- •Uveitis
- •Foreword
- •Preface
- •Dedication
- •Acknowledgments
- •Elements of the Immune System and Concepts of Intraocular Inflammatory Disease Pathogenesis
- •Elements of the immune system
- •Macrophages/monocytes
- •Dendritic cells
- •T cells
- •Major subsets of T cells
- •Cytokines
- •T-cell subsets
- •T-regulatory cells
- •T-cell receptor
- •Chemokines
- •Thymic expression and central immune tolerance
- •B cells
- •Classes of Immunoglobulin
- •Other cells
- •Mast Cells
- •Eosinophils
- •Neutrophils
- •Resident Ocular Cells
- •Complement system
- •Cellular interactions: hypersensitivity reactions
- •Classic immune hypersensitivity reactions
- •Type I
- •Type II
- •Type III
- •Type IV
- •Type V
- •Concepts of disease pathogenesis
- •Immune characteristics of the eye
- •Absence of lymphatic drainage
- •Intraocular microenvironment
- •Anterior Chamber-Associated Immune Deviation (ACAID)
- •Fas-Fas Ligand Interactions and Programmed Cell Death (Apoptosis)
- •Resident Ocular Cells and Immune System
- •Cytokines and Chemokines and the Eye
- •Oral Tolerance
- •Choroidal circulation and anatomy
- •Retina
- •Immunogenetics
- •Class I antigens
- •Class II and class III antigens
- •Histocompatibility lymphocyte antigens
- •Single-nucleotide polymorphisms (SNPs)
- •Epigenetics
- •Immune complex-mediated disease
- •Gene expression profiling
- •Tissue damage in the eye
- •T-cell responses and autoimmunity
- •T-cell receptor and the expression of disease
- •Ocular autoimmunity
- •Uveitogenic antigens
- •Retinal S-Antigen (Arrestin)
- •Interphotoreceptor Retinoid-Binding Protein
- •Recoverin
- •Bovine Melanin Protein
- •Rhodopsin
- •Phosducin
- •Tyrosinase
- •Other Antigens
- •Endotoxin and Other Bacterial Antigens
- •Importance of Antigen Studies
- •Cell adhesion molecules and their role in lymphocyte homing and in disease
- •Immune responses to invading viruses and parasites
- •Suggested Readings
- •References
- •Medical History in the Patient with Uveitis
- •References
- •Sample Uveitis Questionnaire
- •FAMILY HISTORY
- •SOCIAL HISTORY
- •PERSONAL MEDICAL HISTORY
- •MEDICAL HISTORY
- •Examination of the Patient with Uveitis
- •Visual acuity
- •External examination
- •Pupils and extraocular muscles
- •Intraocular pressure measurement
- •Slit-lamp biomicroscopy
- •Conjunctiva
- •Cornea
- •Keratic Precipitates
- •Other Corneal Findings
- •Anterior chamber
- •Iris
- •Anterior chamber angle
- •Lens
- •Vitreous
- •Retina and choroid
- •Optic nerve
- •References
- •Development of a Differential Diagnosis
- •Forming a differential diagnosis
- •Classifying uveitis
- •Is the disease acute or chronic?
- •Is the inflammation granulomatous or nongranulomatous?
- •Is the disease unilateral or bilateral?
- •Where is the inflammation located in the eye?
- •What are the demographics of the patient?
- •What associated symptoms does the patient have?
- •What associated signs are present on physical examination?
- •What is the time course of the disease and response to previous therapy?
