Review of Uveitis [1 ed.] 9781617116711, 9781556428227

Citation preview

Van Gelder • Prasad

Review of Uveitis As the first text geared specifically toward reviewing current information on ocular inflammation and uveitic disease, Review of Uveitis is an essential resource for students, residents, fellows, and practicing clinicians, as well as general and subspecialist ophthalmologists looking to refresh their knowledge in the field. Drs. Russell N. Van Gelder and Anita G. Prasad have organized Review of Uveitis in a useful Q&A format, covering both basic mechanisms of ocular inflammation and specific clinical entities. The in-depth review answers provide focus on understanding disease processes, diagnosis, and treatment.

• • • • • • • • • •

Basic mechanisms of ocular inflammation Signs, symptoms, and classification of uveitis Laboratory testing for uveitic disease Local and systemic treatments for all forms of uveitis Complications of uveitis Systemic disease associations of uveitic conditions Differential diagnosis of different presentations of uveitis Pars planitis and intermediate uveitis Infectious and autoimmune forms of posterior uveitis A review of the white dot syndromes

Review of Uveitis

Some topics include:

Review of Uveitis

Special Features: • User-friendly Q&A format, with chapters organized by topic • Illustrations of disease processes and mechanisms, including many color photographs and diagrams • Review of current recommendations regarding systemic and surgical treatment of uveitis • Inclusion of over 200 clinically based questions ranging from basic to advanced • In-depth answers to most uveitis questions encountered by the comprehensive and specialty clinician • Up-to-date primary literature references for each chapter

®

slackbooks.com

I N C O R P O R A T E D

I N C O R P O R A T E D

SLACK

SLACK

®

Russell N. Van Gelder Anita G. Prasad

MEDICAL/Ophthalmology

SLACK Incorporated _08-0329_VanGelderCvr.indd 1

2/3/2012 1:27:23 PM

Review of Uveitis

Review of Uveitis

Russell N. Van Gelder, MD, PhD Boyd K. Bucey Professor and Chair Department of Ophthalmology University of Washington Medical School Seattle, WA

Anita G. Prasad, MD Wills Eye Hospital Philadelphia, PA

Delivering the best in health care information and education worldwide

www.slackbooks.com ISBN: 978-1-55642-822-7 Copyright © 2008 by SLACK Incorporated All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher, except for brief quotations embodied in critical articles and reviews. The procedures and practices described in this book should be implemented in a manner consistent with the professional standards set for the circumstances that apply in each specific situation. Every effort has been made to confirm the accuracy of the information presented and to correctly relate generally accepted practices. The authors, editor, and publisher cannot accept responsibility for errors or exclusions or for the outcome of the material presented herein. There is no expressed or implied warranty of this book or information imparted by it. Care has been taken to ensure that drug selection and dosages are in accordance with currently accepted/recommended practice. Due to continuing research, changes in government policy and regulations, and various effects of drug reactions and interactions, it is recommended that the reader carefully review all materials and literature provided for each drug, especially those that are new or not frequently used. Any review or mention of specific companies or products is not intended as an endorsement by the author or publisher. SLACK Incorporated uses a review process to evaluate submitted material. Prior to publication, educators or clinicians provide important feedback on the content that we publish. We welcome feedback on this work. Published by:

SLACK Incorporated 6900 Grove Road Thorofare, NJ 08086 USA Telephone: 856-848-1000 Fax: 856-853-5991 www.slackbooks.com

Contact SLACK Incorporated for more information about other books in this field or about the availability of our books from distributors outside the United States. Library of Congress Cataloging-in-Publication Data Van Gelder, Russell N. Review of uveitis / Russell N. Van Gelder, Anita Prasad. p. ; cm. Includes bibliographical references and index. ISBN 978-1-55642-822-7 (alk. paper) 1. Uveitis--Problems, exercises, etc. I. Prasad, Anita, 1978- II. Title. [DNLM: 1. Uveitis--Problems and Exercises. WW 18.2 V217r 2008] RE351.V37 2008 617.7’20076--dc22 2008004629 For permission to reprint material in another publication, contact SLACK Incorporated. Authorization to photocopy items for internal, personal, or academic use is granted by SLACK Incorporated provided that the appropriate fee is paid directly to Copyright Clearance Center. Prior to photocopying items, please contact the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923 USA; phone: 978-750-8400; website: www.copyright.com; email: [email protected]

Printed in the United States of America. Last digit is print number: 10 9 8 7 6 5 4 3 2 1

Dedication For Suzy, Rachel, and Max Russell N. Van Gelder For my parents and Ramin Anita G. Prasad

Contents Dedication ....................................................................................................................................... v Acknowledgments .......................................................................................................................... ix About the Authors ......................................................................................................................... xi Preface ..........................................................................................................................................xiii Introduction .................................................................................................................................. xv Chapter 1:

Basic Concepts in Immunology and the Immune Response Arc.................1

Chapter 2:

Ocular Immune Responses and Immune Tolerance ......................................9

Chapter 3:

Mechanisms of Immune Effector Reactivity .................................................15

Chapter 4:

Signs, Symptoms, and Classification of Uveitis ............................................25

Chapter 5:

Laboratory Evaluation of Uveitis .....................................................................37

Chapter 6:

Medical and Surgical Management of Uveitis ..............................................45

Chapter 7:

Complications of Uveitis ...................................................................................53

Chapter 8:

Human Leukocyte Antigen-B27–Associated Diseases.................................61

Chapter 9:

Juvenile Idiopathic Arthritis-Related Uveitis ................................................69

Chapter 10:

Lens-Induced Uveitis ........................................................................................75

Chapter 11:

Other Anterior Uveitides ..................................................................................85

Chapter 12:

Intermediate Uveitis and Pars Planitis ...........................................................93

Chapter 13:

Viral Retinitis ......................................................................................................99

Chapter 14:

Fungal, Protozoal, and Helminthic Posterior Uveitis.................................109

Chapter 15:

Masquerade Syndromes ..................................................................................121

Chapter 16:

Collagen Vascular and Other Autoimmune Posterior Vasculitides.........131

Chapter 17:

Bacterial Panuveitis ..........................................................................................139

Chapter 18:

Ocular Sarcoidosis ...........................................................................................147

Chapter 19:

Sympathetic Ophthalmia and Vogt-Koyanagi-Harada Disease ...............155

Chapter 20:

White Dot Syndromes .....................................................................................163

viii

Contents

Chapter 21:

Ocular Involvement in Acquired Immunodeficiency Syndrome .............173

Index ............................................................................................................................................181

Acknowledgments We thank Morton Smith, MD, who provided knowledge and histopathology examples essential to this book. We also thank our colleagues and residents, who inspired us with their curiosity and clinical cases. We especially thank Arghavan Almony, MD, who provided a number of questions used in this book.

