteritic, 884 non-arteritic, 884 Behçet’s disease-associated uveitis, 758 central serous chorioretinopathy, 606–607 choroidal/ciliary body melanoma, 804–805 choroidal hemangioma, 826 choroideremia, 504 complications, 441–442 cystoid macular edema, 629 epiretinal membrane, 617 histoplasmosis, 730 interpretation of results, 442–444 macular hole, 611 metastases, 811 normal angiogram, 442–443 ocular ischemic syndrome, 552 optic nerve, 1048 procedure, 441 properties of dye, 440 purpose of using, 440 radiation retinopathy, 565–566 retinal arterial macroaneurysms, 576 retinal inherited degenerations, 482 retinal serous detachment, 658 retinal telangiectasia and Coats’ disease, 561 retinal tumors astrocytoma, 833–834 capillary hemangioma, 837 cavernous hemangioma, 838 retinal vein occlusion branch, 532–533 central, 529 retinopathy of diabetes, 545 scleritis, 212 serpiginous choroiditis, 781 vs. tuberculous uveitis, 717–718 fluorescein staining in excretory tests (Jones), 1347 dry eye syndrome, 277 tear film, 61, 62f fluorescence, 26 fluorescent antibody testing, HSV, 235 fluoroquinolones, keratitis, 222 5-fluorouracil injection in glaucoma surgery in high risk of scarring, 1153 improvements, 1156b in intermediate/low risk of scarring, 1153–1154 postoperative, 1156 studies, 1177b, 1178 flutter, ocular, 956 focal laser, macular edema in diabetic retinopathy, 548

G

gadolinium-enhanced MRI, 853 angiography, 854 optic nerve sheath meningioma, 896 gain-of-function dominant negative effect, 7 galactosemia, cataracts, 415 pediatric surgery, 390 Galilean telescope, 72 gallium-67 scan, sarcoidosis, 755 game therapy in amblyopia, 1242 gamma knife radiotherapy, choroidal/ciliary body melanoma, 807 ganciclovir, cytomegalovirus retinitis, 706 intravitreal implants, 478 ganglion cells, retinal (RGCs), 45, 420–422, 866–867 apoptosis, 867 axons see axons glaucomatous optic neuropathy and, 454, 1016–1017 melanopsin, 867, 965–966 gangliosidosis II, 293t gap junctions and aqueous humor secretion, 1014 Gardener’s syndrome and retinal pigment epithelium hypertrophy, 843 gas bubbles in anterior chamber in LASIK, 114 gas lasers see lasers gas tamponade, 474 Gaucher’s disease, 294t gaze-evoked nystagmus, 952f, 953–954 gaze palsies acquired, 918 congenital, 918 see also downgaze; side-gaze; upgaze gel injection adjustable keratoplasty, 148 gelatinous drop-like dystrophy, 260 gender (sex), glaucoma and primary angle-closure, 1004 primary open-angle, 1002 gene(s) expression profiling, uveal melanoma, 805–806 phenotypes and, 4 gene therapy, 7–8 inherited retinal degenerations, 489 Stargardt’s disease, 494 general anesthesia cataract surgery, 360 conjunctival surgery, 312–313 strabismus surgery, 1247 vitrectomy, 471 genetic counseling, 16–17 indications for referral, 17 X-linked juvenile retinoschisis, 511 genetic disease, 9–14 choroid see choroid, degenerations/dystrophies complex, 14 corneal and external eye manifestations, 290–295 macula see macula, degenerations molecular mechanisms, 7, 9–14 retinal see retina

1379

Index

1380

genetic disease (Continued) risk prediction based inheritance, 16–17 vitreoretinopathies, 508–513 genetic factors age-related macular degeneration, 581 cataracts, 412 Coats’ disease, 560 glaucoma, 1170–1172 angle-closure, 1004, 1171 congenital, 1101, 1170 normal-tension/low-tension, 14t, 1171 open-angle, 10, 14t, 1004, 1013, 1171 pseudoexfoliation, 1070, 1171 histoplasmosis, 729 optic neuropathies see optic neuropathies retinal neovascularization, 570, 572–574 retinopathy of prematurity, 535 sarcoidosis, 753 uveitis, 692 genetic testing, 15–16 current recommendations, 16 inherited retinal degenerations, 483 reports, 16 genetics, 1–8 fundamentals, 1–8 Mendelian, 2–3 molecular see molecular genetics see also inheritance geniculate nuclei/bodies, lateral, 909 lesions, diagnostic features, 910 genome (human), 1–2 gentamicin, keratitis, 222 geographic atrophy in age-related macular degeneration, 582 geographic ulcer, 234 geographical helicoid peripapillary choroidopathy see serpiginous choroiditis germinal retinoblastoma, 793, 795–796, 799 ghost cell (hemolytic) glaucoma, 1087–1088, 1094 giant-cell arteritis see temporal arteritis giant papillary conjunctivitis, 194–195 contact lenses and, 56, 283 glabellar furrows, botulinum toxin, 1364 glare, 27 with cataract, 337, 405, 417 effects of surgery, 404 with IOLs AC angle-supported phakic IOLs, 133 AC iris-supported phakic IOLs, 137 PC phakic IOLs, 138–139 with spectacles/sunglasses, reducing sensitivity, 30 glasses see spectacles; sunglasses glatiramer acetate, optic neuritis in multiple sclerosis, 882 glaucoma, 454–456, 1001–1006 angle-closure see angle-closure glaucoma cataract surgery-related, 1072 pediatric, 1102, 1105 clinical examination, 1019–1028, 1041, 1051 congenital see congenital glaucoma diabetes and, 545, 1003 diagnostic testing, evaluation, 1175–1176 endothelial cell loss in, 165–166 epidemiology (incl. incidence and prevalence), 1001–1006, 1054, 1107f episcleral venous pressure elevation-related, 1081, 1090–1091 in Fuchs’ heterochromic iridocyclitis, 772–773, 1083 genetic factors see genetic factors as iris-supported phakic IOL complication, 138 juvenile, 10, 1171 juvenile idiopathic arthritis and, 751 lens-induced/phacolytic, 764–765, 1088 as surgical indicator, 344 malignant (=aqueous misdirection syndrome), 1061, 1063, 1092–1093 mechanisms/pathogenesis, 1012–1018 neovascular, 530, 1076–1079 normal-tension/low-tension see normal-tension glaucoma open-angle see open-angle glaucoma optic nerve in see optic nerve optical coherence tomography, 454–456 pigmentary, 1073–1075

glaucoma (Continued) progression and its assessment, 1031–1034, 1037–1038 in normal-tension glaucoma, 1058 pseudoexfoliation see pseudoexfoliation syndrome refractive surgery contraindicated in, 92 risk factors, 1107–1109 analysis, 1107 scleral buckling complicated by, 469 screening, 1007–1011 alternative tests, 1010 future directions, 1010–1011 historical review, 1007–1008 procedure, 1009–1010 purpose, 1008 risks associated with, 1010 utility and interpretation of results, 1008–1009 secondary, 1022t adnexal abnormalities and systemic findings, 1022t cataract surgery-related see subheading above children, 1101–1102 epidemiology, 1005 inflammatory causes, 1080–1083, 1319 normal-tension glaucoma vs., 1058 steroid-induced see steroids traumatic causes, 1019, 1084–1089 to tumors and corneal/iris/retinal abnormalities and, 1094–1100 vascular disease, 1049, 1090t severity assessment, 1030 subretinal fluid drainage complicated by, 469 suspect children, definition, 1105 in population studies, 1005 syphilis and, 710 treatment, 1107–1110 algorithms, 1112–1113 choice, 1111–1113 evidence-based, 1173–1179 goal, 1111 historical review, 1111, 1120, 1122, 1125, 1159 initiation, 1107–1110 medical see drugs principles of initiation, 1109–1110 second/retreatment, 1121–1123 surgical see surgery visual field testing see visual field Glaucoma Laser Trial (GLT), 1112, 1173–1174, 1177b, 1178 Glaucoma Laser Trial Follow-UP Study, 1177b Glaucoma Probability Score (GPS), 1041–1042 glaucomatocyclitic crisis (Posner–Schlossman syndrome), 773, 1083 GLC1A see myocilin GLC1G (WDR36) and glaucoma, 1013, 1171 GLC3A (CYP1B1) and congenital glaucoma, 1101, 1170 glia (retinal), 867 Müllerian, 419f, 420–422 gliomas, optic nerve (incl. pilocytic astrocytoma of childhood), 895–896, 903, 907, 1324 chiasmal/hypothalamic, 905, 907–908 compressive, 895–896 neurofibromatosis type I, 845, 895, 1324 treatment, 908, 1324 globe (eyeball) axial-displacing lesions, 1319b perforation see perforation prolapse from muscle cone, esotropia relating to, 1213 removal see enucleation; evisceration; exenteration glucose-6-phosphate (G6P) and the lens, 330 glues see adhesives glutamate excitotoxicity and glaucomatous optic neuropathy, 1017 glycoproteins, vitreous, 430, 432–433 GMS (SOLX Gold micro-shunt), 1142–1143 gnathostomiasis, 747 Goldenhar syndrome, 290t Goldmann applanation tonometer, 59–61, 1020, 1021t, 1053

Goldmann contact lenses in gonioscopy, 1025 in slit-lamp microscope, 59 three-mirror, 59 Goldmann visual field tests in inherited retinal degenerations, 481 goniolens, laser trabeculoplasty, 1121 goniopuncture, 1134 gonioscopy, 1024–1026 angle-closure glaucoma, 1064–1065 angle recession, 1087 grading systems, 1025–1026 goniosynechialysis, 1068 goniotomy, 1129–1132 children, 1105 modified, 1083 procedure, 1130–1131 gonococcus see Neisseria gonorrhoeae Gorlin–Goltz syndrome, 294t, 1307 graded optotypes, 1190 Gradenigo’s syndrome, 931 gradient echo MRI, 852 gradient method (AC/A ratio calculation), 1209 graft-versus-host disease, 190–191 see also transplantation Gram staining bacterial keratitis, 221 gram-negative cocci, 220 gram-negative rods, 220 gram-positive bacilli, 219 gram-positive cocci, 218–219 gram-positive filamentous bacteria, 219–220 endophthalmitis, 725 granular corneal dystrophy superficial, 258 type I (Groenouw’s), 261 type II (Avellino’s), 9, 261 type III, 257–258 granular type I corneal dystrophy, 9, 261 granulocytes, 690 granuloma eosinophilic, 1326–1327 posterior pole, toxocariasis, 744–745 pyogenic, 1300 granulomatosis, Wegener’s see Wegener’s granulomatosis grating-focus principle in automated objective refractometry, 67 Graves’ dysthyroid ophthalmopathy see thyroid eye disease gray optic discs, 873 gray scale (ultrasound), 437 green filter, direct ophthalmoscope, 70 Groenouw (granular) type I corneal dystrophy, 9, 261 growth factors angiogenic see angiogenic growth factors neurotrophic, retinal degeneration treatment, 489 retinal pigmented epithelium, 423 growth hormone-secreting pituitary tumor, 907 Guided Progression Analysis 2 (GPA 2), 1037 Guillain–Barré syndrome, 940t Guillermo Avalos (PARM) technique, 152f Gundersen flap, partial, 312 guttae, peripheral corneal, 270 gyrate atrophy, 12, 505–507 choroideremia vs., 504

H

Haab’s stria, 1023–1024 HAART and CMV infection, 706–707 Haemophilus influenzae conjunctivitis, 183 keratitis, 220 hair follicles, benign lid lesions derived from, 1299 Haller layer, 426 Hallermann–Streiff syndrome, 290t hallucinations, drug and toxin-induced, 990–991 halo(s) AC angle-supported phakic IOLs, 133 AC iris-supported phakic IOLs, 137 PC phakic IOLs, 138–139 hamartoma, retinal astrocytoma regarded as, 834 combined, 840–841

hemicentral retinal vein occlusion, 528 hemicrania, chronic paroxysmal, 975 hemifacial spasm, 1293t, 1294 hemislide (hemifield slide) phenomenon, 904, 921 hemoglobinopathies, 555–559, 572 hyphema, 1085 retinal neovascularization, 572 hemolytic glaucoma, ghost cell, 1087–1088, 1094 hemorrhage (bleeding) anterior segment, in cataract surgery, 399 choroidal, 660–664, 1085–1086 complicating subretinal fluid drainage, 469 massive, 1085–1086 intracranial see intracranial hemorrhage intravitreal injection-related, 478 macular, traumatic causes, 674 orbital, surgery complicated by, 1338 blepharoplasty, 1356 orbital, traumatic, 898–899, 1333 retinal in infants, causes, 681b in ocular ischemic syndrome, 552 in sickle cell hemoglobinopathy, 556 retrobulbar, in peribulbar block, 358 subretinal in age-related macular degeneration, 585 complicating subretinal fluid drainage, 469 suprachoroidal see suprachoroidal hemorrhage in trabeculectomy, intraoperative, 1164–1165 vitreous cavity in diabetic retinopathy, 544 ghost cell glaucoma caused by, 1087–1088, 1094 in sickle cell hemoglobinopathy, 556, 558–559 traumatic intracranial hemorrhage associated with (=Terson’s syndrome), 678–679 ultrasound, 438 hemorrhagic conjunctivitis, acute, 185 heparin surface-modified PMMA IOLs in patients with history of uveitis, 388–389 hepatocorneal syndromes, 294t hepatolenticular degeneration (Wilson’s disease), 291t, 292f, 294t, 919 heredity see genetics; inheritance Hering’s law, 1186, 1272 herpes simplex virus/HSV (eye disease), 232–237 conjunctivitis, 186 eyelid infection and (blepharoconjunctivitis), 232 neonatal, 188 epidemiology and clinical importance, 232 keratitis, 232–237, 240f HEDS trial, 235–236 prevention of recurrence, 236 recurrence, 234–235 life cycle, 232 primary infection, 232 refractive surgery contraindicated in, 92 uveitis, 181, 700–701 herpes zoster see varicella zoster virus herpesviruses, nomenclature and diseases caused, 232 see also specific herpesviruses Hessburg–Barron suction trephine, 300 heterochromic iridocyclitis, Fuchs’, 772–773, 1083 heterophoria method (AC/A ratio calculation), 1209 heteroplasmy, mitochondrial, 4f, 6, 17, 371 heterozygote autosomal dominant, 4–5 autosomal recessive, 5 hexagonal keratotomy, 87 hidrocystoma apocrine, 1298 eccrine, 1298 high speed ultra-high optical coherence tomography, 448–449 higher cortical functions, 910 highly active antiretroviral therapy (HAART) and CMV infection, 706–707 Hirschberg method, 1193 histiocytic tumors, 1326–1327 fibrous histiocytoma, 1320–1321 histiocytosis X, 1326–1327 histopathology (after biopsy) see biopsies

histoplasmosis, 729–732 endophthalmitis, 734–737 history-taking blepharoplasty, 1353 cataract surgery, 334–335 epiphora, 1346 eyelid conditions ectropion, 1284 ptosis, 1272–1277 retraction, 1268 trauma, 1312 glaucoma, 1019 headache, 969–970 HIV disease and AIDS CMV infection in HAART and, 706 cranial neuropathies, 933 dementia, 981 herpes zoster, 181 Kaposi sarcoma, 202 microsporidial keratitis, 230 optic neuritis, 881 HLA-B27-related uveitis, 748–752, 770 HMMA contact lenses, 52 holes (retina) see macula; round holes holmium:YAG (Ho:YAG) laser, thermokeratoplasty, 87–88 homonymous hemianopia with retrochiasmal lesions, 910–911 in stroke, 998–999 homozygote autosomal dominant, 4–5 autosomal recessive, 5 honeycomb dystrophy, 258 hordeolum, 1304 HORIZON study age-related macular degeneration, 592 branch retinal vein occlusion, 533 central retinal vein occlusion, 530 horizontal eye movements, 915–916 horizontal eyelid laxity see laxity horizontal eyelid shortening and blepharoplasty, 1288 by full-thickness wedge excision, 1287 medial diamond excision plus, 1287 horizontal tarsal kink syndrome, 1279 hormonal therapy, metastases, 813 horn, cutaneous, 1295–1296 Horner’s syndrome, 962–963 blepharoptosis, 1274 children/infants, 962–963 cluster headache and, 973–974 diagnosis, 962 pupillary abnormalities, 960–962 hot spots (indocyanine green angiography), 445 HOTV test, young children, 1190 Hruby contact lens, slit-lamp microscope, 59 HSV see herpes simplex virus HTLV1, 702 Hudson–Stähli line, 271 Hughes tarsoconjunctival flap for lid repair, 1315 human bite wounds to lids, 1312 human immunodeficiency virus see HIV human leukocyte antigens (HLA)-B27-related uveitis, 748–752, 770 human papillomavirus, 1305 human T cell lymphotropic virus type 1 (HTLV1), 702 Hummelsheim procedure, 1231 Humphrey Matrix frequency doubling technology, 1036, 1038f Humphrey Visual Field Analyzer, 1030, 1033–1034 Huntington’s disease, 980–982 Hutchinson’s melanotic freckle (=lentigo maligna melanoma), 1310–1311 hyalocytes, 432 hyalosis, asteroid, 436 hyaluronan (of vitreous), 430 hyaluronic acid fillers, 1359 zones of placement, 1360f hyaluronidase in peribulbar block, 358 hydrodelineation (small-incision cataract surgery), 372

Index

handpieces and tips, phacoemulsification, 361–362 haploidy as defect, 4 in meiosis, 3f haploinsufficiency, 7 haploscopic devices, 1195, 1203 haptics placement asymmetrical, 401 options, 387t HARBOR trial, 592 Hartmann–Shack aberrometry, 73–75, 80, 123, 170 Hassall–Henle warts, 270 haze (postoperative corneal) LASEK and epiLASIK, 104 phototherapeutic keratectomy, 310 LASIK, 115 photorefractive keratectomy, 99–101 head coils (MRI), 853 head tilt Bielschowsky (Parks–Bielschowsky) three-step head-tilt test, 929, 1228–1229 esotropia relating to, in trisomy 21, 1212 eye position during, 916f, 920 in fourth cranial nerve palsy, 1228 head trauma, 988–989 headache, 969–975 with aneurysms, 993 with increased intracranial pressure, 876 with optic chiasma/parasellar/pituitary fossa lesions, 906 healing and repair (wound), corneal, 166–167 post-procedural astigmatic or radial incisional keratotomy, cornea, 141–142 intrastromal corneal ring segments or collagen cross-linking, 149 phototherapeutic keratectomy, 310 healing and repair (wound), glaucoma surgery, 1152 antifibrotic agents in modulation of, 1083, 1152–1158 health and cataracts, 412 hearing problems in Vogt–Koyanagi–Harada disease, 762 heart conduction abnormalities in mitochondrial disorders, 944 disease cataract surgery and, 356 central retinal artery obstruction, 521 sarcoidosis involving, 756 heavy eye syndrome, 1236–1237 Heidelberg edge perimetry, 1037 Heidelberg Retina Tomograph (HRT), 1041–1043 helicoid peripapillary chorioretinal degeneration/ choroidopathy see serpiginous choroiditis Helmholtz ophthalmoscope, 69–70 helminths keratitis, 231 posterior uveitis, 745–747 hemangioblastoma (cerebellar) in von Hippel– Lindau syndrome, 847 hemangioendothelioma, benign see capillary hemangioma hemangioma choroidal, 654, 825–829 retinal neovascularization, 573 serous retinal detachment with, 654 in Sturge-Weber syndrome, 826, 848 eyelid capillary, 1299–1300 cavernous, 1300 infant, 1239f retinal, 836–839 capillary see capillary hemangioma cavernous, 838–839 retinal arterial macroaneurysm vs., 577–578 hematoma (postoperative) brow lift, 1358 cataract surgery, 401 entropion surgery, 1283 hemianopia with chiasmal lesions, 904 with retrochiasmal lesions, homonymous, 910–911 in stroke, homonymous, 998–999

1381

Index

hydrodissection (small-incision cataract surgery), 372 complications, 396 cortical cleaving, 408 in mini-nuc technique, 380–381 hydrodynamics in phacoemulsification, anterior chamber, 362–363 hydrogel contact lenses, complications, 280 infectious keratitis, 288 tight lens syndrome, 286 hydrogel refractive presbyopic implants, 157 hydroxyamphetamine test, 962 hydroxyapatite fillers, 1359–1360 hydroxychloroquine retinotoxicity, 683–684 hydroxyethyl methacrylate contact lenses, 52 hydroxyurea, sickle cell hemoglobinopathy, 558 Hydrus microstent scaffold, 1136–1137 hyperbaric oxygen, in non-arteritic anterior ischemic optic neuropathy, 887 hypercyanescence, 445 hyperemia contact lens-induced, 55 prostaglandin analog-induced, 1118 hyperfluorescence, 443b, 444 hyperopia anisometropic, 1239 IOLs phakic, 128 refractive lens exchange, 338 LASIK, 107–108, 117 photorefractive keratectomy, 95, 100 as surgical complication astigmatic or radial incisional keratotomy, progressive, 145 phototherapeutic keratectomy, 310 hyperosmolarity, tear, 274, 277 hyperosmotic agents in glaucoma, 1112 adverse effects, 1023t hyperpigmentation of retinal pigment epithelium in age-related macular degeneration, focal, 582 hypersensitivity reactions/allergies to fillers, 1360 type I-IV, 692 hypertension intraocular see intraocular pressure systemic, glaucoma risk, 1003 hypertensive retinopathy, 514–517 acute, differential diagnosis, 516b chronic, 514–516 cystoid macular edema, 626–627 malignant, 514, 516–517 differential diagnosis, 515b hyperthyroidism in Graves’ disease see thyroid eye disease hypertropia, cover test, 1194f hyperviscocity syndromes, 571 central retinal vein occlusion vs., 529 retinal neovascularization, 571 hyphema, 1085 as cataract surgery complication, 400–401 as laser iridectomy complication, 1124 hypocyanescence, 445 hypofluorescence, 443, 443b hypopyon, 771 hypotension, nocturnal, 1058 hypothalamic dysfunction, 906 hypotony (as complication) antimetabolite, 1157, 1167–1168 drainage implant surgery, 1162 hypoxia (corneal) with contact lenses, 286

