The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology, 4th Ed.

10. Retina and Choroid

Trauma

Hemorrhages

Cotton-Wool Spot

Branch Retinal Artery Occlusion

Central Retinal Artery Occlusion

Ophthalmic Artery Occlusion

Branch Retinal Vein Occlusion

Central / Hemiretinal Vein Occlusion

Venous Stasis Retinopathy

Ocular Ischemic Syndrome

Retinopathy of Prematurity

Coats’ Disease / Leber’s Miliary Aneurysms

Familial Exudative Vitreoretinopathy and Norrie’s Disease

Incontinentia Pigmenti

Eales’ Disease

Macular Telangiectasia

Retinopathies Associated with Blood Abnormalities

Diabetic Retinopathy

Hypertensive Retinopathy

Toxemia of Pregnancy

Acquired Retinal Arterial Macroaneurysm

Radiation Retinopathy

Age-Related Macular Degeneration

Retinal Angiomatous Proliferation

Polypoidal Choroidal Vasculopathy

Myopic Degeneration / Pathologic Myopia

Angioid Streaks

Central Serous Chorioretinopathy

Cystoid Macular Edema

Macular Hole

Vitreomacular Adhesion and Traction

Epiretinal Membrane / Macular Pucker

Myelinated Nerve Fibers

Solar / Photic Retinopathy

Toxic Maculopathies

Lipid Storage Diseases

Peripheral Retinal Degenerations

Retinoschisis

Retinal Detachment

Choroidal Detachment

Chorioretinal Folds

Chorioretinal Coloboma

Proliferative Vitreoretinopathy

Intermediate Uveitis / Pars Planitis

Neuroretinitis

Posterior Uveitis: Infections

Posterior Uveitis: White Dot Syndromes

Posterior Uveitis: Other Inflammatory Disorders

Posterior Uveitis: Evaluation / Management

Hereditary Chorioretinal Dystrophies

Hereditary Macular Dystrophies

Hereditary Vitreoretinal Degenerations

Leber’s Congenital Amaurosis

Retinitis Pigmentosa

Albinism

Phakomatoses

Tumors

Paraneoplastic Syndromes

Trauma

Choroidal Rupture

Tear in choroid, Bruch’s membrane, and retinal pigment epithelium (RPE) is usually seen after blunt trauma. Acutely, the rupture site may be obscured by hemorrhage; scars form over 3–4 weeks with RPE hyperplasia at the margin of the rupture site. Anterior ruptures are usually parallel to the ora serrata; posterior ruptures are usually crescent-shaped and concentric to the optic nerve. Patients may have decreased vision if commotio retinae or subretinal hemorrhage is present, or if the rupture is located in the macula; increased risk of developing a choroidal neovascular membrane (CNV) during the healing process (months to years after trauma). Good prognosis if the macula is not involved, but poor if the fovea is involved.

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FIGURE 10-1 Crescent-shaped, choroidal rupture that is concentric to the optic nerve with surrounding subretinal hemorrhage.

• No treatment recommended, unless CNV occurs.

• Laser photocoagulation of juxtafoveal and extrafoveal CNV; consider anti-VEGF agent for subfoveal CNV (experimental).

• Monitor for CNV with Amsler grid.

Commotio Retinae (Berlin’s Edema)

Gray-white discoloration of the outer retina due to photoreceptor outer segment disruption following blunt eye trauma; can affect any area of the retina and may be accompanied by hemorrhages or choroidal rupture. There is no intercellular edema; whitening is due to intracellular edema and disorganization of outer retinal layers. It is termed Berlin’s edema if involving the macula, and commotion retinae in all other areas. Can cause acute decrease in vision if located within the macula, which resolves as the retinal discoloration disappears; may cause permanent loss of vision if the fovea is damaged, but usually resolves without sequelae. Visual acuity does not always correlate with the degree of retinal whitening seen on exam. Occasionally, a macular hole can form in the area of commotio with variable prognosis.

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FIGURE 10-2 Gray-white discoloration of the outer retina in a patient with commotio retinae.

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FIGURE 10-3 Commotio retinae following blunt trauma demonstrating retinal whitening. Note subretinal hemorrhage from underlying choroidal rupture.

• Fluorescein angiogram: Early blocked fluorescence in the areas of commotio retinae.

• No treatment recommended.

Purtscher’s Retinopathy

Multiple patches of retinal whitening, large cotton-wool spots, and hemorrhages that surround the optic disc following multiple long-bone fractures with fat emboli or severe compressive injuries to the chest or head. May have optic disc edema and a relative afferent pupillary defect (RAPD). Usually resolves over weeks to months.

In the absence of trauma, a Purtscher’s-like retinopathy may be associated with acute pancreatitis, collagen–vascular disease, leukemia, dermatomyositis, and amniotic fluid embolus.

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FIGURE 10-4 Multiple patches of retinal whitening, cotton-wool spots, and intraretinal hemorrhages secondary to Purtscher’s retinopathy.

• Fluorescein angiogram: Leakage from retinal vasculature with late venous staining.

• No treatment recommended.

Traumatic Retinal Holes

Full-thickness tear in the retina, often horseshoe shaped; usually occurs along the vitreous base, posterior border of lattice degeneration, or at cystic retinal tufts (areas with strong vitreoretinal adhesions). As most patients are young, the formed vitreous tamponades the tear and prevents a retinal detachment. Associated with pigmented vitreous cells (“tobacco-dust”, also known as Schaffer’s sign), vitreous hemorrhages, operculum (often located over the retinal hole), and posterior vitreous detachment. Patients usually report photopsias and floaters that shift with eye movement. Liquefied vitreous can pass through the tear into the subretinal space, causing retinal detachment even months to years after the tear forms; chronic tears have a ring of pigment around the retinal hole.

Giant Retinal Tear

Traumatic retinal hole measuring > 90° in circumferential extent or > 3 clock hours.

Avulsion of Vitreous Base

Separation of vitreous base from ora serrata that is pathognomonic for trauma.

Oral Tear

Tear at the ora serrata due to split of vitreous that has a fish-mouth appearance.

Preoral Tear

Tear at anterior border of vitreous base most often occurs superotemporally.

Retinal Dialysis

Most common form after trauma; circumferential separation of the retina at the ora serrata, usually in superotemporal (22%) or inferotemporal (31%) quadrant. Risk of retinal detachment increases over time with 10% at initial examination and 80% by 2 years.

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FIGURE 10-5 Two horseshoe-shaped retinal tears with a bridging retinal vessel seen across the larger tear.

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FIGURE 10-6 Very posterior giant retinal tear that extends for more than 3 clock hours.

• If symptomatic (photopsias and floaters), treatment with cryopexy along edge of tear (do not treat bare retinal pigment epithelium) or two to three rows of laser photocoagulation demarcation around the tear if no retinal detachment present.

• Retinal surgery required if rhegmatogenous retinal detachment, retinal dialysis, avulsion of the vitreous base, or giant retinal tear exists; should be performed by a retina specialist.

Chorioretinitis Sclopeteria

Trauma to retina and choroid caused by transmitted shock waves from high-velocity projectile that causes choroidal rupture, retinal hemorrhages, and commotio retinae. Vitreous hemorrhage is common. Lesions heal with white fibrous scar and RPE changes. Low risk of retinal detachment in young patients with a formed vitreous; however, the appearance can simulate retinal detachment in these patients.

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FIGURE 10-7 Chorioretinitis sclopeteria with subretinal hemorrhage and commotio retinae (same patient as Figure 1-6).

• No treatment recommended. Close observation for late-onset retinal detachment in young patients with a formed vitreous, as they can develop retinal detachments at a later date.

Hemorrhages

Preretinal Hemorrhage

Hemorrhage located between the retina and posterior vitreous face (subhyaloid) or under the internal limiting membrane of the retina (sub-ILM). Often amorphous or boat-shaped, with flat upper border and curved lower border, which obscures the underlying retina. Caused by trauma, retinal neovascularization (diabetic retinopathy, radiation retinopathy, breakthrough bleeding from a choroidal neovascular membrane), hypertensive retinopathy, Valsalva retinopathy, retinal artery macroaneurysm, posterior vitreous detachment, shaken-baby syndrome, or retinal breaks, and less frequently by vascular occlusion, retinopathy of blood disorders, or leukemia.

Intraretinal Hemorrhage

Bilateral intraretinal hemorrhages are associated with systemic disorders (e.g., diabetes mellitus and hypertension); unilateral intraretinal hemorrhages generally occur in venous occlusive diseases or ocular ischemic syndrome.

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FIGURE 10-8 Diabetic retinopathy demonstrating intraretinal and preretinal (boat-shaped configuration due to attached hyaloid containing the blood) hemorrhages.

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FIGURE 10-9 Valsalva retinopathy demonstrating vitreous, preretinal, and subretinal hemorrhages.

Flame-Shaped Hemorrhage

Located in the superficial retina oriented with the nerve fiber layer; feathery borders. Usually occurs in hypertensive retinopathy and vein occlusion; may be peripapillary in glaucoma, especially in normal-tension glaucoma (splinter hemorrhage) and disc edema.

Dot / Blot Hemorrhage

Located in the outer plexiform layer, confined by the anteroposterior orientation of the photoreceptor, bipolar, and Müller’s cells; round dots or larger blots. Usually occurs in diabetic retinopathy.

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FIGURE 10-10 Intraretinal dot and blot hemorrhages in a patient with nonproliferative diabetic retinopathy.

Roth Spot

Hemorrhage with white center that represents an embolus with lymphocytic infiltration. Classically associated with subacute bacterial endocarditis (occurs in 1–5% of such patients); also occurs in leukemia, severe anemia, sickle cell disease, collagen vascular diseases, diabetes mellitus, multiple myeloma, and acquired immunodeficiency syndrome (AIDS) (see Figures 10-4010-43).

Subretinal Hemorrhage

Amorphous hemorrhage located under the neurosensory retina or RPE; appears dark and is deep to the retinal vessels. Associated with trauma, subretinal and choroidal neovascular membranes, and macroaneurysms (see Figure 10-71).

All three types of hemorrhages may occur together in several disorders including age-related macular degeneration (AMD), acquired retinal arterial macroaneurysm, Eales’ disease, and capillary hemangioma.

Cotton-Wool Spot

Asymptomatic, yellow-white, fluffy lesions in the superficial retina (see Figure 10-4). Nonspecific finding due to multiple etiologies including: retinal ischemia (retinal vascular occlusions, severe anemia, ocular ischemic syndrome), emboli (Purtcher’s retinopathy [white blood cell emboli], intravenous drug abuse [talc], cardiac/carotid emboli, deep venous emboli), infections (acquired immunodeficiency syndrome, Rocky Mountain spotted fever, cat-scratch fever [Bartonella henselae], leptospirosis, onchocerciasis, bacteremia, fungemia), collagen vascular diseases (systemic lupus erythematosus, dermatomyositis, polyarteritis nordosa, scleroderma, giant cell arteritis), drugs (interferon, chemotherapeutic agents), neoplasms (lymphoma, leukemia, metastatic carcinoma, multiple myeloma), retinal traction (epiretinal membrane), trauma (nerve fiber layer laceration, long-bone fractures, severe chest compression [white blood cell emboli]), systemic diseases (acute pancreatitis, hypertension, diabetes mellitus, high-altitude retinopathy), and radiation. Appears as thickening of the nerve fiber layer on OCT. Thought to develop secondary to obstruction of a retinal arteriole with resultant ischemia leading to blockage of axoplasmic flow within the nerve fiber layer.

• Treat underlying etiology (identified in 95% of cases).

Branch Retinal Artery Occlusion

Definition

Disruption of the vascular perfusion in a branch of the central retinal artery, leading to focal retinal ischemia.

Etiology

Mainly due to embolism from cholesterol (Hollenhorst’s plaques), calcifications (heart valves), platelet–fibrin plugs (ulcerated atheromatous plaques due to arteriosclerosis); rarely due to leukoemboli (vasculitis, Purtcher’s retinopathy), fat emboli (long-bone fractures), amniotic fluid emboli, tumor emboli (atrial myxoma), or septic emboli (heart valve vegetations in bacterial endocarditis or IV drug abuse). The site of the obstruction is usually at the bifurcation of retinal arteries. May result from vasospasm (migraine), compression, or coagulopathies.

Epidemiology

Usually occurs in elderly patients (seventh decade); associated with hypertension (67%), carotid occlusive disease (25%), diabetes mellitus (33%), and cardiac valvular disease (25%). CRAO is more common (57%) than BRAO (38%) or cilioretinal artery occlusion (5%) (in 32% of eyes, a cilioretinal artery is present).

Symptoms

Sudden, unilateral, painless, partial loss of vision, with a visual field defect corresponding to the location of the occlusion. May have history of amaurosis fugax (fleeting episodes of visual loss), prior cerebrovascular accident (CVA), or transient ischemic attacks (TIAs).

Signs

Visual field defect with normal or decreased visual acuity; focal, wedge-shaped area of retinal whitening within the distribution of a branch arteriole; 90% involve temporal retinal vessels; emboli (visible in 62% of cases) or Hollenhorst’s plaques may be visible at retinal vessel bifurcations. Retinal whitening resolves over several weeks and visual acuity can improve. In chronic stages, arterial attenuation with sector nerve fiber layer loss may be seen; artery-to-artery collaterals may form and are pathognomonic.

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FIGURE 10-11 Superior branch artery occlusion with retinal edema extending in a wedge-shaped pattern from the artery occluded by the Hollenhorst plaque.

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FIGURE 10-12 Inferior branch retinal artery occlusion with Hollenhorst plaque and wedge-shaped retinal edema.

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FIGURE 10-13 Superior branch artery occlusion demonstrating retinal edema.

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FIGURE 10-14 Fluorescein angiogram of same patient as Figure 10-13 demonstrating no filling of superior retinal vessels and delayed filling of affected veins.

Differential Diagnosis

Commotio retinae, branch retinal vein occlusion, CRAO with cilioretinal artery sparing, combined artery and vein occlusion.

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy (retinal vasculature and arteriole bifurcations).

• Check blood pressure.

• Lab tests: Fasting blood glucose (FBS), glycosylated hemoglobin, and complete blood count (CBC) with differential. Consider platelets, prothrombin time/partial thromboplastin time (PT / PTT), protein C, protein S, factor V Leiden mutation, antithrombin III, homocysteine level, antinuclear antibody (ANA), rheumatoid factor (RF), sickle cell disease, antiphospholipid antibody, serum protein electrophoresis, hemoglobin electrophoresis, Venereal Disease Research Laboratory (VDRL) test, and fluorescent treponemal antibody absorption (FTA-ABS) test in patients < 50 years of age. In patients > 50 years old, check erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to rule out arteritic ischemic optic neuropathy due to giant cell arteritis. If positive and / or if the patient’s history and exam are consistent, start giant cell arteritis treatment immediately (see Chapter 11). If the BRAO is accompanied by optic nerve edema and / or retinitis, consider serologic testing for infectious etiologies such as Bartonella, Lyme, and toxoplasmosis.

• Fluorescein angiogram: Delayed or absent retinal arterial filling in a branch of the central retinal artery; delayed arteriovenous transit time; capillary nonperfusion in wedge-shaped area supplied by the branch artery; staining of occlusion site and vessel wall in late views. When occlusion dissolutes, retinal blood flow is usually restored.

• Optical coherence tomography (OCT): Thickened and hyperreflective inner retinal layers during acute occlusion that corresponds to intracellular edema. Reflectivity of outer retina is blocked. Later, the retina is thinned with atrophy of the inner retina.

• Consider B-scan ultrasonography or orbital computed tomography (CT) scan to rule out a compressive lesion if the history suggests this etiology.

• Medical consultation for complete cardiovascular evaluation including baseline electrocardiogram, echocardiogram (may require transesophageal echocardiogram to rule out valvular disease), and carotid Doppler ultrasonography.

• In patients < 50 years of age, a hypercoagulability evaluation should be considered.

Management

• Same treatment as CRAO (see below) if foveal circulation affected, but this is controversial owing to good prognosis and questionable benefit of treatment.

Prognosis

Retinal pallor fades and circulation is restored over several weeks. Good if fovea is spared; 80% have ≥ 20 / 40 vision, but most have some degree of permanent visual field loss; 10% risk in fellow eye.

Central Retinal Artery Occlusion

Definition

Disruption of the vascular perfusion in the central retinal artery (CRAO) leading to global retinal ischemia.

Etiology

Due to emboli (only visible in 20–40% of cases) or thrombus at the level of the lamina cribosa; other etiologies are the same as for BRAO including temporal arteritis, leukoemboli in collagen vascular diseases, fat emboli, trauma (through compression, spasm, or direct vessel damage), hypercoagulation disorders, syphilis, sickle cell disease, amniotic fluid emboli, mitral valve prolapse, particles (talc) from IV drug abuse, and compressive lesions; associated with optic disc drusen, papilledema, prepapillary arterial loops, and primary open-angle glaucoma.

Epidemiology

Usually occurs in elderly patients; associated with hypertension (67%), carotid occlusive disease (25%), diabetes mellitus (33%), and cardiac valvular disease (25%). CRAO is more common (57%) than BRAO (38%) or cilioretinal artery occlusion (5%) (in 32% of eyes, a cilioretinal artery is present); rarely bilateral.

Symptoms

Sudden, unilateral, painless, profound loss of vision; may have history of amaurosis fugax (fleeting episodes of visual loss), prior CVA, or TIAs.

Signs

Decreased visual acuity in the count fingers (CF) to light perception (LP) range; RAPD may be present; diffuse retinal whitening and arteriole constriction with segmentation (boxcaring) of blood flow; visible emboli (20–40%) rarely occur in central retinal artery; cherry-red spot in the macula (thin fovea allows visualization of the underlying choroidal circulation). In ciliary retinal artery sparing CRAO (25%), a small wedge-shaped area of perfused retina may be present temporal to the optic disc (10% spare the foveola, in which case visual acuity improves to 20 / 50 or better in 80%). Note: Ophthalmic artery obstruction usually does not produce a cherry-red spot owing to underlying choroidal ischemia.

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FIGURE 10-15 Central retinal artery occlusion with cherry-red spot in the fovea and surrounding retinal edema.

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FIGURE 10-16 Central retinal artery occlusion with cherry-red spot.

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FIGURE 10-17 Cilioretinal artery sparing central retinal artery occlusion with patent cilioretinal artery allowing perfusion (thus no edema) in a small section of the macula.

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FIGURE 10-18 Fluorescein angiogram of same patient in Figure 10-17 demonstrating no filling of retinal vessels except in cilioretinal artery and surrounding branches.

Differential Diagnosis

Ophthalmic artery occlusion, commotio retinae, cherry-red spot due to inherited metabolic or lysosomal storage diseases, methanol toxicity.

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy (retinal vasculature).

• Check blood pressure.

• Lab tests: Fasting blood glucose (FBS), glycosylated hemoglobin, and complete blood count (CBC) with differential. Consider platelets, prothrombin time/partial thromboplastin time (PT / PTT), protein C, Protein S, factor V Leiden mutation, antithrombin III, homocysteine level, antinuclear antibody (ANA), rheumatoid factor (RF), sickle cell disease, antiphospholipid antibody, serum protein electrophoresis, hemoglobin electrophoresis, Venereal Disease Research Laboratory (VDRL) test, and fluorescent treponemal antibody absorption (FTA-ABS) test in patients < 50 years of age. In patients > 50 years old, check erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to rule out arteritic ischemic optic neuropathy due to giant cell arteritis. If positive and /or if the patient’s history and exam are consistent, start giant cell arteritis treatment immediately (see Chapter 11). If the CRAO is accompanied by optic nerve edema and /or retinitis consider serologic testing for infectious etiologies such as Bartonella, Lyme disease, and toxoplasmosis.

• Fluorescein angiogram: Delayed retinal arterial filling and arteriovenous transit time with normal choroidal filling and perfusion of optic nerve from ciliary branches; prolonged arteriovenous circulation times; extensive capillary nonperfusion.

• Optical coherence tomography: Thickened and hyperreflective inner retinal layers during acute occlusion that corresponds to intracellular edema. Reflectivity of outer retina is blocked. Later, the retina is thinned with atrophy of the inner retina.

• Electrophysiologic testing: ERG (reduced b-wave amplitude, normal a-wave).

• Consider B-scan ultrasonography or orbital CT scan to rule out compressive lesion if history suggests compression.

• Medical consultation for complete cardiovascular evaluation including electrocardiogram, echocardiogram (may require transesophageal echocardiogram to rule out valvular disease), and carotid Doppler ultrasound.

Management

OPHTHALMIC EMERGENCY

• Treatment is controversial owing to poor prognosis and questionable benefit of treatment. Goal is to move emboli distally to restore proximal retinal blood flow; most maneuvers are aimed at rapid lowering of the intraocular pressure (IOP).

• Treat immediately before starting workup (if patient presents within 24 hours of visual loss), but best hope is to treat within 90 minutes.

• Digital ocular massage to try to dislodge emboli.

• Systemic acetazolamide (Diamox 500 mg IV or po).

• Topical ocular hypotensive drops: β-blocker (timolol 0.5% 1 gtt q15min × 2, repeat as necessary).

• Anterior chamber paracentesis (immediately lowers IOP to 0 mmHg): This procedure is easily performed at the slit lamp after prepping the eye with topical anesthetic, broad-spectrum antibiotic, and povidone-iodine. A lid speculum is placed, the eye is grasped with forceps at the nasal limbus to prevent movement and provide counter-traction, and either a disposable microsurgical knife (15° or MVR blade) or else a 30-gauge si1 inch (13 mm) needle on a 1 mL syringe without the plunger, is inserted parallel to the iris through the peripheral cornea at the temporal limbus. If necessary, gentle pressure can be applied to the posterior lip of the paracentesis site so that aqueous can be released in a controlled fashion. Treat with a topical broad-spectrum antibiotic (gatifloxacin [Zymaxid] or moxifloxacin [Vigamox] qid for 3 days).

• Consider admission to hospital for carbogen treatment (95% oxygen–5% carbon dioxide for 10 minutes q2h for 24–48 hours) to attempt to increase oxygenation and induce vasodilation.

• Unproven treatments include hyperbaric oxygen, antifibrinolytic drugs, retrobulbar vasodilators, sublingual nitroglycerine, and Nd : YAG laser to dislodge the emboli.

• If arteritic anterior ischemic optic neuropathy (see Chapter 11) is suspected: Systemic steroids (methylprednisolone 1 g IV qd in divided doses for 3 days, then prednisone at least 1 mg / kg po qd for at least a month with a very slow taper; decrease by no more than 2.5 mg /wk). Most patients will require a year of high-dose steroid treatment.

Prognosis

Retinal pallor fades and circulation is restored over several weeks. Poor prognosis; most have persistent severe visual loss with constricted retinal arterioles and optic atrophy. Rubeosis (20%) and disc /retinal neovascularization (2–3%) can rarely occur. Presence of visible embolus associated with increased mortality; most common cause of mortality is myocardial infarction.

Ophthalmic Artery Occlusion

Definition

Obstruction at the level of the ophthalmic artery that affects both the retinal and choroidal circulation leading to ischemia more severe than CRAO.

Etiology

Usually due to emboli or thrombus, but can be caused by any of the etiologies listed for CRAO.

Epidemiology

Usually occurs in elderly patients; associated with hypertension (67%), carotid occlusive disease (25%), diabetes mellitus (33%), and cardiac valvular disease (25%).

Symptoms

Sudden, unilateral, painless, profound loss of vision up to the level of light perception or even no light perception.

Signs

Marked constriction of the retinal vessels, marked retinal edema often without a cherry red spot (although it may be present); may have RAPD; later, optic atrophy, retinal vascular sclerosis, and diffuse pigmentary changes.

Differential Diagnosis

Central retinal artery occlusion, commotio retinae, cherry-red spot due to inherited metabolic or lysosomal storage diseases, methanol toxicity.

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Check blood pressure.

• Lab tests: Fasting blood glucose (FBS), glycosylated hemoglobin, and complete blood count (CBC) with differential. Consider platelets, prothrombin time/partial thromboplastin time (PT / PTT), protein C, Protein S, factor V Leiden mutation, antithrombin III, homocysteine level, antinuclear antibody (ANA), rheumatoid factor (RF), sickle cell disease, antiphospholipid antibody, serum protein electrophoresis, hemoglobin electrophoresis, Venereal Disease Research Laboratory (VDRL) test, and fluorescent treponemal antibody absorption (FTA-ABS) test in patients < 50 years of age. In patients > 50 years old, check erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to rule out arteritic ischemic optic neuropathy due to giant cell arteritis. If positive and / or if the patient’s history and exam are consistent, start giant cell arteritis treatment immediately (see Chapter 11).

• Fluorescein angiogram: Delayed or absent choroidal and retinal vascular filling, extensive capillary nonperfusion.

• Electrophysiologic testing: ERG (reduced or absent a and b wave amplitudes).

• Medical consultation for complete cardiovascular evaluation including electrocardiogram, echocardiogram (may require transthoracic echocardiogram to rule out valvular disease), and carotid Doppler ultrasound.

Management

OPHTHALMIC EMERGENCY

• Same treatment as CRAO (see above).

Prognosis

Severe visual loss is usually permanent.

Branch Retinal Vein Occlusion

Definition

Occlusion of a branch retinal vein (BRVO). Two types:

Nonischemic (64%)

< 5 disc areas of capillary nonperfusion on fluorescein angiogram.

Ischemic

≥ 5 disc areas of capillary nonperfusion on fluorescein angiogram.

Etiology

Usually caused by a thrombus at arteriovenous crossings where a thickened artery compresses the underlying venous wall due to a common vascular sheath; associated with hypertension, coronary artery disease, diabetes mellitus, and peripheral vascular disease; rarely associated with hypercoagulable states (e.g., macroglobulinemia, cryoglobulinemia), hyperviscosity states (polycythemia vera, Waldenström’s macroglobulinemia), systemic lupus erythematosus, syphilis, sarcoid, homocystinuria, malignancies (e.g., multiple myeloma, polycythemia vera, leukemia), optic nerve drusen, and external compression. In younger patients, associated with oral contraceptive pills, collagen vascular disease, AIDS, protein S /protein C /antithrombin III deficiency, factor XII (Hageman factor) deficiency, antiphospholipid antibody syndrome, or activated protein-C resistance (factor V Leiden PCR assay).

