Lee's Ophthalmic Histopathology [4th ed. 2021] 3030765245, 9783030765248

Table of contents :
Preface to the Fourth Edition
Preface to the Third Edition
Preface to the Second Edition
Preface to the First Edition
Acknowledgements
Contents
1: Examination of the Globe. Technical Aspects
Introduction
Clinical Correlation
Background Information
Clinical Techniques for Investigation, Illustration, and Documentation
Equipment for Macroscopic Examination
Basic Gross Anatomy: External Features
Measurement of Ocular Dimensions
The Anterior Segment
The Cornea
The Anterior Ocular Structures
The Sclera
The Posterior Aspect
The Optic Nerve
The Vortex Veins
Orientation of the Primary Cuts into the Globe
Transillumination/Retroillumination
Vertical Calottes
Horizontal Calottes
Oblique Calottes
The Unfixed Globe
Basic Gross Anatomy: Internal Features
Examination of Specific Features
Cornea
Anterior Chamber (Fig. 1.11a, b)
Iridocorneal Angle (Fig. 1.11a, b)
Iris
Ciliary Body
Pars Plicata
Pars Plana
Lens
Vitreous
Retina
The Peripheral Retina
The Posterior Retina
The Macula
Optic Disc
Choroid
Sclera
Retrieval of Tissue from the Calottes
Radiological Examination of the Globe
Common Artefacts
Myelin Artefact
Shrinkage Artefact
Autopsy Material
Fixation Techniques
Formalin-Based Fixatives
Formaldehyde
Glutaraldehyde (2–4%)
Embedding Techniques
General Considerations
Histological Examination of a Section of the Globe and Preparation of a Pathological Report
Specialised Techniques
Introduction
Retinal Digest Preparations
Injection Techniques (Carbon, Plastic)
Frozen Sections for Fat
Stains for Microscopy
Conventional Stains
Immunohistochemistry
In Situ Hybridisation (ISH)
Polymerase Chain Reaction (PCR)
Tumour Cytogenetics
Next Generation Sequencing
Flow Cytometry
Techniques for Illustration and Documentation
Photomacrography
Photomicroscopy and Digital Pathology
Polarised Light
Fluorescence Microscopy
Electron Microscopy
Diagnostic Cytopathology
Normal Ocular Histology
References
2: The Traumatized Eye
Introduction
The “Irreparable Eye”
Large Penetrating or Perforating Wounds of the Corneoscleral Envelope
Macroscopic Examination
Microscopic Examination
The Globe Removed in the Short Term After Attempted Repair
Reparative Changes in Ocular Tissues
Fibrous Ingrowth
Organization of Blood
Hypotonia
Retina and Optic Nerve
Photoreceptor Disintegration
Lens
Haemosiderosis Bulbi
Globe Containing a Metallic Foreign Body
Macroscopic Examination
Types and Effects of Metallic Foreign Bodies
Siderosis
Chalcosis
Long-Term Effects of Ocular Trauma
Macroscopic Examination
Post-traumatic Glaucoma
Secondary Angle Closure
Secondary Open Angle Glaucoma
Angle Recession
Epithelial Downgrowth
Lens Abnormalities
Lens Dislocation
Lens-Induced Uveitis
Post-traumatic Retinal Changes
Haemorrhage and Traumatic Detachment
Post-traumatic Pseudoretinitis Pigmentosa
Sympathetic Ophthalmitis
Macroscopic Examination
Microscopic Examination
Post-traumatic Phthisis
General
Cyclitic Membrane
Lens in Phthisis Bulbi
Retinal Gliosis
Retinal Pigment Epithelium in Phthisis Bulbi
Choroid in Phthisis Bulbi
Optic Nerve in Phthisis Bulbi
Hot Metals, Acids, and Alkalis
Effects of Ionizing Radiation
The Infant Eye in Abusive Head Trauma
References
3: Absolute Glaucoma
Introduction
The Functional Morphology of the Outflow System
Aqueous Inflow
Aqueous Outflow
The Trabecular Meshwork
The Canal of Schlemm
Classification of Glaucoma
Primary Open Angle Glaucomas (POAG)
Normal Tension Glaucoma (NTG)
Primary Acute Angle Closure Glaucoma
Primary Congenital Forms/Childhood Glaucomas
Secondary Glaucomas
Primary Open Angle Glaucoma
Treatment of Primary Open Angle Glaucoma
Surgical Trabeculectomy
Pathological Features
Laser Treatment
“Low Tension” Glaucoma
Primary Acute Angle Closure Glaucoma
Clinical Features and Pathogenesis
Chronic Angle Closure Glaucoma
Iridectomy Specimen
Trabeculectomy Specimens
Unsatisfactory Response to Treatment
Congenital Glaucoma: Buphthalmos
Goniodysgenesis
The Phakomatoses
Secondary Open Angle Glaucoma
Introduction
Iatrogenic Glaucoma
Steroid-Induced Glaucoma
Silicone Oil
Viscoelastic Substances
Melanotic Glaucoma
Introduction
Pigmentary Glaucoma
Melanomalytic Glaucoma
Blood Products (Haemolytic Glaucoma)
Lens Protein Glaucoma
Phacolytic Glaucoma
Glaucoma in the Exfoliation Syndrome (ES/PEX/PXS)
Post-traumatic Glaucoma
Schwartz-Matsuo Syndrome
Glaucoma Associated with Tumours
Malignant Tumours
Iris Naevus Syndrome
The Cogan-Reese Syndrome
Juvenile Xanthogranuloma
Mucogenic Glaucoma
Secondary Angle Closure Glaucoma
Neovascular Glaucoma
Inflammatory Disease
Retinal Detachment
Tumours
Trauma
Malignant Glaucoma
Iridocorneal-Endothelial (ICE) Syndrome
Tissue Effects of Glaucoma
Acute Glaucoma
Cornea
Iris
Lens
Retina and Optic Nerve
Tissue Changes in Long-Standing Glaucoma
Cornea
Chamber Angle
Endothelial Downgrowth
Outflow System
Iris
Ciliary Body
Lens
Vitreous
Retina
Optic Disc and Optic Nerve
The Pathogenesis of Glaucomatous Optic Atrophy
Choroid
Corneoscleral Envelope
Evolution of End-Stage Pathology
Complications in the Surgical Treatment of Glaucoma
Trabeculectomy
Ciliary Body Surgery: Cyclodestructive processes
Other Cyclodestructive Techniques
Laser Trabeculoplasty
Glaucoma Drainage Device
Retrobulbar Alcohol
References
4: Retinal Vascular Disease
Introduction
Retinal Ischaemic Disease
Pathogenesis of Retinal Ischaemia
Characteristic Pathological Features of Focal Ischaemic Retinal Disease
Microinfarction or “Cotton Wool Spots”
Exudation of Plasma or “Hard” Exudates
Haemorrhage
Microaneurysms
Neovascularisation
Clinical Relevance (Fig. 4.9)
Macroscopic Features of the Enucleated Globe
Microscopic Features
Arteriolosclerosis and Venulosclerosis
Common Disease Entities Associated with Intraocular Neovascularisation
Retinal Vein Occlusion (RVO)
Central Retinal Vein Occlusion (CRVO)
Pathogenesis of Central Vein Occlusion
Additional Features
Branch Vein Occlusion
Diabetes
Clinical Background
Macroscopic Examination
Microscopic Examination
Pathogenesis and Effects of Treatment in Proliferative Diabetic Retinopathy
Recent Advances
Rarer Vascular Disorders Leading to Neovascular Glaucoma
Coats’ Disease
Macroscopic Examination
Microscopic Examination
Coats’ Reaction, Coats’ Response or Coats’ Syndrome
Idiopathic Juxtafoveolar Retinal Telangiectasis
Retinopathy of Prematurity
Haemoglobinopathies
Radiation Retinopathy
Norrie Disease
Vascular Disorders That Rarely Lead to Neovascular Glaucoma in Adults
Central Retinal Artery Occlusion
Posterior Ciliary Artery Occlusion
Ophthalmic Artery Occlusion
Hypertension
Disseminated Intravascular Coagulopathy (DIC)
Choroidal Neovascularisation and Age-Related Macular Degeneration (ARMD)
Choroidal Neovascularisation
Age-Related Macular Degeneration (ARMD)
Disciform Degeneration
Excised Submacular Membranes
Inflammatory Disease Associated with Neovascularisation
References
5: Intraocular Tumours
Introduction
Melanocytic Tumours
Introduction
Benign Melanocytic Tumours (Naevi)
Incidence
Iris Naevus
Iris Naevus Syndrome
Ciliary Body Naevi
Ciliary Body Melanocytoma (Magnocellular Naevus)
Choroidal Naevus
Bilateral Diffuse Uveal Melanocytic Hyperplasia
Dysplastic Naevus Syndrome
Rare Benign Melanocytic Proliferation
Ocular Melanocytosis
Melanocytomas of the Optic Nerve Head
Malignant Melanoma of the Uveal Tract
Malignant Melanoma of Iris
Clinical and Macroscopic Aspects
Histopathology of Iris Melanoma
Malignant Melanoma of the Ciliary Body and Choroid
Clinical Aspects
Pathological Features of Ciliary Body and Choroidal Melanoma
Transillumination and Orientation
Macroscopic Appearances of Ciliary Body and Choroidal Melanomas
Extrascleral Spread
Optic Nerve Extension
Cavitary Melanoma
Microscopic Features
Tumour Cell Morphology
Spindle Cell Type Variants
Epithelioid Cells
Mixed Cell Type
PAS Positive Patterns
Melanin Content, Inflammatory Cell Infiltration, Proliferation and Mitotic Activity
Pathological Factors Indicating a Poor Prognosis
Genetic Abnormalities
Management of Uveal Melanoma
Pathological Management of Specimens for Ciliary Body and Choroidal Melanoma
Iridocyclectomy
Choroidectomy
Exoresection (Transcleral Resection)
Endoresection (Transretinal Resection)
Ionising Radiation in the Treatment of Uveal Melanomas
Brachytherapy
Proton Beam Radiotherapy
Light and Heat Effects on Uveal Melanomas
Trans-Pupillary Thermotherapy (TTT)
Other Iris Tumours
Spindle Cell Tumours
Histiocytic Tumours
Adenomas
Cysts
Metastatic Tumours
Other Tumours of the Ciliary Body
Spindle Cell Tumours
Tumours of the Epithelium of the Ciliary Processes and the Pars Plana
Adenomas/Adenocarcinomas
Medulloepithelioma
Other Tumours of the Choroid
Metastatic Tumours
Choroidal Lymphoma and Leukaemia
Vascular Tumours
Choroidal Osteoma
Tumours of the Retinal Pigment Epithelium (RPE)
Adenomas and Adenocarcinomas of the RPE
Reactive Hyperplasia of the RPE
Congenital Hypertrophy of the RPE (CHRPE)
Simple and Combined Hamartoma of the RPE
Non-neoplastic Lesions Simulating Malignant Melanoma
Uveal Effusion Syndrome
Choroidal Haemorrhage
Retinal Macrocyst
Tumours of the Retina
Primary Vitreo-Retinal Lymphoma (PVRL)
Differential Diagnoses
Treatment
Retinoblastoma
Introduction
Genetic Features
Clinical Features
Pathological Features of Retinoblastoma
Macroscopic Examination
Danger of Artefact
External Examination
Tumour Appearances
Clinical Effects of Irradiation
Microscopic Features
Differentiation within Retinoblastoma
Microscopic Effects of Irradiation
Hazards in the Histological Assessment of Retinoblastoma
Prognostic Indicators
Tumours That May Simulate Retinoblastoma
Retinocytoma
Nodular and Massive Retinal Gliosis
Astrocytic Hamartoma
Miscellaneous
Tumours Metastasising to the Retina
Non-Neoplastic Lesions That Mimic Retinoblastoma
References
6: Ocular Inflammation
Introduction
The Anatomy of the Eye in Relation to Infective Processes
Pyogenic Bacterial Infections
Introduction
Corneal Ulceration
Acute Bacterial Pyogenic Endophthalmitis
Common and Rare Pathogenic Bacteria
Macroscopic Features
Microscopic Features
The Evisceration Specimen
Implants
Fungal Infection
Viral Infection
Introduction
Measles (Rubeola)
Rubella (German Measles)
Acute Retinal Necrosis (ARN) Syndrome
Cytomegalovirus
Retinal Biopsy
Acquired Immunodeficiency Syndrome (AIDS)
Herpes Zoster
Chronic Specific Granulomatous Inflammation
Introduction
Tuberculosis
Sarcoidosis
Syphilis
Rheumatoid Eye Disease: “Scleritis” and “Sclerokeratitis”
Scleritis: Causes Other than Autoimmune Disease
Infectious Scleritis
Surgically Induced Necrotising Scleritis (SINS)
Risedronate Associated Scleritis
Irradiation Scleritis
IgG4 RD Scleritis
Masquerade Scleritis
Protozoal Disease: Toxoplasmosis and Malaria
Ocular Toxocariasis
Chronic Uveitis
HLA B27 Associated Uveitis
Behçet’s Disease
Vogt-Koyanagi-Harada Syndrome (VKH)
Fuchs Heterochromic Cyclitis
White Dot Syndromes (WDS)
References
7: Treatment of Retinal Detachment
Introduction
Classification of Retinal Detachment
Rhegmatogenous Detachment
Exudative Detachment
Central Serous Chorioretinopathy
Tractional Detachment
Degenerative and Other Conditions That Predispose to Retinal Detachment
Lattice Degeneration
Retinal Holes and Tears
Peripheral Microcystoid Degeneration
Vitreomacular Disease
Posterior Vitreous Detachment (PVD)
Vitreomacular Adhesion (VMA)
Vitreomacular Traction (VMT)
Lamellar Macular Hole (LMH)
Impending Macular Hole (IMH)
Full-thickness Macular Hole (FTMH)
Macular Pseudohole
Inherited Vitreoretinopathy
Hereditary Progressive Arthro-Ophthalmopathy (Stickler Syndrome)
Innocuous Peripheral Retinal Disease
Paving Stone or Cobblestone Degeneration
Lipoidal Degenerations
Meridional Folds
Retinal Tissue Rarefaction
Pigmentation
Retinoschisis
Peripheral Reticular Degeneration
Myopia
Effects of Detachment on the Ocular Tissues
Introduction
Changes in the Neural Retina
Changes in the Retinal Pigment Epithelium
Secondary Effects in the Vitreous
Effects on Lens
Pathology of Treatment of Retinal Detachment
Buckling or Scleral Indentation
Cryotherapy or Laser Photocoagulation
Replacement of Vitreous
Intraocular Silicone Oil
Sulphur Hexafluoride (SF6)
Heavy Liquids
Retinal Tacks
Retinotomy and Retinectomy
Human Amniotic Membrane Plug
Vitrectomy Procedure
Vitrectomy Specimens and Epiretinal Membranes
Retinal Detachment and Reattachment
Retinal Displacement Without Detachment
The Extruded Silicone Sponge or Plomb
Asteroid Hyalosis
References
8: The Malformed Eye
Introduction
Relevant Basic Ocular Embryology
Gross Malformations Due to Abnormal Development in the First 4 Weeks of Embryonic Life
Malformation of the Optic Vesicle
Anophthalmia
Nanophthalmia and Microphthalmia
Synophthalmia and Cyclopia
Malformation of Optic Cup: Closure of Optic Fissure
Congenital Cystic Eye
Coloboma
Colobomatous Cysts
Amniotic Band Syndrome
Malformations of the Anterior Segment
Cornea and Chamber Angle
Lenticulocorneal Fusion
Corneal Malformation
Peters Anomaly
Sclerocornea
Megalocornea
Axenfeld-Rieger Syndrome
Fetal Alcohol Syndrome
Chamber Angle Malformation or Goniodysgenesis
Aniridia
Malformation of Lens
Malformations of the Vitreous and Hyaloid Artery System
Pure Anterior Persistent Fetal Vasculature (Anterior PFV)
Pure Posterior Persistent Fetal Vasculature (Posterior PFV)
Combined Persistent Fetal Vasculature (Combined PFV)
Malformations of the Retina
Malformations of the Optic Nerve Head
Colobomata and Optic Disc Pits
Axial Coloboma or “Morning Glory Disc Anomaly”
Lipomatosis of the Optic Nerve
Myelinated Nerve Fibres
The Phakomatoses
Definition
Neurofibromatosis
Neurofibromatosis Type 1 (Von Recklinghausen’s Disease)
Neurofibromatosis Type 2 (Central Neurofibromatosis)
Tuberous Sclerosis (Bourneville’s Disease)
von Hippel-Lindau Disease
Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis)
Syndromes Associated with Chromosomal Abnormalities
Introduction
Trisomy 13 (Patau Syndrome)
Trisomy 18 (Edwards Syndrome)
Trisomy 21 (Down Syndrome)
References
9: “Autopsy Eye”: The Eye in Systemic Disease
Introduction
Methods for Obtaining Ocular Tissue at Autopsy
Donated Material
Anterior Enucleation Technique
Removal of the Posterior Part of the Globe
Removal of the Globe and Orbital Contents
Value of Autopsy Material in Ophthalmology
Vascular Disease
Introduction: Ischaemic Ocular Disease
Malignant Hypertension
Collagen Vascular Diseases
Temporal Arteritis
Non-arteritic Optic Neuropathy: Anterior Ischaemic Optic Neuropathy (AION)
Subarachnoid Haemorrhage
Choroideraemia
Haematological Disorders
Leukaemia and Lymphoma
Anaemia and Thrombocytopenia
Macroglobulinaemia
Disseminated Intravascular Coagulopathy (DIC)
Langerhan’s Cell Histiocytosis
Degenerative Disease
Myopia
Angioid Streaks
Tapetoretinal Degeneration
Introduction
The Anatomy of the Photoreceptors
The Anatomy of the Retinal Pigment Epithelium
Interrelationship Between the Retinal Pigment Epithelium and the Photoreceptors
Importance of Vitamins A and E
Retinitis Pigmentosa
The Ciliopathies
Usher Syndrome
Leber’s Congenital Amaurosis
Sorsby’s Fundus Dystrophy
Metabolic Deficiencies Associated with Pigmentary Retinopathy
Lysosomal Disorders
Mucopolysaccharidoses
Fucosidosis
Neuronal Ceroid Lipofuscinosis (NCL)
Cystinosis
Peroxisomal Disorders
Zellweger Spectrum Disorders
Adult Refsum’s Disease
Hyperoxaluria
Homocystinuria
Myotonic Dystrophy (Type 1)
Mitochondrial Diseases
Kearns-Sayre Syndrome (KSS)
MELAS Syndrome
Leigh Syndrome
Leber’s Hereditary Optic Neuropathy
Gyrate Atrophy
Disorders of Sphingolipid Metabolism
GM 2 Gangliosidosis (Types I, II, and III)
Tay-Sachs Disease (GM2-Gangliosidosis Type 1)
Association with Gastrointestinal and Hepatic Disease
Familial Adenomatous Polyposis (Gardner Syndrome)
Alagille Syndrome (Arteriohepatic Dysplasia)
Pigment Epitheliopathies Limited to the Macula
Best Vitelliform Macular Dystrophy
Stargardt Disease and Fundus Flavimaculatus
Lipofuscin in the Retinal Pigment Epithelium
Neurological Disorders
Papilloedema
Drusen of the Optic Disc
Immune Mediated Diseases
Multiple Sclerosis
The Empty Sella Syndrome
Paraneoplastic Syndromes
Wolfram Syndrome (DIDMOAD)
Deficiency Diseases
Nutritional Amblyopia: Tobacco Alcohol Amblyopia
Other Systemic Metabolic Diseases
Albinism
Marfan’s Syndrome
Toxicity
Toxic Compounds
Therapeutic Agents
Tamoxifen Retinopathy
Chloroquine
Phenothiazines
Methyoxyfluorane
Amiodarone
References
10: Biopsy of the Eyelid, the Lacrimal Sac, and the Temporal Artery
Introduction
Relevant Functional Anatomy of the Eyelid
Surgical Anatomy and Surgical Pathology
Incidence of Various Types of Eyelid Pathology
Eyelid Cysts: “Excision of Subcutaneous Nodule”
Epidermal Cysts
Intratarsal Keratinous Cysts
Sweat Gland Cysts
Meibomian Cyst: Chalazion
Benign Epithelial Tumours
Basal Cell Papilloma and Squamous Cell Papilloma
Inverted Follicular Keratosis
Keratoacanthoma
Viral Wart
Molluscum Contagiosum
Other Benign Adnexal Tumours
Adnexal Tumours with Follicular Differentiation
Adnexal Tumours with Sweat Gland Differentiation
Adnexal Tumours with Sebaceous Differentiation
Naevi
Junctional Naevus
Compound and Intradermal Naevi
Rare Benign Melanocytic Tumours
Spitz Naevus
Blue Naevus
Oculodermal Melanocytosis (Naevus of Ota)
Malignant Epithelial Tumours
Premalignant Change
Actinic, Solar, or Senile Keratosis
Bowen’s Disease
Basal Cell Carcinoma (BCC)
Squamous Cell Carcinoma
Sebaceous Carcinoma
Merkel Cell Carcinoma
Other Malignant Adnexal Tumours
Microcystic Adnexal Carcinoma
Endocrine Mucin Producing Sweat Gland Carcinoma
Signet Ring Cell Carcinoma
Staging of Eyelid Carcinoma
Malignant Melanoma
Metastatic Tumours
Irradiation Effects
Some Unusual Disorders in the Eyelid
Bacterial and Metazoal Infections
Ligneous Conjunctivitis
Amyloidosis
Focal Mucinosis/Calcinosis
Floppy Eyelid Syndrome
Melkersson-Rosenthal Syndrome
Lipoid Proteinosis
Solid Nodules and Plaques
Xanthelasma
Hamartomas and Choristomas
Angiomas and Lymphangiomas
Calibre-Persistent Artery
Encephalocele
Phakomatous Choristoma
Miscellaneous Tumours
Juvenile Xanthogranuloma
Langerhan’s Cell Histiocytosis
Epithelioid Haemangioma (Angiolymphoid Hyperplasia with Eosinophilia)
Granular Cell Tumour
Neural Tumours
Lacrimal Sac
Functional Anatomy
Inflammatory Disease
Non-granulomatous Inflammation
Dacryolith
Lacrimal Sac Tumours
Temporal Artery Biopsy
References
11: The Conjunctival Biopsy
Functional Anatomy
Surface Epithelium
Stroma
Conjunctival Immunity
Medial Canthus
Tear Film
Keratoconjunctivitis Sicca
Biopsy Technique
Practical Aspects
“Conjunctival Scrapings”
Bacterial Infection
Viral Infection
Chlamydial Infection
Allergy and Foreign Body
Impression Cytology
Inflammatory Disease: Diffuse
Bacterial Infection
Lyme Disease
Bacillary Angiomatosis
Atopic Keratoconjunctivitis (AKC): Papillary Conjunctivitis
Contact Lens Wear
Viral Infections (Follicular Conjunctivitis)
Adenoviral Infections
Molluscum Contagiosum
Chlamydial Infections
Chlamydiaceae
Trachoma
Inclusion Conjunctivitis
Sarcoidosis
Fungal Infection
Parasitic Infection
Foreign Material
Mascara
Other Foreign Materials and Compounds
Conjunctivitis Artefacta
Inflammatory Disease: Localised
Episcleritis
Phlycten
Allergic Granulomatous Nodule
Ophthalmia Nodosa
Periocular Granuloma Annulare
Idiopathic Conjunctival Granulomas
Specific Foreign Body Granulomas
Stitch Granuloma
Golf Ball Granuloma
Synthetic Fibre Granuloma
Amyloid
Ligneous Conjunctivitis
Bullous Disease and Cicatrising Conjunctivitis
Ocular Cicatricial Pemphigoid (OCP)
Stevens-Johnson Syndrome
Acne Rosacea
Systemic Lupus Erythematosus
Lichen Planus
Symblepharon: Reconstructive Surgery
Non-neoplastic Tumour-Like Lesions of the Conjunctiva
Cysts
Reactive Epithelial Hyperplasia
Pseudoglandular and Pseudoepitheliomatous Hyperplasia
Pterygium and Pinguecula
Pseudopterygia (Hypertrophic Conjunctival Scar)
Actinic Granuloma
Hamartomatous and Choristomatous Tumours
Intrascleral Nerve Loop and Neural Tumours
Haemangiomas
Lymphangiectasis and Lymphangioma
Epibulbar Dermoid, Dermolipoma and Complex Choristoma
Epibulbar Osteoma/Osseous Choristoma
Prolapsed Fat
Benign, Premalignant, and Malignant Tumours of Epithelium
Pedunculated Papillomas
Placoid or Sessile Papillomas
Conjunctival Squamous Intraepithelial Neoplasia [Conjunctival Intraepithelial Neoplasia (CIN) and Carcinoma In Situ (CIS)]
Squamous Cell Carcinoma
Spindle Cell Carcinoma
Hereditary Benign Intraepithelial Dyskeratosis of the Conjunctiva
Intraepithelial Sebaceous Carcinoma
Melanocytic Tumours
Naevi
Junctional Naevi
Compound and Intrastromal/Subepithelial Naevi
Inflamed Juvenile Conjunctival Naevi
Spitz Naevi
Blue Naevi
Balloon Cell Naevi
Benign Acquired Melanosis/Benign Epithelial Melanosis of the Conjunctiva
Conjunctival Melanocytic Intraepithelial Neoplasia (C-MIN)/Primary Acquired Melanosis (PAM)
Primary Acquired Melanosis Without Atypia/C-MIN Score = 1
Primary Acquired Melanosis with Atypia/C-MIN Score = 2–5
Conjunctival Melanoma
Lymphoid Proliferations
Reactive Lymphoid Hyperplasia
Malignant Lymphoma
Sinus Histiocytosis (Rosai-Dorfman Disease)
Miscellaneous Soft Tissue Tumours of Conjunctiva and Caruncle
Haemangiomas
Kaposi’s Sarcoma
Angiosarcoma
Fibrous Histiocytoma and Related Entities
Myxoma
Conjunctival Stromal Tumour
Juvenile Xanthogranuloma
Leiomyosarcoma
Rhabdomyosarcoma
Neurofibroma
Schwannoma
Secondary Tumours of the Conjunctiva
Other Tumours of the Caruncle
Naevus
Sebaceous Adenoma
Sebaceous Carcinoma
Oncocytoma
References
12: The Orbit: Biopsy, Excision Biopsy, and Exenteration Specimens
Introduction
Clinicopathologic Background
Orbital Cysts
Simple Cysts
Haematic Cyst
Mucocele
Dermoid Cysts
Enterogenous Cyst
Idiopathic Orbital Inflammatory Disease
Orbital Apical Syndrome (Tolosa-Hunt Syndrome)
Idiopathic Sclerosing Inflammation of the Orbit
Multifocal Fibrosclerosis
IgG4 Related Disease (IgG4RD)
Inflammation in Extraocular Muscle and Optic Nerve
Endocrine Exophthalmos: Thyroid Associated Ophthalmopathy
Orbital Myositis
Specific Inflammatory Disease
Bacterial Infection: Orbital Cellulitis
Fungal Infection
Aspergillosis
Mucormycosis
Parasitic Infection
Sarcoidosis
Amyloidosis
Granulomatosis with Polyangiitis (Formerly Wegener’s Granulomatosis)
Tumours of the Orbit
Lymphoid Tumours
Benign Lymphoid Hyperplasia
Lymphoma
Extra-Nodal Marginal Zone Lymphoma (EMZL)
Diffuse Large B Cell Lymphoma
Follicular Lymphoma
Other B Cell Lymphomas
T-Cell Lymphomas
Hodgkin Disease
Plasma Cell Neoplasms
Other Haematological Neoplasms
Vascular Lesions
Vascular Hamartomas
Epithelioid Haemangioma (Angiolymphoid Hyperplasia with Eosinophilia)
Lymphangioma
Other Vascular Lesions
Malignant Vascular Tumours
Fibroblastic Tumours
Solitary Fibrous Tumour
Myogenic Tumours
Rhabdomyosarcoma
Adipocytic Tumours
Lipomas
Liposarcoma
Atypical Lipomatous Tumour (ALT)
Myxoid Liposarcoma
Neural Tumours
Neurofibroma
Schwannoma
Malignant Peripheral Nerve Sheath Tumour
Olfactory Neuroblastoma
Other Soft Tissue Tumours
Granular Cell (Myoblastoma) Tumour
Alveolar Soft Part Sarcoma
Epithelioid Sarcoma of the Orbit
Other Soft Tissue Tumours
Miscellaneous Tumours and Tumour-Like Conditions
Orbital Teratoma
Sinus Histiocytosis with Massive Lymphadenopathy
Orbital Xanthogranulomatous Disease
Juvenile Xanthogranuloma
Nodular Fasciitis
Tumours of the Bony Orbit
Orbital Osteoma
Osteosarcoma
Ewing Sarcoma
Fibroosseous Lesions
Aneurysmal Bone Cyst
Langerhans Cell Histiocytosis (Eosinophil Granuloma)
Disorders of the Optic Nerve
Benign Intracranial Hypertension (Pseudotumour Cerebri)
Primary Tumours of the Optic Nerve
Meningiomas of the Optic Nerve
Lacrimal Gland Tumours
Normal Anatomy
Inflammatory Conditions of the Lacrimal Gland
Sarcoidosis
Necrotizing Sialometaplasia
Sjögren Syndrome and Mikulicz Disease
Non-epithelial Tumours
Epithelial Tumours
Dacryops
Pleomorphic Adenoma
Pleomorphic Carcinoma (Malignant Mixed Tumour)
Adenoid Cystic Carcinoma
Mucoepidermoid Carcinoma
Other
Lymphoma
Secondary and Metastatic Tumours in the Orbit
Metastatic Tumours
Endocrine Exophthalmos/Thyroid-Associated Ophthalmopathy
The Exenteration Specimen
Orbital Implant
References
13: The Corneal Disc
Introduction
Relevant Functional Anatomy
Corneal Transparency
Background: Clinical Aspects of Keratoplasty
Macroscopic Examination of the Excised Cornea Disc
Non-specific Changes in a Keratoplasty Specimen
Epithelial Reactions
Anterior Fibrosis/Pannus
Refractive Eye Surgery
Radial Keratotomy
Photorefractive Keratectomy (PRK)
Laser-Assisted In Situ Keratomileusis (LASIK)
Laser-Assisted Subepithelial Keratectomy
Corneal Inlays and Onlays
Deposition of Extracellular Material
Stromal Abnormalities
Descemet’s Membrane and Endothelium
Common Disorders Treated by Keratoplasty
Post-aphakic Decompensation: Pseudophakic Bullous Keratopathy
General Considerations
Pathological Features of Endothelial Decompensation
Keratoconus
General Considerations
Macroscopic Examination
Microscopic Features
Keratoglobus
Herpes Simplex (HSV) Keratitis
Pathogenesis
Macroscopic Examination
Microscopic Features
Other Viral Infections
Rheumatoid Ulceration and Vasculitic Keratitis
Mooren’s Ulcer and Terrien’s Marginal Degeneration
Repeat Keratoplasty
General Considerations
Pathological Features of Graft Rejection
Corneal Ulceration
General
Corneal Scrapings
Pathology of the Ulcerated Cornea
Emergency Treatment of a Corneal Ulcer
Uncommon Corneal Infections
Bacterial “Crystalline” Keratopathy
Acanthamoeba Keratitis
Exotic Organisms
Specific Forms of Keratitis
Interstitial Keratitis
Rosacea Keratitis
Vernal Plaque
Aniridia Keratopathy
Recurrent Erosions
Salzmann’s Nodular Degeneration
Corneal Dystrophies
General Considerations
Epithelial and Subepithelial Corneal Dystrophies
Epithelial Basement Membrane Dystrophy (EBMD)
Meesmann’s Dystrophy
Lisch Epithelial Dystrophy
Gelatinous Drop-Like Corneal Dystrophy (Subepithelial Amyloidosis)
Epithelial-Stromal TGFBI Dystrophies
Reis-Bückler Dystrophy
Thiel-Behnke Dystrophy
Lattice Corneal Dystrophy (Type 1)
Granular Corneal Dystrophy (Type 1 Classic)
Granular Corneal Dsytrophy (Type 2)
Stromal Dystrophies
Macular Corneal Dystrophy
Schnyder Corneal Dystrophy
Endothelial Dystrophies
Fuchs’ Endothelial Dystrophy
Posterior Polymorphous Corneal Dystrophy (PPCD)
Congenital Hereditary Endothelial Dystrophy (CHED)
X-linked Endothelial Dystrophy (XECD)
Other Endothelial Abnormalities
The Iridocorneal Endothelial Syndrome (ICE Syndrome)
Deposition of Exogenous Materials
Calcium
Pigmentation
Corneal “Gammopathy”
Climatic Droplet Keratopathy
Silicone Oil Keratopathy
Trauma
Chemical Burns
Damage by Heat and Irradiation
Developmental Abnormalities
Corneal Hamartomas: Dermoid
Corneal Tumours
Miscellaneous Disorders of the Cornea
Mucopolysaccharidoses
Climatic Proteoglycan Stromal Keratopathy
Lipofuscinosis of the Cornea
Familial LCAT Deficiency: Fish Eye Disease (FED)
References
14: Lens
Introduction
Part 1: The Normal Lens
Part 2: Cataract
Congenital Cataract
Absence or Deformation of the Lens
Some Important Disease Entities Associated with Cataract
Rubella Cataract
Marfan’s Syndrome
Homocystinuria
Lowe’s (Oculocerebral) Syndrome
Galactosaemia
Myotonic Dystrophy
Uncombable Hair Syndrome
Non-specific Degenerative Changes in the Lens Substance
Introduction
Cortical Abnormalities
Nuclear Abnormalities: Pigmentation (or Brunescent Cataract)
Lens Epithelial Abnormalities
“Glaucomflecken”
Metaplasia
Traumatic Cataract
Civil Trauma
Indirect Surgical Trauma
Irradiation Cataract
Microwave
Infrared Cataract
Part 3: Surgical Techniques in the Treatment of Cataract
Introduction
Intracapsular Cataract Extraction (ICCE)
Extracapsular Cataract Extraction (ECCE)
Phacoemulsification
Femtosecond Laser-Assisted Cataract Surgery (FLAC)
Nanosecond Laser Cataract Surgery
Intraocular Lens Implants
Anterior Chamber Lens Implants
Posterior Chamber Lens Implants
Complications of Phacoemulsification
Part 4: Pathology of the Enucleated Eye After Lens Extraction
Soemmering’s Ring (Donut) Cataract
Peripupillary Fibrosis
Cornea
Iris
Aphakic Maculopathy: Cystoid Macular Oedema (CME)
Epiretinal Membrane Formation
Effects on the Retinal Photoreceptors
Vitreous Prolapse/Vitreocorneal Contact/Malignant Glaucoma
Expulsive Haemorrhage
Retinal Detachment
Endophthalmitis
Acute Infection
Chronic Inflammation
References
Index

Citation preview

Fiona Roberts Chee Koon Thum

Lee's Ophthalmic Histopathology Fourth Edition

123

Lee’s Ophthalmic Histopathology

Fiona Roberts • Chee Koon Thum

Lee’s Ophthalmic Histopathology Fourth Edition

Fiona Roberts Department of Pathology Queen Elizabeth University Hospital Glasgow, UK

Chee Koon Thum Department of Pathology Royal Infirmary of Edinburgh Edinburgh, UK

ISBN 978-3-030-76524-8    ISBN 978-3-030-76525-5 (eBook) https://doi.org/10.1007/978-3-030-76525-5 © Springer Nature Switzerland AG 1993, 2002, 2014, 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

For Lucy, Patrick, Thum San and Liew Yoke Chan

Preface to the Fourth Edition

Over the last six years ophthalmic pathology continues to expand particularly in the fields of immunohistochemistry, molecular pathology and digital pathology. Maintaining the original format, based on the specimens as they are received in the laboratory and including these developments, has been a major challenge. Again we have aimed to maintain helpful and entertaining anecdotal cases and continued the heavy emphasis on illustrations. References, with an emphasis on reviews, have been extensively updated. This updated version will hopefully provide a sound starting point for those interested in or dealing with ophthalmic pathology specimens. Glasgow, UK

Fiona Roberts

vii

Preface to the Third Edition

The second edition of this book was written by my predecessor, Professor William Lee, more than 10 years ago. Over that time, the field of ophthalmic pathology has massively expanded— particularly in the fields of tumour diagnosis and molecular biology. The aim of the third edition is to provide a summary of these developments but also to maintain the original approach of this book to ophthalmic pathology based on specimen handling, basic morphology, and producing a comprehensive and relevant report for the ophthalmologist. The text has been extensively revised but I have aimed to maintain Professor Lee’s helpful and entertaining anecdotal cases and added a few of my own. The heavy emphasis on illustrations has also been carried over from the second edition and almost all images (barring the esoteric cases) are now in colour. A list of recent references has been included for each chapter. Hopefully this book will provide the basis for the reader to further explore the literature in areas of interest. Glasgow, UK

Fiona Roberts

ix

Preface to the Second Edition

The first edition of this book was written prior to 1991, and it seemed appropriate to revise and update the text in view of the rapid expansion in information which has occurred in the last decade. Furthermore, in the first edition, the reproduction of some of the illustrations was not of sufficient standard to be of value to the reader. Accordingly some of the inadequate figures have been replaced by colour figures which have been inserted into the text. Colour has also been included because many histopathological illustrations, e.g. special stains such as Gram, PAS, trichrome stains, etc., and immunohistochemical reactions, are much better appreciated. With regard to references, I have taken advantage of the currently available access to all the medical literature, which is what I anticipate will be the course of action of the reader. Glasgow, UK

W. R. Lee

xi

Preface to the First Edition

This book has been written to give guidance to histopathologists who are dealing with pathological specimens submitted by ophthalmologists, whether in a general pathology laboratory or in a specialist ophthalmic pathology laboratory. The bias has been given to the diseases encountered commonly in the routine service or in the autopsy room, and the intention is to show how to achieve the maximum information from each specimen. Conventional textbooks deal with diseases of the eye on an anatomical basis, but this is inappropriate for a histopathologist who is studying a globe in which the disease has varying effects on each of the individual tissue components. While unconventional, it seemed more acceptable to lay the book out under the relatively limited and broad headings which ophthalmologists use as indications for enucleation: “trauma”, “tumour”, “endophthalmitis”, “vascular disease”, etc. It also seemed logical to include a separate chapter on ocular disease as it is encountered in the autopsy room and, continuing the theme, to consider a keratoplasty specimen and the topics of orbital biopsy and conjunctival biopsy in separate chapters. In each pathological process, whenever appropriate, it was important to include the effects of modern therapeutic measures because this is one of the main features of interest for the clinician. For the beginner, an introductory chapter on the techniques and rationale of the preliminary systematic macroscopic examination of a globe has been included with an account of the supplementary techniques which are essential for an accurate diagnosis. There are many excellent textbooks in ophthalmic pathology, and the larger books carry extensive bibliographies. One or more of the comprehensive textbooks should be available for consultation to supplement the information provided here. Since it is now relatively simple to carry out literature searches using computerised systems, the bibliography in this book has been limited to the most recent references available at the time of writing. Glasgow, UK

W. R. Lee

xiii

Acknowledgements

We are indebted to Julie MacLean, Tom Morin and Ian Downie all from the Department of Pathology, Queen Elizabeth University Hospital, Glasgow. In our pursuit of new images Julie has interrogated our data base, Tom retrieved endless cases for us from archive and Ian digitised all images. We are grateful to them all.

xv

Contents

1 Examination of the Globe. Technical Aspects�����������������������������������������������������������   1 2 The Traumatized Eye�������������������������������������������������������������������������������������������������  29 3 Absolute Glaucoma�����������������������������������������������������������������������������������������������������  53 4 Retinal Vascular Disease���������������������������������������������������������������������������������������������  89 5 Intraocular Tumours ������������������������������������������������������������������������������������������������� 125 6 Ocular Inflammation ������������������������������������������������������������������������������������������������� 181 7 Treatment of Retinal Detachment����������������������������������������������������������������������������� 211 8 The Malformed Eye ��������������������������������������������������������������������������������������������������� 239 9 “Autopsy Eye”: The Eye in Systemic Disease����������������������������������������������������������� 275 10 Biopsy of the Eyelid, the Lacrimal Sac, and the Temporal Artery������������������������� 305 11 The Conjunctival Biopsy ������������������������������������������������������������������������������������������� 343 12 The Orbit: Biopsy, Excision Biopsy, and Exenteration Specimens ����������������������� 389 13 The Corneal Disc��������������������������������������������������������������������������������������������������������� 423 14 Lens ����������������������������������������������������������������������������������������������������������������������������� 465 Index ����������������������������������������������������������������������������������������������������������������������������������� 485

xvii

1

Examination of the Globe. Technical Aspects

Introduction As in many surgical specialties, much of the tissue that is excised in an ophthalmic operating theatre is not submitted to pathological examination. The common operations such as cataract extraction, corneal graft (keratoplasty), glaucoma surgery (trabeculectomy), and extraocular muscle shortening (squint or strabismus surgery) yield specimens that show tissue changes that are considered by some clinicians to be irrelevant to the further management of the patient, although the material is certainly of value in research institutes. By contrast, an informed opinion is always required for the investigation of inflammatory or neoplastic disease of the globes, the eyelids, the conjunctiva, or the orbit, and such diagnostic histopathology is well within the remit of an experienced general pathologist. Although enucleation of an eye is an infrequent operation for an individual ophthalmologist, there will be great interest in a pathological report if an intraocular tumour is suspected or if there is a possibility of sympathetic ophthalmitis in a traumatised eye. Trauma to the eye is also of increasing medicolegal importance, particularly if criminal charges are to be brought, as in the case of abusive head trauma in an infant. Also the fact that many ocular diseases are bilateral (e.g., macular degeneration, primary open angle glaucoma, and corneal dystrophies) means that a pathological report is relevant to the future management of the patient. If the enucleation was required for pain arising from central vein occlusion or a corneal ulcer, there may be less urgency in the requests for a report, particularly if these events occurred spontaneously in a patient who had not previously been under observation. An eye enucleated in the operating theatre or the autopsy room presents a challenge for the general pathologist, because such specimens are relatively rare and an adequate pathological assessment requires a sound background knowledge of normal ocular anatomy and clinical ophthalmology. In this chapter, therefore, the emphasis is on the methodology that is standard practice in the specialist laboratory, but

it also includes descriptions of the techniques that are recommended for investigation at the level necessary for presentation or publication. It is appropriate at this point to add that now, more than ever in the past, a detailed background knowledge of clinical ophthalmology is required for the interpretation of changes consequent on surgical, radiotherapeutic, and pharmacological intervention. The ever-­ expanding application of chemotherapy [1] will also present a challenge in the interpretation of alterations in neoplastic tissue. Most importantly, accurate documentation of pathological change is essential for correlation with the information that is provided by the study of the molecular genetics of ocular disease [2].

Clinical Correlation Background Information Optimal interpretation of pathological features always depends to a great extent on reliable clinical detail. The ophthalmologist must collaborate by providing an accurate history, the clinical diagnosis, details of present and previous surgical interventions and the findings obtained by fluorescein angiography, ultrasound, X-ray, and imaging techniques such as computerised tomography (CT) or nuclear magnetic resonance (NMR). The responsibility of the pathologist should be to provide macroscopic photography and sections cut at the correct levels for correlation with the in vivo observations. These rules apply particularly in traumatised eyes when there may be important medicolegal implications. It is often reassuring for a clinician to know that no amount of surgical expertise could have saved vision in a totally disorganised globe. Often a traumatised globe is so collapsed and distorted that a prior knowledge of the location of the entry and exit wounds (and of the wounds consequent on attempted surgical repair) is of great advantage to the pathologist. The preparation of paraffin sections is obviously much easier if

© Springer Nature Switzerland AG 2021 F. Roberts, C. K. Thum, Lee’s Ophthalmic Histopathology, https://doi.org/10.1007/978-3-030-76525-5_1

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2

notice is given of the possible presence of intraocular foreign material. When a foreign body is present within the globe at the time of enucleation, this must be retrieved during macroscopic examination and its nature identified by inspection or, if necessary, by submission for elemental analysis. The foreign body must be carefully stored so that it is available as evidence for criminal or civil proceedings in court. The clinician should also provide details of the site of the anatomical location of a tumour. Details of any previous treatment (e.g., laser treatment, cryotherapy, irradiation or chemotherapy) should be provided. A correct cut must provide histology not only through the centre of the tumour but also, in the case of a melanoma, a demonstration of the potential routes of extraocular spread through the scleral canals or into the vortex veins. The pathological information is essential for further interpretation of the images obtained from ultrasound (US), CT scan, and NMR. If comparisons are required, it should be remembered, however, that US, CT, and NMR images are usually created in the vertical and horizontal planes.

Clinical Techniques for Investigation, Illustration, and Documentation In modern clinical ophthalmology, the eye is examined by: 1. Slit-lamp microscopy: for study of the conjunctiva, cornea, lens, and vitreous. 2. Specular microscopy: for qualitative and quantitative examination of corneal endothelium. 3. Gonioscopy (3- or 4-mirror gonioscopy): for study of the chamber angle and the iris root. 4. Direct ophthalmoscopy: for examination of the vitreous, retina, choroid, and disc. 5. Indirect ophthalmoscopy: for examination of the fundus and the retinal periphery. 6. Fluorescein angiography: this technique is used to study the integrity of the endothelium of iris blood vessels and retinal blood vessels; the complications of ischaemic disease (e.g., exudation, infarction, and neovascularisation) are therefore readily identified. 7. Fluorophotometry is a sophisticated technique for the measurement of fluorescein concentration in vitreous and hence the rate of aqueous inflow. 8. Indocyanine green is also injected intravenously in order to demonstrate choroidal vessels and the presence of deposits under the retinal pigment epithelium in age-­ related macular degeneration.

1  Examination of the Globe. Technical Aspects

9. Scanning laser ophthalmoscopy uses infrared light to demonstrate the retinal vasculature. 10. Ultrasonography is used for investigation of ocular and orbital malformations, trauma, intraocular tumours, and foreign bodies. 11. Computerised tomography (CT scan) is used to differentiate structures by differential radiographic absorption. This is mainly applicable in neuro-ophthalmology. 12. Nuclear magnetic resonance (NMR) or magnetic resonance imaging (MRI) uses two forms of weighting that demonstrate the behaviour of hydrogen atoms after a pulse of radiofrequency energy. T1 signals are bright in fat; moderate in neural tissue; and low in bone, fluid, and air. T2 signals are bright in fluid, intermediate in fat and neural tissue, and low in blood and bone. Gadolinium contrast agent increases the signal intensity in T1 images and is used for the detection of breakdown in the vascular barriers. This technology is mainly applied to tumours within the globe, the optic nerve, and the orbit, but is also invaluable in the intracranial disorders that lead to neuro-­ ophthalmic disorders. 13. Optical coherence tomography (OCT)/scanning laser ophthalmoscopy (SLO) can provide cross-sectional images that can be correlated with the corresponding SLO image, allowing localisation of pathology to specific retinal layers. By each of these techniques, documentation by photography or electronic imaging is standard practice, and in this way clinicopathological correlation is an invaluable exercise for the clinician, the radiologist, and the pathologist.

Equipment for Macroscopic Examination A correct approach to the macroscopic examination of the globe is essential for the study of ocular disease (Fig. 1.1a, b). A good dissecting microscope with variable zoom magnification and bright illumination sources is essential. For manipulation of the specimen, straight and curved jewellers’ forceps are advantageous to grip the soft tissues on the external surface of the globe so that the specimen can be viewed from any angle. The forceps must not be used to grip the inside of the globe and should not touch the retina, which is extremely friable. For elimination of reflective highlights, it is advantageous to examine the globe under fluid in an appropriate container (say 10 × 10 cm at the base and at least 4 cm deep). Buffered normal saline or 50% alcohol can be used, but the latter solu-

Basic Gross Anatomy: External Features

a

3

b

Fig. 1.1  Equipment recommended for macroscopic examination of the globe. (a) The stereo dissecting microscope must have good illumination for dissection of the specimen. (b) The cut surface of the bisected

globe is best examined in a bath filled with saline. An engineers’ caliper is an excellent tool for measuring the dimensions of the globe and an intraocular mass

tion rapidly coagulates the proteins in the vitreous and causes opacification, although the tissue colours are enhanced. It is useful to use a small cup or three closely sited pins to prevent the globe from floating. Engineers’ callipers and a plastic ruler are useful for the measurement of the dimensions of the globe and optic nerve and the dimensions of structures within it; e.g., foreign bodies, tumours, etc. A razor blade is useful for dividing the optic nerve or cutting out particular features of interest, such as the macula, the site of previous surgery, or for removing tissue for electron microscopy (Fig. 1.2a–f). Surgical scalpels are too thick for this purpose. Excision of the outer half of the sclera makes it easier to do block excisions of choroid and retina, which separate and become distorted if a cut is made through the full-thickness sclera. For cuts across the whole eye, large skin graft blades or disposable microtomy blades are ideal. Fixatives dull the blade edge and, since the cuts should be accurate, fresh blades should be taken sooner rather than later. Cotton buds are useful for removal of the vitreous gel if this obscures the retina or the pars plana.

Basic Gross Anatomy: External Features Measurement of Ocular Dimensions Before any cuts are made into the eye, it is advantageous to remove blood and fatty tissue from the surface of the eye in order to identify the extraocular muscles. When blood is clotted it can be scraped from the surface with curved forceps or wiped off with disposable paper tissue. It is a convention in ophthalmic pathology to measure the maximum dimensions of the globe in the following sequence: 1. Anteroposterior (normal 22–23 mm) 2. Horizontal (normal 22–23 mm) 3. Vertical (normal 22–23 mm) An increase in anteroposterior dimension indicates axial myopia (28–30  mm), or glaucomatous enlargement due to uveoscleral bulging (staphyloma formation). Isolated or multiple staphylomas can also increase the horizontal and vertical dimensions.

4

1  Examination of the Globe. Technical Aspects

a

b

c

d

e

f

Fig. 1.2 (a) The posterior surface of a left globe after the episcleral tissues have been removed to show the relationships of the superior oblique muscle (s.o.) and the inferior oblique (i.o.) with the four vortex veins. (b) After measurement of the length of the optic nerve, a transverse cut is made about 3–4 mm behind the sclera. (c) If the presence of a melanoma is suspected, the vortex veins (inferonasal: e.g., I.N.v.v.; S.N.v.v; S.T.v.v.; I.T.v.v.) should be identified and submitted separately

for histology. (d) For a vertical parasagittal cut it is worthwhile to draw a line with an indelible marker to ensure that the knife passes close to the disc and into the edge of the anterior chamber. (e, f) To make the second cut place the cut surface of the globe on a flat surface and draw a microtomy knife across the globe from posterior to anterior, parallel to the original cut

Basic Gross Anatomy: External Features

5

A decrease in ocular dimensions (15–18 mm) occurs in age-related atrophy of the globe (hypermetropia) and in shrinkage (hypotonia, or atrophia bulbi and phthisis bulbi)— which occurs after prolonged loss of pressure in the eye. Ocular hypotonia is the consequence of inflammatory damage to the ciliary processes or to leakage of intraocular fluids through a defect in the corneoscleral envelope.

The Anterior Segment The Cornea The normal adult cornea is oval in shape and the dimensions are 12  mm horizontal and 11  mm vertical. The surface is smooth and the stroma can remain transparent even after fixation: The normal corneoscleral junction at the limbus should have an even surface and limbal blood vessels do not normally pass into the corneal stroma. Features to be sought and that are found commonly include: 1. Epithelial separation (which occurs in glaucoma): the anterior surface of the cornea is covered by a semitransparent folded epithelial sheet (bullous keratopathy). A pyogenic ulcer is sometimes a sequel to corneal oedema and appears as a yellow opacity with surface erosion. 2. Crescentic opaque scars were found in the past at the superior limbus where cataract and glaucoma surgery was most commonly performed. Currently, “small incision surgery” for glaucoma and cataract extraction will not lead to the formation of obvious scars. Look also for sutures that are often buried and almost invisible. Glaucoma surgery is intended to provide a filtration bleb at the limbus between 11 and 1 o’clock, and scar tissue in this region indicates this form of intervention. 3. A superficial white oval area below the horizontal line is caused by deposition of calcium salts in Bowman’s layer of the superficial cornea, so-called “band keratopathy” (Fig. 1.3). 4. A pale yellow circle (arcus senilis) in the stroma immediately internal to the limbus represents fat deposition and is a feature of normal ageing, or in a young person the possibility of hypercholesterolaemia. 5. Stromal pigmentation, when brown, is most commonly due to blood staining (Fig. 1.4). A pale yellow, opaque, and thickened surface layer is due to keratinisation of the corneal epithelium. 6. Stromal vascularisation particularly at the periphery is a non-specific end-stage phenomenon and is usually associated with previous inflammation and corneal fibrosis. Yellow patches in the stroma are due to leakage of plasma lipids from corneal blood vessels (secondary lipid keratopathy).

Fig. 1.3  In band keratopathy, an opaque horizontal band (arrows) due to the deposition of calcium salts runs across the inferior part of the cornea

Fig. 1.4  After extensive haemorrhage in the anterior chamber, the cornea becomes bloodstained. The entry wound of an airgun pellet is shown by an arrow

If corneal pathology is one of the major causes for enucleation (e.g., intractable ulceration and perforation) the block through the pupil and optic nerve should be cut so that serial sections will include the perforation.

 he Anterior Ocular Structures T When the cornea is transparent it will be possible to examine the iris, the pupil, and centre of the lens. A peripheral iridectomy defect, formed as part of the treatment of glaucoma or a lens extraction, is best demonstrated by retro-illumination. A black ring extending onto the anterior pupillary part of the iris—an “ectropion” of the iris pigment epithelium—is a manifestation of a neovascular membrane on the anterior iris surface (so-called “rubeosis iridis”). Iris neovascularisation

6

1  Examination of the Globe. Technical Aspects

is pathognomonic for diseases that cause retinal ischaemia (e.g., central retinal vein occlusion and diabetes). The anterior chamber may contain pus—“hypopyon”, with a fluid level after corneal ulceration; or it may be filled with organising or recent haemorrhage—a “hyphaema”—after trauma. NB: After enucleation the material in the anterior chamber may shift as the globe rolls in the fixative.

melanoma may be present in an eye with opaque media. After proton beam therapy for treatment of choroidal melanomas, tantalum discs may be adherent to the sclera (Fig. 1.7). Previous retinal detachment surgery can be recognised by episcleral scarring and plastic indentation bands or tubes around the equator of the eye (Fig. 1.8).

The Sclera The anterior sclera should be examined for the presence of wounds (sutured or unsutured) in cases of trauma, and in glaucoma for staphylomas—swellings of the thinned sclera over uveal tissue (Fig. 1.5). The vortex veins should be identified (Fig. 1.6), because there is always a possibility that a

The Posterior Aspect

Fig. 1.5  In posterior staphylomas (arrow), the areas of scleral thinning expose the underlying choroid adjacent to the optic nerve

Fig. 1.6  The vortex veins (arrows) are often congested and the fixed blood may lead to the impression that the vessels are filled by tumour

 he Optic Nerve T The length of the attached optic nerve should be noted and one or more transverse blocks should be taken before the eye is opened (particularly if the presence of a retinoblastoma is

Fig. 1.7  Small tantalum discs on the scleral surface (arrows) indicate the location of previous proton beam irradiation of a choroidal melanoma

Fig. 1.8  There is often extensive fibrosis (*) around encircling bands (arrows) used for the treatment of retinal detachment

Basic Gross Anatomy: External Features

7

suspected) (see Chap. 5). If there is a sufficient length of nerve, it is advantageous to take the transverse block some 3–4 mm behind the globe where the central retinal artery and vein are in situ. This level should leave 1–2 mm on the back of the globe (Fig. 1.2b, c) in order to help the microtomist to take longitudinal sections through to the level of the central retinal artery and vein in the middle of the nerve. In a glaucomatous eye, a cut across the nerve too close to the sclera may pass through the base of a deeply cupped optic disc: This error produces an embarrassing hole at the posterior pole in sections of the eye! Redundant meninges indicate atrophy of the optic nerve, which has a normal diameter of 4  mm. The central retinal artery and vein run side by side in the horizontal plane and the artery is usually nasal (remember Army/Navy: Artery/ Nasal) and the vessels can be seen clearly in blocks taken within the most anterior 6  mm of the optic nerve after the point of entry of the vessels. If the correlation of sectorial atrophy or demyelination in the nerve is of importance in a case in which there was a defect in the visual field, a razor-­ nick in the superior dura of the nerve can be helpful in orientation after Indian ink or Alcian blue is applied to the posterior surface of the block. The coloured surface should Fig. 1.9  The first cut into this specimen revealed a large melanoma, be on top when the block is embedded.

 he Vortex Veins T When an intraocular melanoma is suspected (Fig.  1.9), the vortex veins should be identified as they pass obliquely through the scleral canals. The veins may be obscured by blood clot or episcleral connective tissue and this material should be gently dissected off with fine forceps. If the vein contains tumour it will project like a sausage from the sclera, but clotted blood within the vein may be deceptive (Figs. 1.6 and 1.10). The veins are best located by drawing an imaginary line at 45° from the centre of the optic nerve and searching about 6–9 mm from the nerve (Fig. 1.2c). The canals for the veins are oblique slits that admit the tip of a pair of fine forceps. The veins should be cut close to the sclera, removed separately for histological examination (Fig. 1.2c) and labelled superotemporal (ST), superonasal (SN), inferotemporal (IT), and inferonasal (IN). (Processing all the specimens together increases the likelihood of loss of one or more.) If the veins are not identified, a slice of sclera across the canal of the vein is an acceptable substitute. A higher proportion of patients with vortex vein invasion by a melanoma develop liver metastases compared with all patients with melanoma [3].  rientation of the Primary Cuts into the Globe O The correct orientation of the globe is facilitated by identification of the pale brown (obviously muscular) inferior oblique muscle that is attached just below the horizontal line

which was first observed as a small tumour some 10 years previously when the patient was 80 years old and had suffered from several strokes. The ophthalmologists decided at that time that enucleation of a small melanoma was inappropriate in view of the poor prognosis for life. The patient survived for a further 10 years and did not appear at the age of 90 to be suffering from metastatic disease!

Fig. 1.10  This is a normal eye that has been sectioned in the horizontal plane through the optic nerve (o) and the centre of the lens (l) and the macula (m). This cut was made for demonstration purposes but it is too close to the centre line for a paraffin section to pass through the centre of the globe. Note the length of the temporal side (T) as compared with the nasal side (N)

8

to the posterotemporal part of the sclera (Fig. 1.2a). Above the insertion it will be possible to identify the long posterior ciliary artery. The white superior oblique tendon is attached to the superotemporal sclera close to (and sometimes perforated by) the superotemporal vortex vein. The long ciliary arteries run horizontally and are useful indicators of the horizontal plane. The area on the sclera corresponding to the macula is located about 2 mm below the horizontal midline. Traumatised eyes are usually collapsed and covered with a thick layer of clotted blood that must be carefully scraped off the episclera to identify the normal episcleral structures and to orientate the eye. Clotted blood, when fixed, becomes black and this can easily be mistaken for extraocular spread of a melanoma: histology of the suspect areas is essential in this event. In intraocular inflammation, endophthalmitis or panophthalmitis, or spontaneous necrosis of an intraocular tumour, the episcleral tissues may be congested, thickened, and gelatinous. The foregoing description applies to surgical enucleations that are easy to handle. Eyes removed at autopsy are softer and slipperier—a better grip can be obtained if absorbent paper is applied to the surfaces.

Transillumination/Retroillumination These techniques can provide very useful preliminary information before the globe is divided. A bright light source (fibre-optic for preference) is placed behind the globe, which is rotated and shielded by the fingers so that light passes through the specimen. Alternatively, the globe can be held within a black box that has a 2 cm hole cut into the back wall: a bright light is shone through the hole from behind. The normal globe is translucent, and shadows (which may be due to intraocular haemorrhage or tumour) are easily apparent and can be outlined on the sclera with indelible ink after the scleral surface has been dried. Vertical Calottes The cuts are referred to as lateral parasagittal (LPS) and medial parasagittal (MPS) and they are made at right angles to the long ciliary arteries. The paraffin sections should include the centre of the nerve, the pupil, and relevant pathology; e.g., a previous surgical procedure located between 12 and 1 o’clock. Two or three notches cut into the surface of the superior sclera are valuable for orientation of the paraffin section if the pathology does not provide a clue as to the superior or inferior parts. The accurate anatomical location of abnormalities is particularly important in ophthalmic pathology, because the ophthalmologist is well aware of the position of each feature prior to enucleation and it is much easier to write an informed pathological report if structures

1  Examination of the Globe. Technical Aspects

are described in their correct quadrants—referred to as the superior, inferior, temporal, and nasal. Vertical cuts are the choice in surgical lens extractions (aphakia) for the study of the surgical site, but beware of the presence of a plastic intraocular lens implant (IOL) that will impede the knife and cause disruption of the tissues in the anterior segment. If there is any possibility that an IOL is present, the first cut must be well outside the limbus. The macroscopic cuts must form a wedge that is thicker anteriorly, and the first cut is started 1 mm at the edge of the optic nerve and 2 mm into the corneal periphery, thus skimming the edge of the lens. This is referred to as the pupil-­ optic nerve or PO block and this part of the specimen is processed first for paraffin histology. An indelible ink pen can be used to mark the line of the cut on the sclera. To make the first cut, hold the lower part of the eye so that the nerve stump is vertical and the cornea rests on the cutting block. Draw a long blade (4–6 in./10–15 cm) across the posterior pole along the line drawn on the sclera as far as the corneal rim (Fig.  1.2e, f). It is essential to avoid a cut through the centre of the eye, because this dislocates the lens, which tears the iris. Before going any further the cut surface should be examined and photographed if documentation is required (Fig. 1.9). The inferior calotte is removed by placing the cut surface of the eye on a flat cutting block and, while the top of the specimen is held, the blade should be drawn horizontally across the eye in a direction that is again orientated to avoid dislocation of the lens (Fig.  1.2f). The PO block and the calottes (temporal and nasal) should now be transferred for examination under fluid. When embedding in paraffin, the posterior part of the globe is lifted so that it is in the same plane as the centre of the cornea. This will ensure correct orientation of the plane of section.

Horizontal Calottes In the horizontal plane, the paraffin sections should include the centre of the pupil, the lens, the macula, and the optic nerve (Fig. 1.10). The temporal side of the eye is longer than the nasal side, so that a horizontal cut can be recognised in a section even when the retina and macula are atrophic: the inferior oblique muscle when present is useful to identify the posterior temporal sclera. If it is important to have the centre of the macula in line with the centre of the optic nerve, the first cut must be tilted slightly down on the temporal side, because the macula is 2 mm below the horizontal line. Oblique Calottes The paraffin section should include the pupil, the optic nerve, and the centre of a specific item; e.g., a tumour, a corneal wound or scar, or the site of a foreign body (previ-

Basic Gross Anatomy: Internal Features

ously identified by X-ray of the specimen). The central part of a tumour should be in the same plane as the pupil and the optic nerve.

 he Unfixed Globe T On some occasions, it may be necessary to open an unfixed globe (surgical or autopsy) in order to provide tissue for biochemical analysis, polymerase chain reaction (PCR), or bacteriological examination, or for in vitro cell or tissue culture. The orientation of the caps (or calottes) should be chosen and the line of the cut marked out by an indelible ink on the scleral surface dried with paper. A wedge is cut carefully into the sclera and cornea along this line, but care must be taken not to cut as far as the choroid (particularly at the equator where the sclera is thinnest). The sclera, choroid, and retina are then divided along the groove with fine (but strong) sharp scissors. If the globe is suspended in a bath of sterile saline, support can be provided by curved forceps for the cuts made by scissors. The ciliary body, iris, and cornea are divided in the same way, but great care must be taken to avoid dislocation of the lens. After a calotte or the anterior segment is removed for research purposes, the unfixed globe may collapse. If the specimen is kept in the saline bath, the solution can be progressively replaced with fixative and the tissue will harden, leaving a satisfactory specimen for further manipulation. Later, the fixed specimen can be divided and processed routinely. If the central part of an unfixed cornea is required for additional studies, an obliging surgeon should remove the tissue from an enucleated eye with a trephine in the theatre. If fresh tissue is required from a melanoma for cytogenetics, this can be sampled by creating a small scleral window with a sharp blade.

Basic Gross Anatomy: Internal Features It is desirable to consider the section plane with some care before the calottes are removed. The most prized histological section in ophthalmic pathology is one that includes all the relevant pathological features and this is only obtained with an intact ring of the collagenous cornea and sclera. Sectors of the globe usually come apart during processing and sectioning so that normal tissue relationships (i.e., retina and choroid) may be completely lost: this can be avoided if the calotte is processed though paraffin and then divided in the appropriate plane. For most routine work, horizontal cuts are the most advantageous, but for some pathologists, vertical cuts are routine and the temporal calotte is taken separately for study of the macula.

9

a

b

Fig. 1.11 (a) The chamber angle is most easily examined in the calotte (arrowhead). (b) When examining the iris surface (i), look for the pupillary rim; the pigment epithelium of the iris should not be visible in the normal eye and the iris surface should have a carpet-like appearance

Examination of Specific Features A systematic examination of the cut surface and interior of an eye must include a systematic appraisal for the following features:

Cornea 1. Surface: keratinisation, ulceration, surface calcification. 2. Stroma: thinning or thickening, scarring, neovascularisation (usually peripheral). It should also be noted that the corneal shape is subject to artefactual distortion (possibly hypertonicity of the fixative) and may be concave. Anterior Chamber (Fig. 1.11a, b) 1. Shape: deep or shallow. 2. Content—blood, pus, lipid or proteinaceous exudate. Iridocorneal Angle (Fig. 1.11a, b) 1. Shape, open (normally 45°), narrow angle (5–30°), deeply recessed (post traumatic) or closed (peripheral anterior synechiae, PAS). 2. Look also for pigmentation of trabecular meshwork (exfoliation syndrome or iris atrophy). Iris 1. Pupil: constricted or dilated. 2. Surface: lined by a neovascular membrane (rubeosis iridis); displacement of the pigment epithelium around the pupil (ectropion uveae).

10

3. Stroma: fibrous, swollen, atrophic. 4. Pigment epithelium: post-inflammatory adhesion to lens. (NB: Iris pigment epithelium commonly adheres by artefact—pre and post-fixation—to the lens surface.) 5. Iridectomy defects: the location and size.

Ciliary Body Pars Plicata 1. Ciliary processes: atrophy in glaucoma; nodularity— non-specific ageing. 2. Zonule: fluffy white material on the zonular fibres is diagnostic of the “exfoliation syndrome”. Pars Plana 1. Pigmentary disturbance: areas of pallor indicate inappropriately placed cryotherapy or diathermy (treatment of glaucoma). 2. Exudates: a solid pale brown exudate between the ciliary body and the sclera indicates hypotonia. An opaque vitreous base over the pars plana indicates previous inflammation or organisation of vitreous haemorrhage. 3. Scars: small scars with fibrous ingrowth into the vitreous represent the ports used for a surgical vitrectomy procedure. 4. Snow-bank-like fibrosis on the surface of the pars plana (pars planitis) or cysts in the epithelium (hyperglobulinaemia)

Lens 1. General: size, shape, colour, degree of transparency. This of course varies with fixation. 2. Opacities: a white anterior subcapsular fibrous mound indicates previous or continuing iridocyclitis. A posterior opacity occurs in diabetes or after topical steroid therapy, and detachment surgery, but it is often non-specific. 3. Fixation artefact rapidly causes lens opacification and this process is accelerated by rupture of the capsule. NB: In neonates, the posterior lens surface is concave. Vitreous 1. Blood: in the base or vitreous stalk indicates neovascularisation in the retina and at the disc. Long-standing haemorrhages organise to form brown (ochre) membranes. 2. Retinal detachment: in long-standing retinal detachment, the vitreous condenses into dense membranes that distort the retina. 3. Silicone oil: this is used to replace the vitreous after detachment surgery and it escapes in profusion when the eye is opened. The oil is sticky, and “clings” to the blades, instruments, water baths, etc. Variants of this compound (e.g., heavy liquid) are constantly being introduced (see Chap. 7).