I

1382

ice-pick headaches, 975 ichthyosis, 294t cataracts and, 416 ICL (implantable Collamer Lens), 138 idiopathic juxtafoveal retinal telangiectasia, 562–563 idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome, 578 ignorance (immune), 692 illumination (lighting) automated refractometers, 67 fundus photography, 70–71

illumination (lighting) (Continued) ophthalmoscope binocular indirect, 69 direct, 70 safety considerations, 70 slit lamp microscopy, 58 image cranial nerve III palsies, 933–934 of high resolution/quality, 20 inverted, with binocular indirect ophthalmoscope, 69 object identification and retention in memory of, 911–912 retina–brain system processing, 45 imaging (radiology) Coats’ disease, 562 eyelid trauma, 1312 functional, 855–856 lacrimal drainage system, 1347–1348 neuro-ophthalmology see neuroimaging optic nerve head, 1041 orbital, 856t, 1264–1267 adenoid cystic carcinoma, 1320 arteriovenous fistula, 1332 atypical lymphoid hyperplasia, 1325 benign reactive lymphoid hyperplasia, 1325 capillary hemangioma, 837, 1330 cavernous hemangioma, 1331 cellulitis, 1328 dermoid cyst, 1329 eosinophilic granuloma, 1326 fibrous histiocytoma, 1321 lymphangioma, 1331 lymphoma, 1326 metastatic carcinoma, 1319 mucocele, 1329–1330 myositis, 1327 neuroblastoma, 1324 neurofibroma, 1323 optic nerve glioma, 895–896, 1324 optic nerve sheath meningioma, 896, 1325 pleomorphic adenoma, 1320 posterior segment trauma, 670–671 pseudotumor, 1327 rhabdomyosarcoma, 1321 schwannoma (benign), 1323 schwannoma (malignant), 1324 thyroid orbitopathy, 1236, 1327 Wegener’s granulomatosis, 1328 scleritis, 212 serous retinal detachment, 658 see also specific imaging modalities imatinib retinotoxicity, 686 immediate hypersensitivity, 692 immediate phase of wound healing, 297 immune complex disease, 692 immune privilege, 693 immune stromal keratitis, 235 immune system, 690–691 adaptive, 690 cells, 690–691 glaucomatous optic neuropathy and, 1017 graft rejection by see rejection inflammation and the, 692 innate, 690 recovery in HIV disease (with HAART), 706–707 tolerance, 690–691 toxoplasmosis and the, 739 uveitis and the, 691–693 see also autoimmune mechanisms; defensive mechanisms immunization (and vaccination) influenza A, 702–703 tetanus, 1312, 1313t varicella, 182 immunocompromised persons see immunosuppressed persons immunoglobulin see antibody immunomodulatory and biological agents blepharitis, 179 peripheral ulcerative keratitis, 240b, 241, 241t scleritis, 215 uveitis, 1082 juvenile idiopathic arthritis-related, 751 immunophilin ligands in Behçet’s disease, 760

immunosuppressed/immunocompromised persons CMV infection, 704 retinitis, 704–705 HSV or VZV retinitis, 700–701 toxoplasmosis, 739, 742 see also HIV disease immunosuppressive drugs blepharitis, 179 cicatricial pemphigoid, 208 Graves’ ophthalmopathy, 948 myasthenia gravis, 940 peripheral ulcerative keratitis (incl. Mooren’s ulcer), 240, 246 scleritis, 215–216 uveitis, 697–699, 757, 1082 Behçet’s disease, 760 juvenile idiopathic arthritis-related, 751 sympathetic, 768 Vogt–Koyanagi–Harada disease, 763 immunotherapy, corneal intraepithelial neoplasia, 197 implants and prostheses corneal (keratoprosthesis), 305–306 drainage (in glaucoma ) see drainage implants intraocular lens see intraocular lens intravitreal see intravitreal implants orbital (after enucleation), 1340–1341 complications, 1344 orbital (after evisceration), 1342 complications, 1343–1344 retinal, 490 imprinting, 6–7 in-the-bag (endocapsular) IOL fixation, 393, 408 incision(s) blepharoplasty skin, 1355 transconjunctival, 1355 brow plasty, 1357, 1357f corneal/corneal tunnel (for cataract surgery/IOL insertion), 377 astigmatism prevention and, 366–367 complications, 395 pediatric patients, 391–392 perforation, 395 planning, 341 see also large-incision cataract surgery; smallincision cataract surgery orbitotomy anterior, 1334 lateral, 1335 in strabismus surgery, 1248 see also entries under micro-incisional incisional keratotomy, 141 astigmatic see astigmatic keratotomy corneal wound healing after, 141–142 inclusion conjunctivitis, adult, 186–187 inclusion cyst epidermal, 1297 epithelial, complicating strabismus surgery, 1254 incomitant (deviation), 928 incontinentia pigmenti, X-linked, 6, 416, 572 retinal neovascularization, 572 indirect gonioscopy, 1025 indirect ophthalmoscope binocular, 69 phototoxic damage by, 465 retinoblastoma, 794 retinopathy of prematurity, 539 indocyanine green angiography, 444–447 age-related macular degeneration, 585 choroidal or ciliary body melanoma, 805 choroidal hemangioma, 826 choroidal metastases, 811 complications, 444–445 interpretation of results, 445–447 optic nerve, 1048 procedure, 444 properties of dye, 444 serous retinal detachment, 658 indocyanine green-assisted peeling of internal limiting membrane in macular hole repair, 612 infants aphakic, choice of correction method, 392–393 botulism, 941

infranuclear lesions see nucleus (cranial nerve) infraorbital artery, 1184 infrared laser therapy see transpupillary thermotherapy infrared systems in automated refractometers, 67 inheritance keratoconus, 253 Mendelian, 2–3 patterns, 4–7 retinoblastoma, 12, 16, 793 risk prediction (of disorder) based on, 16–17 see also entries under genetic injectable fillers, 1359–1361 injection adjustable keratoplasty, 148 injury traumatic see trauma wound healing following see healing innate immunity, 690 innervation see nerve supply insertion mutations, 4 instrastromal thermokeratoplasty, radial, 87–88 instrumentation and equipment, 57–75 goniotomy and trabeculotomy, 1130t phacoemulsification, 361–362 refraction testing, 47, 66–68 retinal phototoxicity from, 463–465 Intacs, 147 for keratoconus and after LASIK, 149 outcome, 149 intercapsular techniques in extracapsular cataract extraction, 379 interface debris in LASIK, 115 interference, 24–25 interferon therapy (IFN) corneal intraepithelial neoplasia treated with IFN alpha-2 beta, 197 optic neuritis in multiple sclerosis IFN β-1a, 882 IFN β-1b (Betaseron), 882 uveitis, 698t interlenticular opacification (ILO), 407, 409 International Classification of Retinopathy of Prematurity, 535–536 International Headache Society (IHS) classification of headache, 970, 971b International Society for Clinical Electrophysiology of Vision (ISCEV), 458, 460 internuclear ophthalmoplegia, 919 abducting nystagmus in, 955, 955t interphotoreceptor matrix, 424–425 intersecting incisions in astigmatic or radial incisional keratotomy, 144 interstitial keratitis, non-syphilitic, 246–247 intracanalicular optic nerve, 867 compressive lesions, 897 traumatic swelling, 898 intracapsular (total) cataract extraction (ICCE), 345–347, 379 history, 378 INTRACOR, 90, 153–155 intracorneal inlays, 86 intracorneal ring, 86–87 intracorneal ring (intrastromal ring) segments, 87, 147–150 keratoconus, 149, 254 intracranial hemorrhage/bleeding, traumatic in shaken baby syndrome, 680 vitreous hemorrhages associated with (Terson’s syndrome), 678–679 intracranial optic nerve, 867 compressive lesions, 897 intracranial pressure (ICP), raised (intracranial hypertension) idiopathic (IIH), 875–877 papilledema, 875 symptoms, 876 intracranial processes in headache pathogenesis, 974 intracranial thrombosis see thrombosis intracranial tumors see tumors intradermal nevus, 1303 intraepithelial neoplasia, corneal or conjunctival, 197

intraocular lens (IOL), 88–89, 127–140, 157–160, 330–333 aphakic children, 392–393 biocompatible, posterior capsule opacification, 409 in combined procedures lens surgery + keratoplasty, 383–384 lens surgery + vitrectomy, 385 complications of insertion, 398, 401–402 decentration see decentration diffraction, 25 endocapsular/in-the-bag fixation, 393, 408 evolution/history, 331–333, 365 recent advances, 332–333 in manual cataract surgery after extracapsular extraction, 380–381 after intracapsular extraction, 379 measurements and calculations, 337–341 miscalculations, 401 post-LASIK, 119 optics see optics in penetrating keratoplasty, removal and replacement, 300, 301f placement options, 387t in presbyopia, 157–160 in pseudophakic eyes see pseudophakia secondary for aphakia, 340 for pseudophakia (add-on/piggy-back IOLs), 89, 340–341, 370 for spherical aberration, 78 triple procedure of keratoplasty and cataract extraction and, 305, 383–384 types, 88–89 capsular bag see capsular bag IOL light-adjustable, 88, 370 phakic see phakic IOLs toric, 88, 368–369 UV filters, 30 in uveitis (patients with history of), 387–389 in zonular instability, 387, 1234 intraocular pressure (IOP) in anterior uveitis, 771 measurement see tonometer in trabeculectomy, postoperative management, 1150 of low pressure, 1150t, 1165 intraocular pressure (IOP) elevation (hypertension), 1050–1051 AC angle-supported phakic IOLs, 134–135 in cataract surgery, 401 diagnosis, 1051 in endothelial keratoplasty, 319 glaucoma and, 1080–1081 in drainage implant surgery, 1162 epidemiology in primary angle-closure glaucoma, 1005 mechanical theory of elevated IOP, 1016–1017 and optic neuropathy, 1016 as risk factor in development/pathogenesis, 1003f, 1012, 1050, 1080–1081, 1107–1109 in trabeculectomy, 1150t, 1165 hyphema, 1085 intravitreal injection, 478 in laser trabeculoplasty, IOP spikes, 1122 medical treatment see drugs PC phakic IOLs, 139 in penetrating keratoplasty, 301 in phacoemulsification, post-occlusion, 363f scleritis, 211 steroid-induced see steroids intraocular tumors see tumors intraorbital optic nerve, 867 intraretinal fluid accumulation in cystoid macular edema, 625 intraretinal microvascular abnormalities (IRMAs) in diabetic retinopathy, 543–544 intrastromal laser ablation, 86 presbyopia correction, 153–155 intrastromal lenticule extraction (ReLEx), 86 intrastromal ring segments see intracorneal ring segments intravenous chemotherapy, retinoblastoma, 796–797

Index

infants (Continued) cataracts, 417b pars plana approach to surgery, 391 glaucoma, primary (=congenital glaucoma), 11, 1101–1106 hemangioma of eyelid, 1239f Horner’s syndrome, 962–963 newborn see neonates ocular motor system, transient abnormalities, 921 pupillary light reflex assessment, 960 retinopathy of prematurity, 433, 535–540 shaken baby syndrome, 680–681 spasms (spasmus nutans), 952t, 953 vision evaluated in, 1188–1191 infections in blepharitis, treatment, 179 conjunctival, 183–188 corneal see keratitis eyelid, 1304–1305 from eyelid bite wounds, prophylaxis, 1312– 1313, 1316–1317 interstitial keratitis associated with, 246 intracranial/CNS, 976–977 nasolacrimal sac, 1349 optic neuritis and neuroretinitis associated with, 879–880 orbital, 1328 myositis caused by, 948 in penetrating ocular injury, secondary, 675 retinal see neuroretinitis; retinitis retinopathy following, 485t scleritis associated with, 213 serous retinal detachment associated with, 656 surgical risk of blepharoplasty, 1356 evisceration, 1343–1344 exenteration, 1344–1345 LASEK and epiLASIK, 104 photorefractive keratectomy, 101 scleral buckling, 469 systemic, central retinal artery obstruction, 521 uveitis due to, 700–703 intermediate uveitis, 774 as uveitogenic process, 692 see also specific pathogens infiltrates with contact lenses (and infiltrative keratitis), 55, 287–288 in LASEK or epiLASIK, postoperative, 104 infiltrative myopathies, 948 inflammation, 692 brain, 977–979 mechanisms, 692 ocular lens-induced, as surgical indicator, 344 mechanisms inhibiting, 693 surface, 278 orbital, 1327–1329 in Graves’ ophthalmopathy, 947, 1327–1328 headache in, 974 non-specific, 972 see also anti-inflammatory agents inflammatory bowel disease and HLA-B27associated uveitis, 749 inflammatory cytokines see cytokines inflammatory disorders/lesions choroidal neovascularization in, 603–604, 627b corneal thinning and melting in, 325 cranial neuropathies due to, 932 cystoid macular edema in, 626, 630 eyelid, 1304 glaucoma in, 1080–1083, 1319 iris neovascularization in, 1076b neoplasms masquerading as, 788–792 retinal neovascularization in, 570, 572–573 inflammatory glaucoma see glaucoma inflammatory myopathies, 946–949 inflammatory optic neuropathies see optic neuritis infliximab in uveitis in Behçet’s disease, 760 in juvenile idiopathic arthritis, 751 in sarcoidosis, 757 influenza A virus, 702–703 information bias, glaucoma therapy studies, 1175 informed consent see consent

1383

Index

1384

intravitreal implants, 478 diabetic retinopathy, 547 intravitreal route (injections), 476–479 in age-related macular degeneration, 590–596 plus photodynamic therapy, 596–597 in branch retinal vein occlusion, 530 in central retinal vein occlusion, 533 chemotherapy in retinoblastoma, 799 in Coats’ disease, 563–564 complications, 564 complications, 478 endophthalmitis, 478, 724–725 with macular hole, 612 post-injection care, 476–477 pre-injection evaluation, 476–477 in radiation papillopathy, 569 in radiation retinopathy, 568 in retinal arterial macroaneurysms, 579 technique, 477 in uveitis, steroids (and other drugs), 697 in intermediate uveitis, 775 in sarcoidosis, 756–757 inverted follicular keratosis, 1296 involutional entropion surgery, 1280–1281 Invue Lens, 157 iridectomy, laser, 1122–1124, 1123t angle-closure glaucoma, 1066–1067 diagnostic, 1122 malignant glaucoma (aqueous misdirection syndrome), 1093 prophylactic, 1122 therapeutic, 1122 uveitis, 699 iridocorneal endothelial (ICE) syndrome, 268, 1095–1096 iridocyclitis see uveitis, anterior iridoplasty, laser, 1124 in angle-closure glaucoma, 1066, 1067b iridotomy, laser, glaucoma, 1082 angle-closure, 1066, 1067b, 1069 malignant (=aqueous misdirection syndrome), 1093 pigmentary, 1074–1075 iris, 687 anatomy, 687 atrophy or dislocation with iris-supported phakic IOLs, 138 progressive/essential, 1095 in cataract surgery complications, 396–397 in manual surgery, management, 379 defect, prosthesis (IOL), 344, 344f glaucoma patients abnormalities causing glaucoma, 1094–1100 in angle-closure glaucoma pathophysiology, 1061, 1061b examination, 1024 major arterial circle of, 1184 neovascularization (NVI) in central retinal vein occlusion, 530, 1076 in diabetic retinopathy, 545, 550 in glaucoma patients, 1024 in ocular ischemic syndrome, 554 registration systems in photorefractive keratectomy, 96 slit-lamp examination, 964 sphincter paralysis, 964 transillumination defect, 1024, 1071, 1073–1074 tumors medulloepithelioma, 819 melanoma, 801–803, 1099 metastases, 812, 1099 nevi, 821–824 see also iris–nevus syndrome see also aniridia iris–nevus syndrome, 1095 iris-supported/fixated IOLs, 127, 135–138, 398 advantages and disadvantages, 129t history, 127 results, 131t sizing, 130 iritis see uveitis, anterior iron-containing foreign bodies, 675 iron deposition, 270–271 with small aperture corneal inlay, 156–157

irradiation see radiation irrigation–aspiration in cataract surgery additives, 352–353 capsular rupture during cortical irrigation, 398 solutions, 353 IRVAN (idiopathic retinal vasculitis, aneurysms and neuroretinitis) syndrome, 578 Irvine–Gass syndrome (cystoid macular edema complicating cataract surgery), 354–355, 402, 452, 627 ischemia anterior segment in sickle cell hemoglobinopathy, 559 strabismus surgery complicated by, 1227, 1254 retinal, iris neovascularization, 1076b ischemic attacks, transient see transient ischemic attacks ischemic central retinal vein obstruction, 527–528 ischemic heart disease and cataract surgery, 356 ischemic optic neuropathy (ION), 884–887 anterior, 877, 884–887 arteritic (AAION), 884–886 non-arteritic see non-arteritic anterior ischemic optic neuropathy cilioretinal artery obstruction with, 524 posterior, 887 ischemic syndrome, ocular, 551–554, 571 ISNT rule, 1027, 1040–1041 iStent G1, 1136 iStent G2 Inject, 1135–1136 iStent G3 Supra, 1144 IVAN (Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularization) trial, 596 ivermectin, onchocerciasis, 231, 747

J

jabs and jolts syndrome, 975 Jackson Cross-Cylinder (JCC) test, 46, 48, 51 Jankovic rating scale for essential blepharospasm, 1292 jaundice, neonatal, 919 jaw-winking syndrome, 1273 Jones fluorescein dye test see fluorescein staining Jonker’s dystrophy, 258 Joubert syndrome, 485t junctional nevus, 1303 JuvedermR[0], 1359–1360 juvenile glaucoma, 10, 1171 juvenile idiopathic arthritis, 750–751 juvenile retinoschisis, X-linked (congenital), 5–6, 12, 485t, 509–511, 573, 640 juvenile xanthogranuloma see xanthogranuloma juxtafoveal retinal telangiectasia, 625, 630 idiopathic, 562–563

K

K (keratometer)-readings, 57–58 cataract surgery, 340–341 KAMRA, 155–157 Kaposi’s sarcoma, 202 Kay picture test, 1190 Kayser–Fleischer ring, 919 Kearns–Sayre syndrome, 485t, 943–945 Kelman Duet, 132 Kelman tip, 361–362 keloids, corneal, 174, 272 KeraRings, 147, 149 keratan sulfate and macular corneal dystrophy, 261–262 keratectasia (corneal ectasia) congenital, 174 post-LASIK, 116 treatment, 116, 150 keratectomy laser see photorefractive keratectomy; phototherapeutic keratectomy superficial, 306 in anterior basement membrane dystrophy, 257 keratitis, 217–224 autosomal dominant, 9–10 diffuse lamellar, in LASIK, 115 infiltrative, infiltrates and, with contact lenses, 55, 287–288

keratitis (Continued) microbial/infectious, 217–224 in astigmatic or radial incisional keratotomy, 146 bacteria causing, 217–224 contact lenses, 56, 288 fungi causing see fungal infections in LASIK, 115–116 parasites causing see parasites in photorefractive keratectomy, 101 in phototherapeutic keratectomy, 310 recurrence following penetrating keratoplasty, 302 systemic associations, 221 viruses causing see viral infections noninfectious, 242–251 exposure following surgery see exposure of ocular surface peripheral ulcerative (PUK), 238–241, 245, 249– 250, 325 scleritis and, 211 superficial punctate see punctate epithelial erosion keratitis-ichthyosis deafness syndrome, 294t keratoacanthoma, 1296 keratoconjunctivitis atopic (chronic), 192–194 epidemic, 184 microsporidial, 188 phlyctenular, 194 Theodore’s superior limbal, 243–244, 283–284 keratoconus, 252–254 intracorneal ring segments for, 149, 254 posterior, 255 screening, 168 keratoepithelin gene defects, 259t keratoglobus, 254–255 keratolimbal stem cells see stem cells keratolysis, rheumatoid-associated, 249–250 keratometer, 57–58 preoperative cataract surgery, 339–340 refractive surgery, 93 keratomileusis, 85 laser (excimer), 95 laser subepithelial see LASEK laser-assisted in situ, see also LASIK; LASIK extra keratopathy bullous, after cataract surgery, 400 calcific band see band keratopathy climatic proteoglycan stromal, 273 contact lens-induced, 284–285 deposition, 164 exposure see exposure of ocular surface infectious crystalline, 218–219 lipid, 269–270 superficial punctate see punctate epithelial erosion keratophakia, 86, 155 keratoplasty (corneal transplantation) gel injection adjustable, 148 LASIK combined with, 90 rejection see rejection therapeutic, 299–306, 323 Acanthamoeba keratitis, 229 anesthesia, 299 bacterial keratitis, 223 endothelial see endothelium Fuchs’ dystrophy, 266 fungal keratitis, 227 historical review, 299 HSV keratitis, 236 lamellar see lamellar keratoplasty penetrating see penetrating keratoplasty triple procedure (with cataract surgery + IOL), 305, 383–384 see also epikeratophakia/epikeratoplasty; thermokeratoplasty keratoprosthesis, 305–306 keratorefractive (corneal refractive) surgery, 84–88 aphakic IOL surgery with (=bioptics), 119 cataract surgery with no previous, 338 cataract surgery with previous, 339–340 central cornea, 84–86 corneal stroma see stroma

L

laboratory evaluation/tests eyelid trauma, 1312 giant-cell arteritis, 984 ocular alignment, 1192 for pediatric cataract surgery, 390, 390b uveitis, 696 lacerations, eyelid, 1313 lacrimal artery, 1261–1262 lacrimal canaliculi see canaliculi lacrimal gland (and drainage system) anatomy, 1346 lesions/disorders, 1319–1320 causing obstruction, 1348–1349 tumors, 1350 physiology, 274, 1346 secretagogues, 278 surgery, 1333–1338 syringing, 1347 lacrimal nerve, 1261 lacrimal puncta, 1346–1351 anatomy, 1346 position, 1285 stenosis, 1350–1351 lacrimal sac and duct see nasolacrimal sac and duct LADARWave map, 124f–125f lagophthalmos, 1277 following blepharoplasty, 1356 Lambert–Eaton myasthenic syndrome, 937t, 940t, 941–942 lamella, posterior, assessment (for contracture), 1279 lamellar cataract, 417 lamellar keratitis, diffuse, in LASIK, 115 lamellar keratoplasty, 302–305, 323 anterior (ALK), 302–304 deep see deep anterior lamellar keratoplasty posterior (PLK), 302–304 lamellar keratotomy, 86 lamellar macular hole, 611 optical coherence tomography, 452 lamina fusca, 688–689 Lancaster red–green test, 1195 Landholt rings, 1190 Lang test, 1204 large-incision cataract surgery, 378–379 nuclear expression, 347, 380 larval migrans, visceral, 744 LASEK (laser subepithelial keratomileusis), 85, 102–106 advantages, 102 complications, 104 early, 104 late, 104 indications, 102

LASEK (laser subepithelial keratomileusis) (Continued) LASIK vs., 106, 111 outcomes, 105–106 postoperative management, 104 preoperative evaluation, 102 technique, 102–104 laser (gas), 32–37 clinical use (laser therapy in general), 33–35 choroidal/ciliary body melanoma, 808 choroidal neovascularization and ocular histoplasmosis, 732 cystoid macular edema as complication, 627 macular edema in diabetic retinopathy, 548 refractive surgery see subheading below retinal arterial macroaneurysms, 578–579 retinoblastoma, 798 color, 33 continuous, 33 decentration see decentration femtosecond see femtosecond laser lens capsule surgery, 348 photoablation see photoablation photocoagulation see photocoagulation photodisruption see photodisruption principles and fundamentals, 26, 32–37 mechanisms of action, 32–33 pulsed, 26, 33 refractive/photorefractive surgery with, 81–83 arcuate resection, 143 epiLASIK and LASEK see epiLASIK; LASEK keratectomy using see photorefractive keratectomy LASIK see LASIK post-cataract surgery for astigmatism, 369–370 in presbyopia, 83, 151–153 retinal damage from, 465 secondary cataract prevention, 407 tissue interactions, 26–27 see also scanning laser ophthalmoscopy and specific types of laser; scanning laser polarimetry laser-assisted procedures deep anterior lamellar keratoplasty see deep anterior lamellar keratoplasty endoscopic trabeculostomy, 1134 in situ keratomileusis see LASIK; LASIK extra presbyopia reversal, 160–161 laser Doppler velocimetry and flowmetry optic nerve blood flow, 1048 retinochoroidal blood flow, 428–429 laser iridectomy see iridectomy laser iridoplasty see iridoplasty laser keratectomy see keratectomy laser ophthalmoscopic angiography, scanning, choroidoretinal vessels, 428, 441 laser photocoagulation see photocoagulation laser pointers, retinal damage, 465–466 laser subepithelial keratomileusis see LASEK laser thermokeratoplasty, 87–88 laser trabeculoplasty see trabeculoplasty laser trabeculostomy endoscopic erbium:YAG, 1135 endoscopic excimer laser, 1134 LASIK (laser-assisted in situ keratomileusis), 35, 85–86, 107–119 cataract surgery followed by, for astigmatism, 369–370 cataract surgery in patients with previous, 339 complex cases, 118 complications, 113–116 enhancements, 117–118 epiLASIK vs., 106, 111 historical review, 107 intrastromal corneal ring segments after, 149–150 LASEK vs., 106, 111 operative technique, 111–113 ophthalmic contraindications, 91–92 patient selection, 110–111 photorefractive keratectomy indications and cautions over, 97b, 111 postoperative care, 113 presbyopia treatment based on, 151–153 results, 116–117, 125 systemic contraindications, 91

LASIK (laser-assisted in situ keratomileusis) (Continued) topography-guided, 110 wavefront-guided (custom LASKI), 107, 109– 110, 117, 120–126 devices, 123–125 higher-order aberrations, 120 ideal corneal shape, 120 measurement of wavefront aberrations, 120–123 optics see optics platforms, 125t quality of vision, 123 results, 125 wavefront-optimized, 109–110, 117 LASIK extra, 89 latanoprost glaucoma, 1116–1117 side effects, 1117–1118 systemic safety, 1118 latent nystagmus, 952–953, 952t manifest (MLN), 952–953, 952t, 957 latent transforming growth factor beta binding protein 2 (LTBP2), 11, 1170 lateral geniculate bodies see geniculate nuclei lateral tarsal strip procedure in ectropion, 1287 in entropion, 1281–1282 Latrodectus mactans bite, 937t lattice degeneration (peripheral retina), 640–641 asymptomatic holes in, 644 lattice dystrophy (cornea), 9 type I, 9, 259–260 type II, 260, 291t type III, 260 law see legal/medicolegal issues laxity, 1285 capsulopalpebral fascia, assessment, 1278–1279 horizontal eyelid assessment, 1279 surgery, 1280 inferior lid retractor, 1285–1286 lateral canthal tendon, 1285 medial canthal tendon, 1285 Leber’s congenital/hereditary amaurosis, 7, 13, 15, 484, 485t, 890–893 gene therapy, 489 Leber’s hereditary optic neuropathy (LHON), 860– 864, 890–893, 959 Lecithin–cholesterol acyltransferase (LCAT) deficiency, 293t legal/medicolegal issues cataract surgery, 341–342 trauma surgery, 1312 lens (artificial/man-made) binocularity and retinal correspondence testing, 1203 contact see contact lenses in exotropia, 1215 fundus, in slit lamp microscopy, 58–59 in gonioscopy, 1025 implanted see intraocular lens spectacles see spectacles; sunglasses lens (biological/human – lenticule), 329–330 aberrations, 73 absence see aphakia basic science/anatomy/function, 329–330 capsule see capsule cataract see cataract crystalline, optical properties, 39 in diabetic retinopathy, 545 dislocation, 1088 fragmentation with femtosecond laser, 376 in glaucoma aqueous flow obstruction relating to (in angleclosure glaucoma ), 1061 as cause of glaucoma see glaucoma examination, 1024 extraction in angle-closure glaucoma, 1068 growth anomalies, 417 malformation indicating surgery, 344 malposition indicating surgery, 344 nucleus see nucleus ocular inflammation induced by, as surgical indicator, 344 opacities see cataracts