Epidemiology

Usually occurs in elderly patients, 60–70 years old; associated with hypertension (50–70%), cardiovascular disease, diabetes mellitus, increased body mass index, and open-angle glaucoma; slight male and hyperopic predilection. Second most common vascular disease after diabetic retinopathy.

Symptoms

Sudden, unilateral, painless, visual field loss. Patients may have normal vision, especially when macula is not involved.

Signs

Quadrantic visual field defect; dilated, tortuous retinal veins with superficial, retinal hemorrhages, and cotton-wool spots in a wedge-shaped area radiating from an arteriovenous crossing (usually arterial over-crossing where an arteriole and venule share a common vascular sheath). More common superotemporally (60%) than inferotemporally (40%; rare nasally since usually asymptomatic). The closer the obstruction is to the optic disc, the greater the area of retina involved and the more serious the complications. Microaneurysms or macroaneurysms, macular edema (50%), epiretinal membranes (20%), retinal and /or iris /angle neovascularization (very rare), and vitreous hemorrhage may develop; neovascular glaucoma is rare.

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FIGURE 10-19 Inferior branch retinal vein occlusion demonstrating wedge-shaped area of intraretinal hemorrhages and cotton-wool spots.

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FIGURE 10-20 Fluorescein angiogram of same patient as Figure 10-19 demonstrating lack of perfusion in inferior retinal vein with blocking defects from the intraretinal hemorrhages. Site of occlusion is shown with an arrowhead.

Differential Diagnosis

Venous stasis retinopathy, ocular ischemic syndrome, hypertensive retinopathy, leukemic retinopathy, retinopathy of anemia, diabetic retinopathy, papilledema, papillophlebitis (in young patients).

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, tonometry, gonioscopy, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Check visual fields.

• Check blood pressure.

• Lab tests: Fasting blood glucose, glycosylated hemoglobin; consider CBC with differential, platelets, PT / PTT, ANA, RF, angiotensin converting enzyme (ACE), ESR, serum protein electrophoresis, lipid profile, hemoglobin electrophoresis (in African Americans), VDRL, and FTA-ABS depending on clinical situation. In a patient < 40 years old and in whom a hypercoagulable state is being considered: check human immunodeficiency virus (HIV) status, functional protein S assay, functional protein C assay, functional antithrombin III assay (type II heparin-binding mutation), antiphospholipid antibody titer, lupus anticoagulant, anticardiolipin antibody titer (IgG and IgM), homocysteine level (if elevated test for folate, B12, and creatinine), factor XII (Hageman factor) levels, and activated protein C resistance (factor V Leiden mutation PCR assay); if these tests are normal and clinical suspicion for a hypercoagulable state still exists: add plasminogen antigen assay, heparin cofactor II assay, thrombin time, reptilase time, and fibrinogen functional assay.

• Fluorescein angiogram: Delayed retinal venous filling in a branch of the central retinal vein, increased transit time in affected venous distribution, blocked fluorescence in areas of retinal hemorrhages, and capillary nonperfusion (ischemic defined as ≥ 5 disc areas of capillary nonperfusion) in the area supplied by the involved retinal vein. Retinal edema with cystic changes is not present acutely, but appears later. Wide-field angiography is being used increasingly to visualize peripheral nonperfusion.

• Optical coherence tomography: Monitor for cystic macular edema and intraretinal swelling. Useful to monitor treatment response.

• Medical consultation for complete cardiovascular evaluation.

Management

• Quadrantic scatter laser photocoagulation (500 μm spots) when rubeosis (≥ 2 clock hours of iris or any angle neovascularization), disc /retinal neovascularization, or neovascular glaucoma develops (Branch Vein Occlusion Study-BVOS conclusion); prophylactic laser was not evaluated in BVOS, and is not recommended.

• Macular grid/focal photocoagulation (50–100 μm spots) when macular edema lasts > 3 months and vision is < 20/ 40 (BVOS conclusion).

• Currently the best therapy for macular edema due to BRVO is intravitreal anti-VEGF agents such as 0.5 mg ranibizumab [Lucentis] (BRAVO Study result), 2.0 mg aflibercept [Eylea] (VIBRANT Study result) or 1.25 mg bevacizumab [Avastin] monthly for the first 6 months with as needed treatment thereafter.

• Second-line intravitreal steroid therapy consists of intravitreal 4 mg triamcinolone acetonide [Triessence] (SCORE Study result) and the sustained-release biodegradable dexamethasone implant [Ozurdex] (GENEVA Study result).

• Discontinue oral contraceptives.

• Consider aspirin (80–325 mg po qd).

• Treat underlying medical conditions.

Prognosis

• Good; 50% have ≥ 20/ 40 vision unless foveal ischemia or chronic macular edema is present. Risk of another BRVO in same eye is 3% and in fellow eye is 12%.

Central / Hemiretinal Vein Occlusion

Definition

Occlusion of the central retinal vein (CRVO); hemiretinal occlusion (HRVO) occurs when the superior and inferior retinal drainage does not merge into a central retinal vein (20%) and is occluded (more like CRVO than BRVO). Two types:

Nonischemic / Perfused (67%)

< 10 disc areas of capillary nonperfusion on fluorescein angiogram.

Ischemic / Nonperfused

 ≥ 10 disc areas of capillary nonperfusion on fluorescein angiogram.

Etiology

Usually caused by a thrombus in the area of the lamina cribosa; associated with hypertension (60%), coronary artery disease, diabetes mellitus, peripheral vascular disease, and primary open-angle glaucoma (40%); rarely associated with hypercoagulable states (e.g., macroglobulinemia, cryoglobulinemia), hyperviscosity states especially in bilateral cases (polycythemia vera, Waldenström’s macroglobulinemia), systemic lupus erythematosus, syphilis, sarcoid, homocystinuria, malignancies (e.g., multiple myeloma, polycythemia vera, leukemia), optic nerve drusen, and external compression. In younger patients, associated with oral contraceptive pills, collagen vascular disease, acquired immunodeficiency syndrome (AIDS), protein S /protein C /antithrombin III deficiency, factor XII (Hageman factor) deficiency, antiphospholipid antibody syndrome, or activated protein C resistance (factor V Leiden polymerase chain reaction [PCR] assay).

Epidemiology

Usually occurs in elderly patients (90% are > 50 years old); slight male predilection. Ischemic disease is more common in older patients and those with cardiovascular disease. Younger patients can get inflammatory condition termed papillophlebitis or benign retinal vasculitis with benign clinical course.

Symptoms

Sudden, unilateral, loss of vision or less frequently history of transient obscuration of vision with complete recovery. Some report pain and present initially with neovascularization of the iris and neovascular glaucoma following a loss of vision 3 months earlier (“90-day glaucoma”). Patients may have normal vision if perfused, especially when the macula is not involved.

Signs

Decreased visual acuity ranging from 20 / 20 to hand motion (HM) with most worse than 20 / 200 (vision worse in ischemic type; usually > 20/ 200 in nonischemic); dilated, tortuous retinal veins with superficial, retinal hemorrhages, and cotton-wool spots in all four quadrants extending to periphery; optic disc hyperemia, disc edema, and macular edema common; RAPD (degree of defect correlates with amount of ischemia). Nonischemic disease rarely produces neovascularization; ischemic disease can produce rubeosis (20% in CRVO, rare in BRVO), disc/retinal neovascularization (border of perfused/nonperfused retina), neovascular glaucoma, and vitreous hemorrhages. Collateral optociliary shunt vessels between retinal and ciliary circulations (50%) occur late. Impending CRVO may have absence of spontaneous venous pulsations (but this can also occur in normal individuals). Transient patchy ischemic retinal whitening may occur early in nonischemic CRVO.

Differential Diagnosis

Venous stasis retinopathy, ocular ischemic syndrome, hypertensive retinopathy, leukemic retinopathy, retinopathy of anemia, diabetic retinopathy, radiation retinopathy, and papilledema.

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FIGURE 10-21 Hemiretinal vein occlusion with exudates forming partial macular star.

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FIGURE 10-22 Fluorescein angiogram of a patient with a retinal vein occlusion demonstrating peripheral capillary nonperfusion.

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FIGURE 10-23 Central retinal vein occlusion demonstrating hemorrhages in all four quadrants.

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FIGURE 10-24 Fluorescein angiogram demonstrating no filling of the central retinal vein.

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FIGURE 10-25 Optociliary shunt vessels in a patient with an old central retinal vein occlusion.

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity (worse than 20 / 400 likely ischemic), pupils (ischemic likely to have RAPD), Golmann visual fields (ischemic cannot see I4e), tonometry, gonioscopy, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Check blood pressure.

• Lab tests: Fasting blood glucose, glycosylated hemoglobin; consider CBC with differential, platelets, PT / PTT, ANA, RF, ACE, ESR, serum protein electrophoresis, lipid profile, hemoglobin electrophoresis (in African American), VDRL, and FTA-ABS depending on clinical situation. In a patient < 40 years old and in whom a hypercoagulable state is being considered: check human immunodeficiency virus (HIV) status, functional protein S assay, functional protein C assay, functional antithrombin III assay (type II heparin-binding mutation), antiphospholipid antibody titer, lupus anticoagulant, anticardiolipin antibody titer (IgG and IgM), homocysteine level (if elevated test for folate, B12, and creatinine), factor XII (Hageman factor) levels, and activated protein C resistance (factor V Leiden mutation PCR assay); if these tests are normal and clinical suspicion for a hypercoagulable state still exists: add plasminogen antigen assay, heparin cofactor II assay, thrombin time, reptilase time, and fibrinogen functional assay.

• Fluorescein angiogram: Delayed retinal venous filling, increased transit time (> 20 seconds increases risk of rubeosis), extensive capillary nonperfusion (ischemic defined in CVOS as ≥ 10 disc areas of capillary nonperfusion), staining of vascular walls, and blocking defects due to retinal hemorrhages. Retinal edema with cystic changes that are not present acutely, but appear later. Wide-field angiography is being used increasingly to visualize peripheral nonperfusion.

• Optical coherence tomography: monitor for cystic macular edema and intraretinal swelling. Useful to monitor treatment response.

• Electrophysiologic testing: ERG (reduced b wave amplitude [< 60% of normal more likely ischemic], reduced b : a-wave ratio [< 1 associated with increased risk of ischemia and neovascularization], prolonged b-wave implicit time).

• Medical consultation for complete cardiovascular evaluation.

Management

• Panretinal laser photocoagulation (PRP) (500 μm spots) when rubeosis (≥ 2 clock hours of iris or any angle neovascularization), disc/retinal neovascularization, or neovascular glaucoma develops; no benefit to prophylactic PRP (Central Retinal Vein Occlusion Study-CVOS conclusion).

• Currently the best therapy for macular edema due to CRVO is intravitreal anti-VEGF agents such as 0.5 mg ranibizumab [Lucentis] (CRUISE Study result), 2.0 mg aflibercept [Eylea] (COPERNICUS / GALILEO Study result), or 1.25 mg bevacizumab [Avastin] monthly for the first 6 months, with as-needed treatment thereafter.

• Second-line intravitreal steroid therapy consists of intravitreal 4 mg triamcinolone acetonide [Triessence] (SCORE Study result) and the sustained-release biodegradable dexamethasone implant [Ozurdex].

• Focal laser photocoagulation decreases macular edema, but has no effect on visual acuity (CVOS conclusion), although there was a trend in the CVOS for focal laser to work in younger patients.

• Creation of chorioretinal venous anastomosis by intentional rupture of Bruch’s membrane with high-intensity laser photocoagulation or surgical blade reportedly successful in ⅓ of cases, but still experimental. Intravenous injection of tissue plasminogen activator (tPA) into the lumen of the central retinal vein is also experimental.

• May require treatment of increased intraocular pressure (see Primary Open-Angle Glaucoma section in Chapter 11).

• Discontinue oral contraceptives and change diuretics to an alternate antihypertensive.

• Consider aspirin (80–325 mg po qd).

• Treat underlying medical condition.

Prognosis

Clinical course is variable; evaluate monthly for first 6 months. Nonischemic type has better prognosis (10% will completely resolve). Risk of neovascularization depends on amount of ischemia (CVOS conclusion); 16% of nonischemic patients progress to ischemic disease; 60% of ischemic patients develop neovascularization and 33% develop neovascular glaucoma.

Venous Stasis Retinopathy

Milder form of nonischemic central retinal vein occlusion (CRVO) representing patients with better perfusion. Dot/blot/flame hemorrhages, dilated/tortuous vasculature, and microaneurysms occur, usually bilateral; more benign course. Associated with hyperviscosity syndromes including polycythemia vera, multiple myeloma, and Waldenström’s macroglobulinemia.

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FIGURE 10-26 Dilated, tortuous, retinal vessels in a patient with hyperviscosity syndrome.

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FIGURE 10-27 Intraretinal hemorrhages in a patient with venous stasis retinopathy.

Ocular Ischemic Syndrome

Definition

Widespread ischemia of both the anterior and posterior segments of one eye due to ipsilateral carotid occlusive disease (less frequently obstruction of the ipsilateral ophthalmic artery), carotid dissection, or arteritis (rare).

Etiology

Due to a 90% or greater occlusion of the ipsilateral carotid artery or rarely ophthalmic artery.

Epidemiology

Usually occurs in patients aged 50–70 years old (mean = 65 years); 80% unilateral; male predilection (2 : 1). Associated with atherosclerosis, ischemic heart disease (50%), hypertension (67%), diabetes mellitus (50%), previous stroke (25%), and peripheral arterial disease (20%); rarely due to inflammatory conditions including giant cell arteritis. Blood flow to the eye is relatively unaffected until carotid obstruction exceeds 70%; ocular ischemic syndrome usually does not occur until it reaches 90% (decreasing CRA perfusion by 50%); 50% of patients have complete ipsilateral carotid artery obstruction.

Symptoms

Gradual loss of vision (90%) over days to weeks with accompanying dull eye pain/headache (40%) or “ocular angina”; patients may also report amaurosis fugax (10%) or a delayed recovery of vision after exposure to bright light due to impaired photoreceptor regeneration. May occur suddenly in 12% of cases where a cherry-red spot is also present.

Signs

Gradual or sudden decreased visual acuity ranging from 20 / 20 to NLP; retinal arterial narrowing and venous dilatation without tortuousity, retinal hemorrhages (80% midperipheral), microaneurysms, macular edema, cotton-wool spots, disc/retinal neovascularization (37%), and spontaneous pulsations of the retinal arteries; anterior segment signs including episcleral injection, corneal edema, anterior chamber cells and flare (keratic precipitates are absent and flare is often disproportionate to the amount of cell present), iris atrophy, chronic conjunctivitis, and rubeosis (66%) are common. Intraocular pressure may be elevated, but may also be normal even with 360° synechia. Light digital pressure on the globe through the eyelid often produces arterial pulsations (does not occur in other diseases in differential) and can shut down perfusion of the central retinal artery.

Differential Diagnosis

Nonischemic CRVO, venous stasis retinopathy, diabetic retinopathy, hypertensive retinopathy, aortic arch disease, parafoveal telangiectasis, radiation retinopathy, Takayasu’s disease.

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, tonometry, anterior chamber, gonioscopy, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy. Digital pressure on eye causes arterial pulsation.

• Check blood pressure.

• Fluorescein angiogram: Delayed arteriovenous transit time (> 11 seconds) in 95%; delayed or patchy choroidal filling (> 5 seconds) in 60%, arterial vascular staining in 85%.

• Electrophysiologic testing: ERG (reduced or absent a-wave and b-wave amplitudes).

• Medical consultation for complete cardiovascular evaluation including duplex and carotid Doppler ultrasound scans (≥ 90% obstruction of the ipsilateral internal or common carotid arteries). Carotid angiography is usually not needed except in cases where ultrasound is equivocal.

Management

• Panretinal laser photocoagulation (PRP) (500 μm spots) when anterior or posterior segment neovascularization develops.

• Consider carotid endarterectomy if carotid obstruction exists; more beneficial if performed before rubeosis develops.

• May require treatment of increased intraocular pressure (see Primary Open-Angle Glaucoma section in Chapter 11).

• Glaucoma surgery when anterior chamber angle is closed.

Prognosis

Poor prognosis; 5-year mortality rate is 40% mainly owing to cardiovascular disease. Sixty percent of patients have count fingers or worse vision at 1 year follow-up; only 25% have better than 20 / 50 vision. When rubeosis is present, 90% will be count fingers or worse within 1 year. One-third of patients have improved vision after carotid endarterectomy, one-third remain unchanged, and one-third worsen despite surgery.

Retinopathy of Prematurity

Definition

Abnormal retinal vasculature development in premature infants, especially after supplemental oxygen therapy.

Epidemiology

Usually bilateral; associated risk factors include premature birth (< 32 weeks’ gestation), low birth weight (< 750 g: 90% develop ROP and 16% develop threshold disease; 1000–1250 g: 45% develop ROP and 2% develop threshold disease), supplemental oxygen therapy (> 50 days), and a complicated hospital course.

Symptoms

Asymptomatic; later may have decreased vision.

Signs

Shallow anterior chamber, corneal edema, iris atrophy, poor pupillary dilation, posterior synechiae, ectropion uveae, leukocoria, vitreous hemorrhage, retinal detachment, and retrolental fibroplasia; may have strabismus.

International classification of ROP describes the retinal changes in five stages:

Stage 1

Thin, circumferential, flat, white, demarcation line develops between posterior vascularized and peripheral avascular retina (beyond line).

Stage 2

Demarcation line becomes elevated and organized into a pink-white ridge, no fibrovascular growth visible.

Stage 3

Extraretinal fibrovascular proliferation from surface of the ridge.

Stage 4

Dragging of vessels, and subtotal traction retinal detachment (4A is macula attached, 4B involves the macula).

Stage 5

Total retinal detachment (almost always funnel detachment).

International classification of ROP also describes the extent of retina involved by number of clock hours and location by zone (centered on optic disc, not the fovea because retinal vessels emanate from disc):

Zone 1

Inner zone (posterior pole) corresponding to the area enclosed by a circle around the optic disc with radius equal to twice the distance from the disc to the macula (diameter of 60°).

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FIGURE 10-28 Retinopathy of prematurity (ROP) demonstrating extraretinal fibrovascular proliferation along the ridge (Stage 3 ROP).

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FIGURE 10-29 Retinopathy of prematurity (ROP) demonstrating dragged vessels, traction retinal detachment, and laser spots anterior to the regressed fibrovascular proliferation (Stage 4a ROP).

Zone 2

The area between zone 1 and a circle centered on the optic disc and tangent to the nasal ora serrata.

Zone 3

Remaining temporal crescent of retina (last area to become vascularized).

Finally, international classification of ROP defines “plus” disease:

“Plus” Disease

At least two quadrants (usually 6 or more clock hours) of shunted blood causing vascular engorgement in the posterior pole with tortuous arteries, dilated veins, pupillary rigidity due to iris vascular engorgement, and vitreous haze.

Differential Diagnosis

Coats’ disease, Eales’ disease, familial exudative vitreoretinopathy, sickle cell retinopathy, juvenile retinoschisis, persistent hyperplastic primary vitreous, incontinentia pigmenti (Bloch–Sulzberger syndrome), and other causes of leukocoria (see Chapter 7).

Evaluation

• Screen all premature infants who weighed < 1500 g at birth or under 30 weeks gestational age at birth, and infants > 1500 g at birth who experienced an unstable postnatal course (AAO guidelines).

• The first exam should be either prior to discharge from the hospital, 4 weeks chronological age, or by 31 weeks postgestational age, whichever is later.

• Complete ophthalmic history with attention to birth history and birth weight.

• Complete eye exam with attention to iris, lens, and ophthalmoscopy (retinal vasculature and retinal periphery with scleral depression).

• Cycloplegic refraction as many develop refractive errors especially myopia.

• Pediatric consultation.

Management

• Treat with ablation of peripheral avascular retina when patient reaches type 1 ROP, defined as: zone 1, any stage of ROP with plus disease; zone 1, stage 3 with or without plus disease; zone 2, stage 2 or 3 with plus disease (Early Treatment of Retinopathy of Prematurity [ETROP] study conclusion).

Note: This means treating earlier than the older “threshold” definition = stage 3 plus disease with at least 5 contiguous or 8 noncontiguous, cumulative clock hours involvement in zone 1 or 2.

• Indirect argon green or diode laser photocoagulation (500 μm spots) to entire avascular retina in zone 1 and peripheral zone 2; laser is at least as effective as cryotherapy (Laser-ROP study conclusion) or

• Cryotherapy to entire avascular retina in zone 2, but not ridge (Cryotherapy for ROP [CRYO-ROP] Study conclusion).

• Serial exams with type 2 ROP, defined as zone 1, stage 1 or 2 without plus disease; zone 2, stage 3 without plus disease.

• Tractional retinal detachment or rhegmatogenous retinal detachment (cicatricial ROP, stages 4–5) require vitreoretinal surgery with pars plana vitrectomy, with/without lensectomy, membrane peel, and possible scleral buckle; should be performed by a retina specialist trained in pediatric retinal disease.

• Follow very closely (every 1–2 weeks depending on location and severity of the disease) until extreme periphery is vascularized, then monthly therafter. Beware of “rush” disease (aggressive posterior [AP] ROP) defined as plus disease in zone 1 or posterior zone 2. “AP-ROP” disease has a significant risk of rapid progression to stage 5 within a few days.

• Anti-VEGF agents such as bevacizumab [Avastin] have been used experimentally with positive preliminary results, but safety is not proven.

Prognosis

Depends on the amount and stage of ROP; 80–90% will spontaneously regress; may develop amblyopia, macular dragging, strabismus; stage 5 disease carries a poor prognosis (functional success in only 3%); may develop high myopia, glaucoma, cataracts, keratoconus, band keratopathy, and retinal detachment.

Coats’ Disease / Leber’s Miliary Aneurysms

Unilateral (80–95%), idiopathic, progressive, developmental retinal vascular abnormality (telangiectatic and aneurysmal vessels with a predilection for the macula); usually occurs in young males (10 : 1) < 20 years old (two-thirds present before age 10). Retinal microaneurysms, retinal telangiectasia, lipid exudation, “light-bulb” vascular dilatations, capillary nonperfusion and occasionally neovascularization, exudative retinal detachments, and subretinal cholesterol crystals occur primarily in the temporal quadrants, especially on fluorescein angiogram where microaneurysm leakage is common. May present with poor vision, strabismus, or leukocoria. Spectrum of disease from milder form in older patients with equal sex predilection and often bilateral (Leber’s miliary aneurysms) to severe form with localized exudative retinal detachments and yellowish subretinal masses, and is included in the differential diagnosis of leukocoria (Coats’ disease). Clinical course varies but generally progressive. Rarely associated with systemic disorders including Alport’s disease, fascioscapulohumeral dystrophy, muscular dystrophy, tuberous sclerosis, Turner’s syndrome, and Senior–Loken syndrome. On histopathologic examination there is loss of vascular endothelium and pericytes with subsequent mural disorganization. Classified into five stages:

Stage 1

Telangectasia only

Stage 2

Exudation (a = extrafoveal, b = subfoveal)

Stage 3

Exudative retinal detachment (a = subtotal, b = total)

Stage 4

RD with glaucoma

Stage 5

End-stage disease

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FIGURE 10-30 Coats’ disease demonstrating leukocoria due to exudative retinal detachment.

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FIGURE 10-31 Coats’ disease with massive exudative retinal detachment.

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FIGURE 10-32 Leber’s miliary aneurysms demonstrating dilated arterioles with terminal “light-bulbs.”

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FIGURE 10-33 Fluorescein angiogram of same patient as Figure 10-32 demonstrating capillary nonperfusion, microaneurysms, and “light-bulb” vascular dilations.

• Fluorescein angiogram: Capillary nonperfusion, microaneurysms, light-bulb vascular dilatations, leakage from telangiectatic vessels, and macular edema. Wide-field angiography is very useful to identify full extent of disease.

• Treatment: Scatter laser photocoagulation to posterior or cryotherapy to anterior areas of abnormal vasculature, telangiectasia, and areas of nonperfusion when symptomatic. May require multiple treatment sessions. Goal is to ablate areas of vascular leakage and to allow resorption of exudate.

Familial Exudative Vitreoretinopathy and Norrie’s Disease (X-Linked Recessive)

(See Hereditary Vitreoretinal Degenerations section below.)

Incontinentia Pigmenti (X-Linked Dominant)

Ocular, CNS, dermatologic, and dental findings including skin blisters, retinal neovascularization, vitreous hemorrhage, and traction retinal detachment. Associated with mutation in the NEMO gene located on chromosome Xq28.

• Fluorescein angiogram: Shows perpheral nonperfusion; wide-angle angiography is especially useful.

• Treatment: Scatter laser photocoagulation to ischemic retina when neovascularization develops. Consider vitrectomy when traction retinal detachment or nonclearing vitreous hemorrhage is present should be performed by a retina specialist.

Eales’ Disease

Bilateral, idiopathic, peripheral obliterative vasculopathy that occurs in healthy, young adults aged 20–30 years old, with male predilection. Patients usually notice floaters and decreased vision and have areas of perivascular sheathing, vitreous cells, peripheral retinal nonperfusion, microaneurysms, intraretinal hemorrhages, white sclerotic ghost vessels, disc/iris/retinal neovascularization, and vitreous hemorrhages. Fibrovascular proliferation may lead to tractional retinal detachments. May have signs of ocular inflammation with keratic precipitates, anterior chamber cells and flare, and cystoid macular edema; variable prognosis. Eales’ disease is a diagnosis of exclusion; must rule out other causes of inflammation or neovascularization including BRVO, diabetic retinopathy, sickle cell retinopathy, multiple sclerosis, sarcoidosis, tuberculosis, SLE, and other collagen–vascular diseases.

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FIGURE 10-34 Eales’ disease with ghost vessels, peripheral capillary nonperfusion, and neovascularization.