- •Case 4-1
- •Case 4-2
- •References
- •Diagnostic Testing
- •Pretest likelihood of disease
- •Receiver operating characteristic (ROC) curve
- •Diagnostic tests for uveitis
- •Laboratory tests
- •Image analysis
- •Skin testing
- •Tissue samples
- •Ancillary ophthalmic tests
- •Electrophysiology
- •Laser interferometry
- •Fluorescein angiography
- •Indocyanine green
- •Laser flare photometry
- •Optical coherence tomography
- •High-frequency ultrasound biomicroscopy and multifrequency ultrasound
- •Fundus autofluorescence
- •Other diagnostic tests
- •Polymerase chain reaction (PCR)
- •Rapid tests for herpes simplex and herpes zoster
- •Bone mineral density studies
- •Genetic testing for steroid-induced glaucoma
- •Neurologic tests
- •References
- •Evidence-Based Medicine in Uveitis
- •Study design
- •Clinical trials in uveitis
- •References
- •Philosophy, Goals, and Approaches to Medical Therapy
- •Goals and philosophy
- •Pain, photophobia, and discomfort
- •Degree and location of inflammatory disease
- •Evaluation of visual acuity and prospect of reversibility
- •Follow-up procedures and standardization of observations
- •General health and age of patient
- •Patient reliability, preferences, and understanding
- •Nonsurgical therapeutic options
- •Corticosteroids
- •Mode of Action
- •Preparations, Dosage Schedules, and Complications
- •Ozurdex.
- •Secondary Effects
- •Cytotoxic agents
- •Alkylating agents
- •Mode of Action
- •Indications and Dosages
- •Secondary Effects
- •Antimetabolites
- •Azathioprine
- •Mode of Action
- •Indications and Dosages
- •Secondary Effects
- •Mycophenolate mofetil
- •Methotrexate
- •Mode of Action
- •Indications and Dosages
- •Secondary Effects
- •Ciclosporin
- •Mode of Action
- •Dosages and Indications
- •Secondary Effects
- •Tacrolimus
- •Mode of Action
- •Indications and Dosages
- •Secondary Effects
- •Lx 211 (Voclosporin)
- •Rapamycin
- •Mode of Action
- •Indications and Dosages
- •Toxicity
- •Antibodies and monoclonal antibodies
- •Daclizumab
- •Etanercept
- •Infliximab (Remicade)
- •Adalimumab (Humira)
- •Efalizumab (Raptiva)
- •Rituximab (Rituxan)
- •Anakinra (Kineret)
- •Alemtuzumab (Campath-1H)
- •Abatacept (Orencia)
- •Intravenous immunoglobulin therapy
- •Oral tolerance
- •Interferon-α
- •Antiviral therapy
- •Aciclovir
- •Ganciclovir
- •Valaciclovir
- •Famciclovir
- •Foscarnet
- •Combined ganciclovir and foscarnet
- •Cidofovir
- •Fomivirsen
- •Colchicine
- •Mode of Action
- •Indications and Dosages
- •Secondary Effects
- •Mydriatic and cycloplegic agents
- •Antitoxoplasmosis therapy
- •Other therapeutic approaches
- •Immunostimulators
- •Plasmapheresis
- •Nonsteroidal antiinflammatory agents
- •References
- •Role of Surgery in the Patient with Uveitis
- •Considerations
- •Removal of band keratopathy
- •Corneal transplantation
- •Cataract surgery
- •Glaucoma surgery
- •Treatment of vitreoretinal disease
- •Laser treatment
- •Photodynamic therapy
- •Diagnostic surgery
- •Anterior chamber paracentesis
- •Chorioretinal biopsy
- •Subretinal surgery
- •Case 8-1
- •References
- •Bacterial and Fungal Diseases
- •Introduction
- •Leprosy
- •Clinical findings
- •Immunology and pathology
- •Therapy
- •Tuberculosis
- •Systemic disease
- •Ocular disease
- •Diagnosis
- •Therapy
- •Other bacterial infections
- •Brucellosis
- •Whipple’s disease
- •Treatment and prognosis
- •Chronic granulomatous disease
- •Fungal disease
- •Neuroretinitis
- •References
- •Spirochetal Diseases
- •Spirochetal infections and the eye
- •Spirochetes
- •Definition
- •Venereal treponemal diseases
- •Syphilis
- •Etiology and Epidemiology
- •Clinical Manifestations
- •Primary syphilis.
- •Secondary syphilis.
- •Latent syphilis.
- •Tertiary syphilis.
- •Benign tertiary syphilis.
- •Cardiovascular syphilis.
- •Neurosyphilis.
- •Congenital syphilis.
- •Ocular Manifestations
- •Diagnosis
- •Prognosis
- •Treatment
- •General recommendations.