Index

keratorefractive (corneal refractive) surgery (Continued) peripheral cornea, 87–88 phakic IOL surgery with (=bioptics), 119, 140 preoperative evaluation, 91–94 in presbyopia, 151–157 wavefront analysis see wavefront analysis keratorrhaphy, circular, 88 keratosis actinic/senile/solar, 1296–1297 inverted follicular, 1296 seborrheic, 1296 keratotomy astigmatic see astigmatic keratotomy hexagonal, 87 incisional see astigmatic keratotomy lamellar, 86 radial see radial keratotomy keratouveitis, 235–236 kernicterus (neonatal jaundice), 916 kidney see entries under renal kissing nevi, 1303 Klebsiella keratitis, 220 Knapp classification superior oblique muscle paresis, 1229b Koeppe diagnostic infant lens, 1104 Krimsky test, 1193 Krukenberg’s spindle, 1073–1074 Kuhnt–Symanowski procedure, 1288

1385

Index

1386

lens (biological/human – lenticule) (Continued) subluxation, in phacoemulsification, 397 surgery cataract see cataract extracapsular/partial see extracapsular cataract extraction indications for, 343–350 indications for different techniques of, 345–350 intracapsular/total extraction see intracapsular cataract extraction in presbyopia, 157–160 replacement see intraocular lens; lens replacement surgery repositioning, 346 techniques, 346b see also phacoemulsification swelling, 1088 thickness, and primary angle-closure glaucoma, 1005 in trabeculectomy, as preoperative factor, 1148t uveitis induced by, 764–766 lens particle glaucoma, 1088 lens replacement surgery (refractive lens exchange; clear lens extraction), 88, 338, 402 children, 393–394 complications, 402 hyperopia, 338 myopia, 88, 338 refractive errors, 345 lens(o)meter, 68 lensectomy, 472–473 refractive, 88–89 lenticonus, 418 lentiglobus, 418 lentigo, solar, 1302–1303 lentigo maligna, 1310–1311 lentigo maligna melanoma, 1310–1311 lentigo simplex, 1302 Lentis Mplus LS-312, 158 clinical studies, 158–159 leprosy, 718–719 leptospirosis, 714 Leser-Trélat sign, 1296 leukemia conjunctival infiltrates, 202 intraocular metastatic/secondary, 790–791, 817–818 leukocytes lymphocytic see B cells; T cells non-lymphocytic, 690 leukokoria (white glow) differential diagnosis, 795 retinoblastoma, 794 levator palpebrae (superioris), 1256, 1261 developmental myopathy, 1272 functional assessment, 1272 retraction relating to, 1269 levator palpebrae (superioris) aponeurosis, 1256 in ptosis advancement/reattachment or resection, 1275–1276 redundancy or dehiscence of, 1274–1275 in retraction, resection, 1270 levodopa, amblyopia, 1242 lids see eyelids and entries under blepharligament of Lockwood, 1184–1185 of Whitnall, 1256, 1261 light (visible), 19–22 dispersion, 25–26 injury/damage to eye (incl. retina), 28–31, 461–466 age-related macular degeneration and, 465, 581 in direct ophthalmoscopy, 70 origin, 19 protection from, 30–31 pupillary inequality increasing with, 963–964 quantum theory, 23, 26 retinal interactions with, 461 scattering see scattering sensing, 19 see also photoreceptors sensitivity, 21 speed, 25–26

light (visible) (Continued) tissue interactions, 26–27 see also dark; illumination; optics light-adjustable IOLs, 88, 370 light reflex, corneal, tests, 1193 light reflex, pupillary (pupillary response) assessment, 958, 960 glaucoma patients, 1020 preverbal infants, 1188 retinal origin, 964 lighting see illumination lightly-pigmented people, UV vulnerability, 29 lightning retinopathy, 463 likelihood ratio, 1175 limbal anterior chamber depth, angle-closure glaucoma, 1005, 1064 limbal approach in pediatric cataract surgery, 391–392 limbal-based trabeculectomy, 1146f, 1148 limbal dermoid, 201 limbal furrow, 249 limbal girdle, Vogt’s white, 270 limbal keratoconjunctivitis, Theodore’s superior, 243–244, 283–284 limbal-relaxing incisions in cataract surgery in treatment of astigmatism, 367 limbal tissue (stem cell) transplantation see stem cells limbal vernal conjunctivitis, 192 limiting membrane/lamina external, 421 internal (ILM), 420–421, 432–433, 473 with macular hole, 612 in proliferative diabetic retinopathy, 544 linear capsulotomy, 379 linear endotheliitis, HSV, 234–235 α-linolenic acid, 278 lipid keratopathy, 269–270 lipofuscin, pigmented epithelium, 423 lipoprotein abnormalities (dyslipoproteinemias), 291, 293t liquefaction, vitreous, 433–434 liquid currents and rhegmatogenous retinal detachment, 648 Lisch nodules, 822, 845 lisinopril, diabetic retinopathy, 546 listerial keratitis, 219 liver and corneal combined abnormalities (hepatocorneal syndromes), 294t loa loa, 188 local anesthesia brow lift, 1357 cataract surgery, 356–359 corneal surgery endothelial keratoplasty, 316 keratoplasty, 299 superficial procedures, 306 eyelid conditions ectropion, 1286 entropion, 1280 ptosis, 1275 retraction, 1270 intravitreal injection, 477 retinal break surgery, 645 scleral buckling, 467 skin fillers, 1360 strabismus surgery, 1247–1248 vitrectomy, 471 Lockwood’s (suspensory) ligament, 1184–1185 loiasis, 188 Los Angeles Latino Eye Study, 1009, 1020, 1109 loss-of function mutations, 7 Louis–Bar’s syndrome, 980 loupe, operating, 72 low-tension glaucoma see normal-tension glaucoma low-vision aids in age-related macular degeneration, 597–598 Lowe’s syndrome, 294t, 415 LOXL1 gene and pseudoexfoliation glaucoma, 1070, 1171 LRP5 and familial exudative vitreoretinopathy, 511–512 LTBP2 (latent transforming growth factor beta binding protein 2), 11, 1170 Lyme disease, 712–714, 881

lymphadenopathy in sarcoidosis, peripheral, 756 lymphangioma eyelid, 1300 orbit, 1331 lymphatic drainage, eyelids, 1257 lymphocyte migration inhibitors in uveitis, 698t see also B cells; T cells lymphocytic adenohypophysitis, 901 lymphoid hyperplasia atypical, 1325 benign reactive, 1325 lymphoid tumors, corneal/conjunctival, 200–201 lymphoma (lymphosarcoma), 815–817, 1325–1326 corneal/conjunctival, 200–201 intermediate uveitis and, 775 intraocular, 815–817 choroidal (primary), 789 metastatic/secondary, 790–791 vitreoretinal, 788–789, 815–817 orbital, 1325–1326 lymphoproliferative disorders/diseases, 1325–1326 post-transplant, 789 lymphosarcoma, see also lymphoma lyonization, 5–6 lysyl oxidase-like protein 1 gene and pseudoexfoliation glaucoma, 1070

M

M cells (in retinal ganglion), 867 macroaneurysms, retinal arterial, 575–579 cystoid macular edema, 625, 630 macrosaccadic oscillations, 956 macrosquare-wave jerks, 956 macula (anatomy), 421 centre of, 420 macula (disorders), 580–599 age-related degeneration see age-related macular degeneration cherry-red spot see cherry-red spot choroidal neovascularization, 731–732 degenerations (inherited), 491–501 genes associated with, 14t, 491t–492t dystrophy, Sorsby’s, 12 edema see edema hemorrhage due to trauma, 674 holes, 435, 610–613 optical coherence tomography, 450–452, 611 traumatic, 671 multiple sclerosis, 860 optic nerve disorders coexisting with macular disorders, 631–637 optic nerve disorders vs., 869–870 pucker see epiretinal membrane toxocariasis, 744 toxoplasmosis, 740 vitrectomy, 472 vitreous interactions with surface of, 620 see also fovea; vitreomacular traction macular corneal dystrophy, 261–262 macular neuroretinopathy, acute, 786–787 Macular Photocoagulation Study (MPS), 588–589 maculopathy chloroquine and hydroxychloroquine, 683 clofazimine, 686 nicotinic acid, 684 persistent placoid, 782 radiation, 565–566 Maddox rod test, 928–929, 1195 double, 929 Maddox tangent scale, 1193 magnetic resonance angiography, 854 axial (of orbit), 1265f cranial nerve III palsies, 933–934 CT angiography vs., 854 optic chiasma/parasellar/pituitary fossa lesions, 906 magnetic resonance imaging, 851–854 choroidal or ciliary body melanoma, 805 choroidal metastases, 811 cranial nerve III palsies, 933–934 CT compared with, 851t, 856t imaging parameters, 852 neurological studies, 851–854, 856–857 functional imaging, 856 optic chiasma/parasellar/pituitary fossa lesions, 905–906

megalocornea, 173 pediatric, 1104 megalopapilla, 872–873 megalophthalmos, 173 Meibomian gland dysfunction/disease (MGD) in blepharitis, 177–178, 276 diagnosis of/testing for, 178 treatment, 178–179, 278 Meige’s syndrome, 1293, 1293t meiosis, 2–3 melanin pigmented epithelium, 423 synthesis, and albinism, 12–13 melanocytic nevus see nevus melanocytic proliferation, bilateral diffuse uveal, 792, 822–823 melanocytic tumors/pigmented lesions conjunctiva/cornea, 198–200 eyelid, 1302–1304 melanocytoma (magnocellular nevus), 822–823 glaucoma and, 1099 melanocytosis, oculodermal see Ota’s nevus melanoma, malignant (MM) conjunctival, 198–199 eyelid, 1310–1311 differential diagnosis, 1307t intraocular (incl. uveal), 801–809, 1099 choroid see choroid iris, 801–803, 1099 melanocytic nevus transformation to, 821 metastatic, 792 primary, 789–790 retinopathy associated with, 485t melanopsin retinal ganglion cells, 867, 965–966 melanosis, conjunctival, 205 primary acquired (PAM), 198–199, 205 secondary, 205 MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), 943–945, 944f membrane (cell), retinal pigment epithelium, 423–424 membrane frizzled-related protein (MFRP) gene defects, 1171 memory and object identification, 911–912 Mendelian inheritance, 2–3 Menière-like syndrome in interstitial keratitis, 246 meningiomas, 896–897, 901–902 intracranial/post-optic chiasm, 901–902, 906 optic nerve sheath, 896–897, 1318 meningitis, 977 bilateral ophthalmoplegia, 933 meningococcus see Neisseria meningitides Meretoja’s syndrome, 260, 291 meridional folds, 638–639 MERRF (myoclonic epilepsy with ragged red fibers), 943–946 mesenchymal tumors of orbit, 1320–1322 messenger RNA, 1 meta-analyses in glaucoma trials, 1174 metabolic disorders inherited, 291–294 cataracts, 390, 415 vitreous, 435–436 metabolism in cataract pathophysiology, 413 lens, 329–330 retinal pigmented epithelium, 423 metachromatic leukodystrophy, 293t metaherpetic/trophic ulcer (keratitis), 234, 236 metalloproteinases, matrix (MMPs) glaucoma and, 1013 rheumatoid-associated corneal ulceration and, 249 see also tissue inhibitor of metalloproteinase metallosis, 675 metastases and secondary tumors, 810–814 from conjunctival/corneal tumors, 198 to eye, 810–814 conjunctiva, 202 uvea (incl. choroid), 655, 812, 1099 to orbit, 1318–1319 methotrexate, juvenile idiopathic arthritis-related uveitis, 751

methylprednisolone optic neuritis in multiple sclerosis, 882 scleritis, 215 Meyer–Schwickerath syndrome, 290t MFRP gene defects, 1171 microbial keratitis see keratitis microbiallergic conjunctivitis, 194 micro-bypass stents, 1135–1136, 1143–1144 microcornea, 173 microcyst(s), corneal epithelial, contact lenswearers, 55, 285 microcystic dystrophy, Cogan’s, 256–257 microglia, 690 microglia, retinal, 867 micro-incisional cataract surgery/ phacoemulsification, 363 biaxial see biaxial micro-incisional cataract surgery micro-incisional vitrectomy, 471–472 microkeratomes, 111 microplasmin (ocriplasmin), therapeutic use macular hole, 612 vitreomacular traction syndrome, 621–622 vitreous liquefaction is, 433 microscope confocal scanning laser see confocal scanning laser technology operating see operating microscope simple, 72 slit lamp see slit-lamp (bio)microscope specular see specular microscopy micro-shunt SOLX Gold (suprachoroidal), 1142–1143 subconjunctival, 1142 microspherophakia, 418 microsporidial keratoconjunctivitis, 188 microsurgical resection of choroidal or ciliary body melanoma, 808–809 microwave-induced thermokeratoplasty, 88 midazolam in cataract surgery, 359 with propofol, 359 midbrain cranial nerve nucleus location in IIIrd, 923 IVth, 924–925 reticular formation, 915–916 midfrontal forehead lift, 1357 Mie scattering, 27 migraine, 970–973 aneurysm vs., 985 classification, 971b location of pain, 970f ophthalmoplegic, 929, 933–934, 972 milia, 1298 Miller–Fischer syndrome, 758–760 minimally-invasive glaucoma surgery, 1133–1145 see also endoscopy mini-nuc (small-incision nuclear expression cataract surgery), 347, 380–381 miosis-preventing drugs in cataract surgery, 352 pupillary under-sensitivity to, 964 miosis-producing drugs (miotics), 1116, 1118t accommodative esotropia, 1210 cataract surgery, 352–353 glaucoma, 1116–1118 side-effects, 1116, 1118t missense mutations, 3–4 mitochondria heteroplasmy, 4f, 6, 17, 371 optic neuropathies and, 861, 864, 890–891 mitochondrial DNA disorders, 13, 943–945 optic neuropathies, 861–863, 890–891 risk prediction, 17 glaucomatous optic neuropathy and, 1017 inheritance of genes on, 6 mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 943–945, 944f mitomycin-C (MMC) glaucoma surgery concentration and exposure time, 1155 with high risk of scarring, 1153 with intermediate/low risk of scarring, 1153

Index

magnetic resonance imaging (Continued) optic nerve glioma, 895–896, 905–906 optic nerve sheath meningioma, 896 posterior segment trauma, 670–671 principles, 851–854 retinoblastoma, 795 safety, 854 serous retinal detachment, 658 special sequences and techniques in image production, 852–854 magnetic resonance spectroscopy, 856 magnification, 71–73 binocular indirect ophthalmoscope, 69 devices, 71–73 magnifying glass, 71–72 magnocellular nevus see melanocytoma major amblyoscope, 1195, 1203–1204 major arterial circle of iris, 1184 malattia leventinese (Doyne honeycomb macular dystrophy), 491t–492t, 497, 499 malignant glaucoma (=aqueous misdirection syndrome), 1061, 1063, 1092–1093 malignant hypertensive retinopathy, 514, 516–517 malignant tumors (cancer; oncology) central retinal artery obstruction, 521 eyelid/periocular, 1306–1311 differential diagnosis, 1307t differentiation from benign lesions, 1305 intraocular, 793–800 masquerading as inflammatory disorders, 788–792 optic nerve-compressing, 895–896 orbit, 1320–1324 retinopathy associated with, 485t secondary see metastases and secondary tumors transformation to melanocytic nevus, 821 primary acquired melanosis, 198 see also paraneoplastic syndromes and specific histological types malingering, 912–914 manifest latent nystagmus (MLN), 952–953, 952t, 957, 1031 manual surgery cataract surgery, 378–381 keratometry before cataract surgery, 339–340 manually-operated refractors, 47 map-dot-fingerprint corneal dystrophy, 256–257 Marcus Gunn jaw-winking syndrome, 1273 Marfan syndrome, 291t ectopia lentis, 418f marginal degeneration, Terrien’s, 248–249 marginal furrow, 249 senile degeneration, 270 marginal keratitis, 234 MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD), 590–592 marker testing, glaucoma screening, 1010 masquerade syndromes, neoplastic, 788–792 mast cells, 691 matrix metalloproteinases see metalloproteinases maxillary artery, internal, 1184 mean deviation (MD) in visual field assessment, 1032–1033 measles (rubeola), 186, 702t, 703 mecamylamine, diabetic retinopathy, 547 mechanical causes ectropion, 1284 eyelid ptosis, 1275 eyelid retraction, 1269 IOP elevation, 1016–1017 mechanical problems with contact lenses, 56 medical conditions ocular, comorbid with cataract, 343–344, 416 outcome of surgery, 406 pre-existing see pre-existing medical conditions systemic see systemic disease medical history, glaucoma, 1019 medical management see drugs medications see drugs medicolegal issues see legal/medicolegal issues medulloepithelioma, 819–820 glaucoma with, 1099 Meesmann’s epithelial dystrophy, 257

1387

Index

1388

mitomycin-C (MMC) (Continued) postoperative, 1156 studies, 1178 LASIK with, 118 photorefractive keratectomy with, 99 pterygium excision, 314 mitosis, 2 Mittendorf ’s dot, 417 MIVI-TRUST Study, 621–622 mixed cell tumor, benign see chondroid syringoma Mizuo–Nakamura phenomenon, 510 Möbius’ syndrome, 932, 1211, 1230 mode locking, Nd-YAG laser, 34 modular transfer function (MTF), 44 testing, 44–45, 80 Mohs’ micrographic surgery, 1308 molecular fragment, UV-induced, 30 molecular genetics central dogma, 2f of disorders, 7, 9–14 molecular morphology of vitreous, 430 molluscum contagiosum, 1304 Molteno implant, 1159–1160, 1162–1163 monochromatism, blue cone, 485t, 487–488 monoclonal antibody therapy age-related macular degeneration, 590–592 antifibrotic (in glaucoma surgery), 1156 Behçet’s disease-related uveitis, 760 choroidal neovascularization, 732 retinopathy of prematurity, 538 monocular clues to depth perception, 1201–1202 monocular diplopia, cataracts, 337 monocular elevator deficiency/palsy congenital (=double elevator palsy), 920, 1234–1235 supranuclear/prenuclear, 920 monocular occlusion in exotropia, 1215 monocular subjective refraction, 47–49 monocular visual loss children, 955 characteristics and localizations, 952t strokes, 998 transient, 996, 996t monofixation syndrome, 1198–1200, 1202 test, 1204–1205 monosomy 3, 801, 803, 805–806 monovision therapy, 87–88, 93, 110, 349 MONT BLANC study, 596–597 Mooren’s ulcer, 239, 244–246 Moorfields/Florida (More Flow) regimen, 1154b Moorfields regression analysis, 1041–1042 Moraxella keratitis, 220 M. catarrhalis, 220 morning glory optic disc anomaly, 633–634, 871–872 maculopathy, 633–634 morphea basal cell carcinoma, 1307, 1309 motion see movement motor nerve supply to eyelids, 1256 to orbit, 1261 extraocular muscles see ocular motor nerves; ocular motor system movement (eye), 915–921 anatomy and types of, 915–917 fascicular disorders, 922–926 fast see saccade limitations mechanical tests, 1196 post-drainage implant surgery, 1162 neural and mechanical factors in (current concepts), 1184, 1185f nuclear disorders see nucleus (cranial nerve) subretinal fluid extension associated with, 648 supranuclear control, and related disorders see supranuclear control terminology, 1195t vitreoretinal traction caused by, 647–648, 648f movement (facial) disorders, 1293t movement (motion) of object, detection, 912 mTOR inhibitors with tuberous sclerosisassociated with CNS tumors, 834–835 mucin balls with contact lenses, 285 mucin deficiency, 276 mucocele, 1329–1330 mucolipidoses, 291–294, 294t

mucopolysaccharidoses, 291, 292t mucormycosis (Mucor infection), 932, 984f, 987 mucosal grafts of hard palate for entropion, 1282 for retention, 1270–1271 mucous membrane pemphigoid, 206–208 Müllerian glia, 419f, 420–422 Müller’s muscle, 1256 blepharoptosis and, 1274 excision (in lid retraction), 1270 multifocal choroiditis histoplasmosis vs., 730 and panuveitis, 603, 783 differential diagnosis, 786b multifocal corneal excimer laser ablation, 151–153 multifocal electroretinogram, 458, 460 epiretinal membrane, 614–615 glaucoma screening, 1010 inherited retinal degenerations, 483 multifocal intraocular lenses, 88 presbyopia, 157–159 multifocal placoid pigment epitheliopathy, acute posterior, 779–780 multifocal visual evoked potentials (mVEPs), glaucoma screening, 1010 multifunctional domain optical coherence tomography, 448 multimodal tumor therapy choroidal/ciliary body melanoma, 809 retinoblastoma, 799 multiple benign cystic epithelioma, 1299 multiple evanescent white dot syndrome, 784–786 multiple sclerosis (MS), 859–860, 881–882 brain atrophy, 860 intermediate uveitis and, 774 macular thickness, 860 optic neuritis, 859, 879, 882 optical coherence tomography, 456 pathology, 882 treatment, 882 optical coherence tomography, 859–860 peripapillary retinal nerve fiber layer thickness, 859–860 retinal neovascularization, 571 multi-purpose contact lens solutions, 281 Munnerlyn formula, 82 Munson’s sign, 252 muscarinic antagonists see anticholinergic drugs muscles extraocular see extraocular muscles forehead, 1353 botulinum toxin injection, 1364–1365 see also ciliary muscle-zonular complex; dilator muscle of pupil; levator palpebrae; myopathies; orbicularis; retractor muscles Mustarde flap, 1315 Mustarde lid-switch technique, 1314 mutations, 3–4 mechanisms of diseases caused by, 7 myasthenia gravis, 935, 937–941 eyelids ptosis, 1274 retraction, 1269 nystagmus, 951, 954, 955t myasthenic syndrome, Lambert–Eaton, 937t, 940t mycobacteria M. leprae, 718–719 M. tuberculosis, 716 nontuberculous, causing keratitis, 221 after LASIK, 116 mycotic infections see fungal infections mydriasis adrenergic, 963f atropinic, 963f non-neuronal causes, 964 mydriatic (pupil-dilatory) agents cataract surgery, preoperative, 351 for intravitreal injection, 477 uveitis, 697, 1082 HLA-B27-related uveitis, 749–750 of idiopathic or syndromic causation, 772 myectomy, blepharospasm, 1293 myelination, 867 myelogenous leukemia, chronic, 817, 817f Myobloc, 1363

myocilin (GLC1A; MYOC; TIGR), 10 mutations, 10, 1052 open-angle glaucoma, 10, 1002, 1013, 1171 testing for, 1010 myoclonic epilepsy with ragged red fibers (MERRF), 943–945 myoclonus, ocular, one-eye patching, 957 myogenic disorders see myopathies myokymia facial, 1293t superior oblique, 955t, 956–957 myopathic ptosis, 1272–1273 myopathies, ocular (and myogenic causes of disorders), 943–949 lid retraction, 1269 myopia (incl. high myopia) anisometropic, 1239 cataracts and shift to, 337 cataracts associated with, 413 esotropia associated with, 1213 exotropia associated with, correction, 1215 genes associated with, 14t LASIK, 107 results, 116 lens extraction/refractive lens exchange, 88, 338 night, 78 open-angle glaucoma (primary) and, 1003 pathologic, choroidal neovascularization, 602–603 phakic IOLs, 128, 341 photorefractive keratectomy, 95, 99–100 as phototherapeutic keratectomy complication, 310 retinoscopic estimation, 66 myopic retinal degeneration vs. gyrate atrophy, 505 myositis, orbital, 948–949, 1327 myotonic dystrophy (dystrophia myotonica), 415