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FIGURE 10-35 Fluorescein angiogram of patient with Eales’ disease demonstrating extensive peripheral nonperfusion and neovascularization.

• Fluorescein angiogram: Midperipheral retinal nonperfusion with well-demarcated boundary between perfused and nonperfused areas; microaneurysms and neovascularization.

• Treatment: Scatter laser photocoagulation to nonperfused retina when neovascularization develops. If vitreous hemorrhage obscures view of retina, peripheral cryotherapy can be applied to ablate peripheral avascular retina.

• Consider periocular or systemic steroids for inflammatory component.

Macular Telangiectasia (Idiopathic Juxtafoveal / Perifoveal Telangiectasia)

Group of retinal vascular disorders with abnormal perifoveal capillaries confined to the juxtafoveal region (1–199 μm from center of fovea). Several forms:

Type 1A (Unilateral Congenital Parafoveal Telangiectasia)

Occurs in men in the fourth to fifth decades. Yellow exudate at outer edge of telangiectasis usually temporal to the fovea and 1–2 disc diameters in area; decreased vision ranging from 20 / 25 to 20 / 40 from macular edema and exudate. May represent mild presentation of Coats’ disease in an adult.

• Fluorescein angiogram: Unilateral cluster of telangiectatic vessels with variable leakage; macular edema often with petalloid leakage.

• Optical coherence tomography: Characteristic outer retinal hyporeflective cavities that do not correspond to leakage on FA. May eventually lead to atrophy.

• Treatment: Consider focal laser photocoagulation to leaking, nonsubfoveal vessels.

Type 1B (Unilateral Idiopathic Parafoveal Telangiectasia)

Occurs in middle-aged men. Minimal exudate usually confined to 1 clock hour at the edge of the foveal avascular zone; usually asymptomatic with vision better than 20/25.

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FIGURE 10-36 Macular telangiectasia type 1b with mild retinal pigment epithelium changes at edge of fovea.

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FIGURE 10-37 Fluorescein angiogram of same patient as Figure 10-36, demonstrating hyperfluorescent leakage from telangiectatic vessels.

• Fluorescein angiogram: Unilateral cluster of telangiectatic vessels with variable leakage; macular edema often with petalloid leakage.

• Optical coherence tomography: Characteristic outer retinal hyporeflective cavities that do not correspond to leakage on FA. May eventually lead to atrophy.

• No treatment recommended.

Type 2 (Bilateral Acquired Parafoveal Telangiectasia)

Onset of symptoms in the fifth to sixth decades with equal sex distribution. Symmetric, bilateral, right-angle venules within 1 disc diameter of the central fovea; usually found temporal to the fovea but may surround the fovea; mild blurring of central vision early, slowly progressive loss of central vision over years; blunting or grayish discoloration of the foveal reflex, right-angle retinal venules, and characteristic stellate retinal pigment epithelial hyperplasia/atrophy; leakage from telangiectatic vessels, but no exudates; associated with CNV, hemorrhagic macular detachments, and retinochoroidal anastomosis. May be caused by chronic venous stasis in the macula from unknown reasons.

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FIGURE 10-38 Macular telangiectasia type 2 with abnormal foveal reflex, intraretinal hemorrhages and retinal pigment epithelium changes.

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FIGURE 10-39 Fluorescein angiogram of patient shown in Figure 10-38, demonstrating hyperfluorescent leakage from telangiectatic vessels and blockage from the hemorrhages.

• Fluorescein angiogram: Bilateral, right-angle venules with variable leakage; macular edema often with petalloid leakage; choroidal neovascularization can develop.

• Optical coherence tomography: Characteristic outer retinal hyporeflective cavities that do not correspond to leakage on FA. May eventually lead to atrophy.

• No treatment recommended unless CNV develops because focal laser photocoagulation to leaking, nonsubfoveal vessels and anti-VEGF injections do not prevent visual loss.

• Consider focal laser photocoagulation of juxtafoveal and extrafoveal CNV, and intravitreal anti-VEGF agents such as 1.25 mg bevacizumab (Avastin) for subfoveal CNV (experimental).

Type 3 (Bilateral Perifoveal Telangiectasis with Capillary Obliteration)

Rare form; occurs in adults in the fifth decade; no sex predilection. Slowly progressive loss of vision due to the marked aneurysmal dilatation and obliteration of the perifoveal telangiectatic capillary network; no leakage from telangiectasis; associated with optic nerve pallor, hyperactive deep tendon reflexes, and other central nervous system symptoms.

• Fluorescein angiogram: Aneurysmal dilation of capillary bed with minimal to no leakage; extensive, progressive macular capillary nonperfusion, choroidal neovascularization can develop.

• No treatment recommended unless CNV develops.

• Consider focal laser photocoagulation of juxtafoveal and extrafoveal CNV, and intravitreal anti-VEGF agents such as 1.25 mg bevacizumab (Avastin) for subfoveal CNV (experimental).

• Neurology consultation to rule out central nervous system disease.

Retinopathies Associated with Blood Abnormalities

Retinopathy of Anemia

Superficial, flame-shaped, intraretinal hemorrhages, cotton-wool spots, and rarely exudates, retinal edema, and vitreous hemorrhage in patients with anemia (hemoglobin < 8 g / 100 mL). Retinopathy is worse when associated with thrombocytopenia. Roth spots are found in pernicious anemia and aplastic anemia.

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FIGURE 10-40 Retinopathy of anemia demonstrating intraretinal hemorrhages, cotton-wool spots, and Roth spots.

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FIGURE 10-41 Retinopathy of anemia demonstrating intraretinal hemorrhages and cotton-wool spots.

• Resolves with treatment of anemia.

• Medical or hematology consultation.

Leukemic Retinopathy

Ocular involvement in leukemia is common (80%). Patients are usually asymptomatic. Characterized by superficial, flame-shaped, intraretinal (24%), preretinal, and vitreous hemorrhages (2%), microaneurysms, Roth spots (11%), cotton-wool spots (16%), dilated/tortuous vessels, perivascular sheathing, and disc edema; rarely direct leukemic infiltrates (3%). Direct choroidal involvement appears with choroidal infiltrates, choroidal thickening, and an overlying serous retinal detachment. “Sea fan”-shaped retinal neovascularization can occur late. Retinopathy is due to the associated anemia, thrombocytopenia, and hyperviscosity. Opportunistic infections are also found in patients with leukemia, but are not considered part of leukemic retinopathy.

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FIGURE 10-42 Leukemic retinopathy with macular edema, cotton-wool spots, and intraretinal hemorrhages.

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FIGURE 10-43 Leukemic retinopathy with intraretinal and preretinal hemorrhages, cotton-wool spots, and Roth spots.

• Lab tests: CBC, platelets, bone marrow biopsy.

• Resolves with treatment of underlying hematologic abnormality.

• Treat direct leukemic infiltrates with systemic chemotherapy to control the underlying problem and/or ocular radiation therapy if systemic therapy fails; should be performed by an experienced tumor specialist.

• Medical or oncology consultation.

Sickle Cell Retinopathy

Nonproliferative and proliferative vascular changes due to the sickling hemoglobinopathies; results from mutations in hemoglobin (Hb) where the valine is substituted for glutamate at the 6th position in the polypeptide chain (linked to chromosome 11p15) altering Hb conformation and deformability in erythrocytes. This leads to poor flow through capillaries. Proliferative changes (response to retinal ischemia) are more common with Hb SC (most severe) and Hb SThal variants; Hb SS is associated with angioid streaks; Hb AS and Hb AC mutations rarely cause ocular manifestations. Patients are usually asymptomatic, but may have decreased vision, visual field loss, floaters, photopsias, scotomas, and dyschromatopsia; more common in people of African and Mediterranean descent. Retinopathy follows an orderly progression:

Stage I

Background (nonproliferative) stage with venous tortuosity, “salmon patch” hemorrhages (pink intraretinal hemorrhages), iridescent spots (schisis cavity with refractile elements), cotton-wool spots, hairpin vascular loops, macular infarction, angioid streaks, black “sunburst” chorioretinal scars, comma-shaped conjunctival and optic nerve head vessels, and peripheral arteriole occlusions.

Stage II

Arteriovenous (AV) anastomosis stage with peripheral “silver-wire” vessels and shunt vessels between arterioles and medium-sized veins at border of perfused and nonperfused retina.

Stage III

Neovascular (proliferative) stage with sea-fan peripheral neovascularization (spontaneously regresses in 60% of cases due to autoinfarction); sea-fans grow along retinal surface in a circumferential pattern and have a predilection for superotemporal quadrant (develop approximately 18 months after formation of AV anastamosis).

Stage IV

Vitreous hemorrhage stage with vitreous traction bands contracting around the sea-fans, causing vitreous hemorrhages (most common in SC variant, 21–23%; SS, 2–3%).

Stage V

Retinal detachment stage with tractional/rhegmatogenous retinal detachments from contraction of the vitreous traction bands.

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FIGURE 10-44 Nonproliferative sickle cell retinopathy demonstrating preretinal hemorrhage, iridescent spots, and black sunbursts.

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FIGURE 10-45 Proliferative sickle cell retinopathy demonstrating sea-fans following laser treatment.

• Lab tests: Sickle cell prep, hemoglobin electrophoresis (hemoglobin C disease and sickle cell trait may have negative sickle cell prep).

• Fluorescein angiogram: Capillary nonperfusion near hairpin loops, enlarged foveal avascular zone, peripheral nonperfusion, arteriovenous anastomosis, and sea-fan neovascularization. Wide-field angiography is especially useful to evaluate for peripheral nonperfusion.

• When active peripheral neovascularization develops, scatter laser photocoagulation (500 μm spots) to nonperfused retina.

• If neovascularization persists, then complete panretinal photocoagulation and consider adding direct laser photocoagulation to neovascularization or feeder vessels (increases risk of complications including vitreous hemorrhage).

• The use of triple freeze–thaw cryotherapy for peripheral neovascularization is controversial; should be performed by a retina specialist.

• Retinal surgery for traction retinal detachment and nonclearing, vitreous hemorrhage (> 6 months); should be performed by a retina specialist. Consider exchange transfusion preoperatively (controversial); avoid scleral buckling to prevent ocular ischemia.

• Medical or hematology consultation.

Diabetic Retinopathy

Definition

Retinal vascular complication of diabetes mellitus; classified into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).

Epidemiology

Leading cause of blindness in US population aged 20–64 years old.

Insulin-Dependent Diabetes (Type I)

Juvenile onset, usually occurs before 30 years of age; most patients are free of retinopathy during first 5 years after diagnosis; 95% of patients with insulin-dependent diabetes mellitus (IDDM) get DR after 15 years; 72% will develop PDR and 42% will develop clinically significant macular edema (CSME); severity worsens with increasing duration of diabetes mellitus.

Non-Insulin-Dependent Diabetes (Type II)

Adult onset, usually diagnosed after 30 years of age; more common form (90%) with optimal control without insulin; DR commonly exists at the time of diagnosis (60%) in non-insulin-dependent diabetes mellitus (NIDDM) with 3% having PDR or CSME at diagnosis of diabetes; 30% will have retinopathy in 5 years and 80% in 15 years. Risk of DR increases with hypertension, chronic hyperglycemia, renal disease, hyperlipidemia, and pregnancy.

Symptoms

Asymptomatic, may have decreased or fluctuating vision. Advanced retinopathy can lead to complete blindness.

Signs

Nonproliferative Diabetic Retinopathy

Grading of NPDR (see Box 10-1) and risk of progression to PDR depend on the amount and location of hard and soft exudates, intraretinal hemorrhages, microaneurysms (MA), venous beading and loops, and intraretinal microvascular abnormalities (IRMA). Cotton-wool spots, dot and blot hemorrhages, posterior subcapsular cataracts, and induced myopia/hyperopia (from lens swelling due to high blood sugar) are common; may have macular edema, which can be clinically significant (CSME); usually bilateral.

Box 10-1

Diabetic Retinopathy Definitions

CLINICALLY SIGNIFICANT MACULAR EDEMA (CSME)

Retinal thickening < 500 μm from center of fovea or

Hard exudates < 500 μm from center of fovea with adjacent thickening or

Retinal thickening > 1 disc size in area < 1 disc diameter from center of fovea

HIGH-RISK (HR) CHARACTERISTICS OF PROLIFERATIVE DIABETIC RETINOPATHY (PDR)

Neovascularization of the disc (NVD) > standard photo 10A used in DRS (one-quarter to one-third disc area) or

Any NVD and vitreous hemorrhage (VH) or preretinal hemorrhage or

Neovascularization elsewhere (NVE) > standard photo 7 (one-half disc area) and VH or preretinal hemorrhage

SEVERE NONPROLIFERATIVE DIABETIC RETINOPATHY (NPDR) 4 : 2 : 1 RULE

Diffuse intraretinal hemorrhages and microaneurysms in 4 quadrants or

Venous beading in 2 quadrants or

Intraretinal microvascular abnormalities (IRMA) in 1 quadrant

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FIGURE 10-46 Moderate nonproliferative diabetic retinopathy with intraretinal hemorrhages, microaneurysms, and lipid exudate.

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FIGURE 10-47 Fluorescein angiogram of same patient as Figure 10-46 demonstrating tiny blocking defects from the intraretinal hemorrhages and spots of hyperfluorescence due to microaneurysms.

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FIGURE 10-48 Severe nonproliferative diabetic retinopathy with extensive hemorrhages, microaneurysms, and exudates.

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FIGURE 10-49 Severe nonproliferative diabetic retinopathy with diffuse macular edema and lipid exudate.

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FIGURE 10-50 Spectral domain OCT of diffuse diabetic macular edema with subretinal fluid, intraretinal fluid, and cystoid macular edema.

Proliferative Diabetic Retinopathy

Findings of NPDR often present in addition to neovascularization of the disc (NVD) or elsewhere in the retina (NVE), preretinal and vitreous hemorrhages, fibrovascular proliferation on posterior vitreous surface or extending into the vitreous cavity, and tractional retinal detachments; may develop neovascularization of the iris (NVI) and subsequent neovascular glaucoma (NVG). Usually asymmetric, but eventually bilateral.

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FIGURE 10-51 Proliferative diabetic retinopathy with retinal neovascularization and preretinal hemorrhages.

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FIGURE 10-52 Proliferative diabetic retinopathy demonstrating florid neovascularization of the disc and elsewhere.

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FIGURE 10-53 Proliferative diabetic retinopathy demonstrating neovascularization, fibrosis, and traction retinal detachment.

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FIGURE 10-54 Fluorescein angiogram of patient with proliferative diabetic retinopathy showing extensive capillary nonperfusion, neovascularization elsewhere, and vascular leakage.

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FIGURE 10-55 Proliferative diabetic retinopathy demonstrating neovascularization of the disc.

Differential Diagnosis

Hypertensive retinopathy, CRVO, BRVO, ocular ischemic syndrome, radiation retinopathy, retinopathy associated with blood disorders, Eales’ disease, hypertensive retinopathy.

Evaluation

• Complete ophthalmic history and eye exam with attention to tonometry, gonioscopy (NVG), iris (NVI), lens, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy (retinal vascular abnormalities, optic disc [NVD], and midperiphery [NVE]):

IDDM Type I: Examine 5 years after onset of diabetes mellitus, then annually if no retinopathy is detected.

NIDDM Type II: Examine at diagnosis of diabetes mellitus, then annually if no retinopathy is detected.

During pregnancy: Examine before pregnancy, each trimester, and 3–6 months post partum.

• Lab tests: Fasting blood glucose, hemoglobin A1C, blood urea nitrogen (BUN), and creatinine.

• B-scan ultrasonography to rule out tractional retinal detachment in eyes when dense vitreous hemorrhage obscures view of fundus.

• Fluorescein angiogram: Capillary nonperfusion, microaneurysms, macular edema, and disc/retinal neovascularization. Wide-field angiography is helpful to evaluate peripheral nonperfusion and to find early neovascularization.

• Optical coherence tomography: Increased retinal thickness, cysts, and subretinal fluid in cases of macular edema; can highlight the presence of posterior hyaloidal traction and traction macular detachment.

• Medical consultation with attention to blood pressure, cardiovascular system, renal status, weight, and glycemic control.

Management

• Tight control of blood glucose levels (Diabetes Control and Complications Trial-DCCT conclusion for Type I diabetics and United Kingdom Prospective Diabetes Study-UKPDS conclusion for Type II diabetics).

• Tight blood pressure control (United Kingdom Prospective Diabetes Study-UKPDS conclusion for Type II diabetics).

• Laser photocoagulation using transpupillary delivery and argon green (focal/panretinal photocoagulation) or krypton red laser (panretinal photocoagulation when vitreous hemorrhage or cataract is present), depending on stage of diabetic retinopathy.

• Clinically significant macular edema (CSME; seeBox 10-1): Macular grid photocoagulation (50–100 μm spots) to areas of diffuse leakage and focal treatment to focal leaks regardless of visual acuity (Early Treatment Diabetic Retinopathy Study-ETDRS conclusion). If foveal avascular zone is enlarged (macular ischemia) on fluorescein angiography then light treatment away from the foveal ischemia can be considered. Laser can be either given combined with anti-VEGF agents or deferred (4 months) after starting anti-VEGF agents (DRCR.net Study result).

• Intravitreal anti-VEGF agents such as 0.3 mg ranibizumab [Lucentis] (RISE / RIDE / RESTORE / DRCR.net Study result), 0.3 mg pegaptanib [Macugen], 2 mg aflibercept [Eylea] (VIVID/VISTA Study result), or 1.25 mg bevacizumab [Avastin] have been shown to reduce macular edema, improve visual acuity, and improve diabetic retinopathy severity scores.

• Second-line intravitreal steroid therapy consists of intravitreal 2–4 mg triamcinolone acetonide [Triessence or Kenalog] (DRCR.net Study result) and the sustained-release biodegradable dexamethasone implant [Ozurdex]. In some countries, sustained-release non-readable fluocinolone implant [Iluvien] useful in chronic CMSE patients.

• High-risk (HR) PDR (seeBox 10-1): Scatter panretinal photocoagulation (PRP), 1200–1600 burns, 1 burn-width apart (500 μm gray-white spots) in two to three sessions (Diabetic Retinopathy Study-DRS conclusion). Treat inferior/nasal quadrants first to allow further treatment in case of subsequent vitreous hemorrhage during treatment and to avoid worsening macular edema.

• Additional indications for panretinal photocoagulation: Rubeosis, neovascular glaucoma, widespread retinal ischemia on fluorescein angiogram, NVE alone in type I IDDM, poor patient compliance, and severe NPDR in a fellow eye or patient with poor outcome in first eye.

• Patients approaching high-risk PDR should have focal treatment to macular edema before panretinal photocoagulation to avoid worsening of macular edema with PRP; if high-risk characteristics exist, do not delay panretinal photocoagulation for focal treatment.

• Pars plana vitrectomy, endolaser, and removal of any fibrovascular complexes in patients with nonclearing vitreous hemorrhage for 6 months or vitreous hemorrhage for > 1 month in type 1 IDDM (Diabetic Retinopathy Vitrectomy Study-DRVS conclusions); other indications for vitreoretinal surgery include monocular patient with vitreous hemorrhage, bilateral vitreous hemorrhage, diabetic macular edema due to posterior hyaloidal traction, tractional retinal detachment (TRD) with rhegmatogenous component, TRD involving macula, progressive fibrovascular proliferation despite complete PRP, dense premacular hemorrhage or if ocular media are not clear enough for adequate view of fundus to perform PRP; should be performed by a retina specialist.

• Experimental surgical treatment of refractory, diffuse macular edema include pars plana vitrectomy with peeling of posterior hyaloid with/without removal of the internal limiting membrane especially with the presence of a taut, posterior hyaloid exerting traction on the macula.

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FIGURE 10-56 Proliferative diabetic retinopathy before laser treatment.

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FIGURE 10-57 Same patient as Figure 10-56 demonstrating quiescent proliferative diabetic retinopathy following pan-retinal photocoagulation. Note absence of neovascularization.

Prognosis

Early treatment allows better control. Good for NPDR without CSME. After adequate treatment, diabetic retinopathy often becomes quiescent for extended periods of time. Focal laser photocoagulation improves vision in 17% of cases (ETDRS conclusion). Complications include cataracts (often posterior subcapsular) and neovascular glaucoma.

Hypertensive Retinopathy

Definition

Retinal vascular changes secondary to chronic or acutely (malignant) elevated systemic blood pressure.

Epidemiology

Hypertension defined as blood pressure > 140 / 90 mmHg; 60 million Americans over 18 years of age have hypertension; more prevalent in African Americans.

Symptoms

Asymptomatic; rarely, decreased vision.

Signs

Retinal arteriole narrowing/straightening, copper- or silver-wire arteriole changes (arteriolosclerosis), arteriovenous crossing changes (nicking), cotton-wool spots, microaneurysms, flame hemorrhages, hard exudates (may be in a circinate or macular star pattern), Elschnig spots (yellow [early] or hyperpigmented [late] patches of retinal pigment epithelium overlying infarcted choriocapillaris lobules), Siegrist streaks (linear hyperpigmented areas over choroidal vessels), arterial macroaneurysms, and disc hyperemia or edema with dilated tortuous vessels (in malignant hypertension).

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FIGURE 10-58 Hypertensive retinopathy with disc edema, macular star, and retinal folds in a patient with acute, malignant hypertension. Inset shows arteriovenous nicking.

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FIGURE 10-59 Hypertensive retinopathy demonstrating attenuated arterioles, choroidal ischemia, Elschnig spots, and Siegrist streaks.

Fundus findings are graded/classified as follows:

Keith Wagener Barker grades

Grade 1: Generalized arteriolar constriction, seen as “copper or silver wiring” and vascular tortuosity

Grade 2: Grade 1 + arteriovenous crossing changes (nicking)

Grade 3: Grade 2 + cotton wool spots and flame hemorrhages

Grade 4: Grade 3 + swelling of the optic disc (optic disc edema).

Proposed classification scheme

1. None: No detectable signs

2. Mild: Focal or generalized arteriolar narrowing, AV nicking, silver/copper wiring

3. Moderate: Hemorrhages, microaneurysms, cotton-wool spots, hard exudates

4. Malignant: Moderate plus optic disc swelling or severely elevated blood pressure.

Differential Diagnosis

Diabetic retinopathy, radiation retinopathy, vein occlusion, leukemic retinopathy, retinopathy of anemia, collagen vascular disease, ocular ischemia syndrome, neuroretinitis, anterior ischemic optic neuropathy, papilledema.

Evaluation

• Complete ophthalmic history and eye exam with attention to noncontact biomicroscopic or contact lens fundus exam and ophthalmoscopy (retinal vasculature and arteriovenous crossings).

• Check blood pressure.

• Fluorescein angiogram: Retinal arteriole narrowing/straightening, microaneurysms, capillary nonperfusion, and macular edema.

• Medical consultation with attention to cardiovascular and cerebrovascular systems.

Management

• Treat underlying hypertension.

Prognosis

Usually good.

Toxemia of Pregnancy

Severe hypertension, proteinuria, edema (pre-eclampsia), and seizures (eclampsia) occur in 2–5% of obstetric patients in the third trimester. Patients have decreased vision, photopsias, and floaters usually just before or after delivery. Signs include focal arteriolar narrowing, cotton-wool spots, retinal hemorrhages, hard exudates, Elschnig spots (RPE changes from choroidal infarction), bullous exudative retinal detachments, neovascularization, and disc edema (all due to hypertension-related changes).

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FIGURE 10-60 Toxemia of pregnancy with serous retinal detachment and yellow-white patches.

• Fluorescein angiogram: Poor choroidal filling, capillary nonperfusion, optic disc leakage, and neovascularization.

• Usually resolves without sequelae after treating hypertension and delivery.

• Emergent obstetrics consultation if presenting to ophthalmologist.

Acquired Retinal Arterial Macroaneurysm

Focal dilatation of retinal artery (> 100 μm) often at bifurcation or crossing site; more common in women > 60 years old with hypertension (50–70%) or atherosclerosis. Usually asymptomatic, unilateral, and solitary; may cause sudden loss of vision from vitreous hemorrhage; macroaneurysms nasal to the optic disc are less likely to cause symptoms. Subretinal, intraretinal, preretinal, or vitreous hemorrhages (multilevel hemorrhages) from rupture of aneurysm, and surrounding circinate exudates are common. May spontaneously sclerose forming a Z-shaped kink at old aneurysm site.

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FIGURE 10-61 Acquired retinal arterial macroaneurysm with circinate exudate.

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FIGURE 10-62 Acquired retinal arterial macroaneurysm before laser photocoagulation. Inset shows the same lesion after laser treatment.

• Fluorescein angiogram: Immediate uniform, focal filling of the macroaneurysm early with late leakage.

• Indocyanine green angiogram: Uniform, focal filling of the macroaneurysm; it is very useful to identify RAM in the presence of intra- and preretinal hemorrhage.

• Most require no treatment, especially in the absence of loss of vision.

• Low-intensity, longer-duration, argon green or yellow laser photocoagulation to microvascular changes around leaking aneurysm if decreased acuity is present (direct treatment controversial because it may cause a vitreous hemorrhage, distal ischemia, or a branch retinal artery occlusion).

• Consider pars plana vitrectomy with surgical evacuation of subretinal hemorrhage (with or without injection of subretinal tissue plasminogen activator) in cases of massive, subfoveal hemorrhage < 10 days old (experimental).

• Medical consultation for hypertension.

Radiation Retinopathy

Definition

Alteration in retinal vascular permeability after receiving local ionizing radiation usually from external beam radiotherapy or plaque brachytherapy.

Etiology

Endothelial cell DNA damage secondary to the radiation leading to progressive cell death and damage to the retinal blood vessels.

Epidemiology

Usually requires > 30–35 Gy (3000–3500 rads) total radiation dose; appears 0.5–2 years after ionizing radiation; diabetics and patients receiving chemotherapy have a lower threshold.

Symptoms

Often asymptomatic until retinopathy involves macula; decreased vision.