About the Authors Russell N. Van Gelder, MD, PhD, earned his bachelor’s, PhD, and MD degrees from Stanford University. He completed his ophthalmology residency and uveitis and medical retina fellowships at Washington University in St. Louis. Author of over 100 papers and book chapters in ophthalmology and vision science, Dr. Van Gelder is presently the Boyd K. Bucey Professor and Chair of the Department of Ophthalmology at the University of Washington Medical School in Seattle. Anita G. Prasad, MD, graduated from Northwestern University with a degree in Religion. Dr. Prasad received her medical degree from Northwestern University Medical School. She completed a residency in ophthalmology and a fellowship in uveitis and ocular immunology at Washington University in St. Louis. She is currently completing a retina fellowship at Wills Eye Hospital in Philadelphia.

Preface This book is a review manual for uveitis aimed at two audiences: (1) current ophthalmology residents and fellows in training, and (2) current practitioners wishing to augment their scope and depth of knowledge in the diagnosis and treatment of uveitis. The aim of this book is to present practical knowledge and current developments in uveitis in an engaging question-and-answer format.

Introduction Uveitis is an important clinical subspecialty within ophthalmology. Uveitis is a major cause of blindness worldwide. Because uveitis can affect all portions of the eye, every ophthalmologist must be familiar with the full spectrum of uveitic disease and its management. Recognizing uveitic disease is also essential to the ophthalmologist’s role as physician; many uveitic diseases have important implications for general health that must be recognized. Unfortunately, many training programs do not have a full-time uveitis specialist to provide the necessary education for residents and fellows in uveitic disease and its management. Uveitic disease may be handled in an “ad hoc” manner, which can leave significant holes in the trainees’ knowledge. Even in programs that do have full-time uveitis subspecialty support, lecture time is always at a premium and the complexities and subtleties of uveitic pathogenesis, diagnosis, and management may be excessively compressed. For the ophthalmologist who has completed training, there is, unfortunately, a dearth of opportunities to update and enhance knowledge of uveitic disease. Yet there is clearly a need for such education; continuing medical education and subspecialty day meetings for uveitis are extremely well attended. For the practitioner wishing to enhance his or her knowledge at home, there are a number of excellent textbooks on uveitis; however, these often present material in a manner somewhat divorced from clinical scenarios. To date, there have been no interactive review guides for uveitis. We have written this book to aid both the trainee seeking to solidify and enhance his or her knowledge of uveitis and for the practitioner seeking an engaging way to augment and update his or her knowledge of uveitic disease. The 21 chapters of this book are arranged to roughly mirror the organization of Section 9 of the American Academy of Ophthalmology’s Basic and Clinical Science Course (BCSC). However, we have included much information not covered in the BCSC. The format of this book is question-and-answer followed by an extended explanation of the answers. The questions contain a mix of both didactic questions and clinical scenarios. Both an explanation for the preferred answer as well as enumeration of the incorrect responses will be given for each question. The answers to these questions also contain additional information not directly required to answer the question. References are provided at the end of each chapter for the interested reader. We would encourage the reader to attempt to answer each question before proceeding to the explanation. We have chosen the questions to ensure coverage of the topics we feel are most important to the ophthalmologist-in-training and the practicing ophthalmologist. We hope you will find this book a valuable and enjoyable way to review the uveitis subspecialty. This book is not a substitute for a complete text reference; many excellent and up-to-date uveitis texts are readily available. Many answers of clinical questions are an amalgam of clinical experience and literature support; there are many ways to skin the proverbial cat, and some uveitic subspecialists may disagree with our preferred answers or explanations. The authors take full responsibility for any factual errors within this book, and would be most grateful for any and all feedback on how this work could be improved for future editions.

Chapter 1

BASIC CONCEPTS IN IMMUNOLOGY THE IMMUNE RESPONSE ARC

AND

1. Which of the following is true concerning adaptive immunity? A. Adaptive immunity is determined at birth and identical among individuals within a species. B. The adaptive immune system responds vigorously to bacterial toxins and cell debris. C. T and B cells act in a nonspecific manner to remove foreign antigens from the host organism. D. A unique molecular structure is necessary for an antigen to be identified, processed, and recognized by the adaptive immune system. Answer: D. Adaptive immunity is the acquired host response instigated by a specific stimulus. The environmental trigger is usually foreign to the host, and is recognized as an unfamiliar entity by the immune system. The immune system identifies the antigen’s unique molecular structure, which becomes the template for the generation of antigenspecific receptors. The interaction between the antigen and these specific receptors activates the immune system through antigen-specific effector cells and molecules. The principle players in this process are T and B lymphocytes and antigen-specific antibodies, which function to selectively remove or destroy the antigen from the host. Adaptive immunity is not determined at birth; instead it is an evolving response to the myriad environmental triggers to which the host organism is exposed throughout its life. A mutating virus, for example, can stimulate several different specific responses from the adaptive immune system.1,2

1

2

Chapter 1 2. Which of the following is true concerning innate immunity? A. The innate immune response exhibits memory. B. Recognition of specific three-dimensional structure is necessary to activate innate immunity. C. The innate immune response will be preserved even if the antigen undergoes point mutation. D. The innate immune response is delayed several days after initial exposure to an antigen.

Answer: C. Innate immunity is the generic response of the host organism to foreign stimuli. The immune system identifies the invading organism in an antigen-independent mechanism. The body’s effort to rid the host of the foreign invader is a preprogrammed process mediated through preexisting non-antigen specific receptors. Within a species, all individuals have the same receptors required for activation of the innate immune system. These receptors require specific stimuli in the form of molecular motifs, or certain molecular patterns. These patterns include certain amino acid sequences, lipoproteins, or polysaccharides that are derived from bacterial toxins or host-cell debris during an acute infection. So although the innate immune system is not antigen specific, the biochemical interactions needed for activation are still precise. The major effectors of innate immunity are antigen-independent cells such as macrophages and neutrophils, as well as secreted proteins such as cytokines. The cells and molecules of the innate immune system can also serve to amplify the adaptive immune response via antigen-specific receptor activation. Both the adaptive and innate components of the immune system are crucial for host defense. Although the adaptive immune response can require days to weeks to mature after initial antigen exposure, the innate immune system can launch its preprogrammed response within minutes. However, unlike the innate immune response, the adaptive immune system has memory, such that upon subsequent exposures to an antigen, it responds faster and more vigorously. The cellular mediators active during subsequent exposure to an antigen are memory T and B cells, which are distinct subsets of the lymphocytes involved in the initial adaptive response. The adaptive immune system responds to specific amino acid sequences via T cells, and to specific three-dimensional structures via B cells. A single amino acid substitution or deletion within an antigen will generally deactivate the adaptive immune response to that antigen until it can be reprocessed. A similar change to an antigen will not necessarily affect the innate immune response, as long as the antigenic motif is preserved. The innate and adaptive responses work in concert to attack, disable, and remove pathogens. The immune response becomes clinically apparent as tissue inflammation. Infiltration of effector cells as well as increased vascular permeability result in the five classic clinical signs of inflammation: (1) pain, (2) hyperemia, (3) edema, (4) heat, and (5) loss of function.1 3. Which of the following infections provokes an eosinophilic infiltrate? A. B. C. D.