N

nanophthalmos, 655 angle-closure glaucoma and, 1171 narcotic analgesics in cataract surgery, 359 nasal examination with epiphora, 1346–1347 nasal step (visual field defect), 1030 nasociliary nerve, 1261 nasolacrimal sac and duct endoscopy see endoscopy obstruction, 1348–1349 syndrome, 1349–1350 tumors, 1350 National Eye Institute 5-Fluorouracil Filtration Surgery Study, 1153 natural (innate) immunity, 690 natural killer (NK cells) and NK T cells, 691 Nd-YAG laser see neodymium:YAG laser NDP see norrin near reflex spasm, 921, 935 near refraction/near correction, 50–51 necrosis (tissue) with fillers, 1361 retinal, acute, neovascularization, 573 necrotizing keratitis, 235 necrotizing scleritis, 210, 213, 215–216 necrotizing vasculitides, systemic, 977–979 Neisseria gonorrhoeae (gonococcus) conjunctivitis, 183–184 neonatal, 187–188 keratitis, 220, 222 Neisseria meningitides (meningococcus) conjunctivitis, 183–184 keratitis, 220 nematodes, filarial see loiasis; onchocerciasis neodymium:YAG (Nd:YAG) laser cyclophotocoagulation using, 1125–1126 contact, 1126 noncontact, 1126 outcome, 1128 glaucoma (selective trabeculoplasty; SLT), 1123 iridectomy, 1122–1123 in aqueous misdirection syndrome, 1093 argon laser iridectomy combined with, 1123 argon laser iridectomy vs., 1123 mechanism of action clinical practice, 34 photodisruption by, 461 retinal arterial macroaneurysms, 579 secondary cataract prevention, 407

neuroretina (neural retina), 653–659 anatomy/structure, 419–422 rim, 1040–1041 examination of rim, 1026–1027 serous detachments, 653–659 neuroretinitis, 879–883 idiopathic retinal vasculitis and aneurysm and (IRVAN syndrome), 578 infectious, 636 cat scratch disease (B. henselae) involving, 636, 720–721 neuroretinopathy, acute macular, 786–787 neurosarcoid, 756 neurosyphilis diagnosis, 711, 712t neurotrophic factors, retinal degeneration treatment, 489 neurotrophic keratitis, 247–248 nevoxanthoendothelioma see xanthogranuloma nevus iris see iris; iris–nevus syndrome magnocellular see melanocytoma melanocytic conjunctival, 198–199 eyelid, 1303 of Ota see Ota’s nevus uveal, 821–824 strawberry see capillary hemangioma see also basal cell nevus syndrome; dysplastic nevus syndrome nevus flammeus, 1300 newborns see neonates Newcastle disease, 186 niacin retinotoxicity, 684 nicotinic acid retinotoxicity, 684 night-time/nocturnal conditions congenital stationary nocturnal blindness, 485t, 486 night myopia, 78 nocturnal hypotension, 1058 NK cells and NK T cells, 691 NO SPECS classification, Graves’ ophthalmopathy, 947 Nocardia causing keratitis, 219–220 nocturnal conditions see night-time/nocturnal conditions nodular basal cell carcinoma, 1309 nodular conjunctival melanoma, 199–200 nodular melanoma, 1310 non-arteritic anterior ischemic optic neuropathy (NAION), 858–859, 884–887, 884t amiodarone and, 892 non-compliance, contact lens wearing, 282 non-penetrating glaucoma surgery (NPGS), 1133–1145 non-steroidal anti-inflammatory drugs (NSAIDs) cataract surgery intraoperative, 353t postoperative, 354–355 preoperative, 351 cystoid macular edema, 630 episcleritis, 209–210 scleritis, 213–215 uveitis, 697, 1082 nonsyndromic congenital cataract, 11 normal-tension (low-tension) glaucoma, 1052, 1057–1059 genes associated with, 14t, 1171 IOP as risk factor, 1107–1108 Norrie’s disease, 12, 509, 512–513 cataracts, 416 gene product in see norrin norrin (Norrie disease protein; NDP), 512 familial exudative vitreoretinopathy, 511 gene mutation, 512 and Coats’ disease, 560 and Norrie disease, 512 and retinopathy of prematurity, 535 North Carolina macular dystrophy, 497, 499–500 nose see entries under nasal nuclear medicine see radionuclide/nuclear imaging nucleofractis phacoemulsification, 372–373 nucleus (cranial nerve in brain), lesions, 922–926 differentiation from supranuclear/infranuclear lesions, 917–918

nucleus (lens) dropped, 398–399 opacities, 335–336, 416 removal/delivery, 347 indications, 346 large-incision nuclear expression, 347, 380 posterior capsule rupture before, 397 trapped, in phacoemulsification, 397 NuLens, 88 nutrition cataracts and, 412 optic atrophy/neuropathy relating to, 890–893 see also dietary management; dietary supplementation NuVita MA20 IOL, 127, 134 nystagmus, 950–957 congenital see congenital nystagmus congenital esotropia and, 1207 convergence retraction see convergence retraction nystagmus in myasthenia gravis, 951, 954, 955t optokinetic see optokinetic nystagmus test see-saw, 905, 955, 955t

Index

neonates cataract surgery, pars plana approach, 391 conjunctivitis, 187–188 jaundice, 916 neoplasms see tumors neostigmine test, myasthenia gravis, 939 neovascular age-related macular degeneration, 582 neovascular glaucoma, 530, 1076–1079 neovascular vitreoretinochoroidopathy, autosomal dominant, 509, 511, 574 neovascularization (angiogenesis), 570–574 anterior chamber angle, 1026 anterior segment, glaucoma resulting from, 530, 1076–1079 choroidal see choroid corneal, with contact lenses, 55, 286 everywhere (NVE), in diabetic retinopathy, 544, 547–548 iris see iris optic disc see optic disc retinal, 570–574 in branch retinal vein occlusion, 531–533, 572–573 in retinopathy of diabetes, 550, 571 in retinopathy of prematurity, 535–536, 539, 573 in sickle cell hemoglobinopathy, 556, 572 nephropathy and retinopathy, diabetic, 541 nerve block, cataract surgery, 357–358 nerve fibers see axons nerve sheath tumors malignant peripheral, 1323–1324 optic, 895–897 nerve supply (innervation), orbital, 1261 extraocular muscles see ocular motor nerves to eyelids, 1256–1257 to iris see sympathetic innervation of iris neural networks and glaucoma al, 1179 neural tumors see neurogenic tumors neuralgia, postherpetic, 181–182 neurilemmona see schwannoma neuroblastoma, 1324 neurodegenerative disease, 979–982 optical coherence tomography, 860–861 neuroepithelium, 419 neurofibroma, 1301 in neurofibromatosis type I, 845, 1301 plexiform, 1301, 1322–1323 neurofibromatosis, 844–846 type I (von Recklinghausen’s disease), 844–846 and combined retinal hamartoma, 841 and glaucoma, 1022t and meningiomas, 902 and neurofibroma, 845, 1301 and optic nerve gliomas, 845, 895–896, 1324 and uveal nevi, 822 type II, 844–846 and cataracts, 416 and combined retinal hamartoma, 841 neurogenic retraction, 1268 neurogenic tumors (neural tumors) eyelid, 1301 orbit, 1322–1325 neuroimaging, 851–857 ophthalmologist role, 851 optic nerve gliomas, 895–896 chiasmal/parachiasmal, 905–906 optic nerve sheath meningiomas, 896 principles, 851–857 retrochiasmal lesions, 911 strategies/guidelines for choice of, 856–857 see also specific modalities neurological… see central nervous system neuromuscular junction botulinum toxin action, 1362–1363 disorders, 937–942 neuromyelitis optica (Devic’s disease), 881 optical coherence tomography, 860 neuromyotonia, ocular, 921 neuronal connections in retina, 422f neuro-ophthalmology, 851–857 emergencies, 983–987 imaging see neuroimaging optical coherence tomography, 456 see also brain; central nervous system neuropathies see cranial nerves; optic neuropathies

O

objects fast-moving, 45 identification, 911–912 oblique incidence astigmatism, 78 oblique muscle, inferior action, 1183 blood supply, 1184 course/anatomy, 1183–1184, 1260 double deficiency (palsy) of superior rectus and, 920, 1234–1235 innervation, 1183–1184 insertion, 1182 overaction, 1207–1208, 1207b primary, 1217–1218, 1234 secondary, 1218–1219 surgical weakening in IVth nerve palsy, 1229–1230 underaction, 1219 oblique muscle, superior action, 1183 course/anatomy, 1183, 1260 innervation, 1183–1184 insertion, 1181–1182 Knapp classification of paresis, 1229b myokymia, 955t, 956–957 overaction primary, 1219–1220 secondary, 1220 short anterior tendon sheath (=Brown’s syndrome), 935, 1235–1236 surgical strengthening in IVth nerve palsy, 1230 underaction, 1220 observation (without intervention) choroidal/ciliary body melanoma, 808 retinoblastoma, 799 observation system binocular indirect ophthalmoscope, 69 fundus camera, 71 slit lamp microscope, 58 observational techniques of visual assessment in preverbal infants, 1188 occipital lobe and object identification, 911 occludable anterior chamber angles, 1026 occlusion treatment see patching; sector occlusion Octopus perimeter, 1030 Ocugene, 1010 ocular history-taking, glaucoma, 1019 Ocular Hypertension Treatment Study (OHTS), 1003, 1005, 1008–1010, 1050–1052, 1110, 1173, 1176b, 1177 central corneal thickness assessment, 1021 risk factors in, 1107–1109 visual field testing, 1029–1030 ocular ischemic syndrome, 551–554, 571 ocular motor apraxia, congenital, 918 ocular motor nerves (cranial nerves III/IV/VI) anatomy (incl. extraocular muscle innervation), 923, 923f–925f, 927, 1183–1184, 1261 lesions and palsies, 922–926, 1225–1232 diabetic, 545 fascicular, 922–926

1389

Index

1390

ocular motor nerves (cranial nerves III/IV/VI) (Continued) herpes zoster, 181, 930f nuclear see nucleus peripheral (isolated and multiple), 927–936 strabismus due to, 1225–1232 see also ophthalmoplegia see also specific nerves ocular motor (oculomotor) system development, 921 diagnostic testing, 917–918 see also movement (eye) oculoauriculovertebral dysplasia, 290t oculocephalic reflex, 917 oculocerebrorenal (Lowe’s) syndrome, 294t, 415 oculodentodigital dysplasia, 290t oculodermal melanocytosis see Ota’s nevus oculodermatologic conditions, Mooren’s ulcer, 245 oculoglandular syndrome, Parinaud, 188, 720, 919 oculomotor (IIIrd cranial) nerve anatomy (incl. extraocular muscle innervation), 1183, 1261 block, cataract surgery, 357 lesions and palsies, 923, 1225–1227 aberrant regeneration with, 924, 929–930, 964, 1226 acquired, 1226–1227 aneurysms causing, 992 combined with IVth nerve palsy, 931 congenital, 924, 1226 diagnosis, 926, 933–934 differential diagnosis, 935 divisional, 930 etiology, 923b fascicular, 923b, 924 herpes zoster, 930f isolated, 929–930, 933–935 nonisolated, 933 nuclear, 923, 923b ocular manifestations, 923–924, 1225–1227 ptosis, 1273–1274 pupillary defects incl. anisocoria, 963f, 964 strabismus due to, 1225–1227 treatment, 926, 1227 oculopharyngeal dystrophy, 945–946 Oguchi’s disease, 486 older people (elderly) UV vulnerability, 28–29 vitreous, 433–434 oligoarthritis in juvenile idiopathic arthritis, 750 oligodendrocytes, retinal, 867 Olmstead County Minnesota study, 1008, 1054 omega-3 fatty acids, dietary supplementation, 278 onchocerciasis (river blindness) keratitis, 231 posterior uveitis, 746–747 oncology see malignant tumors opacities corneal elevated, excimer laser treatment, 308–310 pediatric, 1104 lens see cataracts open-angle glaucoma, 1001 definition, 1007–1008 pre-existing, 1081 primary (POAG), 1052 epidemiology, 1001–1004, 1019–1020, 1054, 1107f genes associated with, 10, 14t, 1004, 1013, 1171 intraocular hypertension conversion to, predictive/risk factors, 1050, 1052 juvenile-onset (=juvenile glaucoma ), 10, 1171 normal-tension glaucoma vs., 1058 probability of developing, 1108f steroid-induced glaucoma mimicking, 1013 suspects (in population studies), 1006t treatment and monitoring, 1054–1056 visual loss/blindness, 1002t, 1053–1054 secondary, 1080–1081 neovascularization and, 1077 normal-tension glaucoma vs., 1058 young children, 1102 treatment, principles of initiation, 1109–1110 open-sky cataract extraction, 305, 383–384 operating loupe, 72

operating microscope, 64 retinal phototoxicity from, 463–465 opercula, round holes with, 642 Ophthalmetron, 67 ophthalmia neonatorum, 187–188 ophthalmic artery, 867–868, 1047–1048 aneurysms involving junction with carotid artery, 992 extraocular muscle supply by, 1184 obstruction, 524 ophthalmic artery infusion chemotherapy, retinoblastoma, 797 ophthalmic nerve, 1261 ophthalmic veins, 1262–1263 ophthalmic viscosurgical devices (OVDs), 353–354 entrapment in capsular bag, 401 ophthalmologist role in neuroimaging, 851 ophthalmometers, 57–58 ophthalmoplegia (extraocular muscle paresis or paralysis) with aneurysms, 993 bilateral, 932–933, 935 chronic progressive external see progressive external ophthalmoplegia internuclear see internuclear ophthalmoplegia painful, 934 differential diagnosis, 934b strabismus relating to, 1225–1232 ophthalmoplegic migraine, 929, 933–934, 972 ophthalmoscope (and ophthalmoscopy/fundoscopy) confocal scanning laser see confocal scanning laser technology in cystoid macular edema, 629 direct, 69 indirect see indirect ophthalmoscope in lattice degeneration, 640–641 in retinopathy of diabetes, 545 in retinopathy of prematurity, 538–539 opiate (narcotic) analgesics in cataract surgery, 359 opposite clear corneal incisions (in cataract patients) to treat preoperative astigmatism, 367–368 opsoclonus, 956 optic atrophy autosomal dominant, 13–14, 864, 891 hereditary see optic neuropathies nutritional, 890–893 secondary, with papilledema, 876f toxic, 890–893 optic axis see visual axis optic canal, optic nerve portion in see intracanalicular optic nerve optic chiasm, 900–908 anatomy, 900–901 compression, 859, 891, 894–897 tumors and other mass lesions, 900–908, 976 see also retrochiasmal pathways optic disc (optic nerve head), 867 abnormally large, 872–873 anatomy and physiology, 632–636, 867, 871– 874, 1040–1041, 1048 coloboma, 634–635, 872 maculopathy coexisting with, 632–636 tilted disc, 873 vascular, 1048 congenital anomalies, pit, see subheading below cup, 1041 see also optic nerve, cup-to-disc ratio damage likelihood scale (DDLS), 1027–1028 drusen, optical coherence tomography, 456 edema see papilledema in glaucoma examination, 1040–1046 as risk factor, 1108 glaucomatous-appearing, evaluation for, 1053 magnocellular nevus, 822 medulloepithelioma, 819 metastases, 812 neovascularization in diabetic retinopathy, 544, 547–548 ocular ischemic syndrome, 552 photography, 1041 pigmentation, 873

optic disc (optic nerve head) (Continued) pit (congenital), 632–633, 872 central serous chorioretinopathy vs., 607 cystoid macular edema relating to, 628 maculopathy associated with, 632–633, 635 vasculitis see papillophlebitis see also papillitis; papillopathy; papillophlebitis; papillorenal syndrome optic nerve, 866–868 anatomy and physiology, 866–868, 901f, 1261 historical review, 866 vascular supply, 867, 1047–1049 avulsion, 674 compression see compression cup-to-disc (CDR) ratio, 1051 examination, 1026–1028 genes associated with anomalies, 14t as risk factor for glaucoma, 1108 cystoid macular edema related to anomalies of, 628, 631 in enucleation, cutting and cautery, 1340 in glaucoma blood flow see blood flow pathophysiology see optic neuropathies in glaucoma, parameters/assessment, 1003, 1026–1028, 1040–1046 children, 1103–1104 initiation of therapy and, 1110 glioma see glioma head see optic disc hypofluorescence relating to, 443 hypoplasia, 871 MRI, 857 optical coherence tomography see optical coherence tomography sheath decompression, 887 tumors, 895–896, 1325 size genes associated with abnormalities, 14t measurement, 1027 tumors, 894–897, 976 optic nerve disorders/abnormalities (in general), 454 in cat scratch disease, 720–721, 881 coexisting with macular abnormalities, 631–637 macular disorders vs., 869–870 optical coherence tomography, 454 sarcoidosis, 755–757, 880 toxocariasis, 744 see also optic neuropathies optic neuritis (inflammatory optic neuropathy), 879–883 acute demyelinating, 879–883 anterior ischemic optic neuropathy vs., 886 giant-cell arteritis vs, 985 in multiple sclerosis see multiple sclerosis in neuromyelitis optica, 860 optical coherence tomography, 456 optic neuropathies, 454, 879–883 compressive see compression diabetic, 545 glaucomatous normal-tension glaucoma vs., 1058 pathophysiology, 1016–1017 hereditary, 861–865, 890–893 Leber’s (LHON), 860–864, 890–893, 959 hypertensive, 516 inflammatory see optic neuritis ischemic see ischemic optic neuropathy optical coherence tomography, 454 radiation, 568–569 traumatic, 898–899 optic radiations, 901–904 lesions, diagnostic features, 902–903 optic tracts, 900–901 lesions, diagnostic features, 902 optical breakdown by Nd-YAG laser, 34 optical coherence tomography (OCT), 35, 73, 448– 457, 858–865, 1043–1044 anatomic results, 449 artifacts, 457 clinical applications/image interpretation, 449– 457, 858–865 age-related macular degeneration, 584, 592 anterior ischemic optic neuropathy, 886

orbicularis oculi (Continued) spasm see blepharospasm weakness, 1285 orbit, 1255–1257 anatomy and infrastructure, 1184–1185, 1258–1263 relating to surgery, 1334 apex coronal plane imaging, 1266 extraocular muscle insertion, 1181 apex syndrome course and outcome, 987 diagnosis and testing, 985 differential diagnosis, 985 epidemiology and diagnosis, 983 ocular manifestations, 984 pathology, 986 treatment, 987 fractures see fractures hemorrhage see hemorrhage imaging see imaging inflammation see inflammation lateral wall, 1258 lesions/disorders, 1318–1332 neoplastic see tumors medial wall, 1259 optic nerve portion within, 867 roof, 1258 axial plane imaging, 1265 septums/septal system, 1255–1256, 1259–1260 surgery, 1333–1338 varices, and glaucoma, 1022t see also periorbita orbital myositis, 948–949, 1327 orbital veins, 1184 orbitotomy anterior, 1334–1335 lateral, 1335–1336 ORBSCAN, 83, 168, 170f organophosphate toxicity, 937t ornithine aminotransferase (OAT) mutations, 506 orthokeratology, 88 orthoptics, 1244 osmotic dysregulation in cataract pathophysiology, 413 osteogenesis imperfecta, 291t osteology, orbital, 1258–1259 osteoma, choroidal, 830–832 osteo-odonto-keratoprosthesis, modified, 305–306 Ota’s nevus (oculodermal melanocytosis), 1303 glaucoma and, 1022t outer segment, turnover and UV vulnerability, 29 overcorrection brow lift, 1358 entropion surgery, 1283 in LASIK, 114–115 photorefractive keratectomy, 100 ptosis surgery, 1277 oxidative stress/damage cataracts and, 414 glaucomatous optic neuropathy and, 1017 see also free radicals oximetry, retinal, 1048 oxygen Earth’s atmosphere, in past geologic eras, 28 hyperbaric, in non-arteritic anterior ischemic optic neuropathy, 887 ozone layer, 28

P

P cells (in retinal ganglion), 867 pachymeter/pachymetry, optical, 61–62, 1020–1021 glaucoma patient, 1020–1021 pre-refractive surgery, 93 astigmatic or radial keratotomy, 143 paclitaxel retinotoxicity, 685 pain facial see face ophthalmoplegia with see ophthalmoplegia postoperative LASEK or epiLASIK, 104 phototherapeutic keratectomy, 310 palate, hard, mucosal grafts see mucosal grafts palpebral vernal conjunctivitis, 192 panencephalitis, subacute sclerosing, 702t, 703

panfundoscope contact lens, 59 Panum fusional area, 1201 panuveitis, 694t, 696t multifocal choroiditis and see multifocal choroiditis papillary conjunctivitis, giant see giant papillary conjunctivitis papilledema (optic disc edema), 875–878 in non-arteritic anterior ischemic optic neuropathy, 885 optical coherence tomography, 858–859 traumatic causes, 898–899 papillitis, 877, 879 exudates, 636 papilloma, squamous, 1295 papillopathy diabetic, 877, 887–888 radiation, 568–569 papillophlebitis (optic disc vasculitis), 528–529, 877 diabetic, 985 papillorenal syndrome, 635 Paraboline rotary slide, 48 paraboloid, 77 mathematical formula for, 79 paracentral scotoma, 1030 parafovea, 421 paralytic ectropion, 1284 paralytic strabismus, 1225–1232 paramedian pontine reticular formation, 915, 918 damage, 925 paraneoplastic syndromes (with associated malignancies) Lambert–Eaton myasthenic syndrome, 941–942 retinopathy, 792 parasellar lesions, 900–908 symptoms and signs, 905 parasites chorioretinitis see chorioretinitis conjunctivitis, 188 contact lens-related, 289 keratitis, 228–231 uveitis, 738–743 parasympathetic innervation of iris, 960f parasympatholytics in cataract surgery, preoperative, 351 paratrigeminal syndrome, Raeder’s, 974–975 paresthesia after brow lift, 1358 parietal lobe lesions deep in, diagnostic features, 910 tumors, 976 Parinaud oculoglandular syndrome, 188, 720, 919 Parkinson’s disease and parkinsonism, 860–861, 980 pathology, 981 treatment, 982 Parks–Bielschowsky three-step test, 929, 1228–1229 paroxysmal hemicrania, chronic, 975 paroxysmal positional nystagmus benign, 953, 953t central, 953t paroxysmal tonic upward gaze, benign, 920 pars plana, 638, 687–688 approach to vitrectomy in endophthalmitis, 727 epiretinal membrane, 618 intermediate uveitis, 775 pediatric cataract surgery, 391 proliferative vitreoretinopathy, 668 retinal arterial macroaneurysms, 579 cysts, 639 pars planitis, 774–777 pars plicata, 687–688 partial-thickness lid injuries, 1313 Pasteurella multocida, 1312, 1315–1316 Patau’s syndrome (trisomy 21), 290t, 291f patch graft, perforations, 327 patching (one-eye occlusion treatment) amblyopia, 1240f, 1242 ocular myoclonus, 957 patient information see consent; counseling; education in preoperative period see preoperative/ preprocedural period

Index

optical coherence tomography (OCT) (Continued) central retinal artery obstruction, 520 central retinal vein obstruction, 529 central serous chorioretinopathy, 607 chloroquine and hydroxychloroquine retinotoxicity, 684 choroidal rupture, 671 choroideremia, 503 Coats’ disease, 561 cystoid macular edema, 629 diabetic retinopathy, 545 diabetic retinopathy-related macular edema, 543 epiretinal membrane, 450, 617–618 glaucoma see subheading below hypertensive retinopathy, 516 IOLs, 130 macular hole, 450–452, 611 multiple evanescent white dot syndrome, 785–786 optic nerve head, see subheading below radiation retinopathy, 566 retinal arterial macroaneurysms, 576 retinal inherited degenerations see subheading below retinochoroidal vessels, 429 serous retinal detachment, 658 in shaken baby syndrome (of posterior segment), 681 solar retinopathy, 462–463 sympathetic uveitis, 768 vitreomacular traction syndrome, 449–450, 621 welding arc retinopathy, 463f glaucoma, 1043–1044 angle-closure glaucoma, 1065 open-angle glaucoma (primary), 1003 image optimization, 449 optic nerve (incl. optic nerve head/optic disc), 1043–1044 pit, 632–633 retinal inherited degenerations, 482, 1048 adult vitelliform dystrophy, 495 Stargardt’s disease, 492 technology platforms, 448–449 optical pachymeter see pachymeter optical raytracing, 75, 83–84, 123 optical sectioning in slit lamp microscopy, 58 optical treatment, nystagmus, 957 optical zone invasion in astigmatic or radial incisional keratotomy, 144 optics (IOL) contact between posterior capsule and, 410–411 geometry, 411 materials, 346 position options, 387t types, 346 optics (physics), 19–22 instrumentation and equipment see instrumentation and equipment lens, 329 normal eye, 38–45 individual optic elements, 38 physical, for clinicians, 23–27 pinhole, 41 wavefront-guided keratorefractive surgery, 120 measures of optical quality, 123 optineurin (OPTN), glaucoma and, 1017 normal-tension, 1057, 1171 primary open-angle, 1002, 1013, 1171 optokinetic nystagmus test, 1207 preverbal/preliterate children, 1188–1189, 1191t optokinetic system, 916–917 optotypes, graded, 1190 ora serata, 421, 638 pearls, 639 tearing of retina at, 674 transition of retina to non-pigmented epithelium at, 419f oral symptoms and signs, Sjögren’s syndrome, 276 orbicularis oculi anatomy, 1255 motor innervation, 1256 assessment, 1279 fascia, in eyelid repair, 1315