Signs

Microaneurysms, telangiectasia, cotton-wool spots, hard exudates, retinal hemorrhages, macular edema, vascular sheathing, disc edema, retinal/disc/iris neovascularization; may have cataract, dry eye disease, lid abnormalities.

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FIGURE 10-63 Radiation papillopathy. Note regressed malignant melanoma temporally.

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FIGURE 10-64 Radiation retinopathy with sclerotic vessels overlying regressed malignant melanoma.

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FIGURE 10-65 Radiation retinopathy with sclerotic vessels, neovascularization, and preretinal hemorrhage.

Differential Diagnosis

Diabetic retinopathy, sickle cell retinopathy, hypertensive retinopathy, retinal vascular occlusion, retinopathy of anemia/thrombocytopenia, and leukemic retinopathy.

Evaluation

• Complete radiation history with attention to radiated field, total dose delivered, and fractionation schedule.

• Complete eye exam with attention to tonometry, gonioscopy, iris, lens, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Fluorescein angiogram: Capillary nonperfusion, macular edema, and neovascularization may be present.

• Optical coherence tomography: Intraretinal fluid, cstic spaces, and subretinal fluid; can monitor for treatment response.

Management

• Treatment based on similar principles used in diabetic retinopathy.

• Focal grid laser photocoagulation (50–100 μm spots) to areas of macular edema.

• Intravitreal 4 mg triamcinolone acetonide [Kenalog] and anti-VEGF agents such as 1.25 mg bevacizumab [Avastin] have been shown to decrease macular edema and transiently improve visual acuity; long-term safety and benefits are not proven.

• Panretinal photocoagulation with 1200–1600 applications (500 μm spots) if neovascular complications develop.

Prognosis

Fair; complications include cataract, macular edema/ischemia, optic atrophy, vitreous hemorrhage, and neovascular glaucoma. Two-thirds of patients maintain vision better than 20/200.

Age-Related Macular Degeneration

Definition

Progressive degenerative disease of the retinal pigment epithelium, Bruch’s membrane, and choriocapillaris. Generally classified into two types: (1) nonexudative or “dry” AMD (85%) and (2) exudative or “wet” AMD characterized by CNV and eventually disciform scarring (15%).

Epidemiology

Leading cause of blindness in US population aged > 50 years old, as well as the most common cause of blindness in the Western world; 6.4% of patients 65–74 years old and 19.7% of patients > 75 years old had signs of AMD in the Framingham Eye Study; more prevalent in Caucasians. Risk factors include increasing age (> 75 years old), positive family history, cigarette smoking, hyperopia, light iris color, hypertension, hypercholesterolemia, female gender, and presence of cardiovascular disease; nutritional factors and light toxicity also play a role in pathogenesis. Associated with variants of genes encoding the alternative complement pathway including Y402H single-nucleotide polymorphism (SNP) of complement factor H (CFH) on chromosome 1q31, ARMS2 / HTRA1 on chromosome 10q and LOC387715 on chromosome 10q, tissue inhibitor of metalloproteinase 3 (TIMP3), LIUPC, complement factor B and C2 on chromosome 6p21, complement factor I, and C3. Homozygotes (6 ×) and heterozygotes (2.5 ×) for CFH mutations are more likely to develop AMD. Their risk is even greater if they smoke (odds ratio 34 vs 7.6 in nonsmokers), have elevated ESR, and / or have elevated C-reactive protein.

Nonexudative (Dry) Macular Degeneration

Symptoms

Initially asymptomatic or may have decreased vision, metamorphopsia early. Advanced atrophic form (see Box 10-2) may have central or pericentral scotoma.

Box 10-2

AREDS Study Definitions

Category 1: Less than 5 small (< 63 μm) drusen

Category 2 (mild AMD): Multiple small drusen or single or nonextensive intermediate (63–124 μm) drusen, or pigment abnormalities

Category 3 (intermediate AMD): Extensive intermediate size drusen or 1 or more large (> 125 μm) drusen, or noncentral geographic atrophy

Category 4 (advanced AMD): Vision loss (< 20/32) due to AMD in 1 eye (due to either central/subfoveal geographic atrophy or exudative macular degeneration)

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FIGURE 10-66 Dry, age-related macular degeneration demonstrating drusen and pigmentary changes.

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FIGURE 10-67 Advanced atrophic, nonexudative, age-related macular degeneration demonstrating subfoveal geographic atrophy.

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FIGURE 10-68 Fluorescein angiogram of same patient as Figure 10-67 demonstrating well-defined window defect corresponding to the area of geographic atrophy.

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FIGURE 10-69 Spectral domain OCT of central geographic atrophy. Notice the absence of retinal pigment epithelium in the fovea with increased signal beyond the RPE.

Signs

Normal or decreased visual acuity; abnormal Amsler grid (central/paracentral scotomas or metamorphopsia); small hard drusen, larger soft drusen, geographic atrophy (GA) of the retinal pigment epithelium (RPE), RPE clumping, and blunted foveal reflex.

Differential Diagnosis

Dominant drusen, pattern dystrophy, Best’s disease, Stargardt’s disease, cone dystrophy, and drug toxicity.

Evaluation

• Complete ophthalmic history and eye exam with attention to Amsler grid and noncontact biomicroscopic or contact lens fundus exam.

• Fluorescein angiogram: Window defects from GA and punctate hyperfluorescent staining of drusen (no late leakage).

• Fundus autofluoresence: To evaluate areas of geographic atropy that appear dark. Hyperautofluorescent areas on the edges of GA are likely to portend GA enlargement.

• Optical coherence tomography: Areas of drusen and GA can be quantified on OCT. Also useful to rule out wet AMD.

Management

• Follow with Amsler grid qd and examine every 6 months; examine sooner if patient experiences a change in vision, metamorphopsia, or change in Amsler grid.

• Supplement with high-dose antioxidants and vitamins (vitamin C, 500 mg; vitamin E, 400 IU; lutein, 10 mg; zeaxanthine, 2 mg; zinc, 80 mg; and copper, 2 mg) for patients with category 3 (extensive intermediate-size drusen, 1 large drusen, noncentral geographic atrophy), or category 4 (vision loss due to AMD in 1 eye). Warning: Current smokers should not take beta carotene at such high doses owing to increased risk of lung cancer (Age Related Eye Disease Study-AREDS2 conclusion). No additional benefit was from found from supplementation with omega-3 fatty acids.

• Consider supplement with lower-dose antioxidants (e.g., Centrum Silver, iCaps, Occuvite) for patients with category 1 (few small drusen), category 2 (extensive small drusen, few intermediate drusen), and patients with strong family history.

• Currently, there are no proven, effective therapies for geographic atrophy.

• Low-vision aids may benefit patients with bilateral central visual loss due to geographic atrophy.

Prognosis

Usually good unless central GA or exudative AMD develops. Severe visual loss (defined as loss of > 6 lines) occurs in 12% of nonexudative cases; presence of large soft drusen and focal RPE hyperpigmentation increases risk of developing exudative form (MPS conclusion). Risk of advanced AMD over 5 years varies depending on category: Category 1 and 2 (1.8%), Category 3 (18%), Category 4 (43%) (AREDS conclusion).

Exudative (Wet) Macular Degeneration

Symptoms

Metamorphopsia, central scotoma, rapid visual loss.

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FIGURE 10-70 Exudative age-related macular degeneration with large choroidal neovascular membrane and accompanying subretinal hemorrhage and fibrosis as seen on (A) clinical photo, and (B) fluorescein angiogram.

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FIGURE 10-71 Exudative age-related macular degeneration demonstrating subretinal hemorrhage from choroidal neovascular membrane.

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FIGURE 10-72 Fluorescein angiogram of same patient as Figure 10-71 demonstrating leakage from the CNV and blocking from the surrounding subretinal blood.

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FIGURE 10-73 Exudative age-related macular degeneration drusen, pigmentary changes, and an occult choroidal neovascular membrane with associated serous pigment epithelial detachment (arrowheads).

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FIGURE 10-74 Fluorescein angiogram of same patient as Figure 10-73 demonstrating hyperfluorescent staining of pigmentary changes and drusen, leakage from the CNV and pooling of fluorescein dye within the serous pigment epithelial detachment.

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FIGURE 10-75 Spectral domain OCT of exudative age-related macular degeneration with subretinal pigment epithelium and subretinal fluid from an occult with no classic choroidal neovascular membrane.

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FIGURE 10-76 Spectral domain OCT of exudative age-related macular degeneration.

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FIGURE 10-77 Spectral domain OCT of choroidal neovascular membrane illustrating advanced segmentation algorithms showing the increased retinal thickness and elevated retina on the internal limiting membrane (ILM) map.

Signs

CNV, lipid exudates, subretinal or intraretinal hemorrhage/fluid, pigment epithelial detachment (PED), and retinal pigment epithelial tears; may have late fibrovascular disciform scars.

Differential Diagnosis

Dominant drusen, pattern dystrophy, Best’s disease, central serous retinopathy, Stargardt’s disease, cone dystrophy, drug toxicity, and choroidal neovascularization from other causes, including presumed ocular histoplasmosis syndrome, angioid streaks, myopic degeneration, traumatic choroidal rupture, retinal dystrophies, inflammatory choroidopathies, and optic nerve drusen.

Evaluation

• Complete ophthalmic history and eye exam with attention to Amsler grid and noncontact biomicroscopic or contact lens fundus exam.

• Fluorescein angiogram: Two forms of leakage from CNV: (1) classic leakage, defined as lacy, network of bright fluorescence during early choroidal filling views that increases in fluorescence throughout the angiogram and leaks beyond its borders in late views; (2) occult leakage, defined as stippled nonhomogeneous hyperfluorescence at the level of the RPE (best seen on stereoscopic views) that persists through to late views, but the leakage is not as bright as classic lesions (type 1 or fibrovascular PED), or late leakage of undetermined origin (type 2), where the early views show no apparent leakage, but as the angiogram progresses there is hyperfluorescent stippling at the level of the RPE in late views.

• Indocyanine green angiogram: Useful when the CNV is poorly demarcated or obscured by hemorrhage on fluorescein angiogram, or if fibrovascular pigment epithelial detachment is present (to identify areas of focal neovascularization or polypoidal choroidal vasculopathy); focal hotspots likely represent retinal angiomatous proliferation (see below); CNV also appears as plaque of late hyperfluorescence. In general, ICGA should be performed when there is lack of response to anti-VEGF therapy to rule out PCV and other masquerade syndromes.

• Optical coherence tomography: Increased retinal thickness, intraretinal fluid, cystoid spaces, subretinal fluid, pigment epithelial detachment, drusen, drusenoid PED, and/or CNV may all be seen on scans. Also useful to determine whether the CNV is type 1 (below the RPE) or type 2 (above the RPE). Usually thinned choroid on enhanced depth imaging.

Management

• Focal laser photocoagulation with argon green/yellow or krypton red laser and a transpupillary delivery system to form confluent (200–500 μm spots) white burns over the entire CNV depending on size, location, and visual acuity based on the results of the Macular Photocoagulation Study (MPS) can be performed in very select extrafoveal lesions (treat entire CNV and 100 μm beyond all boundaries). Note: Only patients with a classic, well-defined CNV met eligibility criteria for the MPS study (see Box 10-3).

• Anti-VEGF agents (bevacizumab [Avastin], ranibizumab [Lucentis], and aflibercept [Eylea]) have revolutionized management and prognosis of exudative AMD.

• Monthly injections of ranibizumab is effective in patients with either minimally classic or occult with no classic CNV (MARINA study conclusion). Monthly injections of ranibizumab is superior to PDT in patients with predominantly classic CNV (ANCHOR study conclusion).

• Either monthly or PRN treatment with bevacizumab or ranibizumab is equally effective in treating neovascular AMD at up to 2 years of follow-up (CATT, IVAN, MANTA, and GEFAL study conclusions). However, there are concerns that bevacizumab may have a worse side effect profile owing to its greater systemic bioavailability; PRN dosing was not as efficacious as fixed dosing especially with bevacizumab.

• Aflibercept injected every 2 months is equivalent to ranibizumab injected monthly after 3 monthly loading doses (VIEW studies conclusion).

• The ideal treatment paradigm with anti-VEGF agents has not been determined with various retinal specialists using either monthly injections, treat and extend, and / or PRN injections for different patients.

• The phenomenon of tachyphylaxis has been seen in many patients who develop treatment resistance to a particular anti-VEGF agent but show a good response when switched to an alternative anti-VEGF treatment.

• Submacular surgery for removal of CNV or macular translocation has not been promising in regards to vision potential and has largely been abandoned.

• Low-vision aids and registration with blind services for patients who are legally blind (< 20 / 200 best corrected visual acuity or < 20° visual field in better-seeing eye).

• Treatments currently being evaluated in clinical trials include radiation therapy, modulating (feeder) vessel laser photocoagulation, other anti-VEGF agents, long-acting anti-VEGF agents, and combination therapies.

Box 10-3

Macular Photocoagulation Study (MPS) Definitions

Extrafoveal: 200–2500 μm from center of foveal avascular zone (FAZ)

Juxtafoveal: 1–199 μm from center of FAZ or choroidal neovascular membrane (CNV) 200–2500 μm from center of FAZ with blood or blocked fluorescence within 1–199 μm of FAZ center

Subfoveal: Under geometric center of FAZ

Prognosis

Long-term prognosis is not known. CNV may recur or persist after treatment; the risk of the fellow eye developing CNV is 4–12% annually.

Retinal Angiomatous Proliferation

Type 3 CNV (intraretinal neovascularization) in which neovascularization forms a retinal choroidal anastomosis as the retinal vessels grow into the subretinal space; it is considered a subset of AMD. Angiomatous proliferation within the retina is the earliest finding, which manifests as focal intraretinal hemorrhages at the site of the neovascularization with associated pigment epithelial detachment (PED). The lesions are associated with intraretinal and subretinal hemorrhage and exudates. Generally, RAP lesions are more difficult to treat than other types of CNV.

• Fluorescein angiogram: To evaluate for polypoidal lesions and differentiate from other types of CNV. RAP lesions appear as focal areas of hyperfluorescence within the pooling of fluorescein dye in the PED. There is often indistinct leakage simulating occult CNV surrounding the RAP lesion.

• Indocyanine green angiogram: Ideal for visualizing the focal area of intense hyperfluorescence (hot spot) of a RAP lesion within the hypofluorescent PED. As the RAP lesion anastomoses with the choroidal circulation it may become indistinguishable from an occult CNV.

• Optical coherence tomography: PED is present and often the retinal choroidal anastomosis can be visualized.

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FIGURE 10-78 Retinal angiomatous proliferation with intraretinal and subretinal hemorrhage as seen on (A) clinical photo, and (B) fluorescein angiogram demonstrating the focal leakage from the RAP lesion.

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FIGURE 10-79 Spectral domain OCT of retinal angiomatous proliferation showing pigment epithelial detachment and cystoid macular edema.

• Treat RAP lesions with PDT and anti-VEGF agents such as intravitreal 0.5 mg ranibizumab [Lucentis], 2.0 mg aflibercept [Eylea] or 1.25 mg bevacizumab [Avastin] like AMD (see above).

• Extrafoveal RAP lesions can be treated with focal laser photocoagulation.

Polypoidal Choroidal Vasculopathy

Subretinal, orange-red nodules with polyps seen on ICGA. Variant of type 1 choroidal neovascularization (location below RPE); controversial if this is a subset of AMD or separate disease. Often unilateral presentation, but also bilateral disease consisting of orange-red nodular elevations of the RPE (notched PED) and neurosensory retina, often with subretinal hemorrhage (may be massive), retinal pigment epithelial atrophy, and, in late stages, subretinal fibrosis. More common in African American and Asian patients; in Asians, it is more common in males, macular in location and bilateral; in African American and Caucasian patients it is more common in females, unilateral, and peripapillary in location. Occurs in 4–10% of Caucasians diagnosed with wet AMD. Patients are younger than AMD patients. Risk factors include smoking, hypertension, and diabetes. Genetic factors associated with PCV are similar to AMD and include ARMS2Y402H, and I62V on CFH, HTRA1, and C2. Differential diagnosis includes any disease that can produce occult or minimally classic CNV; usually occurs in patients aged 50–65 years old so a CNV diagnosis in these populations should make one consider PCV. Better prognosis and slower course than typical exudative AMD with loss of one to three lines over 2 years; may spontaneously regress.

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FIGURE 10-80 Polypoidal choroidal vasculopathy demonstrating the multiple, orange, serosanguinous pigment epithelial detachments as seen on (A) clinical photo, and (B) fluorescein angiogram.

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FIGURE 10-81 Indocyanine green angiogram of same patient as Figure 10-80 illustrating the polypoidal choroidal lesions.

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FIGURE 10-82 Spectral domain OCT of polypoidal choroidal vasculopathy demonstrating the multiple pigment epithelial detachments.

• Fluorescein angiogram: To evaluate for polypoidal lesions and differentiate from CNV. PCV is better visualized on ICGA, because ICG absorbs and emits near-infrared light, which readily penetrates the RPE, and the higher binding affinity to plasma proteins of ICG results in less-rapid leakage from the choriocapillaris than fluorescein, and less uptake by RPE.

• Indocyanine green angiogram: Delineates the single or multiple, grape-like, hyperfluorescent polypoidal lesion(s) early with or without an associated branching vascular network (BVN) that appear within the first 5 minutes of ICGA that measure 100–500 μm in width. The vascular abnormalities hyperfluoresce centrally early with a surrounding hypofluorescent halo surrounding the lesions. If an orange-red subretinal nodule corresponds to the hyperfluorescence, this is pathognomonic. With dynamic ICGA, pulsatile filling of the hyperfluorescent nodules may be seen. In the late phase, the lesion core may become hypofluorescent because of washout producing a ring-like appearance to the polyp. The vessels are not located in the choroid. In general, ICGA should be performed for the diagnosis of PCV when routine ophthalmoscopic examination indicates a serosanguineous maculopathy with one of the following features: clinically visible orange-red subretinal nodules, spontaneous massive subretinal hemorrhage, or a notched or hemorrhagic pigment epithelium detachment (PED).

• Optical coherence tomography: RPE detachment; may see “string of pearls” of hyperreflective material underneath RPE detachment. In some cuts, may be able to see ring of hyperreflectance under RPE and above Bruch’s membrance that corresponds to polyp. Usually associated with thickened choroid on enhanced depth imaging.

• Observation in cases without foveal hemorrhage, exudative changes, or signs of symptomatic activity defined as either: a drop in vision of ≥ 5 letters, subretinal/intraretinal fluid, PED, subretinal hemorrhage, or FA leakage.

• Full or reduced fluence verteporfin (Visudyne) photodynamic therapy (PDT) alone or in combination with anti-VEGF agents such as intravitreal 0.5 mg ranibizumab (Lucentis), 1.25 mg bevacizumab (Avastin), 2.0 mg aflibercept (Eylea) has shown benefit (EVEREST 1 study result).

• Can treat the entire lesion including the polyps with focal laser photocoagulation or PDT for extrafoveal lesions.

Myopic Degeneration / Pathologic Myopia

Progressive retinal degeneration that occurs in high myopia (≥ − 6.00 diopters, axial length > 26.5 mm) and pathologic myopia (≥ − 8.00 diopters, axial length > 32.5 mm); incidence of 2% in US population. Findings include scleral thinning, posterior staphyloma, lacquer cracks (irregular, yellow streaks), peripapillary, atrophic temporal crescent, tilted optic disc, Fuchs’ spots (dark spots due to RPE hyperplasia in macula), “tigroid” fundus due to thinning of RPE allowing visualization of larger choroidal vessels, subretinal hemorrhage (especially near lacquer cracks) and chorioretinal atrophy; increased incidence of posterior vitreous detachment, premature cataract formation, glaucoma, lattice degeneration, giant retinal tears, retinal detachments, macular hole, and CNV. Visual field defects may be present.

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FIGURE 10-83 Myopic degeneration with peripapillary and chorioretinal atrophy.

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FIGURE 10-84 Fluorescein angiogram of same patient as Figure 10-83 demonstrating blocking defect from subretinal hemorrhage and window defects from chorioretinal and peripapillary atrophy.

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FIGURE 10-85 Myopic degeneration with peripapillary atrophy.

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FIGURE 10-86 “Tigroid” fundus due to thinning of RPE allowing visualization of larger choroidal vessels.

• Genetics: Mapped to chromosomes 18p11.31 and 12q21-q23.

• Fluorescein angiogram: To evaluate for CNV if suspected clinically. Atrophic areas appear as window defects, lacquer cracks are hyperfluorescent linear areas that stain in late views.

• Correct any refractive error; contact lenses help reduce image minification and prismatic effect of glasses.

• Recommend polycarbonate safety glasses for sports (increased risk of choroidal rupture with minor trauma).

• Follow for signs of complications (CNV, retinal detachment, retinal breaks, macular holes, glaucoma, and cataracts).

• Treat CNV with focal laser photocoagulation per MPS guidelines in extrafoveal lesions (see Age-Related Macular Degeneration section), photodynamic therapy or anti-VEGF agents for juxtafoveal (since laser scar enlargement [“scar creep”] is common in pathologic myopia after laser treatment) and subfoveal lesions (Verteporfin in Photodynamic Therapy Pathologic Myopia Study – VIP-PM conclusion); 1.25 mg bevacizumab (Avastin), 0.5 mg ranibizumab (Lucentis), and 2 mg aflibercept (Eylea) (MYRROR Study result) have shown benefit.

• Treat retinal detachment and macular holes with vitreoretinal surgery performed by a retina specialist.

Angioid Streaks

Definition

Full-thickness breaks in calcified, thickened Bruch’s membrane with disruption of overlying RPE.

Etiology

Idiopathic or associated with systemic diseases (50% of cases) including pseudoxanthoma elasticum (PXE, 60%; redundant skin folds in the neck, gastrointestinal bleeding, hypertension), Paget’s disease (8%; extraskeletal calcification, osteoarthritis, deafness, vertigo, increased serum alkaline phosphatase and urine calcium levels), senile elastosis, calcinosis, abetalipoproteinemia, sickle cell disease (5%), thalassemia, hereditary spherocytosis, and Ehlers–Danlos syndrome (blue sclera, hyperextendable joints, elastic skin); also associated with optic disc drusen, acromegaly, lead poisoning, Marfan’s syndrome, and retinitis pigmentosa.

Symptoms

Usually asymptomatic; may have decreased vision, metamorphopsia if choroidal neovascular membrane develops.

Signs

Normal or decreased visual acuity; linear, irregular, deep, dark red-brown streaks radiating from the optic disc in a spoke-like pattern; often have “peau d’orange” retinal pigmentation, peripheral salmon spots, “histo-like” scars, and pigmentation around the streaks; may have subretinal hemorrhage/fluid, retinal pigment epithelial detachments, macular degeneration, and central/paracentral scotomas if CNV develops.

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FIGURE 10-87 Angioid streaks appear as dark-red, branching lines radiating from the optic nerve.

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FIGURE 10-88 Angioid streaks radiating from the optic nerve.

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FIGURE 10-89 Fluorescein angiogram of same patient as shown in Figure 10-88, demonstrating hyperfluorescent window defects corresponding to the angioid streaks.

Differential Diagnosis

Age-related macular degeneration, lacquer cracks, myopic degeneration, choroidal rupture, choroidal folds, hypertensive retinopathy (Siegrist streaks), ophthalmic artery occlusion.

Evaluation

• Complete ophthalmic history and eye exam with attention to noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Check Amsler grid to rule out CNV.

• Lab tests: Sickle cell prep, hemoglobin electrophoresis (sickle cell disease), serum alkaline phosphatase, serum lead levels, urine calcium, stool guaiac, skin biopsy.

• Fluorescein angiogram: To evaluate for CNV if suspected clinically. Usually occurs along the track of an angioid streak and has granular pattern of hyperfluorescence.

• Medical consultation to rule out systemic diseases including skin biopsy and radiographs.

Management

• Treat CNV with focal photocoagulation similar to MPS guidelines in extrafoveal lesions. For subfoveal CNV, intravitreal 1.25 mg bevacizumab (Avastin) has shown benefit.

• Polycarbonate safety glasses because mild blunt trauma can cause hemorrhages or choroidal rupture.

• Treat underlying medical condition.

Prognosis

Good unless CNV develops (high recurrence rates).

Central Serous Chorioretinopathy

Definition

Idiopathic leakage of fluid from the choroid into the subretinal space (94%), under the RPE (3%), or both (3%), presumably due to RPE or choroidal dysfunction.

Epidemiology

Usually occurs in males (10:1) aged 20–50 years old; in women, it tends to occur at a slightly older age. Usually unilateral, but can be bilateral; more common in Caucasians, Hispanics, and Asians; rare in African Americans. Associated with type-A personality, stress, hypochondriasis; also associated with pregnancy, steroid use, hypertension, Cushing’s syndrome, systemic lupus erythematosus, and organ transplantation.

Symptoms

Decreased vision, micropsia, metamorphopsia, central scotoma, and mild dyschromatopsia; may be asymptomatic.

Signs

Normal or decreased visual acuity ranging from 20 / 20 to 20 / 200 (visual acuity improves with pinhole or plus lenses); induced hyperopia, abnormal Amsler grid (central / paracentral scotomas or metamorphopsia); single or multiple, round- or oval-shaped shallow, serous retinal detachment or pigment epithelial detachment with deep-yellow spots at the level of the retinal pigment epithelium; areas of retinal pigment epithelium atrophy may occur at sites of previous episodes. Subretinal fibrin suggests active leakage. Rarely associated with type 1 CNV and subretinal fluid.

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FIGURE 10-90 Idiopathic central serous retinopathy with large serous retinal detachment.

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FIGURE 10-91 Fluorescein angiogram of same patient as shown in Figure 10-90, demonstrating classic smoke-stack appearance.

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FIGURE 10-92 Spectral domain OCT of central serous retinopathy. Note the normal foveal depression over the subretinal fluid

Differential Diagnosis

Age-related macular degeneration (especially in patients > 50 years old), Vogt–Koyanagi–Harada syndrome or other inflammatory choroidal disorders, uveal effusion syndrome, toxemia of pregnancy, optic nerve pit, choroidal tumors, vitelliform macular detachment, pigment epithelial detachment from other causes including PCV and CNV.