1  Examination of the Globe. Technical Aspects

4. White masses can suggest a lymphoma or an abscess, bacterial or fungal.

Retina The Peripheral Retina 1. Non-specific degenerative changes (see Chap. 7). 2. A grey honeycomb appearance indicates a “peripheral microcystoid degeneration”. 3. A linear circumferential atrophy with palisaded white lines is a “lattice degeneration”. 4. Punched out areas of pallor (1 cm diameter) signify “chorioretinal atrophy” or “paving stone” degeneration. 5. Pigmentary disturbances could mean previous irradiation by plaque, laser coagulation, cryotherapy, retinitis pigmentosa, or previous mechanical trauma. The Posterior Retina 1. If the retina is in situ. In a case of ischaemic disease look for haemorrhages (dot, blot, flame) and intraretinal exudates—fluffy white or discrete and yellow, the former are seen in central retinal vein occlusion and haematological disorders, the latter are more likely in hypertension and diabetes (Fig.  1.12). In trauma or retinitis pigmentosa look for hyperpigmentation. The pigmentary disturbance, spidery black lines and white areas, is an indication of a disorder of the photoreceptors and the retinal pigment epithelium. In atrophy of the choroid and the retinal pigment epithelium, round white areas behind the ora serrata indicate peripheral chorioretinal degeneration while those around the disc are a feature of high myopia.

Fig. 1.12  A horizontal section through a globe removed at autopsy in a leukaemic patient. Note the large haemorrhages (arrow) and the darker disc at the fovea and macula (m). The specimen also illustrates a myelin artefact—the retinal vessels are filled with a white toothpaste-­ like material (arrowhead). Myelin is also present within and beneath the optic disc (d). The lens (l) is transparent

Basic Gross Anatomy: Internal Features

11

1. Cystic swelling of the macula is sometimes seen after cataract surgery currently with an intraocular lens (plastic) implant. 2. Discrete yellow exudates forming a circular (macular) star are a feature of diabetes. 3. Detachment of the macula is most frequently artefactual.

Optic Disc 1. Swelling of the disc with blurring of margins is characteristic of papilloedema. Note that this can also be due to ocular hypotonia and ocular hypertension in addition to raised pressure in the cranial cavity. Malignant hypertension will be associated with haemorrhages and exudates. 2. Cupping of the disc is characteristic of glaucoma, but this may be obscured by new blood vessels after an occlusion of the central retinal vein. 3. Atrophy of the optic nerve: the optic nerve head appears as a flat white disc in primary or secondary atrophy of the optic nerve. 4. Growth of neovascular tissue from the disc: when accompanied by retinal haemorrhages and exudates, this is a feature of diabetes or central retinal vein occlusion.

Fig. 1.13  The pathological changes observed in an aphakic globe after various failed retinal detachment procedures can be somewhat disconcerting. The detached retina becomes gliotic and white (*), particularly if silicone oil was used and strands of blood vessels and glial cells (arrowhead) link the different parts of the retina. Note the equatorial encircling bands

2. If the retina is detached. The detachment may be shallow, partial, or total, or be artefactual after fixation. A solid proteinaceous exudation occurs in association with choroidal or retinal tumours, trauma, and retinal vascular disease. Holes or tears may be the cause of an exudative detachment. Look for plastic encircling bands around the sclera (Figs. 1.8 and 1.13) following surgical treatment of retinal detachment or chorioretinal scarring due to cryotherapy or laser. Cholesterol crystals may be abundant in the subretinal exudate in a child’s eye (Coats’ disease). Vitreous organisation and the formation of preretinal traction bands ultimately progress to a “funnel-shaped” or “table-top” deformation of the detached retina. 3. Depigmentation in the retinal pigment epithelium seen as round white areas behind the equator are due to cryotherapy. Pigment rings around smaller white areas are the result of laser burns.

The Macula This is located just below the horizontal line and is identified by the central yellow macula lutea.

Choroid Thickening due to haemorrhage and exudation occurs in hypotonia. Inflammatory infiltration and tumour infiltrates appear as solid white, brown or black nodules. NB: In sympathetic ophthalmitis, the thickening is due to a granulomatous inflammatory reaction that is manifest as a cut surface resembling marble. Sclera 1. Thickening and folding occurs at the end stage of ocular hypotonia (phthisis bulbi). “Phthisis bulbi” is a term used for end-stage shrinkage of an eye, usually post-­ inflammatory or post-traumatic. Calcification and ossification are frequent in such specimens and it is expedient to make an initial cut in the sclera and to leave the specimen in decalcifying fluid (formic acid/sodium citrate) for 24–48 h until definitive cuts can be made. A matchstick keeps the lips of the cut open to allow better penetration of the decalcifying fluid. 2. Thinning and stretching occur in glaucoma. 3. Pseudopigmentation is artefactual in autopsy material after delayed fixation and is due to an acquired tissue lucency.  etrieval of Tissue from the Calottes R Division of the globe into several parts is totally unsatisfactory, because in small blocks of tissue the lens, retina, and choroid separate from the sclera and from each other during processing. Nonetheless, there are times when serial sections

12

through a small lesion in a calotte are required for detailed study. It will be easier to take a small block of retina and choroid if the adjacent sclera is pared away and the vitreous is removed with a cotton-wool bud on an orange stick. When narrow slices (3–5 mm) of tissue are taken from a globe, there is a tendency for the retina to detach during the cut and to curl during processing. If a small region of the retina is to be examined by serial section, it is often advantageous to take a small block from a calotte after processing through paraffin, because the embedding medium supports the tissue and the appropriate region can be cut out of solidifying paraffin wax.

 adiological Examination of the Globe R Radiological examination of the whole globe, the PO blocks, or the calottes may be very useful for the identification of a foreign body or foci of calcification within the specimen (Fig. 1.14a, b). If the specimen is shrunken and hard on palpation, it is highly likely that there is bone in the eye. X-ray of the specimen simplifies localisation and removal of the foreign body or signifies that decalcifying fluids should be used prior to cutting the calottes. The location of an intraocular radio-opaque area is assisted by the insertion of a needle into the episclera prior to taking the X-rays, which should be done in two or more planes (Fig. 1.14a). It will then be possible to achieve a section that illustrates all the relevant features. An X-ray apparatus that produces soft X-rays for examination of 1  cm bone slices is suitable for an eye. The Faxitron system for examination of slides of breast tissue is also suitable for globes.

1  Examination of the Globe. Technical Aspects

a

b

Common Artefacts Myelin Artefact Some surgeons clamp the optic nerve or divide the nerve with a snare during the enucleation procedure to reduce the risk of haemorrhage from the central retinal vessels and posterior ciliary vessels. The same artefact can be seen in autopsy material. Macroscopically the optic nerve is obviously crushed and myelin, squeezed into the eye like toothpaste, appears as white masses in the optic disc and in the peripapillary subretinal space. Entry into the retinal vessels is less common but is striking when it occurs (Fig. 1.12). Shrinkage Artefact Correct osmolarity and fresh preparation of the fixative is important in maintaining the shape of a globe. Overlong fixa-

Fig. 1.14 (a) Radiological examination of the globe is used to demonstrate the presence of foreign bodies, in this case an airgun pellet. A hypodermic needle passed into the sclera is useful for orientation and the X-ray should be taken in two planes. (b) Identification of the pellet in the X-ray allowed a section to be taken through the globe without disturbing the pellet (P). Note the detached retina, vitreous haemorrhage, anterior displacement of the lens (l) and hypotonia

Fixation Techniques

tion in post-dated, hypertonic, degraded, acidic glutaraldehyde, or formaldehyde can result in undesirable shrinkage with collapse and deformation of a globe. This artefact is particularly common in animal globes, in which penetration is quick so that processing can take place after a short period of fixation.

Autopsy Material Delay in fixation can cause retinal swelling and folding and this may be particularly pronounced in fetal material.

Fixation Techniques Formalin-Based Fixatives Formaldehyde This is the traditional fixative solution in ophthalmic pathology because it has prolonged chemical stability and is reliable for a postal service that covers large geographic areas and may be subject to delay in transportation. Staining systems used in general pathology laboratories are easily modified to produce the best results with formalin fixation after paraffin embedding. Neutral or buffered formalin (10%) is the most suitable fixative for immunohistochemistry. Specimens may be washed in running water and post fixed in ethyl alcohol (50–70%), which brings good colour to the specimen for macrophotography. Glutaraldehyde (2–4%) This fixative is usually buffered with phosphate buffer (Sorensen’s buffer) and provides good fixation for electron microscopy. It is also useful for corneas and globes where immunohistochemistry is unlikely to be required. Penetration of thin ocular tissues is rapid and it provides excellent fixation of the corneal endothelium and retina without the artefacts that may be seen with formalin fixation. This can be particularly useful for post mortem specimens when the tissues are very soft. The biggest disadvantage is the loss of antigenic epitopes for immunohistochemistry a maintain of the modern histopathology laboratory.

Embedding Techniques General Considerations The globe is notoriously difficult to section, because the constituent tissues vary quite considerably in consistency. After

13

processing, the lens and corneoscleral envelope become hard while the retina and uveal tract remain soft. An ideal embedding medium that holds all the layers together and permits easy sectioning is not yet available. Wax embedding has superseded the traditional celloidin and plastic embedding techniques for globes. With both embedding techniques, however, a considerable degree of technical skill is required for the consistent production of top quality sections. With modern microtomes it is possible to provide thinner sections (3 μm). The advantages of paraffin sections are: 1. A short processing cycle (a 16-h tissue processing cycle is adequate). 2. Easy preparation of serial sections. Dry ribbons can be stored between numbered sheets of paper in cardboard boxes (boxes for photographic paper are suitable). 3. Application of special stains: any routine stain, including immunohistochemical stains, can be modified and employed on sections stored as blanks or ribbons. Coated (polylysine) slides are essential for immunohistochemistry. 4. Relatively thin sections may be obtained 5. Storage of paraffin blocks requires little space. The most important factor in paraffin microtomy is the sharpness of the microtome knife. The best results are obtained with disposable blades. Various types of paraffin wax are available and those with a melting point in the range 50–60 °C give the best results. Considerable skill is required for the control of section expansion on the water bath set at the right temperature. The problems that are associated with paraffin embedding are: 1. There may be tissue shrinkage and excessive hardening if the specimen is inadvertently exposed to high temperatures during processing or block embedding. 2. The section expands slowly on the water bath (52–54 °C), and attempts to speed up this process—e.g., by overheating the water bath, or placing a solvent, e.g., alcohol (with a fine paint brush in the centre of the wax within the globe)—may cause excessive stretching and even worse, cracking and splitting in the retina. 3. Poor adhesion between the section and the glass slide. This is a problem when silver stains (e.g., Bodian and reticulin) are used and can be avoided by pre-coating the slides with polylysine or albumin. Alternatively, albumin can be added to the water bath.

14

 istological Examination of a Section H of the Globe and Preparation of a Pathological Report Thorough examination of a section of an eye is essential if the pathological details are to be appreciated and it is helpful to have a scheme so that all of the ocular tissues are examined. At low power, the examination should start at the limbus and traverse the cornea to the opposite limbus. Here the angle should be examined and the nature of changes in the outflow system noted. The slide is then moved along the line of the iris with a note of the shape and content of the anterior chamber. At the opposite angle, move to the ciliary body and then cross the lens to the opposite side of the ciliary body. Start at one pars plana and work back to the disc and round to the other retinal periphery. Then examine the optic nerve and the posterior ciliary vessels and nerves. If the retina is detached, trace the retina from one periphery to the disc and then work round to the opposite periphery. Abnormalities should then be studied in detail. The preparation of a report is made easier if this anatomical approach is followed, although some qualifications should be made with regard to the presumed sequence of events that lead to the end stage.

1  Examination of the Globe. Technical Aspects Table 1.1  Digestion technique for retinal vasculature [3] 1. Fix the eye in 10% formalin. 2. Remove as much vitreous as possible and then remove the retina. 3. Float the retina onto water, making cuts in the periphery to facilitate flattening. 4. Wash overnight in tap water. 5. Digest the net in 3% pepsin in 1% HCl pH 1.5 at 37 °C for 20–30 min. 6. Wash in four changes of distilled water. 7. Transfer to freshly prepared solution of 3% trypsin in a solution of 0.1 M tris buffer pH 7.8 at 37 °C for 1–3 h, depending on speed of digestion. 8. At this stage it is possible to start pulling off the internal limiting membrane, which begins to lift around the disc but remains fast towards the periphery. 9. Place the retina in water in a Petri dish and allow water drop by drop to fall on it, causing the supporting tissue to fall away from the vessels. 10. The solution containing retinal debris is removed with a Pasteur pipette, replacing carefully with fresh water. 11. Float onto slide and dry at room temperature. 12. The preparation is stained with periodic acid-Schiff (PAS) and haematoxylin.

Specialised Techniques Introduction The fact that the ocular tissues can be dissected easily into layers by mechanical separation means that the morphologist has the opportunity to study the semi-transparent tissue in three dimensions. Some 70  years ago, the retinal vessels were studied after coloured media (gelatin/latex) were injected into the ophthalmic artery. The retina, choroid, and sclera can be cleared by dehydration and immersion in cedar wood oil and this provided excellent demonstration of the normal and diseased vasculature. The resolution was improved when the neural tissues were removed by digestive enzymes (retinal digests).

Retinal Digest Preparations Retinal digests are used to demonstrate many important features of retinal vascular disease. The technique to be employed is described in Table 1.1 [4]. Formalin fixation is considered to be essential for retinal digestion and the tissue should not be exposed to alcohol at any stage. The retinal digestion technique requires a great deal of prac-

Fig. 1.15  A retinal digest preparation (in diabetes) shows the capillary free zone around the arteriole (a). There are multiple microaneurysms (PAS ×100)

tice, expertise, and patience. After several hours in the enzyme solutions, the inner limiting membrane can be stripped from the retina and the neural retina disintegrates, leaving the vascular bed separate from the neural tissues. At this point the vessels become sticky. While the enzymes pepsin and trypsin were the traditional choice for digestion of neural tissue, it has been shown that elastase provides cleaner preparations [5]. The resemblance to a spider’s web becomes apparent if the preparation is allowed to stick to the forceps! Staining with periodic acid-Schiff (PAS) and haematoxylin (Fig.  1.15) demon-

Specialised Techniques

a

15

strates the constituents of the vascular bed and in particular endothelial cells, pericytes, microaneurysms, and the basement membrane of the capillary wall (see Chap. 4).

Injection Techniques (Carbon, Plastic)

b

In the past, various methods have been used to study the vascular channels in the canal of Schlemm, the choroid, the orbit, and optic nerve in post-mortem or experimental tissue, by injection of carbon ink or latex suspensions into the appropriate feeder vessels. If the surrounding tissue is taken through alcohol and subsequently cleared by immersion in cedar wood oil, the vascular bed can be readily observed at low to medium magnifications (say ×40) by such techniques. Perfusion with low viscosity plastic solutions (Fig. 1.16a–c) has also proved an effective means of demonstrating the capillary bed by high resolution scanning electron microscopy, which permits the study of endothelial nuclear bulges into the wall or even the presence of fenestrations at magnifications as high as ×20,000 [6]. The intrinsic problem with all perfusion techniques is that failure to fill any part of the vasculature may be due to technical problems, and not necessarily to an occlusive disease.

Frozen Sections for Fat c

Frozen section for demonstration of fat is now rarely used in the laboratory. For tumour diagnosis (sebaceous gland carcinoma) it has been largely superceded by immunhistochemical staining. However, it is sometimes useful to take frozen tissues from an eye in which abnormal fat deposition is suspected (in, for example, the lipodystrophies such as Tay-­ Sachs disease in which retinal degeneration is a feature). Embedding in gelatin before freezing is a useful way to support the tissue sections, which can be stained with oil red O to demonstrate the presence of neutral fat deposits [7]. Cholesterol is birefringent in polarised light (Fig. 1.17).

Stains for Microscopy Fig. 1.16  Scanning electron microscopy can be used to study the vasculature of tissue after injection of a plastic into the vessels; the soft tissue is dissolved leaving a vascular cast. (a, b) This vascular cast is from a guinea pig eye to show the complex arrangement of the capillaries within the ciliary processes (arrows) (a ×150; b ×500). (c) The choriocapillaris (cc) is a two-dimensional mesh of capillaries feeding from and into the underlying choroidal vessels (cv) (×600). (Courtesy of Dr. P. McMenamin)

Conventional Stains Although a good haematoxylin and eosin (HE) stained section will usually suffice for diagnostic purposes, there are many occasions when special stains (Table 1.2) are invaluable for a definitive diagnosis and are essential for a fuller understanding and interpretation of the pathologic changes

16

1  Examination of the Globe. Technical Aspects

[8]. The Masson-Fontana stain for melanin is particularly helpful for identifying melanocytes in neoplastic proliferation (Fig. 1.18a, b).

Immunohistochemistry

Fig. 1.17  Polarised light reveals the birefringence of cholesterol crystals in the corneal stroma in a case of post-herpetic lipid keratopathy. The frozen section was stained with oil red O, which reveals red neutral fat globules in proximity to the cholesterol

Immunohistochemistry has superseded electron microscopy particularly in tumour identification and subtyping. Immunohistochemistry is a method of detecting the presence of specific proteins in cells or tissues. Due to the dramatic expansion in immunohistochemistry this technique is now automated in most departments. The basic steps are as follows: • A primary antibody binds to a specific antigen. • A secondary enzyme-conjugated antibody is then bound to this primary antibody-antigen complex.

Table 1.2  Special stains for light microscopy Alcian blue

Alizarin red Bodian

Colloidal iron Grocott-Gomori methenamine silver stain Gram-Weigert (Gram-­ positive) and Gram-­ Jensen (Gram-negative) Luxol fast blue or “Loyez” Masson-Fontana Periodic acid-Schiff (PAS) Prussian blue Silver Trichrome stains (Masson, Mallory or picro-Mallory) Van Gieson von Kossa stain Warthin-Starry Weigert’s elastica Ziehl-Neelsen

At various pH levels stains acid mucopolysaccharides, keratan sulphate, heparan sulphate, dermatan sulphate and hyaluronic acid. These are normally present in the subretinal space and vitreous. At pH 0.5 strongly sulphated mucins are identified, at pH 1.0 only sulphated mucins react, while at pH 2.5 all acid mucins, carboxylated and sulphated react. Chelates calcium and is a useful reagent for demonstrating foci of calcification. Stains axons purple black but is also useful for lens fibres and demonstrating degeneration in lens cortical substance: this stain outlines scar tissue in the corneoscleral envelope and demonstrate previous areas of haemorrhage in the ocular tissues. Is a useful stain for demonstrating mucopolysaccharides in tissues. This stain is now rarely used due to the toxicity of some of the reagents. Is used for the demonstration of fungal hyphae and may be more reliable than the PAS stain. Stain bacteria in tissue.

Stain myelin blue and nerves black, respectively. Stains melanin granules black: melanin can be bleached with potassium permanganate and oxalic acid. Bleached sections are useful with the melanin pigment obscures cellular detail. Stains basement membranes bright pink; e.g., Descemet’s membrane, lens capsule, inner limiting membrane of retina, glycogen in cells (diastase sensitive), macrophages, renal carcinoma cells, neutral mucopolysaccharides. Fungal elements often stain well, but not always. Stains ferrous and ferric iron dark blue, which is useful to identify the breakdown products of blood and to time the prior occurrence of haemorrhage. Stains for reticulin demonstrate the walls of blood vessels Differentiate between smooth and striated muscle (red) and collagen (green or blue), squamous epithelium (pink), keratin (red) and neural tissue purple. Bowman’s layer of the cornea is clearly outlined. Is also a trichrome stain that stains muscle yellow and connective tissue red. The stain is often combined with stains for elastic tissue. Utilises a silver salt to react with the phosphate in calcified tissue producing a black precipitate. Stains bacteria that may not react well with the Gram stain; e.g., Rochalimaea sp. in bacillary angiomatosis. Stains elastic tissue; used for differentiating between pterygia and pseudopterygia and it provides a good outline of Bruch’s membrane on the inner surface of the choroid. Stains Mycobacterium sp. strongly and Nocardia sp. weakly.

Specialised Techniques

a

17

b

Fig. 1.18 (a) In a haematoxylin and eosin stain the excessive amount of melanin in acquired melanosis appears as brown particles. (b) With the Masson-Fontana stain for melanin, the extensive distribution of the melanosomes is more easily apparent

• An appropriate substrate and chromagen are added and the enzyme catalyses the formation of a coloured deposit at the sites of antibody-antigen binding. The resulting staining is usually brown in colour, but red or purple chromagens may be used in heavily pigmented lesions such as melanoma. The introduction of antigen retrieval techniques including proteolytic digestion and microwave antigen retrieval has vastly improved the range of antibodies that can be used on formalin-fixed, paraffin-embedded tissue sections. Reasonable staining can also be obtained in glutaraldehyde fixed tissue, although it may be necessary to alter the antigen retrieval methods. Immunohistochemistry has an important role in the diagnosis of many tumours. This is particularly the case for lymphomas and soft tissue tumours for which a panel of antibodies are usually required for accurate diagnosis and subtyping. Identifying the primary site of metastatic carcinoma or other tumour may be particularly useful in ophthalmic pathology (Fig.  1.19a, b). Panels of antibodies are also used to accurately subtype

Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma (Fig.  1.19c). Other markers are important in providing prognostic information. For example, the association of high Ki-67 (a cell proliferation marker) labelling indices is a poor prognostic indicator in lymphomas. Certain markers may also indicate likely response to treatment. Positive oestrogen and progesterone receptors in breast cancer indicate a likely response to hormonal therapy. Staining for the protein product of the oncogene c-kit in gastrointestinal stromal tumours and adenoid cystic carcinomas suggests a likely response with the targeted therapy Imatinib. Immunohistochemistry can also be useful for the detection of various infectious agents; e.g. cytomegalovirus, herpes simplex virus, Acanthamoeba, Toxoplasma (Fig. 1.19d). Available antibodies for immunohistochemistry are now extensive. A summary of common antibodies useful in ophthalmic pathology is shown in Table 1.3. Antibodies for common ocular lymphomas and metastatic carcinoma are detailed in Chaps. 11 and 12, respectively.

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1  Examination of the Globe. Technical Aspects

a

b

c

d

Fig. 1.19 (a) Immunohistochemical staining for oestrogen receptors in a case of metastatic breast carcinoma. Note oestrogen receptors are nuclear (×400). (b) Cytoplasmic staining for Melan A in a case of malignant melanoma of the conjunctiva. Note the use of a red chroma-

gen to avoid confusion with melanin pigment (×250). (c) Membranous staining for anti-CD20 a pan B-cell marker in a case of lymphoma (×250). (d) Immunohistochemical staining for Herpes simplex virus within epithelium adjacent to a corneal ulcer (×400)

In Situ Hybridisation (ISH)

Polymerase Chain Reaction (PCR)

In this technique, single-stranded complementary nucleic acid sequences can join with specific DNA or RNA sequences in cells or tissues. These hybridization sites can then be identified by the addition of a fluorescent (FISH) or enzyme labelled probe. FISH is utilized to detect chromosomal gains, losses, and translocations that are important in the diagnosis and prognosis of certain malignancies. It is important in the diagnosis of lymphomas, which often have relatively specific chromosomal translocations. For example, a translocation (14;18) is present in the majority of follicular lymphomas, whereas a translocation (11;18) is present in the majority of extranodal marginal zone lymphomas (Fig. 1.20). In situ hybridization may be used for assessing clonality for kappa or lambda light chains in plasmacytic lesions. It is also useful for detecting virus nucleic acids in infections with Epstein-Barr virus or cytomegalovirus (Fig. 1.21).

PCR involves the selective amplification of specific segments of DNA. Reverse-transcription-PCR is used to detect RNA expression levels. These techniques are used for detection of clonality in lymphoma (immunoglobulin light chains or T-cell receptor), genetic mutations and deletions and detection of pathogens; e.g., Epstein-Barr virus.

Tumour Cytogenetics Karyotypic analysis of malignant tumours shows both numerical and structural chromosomal abnormalities when compared with normal cells. In solid tumours, amplifications and deletions of chromosomal regions are more common. Translocations are important in haematopoietic malignancies.

Specialised Techniques

19

Table 1.3  Some examples of immunohistochemical reagents used in diagnostic pathology Actin Alpha-fetoprotein Amyloid A and P Androgen Receptor Carcinoembryonic antigen (CEA) CD31 and CD34 CD56 CDX2 Chromogranin Common leucocyte antigen (CLA) Cytokeratin/CAM 5.2/ AE1/AE3

Desmin Epithelial membrane antigen (EMA) Factor VIII-related antigen GATA3 Glial fibrillar acidic protein (GFAP) HMB 45 Ki67

Melan A MyoD1 and Myogenin Neurofilaments PAX8 S100 Synaptophysin TTF-1 Vimentin

For smooth muscle cells in ciliary muscle and ciliary body and myofibroblasts, but not fibroblasts Germ cell tumours (metastatic to eye and orbit) Stains some amyloid deposits. Positive in some sebaceous gland carcinomas Metastatic adenocarcinomas to ocular tissues; adnexal skin tumours These stain vascular endothelium. CD34 is also positive in a range of soft tissue tumours including solitary fibrous tumour. This is a neural cell adhesion molecule positive in neuroendocrine and some neural tumours. This is a transcription factor that is useful as a marker of gastrointestinal differentiation especially colorectal. A neuroendocrine secretory granule present in neuroendocrine tumours The antibody against this antigen reacts against lymphoma cells and cells in benign lymphoid infiltrates These antibodies react against intermediate filaments in epithelial cells and are useful for identifying carcinomas, particularly intestinal: CAM 5.2 is less useful for malignant squamous cells, because these cells contain higher molecular weight cytokeratins for which more specific reagents must be sought. The retinal pigment epithelium reacts with these antibodies. Cytokeratin 7 is positive in metastatic carcinoma of upper gastrointestinal, pulmonary or gynaecological origin. CK20 is positive in metastatic colorectal carcinoma. Hyperplastic RPE cells may be CK7 positive Differential cytokeratins (CK19, CK12 and CK3) can be useful in assessing conjunctivalisation of the ocular surface (see Chap. 11) Striated and smooth muscle in tumours, intermediate filaments (muscle specific) Was initially used for epithelia and carcinomas. Plasma cells are also positive. This antibody reacts with sebaceous carcinoma Vascular endothelium, preretinal vascular proliferation; haemangioendothelioma, haemangiosarcoma A transcription factor found in breast and urothelial carcinoma Glial cells and astrocytes (Müller cells) in retina, preretinal membranes and astrocytic tumours of the optic nerve Melanocyte specific intracytoplasmic antigen: not only does this antibody stain malignant melanocytes, it may also react with active melanocytes in a naevus This antibody recognises a labile antigen expressed in cycling cells and absent from quiescent cells. Expression appears in mid to late G1 rising through S phase and G2 to reach a maximum in mitosis. After mitosis the antigen is rapidly degraded A melanocyte differentiation antigen present in benign and malignant melanocytic processes. These are transcription factors important in striated muscle differentiation and are positive in rhabdomyosarcoma. These are intermediate filaments found specifically in neurones. They are useful for staining optic nerve and nerve fibre layer and for identifying corneal nerves. Transcription factor found in thyroid, urinary and reproductive organs This is a useful marker of melanocytes, melanomas, nerve sheath tumours and sustentacular cells in paragangliomas. This is a major synaptic vesicle protein present in neuroendocrine tumours and in retinoblastoma and neuroblastoma. Thyroid transcription factor is a transcription factor positive in tumours of lung and thyroid origin. Stains intermediate filaments, therefore also cells of mesenchymal origin, e.g. sarcomas: lymphomas also react. Müller cells are stained in retina, but not the astrocytes

Chromosomal abnormalities within a tumour cell may fall into one of three categories: 1. Primary abnormality: the change is essential to establish the tumorigenesis. These tend to have strong correlation with tumour type; e.g., deletion of Rb1 gene in retinoblastoma. 2. Secondary abnormalities: these are a manifestation of tumour progression and clonal evolution and are not usu-

ally tumour specific; e.g., loss of p53 and DCC in progression of colonic adenoma to adenocarcinoma. 3. Cytogenetic noise: this is a manifestation of the genetic instability of a tumour cell. These abnormalities are randomly distributed throughout the genome and are not tumour specific. These various chromosomal abnormalities may be detected using a variety of techniques including conventional cytoge-

20

1  Examination of the Globe. Technical Aspects

Fig. 1.21  In this example of herpes simplex retinitis, viral particles have been identified by in situ hybridisation, which reveals the pathogen in the ganglion cells (arrows)

Fig. 1.20  Fluorescent in situ hybridisation demonstrating an 11;14 chromosomal translocation in an unusual case of conjunctival mantle cell lymphoma. Chromosome 11 is red and chromosome 14 is green. Where the translocation has occurred the signal is yellow. Not every cell contains the translocation (×400)

netics, polymerase chain reaction (PCR)-based techniques, fluorescence in situ hybridization (FISH), and comparative genomic hybridization. Specific applications to the eye include changes in the RB1 gene in retinoblastoma and changes in chromosome 3 and 8 copy number in uveal melanoma.

Next Generation Sequencing The Human Genome Project completed in 2003 enabled rapid, affordable and accurate genome analysis encompassed under the term “next generation sequencing” (NGS). These techniques can be used to identify a discrete number of genes of interest which are sequenced. These gene panel techniques are useful for genes in hereditary breast and ovarian cancer and are also useful for identifying drug targetable mutations in certain cancers e.g. EGFR in lung cancer. In retinoblastoma targeted NGS has been used to identify pathogenetic variants in the RB1 gene [9]. The next step up is whole exome sequencing where sequencing of the protein coding region of genes in the genome is undertaken to allow identification of genetic variants that alter protein sequence. This is useful for gene mapping in rare disorders. For example a large number of individual genes have been identified in inherited retinal dystrophies [10]. Using NGS the approach usually involves an initial specific targeted panel of genes followed by whole exome sequencing where this has been unsuccessful. In whole genome sequencing the entire DNA of the genome is sequenced at a single time. This can be used in

metastatic carcinoma where the primary is unknown to identify site specific mutations and mutations which will allow the patient to receive genotype matched targeted therapy. For intraocular infections microbial whole genome sequencing may be useful to identify causative organisms [11]. The cost and speed of whole genome sequencing is declining which will make it more common in routine practice.

Flow Cytometry Using this technique it is possible to separate different cells within a population and this is advantageous, for example, in the study of T and B cells within a lymphoma. Suspensions of cells are incubated with fluorescent-­ labelled antibodies that will identify different cell types, and the suspensions are then passed through a ­fluorescence-­activated cell sorter (FACS scan). The instrument will provide a readout of the number of specified cells in a sample and the ratios between the different cell types. This technique has been used for vitreous samples [12], however, success is limited by low cellularity and often better information can be obtained by undertaking immunohistochemistry on a cell clot preparation.

Techniques for Illustration and Documentation Photomacrography Macrophotography provides an invaluable record for interpretation of microscopy and for teaching purposes where a macrophotograph is often more readily understood by clinical colleagues. Digital photography has rendered photographic film almost obsolete. Photomacrographic systems are available, but a high quality handheld digital camera can provide excellent photographs.

Techniques for Illustration and Documentation

The globe must be photographed as soon as the primary cuts are made. If the specimen lies in a fluid that contains tissue debris, the vitreous quickly becomes contaminated and the photographic result is spoilt. Similarly, the reconstitution of a collapsed eye with an injection of fixative may introduce air bubbles in the vitreous. These are difficult to remove and it is worthwhile making sure that the syringe does not contain air. Highlights can be avoided by photographing the specimen under an appropriate fluid (normal saline) and the globe can be immobilised and angled by fixing it to needle tips glued into a black plastic sheet. Fibre-optic light sources provide an attractive cold light and they allow a manoeuvrability that is essential for illumination of the interior of the globe. A black background (a 5 × 5 cm sheet of 2–3 mm plastic) avoids the shadowing that is seen when coloured backgrounds are used.

Photomicroscopy and Digital Pathology

21

stored alongside scanned microscopic images providing a complete patient record all in one place.

Polarised Light Most microscopes used in a routine laboratory have accessories for polarisation. The primary polarising filter is placed below the condenser and the secondary filter is inserted into the body of the microscope between the objectives and the eyepieces. Rotation of the base plate ensures that light waves in only one plane pass through the tissue while the second plate adsorbs partially or completely (depending on the degree of rotation) all the light transmitted by the primary polarising filter. If the section contains crystalline particles or fibres that have the capacity to rotate light waves, the birefringent structures are seen clearly against a dark background. This technique is very useful for the identification of scar tissue in the corneoscleral envelope and for the demonstration of refractile foreign bodies such as cholesterol (Fig.  1.17) or fragments of sutures or plant fragments (Fig. 1.23).

There are many excellent commercial units that provide excellent photomicrographs with a final image magnification in the range of ×5 to ×1000. Even with digital cameras, perfect resolution of low power images (in the range ×1 to ×4) are challenging. This has now been overcome by the introduction of digital pathology whereby glass slides are converted into digital slides which can be viewed on a computer monitor. By this means perfect, in focus images can be obtained (Fig. 1.22). These images can either be captured for presentation or shared directly for virtual consultation. Digital pathology also provides a means for accurate measurement of, for example, tumour depth and margin clearance (Fig.  1.22). Furthermore macroscopic images can be

Fluorescence Microscopy Epi-illumination (i.e., passing the light through the objective rather than the condenser) with UV-blue light at a wavelength of 365 nm excites fluorophores in tissue so that light at a higher wavelength is emitted. The use of a barrier filter that cuts off light at a wavelength less than 420 nm permits recognition of antibodies labelled with fluorescent markers such as those used in the identification of herpes simplex, adenovirus, and chlamydia trachomatosis. This technique is also useful for identification of immunoglobulin deposits in ocular pemphigoid. Endogenous autofluorescent granules in the retinal pigment epithelium—e.g., lipofuscin (Fig. 1.24)— can be readily identified by this technique. The ocular tissues exhibit green autofluorescence.

Fig. 1.22  Low power view of a full thickness eyelid excision for basal cell carcinoma. Accurate measurements are made much easier using an integrated ruler in digital pathology

Fig. 1.23  A chorioretinal scar contains a fragment of wood (inset), which is birefringent in polarised light. The patient was hit in his only seeing eye by a makeshift arrow fired by a “friend”

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1  Examination of the Globe. Technical Aspects

Fig. 1.25  The anterior segment of a normal eye to show the relationships between the cornea (c), the iris (i), the ciliary body (cb) and lens (l) (×5)

Fig. 1.24  In an unstained section the autofluorescence of lipofuscin is easily demonstrated in the retinal pigment epithelium by UV/blue light. The chorioretinal tissues exhibit apple green autofluorescence

Electron Microscopy Electron microscopy has significantly diminished in pathology in part because of the explosion in immunohistochemistry but also because of the expense of maintaining these specialised units. Electron microscopy still has a role to play in the study of corneal dystrophies, in particular those involving the anterior stromal/Bowman’s layer and endothelial dystrophies. It can also be helpful in identifying viral particles not seen on H&E or immunohistochemical staining. Its role in tumour classification is limited but it is occasionally of help.

Diagnostic Cytopathology Tissue samples can be aspirated from the anterior chamber or from the vitreous and can be extremely useful in the diagnosis of specific infections or tumours [13]. Considerable experience is required for this investigation and the appearance of tumour cells in smears can be quite different to that seen in a paraffin section from the same tumour. In the case of aspirates, a cell block may be made by precipitating the sample with fibrin. This allows examination of the cellular material present but also provides material for immunohistochemistry, special stains, or molecular studies where appropriate.

Normal Ocular Histology It may be useful to those starting in ophthalmic pathology to have brief introductory illustrations of the features in the eye that will have relevance to disease processes. A more detailed functional anatomy is provided where relevant in the subsequent chapters. The corneoscleral envelope provides support

for the delicate tissues within the eye. The cornea forms the anterior boundary of the anterior chamber (Fig. 1.25), which is limited posteriorly by the iris and the pupil. The posterior surface of the iris forms the anterior boundary for the posterior chamber located posteriorly between the lens and ciliary body. The lens is formed by cells that contain transparent crystalline proteins and the shape is maintained by an elastic capsule supported by zonular fibres arising in the clefts between the ciliary processes. In a paraffin section, the stroma of the cornea predominates (Fig. 1.26) in the tissue. The corneal epithelium is five to six cells thick and of stratified type and is replenished by stem cells in the limbal epithelium [14]. Both the corneal epithelium and the bulbar conjunctiva contain antigen-­ presenting cells (Langerhans) and upregulation from type I to type II MHC antigens is common in many of the inflammatory reactions in the surface of the epithelium. The epithelium is attached to Bowman’s layer by an attachment system in which intracellular filaments pass through basal hemidesmosomes to fuse with anchoring fibrils and collagenous complexes in the inner part of Bowman’s layer [15]. The stroma contains inconspicuous keratocytes that possess long processes linked by cell junctions. The stromal collagen bundles are arranged in lamellae within which the bundles are aligned in different planes. The endothelium is a cubical monolayer that secretes a PAS-positive basement membrane (Descemet’s membrane) and controls the flow of aqueous across the tissue. Although the cornea is acutely sensitive to touch and pain, it is not possible to demonstrate nerves by light microscopy; electron microscopy, however, reveals nerves in abundance [16]. The angle of the anterior chamber is formed by the corneal periphery and the trabecular meshwork in the anterior part and by the iris stroma in the posterior part. Drainage of aqueous is via the trabecular meshwork, a series of collagenous plates, lying within the scleral sulcus (Fig.  1.27a, b). The sulcus is bounded posteriorly by the scleral spur, which serves for the insertion of the longitudinal fibres of the ciliary muscle. The outflow system is divided into arbitrary layers

Techniques for Illustration and Documentation

(Fig.  1.27a, b), but the important feature is the outermost, “cribriform layer”, where the interspaces are small, and this is the site of resistance that maintains intraocular pressure. The canal of Schlemm can be of variable outline, sometimes

Fig. 1.26  The corneal epithelium has six to eight layers of cells and Bowman’s layer (B) is directly beneath the epithelium. The stroma contains scattered keratocytes and the interlamellar spaces are widened by artefact. Descemet’s membrane (D) is not clearly defined. In a standard HE preparation the endothelium is a uniform monolayer (×100)

a

Fig. 1.27 (a) The chamber angle extends to a line drawn vertically through the scleral spur (s). Behind Schlemm’s canal (arrow) the ciliary muscle (m) inserts into the scleral spur. In the aged eye there is hyalinisation of the oblique and circular components of the ciliary muscle. Note the thinning of the iris stroma at the periphery (or root) (×40). (b)

23

oval but often duplicated by septae; the lining endothelial cells of the canal possess the potential to form transcellular channels in response to increases in intraocular pressure and aqueous outflow. The uveal tract describes collectively the iris, the ciliary body, and the choroid, and the constituent tissues of the stroma are basically the same. There is a highly complex antigen-detecting system that includes resident macrophages and MHC class II dendritic cells [17] within the uveal tract and the trabecular meshwork. The iris is mobile and the stroma is loosely arranged with the sphincter pupillae and the dilator pupillae located in the posterior part close to the pigment epithelium (Fig. 1.28a, b). The vessels in the iris have thick collagenous walls with an inconspicuous musculature. A study of the normal racial variations in the pigmented cells of the iris (i.e., blue, green, brown, or freckles, etc.) is worthwhile before an opinion is given on a melanocytic iris tumour. The colour of the iris in vivo is not, however, obvious on histological examination and does not depend on the number of stromal melanocytes in Caucasians [18]. Pigmentation, in fact, depends on the degree of melanisation in the melanocytes in the anterior border layer. The pigment epithelium of the iris is derived from the optic cup and is arranged in two layers, which in pathological situations can separate, because the apical parts of the cells are in apposition. The anterior and posterior layers of the pigment epithelium of the iris are lined by a basement membrane that thickens with age [19]. The ciliary body is divided functionally and anatomically into two parts: the pars plicata, which contains the ciliary processes, and the pars plana, which serves as an attachment for the vitreous base (Fig.  1.29a, b). The ciliary muscle is present in both parts and is subdivided into three layers. The b

The trabecular meshwork has three layers: uveal (u), corneoscleral (c) and cribriform (arrow), which is located adjacent to the canal of Schlemm (CS). In the ageing eye the scleral spur encroaches on the corneoscleral layer. Small iridocorneal strands are a normal feature (×250)

24

a

1  Examination of the Globe. Technical Aspects

a

b

b

Fig. 1.28 (a, b) The normal iris stroma consists of loose connective tissue containing melanocytes and vessels (v) with thick acellular walls. The dilator pupillae is formed by a thin and barely visible layer of spindle cells on the anterior surface of the iris pigment epithelium (p). At the pupillary margin, the sphincter pupillae (s) forms a horizontal band in the pupillary portion (a ×100; b ×250)

outer meridional fibres insert into the scleral spur and, by rotating the structure, act on the trabecular meshwork. The inner layers of the muscle are oblique and circular, and through the zonular fibres, the muscular contraction alters the shape of the lens in accommodation for near and distance. The transparent vitreous gel consists mainly of water, which is retained by acid mucopolysaccharides and is supported by a loose collagenous framework (type II collagen).

Fig. 1.29 (a) The anterior part of the ciliary body consists of the pars plicata (pli) formed by the ciliary processes and the ciliary muscle (cm). The pars plana ciliaris (pla) extends back to the retinal periphery and is the site of attachment of the vitreous base (vb). The zonular fibres are shown by arrows (×40). (b) The ciliary processes are lined on the inner surface by a hypopigmented epithelium (npe) and external to this there is a pigmented epithelial layer (pe) with an underlying basement membrane (arrowhead) (×250)

In life, the retina is transparent and light passes through three layers of cells to excite an electrical impulse in the photoreceptors (Fig.  1.30a–c). Electrical signals pass from the photoreceptor cells to the bipolar cells, which form a layer in the middle of the tissue and these cells in turn synapse with

Techniques for Illustration and Documentation

a

25

c

b

Fig. 1.30  The retina varies in thickness and appearance in different regions. (a) At the periphery, ganglion cells are sparse (g) and the nerve fibre layer (n) is thin. Cones stand out between the rods. (b) In the peripapillary region, the nerve fibre layer (n) is thick as the axons pass into the optic nerve. The photoreceptors are predominantly of cone type. (c) At the macula, the ganglion cell layer (g) and the bipolar cell layer (b)

are markedly thickened. In all three locations, the nuclei of the photoreceptor (p) cells are similar in density. The retinal pigment epithelium (r) is thicker at the macula and contains more lipofuscin as ageing proceeds. Bruch’s membrane (arrows) may become calcified with age and this may be accompanied by hyalinisation of the choriocapillaris (each ×250)

the ganglion cells. Ganglion cells are of two types (which are not identifiable in routine paraffin sections but are extremely relevant to pathological situations). The magnocellular cells are large and make up 10% of the total population of ganglion cells. The smaller parvocellular cells serve in the recognition of high contrast and small detail images. The synapses of these cells are found in the dorsal part of the lateral geniculate body. The magnocellular ganglion cells serve for recognition of moving and flickering images and the synapses are located in the ventral part of the lateral geniculate body: this cell population is more sensitive to the pressure rise that occurs in glaucoma (see Chap. 3). High resolution of the focused image depends on the integrity of the foveal and macular regions where the cone photoreceptors are tightly packed and the cells are arranged so that there is the least amount of tissue between the photoreceptors and the focused light rays (Fig.  1.31). Arterioles

derive from the central retinal artery branch around the macula, which is supplied as far as the perifoveolar zone by radiating small arterioles, venules, and capillaries. At the far periphery of the retina, the venules and arterioles form arcades. The retinal capillary bed drains into venules that unite as tributaries of the central retinal vein. The vein is constricted behind the lamina cribrosa and this valve serves to maintain pressure in the vascular bed in the retina [20, 21]. In some individuals the retina is also supplied by a cilioretinal artery that arises from one of the posterior ciliary arteries. The optic disc is within the eye and the axons in the nerve fibre layer form a bulge as they pass through the prelaminar region (Fig. 1.32): The bulge is larger on the nasal side. The lamina cribrosa is derived by an ingrowth of fibroblasts from the posterior part of the adjacent sclera canal and this takes place in the seventh month of intrauterine life after the axonal connections have been established between the ganglion

26

Fig. 1.31  At the fovea (in a baboon) the retina consists of the outer plexiform layer and the photoreceptors (×200)

cells in the retina and the lateral geniculate body. The tissue anterior to the lamina has a blood supply derived from the posterior ciliary arteries, which form an incomplete circle (of Zinn-Haller) in the peripapillary choroid. The retrolaminar part of the optic nerve is supplied by meningeal branches that branch from the ophthalmic artery and the central retinal artery. The presence of a watershed zone in the retrolaminar part of the optic nerve places this area at risk from infarction in vascular occlusive disease. The choroid is lined internally by Bruch’s membrane and the tissue contains numerous blood vessels that serve to supply the outer retina via the choriocapillaris, which forms a vascular bed in two dimensions (Figs.  1.16c, 1.30a–c, and 1.31). The number of melanocytes in the stroma varies and is related to race and species. Ganglion cells are plentiful in the choroidal stroma when appropriate stains are used [22]. Extramedullary haematopoiesis is sometimes found in the premature and neonatal infant eye and in trauma [23]. Nerves (long ciliary) are prominent in the choroid in a horizontal section through the globe, while the four vortex veins draining the choroid emerge at 45° to the horizontal. The sclera is thinnest at the equator and anterior to this the tissue contains nerves and the collector channels that drain the canal of Schlemm. In the posterior part, the sclera contains canals for the ciliary arteries, the vortex veins, and the ciliary nerves. The collagens in the cornea and sclera are of similar composition, but in the cornea the arrangement of the fibres is such that the tissue is transparent. Polarised light is useful in demonstrating the two forms of fibre arrangement. The central retinal artery and the long and short posterior ciliary arteries are of small muscular type: It must be stressed that within the globe, arterioles and venules are the sole supply for the capillary networks. In conclusion, the acquisition of good quality archival sections of normal eyes at various stages of development and

1  Examination of the Globe. Technical Aspects

Fig. 1.32  The normal optic nerve head consists of the prelaminar part (p), the lamina cribrosa (lc) and the retrolaminar region (r). The central retinal vein (v) is thin walled and the central retinal artery (a) has a more obvious muscular coat (×60)

ageing is essential to a proper understanding of pathological disorders.

References 1. Wilson MW, Czechonska G, Finger PT, Rausen A, Hooper ME, Haik BG.  Chemotherapy for eye cancer. Surv Ophthalmol. 2001;45:416–44. 2. Sherwin JC, Hewitt AW, Ruddle JB, Mackey DA. Genetic isolates in ophthalmic diseases. Ophthalmic Genet. 2008;29:149–61. 3. Raoof N, Rennie IG, Salvi SM, Sisley K, Caine A, Mudhar HS. What is the significance of vortex vein invasion in uveal melanoma? Eye (Lond). 2009;23:1661–7. 4. Kuwabara T, Cogan DG.  Studies of retinal vascular patterns. I. Normal architecture. Arch Ophthalmol. 1960;64:904–11. 5. Laver NM, Robison G, Pfeffer BA. Novel procedure for isolating intact retinal vascular beds from diabetic humans and animal models. Invest Ophthalmol Vis Sci. 1993;34:2097–104. 6. Olver JM, McCartney ACE.  Anterior segment vascular casting. Eye. 1989;3:303–7. 7. Karcioglu ZA, Caldwell DR. Frozen section diagnosis in ophthalmic surgery. Surv Ophthalmol. 1984;28:323–32. 8. Margo CE. Special histochemical stains in ocular pathology. Surv Ophthalmol. 1986;31:131–5. 9. Devarajan B, Prakash L, Kannan TR, Abraham AA, Kim U, Muthukkapruppan V, et  al. Targeted next generation sequencing of RB1 gene for the molecular diagnosis of retinoblastoma. BMC Cancer. 2015;15:320. 10. Broadgate S, Yu J, Downes SM, Halford S. Unravelling the genetics of inherited retinal dystrophies: past, present and future. Prog Retin Eye Res. 2017;59:53–96. 11. Ma L, Jakobiec F, Drya TP. A review of next-generation sequencing (NGS): applications to the diagnosis of ocular infectious diseases. Semin Ophthalmol. 2019;34:223–31. 12. Reichstein D.  Primary vitreoretinal lymphoma: an update on pathogenesis, diagnosis and treatment. Curr Opin Ophthalmol. 2016;27:177–84. 13. Lavar NMV.  Ocular cytopathology: a primer for the generalist. Semin Diagn Pathol. 2015;4:311–22.

1  Examination of the Globe. Technical Aspects 14. Seyed-Safi AG, Daniels JT. The limbus: structure and function. Exp Eye Res. 2020;197:108074. 15. Marshall GE, Konstas AG, Lee WR. Collagens in ocular tissue. Br J Ophthalmol. 1993;77:515–24. 16. Müller LJ, Pels L, Vrensen GFJM. Ultrastructural organisation of human corneal nerves. Invest Ophthalmol Vis Sci. 1996;37:476–8. 17. Forrester JV, Xu H, Kuffova L, Dick AD, McMenamin PG.  Dendritic cell physiology and function in the eye. Immunol Rev. 2010;234:282–304. 18. Wilkerson CL, Syed NA, Fisher MR, Robinson NL, Wallow IHL, Albert DM.  Melanocytes and iris colour. Arch Ophthalmol. 1996;114:437–42. 19. Khalil AK, Kubota T, Tawara A, Inomata H.  Ultrastructural age-­ related changes on the posterior iris surface. A possible relationship to the pathogenesis of exfoliation. Arch Ophthalmol. 1996;114:721–5.

27 20. Taylor AW, Sehu KW, Lee WR, Williamson TW.  Morphometric assessment of the central retinal artery and vein in the optic nerve head. Can J Ophthalmol. 1993;28:320–4. 21. Kang MH, Balaratnasingam C, Yu PK, Morgan WH, McAllister IL, Cringle SJ, Yu D-Y. Morphometric characteristics of central retinal artery and vein endothelium in the normal human optic nerve head. Invest Ophthalmol Vis Sci. 2011;52:1359–67. 22. May CA, Neuhuber W, Lutjec-Drecoll E.  Immunohistochemical classification and functional morphology of human choroidal ganglion cells. Invest Ophthalmol Vis Sci. 2004;45:361–7. 23. Mudhar HS, Ford AL, Ebrahimi KB, Farr R, Murray A. Intraocular choroidal extramedullary heamatopoiesis. Histopathology. 2005;46:694–6.

2

The Traumatized Eye

Introduction Some one-third of all the globes received in a routine laboratory service will exhibit pathological changes that illustrate the final stages of processes initiated by trauma. While “trauma” embraces all forms of insult (e.g., chemical, toxic, radiation, etc.), in practice, mechanical injury is the most frequently encountered. In terms of incidence, the specimen most commonly received in the laboratory is the “irreparable” eye, enucleated immediately or within a day or 2 of an injury, which has initiated massive intraocular haemorrhage. A second and important group is that in which a traumatized eye (accidental or surgical) “does not settle;” i.e., there is clinical evidence of continuing inflammation after a surgical repair. On slit lamp examination the aqueous and vitreous contain cells and there is a “flare” in the fluid around the light beam. Enucleation in such a case markedly reduces the risk of a bilateral autoimmune granulomatous uveitis (sympathetic ophthalmitis) (discussed later in this chapter). The final group includes injured eyes that retain some vision after treatment and are without inflammatory complications, but that progress over months or years either to hypotonia and shrinkage (atrophia bulbi) or to secondary glaucoma and its complications. Eyes injured after acid or alkali burns or by irradiation may also fall into the latter group. Several decades ago the most common causes of irreparable damage to the eye were industrial trauma and perforation by broken glass, usually in a windscreen injury during a car crash. The enforced wearing of seat belts in most types of vehicles has reduced the incidence of glass windscreen lacerations to insignificant levels and safety at work legislation has had a similar encouraging effect. Despite initial reports to the contrary airbag related eye injuries occur rarely in car accidents when restraints are used and rarely compromise vision [1, 2]. Currently the most serious trauma to the eye is the consequence of violent behaviour between individuals, with broken bottles, knives, air guns, etc. as the common weapons. Significant ocular trauma occurs during warfare and whilst

these injuries are more severe than in civilian practice they are becoming less common and visual outcome has improved [3, 4]. By contrast sport-associated injuries and home handyman-­ based accidents (e.g., nail gun) are becoming more frequent although sometimes less disastrous [5–8]. Auto-enucleation is a severe form of self-injurious behaviours presenting as an ophthalmic and psychiatric emergency usually as a result of untreated psychosis [9]. Abusive head trauma in infants from shaking or impact trauma leads to bleeding in the retina, optic nerve sheath and orbital tissues [10]. An important feature of the pathology of ocular trauma is that an improvement in the surgical techniques available for repair of injured eyes (e.g., the removal of blood from the anterior chamber and the vitreous cavity and surgery for reattachment of the retina, etc.), has per se produced modifications in the previously documented patterns. Surgical treatment for non-traumatic ocular disease is not without complications: these topics are dealt with in the appropriate chapters (see Chaps. 3, 7, 13, and 14).

The “Irreparable Eye” A ruptured or perforated globe that demonstrates the signs of continuing inflammation will be enucleated within a few days of admission if there is evidence to indicate that a repair will not restore visual function to any useful level. An accurate description of the pathology is essential in order to reassure the surgeon that the damage was irretrievable and to provide evidence in a subsequent court case either for litigation against the surgeon or for criminal or civil injury compensation against the perpetrator. In cases in which the corneoscleral coat is not ruptured, so-called “concussion injury” or “blunt trauma,” there is negligible risk of sympathetic ophthalmitis and many surgeons are reluctant to enucleate, even though there may be evidence of severe disorganization; e.g., iridocyclodialysis, lens dislocation, cataract and retinal detachment (Fig.  2.1). Clinical experience has shown that initially there may be

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some retention of vision in such cases, even though the majority will progress to hypotonia and phthisis bulbi.

2  The Traumatized Eye

a

 arge Penetrating or Perforating Wounds L of the Corneoscleral Envelope In such a case, following laceration or a blunt injury causing rupture, there will be a large tear in the corneoscleral envelope of the enucleated eye and through this, intraocular contents and clotted blood will protrude. A simplified diagram (Fig. 2.2) illustrates the commonly observed features in a traumatized eye. Traditionally, a distinction is made between “penetration” and “perforation.” Penetration refers to a defect that passes into but does not pass through a tissue layer, while perforation, of for example a globe, means that there is an entry wound and an exit wound. It is surprising how often the lens is dislocated (Figs. 2.3a and 2.4) or absent (unsuspected aphakia) when the cornea or anterior sclera is cut or ruptured and it must be assumed that the lens had been expelled from the eye at the time of initial injury. In addition, it is common to find that the iris has been torn at the root, iridodialysis, and is either absent or is found as a necrotic fragment in a corneal or limbal wound. Rupture of the blood vessels in the iris, ciliary body or choroid are the source of bleeding which fills the anterior and posterior chambers and/or the vitreous (Fig. 2.3b). The ciliary body and vitreous prolapse through a corneal wound and the retina, torn at the periphery or at the optic disc, may also prolapse into or through the wound. A biopsy of episcleral tissue may be submitted if the surgeon requires confirmation of uveal or retinal prolapse. Tears in the choroid are a source of massive subretinal haemorrhage while separation of the ciliary body (cyclodialysis) combined with sudden hypotonia leads to exudative and haemorrhagic detachment of the choroid. Massive bleeding into the supraciliary and suprachoroidal spaces can expel most of the ocular contents resulting in an “expulsive haemorrhage” (Fig.  2.4d). A tear across the long ciliary arteries in the equatorial choroid will cause infarction of the ciliary body and iris. When the peripapillary retina is torn, branches of the central retinal artery and vein are the source of bleeding into the vitreous and the retina peripheral to the gap undergoes necrosis. Avulsion of the retina at the disc is followed within a week by ascending degeneration of axons in the optic nerve. Blind eyes do not have protective eyelid reflexes, so that it is always useful to examine longitudinal and transverse sections of the optic nerve carefully for evidence of pre-existing optic atrophy.

b

Fig. 2.1 (a) In this case an airgun pellet entered the orbit of a 6-year-­ old boy and caused a severe concussion injury with an iridocyclodialysis (arrowheads) and bleeding into the anterior chamber and the vitreous—the latter from a tear in the pars plana (arrow). (b) Histology of the globe shown in (a) reveals shrinkage artefact that has enhanced the iridocyclodialysis (the outflow system is shown by arrowheads), a tear in the pars plana (arrow), and a retinal detachment. The retina and optic nerve were infarcted. The location of the pellet was adjacent to the optic nerve (*)

Macroscopic Examination It is advisable for medicolegal purposes to record the size, shape, and anatomical location of lacerations or wounds; this may require time and patience in a collapsed and disorganized specimen, particularly when the episcleral tissues are

The “Irreparable Eye”

31

covered with clotted blood. Usually the site and size of a laceration or wound is located at surgery, but may extend further into the posterior sclera than suspected and may not have been identified clinically (Fig. 2.5). Surgeons often use crude white silk sutures to hold the globe together to facilitate enucleation and these differ from the delicate monofilament sutures used in the initial attempts at repair. Enucleation of a collapsed globe may be technically difficult and the pathologist may occasionally encoun-

Prolapse of lens through corneal wound

Iridocyclectomy Retinal tear Papilloedema

Hyphaema Vitreous haemorrhage Supraciliary exudation

Exudative detachment of retina

Fig. 2.2  Diagram to show the features common to a blunt or penetrating injury

a

Fig. 2.3 (a) A perforating injury at the limbus (arrow) with prolapse of the lens (l) onto the episclera. The vitreous (v) contains blood and exudate but the retina (r) is in situ albeit folded due to oedema. (b) Injury

ter a globe in which the optic disc and peripapillary sclera had been divided and left in the orbit. In missile injuries, the entry and exit sites should be noted. The globe should be x-rayed if the clinical findings indicate the possible presence of a radio-opaque foreign body (see Chap. 1). There are no hard and fast rules for the location of the cuts for the calottes and the pupil-optic nerve (PO) blocks. If possible, a corneal or limbal wound is best studied by a transverse section across the deficits. A large anteroposterior scleral laceration can be studied by secondary coronal slices after an anteroposterior PO block has been taken through the intact part of the envelope. If the globe is opaque on transillumination it is safe to assume that the ocular compartments are filled with blood. Careful examination of the cut surfaces of the slices will provide documentation of the tissues retained within the blood-filled ocular compartments and may also reveal slivers of wood, glass, or metal, which should be removed and retained for further reference or medicolegal purposes. Glass fragments can only be identified by light reflection and probing with a fine needle. Identification and removal of foreign material is advantageous to the microtomist, because such hard materials will destroy the edge of a microtome knife and produce scratches in the sections.

b

with a staple gun caused a wound (w) at the equator. The vitreous (v) is detached and filled with blood and there is some blood on the inner surface (arrow) of the retina (r), which is opaque due to oedema

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2  The Traumatized Eye

a

c

b

d

Fig. 2.4 (a) A macroscopic view of the anterior segment in which a central corneal wound is the source of a fibrous ingrowth (arrow) that fuses with the surface of the fibrotic vitreous (V). The lens is opaque and calcified in the anterior part (*). The iris is adherent to the posterior corneal surface. (b) A post-traumatic fibrous scar extends from the cornea to fuse with the lens capsule (arrowheads): The nucleus was removed during the attempted surgical repair. The fragment of lens mat-

ter (*) is adherent to the posterior surface of the iris. (c) Severe trauma led to aphakia and a giant retinal tear seen here as a folded mass of gliotic retina in the centre of the specimen (arrowheads). The ciliary body is thickened due to hypotonia (*). (d) After a lens extraction there was a massive choroidal haemorrhage (*), which closed the adjacent angle (arrowhead). A smaller choroidal haemorrhage is present at the opposite equator

Useful histology in a globe filled with clotted blood requires adequate penetration of fixative and of the embedding medium. The use of extended fixation (48 h in glutaraldehyde or formalin) of the blocks, prior to paraffin processing, is strongly recommended.

degeneration in uveal and retinal tissues and the rapidity with which healing may occur. Unusual features of interest include photoreceptor shearing (Fig. 2.6) and collections of cytoid bodies in the nerve fibre layer at the edge of the optic disc considered secondary to ischaemia caused by arteriolar spasm due to traction on the retina in blunt injury. A wide range of foreign materials (lashes, wood fragments, grit, etc.) may be present in the section and polarized light is a useful tool for detection of birefringent material (see Fig. 1.24). It is rare in an acute traumatic case to find a significant degree of inflammatory cell infiltration in the choroid. A scattered

Microscopic Examination Histological documentation of the destruction of ocular tissue in a blood-filled eye provides insight into the stages of

The Globe Removed in the Short Term After Attempted Repair

33

 he Globe Removed in the Short Term After T Attempted Repair After a primary surgical repair of a traumatized eye has been attempted, the eye may or may not recover. The surgical procedures intended to save the eye might include removal of lens fragments, excision of necrotic anterior uveal tissue (iridocyclectomy), washout of fluid or clotted blood (hyphaema) in the anterior chamber (A/C washout), and finally, excision of degenerate, disorganized blood-containing vitreous (by vitrectomy). In some cases there may have been an attempt to re-attach a detached retina and a plastic encircling band will be attached to the equator or the globe may be filled with silicone oil. In the subsequent postoperative period, there is inevitably a clinical “uveitis,” which is manifest on slit lamp microscopy as protein “flare” and cells in the anterior chamber, but this should settle quickly and if it continues sympathetic ophthalmitis (discussed later in this chapter) should be considered. The orientation of tissue blocks taken from the enucleated eye is again governed by the need to obtain sections through the regions of importance.

Fig. 2.5  This eye was ruptured when a 16-year-old boy hit a golf ball against a wall. The cut surface shows a traumatic iridocyclectomy (i) with dislocation of the disorganised lens (l) towards the defect. The retina (r) is detached and folded and the choroid (c) is thickened by massive exudation of plasma. The site of the scleral rupture (sr) is in the posterior globe

Fig. 2.6  In acute trauma, the photoreceptor outer segments are sheared from the inner segments to form masses of pale-staining palisaded structures (arrows). Note the normal photoreceptors (pr) (×250)

infiltration of lymphocytes and plasma cells is the rule but this is not sufficient for the diagnosis of sympathetic ophthalmitis.

Reparative Changes in Ocular Tissues Traumatized eyes enucleated at periods between 2 and 3  weeks after trauma will in most cases show a pattern of repair in which granulation tissue formation and fibrosis are prominent in the region of the perforating wound.

Fibrous Ingrowth At the earliest and mildest phase, a corneal wound is filled with fibrin and transformed corneal keratocytes. Later a firm fibrous union occurs (Fig. 2.7), but if the corneal endothelium does not slide across and seal the scar with a secondary Descemet’s membrane, the exposed stroma may be the source of a fibrous ingrowth into the anterior chamber (Fig. 2.8a–c). When the anterior chamber is filled with blood, organization of fibrin provides a scaffold for fibroblastic proliferation, which is also stimulated by macrophagic removal of red cell debris. An organizing hyphaema can be recognized by the presence of iron in the cells, which allows the distinction from a purely fibrous ingrowth from the corneal wound. The inflammatory response in most cases will be confined to an unimpressive lymphocytic and plasma cell infiltrate in the choroid and iris, because intensive antibiotic treatment usually prevents bacterial endophthalmitis. Fibrous proliferation occurs: 1. into the anterior chamber from the unopposed lips of a corneal wound (Figs. 2.4a, b and 2.8a, b);

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2  The Traumatized Eye

2. through the ciliary body into the vitreous via an anterior scleral wound (Figs. 2.4c and 2.8c); and 3. into the subretinal space from a choroidal tear, particularly when the inner sclera is damaged.

Fig. 2.7  A healed corneal wound appears as a scar (s), the cellularity of which decreases over time. Blood vessels (v) and inflammatory cells may be present at the margins (×100)

Organization of Blood Organization of haemorrhage in the vitreous, which is inaccessible to fibrovascular proliferation, leads to a macrophage response, in which red cells are slowly broken down [11]. By light microscopy, haemo-macrophages are inconspicuous and are located at the edge of the blood clot, which they reach by migration from the disc or pars plana; ultrastructural examination reveals extensive phagocytosis of intact cells, haemoglobin, and red cell membranes (Fig. 2.9). This process, although slow, has the advantage that there is no requirement for extracellular lytic enzymes, which would damage the retina. Sometimes a “haemogranuloma” is formed with palisading of macrophages containing stainable iron and debris around a fibrin clot; such granulomas are usually subretinal.

a

b

c

d

Fig. 2.8  Examples of post-traumatic fibrous ingrowth. (a) Fibrous tissue has grown across the anterior surface of the iris (arrows) around the pupil to fuse with the remnants of the lens (l) (×4). (b) A wound at the limbus was the source of fibrous tissue (arrow), which filled the gap left by an iridectomy and extended on to the pars plana, incarcerating the ciliary processes (arrowheads), and formed a mass around the lens

equator (l) (×15). (c) Fibrous tissue (arrow) has grown across a wound in the pars plana (which divided the ciliary body) and has proliferated in the vitreous where there is fibrovascular proliferation (arrowheads) behind the ciliary processes (cp) (×45). (d) A fibrous ingrowth in the peripheral cornea (arrow) which has incarcerated and distorted the iris (i). (×4)

The Globe Removed in the Short Term After Attempted Repair

35

Fig. 2.10  Early oedema of the optic disc in hypotonia. Note the displacement of the photoreceptors from the edge of Bruch’s membrane (bm) by the swollen nerve fibre layer. The retina is detached with displacement of photoreceptors (arrowhead) (×250)

Fig. 2.9  Electron microscopy of haemo-macrophages filled with red cell debris at the edge of a vitreous haemorrhage: Note the various degradation products of red cells, haemoglobin fragments (hb) and ghost red cells (arrowheads). The cytoplasm of the macrophages sometimes bursts as a consequence of the overload (×3000)

Red cells and plasma enter the anterior chamber by damage to the endothelium of the iris vessels or direct rupture of capillaries or larger vessels, such as the large arteriole in the iris root. Aqueous contains fibrinolysins and fibrin formation does not occur if the volume of blood is small. Larger quantities of fibrin overload the fibrinolytic mechanism and blood products stimulate the migration of macrophages through the walls of the iris blood vessels into the anterior chamber so that the inferior part of the outflow system becomes filled by haemolysed red cells and haemomacrophages. Dispersion of red cells into the trabecular meshwork leads eventually to phagocytosis by the trabecular endothelial cells, which later stain positively for iron; ultimately the meshwork is replaced by fibrovascular tissue. Organization of blood may fill the anterior chamber with granulation tissue (see Chap. 3).

Hypotonia Bleeding and exudation of plasma into the supraciliary space are indications of a very low intraocular pressure (ocular hypotonia or hypotony), which is extremely important in ophthalmic surgery [12]. Levels of the order of 2–4 mmHg

are consequent both upon inadequate apposition of wounds in the corneoscleral envelope and upon reduction in blood flow to the ciliary processes (aqueous inflow system), which occurs when there is separation of the ciliary body from the sclera (Fig. 2.4c). The presence of a pale brown solid exudate in the ciliary body and supraciliary space must be sought as a specific sign of hypotonia. Massive bleeding into the choroid and the subretinal space can complicate lens extraction, glaucoma surgery, retinal detachment surgery, and keratoplasty (Fig.  2.4d). However, cataract surgery is the most common procedure to carry the risk of expulsive haemorrhage. The blood-retinal barrier is affected by hypotonia and this is most easily recognized macroscopically and microscopically by oedema of the optic disc (Figs. 2.10 and 2.11a, b) and by exudation and bleeding into the retina (Fig. 2.12).

 etina and Optic Nerve R After relatively mild concussion injury, the retina becomes oedematous—Berlin’s oedema [13]. Histologically, the nerve fibre layer of the retina is pale staining and the axons become visible; pools of proteinaceous exudate appear in the outer plexiform layer (Fig. 2.12). The loss of integrity in the endothelial cell attachments, which are responsible for the blood-retinal barrier, is probably due to arteriolar vasospasm and ischaemia in the capillary bed, but the cause is not fully understood. In the case of severe concussion injury, there may be retinal tears and fragmentation of the axons in the optic nerve as the shock wave passes through the tissue. Traumatic tears can occur anywhere in the substance of the neural retina and be due to perforating wounds or con-

36

2  The Traumatized Eye

a

b

Fig. 2.11 (a) Oedema of the optic disc and macula (arrowhead) in a severely hypotonic eye. (b) Microscopy of advanced papilloedema in hypotonia. Note the thickened nerve fibre layer (*) and the outward displacement of the photoreceptors (arrowheads)

cussion. The term “retinal dialysis or retinal disinsertion” is used when the retinal periphery separates from the ora serrata. Large or complete circumferential tears are referred to as “giant” retinal tears (Fig. 2.4c). Less commonly the retina may be avulsed from the optic disc. When a foreign body in the form of a missile perforates the posterior part of the retina and choroid in any sector, fibrous tissue grows into the interior from the damaged sclera.