1391

Index

1392

patient (Continued) as risk factor for contact lens complications, 281–282 for scarring risk after filtration surgery, 1153t self-assessment of visual outcome after cataract surgery, 405 pattern dystrophies, macular, 494–495, 498 pattern standard deviation (PSD), 1032–1033, 1051 paving stone degeneration, 640 PAX6 mutations, 9–10, 1171 Peters’ anomaly and, 175–176, 1171 pearls, ora serata, 639 Pediatric Eye Disease Investigator Group (PEDIG), 1179 see also children pedicle transposition flap (for ectropion), 1288–1289 pegatinib sodium age-related macular degeneration, 589–590 diabetic retinopathy, 546–547 pellucid corneal degeneration, 254 pemphigoid, cicatricial, 206–208 penalization therapy, 1242 pendular nystagmus, acquired, 955, 955t, 957 penetrating injury iatrogenic see perforation posterior segment, 670, 674–676 penetrating keratoplasty (PKP), 299–302, 315, 323, 1099–1100 chemical burns, 298 endophthalmitis following, 301, 724 Fuchs’ dystrophy, 266 glaucoma following, 1099–1100 HSV keratitis, 236 keratoconus, 254 LASIK after, 118–119 lattice dystrophy type I, 260 perforations, 326–327 penicillins, keratitis, 222 penlight examination, glaucoma angle-closure, 1063–1064 children, 1103 pentraxin-2 as antifibrotic agent, 1156 perennial allergic conjunctivitis, 192 PerfectCapsule™, 407 perfluorocarbon liquids, 473 perforation (penetration) corneal in astigmatic or radial incisional keratotomy, 144–145 in cataract surgery, 395 surgical treatment, 325–327 globe in peribulbar block, 358 in strabismus surgery, 1254 scleral (in scleral buckling), 469 peribulbar block, cataract surgery, 357–358 perifovea, 421 perimetry, 913 in glaucoma diagnosis (incl. screening), 1010, 1029–1034 frequency-doubling, 1009–1010 new methods, 1036–1037 visual loss before (in primary open-angle glaucoma), 1053 periocular route chemotherapy for retinoblastoma, 798–799 steroids in uveitis, 697 periodic alternating nystagmus, 954, 957 periorbita (incl. periosteum), 1259 aesthetic procedures, 1352–1358 peripapillary atrophy, 1041 primary open-angle glaucoma and, 1003 peripapillary choroidal neovascularization (PCNV), 636 peripheral corneal guttae, 270 peripheral infiltrates with contact lenses, 287–288 peripheral nerve sheath tumors, malignant, 1323–1324 peripheral presby-LASIK, 152, 154f peripheral retinal lesions see retina peripheral tolerance, 692 peripheral ulcerative keratitis (PUK), 238–241, 244–246, 249–250, 325 peripheral vestibular nystagmus, 953

peripheral visual confusion, 1197–1198 peripherin/RDS gene mutations, 483, 494, 498 periphlebitis in sarcoidosis, 754 peristaltic phacoemulsification, 362 peritomy in scleral buckling, 467 Perlane, 1359–1360 permutation analysis, 1037–1038 persistent fetal vascular (PFV) syndrome, 433 Norrie’s disease and, 512 persistent placoid maculopathy, 782 Peters’ anomaly, 9–10, 175–176 PAX6 mutations and, 175–176, 1171 phaco chop, 373 phacoemulsification, 347–348, 361–364, 371–377 complications, 396–397, 452 thermal burns, 396 handpieces and tips, 361–362 history, 361 post-occlusion surge, 363–364 power modulation, 362 pumps and fluidics, 362–363 trabeculectomy and, 382 vitrectomy and, 384–385 phacogenic uveitis, 764–766 phacolytic glaucoma see glaucoma phacomorphic glaucoma indicating lens surgery, 344 phagocytosis, photoreceptor, 424 phakic IOLs, 89, 127–140 advantages and disadvantages, 129 ancillary tests, 129–130 angle-supported see angle-supported IOLs corneal refractive surgery combined with (=bioptics), 119, 140 history, 127–128 indications, 128–129 myopia, IOLs, 128, 341 iris-supported see iris-supported/fixated IOLs posterior chamber see posterior chamber (sulcussupported) phakic IOLs power calculations, 129 visual outcomes, 130–131 phakomatoses, 844–849 pharmacological agents see drugs pharmacology and optic nerve blood flow, 1049 Pharyngoconjunctival fever, 184 phase-contrast angiography, 854 phenotypes and genes, 4 phlebitis see papillophlebitis; periphlebitis phlyctenular keratoconjunctivitis, 194 phonological dyslexia, 917 phorias, 928 cover tests, 1194, 1194f phosphorescence, 26 photic retinopathy, 461–465 photoablation, laser (cornea), 27, 34, 81–83 clinical use, 34–35 photochemical damage, 461–463 photochromic lenses, spectacles/sunglasses, 30–31 photocoagulation (laser), 26, 33, 461 clinical use, 34 angioid streaks (for choroidal neovascularization), 605 branch retinal vein occlusion, 533 capillary hemangioma, 837 choroidal or ciliary body melanoma, 808 ciliary body (in glaucoma) see cyclophotocoagulation Coats’ disease, 563–564 diabetic retinopathy, 547–548 radiation retinopathy, 566–568 retinal breaks, 474, 644 retinal neovascularization, 574 retinal serous detachment (incl. central serous chorioretinopathy), 609, 658 retinoblastoma, 798 retinopathy of prematurity, 538 sickle cell retinopathy, 558–559 complications, 466, 564, 609 retinal damage, 465–466, 564 photodisruption (laser), 27, 33, 461 clinical use, 34 photodynamic therapy (with verteporfin) age-related macular degeneration, 589 plus anti-VEGF therapy, 596–597

photodynamic therapy (with verteporfin) (Continued) choroidal hemangioma, 828 outcome, 829 choroidal neovascularization, 732 with angioid streaks, 605 in choroidal osteoma, 831 with optic disc abnormalities, 636 with pathologic myopia, 605–606 eyelid basal cell carcinoma, 1308 retinal tumors astrocytoma, 834–835 capillary hemangioma, 837–838 serous retinal detachment (incl. central serous chorioretinopathy), 609, 659 photography fundus, 70–71 iris melanoma, 802 optic disc, 1041 Scheimpflug, in angle-closure glaucoma, 1065 photonics, 22 photoreceptors, 20–22, 39, 420, 424–425 in dark adaptation, 45 as light guide, 21–22 renewal and phagocytosis, 424 retinal pigmented epithelium and, interactions, 424–425 shape, 20–21 size, 20–21 see also cone; rod photorefractive keratectomy (excimer laser PRK), 35–36, 81–83, 85 ablation profiles, 81–82, 95–96 cataract surgery in patients with previous, 339 complications, 100–101 epiLASIK vs., 106 historical background, 81 LASEK vs., 106 LASIK after, 108 LASIK vs., 97b, 111 with mitomycin-C, 99 ophthalmic contraindications, 91–92 postoperative management, 98–99 preoperative evaluation, 96 procedure, 97–99 results, 99–100 systemic contraindications, 91 tracking systems, 96 PHOTO-ROP study, 539 photosensitive (light-adjustable) IOLs, 88, 370 photosensitizing drugs, UV vulnerability, 29 phototherapeutic keratectomy (PAK), excimer laser, 308–310, 349–350 in anterior basement membrane dystrophy, 257 phototherapeutic keratectomy see keratectomy phototoxicity, retinal, 461–462 from ophthalmic instruments, 463–465 from welding arc, 463 phototransduction, genes/mutations affecting, 484, 486 photovaporization (laser), 26–27 physical examination of eye see examination physical problems with contact lenses, 56 PIER study (ranibizumab in age-related macular degeneration), 591–592 piggy-back (add-on) IOLs in pseudophakic eyes, 89, 340–341, 370 pigment of pigmented epithelium, 423 visual, regeneration, 424 pigment dispersion, 1073 AC iris-supported phakic IOLs, 138 PC phakic IOLs, 139 pigment dispersion syndrome (PDS), 1073, 1171 epidemiology and pathogenesis, 1073 pseudoexfoliation glaucoma vs., 1071 treatment, 1074–1075 pigment epitheliopathy, acute posterior multifocal placoid, 779–780 pigmentary glaucoma, 1073–1075 pigmentary retinopathy (in general), systemic associations and differential diagnosis, 485–486

pleuropulmonary blastoma family tumor and dysplasia syndrome, 820 plexiform neurofibroma, 1301, 1322–1323 ploidy, 4 abnormalities, 4 PMMA see polymethylmethacrylate pneumatic retinopexy, 467 in rhegmatogenous retinal detachment, 651 pneumococcal (S. pneumoniae) keratitis, 218 pneumo-tonometry, 1021t point mutations, 3–4 point spread function, 80 polar cataract, anterior, 417 polarimetry, 22 scanning laser (SLP), glaucoma screening, 1009–1010 polarization, 23–24 polyarteritis nodosa, 977–978 diagnosis and testing, 979 pathology, 979 polyarthritis, rheumatoid factor-negative (in juvenile idiopathic arthritis), 750 polyene antifungals, keratitis, 226 polygenic inheritance, 6 poly-L-lactic acid filler, 1360 polymegathism with contact lenses, 55–56 polymerase chain reaction (PCR) fungal keratitis, 226 leptospirosis, 715 toxoplasmosis, 741 polymethylmethacrylate (PMMA) contact lenses, 52, 55 intrastromal corneal ring segments, 147–148, 150 IOLs children, 392 heparin surface-modified, with history of uveitis, 388–389 osteo-odonto-keratoprosthesis, 306 polymorphic amyloid degeneration, 273 polymorphic corneal dystrophy, posterior, 267–268 polymorphisms (gene), 4 single nucleotide, 1–2 polyneuropathy, familial amyloid, type IV (lattice dystrophy type II), 260 polyp, fibroepithelial, 1295 polypoidal choroidal vasculopathy vs. central serous chorioretinopathy, 607 pons stroke, 999 VIth cranial nerve nucleus in, 925 pooling, hyperfluorescence due to, 443b, 444 porous implants (after enucleation), 1340–1341 port-wine stain, 1300 positional vestibular nystagmus, 953, 953t positron emission technology (PET), 855 Posner–Schlossman syndrome (glaucomatocyclitic crisis), 773, 1083 posterior amorphous corneal dystrophy, 263 posterior chamber (sulcus-supported) IOLs (PCLs), 89, 138–140, 347, 398 advantages and disadvantages, 129 complications, 138–140 dislocation, 402 improved (generation IV IOLs), 331–332 renewed interest, 332 results, 131t Ridley (generation I IOLs), 331 sizing, 130 surgical technique, 138 in zonular instability, 382 posterior chamber, sutured (IOL), 398 posterior embryotoxin, 174 posterior keratoconus, 255 posterior polymorphous corneal dystrophy, 267–268 posterior segment herpes zoster manifestations, 181 ocular ischemic syndrome, 551–552 sarcoidosis involvement, 754 trauma affecting direct, 670–677 distant, 678–682 vascular anatomy, 426 postganglionic Horner’s syndrome, 961f postherpetic neuralgia, 181–182

postinfectious retinopathy, 485t postnatal vitreous development, 433 postoperative/postprocedural management astigmatic or radial keratotomy, 144 blepharoplasty, 1356 cataract surgery, 360 drugs, 354 pediatric, 393 residual or induced astigmatism, 368–369, 405 conjunctival flap, 312–313 corneal biopsy, 307 epiLASIK, 104 exenteration, 1343 eyelid trauma, 1315 glaucoma surgery antifibrotic agent injection, 1156 drainage implants, 1161–1162 goniotomy and trabeculotomy, 1131 trabeculectomy, 1150 intrastromal corneal ring segments or collagen cross-linking, 149 intravitreal injections, 476–477 keratoplasty endothelial, 318 lamellar, 304–305 penetrating, 300–302, 327 superficial, 306 LASEK, 104 LASIK, 107 photorefractive keratectomy, 98–99 phototherapeutic keratectomy, 310 post-transplant lymphoproliferative disorders, 789 post-traumatic fusion deficiency, 921 postviral disorders oculomotor paresis, 929 optic neuritis and neuroretinitis, 880 potential retinal acuity testing after cataract surgery, 404 povidone–iodine, intravitreal injection, 477 power IOLs (calculations), 337–338, 341 phakic IOLs, 129 with previous keratorefractive surgery, 339–340 specific limitations, 340 in phacoemulsification, modulation, 362, 373–374 preaponeurotic fat pockets, 1256 PreCISe study, 882 prednisone myasthenia gravis, 940 optic neuritis in multiple sclerosis, 882 scleritis, 215 pre-existing medical conditions cataract surgery and, 334, 356 contact lens complications relating to, 282 preganglionic Horner’s syndrome, 961f pregnancy and diabetic retinopathy, 541–542 preliterate children, evaluation of vision, 1188–1191 prematurity, retinopathy of, 433, 535–540, 573 cystoid macular edema, 625–626 neovascularization, 550, 571 prenuclear elevator palsy, monocular, 920 preoperative/preprocedural period (incl. patient evaluation/workup/preparation/selection) blepharoplasty, 1353–1354 brow lift, 1357 cataract surgery, 334–342 drugs, 351–352 pediatric, 390 phacotrabeculectomy, 382 conjunctival surgery flap, 312 pterygium, 313 corneal biopsy, 306 counseling see counseling enucleation, 1339 evisceration, 1339 exenteration, 1339 eyelid surgery for ectropion, 1284–1286 for entropion, 1278–1279

Index

pigmentation congenital optic disc, 873 skin, UV vulnerability of lightly-pigmented people, 29 pigmented basal cell carcinoma, 1309 pigmented ciliary epithelium (PE) and aqueous inflow, 1013–1016 pigmented epithelium, retinal (RPE), 419, 423–425 adhesion created between retina and, 468 in age-related macular degeneration detachment, 582 focal hyperpigmentation, 582 contusion, 674 detachment (RPED) or tears in age-related macular degeneration, detachment, 582 in central serous chorioretinopathy, 606 optical coherence tomography, 454 pathology, 585–586 fluid transport, 423–424 in hypertensive retinopathy, 515–516 hypertrophy, 842–843 intravitreal injection-associated tears, 478 membrane properties, 423–424 photoreceptors and, interactions, 424–425 phototoxic damage by operating microscope, 463–464 in proliferative vitreoretinopathy in pathogenesis, 665–666 pathology, 667 repair and regeneration, 425 serous detachment of neural retina and role of, 653–654, 656–658 structure, 423 see also pigment epitheliopathy pigmented melanocytic lesions see melanocytic tumors pilar cyst, 1297 pilocarpine with dry eyes, 278 glaucoma treatment, 1116 pupillary supersensitivity, 964 pupillary undersensitivity, 964 pilocytic astrocytoma see glioma pilomatrixoma, 1299 pincushion distortion, 78 pinguecula, 203 pinhole optics, 41 pinpoint illumination in slit lamp microscopy, 58 piston error, 78 pituitary apoplexy course and outcome, 987 diagnosis and testing, 985 differential diagnosis, 986 epidemiology and pathogenesis, 901, 983 ocular manifestations, 932, 984 pathology, 986 pituitary fossa lesions, 900–908 pituitary gland anatomy, 900–901 tumors, 901, 906–907, 983 cranial neuropathies, 934 PITX2 gene, 10 mutations, 1170–1171 placido disc image, 168 placoid chorioretinitis, relentless, 781–782 placoid maculopathy, persistent, 782 placoid pigment epitheliopathy, acute posterior multifocal, 779–780 plano-concave contact lens, slit-lamp microscope, 59 plaque(s), indocyanine green angiography, 445 plaque radiation therapy choroidal/ciliary body melanoma, 807–808 choroidal hemangioma, 828 metastases, 813 retinal capillary hemangioma, 838 retinoblastoma, 798 plateau iris configuration, 1061 platelet(s), diabetic retinopathy inhibitors in treatment, 546 in pathogenesis, 541 platelet-fibrin emboli, 522 pleomorphic adenoma see chondroid syringoma pleoptics, 1242

1393

Index

1394

preoperative/preprocedural period (incl. patient evaluation/workup/preparation/selection) (Continued) for reconstruction following trauma, 1312–1313 for retraction, 1268 glaucoma drainage implants, 1159–1160 goniotomy and trabeculotomy, 1129 laser trabeculoplasty, 1120–1121 minimally-invasive surgery, 1133–1134 trabeculectomy, 1147 intravitreal injection, 476–477 keratoplasty endothelial, 316 lamellar, 303 penetrating, 299–300 superficial, 306 in triple procedure, 305 orbital surgery, 1333 phototherapeutic keratectomy, 308–310 reconstructive surgery of ocular surface, 320–321 in refractive surgery, 91–94 astigmatic or radial keratotomy, 142–143 epiLASIK, 102 LASEK, 102 LASIK, 110 photorefractive keratectomy, 96 scleral buckling surgery, 467 strabismus surgery, 1247 vitrectomy, 471 PresbyLens, 157 presbyopia, 151–161, 967–968 contact lenses, 53 surgical correction, 151–161, 349 laser, 83, 151–153 prescription intolerance with automated refractometry, 68 Prevent Blindness America (PBA) Glaucoma Advisory Committee on glaucoma screening, 1008–1009 preverbal children, evaluation of vision, 1188–1191 Prince rule, 968 prion diseases, 981 diagnosis and testing, 981 management, 982 prism (in assessment of strabismus), 1193–1195 simultaneous cover test and, 1193–1194 prism spectacles/prism therapy, 1245 brain trauma, 989 strabismus, 1245 adaptation test, 1245 in exotropia, 1215 IIIrd nerve palsy, 1227 IVth nerve palsy, 1229 superior oblique overaction, 1219 PRL (phakic Refractive Lens), 138 procerus muscle, 1353 glabellar furrows and botulinum toxin and, 1364 progressive external ophthalmoplegia, chronic (CPEO), 938, 940t, 943–945, 980, 1274 blepharoptosis, 1274 course and outcome, 945 diagnosis, 944 sytemic findings, 944 treatment, 944–945 progressive subretinal fibrosis and uveitis syndrome, 784 progressive supranuclear palsy, 919 prolactinoma, 907 proliferative retinopathies, 570–574 diabetic, 541–542, 544–545, 571 pharmacotherapy, 547 surgery, 548 sickle cell (PSR), 555–556, 558–559, 572 proliferative vitreoretinopathies see vitreoretinopathies PrONTO (Prospective OCT Imaging study of Patients with Neovascular AMD Treated with Intraocular Ranibizumab), 592 Propionobacterium acnes endophthalmitis, 725 keratitis, 219

propofol in cataract surgery, 359 with midazolam, 359 prostaglandin analogs (in glaucoma treatment), 1112, 1116–1118 adverse effects, 1022, 1023t prostheses see implants and prostheses protein lens, 330 cataracts and modification of, 414 metabolism, inherited defects, 291, 291t protein kinase C inhibitors in diabetic retinopathy, 547 proteoglycans, vitreous, 430 see also climatic proteoglycan stromal keratopathy Proteus keratitis, 220 protons in MRI, 851–852 protozoal infections keratitis, 228–230 uveitis, 738–743 posterior, 744–745 provocative tests in angle-closure glaucoma, 1065 proximal indirect illumination in slit lamp microscopy, 58 pseudoaccommodation, 151 pseudodominance, 6 pseudodrusen, reticular, 581–582 pseudoexfoliation syndrome (and associated glaucoma), 1070–1072, 1074 epidemiology, 1005, 1070 examination, 1024 genetic factors, 1070, 1171 pseudohole (macula), optical coherence tomography, 452 Pseudomonas aeruginosa keratitis, 220, 222 pseudophakia cystoid macular edema, 630 IOLs in, 340–341, 384 accommodative, 160 add-on/piggy-back, 89, 340–341, 370 pseudophakic glaucoma, examination, 1024 pseudoretraction, 1268 pseudostrabismus, 1207 pseudotumor, orbital, 1327 pseudotumor cerebri (idiopathic intracranial hypertension), 875–876 pseudoxanthoma elasticum (PXE), 601–602 psoriasis arthritis and, 749–750 uveitis and, 749 psychological considerations evaluation for blepharoplasty, 1353 see also counseling psychophysical tests in glaucoma, advanced, 1036–1039 pterygium, 203–204, 313–314 surgery, 204, 313–314 history, 312 ptosis see blepharoptosis pulley issues in strabismus, 1185 pulsar perimetry, 1036 pulse(s), saccadic, 956 pulsed lasers, 26, 33 pulseless disease see Takayasu’s arteritis pumps, phacoemulsification, 362–363 puncta see lacrimal puncta punctate epithelial erosion (superficial/epithelial punctate keratopathy/keratitis) with contact lenses, 55, 284 with LASIK, 115 Thygeson’s, 242–243 punctate inner choroidopathy/choroiditis, 783–784 histoplasmosis vs., 730 pupil, 958–966 aneurysms affecting, 993 anticholingergic supersensitivity, 964 block, 1061 aqueous misdirection syndrome vs., 1093, 1093t indicating lens surgery, 344 reverse, 1073 constriction see miosis dilatation drugs causing see mydriatic agents lag, 961–962

pupil (Continued) poor, 964–965 rate, assessment, 961–962 dilator muscle, 687 efferent pupillary defects, 960–964 IOL capture, 401–402 light reflex/response to light see light reflex in non-organic visual loss, evaluation, 913 optical function, 38 ovalization with AC angle-supported phakic IOLs, 133 pre-refractive surgery pupillometry/diameter assessment, 93 in LASIK, 110, 120 relative afferent pupillary defects, 958–960, 1020 see also transpupillary thermotherapy pursuit (eye movements), 916 disorders, 918–919 diagnostic features, 910 examination, 917 Purtscher’s retinopathy, 679–680 pyogenic granuloma, 1300 pyridostigmine, myasthenia gravis, 939–940

Q

Q factor see asphericity factor quantum dots, 22 quantum theory of light, 23, 26 Quickert–Rathbun sutures, 1280