Evaluation

• Complete ophthalmic history and eye exam with attention to Amsler grid, noncontact biomicroscopic or contact lens fundus examination, and ophthalmoscopy.

• Fluorescein angiogram: Focal dot of hyperfluorescence early that leaks in a characteristic smoke-stack pattern (10%) or gradually pools into a pigment epithelial detachment (90%); more than one site may be present simultaneously (30%); often punctate window defects are seen in other areas in both eyes; recurrent leakage sites are often close to original sites.

• Indocyanine green angiogram: Choroidal hyperpermeability.

• Optical coherence tomography: Enhanced depth imaging of the choroid shows a thickened choroid in affected eye and often in the fellow eye; subretinal fluid and often sub-RPE fluid visible. Useful to follow patients for progression/regression.

• Fundus autofluorescence: Characteristic teardrop-shaped hyperautofluorescence pattern extending from the site of leakage downward. May have other hyperautofluorescent areas from previous episodes.

Management

• Taper and stop all corticosteroid-containing products. Often need to confirm that there is no topical, intra-articular, intravenous, or inhaled corticosteroid use.

• No treatment required in most cases; usually resolves spontaneously over 6 weeks.

• Treatment considered for patients who require quicker visual rehabilitation for occupational reasons (monocular, pilots, etc.), poor vision in fellow eye due to central serous retinopathy, no resolution of fluid after several months, recurrent episodes with poor vision, or in severe forms of central serous retinopathy known to have a poor prognosis.

• Laser photocoagulation to the hot spot has been shown to reduce duration of symptoms, but not affect final acuity. There have been some reports that photocoagulation reduces the recurrence rate, but others have observed no difference.

• Full or reduced fluence photodynamic therapy (PDT) to the hot spot or area of leakage has been shown to improve vision and resolve leakage (experimental). Fluid reduction has been shown to be more rapid with PDT than laser. Combination treatment with PDT and anti-VEGF injection has been tried, but has not been shown to be better than PDT alone.

• Mifepristone (oral glucocorticoid antagonist), eplerenone (mineralocorticoid receptor antagonist), spironolactone (in females) and rifampin, a cytochrome P450 inhibitor, have been tried in more chronic cases with some early success especially in chronic, bilateral, and / or multifocal cases, but is still considered experimental.

Prognosis

Good; 94% regain ≥ 20 / 30 acuity; 95% of pigment epithelial detachments resolve spontaneously in 3–4 months, acuity improves over 21 months; recurrences common (45%) and usually occur within a year. Recovery of visual acuity is faster following laser treatment but recovery of contrast sensitivity is prolonged and may ultimately be reduced; 5% develop PCV or CNV. Prognosis is worse for patients with recurrent disease, multiple areas of detachment, or chronic course.

Cystoid Macular Edema

Definition

Accumulation of extracellular fluid in the macular region with characteristic cystoid spaces in the outer plexiform layer.

Etiology

Postoperative (especially in older patients and if the posterior capsule is violated with vitreous loss; CME following cataract surgery is called Irvine–Gass syndrome with peak incidence 4–6 weeks after surgery), post laser treatment (neodymium : yttrium–aluminum– garnet [Nd : YAG] laser capsulotomy, especially if performed within 3 months of cataract surgery), uveitis, diabetic retinopathy, macular or retinal telangiectasia, retinal vein occlusions, retinal vasculitis, epiretinal membrane, hereditary retinal dystrophies (dominant CME, retinitis pigmentosa), medications (epinephrine in aphakic patients, dipivefrin, and prostaglandin analogues), hypertensive retinopathy, exudative AMD, occult rhegmatogenous retinal detachment, intraocular tumors, collagen vascular diseases, hypotony, and chronic inflammation.

Symptoms

Decreased or washed-out vision.

Signs

Decreased visual acuity, loss of foveal reflex, thickened fovea, foveal folds, intraretinal cystoid spaces, lipid exudates; may have signs of uveitis or surgical complications including open posterior capsule, vitreous to the wound, peaked pupil, or iris incarceration in wound.

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FIGURE 10-93 Cystoid macular edema with decreased foveal reflex, cystic changes in fovea, and intraretinal hemorrhages.

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FIGURE 10-94 Fluorescein angiogram of same patient as shown in Figure 10-93 demonstrating characteristic petalloid appearance with optic nerve leakage.

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FIGURE 10-95 Spectral domain OCT of cystoid macular edema demonstrating intraretinal cystoid spaces and dome-shaped configuration of fovea.

Differential Diagnosis

Macular hole (stage 1), foveal retinoschisis, central serous retinopathy, choroidal neovascular membrane, pseudocystoid macular edema (no leakage on fluorescein angiography) such as x-linked retinoschisis, Goldmann–Favre disease, and nicotinic acid maculopathy.

Evaluation

• Complete ophthalmic history and eye exam with attention to cornea, anterior chamber, iris, lens, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Fluorescein angiogram: Early, perifoveal, punctate hyperfluorescence and characteristic late leakage in a petalloid pattern. Late leakage of optic nerve head seen with Irvine–Gass syndrome. Note: No leakage occurs in pseudocystoid macular edema from juvenile retinoschisis, nicotinic acid (niacin) maculopathy, Goldmann–Favre disease, and some forms of retinitis pigmentosa.

• Optical coherence tomography: Increased retinal thickness with round, cystoid spaces and loss of normal foveal contour with or without subsensory fluid.

Management

• Treat underlying etiology if possible.

• Discontinue topical epinephrine, dipivefrin, or prostaglandin analogue drops, and nicotinic-acid-containing medications. Rarely, diuretics and oral contraceptive pills can cause an atypical CME that resolves on discontinuing medication.

• Topical nonsteroidal anti-inflammatory drugs (NSAIDs, diclofenac [Voltaren] or ketorolac [Acular] qid, nepafenac [Nevanac/Ilevro] tid/qd, or bromfenac [Bromday/Prolensa] qd and/ or topical steroid (prednisolone acetate 1% qid for 1 month, then taper slowly). One randomized study suggested that combination treatment with NSAID and steroid drops were more effective than either alone.

• Consider posterior sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg/mL) in patients who do not respond to topical medications.

• If no response, consider oral NSAIDs (indometacin 25 mg po tid for 6–8 weeks), oral steroids (prednisone 40–60 mg po qd for 1–2 weeks, then taper slowly), and/ or oral acetazolamide (Diamox 250 mg po bid); all are unproven.

• In refractory cases consider intravitreal injection of 4 mg triamcinolone acetonide (experimental).

• If vitreous is present to the wound and vision is < 20 /80, consider Nd : YAG laser vitreolysis or perform pars plana vitrectomy with peeling of posterior hyaloid (Vitrectomy-Aphakic Cystoid Macular Edema Study conclusion).

Prognosis

Usually good; spontaneous resolution in weeks to months (postsurgical); poorer for chronic CME (> 6 months), may develop macular hole.

Macular Hole

Definition

Retinal hole in the fovea.

Etiology

Idiopathic; other risk factors are cystoid macular edema, vitreomacular traction, trauma, post surgery, myopia, post laser treatment and post inflammatory.

Epidemiology

Senile (idiopathic) macular holes (83%) usually occur in women (3 : 1) aged 60–80 years old; traumatic holes rare (5%); 25–30% are bilateral.

Symptoms

Decreased vision, metamorphopsia, and less commonly central scotoma.

Signs

Decreased visual acuity ranging from 20 / 40 in stage 1 to 20 / 100 to HM in stages 3 / 4; retinal detachments rare except in high myopes. Fundus findings were classified into five stages by Gass:

Stage 0

Vitreomacular adhesion or traction in fellow eye of patient with full-thickness macular hole in other eye.

Stage 1

Premacular hole (impending hole) with foveal detachment, absent foveal reflex, macular cyst (1A = yellow foveal spot, 100–200 μm in diameter, 1B = yellow ring, 200–350 μm in diameter); in OCT classification scheme.

Stage 2

Early, small, full-thickness hole either centrally within the ring or eccentrically at the ring’s margin. Seventy-five percent will progress to stage 3 or 4 holes.

Stage 3

Full-thickness hole (≥ 300 μm) with yellow deposits at level of retinal pigment epithelium (Klein’s tags), operculum, cuff of subretinal fluid, cystoid macular edema, and positive Watzke–Allen sign (subjective interruption of slit beam on biomicroscopy).

Stage 4

Stage 3 and posterior vitreous detachment (PVD).

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FIGURE 10-96 Macular hole with multiple yellow spots (Klein’s tags) at the base of the hole.

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FIGURE 10-97 Fluorescein angiogram of same patient in Figure 10-96 demonstrating early hyperfluorescence of the hole that does not leak in late views.

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FIGURE 10-98 OCT demonstrating cross-sectional image of all stages 1–4 (A–D, respectively) of macular hole formation and the full-thickness retinal defect characteristic of stage 3 and 4 holes.

Also can be classified by OCT findings with subclassification based on size of smallest retinal aperature, presence/absence of traction, and presence/absence of other conditions (e.g., trauma, high myopia):

Small: < 250 μm

Medium: 250–400 μm

Large: > 400 μm.

Differential Diagnosis

Epiretinal membrane with pseudohole, solar retinopathy, central serous chorioretinopathy, vitreomacular traction syndrome, cystoid macular edema, solitary druse, and lamellar holes can appear clinically like MH, but are easily differentiated by OCT.

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity, Amsler grid, Watzke–Allen test, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Fluorescein angiogram: Hyperfluorescent window defect in the central fovea.

• Optical coherence tomography: Full-thickness defect in retina with or without traction on edges of hole; can differentiate lamellar holes and cysts from true macular holes; useful for determining treatment options and surgical planning.

Management

• No treatment recommended for stage 0 and 1 holes because spontaneous hole closure can occur, but 50% progress necessitating surgery.

• Macular holes < 400 μm in width with evidence of vitreomacular traction can be treated with intravitreal injection of 2.5 mg / mL ocriplasmin (Jetrea) (MIVI-TRUST Study result), with 50% closure rate without surgery.

• Pars plana vitrectomy, membrane peel, gas fluid exchange, and gas injection with 7 days prone positioning for full-thickness macular holes; should be performed by a retina specialist.

Prognosis

Good for recent-onset holes; surgery has successful anatomic results in 60–95% depending on duration, of which 73% have improved acuity; preoperative visual acuity is inversely correlated with the absolute amount of visual improvement; poor for holes > 1 year’s duration.

Vitreomacular Adhesion and Traction

Vitreomacular traction (VMT) is defined as complete or partial adhesion of the vitreous cortex to the macular surface due to anomalous posterior vitreous detachment. Usually not symptomatic and can be observed until symptoms develop.

• Optical coherence tomography: Traction of the vitreous cortex to the retina leading to retinal architectural changes.

• Symptomatic vitreomacular traction can be treated with intravitreal injection of 2.5 mg / mL ocriplasmin (Jetrea) (MIVI-TRUST Study result). Good candidates would have one or more of the following features: no epiretinal membrane, adhesion < 1500 μm in width, age < 65 years, and phakic.

• In severe cases, vitrectomy and membrane peel can be performed by a retina specialist.

Epiretinal Membrane / Macular Pucker

Definition

Cellular proliferation along the internal limiting membrane and retinal surface; contraction of this membrane causes the retinal surface to become wrinkled (pucker/cellophane maculopathy).

Etiology

Risk factors include prior retinal surgery, intraocular inflammation, retinal vascular occlusion, sickle cell retinopathy, vitreous hemorrhage, trauma, macular holes, intraocular tumors such as angiomas and hamartomas, telangiectasis, retinal arterial macroaneurysms, retinitis pigmentosa, laser photocoagulation, PVD, retinal break, and cryotherapy; often idiopathic.

Epidemiology

Incidence increases with increasing age; it occurs in 2% of population > 50 years old and in 20% > 75 years old; 20–30% are bilateral, although often asymmetric. Slight female predilection (3 : 2); diabetes has been found to be associated with idiophathic ERMs.

Symptoms

Asymptomatic with normal or near-normal vision; mild distortion or blurred vision; less commonly macropsia, central photopsia, or monocular diplopia if macular pucker exists.

Signs

Normal or decreased visual acuity; abnormal Amsler grid; thin, translucent membrane appears as mild sheen (cellophane) along macula; may have dragged or tortuous vessels, retinal striae, pseudoholes, foveal ectopia, and cystoid macular edema. Occasionally multiple punctate hemorrhages occur in the inner retina.

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FIGURE 10-99 Cellophane epiretinal membrane with retinal striae.

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FIGURE 10-100 Epiretinal membrane with dragged vessels.

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FIGURE 10-101 Spectral domain OCT of epiretinal membrane with increased retinal thickening.

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FIGURE 10-102 Spectral domain OCT of pseudohole due to an epiretinal membrane. Since the defect is not full thickness, this is not a macular hole.

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FIGURE 10-103 Spectral domain OCT of epiretinal membrane illustrating advanced segmentation algorithms showing the increased retinal thickness and surface wrinkling on the ILM (internal limiting membrane) map.

Differential Diagnosis

Traction retinal detachment from diabetic retinopathy, sickle cell retinopathy, or radiation retinopathy; choroidal folds.

Evaluation

• Complete ophthalmic history and eye exam with attention to noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Optical coherence tomography to evaluate retinal thickening, hole status, and traction.

Management

• Treatment rarely required unless visual changes become problematic.

• Pars plana vitrectomy and membrane peel in patients with reduced acuity (e.g., < 20 / 50) or intractable symptoms; should be performed by a retina specialist.

Prognosis

Good; 75% of patients have improvement in symptoms and acuity after surgery.

Myelinated Nerve Fibers

Abnormal myelination of ganglion cell axons anterior to the lamina cribosa; appears as yellow-white patches with feathery borders in the superficial retina (nerve fiber layer). Typically unilateral (80%) and occurs adjacent to the optic nerve, but can be located anywhere in the posterior pole. Obscures underlying retinal vasculature and can be confused with cotton-wool spots, astrocytic hamartomas, commotio retinae, or rarely retinal artery occlusion if extensive. Patients are usually asymptomatic, but scotomas corresponding to the areas of myelination can be demonstrated on visual fields; slight male predilection.

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FIGURE 10-104 Myelinated nerve fibers demonstrating fluffy white appearance extending from optic nerve and partially obscuring disc margins and retinal vessels.

• No treatment required.

• Consider visual fields.

Solar / Photic Retinopathy

Bilateral decreased vision ranging from 20 / 40 to 20 / 100, metamorphopsia, photophobia, dyschromatopsia, after-images, scotomas, headaches, and orbital pain 1–4 hours after unprotected, long-term sun gazing. Retinal damage ranges from no changes to a yellow spot with surrounding pigmentary changes in the foveolar region in the early stages. Late changes include lamellar holes or depressions in the fovea. Vision can improve over 3–6 months, with residual scotomas and metamorphopsia. Similar problems may occur from unprotected viewing of lasers, welding arcs, and extended exposure to operating microscope lights (unilateral).

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FIGURE 10-105 Photic retinopathy demonstrating retinal edema secondary to operating-room microscope overexposure.

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FIGURE 10-106 Solar retinopathy. Note pigmentary changes in the macula.

• No effective treatment.

Toxic (Drug) Maculopathies

Aminoglycosides (Gentamicin / Tobramicin / Amikacin)

Aminoglycosides may be toxic when delivered into the eye by any technique including subconjunctival injection without apparent scleral perforation, diffusion through cataract wound from subconjunctival injection, or when used with a collagen corneal shield. Gentamicin (Garamycin) demonstrates more toxicity than amikacin (Amikin) or tobramycin (Nebcin). Toxicity, due to occlusion of the retinal capillaries by granulocytes, has occurred at doses as low as 0.1 mg of gentamicin or 0.2 mg of amikacin. It leads to acute, severe, permanent visual loss. Retinal toxic reaction with marked retinal whitening (especially in macula), arteriolar attenuation, venous beading, and widespread retinal hemorrhages; optic atrophy and pigmentary changes occur later. Poor visual prognosis.

• Fluorescein angiogram: Sharp zones of capillary nonperfusion corresponding to the areas of ischemic retina.

• No effective treatment.

Canthaxanthine (Orobronze)

The carotenoid pigment canthaxanthine is prescribed for photosensitivity disorders and vitiligo. Toxicity produces characteristic refractile yellow spots in a wreath-like pattern around the fovea (gold-dust retinopathy). Usually asymptomatic or causes mild metamorphopsia and decreased vision while this oral tanning agent is being taken. Occurs with cumulative doses > 35 g.

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FIGURE 10-107 Crystalline maculopathy due to canthaxanthine.

• Check visual fields (central 10°).

• Decrease or discontinue the medication if toxicity develops.

Chloroquine (Aralen) / Hydroxychloroquine (Plaquenil)

Quinolines were first used as an antimalarial agent in World War II and now are used to treat rheumatologic disorders such as systemic lupus erythematosis, rheumatoid arthritis, and for short-term pulse treatment for graft-versus-host disease, as well as amoebiasis. Toxicity produces central/paracentral scotomas, blurry vision, nyctalopia, photopsias, dyschromatopsia, photophobia, and, in late stages, constriction of visual fields, loss of color vision, decreased vision, and absolute scotomas. Early retinal changes include loss of foveal reflex and abnormal macular pigmentation (reversible); “bull’s eye” maculopathy (not reversible), peripheral bone spicules, vasculature attenuation, and disc pallor appear later; late stages can appear similar to end-stage retinitis pigmentosa. May also develop eyelash whitening and whorl-like subepithelial corneal deposits (cornea verticillata, vortex keratopathy). Doses > 3.5 mg / kg / day or 300 g total (chloroquine), and > 6.5 mg / kg / day of ideal body weight or 700 g total (hydroxychloroquine) may produce the maculopathy; total daily dose seems more critical than total accumulative dose; in patients with renal insufficiency, lower doses are required. Ideal body weight for men is calculated as 110 pounds (50 kg) for 5 feet (1.52 m) tall, plus 5 pounds (2.27 kg) for each inch (2.54 cm) in height over 5 feet, for women it is calculated as 100 pounds (45 kg) for 5 feet tall, plus 5 pounds for each inch in height over 5 feet. Quinolines are stored to a greater degree in lean body tissues than in fat; dosages based on actual, rather than ideal, body weight will lead to overdoses in obese patients; toxicity often progresses after medications are discontinued because the drug concentrates in the eye. Hydroxychloroquine appears safer since it does not readily cross the blood–retinal barrier (toxicity rarely occurs with use < 7 years).

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FIGURE 10-108 Bull’s eye maculopathy due to Plaquenil toxicity as seem on (A) clinical photo, and (B) fluorescein angiogram demonstrating same pattern with a circular window defect.

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FIGURE 10-109 Fundus autofluorescence showing hypoautofluorescence in the area of damaged RPE.

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FIGURE 10-110 OCT of same patient as Figure 10-108 demonstrating thinning of the retina in the area of the bull’s eye.

• Differential diagnosis of “bull’s eye” maculopathy includes cone dystrophy, AMD, Stargardt’s disease/fundus flavimaculatus, Spielmeyer–Vogt disease, albinism, fenestrated sheen macular dystrophy, central areolar choroidal dystrophy, benign concentric annular macular dystrophy, clofazimine toxicity, fucosidosis.

• Check visual acuity, visual field (central 10° with white test object), and if available one or more of the following: spectral domain optical coherence tomography (flying saucer sign), multifocal electroretinogram, or fundus autofluoresence at baseline and every 6 months (chloroquine) or 12 months (hydroxychloroquine) after 5 years of use while patient is taking medications; patients with drug use > 5 years with high-fat-level body habitus, renal or liver disease, and age > 60 years old, especially if frail or extremely thin, are at higher risk of developing toxicity and should be checked more frequently.

• Low-risk patients (defined as nonobese individuals under age 60 years old, using less than 3 mg/ kg /day of chloroquine or 6.5 mg / kg /day of hydroxychloroquine for fewer than 5 years, and without concomitant renal, hepatic, or retinal disease) require no additional screening evaluations.

• Decrease or discontinue the medication if toxicity develops.

Chlorpromazine (Thorazine)

Patients have pigment deposition in eyelids, cornea, lens, and retina with toxic doses > 1200–1400 mg /day for at least 1 year.

• Decrease or discontinue the medication if toxicity develops.

Deferoxamine (Desferal)

Chelator of iron and aluminum that is prescribed for patients undergoing multiple blood transfusions. Toxicity causes decreased vision, nyctalopia, and visual field loss. The most common initial finding is a subtle gray macular discoloration, although a bull’s eye lesion may develop; a generalized pigmentary disturbance develops over weeks, which may persist despite drug discontinuation. Toxicity may occur after a single dose.

• Decrease or discontinue the medication if toxicity develops.

Interferon α

Interferon-α antiviral agents used to treat hepatitis cause vascular occlusion due to presumed immune-complex deposition. Toxicity causes cotton-wool spots, intraretinal hemorrhages, cystoid macular edema, capillary nonperfusion, and rarely vascular occlusion.

• Decrease or discontinue the medication if toxicity develops.

Methoxyflurane (Penthrane)

This inhaled anesthetic that is rarely used today may cause irreversible renal failure, partly through calcium oxalate crystalline deposition and retinal toxicity with yellow-white crystalline deposits in the posterior pole and along the arterioles. Methoxyflurane is metabolized to oxalate, which binds calcium to form insoluble calcium oxalate salts that are permanent.

• No effective treatment.

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FIGURE 10-111 Methoxyflurane toxicity demonstrating crystalline deposits along the retinal arterioles.

Niacin

Used to treat hypercholesterolemia. May produce decreased vision and metamorphopsia due to pseudocystoid macular edema (nicotinic acid maculopathy) caused by intracellular edema of Müller’s cells.

• Fluorescein angiogram: Early, perifoveal, punctate hyperfluorescence as in CME but no leakage.

• Optical coherence tomography: Cystoid spaces.

• Decrease or discontinue the medication if toxicity develops.

Quinine (Quinamm)

A quinolin, used to treat benign muscle cramps, that acutely causes retinal edema with venous engorgement and a cherry-red spot progressing to RPE mottling, retinal vascular attenuation, and optic atrophy; although the end stage resembles a vascular occlusion, the toxic effects appear to concentrate within the neurosensory retina. Toxicity causes generalized neurologic symptoms and blurred vision, visual field loss, and photophobia; acute overdose (single dose > 4 g) may cause permanent blindness.

• No effective treatment.

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FIGURE 10-112 Bull’s eye maculopathy due to quinine toxicity.

Sildenafil (Viagra)

This selective phosphodiesterase 5 (PDE-5) inhibitor commonly prescribed for erectile dysfunction, demonstrates cross-activity with the PDE-6 receptors in the photoreceptor layer. Produces reversible changes in color perception including a blue or blue-green tint or central haze of vision (may be pink or yellow); changes in light perception including darker colors appearing darker, increased perception of brightness, and flashing lights within 15–30 minutes of ingesting drug that peak within 1–2 hours; may also have photophobia and conjunctival hyperemia; resolves within 1 hour at doses < 50 mg, 2 hours with 100 mg, and 4–6 hours for 200 mg. The drug modifies the transduction cascade in photoreceptors (blocks PDE-5 10 × more than PDE-6 leading to interference in cGMP); occurs in 3% of patients taking a dose of 25–50 mg, 11% of those taking 100-mg dose, and in 40–50% of those taking > 100 mg; incidence is the same for all ages. No permanent visual effects have been reported; long-term effects are not known. Use with extreme caution in patients with retinitis pigmentosa (RP) and congenital stationary night blindness. There have been some reports of ischemic optic neuropathy, although no true association or causal relationship has been determined.

• Electrophysiologic testing: Electroretinogram (ERG) mildly reduced photopic and scotopic b-wave amplitudes and less than 10% decrease in photopic a- and b-wave implicit times during acute episode; reverts back to normal over time, no permanent effects seen.

• Decrease or discontinue the medication if toxicity develops.

• No effective treatment of ischemic optic neuropathy.

Tadalafil (Cialis) / Vardenafil (Levitra)

Similar to sildenafil; there have been some reports of ischemic optic neuropathy, although no true association or causal relationship has been determined. The FDA has advised patients to discontinue the use of these medications if they experience sudden or decreased vision loss in one or both eyes.

• No effective treatment of ischemic optic neuropathy.

Talc

Magnesium silicate (talc) has no medicinal value, but serves as a vehicle for several oral medications, including methylphenidate (Ritalin) and methadone. Refractive yellow deposits near or in arterioles occur in IV drug abusers; similar findings occur in IV drug abusers injecting suspensions of crushed methylphenidate (Ritalin) tablets. Talc particles smaller than an erythrocyte will clear the pulmonary capillary network and enter the arterial system. Repeated intravenous injection appears to induce shunt formation, allowing larger particles access to the ophthalmic artery.

• No effective treatment.

Tamoxifen (Nolvadex)

Used to treat metastatic breast adenocarcinoma. Produces refractile yellow-white crystals scattered throughout the posterior pole in a donut-shaped pattern, mild cystoid macular edema, and retinal pigmentary changes later; may develop whorl-like, white, subepithelial corneal deposits. Usually asymptomatic, but may cause mild decreases in vision and dyschromatopsia. Occurs with doses > 30 mg /day; at the initial higher dosage levels crystals often occur, but can resolve with a lowered dose.

• Fluorescein angiogram: Characteristic petalloid leakage from CME.

• Optical coherence tomography: Cystoid spaces from CME.

• Decrease or discontinue the medication if toxicity develops.

Thioridazine (Mellaril)

Phenothiazine, introduced in 1952 for the treatment of psychoses, may produce nyctalopia, decreased vision, ring/paracentral scotomas, and brown discoloration of vision. Pigment granularity/clumping in the midperiphery appears first (reversible), then progresses and coalesces into large areas of pigmentation (salt-and-pepper pigment retinopathy) or chorioretinal atrophy with short-term, high-dose use. A variant, termed nummular retinopathy, with chorioretinal atrophy posterior to the equator occurs with chronic use. Late stages can appear similar to end-stage retinitis pigmentosa or tapetoretinal degeneration with arteriolar attenuation, optic atrophy, and widespread pigmentary disturbances. Doses > 800 mg /day (300 mg recommended) can produce retinopathy; total daily dose seems more critical than total accumulative dose; may progress after medication is withdrawn because the drug is stored in the eye.