Toxocariasis Tuberculosis Mucormycosis Candidiasis

Basic Concepts in Immunology and the Immune Response Arc

3

Answer: A. Eosinophils are named for their granules, which stain with eosin. Toxic granule products including basic proteins and hydrogen peroxide are adept at fighting parasites, and eosinophils are often seen at sites of parasitic infections. Eosinophils also play an important role in the pathogenesis of asthma and allergy, and may be found in atopic skin lesions as well as in pulmonary allergic infiltrates. A key activation molecule for eosinophils is interleukin (IL)-5, which is produced by T cells within the eye. Eosinophils are involved in vernal and allergic conjunctivitis, and are principle effector cells for fighting helminithic intraocular infections, most commonly toxocariasis. Fungal infections such as mucormycosis and candidiasis, or a mycobacterial infection such as tuberculosis, would not provoke an eosinophilic infiltrate.1 4. Which of the following cell types comprise the typical pathologic finding in the process depicted below? A. B. C. D.

Macrophages Mast cells Eosinophils Lymphocytes

Figure 1-1. Courtesy of Morton E. Smith, MD.

Answer: A. The pathologic slide (Figure 1-1) depicts a sarcoid granuloma, which is composed of macrophages that have formed multinucleated giant cells. Monocytes and macrophages are important in all forms of the immune response. Monocytes circulate within the bloodstream, and are considered macrophages once they infiltrate into tissue. However, most tissues also contain resident macrophages that probably represent monocytes that migrated during embryologic development. These tissue-specific macrophages are called Kupffer cells in the liver, alveolar macrophages in the lung, and microglia in the brain and retina. Macrophages act to scavenge cell debris and pathogens and are considered “professional” antigen presenting cells for T cells. Resting monocytes can be activated into effector cells by bacterial toxins, phagocytosis of antibody or complementcovered pathogens, or by inflammatory mediator molecules such as IL-1 and interferon (IFN)-γ. Macrophages are found in many types of overt as well as subclinical inflammation. For instance, macrophages may morph into epithelioid cells, which then coalesce to create a multinucleated giant cell as is seen in sarcoidosis and tuberculosis.1,2

4

Chapter 1 5. Which of the following antibody types trigger histamine release? A. B. C. D.

IgG IgE IgM IgA

Answer: B. Mast cells are the primary cells involved in immunoglobulin E (IgE)-mediated allergic hypersensitivity. Mast cells are primarily activated by a specific interaction between IgE and high-affinity Fc receptors expressed on the cell surface, which induces release of histamine. Mucosal mast cells also require T-cell activation, and contain relatively low levels of histamine. Connective tissue mast cells contain abundant granules laden with histamine and heparin. Basophils and mast cells are similar to each other, except that basophils circulate, while mast cells are found within mucosa and connective tissue.1,2 6. Granulocytes include all of the following except: A. B. C. D.

Polymorphonuclear leukocytes Lymphocytes Eosinophils Basophils

Answer: B. The major cellular components of the immune system include lymphocytes, neutrophils (also called polymorphonuclear leukocytes or PMNs), eosinophils, basophils, mast cells, monocytes, macrophages, and antigen-presenting cells. These cells may be identified histologically by their characteristic nuclear shape, the presence or absence or granules, or by specific stains. Lymphocytes are smaller cells with relatively large nuclei and no granules. Three subsets of lymphocytes have been identified: T cells, B cells, and non-T and non-B cells. Like other leukocytes, lymphocytes are derived from pluripotent stem cell precursors in the bone marrow. Monocytes and granulocytes leave the bone marrow as effector cells. B cells continue to mature within the bone marrow, but immature T-cell precursors travel to the thymus, where they complete maturation. Mature but naïve B and T cells then go into the circulation, where they circulate through lymphoid tissue including lymph nodes and the spleen, where B and T cells encounter and process antigen. Peripheral lymphoid tissue, including the skin and mucosa, also acts as a primary site of B- and T-cell exposure to antigen.3 Dendritic cells activate resting T cells by processing and presenting antigen to instigate an antigen-specific response. Langerhans cells are the best described type of dendritic cells and reside in epithelial tissues including mucosa and the cornea. Langerhans cells are involved in antigen presentation, direction of lymphoid cell migration, differentiation of lymphoid cells, and initiation of delayed hypersensitivity. They are a key component in contact hypersensitivity reactions.

Basic Concepts in Immunology and the Immune Response Arc

5

Neutrophils are the most abundant circulating granulocytes. These cells degrade ingested material and release cytokines and granule products when activated by molecules such as complement. Neutrophils are the most numerous effector cells in several different types of inflammation, including bacterial infections and herpes simplex activation.1,2 7. Which of the following is true regarding major histocompatibility complex (MHC) molecules? A. B. C. D.

MHC class II cells mainly act to rid the host organism of virus-infected cells. MHC molecules do not vary among individuals within a species. MHC class I molecules are expressed on most nucleated cells. MHC molecules present whole antigen to T cells.

Answer: C. Class II MHC molecules are the antigen-presenting molecules that allow CD4+ or helper T cells to recognize antigen. In order to stimulate CD4+ T cells, antigenpresenting cells (APCs) must express class II MHC molecules. Antigen-presenting cells (mainly macrophages and dendritic cells) endocytose and process extracellular antigens into peptide fragments, which are then placed into a groove within the class II MHC molecule. The MHC molecule is conveyed to the cell surface, where it serves as a platform for the fragment of antigen as it is presented to the CD4+ helper T cell. MHC class II–dependent immunity principally processes exogenous protein antigens, such as bacterial and fungal proteins. Class I MHC molecules are present on nearly all nucleated cells. However, corneal endothelial cells express class I MHC at a very low level. This down-regulation of class I MHC expression is likely mediated by transforming growth factor (TGF)-β present in the aqueous humor.4 Any cell that expresses class I MHC may present antigen to CD8+ cells, which act to target intracellular antigens, such as virus and endogenous tumor antigens. Antigen-presenting cells from one individual will not be recognized by CD8+ cells from another individual, unless the class I MHC molecules specifically match. In humans, class I and II MHC molecules are referred to as the HLA (human leukocyte antigens).1,2 8. Which subset of T cells acts to stimulate B cells to produce IgE? A. B. C. D.