- •Approach to Syphilis in Patients with AIDS
- •Nonvenereal treponematoses
- •Endemic syphilis
- •Etiology and Epidemiology
- •Clinical Manifestations
- •Ocular Manifestations
- •Diagnosis
- •Prognosis
- •Treatment
- •Yaws and pinta
- •Ocular Manifestations
- •Diagnosis
- •Prognosis
- •Treatment
- •Borrelia infection
- •Lyme disease
- •Etiology and Epidemiology
- •Clinical Manifestations
- •Ocular Manifestations
- •Diagnosis
- •Prognosis
- •Treatment
- •Relapsing fever
- •Etiology and Epidemiology
- •Clinical Manifestations
- •Ocular Manifestations
- •Diagnosis
- •Prognosis
- •Treatment
- •Leptospirosis
- •Etiology and Epidemiology
- •Clinical Manifestations
- •Ocular Manifestations
- •Weil’s disease
- •Diagnosis
- •Prognosis
- •Treatment
- •Case 10-1
- •References
- •Acquired Immunodeficiency Syndrome
- •Human immunodeficiency virus
- •Epidemiology
- •Diagnosis
- •HIV disease
- •HIV therapy
- •Ocular manifestations of HIV infection
- •Ocular infection
- •Cytomegalovirus retinitis
- •Progression
- •CMV retinitis in the era of highly active antiretroviral therapy
- •Treatment
- •Intravitreal ganciclovir implant
- •Current therapeutic approach to CMV retinitis in the era of HAART
- •Retinal detachment
- •Prognosis
- •Immune recovery uveitis
- •Herpes zoster
- •Pneumocystis jirovecii choroiditis
- •Mycobacterium avium-intracellulare choroiditis
- •Other diseases
- •Drug-related ocular inflammation
- •Case 11-1
- •Case 11-2
- •References
- •Acute retinal necrosis
- •Epidemiology
- •Clinical features
- •Etiology
- •Differential diagnosis
- •Therapy
- •Progressive outer retinal necrosis
- •Diagnosis
- •Differential diagnosis
- •Etiology
- •Therapy
- •Case 12-1
- •Case 12-2
- •References
- •Other Viral Diseases
- •Herpes simplex virus kerititis and keratouveitis
- •Pathogenesis
- •Diagnosis
- •Treatment
- •Herpes zoster ophthalmicus
- •Treatment
- •West Nile virus
- •Epidemiology
- •Diagnosis
- •Clinical description
- •Ophthalmic manifestations
- •Treatment
- •Prognosis
- •Other viral infections
- •Human T-lymphotropic virus type I
- •Case 13-1
- •References
- •Ocular Toxoplasmosis
- •Organism
- •Clinical manifestations
- •Systemic
- •Ocular
- •Decreased Vision
- •Loss of Vision
- •Effects in immunocompromised host
- •Histopathology and immune factors
- •Immune response
- •Inflammatory response
- •Methods of diagnosis
- •Pregnancy
- •Other methods
- •Congenital versus acquired disease
- •Therapy
- •Additional therapeutic approaches
- •Case 14-1
- •Case 14-2
- •Case 14-3
- •Case 14-4
- •References
- •Ocular Histoplasmosis
- •Systemic findings
- •Ocular appearance
- •‘Histo’ spots
- •Maculopathy
- •Peripapillary pigment changes
- •Clear vitreous
- •Etiology and immunology
- •Nonsurgical therapies
- •Laser therapy
- •Subretinal surgery
- •References
- •Toxocara canis
- •Ocular manifestations
- •Histopathology and immune factors
- •Enzyme-linked immunoabsorbent assay
- •Treatment
- •Case 16-1
- •References
- •Onchocerciasis and Other Parasitic Diseases
- •Onchocerciasis
- •Clinical appearance
- •Immune characteristics
- •Therapy
- •Giardiasis
- •Ophthalmomyiasis
- •Cysticercosis
- •Caterpillar hairs
- •Amebiasis