Photoreceptor Disintegration Once the retina is detached, the metabolic support provided by the retinal pigment epithelium and the choriocapillaris is lost and both the inner and outer segments of the photoreceptors become swollen (Fig.  2.12). After about 3  months or less, the outer segments are lost and the inner segments become stunted; in the outer nuclear layer there is a corresponding loss of nuclei that show the changes of apoptosis. By comparison, shearing of the outer segments from the inner segments of the photoreceptors (Fig. 2.6) is an acute phenomenon. A tear at the retinal periphery can lead to glaucoma if fragments of photoreceptors find access to the ante-

Fig. 2.12  The retina in traumatic oedema shows swelling of the nerve fibre layer (nfl). The photoreceptors (pr) are degenerate and swollen over a subretinal eosinophilic proteinaceous exudate (×250)

rior chamber (Schwartz-Matsuo syndrome) (see Chap. 3). It is quite common to find lymphocytes and macrophages in the region of the outer retina in a traumatised eye and it is tempting to speculate that this may be the initial stage in autoimmune recognition.

Lens The lens may be dislocated into the anterior chamber or the vitreous (Fig. 2.5) and almost inevitably there will be breakdown of the lens substance with cleft and globule formation (see Chap. 14). When the capsule is ruptured, release of antigenic protein may initiate an autoimmune lens-induced uveitis (discussed later in this chapter). Haemosiderosis Bulbi The location of blood breakdown products within the eye— haemosiderosis bulbi—is easily demonstrated by a positive Prussian blue reaction. The inner retina, the ciliary epithelium, and the lens epithelium take up diffusible iron salts. The vitreous and the choroid often contain iron-positive

Globe Containing a Metallic Foreign Body Fig. 2.13  Airgun pellets come in a wide variety of shapes. The flat nosed wadcutter (a) is ideal for target practice. The pointed tip (b) is used for penetration and accuracy at close range. The “Prometheus” (c) is a lead free high velocity pellet

a

macrophages. Intrinsic breakdown of red cells can obscure the more subtle damage produced by slow diffusion of metallic ions from an intraocular iron-containing foreign body. Prolonged bleeding into the anterior chamber is associated with brown staining of the cornea—corneal blood staining—which resolves with time. Histological examination reveals granular eosinophilic material in the corneal stroma and this is associated with necrosis of the keratocytes. This material is negative with iron stains but often stains red with Masson’s trichrome. The corneal endothelium is usually of normal appearance and the mechanism by which the red cell debris passes into the stroma is not understood. A bloodstained cornea exhibits autofluorescence and it has been suggested that the eosinophilic granules are haematoporphyrin derivatives that could act as photosensitisers and cause the release of singlet oxygen [14].

Globe Containing a Metallic Foreign Body Macroscopic Examination If the presence of a metallic intraocular foreign body (IOFB) is suspected, the globe must be x-rayed (see Fig. 1.15), before the specimen is divided. A needle inserted into the episcleral soft tissues will provide a marker for orientation purposes. It is important to know the exact location of a foreign body so that the calottes are taken in the appropriate place for a PO section to demonstrate the site of the foreign body and to permit removal of the foreign body without excessive damage to the surrounding tissues. Air gun pellets are relatively soft and a ricochet will cause deformation of a pellet; the legal defense is often the excuse that the pellet hit the victim by bouncing off a wall. It is also important to try not to damage the foreign body when the globe is opened as this may displace it. The choice of air gun pellets depends on the air gun used and their purpose (e.g., target practice versus

37

b

c

hunting) (Fig. 2.13a–c). Once the foreign body is retrieved it must be stored safely for possible medicolegal use at a later date. If the foreign body is not too large it can be sellotaped to the master report or to the X-ray sheet. When the surface of the globe has been cleansed, the sclera must be examined for scar tissue or suture material, which will be overlying the entry wound and, when present, the exit wound. A high velocity foreign body (e.g., 12 bore, 22 sporting, birdshot/or shotgun, military missile) can pass through the eye in any direction but an exit through the optic canal is unusual and may be unsuspected. In the latter case, the origin of the defect may be mistaken for an excessively close, surgical cut through the optic nerve. Posterior trans-­ scleral wounds are rarely sealed or sutured and may be demonstrated by the use of a blunt probe. A metallic foreign body may ricochet within the globe. Thus the entry wound may be at the limbus and the foreign body may be found lying on the opposite pars plana (Fig. 2.14). Careful orientation and serial section will demonstrate the ricochet site by a tear in the retina accompanied by bleeding from the choroid into the vitreous.

Types and Effects of Metallic Foreign Bodies A surprising variety of metallic and non-metallic foreign bodies (of all forms of chemical constitution) will be encountered by an ophthalmic pathologist. The commonest will be either lead (air gun pellets, lead shot) or iron and steel fragments (“do-it yourself” hammering injuries or industrial injuries). Copper or brass fragments in the eye usually result from industrial drilling or “turning” on a lathe. The long-­ term effects of iron or copper release in the eye (siderosis and chalcosis, respectively) are now rarely observed, because foreign bodies can be extracted with a magnet or removed surgically with restoration of anatomy. Alternatively, the eye is enucleated before the metallic salts diffuse out of the fragment.

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2  The Traumatized Eye

Fig. 2.15  A brass foreign body within the globe is surrounded by a purulent reaction (arrowhead). The vitreous (v) is opaque and detached and the choroid is thickened by hypotonic effusion. The optic nerve was clamped with toothed forceps during the enucleation Fig. 2.14  A shotgun pellet penetrated the superior limbus, tore off the iris and damaged the lens, which is opaque. The pellet bounced off the inner posterior sclera and came to rest behind the iris: The path is shown by arrows. The vitreous is filled with blood, but the retina is in situ

Long-Term Effects of Ocular Trauma

Many patients will refrain from attending an out-patient clinic for some years (and even decades) if a traumatized eye is blind but not painful, so that a reliable history in such cases Siderosis may not be available. Usually the pain of secondary glauFree iron radicals diffuse through the ocular tissues and coma, uveitis, or the ugliness of a phthisical eye motivates a interfere with the function of intracellular enzymes. The request for enucleation. It is important to appreciate that simple concussion injumost serious effects are found in the retina where the ganglion cell and photoreceptor layers are severely affected. ries to the globe lead to complications, which in the long Perls’ stain for iron, however, is more strongly positive in the term can have disastrous functional effects. Examples inner retina when the foreign body rests in the vitreous. At include separation of the ciliary body (cyclodialysis), lens the end stage of siderosis, iron can be identified in most of dislocation, retinal tears and detachment, non-specific uvethe intraocular tissues, the pattern being similar to itis and post-traumatic pseudoretinitis pigmentosa, and other ­haemosiderosis bulbi (see earlier in this chapter), which is disorders, which will be dealt with in subsequent sections. For the pathologist, the evaluation of such late-stage enumuch more common than siderosis. cleated eyes can provide a fascinating academic exercise, particularly if the eye had been subjected to immediate or subsequent surgical intervention and the clinical documentaChalcosis tion is sound. It must be admitted, however, that frequently Copper-containing alloys (brass) and pure copper are non-­ the secondary changes are so complicated that the primary magnetic and are not so easily removed from an eye. Pure pathology is not detectable. copper is not as toxic as the alloys of tin and copper, which induce a purulent reaction (Fig. 2.15), although the degree of inflammation depends to some extent on the concentration of Macroscopic Examination cuprous ions. While the diffusion of copper ions into transparent corneal and lens tissue produces elegant clinical man- External macroscopic examination is of value for the identiifestations—a blue-green ring in Descemet’s membrane and fication of healed corneal wounds, which are easily identia “sun-flower” cataract, respectively—the deposits of copper fied by scars and suture tracks. Limbal or scleral wounds may be difficult to identify, if sutures have been removed, at the level of microscopy are far less impressive.

Long-Term Effects of Ocular Trauma

39

and episcleral thickening may be the sole indication of the site of perforation.

Post-traumatic Glaucoma Damage to the anterior segment can interfere with aqueous outflow and lead to prolonged ocular hypertension with its associated tissue effects (see Chap. 3). The important exercise in a traumatized eye will be to elucidate the mechanisms causing long-standing glaucoma.

 econdary Angle Closure S In the majority of cases, the anterior chamber will be shallow and the angles will be closed as a consequence of post-­ inflammatory exudation and adhesion, of iris neovascularisation or of pupil block due to lens swelling or displacement (see Chap. 3).

Fig. 2.16  An example of a recessed angle in post-traumatic glaucoma. The root of the iris (i) is attached to the circular fibres of the ciliary muscle (cm) and the trabecular meshwork (tm) is compressed beneath an open canal of Schlemm (cs) (×40)

Secondary Open Angle Glaucoma Angle Recession Blunt injury to an eye can produce a tear into the face of the ciliary body or into the potential space between the meridional fibres and the sclera and it may seem strange that the creation of an additional outflow pathway leads to resistance to outflow. However, loss of support from the ciliary muscle insertion is followed by collapse of the uveal layer of the trabecular meshwork. Fusion of the trabeculae and damage to the endothelium allows the corneal endothelium to spread across the meshwork in the form of a sheet of cells, which acts as an effective barrier to fluid movement. For the pathologist this disease is recognized at a later stage by deep open angles on gross and histological examination. The trabecular meshwork is collapsed due to a breakdown in support provided by the ciliary muscle (Fig. 2.16). Angle recession glaucoma is probably more complicated than a simple mechanical process. It is detected clinically soon after trauma and at this stage there is almost certainly infiltration of the trabecular meshwork by inflammatory cells released from the damaged iris. Epithelial Downgrowth If a corneal or limbal wound is not adequately apposed, corneal or conjunctival epithelium can slide through the gap into the anterior chamber [15]. The chamber angle is lined by an ingrowth of corneal or conjunctival epithelium (depending on the site of the entry wound). This is referred to as an epithelial downgrowth and intractable glaucoma is caused by this form of obstruction to aqueous outflow. On histological examination, the invading epithelial cells (free from contact inhibition) grow readily as a sheet on any of the available surfaces—e.g., iris stroma, lens capsule, vitreous face and

Fig. 2.17  The outflow system is obstructed by a layer of corneal epithelium (arrowheads) that has also spread across the iris. The trabecular meshwork (tm) is disorganised and the canal of Schlemm (sc) is narrowed (×160)

zonular fibres (Figs. 2.17 and 2.18a, b)—and this process can be treated by block excision [16]. Alternatively, the epithelial cells can form a slowly enlarging cyst in the anterior chamber (post-traumatic inclusion cyst) and the only effective treatment is surgical removal [17]. This dissection is technically difficult because the epithelium is firmly adherent to the underlying tissues and cyst rupture is often unavoidable. Some success has been obtained by wide clearance surgery by means of an iridocyclectomy combined with a partial corneosclerectomy and such a specimen should be examined specifically for clearance of epithelium. Failure to remove the epithelium in toto will result in widespread proliferation of the cells over the trabecular

40

2  The Traumatized Eye

a

b Fig. 2.19  End-stage trauma in a hypotonic eye with effusion into the ciliary body (ue) and secondary angle closure with anterior synechiae (as). The angle is shown by an arrowhead. The lens substance is replaced by fibrous tissue undergoing dystrophic calcification (arrow) (×16)

Fig. 2.18 (a) In this epithelial downgrowth after a lens extraction, the cells slid over the iris surface (i) onto lens remnants (lr) and finally onto the anterior vitreous face (avf) (×100). (b) Detail of the migrating epithelium from another case in which a fibrovascular membrane (f) grew across the pupil (×250)

meshwork and the consequent glaucoma: after this complication, it is unlikely that the eye will be saved.

Lens Abnormalities Lens Dislocation After blunt or penetrating injury, the lens may have dislocated into the anterior chamber or into the vitreous of the enucleated eye. As long as the lens capsule remains intact, the only recognizable histological consequence will be degeneration of the lens substance, initially with cleft and globule formation and liquefaction in the cortical fibres (see Chap. 14); later there is secondary calcification seen as deposition of basophilic granules in a hyaline stroma (Fig. 2.19). If the capsule ruptures with release of antigenic lens protein, lens-induced uveitis may develop. More commonly, the most striking feature in an end-stage eye is a band of fibrous tissue, sometimes accompanied by calcification, within the anterior cortex and beneath the lens capsule. The reaction is most commonly the result of fibrous metaplasia in the lens

epithelium and is thought to be the consequence of chronic inflammation in the iris and ciliary body. This form of fibrosis can progress to ossification—so-called “cataracta ossea.”

Lens-Induced Uveitis The description of this disease is located in the trauma chapter because the pathologist is more likely to encounter autoimmune reactions to lens protein in irretrievably disorganized globes. However, it should be noted that in the minority of cases, an autoimmune reaction to a degenerate lens can occur spontaneously and an astute clinician may achieve a cure by removing the degenerate lens matter, which is providing the antigenic source for a humoral and cell-mediated response. In the majority of pathological specimens, the presence of an inflammatory reaction in and around the lens is not appreciated clinically, due to complicated anterior segment pathology. The clinical assessment is sometimes restricted to “hypotonia with uveitis,” and “keratic precipitates” are seen on slit lamp examination (the latter correspond histologically to clumps of macrophages on the corneal endothelium). The failure to provide a substantive clinical diagnosis of lens-­ induced uveitis is in part due to the fact that serology has not so far provided definitive results for diagnostic purposes. Expansion in understanding of biochemical changes in lens protein that occur in the ageing process will hopefully allow the identification of the specific antigens that generate the immune response. The most interesting aspect of lens-­induced uveitis is the rarity of occurrence in patients who are exposed to the antigens of a cataractous lens after

Long-Term Effects of Ocular Trauma

an extra-­capsular lens extraction. In this form of cataract surgery, some lens substance is left within the lens capsule (see Chap. 14). There are multiple synonyms for lensinduced uveitis; e.g., phacogenic/phacotoxic/phacoallergic/uveitis and finally “phacoanaphylactic endophthalmitis.” The uveitic form of the disease seems to be the end stage in the spectrum of cellular immune response to degenerate lens matter. At an early stage, cellular infiltration may be restricted to the lens (Fig. 2.20) and consists of a granulomatous reaction around residual lens substance. The edges of the lens capsular tear may be split into layers and eroded by mononuclear or multinucleate macrophages (Fig. 2.20f). The cellular infiltrate within the cortex may be lymphoplasmacytoid with macrophages, but neutrophils and eosinophils are commonly encountered—hence the term “phacoanaphylactic.” Fibrovascular reactions are stimulated within the iris, which often shows marked stromal thickening consequent upon lymphoplasmacytoid infiltration. Only very rarely is a lens-induced cellular response induced after extra-capsular lens extraction (Fig.  2.20e), but the process may be responsible in part for low-grade tissue reactions, which are sometimes associated with intraocular lens implantation (see Chap. 14). The most striking cellular inflammatory responses are seen when lens matter dislocates into the vitreous and lies against the iris or ciliary body; these are sites where there is ready access for migrating inflammatory cells (Fig. 2.20c–e). Secondary intraocular inflammation can lead to serious corneal complications with ulceration. Retinal vasculitis with lymphocytic and plasma cell infiltration in the retina is a consistent (and useful) diagnostic feature of advanced lens-induced uveitis and is associated with macrophage accumulations in the vitreous base and on the inner retinal surface over the retinal veins [18]. Lens-induced uveitis is predominantly anterior and if a granulomatous reaction is observed in the choroid and around the structures in the scleral canals, the diagnosis of concomitant sympathetic ophthalmitis is mandatory (discussed later in this chapter). Subsequent bilateral disease is a theoretical possibility.

Post-traumatic Retinal Changes  aemorrhage and Traumatic Detachment H Haemorrhage in the retina and vitreous may be associated with subarachnoid haemorrhage (Terson’s syndrome) or with an acute rise in pressure in the veins in the chest and neck as in the Valsalva phenomenon [19]. They are also an important feature of non-accidental injury infants (see later in chapter).

41

It would be a rarity in the laboratory to find that the retina is in situ after a concussive or perforating injury. The totally or partially detached retina becomes thickened by reactive proliferation of Müller cells and astrocytes (gliosis) as the neural cells atrophy (see Chap. 7). Bands and strands in the vitreous will be derived from neovascular proliferation and organization of haemorrhage. Tears and holes are the result of vitreous traction and are seen at the periphery. At a later stage, traction bands form on the inner limiting membrane of the retina when glial cells perforate the inner limiting membrane and proliferate on the inner surface of the retina. Wrinkling of the inner limiting membrane is best demonstrated by the Periodic Acid Schiff (PAS) and Bodian stains. Subretinal bands form within the gelatinous subretinal exudates mainly as a consequence of reactive proliferation of the retinal pigment epithelium, but sometimes with a contribution from retinal glial cells.

Post-traumatic Pseudoretinitis Pigmentosa Even if the retina remains in situ, there may be widespread atrophy of the photoreceptor layer due to a concussion shock wave after a blunt injury. The retinal pigment epithelium reacts in a non-specific way to this form of atrophy and the cells proliferate and migrate into the retina. On macroscopic examination, heavily pigmented stellate strands and perivascular pigment accumulations are seen in the mid-periphery and at the extreme periphery (Fig.  2.21). The pattern is coarser than that seen in retinitis pigmentosa and the clinical history of unilateral trauma excludes a primary retinal pigment epithelial dystrophy. The histological features are indistinguishable from those seen in retinitis pigmentosa (see Chap. 9) and will reveal photoreceptor atrophy and replacement of the outer nuclear layer by glial cells, a change that is most severe at the periphery (Fig. 2.22). The retinal pigment epithelium is either atrophic or forms nodules and strands that extend into the retinal substance and surround the retinal vessels. The pathogenesis of this condition is poorly understood. Attempts to simulate concussion injuries in experimental animals have shown an extensive disintegration of the photoreceptors, apparently due to a shock wave effect [20] and a similar disruption of photoreceptors has been reported in a human eye injured by blunt trauma [21]. It seems likely that the photoreceptor cells are unable to recover from this insult, which leads to a white appearance in the deeper part of the retina (Purtscher’s retinopathy). At a later stage the outer nuclear layer is replaced by reactive proliferation of Müller cells. The absence of the inner and outer segments of the photoreceptors stimulates migration and proliferation of the retinal pigment epithelium.

42

2  The Traumatized Eye

a

b

c

d

e

f

Fig. 2.20 (a) Macroscopic appearance of the anterior segment in lens induced uveitis. An inflammatory reaction is present around the brown lens nucleus and the anterior chamber contains an exudate. Note the thickened iris (arrow) due to lymphocytic infiltration and the exudate in the ciliary body due to hypotonia (arrowheads). (b) In this example, the reaction has progressed to fibrosis around the residual lens. (c) After a failed lens extraction, the lens nucleus was displaced onto the inferior pars plana where it was surrounded by inflammatory cells in the vitre-

ous. (d) A section through the specimen shown in (c) reveals a giant cell granulomatous reaction (arrowheads) around the lens nucleus adjacent to the pars plana. (e) After a repair of a corneal wound and removal of the damaged lens, a giant cell granulomatous reaction developed around a small fragment of lens matter (arrowhead) behind the iris. The inflammatory reaction is also present in the fibrous ingrowth from the corneal wound. (f) In more advanced lens induced disease the granulomatous inflammatory reaction destroys the lens capsule (arrowheads) (×40)

Sympathetic Ophthalmitis

Fig. 2.21  A vertical section to show the posterior pole of the eye in post-traumatic pseudoretinitis pigmentosa. The disc (arrow) and macula (arrowhead) are less severely pigmented

Fig. 2.22  In pseudoretinitis pigmentosa the photoreceptors and the outer nuclear layer are replaced by glial cells (arrowheads). The retinal pigment epithelial cells have survived and have migrated to the wall of a blood vessel (arrow) in the inner retina (×150)

Sympathetic Ophthalmitis Bilateral granulomatous uveitis, which is of such severity that blindness is almost inevitable without heavy steroid and other immunosuppressive treatment, can follow unilateral trauma in which uveal tissue is incarcerated in the corneoscleral envelope [22, 23]. Incarceration of uveal tissue may not be as significant as uveal tissue destruction per se, because sympathetic ophthalmitis has been shown to follow laser coagulation of the ciliary body, infectious or chemical keratitis and non-penetrating procedures including irradiation of melanomas [24–27].

43

The word sympathetic is hardly appropriate for this aggressive form of bilateral uveitis, but refers to the fact that a normal eye “sympathizes” (i.e., becomes inflamed) with its fellow (injured and exciting) eye. The initial trauma may be war-related, civil, or surgical, and the bilateral disease can occur as late as 50 years after the original injury. Enucleation within 14 days of injury reduces the risk of sympathetic ophthalmitis to a very low level, but there have been a few recorded cases in which this strategy has been unsuccessful. The incidence of sympathetic ophthalmitis is now low in terms of the total numbers of eyes injured and with the effectiveness of modern immunosuppressive therapy (steroids and cyclosporin), pathologists will only rarely see this condition. The aetiology and pathogenesis of this condition is still not clearly elucidated. The initiating injury to the exciting eye is thought to disrupt uveoscleral tissue and to compromise the relative immune privilege of the eye. Subsequent sensitization to previously sequestered ocular antigens leads to posterior uveitis mediated by major histocompatibility complex class 2-restricted CD4+ T cells, which affect both the exciting eye and controlateral sympathizing eye. This immune response is directed against ocular self antigens. The location of these antigens is controversial but may be located in the retina, uvea, or choroidal melanocytes [27]. Individuals who develop sympathetic ophthalmitis are more likely to express specific HLA alleles include HLA A11, DRB41*04, DQA*03 and DQB1*04 [27]. Cytokine gene polymorphisms that result in upregulation of proinflammatory cytokines or downregulation of anti-inflammatory cytokines also affect the severity of disease in individuals [28]. In terms of diagnosis, there is lack of a laboratory test that will provide the clinician with support for a diagnosis of sympathetic ophthalmitis and the diagnosis is based on history (with particular attention to penetrating ocular trauma) and clinical examination. It should be remembered that sympathetic ophthalmia is not necessarily the only cause of uveitis after a penetrating injury, particularly if there is a possibility of an intraocular foreign body.

Macroscopic Examination The key to the diagnosis at the macroscopic level is the characteristic thickening of the posterior choroid, which has a marble-like appearance due to the presence of granulomas and a dense lymphocytic infiltrate (Fig.  2.23). The other pathological features in the eye almost inevitably will include

44

2  The Traumatized Eye

a

b

c

d

e

f

Fig. 2.23 (a) Macroscopic appearances of sympathetic ophthalmitis. The choroid is pale and thickened (arrow) and the retina is detached by a solid exudate. (b) Massive thickening of the choroid by a granulomatous inflammatory reaction (arrow) in sympathetic ophthalmitis. This case was complicated by a lens-induced uveitis (arrowheads). (c) Granulomatous foci in the choroid (arrows) are feature of sympathetic uveitis. (d) Infiltration of the retinal pigment epithelium by macro-

phages in sympathetic ophthalmitis is responsible for the clinical appearance of Dalen-Fuchs nodules. The choroid contains lymphocytes (×250). (e) The cytoplasm of the macrophages in the granulomas contains fine melanin granules (arrows). (f) A granulomatous reaction around a nerve (arrow) or a blood vessel in a scleral canal is strong support for the diagnosis of sympathetic ophthalmitis

Post-traumatic Phthisis

45

exudative retinal detachment, haemorrhage into the ocular compartments and iridocorneal and iridolenticular contact with superadded ocular shrinkage and scleral thickening. The changes around the lens are important and may include a pericapsular fibrous mass; this should suggest a concomitant lens-induced uveitis [29], which is a well-known association with sympathetic ophthalmitis.

Microscopic Examination The diagnosis of sympathetic ophthalmitis in a previously traumatized eye should not present any difficulty, because the following features are characteristic. However, this is one of the conditions in which a mistake by a pathologist can lead to contralateral blindness and, as a consequence, litigation. The choroid is thickened by a non-caseating giant cell granulomatous reaction derived from (epithelioid) macrophages and accompanied by a dense lymphocytic infiltrate (Fig.  2.23). Other inflammatory cells are sparse. The presence of fine melanin granules in the cytoplasm of the macrophages and the multinucleate giant cells, which contain between two and ten nuclei, is also characteristic. In some cases the macrophages, which also includes depigmented retinal pigment epithelium (RPE) cells, spill into the RPE to form Dalen-Fuchs nodules; although these are uncommon in histological sections. It is valuable to discover the spread of the granulomas around nerves in the scleral canals (Fig. 2.23). It is generally accepted that the inflammatory reaction is identical in the exciting and in the sympathizing eye (although without the obvious signs of trauma in the latter). The histology of chronic Vogt-Koyanagi-Harada disease can also be similar (but the history of trauma will be lacking) [29].

Post-traumatic Phthisis The enucleated eye will be submitted with the clinical diagnosis of atrophia bulbi or phthisis bulbi and it is unlikely that there will be a clear history in view of the prolonged interval elapsing after the primary insult, which was most likely trauma or inflammatory disease such as uveitis. Distinction between the terms is based on the degree of disorganization. In atrophia bulbi, the choroidal and retinal anatomy is preserved, while in phthisis bulbi these tissues are severely disorganized. Ossification commonly occurs in fibrous tissues derived from fibrous metaplasia in the retinal pigment epithelium in both atrophia and phthisis. When the globe feels extremely hard on palpation, it is likely that subretinal ossification has occurred and 24–48 h in a decalcifying fluid (formic or citric acid) will be necessary before

Fig. 2.24 An X-ray of a phthisical eye reveals calcification and ossification

cuts can be made through the globe. An X-ray of the specimen can demonstrate the degree of calcification and ossification (Fig. 2.24). The pathogenesis of the changes in any eye that is disorganized and shrunken after trauma can, on occasion, be extremely difficult to document and to understand (Fig. 2.25).

General The morphology, macroscopic and microscopic, is dominated by reactive proliferation of three cell types: fibroblasts, retinal glial cells, the epithelium of the ciliary body and the pigment epithelium of the retina. Fibroblasts proliferate within the anterior and posterior chambers to form fine or broad bands or sheets of contractile scar tissue. The source of these cells can be from a wound in the corneoscleral envelope (Fig. 2.26), the iris, or the choroidal stroma. The disorganization may be so extensive that it is impossible to recognize normal tissue.

Cyclitic Membrane The epithelium of the pars plana has the capacity to undergo fibrous metaplasia and contraction of the “cyclitic membrane” thus formed (Fig. 2.25) causes: 1. A reduction of aqueous inflow from the ciliary body and hypotonia.

46

2  The Traumatized Eye

a

b

d

Fig. 2.25 (a) The anterior segment of a phthisical eye to show a cataractous and calcified lens and a cyclitic membrane (arrows). (b) When this phthisical globe was opened, fragments of fractured bone were displaced (arrowheads). The inner surface of the choroid is lined by bone (arrow). A cyclitic membrane is fused with the anterior part of the funnel-shaped detached retina. (c) This phthisical eye is from an elderly patient who was injured in childhood. The centre of the globe is filled

c

e

with vascularised glial tissue (arrowhead), so-called “massive retinal gliosis”. Note the hypotonic thickening of the ciliary body (*) and the cyclitic membrane (arrow). The sclera is also thickened and distorted. (d) Compact and cancellous bone (*) line the inner surface of the choroid on each side of the stalk of a detached retina. (e) The anterior segment of a phthisical eye in which the lens was replaced by osseous tissue

Post-traumatic Phthisis

Fig. 2.26  A phthisical eye after a penetrating injury through the cornea resulting in a fibrous ingrowth (fi) entrapping the iris. Both layers of the ciliary epithelium in the pars plana (pp) have proliferated and undergone fibrous metaplasia to form a membrane—a “cyclitic membrane” (arrows) (×20)

47

Fig. 2.27  The completely gliotic retina contains foci of calcification, calcospherites (c), and the capillaries (h) are basophilic due to iron impregnation (hyphaenoid degeneration) (×100)

Retinal Pigment Epithelium in Phthisis Bulbi

The retinal pigment epithelium has a remarkable capacity for reactive proliferation. The cells commonly undergo metaplasia to form fibroblasts and the collagen and ground substance formed by these cells has a high affinity for calcium salts. The deposition of calcium salts stimulates osseous metaplasia and it is not uncommon to find trabecular bone of woven and lamellar type on the inner surface of Bruch’s membrane Lens in Phthisis Bulbi in a phthisical eye (Fig. 2.25d). Fat is always present in the The abnormalities found in the lens are often an extension of interspaces of the bone, but myeloid metaplasia is rare. those that were described previously in the section on lens Proliferation of fibroblasts within the choroid also produces abnormalities (see earlier in chapter); but an unusual end-­ ossification to a lesser degree. The proliferative capacity of the retinal pigment epithestage feature is ossification within the cortex and nucleus, lium is such that the subretinal space may be filled by pigwhich occurs against a background of dystrophic calcificamented cuboidal and spindle cells within fibrous tissue; the tion and rupture of the lens capsule (Fig. 2.24). process may be incorrectly considered as neoplastic. 2. Disruption of the posterior lens capsule with disorganization of lens matter (and occasionally lens-induced uveitis). 3. Retinal detachment.

Retinal Gliosis The retina in such a specimen is thickened and folded and much of the thickening may be the result of glial cell proliferation and replacement of the intrinsic neural cells (Fig. 2.27). The glial cells may achieve considerable size and appear pleomorphic: the diagnosis of neoplasia should not be entertained, although it may be tempting to make the diagnosis of glioma. A convincing example of a glial tumour arising in a traumatized eye has not been reported. The matrix formed by glial cells has an affinity for calcium salts, and calcospherites may be numerous. When haemosiderosis is extensive, iron impregnation of capillaries can give a false impression that fungal hyphae are present in the tissue (hyphaenoid degeneration). Cysts form readily in such specimens and can reach a large size.

Choroid in Phthisis Bulbi Tears in the choroid, with defects in Bruch’s membrane, are seen macroscopically as linear white lines or oval areas. In this situation, histology reveals fusion of retina with choroid or sclera. At a later stage there may be fibrosis on the inner surface of Bruch’s membrane. The choroid may also be the location of heterotopic bone formation and there is exudation of proteinaceous eosinophilic material, which thickens the tissue. Inflammatory cell infiltration is minimal and indeed if there is an impressive reaction, the possibility of sympathetic ophthalmitis should be entertained. It is worth noting that in individuals with darker racial pigmentation there may be prominent accumulation of melanocytes in the choroid in phthisis bulbi.

48

2  The Traumatized Eye

Optic Nerve in Phthisis Bulbi At the late stage of atrophia or phthisis, the optic nerve is usually completely atrophic and it may be difficult to find the nerve within the massively thickened posterior sclera. The meninges are redundant around the string-like residue of the nerve, the substance of which is devoid of myelinated axons and consists of fibrous tissue derived from thickening of the pial septae.

Hot Metals, Acids, and Alkalis Hot metal fragments cause a coagulative necrosis within periocular tissues and sometimes an exuberant fibrous reaction (Fig. 2.28). Acid burns to the eye are usually the consequence of industrial injury or the bursting of car batteries by incorrect charging. Concentrated acid coagulates tissue proteins in the eyelid, conjunctiva, and cornea and this limits, to some extent, diffusion into the globe; although secondary corneal or scleral necrosis has a disastrous effect on vision. This a

form of trauma will be encountered in the laboratory most commonly in the form of a corneal disc after a graft has been performed (see Chap. 13). As a variant of malicious civil trauma, sodium hydroxide or ammonia solutions thrown into the face can lead to severe damage to the eye, although the former fluid causes more damage because the potential for diffusion through tissue is greater. Caustic soda diffuses through the ocular tissues and death of the cells leaves a curious acellularity. This acellularity is usually confined to the anterior segment, but the insult also stimulates an acute inflammatory infiltration within the ocular compartments (Fig. 2.29). Necrosis of the optic nerve may occur if the alkali passes down the hyaloid canal in the vitreous. The secondary dissolution of the cornea is attributed to release of collagenases (metalloproteinases) and mild alkali burns have been used experimentally to investigate corneal neovascularization. In the case of particulate alkaline material (e.g., lime), the insoluble salts produce marked corneal fibrosis and squamous metaplasia of the epithelium. Particles of soda lime may remain unnoticed in the fornices of the conjunctival sac for some considerable time.

b

Fig. 2.28 (a) After a burn due to molten aluminium a large fibrous mass (arrow) grew on the cornea. (b) Histological examination revealed a massive fibrovascular reaction (*): Many of the tumours reported as fibromas are probably reactive

a

b

Fig. 2.29 (a) An alkali burn causes severe corneal ulceration (arrow) with associated congestion of the conjunctiva. (b) Severe optic atrophy (*) after an alkali burn. Fibrous contraction in the vitreous led to deformation of the retina, which formed a funnel-shaped mass in the vitreous

Effects of Ionizing Radiation

Effects of Ionizing Radiation The pathology of ocular tissue damage due to ionizing radiation will be encountered most frequently in the following circumstances: 1. Globes exposed to external tumoricidal irradiation by X-rays in treatment of carcinomas invading the eyelid or orbit. 2. Globes treated by external radiotherapy, currently with a proton beam, for intrinsic intraocular tumours; e.g., retinoblastoma or a metastatic tumour. 3. Globes treated by radioactive applicators (60Co, 131I, 106 Ru), in treatment of retinoblastoma or uveal melanoma. While there is extensive literature on the experimental effects of radiation of all types on the eye, in practice in the situations previously cited, it is unlikely that specific and incontrovertible pathology will be demonstrated. Apart from a radiation cataract, most of the changes observed will be secondary to dry eye or radiation vasculopathy, unless in a rare case, the tissues have been accidentally overexposed to

49

levels that are grossly excessive. An acute effect of tissue damage can be seen by, for example, 2000 cGy in a single dose. This induces necrosis of corneal keratocytes and endothelial cells, the pigment epithelium of the iris and retina, and the equatorial epithelial cells of the lens. Heavy dosage to the sclera, delivered by means of a plaque, can lead to a necrotizing scleritis and anterior segment necrosis if the ciliary arteries are thrombosed [30]. Reaction to tissue damaged by irradiation can be exuberant and the fibroblasts can adopt quite bizarre shapes and nuclear characteristics. Even with proper summation of dose, undesirable long-­ term side effects can occur after 1 year. The “dry eye,” with secondary corneal complications, is consequent upon destruction of accessory lacrimal gland tissue and the effect on the cornea is ulceration due to an inadequate tear film. Radiation retinopathy usually appears about 3 years after irradiation and is basically an ischaemic retinopathy consequent upon damage to the endothelium of the retinal vascular bed. The life span of capillary endothelial cells in the retina is about 3 years and a failure to maintain the population leads to endothelial cell depletion. After a year or 2, this presents as haemorrhages, microinfarcts and exudates, which sometimes have lipid constituents (Figs.  2.30 and 2.31).

a

b

c

d

Fig. 2.30 (a) Early exudative retinopathy (arrow) following irradiation of an orbital tumour. (b) Advanced exudative retinopathy (arrow) following irradiation. The detached vitreous is filled by an opaque exudate. (c, d) Lipid within the retina, the subretinal space and choroid in a

frozen section (gelatin embedding and stained with oil red O) in radiation retinopathy. Neutral fat is red and in polarised light cholesterol is birefringent

50

Convincing evidence of an endarteritis, such as is seen in skin, is not present in the retinal arterioles and venules, which sustain damage to the smooth muscle of the media. The major effect is on the capillary bed in which loss of endothelial cells and pericytes leads to micro-aneurysm formation, and an important feature is that occasionally capillaries are filled by glial cells [31]. Exudation of lipid can be striking and this is accompanied by an infiltration of lipid-­ laden macrophages in the retina and subretinal space and the presence of cholesterol clefts in the cellular infiltrate.

Fig. 2.31  Radiation retinopathy in a globe containing a melanoma (m) that was treated by a ruthenium plaque: There is pronounced leakage of lipid-rich plasma into the retina, giving a distinctive yellow appearance

a

2  The Traumatized Eye

The Infant Eye in Abusive Head Trauma Occasionally a pathologist may be asked to examine the eyes from an infant who has died from suspected abusive head trauma (AHT). The most common form of injury is that associated with intracerebral injury and has been attributed to vigorous shaking with or without impact injury. The characteristic findings in such eyes are those of multifocal or widespread retinal haemorrhages involving all retinal layers and there may in addition be subretinal haemorrhages (Fig. 2.32) [31, 32]. When haemorrhage is severe it may be possible on closer inspection to identify a small central white dot in some of the haemorrhages, reminiscent of a Roth’s spot. The haemorrhages usually reach the periphery and there is often equatorial accentuation of the haemorrhages. These haemorrhages are often accompanied by a circular fold around the macular region (so-called perimacular fold), although sometimes this extends to the nasal side of the optic disc (Fig. 2.33). This combination of findings in conjunction with subdural haemorrhages and encephalopathy (“the Triad”) would until recently have been considered pathognomonic of shaking. There are, of course, numerous other causes of retinal haemorrhages in infants including birth haemorrhages and the pathologist should make sure that these have been considered and excluded by thorough post mortem. The mechanism of these injuries is generally considered to be caused by rapid, abrupt acceleration and deceleration of the cranium with a rotational element resulting in vascular shearing. However, it is now clear that this is not the only mechanism since identical ocular findings have been described following severe crush injury where the suggested mechanism is a rapid rise in intracranial pressure being transmitted through the optic nerve [33]. Retinal haemorrhages have also been described in infants following short

b

Fig. 2.32 (a) In this case there are widespread retinal haemorrhages extending from the ora serrata to the posterior pole. (b) Microscopic examination shows that the haemorrhages are present in all the retinal layers

The Infant Eye in Abusive Head Trauma

distance falls, although these are rarely as severe as those seen in AHT [34]. It has been suggested that shearing forces are not the only mechanism and the alternative hypothesis of brain hypoxia and subsequent swelling leads to subdural haemorrhage and, by implication, retinal haemorrhages [35, 36]. It has also been postulated that the retinal haemorrhages may occur secondary to the intracerebral haemorrhages following a rise in intracerebral pressure. It has been suggested that the sustained rise in intrathoracic pressure that may

Fig. 2.33  A perimacular fold (*) with the internal limiting membrane spanning the gap (arrows) and subinternal limiting membrane haemorrhage. There is also diffuse retinal haemorrhage

a

51

result from choking and coughing could be transmitted to cerebral and retinal vessels resulting in similar haemorrhages but this has not been supported by studies of children with whooping cough [37–39]. Although the retinal haemorrhages are usually severe, bilateral and diffuse cases with unilateral, focal or no retinal haemorrhages are recognized [40]. As such there is increasing interest in the importance of posterior optic nerve and orbital findings in abusive head trauma. Studies have shown optic nerve sheath haemorrhages are found in over half of cases with AHT and over 80% when there is a history of AHT and retinal haemorrhages (Fig.  2.34a) [41]. This is more commonly in a subdural than subarachnoid location (Fig. 2.34b). Although there are few studies on this subject where haemorrhage within orbital fat and extraocular muscle has been sought it appears to be more common in AHT than in accidental injury [42]. Similarly peripapillary intrascleral haemorrahge in the region of the vascular circles of Zinn and Haller has also been described [43]. When examining these cases the pathologist should remember that they may be asked to give evidence and therefore thorough documentation is important. In order to fully examine the optic nerve with attached orbital contents in cases of suspected AHT the eyes should be removed using a combined anterior and posterior approach to produce an en bloc specimen of the eye and orbital contents with complete muscle cone [44]. Detailed macrophotography of the specimen should be undertaken including serial sections through the orbital ­contents including the optic nerve, the optic nerve sclera junction and the macular region. The report should detail the extent and location of haemorrhages and the Prussian blue stain for iron should be undertaken since haemosiderin will not be apparent until approximately 48 h after injury. Further studies are beyond the scope of this chapter but immunohisb

Fig. 2.34 (a) Transverse sections of the optic nerve will show haemorrhage within the optic nerve sheath (arrowheads). (b) On histological examination the optic nerve sheath haemorrhage is predominantly subdural in location (arrows)

52

tochemistry to include Beta amyloid precursor protein to assess optic nerve damage [45], CD15 or GFAP for reactive Müller cells and gliosis may be useful.

References 1. Koisaari T, Leivo T, Sahraravand A, Haavisto AK, Sulander P, Tervo TMT. Airbag deployment-related eye injuries. Traff Inj Prev. 2017;18:493–9. 2. Rao SK, Greenberg PB, Filippopoulos T, Scott IU, Katsoulakis NP, Enzer YR. Potential impact of seatbelt use on the spectrum of ocular injuries and visual acuity outcomes after motor vehicle accidents with airbag deployment. Ophthalmology. 2008;115(3):573–576.e1. 3. Blanch RJ, Bindra MS, Jacks AS, Scott RA. Ophthalmic injuries in British Armed Forces in Iraq and Afghanistan. Eye (Lond). 2011;25:218–23. 4. Gurler B, Coskun E, Oner V, Comez A.  Syrian civil-war-related intraocular foreign body injuries: a four-year retrospective analysis. Semin Ophthalmol. 2017;32:625–30. 5. Bhogal G, Tomlins PJ, Murray PI. Penetrating ocular injuries in the home. J Public Health (Oxf). 2007;29:72–4. 6. Micieli JA, Easterbrook M. Eye and orbital injuries in sports. Clin Sports Med. 2017;36:299–314. 7. Kolomeyer AM, Shah A, Bauza AM, Langer PD, Zarbin MA, Bhagat N.  Nailgun-induced open-globe injuries: a 10-year retrospective review. Retina. 2014;34:254–61. 8. Nemet AY, Asalee L, Lang Y, Bricoe D, Assia E. Ocular paintball injuries. Isr Med Assoc J. 2016;18:27–31. 9. Davis LE, Tripathi S.  A case of self-enucleation in an incarcerated patient: case report and review of literature. J Forensic Sci. 2018;63:1908–10. 10. Elner VM. Ocular manifestations of child abuse. Arch Ophthalmol. 2008;126:1141–2. 11. Spraul CW, Grossniklaus HE.  Vitreous haemorrhage. Surv Ophthalmol. 1997;42:3–39. 12. Schubert HD.  Postsurgical hypotony: relationship to fistuliza tion, inflammation, chorioretinal; lesions and the vitreous. Surv Ophthalmol. 1996;41:97–125. 13. Pulido JS, Blair MP. The blood retinal barrier in Berlin’s oedema. Retina. 1987;7:233–6. 14. McDonnell PJ, Gritz DC, McDonnell JM, Zarbin MA. Fluorescence of blood stained cornea. Cornea. 1991;10:445–9. 15. Kuchle M, Green WR. Epithelial ingrowth: a study of 207 histopathologically proven cases. Ger J Ophthalmol. 1996;5:211–23. 16. Viestenz A, Seitz B, Viestenz A, Naumann GOH. Epithelial invasion after open globe injury. Clin Anat. 2018;31:68–71. 17. Viestenz A, Naumann G. Block-excision of cystic epithelial downgrowth as the treatment of choice. Eye (Lond). 2005;19:1. 18. Lee WR, Grierson I. Macrophage infiltration in the human retina. Graefes Arch Clin Exp Ophthalmol. 1977;203:293–309. 19. Williams DF, Mieler WF, Williams GA. Posterior segment manifestations of ocular trauma. Retina. 1990;10:S35–44. 20. Blight R, Hart CD.  Structural changes in the outer retinal layers following blunt mechanical non-perforating trauma to the globe. An experimental study. Br J Ophthalmol. 1977;61:573–87. 21. Mansour AM, Green WR, Hogge C. Histopathology of commotio retinae. Retina. 1992;12:24–8. 22. Damico FM, Kiss S, Young LH.  Sympathetic ophthalmia. Semin Ophthalmol. 2005;20:191–7. 23. Castiblanco CP, Adelman RA.  Sympathetic ophthalmia. Graefes Arch Clin Exp Ophthalmol. 2009;247:289–302. 24. Guerriero S, Montepara A, Ciraci L, Monno R, Cinquepalmi V, Vetrugno M. A case of sympathetic ophthalmia after a severe acanthamoeba keratitis. Eye Contact Lens. 2011;37:374–6.

2  The Traumatized Eye 25. Shen J, Fang W, Jin XH, Yao YF, Li YM. Sympathetic ophthalmia caused by a severe ocular chemical burn: a case report and literature review. Int J Clin Exp Med. 2015;15:2974–8. 26. Brour J, Desjardins L, Lehoang P, Bodaghi B, Lumbrosa-Lerouic L, Dendale R, Cassoux N.  Sympathetic ophthlamia after proton beam irradiation for choroidal melanoma. Ocul Immunol Inflamm. 2012;20:273–6. 27. Chu XK, Chan C-C.  Sympathetic ophthalmia: to the twenty-first century and beyond. J Ophthalmic Inflamm Infect. 2013;3:49. 28. Atan D, Turner SJ, Kilmartin DJ, Forrester JV, Bidwell J, Dick AD, Churchill AJ.  Cytokine gene polymorphism in sympathetic ophthalmia. Invest Ophthalmol Vis Sci. 2005;46:4245–50. 29. Chan CC.  Relationship between sympathetic ophthalmia, phacoanaphylactic endophthalmitis and Vogt-Koyanagi-Harada disease. Ophthalmology. 1988;95:619–24. 30. Passarin O, Zografos L, Schalenbourg A, Moulin A, Guex-Crosier Y.  Scleritis after proton therapy in uveal melanoma. Klin Monbl Augneheilkd. 2012;229:395–8. 31. Archer DB. Responses of retinal and choroidal vessels to ionising radiation. Eye. 1993;7:1–15. 32. Levin AV. Retinal hemorrhage in abusive head trauma. Pediatrics. 2010;126:961–70. 33. Levin AV. Retinal hemorrhages of crush head injury. Learning from outliers. Arch Ophthalmol. 2006;124:1773–4. 34. Plunkett J.  Fatal pediatric head injuries caused by short-distance falls. Am J Forensic Med Pathol. 2001;22:1–12. 35. Geddes JF, Whitwell HL. Inflicted head injury in infants. Forensic Sci Int. 2004;146:83–8. 36. Cohen MC, Scheimberg I.  Evidence of occurrence of intradural and subdural hemorrhage in the perinatal and neonatal period in the context of hypoxic ischemic encephalopathy: an observational study from two referral institutions in the United Kingdom. Pediatr Dev Pathol. 2009;12:169–76. 37. Geddes JF, Talbert DG.  Paroxysmal coughing, subdural and retinal bleeding: a computer modelling approach. Neuropathol Appl Neurobiol. 2006;32:625–34. 38. Goldman M, Dagan Z, Yair M, Elbaz U, Lahat E, Yair M. Severe cough and retinal haemorrhage in infants and young children. J Pediatr. 2006;148:835–6. 39. Raoof N, Pereira S, Dai S, Neutze J, Grant CC, Kelly P.  Retinal haemorrhage in infants with pertussis. Arch Dis Child. 2017;102:1158–60. 40. Morad Y, Kim YM, Armstrong DC, Huyer D, Mian M, Levin AV.  Correlation between retinal abnormalities and intracranial abnormalities in the shaken baby syndrome. Am J Ophthalmol. 2002;134:354–9. 41. Royal College of Paediatric and Child Health and The Royal College of Ophthalmologists. Abusive head trauma and the eye in infancy. Eye (Lond). 2013;27(10):1227. 42. Wygnanski-Jaffe T, Levin AV, Shafiq A, Smith C, Enzenauer RW, Elder JE, Morin JD, Stephens D, Atenafu E.  Postmortem orbital findings in shaken baby syndrome. Am J Ophthalmol. 2006;142:233–40. 43. Emerson MV, Jakobs E, Green WR. Ocular autopsy and histopathologic features of child abuse. Ophthalmology. 2007;114:1384–94. 44. Gilliland MG, Levin AV, Enzenauer RW, Smith C, Parsons MA, Rorke-Adams LB, Lauridson JR, La Roche GR, Christmann LM, Mian M, Jentzen J, Simons KB, Morad Y, Alexander R, Jenny C, Wygnanski-Jaffe T.  Guidelines for postmortem protocol for ocular investigation of sudden unexplained infant death and suspected physical child abuse. Am J Forensic Med Pathol. 2007;28:323–9. 45. Gleckman AM, Evans RJ, Bell MD, Smith TW. Optic nerve damage in shaken baby syndrome: detection by beta-amyloid precursor protein immunohistochemistry. Arch Pathol Lab Med. 2000;124:251–6.

3

Absolute Glaucoma

Introduction Until recent years up to 30% of the globes received in the laboratory will have been enucleated in treatment of the complications and the intractable pain that are the features of secondary end-stage or “absolute” glaucoma. The commonest cause of secondary absolute glaucoma in the elderly patient was previously thrombotic occlusion of the central retinal vein (see Chap. 4), but, like diabetic eye disease, this is now less common due to effective suppression of intraocular neovascularisation by panretinal laser treatment (photoablation) and intravitreal anti-vascular endothelial growth factor (VEGF). Secondary “neovascular glaucoma” is brought about by proliferation of fibrovascular tissue in the chamber angle and this vasoproliferation is a response to transport, via the ocular fluids, of vasoformative biochemical agents synthesised in the retina in conditions in which there is underperfusion and hypoxia in the neural tissues. Ischaemic disease is often present in several tissue components in the elderly eye, and this is often the final stage in a process that may have been initiated by the primary and secondary glaucomas that will be described in this chapter. For the pathologist about to embark on the study of a glaucomatous eye, there is one important caveat. If, as is often the case in end-stage glaucoma, the cornea and lens are opaque, the clinician may not have been aware that an intraocular malignant melanoma (see Chap. 5) was the underlying cause of raised intraocular pressure (IOP). The presence of a tumour should be suspected if the globe is unusually firm on palpation, particularly in one quadrant. Thus, during this preliminary stage of the macroscopic examination, it is important to identify and retain the vortex veins, because these structures are much harder to find after the eye has been bisected.

 he Functional Morphology of the Outflow T System The corneoscleral envelope of the eye may be compared with the casing of an inflated football. Pressure within the inelastic collagenous casing is maintained at normal levels (13– 21  mmHg) by a balance between the pressure of aqueous inflow and the resistance in the outflow system [1].

Aqueous Inflow Aqueous fluid is pumped into the eye by the ciliary epithelium utilising a bicarbonate pump mechanism. However, the inflow pressure is also dependent on the hydrostatic pressure in the fenestrated ramifying capillary bed in the ciliary processes. The anatomy of the two-layered epithelium of the ciliary processes is such that the inner, non-pigmented layer is united by tight junctions (zonulae occludentes). The inner part of the intercellular space is used for pumping anions and cations, which attract water by osmosis; and the ultrafiltrate, produced in the blood-aqueous barrier, consists of salts and low molecular weight substances [2].

Aqueous Outflow The Trabecular Meshwork Aqueous passes through the pupil to the chamber angle and leaves the eye via the outflow system or trabecular meshwork (Figs. 3.1 and 3.2). Resistance to aqueous outflow resides mainly in the trabecular meshwork and to a lesser extent in the collector channels in the sclera. These are the most important pathways for aqueous drainage, but a small amount of aqueous can pass into the space

© Springer Nature Switzerland AG 2021 F. Roberts, C. K. Thum, Lee’s Ophthalmic Histopathology, https://doi.org/10.1007/978-3-030-76525-5_3

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Fig. 3.1  Upper: a diagram to illustrate the anatomical features of the outflow system. Lower: a semithin Araldite-embedded section to show giant vacuoles in the lining endothelium of Schlemm’s canal (arrowheads)

Fig. 3.2  A bifurcation in the canal of Schlemm (cs) (arrow). Note the corneoscleral layer (c) and uveal layer (u) of the trabecular meshwork (×250)

between the ciliary body and the sclera through the interspaces of the ciliary muscle (uveoscleral outflow route). The anatomical arrangement of the spaces in the trabecular meshwork is such that resistance is greatest in the outermost layer—the cribriform layer—where the endothelial cells lie within loose connective tissue. The inner trabeculae are divided into two layers: the uveal and corneoscleral layers; these are formed from sheets of collagen, which contain relatively large perforations. The perforated sheets, or beams as they appear in section, are lined by a syncytium of endothelial cells, which have processes interconnected by gap junctions. The contractile endothe-

3  Absolute Glaucoma

lial cells [3] “maintain” the collagens and glycosaminoglycans in the beams and in addition have the capacity to phagocytose particles (e.g., melanin granules and cell debris), which are washed through the putative filter by the aqueous fluid. The outermost layer described as “juxtacanalicular” or “cribriform” contains cells supported by loose extracellular materials, collagens of various type, laminin, etc. [4] and this is regarded as the major site of resistance to aqueous outflow. It is likely that hyalinisation in the inflow system, which occurs in the normal individual with ageing, is paralleled by hyalinisation in the outflow system, so that in the elderly there is a reduction in the volume of aqueous produced [5] and intraocular pressure does not rise in the ageing eye. Therefore the outflow system serves as a one-way valve, preventing reflux of blood into the anterior chamber, a resistor to maintain intraocular pressure, and a filter to remove debris from the aqueous. In addition, there are dendritic cells in the cribriform layer so that the tissue may modulate immune responses in the anterior segment and nerves in the region of the scleral spur may be involved in the recognition of the levels of intraocular pressure.

 he Canal of Schlemm T The circumferential canal of Schlemm lies within the scleral sulcus and from it a series of collector channels drain into the episcleral venous system. The canal often bifurcates and trifurcates (Fig.  3.2), so that a single large channel is rarer than might be supposed from diagrammatic representations. Similarly, collector channels are rarely seen in routine paraffin sections. The pressure within the orbital venous system is around 8  mmHg, but even when the intraocular pressure is lower than this, venous blood will not reflux into the anterior chamber because the endothelial monolayer of the canal forms a barrier supported by the compressed cribriform layer. Although the intraocular pressure fluctuates (15–18  mmHg) there is sufficient pressure to transfer aqueous into the canal of Schlemm. At higher intraocular pressures, the cribriform layer becomes distended and, in addition to diffusion and paracellular pathways [6], the lining endothelium of the canal transfers aqueous by utilising a pressure-­d ependent transcellular fluid transport system [7]. As in the arachnoid granulations in the cerebral venous sinuses, the endothelium uses an invagination-vacuole system for the transfer of fluid (Fig.  3.1). The invaginations reach a large size (5–10  mm) and can be seen easily as giant vacuoles in semithin plastic (1 mm) sections, but never with confidence in paraffin sections. Small circular openings form in the cytoplasm on the canal side of the invagination and this permits rapid bulk flow of aqueous from the cribriform layer into Schlemm’s canal. An important point to appreciate is that the trabecular tis-

Primary Open Angle Glaucoma

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sues are much more malleable and delicate than conventional morphology might suggest.

push the iris onto the trabecular meshwork in some individuals [10].

Classification of Glaucoma

 rimary Congenital Forms/Childhood P Glaucomas

Glaucoma is a generic term used to describe diseases in which the intraocular pressure is at a level sufficient to cause damage to the tissues within an individual eye, resulting in “glaucomatous optic neuropathy” (GON). This qualified definition is required because some individuals (ocular hypertensives) can tolerate relatively high intraocular pressure without damage to the neural conducting tissues of the visual system. An abnormally high pressure (i.e., greater than 24 mmHg) is always the consequence of impaired aqueous outflow and the most serious effect in the susceptible eye is blindness due to atrophy of the axonal bundles in the optic disc. There is, as yet, no firm evidence that an intraocular pressure above the normal range is due to excessive inflow. It is conventional to use five subdivisions for the classification of the abnormalities in the outflow system and chamber angle in glaucoma.

Primary Open Angle Glaucomas (POAG) This is a primary acquired unilateral or bilateral disease of the trabecular meshwork combined with reductions in the blood supply to the optic nerve head (syn, chronic simple glaucoma); the condition occurs predominantly in the elderly, often with a familial component.

 ormal Tension Glaucoma (NTG) N Normal tension glaucoma (NTG) may be a subtype of POAG whereby patients develop glaucomatous optic neuropathy (GON) without elevated IOP or any identifiable pathological cause. While the existence of NTG as a separate disease process is disputed [8], reducing the IOP in individuals with NTG can modify the natural history of the disease [9].

Primary Acute Angle Closure Glaucoma In this unilateral or bilateral disease of the middle-aged and elderly, high pressures are reached when aqueous outflow is obstructed by apposition of the iris to the inner surface of the cornea and the trabecular meshwork. Generally, the mechanism ascribed to primary angle closure involves the pupil block, which is the relative increase in fluid resistance to flow between lens and iris. The pressure required to drive flow across this segment creates a pressure differential between anterior and posterior chambers, tending to

This is manifest either as a malformation of the trabecular meshwork—“goniodysgenesis”—or as a persistence of embryonic tissue in the chamber angle. The latter is due to a failure of a cleavage process that normally separates the developing iris from the trabecular meshwork. Barkan’s membrane consists of a layer of tissue resembling the iris stroma lining the inner surface of the iris. These two forms of congenital abnormality are also found in the phakomatoses (see later in this chapter and Chap. 8).

Secondary Glaucomas This is a group of diseases in which the mechanism by which aqueous outflow is obstructed (e.g., by cells or particulate material) is usually obvious, but basically there is either: 1. aqueous outflow obstruction with open angles; i.e., secondary open angle glaucoma, or 2. aqueous outflow obstruction with closed angles; i.e., secondary angle closure glaucoma.

Primary Open Angle Glaucoma Less than 10% of POAG are attributable to a monogenic, autosomal dominant trait. These genes include myocilin (MYOC, GLC1A), optineurin (OPTN, GLC1E) and WD repeat domain 36 (GLC1G) [11]. Myocilin mutations generally occur in juvenile or early adult forms. The prevalence of myocilin mutations is 3–5% with glaucoma developing in 90% of cases [11]. The mechanism of myocilin-related glaucoma is not understood. Myocilin is involved in the contractile functions of the trabecular meshwork and when mutated misfolded proteins accumulate in the cell cytoplasm [12]. The second POAG gene identified was the optineurin (OPTN) gene. This is located on the short arm of chromosome 10 [13]. OPTN has a role in exocytosis and Golgi ribbon formation. Individuals with OPTN gene mutations usually have normal levels of intraocular pressure. Genome scans for glaucoma susceptibility loci have shown CAV1/CAV2 locus on 7q34 may be associated with POAG in European populations [14]. These genes encodes caveolins which are invaginations of the cell membrane involved in cell signalling and endocytosis. The CDKN2BAS locus on 9p21 was shown to be related to glaucoma risk in

56

multiple cohorts but again the mechanisms involved have not been elucidated [15]. Patterns of the disease are variable and response to the available forms of treatment are also variable in different individuals, so that it is attractive to postulate that there are several primary causes that lead to the clinically detected disease. By accepted definition, the intraocular pressure in the disease state is greater than 24 mmHg and is accompanied by atrophy of the prelaminar part of the optic nerve, which is seen as cupping on ophthalmoscopy and manifest as a field defect (arcuate scotoma) with a decline in visual acuity and an impairment of colour vision. It is presumed that the abnormally high intraocular pressure is due to an abnormal resistance in the outflow system, but after decades of morphological research, it has not been possible to identify the precise abnormality of the tissues in the outer part of the trabecular meshwork [16, 17]. This is partly due to the fact that suitable samples of the trabecular meshwork in this disease will rarely be available for pathological study, either in trabeculectomy specimens or in a surgically enucleated eye. In almost every case, even in autopsy material, medication will have been prolonged or fistulising surgery (to reduce intraocular pressure) will have been performed, so that many observed disturbances in the morphology of the trabecular meshwork could be regarded as secondary.

Treatment of Primary Open Angle Glaucoma Further loss of visual field can be prevented by lowering the intraocular pressure with topical drugs or by surgery intended to produce a controlled fistula, sufficient to lower pressure to a desired level without the complication of severe hypotonia. For a pathologist, a working knowledge of glaucoma pharmacology is desirable because details are usually submitted with the request form. Drugs used to lower and maintain intra-ocular pressure (IOP) are generally classified into two categories: Inflow drugs and outflow drugs. Inflow drugs, like β (beta) adrenergic antagonists and carbonic anhydrase inhibitors, reduce the rate of aqueous humour production. Outflow drugs, like prostaglandin analogs, cholinergic agonists, and sympathomimetics, increase the rate of drainage through the uveoscleral outflow pathway and/or increase the facility of outflow through the trabecular meshwork [18]. β (beta) adrenergic antagonists, such as timolol and betaxolol, block β (beta)-adrenoceptors located in the ciliary processes, reduce the production of should be cAMP, and slow ciliary epithelial secretion of aqueous humour. Carbonic anhydrase inhibitors, such as acetazolamide and dorzolamide, block carbonic anhydrase in the non-­pigmented ciliary epithelium, may block the first step in aqueous humour formation by inhibiting NaCl uptake from the stroma [16], and slow the rate of water movement into the posterior chamber, thus reducing IOP.  Prostaglandin F2α (alpha) analogs,

3  Absolute Glaucoma

such as latanoprost and bimatoprost, biochemically alters the extracellular matrix of the ciliary muscle and/or trabecular meshwork contractility. Latanoprost, or Xalatan, does not cause cardiovascular or respiratory complications, but has an unexplained effect of hyperpigmentation of the melanocytes in the anterior border layer of the iris in patients with blue-­ green irides and an increased growth of lashes at the lid margin. Sympathomimetics, such as epinephrine, apraclonidine, and brimonidine, have multiple effects related to the multiple receptors stimulated resulting in vasoconstriction and relaxation of ciliary muscle. Parasympathomimetics, such as pilocarpine, contracts ciliary muscle and pulls on the scleral spur to open up the trabecular meshwork and widens Schlemm’s canal; cholinesterase inhibitors, such as demecarium, blocks the metabolism of acetylcholine by acetylcholinesterase at cholinergic nerve endings resulting in acetylcholine accumulation at the neuromuscular junction to stimulate postjunctional and postsynaptic receptors. Hyperosmostics, such as glycerin and mannitol, rapidly increasing blood osmolality drawing fluid out of the eye into the intraocular vessels. If medical treatment does not achieve adequate control of intraocular pressure laser or surgery may be required. This represents a small number of individuals with glaucoma. Various surgical procedures have been devised to produce a modified fistula in the corneoscleral envelope in order to reduce intraocular pressure to a level (8–18 mmHg) that will reduce the risk of further damage to the optic disc. All fistulising procedures carry the risk of uveal incarceration, which is an undesirable complication because of the increased risk of sympathetic ophthalmitis (see Chap. 2). Equally important, the fistula must be designed to avoid prolonged hypotonia (see Chap. 2) with its attendant complications.

Surgical Trabeculectomy From a posterior approach a block (3 × 3 mm) of limbal tissue is removed under a scleral flap, which is sutured back over the deficit (Fig. 3.3a). Since haemorrhage is a complication of the procedure, damage to the vessels in the iris root can be avoided by a corneal approach, which avoids a cut through the scleral spur: Specimens thus obtained almost always consist of corneal tissue with a few anterior trabeculae. The drainage of aqueous is through the thin scleral flap into an overlying bleb covered by conjunctival epithelium. Subsequently aqueous diffuses into the adjacent episcleral tissue. The procedure also provides uveoscleral outflow by opening up the potential drainage space between the ciliary body and the sclera (Fig.  3.3b). Intraoperative antimitotic drugs, namely 5-fluorouracil and mitomycin C, may be applied to prevent scarring. From a research pathologist’s point of view, a trabeculectomy specimen should include the inner peripheral cornea, the outflow system, and the peripheral sclera with the

Primary Open Angle Glaucoma

a

b

Fig. 3.3  Diagrams to illustrate the trabeculectomy procedure using the posterior approach. (a) The shaded tissue is removed as a 3 × 3 mm block beneath a loosely sutured scleral flap. (b) This leaves a fistula that communicates with an overlying conjunctival bleb and with the (supraciliary) space between the ciliary body and the sclera (uveoscleral drainage)

Fig. 3.4  The outflow system in primary open angle glaucoma in an enucleated eye. The trabeculae are thickened and the cribriform layer (arrowhead) is acellular and hyalinised. The canal of Schlemm (cs) is often open and the scleral spur (ss) is enlarged (×250)

attached spur and the ciliary muscle insertion. Unfortunately, trabeculectomy specimens have not provided as useful an opportunity to study the pathology of glaucoma as was originally anticipated. The reason is that the trabecular meshwork

57

is easily traumatised by the procedure and interpretation of the tissue abnormalities is difficult. Macroscopic examination of a trabeculectomy specimen requires magnification. The specimen may be square or rectangular (1 × 1 × 0.5 mm to 4 × 4 × 0.5 mm). The outflow system is often pigmented and may be identifiable while some attached ciliary muscle may also be seen on the inner surface behind the meshwork and the clear band of cornea. The block should be bisected at right angles to the trabecular meshwork and a strip retained for research if required. Orientation of the block during paraffin embedding and sectioning in a meridional plane requires skill and experience. Serial sections should be cut and mounted, ten sections per slide, on five slides; three slides should be stained with haematoxylin and eosin (H&E) and two saved for special stains. In many cases, on histological examination, the trabecular tissue is disrupted or may not even be present. At best, only the inner (uveal) trabecular endothelial cells will show signs of damage, but the canal of Schlemm and the surrounding tissues should be preserved. With the more commonly used corneal approach (i.e., removes the trabeculectomy block from the corneal rather than the scleral aspect), it is highly unlikely that the outflow system will be included in toto.

Pathological Features The most common features seen in serial paraffin sections from well-preserved specimens in POAG are hyalinisation and acellularity of the outer part of the trabecular meshwork (Fig.  3.4). Melanin granules in the endothelial cells are a non-specific feature, but in excess should raise the possibility of the exfoliation syndrome (discussed later in this chapter) or pigmentary glaucoma [18]. Outflow resistance increases with age alongside alterations of the extracellular matrix in the juxtacanalicular region [19]. Abundant evidence has been produced in support of the important role that oxidative stress plays in the pathogenesis of primary open-angle glaucoma [20, 21]. Several mechanisms where oxidative stress may play its significant role had been postulated. These include causing the loss or altered functionality of endothelial cells in the trabecular meshwork [22], affecting the adhesion of trabecular endothelial cells to extracellular matrix proteins that results in disruption, influencing biological reactions of trabecular meshwork endothelial cells [22], and contributing to changes such as trabecular thickening and trabecular fusion [23]. It was assumed that, with the application of electron microscopy to trabeculectomy specimens, this tool would identify the primary pathology in early primary open angle glaucoma. However, careful study of normotensive age-­matched control

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eyes has shown that it is often impossible to detect significant differences between age-related changes and those found in primary open angle glaucoma when the disease is studied at an early stage and without prior topical treatment. By electron microscopy the following features have been recorded in primary open angle glaucoma and the significance has been extensively discussed [24–27]. 1. Thickening of the trabecular beams by accumulation of wide-banded collagen and homogenous elastic-like material. 2. Loss of the cover provided by endothelial cells with swelling and fusion of the thickened beams: this is most pronounced in the posterior part of the meshwork. 3. The extracellular matrix contributes to the resistance of the trabecular meshwork. Increased resistance to aqueous outflow may be due to changes in the glycosaminoglycans or alteration in the collagens of the extracellular tissues of the trabecular meshwork [28, 29]. 4. Focal closure of the canal of Schlemm although this may be a mechanical artifact in trabeculectomy specimens. 5. Factors 1–4 could all be explained by an overall depletion of the endothelial cell population [30].

3  Absolute Glaucoma

a

b

Laser Treatment The effects of laser treatment on the outflow system are considered in the sections on argon laser trabeculoplasty and YAG (yttrium aluminium garnet) laser trabeculotomy (see later in this chapter).

“Low Tension” Glaucoma In certain cases, the field defect and the appearance of the optic cup are typical for glaucoma, but the intraocular pressure is below the normal range. Possible mechanisms include lower tolerance to normal intraocular pressure, vascular dysregulation leading to perfusion deficit, abnormal translaminar pressure gradient due to CSP pressure possibly with impaired CSF circulation [31–33].

Primary Acute Angle Closure Glaucoma Clinical Features and Pathogenesis The pathogenesis of this disorder is easy to understand at a superficial level: Intraocular pressure will rise when the chamber angle is partially closed off by iridotrabecular contact and iridocorneal contact (Fig.  3.5a, b). As inflow continues, there is increasing pressure on the posterior iris surface and this results in greater occlusion of the angle and hence a further pressure rise.