R

Rab escort protein-1 (REP-1) and choroideremia, 502, 504 rabies, 1312, 1315–1316 race (ethnicity), glaucoma and, 1019–1020, 1109 primary angle-closure and, 1004, 1019–1020 primary open-angle, 1001 radial folds, 638–639 radial intrastromal thermokeratoplasty, 87–88 radial keratotomy, 87 complications, 144–146 definition, 141 LASIK after, 118 surgical technique, 142–144 radial tears in anterior capsulectomy, 396 radiation (irradiation) cystoid macular edema caused by, 625, 630 iris neovascularization caused by, 1076b papillopathy caused by, 568–569 retinopathy caused by, 565–568 radiation therapy (radiotherapy) choroidal hemangioma, 828 choroidal/ciliary body melanoma, 807–808 outcome, 829 corneal/conjunctival tumors epithelial, 197 lymphoid, 200–201 melanocytic, 199 craniopharyngioma, adjunctive, 907–908 eyelid malignancy basal cell carcinoma, 1308 squamous cell carcinoma, 1310 Graves’ ophthalmopathy, 948 leukemia, 818 metastases, 812–813 optic nerve sheath meningioma, 897 pituitary tumors, 907 pterygium, 204, 314 retinal tumors astrocytoma, 834–835 capillary hemangioma, 838 retinoblastoma, 797–798 vitreoretinal lymphoma (primary), 788–789 Radiesse, 1359–1360 radiology see imaging radionuclide/nuclear imaging lacrimal drainage system, 1348 sarcoidosis, 755 radiotherapy see radiation therapy Raeder’s paratrigeminal syndrome, 974–975 Ramsay Hunt syndrome, 980 randomized clinical trials in glaucoma, 1173–1174 Randot test, 1204

refraction (Continued) keratoplasty-related changes, 318 as lens surgery indication, 344–345 testing/assessment, 46–51 glaucoma patient, 1019 historical review, 46 instrumentation and equipment, 47, 66–68 pre-cataract surgery, 340–341, 365 procedure, 46–51 purpose, 46 utility, 46 refractive error primary angle-closure glaucoma and, 1003 scleral buckling-related changes in, 469 in trabeculectomy, as preoperative factor, 1148t refractive lens exchange see lens replacement surgery refractive lenticule extraction (ReLEx), 86 refractive surgery, 81–90 cataract surgery and, blurring of boundary between, 343 classification of procedures, 84–90 concepts in development, 83–84 corneal see keratorefractive surgery preoperative evaluation see preoperative/ preprocedural period previous glaucoma patient, 1019 LASIK following, 118–119 photorefractive keratectomy following, 99–100 wavefront analysis see wavefront analysis Refsum disease, 485t registration (eye) in wavefront-based surgery, 125 Reis–Bücklers dystrophy, 9, 257–258 rejection (allograft) in endothelial keratoplasty, 319 of keratolimbal stem cells, 322 in penetrating keratoplasty, 301–302 in phototherapeutic keratectomy, 310 relative afferent pupillary defects, 958–960, 1020 relentless placoid chorioretinitis, 781–782 ReLEx (refractive lenticule extraction), 86 RELIEF classification, Graves’ ophthalmopathy, 947 remifentanil, cataract surgery, 359 renal cell carcinoma in von Hippel–Lindau syndrome, 847 renal disease/disorders corneal abnormalities combined with (corneorenal syndromes), 294, 294t diabetic, and retinopathy, 541 see also papillorenal syndrome REP-1 and choroideremia, 502, 504 reparative phase of wound healing, 297–298 repetition time (TR) in MRI, 852 resolution, 21, 21f, 40 angle of, 21 high, image of, 20 resonator (laser), 33 respiration, spontaneous, in general anesthesia in cataract surgery, 360 restrictive ophthalmopathy of medial rectus, 935 Restylane, 1359–1360 reticular formation midbrain, 915–916 paramedian pontine, 915 reticular pseudodrusen, 581–582 retina, 419–422 adhesion, 424–425 anatomy/structure, 419–422 neural retina, 419–422 periphery, 638 arteriovenous malformations (AVMs) in WyburnMason syndrome, 848–849 blood flow see blood flow breakdown leading to serous retinal detachment, 656–658 breaks, 640–649 photocoagulation, 474, 644 degenerations (inherited), 480–490 macular, 491–501 myopic, vs. gyrate atrophy, 505 progressive diffuse/pan-retinal, 480–486 retinal neovascularization in, 573–574 stationary, 486–490

retina (Continued) degenerations (non-inherited/in general) choroidal neovascularization, 627 peripheral, 640–641 detachment, 638–641 with AC angle-supported phakic IOLs, 135 in cataract surgery, 403 in diabetic retinopathy, 545 distinction between various types of, 649–651 preventing breaks progressing to, 643–645 in retinopathy of prematurity, surgery, 539 rhegmatogenous see rhegmatogenous retinal detachment secondary to optic disc abnormalities, 633, 635–636 serous, 423–424, 653–659 in sickle cell hemoglobinopathy, 559 tractional see traction traumatic, 671–674 ultrasound, 438 in uveitis, 699 vitrectomy, 467, 472 dialysis, 674 dystrophies, 480–490 cystoid macular edema complicating, 626, 628, 631 emboli emboli, retinal, 522, 996 exudates see exudates in glaucoma abnormalities causing glaucoma, 1094–1100 histopathology, 1054f hemorrhages see hemorrhage inherited degenerations see subheading above investigations and ancillary tests, 437–439 ischemia, iris neovascularization in, 1076b in laser photocoagulation, damage, 465–466, 564 light interaction, 461 light sensing, 19 see also photoreceptors necrosis acute (ARN), with VZV or HSV, 700–701 progressive outer (PORN), with VZV or, 700–701 nerve fibers see axons neural see neuroretina optical coherence tomography of, 449 various pathologies, 448 as optical element, 39–40 oximetry, 1048 peripheral ablation in retinopathy of prematurity, 538 peripheral lesions, 638–641 in toxocariasis, 744 pigment epithelium see pigment epitheliopathy; pigmented epithelium in proliferative vitreoretinopathy, 668 shortening, 666 prostheses/implants, 490 raytracing technique, 75, 78 surgery (basic principles), 461–466 tears (=full-thickness breaks), 642, 671 at ora serrata, 674 traumatic, 671, 674 telangiectasia, 560–564 toxicity of systemically-administered drugs, 683–686 traction on see traction trauma, 670–677 breaks due to, 642 intravitreal injection-associated, 478 light-related see light tumors (discrete), 654–655 astrocytoma, 833–835 differential diagnosis, 795 hemangioma, 836–839 leukemic infiltrates, 817 medulloepithelioma, 819 metastatic, 812 retinoblastoma see retinoblastoma serous retinal detachment with, 654–655 vasculature see vascular disorders; vascular supply see also fovea; Heidelberg Retina Tomograph; macula; subretinal cysticercosis

Index

ranibizumab in age-related macular degeneration, 589–592 bevacizumab vs., 592–596 photodynamic therapy plus, 596–597 choroidal neovascularization, 732 diabetic retinopathy, 546–547 retinal arterial macroaneurysms, 579 retinal vein occlusion-related macular edema branch vein occlusion, 533 central, 530 rarebit perimetry, 1037 Rathke’s pouch, 900–901 craniopharyngiomas and, 902–903 ray tracing, optical, 75, 83–84, 123 Rayleigh scattering, 27 RDS/peripherin gene mutations, 483, 494, 498 reactive arthritis and HLA-B27-associated uveitis, 749 reactive lymphoid hyperplasia, benign, 1325 reactive oxygen species see free radicals reading, visual processing in, 912 real-time ultrasound, 437 rebound nystagmus, 954, 954t rebound tonometry, 1021t receiver operating characteristic (ROC) curve, 1175–1176 receptors, light see photoreceptors recessive inheritance see autosomal recessive inheritance; X-linked recessive inheritance recombination (genetic), 2–3 reconstructive surgery eyelid, 1312–1317 ocular surface, 320–324 rectus muscles, 1260 blood supply, 1184 inferior capsulopalpebral head, 1184–1185 course and action, 1183, 1183f entrapment with orbital floor fractures, 1236 innervation, 1183 insertion, 1181 lateral course and action, 1182, 1183f recession, 1251 resection, 1253 medial course and action, 1182, 1183f recession, 1248–1251 resection, 1251–1253 restrictive ophthalmopathy, 935 origin, 1181 structure, 1184 superior course and action, 1182–1183, 1183f double deficiency (palsy) of inferior oblique and, 920, 1234–1235 surgery in congenital esotropia, 1208 in Graves’ dysthyroid orbitopathy, 1236–1237 in sixth nerve palsy, 1231 in third nerve palsy, 1227 vertical recession, 1251 resection, 1253 red blood cell lysis leading glaucoma (ghost cell glaucoma), 1087–1088, 1094 red eye, acute, with contact lenses, 286–287 red glass test, 1195 red–green color deficiency, congenital, 487 red–green glasses, 913 red–green test, Lancaster, 1195 red nucleus lesions (Benedickt’s syndrome), 924t, 955, 998–999 red reflex (fundus), 64, 70 reflection with fundus camera (from cornea and instrument), reducing, 71 specular, in slit lamp microscopy, 58 refraction cataract patients, 365–370 testing after surgery, 405 testing before surgery, 340–341, 365 compounds with different indexes of, 90 in esotropia (treatment of errors) accommodative esotropia, 1209–1210 congenital esotropia, 1208

1395

Index

1396

Retina Society classification of proliferative vitreoretinopathy, 667 retinal acuity testing, potential, after cataract surgery, 404 retinal arteries, 426, 518–525 branch, obstruction, 522–524 combined with central retinal vein obstruction, 525 central, 426, 1047–1048, 1261–1262 central, obstruction, 518–522 combined with central retinal vein obstruction, 524–525 ocular ischemic syndrome vs., 553 macroaneurysms see macroaneurysms in ocular ischemic syndrome, 552 retinal correspondence, 1198f anomalous (ARC), 1197–1198, 1202 normal (NRC), 1198f, 1202 testing, 1197–1198, 1203–1204 retinal migraine, 972 retinal veins, 526–534 anatomy, 426 macroaneurysms, 577 obstruction/occlusion, branch (BRVO), 526–534, 570, 877 cystoid macular edema complicating, 533, 625 medical and ophthalmic work-up, 529 neovascularization, 531–533, 572–573 obstruction/occlusion, central (CRVO) combined with branch retinal artery obstruction, 525 combined with central retinal artery obstruction, 524–525 combined with cilioretinal artery obstruction, 524 cystoid macular complicating, 530, 626 iris neovascularization in, 530, 1076 ischemic, 527–528 nonischemic, 527 in ocular ischemic syndrome, 552 retina–brain (neural) system contrast sensitivity function, 44 image processing, 45 retinitis CMV see cytomegalovirus VZV or HSV, 700–701 see also chorioretinitis; neuroretinitis retinitis pigmentosa, 11–12, 480 courses and outcomes, 486 diagnosis and ancillary tests, 482–483 electroretinogram, 459 differential diagnosis, 485t epidemiology and pathogenesis, 480–481 genetics and pathology, 11–12, 480, 483–485, 485t inverse, 484 neovascularization, 573 ocular findings/manifestations, 483–484 rod–cone dystrophy, 481 systemic associations, 485–486 treatment, 489 acetazolamide therapy, 489, 631 X-linked (XLRP), 484, 485t, 486, 488, 504 retinoblastoma, 793–800 germinal, 793, 795–796, 799 glaucoma and, 1099 inheritance, 12, 16, 793 serous retinal detachment, 655 retinochoroidal… see chorioretinal… retinochoroiditis see chorioretinitis retinochoroidopathy see chorioretinopathy retinoma, 794–795 observation, 799 retinopathy acute zonal occult outer, 786 cancer-associated, 485t diabetic see diabetes hypertensive see hypertensive retinopathy lightning, 463 melanoma-associated, 485t, 792 paraneoplastic syndrome-associated, 792 photic, 461–465 pigmentary, systemic associations and differential diagnosis, 485–486 postinfectious, 485t of prematurity see prematurity

retinopathy (Continued) proliferative, 570–574 proliferative sickle (PSR), 555–556, 558–559 Purtscher’s, 679–680 radiation see radiation solar, 462–463 toxic, 485t Valsalva, 681–682 see also chorioretinopathy; neuroretinopathy; vitreoretinochoroidopathy; vitreoretinopathies retinopexy, 644–645 pneumatic see pneumatic retinopexy in rhegmatogenous retinal detachment, 651 retinoschisis, 573 degenerative adult, 640 detachment associated with, 649–651 X-linked (juvenile/congenital), 5–6, 12, 485t, 509–511, 573, 640 retinoscopic principle in automated objective refractometry, 67 retinoscopy, 51, 53–54, 64–66 retraction, eyelid see eyelid retractor muscles of eyelid inferior, laxity, 1285–1286 major, 1256 reattachment in entropion, 1280–1281 sympathetic accessory, 1256 retrobulbar block cataract surgery, 357 strabismus surgery, 1247 retrobulbar hemorrhage in peribulbar block, 358 retrochiasmal pathways, 909–911 anatomy, 909–910 topographical diagnosis of disease, 910–911 retroillumination in slit lamp microscopy, 58 retrolental debris with contact lenses, 285 retroviral vector in gene therapy, 7f Rezoom, 158 clinical studies, 158–159 rhabdomyosarcoma, 1321–1322 rhegmatogenous retinal detachment, 646–652 glaucoma and, 1088–1089 predisposing conditions, 648–649 diabetic retinopathy, 545 sickle cell hemoglobinopathy, 559 surgical repair see sclera, buckling rheology, aging vitreous, 433 rheumatoid arthritis, corneal ulceration in, 249–251 peripheral ulcerative keratitis, 238–239, 250 rheumatoid factor-negative polyarthritis (in juvenile idiopathic arthritis), 750 rhodopsin, 19 genes, 484 mutations, 11–12, 483–485 rhytids see wrinkles riboflavin–UVA in keratoconus and other ectasias, 116 RIDE studies, 547 Ridley posterior chamber IOL, 331 Rieger’s syndrome, 10, 175 rigid (gas permeable/GP) contact lenses, 52 aspheric, 53 astigmatism, 53 colored, 53 complications with, 280 fitting, 54 unusual surface configuration, 53 rigid IOLs, modern, 332 RISE studies, 547 rituximab in juvenile idiopathic arthritis-related uveitis, 751 river blindness see onchocerciasis Rizutti’s sign, 252 RNA, messenger (mRNA), 1 rod(s) (bacteria), gram-negative, causing keratitis, 220 rod(s) (photoreceptors), 39 dark adaptation and, 45 see also cone-rod dystrophy rod–cone dystrophy, 481 Rodenstock contact lens, 59 root mean square of wavefront errors, 117, 120– 123, 172 rosacea (acne rosacea) and blepharitis, 178–179

Rothmund–Thompson syndrome, 415 round holes (retina) with opercula, 642 without opercula, 642 rubella, 186, 702t, 703 Fuchs’ heterochromic iridocyclitis and, 773 rubeola (measles), 186, 702t, 703 rubeosis iridis, 1077b ruboxistaurin, diabetic retinopathy, 547

S

saccades (fast eye movements), 915–916 disorders/abnormalities, 918, 919b intrusions and oscillations, 950–957 examination, 917 in non-organic visual loss, 913 saccular aneurysms, 932, 983, 985 SAILOR study, 592 salmon patch (retina) in sickle cell hemoglobinopathy, 556 Salzmann’s corneal degeneration, 272 SANA (Systemic Avastin Therapy for Neovascular AMD) study, 592 Sands of Sahara syndrome in LASIK, 115 sarcoidosis, 572, 753–757 ocular involvement, 753–754, 978 optic nerve, 755–757, 880 retinal neovascularization, 572 serous retinal detachment, 656 treatment, 756–757, 978 sarcoma, Kaposi’s, 202 see also lymphoma; rhabdomyosarcoma Sattler’s layer, 426 SC scaffold, ab interno, 1136–1137 scaffold device in glaucoma, 1136–1137 scalar waves, 23 scanning laser ophthalmoscopy choroidoretinal vessels, 428, 441 confocal see confocal scanning laser technology scanning laser polarimetry (SLP), glaucoma screening, 1009–1010 scanning peripheral anterior chamber depth analyzer, 1065 scanning slit refractometer, 108, 123–125 scar brow lift, 1358 corneal, 308–310 as photorefractive keratectomy complication, 99–101 phototherapeutic keratectomy for, 308–310 glaucoma surgery-related, antifibrotic agents preventing formation, 1083, 1152–1158 scattering (of light), 27 corneal, after phototherapeutic keratectomy, 310 intraocular, 39 sclerotic, in slit lamp microscopy, 58 Scheie grading system, angle-closure glaucoma, 1065 Scheie line, 1024 Scheimpflug photography in angle-closure glaucoma, 1065 Scheiner’s method and corneal measuring instruments, 57–58, 67 Schiøtz indentation tonometry, 1021t Schirmer’s test, 277, 1347 Schlemm’s canal (SC) in glaucoma canaloplasty, 1140–1142, 1145 in minimally-invasive surgery, 1134 stents, 1135–1136 obstruction, 1081 Schmidt–Rimpler refractor, 66 Schnyder crystalline dystrophy, 262 Schwalbe’s line (posterior embryotoxon), 174–175, 1024, 1065, 1096, 1121 identification for laser trabeculoplasty, 1121 schwannoma (neurilemmona) benign, 1323 malignant, 1323–1324 Schwartz (Schwartz–Matsuo) syndrome, 773, 1094–1095 scintillating scotoma, migraine with aura, 971

senile scleral plaques, 204 senile verruca, 1296 Senior–Loken Syndrome, 485t sensation, corneal, decreased, differential diagnosis, 247b sensing of light see light; photoreceptors sensitivity of tests (in glaucoma ), 1175–1176 sensory adaptations in strabismus, 1197–1200 sensory fusion, 1201 sensory nerve supply to orbit, 1261 eyelids, 1256–1257 sensory status in strabismus (and its assessment), 1199, 1201–1205 septic cavernous sinus thrombosis, treatment, 987 septo-optic dysplasia, 871 serological detection (of antibodies) Epstein-Barr virus, 701–702 herpes simplex keratitis, 235 herpes zoster disease, 181–182 leptospirosis, 715 toxoplasmosis, 741 Treponema pallidum, 711 serous chorioretinopathy, central, 423–424, 605– 609, 653–654 serous choroidal detachment, 660–662 serous choroidal effusions vs. aqueous misdirection syndrome vs., 1093t serous detachments of neural retina, 424, 653–659 see also central serous chorioretinopathy serpiginous choroiditis (helicoid peripapillary chorioretinal degeneration; geographical helicoid peripapillary choroidopathy), 780–781 inherited form, 500 tuberculosis, 717–718 Serratia keratitis, 220 setons, 1159 sex see gender sex-linked recessive inheritance see X-linked recessive inheritance Shaffer grading system, 1025 angle-closure glaucoma, 1065 shaken baby syndrome, 680–681 Sheridan–Gardner method, 1190 Sherrington’s law, 1186 shingles see varicella zoster virus shunt devices in glaucoma subconjunctival micro-shunt, 1142 suprachoroidal shunts ab externo, 1142–1143 ab interno, 1143–1144 tube shunt see drainage implants/devices sickle cell hemoglobinopathy, 555–559, 572 hyphema, 1085 neovascularization, 556, 572 proliferative retinopathy (PSR), 555–556, 558– 559, 572 side-gaze observations in esotropia, 1207 siderosis with iron-containing foreign bodies, 675 sight see vision sildenafil retinotoxicity, 684 silicon oil tamponade, 474 silicone hydrogel contact lens follow-up, 56 problems with, 56 infectious keratitis, 288 silicone tube shunts see drainage implants/devices simultaneous contact lens design, 53 simultaneous perception (binocular vision), 1202–1203 sine waves and contrast sensitivity testing, 43–44 single fiber electromyography (SFEMG), myasthenia gravis, 939 single nucleotide polymorphisms, 1–2 single-photon emission tomography (SPECT), 855 sinus disease (incl. sinusitis), headache due, 974 location of pain to, 970f Sjögren’s syndrome diagnosis and testing, 979 epidemiology and pathogenesis, 977 ocular manifestations, 978 tear deficiency (SSTD), 275–276 skew deviation, 920, 935 transient, infancy, 921 skin conditions see entries under dermatograft, ectropion, 1289

skin (Continued) incision for blepharoplasty, 1355 injectable fillers, 1359–1361 lightly-pigmented people, UV vulnerability, 29 scar, from brow lift, 1358 wrinkles see wrinkles skin tag, 1295 skull fracture, 989 slit-lamp (bio)microscope, 58 cataracts, 335 glaucoma, 1022–1024 angle-closure, 1064 iris examination, 964 macular hole, 611 posterior polymorphous corneal dystrophy, 267 posterior segment trauma, 670 preoperative (in refractive surgery), 93 retinoblastoma, 794 slow eye movements, 915–916 small aperture corneal inlay (Acufocus KAMRA), 155–157 small-incision cataract surgery, 371–377 incision construction and architecture, 371–372 lenticule extraction (SMILE), 86 nuclear expression (=mini-nuc technique), 347, 380–381 SMILE (small-incision lenticule extraction), 86 smoking cataracts and, 413 contact lens problems and, 282 glaucoma and, 1003–1004 see also tobacco–alcohol amblyopia Snellen chart, 42–43 young children, 1190 social aspects of cataract surgery, 341–342 social history, cataract surgery, 334 sodium ions and aqueous inflow, 1014–1015 soft contact lenses aspheric, 53 colored, 53 complications with, 280 fitting, 54 unusual surface configuration, 53 soft foldable IOLs, 332 solar keratosis, 1296–1297 solar lentigo, 1302–1303 solar retinopathy, 462–463 solute transport and aqueous humor formation, 1014 SOLX Gold micro-shunt, 1142–1143 Sorsby’s macular dystrophy, 12, 499 spacers (spacer grafts) in lid retraction surgery, 1270–1271 Spaeth angle grading system, 1025–1026, 1065 Spaeth colored glaucoma graph, 1027f Spaeth optic disc damage likelihood scale, 1027–1028 spasm hemifacial, 1293t, 1294 infantile (spasmus nutans), 952t, 953 near reflex, 921, 935 orbicularis oculi see blepharospasm spatial localization testing anisometropic amblyopia, 1238 stimulus–deprivation amblyopia, 1239 specificity of tests (in glaucoma ), 1175–1176 speckle dystrophy, 263 spectacles (glasses) accommodative esotropia, 1210 teenagers, 1211 aphakic children, 392 after IOL implantation, 393 in brain trauma, 989 color contrast with, improving, 30 contact lens-related blurring with, 52 contrast sensitivity, improving, 30 dark adaptation, improving, 30 glare sensitivity with, reducing, 30 nystagmus treatment, 957 photochromic lenses, 30–31 prism see prism spectacles UV-absorbing, 31 see also prescription; sunglasses

Index

sclera bare (technique), 313–314 buckling surgery (for retinal detachment incl. rhegmatogenous detachment), 467–470, 651 in Coats’ disease, 563 epiretinal membrane complicating, 469, 652 in proliferative vitreoretinopathy, 668 in retinopathy of prematurity, 539 in evisceration, 1342 fluid outflow deficits leading to serous retinal detachment, 655–656 in glaucoma, examination, 1022 oblique muscle insertion into, 1181–1182 perforation (in scleral buckling), 469 in presbyopia, surgery, 160–161 rectus muscle insertion into, 1181 section in large-incision cataract surgery, 378 senile plaques, 204 see also trans-scleral cyclophotocoagulation; trans-scleral resection scleral flap in trabeculectomy, 1148, 1150 antimetabolite agents under, 1155 closure, 1155–1156 tear/disinsertion, 1164 scleritis, 210–216 antimetabolite-related, 1157 posterior, 655–656 headache, 974 serous retinal detachment, 655–656 sclerocornea, 176 sclerocorneal pocket tunnel in mini-nuc extracapsular cataract extraction, 380 sclerokeratitis, 211 scleromalacia perforans, 210 sclerosing basal cell carcinoma, 1307, 1309 sclerosing keratitis, 250 sclerotic scatter in slit lamp microscopy, 58 sclerotomy posterior, in choroidal hemorrhage, 662 historical introduction, 662 relaxing, in evisceration, 1342 SCORE study branch retinal vein occlusion, 533 central retinal vein occlusion, 530 scorpion toxin, 937t scotoma in migraine with aura, 971 in monofixation syndrome, 1204 with optic chiasmal lesions, 904–905 paracentral, 1030 suppression, 1197–1199, 1202–1203 screening for glaucoma see glaucoma for retinopathy of chloroquine and hydroxychloroquine toxicity, 683–684 for retinopathy of prematurity, 538, 538b telemedicine, 539 for uveitis in juvenile idiopathic arthritis, 751 for von Hippel–Lindau syndrome, 847b seafans, retinal, in sickle cell hemoglobinopathy, 556 seasonal allergic conjunctivitis, 192 sebaceous gland lesions of lids benign, 1298 malignant (=carcinoma; SGC), 1309–1310 differential diagnosis, 1307t seborrheic keratosis, 1296 secretion of tears see tears sector occlusion, 1244 sedatives, cataract surgery, 359 see-saw nystagmus, 905, 955, 955t segmental buckles, 468 segregation (in genetics), 2 seizure, facial, 1293t selection bias, glaucoma therapy studies, 1175 self-sealing corneal perforations with incisional keratotomy, 144–145 sellar region anatomy, 901f neuroimaging of lesions, 905–906 semi-automated laser photocoagulation in diabetic retinopathy, 548 senile arcus, 269 senile corneal furrow degeneration, 270 senile keratosis, 1296–1297 senile lentigo, 1302–1303