- •Diffuse unilateral subacute neuroretinitis (DUSN)
- •Malaria
- •Seasonal hyperacute panuveitis (SHAPU)
- •References
- •Postsurgical Uveitis
- •Acute bacterial endophthalmitis
- •Chronic bacterial endophthalmitis
- •Fungal endophthalmitis
- •Endogenous endophthalmitis
- •Lens-induced uveitis
- •Toxic anterior segment syndrome (TASS)
- •Laser-induced uveitis
- •Case 18-1
- •References
- •Anterior Uveitis
- •Epidemiology
- •Clinical description
- •Idiopathic anterior uveitis
- •Diagnostic workup
- •Treatment
- •HLA-B27–associated anterior uveitis
- •Epidemiology
- •Demographics and clinical findings
- •Etiology
- •HLA-B27–associated anterior uveitis with systemic disease
- •Ankylosing spondylitis
- •Etiology
- •Treatment
- •Reactive arthritis (Reiter’s syndrome)
- •Juvenile idiopathic arthritis
- •Diagnosis
- •Pathology
- •Differential diagnosis
- •Treatment and prognosis
- •Psoriatic arthropathy
- •Inflammatory bowel disease
- •Whipple’s disease
- •Disease associations
- •Fuchs’ heterochromic iridocyclitis
- •Etiology
- •Treatment and prognosis
- •Kawasaki disease
- •Tubulointerstitial nephritis and uveitis syndrome (TINU)
- •Pathogenesis
- •Glaucomatous cyclitic crisis
- •Schwartz syndrome
- •Anterior segment ischemia
- •Lens-induced uveitis
- •Anterior uveitis associated with AIDS
- •Other disease associations
- •References
- •Scleritis
- •Episcleritis
- •Scleritis
- •Disease associations
- •Other causes of scleritis
- •Diagnostic testing
- •Pathogenesis
- •Differential diagnosis
- •Treatment
- •References
- •Intermediate Uveitis
- •Epidemiology
- •Clinical manifestations
- •Prognosis
- •Differential diagnosis
- •Multiple sclerosis
- •Etiology
- •Treatment
- •Corticosteroids
- •Immunosuppressive agents
- •Surgery
- •Case 21-1
- •Case 21-2
- •References
- •Sarcoidosis
- •Epidemiology
- •Etiology
- •Clinical manifestations
- •Anterior uveitis
- •Posterior segment findings
- •Systemic involvement
- •Pathology
- •Diagnosis
- •Treatment
- •Case 22-1
- •References
- •Sympathetic Ophthalmia
- •Clinical appearance and prevalence
- •Classic presentation
- •Sequelae
- •Tests and immunologic characteristics
- •Dalen–fuchs nodules
- •Preservation of the choriocapillaris
- •Therapy
- •Corticosteroids
- •Immunosuppressive agents
- •Case 23-1
- •Case 23-2
- •References
- •Vogt–Koyanagi–Harada Syndrome
- •Clinical aspects
- •Systemic findings
- •Ocular findings
- •Course of disease
- •Laboratory tests, etiology, and histopathology
- •Antigen-specific and immune responses
- •Vogt–Koyanagi–Harada syndrome versus sympathetic ophthalmia
- •Therapy
- •Cataract extraction
- •Case 24-1
- •Case 24-2
- •References
- •Birdshot Retinochoroidopathy
- •Clinical manifestations
- •Ocular examination and ancillary clinical tests
- •Tests, histology and etiology
- •Therapy
- •Case 25-1
- •Case 25-2
- •References
- •Behçet’s Disease
- •Clinical manifestations
- •Oral aphthous ulcers
- •Skin lesions
- •Genital ulcers
- •Ocular disease
- •Retinal disease
- •Complications
- •Minor criteria
- •Arthritis
- •Vascular alterations
- •Neurologic involvement (neuro-Behçet’s disease)
- •Immunologic and histologic considerations
- •Role of T cells (but other cells count too!)