Fig. 3.5  Features of angle closure glaucoma. (a) The iris surface is in contact with the uveal layer of the meshwork (arrowheads), which is compressed. The canal of Schlemm (cs) remains open and reference to the scleral spur (ss) reveals the extent to which the angle is closed (×250). (b) The macroscopic appearance of a plateau iris resulting in a shallow angle with iridocorneal contact (arrowhead)

The mechanisms that lead initially to angle closure are still under debate and concepts are based on in vivo measurements of chamber depth and gonioscopic examination with a lens that contains one or more mirrors: Ultrasound biomicroscopy has improved the diagnostic precision in this disease [34]. Generally, the mechanism ascribed to primary angle closure involves the pupil block, which is the relative increase in fluid resistance to flow between lens and iris [35]. The pressure required to drive flow across this segment creates a pressure differential between anterior and posterior chambers, tending to push the iris onto the trabecular meshwork in some individuals [36]. So rarely does a pathologist encounter angle closure in an untreated form, that published work is very limited [37]. Indeed, should the opportunity for study arise the greatest care should be taken in opening the (precious) specimen so as not to disturb the chamber angle and the lens-iris diaphragm. For the clinician, primary closed angle glaucoma is most commonly an acute unilateral process that causes a rapid and

Primary Acute Angle Closure Glaucoma

a

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A

C

B

D

b

Fig. 3.7  Diagram to illustrate the presumed pathogenesis in primary closed angle glaucoma. In A the pupil is dilated and there is space for aqueous to pass between the pupil and the lens. In B the pupil is in constriction and the iris is pulled away from the lens. In C the lens is enlarged (arrowheads) and the space between the pupil and the lens is constricted which increases the pressure behind the iris root. In D there is a functional block at the pupil in mid-dilatation and the peripheral iris is now in contact with the trabecular meshwork: the angle is now closing and the pressure is rising progressively

Fig. 3.6 (a) In this extreme example of pupil block glaucoma an enlarged lens flattens the anterior chamber. (b) In a less severe case, the degenerate lens matter contains clefts: the enlarged lens is displacing the iris with shallowing of the anterior chamber and narrowing of the angle (arrow)

painful rise in intraocular pressure in a congested eye (pressures of 80 mmHg may be reached within 24 h). The pathogenesis of angle closure glaucoma, both acute and chronic, appears to be in part related to three ageing processes: shrinkage of the whole eye (presbyopia), reduction in depth of the anterior chamber (to less than 2  mm) and an age-related increase in the size of the lens (Fig. 3.6a, b). In addition, the configuration of the angle can vary and those individuals who have a plateau iris or an intrinsically shallow angle are more at risk. As the lens enlarges, there is a tendency for the anterior surface to approach the posterior surface of the iris, particularly when the pupil is in mid-dilation (Fig.  3.7a, b). In mid-dilation, contraction of the sphincter and dilator pupillae muscles produces a vector that swings the elastic iris stroma backwards to narrow the gap between the lens surface and the pupil. Posterior displacement of the pupillary part of the iris impedes aqueous flow from the posterior chamber. Increased hydrostatic pressure behind the thin peripheral iris leads to bowing at the periphery and the

iris stroma comes into contact with the trabecular meshwork and the peripheral cornea. As the pressure imbalance between the posterior and anterior chambers increases, iridotrabecular contact spreads around the angle from 12 o’clock to 6 o’clock, outflow obstruction increases, and a vicious circle is initiated. It seems possible that the parts of the meshwork that are not protected by angle closure will be damaged by the excess flow at a high pressure if the process is not relieved by surgical intervention [38]. If a perforation is made in the peripheral iris, either surgically (peripheral iridectomy) or by means of a YAG laser (laser iridotomy), the pressure between the two chambers is equalised and the iris root separates from the peripheral cornea and the trabecular meshwork. The YAG laser produces a well-circumscribed full-thickness hole in the iris without any evidence of a fibroblastic response [39]. After early treatment is instituted, the condition is cured in the majority of cases. If an enlarged lens is responsible for the anterior displacement of the iris pupil, then removal and replacement with an intraocular lens will make room for the iris to move backwards thus allowing drainage of the angle. The second eye may develop acute angle closure glaucoma after some months or years and contralateral prophylactic intervention is favoured by some surgeons. In view of the relatively high recurrence rate of angle closure glaucoma after iridotomy or iridectomy procedures, surgical procedures such as trabeculectomy, goniosynechialysis, glaucoma implant or cyclodestructive procedures may be required [39].

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Chronic Angle Closure Glaucoma Angle closure may be insidious in some cases and the assumption is that iridotrabecular contact progresses at a much slower rate than that in the acute disease. This disease mimics open angle glaucoma and is referred to as “creeping angle closure glaucoma”.

Iridectomy Specimen The surgeon may rarely submit the nub of iris removed during a peripheral iridectomy for histology in cases of angle closure that may have atypical features. Care should be taken to divide the triangular specimen under magnification, so that sections are taken at right angles to the stroma, pigment epithelium, and muscle. In glaucoma the iris stroma may contain a low-grade chronic inflammatory infiltrate and may show evidence of stromal necrosis and infarction of the smooth muscle if the intraocular pressure was extremely high prior to surgery. Focal sector infarction of the sphincter or dilator pupillae is responsible for the fixed oval or irregular pupil that is a characteristic clinical sequel (Fig. 3.5b).

3  Absolute Glaucoma

trabeculectomy will be required to achieve a permanent lowering of pressure. Sometimes the pressure remains high when the angle appears to have been reopened. Morphological explanations for the failure of an iridectomy (with opening of the angle) to return the resistance to outflow to normal have not been extensive, but a few cases of angle closure glaucoma have shown that fragments of iris stroma can be incarcerated in the interspaces of the uveal meshwork and may persist there when the angle reopens. In addition, the redirection of aqueous through patent sectors of the outflow system leads to disruption of the cribriform layer [38]. This mechanical pressure leads to fusion of the uveal trabecular beams (Fig. 3.8). In some cases a prompt laser iridotomy fails to control angle closure glaucoma. The reasons for this are not fully elucidated. One reason is that the laser iridotomy may not be functional if the iris has not been perforated to full thickness. Another reason may be that the trabecular meshwork cells are overburdened by the need to phagocytose excessive melanin released by destruction of stromal melanocytes and the pigment epithelium of the iris. The delicate trabecular endothelial cells may also be adversely affected by inflammatory

Trabeculectomy Specimens The appearance of the outflow system in angle closure glaucoma in well-preserved trabeculectomy specimens is often within normal limits, but there are two interesting and possibly relevant changes: 1. an intertrabecular infiltration by inflammatory round cells, and 2. hyperpigmentation of the trabecular endothelial cells. These features are not unexpected, because of the necrotising effects of an acute onset of high pressure on the iris tissues. Inflammatory stimulating factors (e.g., prostaglandins) diffuse into the iris stroma and aqueous so that a non-­ granulomatous iritis contributes to the trabeculitis. The presence of synechiae may cause a tear in the inner meshwork and some of the trabeculae may be missing.

Unsatisfactory Response to Treatment When irido/trabecular/corneal contact becomes permanent, the term “synechia formation” is applied: Focal attachments are referred to as peripheral anterior synechiae. A perforation of the iris may equalise the pressure between the anterior and posterior chambers, but it will not expose the trabecular meshwork to aqueous if synechiae persist. At this stage a

Fig. 3.8  An electron micrograph of separation of pre-existing iridotrabecular contact in closed angle glaucoma. Iris stromal fragments (isf) are attached to the uveal trabeculae, which in some parts (arrowheads) are compressed and fused (×2000)

Congenital Glaucoma: Buphthalmos

mediators and increased resistance may be due to blockage of the trabecular interspaces by inflammatory cells.

Congenital Glaucoma: Buphthalmos With the advances of research in avian eyes, it is shown that the trabecular meshwork develops from neural crest derived cells, which migrate between the surface ectoderm and the periphery of the optic cup in the developing anterior segment. The trabecular meshwork emerges by proliferation and reorganisation of germinal tissue in the chamber angle and the separation of the trabeculae from the iris stroma is most likely to be the result of programmed cell death rather than the outcome of mechanical cleavage of tissue, which previously was thought to be due to the differential growth of tissues in the anterior segment [40–42]. If the outflow system and the structures of the anterior segment fail to develop normally, the resistance to aqueous outflow is impaired and even before birth the intraocular pressure is abnormally high. The spectrum of abnormality in both dysfunction and malformation is wide, and, as a consequence, the severity of glaucoma is variable, as is the age of onset. It is convenient to classify the disease according to the stage of development; e.g., at birth or soon after (neonatal), up to 24 months (infantile), or older than 2  years (late onset). It is also important to appreciate that a chamber angle malformation often occurs as part of more complex diseases involving either other ocular tissues and/or other organ systems; e.g., in neurofibromatosis and the SturgeWeber syndrome (encephalo-trigeminal-angiomatosis). In contrast to the adult eye, the corneoscleral envelope of the infant and child is elastic and distensible so that a raised intraocular pressure can produce a uniform enlargement. The globe may achieve diameters of the order of 40 mm, in which case the reference to an ox eye (buphthalmos) is appropriate. Glaucoma due to congenital malformation is rare and is treated, often effectively, by surgery. The traditional treatment has been to cut into the trabecular meshwork with a fine-bladed knife, which passes across the anterior chamber via a cut in the opposite part of the cornea (internal goniotomy). The rationale is that aqueous obstruction is due to persistence of embryonic tissue in the chamber angle and the assumption is that the canal of Schlemm is normally formed. Thus the tip of the knife opens up the abnormal embryonic tissue and exposes the canal of Schlemm to aqueous. More recently the approach has tended toward the use of trabeculectomy, which is not so technically demanding. The pathologist usually encounters congenital glaucoma in the form of a surgically enucleated and massively enlarged eye, which has probably been subjected to a number of sur-

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gical procedures (goniotomy, iridectomy, trabeculectomy, etc.) to improve drainage. In addition, it is likely that attempts were made to ablate the inflow system by destroying the ciliary processes either with heat (cyclodiathermy) or with ice crystal formation (cyclocryotherapy). It is now more common to see congenital glaucoma in a trabeculectomy specimen. A recent paper by Perry et al. [43] described the histopathological abnormalities of the anterior chamber in an enucleated specimen from a patient with underlying primary congenital glaucoma. The major findings described include partial absence and retrodisplacement of Schlemm’s canal, hypoplasia of the trabecular meshwork, broad attachment of ciliary muscle to the meshwork, and anterior insertion of hypoplastic iris with the formation of a pseudomembrane. Goniodysgenesis may be observed in malformed eyes obtained at autopsy in neonates or stillborns with systemic malformations.

Goniodysgenesis The Hoskins classification of congenital glaucoma identifies the area of dysgenesis [44]. Trabeculodysgenesis refers to a maldeveloped, with absence of angle recess and iris often inserted directly onto the trabecular meshwork. Additional iris abnormalities including stromal defects, anomalous vessels and structural defects such as coloboma and aniridia occur in iridotrabeculodysgenesis. Corneotrabeculodysgenesis is used for more complex abnormalities such as Axenfled’s, Reiger’s and Peter’s anomalies (Described in Chap. 8). A myriad of histological features had been described in trabeculodysgeneses as follows and are shown in Fig. 3.9a, b: 1. An elongated and flattened canal of Schlemm, with distention of the uveoscleral outflow pathway [45]. 2. Hypercellular trabecular tissue or a connective tissue band, particularly in the cribriform layer, with accumulation of proteoglycans in multilayered basement membrane-­ like material: the trabeculae appear to be thickened [45–47]. 3. An abnormal anteriorly placed insertion of the meridional (outer longitudinal) fibres of the ciliary muscle [48]. 4. An anteriorly located attachment of the iris root with internal displacement of the ciliary processes. It follows that only the features 1–3 will be identifiable in a trabeculectomy specimen and that some caution should be observed in writing the pathological report since the surgical procedure tends to compress the canal, to distort the trabecular tissue, and to displace the ciliary muscle.

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a

3  Absolute Glaucoma

The most attractive theory with regard to the pathogenesis of trabeculodysgenesis is that there is a failure of, or a delay in, remodelling in the tissues of the angle [49]. For many years congenital glaucoma was referred to as “the anterior chamber cleavage syndrome”, the implication being that there was a failure of cleavage of the mesoderm in the angle. This is now regarded as an over-simplification and it is apparent that the disorder is due to a disturbance in trabecular tissue remodelling. Trabecular cells are derived from neural crest and the meshwork is formed by cell proliferation and possibly by programmed cell death (apoptosis), in which pyknotic cell debris is endocytosed by a neighbouring cell. The adjustment of the individual components of the trabecular meshwork is also dependent on the growth of the chamber angle, iris, and cornea.

b

The Phakomatoses Malformations in the chamber angle are also associated with systemic disorders; e.g., neurofibromatosis (see Chap. 8) and the encephalo-trigeminal-angiomatosis or Sturge-Weber syndrome (see Chap. 8). The Sturge-Weber syndrome also includes meningeal, choroidal, ciliary, and iris vascular malformations and hamartomas (usually cavernous haemangiomas). Glaucoma, is difficult to treat in this condition and may be due to angle closure or to malformation in the drainage veins—episcleral or intraocular. An outside possibility is that the choroidal tumour may interfere with drainage into the supraciliary space (uveoscleral drainage). Fig. 3.9  The outflow system in trabeculodysgenesis. (a) The canal of Schlemm (cs) is present and serves to demonstrate the anterior insertion of the ciliary muscle (cm) into a hypercellular trabecular meshwork. The scleral spur is not formed (×100). (b) In this trabeculectomy specimen removed in treatment of congenital glaucoma, a Barkan’s membrane (arrowheads) lines the inner surface of the meshwork (×100)

The study of the chamber angle in enucleated end-stage buphthalmic eyes may not be rewarding because the generalised tissue stretching tends to elongate and flatten the pre-­ existing trabecular meshwork, which is frequently unrecognisable in these specimens. The pathology of trabeculodysgenesis is poorly documented because of the rarity of the condition and because so many cases have been studied at the end stage when high intraocular pressure and treatment have produced secondary changes in the meshwork. Consequently, there are some discrepancies between pathological and clinical opinions. The ophthalmologist, using gonioscopy, sees a transparent membrane (Barkan’s membrane) or a diaphanous layer of tissue in the chamber angle, likened to a “morning mist”. An intact membrane across the inner surface of the meshwork has been described only once in the morphological literature. This membrane, consisted of an extension of Descemet’s membrane, which could have been due to corneal endothelial cells sliding across trabecular beams that had been denuded of endothelial cells (Fig. 3.9b).

Secondary Open Angle Glaucoma Introduction Resistance in the outflow system increases rapidly when the trabecular interspaces are filled with particulate or cellular elements [38]. For example, red cell debris accumulating in the anterior chamber after continuing haemorrhage can block the outflow system, as can melanosomes released from necrotic melanocytes in an anterior segment melanoma. Similarly, inflammatory cells such as lymphocytes and plasma cells may be responsible for mechanical obstruction and/or damage to the trabecular endothelial cells in anterior uveitis, so-called “uveitic” glaucoma [50, 51]. Previous lens surgery with implantation of an intraocular lens may be complicated by uveitis and hyphaema (uveitis-glaucoma-­ hyphaema, or the “UGH” syndrome). Examples of this are rare but the outflow system is blocked by lymphoplasmacytoid cells and red cells, and the scleral sulcus is filled with fibrovascular tissue. Most types of particulate material (e.g., fragments of lens cortical matter) stimulate a macrophagic response and these large cells simply fill up the trabecular interspaces

Secondary Open Angle Glaucoma

63

resulting in a mechanical blockage of the outflow system (Fig. 3.10).

Iatrogenic Glaucoma While all the various forms of secondary open angle glaucoma are rare, iatrogenic disease provides some interesting problems.

Steroid-Induced Glaucoma In the treatment of ocular inflammatory disease to prevent glaucoma, topical steroids can per se bring about changes in the outflow system that cause an increase in resistance to aqueous outflow. A common example is the exacerbation of secondary glaucoma following the use of topical steroids for trabeculitis associated with iritis or iridocyclitis. The exact mechanism of steroid-induced glaucoma is not yet known. The genetics are not fully understood. The precise mechanisms of steroid induced glaucoma are not fully understood. The trabecular meshwork cells express steroid receptors and in some patients there is accumulation of extracellular matrix material particularly in the juxtacanalicular tissue and along Schlemm’s canal [52]. This consists of glycosaminoglycans as well as other proteins. There are also changes in intracellular cytoskeletal actin tangles known as CLANS ­(cross-­linked actin networks) which may contribute to stiffness of the trabecular meshwork [53]. A vast majority of cases of steroid-induced iatrogenic glaucoma can be treated successfully by discontinuance of the steroid or resection of the remainder of the repository steroid, coupled with topical glaucoma medications. However, about 1–5% of patients with steroid-induced iatrogenic glaucoma do not respond to medical therapy and require surgery, such as trabeculectomy, trabeculotomy, glaucoma drainage device, or cyclodestructive procedures [54]. Silicone Oil Two forms of surgical intervention require viscous substances (silicone oil and Healon, a hyaluronic acid substitute) for their success. A silicone oil bubble may be inserted into the vitreous to hold the retina in place during detachment surgery (see Chap. 7). Several mechanisms of silicone oil-induced secondary glaucoma have been proposed [55] as follow: 1. Overfill of the anterior chamber due to leakage of silicone oil from the posterior chamber could lead to mechanical obstruction of the trabecular meshwork. 2. Silicone oil could cause pupillary block resulting in secondary angle-closure glaucoma. 3. If the surface of the silicone bubble is disturbed, the oil at the periphery emulsifies and small globules of oil are

Fig. 3.10  A scanning electron micrograph to show the chamber angle in phacolytic glaucoma. The canal of Schlemm (cs) is open, but the trabeculae (tm) are compressed. Numerous macrophages (arrowheads) fill the space between the uveal beams (ub) (×220)

Fig. 3.11  The trabecular meshwork contains macrophages filled with silicone oil droplets (arrowheads) in an eye that was treated for retinal detachment (×1000)

found in the anterior chamber with obstruction to the outflow system (Fig. 3.11). 4. The oil stimulates an inflammatory response and these can obstruct outflow or stimulate neovascularisation

Viscoelastic Substances Commercial forms of hyaluronic acid are used widely to coat an intraocular lens implant to protect the corneal endothelium from damage as the lens is passed through the corneal incision (see Chap. 14). Viscoelastic substances are usually removed from the anterior chamber at the end of

64

the cataract extraction and intraocular lens implantation. However, any remaining viscoelastic substance can cause a transient postoperative rise in intraocular pressure, but as yet this phenomenon has not been studied by morphologists.

Melanotic Glaucoma Introduction This is not a conventional term but it is a convenient umbrella for a group of conditions in which the outflow system is blocked by melanin granules. Melanin pigment granules are released from the iris stroma or the iris pigment epithelium in large numbers, when the iris is traumatised (see previous section on laser iridotomy) and in the exfoliation syndrome (see later in this chapter) but the phagocytic capacity of the trabecular endothelial cells usually prevents a significant secondary glaucoma. Melanosomes are probably small enough to pass through the trabecular meshwork and aqueous outflow obstruction is more commonly due to the presence of melanophages in the interspaces of the meshwork. Pigmentary Glaucoma This rare form of open angle glaucoma typically occurs in young myopic adults (20–40 years old). It is essentially glaucomatous optic neuropathy associated with pigment dispersion syndrome. Posterior bowing of the iris causes rubbing of the pigmented iris epithelium against lens structures, liberating pigment, and results in pigment deposition on the posterior corneal surface (Kruckenberg’s spindle) and in the outflow system. The changes in the trabecular meshwork can lead to reduced aqueous outflow with the risk of glaucoma [56–58]. In a trabeculectomy specimen (Fig.  3.12), the outflow system is heavily laden with melanin granules, but this deposition may not be a complete explanation for increased outflow resistance [59]. In addition to pigmentation of native endothelial cells, pigment-laden macrophages are found within the intertrabecular spaces. The current understanding is that phagocytic overload of the trabecular endothelial cells leads to their death. The necrotic cells and the pigment are then removed by macrophages. The loss of endothelial cells within the trabecular meshwork causes collapse and fusion of the denuded trabecular beams, resulting in obliteration of the meshwork channels, outflow obstruction and elevated IOP [56]. Histology has revealed that there is loss of pigment epithelium within the iris trans-illumination defects [60]. Scanning electron microscopy of early defects have shown disruption of pigment epithelial cell membranes with dispersion of their pigment granule contents. As the condition progresses, there is loss of the entire iris pigmented epithelial layer within these defects [61]. The source of melanin gran-

3  Absolute Glaucoma

ules is degeneration of iris pigment epithelial cells that rupture and release melanin granules. The cause of this abiotrophic process is unknown, but it is of interest that the condition improves with time, presumably because the source of melanin, the iris pigment epithelium, becomes atrophic and is non-renewable. For this reason, it may not be necessary to perform surgery in this disease.

Melanomalytic Glaucoma As a rare event, a melanoma of the iris or ciliary body or melanocytoma arising in these tissues (see Chap. 5) can undergo a massive spontaneous necrosis. If the tumour is heavily pigmented the anterior chamber and outflow system are flooded with melanin granules and with melanophages (see Fig.  3.13). The trabecular endothelial cells are overloaded with melanin granules and this has a deleterious effect on the trabecular meshwork [62–64].

Blood Products (Haemolytic Glaucoma) The presence of fibrinolysins in the aqueous and the ability of malleable red cells to pass through the trabecular meshwork are the two important factors that prevent damage to the outflow system after haemorrhage into the anterior chamber. A sustained hyphaema (post-traumatic or post-surgical) that saturates the fibrinolytic mechanism and overloads the meshwork may proceed to glaucoma. Several mechanisms may be involved in blockage of the outflow system: 1. the volume of intact red cells and haemoglobin debris is excessive, 2. macrophages that have phagocytosed blood products may become so swollen they are unable to pass through the system (Fig. 3.14a, b), or

Fig. 3.12  The outflow system in pigmentary glaucoma (trabeculectomy specimen). The endothelial cells are packed with melanin and occasional melanomacrophages (×400)

Secondary Open Angle Glaucoma

a

65

b

Fig. 3.13  A case of melanomalytic glaucoma. (a) Melanin-containing macrophages in the chamber angle were immunostained for macrophages (Anti-CD68) using a red chromagen (×250) (b) The appearance

of the macrophages immunostained and visualized with a standard brown chromagen is difficult to interpret due to the excessive melanin pigmentation (×250)

3. lysed (or ghost) red cells that escape from the vitreous some time after an intravitreal haemorrhage (see Fig. 2.9) by passing through a rupture in the anterior vitreous face.

system is filled with large macrophages containing submicroscopic lens cell fragments (phacolytic glaucoma). Both forms of glaucoma are now uncommon due to earlier cataract surgery.

The trabecular endothelial cells are capable of haemophagocytosis and ultimately these cells contain yellow brown haemosiderin granules (Fig. 3.14a, b) and stain positively for iron (siderotic glaucoma).

Lens Protein Glaucoma The crystalline proteins in the lens substance deteriorate in response to a variety of insults, but most commonly as part of the ageing process. Sometimes the process is one of simple liquefaction and release of submicroscopic particles through the lens capsule, which produces a simple mechanical obstruction within the intertrabecular spaces [65]. If the bloodborne mononuclear phagocytic cell system “recognises” the degenerate crystalline protein [66], the outflow

Phacolytic Glaucoma Acute phacolytic glaucoma is characterised clinically by a milky exudate in the anterior chamber of an eye in which a hypermature cataract was known to be present (Figs. 3.15a, b and 3.16a, b). If the correct diagnosis of phacolytic glaucoma is made, the lens will be removed, the anterior chamber will be washed out and the condition will be cured. The diagnosis can be confirmed if the aqueous fluid is spun down and stained with periodic acid-Schiff (PAS). If the eye is enucleated, the lens capsule will form a loose bag containing milky fluid around a sclerotic nucleus and on microscopy the open angle will be filled with large PAS-positive macrophages, which at the ultrastructural level will contain disorganised lens cortical fibre debris.

66

a

b

Fig. 3.14 (a) A patient sustained bleeding from an iris vessel after trauma. In this trabeculectomy specimen the trabecular endothelial cells and macrophages contain fine granules of haemosiderin (arrowheads) (×630). (b) In a long-standing hyphaema, the inner surface of the trabecular meshwork is lined by large macrophages (m) packed with red cell ghosts and haemoglobin fragments (×5000)

3  Absolute Glaucoma

Glaucoma in the Exfoliation Syndrome (ES/PEX/PXS) The exfoliation syndrome, also referred to as the pseudoexfoliation syndrome (PXS or PEX), is a disease of unknown aetiology but is a significant cause of secondary open-angle glaucoma. It is now well-recognised as a systemic condition with significant ocular manifestations and the pseudoexfoliation material has been described in many organs including lung, liver, kidney, gallbladder and meninges [59]. PXS has a strong familial association and has a high prevalence in Iceland and Finland [67]. A number of genes have been associated with PXS, but particularly lysyl oxidase-like 1 (LOXL1) gene on chromosome 15q24.1, which demonstrated a strong association of PXS and glaucoma conferred by three single nucleotide polymorphisms [68]. These LOXL1 polymorphisms have been replicated in other populations [67]. This disease is associated with precipitation of an amorphous powdery material on the ciliary processes, the zonular fibres (Figs. 3.17a, b and 3.18a–c), the anterior surface of the lens, the anterior and posterior surfaces of the iris and in the trabecular meshwork [69, 70]. The exfoliation substance is PAS positive and by electron microscopy is seen to consist of beaded fibrillar strands within a finely granular deposit (Fig.  3.18c). Immunohistochemical studies have demonstrated the presence of components of the elastic fibre and basement membrane, such as elastin, laminin, fibrillin-1, fibulin-2, vitronectin, and amyloid-P [71–73] in the exfoliation substance. A useful diagnostic feature for the histologist is an irregular deposit that distorts the pigment epithelium on the posterior surface of the iris in a saw-tooth manner (Fig.  3.17b). Breakdown of the iris pigment epithelial cells releases melanin, which is phagocytosed by the trabecular endothelial cells: Heavy trabecular pigmentation is recognised gonioscopically and is a clinical and pathological diagnostic feature. By electron microscopy, exfoliation material can be found as plaques in the cribriform layer and as a band on the inner surface of the uveal trabecular beams. Later in the disease, the cribriform layer becomes disorganised by the deposition of the material and this leads to disorganisation of Schlemm’s canal [74]. Exfoliation substance also accumulates in the corneal endothelium [75].

Post-traumatic Glaucoma Rupture of the anterior face of the ciliary body (angle recession) and migration of conjunctival or corneal epithelium (Fig.  3.19) along the surfaces within the anterior chamber (epithelial downgrowth) are important causes of delayed glaucoma after trauma and are considered in detail in Chap. 2.

Secondary Open Angle Glaucoma

a

67

mechanical displacement of the lens causes secondary angle closure glaucoma due to pupil block. Retinoblastomas that undergo spontaneous necrosis with release of necrotic debris into the anterior chamber can present as an acute red eye accompanied by an orbital inflammation (see Chap. 5). In an aqueous tap, the necrotic cells may be mistaken for neutrophils leading to an erroneous diagnosis of endophthalmitis. Infiltration of the trabecular meshwork and outflow channels by viable retinoblastoma cells is seen only in advanced cases.

b

Iris Naevus Syndrome

Fig. 3.15 (a) The anterior segment in a case of phacolytic glaucoma. The sclerotic nucleus lies within milky liquefied lens cortex (arrowheads) and a pseudo “hypopyon” is present (arrow). (b) An aspirate from the anterior chamber in phacolytic glaucoma will reveal macrophages containing intracytoplasmic lens debris and melanosomes (PAS stain)

Schwartz-Matsuo Syndrome Obstruction to aqueous outflow can occur as a consequence of release of damaged photoreceptors from the subretinal space when there is a traumatic detachment at the retinal periphery. Electron microscopy of an anterior chamber aqueous tap will reveal photoreceptor outer segments [76–79].

Glaucoma Associated with Tumours Malignant Tumours The two important malignant tumours in the eye, malignant melanoma and retinoblastoma, can result in a raised intraocular pressure. Malignant cells derived from an iris melanoma, can spread around the chamber angle (see Chap. 5) and form an impermeable sheet on the inner surface of the trabecular meshwork [80]. Ciliary body tumours can invade and spread around the angle, but this is rare. More commonly

A naevus of the iris may break down and release melanin pigment, which overloads the phagocytic capacity of the trabecular endothelial cells. Subsequent to this, the trabecular tissue becomes hyalinised and the corneal endothelial cells grow down across the meshwork to form a secondary Descemet’s membrane (see ICE syndrome, Chap. 13). The management of glaucoma in a case in which there is a low-­ grade melanocytic neoplasia in the iris can be very difficult. Because vision is often preserved to a reasonable level and the survival rate for iris melanomas is 95% or better, there is a reluctance to enucleate [81]. If iris biopsy and/or trabeculectomy is performed the specimens should be handled with great care so that the best possible histology is available for the assessment of the degree of malignancy.

 he Cogan-Reese Syndrome T In a very rare form of glaucoma associated with a naevus (the Cogan-Reese syndrome), the corneal endothelium grows across the heavily pigmented trabecular meshwork onto the iris surface and a secondary Descemet’s membrane is laid down. Nodules of naevus cells project from the surface of the membrane and have a characteristic clinical and histological appearance (see Chap. 5). Juvenile Xanthogranuloma Acute open angle glaucoma occurs in juvenile xanthogranuloma, when the iris and anterior chamber are filled with macrophages, lymphocytes, eosinophil, neutrophils, and multinucleate cells. This extremely rare condition, which is easily recognised clinically and can be confirmed by cytology of an anterior chamber aspirate, responds rapidly to steroid therapy. Mucogenic Glaucoma Rupture of an iris inclusion cyst (which may be lined by an epithelium containing goblet cells) releases mucus into the anterior chamber. This mucus fails to penetrate the outflow system and removal by excision of the cyst and washout of

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a

3  Absolute Glaucoma

b

Fig. 3.16 (a) In phacolytic glaucoma, the iris surface is lined by large macrophages (arrowheads), which contain lens debris. These cells pack the outflow system (×160). (b) An electron micrograph of the same tis-

sue shows the macrophages (m) to contain lens cortical debris; the trabecular endothelial cells (te) have phagocytosed melanin granules (×5000)

the anterior chamber is necessary to bring the intraocular pressure back to normal [82].

of the iris, but may not be so easily recognised between the iris and the trabecular tissue when the contact is long established and the tissue is compressed (Fig.  3.20b). Nevertheless, the assumption is made that the angle has been closed by traction secondary to fibrovascular proliferation (zipping up), a process identical to that which pulls the iris pigment epithelium around the pupil (ectropion uveae). Ectropion uveae should be detected on macroscopic examination (Fig.  3.20c), but will not be present if the fibrovascular tissue crosses the pupil to form a pupillary membrane. In rare cases there may be a layer of fibrovascular tissue between the iris pigment epithelium and the dilator pupillae. While the causes of neovascular glaucoma are plentiful, the pathogenesis is not properly understood. Good evidence exists for the concept that vasoproliferative factors (principally, vascular endothelial growth factor (VEGF)) are pres-

Secondary Angle Closure Glaucoma Neovascular Glaucoma By far the commonest finding in eyes enucleated in treatment of absolute glaucoma will be the presence of closed angles with iridotrabecular and iridocorneal contact. It is usually possible to demonstrate blood vessels on the iris surface and the uveal layer of the meshwork in a H&E stain in the majority of cases (Fig. 3.20a), but a PAS stain and sometimes the Bodian stain can be helpful. The newly formed capillaries and loose fibrous tissue tend to be located on the stromal surface at the pupil and in the centre

Secondary Angle Closure Glaucoma

a

69

a

b

b

Fig. 3.17 (a) Exfoliation substance is prominent on the zonular fibres (arrows). This is also an example of cortical liquefaction around a sclerotic nucleus (black arrow). (b) The iris in the exfoliation syndrome provides an immediate diagnosis, due to the saw-tooth distortion of the pigment epithelium caused by the fluffy pink exfoliation deposits (arrows). On the anterior surface there is a continuous band of exfoliation substance(*) and the same material is seen in the walls of the iris vessels (arrowheads)

ent in aqueous fluid in conditions in which the retina is ischaemic due to degenerative disease (e.g., diabetes and central retinal vein occlusion). With that in mind, recent advances have provided encouraging results in the treatment of neovascular glaucoma with anti-VEGF [84, 85]. Other causes of neovascular glaucoma include the juvenile vasculopathy of Coats’ disease (see Chap. 4) and intraocular tumours (melanomas and retinoblastomas), which release tumour-derived vasoformative factors. The presumed presence of aqueous-borne vasoformative factors is substantiated by the finding that when neovascular glaucoma is treated by a fistulising operation or a tube implanted into the anterior chamber (e.g., Molteno implant, Ahmed valve—see later in this chapter), the redirection of aqueous is associated with regression of blood vessels in the iris in the regions that are relatively underperfused by aque-

c

Fig. 3.18 (a) In the trabecular meshwork the exfoliation substance tends to accumulate as acellular masses in the cribriform layer (arrowheads) and this is not as easy to identify as the substance on the anterior surface of the lens shown in (b), where the tree-like deposits have incorporated melanin granules. The trabecular endothelial cells also contain identifiable melanin granules. The ultrastructural features of exfoliation material within giant vacuoles are shown in (c) (a ×630; b ×250; c ×3000)

ous. Conversely, standard surgical procedures (e.g., trabeculectomy) do not control absolute neovascular glaucoma, because the fistula that drains most of the aqueous is rapidly

70

Fig. 3.19  A trabeculectomy was performed in treatment of glaucoma after a cataract extraction: The epithelial downgrowth (arrowheads) covering the trabecular meshwork (TM) was not suspected clinically (×100)

filled by fibrovascular tissue. It is useful for the pathologist to document the tissue changes in the occluded fistula in an enucleated eye, but it should be appreciated that identification of the trabeculectomy site is far from easy. The best approach is to request serial sections through a rectangular block that includes the cornea, iris, and ciliary body at the site of an iridectomy. In most cases the trabeculectomy defect is overgrown with fibrous tissue. Elsewhere the outflow system will be compressed, hyalinised, and fused. In some specimens the corneal endothelium extends across the false angle (endothelial downgrowth) and forms a secondary Descemet’s membrane on the anterior surface of the iris (Fig. 3.21). Iris neovascularisation is accompanied by bleeding in many cases and it is likely that the trabecular endothelial cells will contain identifiable iron derived from red cell debris that passed through the outflow system before the angle was closed. At the end stage, exudation from the vessels on the surface may lead to a yellow “pseudo” hypopyon in the anterior chamber, which contains cholesterol crystals and neutral lipids (Fig. 3.22a, b). The irritant lipids induce a giant cell granulomatous reaction in the exudate around the cholesterol clefts and a secondary iritis.

Inflammatory Disease Secondary angle closure glaucoma can occur as a complication of inflammatory disease of the cornea, iris, and ciliary body. In the absence of keratitis, “iridocyclitis” is usually a chronic non-granulomatous process, which is of unknown aetiology and is effectively controlled by topical steroids. Angle closure is probably dependent on: 1. A relative hypotonia with shallowing of the anterior chamber and narrowing of the angles.

3  Absolute Glaucoma

2. Release of fibrin from the inflamed vasculature: Inflammation also promotes neovascularisation on the iris ­surface. Fibrin forms a framework for fibrovascular tissue that originates in the iris stroma and proliferates to fill the angle. Secondary angle closure glaucoma was previously secondary to corneal disease, principally herpes simplex keratopathy, which in enucleated eyes was found to be complicated by ulceration, perforation, and hypotonia. The use of effective topical antiviral agents has minimised these complications. Glaucoma in Fuchs heterochromic iridocyclitis is dealt with in Chap. 6.

Retinal Detachment While retinal detachment from whatever cause may leave the anterior segment undisturbed in the majority of cases, it is not uncommon for pathologists to see enucleated eyes treated for detachment that have progressed to neovascular glaucoma. Factors often involved in angle closure after retinal detachment include anterior displacement of the lens with pupil block or displacement of the lens by fibrosis in the vitreous. Detachment of the retina is a rare complication of lens surgery and this form of primary intervention pathology must also be documented. Iris neovascularization and NVG associated with rhegmatogenous retinal detachment is reported to be mediated by the release of angiogenic factors from the detached retina or retinal pigment epithelium, especially when detachment is complicated by proliferative vitreoretinopathy [86].

Tumours Any uveal or retinal tumour that is large enough to cause retinal detachment by leakage of proteinaceous fluid into the subretinal space can cause secondary angle closure glaucoma by pupil block or release of tumour- or retina-derived vasoproliferative factors.

Trauma In an enucleated eye, the changes of angle-closure glaucoma are just as likely to be encountered after surgical intervention as after civil trauma and the following complications may be responsible: 1. Poor apposition of a corneoscleral wound with collapse of the anterior chamber and the formation of permanent iridocorneal contact (synechia formation).

Secondary Angle Closure Glaucoma

71

a

b

c

d

e

f

Fig. 3.20 (a) In the earliest form of neovascularisation of the chamber angle, a thin layer of capillaries (arrowheads) grows on the iris surface and over the meshwork. Reference to the scleral spur (ss) confirms that the angle is open (×160). In (b), the process is advanced and a thick band of fibrovascular tissue (arrowheads) has fused the iris to the cornea to form a false angle (×250). (c) Macroscopic appearance of neovascular glaucoma with closed angles. A membrane is present on the surface of the iris and there is displacement of the iris pigment epithe-

lium around the pupil (Reproduced with permission from Sehu and Lee [83]). (d) The angle is closed by fibrovascular tissue, which lines the iris surface: Note location of the scleral spur (arrowhead) (×40). (e) In the pupillary part of the iris, the fibrovascular membrane (fv) bends the sphincter pupillae (sp) as the pigment epithelium is drawn around the pupil (×250). (f) In this case the fibrovascular membrane crosses the pupil to form a pupillary membrane (pm)

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3  Absolute Glaucoma

2. Contraction of a fibrous downgrowth from a corneal wound with the formation of iridocorneal adhesion. 3. Prolapse of an intact anterior vitreous face into the pupil after removal of an intact lens; this complication can now be treated by vitrectomy. 4. Prolapse of the anterior vitreous face and lens after glaucoma surgery leads to a vitreous plug in the posterior opening of a peripheral iridectomy—this process is relevant in the pathogenesis of malignant glaucoma (see next section).

ocular pressure (to levels of 80 mmHg or more) after surgery for angle closure glaucoma or for cataract extraction. The pathogenesis is multifactorial, but an important component is displacement of the anterior vitreous face, which blocks the iridectomy orifice in glaucoma surgery or the pupil after lens surgery. Aqueous fluid is redirected into the vitreous, which reinforces the pressure on the iris. This acute emergency requires prompt treatment by laser “vitrotomy” (i.e., rupture of the anterior vitreous face), vitrectomy, and/or lens extraction.

Malignant Glaucoma

Iridocorneal-Endothelial (ICE) Syndrome

Malignant glaucoma [87, 88] is a term that is variously interpreted, but is best defined as a precipitous rise in intra-

A trabeculectomy specimen and an iridectomy specimen may be submitted with the appellation “ICE” syndrome [89]. While there are several separate entities in one definition of this syndrome—viz. “iris naevus (Cogan-Reese) syndrome”, “Chandler’s syndrome” and “essential iris atrophy”—they have in common, corneal endothelial disease (see Chap. 13), iridocorneal adhesion, and “Descemetisation”; i.e., endothelial downgrowth across the trabecular meshwork. It is usually unilateral, nonfamilial, and typically occurs in young adult females. In Chandler’s syndrome [90] and in essential iris atrophy [91], the outflow system is compressed around non-pigmented endothelial cells and lined internally by a secondary Descemet’s membrane. In the iris naevus syndrome, the trabecular endothelial cells contain melanosomes, and small nodules formed by spindle cells are found in the anterior iris stroma. The iris is normal in Chandler’s syndrome, but in essential iris atrophy there are defects in the stroma. Another definition of ICE syndrome (the iridocorneal endothelial syndrome) is based on the presence of speckling of the corneal endothelial cells when examined by

Fig. 3.21  Neovascularisation has formed a false angle as evidenced by the presence of Descemet’s membrane (D) and the endothelium (arrowhead) has spread on to the neovascular membrane on the iris surface (endothelial downgrowth) (×300)

a

Fig. 3.22 (a, b) The anterior segment in end-stage neovascular glaucoma. The anterior chamber is filled with fibrous tissue containing neutral fat (oil red O positive) and birefringent cholesterol crystals (arrows).

b

Note the migration of the iris pigment epithelium around the pupil (ectropion uveae) (Frozen section embedded in gelatin)

Tissue Effects of Glaucoma

specular microscopy. Glaucoma associated with ICE syndrome is usually managed successfully with glaucoma filtering surgery if done early. However, endothelialization of the fistula by the abnormal corneal endothelium remains a potential cause of failure [92, 93].

Tissue Effects of Glaucoma Acute Glaucoma The tissue response in glaucoma depends upon the rapidity of the rise in pressure and the level achieved. Thus in acute angle closure with a pressure rise to 80  mmHg within 24–48  h, the reflex circulatory disturbance leads to breakdown of the endothelial barriers in the cornea, the uveal tissues, the retina, and the disc.

Cornea The corneal endothelial pumping system (see Chap. 13) is “decompensated” by an acute pressure rise, and in acute angle closure glaucoma, rapid accumulation of fluid in the stroma explains the classic visual symptoms of blurring and haloes around street lamps at night. The histological demonstration of corneal oedema is difficult because paraffin processing produces artefactual clefts between the stromal lamellae. By electron microscopy, the interspaces between

Fig. 3.23  Necrosis of a keratocyte in the cornea in acute oedema due to a rapid rise in intraocular pressure (EM ×2240)

73

the corneal collagen fibres are widened and the keratocytes are initially swollen by cytoplasmic vacuolation; later the cells degenerate (Fig. 3.23). For the histological diagnosis of corneal oedema, more credence can be placed upon the presence of prominent intercellular spaces within the epithelial basal layers, which may also show cytoplasmic swelling, lucency, and a tendency to detach from the basement membrane (Fig. 3.24).

Iris Reflex vascular spasm leads to sector infarcts within the iris stroma and dilator muscle; this explains the clinical findings of distortion or peaking of the pupil in acute glaucoma. At a later stage there is focal iris stromal atrophy. Lens As a consequence of high pressure and metabolic disturbance, the lens epithelium and the underlying lens fibres undergo focal necrosis (Glaukomflecken). With time these small areas of opacification become buried by further growth and extension of lens fibres from cells at the equator and are characteristic on clinical examination. These necrotic lens epithelial and fibres cells have rarely been demonstrated on histology [94, 95].  etina and Optic Nerve R Retinal oedema occurs in acute glaucoma, but the process is not always easy to recognise histologically, the appearances being similar to those seen in hypotonia. Papilloedema is more easily detected macroscopically and microscopically (Fig. 2.10): The process is not due to accumulation of interstitial fluid but to axonal swelling consequent on a disturbance in axoplasmic flow in the neurones in the retinal ganglion cell layer as they pass through the optic disc. Slowing of axoplasmic flow could be due to compression of the prelaminar capillary bed or to distortion and bowing of

Fig. 3.24  Acute oedema in the corneal epithelium in glaucoma: The swollen cells are paler staining and separating from each other and the basement membrane (arrowhead) (×400)

74

the lamina cribrosa. It is possible to detect axonal disruption in the retrolaminar part of the optic nerve in some cases of acute glaucoma (Fig. 3.25a–d). This may be related to the anatomical distribution of blood flow to the optic nerve head. The retrolaminar region is the watershed zone between the supply from the posterior ciliary arteries and the meningeal branches of the ophthalmic artery, so it could be assumed that pressure on the prelaminar vascular bed is responsible for the retrolaminar infarction. After a prolonged exposure to high intraocular pressure, infarction and liquefaction occurs in the retrolaminar part of the optic nerve and the empty spaces between the pial septae become filled with hyaluronic acid, which seeps in from the vitreous (Schnabel’s cavernous degeneration). At a later stage this results in bowing of the lamina cribrosa posteriorly and advanced cupping (Fig. 3.26).

Tissue Changes in Long-Standing Glaucoma The following abnormalities are to be anticipated in any enucleation specimen labelled “absolute glaucoma”.

3  Absolute Glaucoma

Cornea Recurrent oedema and separation (somehow) stimulate focal subepithelial vascular and fibrous invasion without erosion of Bowman’s layer. However, if pre-existing separation of the epithelium has rendered the cornea susceptible to secondary infection, inflammatory cell infiltration will be found in the stroma and Bowman’s layer will have been destroyed by previous ulceration. The corneal periphery is usually invaded and destroyed by fibrous tissue ingrowth with an accompaniment of lymphocytes and macrophages (in conventional terminology “peripheral degenerative pannus”) (Fig. 3.27). Amorphous hyaline bodies, which stain red with the Masson trichrome stain, and are called hyaline or keratinoid bodies, may also be found in the superficial corneal periphery, but this is probably a non-specific ageing change (Fig. 13.60 in Chap. 13). Deposition of blue-staining granular calcium salts (see Chap. 13) occurs in Bowman’s layer in the horizontal plane (band keratopathy) in some cases of long-standing glaucoma (Fig. 1.3). This is probably secondary to an anterior uveitis associated with chronic keratitis, but the mechanism for calcium and phosphate deposition has not been elucidated.

a

b

c

d

Fig. 3.25 (a, b) Low power and high power of a glaucomatous nerve head in acute glaucoma stained with the Bodian stain to show axonal disruption (arrow) in the retrolaminar region (rl). (c, d) More advanced

axonal disruption with the formation of swellings in the interrupted axons (cytoid bodies) in the retrolaminar region (arrows). Some bundles of axons survive (arrowhead) (Bodian stain)

Tissue Effects of Glaucoma

After secondary infection with superadded ulceration, be it acute or chronic, bacterial and fungal forms are not commonly observed in enucleated eyes, because intensive antibiotic therapy is standard treatment. Paradoxically, if the treatment was by atropine and steroids to “keep the eye quiet” and pain free in prolonged neovascular glaucoma, it is sometimes possible to encounter cases in which there is uninhibited proliferation of bacteria (crystalline keratopathy), fungi, or acanthamoebae (see Chap. 13), with only a token inflammatory response.

Chamber Angle In absolute glaucoma, the angle will almost certainly be closed and it is almost equally predictable that the primary cause for glaucoma will not be apparent without a clinical history. Endothelial Downgrowth It is often possible to identify a secondary corneal endothelial downgrowth across the false angle onto a neovascular membrane on the iris: this leads to deposition of a secondary

Fig. 3.26  Extremely advanced cupping of the optic disc (×40)

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Descemet’s membrane and indicates the long-standing nature of the process (Fig.  3.21). The endothelial downgrowth may extend for some considerable distance; i.e., around the pupil and onto the lens or the anterior vitreous face in an aphakic eye. Outflow System After prolonged iridotrabecular contact, the intertrabecular spaces and the canal of Schlemm are obliterated and the collagenous tissues are fused and hyalinised. The location of the trabecular meshwork is aided by the PAS stain, which illustrates the limit of Descemet’s membrane. Occasionally there is some recognisable trabecular tissue and the interspaces will contain inflammatory round cells and iron-containing endothelial cells. Frequently, the canal of Schlemm is replaced by fibrovascular tissue. The Bodian stain can be useful in identifying the scleral sulcus and the trabeculae.

Iris Long-standing glaucoma leads to atrophy and replacement fibrosis of the iris stroma. If there is corneal inflammation, there may be a dense lymphocytic and plasma cell inflammatory infiltrate in the iris stroma. In the commonest circumstance, a neovascular membrane with variable fibrosis will

Fig. 3.27  The cornea in long-standing angle closure glaucoma. Note the location of the scleral spur (ss). The peripheral cornea is invaded by a fibrous ingrowth (fi) (×40)

76

be present on the anterior iris surface and the pigment epithelium will be drawn around the pupil with a bowing of the sphincter pupillae. Pre-existing adhesions between the posterior iris surface and the lens are identified only rarely and if present should indicate a primary angle closure or inflammation-­induced attachment. It should be noted that adhesions between the iris and lens can be disrupted artefactually if the globe is opened carelessly. If the iris pigment epithelium is vacuolated and contains PAS-positive granules, diabetes will be the accompanying primary disease (see Chap. 4).

Ciliary Body Inflammatory cell infiltration in the stroma of the ciliary body is rarely impressive in advanced glaucoma. The ciliary muscle becomes atrophic and there is replacement fibrosis of the oblique and inner circular muscle fibres; this is an accentuation of normal ageing. The outer meridional fibres of the ciliary muscle are often preserved and this is not easily explained. The ciliary processes are usually described as stunted or atrophic in advanced glaucoma, but it must be remembered that the section may have passed through a trough between the ciliary ridges. Replacement fibrosis of the capillary bed with thickening of the basement membrane of the ciliary processes are features of ageing, but when marked thickening of the PAS positive basement membrane occurs, diabetes should be suspected. Lens Non-specific changes in the lens matter will inevitably be present; this pathology is dealt with in Chap. 14. The abnormalities can be summarised as follows: 1. Sclerosis of the nucleus; i.e., replacement of the normal lens fibres by amorphous granular material. 2. Focal disintegration of the cortical fibres with the formation of fluid filled clefts. 3. Rounding of residual fibres to form globules. 4. Migration of swollen epithelial cells (bladder or “Wedl” cells) to the posterior cortex. Previous iridocyclitis and corneal disease may have induced fibrous metaplasia in the anterior lens epithelial cells. Focal calcification of cortical substance may occur in glaucoma but is more often a feature of hypotonia. Vitreous Since the commonest cause of “absolute” glaucoma is retinal vascular disease with intravitreal neovascularisation, the vitreous will most probably contain blood and haemomacrophages. These elements often lie against the inferior part of

3  Absolute Glaucoma

the pars plana in the vitreous base and the source of bleeding is probably the optic disc. Fibrous strands are derived from pre-retinal glial membranes or neovascular membranes and there may be partial or total posterior detachment of the vitreous. In general, the vitreous is unaffected in glaucoma but central liquefaction and peripheral condensation are non-specific but associated features.

Retina It is generally accepted that the primary site of axonal damage in primary open angle glaucoma is the prelaminar temporal part of the optic disc. Consequently, in an uncomplicated case, ascending retinal atrophy will be confined to the nerve fibre layer and the ganglion cell layer. Initially the ganglion cells become atrophic and rounded (Fig. 3.28) and later there may be some glial cell reaction in the inner retina (Fig. 3.29). Primary open angle glaucoma is often associated with arteriolosclerosis and venulosclerosis and is complicated by central retinal vein occlusion with secondary neovascular glaucoma. In that case transneuronal degeneration is accelerated by ischaemia and will be manifest as atrophy of the inner nuclear layer and inner plexiform layer. However, in many routine globes it is common to find good preservation of the photoreceptor layer and the pigment epithelium. Gliosis is not a feature of retinal atrophy in uncomplicated glaucoma. Optic Disc and Optic Nerve The Pathogenesis of Glaucomatous Optic Atrophy Because of the importance of diagnosis in primary open angle glaucoma, the nature and assessment of early optic atrophy (manifest on ophthalmoscopy by cupping of the optic disc) has been the subject of intense investigation for decades [89, 90, 96–99]. Various controversies have arisen with regard to pathogenesis, and disagreements have been compounded by an absence of strictly defined criteria for the identification of early cupping and a lack of human tissue for pathological investigation at an early stage in the disease. A vertical diameter of the cup relative to the horizontal diameter of the disc is greater than 0.6 in POAG, but it is important that this measurement is related to the overall dimensions of the optic disc. Clinical investigations have established that the absolute size of the neuroretinal rim is very important when correlation with visual field loss is under investigation [91]. For example, a patient with a large cup may not have a field defect if the neuroretinal rim is large. With the recent advances in imaging technology it is possible to assess the structure of the optic nerve head (ONH) and retinal nerve

Tissue Effects of Glaucoma

77

Fig. 3.29  A more advanced stage of atrophy in which glial cell proliferation (g) is occurring in the inner retina (×250)

Fig. 3.28  Early glaucomatous atrophy in the retina: The ganglion cells (arrowheads) are atrophic and the nerve fibre layer is reduced in thickness (×250)

fibre layer (RNFL) in  vivo using confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography (OCT). These devices provide a quantification of the neuroretinal rim area (in mm2) or RNFL thickness (in μ [mu] m). Changes can then be assessed on repeated scanning. However, the imaging measurements of neuroretinal rim in the ONH and of thickness of the RNFL also include non-neural elements such as lamina cribrosa, glial tissue, and blood vessels. These variables therefore influence the measurement integrity of the quantification of retinal ganglion cells [92]. Hence, caution should be used when interpreting imaging results. From the pathological point of view, the early recognition of atrophy in the nerve fibre layer at the disc is difficult, although in most specimens the disease is advanced (Fig. 3.30a, b). It is important to appreciate the volume of tissue that is present in this region in the normal disc and how easy it is to fail to appreciate the neural atrophy (Fig. 3.31a, b). In routine horizontal cuts, the atrophy may not be apparent, because the earliest axonal loss is sectorial, more specifically in the prelaminar region above and below the standard horizontal PO plane and temporal to a standard vertical section. The fallout of axons is quantitative and the morphological studies such as those of Quigley and his colleagues [97] have demonstrated that the largest axons in the optic nerve are the most sensitive to ocular hypertension. The tissue shrinkage is deceptive when the nerve is studied with an axon stain (Bodian), because the

surviving axons become condensed; thus the concentration or density of axons per unit area may not appear to be reduced. In the routine laboratory, the enucleated glaucomatous eye, however, exhibits obvious cupping and the neural tissue shrinks down to the lamina cribrosa, which becomes bowed posteriorly. Not uncommonly, if the case is complicated by ischaemic disease, the cupped disc is filled with proliferating fibrovascular tissue. In longitudinal and transverse sections through the retrolaminar part of the optic nerve, axonal loss is accompanied by demyelination. The nerve shrinks in Toto and the meninges are folded around an enlarged subarachnoid space. Thickening of the pial septae around the atrophic nerve bundles provides the most characteristic feature of this secondary optic atrophy. The pathogenesis of optic atrophy in glaucoma remains a contentious subject. Abundant evidence has been produced in support of the important role that oxidative stress plays in the pathogenesis of primary open-angle glaucoma, damaging both the endothelial cells of the trabecular meshwork as well as the optic nerve head [20, 21]. The prelaminar part of the optic nerve is supplied by a capillary arcade derived from an interrupted vascular circle (of Zinn-Haller) that is fed by a dozen or so short posterior ciliary arteries penetrating the sclera around the optic nerve (Fig. 3.32). It seems reasonable to argue that such a vascular system, in the elderly, could be susceptible to a diminution of blood flow by degenerative occlusive disease in the ophthalmic and ciliary arteries. If the arterial perfusion thresholds are lowered, the capillary bed would become unduly sensitive to the well-documented diurnal fluctuations in levels of intraocular pressure that might otherwise be harmless (the intraocular pressure is highest in early morning). Recent studies had shown that vascular dysregulation of the vasculature supplying the optic nerve and surrounding retinal tissue is an important factor in the pathogenesis of glaucoma, in particular POAG including

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3  Absolute Glaucoma

NTG [93–95]. It is postulated that the vascular abnormalities are associated with an imbalance of certain vasoactive fac-

a

b

tors, especially ET-1 (endothelin 1) and NO (nitric oxide), which are mainly produced by the vascular endothelium and regulate blood flow by acting upon the surrounding smooth muscle cells [100–103]. It must also be assumed that there are sectors of the vascular bed in the optic disc that are more prone to ischaemia, because an explanation must be provided for the characteristic arcuate areas of field loss (scotomata). A useful clinical observation is that the field defects are preceded by haemorrhages in the disc. An alternative theory is that a higher than normal pressure in the eye interferes with the flow of cytoplasmic constituents (axoplasmic flow) in certain bundles of axons (from the magnocellular ganglion cells) as they pass through the lamina cribrosa. Axoplasmic flow from the ganglion cells in the retina to the lateral geniculate body can be rapid (15 mm/h) or slow (1–2  mm/day), and the retrograde return is about 2 mm/h. Mild distortion of the axons as they pass through the lamina cribrosa as it becomes displaced (bowing) posteriorly could lead to progressive ascending atrophy. Again it is necessary to postulate that there will be sectors within the optic disc that will be more sensitive to pressure. The variation in the size of the spaces in the lamina cribrosa for the superior and inferior bundles that pass to the optic nerve lends some support to this hypothesis [104]. It seems likely that the various hypotheses for the pathogenetic processes will prove to be inter-dependent.

Choroid

Fig. 3.30 (a) Moderate glaucomatous cupping of the optic nerve head with peripapillary atrophy. The macula is atrophic (arrow). (b) Severe glaucomatous cupping of the optic nerve head with peripapillary atrophy. The macula is atrophic (arrow) and the retinal vessels are hyalinised (NB: this is a vertical section)

a

The choroid, choriocapillaris, and retinal pigment epithelium are able to withstand the effects of raised intraocular pressure and it is only at the very latest stages that atrophy and fibrosis are observed. Choroidal pathology is often most striking when there is gross stretching of the sclera in b

Fig. 3.31 (a) A normal optic disc to show the pronounced nasal bulge of the axons (arrow) as they pass into the prelaminar part of the optic nerve (×40). (b) In severe glaucomatous optic atrophy the prelaminar part of the nerve is atrophic and the lamina cribrosa (lc) is bowed posteriorly (×40)

Tissue Effects of Glaucoma

79

Intraocular pressure

Fig. 3.33  When the sclera stretches in advanced glaucoma the retina (gr) becomes thin and gliotic and the choroid (ch) equally so (×100)

Central retinal artery

Posterior ciliary artery

Fig. 3.32  A diagram to illustrate the contribution of the posterior ciliary artery circulation to the nutrition of the retrolaminar part of the optic nerve. The anastomosis is with the meningeal branches of the ophthalmic artery. The central retinal artery does not make a contribution to the retrolaminar region in the majority of individuals

staphyloma formation (Figs.  3.33 and 3.34a–f). Genuine thinning of the choroid by mechanical compression is more common in the younger eye subject to high pressure.

Corneoscleral Envelope An acute rise in pressure leads to rupture of Descemet’s membrane, which becomes rolled up: these tears are visible clinically (Haab’s striae). In prolonged glaucoma, staphylomas tend to occur at sites where there are pre-existing canals in the envelope; e.g., the routes for the long posterior ciliary arteries and the vortex veins in the posterior segment (Fig. 3.34a–f). In the anterior part of the globe, corneal, limbal (intercalary), and ciliary staphylomas appear to be abetted by pre-existing inflammatory destruction of the sclera with fibrous replacement. If the cornea is not lined by uveal tissue the abnormal stretching is referred to as a keratectasia.

Evolution of End-Stage Pathology At the conclusion of a descriptive pathological report, it is worthwhile to consider the possibilities that could have led to the final outcome. Indeed this exercise is sometimes

n­ ecessary, because the clinician may not have a detailed past history to hand at the time of enucleation: This is a generous explanation for the minuscule information provided by some clinicians on request forms. For example, primary open angle glaucoma is commonly complicated by central retinal vein occlusion, which in turn causes neovascular glaucoma. Demonstration of a trabeculectomy suggests that the initiating disease was POAG because neovascular glaucoma secondary to vein occlusion would not be an indication for a trabeculectomy and would probably be treated by a Molteno implant (see later in chapter). Identification of severe hyalinisation of the retinal blood vessels with haemorrhages and exudates (see Chap. 4) would suggest that primary degenerative disease or inflammatory disease of the retinal vasculature had predisposed to central retinal vein occlusion and subsequent neovascular glaucoma. In neovascular glaucoma, there is frequently secondary corneal oedema, sometimes with ulceration, but it should not be forgotten that primary corneal disease causes iridocyclitis, which leads to secondary angle closure and neovascularisation. It would not be wise to take odds on primary acute closed angle glaucoma as an initiating cause of the final scenario, because of the relative rarity and the fact that this form of glaucoma is successfully treated. Acute closed angle glaucoma is not commonly complicated by central retinal vein occlusion and such a specimen would be a rarity.

Complications in the Surgical Treatment of Glaucoma This aspect will be seen by the pathologist in two circumstances. In surgical enucleations, the procedure(s) will most probably have failed and the site of intervention will be difficult to demonstrate due to fibrosis or tissue prolapse. Serial sections may be necessary in such a case. Occasionally drainage surgery may be followed by endophthalmitis, and lysis of the residual scar tissue will obscure the alterations brought about by surgery. It should

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3  Absolute Glaucoma

a

b

c

d

e

f

Fig. 3.34  The effects of prolonged glaucoma on the corneoscleral envelope. (a) The ruler demonstrates the overall enlargement (30 × 30 × 30 mm) of this buphthalmic globe in a child. (b) In an adult, long-standing glaucoma leads to a posterior staphyloma and patches of chorioretinal atrophy (arrowheads). (c, d) Glaucoma developed after

lens surgery (arrow) and this led to the formation of a large peripheral temporal staphyloma (arrowhead). (e, f) Glaucoma developed in this aphakic eye and a keratectasia formed at the site of surgery (white arrow and black arrowheads). Exfoliation substance is present on the ciliary processes (white arrowheads)

Complications in the Surgical Treatment of Glaucoma

Fig. 3.35  A historical specimen showing a simple fistula (f) after a Scheie’s procedure with an updrawn wick of iris (arrows). This procedure has now been superseded (×40)

be stressed that autopsy specimens can be very useful for demonstrating successful surgery and even without notification, iridectomies and filtration blebs can be recognised easily in the cadaver.

Trabeculectomy The procedure referred to as a “trabeculectomy” has already been described (see previous). Histology of failed trabeculectomies in surgical enucleations is now rarely encountered. Failed trabeculectomies usually reveals incarceration of the iris root or the ciliary processes (Fig. 3.35). The procedure was designed for the treatment of primary open angle glaucoma but subsequently this successful means of control of intraocular pressure was applied to the treatment of angle closure glaucoma and congenital glaucoma. In children and races in which keloid formation occurs readily (Fig. 3.36a, b), successful drainage can be frustrated by fibrosis of the bleb [105, 106]. The most common means of dealing with trabeculectomy failure due to fibrosis is using antimetabolites such as mitomycin C and 5-fluorouracil which act as antifibrotic agents during wound healing [107]. The response may be the formation of an overlarge bleb, which may leak intermittently and require excision; histological examination

81

will reveal oedematous collagenous tissue with a thin overlying epithelium (Fig.  3.36b). Newer alternatives to antimetabolites include biodegradable collagen matrix implants which acts as a scaffold controlling wound healing [108]; biological tissue adhesives such as fibrin glue which alter healing of blebs and can be used to control bleb leaks [109]; and amniotic membrane which can suppress fibroblast production, inhibits proinflammatory cytokines and traps inflammatory cells [110]. For the surgeon, one risk of the trabeculectomy procedure is haemorrhage following a cut across the major circular artery of the iris. The complication of bleeding can be better avoided by a corneal approach. The presence of a bleb over the site of the fistula is an indication of the success of drainage, but there is an attendant risk of infection of the bleb and this may in rare cases be accompanied by an endophthalmitis (Fig. 3.37).

 iliary Body Surgery: Cyclodestructive C processes Historically incision at the scleral spur could open 20°–30° of the supraciliary space and allow this space to be used for drainage. This resulted in complications such as hypotony. Later techniques involved destruction of the ciliary processes were introduced. These included cyclodiathermy, cyclocryotherapy and cyclophotocoagulation. Uncommonly used now, cyclocryotherapy and cyclodiathermy use cold or heat to ablate the ciliary processes (Fig. 3.38). The pathologist is more likely to observe failures rather than successes in this treatment modality. Freezing of the tissues results in thrombosis of the vascular bed in the tissue. Histology (Fig. 3.39) reveals necrosis of both layers of the ciliary epithelium as an acute response followed by atrophy and fibrosis of the pigment epithelium at the later stages [111].

Other Cyclodestructive Techniques Non-invasive (trans-scleral) lasers to destroy the ciliary epithelium are now commonplace. Initially this was with neodymium-­YAG (Nd:YAG laser). Nd:YAG laser CPC has been shown to destroy less tissue compared with cyclodia-

82

a

3  Absolute Glaucoma

sues and less damage to the surrounding ocular tissues [112]. Initially this was performed as a continuous delivery of laser energy but this treatment is now usually micropulsed as this causes less severe tissue damage and scar formation.

Laser Trabeculoplasty

b

Fig. 3.36 (a) Massive fibrosis in a trabeculectomy bleb. (b) The presence of rarefied cystic spaces (arrows) is an indication of successful drainage in a trabeculectomy bleb

The development of lasers and optical systems that can deliver energy with the appropriate spot size (100–200 μm) to produce photocoagulation scarring of the iris root with traction on the trabecular meshwork has provided an alternative approach to medical and surgical treatment [113]. The pressure lowering effect is not always sustained, and later a trabeculectomy may be performed at the treated site or ultimately the globe may be enucleated; a careful and comprehensive study of the treated area will be of great value. Argon laser which provides a continuous wave (CW) green light was historically the preferred laser treatment. This laser is absorbed by pigmented tissue with release of heat and destruction of the tissue. The application of multiple circumferential argon laser burns to the inner surface of the trabecular meshwork initially brings about a fall in intraocular pressure in POAG, but later may lead to fibrosis (Fig. 3.41). The likeliest possibility is that the production of scar tissue on the inner surface of the meshwork opens the intertrabecular spaces by internal traction. Another interesting theory for the success of the procedure is that the trabecular endothelial cell population is stimulated to divide by the need to phagocytose debris and by the need to cover the surfaces of the denuded trabeculae. There has been a shift from ALT to selective laser trabeculoplasty. Using this procedure 360º of the trabecular meshwork is treated with similar efficacy to the 180º ALT in lower IOP. This procedure can then be repeated annually as required. This treatment can be micropulsed similar to cyclophotocoagulation to reduce the build-up of thermal energy and minimise tissue damage [114, 115].

Glaucoma Drainage Device Fig. 3.37  Some 15 years after a trabeculectomy, the bleb (b) became infected and the bacterial infection spread into the vitreous (v). The globe collapsed as a consequence of loss of intraocular pressure and an attempt to remove vitreous for bacteriological examination. The lens has prolapsed and pushed the iris against the cornea. Histology revealed Gram-positive diplococci in the vitreous abscess

thermy or cyclocryotherapy (Fig. 3.40) [111]. Diode laser is now more commonly used. This provides a wavelength that is mostly absorbed by the melanin pigment of the ciliary epithelium, causing thermal destruction of the ciliary body tis-

In refractory glaucoma where medical and fistulating procedures have failed the intraocular pressure may be controlled (and enucleation avoided) by the implantation of a glaucoma drainage device. Glaucoma drainage device implantation is usually indicated when trabeculectomy has failed or is most likely to fail (e.g., neovascular and uveitic glaucoma). Molteno tube implant was the first established, involving the insertion of a fine plastic drainage tube (or seton) into the anterior chamber and leading it into the episclera. Initially, this procedure results in hypotonia and later, a failure to con-

Complications in the Surgical Treatment of Glaucoma

83

Fig. 3.38  Very extensive diathermy has destroyed the ciliary body (arrow) and iris, producing an angle closure. The lens is displaced into the anterior chamber Fig. 3.40  Obliteration of the ciliary body by YAG cyclodestruction had destroyed the ciliary processes and stimulated a fibrous ingrowth into the vitreous (*)

Fig. 3.39  The ciliary body after cyclocryotherapy. The pigment epithelium (pe) is necrotic and there is neovascularisation growing into the vitreous. The stroma of the ciliary body is oedematous due to hypotonia (×100)

trol pressure is due to fibrosis into the orifice. Molteno has shown that hypotonia can be avoided by joining the anterior chamber tube to a plastic disc embedded in the episclera for some weeks before the drain is established (Fig. 3.42a, b). Once there is a fibrous capsule around the plastic disc, the connecting tube can be inserted into the anterior chamber without excessive hypotonia [116]. This procedure is also complicated by fibrosis in some individuals so that antimetabolites (steroids and colchicine) may be required to suppress fibroblastic activity. When the anterior tube is in place, failure of drainage may be due to fibrous tissue growing into the tube (Fig. 3.43). Following the establishment of Molteno tube implant, commonly used glaucoma drainage devices now include the Ahmed glaucoma valve (AGV, New World Medical, Cucamonga, CA), the Baerveldt glaucoma implant (Abbott Medical Optics, Abbott Park, IL), and the Molteno implant (Molteno Ophthalmic Limited, Dunedin, New Zealand). These implants share a common design, consisting of a tube that shunts aqueous humour from the anterior chamber to an end plate located at the equatorial region of the globe. They differ in terms of materials and design features, including the presence or absence of a valve (Molteno and

Fig. 3.41  After four treatments with the argon laser, the outflow system (arrow) was fused and the angle deeply recessed

Baerveldt implants are non-valved) that limits aqueous flow through the device if the intraocular pressure (IOP) becomes too low [117, 118]. Potential complications with glaucoma drainage devices include hypotonia, wound dehiscence or leakage, endophthalmitis, and epithelial ingrowth into the anterior chamber. The management of a specimen containing a glaucoma drainage device is not easy because the plate is embedded in dense fibrous tissue, which is difficult to separate from the plastic plate. The drainage tube is made from soft plastic that dissolves in standard processing solutions, but the orientation of the specimens will not permit a section that passes along the full length of the tube. In a successful implant the connective tissue around the plastic disc contains necrotic debris and there may be a low-­ grade inflammation in the adjacent sclera [119]; this suggests that stagnation of metabolites occurs in the aqueous that has accumulated in the reservoir. Excessive fibrosis and endothelial migration may occur in the bleb over a drainage seton [120].