1397

Index

1398

spectral domain optical coherence tomography, 448 artifacts, 457 chloroquine and hydroxychloroquine retinotoxicity, 684 optic nerve head/optic disc, 1043–1044 pit, 632 retinal arterial macroaneurysms, 576 specular microscopy, 62–64 Fuchs’ corneal dystrophy, 265 posterior polymorphous corneal dystrophy, 267 specular reflection in slit lamp microscopy, 58 spherical aberration, 77–78, 171 correction, 73, 78 LASIK for spherical hyperopia or astigmatism, 117 spheroidal degeneration, 270–271 sphingolipidoses, 291, 293t spin echo MRI, 852 spindle nevus cells, 823 spinocerebellar ataxia (SCA), 980 spiral of Tillaux, 1181 spirochetal uveitis, 709–715 sponges for antifibrotic agent delivery, 1155 spontaneous respiration with general anesthesia in cataract surgery, 360 squamous cell carcinoma (SCC), 1308–1309 differential diagnosis, 1307t squamous epithelium (conjunctival/corneal), stratified, tumors, 196–198 squamous papilloma, 1295 square-wave jerks, 956 squint see strabismus SRK equation, 57–58 staining bacterial, keratitis, 221 corneal, with contact lenses, 284 hyperfluorescence due to, 443b, 444 intraoperative tissue staining, 473 Standards for Reporting of Diagnostic Accuracy (STARD) initiative, 1176 staphylococci conjunctivitis, 184 keratitis, 219 star folds, proliferative vitreoretinopathy and, 666 Stargardt’s disease, 12, 491–494 Steele–Richardson–Olszewski syndrome, 919 stem cells (keratolimbal), 164 deficiency/failure, 320 with chemical burns, 320f partial, operative procedures, 321–323 total, operative procedures, 321–323 in retinal degeneration therapy, 489–490 transplantation (predominantly autografts), 321 with chemical burns, 298 historical perspectives, 312, 320 stenopeic slit, 51 stents, bypass, 1135–1136, 1143–1144 stereoacuity, 1201–1202 stereopsis, 1201–1202 binocular indirect ophthalmoscope, 69 tests, 1204 stereotactic radiotherapy, choroidal/ciliary body melanoma, 807 steroids (corticosteroids; glucocorticoids) acid/alkali burns, 297 arteritic anterior ischemic optic neuropathy, 887 blepharitis, 179 cataract surgery intraoperative, 353t postoperative, 354 Coats’ disease, intravitreal, 563–564 complications, 564 diabetic retinopathy, 547 endophthalmitis, 727 episcleritis, 209–210 giant-cell arteritis, 986–987 Graves’ ophthalmopathy, 948 herpes zoster, 182 inflammatory myopathies, 949 IOP elevation and glaucoma induced by, 1019, 1080–1083 mimicking primary open-angle glaucoma, 1013

steroids (corticosteroids; glucocorticoids) (Continued) keratitis Acanthamoeba, 229 bacterial, 223 fungal, 227 HSV, 235–236 peripheral ulcerative, 240, 250 myasthenia gravis, 940 optic nerve trauma, 899 optic neuritis in multiple sclerosis, 882 pseudophakic cystoid macular edema, 630 radiation papillopathy, 569 radiation retinopathy, 568 preventive use, 568 retinal vein occlusion branch, 533 central, 530 scleritis, 213, 215 Tolosa–Hunt syndrome, 936 uveitis, 697, 698t, 1081–1082 in Behçet’s disease, 760 in birdshot chorioretinopathy, 779 of idiopathic or syndromic causation, 772 intermediate uveitis, 775 intravitreal implants, 478 in progressive subretinal fibrosis and uveitis syndrome, 778 in relentless placoid chorioretinitis, 782 in sarcoidosis, 756–757 in serpiginous choroiditis, 781 sympathetic, 768 in Vogt–Koyanagi–Harada disease, 763 Stevens–Johnson syndrome, 189–190 Stickler’s syndrome (hereditary arthroophthalmopathy), 508–509 proliferative vitreoretinopathy and, 667 stimulus–deprivation amblyopia, 1238 diagnosis/ancillary testing and experimental anatomic and physiological changes, 1241 epidemiology and pathogenesis, 1238 ocular manifestations, 1239 strabismus/squint (adult and pediatric), 1181–1187 alphabet-pattern, 1214–1215, 1221–1224 V-pattern, 1217–1218 X-pattern, 1223 amblyopia with, 1238 diagnosis/ancillary testing and experimental anatomic and physiological changes, 1241 epidemiology and pathogenesis, 1238–1239 ocular manifestations, 1239 anatomical correlates, 1185–1186 diagnosis, 1188–1191 evaluation and diagnosis, 1188–1191 ocular manifestations, 1201–1205 paralytic, 1225–1232 pulley issues, 1185 sensory adaptations, 1197–1200 sensory status and its assessment, 1199, 1201–1205 treatment, 1208, 1210–1211, 1244–1246 non-surgical, 1244–1246 surgical see surgery vertical non-paretic, 1233–1237 strabismus fixus, 1212 convergent, 1237 stratified squamous epithelium (conjunctival/ corneal), tumors, 196–198 strawberry nevus see capillary hemangioma stress headache precipitated by see tension-type headache physiological corneal endothelium responses to, 165–166 glaucomatous optic neuropathy in response to, 1016 see also oxidative stress stroke, 998–999 Amsler chart testing, 998 gaze palsy, 918 stroma, choroidal, 688–689 stroma, ciliary process, fluid uptake from, 1014 stroma, corneal acute (non-infectious), 250 anatomy/embryology/physiology, 164

stroma, corneal (Continued) in anterior basement membrane dystrophy, treatment via puncture, 257 in Descemet’s membrane endothelial keratoplasty hybrid technique (DMEK-S), 316, 318 dystrophies, 259–263 HSV keratitis/keratouveitis involving, 234–235 treatment, 235–236 injury responses (healing), 166 in keratorefractive surgery, 164 addition, 84 melting after astigmatic or radial incisional keratotomy, 145–146 subtraction/ablation, 84–85, 97 wound healing after incisional keratotomy, 141 see also entries under intrastromal Sturge-Weber syndrome, 848 choroidal hemangioma, 826, 848 choroidal hemorrhage, 664 glaucoma, 1022t subacute sclerosing panencephalitis, 702t, 703 subarachnoid lesions, bilateral ophthalmoplegia, 933 subcapsular opacities, posterior, 336 subconjunctival cysticercosis, 745 subconjunctival micro-shunt, 1142 subepithelial amyloidosis of the cornea, familial, 260 subepithelial keratomileusis, laser see LASEK subgleal fat pads, 1353 subjective alignment in automated refractometry, 67 subretinal cysticercosis, 746 subretinal fluid, 454 in age-related macular degeneration, 585 in central serous chorioretinopathy, 606 drainage (during scleral buckling), 468–469 complications, 469 eye movement effects on, 648 in optic disc abnormalities, 635 optical coherence tomography, 454 in rhegmatogenous retinal detachment, 648 subretinal hemorrhage see hemorrhage subretinal membranes in proliferative vitreoretinopathy, 668 sub-Tenon’s block, 358–359 suction trephine, Hessburg–Barron, 300 sulcus-supported posterior chamber IOLs see posterior chamber (sulcus-supported) IOLs sumatriptan, migraine, 971–972 sun, light from, 19 see also ultraviolet and entries under solar sunglasses color contrast with, improving, 30 contrast sensitivity improvement, 30 dark adaptation, improving, 30 glare sensitivity with, reducing, 30 photochromic lenses, 30–31 UV-absorbing, 31 UV damage by, suggestion of, 31 sunlight, UV from see ultraviolet sunset syndrome, 401 superficial basal cell carcinoma, 1307 superficial corneal procedures, 306–307 keratectomy see keratectomy superficial granular dystrophy, 258 superficial punctate keratopathy see punctate epithelial erosion superficial spreading melanoma, 1310–1311 superior vena cava syndrome, glaucoma, 1022t suppression, 1197–1198 scotoma, 1197–1199, 1202–1203 suprachoroidal drainage devices, 1142–1144 suprachoroidal hemorrhage aqueous misdirection syndrome vs., 1093t trabeculectomy complicated by, 1164–1165 supranuclear control of ocular motility, 915–921 anatomy, 915–917 disorders, 918–920 diagnostic testing, 917–918 surface, corneal (in refractive surgery) ablation/subtraction, 81, 84–85 excimer laser keratomileusis, 95 addition, 97

surgery (ocular) (Continued) in pigmentary glaucoma, 1074–1075 in pseudoexfoliation glaucoma, 1072 keratitis Acanthamoeba, 229 bacterial, 223 fungal, 227 HSV, 236 peripheral ulcerative (incl. Mooren’s ulcer), 241, 246, 250 keratoconus, 254 macular hole, 610–612 nystagmus, 957 operating microscope, 64 optic nerve and chiasm (intracranial) tumors glioma, 908 meningioma, 907 optic nerve sheath decompression, 887 in dysthyroid optic neuropathy, 887, 948 orbital, 1333–1338 penetrating posterior segment injury, 675 pituitary tumors, 907 proliferative vitreoretinopathy, 668–669 protection from light in, 30 refractive see refractive surgery retina basic principles, 461–466 retinal breaks, 644–645 retinal serous detachment, 659 retinopathy of diabetes, 547–550 of prematurity, 539 scleral buckling surgery see sclera scleritis, 216 sickle cell hemoglobinopathy, 559 strabismus, 1247–1254 in accommodative esotropia, 1208, 1210–1211 amblyopia and, 1243 anesthetic, 1247–1248 complications, 1254 in dissociated vertical deviation, 1234 in exotropia, 1215–1216 general techniques, 1248 historical review, 1247 paralytic, 1227, 1229–1231 preoperative evaluation and testing, 1247 specific techniques, 1248–1254 uveal and intraocular tumors choroidal/ciliary body melanoma, 806–809 iris melanoma, 803 medulloepithelioma, 820 retinal astrocytoma, 834–835 uveitis intermediate, 775 toxoplasmosis-associated, 742 vitreomacular traction syndrome, 621 see also postoperative/postprocedural management; preoperative/preprocedural period and specific techniques suspensory ligament of Lockwood, 1184–1185 suture(s) in entropion, in non-surgical management, 1280 in lamellar keratoplasty, 304 in penetrating keratoplasty, 300 problems, 301 sutured posterior chamber IOL, 398 Sveinsson chorioretinal atrophy, 500 Swan’s approach, 1248 Swedish Interactive Threshold Algorithm (SITA), 1029, 1036 sympathetic innervation of iris, 960f denervation see Horner’s syndrome pupillary inequalities/anisocoria relating to, 960–963 diagnosis of location of damage, 962 sympathetic innervation of orbit, 1261 accessory retractor innervation, 1256 sympathetic ophthalmia in penetrating injury, 676 post-cyclophotocoagulation, 1106 serous retinal detachment in, 656 sympathetic uveitis, 762, 767–769 sympathomimetics in cataract surgery, preoperative, 351 Synchrony dual optic lens, 88, 160

synchysis scintillans, 435–436 synechiae peripheral anterior, 1081, 1087 posterior, 1081 synkinesis, facial, 1293t syphilis (Treponema pallidum infection), 709–712 optic neuritis, 881 syringoma, 1298 chondroid, 1298 systemic congenital anomalies genetic counseling, 17 in Peters’ anomaly, 175–176 systemic disease in Behçet’s disease, 759–760 brain/CNS associations brain injury, 989 drugs and toxins, 990 cataracts and causation in systemic disease, 415 surgery and history of systemic disease, 334, 335t central serous chorioretinopathy associations, 605, 607–608 choroidal blood flow disruption in, 655 choroidal dystrophy associations, 505 choroidal hemangioma associations, 826 choroidal hemorrhage associations, 660 Coats’ disease, 563 conjunctival amyloid in, 204 corneal dystrophy macular dystrophy, 262 Schnyder crystalline dystrophy, 262 external ocular (incl. corneal) manifestations, 290–295 Coogan’s syndrome in, 246 corneal dystrophy see subheading above keratoconus, 253 onchocerciasis, 231 scleritis, 212–213 eyelid malignancies basal cell carcinoma, 1306–1308 melanoma, 1310 glaucoma associations episcleral venous pressure elevation-related, 1091 normal-tension, 1058 primary angle-closure, 1005 primary open-angle, 1003–1004 pseudoexfoliation, 1070 hypertensive retinopathy, 516 ischemic optic neuropathy associations, 886 leukemia associations, 818 lymphoma associations, 816 medulloepithelioma associations, 820 metastatic cancer associations, 812 myopathy associations dystrophic, 945–946 in Graves’ disease, 948 mitochondrial, 944 neuromuscular disorder associations botulism, 941 Lambert–Eaton myasthenic syndrome, 942 myasthenia gravis, 939 nutritional optic neuropathy associations, 892 ocular ischemic syndrome associations, 553 optic chiasma/parasellar/pituitary fossa lesions, 906 optic disc edema associations, 877 optic nerve/nerve sheath tumor associations, 896 in posterior uveitis of unknown cause acute posterior multifocal placoid pigment epitheliopathy, 780 multifocal choroiditis and panuveitis, 783 pseudoexfoliation syndrome, 1070 Purtscher’s retinopathy association, 679b as refractive surgery contraindication, 91 retinal arterial macroaneurysms associations, 578 retinal artery obstruction branch, 523 central, 520–521 retinal break associations, 643 retinal degeneration (incl. retinitis pigmentosa) associations, 485–486, 485t retinal detachment (rhegmatogenous) associations, 651

Index

surface, ocular (in general), 163–167 diseases, 163–167 excessive exposure of see exposure glaucoma medications and the, 1022 inflammation, 278 reconstructive surgery, 320–324 surface coils (MRI), 853 surgery (ocular) aneurysm (intracranial), 987 blepharoptosis, 1275–1276 complications, 1276–1277 blepharospasm, 1292 carotid–cavernous fistula, 936 cataract see cataract choroidal hemorrhage, 662–663 choroidal neovascularization, 732 cicatricial pemphigoid, 208 Coats’ disease, 563 conjunctival, 312–314 pterygium see pterygium tumors see subheading below corneal, non-refractive/therapeutic (and incl. other ocular surfaces), 299–307 chemical burns, 298 keratitis see subheading below perforations, 325–327 reconstructive surgery, 320–324 superficial procedures, 306–307 tumors see subheading below corneal, refractive see keratorefractive surgery corneal and conjunctival tumors choristoma, 201 epithelial, 197 melanocytic nevi, 199 melanoma, 199–200 cosmetic, 1352–1358 cranial nerve palsies IIIrd, 926, 1227 IVth, 926, 1229–1230 VIth, 926, 1231 craniopharyngioma, 907–908 cystoid macular edema following, 626–627, 630 cystoid macular edema treated by, pseudophakic eyes, 630 endophthalmitis bacterial, 727 fungal, 737 epiretinal membrane, 618 extraocular muscles in Brown’s syndrome, 1235–1236 in double elevator palsy, 1234 in Graves’ dysthyroid orbitopathy, 1236–1237 inferior oblique muscle overaction, 1218, 1234 in orbital floor fracture, 1236 rectus muscles in congenital esotropia, 1208 in strabismus see subentry below eyelid ectropion, 1286–1290 alternatives to, 1286 complications, 1290–1291 eyelid entropion, 1280–1282 alternatives to, 1279–1280 complications, 1282–1283 eyelid malignancies basal cell carcinoma, 1308 melanoma, 1311 squamous cell carcinoma, 1309–1310 eyelid ptosis (blepharoptosis) see subheading above eyelid retraction, 1270–1271 alternatives to, 1269–1270 complications, 1268 eyelid trauma, reconstructive, 1312–1317 in glaucoma, 1082–1083, 1112–1113, 1120–1124 in angle-closure glaucoma, 1066–1069 antifibrotic agents see antifibrotic agents in aqueous misdirection syndrome, 1093 complications, 1164–1169 endophthalmitis following, 724 in episcleral venous pressure elevation-related glaucoma, 1091 minimally-invasive and non-penetrating, 1133–1145 in normal-tension glaucoma, 1059 pediatric, 1105 phacoemulsification combined with, 382

1399

Index

systemic disease (Continued) retinal neovascularization associations, 570–572 retinal pigment epithelium hypertrophy, 843 retinal tumor associations astrocytoma, 834 capillary hemangioma, 837 cavernous hemangioma, 839 combined hamartoma, 841 retinoblastoma, 795–796 retinal vein occlusion branch, 533 central, 529 retinopathy of prematurity associations, 537 in sarcoidosis, 755–756 sickle cell hemoglobinopathy associations, 557–558 Stickler’s syndrome associations, 509 strabismus associations in Duane’s syndrome, 1212 in Möbius’ syndrome, 1211 in sympathetic uveitis, 768 uveal nevus associations, 822–823 uveitis associated with, 748–752 HLA-B27 and, 749 in uveitis-causing infections leptospirosis, 714 Lyme disease, 713 onchocerciasis, 746 syphilis, 711 toxoplasmosis, 739 in Vogt–Koyanagi–Harada disease, 762 see also pre-existing medical conditions systemic lupus erythematosus (SLE), 978 optic neuritis and, 881 pathology, 979 retinal neovascularization, 572 serous retinal detachment, 655 systemic necrotizing vasculitides, 977–979 systemic reviews of glaucoma trials, 1174 systemic stabilization of traumatized patient, 1312

T

1400

T cells, 690–691 inhibitors, in uveitis, 698t NK, 691 see also human T cell lymphotropic virus type 1 T1 and T2 weighting in MRI, 852 tacrolimus, Behçet’s disease, 760 Taenia solium and cysticercosis, 745–746 Takayasu’s arteritis (pulseless disease; aortic arch syndrome) ocular ischemic syndrome vs., 553 retinal neovascularization, 571 talc embolization, 573 tamoxifen retinotoxicity, 685 tangential illumination in slit lamp microscopy, 58 tapeworm, port (Taenia solium and cysticercosis), 745–746 target postoperative refraction in cataract surgery, 405 tarsal muscle, inferior, 1184–1185 tarsoconjunctiva diamond excision, 1286–1287 flap, for trauma repair, 1315 tarsorrhaphy, lateral, 1290 tarsotomy, transverse, 1280, 1282 tarsus/tarsal plates anatomy, 1256 assessment, 1278 see also horizontal tarsal kink syndrome; lateral tarsal strip procedure TBK1 gene duplication, 1171 tears artificial, 277 colored swirls in tear film, 25 deficiency, 274–278 fluorescein staining of tear film see fluorescein staining physiology, 274, 1346 production/secretion agents stimulating (secretagogues), 278 excessive, 1346–1348 measurement, 277, 1347 reduced/deficient, 274–278 stability of tear film, assessment, 277

TECHNOLAS femtosecond laser, presbyopia, 153–154 teenagers, bifocals for accommodative esotropia, 1211 telangiectasia, retinal, 560–564 juxtafoveal see juxtafoveal retinal telangiectasia see also ataxia telangiectasia; Coats’ disease telemedicine glaucoma screening, 1010 retinopathy of prematurity screening, 539 telescope, Galilean, 72 Teller acuity cars, 1189f temporal (giant-cell) arteritis, 974, 977, 983 course and outcome, 987 diagnosis and testing, 979, 984–985 differential diagnosis, 985 epidemiology and pathogenesis, 976 ischemic optic neuropathy and, 884–886 ocular manifestations, 978, 983–985 pathology, 979, 986 treatment, 986–987 temporal lobe injury, visual field defects, 910, 910f medial (MT), motion detection and, 912 tumors, 976 temporal onset of orbital diseases, 1318t tendency-oriented perimetry, 1036 tendon sheath of superior oblique muscle, short anterior (=Brown’s syndrome), 935, 1235–1236 Tenon’s capsule, 1184, 1260 clinical correlates, 1185 posterior, violation in strabismus surgery, 1254 in scleral buckling, 469 tension (stress)-type headache, 973 classification, 971b location of pain, 970f Tenzel flap, 1314f Terrien’s marginal degeneration, 248–249 Terson’s disease, 678–679 tetanus immunization, 1312, 1313t tether phenomenon/effect Duane’s syndrome, 1211–1212 X-pattern strabismus, 1223 Tetraflex lens, 88 TGF, monoclonal antibody to, as antifibrotic agent, 1156 Theodore’s superior limbal keratoconjunctivitis, 243–244, 283–284 thermal burns see burns thermokeratoplasty, 87–88 microwave-induced, 88 thermotherapy, transpupillary see transpupillary thermotherapy thiazolidinedione retinotoxicity, 686 Thiel–Behnke dystrophy, 258 thin film interference, 25 thioridazine retinotoxicity, 684 three-dimensional analysis, ultrasound, 437 threshold Amsler chart testing, optic nerve vs. macular disorders, 869–870 threshold visual field in primary open-angle glaucoma, 1053–1054 thrombosis, intracranial cavernous sinus see cavernous sinus venous, 875 Thygeson’s superficial punctate keratitis, 242–243 thymectomy, myasthenia gravis, 940 thyroid eye disease (Graves’ dysthyroid ophthalmopathy/orbitopathy), 895, 940t, 1236–1237, 1327–1328 cavernous sinus thrombosis or orbital apex syndrome vs., 985 glaucoma and, 1022t lid retraction, 1269 repair, 1270f–1271f neuromuscular junction, 940t orbital inflammation, 947, 1327–1328 tic, facial, 1293t tic douloureux see trigeminal neuralgia tick paralysis, 937t tight junctions (blood–retinal barrier), 426–427 tight lens syndrome, 286 TIGR see myocilin Tillaux’s spiral, 1181

tilt head, eye position during, 916f, 920 ocular tilt reaction, 920, 935 tilted disc syndrome, 873 time domain optical coherence tomography, 448 artifacts, 457 time encoded domain optical coherence tomography, 448 time factors in onset of orbital diseases, 1318t time-of-flight MRA, 854 tissue(s) contrast see contrast eyelid injuries with loss of, 1314–1315 light interactions with, 26–27 necrosis with fillers, 1361 staining, intraoperative, 473 tissue adhesives see adhesives tissue plasminogen activator, intravitreal injections with retinal arterial macroaneurysms, 579 Titmus stereotest, 1204 TNF see tumor necrosis factor tobacco–alcohol amblyopia, 890 see also smoking tobramycin, keratitis, 222 tolerance (immune), 691–692 Tolosa–Hunt syndrome, 934, 936 cavernous sinus thrombosis or orbital apex syndrome vs., 985 tonic downward deviation of gaze (forced downgaze), 920 transient, infancy, 921 tonic pupil, Adie’s syndrome, 963f, 964 tonic upward deviation of gaze (forced/tonic upgaze), 920 transient, infancy, 921 tonic upward gaze, benign paroxysmal, 920 tonometer (IOP measurement and tonometry), 1020 children, 1103 Goldmann applanation tonometer, 59–61, 1020, 1021t, 1053 Tono-pen, 1021t topical anesthesia, cataract surgery, 356–357 Topographic Change Analysis (TCA), 1042–1043 topography, corneal, 57–58, 168, 341 in guidance of photoablation, 83, 110 combinations treatments with, 150 preoperative cataract surgery, 339, 341, 365 refractive surgery, 93 toric intraocular lenses, 88, 368–369 torsional phacoemulsification, 361f toxic agents (in causation) cataracts, 416 conjunctivitis contact lens-related, 284 toxic follicular conjunctivitis, 188–189 drugs as see drugs retinopathy, 485t visual pathway lesions see visual pathway lesions toxic epidermal necrolysis, 189–190 toxocariasis, 744–745 toxoplasmosis, 738–743, 881 Trabectome, 1137–1139, 1145 trabecular meshwork (TM) in glaucoma causation, 1012, 1080–1081 traumatic disruption, 1084–1085 micro-bypass stents, 1135–1136, 1143–1144 in minimally-invasive surgery, 1134–1135 Trabectome ablation, 1137–1139, 1145 trabecular meshwork glucocorticoid-inducible response protein (TIGR) see myocilin trabeculectomy (bleb filtration surgery), 1083, 1146–1151 ab interno (=Trabectome), 1137–1139, 1145 angle-closure glaucoma, 1068–1069 children, 1105 complications, 1164–1168 avoidance, 1150 bleb-related, 1154, 1165, 1168 drainage area under eyelid, position, 1155 indications, 1147 patient counseling, 1148 penetrating keratoplasty-related glaucoma, 1100 phacoemulsification and, 382

trial hard contact lenses before cataract surgery, 339 triamcinolone branch retinal vein occlusion, 530 Coats’ disease, 563–564 complications, 564 diabetic retinopathy, 546–547 radiation papillopathy, 569 radiation retinopathy, 568 preventive use, 568 trichiasis vs. entropion, 1279 trichilemmoma, 1299 trichoepithelioma, 1299 trichofolliculoma, 1299 trigeminal nerve branches supplying orbit, 1261 eyelids, 1256–1257 dysfunction with intracavernous aneurysms, 992–993 trigeminal neuralgia (tic doloureux), 974 location of pain, 970f triple procedure (keratoplasty + cataract surgery + IOL), 305, 383–384 triploidy, 4 triptans, migraine, 971–972 trisomies, 290t trisomy 13, 290t, 291f trisomy 21 see Down’s syndrome trochlear (IVth cranial) nerve, 1227–1230 anatomy, 927, 1261 extraocular muscle innervation, 1183, 1261 palsies, 924, 1227–1230 bilateral (peripheral), 932–933 combined with other cranial nerve, palsies, 931 congenital, 924, 1228–1229 diagnosis, 926, 932–933 differential diagnosis, 935 epidemiology, 1228 etiology and pathogenesis, 923b, 1228 isolated (peripheral), 933, 935 nuclear and fascicular, 924–925 oculomotor manifestations, 924–925, 929, 1228–1229 treatment, 926 Tropheryma whippelii, 721–722 trophic/metaherpetic ulcer (keratitis), 234, 236 tropias, 928 cover test, 1193–1194, 1194f see also cyclotropia; esotropia; exotropia; hypertropia Tscherning aberrometry, 75, 79, 123 TSPAN12 and familial exudative vitreoretinopathy, 511 tube shunt drainage devices see drainage implants Tube Versus Trabulectomy (TVT) Study, 1133, 1136, 1159–1160, 1162–1163, 1168–1169, 1178, 1178b tuberculoid leprosy, 719 tuberculosis, 716 tuberous sclerosis, 846–847 CNS tumors associated with see central nervous system glaucoma and, 1022t Tukel syndrome, 1236 tumbling E test, 1190 tumor(s) (neoplasms) conjunctival, 196–202 corneal, 196–202 cystoid macular edema with, 628, 631 eyelid benign, 1295–1304 malignant see malignant tumors intracranial/brain/CNS, 900–908, 976 pituitary see pituitary gland intraocular, 793–800 benign, 821–824 glaucoma secondary to, 1098–1099 iris neovascularization, 1076b malignant see malignant tumors; metastases masquerading as inflammatory disorders, 788–792 optic nerve-compressing, 894–897 ultrasound, 438 vitrectomy, 472 lacrimal sac, 1350

tumor(s) (neoplasms) (Continued) orbital, 1318–1327, 1330–1332 headache, 974 see also specific histological types tumor necrosis factor-α and glaucomatous optic neuropathy, 1017 and low-tension glaucoma, 1171 tumor necrosis factor inhibitors, scleritis, 216 tunnel field, 913 Turcot’s syndrome and retinal pigment epithelium hypertrophy, 843 Tyndall effect, 27 tyrosinase deficiency and albinism, 12–13 tyrosinemia, 291t Tzancksmear in HSV keratitis, 235