T helper 0 (Th0) cells T helper 1 (Th1) cells T helper 2 (Th2) cells Cytotoxic T cells

Answer: C. Helper T cells are divided into four groups based on their activity and cytokine secretion. T helper 1 (Th1) cells secrete tumor necrosis factor-β, IFN-γ, IL-1, and IL-12. T helper 2 (Th2) cells secrete IL-4, IL-5, and IL-10. Most uveitis is thought to be Th1 mediated, whereas atopic dermatitis is Th2 mediated. In general, Th1 cells stimulate B cells to produce an IgG response towards an antigen, whereas Th2 cells stimulate an IgE and IgA response. The Th1 and Th2 cell subsets block each other’s activity by the regulatory

6

Chapter 1

actions of their specific cytokines. T helper 0 (Th0) cells refer to cells that have not differentiated into either Th1 or Th2 cells. Recently, two additional subsets of CD4-positive helper T cells—Treg and Th17 cells—have been described, but their direct role in uveitic disease has not yet been established. Cytotoxic T cells are another subtype of T cells that express CD8. They act as effector cells that kill tumor cells or cells infected with virus through the induction of apoptosis and the formation of pore-forming molecules (perforin).1,2,5 9. Which cells serve as antigen-presenting cells for B cells? A. B. C. D.

Macrophages Dendritic cells T helper cells None of the above

Answer: D. B cells begin as naïve lymphocytes that express IgM and IgD on their cell surface. These immunoglobulins are able to detect directly antigenic epitopes, and therefore B cells do not require antigen processing and presentation via an antigen-presenting cell.1 10. How does the immune system regulate the class of antibody produced in reponse to an antigen? A. Activated B cells undergo a cytokine-induced change in genetic expression so as to produce different types of immunoglobulin. B. Different subsets of B cells that produce different classes of immunoglobulins are activated in a cytokine-dependent manner. C. After a certain period of time of antibody production, B cells undergo an selfinduced change in the class of expressed immunoglobulin. D. None of the above. Answer: A. Once an antigen-antibody interaction occurs, helper T cells serve to stimulate B cells to differentiate and amplify their response towards an antigen through specific cytokines. Upon stimulation, B cells are able to change their production of antibody from IgM to another class of immunoglobulin (IgG, IgA, IgD, or IgE), via a cytokine-induced change in genetic expression, known as class switching.1,2

References 1. Basic concepts in immunology and immunization and adaptive immunity: the immune response arc. In: Opremcak EM, et al, eds. Intraocular Inflammation and Uveitis. Basic and Clinical Science Course. Singapore: American Academy of Ophthalmology; 2006:9-30. 2. Nussenblatt RB. Elements of the immune system and concepts of intraocular inflammatory disease pathogenesis. In: Nussenblatt RB, Whitcup SM, eds. Uveitis: Fundamentals and Clinical Practice. Philadelphia, PA: Mosby; 2004:3-46.

Basic Concepts in Immunology and the Immune Response Arc

7

3. Dorner T. Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. J Rheumatol. 2006;Suppl 77:3-11. 4. Apte RS, Niederkorn JY. Isolation and characterization of a unique natural killer cell inhibitory factor present in the anterior chamber of the eye. J Immunol. 1996;156:2667-2673. 5. Croitoru K, Zhou P. T-cell-induced mucosal damage in the intestine. Curr Opin Gastroenterol. 2004;20:581586.

Chapter 2

OCU LAR IM M U NE RE SP ONS E S IM M U NE TOLE RANCE

AND

1. Which of the following is true regarding the process depicted in Figure 2-1?

Figure 2-1. Courtesy of Anthony J. Lubniewski, MD.

A. Antigen processing occurs within conjunctival follicles and local lymph nodes. B. Early production of antiviral immunoglobulin M (IgM) is the most effective response against acute viral conjunctivitis. C. Mucosal associated lymph tissue (MALT) serves as a reservoir for virus and may provoke reinfection. D. Corneal subepithelial infiltrates represent collections of antiviral antibodies in late stages of viral infection. Answer: A. Figure 2-1 demonstrates conjunctival membranes and follicles characteristic of viral conjunctivitis. Adaptive immunity is the principle response to acute viral infection of the conjunctiva. Initially, macrophages and dendritic cells become infected with virus and, along with cell debris, follow lymphatic channels to the submandibular

9

10

Chapter 2

and preauricular lymph nodes. Immune processing occurs in these lymph nodes, as well as in conjunctival follicles, which are active lymph tissue. Production of IgM is an early response to viral antigen. It is not effective in controlling local infection, although it may help to prevent systemic viremia. Control of local infection occurs by directed killing of infected epithelial cells, which express major histocompatibility complex (MHC) class I, by CD8+ cytotoxic T cells and natural killer cells. Adenovirus may block MHC class I expression, and thereby avoid CD8+-driven cell death. MALT plays a role in preventing secondary infection by serving as a reservoir of specific antiviral IgA, which is shed into tears. If the viral load overwhelms the antibody defense, memory cytotoxic T cells act to clear a recurrent viral infection. Corneal subepithelial infiltrates are likely a result of macrophage migration as part of a late delayed hypersensitivity response to viral infection.1 2. Which antibody class is the most abundant in the tear film? A. B. C. D.

IgA IgE IgG IgM

Answer: A. Although all antibody types are present in the tear film, IgA is the most abundant. Antibodies in the tear film are probably produced locally by B cells within conjunctival follicles. IgE also plays an important role in local immunity via mast cell degranulation. Immunoglobulins in the form of IgG and IgA are plentiful within the choroid, but are rare in the rest of the eye.1,2 3. Which of the following is true regarding corneal immunity? A. Resident antigen-presenting cells are found throughout the normal cornea. B. Lymphangiogenesis accompanies neovascularization in an inflamed cornea. C. Replacement of donor epithelium by host epithelium may trigger corneal graft rejection. D. The Khodadoust line of corneal graft rejection indicates stromal rejection. Answer: B. Resident antigen-presenting cells (APCs) are normally found only in the corneal limbus. The peripheral, paracentral, and central cornea are typically devoid of APCs. However, in experimental models of endotoxin-induced keratitis, confocal microscopy has confirmed chemokine-directed migration of inflammatory cells throughout the cornea.3 Although the ocular lymphatic system is limited, studies have shown that angiogenesis in the cornea following an inflammatory insult is accompanied by the development of lymphatics. Regression of pathologic lymphatic vessels typically precedes regression of neovascularization.4 The rapid replacement of donor epithelium by host epithelium following penetrating keratoplasty may help to prevent corneal graft rejection by lessening antigenic stimulus. The Khodadoust line seen in corneal graft rejection represents endothelial rejection, and may be accompanied by keratic precipitates.1