84

3  Absolute Glaucoma

a

feature if the clinical information concerning the injection is withheld [121].

References

b

Fig. 3.42 (a) One part of a Molteno implant is a large plastic disc (*), which is embedded in dense fibrous tissue in the equatorial sclera. (b) The other part of the implant is a fine plastic tube, which is passed into the anterior chamber (arrow)

Fig. 3.43  After paraffin processing the plastic drainage tube of the Molteno implant dissolves. The space occupied by this Molteno tube in the anterior chamber is surrounded by fibrous tissue, which has also blocked the orifice (×100)

Retrobulbar Alcohol As a last resort an injection of ethyl alcohol into the muscle cone on the lateral side of the optic nerve, “denervates” the ciliary ganglion and abolishes the pain of glaucoma. The injection can produce a giant cell lipogranulomatous inflammatory reaction in the retro-ocular fat and can be a puzzling

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3  Absolute Glaucoma 93. Grieshaber MC, Mozaffarieh M, Flammer J.  What is the link between vascular dysregulation and glaucoma? Surv Ophthalmol. 2007;52:S144–54. 94. Pasquale LR.  Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol. 2016;27:94–101. 95. Nicolela MT. Clinical clues of vascular dysregulation and its association with glaucoma. Can J Ophthalmol. 2008;43:337–41. 96. Radius RL. Anatomy of the optic nerve head and glaucomatous optic neuropathy. Surv Ophthalmol. 1987;32:35–44. 97. Quigley HA, Sanchez RM, Dunkelberger GR, L’Hernault NL, Baginski TA. Chronic glaucoma selectively damages large optic nerve fibres. Invest Ophthalmol Vis Sci. 1987;28:913–20. 98. Jonas JB, Muller Bergh JA, Schlotzer-Schrehardt UM, Naumann GOH.  Histomorphometry of the human optic nerve. Invest Ophthalmol Vis Sci. 1990;31:736–44. 99. Jonas JB, Fernandez MC, Naumann GOH.  Correlation of the optic disc size to glaucoma susceptibility. Ophthalmology. 1991;98:675–80. 100. Yorio T, Krishnamoorthy R, Prasanna G. Endothelin: is it a contributor to glaucoma pathophysiology? J Glaucoma. 2002;11:259–70. 101. Polak K, Luksch A, Berisha F, Fuchsjager-Mayrl G, Dallinger S, Schmetterer L. Altered nitric oxide system in patients with open-­ angle glaucoma. Arch Ophthalmol. 2007;125:494–8. 102. Pournaras CJ, Rungger-Brandle E, Riva CE, Hardarson SH, Stefansson E. Regulation of retinal blood flow in health and disease. Prog Retin Eye Res. 2008;27:284–330. 103. Venkataraman ST, Flanagan JG, Hudson C. Vascular reactivity of optic nerve head and retinal blood vessels in glaucoma – a review. Microcirculation. 2010;17:568–81. 104. Miller KM, Quigley HA.  The clinical appearance of the lamina cribrosa as a function of the extent of glaucomatous optic nerve damage. Ophthalmology. 1988;95:135–8. 105. Leung DY, Tham CC.  Management of bleb complications after trabeculectomy. Semin Ophthalmol. 2013;28:144–56. 106. Lu LJ, Hall L, Liu J. Improving glaucoma surgical outcomes with adjunct tools. J Curr Glaucoma Pract. 2018;12:19–28. 107. Mietz H, Arnold G, Kirchof B, Diestelhort M, Krieglstein GK.  Histopathology of episcleral fibrosis after trabeculectomy with and without mitomycin C.  Graefes. Arch Clin Exp Ophthalmol. 1996;234:364–8. 108. Cillino S, Casuccio A, Di Pace F, Cagini C, Ferraro LL, Cillino G.  Biodegradable collagen matrix implant versus mitomycinC in trabeculectomy: five-year follow-up. BMC Ophthalmol. ­ 2016;16:24. 109. Sakarya Y, Sakarya R, Kara S, Soylu T. Fibrin glue coating of the surgical surfaces may facilitate formation of a successful bleb in trabeculectomy surgery. Med Hypotheses. 2011;77:263–5. 110. Sethi P, Patel RN, Goldhardt R, Ayyala RS. Conjunctival advancement with subconjunctival amniotic membrane draping technique for leaking cystic blebs. J Glaucoma. 2016;25:188–92. 111. Hampton C, Shields MB.  Transscleral neodymium-YAG cyclophotocoagulation: a histologic study of human autopsy eyes. Arch Ophthalmol. 1988;106:1121–3. 112. Ndulue JK, Rahmatnejad K, Sanvicente C, Wizov SS, Moster MR. Evolution of cyclophotocoagulation. J Ophthalmic Vis Res. 2018;13:55–61. 113. Van Buskirk EM. Pathophysiology of laser trabeculoplasty. Surv Ophthalmol. 1989;33:264–72. 114. Garg A, Gazzard G. Selective laser trabeculoplasty: past, present, and future. Eye (Lond). 2018;32:863–76. 115. Tsang S, Cheng J, Lee JWY.  Developments in laser trabeculoplasty. Br J Ophthalmol. 2016;100:94–7. 116. Melamed S, Fiore PM.  Molteno implant surgery in refractory glaucoma. Surv Ophthalmol. 1990;34:441–8. 117. Giovingo M. Complications of glaucoma drainage device surgery: a review. Semin Ophthalmol. 2014;29:397–402.

References 118. Aref AA, Gedde SJ, Budenz DL. Glaucoma drainage implant surgery. Dev Ophthalmol. 2017;59:43–52. 119. Loeffler KU, Jay JL.  Tissue response to aqueous drainage in a functioning Molteno implant. Br J Ophthalmol. 1988;72:29–35. 120. Classen L, Kivela T, Tarkkaanen A.  Histopathologic and immunohistochemical analysis of the filtration bleb after unsuccessful glaucoma seton operation. Am J Ophthalmol. 1996;122:205–12.

87 121. Eftekhari K, Shindler KS, Lee V, Dine K, Eckstein LA, Reza VM.  Histologic evidence of orbital inflammation from retrobulbar alcohol and chlorpromazine injection: a clinicopathologic study in human and rat orbits. Ophthal Plast Reconstr Surg. 2016;32:302–4.

4

Retinal Vascular Disease

Introduction This chapter describes the ischaemic retinal vascular diseases that ultimately lead to glaucoma and are found in the globes that are enucleated to relieve pain in a blind eye. The clinical diagnosis is usually “neovascular glaucoma” (NVG) with the addition of “central retinal vein occlusion” (CRVO) or “diabetes,” but occasionally, rarer entities such as retinopathy of prematurity (ROP) or Coats’ disease will be seen at this end stage. Although choroidal neovascularisation (disciform degeneration) does not per se lead to anterior segment neovascularisation, this is the end stage of wet age-related macular degeneration (ARMD), so that inclusion of this topic in the present chapter is appropriate.

Retinal Ischaemic Disease Pathogenesis of Retinal Ischaemia

With regard to the spectrum of inner retinal ischaemia and infarction, the range extends from total (white) infarction of the inner retina (after occlusion of the central retinal artery (CRAO)) to total red (haemorrhagic) infarction (after thrombosis of the central retinal vein (CRVO)). Between these two ends of the spectrum, a variety of disease processes (which occlude individual branch arterioles or venules) can produce areas or sectors of focal ischaemia. The end-stage effects of focal retinal ischaemia are shown diagrammatically in Fig. 4.2 and are characterised by: 1. Localised areas of breakdown in the retinal vasculature with leakage of plasma and red cells 2. Intra- and preretinal neovascularisation 3. The formation of microaneurysms on the capillaries 4. Secondary angle closure with bullous keratopathy and ulceration 5. Cataract

The consequences of retinal ischaemia in terms of the end result, neovascular glaucoma, have already been discussed (see Chap. 3). While the retina has a dual blood supply, it is disease in the branches and tributaries of the central retinal artery and vein that are of greater importance in vasoproliferative disorders and these in turn lead to retinal detachment and blindness. The arterioles and venules radiate from the disc and on the temporal side bend around to form a spoke-­ like pattern around the macula (Fig. 4.1). The capillary bed connecting the arterioles and venules loops down to supply the inner layers of the retina. The outer layers (outer nuclear and photoreceptor) of the retina are maintained by the posterior ciliary arteries via the choriocapillaris, and the ischaemic responses in this vascular territory are far less well defined. An important consequence of the dual blood supply is that there is a watershed zone in the outer plexiform layer and the Fig. 4.1  Congested retinal blood vessels in a glaucomatous eye with a effects of ischaemic capillary endothelial damage are seen deeply cupped disc: The column of blood in the venules is thicker than that in the arterioles. Note the pattern of supply to the macula here as leakage of plasma. (arrowhead)

© Springer Nature Switzerland AG 2021 F. Roberts, C. K. Thum, Lee’s Ophthalmic Histopathology, https://doi.org/10.1007/978-3-030-76525-5_4

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90 Fig. 4.2  Diagram to summarise the common features of ischaemic retinopathy in a globe enucleated in treatment of neovascular glaucoma

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Hard exudates

Sclerotic blood vessels

Neovascularisation in a cupped disc Preretinal neovascularisation

Haemorrhages Flame Blot Dot

Dilated veins

Cataract Closed angle

Bullous Keratopathy

The changes produced in ocular tissues as a result of inadequate metabolic exchange and hypoxia have a limited range of morphological expression, although the pattern is variable. An important feature of sectorial disease is that fluorescein angiography reveals areas of non-perfusion. Studies have shown that in these areas the vascular lumen is occluded by glial cells [1]. The most important consequence of progressive ischaemia in the retina is the release of angiogenic factors [2, 3]. Angiogenic factors have been shown to be central in the pathogenesis of proliferative retinopathies. Many of these factors—e.g., vascular endothelial growth factor (VEGF) and fibroblastic growth factor—released from ischaemic tissues have been identified [4, 5] and the most significant of these is VEGF. VEGF has been implicated in the pathogenesis of retinal diseases associated with neovascularisation and oedema, including wet age-related macular degeneration [6, 7], diabetic retinopathy [8, 9], and retinal vein occlusion (RVO) [3, 8, 10, 11], as well as other ocular diseases such as retinopathy of prematurity (ROP) [8]. VEGF is associated with breakdown of blood-retina barrier and increased vascular permeability of the retinal blood vessels [12, 13]. The ultimate aim for the control of retinal neovascularisation is to find a therapeutic strategy such as intravitreal injection of a non-toxic inhibitor of the factors that promote endothelial cell proliferation. Hence, anti-VEGF therapies (e.g. Ranibizumab and Bevacizumab), used as monotherapy or in combination with other treatment modalities, have become the standard ophthalmic care in preventing vision loss from the neovascular and exudative complications of retinal diseases, particularly in central retinal vein occlusion (CRVO) [14], age-related macular degeneration (ARMD) [15–19] and diabetic retinop-

Ectropion uveae

athy (DR) [20–23]. In addition, Placental Growth Factor (PlGF), a member of the VEGF family, has been shown to be selectively associated with pathological angiogenesis and inflammation, with high levels of PlGF detected within the aqueous humor, vitreous and retina in DR and neovascular ARMD. Recent studies have suggested that blockade of PlGF does not affect the healthy vasculature, making this an attractive potential therapeutic target [24, 25]. Interestingly, recent emerging evidence suggests that the pathogenesis of DR is beyond a microvasculopathy with dysfunctional neurovascular communication also playing an important role [26–28].

 haracteristic Pathological Features of Focal C Ischaemic Retinal Disease  icroinfarction or “Cotton Wool Spots” M One of the earliest responses to focal ischaemia is seen as microinfarction, which was previously a major feature of malignant hypertension. Successful treatment of hypertension has almost entirely excluded this particular manifestation of retinal ischaemia in the laboratory. On fundoscopy and macroscopic examination “cotton wool” spots appear as small white swellings in the inner part of the retina and are usually found near to the optic disc (Fig. 4.3). This pathology is a response to acute occlusion of an arteriole as would occur in angiospastic hypertensive retinopathy, but the vasculopathy is more difficult to demonstrate histologically than, for example, in the kidney. Microscopically in a haematoxylin and eosin (H&E) section, the inner retina is thickened by oedema and an accumulation of eosinophilic bodies

Retinal Ischaemic Disease

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b

Fig. 4.3 (a) Microinfarcts in the retina (arrows) in malignant hypertension. Note severe papilloedema and peripapillary flame haemorrhages. (b) The Bodian stain reveals the swollen axons (arrows) within the microinfarct

a

b

Fig. 4.4 (a) A macular star (arrows) in a diabetic globe in which the disc is cupped. (b) Foamy macrophages (arrows) are present within the lipoproteinaceous material in a hard exudate

or cytoid bodies, the true nature of which is revealed by a Bodian stain for axons or immunohistochemical staining for neurofilaments. Ultrastructural examination has revealed that cytoid bodies represent the swollen ends of axons that were packed with cytoplasmic organelles. The mechanism by which the interrupted axons become distended is thought to be continuing axoplasmic flow from the parent ganglion cell. It is generally accepted that the centre of the infarct is totally necrotic and that the sealed and swollen axon bulbs are seen only at the periphery of the infarct. The synonym “soft exudate” is therefore misleading as it is not actually “exudate.” The process of resorption is by removal of water and salts and glial replacement of the necrotic axons and ganglion cells. On fundoscopy cotton wool spots vanish in about 6 weeks: The residue appears as a sector of gliosis in the inner retina in a histological preparation.

 xudation of Plasma or “Hard” Exudates E Ischaemic damage to the endothelial cells in the capillaries as they loop into the outer plexiform layer leads to pooling of plasma. On macroscopic examination, plasma rich exudates have a discrete yellow appearance and initially they tend to form clusters often near the macula (Fig. 4.4), where a radiating circular formation can resemble a star (macular star). In advanced disease, extensive exudation may dominate the picture and the posterior retina is transformed into a yellow sheet. Histologically, plasma exudates are found in the outer plexiform layer and appear as pink-staining proteinaceous lakes constrained by Müller cells. Infiltration by lipid-laden macrophages removes the lipoproteinaceous exudates, and by a slow process the cells migrate to the venules. On fundoscopy, hard exudates may persist for several months.

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Haemorrhage The appearances of haemorrhages depend on the source of the bleeding and on the site of accumulation (Fig.  4.5). Bleeding from small arterioles tracks into the nerve fibre layer of the retina (flame haemorrhage), while capillary oozing into the outer plexiform layer produces small dot haemorrhages. Subretinal haemorrhages appear as blots. If bleeding can penetrate the inner limiting membrane of the retina, the pool is “subhyaloid” (i.e., between the posterior vitreous face and the inner retina) and it tends to have a meniscus on fundoscopy; this form of haemorrhage obscures the underlying retina. Retinal vessels are visible when the bleeding is subretinal (i.e., between the photoreceptors and the retinal pigment epithelium) so the various forms of haemorrhage are easily distinguished. In arterioles, occlusion by spasm or fibrin/platelet/fat emboli leads to capillary endothelial necrosis or even breakdown of the wall of precapillary arterioles. A classic form of haemorrhage is seen in inflammatory embolisation (Roth’s

4  Retinal Vascular Disease

spots) in subacute bacterial endocarditis, when circular haemorrhages containing a white centre appear in the retina. In inflammatory embolisation the white spot is a leucocytic embolus (Fig. 4.6). More commonly in contemporary practice, Roth’s spots are seen in deficient haemostasis (Fig. 4.7) as in treated leukaemia or malignant lymphoma, and consist of an infarct surrounded by superficial retinal bleeding.

Microaneurysms Microaneurysms were best studied in retinal digest preparations (see Chap. 1) in which the vascular bed was seen in two dimensions (Fig. 4.8): newer technologies such as spectral domain optical coherence tomography (SD-OCT) can provide three-dimensional images that illustrate the location and relationships of the structures [29]. While retinal capillaries are visible clinically, they cannot be identified with confidence on macroscopic examination and are seen only rarely by conventional histology. In paraffin sections, the wall of the microaneurysm appears as a circular or oval periodic acid Schiff (PAS)-positive

a

b

c

d

Fig. 4.5 (a) Blood in all layers of the retina corresponding to flame (*), dot (arrowheads), and blot (arrows). The largest haemorrhage (sh) is subhyaloid. (b) Haemorrhages in the nerve fibre layer (*), within the retina (arrowhead) corresponding to “dot” haemorrhages and subreti-

nal (arrow) corresponding to blot haemorrhages. (c) Subretinal (arrow) and vitreous haemorrhage (arrowheads) arising from a small retinal haemorrhage. (d) Extensive haemorrhages in the retina in central retinal vein occlusion

Retinal Ischaemic Disease

a

Fig. 4.6 (a) Macroscopic appearance of the retina in septicaemia due to subacute bacterial endocarditis. Note the Roth’s spots (arrowheads). (b) Histology from the case shown in (a). The retinal vessel (arrow) is surrounded by fibrin and the adjacent retina contains blood (red cells

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b

are orange with the Martius scarlet blue stain). An infarct is present in the retinal pigment epithelium. Inset: Gram-positive bacteria (arrowheads) were identified in the septic infarction of the retinal pigment epithelium

Neovascularisation

Fig. 4.7  Circular areas (arrowheads) of haemorrhage (Roth’s spots) in an autopsy case of Hodgkin’s disease. A flame haemorrhage (f) is included. The disc (d) and macula (m) are swollen by autolysis. (Reproduced with permission from Sehu and Lee [236])

structures and the lumen contains endothelial cells and leucocytes. Somewhat similar structures more closely resemble kinks in the capillary. Microaneurysms are a feature of the posterior retina in diabetes and are found at the periphery in central retinal vein occlusion (CRVO). This is not the only difference because in diabetes the most striking feature is that there is a dropout in the pericytes in the capillary wall, while in CRVO the endothelial cell population is reduced in number. Pericytes are contractile cells wrapping around retinal capillaries, providing structural support as well as modulating the expression of tight junction proteins in the adjacent endothelial cells [30, 31]. It seems reasonable to believe that their absence would weaken the wall, but this hypothesis is an over-­ simplification and does not explain microaneurysm formation in CRVO.

Clinical Relevance (Fig. 4.9) The final consequences of retinal ischaemia involve the whole eye when secondary glaucoma and vitreous haemorrhage supervene. Conventional treatments with extremely uncontrolled cases are retinal cryotherapy or enucleation. Currently, management of this medical condition is directed toward a new era with great advancement in diagnosis and treatment. Glaucoma drainage implant surgery (e.g., Ahmed valve, Molteno implant) [32, 33] brings a time window of normal range of intraocular pressure (IOP) for physicians to treat the underlying disease of NVG. Regression of iris neovascularization by employing panretinal photocoagulation (PRP) [34, 35] or intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) antibodies promotes the surgical success rate for anti-glaucomatous surgery [36–38]. Therefore, enucleation for neovascular glaucoma is becoming less common. Macroscopic Features of the Enucleated Globe If the cornea is transparent, external examination of the globe will reveal an ectropion of the iris pigment epithelium due to the presence of a neovascular membrane on the iris surface (Fig.  4.10a). In many specimens the disease progresses to corneal ulceration and cataract formation (Fig. 4.10b). The angles are usually closed and the shallow anterior chamber may contain blood or plasma. Cholesterol crystals can be identified when haemorrhage from the new blood vessels on the iris surface is long-standing (see Chap. 3). The pupil may be fused with the degenerate opaque lens if a neovascular pupillary membrane promotes the formation of posterior synechiae. The cataractous lens will be opaque and may contain white flecks of calcium oxalate.

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a

Fig. 4.8 (a) Microaneurysms in central retinal vein occlusion (CRVO): note the relative preservation of pericytes (arrowheads). The microaneurysms contain cells which are thought to be migrating endothelial cells and entrapped leucocytes (arrow). Eventually the microaneurysms

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b

become filled with basement membrane material (arrows). (b) Microaneurysms in diabetic vasculopathy in which there is some survival of endothelial cells (arrowheads) and a loss of pericytes

a

b Fig. 4.9  Preretinal neovascularisation causes distortion of the retinal vessels (*): Note the subhyaloid haemorrhage (arrowheads) that obscures the sclerotic artery

Similar organisation occurs in the vitreous if bleeding has resulted from rupture of blood vessels that have grown onto the inner surface of the retina. Bleeding most commonly occurs at the vitreous base (over the pars plana) and at the disc; in the latter case, prelaminar and preretinal neovascularisation is found easily, but it is difficult to demonstrate the source of bleeding into the peripheral vitreous. Small foci of neovascularisation extending from the retina into the vitreous are not a common finding and may be missed. With a high power on the dissecting microscope, neovascularisation appears as a fine white feltwork (Fig. 4.9) or as tiny mulberry nodules (Fig. 4.11). Such neovascularisation may arise from the capillary bed at the edge of an

Fig. 4.10 (a) The anterior segment in an uncomplicated case of central retinal vein occlusion (CRVO). Note the closed angle and the atrophic iris with an extension of the iris pigment epithelium (arrowhead) around the pupil (ectropion uveae). (b) In an advanced case of CRVO the cornea is ulcerated (arrowhead) and the shallow anterior chamber contains pus. The lens is cataractous and the vitreous contains blood

Retinal Ischaemic Disease

a

Fig. 4.11 (a) A plaque of neovascularisation (arrowheads) on the inner surface of the retina is supplied by a channel that communicates with the lumen of a hyalinised intraretinal vessel (arrow). (b) Small

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nodules of neovascularisation (arrowheads) are present on the hyalinised blood vessels in this end stage CRVO. See Fig. 4.12 for the histological equivalent

Fig. 4.13  Proliferation of endothelial cells and pericytes within the retina (arrowheads) and vitreous in an infant retina. The vasoproliferation in the retina was attributed to the ischaemia due to a retinoblastoma, but this is not a common finding (×250)

Fig. 4.12  A tree-like proliferation of capillaries and fibroblasts into the vitreous. In this case the endothelial cells have grown out of a hyalinised vessel wall (×250)

infarcted area of retina, from the wall of a thickened venule or less commonly from the wall of a hyalinised arteriole (Figs. 4.11a and 4.12). Microscopic Features Intraretinal neovascularisation can take a variety of forms. In a child’s eye, the new vessels take the form of solid cords of endothelial cells and pericytes that project into the retina and pass through the inner limiting membrane into the vitreous (Fig.  4.13). Endothelial cells are distinguished from glial

cells, which are GFAP positive, by positive staining with antiCD31 antibody. In the retina in old age, the endothelium in hyalinised arterioles and venules (Figs.  4.11a and 4.12) appears to be the source for the stem cells [39, 40]. Proliferation into the vitreous leads to the formation of mulberry sprouts or larger tree-like structures (rete mirabile), and rupture of the delicate capillaries releases blood that stimulates a macrophagic and fibroblastic reaction to continue the vicious circle. Alternatively, when the posterior vitreous face detaches from the inner limiting membrane, sheets of capillaries and fibroblasts spread onto the outer surface of the posterior vitreous face (Fig.  4.14). Condensation of bands of tissue with capillaries supported by glial cells and fibroblasts causes wrinkling of the inner limiting membrane.

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 ommon Disease Entities Associated C with Intraocular Neovascularisation Retinal Vein Occlusion (RVO) Following diabetic retinopathy, retinal vein occlusion (RVO) is the second most common type of retinal vascular diseases [42, 43]. The ischaemic form of RVO is often complicated by macular oedema, retinal, and iris neovascularisation, leading to substantial visual loss. RVO is usually classified into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). Fig. 4.14  When the posterior vitreous face detaches, the neovascular membranes grow onto the posterior surface (arrowheads) of the vitreous face. Note the lipomacrophages in the outer plexiform layer. The separation in the photoreceptor layer is artefactual (×100)

Fig. 4.15  A hyalinised vessel in an ischaemic retina with atrophy and gliosis in the inner layers (×250)

Arteriolosclerosis and Venulosclerosis Age-related degenerative vascular disease, associated with mild or controlled hypertension, is a common finding in enucleated eyes and is manifest macroscopically as prominent white walls and empty lumina. This sheathing and luminal narrowing is particularly a feature of central retinal vein occlusion (discussed later in chapter). The muscle in the vessel wall is replaced by semitransparent collagenous tissue (hyalinisation) and the luminal diameter is decreased as the vessel wall thickens [41]. This process is equally prominent in both arterioles and venules and the effect is to lower the rate of blood flow through the vascular bed and to reduce the capacity of the vasculature to respond to hypotension. At a microscopic level there is a gradual replacement of the smooth muscle of the media with superadded collagen d­ eposition by perivascular astrocytes (Figs.  4.11 and 4.15). The cells responsible for the collagen deposition are most probably the Müller cells or the perivascular astrocytes.

Central Retinal Vein Occlusion (CRVO) While the aetiology of this common condition is uncertain, the clinical features and associations are well known and the pathology is well established [44]. An elderly, often hypertensive, patient is suddenly aware of visual loss in the affected eye, often on rising in the morning. The disease is unilateral and is sometimes a complication of primary open angle glaucoma. On ophthalmoscopy, there are extensive haemorrhages within the retina—the so-called “wrath of God” fundus. Impaired venous drainage leads to retinal hypoxia with upregulation and release of vascular endothelial growth factor (VEGF). VEGF increases vascular permeability and leads to the breakdown of the blood-retinal barrier, with the development of macular oedema [8, 10]. In a large percentage of cases, if untreated by panretinal laser photocoagulation (PRP), neovascular glaucoma (see Chap. 3) will supervene within 3 months (the “100 day” glaucoma). With the advancement in treatment, such as glaucoma drainage implants and intravitreal anti-VEGF injections, it is increasingly uncommon to receive enucleation specimens for neovascular glaucoma at a later date when all treatment modalities (see Chap. 3) have failed to control the high pressure. Central venous occlusive disease is also seen in younger age groups and is associated with retinal vasculitis or thrombosis, and, in some cases, a female patient using oral contraception. These less common forms of CRVO have a better prognosis and cases of this aetiology do not usually progress to neovascular glaucoma and enucleation. On macroscopic examination the pathologist rarely sees the disease at the 100 day stage (Fig. 4.5d), when the haemorrhagic retinopathy is at its most striking. More commonly, the disease is held in abeyance by PRP for a year or more and by this time the haemorrhages will have resolved, leaving a cupped disc and an atrophic retina containing prominent white sclerotic (or hyalinised) vessels and small scattered haemorrhages (Fig. 4.16). Atheromatous degeneration (with obvious sub-intimal lipid deposition) in the branch arteries of the retina is rare, and when found is most likely to be in a diabetic eye.

Common Disease Entities Associated with Intraocular Neovascularisation

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Fig. 4.16  Haemorrhagic retinopathy in central retinal vein occlusion at a later stage. The haemorrhages are intraretinal and subretinal and the sclerotic vessels pass over the blot haemorrhages. Note the deep cupping of the optic disc

Fig. 4.18  The markedly hyalinised retinal vessels in CRVO contain intramural channels, which communicate with the preretinal neovascular membrane (prm): Note the exudates (e) in the outer plexiform layer (×160)

Fig. 4.17  The optic disc in a glaucomatous eye after neovascularisation has complicated a central vein occlusion. The lamina cribrosa (lc) is bowed posteriorly and the optic nerve is atrophic. There are hyalinised vessels in the optic disc (arrowhead) (×40)

Histologically pre-existing haemorrhage will be identifiable by sectors of gliotic retina, which stain positively for iron. Transverse serial sections through the optic disc will usually reveal evidence of recanalisation of the central retinal vein with intimal fibroplasia in the central retinal artery. A fibrin thrombus, undergoing organisation, in the vein is a rarity for a pathologist, but this justifies the clinical term of central retinal vein “thrombosis.” The central retinal artery and the posterior ciliary arteries will exhibit in many cases the hyalinisation characteristic of degenerative disease in the elderly. Pre-existing glaucoma may be obscured partially or totally by neovascularisation within the cupped disc, which is often distorted (Figs.  4.9 and 4.17). In the peripapillary retina, the arterioles and venules will be hyalinised and communicating channels between the lumen and proliferating blood vessels on the retinal surface can be demonstrated by serial sections (Figs. 4.11 and 4.18).

 athogenesis of Central Vein Occlusion P It is noteworthy that the cross-sectional radius of the central vein in the lamina cribrosa, is about 50% of that in the tributaries of the prelaminar part and smaller than that in the retrolaminar region, and this narrowing within the lamina cribrosa becomes more irregular with age [45]. This is an unusual configuration (in most venous drainage systems the tributaries have a smaller radius than the trunk vessels) and it might be explained by the necessity to maintain a high pressure in the retinal capillary bed against an intraocular pressure of 10–20 mmHg. The resistance provided by intralaminar venous narrowing is disadvantageous in that flow is markedly increased in the narrowed segment and the resultant turbulence could predispose to thrombosis. The early studies on CRVO implicated focal endothelial proliferation (Fig. 4.19) as a cause for thrombosis, but this abnormality is only rarely detected. Another hypothesis was that the expanding fibrous tissue between the artery and the vein could impinge and distort the lumen of the vein and damage the endothelium. Other important systemic factors in central retinal venous thrombosis are hyperviscosity of the blood and an abrupt fall in pressure in the central artery [46]. If these are coupled with a diseased retinal vasculature, which predisposes to under-perfusion and stasis in the vascular bed, the criteria for Virchow’s triad are fulfilled. However, the systemic predisposing factors are applied equally to both eyes so the unilateral nature of this disease must be dependent on local anatomical factors. To date, the exact pathogenesis of RVO remains elusive.

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non-perfusion area in comparison with arterial overcrossing [52–54]. However, such pathology has rarely been seen in enucleation specimen as it never progresses to neovascularization following appropriate treatment.

Diabetes The end stage of diabetic eye disease is, for the surgical pathologist, somewhat similar to CRVO and indeed the diseases may be coincidental. In diabetes, retinal detachment due to preretinal neovascularisation is a more prominent feature. Diabetic eyes may also be obtained at autopsy, in which case the disease may be observed at an earlier stage. Diabetic retinopathy is the third most common cause of blindness and partial sight certifications for all age groups in the United Kingdom (6.3% and 7.6% respectively) [43]. However, diabetic retinopathy is the leading cause of sight-loss in the working age population worldwide with expected rise of affected patients to more than 190 millions by 2030 [55].

Fig. 4.19  The lumen of the central vein (v) is narrowed in the region of the lamina cribrosa by endothelial proliferation (arrowhead). The lumen of the artery (a) is patent (×100)

Additional Features One of the principal causes of discomfort in neovascular glaucoma is corneal oedema. Palliation of symptoms using atropine and topical steroids can be very effective, but in some cases there may be uninhibited proliferation of bacteria (bacterial crystalline keratopathy) or fungi (see Chap. 13) within the corneal ulcers that develop.

Branch Vein Occlusion A thrombus can occur in a first or second order branch vein— branch retinal vein occlusion (BRVO) and this is recognised clinically by haemorrhages in one or two sectors of the fundus. The crossing point of an arteriole and a venule (AV crossing) is the usual site of thrombotic occlusion [47, 48]. The affected AV crossing could either be an arterial overcrossing (adjacent retinal artery runs over the affected vein) or a venous overcrossing (the affected vein runs over the adjacent artery) [49– 51]. With the advent of optical coherence tomography (OCT) and OCT-Angiography (OCT-­A), it is now possible to visualize the changes at the acute stage of BRVO. Studies using these modalities have shown that venous overcrossing is more prevalent, with greater venous narrowing and larger retinal

Clinical Background Since the establishment of the English National Screening Programme for Diabetic Retinopathy (ENSPDR) and similar programmes in Scotland, Wales, and Northern Ireland, annual photographic retinal screening is offered to all people with diabetes over the age of 12. All patients identified by screening as having sight-threatening diabetic retinopathy are referred to ophthalmology clinics. The aim of the screening process is the prevention, detection, and treatment of sightthreatening maculopathy and proliferative retinopathy [56]. There are many clinical classifications of diabetic retinopathy, but for simplicity the process can be classified as follows: 1. “Background retinopathy” with microaneurysms, scattered hard exudates and scattered haemorrhages, based on abnormalities of the capillary basement membrane [57]. 2. “Diabetic macular oedema” can occur at any stage of diabetic retinopathy. It results from the accumulation of extracellular fluid within the retinal tissue caused by breakdown of retina-blood barrier. Several mechanisms have been proposed to explain the pathogenesis of macular oedema, but VEGF was found to induce structural changes in the endothelial tight junctions leading to increased permeability [58]. This is usually associated with reduced visual acuity. 3. “Preproliferative retinopathy” with signs of increasing inner retinal hypoxia, including cotton wool spots, large areas of capillary underperfusion (as seen by fluorescein angiography), IRMA (intraretinal microvascular abnormalities), venous beading, and loops. IRMA are arterio-­ venular shunts that act as collateral channels bypassing the capillaries.

Common Disease Entities Associated with Intraocular Neovascularisation

4. “Proliferative retinopathy.” Proliferation of blood vessels may be intra- and preretinal and on the anterior surface of the optic disc [59]. Traction may lead to displacement of the macula (heterotopia) [60]. 5. End stage. Intraretinal and/or intravitreal haemorrhages from new vessels with fibrovascular proliferation, ­contraction of fibrous tissue resulting in tractional retinal detachment, and anterior segment neovascularization leading to neovascular glaucoma. It is obvious from the pattern of disease in diabetic retinopathy that a small series of sections in the horizontal plane will not suffice and where detailed study is required the “serial 10th H&E system” is to be recommended (see Chap. 1).

Macroscopic Examination This will reveal changes in the anterior segment similar to those seen in CRVO.  The regions of the fundus that are affected in the early stages include the macula where there may be star-like exudates (Fig. 4.4a) and the disc where there may be preretinal membranes and exudation (Fig.  4.20). Traction from epiretinal membranes may lead to retinoschisis [61]. The retinal vessels may be hyalinised and occasionally there may be intravascular accumulations of lipid-laden macrophages with leakage into the adjacent retina (Fig.  4.20c). Occasionally it may be possible to identify loops in the veins, so-called “omega loops,” which are thought to be due to vitreous traction on congested venules so that these structures are displaced into the vitreous (Fig. 4.20c, d). At a more advanced

a

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c

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Fig. 4.20 (a) Preretinal neovascularisation in diabetes extends into the vitreous with resultant haemorrhage and organisation leading to traction detachment. (b) In this advanced stage of diabetic retinopathy the retina is detached by a proteinaceous exudate and the preretinal membranes extend into the organised vitreous. The anterior chamber is shallow and the angles are closed. (c) In this background diabetic retinopathy

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there are scattered hard exudates and the congested vein forms a loop (arrowhead). An artefactual tear was made in the retina when the globe was divided. The retinal vessels contain segments that are filled with lipid-laden macrophages (arrow), which are migrating into the adjacent retina. (d) The histological examination of the omega loop shown in (c) revealed that the loop projected into the vitreous

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stage there is bleeding into the vitreous, which is often detached, and subretinal exudation is pronounced (Fig. 4.20b). At a late stage, altered blood on the posterior surface of a detached vitreous is known as an ochre membrane due to its yellow-brown colour. Typically at the end stage the retina is detached and funnel shaped and the changes of neovascular glaucoma are observed.

Microscopic Examination Many of the features of diabetic retinal vasculopathy have already been described under the general headings of capillary microaneurysms, haemorrhage, soft and hard exudates, and neovascularisation. Vascular sclerosis is often pronounced and the vessels tend to have more eosinophilic walls than in simple degenerative disease. Exudation is prominent throughout the Fig. 4.21 (a) The iris in some cases of diabetes possesses a vacuolated pigment epithelium that contains PAS-positive material (arrowheads). (b) The ciliary processes in diabetes exhibit marked thickening of the basement membrane (arrowheads)

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retina and the preretinal neovascularisation occurs in the midperiphery as well as in the region of the disc. At the periphery the intravitreal neovascularisation is sometimes derived from the choroid [62]. At the ultrastructural level the basement membrane of the capillaries is multilayered, particularly in the regions adjacent to the arterioles [63], and the pericytes show cytoplasmic vacuolation. The reason for selective damage in diabetics has not been satisfactorily explained, but recent evidence has suggested that circulating antibodies to pericytes in diabetic patients may be of importance [64]. Important hallmarks of diabetes may be found in the iris and ciliary body. The pigment epithelium of the former is sometimes vacuolated and contains PAS-­positive material (“diabetic iridopathy”), while in the ciliary processes there may be prominent thickening of the basement membrane (Fig. 4.21).

Common Disease Entities Associated with Intraocular Neovascularisation

 athogenesis and Effects of Treatment P in Proliferative Diabetic Retinopathy A great deal of research has been directed toward the pathogenesis and treatment of diabetic retinopathy because of the socioeconomic consequences [65, 66]. As the current treatment strategy focuses on halting the progression of DR, it is highly likely that in some diabetic eyes, there will have been treatment by procedures designed to prevent or alleviate macular oedema and/or neovascularisation, which is the primary cause of vitreous haemorrhage and retinal detachment. Panretinal laser photocoagulation (PRP) had remained the standard care for both of these complications in the past. One of the rationales is that the destruction of the highly metabolically active peripheral retinal tissue will reduce oxygen requirement and improve retinal oxygenation from choroidal circulation. However, the destruction of the photoreceptor layer and the retinal pigment epithelium (RPE) may provide a route for drainage of vasoformative factors into the choroid, which has a higher osmotic pressure than the retina. Therapeutic burns made by argon laser (green light at 488 and 514  nm wavelengths) to the retina appear as circular white areas (Fig. 4.22). The histopathology of retinal burns depends to some extent on the energy source and levels and the spot size [67, 68]. In the majority of globes, the burns appear as retinal thinning with replacement of the normal cell constituents by glial cells. The pigment epithelium is atrophic or obliterated in the centre of the burn, but at the edge there is often reactive proliferation and migration: The choroid is usually fibrotic and atrophic. After panretinal photocoagulation (PRP) has failed and retinal detachment is

Fig. 4.22  Macroscopic appearance of photocoagulation burns (arrowheads) in the retina

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Fig. 4.23  After a retinal detachment, the site of a pre-existing retinal burn can be seen as a mound of gliotic retina, which is fused with Bruch’s membrane: clumps of RPE cells are incorporated within the scar (×50)

established, it is common to find bands of gliotic retina attached to Bruch’s membrane: These represent pre-existing sites of fusion (Fig. 4.23). Extensive research into understanding the pathophysiology of DR has led to significant advances in its treatment through the advent and widespread use of anti-­ VEGF.  Whether used as monotherapy or in combination with other treatment modalities (e.g. panretinal photocoagulation (PRP), intravitreal corticosteroid), these agents have markedly reduced the incidence of severe vision loss in diabetes [20–23, 69, 71–74]. Vitreoretinal surgery is reserved for a minority of patients who develop severe diabetic eye disease despite treatment. Previously, in some centres, attempts are made to remove the fibrovascular tissue in the vitreous [75] by means of vitreous cutting instruments (SITE machines or vitrectomy machines). The pathologist may see successful surgery in autopsy material or in failed procedures when the disease has progressed to further vitreous traction, retinal detachment, and neovascular glaucoma [76]. In the former case, study of the cellular nature of the preretinal membranes, which contain astrocytes and Müller cells, in addition to endothelial cells and pericytes, is of interest to the clinician. An attempt should be made to find the tracks in the anterior sclera and ciliary body where the vitrectomy instruments have been introduced. It must be admitted that the pathological study of the failed procedure is difficult and unrewarding since the secondary haemorrhage and extensive vitreous fibrosis obscures most of the earlier pathology. In some centres, the vitreoretinal surgeon may submit vitrectomy specimens and these will appear as tiny strips of transparent tissue. The addition of a few drops of carbol fuchsin to the fixative will stain the tissue and reduce the risk that the specimen will be lost in processing and embedding. Histology of diabetic membrane peels will reveal fibrous tissue containing capillaries, which paradoxically possess pericytes (Fig. 4.24). In a routine specimen it is no longer practical to look for microaneurysms by the retinal digest technique (see Chap. 1), but if this investigation is required, formalin fixation is essential. The characteristic feature of diabetes is survival of the endothelial cells and a loss of pericytes from the retinal capillaries (Fig. 4.8).

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4  Retinal Vascular Disease

 arer Vascular Disorders Leading R to Neovascular Glaucoma Coats’ Disease

b

Fig. 4.24 (a) A diabetic epiretinal membrane may consist of dense hypercellular fibrovascular tissue. (b) More commonly an epiretinal membrane consists of loose collagen containing a few small vessels (Semithin section, toluidine blue stain)

Recent Advances Recent advances in retinal imaging has permitted detection of early changes within the retina prior to clinically visible microvascular lesions. OCT-Angiography which is capable of high resolution imaging of retinal capillary networks, allows detection of early characteristic changes such as increased area and irregularity of the foveal avascular zone in diabetic patients without DR [77, 78]. In addition, widefield scanning laser ophthalmoscopyassisted angiography renders the ability to detect capillary non-perfusion in the retinal periphery before patients develop neovascularisation [79]. Whilst the current pharmacotherapies focus on halting the progression of late stage DR, future treatment strategy would take a preventative approach in targeting the preclinical neuroretinal disease of the retina [27, 28].

This is an idiopathic ophthalmic condition characterised by retinal telangiectasia, haemorrhage, intraretinal and subretinal exudation [80–82]. It is typically seen in young children between 8 and 16 years of age, although several cases have also been reported in adults [83, 84]. While most commonly this is due to a sectorial abnormality of the retinal vasculature (presumed to be congenital) and is unilateral, bilateral disease is recorded and male preponderance is consistently demonstrated in the literature [85]. Most patients present clinically with unilateral decreased vision, strabismus, or leucocoria [86, 87]. Massive secondary exudation leads to retinal detachment and the condition may simulate an exophytic retinoblastoma, which remains the most important differential diagnosis. Previously, enucleation of the eye was advised, but advances in several conservative treatment modalities have rendered enucleation a last resort in most cases. Studies have shown that younger patients tend to have more severe disease, poorer visual outcome and more likely to require primary enucleation [88, 89]. Argon laser photocoagulation is utilized to cauterize abnormal retinal vasculatures with some success, particularly in mild disease with limited exudation [90, 91]. Cryotherapy becomes a favoured choice of treatment in patients presenting with exudative disease and retinal detachment [70]. Vitreo-retinal surgery such as vitrectomy still plays a great role in severe form of Coats’ disease [92, 93]. Enucleation is only reserved for complicated Coats’ disease, such as by neovascular glaucoma. Therefore, enucleation specimens with Coats’ disease are rare now. Intravitreal triamcinolone and dexamethasone implant have been found to be effective as an adjuvant therapy in combination with laser photocoagulation and/or cryotherapy [94, 95]. Most recently, intravitreal anti-VEGF injections have been reported with variable success as an adjunctive to other treatment options [96–99]. The exact pathogenesis of Coats’ disease remains unclear. Most authors propose that sectorial telangiectasia of the peripheral vessels is the basic pathology in this condition; although in some specimens the presence of large dilated blood vessels at the retinal periphery suggests a vascular malformation. It has been postulated that abnormal endothelial cells and pericytes, which subsequently degenerate, cause abnormal retinal vasculature and formation of

Rarer Vascular Disorders Leading to Neovascular Glaucoma

a­neurysms, as well as closure of vessels, leading to ischaemia. Subsequent breakdown of the blood-retinal barrier leads to leakage of exudate into the retina [100, 101]. The effect of leakage of a proteinaceous exudate, fibrin, and red cells into the retina is to destroy the neuronal constituents. Macrophagic infiltration accompanies reactive gliosis and exudation proceeds to intraretinal cyst formation. The exudation of lipid-­rich plasma extends into the subretinal space and anterior chamber, so that the subretinal exudate contains myriads of cholesterol crystals, which attracts numerous lipid- and melanin-­laden macrophages. Studies have shown that nitric oxide and VEGF are significantly elevated in the aqueous humour in advanced Coats’ disease [102, 103]. This finding supports the usefulness of anti-VEGF treatment in Coats’ disease. However, it is thought that the raised VEGF level is more likely to be a sequelae in this disease rather than playing a primary role in the pathogenesis [85]. Proteomic profiling demonstrated the decreased level of several crystalline-related proteins, vitamin A-related proteins and tropomyosin skeleton proteins within the aqueous humour which may provide further insight into the pathogenesis of Coats’ disease [104]. Mutations in NDP gene [105], and ABCA4 gene [106] had been reported in individual cases. Despite several hypotheses and attempts, there is no clear evidence to support the genetic bases of this disease [107–110]. Given the classical lack of family history at presentation, a somatic mutation makes a more compelling hypothesis [105].

Macroscopic Examination In the enucleated eye, the anterior segment will show the changes of neovascular glaucoma and almost invariably there will be a funnel-shaped retinal detachment with one or more thickened yellow plaques at the periphery. Haemorrhagic areas or telangiectatic spots may be evident on the surface of the yellow plaques. In addition to cholesterol crystals, the subretinal space may contain pigmented nodules and subretinal strands derived from the retinal pigment epithelium. Haemogranulomas may also be present. Pronounced thickening and haemorrhage should rouse the possibility of unsuccessful laser treatment (Fig. 4.25a, b). Microscopic Examination Careful histological examination by serial sections is mandatory if dilated thin-walled telangiectatic vessels are to be demonstrated. In some cases it is possible to identify large dilated vessels at the retinal periphery (Fig. 4.25c), while in others the configuration of the vessels appears abnormal. In addition to the telangiectatic vessels, the retinal arterioles and venules show mural thickening either with deposition of PAS-positive material or by subendothelial accumulation of more transparent “watery” material (Fig. 4.25c, d). Exudation into the gliotic tissue may also be in the form of non-staining

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spaces, but more striking are plasma-derived protein-rich exudates containing obvious fibrin. The retina contains foamy macrophages and some of these cells undoubtedly enter the tissue through the intima of the vessels with migration of macrophages and lymphocytes into the subintimal exudates. Frank haemorrhage into the vessel walls and the adjacent tissues may also be a prominent feature. The accumulation of fat (seen as cholesterol clefts) and melanin-laden and lipid-laden macrophages in the subretinal space remain one of the important characteristics of the disease (Fig. 4.25e, f). The retinal pigment epithelium appears to be intact and mitotic figures have not been observed in the monolayer. There is very little evidence of migration of macrophages through Bruch’s membrane, although the cells in the subretinal exudate stain positively with macrophage markers (Fig. 4.25g, h). Non-granulomatous choroiditis has been described in association with exudative retinopathy, but this seems to be a reaction to the exudate rather than the initiating cause. Similarly, neuronal atrophy in the retina is considered to be secondary to ischaemia and retinal detachment. A paradoxical feature of this disease is that a significant proliferative retinopathy does not occur, even though neovascular glaucoma is the cause for enucleation. In advanced disease, calcification due to osseous metaplasia may occur [111].

 oats’ Reaction, Coats’ Response or Coats’ C Syndrome Examination of the literature will reveal that the aetiology of this condition has been a contentious subject, because the secondary changes are so complex that an understanding of the primary disease process is remarkably elusive. This has led to the adoption of the terms “Coats’ reaction”, “Coats’ response” or “Coats’ syndrome” by some authors. These terms had been used to blanket cover the fundal changes which could be observed in a variety of exudative retinopathies [112]. These include retinal vein occlusion [113], retinitis pigmentosa [114], ocular toxoplasmosis [115], familial exudative retinopathy, retinal macroaneurysms and retinal capillary hemangiomatosis [86]. With the advent of fluorescein angiography, it was appreciated that the aforementioned conditions could all produce the end-stage picture described in Coats’ disease. To avoid confusion concerning the differential diagnosis, strict clinical criteria [86] and the patterns seen by fluorescein angiography should be taken into account for the provision of an accurate diagnosis and the assessment of treatment. Other investigative modalities—such as ultrasonography, computed tomography (CT) scan, and magnetic resonance imaging (MRI)—should be employed to exclude retinoblastoma due to its significant implications. In adults, fluorescein angiography will enable a distinction to be made between macroaneurysms, telangiectatic areas, miliary aneurysms, retinal angiomas, and arte-

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Fig. 4.25 (a) The macroscopic appearance of a case of Coats’ disease, which was treated unsuccessfully by laser ablation, which caused retinal haemorrhages (arrowheads). The subretinal exudate contains compact granulomas (*), which could be mistaken for exophytic retinoblastoma tumour tissue. (b) The paraffin section of the globe shown in (a) reveals the true nature of the subretinal masses (*). Note the absence of preretinal neovascularisation. (c) The walls of the vessels in the retina are thickened by exudation in Coats’ disease (arrowheads) and this is accompanied by cellular infiltration. (d) A semithin section

demonstrates infiltration of the subintimal exudate (*) by inflammatory cells (arrowhead). (e) The subretinal proteinaceous exudate contains numerous cholesterol crystal clefts (arrowheads) and foamy macrophages. (f) When the subretinal exudate is spread on a slide and examined by polarised light the birefringent cholesterol crystals are square or rectangular. (g, h) The cells in the subretinal exudate (arrowheads) stain positively with the CD68 antibody, which demonstrates the predominance of infiltrating macrophages

Rarer Vascular Disorders Leading to Neovascular Glaucoma

g

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h

Fig. 4.25 (continued)

riovenous shunts [116]. Macroaneurysms are observed clinically as relatively large isolated ovoid structures projecting from the wall of an arteriole: Identification in a pathological specimen is a rarity. All of these vascular abnormalities may be associated with macular oedema and retinal exudation, but the process is not as extensive as that seen in the globes of children whose disease presents to the pathologist at the end stage of the disease. There seems to be little advantage in grouping the adult entities under the umbrella of Coats’ syndrome.

I diopathic Juxtafoveolar Retinal Telangiectasis Idiopathic juxtafoveolar retinal telangiectasis (IJRT), also known as parafoveal/perifoveal telangiectasis or idiopathic macular telangiectasia, refers to a group of clinical entities characterized by incompetent, telangiectatic capillary network affecting only the juxtafoveolar region of one or both eyes. These entities differ in appearance, presumed pathogenesis, and management strategies. They are distinguished from more generalized retinal telangiectasis (such as in Coats’ disease) or secondary juxtafoveal retinal telangiectasis due to retinal vein occlusion, diabetes, irradiation, or carotid artery obstruction. Based largely on the clinical and fluorescein angiographic (FA) features, the Gass–Blodi classification is the most commonly used to date [117]. IJRT is divided into three distinct groups I, II, and III, with two subgroups in each (A and B), based on demographic difference or clinical severity [118]. Group I is congenital and predominantly presenting in males with unilateral easily visible telangiectasia on fundoscopy and macular oedema. Vision loss is usually due to exudation in the macula. Histopathological examination of IJRT I shows dilation of capillaries, aneurysms, leakage, and minimal nonperfusion. Photocoagulation remains the mainstay of treatment in controlling the macular oedema. Due to the rarity of the condition, only two cases with the use of anti-­ VEGF therapy reported recently showing promising outcome [119, 120].

Group II is acquired and the commonest. It is bilateral, commonly seen in both middle-aged men and women. Telangiectasia in this group is much more difficult to detect on biomicroscopy, but with characteristic and diagnostic features on fluorescein angiography (FA) and optical coherence tomography (OCT). These features include the absence of prominent aneurysms or haemorrhage, cystic macular oedema, or lipid exudation (unless subretinal neovascularization has developed). Foveal atrophy may be visualised with OCT [118, 121]. Progressive visual loss is due to retinal atrophy rather than exudation. Subretinal neovascularization (SRNV) is common and can result in rapid visual loss. Most histological studies document the late stage of abnormalities including: parafoveal telangiectasis, macular oedema, neovascularisation in all layers of the retina, retinal pigment epithelium proliferation, and retinochoroidal anastomoses [122]. Treatment options are limited but anti-VEGF injections in combination with photodynamic therapy (PDT) have shown encouraging results [123–125]. Group III is very rare and poorly understood. It is characterized predominantly by bilateral easily visible telangiectasis, minimal exudation, and progressive obliteration of the perifoveal capillary network [118].

Retinopathy of Prematurity Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder affecting premature infants. In the most extreme form, exuberant neovascularisation at the periphery with ingrowth into the vitreous leads to retinal detachment and the formation of a white retrolental fibrous membrane in both eyes. Formerly the term “retrolental fibroplasia” was used for the bilateral blinding condition, which was sometimes treated by enucleation to exclude the possibility of retinoblastoma. The majority of cases, however, suffer from mild retinal disease and in many there is spontaneous regression. Non-invasive techniques for the measurement of blood

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oxygen levels permit a more appropriate control of the oxygen levels in the incubator. Despite this, the incidence of ROP continues to increase due to the advances in neonatal care resulting in improved survival of extremely low birth weight infants. Currently, oxygen use and gestational age/ birth weight of the baby remain to be the major risk factors for ROP [126, 127]. The pathogenesis is not fully understood. Based on animal models, it is thought that ROP is a biphasic disease. As retinal blood vessels only reach the periphery just prior to birth, premature infants will therefore have a peripheral retinal avascular zone at birth. If given high oxygen supplementation at birth, physiological secretion of angiogenic growth factors will be suppressed, leading to a regression of existing blood vessels—the “loss phase” of ROP.  Once returned to atmospheric oxygen level, the retina becomes ischaemic due to the under-developed vascular system, triggering the hypoxia-induced secretion of angiogenic growth factors, resulting in the “vessel-proliferation phase” of ROP [128, 129]. Several angiogenic factors have been implicated in the intravitreal neovascularisation in ROP, including VEGF [130], Placental Growth Factor (PlGF) [131], Insulin-like growth factor-1 (IGF-1) [132, 133] and erythropoietin (EPO) [134]. Recent studies have shown that hypoxia- or oxidative-­ induced factors in glial or neural cells mediate overactive signalling of VEGF through VEGF receptor 2 (VEGF2) in endothelial cells. This in turn triggers downstream signalling events that result in the disorientation of endothelial cell divisions and enabling cells to grow outside the plane of the retina, i.e. into the vitreous [135–137]. Continuing neovascularisation leads to extraretinal fibrovascular proliferation, producing a fibrous scar extending from the retina to the vitreous gel and lens. Retraction of this scar tissue can result in tractional detachment of the retina. According to the International Committee’s (CCRP/ CRPCG) recommendation [138, 139], the disease should be accurately staged in order to assess the effects of cryotherapy, which has proved to be advantageous in arresting the disease. The staging, which is performed by indirect ophthalmoscopy, is as follows [139]: 1. Stage 1 (Demarcation line): A demarcation line is seen between the vascularised retina and the avascular retina. 2. Stage 2 (Ridge): Neovascularisation occurs as isolated tufts within the vascularised retina and a ridge forms between the avascular and vascular tissue. 3. Stage 3 (Extraretinal fibrovascular proliferation): Extra-­ retinal neovascularisation extends from the ridge into the vitreous. 4. Stage 4 (Partial retinal detachment): Typically, retinal detachments begin at the point of fibrovascular attachment to the vascularised retina.

4  Retinal Vascular Disease

5. Stage 5 (Total retinal detachment): These are usually tractional with funnel shape and rarely exudative in nature. “Plus disease” is a clinical term used to describe dilation and tortuosity of retinal arterioles and veins in ROP.  This can now be assessed by computer owing to the advances in retinal imaging such as contact imaging which produces wide angle retinal images of infant retina [140–142]. In addition, sd-OCT has also become a useful tool to show structural features that correspond to the histologic changes described in premature and developing infant retinas [143, 144]. Inner retinal layers typically remains into later years [145]. The photoreceptor layer is found to be thinner or absent at early post-gestational ages and develop later in life [146]. Cysts within the inner layers of the retina could be seen [147]. The standard of care for ROP now is laser ablation to the peripheral avascular retina through indirect laser delivery system. Cryotherapy has fallen out of favour since the advent of indirect laser delivery system [148]. The use of anti-VEGF factors have shown initial satisfactory results in selected reports [149–152]. Autopsy material may provide the rare opportunity to study the disease in Stages 1, 2, and 3. In the region of neovascularisation, proliferating endothelial buds are prominent within the retina and the preretinal capillaries form delicate fronds on the inner limiting membrane (Fig. 4.26). At the end stage of the disease, in which neovascular glaucoma leads to enucleation, it is often impossible to make more than a confirmative histopathological diagnosis. Macroscopically, the retina is distorted into a table-top detachment over a solid proteinaceous exudate (Fig. 4.27a). The preretinal fibrovascular proliferation within the organised vitreous leads to marked corrugation and folding of the

Fig. 4.26  At an early stage in retinopathy of prematurity the ischaemic retina is gliotic and avascular. The wave of new blood vessels is both intraretinal (irn) and preretinal (prn) (×160). (Section provided by courtesy of Dr. David Lucas)

Rarer Vascular Disorders Leading to Neovascular Glaucoma

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b

Fig. 4.27 (a) The macroscopic appearances of retinopathy of prematurity at the end stage are not specific, but in many cases the distorted retina (r) forms a seemingly rigid straight band behind the lens (l), which in this specimen is calcified. The white flecks in the retina are

due to calcium deposits. (b) Histology from the case shown in (a) revealed retinal gliosis and optic atrophy: note the redundant meninges (×2)

retina with secondary ischaemic infarction at the periphery and gliosis and neuronal atrophy in the posterior retina (Fig. 4.27b).

been reported [154–156]. Current treatment options include laser photocoagulation, cryotherapy, and diathermy to induce involution of the neovascular lesions. Recent advent of antiVEGF therapy has shown promising results in the treatment of proliferative sickle retinopathy [157–159]. In addition, vascular growth factor Angiopoietin-like 4 (ANGPTL4) has been identified as potential contributor in the progression to proliferative retinopathy in sickle-cell retinopathy [160]. This may provide further pharmacological target for future treatment.

Haemoglobinopathies A wide variety of retinal vascular abnormalities are found in the most severe form of haemoglobinopathy: sickle cell disease; i.e., in those patients who inherit the SS alleles rather than normal AA haemoglobin alleles. The occlusion of vessels by the abnormally rigid red cells, combined with stasis, haemolysis, and anoxia, leads to intraretinal and subretinal haemorrhage with subsequent neovascularisation. The neovascularisation is unique, because disc-like areas develop in the mid periphery and the new vessels form a “sea-fan” like structure. The new vessels originate from hyalinised arterioles and venules, the appearance being similar to that seen in central retinal vein occlusion [153]. Even though untreated neovascularisation could lead to vitreous haemorrhage and/or retinal detachment, spontaneous regression in which the proliferated vessels auto-infarct have

Radiation Retinopathy Ionising radiation has been used for some time in the treatment of orbital and periorbital malignant disease and more recently in the treatment of choroidal melanomas; e.g., radioactive plaques and proton beam therapy (see Chap. 5). Radiation damages the endothelial cells of the retinal vasculature and may lead to radiation retinopathy. Many factors are known to potentiate radiation retinopathy, including increased radiation dosage, increased radiation fraction size, coexisting systemic vascular disease, and

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concurrent chemotherapy [161]. Histologically, there is thickening of arteriolar and capillary walls with loss of endothelial cells. The response is focal closure of the capillary bed, microaneurysm formation, and exudation of lipid-rich plasma into the retina and the subretinal space (see Chap. 2). Retinal ischaemia may lead to neovascularisation on the optic disc, which can result in vitreous haemorrhage and subsequent retinal detachment. Presently there are no guidelines available for the treatment of radiation retinopathy. However, as for other forms of proliferative vascular retinopathy, panretinal laser photocoagulation is the tested treatment option. Encouraging outcomes have been reported with intravitreal anti-VEGF therapy [162–164].

Norrie Disease This rarity is a congenital X-linked recessive disease, which is characterized by atrophic irides, corneal clouding, cataract, and retinal dysplasia with preretinal neovascularisation, which results in retinal detachment followed by phthisis bulbi. Deafness and mental retardation are accompanying features—hence the cumbersome term “progressive oculoacousticocerebral degeneration” [165]. By linkage analysis and positional cloning, mutations in Norrie Disease Protein (NDP) gene on Xp11.3 were identified as cause of Norrie disease [166, 167]. Norrin is the product of the NDP gene. The exact functional roles of Norrin remain elusive. However, research in animal models indicate that Norrin plays an important role in the development of retinal vascularisation by inducing proliferation, migration, and tube formation in retinal microvascular endothelial cells [168, 169]. In addition, studies have also demonstrated the possible neuroprotective properties in Norrin [170, 171]. A range of histological changes have been documented, including retrolental mass consists of proliferation of preretinal fibrovascular tissue and retinal pigment epithelium, retinal haemorrhage, retinal detachment and gliosis, retinal dysplasia with rosettes. These changes in turn result in cataract, iris neovascularisation with glaucoma, and finally, phthisis bulbi [164, 172, 173]. Most pathological studies have been carried out on end-stage specimens, but a relevant report describes avascularity in a retina exhibiting delayed maturation and a retrolental mass that contained collagen and blood vessels [174]. With the advance in genetic testing, several cases of preterm diagnosis with laser photocoagulation immediately after birth have been reported to preserve some vision in patients [175, 176].

4  Retinal Vascular Disease

 ascular Disorders That Rarely Lead V to Neovascular Glaucoma in Adults Central Retinal Artery Occlusion The central retinal artery is an end-artery and obstruction of flow leads to immediate blindness: The retina is white and opaque and the only visible coloration is at the macula where the choroidal circulation provides the classical cherry red spot. Thrombosis (Fig. 4.28) in a degenerate central retinal artery is one cause, but the predisposing causes for endothelial damage are obscure. Atheroma is only rarely encountered (Fig. 4.29). Acute visual loss is more often due to an embolus, typically from the endocardium after an infarct or from an atheromatous plaque in the carotid artery. A variety of other causes of embolisation (even amniotic embolism, or talc particles in steroid suspensions) are cited in the ophthalmological literature, but are rarely encountered in pathological practice. This is because a total infarction of the retina prohibits the release of vasoformative factors and neovascular glaucoma is a complication in fewer than 5% of cases so that there is rarely the necessity to perform an enucleation. At the end stage, the surviving retina consists of the photoreceptors, the outer nuclear layer and a thin layer of cells in the inner nuclear layer. The way in which the retina disposes of the infarcted tissue remains obscure. A population of microglial cells is present in the normal retina and it must be assumed that such cells are able to phagocytose neuronal debris and leave via the retinal venular bed.

Fig. 4.28  A fibrin (f) thrombus in the central retinal artery (a) stained with Martius Scarlet Blue: note the luminal narrowing (arrowhead). The vein (v) is duplicated (×100)

Vascular Disorders That Rarely Lead to Neovascular Glaucoma in Adults

109

autopsy. If the choriocapillaris is involved there will be exudation beneath the pigment epithelium (Elschnig’s spots), sections of which undergo atrophy or necrosis (Fig. 4.30).

Disseminated Intravascular Coagulopathy (DIC) Any disorder that leads to the formation of small thrombotic microemboli can give rise to visual symptoms due to ­occlusion of the terminal arterioles and the choriocapillaris. The consequent infarction of the retinal pigment epithelium leads to exudative detachments of the retina (Fig.  4.31). Similar intraocular tissue infarction can occur in systemic lupus erythematosus and in the catastrophic antiphospholipid syndrome [178].

Fig. 4.29  Atheroma is something of a rarity in the central retinal artery. A vessel (v) is present in the centre of the plaque, which contains numerous lipomacrophages (l) (×250)

Posterior Ciliary Artery Occlusion The blood supply to the choroid is only endarteriolar at the level of the choriocapillaris (which is supplied in 1 cm wide hexagons). Ischaemia in this tissue is rarely proven but commonly suspected clinically. The response is a total loss of the outer retinal layers.

Ophthalmic Artery Occlusion When the ophthalmic artery is obstructed the dual supply to the globe is cut off and there is ischaemic infarction of all the retinal layers and the uveal tract: Choroidal neovascularisation may nonetheless be observed [177].

Fig. 4.30  An infarct of the retinal pigment epithelium (arrowheads) in a case of malignant hypertension. The walls of the choroidal vessels contain fibrin (arrows) (×300). (Courtesy of the late Dr. Bertha Klein)

Hypertension With current and highly effective therapy, the classical retinal changes in idiopathic malignant hypertension, viz. haemorrhage, exudates, and papilloedema, will not be available for pathological investigation in human eyes, although experimental work continues and hypertension is end stage in domestic pets. In the older literature the retinal vessels were described as narrowed or occluded by fibrinoid necrosis and there was swelling and degeneration of the endothelium distal to the occlusion. A necrotic muscularis, such as is characteristic of hypertensive renal vasculopathy, must be sought for in serial sections. By contrast, the walls of choroidal rather than retinal vessels are often found to be thickened by deposition of PAS-positive material in a hypertensive globe removed at

Fig. 4.31  Occlusion of the terminal arterioles and the choriocapillaris by fibrin thrombi (arrowheads) in a case of DIC following thrombocytopenia during treatment for chronic myeloid leukaemia (×350). (Courtesy of Professor Ahti Tarkkanen)

110

 horoidal Neovascularisation and Age-­ C Related Macular Degeneration (ARMD) Choroidal Neovascularisation The term choroidal neovascularisation (CNV) refers to fibrovascular proliferation, initially between Bruch’s membrane and the retinal pigment epithelium and subsequently between a

c

e

4  Retinal Vascular Disease

the latter and the photoreceptor layer of the retina (Fig. 4.32). This process can occur at the retinal periphery [179] and at the edge of the optic disc, but most importantly, macular involvement is sight threatening. The fragile capillaries tend to bleed and subretinal neo-vascularisation is complicated by macrophagic organisation of haemorrhage with ultimately the formation of dense fibrous tissue (a disciform scar). CNV is most frequently seen in “wet/exudative age-related macub

d

f Choroidal neovascularisation or Sub RBE neovascularisation

Soft drusen

Fig. 4.32 (a) In the pathogenesis of exudative ARMD it is assumed that an abnormal deposit (arrowheads), in this case basement membrane deposit (bmd), stimulates invasion by endothelial cells (arrow) and macrophages. (b) Separation of the RPE from Bruch’s membrane allows migration of macrophages—in this example, in the form of multinucleate giant cells (arrows) (picro-Mallory V). (c) As the disease progresses it is possible to identify feeder vessels (arrows) that supply the fibrovascular mass beneath the RPE.  Note also the layer of pink

Basement membrane deposit

staining basement membrane deposit beneath the retinal pigment epithelium (arrowhead) (PAS). (d) Toward the edge of the sub RPE plaque the fibrovascular tissue (arrow) thins out (Picro-Mallory V). (e) Photoreceptor atrophy has occurred over this thicker fibrovascular plaque. Note the blue staining basement membrane deposit (arrowheads) beneath the RPE. (Picro-Mallory V). (f) A diagram to illustrate the two types of deposit (soft drusen and basement membrane deposit) that are thought to stimulate (choroidal neovascularisation)

Choroidal Neovascularisation and Age-Related Macular Degeneration (ARMD)

lar degeneration (ARMD).” This is in contrast to a second form of age-related macular degeneration manifest simply as progressive atrophy of the RPE and photoreceptor layer— areolar/geographic atrophy (“dry age-related macular degeneration”) (see later in this chapter). However, CNV can also be seen in pathological myopia, angioid streaks, ocular histoplasmosis, and traumatic choroidal rupture. Reduced visual acuity is the inevitable outcome when choroidal neovascularisation destroys the macular photoreceptors and considerable effort has gone into the investigation of the pathogenesis and treatment of ARMD in the elderly.