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FIGURE 10-113 Diffuse pigmentary retinopathy in end-stage thioridazine toxicity

• Check vision, color vision and visual fields every 6 months while on medication.

• Fluorescein angiogram: Salt-and-pepper pattern of hypofluorescent spots and hyperfluorescent window defects; nummular pattern produces large areas of RPE loss.

• Optical coherence tomography: Inner retinal striae may be visible. All changes are reversible with cessation of the drug.

• Electrophysiologic testing: Electroretinogram (ERG) (normal early; reduced amplitude and abnormal dark adaptation later).

• Decrease or discontinue the medication if toxicity develops.

Topiramate

Oral anticonvulsant used for the treatment of seizures, prophylaxis for migraines and off-label in the treatment of bipolar disorder as well as second-line therapy for idiopathic intracranial hypertension for patients intolerant of acetazolamide. May produce induced myopia, bilateral angle-closure glaucoma, and retinal striae caused by vitreomacular traction. It is postulated that uveal effusion or ciliary edema leads to forward displacement of the lens–iris diaphragm and thickening of the lens by relaxation of the zonules. Laser iridotomy is not useful in correcting the angle closure as the mechanism of angle closure is not pupillary block.

• Optical coherence tomography: Inner retinal striae may be visible.

• All changes are reversible with cessation of the drug.

Lipid Storage Diseases

Sphingolipid storage diseases cause accumulation of ceramide in liposomes, especially in retinal ganglion cells, giving a characteristic cherry-red spot in the macula.

Farber’s Disease (Glycolipid) (Autosomal Recessive [AR])

Mild cherry-red spot, failure to thrive, subcutaneous nodules, hoarse cry, progressive arthropathy, and early mortality by 6–18 years of age.

Mucolipidosis (Mucopolysaccharidoses) (AR)

Cherry-red spot, nystagmus, myoclonus, corneal clouding, optic atrophy, cataracts, Hurler-like facies, hepatosplenomegaly, and failure to thrive.

Niemann–Pick Disease (Ceramide Phosphatidyl Choline) (AR)

Prominent cherry-red spot, corneal stromal opacities, splenomegaly, bone marrow foam cells, and hyperlipidemia.

Sandhoff’s Disease (Gangliosidosis Type II) (AR)

Prominent cherry-red spot and optic atrophy with associated lipid-storage problems in the kidney, liver, pancreas, and other gastrointestinal organs.

Tay–Sachs Disease (Gangliosidosis Type I) (AR)

Prominent cherry-red spot, blindness, deafness, convulsions; mainly occurs in Ashkenazic Jewish children.

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FIGURE 10-114 Cherry-red spot in an infant with Tay–Sachs disease.

Peripheral Retinal Degenerations

Lattice Degeneration

Occurs in 7–10% of general population; more common in myopes; 33–50% are bilateral. Oval, circumferential area of retinal thinning and overlying vitreous liquefaction are found anterior to the equator; appears as criss-crossing, white lines (sclerotic vessels) with variable overlying retinal pigmentation that clusters in the inferior and superior peripheral retina. Atrophic holes (25%) are common; retinal tears can occur with posterior vitreous separation pulling on the atrophic, thinned retina; increased risk of retinal detachment.

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FIGURE 10-115 Lattice degeneration demonstrating retinal pigment epithelium changes and characteristic linear branching pattern.

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FIGURE 10-116 Atrophic retinal hole within an area of lattice degeneration.

• Asymptomatic lattice degeneration and atrophic holes do not require treatment; consider prophylactic treatment in patients with high myopia, aphakia, history of retinal detachment in the fellow eye, or strong family history of retinal detachment. Prophylactic treatment before cataract extraction or LASIK is controversial.

• Symptomatic lesions (photopsias/floaters) should receive prophylactic treatment with either cryopexy or two to three rows of laser photocoagulation around lattice degeneration and holes.

Pavingstone (Cobblestone) Degeneration

Occurs in 22–27% of general population; 33% bilateral. Appears as round, discrete, yellow-white spots ½ to 2 disc diameters in size with darkly pigmented borders found anterior to the equator adjacent to ora; corresponds to areas of thinned outer retina with loss of choriocapillaris and retinal pigment epithelium; usually found inferiorly; normal vitreous over lesions. May protect against retinal detachment due to adherence of thinned retina and choroid; increased incidence with age and myopia.

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FIGURE 10-117 Yellow-white, pavingstone lesions with pigmented borders characteristic of peripheral cobblestone degeneration.

• No treatment recommended.

Peripheral Cystoid Degeneration

Clusters of tiny intraretinal cysts (Blessig–Iwanoff cysts) in the outer plexiform layer just posterior to ora serrata; the bubble-like cysts can coalesce and progress to typical degenerative retinoschisis; no increased risk of retinal detachment.

• No treatment recommended.

Snail Track Degeneration

Chains of fine, white dots that occur circumferentially in the peripheral retina; it is associated with myopia. Atrophic holes may develop in the areas of degeneration, increasing the risk of retinal detachment.

• Asymptomatic snail track degeneration, atrophic holes, and tears do not require treatment; consider prophylactic treatment in patients with high myopia, aphakia, history of retinal detachment in the fellow eye, or strong family history of retinal detachment. Prophylactic treatment before cataract extraction is controversial.

• Symptomatic lesions (photopsias/floaters) should receive prophylactic treatment with either cryopexy or two to three rows of laser photocoagulation around tears or holes.

Retinoschisis

Definition

Splitting of the retina. Two types:

Acquired

Senile, degenerative process with splitting between the inner nuclear and outer plexiform layers.

Juvenile

Congenital process with splitting of the nerve fiber layer.

Epidemiology

Acquired

More common; occurs in 4–7% of general population especially in patients > 40 years old; 50–75% bilateral, often symmetric; also associated with hyperopia.

Juvenile (X-linked recessive)

Onset in first decade; may be present at birth. Mapped to XLRS1 / Retinoschisin gene on chromosome Xp22 that codes proteins necessary for cell–cell adhesion; rarely autosomal; 98% bilateral.

Symptoms

Acquired

Usually asymptomatic and nonprogressive; may have visual field defect with sharp borders.

Juvenile

Decreased vision (often due to vitreous hemorrhage), or may be asymptomatic.

Signs

Acquired

Bilateral, smooth, convex, elevated schisis cavity usually in inferotemporal quadrant (70%); height of elevation constant even with change in head position; white dots (Gunn’s dots), “snowflakes” or “frosting” and sheathed retinal vessels (sclerotic in periphery) occur in the elevated inner retinal layer; outer layer breaks are common, large, well-delineated, have rolled margins, and appear pock-marked on scleral depression; inner layer breaks, vitreous hemorrhage, and rhegmatogenous retinal detachments are rare; intact outer retinal layer whitens with scleral depression; cystoid degeneration at the ora serrata; absolute scotoma.

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FIGURE 10-118 Acquired retinoschisis with outer layer breaks.

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FIGURE 10-119 Acquired retinoschisis with evident demarcation line at edge of elevated schisis cavity.

Juvenile

Slowly progressive decreased visual acuity ranging from 20 / 25 to 20 / 80; nystagmus and strabismus often occur; foveal schisis with fine, radiating folds from fovea (occurs in 100% of cases), spoke-like foveal cysts, pigment mottling, and microcystic foveal elevation (looks like cystoid macular edema but does not stain on fluorescein angiogram) are common; may have vitreous hemorrhage, vitreous veils, retinal vessels bridging inner and outer layers; peripheral retinoschisis (50%) with peripheral pigmentation and loss of retinal vessels, especially in inferotemporal quadrant, is often found.

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FIGURE 10-120 Juvenile retinoschisis with foveal and peripheral schisis. Note bridging retinal vessel.

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FIGURE 10-121 Foveal retinoschisis with fine, radiating folds and spoke-like cysts in a patient with juvenile retinoschisis.

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FIGURE 10-122 Spectral domain OCT of foveal retinoschisis.

Differential Diagnosis

Retinal detachment, Goldmann–Favre disease, hereditary macular disease. Differentiating features from retinal detachment include no underlying RPE degeneration, blanching of RPE with laser treatment (no blanching with RD), no tobacco dust, and absolute scotoma (relative scotoma with RD).

Evaluation

• Complete ophthalmic history and eye exam with attention to color vision, noncontact biomicroscopic or contact lens fundus exam, ophthalmoscopy, and depressed peripheral retinal exam.

• Color vision: Initial tritan defect followed by deutan–tritan defect (less severe than for cone–rod dystrophy).

• Visual fields: Absolute scotomas corresponding to areas of schisis.

• Fluorescein angiogram: Macular cysts in foveal schisis do not leak fluorescein.

• Optical coherence tomography: Macular cysts occur in foveal schisis; can also differentiate retinoschisis from retinal detachment.

• Electrophysiologic testing (in juvenile cases): Electroretinogram (ERG) (select decrease in b-wave amplitude, normal a-wave; Schubert–Bornsheim tracing or electronegative ERG), electro-oculogram (EOG) (normal in mild cases to subnormal in advanced cases), and dark adaptation (normal to subnormal).

Management

• No treatment recommended; follow closely if breaks are identified.

• Children with juvenile retinoschisis should be counseled to avoid physical activity since even minor trauma can lead to vitreous hemorrhage and/or retinal detachment.

• If symptomatic rhegmatogenous retinal detachment occurs, may require retinal surgery to repair; should be performed by a retina specialist.

• If vitreous hemorrhage occurs, treat conservatively (occlusive patching in child); rarely, pars plana vitrectomy is required.

Prognosis

Good; usually stationary for years.

Retinal Detachment

Separation of the neurosensory retina from the retinal pigment epithelium. Three types:

Rhegmatogenous Retinal Detachment

Definition

From Greek rhegma = rent; retinal detachment due to full-thickness retinal break (tear/hole/dialysis) that allows vitreous fluid access to subretinal space.

Etiology

Lattice degeneration (30%), posterior vitreous detachment (especially with vitreous hemorrhage), myopia, trauma (5–10%), and previous ocular surgery (especially with vitreous loss) increase risk of rhegmatogenous retinal detachments; retinal dialysis and giant retinal tears (> 3 clock hours in extent) more common after trauma.

Symptoms

Acute onset of photopsias, floaters (“shade” or “cobwebs”), shadow or curtain across visual field, decreased vision; may be asymptomatic.

Signs

Undulating, mobile, convex retina with corrugated folds; clear subretinal fluid that does not shift with body position; retinal break usually seen; may have “tobacco-dust” (Shafer’s sign: pigment cells in the vitreous), vitreous hemorrhage, or operculum; usually lower intraocular pressure in the affected eye and may have RAPD; chronic rhegmatogenous retinal detachments (RRD) may have pigmented demarcation lines, intraretinal cysts, fixed folds, or subretinal precipitates. Configuration of detachment helps localize retinal break:

Superotemporal/nasal detachment: Break within 1–1.5 clock hours of highest border.

Superior detachment that straddles 12 o’clock: Break between 11 and 1 o’clock.

Inferior detachment with one higher side: Break within 1–1.5 clock hours of highest border.

Inferior detachment equally high on either side: Break between 5 and 7 o’clock.

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FIGURE 10-123 Rhegmatogenous retinal detachment demonstrating corrugated folds.

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FIGURE 10-124 Same patient as Figure 10-123 demonstrating peripheral horseshoe tear that caused the rhegmatogenous retinal detachment.

Differential Diagnosis

Retinoschisis, choroidal detachment.

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity, pupils, ophthalmoscopy, and depressed peripheral retinal exam to identify any retinal breaks.

• B-scan ultrasonography: If unable to visualize the fundus; smooth, convex, freely mobile retina appears as highly reflective echo in the vitreous cavity that is attached at the optic nerve head and ora serrata; retinal tears can be visualized in the periphery.

Management

• Asymptomatic, not threatening macula: Very rarely can be followed closely by a retina specialist; however, most should be treated (see below).

• Symptomatic: Pneumatic retinopexy or retinal surgery with scleral buckle/cryotherapy, with or without pars plana vitrectomy, drainage of subretinal fluid, endolaser, and / or other surgical maneuvers. Macular threatening (“Mac on”) rhegmatogenous retinal detachment is treated emergently (within 24 to 48 hours); if macula is already detached (“Mac off”), treat urgently (within 48 to 96 hours).

Prognosis

Variable (depends on underlying etiology); 5–10% of rhegmatogenous retinal detachment repairs develop proliferative vitreoretinopathy (PVR).

Serous (Exudative) Retinal Detachment

Definition

Nonrhegmatogenous retinal detachment (not secondary to a retinal break) due to subretinal transudation of fluid from tumor, inflammatory process, vascular lesions, or degenerative lesions.

Etiology

Vogt–Koyanagi–Harada syndrome, Harada’s disease, idiopathic uveal effusion syndrome, choroidal tumors, central serous retinopathy, posterior scleritis, hypertensive retinopathy, Coats’ disease, optic nerve pit, retinal coloboma, and toxemia of pregnancy.

Symptoms

Usually asymptomatic until serous retinal detachment involves macula; may have acute onset of photopsias, floaters (“shade” or “cobwebs”), shadow across visual field, or decreased vision.

Signs

Smooth, serous elevation of retina; subretinal fluid shifts with changing head position; there is no retinal break by definition; mild RAPD may be observed.

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FIGURE 10-125 Exudative retinal detachment secondary to malignant melanoma.

Differential Diagnosis

Retinoschisis, choroidal detachment, rhegmatogenous retinal detachment.

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity, pupils, ophthalmoscopy, and depressed peripheral retinal exam to identify any retinal breaks.

• B-scan ultrasonography: If unable to visualize the fundus, smooth, convex, freely mobile echoes that shifts with changing head position; retina appears as highly reflective echo in the vitreous cavity that is attached at the optic nerve head and ora serrata.

Management

• Treat underlying condition; rarely requires surgical intervention.

Prognosis

Variable (depends on underlying etiology).

Traction Retinal Detachment

Definition

Nonrhegmatogenous retinal detachment (not secondary to a retinal break) due to fibrovascular or fibrotic proliferation and subsequent contraction pulling retina up.

Etiology

Diabetic retinopathy, sickle cell retinopathy, retinopathy of prematurity, proliferative vitreoretinopathy, toxocariasis, and familial exudative vitreoretinopathy.

Symptoms

May be asymptomatic if traction retinal detachment does not involve macula; acute onset of photopsias, floaters (“shade” or “cobwebs”), shadow across visual field, or decreased vision.

Signs

Smooth, concave, usually localized, does not extend to the ora serrata; usually with fibrovascular proliferation; may have pseudoholes or true holes in a combined traction–rhegmatogenous detachment that progresses more rapidly than traction retinal detachment (TRD) alone; if a retinal tear develops, detachment may become convex.

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FIGURE 10-126 Traction retinal detachment due to proliferative vitreoretinopathy following penetrating ocular trauma.

Differential Diagnosis

Retinoschisis, choroidal detachment, rhegmatogenous retinal detachment.

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity, pupils, ophthalmoscopy, and depressed peripheral retinal exam to identify any retinal breaks.

• B-scan ultrasonography: If unable to visualize the fundus; usually has tented appearance with vitreous adhesions; retina appears as highly reflective echo in the vitreous cavity that is attached at the optic nerve head and ora serrata.

Management

• Observation unless traction retinal detachment threatens the macula or becomes a combined traction–rhegmatogenous retinal detachment.

• Vitreoretinal surgery to release the vitreoretinal traction depending on clinical situation should be performed by a retina specialist.

Prognosis

Variable (depends on underlying etiology).

Choroidal Detachment

Smooth, bullous, orange-brown elevation of retina and choroid; usually extends 360° around the periphery in a lobular configuration; the ora serrata is visible without scleral depression. There are two forms:

Choroidal Effusion / Serous

Often asymptomatic with decreased intraocular pressure; may have shallow anterior chamber. Associated with acute ocular hypotony, postsurgical (excessive filtration through filtering bleb, wound leak, cyclodialysis cleft, postscleral buckling surgery), posterior scleritis, Vogt–Koyanagi–Harada syndrome, trauma (open globe), intraocular tumors, or uveal effusion syndrome. It transilluminates.

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FIGURE 10-127 Choroidal detachment demonstrating smooth elevations of eye wall.

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FIGURE 10-128 B-scan ultrasound demonstrating choroidal detachment.

Choroidal Hemorrhage

Causes pain (often severe), decreased vision, red eye, intraocular inflammation, and increased intraocular pressure. Classically occurs acutely during anterior segment surgery, but may be delayed up to 1–7 days after surgery or trauma especially in patients with hypertension or taking anticoagulants. It does not transilluminate.

• B-scan ultrasonography: Smooth, convex, elevated membrane limited in the equatorial region by the vortex veins and anteriorly by the scleral spur; appears thicker and less mobile than retina.

• Treat intraoperative choroidal hemorrhage with immediate closure of surgical wound and, if massive hemorrhage, perform sclerotomies to allow drainage of blood, and to close surgical wound; total intraoperative drainage is usually not possible.

• Topical cycloplegic (atropine 1% bid) and steroid (prednisolone acetate 1% qid); systemic steroids have been reported to have variable effect.

• May require treatment of increased intraocular pressure (see Primary Open-Angle Glaucoma section in Chapter 11).

• Consider surgical drainage when appositional or “kissing” (temporal and nasal choroid touch), severe intraocular pressure elevation despite maximal medical treatment, or corneal decompensation; visual results in appositional choroidal hemorrhage are very poor.

• Treat underlying condition.

Chorioretinal Folds

Definition

Folds of the choroid and retina.

Etiology

Compression of the sclera produces a series of folds in the inner choroid, Bruch’s membrane, RPE, and retina. This may be idiopathic or occur secondarily due to tumors (choroidal, orbital), hypotony, inflammation (posterior scleritis, idiopathic orbital inflammation, thyroid-related ophthalmopathy, and autoimmune disorders), choroidal neovascular membranes, papilledema, and extraocular hardware (scleral buckle, radiotherapy plaque, orbital implants for fractures).

Symptoms

Asymptomatic or may have metamorphopsia or decreased vision if folds involve fovea.

Signs

Normal or decreased visual acuity; may have true or induced hyperopia and abnormal Amsler grid (metamorphopsia); chorioretinal folds appear as curvilinear, parallel, or circular oriented alternating light and dark bands, usually in the posterior pole or temporal fundus; the crest of the fold is pale and broad, while the trough between the folds is darker and narrower; idiopathic folds are usually bilateral and symmetric, while unilateral folds are more common with tumors and external lesions. May have signs of the underlying etiology (i.e., scleral injection, wound leak, proptosis, choroidal lesion, optic disc swelling).

Differential Diagnosis

Retinal folds, which are usually due to epiretinal membranes (thinner, subtler, irregular folds that do not appear on fluorescein angiography), optic disc swelling (Paton’s lines), rhegmatogenous or traction retinal detachments, ROP, toxocariasis, and congenital.

Evaluation

• Complete ophthalmic history and eye exam with attention to refraction (hyperopia), noncontact biomicroscopic or contact lens fundus examination, and ophthalmoscopy.

• Fluorescein angiogram: Characteristic alternating bands of hyper- and hypofluorescence that correspond to the peaks (where the RPE is stretched) and troughs (where the RPE is compressed) of the folds, respectively.

• Optical coherence tomography: Scans perpendicular to the direction of the folds show the hollows and bulges of the folds.

• Consider lab tests (CBC, RF, ANA, C-ANCA) for suspected autoimmune disease.

• Consider B-scan ultrasonography for posterior scleritis and to rule out a tumor.

• Consider orbital CT scan for suspected retrobulbar mass, idiopathic orbital inflammation, and thyroid-related ophthalmopathy.

• May require medical consultation depending on the etiology.

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FIGURE 10-129 Idiopathic chorioretinal folds radiating from optic disc on (A) color photo and red-free image; fluorescein angiogram (B) shows characteristic hyper- and hypofluorescent lines.

Management

• Treat underlying etiology.

Prognosis

Depends on underlying etiology.

Chorioretinal Coloboma

Defect in retina, retinal pigment epithelium, and choroid due to incomplete closure of the embryonic fissure; usually located inferonasally. Variable sizes, may involve macula; appears as yellow-white lesion with pigmented margins. Associated with other ocular colobomata; increased risk of retinal detachment and CNV at margin of coloboma.

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FIGURE 10-130 Inferior chorioretinal coloboma.

Proliferative Vitreoretinopathy

Fibrotic membranes composed of retinal pigment epithelial, glial, and inflammatory cells that form after retinal detachment or retinal surgery (8–10%); the membranes contract and pull on the retinal surface (6–8 weeks after surgery); may be preretinal or subretinal; primary cause of redetachment after successful retinal detachment surgery. Risk factors include previous retinal surgery, vitreous hemorrhage, choroidal detachment, giant retinal tears, multiple retinal breaks, penetrating trauma, excessive cryotherapy, and failure to reattach the retina at primary surgery. Final anatomic reattachment rate is 72–96%, variable visual prognosis (14–37% achieve > 20 / 100 vision).

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FIGURE 10-131 Retinal detachment with proliferative vitreoretinopathy demonstrating retinal folds and dragged vessels.

• Retinal surgery to remove preretinal and subretinal fibrotic membranes and reattach retina using silicone oil or intraocular octafluoropropane (C3F8) gas injection (The Silicone Oil Study conclusions); occasionally requires retinectomy to reattach retina; should be performed by a retina specialist.

Intermediate Uveitis / Pars Planitis

Definition

Intermediate uveitis is an inflammation primarily limited to the vitreous cavity that usually involves the pars plana and ciliary body of unknown etiology. Pars planitis is a form of intermediate uveitis, classically with vitritis, pars plana exudate, and peripheral retinal vasculitis of unknown etiology.

Epidemiology

Occurs in children and young adults; average age 23–28 years old; 75–90% are bilateral; associated with multiple sclerosis (up to 15%) and sarcoidosis. No sexual predilection; rare in African Americans and Asians. Represents roughly 5–8% of all uveitis cases with an incidence between 2 and 5 : 100,000.

Symptoms

Decreased vision, floaters; no red eye, pain, or photophobia.

Signs

Decreased visual acuity, fibrovascular exudates especially along the inferior pars plana (“snow balls or snow bank”), extensive vitreous cells (100%), vitreous cellular aggregates (“snowballs”) inferiorly, posterior vitreous detachment, vasculitis (10–32%), periphlebitis, cystoid macular edema (50–85%), and papillitis (3–20%); minimal anterior segment findings including mild anterior chamber cells and flare, fine keratic precipitate, posterior synechia, and endotheliitis; may develop neovascularization and vitreous hemorrhage in the pars plana exudate.

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FIGURE 10-132 Pars planitis demonstrating snowballs in the vitreous cavity.

Differential Diagnosis

Sarcoidosis, multiple sclerosis, tuberculosis, toxocariasis, Lyme disease, Behçet’s disease, masquerade syndromes (especially lymphoma), syphilis, cat-scratch disease, leptospirosis, Whipple’s disease, HTLV-1-associated uveitis, posterior uveitis, amyloidosis, familial exudative vitreoretinopathy, Irvine–Gass syndrome (cystoid macular edema after cataract extraction), toxoplasmosis, candidiasis, fungal endophthalmitis, Eales’ disease, Vogt–Koyanagi–Harada (VKH) syndrome, Fuchs heterochromic iridocyclitis, and retinoblastoma.

Evaluation

• Complete ophthalmic history and eye exam with attention to anterior chamber, anterior vitreous, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy (cystoid macular edema and retinal periphery).

• Lab tests: Are used to rule out other causes from differentital diagnosis although HLA-DR2 sometimes associated. ACE, chest radiographs, and serum lysozyme (sarcoidosis), CBC (masquerade syndromes), VDRL, FTA-ABS, Lyme titers, toxocariasis and toxoplasmosis IgG and IgM serology (infection).

• Fluorescein angiogram: Petalloid leakage from cystoid macular edema occurs in late views.

• CT scan of the chest to rule out mediastinal lymphadenopathy.

• Consider brain MRI or lumbar puncture to rule out multiple sclerosis if high level of suspicion.

Management

• Posterior sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL) when vision is affected by cystoid macular edema or severe inflammation.

• Oral steroids (prednisone 1 mg / kg po qd pulse with rapid taper to 10–15 mg /day) if unable to tolerate injections or in severe bilateral cases; check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Consider topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid) if severe inflammation or macular edema exists (minimal effect).

• Consider intravitreal steroid injection or implant in severe cases.

• Cryotherapy to the peripheral retina reserved for neovascularization. Pars plana vitrectomy is controversial to treat difficult cases.

• Consider immunosuppressive agents (cyclosporine [Neoral], azathioprine, methotrexate, cyclophosphamide [Cytoxan]) for recalcitrant cases (see Posterior Uveitis Management section).

Prognosis

Fifty-one percent of patients will achieve 20 / 30 vision; 10–20% may have self-limited disease; 40–60% will have a smoldering, chronic course with episodic exacerbations and remissions. Macular edema generally determines visual outcome. Zero tolerance for inflammation and aggressive treatment of active inflammation is a key factor in determining a good outcome.

Neuroretinitis (Leber’s Idiopathic Stellate Neuroretinitis)

Definition

Optic disc edema and macular star formation with no other systemic abnormalities.

Etiology

Due to pleomorphic Gram-negative bacillus Bartonella henselae (formerly known as Rochalimaea); associated with cat-scratch disease.

Symptoms

Mild, unilateral decreased vision, rarely pain with eye movement; may have viral prodrome (52%) with fever, malaise, lymphadenopathy, upper respiratory, gastrointestinal, or urinary tract infection.

Signs

Decreased visual acuity, visual field defects (cecocentral/central scotomas), RAPD, optic disc edema with macular star, peripapillary exudative retinal detachment, vitreous cells, rare anterior chamber cells and flare, yellow-white lesions at level of retinal pigment epithelium.