Ocular Immune Responses and Immune Tolerance

11

4. In the anterior chamber, what structural feature predominantly comprises the blood-ocular barrier? A. The attachment between scleral spur and Schlemm’s canal B. Tight junctions between the pigmented and nonpigmented ciliary epithelial cells C. Descemet’s membrane D. Tight junctions between iris epithelial cells Answer: B. Tight junctions between the pigmented and nonpigmented ciliary epithelial cells are the most important part of the blood-ocular barrier in the anterior chamber, and prevent macromolecules from diffusing directly from the ciliary body into the anterior chamber. Tight junctions between iris vascular endothelial cells also contribute to the blood-ocular barrier. Breakdown of this barrier is seen during iritis as leakage of protein and inflammatory cells into the anterior chamber from the anterior circulation. Even in an uninflamed eye, some macromolecules may bypass the ciliary epithelial barrier and enter the anterior chamber directly through the anterior iris.1 5. Which of the following is not true regarding anterior chamber–associated immune deviation (ACAID)? A. The ACAID response to antigen requires that antigen processing and lymphocyte activation occur completely within the eye. B. The effector response in ACAID is characterized by selective inhibition of CD4+ helper cell response. C. Apoptosis of immune effector cells via a Fas-FasL interaction down-regulates the immune response in ACAID. D. Effector blockade refers to the blunted function of immune effector systems in the eye as compared to other nonimmune privileged sites. Answer: A. ACAID refers to the relative immune privilege of the anterior uvea when compared to other sites, such as the skin. Other examples of immune-privileged organs are the brain and the testes. The ACAID phenomenon is most clearly seen in immunization experiments. Although immunization of foreign protein in the dermis induces delayed-type hypersensitivity, the same antigen injected into the anterior chamber: (1) provokes no delayed-type hypersensitivity, and (2) suppresses existing delayed-type hypersensitivity to the injected antigen. Antibody responses, however, are not altered by intraocular antigen presentation. The low rate of corneal transplant rejection when compared to organ transplant in a nonimmune privileged site is thought to be in part due to ACAID. The precise mechanisms of ACAID are still being elucidated. Splenectomy eliminates ACAID, demonstrating that the phenomenon requires effector-cell interactions outside the eye. Transforming growth factor (TGF)-β2 likely serves as a marker to stimulate immune tolerance in the spleen. In contrast to surface APCs, anterior chamber immune cells do not migrate to regional lymph nodes, even in the presence of chemotactic stimuli.

12

Chapter 2

Fas-FasL (Fas ligand) interactions are important for inducing apoptosis of immune cells, especially on the corneal endothelium.1,2,5,6 6. Which of the following is true regarding immune function in the posterior segment? A. Endothelial cells of the choriocapillaris vessels prevent migration of antibodies into the choroidal space. B. T and B lymphocytes are plentiful in the choriocapillaris. C. Retinal pigment epithelial cells may act as APCs. D. Activation of lymphocytes by APCs and antigen occurs within the eye. Answer: C. The choriocapillaris vessels are highly permeable to most macromolecules including antibodies. In the retina, the blood-ocular barrier is primarily composed of the tight junctions between the endothelial cells of the retinal circulation. Lymphocytes are not normal residents of the retina or choroid. Retinal pigment epithelial cells can be induced to express class II MHC molecules and act as APCs to circulating lymphocytes. Macrophages and dendritic cells, which are also potential APCs, are abundant in the choroid and choriocapillaris. Lymphocyte migration into the choroid and retina has been demonstrated in experimentally induced inflammation of the posterior segment. However, activation of lymphocytes by APC-mediated antigen processing and presentation occurs in the lymph nodes and spleen.1 7. Which of the following is not a mechanism of immune tolerance? A. B. C. D.

Anergy Mimicry Suppression Clonal deletion

Answer: B. Anergy, suppression, and clonal deletion are all mechanisms of immune tolerance. Immune tolerance refers to the ability of the adaptive immune system to distinguish self from non-self. Tolerance limits the inflammatory immune response mounted against normal tissue. Anergy refers to the inactivation of T cells and B cells, which occurs when nonprofessional APCs, or cells that are unable to activate lymphocytes due to their lack of costimulatory activity, present antigen. For example, corneal endothelial cells can render T cells unresponsive to antigen by acting as APCs. Anergy also describes the process whereby B cells are rendered inactive to antigens to which they are exposed early during development. Suppression assumes the presence of a class of down-regulatory T cells that actively regulate tolerance by reducing the activity of effector T cells. The mechanisms underlying suppression have not been clearly delineated, but it is likely an important component of ocular immune tolerance. Clonal deletion occurs when the thymus destroys maturing T cells that have developed reactivity against self-antigens. Mimicry is a mechanism by which autoimmunity may occur following an infection with foreign antigen. Cross-reactivity between structurally similar foreign and self-epitopes

Ocular Immune Responses and Immune Tolerance

13

may result in an autoimmune response, which occurs when antigen-specific T cells and antibodies mounted against the infection also recognize the self-epitope as foreign.7

References 1. Ocular immune responses. In: Opremcak EM, et al, eds. Intraocular Inflammation and Uveitis. Basic and Clinical Science Course. Singapore: American Academy of Ophthalmology; 2006:31-40. 2. Nussenblatt RB. Elements of the immune system and concepts of intraocular inflammatory disease pathogenesis. In: Nussenblatt RB, Whitcup SM, eds. Uveitis: Fundamentals and Clinical Practice. Philadelphia, PA: Mosby; 2004:3-46. 3. Carlson EC, Drazba J, Yang X, Perez VL. Visualization and characterization of inflammatory cell recruitment and migration through the corneal stroma in endotoxin-induced keratitis. Investig Ophthalmol Vis Sci. 2006;47:241-248. 4. Cursiefen C, Maruyama K, Jackson DG, Streilein JW, Kruse FE. Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Cornea. 2006;25:443-447. 5. Yokoi H, Streilein JW. Antigen-presenting cells are targets of regulatory T cells similar to those that mediate anterior chamber-associated immune deviation. Ocul Immunol Inflamm. 2004;12:101-114. 6. Dullforce PA, Garman KL, Seitz GW, Fleischmann RJ, Crespo SM, Planck SR, Parker DC, Rosenbaum JT. APCs in the anterior uveal tract do not migrate to draining lymph nodes. J Immunol. 2004;172:6701-6708. 7. Opremcak EM. Special topics in ocular immunology. In: Opremcak EM, ed. Intraocular Inflammation and Uveitis. Basic and Clinical Science Course. Singapore: American Academy of Ophthalmology; 2006:85-94.

Chapter 3

MECHANISMS OF IMMUNE EFFECTOR REACTIVITY

1. What is the main predictor of disease severity in bacterial endophthalmitis (Figure 3-1) due to Bacillus cereus?

Figure 3-1. Bacterial endophthalmitis.