Age-Related Macular Degeneration (ARMD) This disease is an important cause of visual deterioration in the ageing population and it is classified into two types: the “dry” and the “wet” types. The pathogenesis is still not fully understood but it is believed to be multifactorial with genetic and environmental factors playing their parts. Fifty two variants at 34 genetic loci had been identified to be associated with late ARMD, accounting for more than half of the genomic heritability of ARMD [180]. Of these, large genome-wide association studies suggested the causal roles of variants in Complement H, Complement I and TIMP metallopeptidase inhibitor 3 (TIMP3) in the pathogenesis of ARMD [180, 181]. Dysregulation of the complement system has been shown to have a major part in the pathogenesis of both dry and wet ARMD [182, 183]. In addition, variant of age-related maculopathy susceptibility 2 (ARMS2) locus has also been implicated [184]. There is also emerging evidence of specific epigenetic mechanisms associated with ARMD [185]. VEGF is a key regulator of angiogenesis and is found in high concentrations in the CNV of patients with ARMD [7, 186, 187]. VEGF increases retinal vascular permeability and promotes neovascularization [188]. It is postulated that the two major pathways by which the RPE cells produce and secrete VEGF-A are in response to complement [189, 190] and oxidative stress [191]. The normal process of photoreceptor renewal is probably disturbed (see Chap. 9) and the selective nature of the photoreceptor atrophy confined to the macula implies that this region of the retina with the densest concentration of cone photoreceptor cells is the obvious target for photochemical damage and oxidative stress [192, 193]. Non-genetic risk factors for ARMD have also been implicated in numerous studies, such as age, female gender and race (European Caucasian) [194]. In addition, environmental factors such as smoking and diet are the important modifiable lifestyle risk factors [195, 196]. The clinical and macroscopic changes in the macula, pigmentary stippling and depigmentation, do not always provide an accurate indication of the degree of damage that is apparent on histological examination [197–199]. By fundus

111

examination, it is possible to diagnose early stages of ARMD by identifying confluent regions of small discrete pale yellow dots (hard drusen) and larger pale yellow more diffuse dots (soft drusen) beneath the macula. These are multicomponent, heterogeneous aggregates that lie both external and internal to the RPE cells [200, 201]. By contrast in “geographic” or “areolar” atrophy—the end stage of dry ARMD, owing to the irregular shape of the atrophic area as seen on fundoscopy or macroscopic examination (Fig.  4.33), there are irregular areas of atrophy and pallor with exposure of the underlying choroidal vessels. In dry ARMD, the common denominator at the histological level is atrophy of the inner and outer segments of the photoreceptors and depletion of the outer nuclear layer to a point where this layer is replaced by glial cells. A variety of changes may be found in the retinal pigment epithelium, which may be hypertrophic, hyperplastic, atrophic, or completely absent with fusion of the gliotic outer retina with Bruch’s membrane. Underlying choriocapillaries may also be lost [202]. Several types of deposit can be found by light microscopy in the ageing retina between the RPE and Bruch’s membrane and the abnormality is considered to be the response of the RPE to stress. The terminology of sub-RPE deposits is controversial, but recent review articles by Abdelsalam et  al. [203] and Spraul et al. [204] provide comprehensive contemporary accounts. Drusen (Fig. 4.34) can either be hyaline and well circumscribed, often described as “hard,” or have a granular and vesicular composition with a less distinct border: These structures have been described as “soft drusen” [205]. The latter abnormality can be more extensive and in these circumstances is sometimes referred to as “confluent soft drusen”. Green and Enger [206] have used the term “basal linear deposit” to describe confluent soft drusen. Electron microscopy is helpful in the separation between soft and hard drusen, both of which take the form of deposits between the RPE cell basal membrane and the inner collagenous layer of Bruch’s membrane. Drusen is found to contain neutral lipids with esterified and unesterified cholesterol which accounts for more than 40% of its volume [207]. Other components include more than 129 different proteins [208]—including TIMP3, vitronectin, beta-amyloid, apolipoproteins, proteins involved in complement regulation, and zinc and iron ions [209]. A different type of deposit is found between the cytoplasmic membrane and the basement ­membrane of the RPE; this change has been classified in the past as “basal linear deposit” or “basal laminar deposit” (BLD). By light microscopy, using the Periodic Acid Schiff and picro-Mallory V stains, BLD appears as a series of spiky deposits beneath the RPE (Figs. 4.32 and 4.34) At the ultrastructural level this deposit consists of strands of basement membrane at the earliest stage (Fig. 4.35) later these strands are interspersed between clumps of wide banded collagen.

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4  Retinal Vascular Disease

a

b

c

d

Geographic or Areolar atrophy

Fig. 4.33 (a) On macroscopic examination of dry ARMD, the macular area is atrophic (arrowheads) and the underlying choroid is exposed. The disc is cupped due to glaucoma. The white spot is a photographic artefact. (b) At the edge of the atrophic area there is a progressive depletion of the photoreceptor layer (arrowhead). In the centre the photore-

ceptor layer is lost and the retina fuses with Bruch’s membrane (arrow) (×40). (c) In the centre the outer retina is replaced by glial cells (arrowheads) and the tissue is fused with Bruch’s membrane. The adjacent RPE is hyperplastic (×80). (d) A diagram to illustrate the pathology of areolar or geographic atrophy

Multinucleate giant cells are easily identified in the basement membrane deposit [210–213] and it seems likely that owing to the attraction of this material to macrophages, it is the substrate most likely to be vascularised in the earliest stages of disciform degeneration. It is impossible to identify pre-existing soft drusen in an established disciform mass. It should be noted, however, that by conventional histology it is not uncommon to find all three types of sub-RPE deposit in the early stages of ARMD. To avoid confusion with the acronym BLD, which stands for “basal linear deposit” or “basal laminar deposit” and has been ascribed to different pathologies by different authors, it is preferable to use the term “basement membrane deposit” (the acronym, BMD) for the deposit found between the cell membrane and the basement membrane [214]. Each of the deposits upon Bruch’s membrane has been the subject of intense speculation in terms of their significance in attracting the macrophages, endothelial cells, and pericytes, which are the basis of the pathogenesis of vascular

proliferation under the RPE (disciform degeneration of the macula). Two important changes occur in Bruch’s membrane as part of the ageing phenomenon—deposit of lipids and calcification—and these have been implicated in the pathogenesis of wet and dry ARMD.  Thin layer chromatography has shown that phospholipids, triglycerides, fatty acids, and cholesterol are at higher concentration in the macular region of Bruch’s membrane than in the periphery and this is presumably an effect of the breakdown in synthetic activity of the RPE cells. Alternatively this accumulation could lead to a serious impedance of metabolites from the choriocapillaris to the pigment epithelium [215]. Calcification of Bruch’s membrane, although common, does not appear to be of significance in the photoreceptor atrophy associated with ageing. In some hypercalcaemic states (e.g., Paget’s disease of bone and angioid streaks), Bruch’s membrane also becomes calcified and the membrane may in this circumstance fracture to provide an ingress for mesenchymal cells.

Choroidal Neovascularisation and Age-Related Macular Degeneration (ARMD)

a

113

b

Hard drusen or colloid bodies

Cytoplasmic membrane of cell Basement membrane of RPE cell Inner collagenous layer Elastic layer Outer collagenous layer

Choriocapillaris

d

c

Soft drusen or Basal linear deposit

114.62

Cytoplasmic membrane of cell Basement membrane of RPE cell Inner collagenous layer Elastic layer Outer collagenous layer

Choriocapillaris

Basement membrane deposit

e

f

Cytoplasmic membrane of cell Basement membrane of RPE cell Inner collagenous layer Elastic layer Outer collagenous layer

Choriocapillaris

Fig. 4.34 (a–f) Diagrammatic and histological illustrations of the various forms of sub-RPE deposits; (b, d) are stained with HE; (f) is stained with picro-Mallory V

114

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off-label alternative due to its similar efficacy and lower price tag compared to Ranibizumab [219, 220]. Intravitreal injection of Aflibercept is the most recent emerging treatment which shows promising result by blocking all VEGFA isoforms, VEGFB and placental growth factor (PlGF) [18, 221]. Given the genetic element in the pathogenesis of ARMD, gene therapy involving expression of anti-­angiogenic proteins by gene delivery is being developed [222]. In contrast to wet ARMD, clinical success in treating dry ARMD remains elusive. However, as complement inhibition had been discovered as a potential therapeutic pathway in dry ARMD [223], drugs targeting the complement pathway, such as eculizumab and lampalizumab are being tested in clinical trials [224, 225]. Stem-cell-based therapies are also being explored [222, 226]. With the emphasis of personalized medicine, future therapeutic strategies for ARMD are likely to be a combination of modification of risk factors (diet, lifestyle) and pharmacological intervention whilst taking into account personal genetic information [227].

Disciform Degeneration Disciform degeneration of the macula refers to the full-­ blown manifestation of subretinal neovascularisation and conventionally it was one of the conditions that was listed in the differential diagnosis of choroidal melanoma (Fig. 4.36). Wet ARMD is the commonest precursor of disciform degeneration, but in many cases this primary pathology will have Fig. 4.35  At the ultrastructural level, basement membrane deposits been obliterated by the time a full-blown disciform degenappear as electron dense strands between the cell membrane (arrow- eration is examined. heads) and the basement membrane (arrows). In the ageing eye, Bruch’s In an enucleated eye, the macroscopic appearances are membrane is thickened by deposits of cellular debris and the elastic related to the extent of the haemorrhage and the stages of layer becomes calcified (×5000) resolution. At the earliest, the mass consists of altered blood, Traditionally, fluorescein angiography or indocyanine but later deposits of cholesterol may appear, as may intraretigreen angiography is employed in the diagnosis and manage- nal exudation with cyst formation. At the macula, the process ment of wet-ARMD. With major advances in retinal imag- is usually dominated by fibrosis and this tissue may be piging, the non-invasive spectral-domain optical coherence mented as a consequence of reactive proliferation of the retitomography (sd-OCT) and fundus autofluorescence imaging nal pigment epithelium and deposition of the breakdown with improved resolution, are now the preferred choices in products of blood. There is often exudative detachment of management of the ARMD.  OCT-Angiography has proven the retina so that it is not surprising to find a pseudoretinitis to be a useful non-invasive modality that does not require pigmentosa pattern (see Chap. 2) at the periphery of the disciform lesion. In many cases the picture is obscured by secdye [216]. In the past, laser photocoagulation was the only available ondary haemorrhage. Microscopic study benefits from the use of serial section, treatment option for wet ARMD. Photodynamic therapy with because it is important that the search for the precursors of verteporfin was adopted for wet ARMD with subfoveal choroidal neovascularisation (CNV) [217]. Treatment modali- the degenerative processes should be continued. It is also ties for wet ARMD have improved dramatically over the past noteworthy that it is only with difficulty that the feeder 2 decades with the emergence of anti-VEGFs. Licensed anti-­ vessel(s) that penetrate Bruch’s membrane are found. VEGFs for wet ARMD include pegaptanib (Macugen) [218] Irrespective of section level, the disciform mass will contain and ranibizumab (Lucentis). Ranibizumab is now considered fibroblasts, capillaries, collagen matrix, haemomacrophages, the standard of care for wet ARMD [15, 16]. Bevacizumab lipomacrophages, lymphocytes, and proliferating RPE cells (Avastin), although not licenced for ocular use, is a favourite (Figs.  4.37 and 4.38). The metaplastic RPE cells produce

Choroidal Neovascularisation and Age-Related Macular Degeneration (ARMD)

a

b

c

d

e

f

Fig. 4.36 (a, b) Microscopic and macroscopic features of a globe in which there was extensive haemorrhage to the temporal side (arrow) from a disciform scar at the macula. (c) This disciform scar formed a rounded mass at the macula and simulated a malignant melanoma. (d) On rare occasions the submacular disciform scar may bleed through the retina into the subhyaloid space. (e) Extensive exudation of a lipopro-

115

teinaceous exudate from the disciform scar has detached the retina. (f) Extensive intraocular haemorrhage from a disciform scar in a case of disseminated intravascular coagulation (DIC). The detached retina is necrotic (arrow). This globe was divided before the intraocular blood was fixed and coagulated so that there is unacceptable scleral contamination in terms of presentation

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4  Retinal Vascular Disease

a

b

Fig. 4.37  An early submacular disciform proliferation seen at the ultrastructural level. Capillaries (c) are present in the fibrous tissue under the retinal pigment epithelium. Bruch’s membrane (arrowheads) is intact (×2000)

Fig. 4.38 (a) A typical example of a full-blown disciform degeneration. A fibrovascular mass forms under the retina at the macula (×16). (b) The feeder vessel (fv) with adjacent metaplastic and proliferated retinal pigment epithelium (rpe) is shown at a higher power (×250)

collagen and strands of membrane that resemble thickened basement membrane.

I nflammatory Disease Associated with Neovascularisation

 xcised Submacular Membranes E In the pre-anti-VEGFs era, surgical attempts had been made to improve vision in cases of age-related macular degeneration. The macula is lifted by subretinal fluid injection in order to excise the membranes. When the subretinal or intravitreal bleeding is extensive, vision is lost and an enucleation may be performed to exclude neoplasia (Fig.  4.36). The excised submacular fibrovascular membranes will be submitted for histopathological examination for confirmation of the clinical grading [228, 229]. It is occasionally possible to identify fragments of Bruch’s membrane, the choriocapillaris or the deeper choroid. Specific features to look for within the fibrovascular membrane (Fig. 4.39) are lymphocytes, macrophages, and fibroblasts derived from metaplastic RPE [230–233]. The fibrovascular tissue is often lined by a layer of RPE cells.

In pathological material, focal inflammatory disease in the choroid is not commonly associated with subretinal neovascularisation. In “presumed ocular histoplasmosis” (POH), a triad of signs is identified clinically: scars and haemorrhagic detachment of the macula, peripheral punched out areas of chorioretinal atrophy, and peripapillary chorioretinal scarring (see Chap. 6). In Europe there is no serological evidence of histoplasmosis, but the terminology is now established even though the pathogens have never been demonstrated in this continent. Histology of the disciform scars has been non-­specific and has shown that the subretinal lesions contain RPE cells, lymphocytes, fibroblasts, and capillaries [234]. The histological pattern in presumed ocular histoplasmosis is indistinguishable from early disciform degeneration [235].

References

a

117

b

Fig. 4.39 (a) Tissue excised from a submacular disciform plaque (×40). (b) The surface is lined by RPE cells (arrowheads), which have become detached from Bruch’s membrane. The fibrovascular tissue contains lipid laden macrophages (arrow) (×100)

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5

Intraocular Tumours

Introduction

Melanocytic Tumours

Benign and malignant tumours arise most commonly from melanocytes in the uveal tract, and, prior to modern treatment methodologies, malignant melanoma of the choroid was the most frequently encountered tumour in the routine laboratory. The anatomical distribution frequency of uveal melanomas is 2–3% in iris, 3–5% in ciliary body and more than 90% in choroid [1]. The malignant tumour of retina, retinoblastoma, which is inherited in a small proportion of cases, arises in embryonic tissue rests. Although the incidence in the population is lower than melanoma, the occurrence in infants and the difficulty in the differential clinical diagnosis within a group of entities that may mimic this neoplasm emphasise the importance of this tumour. If a primary site is unknown, metastatic tumours to the uveal tract are a diagnostic problem in clinical practice but are rare in routine pathology, although such tumours are said to be the commonest in autopsy material. Lymphoid tumours occasionally occur in the uveal tract and diffuse large cell B cell lymphoma may involve the central nervous system and the retina sometimes in association with human immunodeficiency virus (HIV). Vascular tumours of the retina and choroid may be associated with malformations in the central nervous system (CNS) and skin (von Hippel-Lindau [familial cerebelloretinal angiomatosis] and Sturge-Weber syndrome[encephalotrigeminal angiomatosis] respectively). Tumours of the epithelium of the ciliary processes and the pigment epithelium of retina are rare as are the tumours derived from the glial cells (astrocytes) of the retina.

Introduction Naevi and malignant melanomas arise in the iris, ciliary body, and choroid and the management of these tumours. Primary enucleation for melanoma is now less common and thus it is increasingly likely that the pathological changes in a globe containing a malignant melanoma will show additional treatment effects due, for example, to photocoagulation, cryotherapy, external irradiation, brachytherapy, or a previous attempt at a tumour excision that included the inner sclera (“local resection” or “eye-wall excision”).

Benign Melanocytic Tumours (Naevi) Incidence Naevi of the iris, ciliary body, and choroid will be found most commonly as an incidental finding in globes enucleated for unrelated disease. The majority of pigmented naevi that are observed in vivo are static or have only a slow growth potential. There is no doubt, however, that some malignant melanomas arise within naevi of the uveal tract. This is difficult to estimate as it depends on age at detection, surveillance and size of the naevus. However, at least 1 in 10 melanomas are considered to arise within pre-existing naevi [2]. The histological distinction between an active naevus and a low-grade melanoma can be difficult. The pathologist should become familiar with differences in uveal pigmentation: this can vary from no pigmentation to diffuse enlargement and prominence of the normal melanocytes throughout the uveal tract.

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Iris Naevus In the iris, the simplest form of melanocytic proliferation is a freckle. In vivo, or by macroscopic examination, freckles are seen as light brown spots on a blue or green iris. The histological equivalent is a cluster of small brown pigmented spindle cells on the anterior surface of the iris stroma. Larger nodules of lightly pigmented uniform spindle cells on the anterior surface of the iris (see Chap. 8) have been described in Down syndrome and neurofibromatosis. An iris naevus forms a flat pigmented patch occupying a sector or an even larger area, and such tumours may be static or enlarge slowly over decades. The cytological characteristics of naevi are somewhat variable and so too is the pigment content, which may be so heavy that bleaching (with permanganate/oxalic acid solutions) will be required for study of the cellular detail. By contrast, large clear “balloon cells” may predominate in a “balloon cell naevus” [3]. Melanocytoma, formed by large innocuous cells containing numerous melanosomes, is rare in the iris [4]. Naevus cells are most commonly spindle-shaped with an even distribution of condensed chromatin in small nuclei of uniform size (Fig. 5.1a, b). Naevi are predominantly situated in the anterior stroma and do not involve the posterior pigment epithelium [5]. Genetic studies on iris naevi have identified mutations in EIF1AX, NRAS, PTEN, KIT, TP53, GNAQ and GNA11 [6]. Naevi that are predominantly stromal and show some cells with recognisable nucleoli may be classified as borderline naevi [5]. A proportion of these harbour BAP1 mutations and may be designated iris melanocytic tumours of uncertain malignant potential [6]. The presence of widespread nucleolation and mitotic figure should arouse a suspicion of a lowgrade melanoma [5].

a

5  Intraocular Tumours

I ris Naevus Syndrome In one rare condition—the iris naevus syndrome—enucleation may be necessary in treatment of the associated severe secondary open angle glaucoma [7, 8]. It is more likely that the pathologist will receive a diagnostic iridectomy specimen. The iris naevus is composed of heavily pigmented small spindle cells of uniform size and the cells may fill the iris stroma. The extensive cellular proliferation may present clinically as a change in colour of the iris (heterochromia). Glaucoma is due to degeneration of the trabecular endothelial cells, which are overburdened with melanin and this leads to fusion of the trabeculae [7]. A secondary downgrowth of the corneal endothelial cells (see Chap. 3) is followed by the formation of a secondary Descemet’s membrane, which lines the chamber angle and the anterior surface of the iris and obstructs aqueous outflow (Fig. 5.2).

Fig. 5.2  This form of iris naevus syndrome is ascribed to Cogan and Reese: nodules of melanocytes are present on the anterior surface of a secondary Descemet’s membrane (arrows), which has spread across the outflow system onto the anterior surface of the iris. The stroma is heavily pigmented. (Courtesy of the late Professor Basil Daicker)

b

Fig. 5.1 (a) Minor thickening of the iris stroma (arrowheads) due to a collection of naevus cells. (b) The anterior iris stroma contains heavily pigmented naevus cells

Melanocytic Tumours

 iliary Body Naevi C The true incidence of naevi of the ciliary body is unknown and tumours similar in histological characteristics to those seen in the iris (i.e., lightly pigmented banal spindle cell tumours) are excessively rare. However, balloon cell naevi have been reported.  iliary Body Melanocytoma (Magnocellular C Naevus) Occasionally a melanocytoma is encountered in the ciliary body [9–12]. Macroscopically this tumour is intensely black and microscopically it is formed from oval cells, which are large and have a remarkably dense cytoplasmic content of small spherical melanin granules: the nucleus is eccentric and small and nucleoli are inconspicuous. Melanin bleaching is essential for the diagnosis (Fig.  5.3a, b). Mitotic figures are not found. Such tumour cells may be present in the chamber angle, in the trabecular meshwork which can result in secondary melanocytomalytic glaucoma [4]. Iris and ciliary body melanocytomas may undergo spontaneous necrosis [4, 13]. Extrascleral extension with an episcleral nodule or visible subconjunctival pigmentation can occur [11]. GNAQ mutations have been identified in melanocytoma [14]. In rare instances malignant transformation may occur and this has been associated with BAP1 mutations [14]. Melanocytomas can be monitored with clinical examination. Surgery is now uncommon except for cases with secondary glaucoma or where growth causes concern for malignant transformation. Choroidal Naevus Choroidal naevi are estimated to have an overall prevalence of around 2% but highest in white populations (around 4%) [15]. The cells in a choroidal naevus are normally of small spindle cell type and are heavily pigmented. The nuclei are uniform and mitotic figures are absent. Naevi in the choroid tend to thicken the tissue, but a useful diagnostic feature is a

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that the choriocapillaris is usually spared. Nonetheless, naevi can, in rare cases, disturb the choroidal circulation and cause an exudative detachment of the overlying retina (Fig. 5.4); the ensuing visual field loss may lead the clinician to suspect malignant transformation, which is a well-­ recognised event in choroidal naevi [16]. Naevus cells in the choroid can be in continuity with similar pigmented dendritic cells in the walls of intrascleral canals; this must not be misinterpreted as a malignant infiltration of perineural sheaths or of perivascular tissue. Similar to iris naevi GNAQ and GNA11 mutations have been reported albeit at low frequency in choroidal naevi [17].

 ilateral Diffuse Uveal Melanocytic Hyperplasia B This disease also known as “bilateral diffuse uveal melanocytic proliferation”, or BDUMP is a rare paraneoplastic syndrome in which there is bilateral diffuse proliferation of benign melanocytes in the uvea in individuals with underlying extraocular malignancy [18–20]. The uveal tract is diffusely thickened with nodular foci of naevus cells which can involve the choriocapillaris [21]. The cells are usually spindle shaped with inconspicuous nucleoli and mitotic figures are usually absent [21]. Cytogenetic studies have shown gains in chromosome 6 and 5 with polysomy 8q [21]. The

Fig. 5.4  A choroidal naevus contains small cells with uniform nuclei similar to those shown in Fig. 5.1. This example is heavily pigmented (×100)

b

Fig 5.3 (a) Melanocytomas of the ciliary body tend to spread to the episcleral (arrow), but this is not of prognostic significance. (b) After bleaching the constituents cells are large with eccentric nuclei. (Courtesy of Professors Naumann and Mark Tso)

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importance is that there may be a primary tumour elsewhere in the body and that the globe may be enucleated with the mistaken diagnosis of diffuse melanoma.

Malignant Melanoma of the Uveal Tract

 ysplastic Naevus Syndrome D In the dysplastic naevus syndrome, also known as familial atypical multiple mole-melanoma syndrome there is autosomal dominant inheritance of unusual or dysplastic naevi and melanomas [22]. It is due to a germline mutation in the cyclin-dependent kinase inhibitor 2A (chromosome 9p21) [23]. Whilst these are predominantly cutaneous the condition is also associated with conjunctival and uveal melanomas [24].

 linical and Macroscopic Aspects C Melanoma of the iris is rare. It only constitutes 2–3% of the uveal melanomas [1]. An iris melanoma can arise de novo or develop within a pre-existing naevus that may have been present for many years. The tumours can manifest either as a black, white, pale brown or patchily pigmented solitary nodule, or as a diffusely spreading flat pigmented growth (Fig. 5.5a–c). Alternatively, and as rarities, the presentation may be in the form of multiple white or pigmented “tapioca”like nodules [31] on the iris surfaces (Fig. 5.5d). Prominent blood vessels may lead to a suspicion of a vascular tumour [32]; this vascular component may appear histologically as hyalinised vessels containing small capillaries. Another interesting clinical and macroscopic feature may be a yellow nodule within a pigmented tumour mass; this will be manifest histologically as a focus of balloon cell change (see later in this chapter). As seen gonioscopically or by high power macroscopic examination, solitary or diffuse tumours may spread circumferentially around the chamber angle (ring melanoma) and cause secondary glaucoma by lining and subsequently infiltrating the trabecular meshwork [33]. With the advance in ocular imaging, non-invasive diagnostic method is preferred nowadays with the new generation of ocular ultrasound providing accuracy in diagnosis and monitoring of iris lesions. Anterior segment ultrasound allows monitoring of iris thickness, detection of tumour involvement into the ciliary body, and identification of iris cysts [34]. Should any uncertainty exist, the easy access to iris melanomas has resulted in successful application of fine needle aspiration biopsy and incisional biopsy [35, 36]. Although incisional biopsy is more invasive than fine needle aspiration biopsy, it provides a better specimen. To avoid the potential of seeding of iris melanoma cells along the biopsy tract, a clear corneal approach is recommended [36]. Management for iris melanoma includes observation, plaque brachytherapy, tumour resection or enucleation. If progressing a solitary iris melanoma can be excised within either a sector or quadrant of iris tissue, a “sector” or “broad” iridectomy (Fig. 5.6) If there is the possibility of extension into the iris root and ciliary body, a block dissection of iris, ciliary body, and inner sclera (iridocyclectomy, iridogoniocyclectomy, and sclerectomy) may be performed. For larger tumours and those involving the iris root plaque brachytherapy can be used. Irreversible site limiting complications are uncommon [37, 38]. With extensive seeding proton beam irradiation [39], or enucleation can be used. Enucleation is

Rare Benign Melanocytic Proliferation Ocular Melanocytosis This is a congenital disorder causing obvious patchy slate grey scleral pigmentation due to the presence of excessive numbers of dendritic melanocytes in the tissue: the disorder affects all races [25, 26]. Pigmentation of the cornea and lens may also occur, although this does not fit with an abnormality of neural crest cells. Dendritic melanocytes are also abnormally abundant throughout the uveal tract and in the trabecular meshwork, which may be malformed so that the disorder may be complicated by open angle or closed angle glaucoma. When associated with melanocytic accumulation in the dermis of the skin of the face, the condition is referred to as oculodermal melanocytosis (also known as naevus of Ota). Ocular and oculodermal melanocytosis are associated with an increased risk of uveal melanoma [25]. Similar to other melanocytic proliferations mutations have been identified in GNA11 and GNAQ. This shared predisposing mutation may account for the predisposition to melanoma [27].  elanocytomas of the Optic Nerve Head M Similar to its counterpart in the ciliary body these are heavily pigmented melanocytic proliferations of the optic nerve head with involvement of the adjacent peripapillary retina or choroid [28, 29]. Such tumours have a characteristic clinical appearance and are usually simply observed. On histology they are composed of densely pigmented cells and bleaching will show these have small nuclei with abundant cytoplasm. A proportion will show progressive growth and local invasion. They may occasionally cause visual disturbances either following spontaneous necrosis or due to compressive neuropathy. Malignant transformation to melanoma may occur in a minority of cases [30].

Malignant Melanoma of Iris

Malignant Melanoma of the Uveal Tract

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a

b

c

d

Fig. 5.5 (a) This solitary melanoma of the iris had spread around the chamber angle. (b) This solitary melanoma of the iris recurred and expanded posteriorly to involve the ciliary body. (c) The iris is thick-

Fig. 5.6  An iridectomy specimen containing a malignant melanoma that is spreading as an amelanotic sheet towards the excision line (arrowheads). The figure illustrates the difficulty in achieving appropriate clearance blocks

generally reserved for cases of diffuse melanoma where more than half of the iris and trabecular meshwork are invaded by tumour or when there is uncontrollable glaucoma [40, 41].

ened by a diffuse melanoma. (d) Small white tumour nodules (arrow) on the iris surface gave rise to the term “tapioca” melanoma. (Reproduced with permission from Sehu and Lee [281])

 istopathology of Iris Melanoma H In many cases the tumour is amelanotic and the extent of neoplasia is not appreciated by either the surgeon or the pathologist, so that careful orientation for clearance is important in iridectomy specimens (Fig.  5.6). Clinical detection of small recurrences at the edge of the surgical coloboma can be delayed if the surgeon is not forewarned of the possibility. On macroscopic examination, the best strategy is to take one radial block through the centre of the specimen and circumferential blocks for lateral clearance. A problem can arise if the tumour and the iris are friable and become fragmented when the blocks are taken—if the intact specimen is processed through paraffin, more reliable clearance blocks can be taken when the specimen is supported by wax as it cools down. The majority of iris melanomas in primary excision specimens have a benign “aura” on histology, consisting of small- or medium-­sized spindle cells with uniform nuclei and absent or inconspicuous nucleoli (Fig.  5.7a, b). Obvious nucleoli are a good indication of the potentially malignant nature of the tumour even though mitotic figures are rarely if ever found even after prolonged search [40].

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a

Fig. 5.7 (a) Histological appearance of an iridocyclectomy specimen to show peripheral clearance of a melanoma (mm) within the iris and the ciliary body (cb): demonstration of lateral clearance depends on

Whilst low grade spindle cell melanomas predominate Spindle B and epithelioid tumours can occur [40]. In low grade tumours surface spread over the iris stroma and erosion of the iris pigment epithelium can be helpful indicators of malignancy [40]. Surface melanoma cells can adopt a smaller more naevoid appearance with lower proliferation than tumour in the stroma. This is due to aqueous humour modification [42]. Immunohistochemistry using melanocytic markers S-100, HMB 45, Melan-A and MiTF (D5) (anti-microphthalmia transcription factor) plays a limited role and are not useful in distinguishing uveal melanoma from nevus [43]. The proliferative activity of iris melanoma is lower than posterior uveal melanomas and proliferation markers (p53 and Ki67) are of limited help [44]. Iris melanomas contain mutations similar to choroidal and ciliary body melanoma including GNAQ, GNA11 [45] and BAP1 mutations [6]. Clinical data on tumour size and extension (ciliary body, choroid, extrascleral), presence of secondary glaucoma, regional lymph nodes, and distant metastasis (tumour, node, metastasis [TNM] data) should be documented to allow for tumour staging based on the 8th edition AJCCUICC (American Joint Commission on Cancer– International Union Against Cancer) TNM classification of iris melanoma [46]. The small size of the tumour at presentation and the lowgrade histology explains the low metastatic rate if the tumour is treated by adequate primary therapy. Recurrent tumour, after surgery, may cause glaucoma by spread of tumour around the chamber angle and infiltration of the trabecular meshwork and collector channels (Fig.  5.8a, b). In some archival examples of tumour recurrence (Fig. 5.9a, b), large oval “epithelioid cells” and bizarre giant cells and plentiful mitotic figures have been seen and this is accompanied by a

b

carefully taken blocks from the cut surface at the radial edges. (b) The histological appearance of an iris melanoma is often banal with small spindle cells possessing open nuclei and inconspicuous nucleoli (×100)

a

b

Fig. 5.8 (a) Recurrent melanoma after a primary iridectomy excision. The tumour is spreading in a ring fashion around the angle (arrowheads). (b) Recurrent tumour, partly necrotic in the iris and ciliary body after a primary excision. Note the spread into a scleral canal (arrowhead)

tendency to ring spread, but not to an increased metastatic death rate [47]. Clinically, metastases are more likely to develop in those patients who are older and show tumour features of iris root/angle location with elevated intraocular pressure and extraocular extension [48]. The primary therapy does not appear to affect the risk of metastasis [48].

Malignant Melanoma of the Uveal Tract

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 alignant Melanoma of the Ciliary Body M and Choroid Clinical Aspects Only about 3–5% of uveal melanomas arise in the ciliary body [49]. Malignant melanomas of the ciliary body present most commonly with visual disturbances, owing to disa

b

Fig. 5.9 (a) An inadequately excised iris melanoma recurred and resulted in glaucoma, which was treated by a trabeculectomy (arrow). The tumour extended over the surface of the ciliary body (arrowheads) (×80). In the initial iridectomy specimen the cells were classified as low-grade spindle cells, but at the time of recurrence the appearance was that of bizarre epithelioid cells shown in (b) (×500)

a

placement of the ciliary body and the lens, which becomes opaque (Fig.  5.10a, b), and less frequently as an “iris tumour” owing to extension into the chamber angle. Episcleral vascular congestion is an associated feature and an episcleral nodule denotes spread via a collector channel. The tumour can grow posteriorly into the choroid, usually with an elongated tail, or can proliferate within and thicken the ciliary processes. Perforation of the ciliary processes or the pars plana permits extension into the posterior chamber, the zonular fibres or the vitreous. Only rarely does a ciliary body tumour invade the peripheral iris and chamber angle and this may be mistaken clinically as a primary tumour in the iris root. Ring spread of tumour cells around the trabecular meshwork is rare and is a very unusual cause of secondary open angle glaucoma. Pressure on the equator of the lens causes opacification in vivo and histological evidence of degeneration of the lens fibres. Angle closure glaucoma occurs if the lens is displaced and blocks the pupil. When extensive spontaneous necrosis occurs there may be release of a shower of pigment into the aqueous fluid and the anterior chamber and outflow system may be packed with melanophages, tumour cells, and cell fragments, including melanosomes (see Chap. 3); this causes a rapid rise in intraocular pressure—secondary open angle “melanomalytic glaucoma” [41]. Direct spread through the trabecular meshwork and collector channels leads to formation of anterior episcleral nodules, which should be sought for on macroscopic examination. Around 90% of uveal melanoma occurs in the choroid [49]. Tumours growing within the choroid interfere with the function of the choriocapillaris and the fluid pumping capacity of the retinal pigment epithelium. Leakage of proteinaceous fluid beneath the photoreceptors causes a field defect, which is soon apparent if the tumour grows behind the macula. Leakage of plasma is more pronounced when the tumour perforates Bruch’s membrane, but gravity can play an important part in the symptomatology; e.g., a superior equatorial

b

Fig. 5.10 (a) A malignant melanoma of the ciliary body is displacing a cataractous lens and infiltrating the chamber angle (arrow): the presentation was that of an iris melanoma. (b) Histology of a similar tumour to show displacement of the lens

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choroidal tumour can cause a larger inferior exudative detachment of the retina. An elderly patient may be unaware of loss of vision in one eye, or may already have poor vision due to macular degeneration or cataract. In such circumstances the tumour may present as a secondary closed angle glaucoma due to retinal detachment and lens-pupil block, or even as a proptosis due to posterior spread of the tumour into the orbit. Exceptionally melanomas can be discovered in phthisical eyes and this is one of the important reasons why such specimens should be examined. While choroidal melanomas occur most frequently in elderly white-skinned individuals, the disease can affect any racial group and can occur at a young age [50, 51]. Bilateral disease is rare [52]. In most specialised centres, diagnostic accuracy is now high, due to the use of indirect ophthalmoscopy, ultrasonography, optical coherence tomography (OCT), and by demonstration of vascular leakage of plasma protein using fluorescein angiography.

5  Intraocular Tumours

fine blade and the scleral surface examined carefully for signs of extraocular spread, before the eye is opened (Fig. 5.12). Melanoma in a vortex vein is usually obvious as a solid brown or black mass that expands the lumen, but sometimes clotted blood can simulate a tumour. Vortex vein spread is more likely to occur if the base of the centre of the tumour is located over the internal orifice of the vein; i.e., in the supero/infero-nasal and temporal quadrants. The vein should be blocked longitudinally to maximize the chance of detecting intravascular invasion. Patients with vortex vein invasion are more likely to develop hepatic metastasis than those without [53].

Transillumination and Orientation Preliminary investigation of the enucleated eye is important if the correct plane of section is to be chosen. The globe should be transilluminated with a bright fibre-optic light source and the shadow of the tumour outlined with a marker pen. Larger tumours can also be palpated through the sclera, owing to their firmer consistency as compared with that of the sclera overlying normal choroid and retina. The globe should be cut so that the principal histological section will pass through the centre of the tumour, the centre of the optic nerve, and the centre of the pupil, although this is not always easy (Fig.  5.11a–f). Other blocks should be taken for a broader sample of tumour morphology and the tumour should be examined at several histological levels in order to identify tumour passing through scleral canals. Where possible the vortex veins should be identified and excised with a

 acroscopic Appearances of Ciliary Body M and Choroidal Melanomas Tumour size is an important prognostic factor, and whenever possible the size of the tumour should be measured accurately at least in two dimensions (scleral base and height) with a reasonable “guestimate” of the third (see Chap. 1). Accurate tumour measurements are usually made preoperatively with ultrasound. Tumour size, ciliary body involvement and extrascleral spread are used to prognostically stratify uveal melanomas in the TNM classification in the eighth edition of the AJCC-UICC (American Joint Commission on Cancer–International Union Against Cancer) TNM classification of uveal melanoma [46]. The appearances of the tumour can vary considerably and it is noteworthy that the stereotype—a heavily pigmented mushroom shape—is rarely to be encountered (Fig.  5.13). This unusual configuration occurs after penetration of Bruch’s membrane when tumour proliferation beneath the retina forms the collar-stud or mushroom shape. Most tumours are ovoid and only lightly pigmented, measuring between 10 mm and 15 mm diameter (Fig. 5.14). The periphery of the tumour may be well circumscribed or there may be a thin extension for a considerable distance into the adjacent sclera: this feature is a pitfall for the surgeon and the radiotherapist in those cases where the limits of the tumour cannot be defined. With increasing size, there is a greater tendency

Fig. 5.11  Illustrations to show the difficulties in achieving the correct plane of section in some specimens. (a) A naevus was observed at the posterior pole in this eye for several years in this blind eye and it was only when a retinal detachment (arrowheads) caused secondary glaucoma that the presence of a malignant melanoma was suspected. (b) In this globe the media were opaque and the globe was enucleated in treatment for secondary (presumed neovascular) glaucoma. The large heavily pigmented tumour has filled the globe and has displaced the iris and closed the chamber angle (arrowhead). (c) In this phthisical eye the lens is calcified (arrowhead) and the sclera is thickened. A large melanoma

is present in the peripheral uvea (arrow). (d) The patient presented with an acute and painful red eye: The globe contains a large malignant melanoma, which has undergone spontaneous infarction. The secondary effect of release of toxic substances is a fibrinopurulent exudate on the surface of the sclera (arrow). (e) After a glaucoma procedure (trabeculectomy and iridectomy) a brown staphylomatous swelling appeared at the limbus (arrow) and this was thought to be an extension of the intraocular tumour shown in (f). (f) A section taken at the appropriate level reveals a staphyloma (arrow) unrelated to the choroidal melanoma, which was not divided at the appropriate level

 athological Features of Ciliary Body P and Choroidal Melanoma

Malignant Melanoma of the Uveal Tract

a

c

e

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d

f

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Fig. 5.12  In this example of vortex vein invasion there is a small episcleral nodule of black tumour and then a small black cylinder of tumour extending down the vortex vein

Fig. 5.14  Macroscopic appearance of an ovoid well-circumscribed amelanotic melanoma above the disc with an inferior exudative retinal detachment

Fig. 5.13  The classic heavily pigmented mushroom shape is rare and in this example penetration of the retina (r) is an unusual feature. Note the spillage of tumour onto the inner surface of the retina (arrow)

to trans-­scleral spread, but this is not necessarily the case (Fig. 5.15a–d). Melanomas may spread diffusely throughout the uveal tract and this variant—diffuse melanoma, defined as a tumour thickness 90% tumour necrosis [261] and severe anaplasia in tumour cells [262]. Retinoblastoma is staged according to the 8th edition of the TNM classification of malignant tumours [263] taking into account the degree of ocular and extraocular invasion and the structures.

Tumours That May Simulate Retinoblastoma The neoplasms that clinically may mimic retinoblastoma and lead to enucleation in children are appropriately considered at this point.

Retinocytoma This is a non-invasive tumour formed of sheets of benign appearing cells with a prominent fleurettes or a rosette pattern (Fig. 5.53g, h). These have been classified as retinocytomas (on histology) or retinoma (clinical) [257, 264–266]. They are recognised as the benign counterpart of retinoblastoma and may transform to retinoblastoma [257, 267]. Similar to retinoblastoma there is loss of both copies of the RB1 tumour suppressor gene [257]. Approximately 2% of indviduals with RB1 mutations are estimated to have retinocytoma [257]. However in contrast with retinoblastoma there are lower levels of genomic instability due to high expression of proteins including p16 and p130 associated with senescence [268].

Non-Neoplastic Lesions That Mimic Retinoblastoma

a

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lesions to massive gliosis is documented and therefore the prognosis is guarded [272]. Treatment includes local excision, plaque brachytherapy, laser and cryotherapy. In some cases enucleation may be required [273].

Astrocytic Hamartoma

b

Benign astrocytic tumours (astrocytic hamartomas) occur in the retina as part of the tuberous sclerosis syndrome and as an isolated feature [274, 275]. A characteristic feature of these tumours is that the retinal layers are spared. The constituent cells are astrocytes, which form a matrix conducive to the deposition of calcospherites (Fig. 5.55a–d). The presence of calcification may lead to an erroneous diagnosis clinically of retinoblastoma [276].

Miscellaneous A glioneuroma, similar to astrocytoma but containing and neural elements, has been described [277] and a neurocytoma, clinically similar to an astrocytoma, has been reported [278]. Retinal vascular tumours (haemangioblastoma) are a feature of the von Hippel-­Lindau syndrome (see Chap. 8).

Tumours Metastasising to the Retina Fig. 5.54 (a) This tumour was removed by local excision from the peripheral retina of a male patient who had a hazy vitreous and a retinal detachment. Postoperatively the retina flattened. (b) The tumour consisted of glial cells with blood vessels and was classified as “nodular retinal gliosis”

Nodular and Massive Retinal Gliosis Initially the term “presumed acquired retinal haemangiomas’ was used to describe a peculiar peripheral fundal mass that clinically simulated a choroidal melanoma or a retinal capillary haemangioma [269]. Later it became apparent that these consisted of an area of retinal gliosis surrounding blood vessels varying in size (Fig. 5.54). They could form a discrete mass [270] or fill the eye [271]. This condition can be idiopathic or secondary to congenital, inflammatory, vascular, traumatic, dystrophic and degenerative ocular diseases [272]. Nodular lesions are often located near the ora serrata in the inferotemporal region [272]. Clinical progression of nodular

Vitreoretinal metastases are relatively rare. They have been described from a range of primary carcinomas and cutaneous melanoma [279, 280]. Immunohistochemistry is invaluable confirming metastasis and identifying a primary site. Genetic profiling can be used to separate cutaneous melanoma metastasis from retinoinvasive uveal melanoma [280].

 on-Neoplastic Lesions That Mimic N Retinoblastoma Amongst those which simulate an endophytic retinoblastoma, solitary Toxocara granuloma (see Chap. 6) is the most important. Those that simulate an exophytic retinoblastoma include persistent hyperplastic primary vitreous (see Chap. 8), retinopathy of prematurity or retrolental fibroplasia (see Chap. 4), Coats’ disease (see Chap. 4) and Norrie’s disease (see Chap. 4).

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5  Intraocular Tumours

b

c

Fig. 5.55 (a) In a solitary astrocytic hamartoma the tumour appears as an ovoid well-circumscribed mass: This patient did not progress to tuberous sclerosis. (b) The glial cell proliferation in the tumour spares the outer layers of the retina (×20). The presence of calcified tissue leads to “cutting out” of the section (arrowheads). (c) In this particular

References 1. Khan S, Finger PT, Yu GP, Razzaq L, Jager MJ, de Keizer RJ, et al. Clinical and pathologic characteristics of biopsy-proven iris melanoma: a multicenter international study. Arch Ophthalmol. 2012;130:57–64. 2. Kivela T, Eskelin S.  Transformation of nevus to melanoma. Ophthalmology. 2006;113:887–8. 3. Morcos MW, Odashiro A, Bazin R, Pereira PR, O’Meara A, Burnier MN Jr. Balloon cell nevus of the iris. Pathol Res Pract. 2014;210:1160–3. 4. Kusunose M, Sakino Y, Noda Y, Daa T, Kubota T. A case of iris melanocytoma demonstrating diffuse melanocytic proliferation with uncontrolled intraocular pressure. Case Rep Ophthalmol. 2017;8:190–4. 5. Jakobiec FA, Silbert G. Are most iris “melanomas” really naevi? Arch Ophthalmol. 1981;99:2117–32. 6. Van Poppelen NM, Vaarwater J, Mudhar HS, Sisley K, Rennie IG, Rundle P, et  al. Genetic background of iris melanomas and iris melanocytic tumors of uncertain malignant potential. Ophthalmology. 2018;125:904–12.

d

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5  Intraocular Tumours 241. Fuiwara T, Fujiwara M, Numoto K, Ogura K, Yoshida A, Yonemoto T, et al. Second primary osteosarcomas in patients with retinoblastoma. Jpn J Clin Oncol. 2015;45:1139–45. 242. Kleinerman RA, Tucker MA, Abramsom DH, Seddon JM, Tarone RE, Fraumeni JF Jr. Risk of soft titsue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99:24–31. 243. Traboulsi EI, Zimmerman LE, Manz HJ.  Cutaneous malignant melanoma in survivors of heritable retinoblastoma. Arch Ophthalmol. 1988;106:1059–61. 244. Kivelä T, Asko-Seljavaara S, Pihkala U, Hovi L, Heikkonen J. Sebaceous carcinoma of the eyelid associated with retinoblastoma. Ophthalmology. 2001;108:1124–8. 245. Meadows AT, Leahey AM. More about second cancers after retinoblastoma. J Natl Cancer Inst. 2008;100:1743–5. 246. Dommering CJ, Marees T, van der Hout AH, Imhof SM, Meijers-­ Heijboer H, Ringens PJ, et  al. RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer. 2012;11:225–33. 247. Temming P, Arendt M, Viehmann A, Eisele L, Le Guin CH, Schündeln MM, et al. Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: a report from the German reference center. Pediatr Blood Cancer. 2017;64:71–80. 248. Camp DA, Yadav P, Dalvin LA, Shields CL. Glaucoma secondary to intraocular tumors: mechanisms and management. Curr Opin Ophthalmol. 2019;30:71–81. 249. Kaliki S, Srinivasan V, Gupta A, Mishra DK, Naik MN. Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients: a case-control study. Ophthalmology. 2015;122:1165–72. 250. Nalci H, Gündüz K, Erden E.  Necrotic intraocular retinoblastoma associated with orbital cellulitis. Surv Ophthalmol. 2018;63:114–8. 251. Traine PG, Schedler KJ, Rodrigues EB. Clinical presentation and genetic paradigm of diffuse infiltrating retinoblastoma: a review. Ocul Oncol Pathol. 2016;2:128–32. 252. Shields CL, Ghassemi F, Tuncer S, Archana T, Shields JA. Clinical spectrum of diffuse infiltrating retinoblastoma in 34 consecutive eyes. Ophthalmology. 2008;115:2253–8. 253. Orellana ME, Net RB, Antecka E, Burnier MN Jr. Immunohistochemical analysis of retinoblastoma cell phenotype using neuronal and glial cell markers. Arq Bras Oftalmol. 2016;79:395–9. 254. Burner MN, McLean IW, Zimmerman LE, Rosenberg SH.  Retinoblastoma. The relationship of proliferating cells to blood vessels. Invest Ophthalmol Vis Sci. 1990;31:2037–40. 255. Dyer MA, Bremner R. The search for the retinoblastoma cell of origin. Nat Rev Cancer. 2005;5:91–101. 256. Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med. 2009;8:203–1209. 257. Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, et al. Loss of RB1 induces non-proliferative retinoma: increasing gneomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008;17:1363–72. 258. Cha SC, Suh KS, Song KS, Lim K. Cell death in retinoblastoma: electron microscopic, immunohistochemical and DNA fragmentation studies. Ultrastruct Pathol. 2000;24:23–32. 259. Karcioglu ZA. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina. 2002;22(6):707–10. 260. Sastre X, Chantada GL, Doz F, Wilson MW, de Davila MT, Rodriguez-­Galindo C, et al. Proceedings of the consensus meetings from the international retinoblastoma staging working group on the pathlogy guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med. 2009;133:1199–202.

5  Intraocular Tumours 261. Chong EM, Coffee RE, Chintagumpala M, Hurwitz RL, Hurwitz MY, Chévez-Barrios P.  Extensively necrotic retinoblastoma is associated with high-risk prognostic factors. Arch Pathol Lab Med. 2006;130:1669–72. 262. Mendoza PR, Specht CS, Hubbard GB, Wells JR, Lynn MJ, Zhang Q, et al. Histopathologic grading of anaplasia in retinoblastoma. Am J Ophthalmol. 2015;159:764–76. 263. Brierley JD, Gospodarowicz MK, Wittekind C.  Retinoblastoma. In: Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th ed. Oxford: WileyBlackwell; 2017. 264. Santos C, Ramalho M, Coutinho I, Teixeira S. Photopsia revealing a retinocytoma. BMJ Case Rep. 2015;bcr2015-211018. 265. Abouzeid H, Balmer A, Moulin AP, Mataftsi A, Zografos L, Munier FL.  Phenotypic variability of retinocytomas: preregression and postregression growth patterns. Br J Ophthalmol. 2012;96:884–9. 266. Marback EF, Sampaio MD, Oliverira RD, Marback RL.  Retinocytoma: a report of 5 cases. Arq Bras Oftalmol. 2009;75:719–22. 267. Kiratli H, Koç I.  Malignant transformation of retinocytoma treated with intra-arterial chemoptherapy. Can J Ophthalmol. 2016;51:e105–7. 268. Dimaras H, Khetan V, Halliday W, Héon E, Chan HS, Gallie BL.  Retinoma underlying retinoblastoma revealed after tumor response to 1 cycle of chemotherapy. Arch Ophthalmol. 2009;127:1066–8. 269. Shields JA, Decker WL, Sanborn GE, Augsburger JJ, Goldberg RE.  Presumed acquired retinal hemangiomas. Ophthalmology. 1983;90:1292–300. 270. Rennie IG.  Retinal vasoproliferative tumours. Eye (Lond). 2010;24:468.

179 271. Jakobiec FA, Thanos A, Stagner AM, Grossniklaus HE, Proia AD. So-called massive retinal gliosis: a critical review and reappraisal. Surv Ophthalmol. 2016;61:339–56. 272. Shields CL, Shields JA, Barrett J, De Potter P. Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients. Arch Ophthalmol. 1995;113:615–23. 273. Hudson LE, Mendoza PR, Yan J, Grossniklaus HE. Reactive retinal astrocytic tumor (Focal nodular gliosis): a case report. Ocul Oncol Pathol. 2017;3:1–7. 274. Pusateri A, Margo CE. Intraocular astrocytoma and its differential diagnosis. Arch Pathol Lab Med. 2014;138:1250–4. 275. Shields JA, Shields CL.  Glial tumors of the retina. The 2009 King Khaled Meomorial Lecture. Saudi J Ophthalmol. 2009;23:197–201. 276. Drewe RH, Lee WR.  Solitary astrocytic hamartoma simulating retinoblastoma. Ophthalmologica. 1985;190:158–67. 277. Kivela T, Kauniskangas L, Miettinen P, Tarkkanen A. Glioneuroma associated with colobomatous dysplasia of the anterior uvea and retina. A case simulating medulloepithelioma. Ophthalmology. 1989;96:1799–808. 278. Metcalf C, Mele EM, McAllister I. Neurocytoma of the retina. Br J Ophthalmol. 1993;77:382–4. 279. Shields CL, McMahon JF, Atalay HT, Hasanreisoglu M, Shields JA.  Retinal metastasis from systemic cancer in 8 cases. JAMA Ophthalmol. 2014;132:1303–8. 280. Padrnos LJ, Houghton OM, Iacob CE, Kurli M, Ocal IT, Byrce AH. Genomic profiling proves metastasis of cutaneous melanoma to vitreal fluid. Melanoma Res. 2020;30:590–3. 281. Sehu KW, Lee WR, editors. Ophthalmic pathology: an illustrated guide for clinicians. Malden: Blackwell; 2008. ISBN 9780727917799.

6

Ocular Inflammation

Introduction This chapter deals predominantly with inflammatory disease in the eye as it is seen in surgical enucleation specimens. The various operative procedures used for the treatment of glaucoma, cataract, and retinal detachment are complicated by secondary exogenous infection in only a small percentage of total cases treated surgically, but the numbers are significant in terms of specimens received in the laboratory. Cases of non-surgical trauma complicated by infection also add to the numbers in the files [1, 2]. If the inflammatory process is restricted to the tissues within the scleral envelope, the condition is referred to as endophthalmitis; if the episcleral tissues are involved, the term panophthalmitis is appropriate. To a lesser extent, ocular inflammatory disease is encountered in autopsy material and, although the conditions are somewhat different in aetiology and pathogenesis, they are appropriately considered in this chapter. The mode of infection is usually via the bloodstream and the infection regarded as endogenous. Immunosuppression alters the range of infectious agents that may be encountered in endogenous endophthalmitis.

 he Anatomy of the Eye in Relation T to Infective Processes The ocular avascular tissues (cornea, sclera, lens, and vitreous) and the fluid-filled intraocular compartments provide an ideal environment for the proliferation of bacterial, fungal, and protozoal pathogens. Abscesses forming within the anterior chamber or the vitreous are difficult to eradicate with topical or systemic antibiotics, because the drugs do not diffuse into the solid mass of cells and cannot therefore inhibit the growth of the pathogens. Enucleation will then be required to relieve pain and to prevent the risk of spread of infection into the orbit or into the cranial cavity. It is now common practice to intervene as an emergency in acute presumed ocular infection by surgical washout of

the anterior chamber, which is often combined with a vitrectomy to remove the pathogens and provide material for diagnostic purposes. Broad spectrum antibiotics are instilled at the time of surgery and appropriate antibiotics are administered when bacterial sensitivities have been determined. It is to be strongly recommended that the surgeon distributes excised tissues to the appropriate microbiological laboratory (bacteriology, mycology, virology—depending on the suspected disease process) in addition to the histopathology laboratory. If all measures to preserve vision fail, enucleation is performed, although some surgeons may elect to eviscerate the ocular contents to prevent the theoretical possibility of spread of pathogenic organisms into the optic nerve and meninges. The disadvantage for the pathologist is that the tissues are often fragmented. While purulent exudation will be a striking feature in cases of panophthalmitis, the pathologist should be aware that a failure to demonstrate bacterial pathogens may occur after intensive antibacterial therapy prior to enucleation. Tissue destruction in pyogenic inflammation is not solely due to release of toxins and enzymes from bacteria or fungi, but is compounded by ischaemia and infarction due to thrombosis in the endarterial systems in the eye. The vessels of the inner retina are particularly prone to vasculitis, and in ischaemic infarction the macrophages within the retina are filled with degradation products of lipoprotein from the fragmented neural cells. When the long ciliary arteries are thrombosed, occlusion of the blood supply to the iris and ciliary body leads to extensive infarction of the anterior uveal tissues. The choroid, with more plentiful sources for input into the vascular bed, is less affected by inflammatory endarteritis. The choroidal stroma, which possesses a resident population of lymphocytes and an antigen detection system, behaves as the lymph node of the globe. Thus, when the eye is affected by chronic granulomatous inflammatory diseases (e.g., tuberculosis, sarcoidosis, and syphilis), the uveal tract is the site where the associated reactive lymphoid infiltrate is most

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pronounced. Such chronic inflammatory diseases cause a slowly progressive deterioration in visual function and are recognised by the clinical appearances of the fundus and vitreous (which contains inflammatory cells). By the use of appropriate serology, treatment at an early stage can be very effective. Enucleation is indicated only when there are advanced secondary complications—e.g., hypotonia and atrophy (atrophia bulbi), which may progress to extreme disorganisation and bone formation (phthisis bulbi) (see Chap. 2). Alternatively granulomatous and non-granulomatous chronic inflammatory reactions can lead to secondary glaucoma (see Chap. 3) or retinal detachment (see Chap. 7). It should also be stressed at this stage, that chronic (idiopathic) non-granulomatous inflammatory disease—i.e., uveitis, retinitis, and optic neuritis—is common in clinical practice and is usually treated successfully or heals spontaneously. The pattern of neurotrophic viral infection in the eye differs markedly from bacterial and fungal infection and is characterised by destruction of either the neural retina (cytomegalovirus [CMV], herpes simplex virus [HSV]) or the nerves within the choroid, sclera and orbit (herpes zoster) with consequent necrosis of the neurones and the supporting cells [3].

Pyogenic Bacterial Infections Introduction The use of powerful antibiotics applied topically, systemically, and by sub-conjunctival injection has saved many eyes in an early stage of infection by pyogenic bacteria. A few days’ delay can be disastrous so that the enucleations received by the pathologist show the irretrievable end stage of pyogenic infection. In the microscopic search for pathogenic organisms, the centre of an abscess in the vitreous or the tissues in the region of a lensectomy are the best places to scrutinise in an enucleated eye. It is essential to appreciate that melanin granules (released from pigment-containing cells in the iris or ciliary body) may lead to misinterpretation, but it should be noted that these brown and refractile structures are larger than bacteria.

Corneal Ulceration The avascular structure of the cornea renders it susceptible to bacterial and fungal colonisation, particularly when the constant protection of the immunoglobulins and lysozyme in the tears is removed by idiopathic atrophy of the lacrimal gland (keratoconjunctivitis sicca). Another important causative factor in ulceration is loss of the epithelial barrier in, for

6  Ocular Inflammation

example, end-stage neovascular glaucoma, when the corneal stroma is oedematous and the epithelium separates from Bowman’s layer (see Chap. 13). In the context of this section, trauma is the most important factor in the loss of protective mechanisms, which permits pathogenic organisms to proliferate in the corneal stroma. The first stage of the response is for neutrophils to pass through the blood vessels in the limbal conjunctiva to reach the damaged corneal epithelium via the tear film. Neutrophils then move into the stroma from the surface bed of the epithelial defect. Later there is an ingrowth of a capillary network that spreads in from the limbus towards the site of infection. The neutrophils migrate through the new vessels and accumulate in clumps between the corneal lamellae. Death of leucocytes releases nuclear dust (which may be easily mistaken for bacterial forms) and collagenolytic enzymes that destroy the stroma. Toxins and inflammatory mediators diffuse into the anterior chamber and promote leucocytic migration into the iris stroma and anterior chamber (hypopyon). If the cornea perforates and the iris prolapses (Fig.  6.1a), the gap may be filled with granulation tissue. Antibiotic therapy often kills the bacteria, so that the Gram stain may be unconvincing: A definitive identification should not be made unless the Gram stains are clearly positive (Fig. 6.1). By contrast, in some cases when a bacterial infection is well established, the bacteria are so numerous and uniform in size that they are recognisable as pink structures in a haematoxylin and eosin (H&E) stained section. Fungi (Candida sp. and Aspergillus sp.) can be introduced into the cornea or the anterior chamber by surgical or accidental trauma and are identified easily in appropriately stained sections (Fig. 6.1e, f).

Acute Bacterial Pyogenic Endophthalmitis Provision of a pathological report on a bacterial pyogenic endophthalmitis is far more frequently required than for the more exotic granulomatous infections. A typical case will be submitted with the diagnosis of “endophthalmitis” or “panophthalmitis”, and the preceding cause will usually be documented—e.g., corneal ulceration, trauma [4] or a postoperative complication [5]. In metastatic infection, the source may be an endocarditis, a mycotic arterial aneurysm, or injection of contaminated material by a drug addict; immunosuppression increases the risk of metastatic endophthalmitis [6, 7].

Common and Rare Pathogenic Bacteria The type of organism varies somewhat according to the mode of entry into the ocular tissues. In most postoperative

Pyogenic Bacterial Infections

183

a

b

c

d

e

f

Fig. 6.1 (a) Corneal perforations (in this case due to rheumatoid disease) may be complicated by secondary infection (even viral). The defect is plugged by prolapsed iris tissue and granulation tissue, which is partially covered by epithelium (arrow). (b) Gram-positive diplococci (arrow) in the corneal stroma. (c) Moraxella sp. appear as Gram-­ negative diplobacilli (arrows) in a case of bacterial keratitis. (d)

Nocardia in the choroid of an immunosuppressed patient. In this Gram stain the fine filamentous organisms branch at right angles (arrow). (e) Candida sp. appear as bulging hyphae and budding yeasts (arrows) in a PAS-stained section. (f) Aspergillus grows as branching septate hyphae (arrow) (methenamine silver)

and traumatic cases staphylococci (S. epidermidis and S. aureus) predominate, whereas in bleb-related infections, streptococci are most frequently cultured. Gram-negative rods (Haemophilus) also form a significant part of the group and there is a steady flow of reports of unusual organisms (e.g., Exophiala dermatitidis [8] and Serratia marcescens [9]) in the literature. Bartonella hensellae, the causative

organisms of cat scratch disease may cause neuroretinitis and optic neuritis [10, 11]. It is not possible to isolate this pathogen and the diagnosis must be made by serology or the identification of bacillary forms using the Warthin-Starry stain. This organism is also responsible for conjunctival infection and an associated regional lymphadenopathy (Parinaud’s ocular glandular syndrome). Whipple’s disease

184

(intestinal tract inflammation, meningitis, lymphadenopathy, and arthritis), caused by Tropheryma whippelii, can be associated with uveitis and vitritis: macrophages containing periodic acid-Schiff (PAS)-positive rods can be identified in a vitrectomy specimen [12]. Cataract surgery performed by phacoemulsification of degenerate lens matter and insertion of a synthetic lens into the capsular bag can be complicated by “capsular endophthalmitis”. This is a chronic condition characterised by recurrent anterior uveitis. Most of these infections are due to anaerobic bacteria of low virulence such as Propionibacterium acnes and coagulase-negative Staphylococcus. Rarely, filamentous fungi such as Aspergillus or yeasts such as Candida albicans may also be responsible for these infections [13].

Macroscopic Features The appearances of an endophthalmitis specimen can vary considerably and much depends on the aetiology (Fig. 6.2a– d). Although the creamy white exudate of a pyogenic reaction is usually unmistakable, simple proteinaceous exudates or lipid-laden exudates can simulate pus. On a practical note, it is useful to make the cut to illustrate the site of perforation of the corneoscleral envelope (Fig. 6.3).

Microscopic Features In addition to the obvious accumulation of viable and necrotic leucocytes and mononuclear cells, there are many important features in the destruction of the ocular tissues in pyogenic infection. The vascular routes by which inflammatory cells pass into the ocular cavities are the iris vessels, the microvasculature of the ciliary body, the retinal vessels, and the vessels within the prelaminar part of the optic disc. In the anterior chamber, gravity leads to pooling of neutrophils in the inferior part of the angle (hypopyon) and infiltration of the trabecular meshwork. Release of vasoformative factors stimulates neovascularisation and the formation of granulation tissue: eosinophilic plasma exudates accumulate in the anterior and posterior chambers. Recovery from the infective process can lead to secondary angle closure glaucoma. Alternatively, interference with aqueous inflow from the ciliary processes lowers the intraocular pressure and hypotonic suprachoroidal exudation is commonly encountered. The iris stroma becomes packed with lymphocytes and plasma cells and this infiltrate can be associated with disorganisation or destruction of the pigment epithelium of the iris. Tissue lysis and disintegration may be so severe that eventually the iris residue consists only of smooth muscle and pigment epithelium embedded in granulation tissue. By contrast, inflammatory cell infiltration in the ciliary body

6  Ocular Inflammation

stimulates the pigmented and non-pigmented layers of the pars plana to proliferate and produce a retrolental or cyclitic membrane (see Chap. 2). The lens, while showing secondary cortical degenerative changes, is not infiltrated by inflammatory cells if the capsule is intact. Rupture of the capsule adds additional immune complexes to the inflammatory response and a giant cell granulomatous reaction in the lens matter may complicate the picture. Sometimes it is difficult to distinguish between a secondary lens abscess following a vitreous abscess and a primary lens-induced autoimmune process that is involving the vitreous (see Chap. 2). An abscess in the vitreous usually contains macrophages in addition to neutrophils and often the cells are necrotic and amorphous. Detection of organisms depends on experience, good quality stains and high resolution optics (Fig.  6.1). Gram-positive cocci are seen most frequently in paraffin sections, but are rarely cultured. Changes within the retina depend on the size and severity of the vitreous abscess. The mildest response is a retinal perivascular infiltrate, which is usually lymphocytic (Fig. 6.4a). The release of inflammatory mediators causes the retinal vessels to leak plasma, red blood cells, and fibrin: Cystic areas may be created within the outer plexiform layer. The retina detaches in the presence of a vitreous abscess and at an early stage the inner layers may be dissolved by autolytic enzymes apparently released from necrotic neutrophils (Fig. 6.4b). With systemic treatment the retinal architecture is sometimes preserved. It is not uncommon to find macrophages filled with neutrophils in the subretinal space (Fig. 6.5). The choroid is involved as the inflammation progresses and the tissue becomes thicker as a consequence of congestion and lymphocytic and plasma cell infiltration. Rarely, if ever, is there optic nerve and meningeal involvement in endophthalmitis.

The Evisceration Specimen If a pyogenic infection has not responded to treatment and there is no prospect of saving vision, it is an accepted practice to remove the cornea and limbus and to “scoop out” the ocular contents. The rationale for this procedure is that intraocular infection is less likely to spread along the optic nerve meninges to the brain, because the lamina cribrosa provides a barrier. As was stated in the previous section, it is almost unknown to see a pyogenic reaction extending into the optic disc and meninges in an enucleated eye that has been protected by systemic antibiotics. Evisceration is a quicker procedure with a faster recovery, and if the implant is placed at the time of evisceration a good cosmetic result may be obtained. It may therefore be the operation of choice in an elderly patient. Rare risks of evisceration are sympathetic endophthalmitis and occurrence of melanoma in the socket

Pyogenic Bacterial Infections

185

a

b

c

d

Fig. 6.2 (a) A patient suffering from subacute bacterial endocarditis noted deteriorating vision. The vitreous contained an abscess and the infection could not be eradicated: The globe was therefore enucleated. Retinal vasculitis and haemorrhage (r) has led to an exudative detachment (arrow). The vitreous (v) is detached and pus is present on the vitreous base. (b) A corresponding section through the centre of the globe, to show the inflammatory exudate in the vitreous (arrowheads). Solid proteinaceous exudates do not process well and there is often

cracking in paraffin-embedded sections (arrow). (c) Anterior panophthalmitis occurred after insertion of an intraocular lens, the edge of which is shown by an arrow. The vitreous contains pus and the retina and choroid are detached by a haemorrhagic exudate. The episcleral tissues are thickened. (d) A section through the centre of the specimen reveals a gap, where the intraocular lens has dissolved during processing (arrow)

due to incomplete removal of the uveal tract [14, 15]. In younger patients the excellent cosmetic results obtained with modern coral implants may make enucleation the preferred option for some surgeons.

When received in the laboratory the “evisceration specimen” will comprise several masses of clotted blood ­containing intraocular tissue. The corneal disc may be submitted separately. Often the tissue is yellow, opaque, and

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ulcerated, but nevertheless the cornea can be recognised as such and large blocks should be taken. Uveal tissue and the lens can be identified—the former by the presence of pigment—but the iris may be destroyed by a pyogenic process or by infarction. The vitreous appears as condensed opaque grey material and in such cases frequently contains an abscess. The retina is destroyed only in the later stages, but detachment causes folding, which makes block orientation difficult. The choroid is rarely involved by the pyogenic process, but will be congested and thickened by lymphocytic infiltration. Histological examination of the various parts of

Fig. 6.3  Infection of the trabeculectomy bleb, 14 years after the procedure, allowed entry of Gram-positive cocci into the vitreous: The surgeon collapsed the globe while trying to withdraw material from the vitreous for bacterial examination. Note the iris (i) prolapse

a

Fig. 6.4  Various changes in the retina in endophthalmitis. (a) Early lymphocytic infiltration in the walls of the blood vessels (arrows). There is a vitreous abscess (×100). (b) At a later stage the inner layers

Fig. 6.5  An inflammatory infiltrate beneath a detached retina: there are macrophages admixed with polymorphs (arrows) (×250)

b

of the retina (R) are dissolved by autolytic enzymes released from polymorphs in the vitreous abscess. There is also a pyogenic choroiditis (c) (×100)

Fungal Infection

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*

Fig. 6.6  A relatively intact evisceration specimen for endophthalmitis. The ciliary body (cb) and residual retina (r) are identified with a central vitreous abscess. Such intact specimens are a rarity (×10)

Fig. 6.7  Mersilene coated implant induces an exuberant multinucleate giant cell inflammatory reaction (arrows) (×250)

the specimen will be directed towards the identification of the infecting organism and the pathogenicity of the process (Fig. 6.6). Gram stain and the PAS stain should be used routinely and the vitreous abscess will be the most promising area in the search for bacteria. Examination of the cornea or sclera will probably reveal a fistula (surgical or traumatic) or a perforated corneal ulcer. The iris and ciliary body stroma may contain a pyogenic inflammatory infiltrate, although more commonly congestion and lymphoplasmacytoid infiltration is observed. The epithelial layers of these tissues will almost invariably show reactive proliferation. The lens may remain intact or be partially dissolved by lytic enzymes released from the cells. It is not always easy to identify organisms in a vitreous abscess owing to the distraction of dispersed uveal pigment granules and the sparsity of organisms after intensive therapy. When bacteria are present in numbers, after inappropriate antibiotic treatment, they can be seen easily in an H&E stained section. The outer retina will be lined by macrophages around stunted photoreceptors if detachment had occurred, and almost invariably the retinal vessels will be surrounded by lymphocytes and plasma cells. Inflammation within the choroid is variable but may be dense; as a rarity, neovascularisation can occur in the choroid. The optic disc and sclera will only be included in the specimen unintentionally. It is possible for the surgeon to remove the ocular contents in one piece—this practice should be encouraged because it makes a histopathological interpretation much easier.