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FIGURE 10-133 Leber’s idiopathic stellate neuroretinitis demonstrating optic disc edema and partial macular star.

Differential Diagnosis

Hypertensive retinopathy, diabetic retinopathy, anterior ischemic optic neuropathy (AION), retinal vein occlusion, syphilis, diffuse unilateral subacute neuroretinitis (DUSN), acute macular neuroretinopathy, viral retinitis, sarcoidosis, toxocariasis, toxoplasmosis, tuberculosis, papilledema.

Evaluation

• Complete ophthalmic history and eye exam with attention to pupils, noncontact biomicroscopic and contact lens fundus exam, and ophthalmoscopy.

• Check blood pressure.

• Lab tests: VDRL, FTA-ABS, PPD and controls, indirect fluorescent antibody test for Bartonella henselae (Rochalimaea).

• Fluorescein angiogram: Leakage from optic disc capillaries, no perifoveal leakage.

Management

• No treatment necessary.

• Use of systemic antibiotics (doxycycline, tetracycline, ciprofloxacin, trimethoprim [Bactrim]) and steroids are controversial.

Prognosis

Good; 67% regain ≥ 20 / 20 vision, and 97% > 20 / 40 vision; usually spontaneous recovery; disc edema resolves over 8–12 weeks, macular star over 6–12 months; optic atrophy may develop.

Posterior Uveitis: Infections

Acute Retinal Necrosis

Fulminant retinitis/vitritis due to the herpes zoster virus (HZV), herpes simplex virus (HSV), or rarely cytomegalovirus (CMV). Occurs in healthy, as well as immunocompromised, patients; male predilection (2 : 1 over females). Patients have pain, decreased vision, and floaters after a recent herpes simplex or zoster infection. Starts with small, well-demarcated, areas of retinal necrosis outside the vascular arcades that spread rapidly and circumferentially into large, confluent areas of white, retinal necrosis with retinal vascular occlusions and small satellite lesions; 36% bilateral (BARN); associated with granulomatous anterior uveitis and retinal vasculitis. In the cicatricial phase (1–3 months later), retinal detachments (50–75%) with multiple holes and giant tears are common; poor visual prognosis (only 30% achieve > 20 / 200 vision).

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FIGURE 10-134 Acute retinal necrosis (ARN) demonstrating hemorrhage and yellow-white patches of necrosis.

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FIGURE 10-135 Same patient as Figure 10-134, 2 days later demonstrating rapid progression with confluence of lesions.

• Lab tests: HZV and HSV (type 1 and 2) immunoglobulin G and M titers or PCR.

• Systemic antiviral (acyclovir 5–10 mg/ kg IV in three divided doses qd until resolution of the retinitis, then acyclovir [Zovirax] 800 mg po 5 × day or famciclovir [Famvir] 500 mg po or valacyclovir [Valtrex] 1 g po tid for 1–2 months); follow blood urea nitrogen (BUN) and creatinine levels for nephrotoxicity.

• 24 hours after acyclovir started, oral steroids (prednisone 60–100 mg po qd for 1–2 months with slow taper); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Topical steroid (prednisolone acetate 1% q2–6 h) and cycloplegic (homatropine 5% bid) in the presence of active inflammation.

• If treatment fails, fulminant course, or patient is HIV-positive, then consider IV ganciclovir and /or foscarnet, as well as intravitreal foscarnet or ganciclovir injections 1–2 times a week (see doses in Cytomegalovirus section).

• Consider three to four rows of laser photocoagulation to demarcate active areas of retinitis and necrosis to prevent retinal breaks and retinal detachments (controversial).

• Retinal surgery for retinal detachment.

• Medical consultation.

Candidiasis

Endogenous endophthalmitis caused by fungal Candida species (C. albicans or C. tropicalis) with white, fluffy, chorioretinal infiltrates and overlying vitreous haze; vitreous “puff-balls,” anterior chamber cells and flare, hypopyon, Roth spots, and hemorrhages occur less often. Occurs in IV drug abusers, debilitated patients especially on hyperalimentation, and immunocompromised patients.

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FIGURE 10-136 Candidiasis demonstrating white fluffy, chorioretinal infiltrate.

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FIGURE 10-137 Vitreous “puff-ball” due to Candida albicans endogenous endophthalmitis.

• Lab tests: Sputum, urine, blood, and stool cultures for fungi.

• Systemic antifungal (fluconazole 100 mg po bid or amphotericin B 0.25–1.0 mg /kg IV over 6 h) if disseminated disease is present.

• If moderate-to-severe inflammation, pars plana vitrectomy and intraocular injection of antifungal (amphotericin B 0.005 mg /0.1 mL) and steroid (dexamethasone 0.4 mg /0.1 mL).

• Topical steroid (prednisolone acetate 1% qid) and cycloplegic (scopolamine 0.25% bid to qid).

• Medical consultation to treat systemic source of infection.

Cysticercosis

Subretinal or intravitreal, round, mobile, translucent, yellow-white cyst due to Cysticercus cellulosae, the larval form of the tapeworm Taenia solium. Asymptomatic until the parasite grows and causes painless, progressive, decreased vision and visual field defects; produces cystic subretinal or intravitreal lesions (cysticercus); worm death may incite an inflammatory response. May also have central nervous system (CNS) involvement with seizures, hydrocephalus, and headaches.

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FIGURE 10-138 Cysticercosis with cyst surrounding the tapeworm.

• Lab tests: Enzyme-linked immunosorbent assay (ELISA) for anticysticercus immunoglobulin G.

• B-scan ultrasonography: Highly reflective echoes from the cyst walls and often the worm within the cystic space.

• No antihelminthic medication is effective for intraocular infection.

• Consider direct laser photocoagulation of worm.

• Pars plana vitrectomy for removal of intravitreal cysticercus.

• Neurology consultation to rule out CNS involvement.

Cytomegalovirus

Hemorrhagic retinitis with thick, yellow-white retinal necrosis, vascular sheathing (severe sheathing with frosted-branch appearance may occur outside the area of retinitis), mild anterior chamber cells and flare, vitreous cells, and retinal hemorrhages. Brush-fire appearance with indolent, granular, yellow advancing border and peripheral, atrophic region is also common. Less commonly, CMV retinitis may present with a clinical picture of frosted branch angiitis. Retinal detachments (15–50%) with multiple, small, peripheral breaks commonly occur in atrophic areas. Usually asymptomatic, but may have floaters, paracentral scotomas, metamorphopsia, and decreased acuity; bilateral on presentation in 40%; 15–20% become bilateral after treatment. Most common retinal infection in AIDS (~ 12%) especially when CD4 < 50 cells/ mm3.

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FIGURE 10-139 Cytomegalovirus (CMV) retinitis demonstrating patchy necrotic lesions, hemorrhage, and vascular sheathing.

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FIGURE 10-140 Cytomegalovirus retinitis with larger areas of necrosis and hemorrhage.

• Lab tests: HIV antibody test, CD4 count, HIV viral load, urine for CMV; consider CMV PCR assay.

• If first episode, induction therapy with either:

• Ganciclovir (Cytovene 5–7.5 mg /kg IV bid for 2–4 weeks then maintenance with 5–10 mg / kg IV qd); follow CBC for neutropenia (worsened by zidovudine [formerly AZT]) and thrombocytopenia; if bone marrow suppression is severe, add recombinant granulocyte colony stimulating factor (G-CSF) (filgrastim [Neupogen]) or recombinant granulocyte–macrophage colony stimulating factor (GM-CSF) (sargramostim [Leukine]).

• Foscarnet (Foscavir, 90 mg/ kg IV bid or 60 mg /kg IV tid for 2 weeks, then maintenance with 90–120 mg / kg IV qd); infuse slowly with 500–1000 mL normal saline or 5% dextrose; push liquids to avoid dehydration; follow electrolytes (potassium, phosphorus, calcium, and magnesium), BUN, and creatinine for nephrotoxicity; avoid other nephrotoxic medications.

• Note: Foscarnet–Ganciclovir CMV Retinitis Trial showed equal efficacy of foscarnet and ganciclovir; possible survival advantage with IV foscarnet.

• Cidofovir (Vistide, 3–5 mg/ kg IV every week for 2 weeks, then maintenance with 3–5 mg / kg IV q2wk) and probenecid (1 g po before infusion, 2 mg po after infusion); does not work in patients with ganciclovir resistance; follow BUN and creatinine for nephrotoxicity.

• Alternatively, combination of intravitreal surgical implantation of a ganciclovir implant (Vitrasert: releases 1 μg/h, lasts ~ 6–8 months) and oral ganciclovir (1000–2000 mg po tid) for systemic CMV prophylaxis; good choice in new-onset, unilateral cases; do not use in recurrent cases; should be performed by a retina specialist.

• Recurrence/ progression can be re-induced with same regimen or new drug regimen (mean time to relapse ~ 60 days in Foscarnet–Ganciclovir CMV Retinitis Trial). In the era of highly active antiretroviral therapy (HAART), there is a much longer period of remission prior to reactivation.

• Treatment failures should be induced with new drug or a combination of drugs (use lower dosages due to the higher risk of toxic side effects); combination treatment is effective against disease progression (Cytomegalovirus Retreatment Trial conclusion).

• Intravitreal injections can be used if there is intolerance to antiviral therapy or progressive retinitis despite systemic treatment (should be performed by a retina specialist):

• Ganciclovir (Cytovene, 200–2000 μg/ 0.1 mL 2–3 times a week for 2–3 weeks then maintenance with 200–2000 μg /0.1 mL once a week).

• Foscarnet (Foscavir, 2.4 mg /0.1 mL or 1.2 mg / 0.05 mL 2–3 times a week for 2–3 weeks, then maintenance with 2.4 mg /0.1 mL 1–2 times a week).

• Vitravene (165–330 μg a week for 3 weeks, then every 2 weeks for maintenance).

• Follow monthly with serial photography (60°, nine peripheral fields) to document inactivity/progression.

• Retinal detachments that threaten the macula with no macular retinitis may be treated with pars plana vitrectomy, endolaser, and gas or silicon oil tamponade; peripheral shallow detachments may be followed closely (especially inferiorly) or demarcated with two to three rows of laser photocoagulation; should be performed by a retina specialist.

• Medical consultation.

Diffuse Unilateral Subacute Neuroretinitis

Unilateral, indolent, multifocal, diffuse pigmentary changes with gray-yellow outer retinal lesions that reflect the movement of a subretinal nematode: Ancylostoma caninum (dog hookworm, 400–1000 μm, endemic in southeastern United States, South America, and the Caribbean) or Baylisascaris procyonis (raccoon intestinal worm, 400–2000 μm, endemic in northern and midwestern United States). Movement of the worm is believed to cause destruction of photorecepter outer segments. Occurs in healthy patients with decreased vision (often out of proportion to retinal findings); usually minimal intraocular inflammation; may have RAPD. Chronic infection causes irreversible poor vision (20 / 200 or worse), visual field defects, optic nerve pallor, chorioretinal atrophy, and narrowed retinal vessels in a retinitis pigmentosa-like pattern. Poor prognosis without treatment; variable prognosis with treatment if worm can be killed.

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FIGURE 10-141 Diffuse unilateral subacute neuroretinitis (DUSN) demonstrating subretinal nematode (inset).

• Complete history with attention to travel and animal exposure.

• Lab tests: Stool for ova and parasites, CBC with differential (eosinophilia sometimes present), LDH and SGOT sometimes elevated.

• Fluorescein angiogram: Lesions hypofluorescent early and stain late, perivascular leakage, and disc staining; more advanced disease shows widespread window defects.

• Electrophysiologic testing: ERG (subnormal, loss of b-wave) helps differentiate from optic nerve abnormalities.

• Most effective treatment is direct laser photocoagulation of the worm. Surgical subretinal removal of the worm is controversial and very difficult.

• Systemic antihelminthic medications (thiabendazole, diethylcarbamazine, pyrantel pamoate) are controversial and often not effective; steroids are usually added since worm death may increase inflammation.

Human Immunodeficiency Virus

Asymptomatic, nonprogressive, microangiopathy characterized by multiple cotton-wool spots (50–70%), Roth spots (40%), retinal hemorrhages, and microaneurysms in the posterior pole that resolves without treatment within 1–2 months. Occurs in up to 50% of patients with HIV infection.

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FIGURE 10-142 Human immunodeficiency virus retinopathy demonstrating cotton-wool spots and one intraretinal hemorrhage.

• Lab tests: HIV antibody test, CD4 count, HIV viral load.

• No treatment necessary.

• Medical consultation.

Pneumocystis carinii Choroidopathy

Asymptomatic, unifocal or multifocal, round, creamy, yellow choroidal infiltrates located in the posterior pole caused by disseminated infection from the opportunistic organism Pneumocystis carinii. Infiltrates enlarge slowly with minimal vitreous inflammation; may be bilateral; resolution takes weeks to months after therapy is initiated. Has become very rare with the elimination of aerosolized pentamidine prophylaxis in AIDS patients.

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FIGURE 10-143 Round, creamy, yellow choroidal infiltrate from Pneumocystis carinii choroidopathy.

• Lab tests: Induced sputum or bronchoalveolar lavage (BAL) for histopathologic staining.

• Fluorescein angiogram: Early hypofluorescence with late staining of lesions.

• Systemic antibiotics (trimethoprim 20 mg/ kg and sulfamethoxazole 100 mg/ kg divided equally IV qid) or pentamidine isothionate (slow infusion 4 mg /kg IV qd) for 14–21 days.

• Medical consultation.

Presumed Ocular Histoplasmosis Syndrome

Small, round, yellow-brown, punched-out chorioretinal lesions (“histo spots”) in midperiphery and posterior pole, and juxtapapillary atrophic changes caused by the dimorphic fungus Histoplasma capsulatum. Endemic in the Ohio and Mississippi river valleys; histo spots occur in 2–3% of the population in endemic areas; rare in African Americans. Usually asymptomatic, no vitritis; macular disciform lesions can occur owing to CNV. Better visual prognosis than CNV owing to age-related macular degeneration, 30% recurrence rate; associated with HLA-B7.

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FIGURE 10-144 Presumed ocular histoplasmosis syndrome (POHS) demonstrating macular and peripapillary lesions.

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FIGURE 10-145 Presumed ocular histoplasmosis syndrome demonstrating CNV and a “histo” spot.

• Check Amsler grid.

• Lab tests: Histoplasmin antigen skin testing (not necessary).

• Fluorescein angiogram: Early hypofluorescence and late staining of histo spots, also identifies CNV if present.

• Extra- and juxtafoveal CNV (see Box 10-3) can be treated with focal laser photocoagulation (MPS-OHS conclusion). Subfoveal CNV should not be treated with laser (14% regress spontaneously).

• Consider combination treatment with PDT (Visudyne in Ocular Histoplasmosis [VOH] Study conclusion) and intravitreal 4 mg triamcinolone acetonide or anti-VEGF agents (experimental) for subfoveal CNV.

• Removal of CNV with subretinal surgery was evaluated in the Subretinal Surgery Trials (Group H); however, up to 50% recur within 1 year (experimental).

• Oral steroids (prednisone 60–100 mg po qd with slow taper) and / or intravitreal steroid injection (4 mg triamcinolone acetonide) are controversial.

Progressive Outer Retinal Necrosis Syndrome

Multifocal, patchy, retinal opacification that starts in the posterior pole and spreads rapidly to involve the entire retina owing to the herpes zoster virus (HZV); minimal anterior chamber cells and flare, vitreous cells, or retinal vasculitis (differentiates from acute retinal necrosis). Occurs in severely immunocompromised patients; poor response to therapy; may develop retinal detachments.

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FIGURE 10-146 Progressive outer retinal necrosis (PORN) with multifocal retinal opacification.

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FIGURE 10-147 Same patient as Figure 10-146, 7 days later with a massive increase in retinal necrosis. The posterior pole lesion has become atrophic.

• Lab tests: HZV immunoglobulin G and M titers.

• Systemic antiviral (acyclovir 5–10 mg / kg IV in divided doses tid until resolution of retinitis, then acyclovir [Zovirax] 800 mg po 5 × day or famciclovir [Famvir] 500 mg po or valacyclovir [Valtrex] 1 g po tid for 1–2 months); follow BUN and creatinine for nephrotoxicity.

• Topical steroid (prednisolone acetate 1% q2–6 h) and cycloplegic (scopolamine 0.25% bid to qid) in the presence of active inflammation.

• If treatment fails or fulminant course, consider IV ganciclovir and /or foscarnet, as well as intravitreal ganciclovir injections (see Cytomegalovirus section for doses).

• Laser demarcation or retinal surgery for retinal detachments; usually requires use of silicon oil.

• Medical consultation.

Rubella

Congenital syndrome classically characterized by congenital cataracts, glaucoma, and rubella retinopathy with salt-and-pepper pigmentary changes; also associated with microphthalmia, iris transillumination defects, bilateral deafness, congenital heart disease, growth retardation, and bone and dental abnormalities. Eighty percent bilateral; vision is generally good (20 / 25); may rarely develop choroidal neovascular membrane (CNV).

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FIGURE 10-148 Rubella retinopathy demonstrating salt-and-pepper fundus appearance.

• Fluorescein angiogram: Mottled hyperfluorescence.

• Electrophysiologic testing: ERG and EOG are normal.

Syphilis (Luetic Chorioretinitis)

Extensive iritis/retinitis/vitritis (panuveitis) occurs in secondary syphilis (6 weeks to 6 months after primary infection) due to the spirochete Treponema pallidum. Signs include anterior chamber cells and flare, keratic precipitates, vitritis, multifocal, yellow-white chorioretinal infiltrates, salt-and-pepper pigmentary changes, flame-shaped retinal hemorrhages, and vascular sheathing; called “great mimic,” since it can resemble many other retinal diseases; associated with sectoral interstitial keratitis, papillitis, and rarely CNV. Variant called acute syphilitic posterior placoid chorioretinitis (ASPPC) with large, placoid, yellow lesions with faded centers. Mucocutaneous manifestations of secondary syphilis are often evident.

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FIGURE 10-149 Multifocal, yellow-white chorioretinal infiltrates and vascular sheathing patient with luetic chorioretinitis

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FIGURE 10-150 Late luetic chorioretinitis with pigmentary changes and resolving chorioretinal infiltrate.

• Lab tests: Rapid Plasma Reagin (RPR, reflects current activity) or Venereal Disease Research Laboratory (VDRL, reflects current activity) and fluorescent treponemal antibody absorption (FTA-ABS) or microhemagglutination for Treponema pallidum (MHA-TP) tests.

• Lumbar puncture for VDRL, FTA-ABS, total protein, and cell counts to rule out neurosyphilis.

• Penicillin G (2.4 million U IV q4h for 10–14 days then 2.4 million U IM every week for 3 weeks); tetracycline if patient is allergic to penicillin.

• Long-term tetracycline (250–500 mg po qd) or doxycycline (100 mg po qd) in HIV-positive or immunocompromised patients.

• Follow serum RPR or VDRL to monitor treatment efficacy.

• Medical consultation.

Toxocariasis

Unilateral, multifocal, subretinal, yellow-white granulomas caused by the second-stage larval form of the roundworm Toxocara canis. Associated with papillitis, serous/traction retinal detachments, dragged macula and retinal vessels, vitritis, dense vitreous infiltrates, and chronic endophthalmitis; gray-white chorioretinal scars remain after active infection. Usually occurs in children (included in differential diagnosis of leukocoria) and young adults; associated with pica (eating dirt) and close contact with puppies; children with visceral larva migrans do not develop ocular involvement.

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FIGURE 10-151 Toxocariasis demonstrating fibrous attachment of peripheral granuloma to optic nerve with dragged retina and vessels.

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FIGURE 10-152 End-stage infection with Toxocara canis demonstrating diffuse chorioretinal scarring, dragged vessels, and granuloma.

• Lab tests: ELISA for Toxocara antibody titers.

• Topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid) for active anterior segment inflammation.

• Posterior sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg/ mL) and oral steroids (prednisone 60–100 mg po qd) for severe inflammation; check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Systemic antihelminthic medications (thiabendazole, diethylcarbamazine, pyrantel pamoate) controversial, since worm death may increase inflammation.

• Retinal surgery for retinal detachment (successful in 70–80%).

Toxoplasmosis

Acquired (eating poorly cooked meat) or congenital (transplacental transmission; accounts for 90% of ocular disease) necrotizing retinitis caused by the parasite Toxoplasma gondii. Congenital toxoplasmosis appears as an atrophic, chorioretinal scar (often located in the macula) with gray-white punctate peripheral lesions; associated with microphthalmia, nystagmus, strabismus, intracranial calcifications, convulsions, microcephaly, and hydrocephalus. Acquired toxoplasmosis (especially in immunocompromised patients) and re-activated congenital lesions present with decreased vision, photophobia, floaters, vascular sheathing, full-thickness retinal necrosis, fluffy yellow-white retinal lesion (solitary in acquired and adjacent to old scars in congenital), overlying vitreous reaction, and anterior chamber cells and flare. May have peripapillary form with disc edema and no chorioretinal lesions (simulating optic neuritis). Treatment is usually reserved for vision-threatening lesions; frequently reactivates (up to 50% by 3 years); poorer prognosis with larger lesions, recurrence, longer duration, and proximity to fovea and nerve.

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FIGURE 10-153 Toxoplasmosis demonstrating active, fluffy white lesion adjacent to old, darkly pigmented scar.

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FIGURE 10-154 Congenital toxoplasmosis demonstrating inactive chorioretinal macular and peripapillary scars.

• Lab tests: ELISA or indirect immunofluorescence assay (IFA) for Toxoplasma immunoglobulin G or M (definitive test) except in immunocompromised patients; elevated IgM indicates acquired active disease, elevated IgG is common in population (> 4 × elevation may indicate active disease).

• Posterior pole lesions (involving macula and optic nerve) or sight-threatening lesions: Pyrimethamine (Daraprim, 75–200 mg po loading dose then 25–50 mg po qd for maintenance up to 4–6 weeks), folinic acid (leucovorin 5 mg po qd), and one of the following: sulfadiazine (2 g po loading dose, then 0.5–1 g po qid for maintenance), clindamycin (300 mg po qid), clarithromycin (0.5 g po bid), azithromycin (250 mg po qd), or atovaquone (750 mg po tid); give plenty of fluids to prevent sulfadiazine renal crystals.

• Peripheral lesions: Clindamycin (300 mg po qid) and trimethoprim-sulfamethoxazole (Bactrim, 1 double-strength tablet po bid). Note: Immunocompetent patients may not require treatment.

• Treat with antibiotic combinations for 4–6 weeks; immunocompromised patients may require indefinite treatment and should be treated regardless of location of lesion with either trimethoprim-sulfamethoxazole (Bactrim, 1 double-strength tablet po bid) or doxycycline (100 mg po qid); may also consider prophylactic treatment in patients with frequent recurrences.

• If lesion is near the optic disc, in posterior pole, or if there is intense vitritis, may add oral steroids (prednisone 20–80 mg po qd for 1 week, then taper) 24 hours after starting antimicrobial therapy (never start steroids alone); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• No subconjunctival or sub-Tenon’s steroid should be given secondary to risk of acute retinal necrosis.

Tuberculosis

Multifocal (may be focal), light-colored choroidal granulomas caused by the bacilli Mycobacterium tuberculosis. May present as endophthalmitis; usually associated with constitutional symptoms including malaise, night sweats, and pulmonary symptoms.

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FIGURE 10-155 Tuberculosis with choroidal tubercle appearing as a large white subretinal mass.

• Lab tests: Positive PPD skin test and chest radiographs.

• Isoniazid (INH, 300 mg po qd) and rifampin (600 mg po qd) for 6–9 months; follow liver function tests for toxicity.

• Consider adding pyrazinamide (25–35 mg /kg po qd) for first 2 months.

• Medical consultation for systemic evaluation.

Posterior Uveitis: White Dot Syndromes

Group of inflammatory disorders that produce discrete yellow-white retinal lesions mainly in young adults; differentiated by history, appearance, laterality, and fluorescein angiogram findings.

Acute Macular Neuroretinopathy

Acute onset of paracentral scotomas usually in 20–30-year-old females (89%) following a viral prodrome (68%). Vision is often normal but may be decreased; usually presents with bilateral (68%) cloverleaf or wedge-shaped, brown-red lesions in the posterior pole with no vitreous cells. Recovery of the visual field defect is rare.

• Check Amsler grid.

• Fluorescein angiogram: Minimal hypofluorescence of the lesions.

• No effective treatment.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy

Rapid loss of central or paracentral vision in 20–30-year-old (mean 29 years), healthy adults after a flu-like, viral prodrome; no sex predilection. Usually bilateral, but asymmetric; multiple, round, discrete, large, flat gray-yellow, placoidlesions scattered throughout the posterior pole at the level of retinal pigment epithelium that later develop into well-demarcated retinal pigment epithelium scars; minimal vitreous cell; may have associated disc edema, cerebral vasculitis, headache, dysacousia, and tinnitus. Spontaneous resolution with late visual recovery within 1–6 months (80% regain ≥ 20 / 40 vision); recurrences rare.

Table 10-1

White Dot Syndromes

t0010

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FIGURE 10-156 Acute posterior multifocal placoid pigment epitheliopathy demonstrating multiple posterior pole lesions.

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FIGURE 10-157 Fluorescein angiogram of same patient as Figure 10-156 demonstrating early hypofluorescence of the lesions.

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FIGURE 10-158 Fluorescein angiogram of same patient as Figure 10-156 demonstrating late staining of the lesions.

• Fluorescein angiogram: Early hypofluorescence and late staining of the placoid lesions.

• Indocyanine green angiogram: Early and late hypofluorescence.

• No treatment necessary, but if macular (sight-threatening) lesions occur, steroids may be helpful.

Acute Retinal Pigment Epitheliitis (Krill’s Disease)

Rare cause of acute, moderate, visual loss in young adults; no sex predilection; no viral prodrome. Discrete clusters of hyperpigmented spots (300–400 μm) with hypopigmented halos at the level of the retinal pigment epithelium in the perifoveal region; usually unilateral with no vitritis. Spontaneous resolution with recovery of visual acuity within 7–10 weeks; recurrences possible.