A. B. C. D.

Bacterial size Bacterial toxin production Previous exposure to the bacteria Bacterial load

Answer: B. Bacterial toxin production by both gram-positive and gram-negative organisms greatly influences inflammatory cell infiltration and retinal cell cytotoxicity during endophthalmitis. Intravitreal injection of cell-free culture fluid containing B. cereus secretions elicits inflammation and loss of retinal function on electroretinogram comparable

15

16

Chapter 3

to that due to B. cereus organisms. Experimental models show that the inflammatory response is greatly diminished when bacteria are genetically altered not to produce toxin. Direct injection of lipopolysaccharide (LPS), the toxic component of gram-negative cell walls, induces a vigorous immune response. In high–toxin-producing bacterial strains such as B. cereus, a small bacterial load can produce a fulminant endophthalmitis. However, bacterial load plays a more important role in infections due to Staphylococcus aureus, a relatively less virulent organism. Antibiotic therapy without antitoxin or antiinflammatory agents may not be sufficient to treat endopthalmitis due to toxin-producing bacteria. Previous exposure to bacteria is unlikely a significant factor in the degree of ocular inflammation because innate immunity, which does not employ antigen memory, plays the key role in mounting a defense response during bacterial endophthalmitis.1,2 2. Phacolytic glaucoma (Figure 3-2) is characterized by which of the following cell types? A. B. C. D.

Macrophages Neutrophils Eosinophils Lymphocytes

Figure 3-2. Lens protein–laden macrophages in phacolytic glaucoma. Courtesy University of Wisconsin ocular pathology division.

Answer: A. Phacolytic glaucoma is caused by clogging of the trabecular meshwork by macrophages that are engorged with lens protein. This occurs when lens protein leaks through the intact capsule of a hypermature or morgagnian cataract. Histopathology of phacolytic glaucoma is notable for the absence of a neutrophilic infiltrate. The degree of inflammation in phacolytic glaucoma is less when compared to other forms of lensinduced uveitis.3 3. Propionibacterium acnes is a: A. Gram-positive aerobe B. Gram-positive anaerobe

Mechanisms of Immune Effector Reactivity

17

C. Gram-negative aerobe D. Gram-negative anaerobe Answer: B. Propionibacterium acnes is a ubiquitous gram-positive organism that may be introduced into the eye during cataract surgery. It can then exist in an indolent state within the sequestered anaerobic area between the intraocular lens implant and lens capsule, appearing as a white plaque. It causes a chronic uveitis that may flare up following capsulotomy with the Nd:YAG laser. P. acnes endophthalmitis can develop into a granulomatous inflammation that involves the rest of the lens capsule and the vitreous.3 4. Match the immune effector mechanism to the corresponding hypersensitivity types. A. Cell-mediated immunity B. Cytotoxic antibody response C. Anaphylactoid D. Immune complex reaction

1. Type I 2. Type II 3. Type III 4. Type IV

Answer: A:4, B:2, C:1, D:3. The classic Coombs and Gell classification of immune hypersensitivity reactions remains useful for understanding basic immune mechanisms. However, the classification was developed prior to the discovery of T-cell function, when all immunity was considered to be primarily antibody mediated. Also, real world immune responses involve multiple effector mechanisms, although one may predominate. Anaphylactoid immunity (type I) refers to immunoglobulin E (IgE)-mediated mast cell degranulation, which occurs during an acute allergic episode or atopy. The cytotoxic antibody response (type II) occurs when antibody binding to a cell membrane activates complement or cytotoxic killer cells to induce cell destruction, as may occur in ocular cicatricial pemphigoid, Hashimoto’s thyroiditis, or antibody-induced hemolytic anemia. The immune complex reaction (type III) is probably not important in most types of uveitis. However, the presence of circulating immune complexes, as well as antiretinal antibodies, has been demonstrated in patients with both isolated retinal and systemic vasculitis.4 Circulating antigen-antibody complexes can induce complement activation in tissue or increase vascular permeability when deposited in blood vessels. The acute Arthus reaction occurs when antigen-antibody complexes are formed locally, inducing acute and vigorous inflammation dominated by an infiltrate of neutrophils and monocytes. The delayed-type hypersensitivity mechanism (type IV) is the most relevant for understanding ocular inflammation. The predominantly cellular response is dominated by T cells and has many clinical manifestations in the eye, including sympathetic ophthalmia and corneal graft rejection.3 5. Which antibody class exists as multiple isotypes? A. B. C. D.

IgM IgE IgD IgG

18

Chapter 3

Answer: D. IgG exists as four isotypes (IgG1 to IgG4) and IgA exists as both IgA1 and IgA2. IgM, IgE, and IgD each occur as a single isotype. An antibody consists of two identical light chains (either κ or λ) and two identical heavy chains. The heavy chains are distinctive for each isotype. The immune system can produce different antibody isotypes with identical binding sites in response to a single antigenic epitope. Because each isotype has a different array of effector characteristics, a single antigen can stimulate multiple different antibody functions through the same binding site. For example, IgA can bind molecules that faciliate active transport of the antibody into mucosal secretions, while IgM and IgG3 are strong activators of complement.3 6. What function does the Fab portion of an antibody perform? A. B. C. D.

Attachment site for effector cells Definition of antibody class Antigen recognition and binding Attachment site for antibody transport out of B cells

Answer: C. Each antibody monomer has specific regions, or domains, which perform certain functions (Figure 3-3). The Fab (fragment antigen binding) domain serves as a site for antigen recognition, binding, and combining. B cells have the potential to form antibodies to innumerable antigens by somatic DNA recombination. This is expressed in the hypervariable regions that confer antibody specificity within the Fab domain. The Fc (fragment crystallizable) domain serves as the attachment site for effector molecules or secretory molecules, and for complement activation.3

Figure 3-3. Structure of antibody molecule.

Mechanisms of Immune Effector Reactivity

19

7. Which antibody class may form a pentamer? A. B. C. D.

IgM IgE IgA IgG

Answer: A. IgM may exist as a pentamer (Figure 3-4) or a hexamer. IgA1 and IgA2 are monomers in serum, but form dimers in mucosal secretions. An antibody monomer is approximately 150 to 180 kilodaltons (2.5 to 3 times the size of albumin).3

Figure 3-4. IgM pentamer.

8. A 35-year-old female with rheumatoid arthritis and uveitis receives monthly intravenous infusions of infliximab. She initially responds, but after 6 months of therapy, the effect of the medication has waned and she develops infusion reactions during treatment. She has likely developed an _______ to infliximab. A. B. C. D.

epitope idiotype isotype anti-idiotype

Answer: D. Infliximab is a chimeric mouse-human monoclonal antibody to tumor necrosis factor alpha. Approximately 30% of patients become refractory to treatment with infliximab. High levels of antibodies to infliximab have been detected in the serum of non-responders when compared to responders. An anti-idiotype refers to an antibody whose antigen is another antibody. These “anti-antibody antibodies” may develop in patients being treated systemically with biologics such as infliximab.5 Anti-idiotypes have

20

Chapter 3

not been found in patients treated with intravitreal injections of antibodies to vascular endothelial growth factor (ranibizumab), which may be due to immune privilege within the eye.6 An epitope is the fragment of foreign protein that is recognized as antigenic. An idiotype is a set of one or more antigenic domains of an antibody. An isotype is an antigenic marker that is similar among antibodies within a subclass of immunoglobulins. 9. Opsonization refers to the process in which: A. Antibody binds to a pathogen, thereby rendering it unable to infect cells. B. Antibody coats a pathogen and enhances its susceptibility to phagocytosis. C. Multiple antigens bind to multiple identical antigenic regions of the pathogen, resulting in precipitation of the complex out of solution. D. Antibodies bind to an infected host cell, inducing cytolysis. Answer: B. Opsonization occurs when either antibodies or complement factor 3b coats an antigen, thereby marking it for phagocytosis by macrophages. Neutralization refers to the process in which antibody binds a pathogen and blocks its ability to infect host cells. Agglutinization occurs when multiple antigens bind to identical antigenic regions of a pathogen and the antigen-antibody complex becomes so large it precipitates out of solution. Antibodies may induce cell lysis when bound to a cell membrane by activating the formation of a pore called the membrane attack complex, part of the complement cascade (type II hypersensitivity).3 10. Which molecule has been identified as an antigen in the inflammatory process underlying cancer-associated retinopathy? A. B. C. D.