Index

trabeculectomy (bleb filtration surgery) (Continued) planning, 1147 postoperative care, 1150 preoperative factors, 1147 pseudoexfoliation glaucoma, 1072 studies, 1177b–1178b techniques, 1148–1150 trabeculodialysis, 1083 trabeculoplasty, laser (LTP), 1082, 1112–1113, 1120–1124, 1173–1174 historical review, 1111, 1120–1122 pigmentary glaucoma, 1074–1075 trabeculostomy/trabeculotomy, 1129–1132 endoscopic excimer laser, 1134 laser-assisted endoscopic, 1134 Trabio, 1156 trachoma, 186 tracking photorefractive keratectomy, 96 wavefront-based surgery, 125 traction (retinal), 647–648 cystoid macular edema in, 626, 628, 631 retinal detachment due to, 647–648 in retinopathy of diabetes, 545, 550 in retinopathy of prematurity, surgery, 539 in sickle cell hemoglobinopathy, surgery, 559 transblepharoplasty brow fixation, 1357 transconjunctival approach to blepharoplasty, 1355 transforming growth factor (TGF), monoclonal antibody to, as antifibrotic agent, 1156 see also latent transforming growth factor beta binding protein 2 transient ischemic attacks, 998–999 transillumination defect, iris, 1024, 1071, 1073–1074 transitional multifocality, presby-LASIK by, 152 transpalpebral tonometry, 1021t transparency, dioptric media, 22 transplantation and grafting amniotic membrane see amniotic membrane with chemical burns, 298 conjunctiva, after pterygium excision, 314 corneal see keratoplasty donor see donor selection in lid surgery for ectropion, 1289 for entropion, 1282 for retraction, 1270–1271 see also graft-versus-host disease; post-transplant lymphoproliferative disorders transposition flap (eyelid) for ectropion, 1288–1289 for trauma, 1315 transpupillary (infra-red laser) thermotherapy choroidal or ciliary body melanoma, 808 retinoblastoma, 798 trans-scleral cyclophotocoagulation (TCP), 1125– 1128, 1126t, 1128t trans-scleral resection of choroidal or ciliary body melanoma, 808–809 trans-sphenoidal encephalocele, 871–872 transverse tarsotomy, 1280, 1282 trauma (mechanical injury), 670–677 blunt see blunt injury brain, 988–989 Bruch’s membrane rupture due to, 600–601 canalicular, 1290–1291 cataracts and, 415 central retinal artery associated with, 521 choroidal hemorrhage due to, 663–664 corneal and ocular surface, chemical burns see chemical burns eyelid, and reconstruction, 1312–1317 glaucoma associated with, 1019, 1084–1089 light-related see light retinal see retina uveitis and, 692, 764–766 vitrectomy, 472 see also fractures travoprost glaucoma, 1117 side-effects, 1118 treponemal tests, 711 see also syphilis trial frames, refraction testing, 47, 50–51

U

ulcer, corneal HSV-related, 234 Mooren’s, 239, 244–246 in penetrating keratoplasty, 302 rheumatoid-associated see rheumatoid arthritis ulcerative keratitis, peripheral (PUK), 238–241, 244–246, 249–250, 325 ultrasound biomicroscopy glaucoma angle-closure, 1065 traumatic, 1084 melanoma, 802 ultrasound imaging (echography; ultrasonography) incl. B-scan mode, 437–439, 854, 1266–1267 choroidal or ciliary body melanoma, 804 choroidal hemorrhage, 661 Coats’ disease, 562–563 concepts in interpretation, 437 devices, 437 digital, 438 display presentation and documentation, 437 examination technique, 437 medulloepithelioma, 819–820 metastases, 811 neuro-ophthalmology, 854 principles, 854 orbital anatomy (in general), 1266–1267 posterior segment trauma, 670–671 principles, 854 retinoblastoma, 795 scleritis, 212 serous retinal detachment, 658 toxocariasis-associated granuloma, 744 see also Doppler studies ultrasound transducer for phacoemulsification (handpieces), 361–362 ultraviolet (UV) (from sunlight etc.), 28–29 damaging effects, 28–30 biochemical mechanisms, 30 cataracts and, 413 vulnerability to, 28–29 filtration, 28 lenses (sunglass/spectacle) absorbing, 31 profile, 28 ultraviolet A–riboflavin in keratoconus and other ectasias, 116 umbo, 420 uncover test, 1194 undercorrection brow lift, 1358 LASIK, 114–115 photorefractive keratectomy, 100 ptosis surgery, 1277 strabismus surgery, 1254 United Kingdom Prospective Diabetes Study (UKPDS), 541 upbeat nystagmus, 954 upgaze A-pattern esotropia increasing from downgaze to, 1223f abnormalities/palsies, 919–920 transient, infancy, 921 V-pattern esotropia increasing from, to downgaze to, 1222f V-pattern exotropia increasing from downgaze to, 1222f US Preventive Services Task Force on glaucoma screening, 1008 Usher’s syndrome, 485t

1401

Index

UV see ultraviolet uvea anatomy, 687–689 bilateral diffuse melanocytic proliferation, 792, 822–823 effusion syndrome, serous retinal detachment, 655 lymphoma, primary, 815–816 melanoma see melanoma metastases to (incl. choroid), 655, 812, 1099 nevus, 821–824 see also choroid; ciliary body; iris uveitis, 387–389, 573, 687–689, 1081–1082 with AC angle-supported phakic IOLs, 135 anterior (iritis and iridocyclitis), 694t, 695, 697, 770–773, 1082b AC iris-supported phakic IOLs, 137–138 acute (in general), 695–696, 696t, 749f, 750 chronic, 696t CMV-related, 707–708 Fuchs’ uveitis syndrome (Fuchs’ heterochromic iridocyclitis), 772–773, 1083 herpes simplex-related, trial treatment, 236 herpes zoster, 181 HLA-B27-related, 748–752, 770 idiopathic and syndromic causes, 770–773 sarcoidosis-related, 753, 756 tuberculosis, 716 cataract surgery in patients with, 387–389 chronic, 696t, 699 classification, 694 clinical features/manifestations, 694–696 cataracts, 695, 750–751 retinal neovascularization, 573 course and outcome, 699 cystoid macular edema complicated by see cystoid macular edema diagnosis, 1081–1082 epidemiology, 694 infections causing, 700–703 intermediate, 696t, 774–777 tuberculosis, 716 as laser iridectomy complication, 1124 mechanisms/pathogenesis, 690–693 phacogenic, 764–766 posterior see chorioretinitis progressive subretinal fibrosis and, 784 sympathetic, 762, 767–769 systemic disease causing, 748–752 traumatic, 692, 764–766 treatment, 697–699 vitrectomy, 472 unknown causes, 770–773 see also keratouveitis; panuveitis

V

1402

V-pattern esotropia, 1209, 1221 V-pattern exotropia, 1222–1223 V-pattern strabismus, 1217–1218 vaccination see immunization vacuum phacoemulsification, 362 valaciclovir, herpes zoster, 182 postherpetic neuralgia, 182 VALIO (Verteporfin with Altered Light in Occult CNV) Study, 589 Valsalva retinopathy, 681–682 van Herick technique, modified, 1165 vancomycin, keratitis, 222 varicella zoster virus (VZV) and herpes zoster (shingles), 180–182 conjunctival involvement, 186 corneal involvement, 180–182 ocular motor palsies, 181, 930f uveal involvement, 181, 700–701 varices, orbital, and glaucoma, 1022t vascular disorders cerebral, 992–999 choroidal polypoid vasculopathy vs. central serous chorioretinopathy, 607 cranial nerve palsies due to IIIrd, 929, 932–934 multiple, 932 in cystoid macular edema etiopathogenesis, 625, 629–630 filler-related, 1359 glaucoma and, 1049, 1090t

vascular disorders (Continued) neoplastic see vascular tumors retina, 514–517 emboli, 522, 996 retinal neovascularization in, 570, 572–573 serous retinal detachment in, 656 vascular endothelial growth factor (VEGF), 570 neovascularization and, 570 glaucoma and, 1076 retinopathy of prematurity pathogenesis, 535 vascular endothelial growth factor (VEGF) inhibitors age-related macular degeneration, 589–596 plus photodynamic therapy, 596–597 choroidal neovascularization, 732 with angioid streaks, 602 with optic disc abnormalities, 636 in pathologic myopia, 603 in traumatic rupture of Bruch’s membrane, 600–601 in glaucoma surgery, wound healing effects, 1156–1157 idiopathic juxtafoveal retinal telangiectasia, 562–563 neovascular glaucoma, 1079 radiation retinopathy, 568 retinal arterial macroaneurysms, 579 retinal serous detachment, 659 retinal vein occlusion-related macular edema branch, 533 central, 530 retinopathy of diabetes, 546–547 retinopathy of prematurity, 538–539 sickle cell hemoglobinopathy, 559 vascular supply (blood supply; circulation), orbital, 1261–1263 extraocular muscles, 1184 eye, 687 eyelids, 1257 optic chiasm, 900–901 optic nerve, 867, 1047–1049 in pathogenesis of papilledema, 876 retinochoroidal, 426–429 anatomy, 426–428 blood flow see blood flow filling defects, 443b hyperfluorescence relating to, 443b hypofluorescence relating to, 443b leakage, 443b, 444 see also vascular disorders vascular theory of glaucomatous optic neuropathy, 1017 vascular tumors, eyelids, 1299–1300 vasculitis central retinal artery obstruction, 521 CNS, 977–979 course and outcome, 979 diagnosis and testing, 979 epidemiology and pathogenesis, 977 pathology, 979 systemic necrotizing vasculitides, 977–979 treatment, 979 interstitial keratitis in, 246 optic disc see papillophlebitis optic neuritis associated with, 881 retinal idiopathic, and aneurysms and neuroretinitis (IRVAN syndrome), 578 neovascularization in, 572 serous retinal detachment, 655 see also temporal arteritis vasoproliferative factors see angiogenic (vasoproliferative) growth factors vasospasm, glaucoma and, 1049 normal-tension, 1058 VEGF and its inhibitors see vascular endothelial growth factor vena cava syndrome, superior, glaucoma, 1022t Venereal Disease Research Laboratory (VDRL), 711 venous beading in diabetic retinopathy, 543–544 inherited retinal, 573 venous drainage orbit, 1262–1263 eyelids, 1257

venous drainage (Continued) retina, 426 obstruction, combined with retinal artery obstruction, 524–525 venous loops in diabetic retinopathy, 543–544 venous outflow obstruction, episcleral, glaucoma and, 1081 venous pressure elevation, glaucoma with, 1081, 1090–1091 venous thrombosis, intracranial, 875 vergence system, 917, 1195–1196 disorders, 920–921 examination, 917 types of vergences, 1195–1196, 1195t Verisyse ICL see Artisan vermiform movements, 964 vernal conjunctivitis, 192–193 Vernier acuity, 45 anisometropic amblyopia, 1238 stimulus–deprivation amblyopia, 1239 strabismic, 1239 verruca common (verruca vulgaris), 1305 senile, 1296 versican mutations, 509 versions, 1186, 1195–1196 types, 1195t vertebrobasilar transient ischemic attack and stroke, 999 verteporfin see photodynamic therapy vertical chop technique (in B-MICS), 375 vertical eye movements/gaze, 916 disorders, 919–920 vertical strabismus, non-paretic, 1233–1237 vestibular eye movements, 916 disorders, 920 nystagmus, 952f, 953, 957 vestibulo-ocular reflex, 916f, 917, 920 testing, 917–918 VIA Study, 596–597 videokeratoscopy and videokeratography, computerized, pre-refractive surgery, 93, 168 LASIK, 110 Vieth–Müller circle, 1201 VIEW 1 and 2 studies, 597 viral infections conjunctivitis, 184–186 neonatal, 188 keratitis herpes simplex see herpes simplex herpes zoster, 180–182 phototherapeutic keratectomy-related, 310 optic neuritis and neuroretinitis associated with, 880 uveitis, 181, 700–703 see also postviral disorders viral vectors in gene therapy, 7 Visante Omni, 168, 170f visceral larval migrans, 744 visco-elastic material with angle-supported phakic IOLs, 136 removal, 137 cataract surgery, 374 viscosurgical devices, ophthalmic see ophthalmic viscosurgical devices vision (sight) binocular see binocular vision brain trauma affecting, 988–989 course and outcome, 989 cataract effects, 336–337, 417 in cataract surgery, outcome, 404–405 in central serous chorioretinopathy, course and prognosis, 609 choroidal osteoma effects, 831 color see color vision confusion, 1197 central, 1197 peripheral, 1197–1198 treatment, 1198 cortical representation, 911–914 critical periods in development, 1241–1242 deficits and loss see visual deficits and loss in endophthalmitis, outcome bacterial endophthalmitis, 727 fungal endophthalmitis, 737 esotropia associated with deficits in, 1212

visual pigment, regeneration, 424 visual system afferent see afferent visual system auditory system and, integration, 912 distribution of higher order visual processing, 866f efferent, 915–921 VISX Wavescan map, 123f–124f vitamin A administration in retinal degenerations, 488–489 vitamin B3 retinotoxicity, 684 vitamin B6 administration in gyrate atrophy, 506–507 vitamin deficiencies, 892 B complex, 890 vitamin E cataracts and, 412–413 visual pigment regeneration and, 424 vitelliform macular dystrophy adult-onset, 494–495 early-onset (Best’s disease), 485t, 494 vitrectomy see vitreous surgery vitreofoveal traction syndrome, 622 vitreomacular traction (syndrome), 620–624 cystoid, 622 cystoid macular edema as complication, 628 optical coherence tomography, 449–450, 621 vitreoretinal lymphoma, primary, 788–789, 815–816 vitreoretinal traction caused by eye movements, 647–648, 648f vitreoretinochoroidopathy, autosomal dominant neovascular, 509, 511, 574 vitreoretinopathies hereditary, 508–513 familial exudative vitreoretinopathy, 509, 511– 512, 573 proliferative (PVRs), 665–669 penetrating trauma leading to, 675 vitreous (humor/gel), 430–436 age-related changes, 433–435 anatomy, 431–433 vitreous base, 638 liquefaction, 434, 647 aging and, 433 metabolic disorders, 435–436 molecular morphology, 430 posterior detachment of (PVD), 434, 647, 649 anomalous, 434–435 in diabetic retinopathy, 544 macular pucker with, 435, 473 optical coherence tomography, 449 presentation or prolapse in manual cataract surgery, 379 removal see vitreous surgery vitreous cavity hemorrhages see hemorrhage injections into see intravitreal route nucleus dropped into, 398–399 seeds, differential diagnosis, 795 ultrasound hemorrhage, 438 normal cavity, 438 in uveitis, 695 steroid administration via see intravitreal route toxocariasis, 744 vitreous cutters, 473 vitreous surgery (vitrectomy), 471–475 anesthesia, 471 Coats’ disease, 563 combined with phacoemulsification, 384–385 combined with posterior capsulectomy, children, 391–392 complications, 474 endophthalmitis, 724 diabetic retinopathy, 472, 548–550 endophthalmitis treatment by, 727 epiretinal membrane, 618 historical review, 471 indications and alternatives, 471 macular hole, 612 pars plana approach see pars plana penetrating injury, 675 preoperative evaluation and diagnostic approach, 471

vitreous surgery (vitrectomy) (Continued) in retinal detachment, 467, 472 in retinopathy of prematurity, 539 retinal neovascularization, 574 specific techniques, 472–474 vitreomacular traction syndrome, 621 vitritis in sarcoidosis, 754 Vogt–Koyanagi–Harada (VKH) disease, 656, 761– 763, 978 serous retinal detachment, 656 Vogt white limbal girdle, 270 voluntary nystagmus, 956 von Helmholtz ophthalmoscope, 69–70 von Hippel–Lindau syndrome, 847–848 retinal capillary hemangioma (von Hippel tumor), 836–838, 847 von Recklinghausen’s disease see neurofibromatosis, type I voriconazole endophthalmitis, 736 keratitis, 226–227 VZV see varicella zoster virus

Index

vision (sight) (Continued) in histoplasmosis, outcome, 732 in optic neuritis and neuroretinitis, 879 diagnosis, 880 outcome, 883 with phakic IOLs, outcome, 130–131 preverbal/preliterate children, evaluation, 1188–1191 in proliferative vitreoretinopathy, outcome, 669 retrochiasmal lesions leading to, 909–914 in rod–cone dystrophy, functional profile, 481 in wavefront-guided laser refractive surgery, assessment, 123 see also low-vision aids VISION (VEGF Inhibition Study in Ocular Neovascularization) trials, 589 visual acuity cataracts reducing, 336–337, 417 Coats’ disease, 561 course/outcome, 564 maturation, 1190 optic nerve vs. macular disorders, 869 postoperative cataract surgery, 404–405 endothelial keratoplasty, 318 testing, 42–43, 404 anisometropic amblyopia, 1238 glaucoma, 1020 preverbal/preliterate children, 1188–1190 stimulus–deprivation amblyopia, 1239 strabismic amblyopia, 1239 visual aura see aura visual axis (optic axis) determination, 1192 and marking in astigmatic or radial keratotomy, 143 inward and outward deviation of see esotropia; exotropia visual cortex, primary (V1), 901, 906 visual deficits and loss (incl. blindness) astigmatic or radial incisional keratotomy complicated by loss of, 145–146 bilateral/binocular see binocular vision, loss blepharoplasty complicated by, 1356 diabetic retinopathy, 551 glaucoma angle-closure, 1002t, 1060 epidemiology, 1001 nature of progressive loss, 1053–1054 primary open-angle, 1002t, 1053–1054 non-organic causes of, 912–914 with optic chiasm/parasellar/pituitary fossa, 904–905 orbital surgery complicated by loss of, 1338 retinal artery obstruction and branch, 522–523 central, 519 transient, 996–998 unilateral/monocular see monocular visual loss visual evoked response/potentials (VEPs) glaucoma screening, 1010 inherited retinal degenerations, 483 optic nerve vs. macular disorders, 870 preverbal/preliterate children, 1189, 1191t visual field blood flow (ocular) and loss of, 1048–1049 cataracts effects of surgery, 405 loss, 337 in glaucoma, deficits in primary open-angle glaucoma, 1053–1054 in glaucoma, testing, 1029–1035, 1053 new methods, 1036–1039 in gyrate atrophy, defects, 506 in optic nerve disorders macular disorders vs., 869–870 optic chiasmal lesions, 904–905 of traumatic origin, 898 in retinal inherited degenerations, 481–482 retrochiasmal lesions, defects, 902f, 910f–911f Visual Field Index (VFI), 1033–1034, 1037 visual pathway lesions diagnostic features, 901–902 drug and toxin-related, 990–991 optic atrophy/neuropathy, 890–893 vascular disorders causing, 992–999

W

WAGR (Wilms’ tumor–aniridia–genitourinary anomalies–mental retardation) syndrome, 294t, 1097–1098 wart, common, 1305 Watzke–Allen sign epiretinal membrane, 616 macular hole, 611 wave theory, 23 wavefront, 76–77 wavefront analysis/testing/aberrometry, 35–36, 45, 73–75 cataracts, 417 in corneal ablative (photorefractive) procedures, 36, 82–83, 120–126 devices, 120 LASIK see LASIK photorefractive keratectomy, 99–100 preoperative, 93 WaveScan, photorefractive keratectomy, 96 WDR36 and glaucoma, 1013, 1171 Weber’s (crus cerebri) syndromes, 924t, 999 wedge resection/excision cornea, 87 full-thickness, horizontal eyelid shortening wedge by, 1287 Wegener’s granulomatosis, 294t, 1328–1329 diagnosis and testing, 979 ocular manifestations, 978 pathology, 979, 1328 treatment, 979, 1328–1329 welding arc exposure, 463 Werner’s syndrome, 415 West Nile virus, 703 wet (neovascular) age-related macular degeneration, 580 natural history and prognosis, 588–589 ocular manifestations, 582 optical coherence tomography, 584 treatment and prevention, 589 whiplash injury, 681 shaken baby syndrome mechanism similar to, 680 Whipple’s disease, 721–722 white glow see leukokoria white limbal girdle, Vogt’s, 270 white ring, Coat’s, 271 white spot syndromes, 778–787 white-to-white measurements with phakic IOLs, 129–130 Whitnall’s ligament, 1256, 1261 Wilbrand’s knee, 900–901 Wilms’ tumor–aniridia–genitourinary anomalies– mental retardation (WAGR) syndrome, 294t, 1097–1098 Wilson’s disease, 291t, 292f, 294t, 919 Wirt stereotest, 1204 ‘with motion’, retinoscopy, 65–66 Worth four-dot test, 1202–1203, 1205t wound closure in manual cataract surgery, 378–379 dehiscence after cataract surgery, 399 edge leaks, antimetabolite-related, 1157

1403

Index

wound (Continued) healing and repair see healing and repair leak cataract surgery, 399 penetrating keratoplasty, 301 see also trauma wrinkles (rhytids), 1363 botulinum toxin, 1363 lateral see crow’s-feet wrong-way eyes, 918 Wyburn-Mason syndrome, 848–849

X

X-linked recessive inheritance, 5–6 color vision, 12 incontinentia pigmenti see incontinentia pigmenti mechanisms of disease with, 7 megalocornea, 173 Norrie’s disease, 12

1404

X-linked recessive inheritance (Continued) retinal degenerations (incl. retinitis pigmentosa), 485t female carriers, 488 retinitis pigmentosa (XLRP), 484, 485t, 486, 488, 504 retinoschisis (juvenile/congenital), 5–6, 12, 485t, 509–511, 573, 640 risk prediction of disorders with, 17 X-pattern strabismus, 1223 xanthelasma, 1302 xanthogranuloma, juvenile (nevoxanthoendothelioma), 1302 glaucoma and, 1022t xanthomatous lesions, 1301–1302 XEN (subconjunctival micro-shunt), 1142 Xeomin, 1363 xeroderma pigmentosa, 191, 294t xerophthalmia see dry eye

Y

YAG laser see erbium:YAG laser; holmium:YAG laser; neodymium:YAG laser

Z

Z-plasty, 1288 ZB (Baikoff lens), 127 ZB5M (Baikoff lens), 127, 134–135 Zeiss lens, 1025 Zellweger syndrome, 294t cataract and, 416 Zernike polynomials, 79, 120, 170 Zinn’s annulus, 1181–1183, 1260 Zippy Estimation of Sequential Thresholds (ZEST) procedure, 1036 zonular instability and its management, 348–349, 382 zoster see varicella zoster virus