- •HLA typing and single nucleotide polymorphisms (SNPs)
- •Therapy
- •Systemic corticosteroids
- •Cytotoxic and antimetabolic agents
- •Colchicine
- •Interferon-α
- •Ciclosporin and tacrolimus (FK506)
- •Anti-TNF therapy (infliximab)
- •Other approaches
- •Case 26-1
- •Case 26-2
- •Case 26-3
- •References
- •Retinal Vasculitis
- •Clinical characteristics
- •Ocular vasculitic disorders without systemic disease
- •Eales’ disease
- •Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN syndrome)
- •Frosted branch angiitis
- •Scleritis
- •Ocular vasculitic disorders with systemic disease
- •Systemic lupus erythematosus
- •Polyarteritis nodosa
- •Wegener’s granulomatosis
- •Whipple’s disease
- •Inflammatory bowel disease
- •Autoantibodies to Sjögren’s syndrome A antigen
- •Retinal vein occlusion
- •Relapsing polychondritis
- •Viral diseases
- •Multiple sclerosis
- •Tuberculosis
- •Rheumatoid arthritis
- •Kikuchi–Fujimoto disease
- •Susac syndrome
- •Sweet syndrome
- •References
- •Serpiginous Choroidopathy
- •Clinical features
- •Pathology
- •Etiology
- •Differential diagnosis
- •Therapy
- •Case 28-1
- •Case 28-2
- •Case 28-3
- •References
- •White-Dot Syndromes
- •Multiple evanescent white-dot syndrome
- •Clinical findings
- •Laboratory findings
- •Therapy
- •Multifocal choroiditis and panuveitis
- •Clinical findings
- •Punctate inner choroidopathy
- •Laboratory findings
- •Therapy
- •Acute retinal pigment epitheliitis
- •Clinical findings
- •Laboratory findings
- •Therapy
- •Acute posterior multifocal placoid pigment epitheliopathy
- •Clinical findings
- •Etiology
- •Therapy
- •Subretinal fibrosis and uveitis syndrome
- •Clinical findings
- •Laboratory findings
- •Therapy
- •Acute zonal occult outer retinopathy (AZOOR) and the azoor complex diseases
- •Case 29-1
- •Case 29-2
- •Case 29-3
- •References
- •Masquerade Syndromes
- •Intraocular lymphoma
- •Non-Hodgkin’s lymphoma of central nervous system
- •Diagnosis
- •Treatment
- •Systemic Non-Hodgkin’s lymphoma metastatic to eye
- •Lymphoid hyperplasia of uvea
- •Other malignant processes manifesting as uveitis
- •Paraneoplastic syndromes
- •Multiple sclerosis
- •Other nonmalignant conditions
- •References
- •Introduction
- •Age-related macular degeneration
- •Animal work
- •Animal laser model
- •Ccl2 and Ccr2 knockout model
- •Ccl2 and Cx3cr1 double knockout model
- •CEP induced AMD-like disease
- •Human data
- •Autoimmunity
- •Gene associations
- •Macrophages and other cells
- •Histopathology
- •The downregulatory immune environment
- •Should we consider immunotherapy?
- •Diabetic retinopathy
- •Diabetes and the immune process
- •Animal work
- •Human observations
- •Can we begin to think about immune therapy for diabetes and diabetic retinopathy?
- •Glaucoma
- •Autoantibodies and glaucoma
- •Cellular immunity and glaucoma
- •Can immune intervention help alter the course of glaucoma?
- •References
- •Index
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14 |
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(number) |
12 |
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10 |
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improvement |
8 |
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6 |
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observedof |
4 |
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2 |
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Lines |
0 |
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–2 |
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–4 |
–4 |
–1 |
2 |
5 |
8 |
11 |
14 |
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Lines of predicted improvement (number) |
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|
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Figure 5-3. Linear regression plot of number of lines of predicted improvement using laser interferometer (slope = 0.40, intercept = 2.96) and observed improvement after ciclosporin therapy (R = 0.53). Outer dotted lines represent 95% confidence limits. (From Palestine AG, Alter GJ, Chan CC, et al. Laser interferometry and visual prognosis in uveitis. Ophthalmology 1985; 92: 1567–9.)
three-line or better improvement in vision compared with the standard measurement of visual acuity (Fig. 5-3). In contrast, only 52% of the patients in whom laser interferometry showed less than a three-line improvement later showed improvement with ciclosporin therapy. There was a moderate correlation between the predicted number of lines of improvement with the laser interferometer and the number of lines actually improved with therapy (R = 0.59, p < 0.001). We therefore perform a laser interferometry visual acuity determination on all patients with uveitis having poor vision. If the laser interferometry acuity is better than the visual acuity measured on an ETDRS chart, we expect to see an improvement in visual acuity with therapy even in patients with cystoid macular edema.