Implants Originally implants were metal or plastic and surrounded by Merseline mesh. This mesh could induce an exuberant foreign body giant cell reaction (Fig.  6.7). More recently, the majority of orbital implants are now porous to allow biointegration and reduce the rate of infection and implant extrusion [16–18]. Hydroxyapatite is the most commonly used implant. Originally derived from coral these are mainly synthetic. Fibrovascular tissue grows into the pores [19]. Although hydroxyapatite incites a foreign body reaction they can be wrapped in polyglactin mesh which reduces this inflammatory reaction and the secondary complications. High density porous polyethylene implants, the second most commonly used implants, also permit fibrovascular ingrowth but this is slower than for hydroxyapatite [16, 18]. Non-porous implants used include acrylic and glass [16].

Fungal Infection Candida species are the commonest fungal pathogen in the eye [20, 21], particularly as the cause of endogenous and exogenous endophthalmitis. It is followed by filamentous fungi, such as Aspergillus [22, 23] and Fusarium [24, 25], which are common following trauma with fungus-­ contaminated plant. Coccidioidomycosis [26], histoplasmosis [27], blastomycosis [28] and other fungal infections are of significance in endemic areas; e.g., cryptococcosis [29]. All of these pathogens (and more) are obviously of importance in immunosuppressed patients.

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a

b

c

d

Fig. 6.8 (a) Small metastatic foci of candidal proliferation (arrows) in a heroin addict who used contaminated lemon juice as a vehicle: The inset shows the giant cell granulomatous reaction (arrow) around the fungus. (b) The hyphae (arrows) and yeasts (arrowheads) are easily

identifiable in a Grocott-Gomori methenamine silver stain. (c) An autopsy specimen in which Candida was proliferating in the vitreous (arrow). (d) Candida in a vitrectomy specimen with hyphae (arrows) and yeast (arrowheads) can be identified in a PAS-stained section

Candida sp. infections can vary in nature and extent. Small emboli form nodules in the choroid and retina, which on histological examination contain a granulomatous reaction with identifiable fungi (Fig.  6.8a, b). As the vitreous abscess forms, the fungi spread in a linear fashion through the vitreous gel with a minimal inflammatory response (Fig.  6.8c, d). However, when the immune system is triggered there may be an intense lymphocytic and macrophage reaction around a fungal abscess in the vitreous (Fig. 6.9a). Retinal destruction is not as extreme as in a bacterial infection, but contraction of membranes in the vitreous leads to severe distortions and an exudative detachment. A similar response (Fig.  6.9b) is seen in Aspergillus infections [30]. Mucor can also involve the globe but the choroid is more often the site of invasion (Fig. 6.10a) [31]. These infections are most commonly reported in immunosuppressed patients and in intravenous drug abusers [32]. Cryptococcus can also parasitise the anterior and posterior segments in immunosuppressed patients: The yeast-like fungus (Fig. 6.10b) is easily demonstrated in PAS, Alcian blue, and methenamine silver-­ stained preparations [33].

Viral Infection Introduction The viruses of the herpes group are of prime significance. Herpes simplex virus (HSV) and Herpes zoster virus (HZV) are responsible for the retinal necrosis syndrome. In addition, Herpes zoster ophthalmicus results in a neuritis and non-granulomatous choroiditis. Cytomegalovirus retinitis occurs in immunosuppressed patients (either in AIDS [acquired immunodeficiency syndrome] or in malignant disease). Rubella (German measles) was of interest as a cause of uveitis and cataract in the foetus and neonate, but in this form the disease has been almost entirely eradicated. Measles retinopathy is equally rare, but the virus is of importance as the causative agent in subacute sclerosing panencephalitis, which can be associated with a necrotising retinitis. Eosinophilic intranuclear inclusion bodies in paraffin sections have been proven to contain the filamentous microtubular inclusions of the paramyxovirus [34]. Rabies is one of the rare viral infections to be described in the ocular tissues [35].

Viral Infection

189

a

b

Fig. 6.9 (a) In advanced infection due to Candida in the vitreous, the retina is detached by exudate and is folded around the abscess (arrowheads). (b) An abscess (arrowheads) due to Aspergillus in the vitreous after a lens extraction

a

b

Fig. 6.10 (a) The large hyphae of Mucor are located on the inner surface of Bruch’s membrane (arrows) beneath a degenerate retinal pigment epithelium. (b) Cryptococci (arrowheads) in the vitreous in an experimental animal model (PAS stain)

Measles (Rubeola)

Rubella (German Measles)

Infection with the measles virus is the cause of subacute sclerosing panencephalitis, a lethal condition in childhood. The ocular tissues are destroyed by the viral infection and by ischaemia secondary to vasculitis [36]. In some cases intranuclear inclusions may be found in the degenerate retina or in the brain. In other cases, the only finding may be atrophy of the ganglion cell layer of the retina.

This condition is rare in societies in which immunisation and therapeutic abortion are practised. However, congenital rubella syndrome (CRS), the consequence of rubella infection in-utero, remains a common cause of congenital cataracts in developing countries [37]. CRS consists of systemic (cardiac and neurological) and ocular manifestations. Cataract (nuclear), microphthalmos, iris abnormalities, and retinopathy are the commonest anomalies see in CRS [38].

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Histologically, the lenticular nucleus is sharply demarcated with cells containing retained and karyorrhectic nuclei. It is thought that the virus enters the lens before the development of the lens capsule that would otherwise act as a barrier to the virus [39, 40]. Viral DNA had been detected from the lens sample via real-time polymerase chain reaction (PCR) [41]. The iris may show hypoplasia or atrophy. Non-­ granulomatous uveitis is frequently accompanied by necrosis of the pigment epithelium of the ciliary body. The most frequent changes seen in retina are the alternating areas of atrophy and hypertrophy within the retinal pigmented epithelium, corresponding to the “salt-and-pepper” fundal appearance clinically [39]. The histological features of rubella may not be apparent in foetal eyes after an elective termination of pregnancy.

Acute Retinal Necrosis (ARN) Syndrome ARN is a unilateral necrotising retinitis due to HSV or HZV infection. The clinical diagnosis of ARN is suspected when the patient presents with rapidly deteriorating vision in one or both eyes: in bilaterality the acronym BARN is used [42]. On ophthalmoscopy, grey serpiginous areas are accompanied by haemorrhage in the fundus and the vessels are sheathed by inflammatory cells. There is usually accompanying vitritis and papillitis and the condition is often painful. Without prompt antiviral therapy the disease progresses in some cases to massive inflammatory cell infiltration of the retina accompanied by haemorrhage and exudative detachment (Fig.  6.11a, b). The repair process takes the form of granulation tissue proliferation (Fig.  6.11c). Viral inclusions may be found, but for precise identification, immunofluorescent or immunohistochemical antibody techniques should be used. Electron microscopy demonstrates the typical viral particles in retinal neurones (Fig.  6.11e), and it is noteworthy that the retinal pigment epithelium and tissue macrophages may also contain viral particles. Clinically, a similar appearance may be seen with other pathogens such as fungal or toxoplasmic infection. Retinal biopsy (see later), may therefore be important in identify-

Fig. 6.11 (a) The macroscopic appearance of an acute retinal necrosis. The haemorrhagic and detached retina is disintegrating and the vitreous is opaque. (b) Section through the specimen shown in (a): The areas of retinal necrosis are shown by the arrows (×3). The inflammatory cell infiltration in the retina is so extensive that the normal layers are not recognisable. (c) In the areas shown by arrows in (b), only the outer retina (or) is identifiable in the detached retina, which is lined on the

6  Ocular Inflammation

ing. It is therefore important that samples are sent to virology and mycology as well as for histopathology. The disease is most commonly described in immunocompetent individuals. In the immunocompromised, similar infection may result in progressive outer retinal necrosis (PORN) [43]. This condition differs from ARN clinically in that there is a lack of inflammation in the aqueous and vitreous humour, retinal vasculitis, and papillitis, accompanied by yellow-white necrotic patches deep in the retina [43]. Histological examination shows initial predominant destruction of the outer nuclear layer of the retina that rapidly coalesces, causing full thickness retinal necrosis. In some areas, choriocapillaris could show intense lymphocytic infiltrates, whereas in other areas all layers of the choroid might be involved [44]. Deep retinal necrosis could be followed by retinal detachment, but, except for macrophages, inflammatory cells are scarce. Following the advent of highly active antiretroviral therapy (HAART), it is now possible to discontinue primary and secondary prophylaxis for many opportunistic infections in HIV-1 infected individuals. Successful tapering of anti-HZV therapy for PORN has been reported after a partial immune recovery on HAART occurred [45].

Cytomegalovirus Cytomegalovirus may cause a retinitis in the immunosuppressed patients. Prior to highly active antiretroviral therapy (HAART) it was the commonest cause of retinitis in patients with AIDS. On clinical and macroscopic examination, the retina contains fluffy white areas combined with areas of retinal necrosis through which the choroid is visible (Fig.  6.12a). Frosted branch angiitis is due to perivascular inflammatory infiltrates [46]. Cytomegaloviral (CMV) infection is recognised histologically by the presence of enlarged cells with intranuclear and intracytoplasmic inclusions (Fig. 6.12b, c). Immunohistochemistry is helpful in identifying viral infected cells. In AIDS the viral infection is preceded by apoptosis of the retinal ganglion cells [47]. At the end stage there is extensive destruction of all layers of the retina with only a minimal inflammatory response.

inner surface by a fibrovascular membrane resembling granulation tissue (gt). (d) In a retinal biopsy in another case, only the photoreceptor layer (arrowheads) has survived over a retinal pigment epithelium (arrow), which contains intranuclear inclusions. The choroid (ch) contains a dense lymphocytic infiltrate. (e) Intranuclear inclusions in the RPE cells are shown by arrows. (f) Herpes virus appearing as crystalline particles (arrows) was identified by electron microscopy in this case

Viral Infection

191

a

b

c

d

e

f

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6  Ocular Inflammation

a

b

c

d

Fig. 6.12 (a) Macroscopic appearances of the globe in cytomegaloviral infection. The macula (arrow) contains a small purulent exudate and the choroid is visible through a triangular area of retinal necrosis (arrowheads). (b) The necrotic retina contains enlarged cells with intra-

nuclear inclusions (arrows) shown at higher magnification in (c). (c) Extremely large cells containing intracytoplasmic and intranuclear inclusions are shown by arrows. (d) The viral particles have a central core and a surrounding envelope (arrows)

Retinal Biopsy

Acquired Immunodeficiency Syndrome (AIDS)

Retinal biopsy can either be through a scleral flap to expose choroid and retina or via the pars plana through the vitreous [48]. Retinal biopsy is now accepted as a diagnostic tool in the investigation of BARN, and electron microscopy, immunocytochemistry, in situ hybridisation, and PCR can be very helpful in the diagnosis [48]. Simultaneous infection with several organisms has been described [49]. Some tissue must be preserved in an appropriate medium for virology and some for mycology and bacteriology if there are indications from rising serological titres of a specific aetiology. Necrosis and fragmentation of the retinal tissue is common (Fig. 6.11d–e). Once received and the appropriate fixation selected, the questions of tissue handling and orientation are important. A variety of techniques have been suggested for the maintenance of stability of a retinal biopsy, viz. cucumber slices [50], gelatin, agar [51], and albumen [52], and tissue glue applied before the choroid and retina have been excised or to orientate the specimen on filter paper. The aim is to provide good stability and a flat specimen.

Infection with the human immunodeficiency virus (HIV) is by sexual contact, drug abuse, or injection of contaminated blood or plasma. The virus can convert its RNA to DNA with a reverse transcriptase enzyme and the DNA is incorporated into the genome of the cells, which allows viral replication. The infection may be latent for many years and the virus is undetectable. Eventually the virus alters the immune system by selectively destroying CD4+ T cells leading to susceptibility to opportunistic pathogens. The first ocular manifestation is not, however, associated with infection and the pathogenesis of what is called HIV microangiopathy is now better understood. Initially the retina in HIV microangiopathy contains numerous cotton wool spots, which appear and regress over a 1–2-month period and are due to viral parasitisation of capillary endothelial cells. HIV microangiopathy is a good reflection of HIV viral load [53]. The incidence of HIV microangiopathy is decreasing in the postHAART era [54].

Viral Infection

Prior to HAART CMV retinitis affected 20–40% of HIV patients. The incidence of CMV retinitis is now substantially lower although it remains an important cause of blindness in the developing world. However in those with previous CMV retinitis an anterior uveitis or vitritis known as immune recovery uveitis can occur [55]. This is an uncommon but an important cause of visual loss in these patients. Although immune reconstitution protects against many opportunistic infections it does not appear to be protective against ocular syphilis [56]. The most frequent form of ocular involvement is a posterior uveitis or panuveitis [56]. Similarly multidrug-resistant tuberculosis can cause ocular infection particularly in countries where tuberculosis remains endemic [57]. The most important AIDS-related neoplasm is Kaposi’s sarcoma, which can involve the eyelid, the conjunctiva, and the orbit. Primary intraocular lymphoma (Chap. 5) may occur in AIDS patients and is usually associated with Epstein Barr virus infection [58]. Involvement of the brain and cranial nerves with opportunistic pathogens can cause field defects, cranial nerve palsies, and optic atrophy.

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a

b

Herpes Zoster If one accepts that the varicella-zoster virus can persist in a sensory ganglion after childhood chicken pox, it is not difficult to appreciate how widespread the inflammatory disease could be, should the virus be reactivated. In the elderly, Herpes zoster ophthalmicus (HZO) is not simply an affection of the eyelid skin—the conjunctiva, cornea, ocular tissues, and orbital tissues are involved. Macroscopic examination contributes only to the recognition of secondary pathology; e.g., corneal ulceration and post-inflammatory angle closure. The diagnosis can be confirmed by serological analysis for IgM and IgG HZO antibodies in cases in which the disease is mild. Histology of the anterior uvea in cases uncomplicated by secondary corneal ulceration reveals a non-granulomatous lymphocytic inflammatory infiltration that spills over into the trabecular meshwork (Fig. 6.13a, b). In the sclera, the disease is characterised by perineural and perivascular inflammation (Fig.  6.14). If orbital tissues are included with the specimen, search for blood vessels and nerves will reveal most commonly a non-granulomatous perineuritis and perivasculitis (Fig.  6.15), although a granulomatous reaction may be observed. Occasionally, thrombosis will be observed in the ophthalmic and ciliary arteries and it must be assumed that focal necrosis in the iris or ciliary muscle has an ischaemic basis. Chronic

Fig. 6.13 (a and b) The anterior segment in herpes zoster ophthalmicus. The non-granulomatous inflammation is located in the ciliary body (arrows) and trabecular meshwork, but not in the iris (a  ×  40; b × 100)

inflammatory disease will be found in the optic nerve meninges, the ciliary ganglion (Fig. 6.16), the episclera, and the extraocular muscle, and at autopsy, the trigeminal ganglion.

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 hronic Specific Granulomatous C Inflammation Introduction

Fig. 6.14  Scleritis in herpes zoster: the inflammatory reaction is perivascular (v) and perineural (n) (×100)

While chronic granulomatous inflammatory disease is encountered clinically, the efficacy of antibiotic and steroid therapy renders tuberculosis, syphilis, and sarcoidosis a ­rarity for a pathologist. In many cases the diagnosis of granulomatous uveoretinitis remains conjectural, even when a biopsy is performed. Rheumatoid disease still remains refractory and this disease will be encountered far more frequently than will the other entities in this group. Toxocariasis and toxoplasmosis are rare but important diseases from the point of view of the social implications.

Tuberculosis

Fig. 6.15  Perivascular and perineural inflammation in herpes zoster involving the posterior ciliary arteries and nerves (×100)

Tuberculosis is encountered clinically as nodules in any of the ocular and adnexal tissues [59]. As a problem in clinical ophthalmology, tuberculosis is a rarity, but the disease remains significant in the developing countries and multidrug resistant tuberculosis is an increasing problem in individuals with HIV. In pathological specimens, caseating masses can be obvious on macroscopic examination in some cases (Fig. 6.17a, b). The histological features are those of a centrally caseating granulomatous reaction (Fig. 6.18a), and a prolonged search may be required before Mycobacterium tuberculosis is found in a Ziehl-Neelsen stained section (Fig. 6.18b). In immunosuppressed individuals, mycobacteria may be numerous in metastatic choroiditis (Fig. 6.18c, d) and granulomas may be poorly formed.

Sarcoidosis

Fig. 6.16  Lymphocytic infiltration of the ciliary ganglion in herpes zoster (×400)

The ocular forms of sarcoidosis are less likely to be encountered by the pathologist than the conjunctival (see Chap. 11) and orbital forms (see Chap. 12). Nonetheless in the clinical context, ocular involvement occurs in 20% of patients with systemic disease and the retina, the uveal tract, and the optic nerve are the sites most commonly affected [60–62]. Characteristic non-caseating granulomata form nodules in the choroid and retina (Figs. 6.19a, b and 6.20a–d). The outflow system, the iris, ciliary body, vitreous, and choroid are also involved. In the optic nerve, the inflammatory reaction is located within the neural tissue and in the meninges.

Chronic Specific Granulomatous Inflammation

a

Fig. 6.17 (a) Macroscopic appearances of tuberculous infection in the anterior segment (arrow). The lens is calcified and the retina is detached (arrowheads). (b) A section taken at a deeper level reveals sparing of

195

b

the ciliary body (cb), but widespread destruction of the anterior segment tissues (a and b Reproduced with permission from Sehu and Lee [120])

a

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Fig. 6.18 (a) A giant cell (arrow) granulomatous reaction in the anterior chamber in tuberculosis. (b) Occasional acid fast bacilli are a feature of long-standing mycobacterial infection. (c) In an immunosuppressed patient (suffering from Hodgkin’s disease) the

inflammatory reaction is characterised by necrosis (arrow) and fibrin deposition (arrowheads). (d) Numerous acid-fast bacilli are present in the necrotic area (Ziehl-Neelsen stain)

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a

b

Fig. 6.19 (a) In sarcoidosis, small granulomas are present in the region of the optic nerve head (arrow) and the retinal vessels are dilated (arrowheads). (b) A retinal vessel surrounded by a granulomatous inflammatory reaction in sarcoidosis

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b

c

Fig. 6.20  Non-caseating granulomas in the ocular tissues in sarcoidosis: in (a) the trabecular meshwork (arrows), (b) the vitreous base (arrow), (c) the choroid and retinal pigment epithelium (arrow), and (d) the dura mater (arrow). The illustrations were taken from both eyes of

d

a patient who had such severe pain from scleritis she demanded bilateral enucleation. The scratch mark in (c) is due to the presence of a calcified nodule (Schaumann body) sometimes found in sarcoidosis

Chronic Specific Granulomatous Inflammation

Despite recent advances, sarcoidosis remains a diagnosis of exclusion best supported by a tissue biopsy specimen that demonstrates non-caseating granulomas in a patient with compatible clinical and radiologic features of the disease. Being less invasive, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-NA) of mediastinal lymph nodes is gaining popularity among physicians in facilitating diagnosis [63]. However, other laboratory tests, such as measurement of the serum (or CSF) angiotensin converting enzyme (ACE) level can be useful in the majority of cases [62]. Positron emission tomography (PET) scan has been shown to be more sensitive than gallium scan in locating occult sites of active disease [64].

Syphilis Congenital interstitial keratitis due to syphilis is dealt with in Chap. 13. Congenital syphilitic chorioretinitis is manifest as focal pigmented scars in the mid and far periphery of the retina (Fig. 6.21a). Histological examination of the areas of hyper- and hypopigmentation reveals chorioretinal lesions that are characterised by penetration of retinal pigment epithelium and retinal glial cells through Bruch’s membrane into the choroid (Fig. 6.21b). The larger black lesions seen on macroscopic examination are the result of exuberant reactive proliferation of the pigment epithelium. In advanced disease, the outer retina is atrophic and inflammatory cell infiltration is not striking. There has been a recent resurgence in ocular syphilis particularly in those with HIV infection [65]. Common syphilitic ocular manifestations in acquired syphilis include a

Fig. 6.21 (a) The macroscopic appearance of healed chorioretinal scars (arrowheads) in congenital syphilis: the disc (d) is atrophic. (b) At the edge of a chorioretinal scar there is a break in Bruch’s membrane (Bm) and this appears to be an entry site for migration of retinal pig-

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interstitial keratitis, anterior, intermediate, and posterior uveitis, chorioretinitis, retinitis, retinal vasculitis, and cranial nerve and optic neuropathies [66, 67]. The most common ocular syphilitic presentation is uveitis [66, 67], with chorioretinitis being the most frequent manifestation in the posterior segment. Syphilis can also present as a necrotizing retinitis in the midperiphery and peripheral retina, imitating acute retinal necrosis (ARN) or progressive outer retinal necrosis (PORN), albeit with a good visual outcome following treatment [68]. This is usually associated with a variable amount of vitreal inflammation. The ocular inflammation may be granulomatous or non-granulomatous [69, 70]. Syphilis is readily diagnosed by serology and treated effectively with penicillin G [67].

 heumatoid Eye Disease: “Scleritis” R and “Sclerokeratitis” Rheumatoid sclerokeratitis is a serious problem in those countries in which rheumatoid disease is common (see also Chap. 13) and surgical intervention—i.e., glaucoma or cataract surgery also increases the risk of corneoscleral inflammation. In globes requiring enucleation in treatment of scleritis, the clinical diagnosis will not be in doubt and the indication for surgery will be pain, visual loss, and a cosmetically unacceptable eye. In most cases of severe scleritis and/or keratitis, the patient is female, elderly, and a known sufferer from rheumatoid arthritis (which may be mild) or is likely, in the future, to suffer from systemic disease. However, a serological screen is important because scleritis and sclerokeratitis b

ment epithelial (rpe) cells. The ingrowth of retinal glial cells (g) is a useful diagnostic feature (Blodi’s sign) and can be demonstrated by immunohistochemistry using anti-GFAP (glial fibrillary acidic protein) antibodies (×250)

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may be associated with granulomatosis with polyangiitis [71, 72]. Other associations that should be included in the differential diagnosis include relapsing polychondritis, polyarteritis nodosa, Crohn’s disease, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis, Reiter’s syndrome, Behćet disease and psoriatic arthritis [73, 74]. Without evidence of corneal involvement, scleritis and episcleritis are differentiated clinically and are treated differently; their clinical features are comprehensively described in standard texts. Up to a third of patients with scleritis have rheumatoid arthritis. By contrast less than 7% of patients with rheumatoid arthritis have scleritis [75]. Scleral biopsy is not often performed and most pathologists will encounter scleral inflammation as part of a larger specimen. In the enucleated eye, rheumatoid eye disease is usually due to involvement of the anterior sclera and adjacent tissue but two forms are described:

6  Ocular Inflammation

1. Anterior scleritis. There are three main subtypes—diffuse, nodular and necrotising. Diffuse anterior scleritis is the most common and benign form of scleritis. In nodular anterior scleritis there are inflamed, tender, erythematous nodules on the anterior sclera. Necrotising anterior scleritis may occur with or without inflammation. When associated with inflammation it is extremely painful and the condition usually accompanies severe systemic connective tissue disease. Necrotizing anterior scleritis without inflammation—better known as scleromalacia perforans—is painless and most frequently occurs in patients with longstanding rheumatoid arthritis (Fig. 6.22). 2. Posterior scleritis. Scleritis occurring behind the equator is much less common than anterior scleritis. It may occur in isolation or in association with anterior scleritis. Diffuse and nodular forms are also recognized. In posterior scleritis there is tissue destruction with extensive

a

b

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Fig. 6.22 (a) After a lens extraction and insertion of an intraocular lens (arrow) a large sector of collagenolysis is plugged by granulation tissue in the gap between the cornea and sclera (shown by arrowhead). (b) Histology through the centre of the globe shown in (a) reveals a large gap in the corneoscleral envelope filled by prolapsed iris and granulation tissue (*): normal tissue is shown by the arrowhead. The lens cap-

sule remains intact (arrow) (PAS × 6). (c) Nodular anterior scleritis in an aphakic eye. Note the symmetrical thickening of the anterior sclera (*). Posterior to this there is an artefactual space in the choroid (×1). (d) Scleramalacia perforans with incipient perforation (arrow). Note the area of collagen necrosis (*) surrounded by inflammation (×1)

Chronic Specific Granulomatous Inflammation

granulomatous or non-granulomatous inflammatory cell infiltration accompanied by a reactive fibrosis and diffuse thickening of the corneoscleral coat (brawny scleritis) (Fig. 6.23). The fibrous reaction may be localised and can extend into the globe with accompanying exudative uveal and retinal detachment clinically mimicking malignant melanoma [76, 77] (Fig. 6.23). As the process burns out

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there may be scleral thinning resulting in staphyloma formation. On macroscopic examination of an enucleated eye (Figs. 6.22 and 6.23), the complications of the scleral inflammation—e.g., exudative uveal and retinal detachment—may be more immediately obvious than the zone(s) of scleritis.

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Fig. 6.23 (a) A historical exenteration specimen. Prior to routine imaging a large focus of necrotising scleritis (arrow) was considered to be a malignant melanoma with extraocular extension. (b)At higher power loss of definition of the sclera within the mass is seen. In tumours the sclera is usually still well-defined. (c) Posterior scleritis showing marked thickening of sclera posterior to the equator most prominent on

the temporal side. There is prominent surrounding inflammation. (d) On higher power there is a central area of necrobiotic collagen (*) surrounded by a granulomatous reaction. (e) In othere cases of posterior scleritis the sclera tissues show lymphocytic infiltration. and the pattern is non-granulomatous. (f) A similar inflammatory infiltrate involves the overlying choroid (c)

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Perforation of the corneoscleral envelope with the complication of hypotonia readily explains exudation into the subretinal space and papilloedema. On histological examination it is sometimes difficult to appreciate the extent of scleral destruction because the necrotic sclera is replaced with granulation tissue that may sometimes undergo necrosis (Figs. 6.22 and 6.23). Polarised light is useful to identify the native scleral collagen within the sclerotic tissue. Uveal tissue, thickened by a lymphoplasmacytoid infiltrate, may plug the deficit caused by lysis of collagen (Fig. 6.22). Zones of bright red fibrinoid necrosis or paler hyaline degeneration are demarcated by palisaded macrophages with a mantle of lymphocytes and plasma cells. Multinucleate giant cells are sometimes a conspicuous component of the cellular infiltration. There will also be focal clusters of polymorphs and where these are necrotic there are areas of nuclear dust. Brawny scleritis (Fig. 6.23) is characterised by the formation of episcleral granulation tissue and a very extensive non-­ granulomatous choroiditis. Several studies on scleritis have looked at inflammatory cell composition. One study showed a greater proportion of CD20+ lymphocytes [78]. This has provided therapeutic opportunities with Rituximab, an anti-CD20 monoclonal antibody [79, 80]. Immune complexes are considered to play in cases of scleritis associated with vasculitis [81]. Studies have shown differences in cytokine expression between necrotizing (TNFα alone) and non-necrotising scleritis (TNFα and IL-2) [78].

 cleritis: Causes Other than Autoimmune S Disease Scleritis is most commonly associated with rheumatoid disease followed by the other autoimmune diseases listed previously. However if there is no apparent underlying autoimmune disease then other causes should be considered.

Infectious Scleritis Infection scleritis is uncommon particularly if there is no accompanying keratitis but may be viral, bacterial, fungal or parasitic [82–84].  urgically Induced Necrotising Scleritis (SINS) S Necrotising scleritis can occur after some forms of ocular surgery e.g.lens extraction, pterygium excision; prospective systemic investigation may reveal an underlying collagenosis or it may follow post-surgical infection [85, 86]. Usually the scleritis is localized but it can be diffuse or multifocal [87].

6  Ocular Inflammation

 isedronate Associated Scleritis R Biphosphonate drugs used for the prevention of osteoporosis are known to cause ocular inflammation including conjunctivitis and uveitis. Scleritis in association with risedronate therapy has also been described [88]. Irradiation Scleritis The fibrous sclera is considered radio-resistant however scleral necrosis following plaque brachytherapy or proton beam therapy can rarely occur [89]. Usually there is an underlying autoimmune disease [90]. I gG4 RD Scleritis IgG4 RD has also been described in the sclera—either as a localized mass simulating a tumour [91] or as diffuse scleritis associated with pachymeningitis [92]. Masquerade Scleritis For obvious reasons there is a reluctance to biopsy inflamed sclera that is undergoing necrobiosis but the possibility of malignancy masquerading as scleritis should be born in mind. This has been described as the initial manifestation of melanoma, metastatic carcinoma and lymphoma [93–95]. Treatment resistant scleritis should raise suspicions of an infectious or malignant masquerade.

Protozoal Disease: Toxoplasmosis and Malaria Toxoplasma gondii is the commonest protozoan parasite to infect the eye [96]. The cat is the definitive host and the sexual stages of the life cycle occur in the small intestine, which results in the production of oocyst that are excreted in the faeces. Animals grazing on contaminated ground may become infected and in the intestine the oocyst converts to the rapidly replicating form of the parasite: the tachyzoite. The tachyzoite may then infect any cell in the body but has a predilection for the brain and muscle. With the onset of protective immunity the tachyzoite is converted to the slower growing bradyzoite stage of the parasite, which resides within tissue cysts. Other animals, including humans can become infected by ingesting meat containing these tissue cysts. If a female becomes infected for the first time during pregnancy she may transmit the infection transplacentally to her foetus. Depending on the stage of pregnancy, congenital infection may be severe and results in a characteristic tetrad of meningoencephalomyelitis, hydrocephalus, intracerebral calcifications, and retinochoroiditis. Due to residual tissue cysts, congenital retinochoroiditis is a recurring disease that can be very destructive. Retinochoroditis may also occur following acute acquired infection in the immunocompetent

Chronic Specific Granulomatous Inflammation

adult. This may be differentiated from congenital infection by the lack of associated retinochoroidal scarring. In the immunocompromised host, severe infection mimicking acute retinal necrosis syndrome may occur. The treatment of toxoplasmic retinochoroiditis is much debated. Active lesions will heal spontaneously but the response may be quicker and recurrence delayed if appropriate antibiotic therapy is (pyrimethamine, sulphonamide, azithromycin, clindamycin) is given. Steroids alone are contraindicated in the treatment of toxoplasmic retinochoroiditis. Toxoplasma scars are large and circular and have prominent pigmented areas. In only a few cases have Toxoplasma cysts been found in the chorioretinal scars in the adult immunocompetent eye, however the tachyzoites are plentiful in active lesions in infected fetuses and in the immunocompromised. Histologically in the acute active disease, the sectorial retinal necrosis is extreme (Fig. 6.24a) and characterised by the presence of pink staining cysts that contain bradyzoites; the cysts are best detected in the retina adjacent to a sector of necrosis and require oil immersion microscopy for identification (Fig. 6.25a, b). It is almost impossible to identify single organisms (tachyzoites or bradyzoites) in tissue sections without the aid of immunohistochemistry. A dense lymphoplasmacytic non-granulomatous reaction is present in the choroid beneath the necrotic area. The ultrastructure of the cysts reveals the morphological complexity of the organisms (Fig. 6.24b). In the adult healed form, the retina is gliotic and fused with Bruch’s membrane; the changes are not specific. In contrast to toxoplasmosis, the microembolic effects of malarial parasites within red cells in the capillaries (Fig. 6.26) lead to extensive haemorrhages within the retina [97, 98].

201

a

b

Ocular Toxocariasis Adult dogs and puppies are the natural host for the intestinal nematode worm Toxocara canis and there is a significant contamination of soil and grass by ova in areas where dogs (which are not regularly wormed) are kept as pets. Accidental ingestion of ova (“dirt eating” or pica in infants) is followed by penetration of the intestinal wall by larvae after the wall of the ovum is destroyed by the gastric juice. If the infestation is massive, the child will suffer from visceral larva migrans (VLM) in which the larvae migrate for periods of up to 10 years, through the body tissues (lung, liver, brain, etc.). The immune system is evaded because the organism is covered by excretory/secretory surface glycoconjugates (ES), which are of variable (and possibly changing) antigenicity. Most commonly, the ocular form of toxocariasis is manifest as unilateral disease without systemic disturbance in children under the age of three, but older children and adults can be affected also [99]. The unilaterality of the disease is

Fig. 6.24 (a) An acute necrotising focus in a neonatal eye in toxoplasmosis. Cysts may be found in the retina at the periphery of the necrotic area (×40). (b) Ultrastructure of a cyst in a murine model reveals bradyzoites within a cystic structure, which has a distinct wall (w). The conoid (c) is a distinctive feature and is the region of the organism that penetrates the cell wall (×7500)

puzzling in view of the fact that haematogenous spread is so extensive. In the eye the disease takes various forms: (1) a solitary nodule in retina, (2) focal retinitis with massive exudative detachment, (3) peripheral retinitis with retinal fold, and (4) pars planitis and iritis.

202

6  Ocular Inflammation

a

b

Fig. 6.27  This fibrous nodule protruding through the retina at the posterior pole of an infant’s eye was found by Ashton [100] in serial sections to contain a Toxocara larva (arrow) which has a cuticle (inset) (×40; inset ×250)

Fig. 6.25 (a) In toxoplasmosis, the cysts possess a pink cytoplasm (arrows) and are easier to identify in the retina in the partially necrotic tissue (b) than in the outer nuclear layer (arrow) where there is some resemblance to glial cell nuclei

Fig. 6.26  In malaria, red cells containing the parasites (arrow) occlude small blood vessels in the brain and presumably in the retina

The classic presentation described by Ashton in 1960 was a solitary organism within a fibrous nodule (Fig. 6.27) within the retina simulating a retinoblastoma [100]. Focal retinitis with exudative detachment of the retina may also simulate a retinoblastoma and be treated by enucleation. Initial pathological examination of the enucleated eye will reveal an exudative detachment of the retina with cholesterol crystals in the solid proteinaceous exudate. Serial sections will be required to find the small focal necrotising granulomas in the vitreous (Fig.  6.28) that may contain viable or fragmented larvae. The presence of eosinophils in the infiltrate or forming small abscesses are often a helpful feature of the inflammatory response and it should be noted that intact larvae are only rarely found. An intact organism has a refractile wall and the nuclei are lined up in a row within the cuticle (Fig. 6.28). Dead and disrupted larvae are identifiable as cell residues and fragmented refractile remnants of the cuticle. With greater clinical awareness and positive serological tests (enzyme-linked immunosorbent assay [ELISA]) for toxocariasis, enucleation of an eye containing a solitary posterior granuloma [101] or a peripheral retinal granuloma is extremely rare. Examination of the vitreous in a

Chronic Specific Granulomatous Inflammation

a

203

b

Fig. 6.28 (a) An abscess due to breakdown of a Toxocara larva in the vitreous (arrow) overlying a detached retina. (b) Adjacent sections of a Toxocara larva (arrow) in the mouse retina. The right-hand figure shows the immunohistochemical reaction to excretory substance

vitrectomy specimen may demonstrate the organism [102], or the excretory substance (ES) antigen [103]. Realtime PCR can also be used to detect parasite DNA in the vitreous [104] A specimen may now contain a lesion treated by a laser if steroids and antihelminthic drugs are ineffective.

tis and low-grade infections with gram negative enteric infections [105].

Behçet’s Disease

Behçet’s Disease is a multisystemic inflammatory disorder with vasculitis of uncertain aetiology as the underlying pathology. It is typically characterised by relapsing episodes Uveitis involves inflammation of the iris, ciliary body, vitre- of oral aphthous ulcers, genital ulcers, skin lesions, and ocuous, retina or choroid. There are multiple causes for uveitis lar lesions. It mainly affects people aged between 20 and 40, however histology is rarely involved in the diagnostic work with male preponderance in Middle Eastern countries. No up. Infectious diseases have been considered. Inflammatory pathognomonic laboratory findings or histopathological feadiseases included HLA B27-associated uveitis, uveitis with tures currently exist for the diagnosis of Behçet’s Disease. chronic inflammatory bowel disease, Behçet disease, Vogt-­ Therefore, diagnoses are made according to clinical criteria Koyanagi-­ Harada disease, multiple sclerosis and juvenile proposed by the International Study Group for Behçet’s idiopathic arthritis. Specific ophthalmic entities Fuchs hetero- Disease or the Behçet’s Disease Research Committee of chromic cyclitis, white dot syndromes and sympathetic oph- Japan [106]. thalmia. Various drugs including bisphosphonates (see earlier) Ocular involvement in Behçet’s Disease is frequent (67– can also induce uveitis. Clinical investigations include exten- 95%) and usually occurs late in the course of the disease sive serology, radiological imaging, and anterior chamber tap [107]. The typical ocular manifestations are usually bilateral as appropriate. A significant number of cases are idiopathic. and consist of relapsing posterior or panuveitis associated Histological descriptions are rare for many of the causes and with retinal vasculitis. Hypopyon may be observed and is the majority of enucleations will show the endstage features usually a sign of severe disease. The ocular complications of and complications of the inflammatory process. Behçet’s Disease have severe effects on visual function. Retinal vasculitis leads to haemorrhage, retinal exudation and detachment and this is accompanied by a non-­ HLA B27 Associated Uveitis granulomatous uveitis. Successive relapses and resolution could lead to severe sequelae such as synechia, cataract, This is a distinct unilateral sudden onset anterior uveitis glaucoma, retinal atrophy, optic atrophy, macular degenerawhich is self-limited and recurrent occurring in those with tion, retinal vein occlusion, optic neuritis, phthisis bulbi, and HLA-B27 alloantigen and linked with ankylosing spondyli- blindness [107].

Chronic Uveitis

204

Although the exact pathogenesis of Behçet’s Disease remains unknown, studies have shown that HLA-B51 is strongly associated with Behçet’s Disease in up to 60% of affected patients [108]. Infectious agents including herpes simplex virus (HSV) and Streptococcus sanguis have been implicated as potential triggers [108].

6  Ocular Inflammation

lary region of the choroid. The inflammatory cells in the vitreous vary in numbers. The convalescent (chronic) phase is characterized by mild to moderate non-granulomatous inflammatory cell infiltration, usually with focal aggregates of lymphocytes containing occasional macrophages. The choroid is depigmented, displaying spindle cells devoid of melanin granules. There are numerous peripheral choroidal depigmented small atroVogt-Koyanagi-Harada Syndrome (VKH) phic lesions involving the overlying choriocapillaris, the RPE, and the outer retina. These lesions consist of focal RPE This condition, also known as uveomeningoencephalitic loss with chorioretinal adhesions, mirroring the clinical syndrome, is a systemic autoimmune disorder directed observations of window defect of at the level of RPE as seen against melanin containing tissues such as the choroid, on fluorescein angiography. meninges, inner ear and skin. It typically affects patients in The chronic recurrent phase typically shows a diffuse the fourth to fifth decades and is more common in those with uveal infiltration consisting of a granulomatous process simdarker skin pigmentation [109]. It is uncommon in Black and ilar to that seen in the acute phase. Chorioretinal adhesions, Caucasian individuals. It is an idiopathic inflammatory dis- with atrophy and/or proliferation of RPE are common. The ease characterised by bilateral, chronic, diffuse granuloma- RPE proliferation may be accompanied by the formation of tous panuveitis leading to severe visual dysfunction due to subretinal neovascular channels or subretinal fibrosis. In optic neuritis and exudative retinal detachment. It is fre- association with the RPE changes, photoreceptor degeneraquently associated with neurological, auditory, and integu- tion and gliosis may be observed in the overlying neural retmentary manifestations [109]. ina. The choriocapillaris is involved in the degenerative VKH syndrome has been linked to HLA-DR4 and HLA-­ process, and chorioretinal adhesions are apparent at these DRw53, along with the most significant risk allele being sites. HLA-DRB1*0405 [110]. Postulation of autoimmune The pathologic features of VKH and sympathetic ophresponse triggered by viral infection, such as Epstein-Barr thalmitis are virtually identical. However, prior penetrating virus (EBV) and cytomegalovirus (CMV) have also been injury is usually characteristic of sympathetic ophthalmitis made [109]. [111]. Similar to the clinical features, the histological features of VKH syndrome vary according to the stage of the disorder [111]. The evolution of the disease is divided into acute, con- Fuchs Heterochromic Cyclitis valescent (chronic), and chronic recurrent stages. In the acute uveitic phase, the retina is detached from the retinal pigment In heterochromic iridocyclitis a change in the colour of the epithelium (RPE) with an eosinophilic proteinaceous exu- iris is accompanied by signs of inflammation in the antedate. The choroid is diffusely thickened and infiltrated by rior chamber (flare and cells), neovascularisation, glaulymphocytes, with focal aggregates of epithelioid histiocytes coma, and cataract (anterior subcapsular fibrous and multinucleated giant cells. The exudative detachment metaplasia), and these are the clinical hallmarks of this indicates alteration in RPE with fluorescein angiography condition [112, 113]. Histological descriptions are rare revealing focal leakage at the RPE level. Although the RPE and the changes are limited to a low-grade inflammatory appears intact on light microscopy, occasional lymphocytes round cell infiltration of the anterior uvea with stromal can be seen under the RPE.  Focal collections of lympho- atrophy and degeneration in the iris melanocytes cytes, pigment-laden macrophages, and epithelioid histio- (Fig.  6.29a–c). The outflow system is also infiltrated by cytes are noted under the proliferated RPE, representing the lymphocytes and inflammatory cells: If the angle remains formation of Dalen-Fuchs nodules. The choriocapillaris and open, the trabeculitis progresses to replacement fibrosis. retina are preserved in the acute phase of the disease. Either Many different aetiologies have been postulated for this granulomatous inflammation or diffuse lymphocytic infiltra- aberrant immune response. tion may be observed in the iris and the ciliary body. Although several infectious agents have been postulated However, it is less intense than those seen in the juxtapapil- current studies support a role for the rubella virus [114].

Chronic Specific Granulomatous Inflammation

a

205

b

c

Fig. 6.29 (a) The anterior segment in a case of heterochromic iridocyclitis: The iris stroma is atrophic and the angle is open (×16). (b) The interspaces of the trabecular meshwork contain lymphocytes (×160). (c) The iris is lined by new blood vessels (nv) and the pigment epithe-

lium is atrophic (a); the iris stroma contains a lymphocytic infiltrate. The lens is thickened by subcapsular fibrous metaplasia (fm) of the epithelium and the underlying cortex is undergoing cortical liquefaction (cl) (×160)

White Dot Syndromes (WDS)

vascular membrane [117]. In a case that was thought to be an example of AMPPE [118] with larger white subretinal mounds (Fig. 6.30a–d), there was invasion of the retinal pigment epithelium (RPE) by lymphocytes and plasma cells with varying degrees of destruction of the photoreceptor layer, which in some areas was gliotic. Gliosis is followed by reactive proliferation of the RPE, which explains the pigmentary disturbances. Clinically similar to the WDS ocular histoplasmosis syndrome (OHS) is a common multifocal chorioretinal disorder characterized by peripapillary atrophy, chorioretinal scars, and possible development of choroidal neovascularization. A high proportion of cases have been shown to occur where Histoplasmosis is endemic however the disease has also be identified in non-endemic areas [119].

These are a diverse group of conditions with posterior uveitis that share similar clinical findings [115]. The group includes Birdshot Chorioretinopathy (BCR), multiple effervescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (AMPPE), multifocal choroiditis with panuveitis (MCP), serpiginous choroiditis (SC), punctate inner choroidopathy/multifocal choroiditis (PIC/MFC) and relentless placoid chorioretinitis (RPC). Whilst there is overlap between the diseases most can be distinguished natural history, clinical appearances and progression and imaging studies [116]. Histological descriptions of these conditions are rare. A case of PIC/ MFC has been described and showed perivascular lymphocytic inflammation in the choroid with an early stage neo-

206

6  Ocular Inflammation

a

b

c

d

Fig. 6.30  A sufferer from AMPPE donated her eyes to research post-­ mortem. (a) Macroscopic examination revealed white areas (arrow), partially pigmented areas (arrowhead) and pigmented scars. (b) In the mildest damage the choroid and RPE (arrow) are infiltrated by lymphocytes and macrophages. Bruch’s membrane in (b) and (c) is shown by

arrowheads. (c) Where there is more extensive infiltration the infiltrate contains capillaries (white arrows) and the photoreceptor layer is lost (black arrow). (d) In an area of extensive retinal scarring the RPE is proliferating (arrowhead) over a dense lymphocytic choroidal infiltrate

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208 national criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop On Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17:160–9. 63. Morgenthau AS, Iannuzzi MC.  Recent advances in sarcoidosis. Chest. 2011;139(1):174–82. 64. Keijsers RG, Grutters JC, Thomeer M, Du Bois RM, Van Buul MM, Lavalaye J, et  al. Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of 67Ga imaging and 18F-FDG PET. Q J Nucl Med Mol Imaging. 2011;55(1):66–71. 65. Fonollosa A, Giralt J, Pelegrín L, Sánchez-Dalmau B, Segura A, Garcia-Arumí J, Adan A. Ocular syphilis- back again: understanding recent increases in the incidence of ocular syphilitic disease. Ocul Immunol Inflamm. 2009;17:207–12. 66. Woolston SL, Dhanireddy S, Marrazzo J. Ocular syphilis: a clinical review. Curr Infect Dis Rep. 2016;18:36. 67. Dutta Majumder P, Chen EJ, Shah J, Ching Wen Ho D, Biswas J, See Yin L, et  al. Ocular syphilis: an update. Ocul Immunol Inflamm. 2019;27:117–25. 68. Kuo A, Ziaee SM, Hosseini H, Voleti V, Schwartz SD, Kim NU, et al. The great imitator: ocular syphilis presenting as posterior uveitis. Am J Case Rep. 2015;16:434–7. 69. Tsan GL, Amin P, Sullivan-MEE M. Non-granulomatous uveitis as the first manifestation of syphilis. Optom Vis Sci. 2016;93:647–51. 70. Wells J, Wood C, Sukthankar A, Jones NP. Ocular syphilis: the reestablishment of an old disease. Eye (Lond). 2018;32:99–103. 71. Cocho L, Gonzalez-Gonzalez LA, Molina-Prat N, Doctor P, Sainz-­ de-­la-Maza M, Foster CS. Scleritis in patients with granulomatosis with polyangiitis (Wegener). Br J Ophthalmol. 2016;100:1062–5. 72. Sims J. Scleritis: presentations, disease associations and management. Postgrad Med J. 2012;88:713–8. 73. Cunningham ET Jr, McCluskey P, Pavesio C, et al. Scleritis. Ocul Immunol Inflamm. 2016;24:2–5. 74. Héron E, Bourcier T.  Scleritis and episcleritis. J Fr Ophtalmol. 2017;40:681–95. 75. Sainz de al Maza M, Molina N, Gonzalez-Gonzalez LA, Doctor PP, Tauber J, Foster CS.  Clinical characteristics of a large cohort of patients with scleritis and episcleritis. Ophthalmology. 2012;119:43–50. 76. Alsharif HM, Al-Dahmash SA. Atypical posterior scleritis mimicking choroidal melanoma. Saudi Med J. 2018;39:514–8. 77. Liu AT, Luk FO, Chan CK.  A case of giant nodular posterior scleritis mimicking choroidal malignancy. Indian J Ophthalmol. 2015;63:919–21. 78. Usui Y, Parikh J, Goto H, Rao NA. Immunopathology of necrotising scleritis. Br J Ophthalmol. 2008;92(3):417–9. 79. Chauhan S, Kamal A, Thompson RN, Estrach C, Moots RJ. Rituximab for treatment of scleritis associated with rheumatoid arthritis. Br J Ophthalmol. 2009;93(7):984–5. 80. Miserocchi E, Pontikaki I, Modorati G, Gattinara M, Meroni PL, Gerloni V. Anti-CD 20 monoclonal antibody (rituximab) treatment for inflammatory ocular diseases. Autoimmun Rev. 2011;11(1):35–9. 81. Wakefield D, Di Girolamo N, Thurau S, Wildner G, McCluskey P. Scleritis: Immunopathogenesis and molecular basis for therapy. Prog Retin Eye Res. 2013;35:44–62. 82. Gonzalez-Gonzalez LA, Molina-Prat N, Doctor P, Tauber J, Sainz de la Maza MT, Foster CS.  Clinical features and presentation of infectious slceritis from herpes viruses: a report of 35 cases. Ophthalmology. 2012;119:1460–4. 83. Reddy JC, Murthy SI, Reddy AK, Garg P. Risk factors and clinical outcomes of bacterial and fungal scleritis at a tertiary eye care hospital. Middle East Afr J Ophthalmol. 2015;22:203–11. 84. Lang SJ, Böhringer D, Reinhard T. Necrotizing scleritis after acanthamoeba keratitis. Opthalmologe. 2020. [Epub ahead of print]. 85. Doshi RR, Harocopos GJ, Schwab IR, Cunningham ET Jr. The spectrum of postoperative scleral necrosis. Surv Ophthalmol. 2013;58:620–33.

6  Ocular Inflammation 86. Yamazoe K, Shimazaki-Den S, Otaka I, Hotta K, Shimazaki J. Surgically induced necrotizing scleritis after primary pterygium surgery with conjunctival autograft. Clin Ophthalmol. 2011;5:1609–11. 87. Akbari MR, Mohebbi M, Jhari M, Mirmohammadsadeghi A, Mahmoudi A.  Multifocal surgically induced necrotizing scleritis following strabismus surgery: a case report. Strabismus. 2016;24:101–5. 88. Hemmati I, Wade J, Kelsall J.  Risedronate-associated scleri tis: a case report and review of the literature. Clin Rheumatol. 2012;31:1403–5. 89. Kaliki S, Shields CL, Rojanaporn D, Badal J, Devisetty L, Emrich J, et  al. Scleral necrosis after plaque radiotherapy of uveal melanoma: a case-control study. Ophthalmology. 2013;120:1004–11. 90. Passarin O, Zografos L, Schalenbourg A, Moulin A, Guex-Crosier Y.  Scleritis after proton therapy in uveal melanoma. Klin Monbl Augenheilkd. 2012;229:395–8. 91. Karim F, De Hoog J, Paridaens D, Verdijk R, Schreurs M, Rothava A, et al. IgG4-related disease as an emerging cause of scleritis. Acta Ophthalmol. 2017;95:e795–6. 92. Kim EC, Lee SJ, Hwant HS, Kim J, Kim MS. Bilateral diffuse scleritis as a first manifestation of immunoglobulin G4-realted sclerosing pachymeningitis. Can J Ophthalmol. 2013;48:e31–3. 93. Shukla D, Kim R. Giant nodular posterior scleritis simulating choroidal melanoma. Indian J Ophthalmol. 2006;54:120–2. 94. Sarah B, Ahmed G, Saloua B, Ibtissam H, Abdeljalil M, Maria D, Anass F, Hanane R. Nodular scleritis revealing metastasis of breast cancer: diagnosis not to be neglected. Case Rep Ophthalmol Med. 2020:8689463. 95. Abramson DH.  Lymphoma mimicking scleritis. Ophthalmology. 2001;108:1517–8. 96. Kochanowsky JA, Koshy AA.  Toxoplasma gondii. Curr Biol. 2018;28:R770–1. 97. Mehta SA, Ansari AS, Jiandani P.  Ophthalmoscopic findings in adult patients with sever falciparum malaria. Ocul Immunol Inflamm. 2008;16:239–41. 98. Barrera V, Hiscott PS, Craig AG, White VA, Milner DA, Beare NA, et al. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brins of Malawian children with fatal cerebral malaria. J Infect Dis. 2015;211:1977–86. 99. Rubinsky-Elefant G, Hirata CE, Yamamoto JH, Ferrieira MU. Human toxocariasis: diagnosis, worldwide seroprevalences and clinical expression of the systemic and ocular forms. Ann Trop Med Parasitol. 2010;104:3–23. 100. Ashton N. Larval granulomatosis of the retina due to Toxocara. Br J Ophthalmol. 1960;44:129–48. 101. Duguid IM.  Chronic endophthalmitis due to Toxocara. Br J Ophthalmol. 1961;45:705–17. 102. Acar N, Kapran Z, Utine CA, Büyükbabani N.  Pars plan vitrectomy revealed Toxocara canis organism. Int Ophthalmol. 2007;27:277–80. 103. Felberg NT, Shields JA, Federman JL. Antibody to Toxocara canis in the aqueous humor. Arch Ophthalmol. 1981;99:1563–4. 104. Agarwal A, Das P, Kumar A, Sharma S, Aggarwal K, Sehgal S, et  al. Multiple granulomas of ocular toxocariasis in an immunocompetent male. Ocul Immunol Inflamm. 2020;28: 111–5. 105. D’Ambrosio EM, La Cava M, Tortorella P, Gharbiya M, Campanella M, Iannetti L.  Clinical features and complications of the HLA-B27-associated acute anterior uveitis: a metanalysis. Semin Ophthalmol. 2017;32:689–701. 106. Kurokawa MS, Suzuki N.  Behçet’s disease. Clin Exp Med. 2004;3:10–20. 107. Bonfioli AA, Orefice F.  Behçet’s diease. Semin Ophthalmol. 2005;20:199–206. 108. Mendoza-Pinto C, García-Carrasco M, Jiménez-Hernàndez M, Jiménez-Hernàndez C, Riebeling-Navarro C, Nava Zavala A,

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209 115. Crawford CM, Igboeli O.  A review of the inflammatory chorioretinopathies: the white dot syndromes. ISRN Inflamm. 2013;2013:783190. 116. Raven ML, Ringeisen AL, Yonekawa Y, Stem MS, Faia LJ, Gottlieb JL. Multi-modal imaging and anatomic classification of the White Dot syndromes. Int J Retina Vitreous. 2017;3:12. 117. Dunlop AAS, Cree IA, Hague S, Luthert PJ, Lightman S.  Multifocal choroiditis: clinicopathologic correlation. Arch Ophthalmol. 1998;116:801–3. 118. Charteris DG, Lee WR. Multifocal posterior uveitis: clinical and pathological findings. Br J Ophthalmol. 1990;74:688–93. 119. Diaz RI, Sigler EJ, Rafieetary MR, Calzada JI. Ocular histoplasmosis syndrome. Surv Ophthalmol. 2015;60:279–95. 120. Sehu KW, Lee WR, editors. Ophthalmic pathology: an illustrated guide for clinicians. Malden: Blackwell Publishing Ltd; 2008. ISBN 9780727917799.

7

Treatment of Retinal Detachment

Introduction This chapter serves primarily as a guide to the causative pathology and the secondary disturbances that are encountered when an enucleated eye is submitted with a clinical history of “Retinal detachment  – treatment unsuccessful.” With technical advancement and a more aggressive surgical approach to trauma and diabetes, such specimens, although rare, are being submitted more frequently than in the past. In addition, clinicopathological correlation is more significant in view of the development of new surgical techniques, which are described in the literature. Initially it should be acknowledged that the term “retinal detachment” is a misnomer, because it implies a separation of the retina from the choroid. What occurs, in fact, is a separation between the neural retina and the retinal pigment epithelium; i.e., a reopening of the embryonic space between the inner and outer layers of the optic cup. Before consideration of the aetiology and pathogenesis of separation at the photoreceptor-pigment epithelial interface (universally, but incorrectly, called the subretinal space), it is relevant to consider the mechanisms that maintain apposition between the two embryonic layers, which are in contact only where the outer segments of the photoreceptors are surrounded by processes from the pigment epithelium. The interphotoreceptor space contains glycoproteins, which on teleological grounds might be considered to be “sticky,” and one might assume that the processes of the retinal pigment epithelium (RPE) cells would grip the photoreceptors, but neither of these structural features can seriously be considered as proven factors in the maintenance of apposition. An important factor might be the effect of a constant bulk flow of water from the ciliary processes through the vitreous and across the retina into the choroid, which has the properties of a heavily vascularized hyperosmotic tissue. What has been established on clinical and experimental grounds is that any retinal perforation (e.g., a tear or hole) that allows fluid movement from the vitreous into the photoreceptor-­ pigment epithelial interface can progres-

sively separate the layers (so-called rhegmatogenous detachment). It is equally possible that a retina can reattach when the fluid is reabsorbed, but frequently the loss of the normal relationship between photoreceptors and the RPE results in photoreceptor atrophy and reactive proliferation in the retinal pigment epithelium. Conversely, it is now accepted that flat holes can occur at the macula and at the periphery and that their presence may not lead to separation. It seems likely that some form of traction by condensed vitreous is essential for maintaining eversion of the lip of the hole to promote fluid movement from the vitreous [1]. For a short period of time, the photoreceptor layer of the retina can survive separation from the RPE, though this period of time is much shorter at the fovea than in the periphery. If the layers are quickly re-apposed, function should be preserved after rhegmatogenous detachment [2]. However the TUNEL technique (for apoptosis) has shown that there is apoptotic photoreceptor death in the outer nuclear layer after traumatic detachment (Fig. 7.1a–g) and this process becomes more extensive the longer the retina is detached [3, 4]. It is also of interest that the blue cones are lost selectively after retinal detachment [5]. Since it is now a routine but emergency procedure to reattach a detached retina with good anatomical and visual results, the surgeon’s interest lies more in the causes of surgical failure and the effects of new forms of treatment on the ocular tissues. Until recently, there are basically two lines of approach to sealing off a hole in the retina after subretinal fluid has been drained: 1. To indent the sclera and choroid so that the retinal hole is sealed. 2. Replacement of the vitreous with a bubble of silicone oil, or inert gas; e.g., air or sulphur hexafluoride (SF6) gas. The vitreous may also be replaced with compounds referred to as “heavy liquids” or more recently “heavy silicone,” which maintain mechanical adhesion particularly in the inferior part of the retina.

© Springer Nature Switzerland AG 2021 F. Roberts, C. K. Thum, Lee’s Ophthalmic Histopathology, https://doi.org/10.1007/978-3-030-76525-5_7

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a

b

c

d

f

e

g

Classification of Retinal Detachment

Both procedures hold the neural retina against the retinal pigment epithelium and allow the surgeon to form adherent glial scars between retina and choroid using photocoagulation (argon or diode laser) or cryotherapy. The introduction of the use of human amniotic membrane (hAM) in vitreoretinal surgery has certainly provided new alternative management in some cases [6]. If this technically challenging technique is widely employed, new pathological features will surely be described in the not too distant future. The formation of epiretinal membranes is a significant contribution to the failure to reattach the retina after surgical intervention, although haemorrhage and infection remain occasional indications for enucleation. These membranes may be formed by glial cells (derived from Müller cells or perivascular astrocytes), or metaplastic spindle-shaped RPE cells that have migrated through retinal holes or possibly through the retina. If the retina is ischaemic, blood vessels and fibroblasts migrate onto the retinal surface. The contractile properties of glial cells and metaplastic retinal pigment epithelial cells within a scaffold on the inner limiting membrane are responsible for wrinkling of the inner retina and distortion of the outer retina—a process referred to as proliferative vitreoretinopathy or “PVR” [7–14]. Aside from the aforementioned epiretinal form, PVR can also assume a subretinal position, forming contractile subretinal bands which prevent retinal reattachment. Subretinal PVR demonstrates a classical appearance of bands of basement membrane type material which could be Periodic Acid Schiffs stain (PAS) positive, around which are cords of RPE cells (Cytokeratin+), myofibroblasts (α-SMA+) and macrophages (CD68+). In addition, a third form of PVR—intraretinal PVR is represented by intraretinal gliosis secondary to hypertrophy and hyperplasia of Müller cells (GFAP+) which result in retinal shortening and distortion [15]. Paradoxically PVR can be the result of surgical intervention as well as the indication for vitrectomy and/or membrane stripping. In vasoproliferative retinopathy or “VPR” (e.g., in diabetes or the retinopathy of prematurity), removal of membranes can lead to the reattachment of the retina. VPR membranes contain small blood vessels that are populated by normal endothelial cells and pericytes in most specimens, but acellularity with ghost vessels may be a feature. Positive staining

213

for vascular endothelial growth factor (VEGF) is present in the membranes in VPR [16, 17]. The surgical removal of such membranes has permitted considerable documentation of this pathological process. The specimens are small and are better handled if a drop of carbol fuchsin is added to the fixative before processing. In addition to the cells described previously, it is worthwhile to search for a thin periodic acid-Schiff (PAS)-positive membrane that indicates the undesirable stripping of the inner limiting membrane of the retina, which may stimulate further epiretinal membrane formation. The contribution of the morphologist to this group of disorders is directed towards (a) the study of retinal abnormalities that predispose to detachment, (b) the description of the pathology found after a detachment has failed to respond to treatment, and (c) the pathology that is specific to the forms of treatment now currently in use. Some of the features that are to be anticipated in the pathology of retinal detachment are illustrated in Fig. 7.2.

Classification of Retinal Detachment “Rhegmatogenous” detachment occurs when fluid passes from the vitreous cavity through a hole in the retina into the “subretinal space.” The “hole” or “tear” is most commonly secondary to degenerative disease in the retina and vitreous (e.g., lattice degeneration) and is probably precipitated by minor trauma. The vitreous is attached at the base on the pars plana and on the inner surface of the peripheral retina so that a vitrectomy is an integral part of the surgical attempt to abolish vitreous traction and to reattach the retina. Vitrectomy is not always required and successful reattachment may also be achieved by a simple scleral buckle. By contrast, “exudative” detachment refers to accumulation of fluid under the neural retina in situations in which there is abnormally excessive permeability in the retinal vessels or in the choroidal vessels. This process is encountered in inflammation or neoplasia and in retinal or choroidal vasculopathy with loss of endothelial cell integrity, and in this event the subretinal space is filled with a more viscous proteinaceous exudate.

Fig. 7.1 (a) The normal photoreceptor layer possesses inner segments (*) that are slightly shorter than the outer segments, the tips of which are surrounded by processes from the retinal pigment epithelium (RPE). Cone inner segments are easily distinguished by their thickness. The outer limiting membrane (OLM) is formed by attachments of the Müller cells. (b) In a successful surgical reattachment, as in this case in the region of the plomb, it was not possible to identify any abnormalities in the photoreceptor layer. (c) Electron microscopy from the same region as shown in (b) reveals normal photoreceptor tips (arrowhead) surrounded by processes (arrow) from the retinal pigment epithelial cell. (d) When the detachment is established the photoreceptors over the exudate (arrow) are atrophic by comparison with those where the retina is in situ (arrowhead) There are exudates in the outer plexiform layer. (e) In this shallow exudative detachment, macrophages (arrowheads) are phagocytosing photoreceptor debris and the outer limiting membrane is distinct (arrow). (f) As the degeneration progresses the photoreceptor nuclei (arrow) in the outer nuclear layer are markedly depleted and the outer limiting membrane is distinct (arrowhead). (g) When the retina is reattached after a prolonged period the outer nuclear layer is reduced to a single and interrupted layer (arrowheads) and the retinal pigment epithelium becomes focally hyperplastic (arrow)

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7  Treatment of Retinal Detachment

a Aphakia Vitrectomy scar Residual silicon oil

Cryotherapy

Retinal tear

Subretinal membranes Preretinal membranes

RPE proliferation

b

Fig. 7.2  Diagram to illustrate the pathology that might be encountered in globes treated surgically for retinal detachment

“Tractional” detachment occurs when there is condensation or (dis)organization of the vitreous, by trauma or neovascularization. In severe trauma the vitreous gel may be invaded by contractile cells (fibroblasts from the scleral coat), which form traction bands and pull the retina internally. In proliferative vitreoretinopathy due to trauma, in both surgical and non-surgical and in idiopathic cases, the retina is lined by cells derived from retinal glial cells or from the retinal pigment epithelial cells (Fig.  7.3a, b) that have migrated through a hole in the retina. In vasoproliferative retinopathy (see earlier), in addition to vessels possessing endothelial cells and pericytes, the membranes contain glial cells, fibroblasts and macrophages.

Rhegmatogenous Detachment Untreated or uncomplicated primary rhegmatogenous detachment due to a hole or tear is rarely, if ever, encountered in the laboratory. (If by chance such a specimen is obtained, it is extremely valuable and should be studied with great care.) By contrast, with the indirect ophthalmoscope, the clinician has the opportunity to document and follow peripheral bilateral retinal disease, which may progress to detachment in one or both eyes. In rhegmatogenous detachment, a history of severe trauma is unusual and the clinical symptoms take the form of premonitory flashes of light (photopsia), due to initial detach-

Fig. 7.3 (a) Retinal detachment due to proliferative vitreoretinopathy. Note the pigmented membrane causing traction on the inner surface of the retina (arrows). The disc (d) is cupped and there is sclerosis in the retinal vessels (s). (b) A preretinal membrane shows elongated pigmented cells (arrowheads) derived from the retinal pigment epithelium (×250)

ment of the posterior vitreous face, before the visual field is progressively reduced by an opaque descending veil or curtain as subretinal fluid separates the inferior neural retina from the retinal pigment epithelium. Should a retinal hole be detected on macroscopic and microscopic examination it may appear to have a lid (operculum) with an anterior hinge (Fig. 7.4a, b) or it may be flat (Fig.  7.5a–d). Successful serial sections will show that the edges of the hole are rounded and that there is glial cell replacement of the inner retinal neurones with an accompanying microcystoid degeneration. An intriguing feature is the presence of vitreous condensation with an apparent anterior traction on the “lid” formed by the horseshoe-shaped tear. It may not be feasible to prepare serial sections from the pupil-optic nerve (PO) block or the calottes to demonstrate a small hole. It is better to process the hole with surrounding support tissues intact and take an appropriate block for

Classification of Retinal Detachment

a

b

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s­ erially sections after the tissue is processed through paraffin (see Chap. 1). In a case of previously diagnosed rhegmatogenous retinal detachment that has failed to respond to surgical intervention, the enucleated eye should be subject to a careful search for the primary hole or tear. However, it should be appreciated that identification of the hole or defect may be impossible, because in the later and complicated stages, the opaque peripheral vitreous becomes condensed and may obscure the inner surface of the retina. Secondary preretinal membranes distort the funnelshaped detachment and may overlie the pre-existing hole. An additional problem is that an over-­eager attempt to dissect tissue from the inner surface of the retina may easily produce artefactual rips or tears (Fig. 7.5d). It is also noteworthy that holes may enlarge as a detachment progresses (Fig. 7.6a–d). Sometimes the presence of retinal pigment epithelial cells on the inner surface of the retina (“tobacco dust”), or in the vitreous, may be the only indication of a pre-existing retinal hole. Occasionally (and fortuitously) sections may reveal a hole that was obscured by folds in a detached retina. It is much more likely that in the routine service, a pathologist will encounter post-traumatic tears in an otherwise normal retina. These can occur at any anatomical location in the tissue and may complicate penetrating wounds or follow concussion or compression injury (as, for example, in boxing or squash ball injuries). The term dialysis is used for separation of the retina from the retinal pigment epithelium at the ora. Severe tearing can extend through more than 90° to produce a “giant” retinal tear: in this event, vitreous may remain attached to the retina anterior to the tear, which interferes with surgical attempts to reattach the retina. If surgical procedures fail, pathological examination reveals a nodular mass of retinal tissue in the centre of a gelatinous exudate (see Fig. 2.4c). Histologically, the changes in the retina at the edge of a healed traumatic tear are similar to those described in rhegmatogenous detachment.