Recoverin Acetylcholine esterase Retinal S-antigen Carcinoembryonic antigen

Answer: A. Recoverin has been identified as an antigen involved in cancer-associated retinopathy (CAR). Recoverin is a normal protein important for the function of photoreceptors, but it can also be produced by small cell carcinoma cells. Circulating recoverin may induce the formation of antibodies, which can passively diffuse into the retina, leading to retinal degeneration and depressed rod and cone function on electroretinography.3 A similar loss of retinal function is seen with interphotoreceptor retinoid binding protein (IPRB)-induced experimental autoimmune uveitis.7 Myasthenia gravis is due to the development of antibodies to acetylcholine esterase receptors. Systemic immunization with S-antigen, a protein unique to the retina and pineal gland, induces experimental autoimmune uveitis. However, antibodies to S-antigen have not been clearly identified as a cause of uveitis in humans. Melanoma-associated retinopathy (MAR) occurs in cases of metastatic melanoma and is associated with the acute onset of night blindness and a decreased b-wave on electroretinogram. The inciting antigen for MAR remains undetected.

Mechanisms of Immune Effector Reactivity

21

11. The Goldmann-Witmer coefficient: A. Is used to determine the degree to which a specific antibody is concentrated within intraocular fluid. B. Is significant when >5.0. C. Is more sensitive and specific for cytomegalovirus infection than for herpes zoster infection. D. Is independent of total serum immunoglobulin levels. Answer: A. The Goldmann-Witmer coefficient is a useful tool used to determine whether a specific antibody (Abs) is concentrated within the eye when compared to total antibody (Abt) levels, albumin, or an antibody to a ubiquitous antigen such as mumps virus. It is calculated as the ratio of Abs in intraocular fluid/Abs in serum compared to Abt in intraocular fluid/Abt in serum. A ratio of >3.0 is considered clinically significant.3 The Goldmann-Witmer coefficient is especially useful in determining the etiology of atypical retinitis due to herpes zoster virus, herpes simplex virus, or Toxoplasma gondii. The Goldmann-Witmer coefficient is more sensitive and specific for retinitis due to herpes zoster than for cytomegalovirus.8 For example, to detect significant levels of toxoplasma IgG in the aqueous humor, the Goldmann-Witmer coefficient could be calculated as follows: (Toxo IgGaqueous/Toxo IgGserum) (Total IgGaqueous/Total IgGserum)

12. Phacoantigenic endophthalmitis is characterized by all of the following except: A. Inner zone of neutrophilic infiltrate surrounding the lens material B. The presence of antibodies to lens crystallin C. Outer zone of macrophages, epithelioid cells, and/or giant cells at the site of disrupted capsule D. An atypical immune response to lens material likely due to aberrant immune tolerance Answer: C. Phacoantigenic endophthalmitis occurs when lens material induces vigorous inflammation in the setting of a disrupted lens capsule, as may occur due to surgery or trauma. Histologically, it is characterized by three zones: an inner zone of neutrophilic infiltrate surrounding the lens material, a second zone of macrophages or their derivatives surrounding the site of capsule injury, and an outer fibrotic zone containing plasma cells. Antibodies directed against crystalline activate complement and neutrophilic infiltration.3 See Chapter 10 for further discussion.

22

Chapter 3

13. Th2-mediated delayed-type hypersensitivity (DTH)-mediated inflammation occurs in which of the following conditions? A. B. C. D.

Sympathetic ophthalmia Toxocara canis granuloma Skin reaction to purified protein derivative (PPD) Chronic corneal graft rejection

Answer: B. The retinal granuloma associated with Toxocara canis infection is an example of Th2-mediated delayed-type hypersensitivity (Figure 3-5). Delayed hypersensivity (type IV) is important in many types of ocular inflammation. Th1 and Th2 refer to 2 subsets of T helper cells that mediate delayed hypersensitivity, and are characterized by their different array of secreted cytokines and the cell types they activate. Sympathetic ophthalmia, the PPD skin reaction, chronic corneal graft rejection, and phlyctenulosis are examples of Th1 responses. The cytokines interferon (IFN)-γ and tumor necrosis factor (TNF)-β activate macrophages, a major effector cell of Th1-mediated inflammation. The Th2 response induces the synthesis of IgE and the activation of eosinophils through the secretion of interleukin (IL)-4 and IL-5. Besides responding to parasitic infections such as Toxocara canis, Th2 cells are responsible for the late phases of allergic reactions, asthma, and atopy.3

Figure 3-5. Toxocariasis. There is an eosinophilic predominance of the infiltrate surrounding the inflammatory nidus in the anterior vitreous. Courtesy of Morton E. Smith, MD.

References 1. Callegan MC, Booth MC, Jett BD, Gilmore MS. Pathogenesis of gram-positive bacterial endophthalmitis. Infect Immun. 1999;67:3348-3356. 2. Callegan MC, Engelbert M, Parke DW 2nd, Jett BD, Gilmore MS. Bacterial endophthalmitis: epidemiology, therapeutics, and bacterium-host interactions. Clin Microbiol Rev. 2002;15:111-124.

Mechanisms of Immune Effector Reactivity

23

3. Mechanisms of immune effector reactivity. In: Opremcak EM, et al, eds. Intraocular Inflammation and Uveitis. Basic and Clinical Science Course. Singapore: American Academy of Ophthalmology; 2006:41-84. 4. Dumonde DC, Kasp-Grochowska E, Graham E, Sanders MD, Faure JP, de Kozak Y, van Tuyen V. Anti-retinal autoimmunity and circulating immune complexes in patients with retinal vasculitis. Lancet. 1982;2:787-792. 5. Van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink G, Dijkmans BA, Aarden LA. Imaging and serum analysis of immune complex formation of radiolabeled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis. 2006;66:253-256. 6. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:623632. 7. Waldrep JC, Ramanadham S, Wood JD, Donoso LA. Temporal analysis of retinal function in IRBP peptideinduced experimental autoimmune uveoretinitis (EAU). Region Immunol. 1990-1991;3:247-253. 8. Abe T, Tsuchida K, Tamai M. A comparative study of the polymerase chain reaction and local antibody production in acute retinal necrosis syndrome and cytomegalovirus retinitis. Graefes Arch Clin Exp Ophthalmol. 1996;234:419-424.