Fluorescein angiography
Fluorescein angiography is an invaluable aid in evaluating the numerous changes in uveitic eyes. The alterations seen are variable and frequently require the observer to evaluate the angiogram for some time before a satisfactory interpretation is made. Some of the more frequently noted ocular changes that are highlighted with fluorescein angiography are listed in Box 5-3. Corresponding stereo photographs may be helpful in establishing the level at which the pathologic condition in the eye is occurring.
Macular edema is one of the major causes of reduced vision in many types of intraocular inflammatory disease. The cause of this is not absolutely known. We assume, logically, that it is due to a swelling of the retinal layers, which disrupts the intimate association of the retinal elements that results in crisp vision or distorts the alignment of the photoreceptors. However, we know that patients with angiographic evidence of mild or moderate macular edema can have good visual acuity. Further, we have been most struck
Ancillary ophthalmic tests
Box 5-3 Major fluorescein angiographic findings
in uveitis
Cystoid macular edema
Subretinal neovascular membranes
Disc leakage
Late staining of retinal vessels
Neovascularization of retinal vessels
Retinal vascular capillary dropout and reorganization
Retinal pigment epithelium perturbations
that patients can have an improvement of vision after therapeutic intervention, yet the fluorescein angiogram shows no change in the leakage of fluorescein. Because late leakage seen on angiography is not strongly correlated with a drop in vision, we explored other possible alterations that might be evaluated with fluorescein angiography. We hypothesized that retinal thickening and not the leakage of fluorescein into the retina was one of the major causes of the decrease in vision. We measured the amount of retinal thickening with the use of standard angiographic photos taken early in the angiogram (Fig. 5-4).39 We noted a strong correlation between retinal thickening and the visual acuity of these eyes (Figs 5-5 and 5-6). The amount of dye leakage in the late phase of the angiogram did not, however, correlate well with visual acuity. More recently, the OCT has been used to assess macular edema in patients with uveitis. Nevertheless, useful information about the vascular morphology and the presence of vasculitis can best be assessed by fluorescein angiography.
In reading the angiogram, it is important to look at the early frames to best visualize the microvasculature surrounding the fovea. To best enhance the stereo effect, we have found it useful to use a ‘map reader’. If one wishes to compare sequential fluorescein angiograms, the photos must be taken with the Allan separator always set at the same value. Differences in the separator settings can induce an artificial increase or decrease in the height of lesions noted when the photos are viewed with the stereo viewer.
Many inflammatory eye diseases are thought to be associated with abnormalities in choroidal blood flow. Unfortunately, the excitation and fluorescence of fluorescein dye are absorbed and scattered by the retinal pigment. In addition, fluorescein dye rapidly leaks from the fenestrated vessels of the choriocapillaris, leading to a diffuse background choroidal fluorescence. Both of these factors combine to obscure a detailed analysis of the choroidal blood flow with fluorescein angiography.
Indocyanine green
Indocyanine green (ICG) is a water-soluble tricarbocyanine dye that was first used to measure cardiac output.40 Unlike fluorescein, ICG is almost completely bound to plasma proteins and does not leak from normal retinal or choroidal vessels. Importantly, the pigment of the retinal pigment epithelium and neurosensory retina does not significantly block the choroidal fluorescence when ICG dye is illuminated with infrared light. ICG fluorescence is also more easily detected through hemorrhage. As a result, ICG angiography, which is recorded on either infrared photography or video angio graphy, is a useful tool for demonstrating abnormalities of
65
Part 2 • Diagnosis
Chapter 5 Diagnostic Testing
A
B
C
D
Figure 5-4. Standard stereoscopic fluorescein angiographic photographs showing varying degrees of macular thickening. A, ‘Normal’. B–D, In order of increasing macular thickening. A strong light source should be placed under photographs, and macular thickening can be best evaluated using ‘map reader’ (Air Photo Supply, model PS-2 stereo viewer), which will yield maximum stereopsis. (From Nussenblatt RB, Kaufman SC, Palestine AG, et al. Macular thickening and visual acuity. Ophthalmology 1987; 94: 1134–9.)
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