Exudative Detachment

Fig. 7.4 (a) A section through a retinal hole with an operculum. The vitreous is indicated by arrowheads and the direction of anterior traction by the arrow. Note the atrophy of the photoreceptors and the rounded edges of the hole with cystic degeneration in the anterior leaf (operculum) (×100). The inset shows the macroscopic appearances of a retinal hole with an operculum (arrowhead): The direction of the pars plana is shown by an arrow. (b) A retinal hole over a subretinal exudate. Note the vitreous traction on the anterior lip (arrow) (×40)

The delicate balance of fluid movement within the globe is easily disturbed and any condition that disrupts the blood-­ ocular barrier or damages the RPE may potentially lead to accumulation of subretinal fluid. The choroid contains a permeable vasculature and the choroidal stroma exerts osmotic pressure on the water that passes through the retina and through the photoreceptor-retinal pigment epithelial interface. Fluid movement is probably impeded or modulated by the retinal pigment epithelial monolayer, which consists of hexagonal cells attached by zonulae occludentes. The archi-

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a

b

c

d

Fig. 7.5 (a) Flat holes (arrow) not associated with a retinal detachment may be found by chance in globes removed at autopsy. (b) Histology reveals a simple hole (arrow) in this case anterior to a zone of retinoschisis (arrowheads). (c) In this autopsy specimen from a treated retinal detachment the hole has an operculum (arrow). Note the dust-like pig-

mentation in the vitreous (arrowheads). (d) Artefactual holes (arrow) may be produced by over-enthusiastic removal of the vitreous. A subretinal white band (arrowhead) is often formed by proliferation and fibrous metaplasia in the retinal pigment epithelium

tecture of the RPE cell with its apical processes and basal infoldings suggests a capacity for “ion” transport, but this aspect of functional morphology has not been fully explored. On a priori grounds, the pathogenesis of exudative retinal degeneration can be explained by leakage of protein-rich fluid from a diseased retinal circulation and this can be observed in congenital vascular malformations; e.g., retinal angiomas or in the exudative retinal vasculopathy of Coats’ disease (see Chap. 4). Exudation through the walls of choroidal vessels occurs in ocular hypotonia and in granulomatous and non-granulomatous inflammatory diseases and in almost all cases, is easily explicable. In the uveal effusion syndrome, the ring-like detachment of anterior choroid and retina may simulate a malignant melanoma, especially when high resolution ultrasound is not available; this rare condition is either idiopathic or, in 50% of cases reported, is associated with rheumatoid scleritis. A neoplasm in the choroid, primary or secondary, can disturb the function of the choriocapillaris and lead to plasma leakage; occasionally an eye containing a tumour will also provide evidence of retinal detachment surgery. Neovascularization in disciform degeneration of the macula (see Chap. 4) will inevitably lead to subretinal exudation.

 entral Serous Chorioretinopathy C A more subtle and apparently self-healing exudative detachment of the macula—so-called central serous chorioretinopathy (CSCR)—occurs in the macular region in young to middle-aged (25 to 50 years) adults with a preponderance in men. It could be recurrent in some cases. Several risk factors, namely “Type-A” personality, raised level of endogenous or exogenous glucocorticoids, sleep disturbance and hypertension have been postulated [18]. Genetic factors may also play a role in CSCR with variants in ARMCS2 and CFH genes implicated, interestingly, overlapping with those implicated in Age-related macular degeneration [19]. However, the exact aetiology remains elusive and pathological material is sparse [20, 21]. This disease is characterised by an accumulation of serous fluid both in the subretinal space and in the sub-RPE space, which could be demonstrated in  vivo by stereoscopic ­fluorescein angiography. Other advances in imaging technologies, especially Indocyanine Green (ICG) angiography, optical coherence tomography (OCT) and OCT-Angiography (OCT-A) have paved way for better understanding of the pathophysiology of CSCR.  High definition optical coherence tomography (HD-OCT) can also be used to demon-

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a

b

c

d

Fig. 7.6 (a) A plomb has indented the retina anterior to the hole with an operculum (arrowhead). (b) The retinal holes have enlarged to expose the underlying choroid in a globe in which treatment of retinal detachment has failed. Note the encircling band (arrowhead) and the plomb (arrow). The curious white appearance of the ocular tissues is associated with emulsification of silicone oil. (c) The pathology in this

aphakic globe with a lens implant (arrow) was complicated by treatment of a retinal detachment using cryotherapy (arrowheads). (d) It was only when sections were taken through the centre of the specimen shown in (c) that a hole was apparent in the retina adjacent to the disc (arrowheads). The peripapillary retina showed an unusual microcystoid degeneration in the outer plexiform layer extending to the disc (arrow)

strate the dome-shaped pool of subretinal fluid associated with loss of photoreceptor layer integrity [22]. Imaging evidence, such as choroidal congestion, hyperpermeability with localised areas of choroidal non-perfusion suggest an important role of primary choriocapillary dysfunction as an underlying cause of RPE dysfunction which leads to breakdown of external blood-retina-barrier that results in subsequent subretinal fluid leakage [23–27]. It is noteworthy that a similar effusion is observed in aphakia or as an agonal event in eyes removed at autopsy (Fig. 7.7). The natural course of CSCR is often self-limiting with excellent visual prognosis and active management is usually not required. However, some ophthalmologists may employ active treatment to hasten the resolution in certain circumstances, such as patient’s demands, recurrent CSCR or a history of poor response in fellow eye to conservative management [28]. Without medical intervention, a significant number of patients with CSCR develop a limited area of RPE atrophy and depigmentation after resolution of the affected retinal area [29]. If treatment such as Argon laser photocoagulation,

photodynamic therapy (PDT) or transpupillary thermotherapy (TTT) was employed, scarring between atrophic retina and underlying Bruch’s membrane with variable amount of RPE cells could be observed. A new treatment—subthreshold micropulse laser (SML) therapy is introduced recently [30]. In addition, intravitreal injections of anti-VEGF has demonstrated a degree of success [31, 32]. Although this condition is usually self-limiting, rarely, the detached retina may trigger the release of VEGF into the subretinal space resulting in the formation of a subretinal choroidal neovascularisation (CNV) [33, 34].

Tractional Detachment In a pure form, tractional retinal detachment is rare in pathological material, although experimental studies are plentiful [8]. The clinician has the opportunity to observe preretinal membranes that wrinkle the inner surface of the retina before the retina is detached and this pathology has only been studied effectively in vitrectomy specimens (see later).

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Fig. 7.8  Traction retinal detachment due to diabetic vasoproliferative retinopathy. The fibrovascular membrane has corrugated the inner limiting membrane of the retina (arrows) (×100)

Spectral-domain optical coherence tomography (sd-OCT) images now enable in vivo viewing of features of tractional detachment reminiscent of histopathological features. The vitreous/epiretinal proliferative membrane is evident as a hyperreflective structure whereas any subretinal fluid present is represented by a hyporeflective area between the neural retina and the retinal pigment epithelium. In addition, OCT can also detect the presence of subretinal bands which is useful in surgery planning [35, 36].

Fig. 7.7  Exudative detachment of the macula at autopsy. There is an exudate (e) behind the fovea, but the photoreceptors are not atrophic and this is probably an agonal phenomenon; reports of the pathology of central serous retinopathy are somewhat similar. The retinal pigment epithelium is elevated by exudate and the choroid contains lymphocytes (×100)

More obvious traction is a feature of preretinal neovascularization in ischaemic disease of the retina (particularly diabetic vasoproliferative retinopathy) (Fig.  7.8). In aphakia after total lensectomy, the vitreous prolapses and there is often kinking and distortion of the retinal periphery behind the vitreous base, which sometimes gives the impression that there is sufficient strength in the condensed vitreous to exert traction. Surgical and civil trauma, however, often provide good examples of tractional detachment. Fibrous ingrowth from any form of scleral and uveal perforation incorporates spindle cells that originate from scleral or choroidal fibroblasts. Traction exerted in this manner can displace the retina across the pars plana and in rare cases the posterior retina remains attached. Haemorrhage, due to any cause, stimulates macrophage and fibrovascular ingrowth.

 egenerative and Other Conditions That D Predispose to Retinal Detachment Lattice Degeneration Clinical and pathological observations on this bilateral disease have stressed its importance as a predisposing factor in rhegmatogenous detachment [37–39]. Prophylactic cryotherapy or photocoagulation is recommended by some surgeons, particularly when there is an associated high myopia or a detachment has occurred in the opposite eye. This form of intervention is also carried out if the patient has symptoms or abnormalities are identified in the peripheral retina. On macroscopic examination, lattice degeneration appears as an oval circumferential zone, 1–3 mm diameter, which is traversed by white hyalinized blood vessels and is speckled by foci of proliferating pigment epithelial cells (Fig.  7.9). Identification requires high magnification on the dissecting microscope and the abnormality is more likely to be identified in the superior and inferior calottes. If this abnormality is studied by serial section, hyalinized and occluded vessels will be observed in the centre of a strip of retina that is atrophic in the outer part and fused with Bruch’s membrane (Fig. 7.10). The pigment epithelium is atrophic in parts but may proliferate and

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Fig. 7.9  Macroscopic appearances of lattice degeneration. The borders are outlined by arrowheads and the sclerotic vessel is shown by an arrow. A band of “honeycomb” peripheral microcystoid degeneration (pmc) is seen between the zone of lattice degeneration and the ora serrata (os). Note the pigmentary disturbance within the region of lattice degeneration

sometimes migrate to surround the hyalinized blood vessel. The internal limiting membrane of retina may be absent over the affected area [40]. The most interesting feature, best demonstrated with Alcian blue or colloidal iron, is an overlying zone in the vitreous, in which there are condensations and liquefactions. Sometimes, as the serial sections progress, an obvious hole will be identified or microcystic nodules may appear. The commonly accepted theory of pathogenesis of hole formation as a consequence of lattice degeneration is that a tear occurs at the junction between the anterior part of the atrophic strip and the adjacent normal retina where firm vitreoretinal adhesion is present, by simple mechanical forces exerted from the vitreous base by ocular movements, particularly following posterior vitreous detachment [41]. With the advances in imaging, sd-OCT had been used to demonstrate the microstructural characteristics of lattice degeneration in myopic eyes in  vivo. These include focal retinal thinning, vitreoretinal traction, retinoschisis, vitreous membrane with deposits (presumably corresponding to the vitreous condensation histologically) and focal retinal breaks with subretinal fluid [42]. These findings largely correspond to the aforementioned histological findings. The aetiology of lattice degeneration is uncertain, but is presumably based on an ischaemic atrophy in the retina due to hyalinisation in the peripheral vascular arcades. Recent genome wide studies have implicated that certain

Fig. 7.10  The section passes through a hole within a sector of lattice degeneration in which there is photoreceptor atrophy. The defect in the overlying vitreous is outlined by arrowheads. Reactive proliferation by retinal pigment epithelial cells (arrow) explains pigment speckling in lattice degeneration (×160)

COL4A4 and COL2A1 gene variants may contribute to the development of lattice degeneration. This hypothesis is reasonable, particularly given that COL4A4 gene encodes a protein in Type IV collagen which is a major component of basement membrane and COL2A1 encodes alpha 1 chain of type II collagen, a major structural component in the vitreous [43, 44].

 etinal Holes and Tears R Simple innocuous holes in the retina are sometimes based on lattice degeneration but often they occur for no obvious reason (Figs. 7.4a, b, 7.5a–d, and 7.6a–d). The fact that holes can be present within an attached retina reinforces the belief that vitreous liquefaction with condensation and traction is somehow involved in the encouragement of fluid seepage into the subretinal space. Clinically, the dilemma is whether or not to treat a simple hole with cryotherapy or laser.

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Peripheral Microcystoid Degeneration

a

This abnormality is commonly seen macroscopically as a honeycomb-like band at the retinal periphery [45] (Fig. 7.9). It is presumed to occur as a consequence of ischaemia due to degenerative occlusive disease in peripheral retinal arterioles. Histologically the disorder takes the form of cystic degeneration in the outer plexiform layer with compression of the bipolar and photoreceptor nuclei and some sparing of Müller cells, which later are the only cells to surround the cystic spaces (Fig.  7.11a, b). Microcystoid degeneration rarely has serious consequences, but sometimes the pillars of Müller cells break down and a split extends posteriorly to separate the two layers to form a retinoschisis. It is not uncommon for tears to occur in either the inner or the outer layers, or both, and this can lead to retinal detachment. A rare complication is haemorrhage into the retinoschisis and this enlarges the slit to form a macrocyst. On occasion (see Chap. 5), a blood-filled macrocyst has been misdiagnosed as a malignant melanoma.

b

Vitreomacular Disease Vitreomacular traction syndrome was a term coined in 1970s, based on histological findings, to denote a status whereby persistent attachment of vitreous to the macula in eyes with an incomplete posterior vitreous detachment (PVD), resulting in traction on the macula which causes decreased vision, metamorphopsia, photopsia and micropsia [46–48]. The advent of optical coherence tomography (OCT) has enabled adequate visualisation and evaluation of the vitreomacular interface (VMI) with great consistency. Various definitions and classification systems were used prior to the introduction of high definition OCT, resulting in confusion in nomenclature and varied practices in managing the disorders of the VMI. Therefore, The International Vitreomacular Traction Study Group (IVTSG) introduced an OCT-based classification system for diseases of the VMI [49].

Posterior Vitreous Detachment (PVD) Vitreous is composed of 98% water and 2% of structural macromolecules with predominantly collagen fibers (mainly Type II collagen) and hyaluronic acid. The posterior vitreous cortex and retinal internal limiting membrane (ILM) are bound at their interface by these macromolecular attachment complex which includes fibronectin and laminin [50–53]. As we age, the vitreous gel liquefies and ultimately collapses—synchysis. This process happens in parallel with the detachment of vitreous cortex from the retina to allow the accumulation of liquid in the intervening space [51]. OCT studies show that PVD typically starts in the perifoveal macular region [52]. Over time, total collapse of the collagen

Fig. 7.11 (a) In peripheral microcystoid degeneration, the cysts appear first in the outer plexiform layer and later involve the inner plexiform layer with sparing of the outer nuclear layer and the Müller cells. Finally the outer nuclear layer atrophies. The sequence is shown by arrows (×16). (b) Scanning electron microscopy reveals the thick strands formed by Müller cells (arrowheads) and an atrophic outer nuclear layer over the retinal pigment epithelium (arrow) (×1000)

fibrils leads to non-pathological complete PVD from the retina with the vitreous gel condensing to the anterior part of the vitreous cavity [50, 54].

Vitreomacular Adhesion (VMA) At birth, complete vitreoretinal adhesion is present in most eyes. In order to avoid confusion, the IVTSG defines VMA as partial detachment of vitreous in the perifoveal area with no detectable change in foveal contour or underlying retinal tissues [49]. Vitreomacular Traction (VMT) Excessive traction on the macula can occur with progressive partial PVD. VMT is defined as when there is partial perifoveal vitreous cortex detachment associated with distortion of the foveal surface, intraretinal pseudocyst formation, elevation of the fovea from the retinal pigment epithelium (RPE) but no full-thickness interruption of all retinal layers [49]. The main reason for medical intervention in VMT is to eliminate the anteroposterior and tangential traction by releasing the residual VMA.  Pars plana vitreoctomy with peeling of any epiretinal membrane (ERM) present, internal limiting membrane (ILM) and the vitreous posterior surface is currently the standard procedure [55, 56].

Degenerative and Other Conditions That Predispose to Retinal Detachment

New treatment options such as intravitreal injections of vitreolytic enzyme (Ocriplasmin) [57, 58] and pneumatic vitreolysis—intravitreal gas injection (eg. C3F8 perfluoropropane) to create a PVD and resolving VMT [59, 60] are showing promising results.

Lamellar Macular Hole (LMH) LMH is defined by combination of an irregular foveal contour and a break in the inner fovea, intraretinal splitting (schisis) which typically occurs between the outer plexiform and outer nuclear layers whilst maintaining an intact foveal photoreceptor layer [49]. It is often associated with epiretinal membrane (ERM) and intraretinal cysts [61–65]. Autopsy studies have shown that residual vitreous remains on the surface of the retina in almost half of the eyes with PVD [66]. It is postulated that ERM is formed by cellular proliferation within this residual vitreous [61, 63, 65, 67]. Further information regarding ERM could be found in the latter part of this chapter. Impending Macular Hole (IMH) This term is used in a case in which full-thickness macular hole (FTMH) is observed in one eye and VMT is observed on OCT in the fellow eye [49]. Histologically, there is liquefaction of the vitreous anterior to the macula, which is lined on the inner surface by a thin layer of cortical collagen and layers of fibrous astrocytes [68, 69]. Full-thickness Macular Hole (FTMH) FTMH is defined as full-thickness lesion that interrupts all macular layers from the internal limiting membrane (ILM) to the RPE.  Several mechanical causes have been implicated, including tractional foveal cystoid space, breakdown and elevation of central photoreceptors and traction on the inner retina. It may also occur with a true retinal operculum. The edge of the hole is usually rounded and may contain intraretinal pseudocysts. The edge may be thicker than neighbouring retinal tissue because of accumulation of intraretinal fluid [49]. FTMH can be divided into two groups—primary and secondary. The primary form (also known as idiopathic) results from vitreous traction on the fovea from anomalous PVD, with or without an ERM. The secondary causes include blunt trauma [70–72], high myopia [73, 74], wet ARMD treated with anti-VEGF injections [75, 76], macular telangiectasia type 2 [77] and surgical trauma [78, 79]. Surgery is aimed at relieving vitreofoveal traction usually by stripping the inner limiting membrane, which helps prevent subsequent premacular fibrosis [80]. Visualization of the inner limiting membrane can be improved with vital dyes such as trypan blue, indocyanine green and brilliant blue G [81]. For the pathologist, macular holes are detectable on macroscopic examination or the opercula may be excised during vitrectomy. Histology will reveal a small detachment with photoreceptor atrophy on either side [82, 83]. The opercula may contain only glial tissue or in addition avulsed

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foveal cones, arising from a full-thickness foveal tear. The latter are associated with a poorer visual outcome [84]. In addition, chronic changes secondary to potential complications of pars plana vitrectomy including cataract formation, cystoid macular oedema, retinal detachment, choroidal neovascularization and endophthalmitis could be seen histologically in an enucleation specimen with such previous history. As per treatment advances for VMT, pharmacological vitreolysis (eg. Ocriplasmin) and gas tamponade with perfluoropropane (C3F8) have also shown variable success in treating FTMH [85–88].

Macular Pseudohole As the term implies, a macular pseudohole does not confer genuine loss of retinal tissue like those seen in LMH or FTMH. It is defined with following 4 characteristics on OCT: (1) invaginated/heaped foveal edges; (2) concomitant ERM with central opening; (3) steep macular contour to the central fovea with near-normal central foveal thickness and (4) no loss of retinal tissue [49]. It is postulated that the contraction of the ERM pulls the underlying retinal tissue toward the center of fovea resulting in the invagination of the perifoveal retina into the shape of a hole without actual loss of foveal tissue [89]. Management is usually conservative with surgery reserved for symptomatic patients. Inherited Vitreoretinopathy The vitreoretinal surgeon will have experience of a group of inherited disorders of retina and vitreous that will require surgical treatment for retinal detachment. The evolution of these disorders has not been documented pathologically in a satisfactory manner. This is because the globe is enucleated at the end stage of the disease, but it is assumed to some extent that the pathology of inherited vitreoretinopathy resembles peripheral reticular degeneration and takes the form of atrophy and schisis in the inner retina, which is associated with vitreous condensation and traction on the retina and the disc. In familial exudative vitreoretinopathy (FEVR) the pattern of inheritance could be autosomal dominant (most common), autosomal recessive or X-linked recessive. Mutations in several genes have been implicated, including frizzled-4 gene (FZD4) [90, 91], NDP gene [92], LRP5 gene [93], TSPAN12 gene [94, 95] and ZNF408 gene [96]. Abnormalities in the Wnt intracellular signalling pathway which orchestrates normal retinal vascular formation are thought to play a significant role in the pathogenesis of FEVR [97]. A hallmark feature of FEVR is the presence of peripheral avascular retina, most readily seen in the temporal periphery. Progressive disease with retinal neovascularisation, vitreous haemorrhage and fibrosis at the junction between vascular and avascular retina leads to traction of macula and tractional retinal detachment in severe cases [92, 98, 99]. An enucleation specimen usually demonstrates complications from FEVR such as retinal detachment, peripheral

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retinal vascular proliferation and fibrovascular preretinal membranes. Inflammation and necrosis can be seen in and around the fibrovascular tissue [92]. Although the pathology of end-stage detachment is non-specific, the presence of hyalinized preretinal membranes and hyalinized blood vessels surrounded by astrocytes may be an important diagnostic histological feature. Telangiectasia can also be present and peripheral retinal vessels can be occluded [100, 101]. Widefield—fluorescein angiography is critical in diagnosis and monitoring of the patients with FEVR. Laser photocoagulation of the avascular peripheral retina remains the mainstay of treatment for FEVR. Anti-VEGF may have a role as an adjunctive option [92, 102, 103]. Congenital X-linked retinoschisis (CXLRS) is an X-linked recessive disorder that occurs mostly in males at an early age with severe visual loss. It is characterised by the splitting of superficial layers of the retina, particularly the nerve fibre layer, which progresses to cyst formation. Causative mutations in the retinoschisin 1(RS1) gene at Xp22.2 locus inhibit the production of retinoschisin, a protein involved in cellular adhesion [104, 105]. Immunohistochemical studies have shown that in the normal eye this protein is secreted by photoreceptors and bipolar cells and is transported by Müller cells into the inner retina where it maintains integrity [106]. CXLRS can be classified into 4 phenotypes: type 1— foveal; type 2—foveolamellar; type 3—complex and type 4—foveoperipheral [107]. The advent of optical coherence tomography (OCT) has enabled early diagnosis and monitoring of these patients. Although most of the retinoschisis remain stable throughout life, a number of patients may show progressive disease that results in complications such as macula-involving peripheral retinoschisis, rhegmatogenous, and combined tractional-rhegmatogenous retinal detachment which require medical intervention [105]. Management of this disorder is complex and is usually designed on a case-based approach. Several case series have shown variable results with topical carbonic anhydrase inhibitors [108–110]. Prophylactic laser retinopexy remains controversial. Vitreoretinal surgery, including vitrectomy and scleral buckling are utilised when required [111, 112].

 ereditary Progressive ArthroH Ophthalmopathy (Stickler Syndrome) Stickler syndrome (SS) is a genotypically and phenotypically heterogeneous multisystem connective tissue disorder. Whilst autosomal dominant is the commonest manner of inheritance, autosomal recessive inheritance has also been reported [113, 114]. To date, pathogenic variants in 6 different genes have been identified. These genes regulate the formation of collagen type II, IX and XI which are expressed within the vitreous, skeleton and inner ear. Mutation of COL2A1 gene on chromosome 12 which controls the normal synthesis of type

7  Treatment of Retinal Detachment

II collagen is the most common—Stickler Syndrome type 1 (STL1), accounting for 80–90% of SS. COL11A1 mutation is responsible for Stickler Syndrome type 2 (STL2). COL11A2 mutation is found in Stickler Syndrome type 3 (STL3)— Otospondylomegaepiphyseal dysplasia (OSMEDA)—previously known as Non-ocular Stickler Syndrome. Individuals with STL3 will express all of the findings of typical SS except for the ocular complication as COL11A2 is not expressed in the eye. Other mutations (COL9A1, COL9A2 and COL9A3) are responsible for Stickler Syndrome types 4–6 (STL4–6) respectively [115–122]. Potential ocular manifestations in SS include myopia, congenital cataracts, congenital abnormalities of anterior chamber drainage angle increasing the risk of glaucoma and paravascular lattice degeneration. However, the salient feature is the presence of condensed vitreous strands at the periphery with optically empty spaces in the central vitreous. The histological features of one untreated case has been reported and showed thick bands of dense collagen lined internally by a layer of glial cells and occasional RPE cells [115, 123, 124]. As the affected collagen genes are also expressed in the cartilage of joints and the ossicles in the middle ear, other systemic manifestations are common, such as micrognathia, cleft palate, hearing loss or early onset osteoarthritis [125].

Innocuous Peripheral Retinal Disease Examination of the retinal periphery with a dissecting microscope is recommended. The pathologist should have knowledge of the normal macroscopic appearances as well as the appearances of the peripheral degenerative diseases that are not associated with detachment.

Paving Stone or Cobblestone Degeneration The terms are synonymous and this degeneration is one of the common abnormalities to be observed in the elderly eye on macroscopic examination (Fig.  7.12a). The “paving stones” are circular white punched out areas (1 mm diameter) in the peripheral retina and on histological examination there is well-delineated atrophy of the RPE, the choroid and the overlying photoreceptor layers (Fig.  7.12b) often with hyperplasia and intraretinal proliferation of the RPE at the periphery. The choriocapillaris may be of normal appearance or may be hyalinized [126].

Lipoidal Degenerations Degeneration of neuronal tissue leads to accumulation of lipoprotein and in some forms of peripheral degeneration, gray/ yellow lines (snail track degeneration) or golden droplets are

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a

b

Fig. 7.12 (a) The peripheral retina in this specimen contains large white areas of cobblestone degeneration. (b) The punched-out white areas in cobblestone degeneration are due to atrophy of the pigment epithelium and choroid (area between arrowheads). The photoreceptor layer is atrophic and gliotic retina is fused with Bruch’s membrane (×160)

seen [127]. Fat stains on frozen sections demonstrate the presence of lipid in globules in the middle layers of the retina.

Meridional Folds As a consequence of abnormal development of the neural retina, there may be a residue of gliotic retina on the inner surface of the pars plana: these heterotopic strands are referred to as meridional retinal folds (Fig. 7.13).

Retinal Tissue Rarefaction In degenerative disease of the retinal vessels, there is a consequent atrophy of the inner retina. However, the anatomy of the vitreous over retinal vessels and the adjacent tissues is such that there is minor traction on paravascular retina. This leads to tearing of small tufts and paravascular retinal pits have been described [128].

Pigmentation Pigmented patches at the retinal mid-periphery resembling paw marks (bear track) are due to hyperpigmentation of the retinal pigment epithelium and may be associated with some photoreceptor atrophy. A more severe form, “clumped pig-

Fig. 7.13  Meridional folds are remnants of gliotic retina, which project over the pars plana (arrowheads). Formalin fixation causes opacification of the retina so that peripheral microcystoid degeneration (m) and lattice degeneration (l) are more easily identified

mentary retinal degeneration” (CRPD), may result in advanced gliosis of the outer retina and detectable loss of peripheral visual field [129]. A mutation in the NR2E3 gene, also called photoreceptor-specific nuclear receptor has been identified in some cases [130].

Retinoschisis Retinoschisis occurs in the peripheral retina as an extension of peripheral microcystoid degeneration (see earlier). Clinically the differential diagnosis for retinal detachment is important. In the earliest stage, holes appear in the outer plexiform layer and these represent dissolution of the neural component with preservation of the Müller cells.

Peripheral Reticular Degeneration Occasionally, in a routine histological section, an atrophy due to schisis in the nerve fiber layer will be noted (Fig. 7.14). This peripheral reticular degeneration usually occurs behind a zone of peripheral microcystoid degeneration but the disorder has no clinical significance [131, 132]. It can be recognized with some difficulty on macroscopic examination at the equator as a triangular zone bounded by the bifurcation of an artery or vein.

Myopia Myopia is a common condition when the plane of focus of the image is in front of the retina. There are two types:

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Fig. 7.14  In peripheral reticular degeneration, there is a schisis in the nerve fibre layer and the ganglion cell layer (arrows). Note the hard drusen beneath the pigment epithelium (arrowheads) (×160)

1 . Index, when the globe dimensions are normal, and 2. Axial, which is characterized by elongation of the anteroposterior length of the eye (>26 mm). The mechanism of this elongation and consequent scleral stretching is unclear. However, the stretching of the eye predisposes to peripheral chorioretinal degenerations, particularly lattice degeneration, with an increased risk of retinal detachment (see Chap. 9). The risk of cataract and glaucoma is also increased so that examination of an enucleated myopic globe may reveal evidence of surgical intervention. Myopia is aetiologically heterogeneous in its development as both genetic and environmental factors play important roles [133]. To date, 25 genetic loci (MYP1–26) associated with myopia have been discovered by linkage analysis and numerous candidate genes inside the linkage intervals have been analysed. Of these, 22 loci are located on autosomal chromosomes and 3 are on the X-chromosome With the advent of Next Generation Sequencing (NGS), at least 17 disease-causing genes for nonsyndromic myopia have been reported. These include 11 autosomal dominant genes, ZNF644, SCO2, SLC39A5, CCDC111, P4HA2, BSG, CPSF1, NDUFAF7, TNFRSF21, XYLT and DZIP1; four autosomal recessive genes, LRPAP1, CTSH, LEPREL1 and LOXL3; and 2 X-chromosome genes, ARR3 and OPN1LW [134]. The genetic contribution of these loci and genes to myopia remains poorly understood.

Effects of Detachment on the Ocular Tissues Introduction Retinal detachment of one form or another is commonly encountered in globes examined in the laboratory: and the changes can vary from a funnel shape (Fig. 7.15) to such an extreme form that the retina is totally replaced by a gliotic mass and the normal anatomy is unrecognizable.

7  Treatment of Retinal Detachment

Fig. 7.15  Retinal detachment in a traumatised eye in which the lens has been removed and there is a scar in the chamber angle. Large cysts (c) are present in the funnel-shaped detached retina (r)

* *

*

Fig. 7.16  There is cystic degeneration (*) in the outer plexiform layers of the retina in retinal detachment (×250)

Changes in the Neural Retina The early effects of separation of the outer part of the neural retina from the retinal pigment epithelium can be studied in exudative detachments secondary to choroidal melanomas in routine specimens. There is one report of changes in the neural retina following untreated acute rhegmatogenous retinal detachment [135]. The photoreceptor atrophy commences with swelling of the outer segment, followed by d­egeneration in the inner segment and the outer nuclear layer (Fig. 7.1a–g). Apoptosis of photoreceptors may be identified in the first 10 days following detachment. Müller cells proliferate in the outer retina and form membranes on the outer surface; this is one factor in the failure of photoreceptors to regenerate [136, 137]. Irreparable damage is said not to occur until about 6 weeks.

Effects of Detachment on the Ocular Tissues

The outer nuclear layer may be well preserved up to 3–4  months but after this, there is atrophy and gliosis, which progresses to cyst formation (Fig. 7.16). Ultimately large cysts are formed on the outer surface of the funnelshaped detached retina (Fig. 7.15). The cells in the inner two-thirds of the retina have a preserved blood supply and are able to survive and there are usually plentiful axons in the stalk of the funnel and in the disc and optic nerve. If, however, there is primary or secondary degenerative disease in the retinal vessels, preretinal membrane formation will be a prominent feature. Glial cells or fibrovascular membranes cause marked wrinkling of the inner retina as do cells of RPE origin (Fig. 7.16) when a hole in the retina provides access. Gliosis may predominate at the end stage and “pseudogliomas” are formed by proliferating glial cells within a totally disorganized and almost unrecognizable retinal substrate (Fig. 7.17).

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Changes in the Retinal Pigment Epithelium Following detachment of the neural retina, the RPE monolayer is stimulated to proliferate and adopt the role of macrophages. However, a mitotic figure has never been demonstrated in the monolayer in routine histological preparations. Most commonly the cells become rounded and phagocytose lipoprotein so that the cytoplasm becomes foamy. In some specimens, plasma proteins are phagocytosed (endocytosed) and the RPE cells incorporate hyaline inclusions, which are PAS positive. The most surprising property of the RPE is that the cells undergo fibrous metaplasia to form large fibrous masses and nodules (“Ringschwiele”—ring scars in three dimensions) at the retinal periphery (Fig.  7.18a). More posteriorly, thin or thick bands of varying size may form beneath the retina and indent it and these may be identified on macroscopic examination when they appear as subretinal cords (Fig. 7.5d). Division of the subretinal cords by surgical manoeuvres does not prevent the tenting of the retina. Migration into the vitreous or subhyaloid space via a retinal hole induces spindle cell metaplasia in the retinal pigment epithelium (Fig. 7.3b). The cells remaining in situ are also stimulated to form giant drusen (Fig. 7.18b). The choroid, optic nerve, and posterior ocular structures are little affected by retinal detachment per se.

Secondary Effects in the Vitreous

Fig. 7.17  In longstanding retinal detachment the retina may form a totally disorganised gliotic mass (×40)

a

Fig. 7.18 (a) The retinal pigment epithelium proliferates and undergoes fibrous metaplasia (arrowheads) at the peripheral attachment of an otherwise detached retina. In a total detachment this process forms a ringshaped scar (Ringschwiele). (b) If a detachment is complicated by

With ageing (particularly in myopic eyes) the vitreous rarely persists as a transparent sphere and there is often a separation from the inner retinal surface; i.e., “detachment of the posterior vitreous face” with “fluid in the subhyaloid space.” After a retinal detachment the vitreous may remain attached to the disc, but if this tears, the vitreous separates and collapses to form a condensed mass that exerts traction on the equatorial retina. Traction may separate the non-pigmented layer of the ciliary epithelium from the pigmented. b

exudation of lipid-rich plasma, cholesterol clefts and foamy macrophages will be prominent. The retinal pigment epithelium synthesises large drusen (arrowhead)

226

7  Treatment of Retinal Detachment

Effects on Lens

commonest indication for surgery is the detachment that follows lens extraction [138] and this procedure itself can lead to Retinal detachment disturbs the function of the lens and sec- unmanageable complications in the anterior segment. ondary swelling in the lens fibres and migration of the epiHistological studies on successfully treated eyes are thelium to the posterior pole lead to opacification (posterior obviously a rarity, but when suitable material has become subcapsular cataract). Swelling of the lens may lead to pupil-­ available, the histology of the reattached retina has in some block glaucoma. cases (Fig.  7.1b, c) approached normal [2]. In other cases there has been a photoreceptor atrophy where the retina is reattached (Fig. 7.1g) and a poor visual outcome has been Pathology of Treatment of Retinal due to this complication and also to cystoid macular oedema. The advent of microsurgery has provided the opportunity Detachment for surgeons to restore vision after retinal detachment with a Since rhegmatogenous detachment is due to a retinal break higher incidence of success than previously. Thus the responsi(hole, tear, or dialysis), the purpose of treatment is to drain bility of the pathologist should now be directed toward careful the subretinal fluid and to form an adhesion between the documentation of those cases that are treated unsuccessfully. retina and choroid around the retinal hole to prevent further movement of fluid into the subretinal space. The modern vitreoretinal surgeon has a variety of tech- Buckling or Scleral Indentation niques available for reattachment of the retina and the pathologist must be aware of the procedures in order to understand Scleral indentation or buckling is used to approximate chothe changes that may be encountered in an eye in which the roid to retina in the region of the hole after subretinal fluid surgery has been successful, but enucleation is required for has been withdrawn, although the fluid may undergo spontasecondary pathology in the anterior segment. Perhaps the neous resorption. The sclera can be indented with plombs, a

Fig. 7.19 (a) Macroscopic appearances of a globe in which retinal detachment was unsuccessfully treated after an encircling band (e) and cryotherapy (c), which is recognised by scarring and pigmentary disturbance. The vitreous substance (v) is condensed and opaque. (b) The

b

tissue reaction to the materials used for indentation buckles (bu) is minimal. The overlying choroid (c) is atrophic (×40) ((a) and (b) Reproduced with permission from Sehu and Lee [193])

Pathology of Treatment of Retinal Detachment

buckles, or silicone “tyres” (some 1 cm wide) held in place by mattress sutures in order to approximate the edges of the retinal hole to the pigment epithelium and Bruch’s membrane (Figs. 7.6a, b and 7.19a, b). Occasionally the buckles or bands erode the sclera and may be visible from the interior of the globe. The tissue reaction to non-absorbable bands or buckles is minimal in most cases, but hydrogel implants induce a granulomatous reaction [139]. Rarely a necrotizing scleritis may occur following scleral buckling (surgically induced necrotizing scleritis or SINS) [140]. Both hypersensitivity reaction and local ischaemia may be involved in the pathogenesis.

Cryotherapy or Laser Photocoagulation

227

Fig. 7.21  Diathermy has destroyed the outer retina and the remaining gliotic retina (r) is fused to Bruch’s membrane (arrowheads) with underlying choroid (c) (×100)

Chorioretinal fusion is established by cryotherapy or laser photocoagulation. These procedures both induce scarring between the retinal break and the underlying RPE in order to seal the retinal defect and promote adhesion. Cryotherapy is used to induce glial replacement of outer retinal tissue and this fuses with scars formed by metaplastic retinal pigment epithelium (Fig. 7.20). Laser photocoagulation destroys the outer retina and pigment epithelium so that the gliotic retina fuses with Bruch’s membrane (Fig. 7.21).

Intraocular Silicone Oil

Replacement of Vitreous

1. Interference with lens metabolism, which induces lens opacities or exacerbates a pre-existing cataract. Often the cataract is characterized by posterior migration of epithelial cells that are surrounded by a prominent PAS-positive basement membrane, but this feature may not necessarily be due to the silicone oil. It is now more common to find that the lens has been removed previously in an end-stage enucleated eye with a retinal detachment. 2. Breakdown of the bubble leads to emulsification and escape of emulsified oil into the anterior chamber (see Chap. 1). The superior part of the outflow system is blocked by small globules of oil and by macrophages laden with oil. Glaucoma surgery may not be performed at the upper limbus for obvious reasons. 3. Silicone oil is cytotoxic to the corneal endothelium [142]. Emulsified oil damages the endothelium on the posterior surface of the cornea, which causes corneal endothelial decompensation and corneal oedema (Fig.  7.22). These changes may be seen in a corneal graft in which silicone oil spaces occur in the endothelium and the corneal stroma [143, 144]. 4. Angle closure glaucoma occurs in an aphakic eye due to the oil bubble pressing on the pupil when the patient is supine.

Internal tamponade holds a reattached retina in place until the scars formed by the laser or the cryoprobe have healed. In current practice, silicone oil and gases including sulphur hexafluoride, hexafluroethane, and octafluoropropane are available to replace the vitreous substance that was removed by vitrectomy. “Heavy liquids” may be used as a temporary tamponade for intraoperative manipulation of the retina.

Fig. 7.20  The response to successful cryotherapy is confined to minor reactive proliferation of the retinal pigment epithelium forming an adhesion to the atrophic outer retina (arrow). Anterior to the fusion, the photoreceptor layer of the detached retina is atrophic (arrowheads) (×100)

Silicone oil is of low specific gravity and the physicochemical characteristics are such that an intact transparent bubble of oil will gently press against the region in the superior retina to be sealed [141]. The oil was not always of consistent and appropriate purity and this may have been a factor in emulsification, which was an unwelcome complication. Some of the features of oil in a pathological specimen are:

In view of the complications described, it is possible that the surgeon will have removed the oil some time before

228

enucleation. The oil vanishes from paraffin-embedded or plastic-­embedded sections and the sole indication of its presence in emulsified form is the presence of circular spaces within tissue or within macrophages. The oil becomes resistant to lipid solvents if a short fixation time is

Fig. 7.22  After retinal detachment surgery, silicone oil globules may be found within the endothelial cells (arrowheads) (×160)

a

7  Treatment of Retinal Detachment

followed by exposure to osmium tetroxide solution: oil red O may then stain the silicone oil droplets red in some cases. Evidence for the presence of oil in routine paraffin sections is provided by clusters of macrophages with large circular intracytoplasmic spaces [145]. The cells may be seen in the posterior chamber, within the retina (Fig. 7.23a), in the vitreous and in membranes on the inner surface of the retina, or the oil penetrates the retina and may be found in the subretinal space if the retina is detached and a retinal hole is not sealed (Fig. 7.23b). Oil may pass into the retrolaminar space if secondary glaucoma has caused infarction of the nerve bundles in this region (Fig.  7.23c). It is extremely rare to see extraocular silicone oil migration. However, emulsified silicone oil could deposit in the eyelids, associated with macrophages, mimicking xanthelasma clinically and histologically (Fig.  7.23d). In one remarkable case report there was migration of silicone oil into the lateral ventricles of the brain [146]. The low specific gravity and “oily” nature of intravitreal silicone oil are only too apparent when the specimen is examined macroscopically. If the specimen is examined under fluid, the surface is covered immediately by a greasy b

c d

Fig. 7.23 (a) Foamy macrophages containing emulsified silicone oil are an unusual finding within the retina (arrowheads). (b) Emulsified silicone oil forming a nodule with the retinal pigment epithelium with clumps of cells detaching into the subretinal space (arrowheads) (×250). (c) If the optic nerve undergoes extensive

optic atrophy, silicone oil migrates into the cystic spaces (arrowheads) (Courtesy of Professor Willem Manschot). (d) Silicone oil can migrate into the tissues of the eyelid where there are large cystic spaces filled with silicone (*)surrounded by silicone containing macrophages (×100).

Pathology of Treatment of Retinal Detachment

229

film and all the instruments are similarly contaminated and require thorough cleaning. It is advisable (since macrophotography is a frustrating exercise in these cases) to open the globe, discard the knife, and repeatedly add fixative or saline to the specimen jar, decanting the surface oil, prior to examination of the specimen. A convenient method is to suck off the oil from the surface of the fluid in the jar with a standard Venturi pump. When perfluoro-octane has been used (see later) this heavier-than-water material sinks to the bottom of the fixative solution and it is not necessary to remove this from the specimen jar. A newer generation of heavy silicone oils have been introduced at the turn of the twenty-first century and are useful to treat inferior and posterior detachments. The associated complications appear similar to conventional silicone oil [147, 148].

(fluorinated silicone and perfluorocarbons) are associated with a high complication rate including raised intraocular pressure and intraocular inflammation such that these have to be removed early after treatment and are now used only intraoperatively to manipulate the retina. The pathology secondary to this form of treatment in the human eye has not been recorded in detail. Macrophages have been identified in epiretinal membranes due to emulsification of perfluorohexyloctane [149]. In one case the subretinal heavy liquid was in the inferior part of the eye and there was considerable degeneration in the adjacent retina. The macrophage response by comparison with emulsified silicone differed with regard to the cytoplasmic features, which comprised a red-brown eosinophilic staining with very fine intracytoplasmic granules (Fig. 7.24a, b).

Sulphur Hexafluoride (SF6) Sulphur hexafluoride is a gas that absorbs nitrogen. Thus a gas bubble in the vitreous will expand and tamponade the retina. If the gas is too concentrated (>30%), expansion leads to a high intraocular pressure and occlusion of the blood supply so that the retina is severely damaged by ischaemia. This is a pathology that has only been documented in the experimental literature.

When the detachment is extensive and established, it has been shown to be helpful in reattachment of the retina to insert titanium tacks into the retina and sclera via the vitreous. While this procedure was claimed to be clinically successful, there has been little in the way of histopathological study of the tissue around the tack: one study has shown that the surrounding scar tissue contains Müller cells in addition to fibroblasts [9]. These are of historical interest as the use of titanium tacks has now been abandoned.

Heavy Liquids

Retinotomy and Retinectomy

These “heavier than water liquids” have been introduced in recent years to treat posterior detachments where silicone oil and gas cannot provide sufficient retinal support. These liquids

To facilitate retinal reattachment, it may be necessary to make relieving incisions in the retina and, in extreme circumstances, to excise the peripheral retina (retinectomy).

a

Fig. 7.24 (a) In this example of a globe enucleated after the introduction of heavy liquid into the vitreous, the compound passed under the retina (arrow). (b) In two specimens containing heavy liquid on file it was not possible to demonstrate the granulomatous reaction seen with

Retinal Tacks

b

silicone oil, but there was an unusual accumulation of macrophages beneath the retinal pigment epithelium (arrowhead) at the edge of the subretinal fluid in the case shown in (a)

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7  Treatment of Retinal Detachment

The surgical technique of this new treatment will continue to evolve. However, the rationale of this procedure involves placing a small disc of carefully measured hAM with chorion facing the RPE within the subretinal space/retinal breaks or defects to induce a recovery process [6]. If this technically challenging new surgical advancement is widely employed, we will no doubt come across new pathological findings in enucleation specimens treated with this method in future.

Vitrectomy Procedure

Fig. 7.25  This example of a retinectomy from a failed case reveals incarcerated vitreous (arrowheads) within a retinal fold at the edge of the incised retina (×40)

The edge of the incised retina may show the effects of folding (Fig. 7.25) with incarceration of vitreous. This surgical procedure may be used for the treatment of retinal detachment associated with proliferative vitreoretinopathy [150]; success has been histologically proven [151]. Retinectomy has also been used to relocate the fovea in disciform degeneration of the macula [152]. However, the technique is difficult to perform and there is limited evidence that it is effective [153].

It is inevitable that an eye containing silicone oil will contain the abnormalities associated with the vitrectomy procedures. There will be three scars in the pars plana where the entry ports of the vitreous cutter, the illumination source, and the infusion tube have been located. The scar tissue that forms in the sclera can penetrate the pars plana and grow into the vitreous, and attempts (by serial section) can be made to demonstrate this feature histologically (Fig. 7.26).

Human Amniotic Membrane Plug Human amniotic membrane (amnion) (hAM) is a semi-­ transparent sheet of tissue measuring 0.02–0.05  mm thick. It is composed of an epithelium, a basement mebrane, a compact layer, a fibroblast layer and a spongy layer [154]. Because of its anti-angiogenic and antimicrobial properties and low immunogenicity, hAM has been used in eye surgery for decades, predominantly as covering for corneal ulcers and the reconstruction of conjunctiva [155–158]. For the past few years, hAM has been introduced in vitreoretinal surgeries with promising results as it demonstrated the induction of a recovery process involving the external retinal layers such as the external limiting membrane (ELM) and the ellipsoid zone [159]. The application of hAM in vitreoretinal surgeries include large macular tears [160], high myopic retinal detachment associated with macular hole [161], paravascular tears [162], serous macular detachment associated with optic pits [163], complicated retinal detachment [159] and advanced Age-related macular Fig. 7.26  A vitrectomy port through which there is a fibrous ingrowth degeneration [164]. into the vitreous base (arrow) (×100)

Pathology of Treatment of Retinal Detachment

Vitrectomy and epiretinal membrane cutting and peeling are now standard procedures and have been of value for the study of the cellular proliferations that cause contraction of the inner surface of the retina and can cause retinal detachment (primary tractional detachment) or contribute to permanent fixation of the retina after an exudative detachment. Complex surgery such as that described previously is performed in sight-threatening disease and the aim is to preserve navigational vision in, for example, severe proliferative diabetic retinopathy; but reattachment of the retina—previously an “anatomical result”—may also give good functional results.

 itrectomy Specimens and Epiretinal V Membranes Using vitrectomy specimens (Fig. 7.27a, b), it has been possible to expand knowledge concerning preretinal, epiretinal, and subretinal membranes [165, 166]. These specimens are very small and may be embedded in agar gel or processed on a “sponge” to prevent loss and aid orientation. Epiretinal membranes (ERM) submitted should be examined to identify the cells within the membrane. ERM can be either primary (idiopathic) or secondary to pre-existing ocular pathology, such as proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), uveitis, vasculitis, branch/central retinal vein occlusion, retinal detachment (RD), ocular trauma or retinal surgical procedures [167–171]. A range of immunohistochemical markers had been widely utilised to ascertain the cellular component of ERM. The antibodies used include [172–179]:

a

Fig. 7.27 (a) This preretinal fibrovascular membrane was removed at vitrectomy. Blood vessels (arrows) and a few inflammatory cells can be identified in routine sections (×250). (b) Immunohistochemical staining

231

–– Glial fibrillary acidic protein (GFAP)—marker of intermediate filaments of glial cells (astrocytes and Müller cells). –– Cellular retinaldehyde-binding protein—marker of glial cells and RPE cells. –– Cytokeratin—RPE cells –– Neurofilament—marker of retinal gaglion cells. –– α-smooth muscle actin (α-SMA)—antibody to intracellular actin filaments (myofibroblasts). –– CD45 and CD64—markers for hyalocytes. –– CD68—marker of macrophages/microglia. The exact pathogenesis of primary/idiopathic ERM formation is still unknown. It is hypothesised that posterior vitreous detachment (PVD) induces the migration, differentiation and proliferation of cells at the vitreomacular interface (VMI). A number of cell types have been implicated, including vitreous cells (hyalocytes and fibroblasts), macroglial cells (astrocytes and Müller cells), RPE cells and microglial cells [180, 181]. Non-angiogenic fibroglial tissue characterises primary idiopathic ERM, as opposed to neovascularisation which is typical in some secondary ERM such as PDR [182, 183]. The most frequently implicated cellular components in idiopathic ERM are hyalocytes and glial cells whereas RPE cells are thought to be the main cell type contributing to ERM formation in rhegmatogenous RD [15, 61, 67, 168, 172–179]. Collagen also plays a crucial role in ERM construction, including types I-IV collagens [184]. Type I and III collagens promote fibrotic process and contribute to the formation of the hard collagen scaffold for the ERM. Type II collagen is usually present in the vitreous. Type IV collagen is produced by modified glial cells, which are consid-

b

for Glial Fibrillary Acidic Protein highlights glial cells derived from the retina (×250)

232

ered to have a role in remodelling of the inner limiting membrane. The term “laminocyte” has been proposed for these modified cells [166]. It is also important to look for the PAS-positive inner limiting membrane in these specimens, which may have been peeled (particularly in relation to macular hole). Epiretinal membranes can be separated into three clinical groups on the basis of light microscopy. Simple idiopathic epiretinal membranes consist of inner limiting membrane and modified glial cells. In the epiretinal form of proliferative vitreoretinopathy (PVR) there is inner limiting membrane, modified glial cells (mainly Müller cell), RPE cells, fibroblasts and inflammatory cells (macrophages and lymphocytes). In vasoproliferative retinopathy, there is no inner limiting membrane and endothelial cells can be identified with various markers such as CD31, CD34 and ERG. Cytokines, including vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF) interleukin-6 (Il-­6), Nerve growth factor (NGF), Insulin-like growth factor (IGF), Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β), have all been implicated in playing a role in the pathogenesis of ERM in various studies [15, 185, 186]. Vitrectomy is increasingly in use as a diagnostic tool in cases of suspected infection. Specimens are submitted in large volume plastic containers that contain the samples in a large volume of perfusion fluid. If the cellular morphology is to be preserved it is critical to obtain the specimen in the shortest time possible. If there is to be a delay then equivalent volume of fixative (cytology fixative such as Cytolyt) should be added to the specimen. Depending on the clinical scenario the specimen can be handled in two main ways: The contents can be spun down to form a cytospin preparation or a cell block preparation can be prepared by the addition of plasma and the sample processed through paraffin in the routine way. Depending on cellularity the latter method has the advantage of providing material suitable for immunohistochemistry and molecular studies including PCR and FISH. For inflammatory conditions appropriate special stains can be undertaken; e.g., Gram, PAS, Grocott, ZiehlNeelsen. Granulomas can be seen in a range of conditions including mycobacterial infection, sarcoidosis, and VogtKoyanagi-­Harada syndrome. Eosinophils can be present in parasitic infections, although may also be seen in sympathetic ophthalmitis. Neoplastic disease can include primary ocular tumours such as lymphoma and retinoblastoma as well as leukaemia, metastatic carcinoma, and metastatic melanoma. The initial morphological assessment will direct appropriate further immunohistochemical and molecular investigations [187].

7  Treatment of Retinal Detachment

Retinal Detachment and Reattachment Delay in reattachment may be recognized in a histological preparation, when the retina is in situ, because there will be extensive photoreceptor atrophy without an obvious explanation, such as disease of the choriocapillaris, choroidal vascular sclerosis, or disease of the posterior ciliary arteries (Fig. 7.1g).

Retinal Displacement Without Detachment On rare occasions, traction on the peripheral retina will draw a fold across the pars plana as far as the ciliary processes or iris. In spite of this deformation, the posterior retina can remain in situ, for reasons which are not easily apparent, unless “shrinkage of the globe” is regarded as an adequate explanation. The cause is usually extensive fibrotic scarring in the anterior segment producing traction via the vitreous base.

The Extruded Silicone Sponge or Plomb The treatment of retinal detachment requires scleral indentation over a retinal hole or tear. Silicone sponges are sutured to the sclera to produce the required degree of indentation and occasionally a scleral sponge may extrude spontaneously through the conjunctiva. If bloodstained, the clinical appearance may resemble a melanoma [188]. Histological examination of a sponge (which can be processed through paraffin wax) may reveal bacteria—usually Gram-positive cocci with occasional inflammatory cells in the interspaces.

Asteroid Hyalosis Occasionally in vitrectomy specimens, asteroid bodies may be identified (Fig. 7.28a–d). In a condition of unknown aetiology and pathogenesis, tiny white bodies are present in the vitreous giving the appearance of a starry sky. Several studies have suggested an association with diabetes and with aging [189]. However, there is no convincing statistical evidence for any definitive association, especially given most of asteroid hyalosis occurs unilaterally [190]. On microscopy the circular bodies stain positively for Ca2, PO4, mucopolysaccharides, and phospholipids, and in an H&E stain are birefringent [191]. The structure of these bodies is similar to hydroxyapatite and appears to have a covering matrix composed of vitreous substances [192]. The bodies are often also encompassed by mononuclear or multinucleate cells.

Pathology of Treatment of Retinal Detachment

233

a

b

c

d

Fig. 7.28 (a) Asteroid hyalosis appears as clusters of shiny white crystals on macroscopic examination (arrowhead). (b) Often the particles are surrounded by macrophages. (c and d) The particles stain positively with Alcian blue and are birefringent

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237 secondary to proliferative vitreoretinopathy. J Vitreoretin Dis. 2019;3(2):69–75. 151. Federman JL, Eagle RC. Extensive peripheral retinectomy combined with posterior 360 degrees retinopathy for retinal reattachment in advanced proliferative vitreoretinopathy cases. Ophthalmology. 1990;97:1305–20. 152. Wong D, Lois N. Foveal relocation by redistribution of the neurosensory retina. Br J Ophthalmol. 2000;84:352–7. 153. Eandi CM, Giansanti F, Virgili G. Macular translocation for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008;4:CD006928. 154. Tosi GM, Traversi C, Schuerfeld K, Mittica V, Massaro-Giordano M, Tilanus MA, Caporossi A, Toti P.  Amniotic membrane graft: histopathological findings in five cases. J Cell Physiol. 2005;202:852–7. 155. Tosi GM, Massaro-Giordano M, Caporossi A, Toti P.  Amniotic membrane transplantation in ocular surface disorders. J Cell Physiol. 2005;202:849–51. 156. Kheirkhah A, Blanco G, Casas V, Hayashida Y, Raju VK, Tseng SC.  Surgical strategies for fornix reconstruction based on symblepharon severity. Am J Ophthalmol. 2008;146:266–75. 157. Niknejad H, Yazdanpanah G, Kakavand M. Extract of fetal membrane would inhibit thrombosis and hemolysis. Med Hypotheses. 2015;85:197–202. 158. Tehrani FA, Ahmadiani A, Niknejad H. The effects of preservation procedures on antibacterial property of amniotic membrane. Cryobiology. 2013;67:293–8. 159. Rizzo S, Caporossi T, Tartaro R, Finocchio L, Franco F, Barca F, Giansanti F.  A human amniotic membrane plug to promote retinal breaks repair and recurrent macular hole closure. Retina. 2019;39(Suppl. 1):S95–S103. 160. Caporossi T, Tartaro R, De Angelis L, Pacini B, Rizzo S. A human amniotic membrane plug to repair retinal detachment associated with large macular tear. Acta Ophthalmol. 2019;97:821–3. 161. Caporossi T, De Angelis L, Pacini B, Tartaro R, Finocchio L, Barca F, Rizzo S. A human amniotic membrane plug to manage high myopic macular hole associated with retinal detachment. Acta Ophthalmol. 2020;98:e252–6. 162. Caporossi T, De Angelis L, Pacini B, Rizzo S.  Amniotic membrane for retinal detachment due to paravascular retinal breaks over patchy chorioretinal atrophy in pathologic myopia. Eur J Ophthalmol. 2020;30:392–5. 163. Rizzo S, Caporossi T, Pacini B, De Angelis L, De Vitto ML, Gainsanti F. Management of optic disk pit-associated macular detachment with human amniotic membrane patch. Retina. 2020;2020. https://doi.org/10.1097/IAE.0000000000002753. 164. Rizzo S, Caporossi T, Tartaro R, et  al. Human amniotic membrane plug to restore age-related macular degeneration photoreceptor damage [published online ahead of print, 2020 Apr 25]. Ophthalmol Retina. 2020;S2468–6530(20)30170–6. https://doi. org/10.1016/j.oret.2020.04.017. 165. Hiscott P, Wong D, Grierson I.  Challenges in ophthalmic pathology: the vitreoretinal membrane biopsy. Eye. 2000;14:5 49–59. 166. Snead DRJ, James S, Snead MP.  Pathological changes in the vitreoretinal junction 1: epiretinal membrane formation. Eye. 2008;22:1310–7. 167. Iannetti L, Accorinti M, Malagola R, Bozzoni-Pantaleoni F, Da Dalt S, Nicoletti F, et al. Role of the intravitreal growth factors in the pathogenesis of idiopathic epiretinal membrane. Invest Ophthalmol Vis Sci. 2011;52(8):5786–9. 168. Kampik A, Kenyon KR, Michels RG, Green WR, de la Cruz ZC. Epiretinal and vitreous membranes. Comparative study of 56 cases. Arch Ophthalmol. 1981;99(8):1445–54. 169. Duan XR, Liang YB, Friedman DS, Sun LP, Wei WB, Wang JJ, et  al. Prevalence and associations of epiretinal membranes in a

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8

The Malformed Eye

Introduction Basically, malformations of the eye, orbit, and adnexa are encountered in three forms. First, there are ocular abnormalities of a relatively minor nature (e.g., colobomata of the uveal tract and minor malformations of the retina and optic nerve head); these are observed in otherwise normal individuals and do not require treatment. Secondly, there are those (e.g., corneal malformations, cataracts, vitreous disorders) that are amenable to surgical intervention and excised tissue may be submitted to the laboratory for investigation. Thirdly, there are those in which major or minor degrees of ocular malformation are associated with severe and often lethal systemic disorders (e.g., synophthalmia, anencephaly, and gross chromosomal abnormalities such as the trisomy D group); these abnormalities may be encountered in the post-mortem room, although antenatal screening is now extremely effective in preventing such foetuses from coming to term. The factual information relevant to ocular malformations associated with genetic abnormalities is increasing so rapidly that the topic cannot be considered in depth in this chapter. The reader is referred to the excellent and comprehensive descriptive accounts provided by the following authors: Jakobiec [1], Stromland et al. [2], Musarella [3], Torczynski [4], McMenamin [5], Fuhrmann [6], Slavotinek [7, 8] and Plaisancié [9].

Relevant Basic Ocular Embryology Differential growth from the prosencephalon leads to the formation of an evagination, the primary optic vesicle (28 days), which invaginates to form the optic cup (36 days). The lumen of the primary optic vesicle thus becomes a potential space compressed between the inner neural retina and the outer pigmented monolayer, the retinal pigment epithelium (Figs. 8.1a, b, e, and 8.2).

The anterior lip of the optic cup migrates behind the mesoderm at the chamber angle (Figs. 8.3 and 8.4) and as the iris stroma is formed, the anterior and posterior lips of the optic cup migrate to form the iris pigment epithelium. There is a potential for cyst formation between the anterior and posterior layers (Fig. 8.4) and pigmented cysts in the posterior part of the iris can present diagnostic problems for the clinician. The dilator and sphincter pupillae are derived from the anterior pigmented layer of the iris pigment epithelium. As the iris develops, the posterior layer of epithelium is formed by cells that are hypopigmented and correspond to the inner layer of the optic cup and neural retina (Fig. 8.5). At a later stage, the posterior surface of the iris is lined by two layers of pigmented cells, which may be due to differentiation of the hypopigmented posterior layer or a sliding process from the anterior pigmented layer. Over the pars plicata and the pars plana the inner lightly pigmented layer of the cuboidal epithelium is continuous with the neural retina, while the outer layer is continuous with the retinal pigment epithelium and is more heavily pigmented (Fig. 8.5). In histological preparations the neural retina separates easily by artefact from the retinal pigment epithelium at all stages of development. The lens epithelium is derived from a placode in the ectoderm overlying the optic vesicle and invagination of the lens placode forms the primary lens vesicle, which detaches from the ectoderm and lies within the optic cup (Fig. 8.1a, b, e). The spherical lens is nourished by mesodermal tissue, which enters the optic vesicle through the optic fissure to form the primary vitreous (Fig. 8.3). The anterior part of the primary vitreous is continuous with a vascular network, “the tunica vasculosa lentis,” which surrounds the lens. The primary vitreous is supplied by the hyaloid artery and vein, and as the optic fissure closes, these vessels are drawn into the optic nerve to become the central retinal artery and vein. The mechanisms for regression within the delicate capillary network in the primary vitreous and tunica vasculosa lentis are now better understood. In human eyes, apoptosis in endothelial cells and pericytes plays an

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8  The Malformed Eye

a Evagination of neural tube

Future pigment epithelium

forms optic vesicle

b

Invagination of optic vesicle forms optic cup

Invagination of lens vesicle forms lens

(7 mm, 4weeks) Future neural retina

Lens placode

(2mm, 2weeks) Open embryonic fissure

c Major anomalies

d Microphthalmic eye

Eyelid

Normal invagination of optic vesicle forms Optic cup (7mm)

Lens

Neural Optic tube vesicle

Cyst lined by pigment epithelium and disorganised retinal tissue

Neural retina Ectoderm Mesoderm Lens placode

Coloboma

Pigment epithelium

(1–2mm,1–2 weeks) Atypical differentiation of midline mesoderm

Suppression before 3 mm 3–4 weeks Lacrimal gland

Muscle

e

f Pigment epithelium

Anophthalmia & synophthalmia (defective evagination of optic vesicle from neural tube)

Minor anomalies Coloboma of iris

Neural retina

Coloboma of lens and ciliary body

Normal 7.5 mm embryo

Coloboma of retina (sclera visible)

Lens Hyaloid artery

g

Primary vitreous

(mesodermal and neuroectodermal)

h

Posterior

Retrolental fibrous mass

Tunica vasculosa lentis Secondary vitreous

Anterior

Retinal folds

(neuroectodermal) Preretinal membranes

Hyaloid artery

Ciliary artery

(35-60 mm, 9 weeks)

Presistent hyaloid artery

Tertiary vitreous Canal of Cloquet Secondary vitreous

Retinal dysplasia

Traction distortion of ciliary processes

Chamber angle malformation

Relevant Basic Ocular Embryology

241

Fig. 8.3  At 10 weeks in the human embryo, the tip of the neural cup is in contact with mesectoderm (m) and mesoderm, which will ultimately form the ciliary body and outflow system. The neural retina (nr), containing a single layer of neuroblastic cells, is apposed to the pigment epithelium (p). The lens is surrounded by the tunica vasculosa lentis (l) (×100) Fig. 8.2  The human fetal eye at 8 weeks. The cornea (c) is formed by three layers. The nuclei of the cells from the posterior part of the lens epithelium (lf) are now lined up across the centre of the lens: These cells will die and become the adult lens nucleus. The cells at the equator forming a “nuclear” bow will produce the cortex of the adult lens. The neural retina (nr), derived from the inner layer of the optic cup, is separated by artefact from the retinal pigment epithelium (p), which is derived from the outer layer of the optic cup (×100)

important role [10, 11], while in animal eyes macrophages are a prominent feature [12]. It is not difficult to appreciate how a failure of this self-disposal system can lead to the persistence of rudimentary fibrovascular tissue around the lens or on the surface of the optic disc. Before markers were available for neural crest cells, the sclera and cornea were thought to arise as condensations in mesoderm, as were the ciliary muscle, the trabecular meshwork, and the vasculature of the retina and choroid. Although unproven in human embryology, it seems from studies in avian tissue that migrating cells from the neural crest (mesectoderm) make a significant contribution to the tissues in the anterior segment [13]. The corneal stromal collagen is formed by surface ectoderm, which forms the epithelium, and a neural crest derived mesectoderm, which becomes the stroma and the endothelium (Figs. 8.2 and 8.3). The trabecular meshwork emerges by proliferation and reorganisation of germinal tissue in the chamber angle (Fig. 8.4), and the separation of the trabecu-

lae from the iris stroma is most likely to be the result of programmed cell death rather than the outcome of mechanical cleavage of tissue, which previously was thought to be due to the differential growth of tissues in the anterior segment [14–16]. With the development of the ciliary muscle and its vasculature, there is concomitant formation of the ciliary processes, which now take over the production of aqueous fluid and the formation of lens zonular fibres and surrounding matrix (tertiary vitreous). The secondary vitreous is the product of the glial supporting cells in the retina (Fig. 8.1g). The intrinsic neural cells of the retina first appear as a band of neuroblastic tissue, which by a combination of cell division, cell death and cell migration from two layers—an inner and an outer neuroblastic layer: The inner neuroblastic layer differentiates to form ganglion cells (Fig.  8.6). The outer layer subdivides into inner and outer nuclear layers (Fig. 8.7). The formation of photoreceptors occurs initially at the posterior pole and migrates forward as the retina differentiates. The inner segments project from the outer limiting membrane and from these a cilium forms on the apex of the bulge. The outer segments are derived from the membrane of the cilium: The membrane invaginates along its length to form the photoreceptor discs. The ganglion cell layer is formed by migration from the inner neuroblastic layer and

Fig. 8.1 (a) Diagram to show the formation of the optic vesicle. (b) Diagram to show the formation of the optic cup. (c) If there is a failure of invagination to form the optic cup the orbit contains a cystic structure lined by rudimentary neural retina and retinal pigment epithelium (congenital cystic eye). If the fissure fails to close, a cyst lined by neural retina projects from a microphthalmic globe (microphthalmos with cyst). (d) If there is a failure to form an optic vesicle, the orbit contains tissue derived from mesoderm and ectoderm (lacrimal gland), but ocular tissue is not identified. If the nasal anlage is deficient, the globes fuse (synophthalmia). (e) The normal optic cup in a 7.5 mm embryo. The hyaloid artery passes through the inferonasal optic fissure. (f) Failure of closure of the embryonic fissure leads to defects in the iris, ciliary body and retina (coloboma). (g) Diagram to illustrate the development of the normal vitreous. (h) If the primary vitreous fails to regress there is persistent fibrovascular tissue behind the lens and on the inner surface of the retina (persistent hyperplastic primary vitreous)

242

Fig. 8.4  At 16 weeks, the tip of the optic cup has differentiated into an anterior pigmented layer and a posterior non-pigmented layer, and these layers are separated by a cystic space or sinus (arrowhead). The primitive iris stroma and trabecular meshwork (m) have now formed (×100)

the axons from these cells pass down the optic nerve at an early stage to connect (in a very specific anatomical pattern) with the cells in the lateral geniculate body and the cranial nerve nuclei in the midbrain. While the meninges of the optic nerve are present at an early stage, the lamina cribrosa appears as a late event (seventh month) and is seen as fibroblastic ingrowth between the nerve bundles. The retinal vessels are distributed within the retina as outgrowths from the branches of the hyaloid artery and the stimulus for the proliferation of the endothelial cells is a relative hypoxia in the rapidly dividing neural tissue. Exposure to high oxygen concentration (as in the treatment of hyaline membrane disease of the lungs in the premature infant) suppresses the proliferation of the cells at the periphery of this vascular network and this is followed by reactive proliferation of the vascular endothelial cells when the oxygen level returns to normal (“retinopathy of prematurity”; see Chap. 4). Ocular malformations are best considered in relation to normal embryonic development, and in the following account, the

8  The Malformed Eye

Fig. 8.5  At 20 weeks, the pars plicata of the ciliary body (cb) is formed and rudimentary iris (i), trabecular meshwork (m) and ciliary muscle (c) are recognisable. The periphery of the neural retina reaches the pars plicata; i.e., the pars plana is not yet formed. Note the non-pigmented layer of cuboidal cells on the posterior surface of the iris (arrowheads) (×40)

embryological information is restricted to those features that are relevant to disordered development. For example, heterotopia and neoplastic proliferations may be of a type unrelated to the cells normally present in a given tissue location. These unexpected findings become more easily understandable when the various tissue migrations and transformations that occur in the developing eye are taken into account.

 ross Malformations Due to Abnormal G Development in the First 4 Weeks of Embryonic Life Malformation of the Optic Vesicle Anophthalmia Evagination from the neural tube takes place at the fourth week (4–5 mm). If there is failure of formation of the optic

Gross Malformations Due to Abnormal Development in the First 4 Weeks of Embryonic Life

vesicle, the orbit will not contain ocular tissue, but the extraocular muscles, which are formed from mesoderm, will be present, as will the lacrimal gland, which is derived from ectoderm (Fig. 8.1d). True anophthalmia is an extreme rarity, but tissue may be submitted from cases of what appear clinically to be anophthalmic orbits as part of cosmetic procedures to stimulate orbital growth by insertion of implants or tissue expanders.

Nanophthalmia and Microphthalmia Formation of the vesicle without proper subsequent development produces a disorganised and rudimentary eye in the orbit, referred to as microphthalmia (Figs. 8.8a, b and 8.9a, b). The International Clearinghouse for Birth Defects Monitoring Systems defines anophthalmia and microphthalmia as “anophthalmos/microphthalmos: apparently absent or small eyes. Some normal adnexal elements and eyelids are usually present. In microphthalmia, the corneal diameter is less than 10 mm, and the antero-­posterior diameter of the globe is less than 20 mm” [17]. Depending on the combination with other ocular findings, microphthalmia can be divided into different types. Simple microphthalmia refers to an anatomically intact eye with the aforementioned reduced size. In contrast, the term complex microphthalmia is used when microphthalmia is associated with abnormalities of the anterior segment (Axenfeld–Rieger anomaly, Peters’ anomaly, sclerocornea, and cataract) or of the posterior segment (persistence of primitive vitreous, chorioretinal coloboma, and retinal dysplasia). When microphthalmia is combined with an optic fissure closure defect, it is referred to as colobomatous microphthalmia. Lastly, posterior microphthalmia, uncommon, affects only the posterior segment of the eye and is thus defined by a reduced total axial length in the presence of normal anterior segment dimensions, including corneal diameter, anterior chamber depth, and anteroposterior length of the lens. Hence, it is associated with high hyperopia and abnormal retinal folds [9]. A small eye with thickened sclera,

Fig. 8.6  The disc and peripapillary retina at 16 weeks. The retinal neuroblasts have now divided into two layers (arrowheads) in the artefactually detached retina. The lamina cribrosa is not formed (×100)

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microcornea, axial length