Chapter 4

SIGNS, SYMPTOMS, AND CLASSIFICATION OF UVEITIS

1. Which uveitic disease is most commonly associated with hypopyon? A. B. C. D.

Glaucomatocyclitic crisis Fuch’s heterochromic iridocyclitis HLA-B27–associated uveitis Juvenile idiopathic arthritis

Answer: C. Human leukocyte antigen (HLA)-B27–associated uveitis, Behçet’s syndrome, and drug-induced uveitis are the noninfectious anterior uveitic diseases most often associated with hypopyon. Glaucomatocyclitic crisis (Posner-Schlossman syndrome) is characterized by episodic inflammation accompanied by elevated intraocular pressure. Fuchs heterochromic iridocyclitis typically manifests as chronic unilateral lowgrade anterior uveitis that is often asymptomatic. Juvenile idiopathic arthritis (JIA)-associated uveitis often presents as significant anterior segment inflammation with relatively white conjunctiva.1 2. What is the most common cause of visual loss due to intermediate uveitis? A. B. C. D.

Vitreous debris Cystoid macular edema Cataract Epiretinal membrane

Answer: B. Intermediate uveitis refers to inflammation mainly involving the vitreous cavity. Cystoid macular edema (CME) (Figure 4-1) is the leading cause of visual loss in patients with chronic intermediate uveitis. Sixty percent of patients with intermediate uveitis have CME, 40% of whom have resulting visual acuity ≤20/60. In patients who develop blindness or visual impairment due to intermediate uveitis, CME is the cause in

25

26

Chapter 4

85%.2 Patients may often be symptomatic from floaters caused by clumps of vitreous cell. Cataracts are also commonly seen in intermediate uveitis. They may result from uveitis or from corticosteroid therapy for the disease. Epiretinal membranes may form after chronic inflammation or CME, and can cause loss of visual acuity, distortion, and macropsia.

Figure 4-1. Inflammatory cystoid macular edema. Late leakage in a petalloid pattern and optic nerve hyperfluorescence are seen.

3. Which of the following typically presents as retinochoroiditis? A. B. C. D.

Toxoplasmosis Vogt-Koyanagi-Harada disease Multiple evanescent white-dot syndrome Systemic lupus erythematosus

Answer: A. Toxoplasmosis is an example of retinochoroiditis. The retina is the primary site of inflammation, with secondary involvement of the choroid. Vogt-Koyanagi-Harada (VKH) disease is a type of bilateral panuveitis usually associated with serous retinal detachment and inflammation of the choriocapillaris. Multiple evanescent white-dot syndrome (MEWDS) is an example of chorioretinitis; the choroid is primarily affected, with secondary involvement of the retina. MEWDS is typically unilateral and self-limited, and may have an associated mild vitritis. Systemic lupus erythematosus (SLE) typically presents as bilateral retinal vasculitis or as cotton wool spots indicating retinal microangiopathy; however, retinitis and/or choroiditis may also occur. 4. According to the Standardization of Uveitis Nomenclature (SUN) guidelines, panuveitis refers to inflammation involving at least the: A. B. C. D.

Anterior chamber and vitreous Vitreous and retina Vitreous, retina, and choroid Anterior chamber, vitreous, and retina and/or choroid

Signs, Symptoms, and Classification of Uveitis

27

Answer: D. The SUN classifications are a standardized nomenclature for categorizing the anatomic subgroups of uveitis. According to SUN, panuveitis refers to ocular inflammation that is present in the anterior chamber, vitreous, and retina and/or choroid.3 The inflammation typically does not predominate at one site. Examples of panuveitis include Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, some cases of sarcoidosis, and endophthalmitis. 5. All of the following are considered types of intermediate uveitis except: A. B. C. D.

Anterior cyclitis Pars planitis Hyalitis Vasculitis with associated vitritis

Answer: A. Intermediate uveitis is inflammation that primarily involved the vitreous cavity. Pars planitis is a subset of idiopathic intermediate uveitis where snowballs and pars plana snowbank forms. Intermediate uveitis in the presence of an associated systemic disease or infection (eg, multiple sclerosis and Lyme disease) is not considered pars planitis. Hyalitis is an older term for vitritis. The presence of macular edema, peripheral vascular sheathing, or neovascularization with intermediate uveitis does not affect the classification. Anterior cyclitis (inflammation of the ciliary body) is classified as anterior uveitis, even if spillover cell is seen in the anterior vitreous.3 6. The SUN classification designates 3+ cell as __________ cells per 1 mm by 1-mm high-powered field. A. B. C. D.

16-25 26-35 26-50 Too numerous to count, but without hypopyon

Answer: C. The SUN group defined clinical measurements of inflammation for the purpose of standard reporting of clinical data. The classification of anterior chamber cell is as follows: 3 Grade 0 0.5+ 1+ 2+ 3+ 4+

Cells per high-powered field 50

28

Chapter 4

Anterior chamber flare is measured as follows: Grade 0 1+ 2+ 3+ 4+

Description None Faint Moderate (iris and lens details clear) Marked (iris and lens details hazy) Intense (fibrin or plastic aqueous)

7. Uveitic disease remission is defined as when uveitis is inactive for A. B. C. D.

≥ 3 months without medications ≥ 3 months with medications ≥ 6 months without medications ≥ 6 months with medications

Answer: A. Disease remission refers to inactive uveitis for ≥3 months after treatment is discontinued. Inactive disease is defined as no cells in the anterior chamber. Disease is considered to be worsening when the inflammation (anterior chamber cells, vitreous haze) becomes ≥2 grades more active, or if the disease intensifies from 3+ to 4+. Conversely, disease improvement is defined as lessening of inflammation ≥2 grades, or decreases to grade 0.3 8. A 33-year-old Caucasian male with HLA-B27–positive ankylosing spondylitis has flares of anterior uveitis lasting 1 month every 6 to 8 months over the past 3 years. His uveitis is quiet between flares. He presents with a 3-day history of unilateral ciliary injection and 2+ anterior chamber cell, and no change in vision. His disease course is illustrated below:

Quiescent disease Active disease

Signs, Symptoms, and Classification of Uveitis

29

His disease would be classified as: A. B. C. D.

Limited and recurrent Limited and chronic Persistent and recurrent Persistent and chronic

Answer: A. This patient’s uveitis would be considered limited and recurrent. Limited disease is present for ≤3 months, whereas persistent disease occurs for >3 months’ duration. Recurrent disease is defined as repeated episodes that occur ≥3 months apart, and are separated by periods of inactivity not requiring treatment. Chronic disease is persistent inflammation that recurs in