• Fluorescein angiogram: Blockage from the central spot and hyperfluorescence corresponding to the halo.

• No effective treatment.

Birdshot Choroidopathy (Vitiliginous Chorioretinitis)

Multiple, small, discrete, ovoid, creamy yellow-white spots scattered like a birdshot blast from a shotgun in the midperiphery (spares macula); often in a vascular distribution; associated with mild vitritis, mild anterior chamber cells and flare (in 25% of cases), cystoid macular edema, and disc edema. Usually bilateral, occurs in 50–60-year-old females (70%), and almost exclusively in Caucasians; associated with HLA-A29 (90–98%). Patients have mild blurring of vision and floaters. Chronic, slowly progressive, recurring disease with variable visual prognosis; choroidal neovascular membranes, epiretinal membranes, and macular cysts/holes are late complications.

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FIGURE 10-159 Birdshot choroidopathy / vitiliginous chorioretinitis demonstrating scattered fundus lesions.

• Fluorescein angiogram: Mild hyperfluorescence, early and late staining of lesions; active lesions may hypofluoresce early. Late views show profuse vascular incompetence with leakage and secondary retinal staining.

• Electrophysiologic testing: ERG (subnormal) and EOG (subnormal); can monitor course of disease with serial ERG and can be used to monitor systemic immunomodulatory therapy.

• Treatment is reserved for patients with decreased visual acuity, significant inflammation, or complications including cystoid macular edema.

• Despite historically poor responses to steroids, initial improvement can occur with oral steroids (prednisone 60–100 mg po qd); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Consider sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg/mL) in patients with severe inflammation or cystoid macular edema.

• Cyclosporine (2–5 mg/ kg / d) can dramatically improve vitritis and cystoid macular edema; should be administered only by a specialist trained in inflammatory diseases.

Multifocal Choroiditis and Panuveitis / Subretinal Fibrosis and Uveitis Syndrome

Spectrum of disorders causing blurred vision, metamorphopsia, paracentral scotomas, and photopsias. Mainly occurs in 30–40-year-old (mean 36 years), healthy, Caucasian (86%), females (3 : 1 over males); etiology unknown. Usually unilateral symptoms with bilateral (80%) fundus findings including small (100–200 μm), round, discrete, yellow-white spots and minimal signs of intraocular inflammation; lesions develop into atrophic scars or subretinal fibrosis; choroidal neovascular membranes and macular edema are late complications. Recurrences are common; poor visual prognosis.

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FIGURE 10-160 Multifocal choroiditis demonstrating small deep spots in the macula.

• Fluorescein angiogram: Early hyperfluorescence and late staining of the lesions.

• Treatment with steroids is controversial.

Punctate Inner Choroidopathy

Acute onset of blurred vision, metamorphopsia, paracentral scotomas, and photopsias. Mainly occurs in 20–30-year-old (mean 27 years), healthy, myopic (mean − 6 diopters) females (> 90%); unknown etiology. Usually unilateral symptoms with bilateral fundus findings including small (100–200 μm), round, discrete, yellow-white spots and minimal to no signs of intraocular inflammation; lesions develop into atrophic scars over 1 month; scars progressively pigment and enlarge; choroidal neovascular membranes and macular edema are common, and late complications. Recurrences are common; good visual prognosis unless CNV or macular edema occurs.

• Fluorescein angiogram: Early hyperfluorescence and late staining of the lesions.

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FIGURE 10-161 Punctate inner choroidopathy (PIC) with small, round, yellow spots in the macula and punched-out, atrophic scars along the inferior arcade.

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FIGURE 10-162 Fluorescein angiogram of same patient as Figure 10-161 demonstrating hyperfluorescence of the active lesions and window defects of the atrophic scars.

• Treatment with steroids is controversial.

• Consider focal laser photocoagulation of juxtafoveal and extrafoveal CNV, and photodynamic therapy (PDT) or anti-VEGF agents such as 1.25 mg bevacizumab (Avastin) for subfoveal CNV (experimental).

Multiple Evanescent White Dot Syndrome

Sudden, unilateral, acute visual loss with paracentral/central scotomas and photopsias. Mainly occurs in 20–30-year-old (mean 28 years), healthy females (4 : 1 over males) after a viral prodrome (occurs in 50% of cases); cause unknown. Multiple, small (100–200 μm), discrete, gray-white spots at the level of the retinal pigment epithelium in the posterior pole sparing the fovea (spots appear and disappear quickly); may have RAPD, foveal granularity, mild vitritis, mild anterior chamber cells and flare, optic disc edema, and an enlarged blind spot. Spontaneous resolution with recovery of vision in 3–10 weeks; white dots disappear first followed by improvement in vision; recurrences rare (10%).

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FIGURE 10-163 Multiple evanescent white dot syndrome (MEWDS) demonstrating faint white spots.

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FIGURE 10-164 Same patient as Figure 10-163 demonstrating late fluorescein angiogram appearance.

• Check Amsler grid or visual fields (central 10°).

• Visual fields: Paracentral/central scotomas.

• Fluorescein angiogram: Early, punctate hyperfluorescence in a wreath-like pattern and late staining of the lesions and optic nerve.

• Indocyanine green angiogram: Early and late hypofluorescence.

• Electrophysiologic testing: ERG (reduced a-wave).

• No treatment recommended.

Acute Idiopathic Blind Spot Enlargement Syndrome

Subset of MEWDS (see above) that occurs in young females with enlargement of the blind spot and no optic disc edema and no visible fundus lesions; usually no RAPD exists. May represent MEWDS after lesions have faded.

• Check Amsler grid or visual fields (central 10°).

• Visual fields: Enlarged blind spot.

• No treatment recommended.

Posterior Uveitis: Other Inflammatory Disorders

Behçet’s Disease

Triad of aphthous oral ulcers, genital ulcers, and bilateral nongranulomatous uveitis; also associated with erythema nodosum, arthritis, vascular lesions, HLA-B5 (subtypes Bw51 and B52), and HLA-B12. The uveitis (see Chapter 6) is severe and recurring, causing hypopyon, iris atrophy, posterior synechiae, optic disc edema, attenuation of arterioles, severe vitritis, cystoid macular edema, and an occlusive retinal vasculitis with retinal hemorrhages and edema. Patients have photophobia, pain, red eye, and decreased vision. Lab tests are positive for antinuclear antibody (ANA), and elevated erythrocyte sedimentation rate (ESR) /C-reactive protein/acute phase reactants/serum proteins, but are not diagnostic. Poor visual prognosis; frequent relapses are common; ischemic optic neuropathy is a late complication.

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FIGURE 10-165 Behçet’s disease demonstrating old vasculitis with sclerosed vessels and chorioretinal atrophy.

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FIGURE 10-166 Behçet’s disease demonstrating acute vasculitis with hemorrhage.

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FIGURE 10-167 Behçet’s disease demonstrating aphthous oral ulcers on tongue.

• Lab tests: Behçetine skin test (prick skin with sterile needle, the formation of a pustule within a few minutes is a positive result), ESR, ANA, C-reactive protein, serum haplotyping.

• Fluorescein angiogram: Extensive vascular leakage early with late staining of vessel walls.

• Topical steroid (prednisolone acetate 1% q2–6h).

• Colchicine (600 mg po bid) is controversial.

• Mild: oral steroids (prednisone 60–100 mg po qd); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Severe: sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL), oral steroids (prednisone 60–100 mg po qd), and either chlorambucil (0.1 mg /kg /d) cyclophosphamide (1–2 mg / kg / d IV) or cyclosporine (2–7 mg /kg /d); should be administered by a specialist trained in inflammatory diseases (see Management section).

• Medical consultation.

Idiopathic Uveal Effusion Syndrome

Bullous serous retinal detachment (with shifting fluid), serous choroidal and ciliary body detachments, mild vitritis, leopard spot retinal pigment epithelium pigmentation, and dilated conjunctival vessels. Occurs in healthy, middle-aged males; patients have decreased vision, metamorphopsia, and scotomas; chronic, recurrent course.

• B-scan ultrasonography: Thickening of the sclera.

• Fluorescein angiogram: No discrete leak under serous retinal detachment.

• Steroids and antimetabolites are not effective.

• Consider decompression of vortex veins and scleral resection in nanophthalmic eyes.

• Surgery to create partial-thickness scleral windows is controversial.

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FIGURE 10-168 Bullous serous retinal detachment in a patient with idiopathic uveal effusion syndrome that shifts with changes in head position.

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FIGURE 10-169 B-scan ultrasound of same patient as Figure 10-168 demonstrating serous retinal detachment with shifting fluid, shallow peripheral choroidal detachment, and diffuse scleral thickening.

Masquerade Syndromes

Systemic and ophthalmologic diseases can mimic uveitis. These should always be considered in the differential diagnosis of uveitis, because they can be life-threatening. The masquerade syndromes can be divided by etiology: malignancies, endophthalmitis and noninfectious/ nonmalignant.

Malignancies

Intraocular lymphoma

This rare and lethal malignancy is commonly a non-Hodgkin’s large B-cell lymphoma of the eye and the CNS; it occurs in later adulthood (median age of 50–60 years old); sex distribution is not clear. The most common symptoms are blurred vision and floaters associated with vitritis. The vitreous has large clumps of cells and the fundus examination is significant for multifocal, large, yellow, subretinal, and sub-RPE infiltrative lesions.

• A high level of suspicion is essential in order to make the diagnosis of this condition.

• Complete neurological evaluation should be performed in search of CNS involvement including magnetic resonance imaging (MRI) and CNS cytology.

• Diagnostic pars plana vitrectomy in cases where diagnosis is in doubt. An undilute vitreous biopsy (approximately 1 mL) should be performed in the eye with vitritis and sent for cytology, flow-cytometry analysis for B- and T-cell markers and kappa/ lambda light chains. Other ancillary tests include the measurement of IL-6 and IL-10 (high IL-10 and high ratio of IL-10 to IL-6 are suggestive of intraocular lymphoma).

• The treatment of primary intraocular lymphoma is controversial and includes intravitreal methotrexate (400 μg in 0.1 mL twice weekly for 1 month, then weekly for 1 month, then monthly for a year) and orbital radiation in cases without CNS involvement. However, most patients develop CNS involvement, which is usually treated with chemotherapy with blood–brain barrier disruption or high-dose systemic methotrexate.

• Medical and oncology consultation.

Other malignancies

Other malignancies that can present as a masquerade uveitis include: leukemias, malignant melanoma, retinoblastoma, and metastatic tumors.

Endophthalmitis

Chronic postoperative endophthalmitis and endogenous endophthalmitis can present as a masquerade syndrome (see Chapter 6).

Nonmalignant / Noninfectious

These forms of masquerade syndromes comprise a group of disorders characterized by the presence of intraocular cells secondary to noninflammatory conditions. Although rare, the following disorders should be considered: rhegmatogenous retinal detachment, retinitis pigmentosa, intraocular foreign body, ocular ischemic syndrome, and juvenile xanthogranuloma.

Posterior Scleritis

Inflammation of the sclera posteriorly; produces orange-red elevation of the choroid and retinal pigment epithelium by the thickened choroid with overlying serous retinal detachments, choroidal folds, vitritis, and optic disc edema; scleral thickening can cause induced hyperopia, proptosis, limitation of ocular motility, and angle-closure glaucoma (anterior rotation of ciliary body with forward displacement of the lens–iris diaphragm). Usually occurs in 20–30-year-old females; 20–30% bilateral. Patients have pain, photophobia, and decreased vision. Associated with collagen vascular diseases, rheumatoid arthritis, relapsing polychondritis, inflammatory bowel disease, Wegener’s granulomatosis, and syphilis.

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FIGURE 10-170 Posterior scleritis with orange-red choroidal elevation superiorly, serous retinal detachments, vitritis, and mild optic disc edema.

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FIGURE 10-171 Fluorescein angiogram of same patient as Figure 10-170 demonstrating punctate hyperfluorescence and early pooling into the serous retinal detachments.

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FIGURE 10-172 B-scan ultrasound of same patient as Figure 10-170 demonstrating scleral thickening and the characteristic peripapillary T-sign.

• B-scan ultrasonography: Diffuse scleral thickening (echolucent space between choroid and Tenon’s capsule), and edema with medium reflectivity in Tenon’s space, T-sign in the peripapillary region from scleral thickening around echolucent optic nerve.

• Fluorescein angiogram: Punctate hyperfluorescence early with pooling late within serous retinal detachments.

• Oral steroids (prednisone 60–100 mg po qd); if severe, consider high-dose IV steroids; check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Oral nonsteroidal anti-inflammatory drugs (NSAIDs; indometacin 25–50 mg po tid).

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids or NSAIDs.

• Sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL) is sometimes required.

• Consider immunosuppressive therapy (azathioprine, cyclosporine) in refractory cases; should be administered by a specialist trained in inflammatory diseases.

• Medical consultation.

Sarcoidosis

Granulomatous panuveitis with retinal vasculitis, vascular sheathing, periphlebitis (candle-wax drippings), vitreous snowballs or string of pearls, yellow-white retinal/choroidal granulomas, anterior chamber cells and flare, mutton fat keratic precipitates, Koeppe /Busacca iris nodules, and macular edema. Disc/retinal neovascularization (often in sea-fan configuration) and epiretinal membranes are late complications. The disease is more severe in young African Americans (incidence 82 in 100,000), but can occur in elderly Caucasian women; bimodal age distribution with peaks at 20–30 years old and 50–60 years old; chronic, relapsing course (72%). Ocular findings occur in 25–75% of patients with sarcoidosis while 94% have lung findings; patients present first with ocular complaints in only 2–3% of cases, 15–40% present with respiratory complaints; African Americans more likely to develop ocular complications. Systemic findings include hilar adenopathy, pulmonary parenchymal involvement, pulmonary fibrosis, erythema nodosum, subcutaneous nodules, lupus pernio (purple lupus), lymphadenopathy; may also have CNS, bone, connective tissue, cardiac, renal, and sinus involvement. Pathologic hallmark is noncaseating granulomas. Most patients are asymptomatic; can have chronic, potentially fatal course.

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FIGURE 10-173 Sarcoidosis with periphlebitis and vascular sheathing.

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FIGURE 10-174 Sarcoidosis demonstrating peripheral granuloma with overlying vitritis and vitreous snowballs.

• Lab tests: ACE, chest radiographs, serum lysozyme, sickle cell prep / hemoglobin electrophoresis (to rule out sickle cell anemia); consider CT scan of the chest to rule out mediastinal lymphadenopathy; consider Gallium scan, Kneim–Silzbach skin test/reaction.

• Fluorescein angiogram: Early hyperfluorescence and late leakage from vascular permeability and macular edema.

• Topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid) for active anterior segment inflammation.

• Oral steroids (prednisone 60–100 mg po qd); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL) when macular edema is severe; topical steroids reserved for only anterior disease.

• Laser photocoagulation to areas of capillary nonperfusion when neovascularization persists or progresses after steroid treatment.

• Consider immunosuppressive therapy (hydroxychloroquine, methotrexate, chlorambucil, azathioprine) in refractory cases; should be administered only by a specialist trained in inflammatory diseases.

• Medical consultation.

Serpiginous Choroidopathy (Geographic Helicoid Peripapillary Choroidopathy)

Bilateral, asymmetric uveitis with peripapillary, well-circumscribed, gray-white active lesions, which extend centrifugally from the disc in a pseudopodal, serpiginous pattern leaving chorioretinal scars in areas of previous involvement; skip lesions common; mild vitritis. Patients have paracentral scotomas and decreased vision. Usually bilateral, slight male predilection, and occurs in the fith to seventh decades; etiology unknown; associated with HLA-B7. Chronic, recurrent disease with fair visual prognosis (severe visual loss rare); CNV develops in 25%.

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FIGURE 10-175 Serpiginous choroidopathy demonstrating typical pattern of atrophic scarring extending from the optic nerve.

• Fluorescein angiogram: Hypofluorescence early and late staining beginning at the borders of the lesion and spreading centrally.

• Indocyanine green angiogram: Early and late hypofluorescence.

• Oral steroids (prednisone 1 mg / kg /day po) and sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL) are controversial (consider when macula is threatened).

• Consider immunosuppressive therapy (azathioprine 5 mg /kg /day, cyclosporine 1.5 mg/ kg /day) in refractory cases; should be administered only by a specialist trained in inflammatory diseases.

• Laser photocoagulation, photodynamic therapy, or anti-VEGF agents for CNV depending on location in relation to the fovea.

Sympathetic Ophthalmia

Rare, bilateral, immune-mediated, mild-to-severe granulomatous uveitis that occurs typically 2 weeks to 3 months (80%) after penetrating trauma or surgery, although there are reported cases even decades later. Scattered, multifocal, yellow-white subretinal infiltrates (Dalen–Fuchs nodules, 50%) with overlying serous retinal detachments, vitritis, and papillitis. Associated with inflammation in sympathizing (fellow) eye and worsened inflammation in exciting (injured) eye (keratic precipitates are an ominous sign); may have meningeal signs, poliosis, and alopecia (as in Vogt–Koyanagi–Harada syndrome). Patients have transient visual obscurations, photophobia, pain, and blurred vision. Male predilection (probably reflects increased incidence of trauma in this group); associated with HLA-A11. Chronic, recurring course; good prognosis (65% achieve > 20 / 60 vision after treatment); spares choriocapillaris, unlike VKH.

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FIGURE 10-176 Early sympathetic ophthalmia demonstrating serous retinal detachment.

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FIGURE 10-177 Dalen–Fuchs nodules in a patient with sympathetic ophthalmia.

• Check for previous history of penetrating surgery or trauma.

• Fluorescein angiogram: Pinpoint areas of hyperfluorescence with central hypofluorescence and patchy areas of choriocapillaris hypoperfusion; leakage late from optic nerve.

• Moderate-to-high-dose oral steroids (prednisone 60–200 mg po qd); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg / mL).

• Topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid).

• Consider immunosuppressive therapy (azathioprine, methotrexate, chlorambucil); should be administered by a specialist trained in inflammatory diseases.

• No proven benefit from enucleating exciting eye, but this option should be considered in eyes with no light perception (NLP) vision, since removal of the eye within 2 weeks of injury may prevent sympathetic ophthalmia.

Vogt–Koyanagi–Harada Syndrome / Harada’s Disease

Bilateral, inflammatory disorder with yellow-white exudates at the level of the retinal pigment epithelium, bullous serous retinal detachments (75%, shifting fluid often present) and focal retinal pigment epithelial detachments; associated with anterior chamber cells and flare, mutton fat keratic precipitates, posterior synechiae, vitritis, choroidal folds, choroidal thickening, Dalen–Fuchs-like nodules, and optic disc hyperemia (Harada’s disease); may have systemic manifestations including meningeal signs (headache, nausea, stiff neck, deafness, tinnitus), poliosis, alopecia, dysacousis, and vitiligo (Vogt–Koyanagi–Harada [VKH] syndrome); late retinal pigment epithelial changes result in yellow-orange (“sunset glow”) fundus. Patients have decreased vision and photophobia. Occurs in pigmented individuals (Native Americans, African Americans, Asians, and Hispanics) 20–40 years old; slight female predilection (60%); associated with HLA-DR4, HLA-DRw53, HLA-DQw7, HLA-DQw3, and HLA-Bw54. Recurrences are common; good visual prognosis.

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FIGURE 10-178 Vogt–Koyanagi–Harada syndrome with multiple serous retinal detachments.

• B-scan ultrasonography: Low reflectivity and choroidal thickening with overlying serous retinal detachment.

• Fluorescein angiogram: Pinpoint areas of hyperfluorescence and delayed choroidal fluorescence.

• Optical coherence tomography: Thickened choroid on enhanced depth imaging. With improved inflammation the choroidal thickening also improves.

• Moderate-to-high-dose oral steroids (prednisone 60–200 mg po qd, then taper slowly); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid) in the presence of active anterior segment inflammation.

• Sub-Tenon’s steroid injection (triamcinolone acetonide 40 mg/ mL) sometimes required.

• Cyclosporine (2–7 mg/ kg / d) or immunosuppressive agents for refractory cases; should be administered by a specialist trained in inflammatory diseases.

Posterior Uveitis: Evaluation / Management

Evaluation

• Complete ophthalmic history and eye exam with attention to visual acuity, pupils, tonometry, anterior chamber, vitreous cells, noncontact biomicroscopic or contact lens fundus exam, and ophthalmoscopy.

• Consider work-up as clinical examination and history dictate (see below).

• Lab tests: Basic testing recommended for intermediate and posterior uveitis with a negative history, review of systems and medical examination: CBC, ESR, Rapid Plasma Reagin (RPR; syphilis) or VDRL (syphilis), microhemagglutination for treponema pallidum (MHA-TP; syphilis) or FTA-ABS (syphilis), Lyme titer, PPD (tuberculosis) and controls, serum lysozyme, ACE (sarcoidosis).

• Other labs tests that should be ordered according to history and / or evidence of granulomatous inflammation: ANA, RF (juvenile rheumatoid arthritis), ELISA for Lyme immunoglobulin M (IgM) and immunoglobulin G (IgG), HIV antibody test, chest radiographs (sarcoidosis, tuberculosis), sacroiliac radiographs (ankylosing spondylitis), gallium scan (sarcoidosis), urinalysis.

• Special diagnostic lab tests: HLA typing (HLA-A29: Birdshot Choroidopathy), in the presence of vasculitis: ANCA (Wegener’s granulomatosis, polyarteritis nodosa), Raji cell and C1q binding assays for circulating immune complexes (SLE, systemic vasculitides), complement proteins: C3, C4, total complement (SLE, cryoglobulinemia, glomerulonephritis), soluble IL-2 receptor.

• Medical consultation.

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FIGURE 10-179 Retinal vasculitis with sheathing of retinal vessels.

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FIGURE 10-180 Fluorescein angiogram of same patient as Figure 10-179 showing retinal vascular leakage.

Management

• Topical steroid (prednisolone acetate 1% q2–6h) and cycloplegic (scopolamine 0.25% bid to qid) for active anterior segment inflammation.

• Consider oral steroids (prednisone 60–100 mg po qd); check PPD and controls, blood glucose, and chest radiographs before starting systemic steroids.

• Add H2-blocker (ranitidine [Zantac] 150 mg po bid) when administering systemic steroids.

• Consider posterior sub-Tenon steroid injection (triamcinolone acetonide 40 mg / mL) or intravitreal steroid injection (triamcinolone acetonide 4 mg /0.1 mL).

• If the uveitis becomes steroid-dependent then consider a step-ladder approach to treat with steroid-sparing agents that would eventually allow the tapering or minimal use of topical and systemic corticosteroids:

• Nonsteroidal anti-inflammatory drugs: Diclofenac (Voltaren) 75 mg po bid or diflusinal (Dolobid) 250 mg po bid. Other nonselective NSAIDs that can be used as a second line of therapy include indometacin (Indocin SR) 75 mg po bid or naproxen (Naprosyn) 250 mg po bid. In patients with a known history of gastritis or peptic ulceration, the use of COX-2 selective inhibitor should be considered (celecoxib [Celebrex] 100 mg po bid).

• Immunosuppressive chemotherapy: Should be managed by a uveitis specialist or in coordination with a medical specialist familiar with these agents; indications include Behçet’s disease, sympathetic ophthalmia, VKH, serpiginous choroidopathy, rheumatoid necrotizing scleritis and /or PUK, Wegener’s granulomatosis, polyarteritis nodosa, relapsing polychondritis, JRA, or sarcoidosis unresponsive to conventional therapy. Methotrexate is most commonly used first.

Antimetabolites: Azathioprine 1–3 mg/ kg /day, methotrexate 0.15 mg /kg /day, mycophenolate mofetil (CellCept) 1–2 g po qd (“off-label” use for autoimmune ocular inflammatory diseases).

Inhibitors of leukocyte signaling: Cyclosporine 2.5–5.0 mg / kg /day, tacrolimus (Prograf) 0.1–0.15 mg / kg /day.

Alkylating agents: Cyclophosphamide 1–3 mg / kg/day, chlorambucil 0.1 mg / kg / day.

Biologic agents: TNF-α inhibitors (infliximab [Remicade], etanercept [Enbrel], adalimumab [Humira]).

Other agents: Dapsone 25–50 mg bid or tid, colchicine 0.6 mg po bid for Behçet’s disease is controversial.

Hereditary Chorioretinal Dystrophies

Central Areolar Choroidal Dystrophy

Starts as mild, non-specific retinal pigment epithelial granularity, mottling, and hypopigmentation in the fovea (stage 1); progresses to a round, well-defined area of geographic atrophy with loss of the choriocapillaris, RPE, and photoreceptors; the area of atrophy slowly enlarges with large choroidal vessels visible underneath; usually bilateral and symmetric. Symptoms appear in third to fifth decades with decreased vision (20/ 25–20 /200).

• Prevalence: 1 to 9 in 1,000,000.

• Inheritance: Autosomal dominant [AD].

• Genetics: Most commonly caused by mutations in the RDS / peripherin gene (now known as the peripherin-2 (PRPH2) gene) on chromosome 6p; less frequently caused by mutations in the CACD gene on chromosome 17p13. There is a high degree of nonpenetrance and variation in disease severity.

• Color vision: Moderate protan–deutan defect.

• Visual fields: Large central scotoma in late stages.

• Fundus autofluorescence: In stage 2, mildly atrophic macular lesions show both hypoautofluorescence and hyperautofluorescence resulting in a typical well-demarcated speckled pattern, which is also demonstrated in stages 3 and 4.

• Fluorescein angiogram: Early lesions may show faint RPE transmission defects within the fovea; later well-circumscribed hyperfluorescent window defects that correspond to the areas of atrophy.

• Optical coherence tomography: Disruption of the photoreceptor inner segment/outer segment junction (IS/OS) and thinning of ONL.

• Electrophysiologic testing: Full-field and multifocal ERG (photopic: normal to slightly subnormal; scotopic: normal), EOG (normal to slightly subnormal), and dark adaptation (normal) and multifocal ERG (abnormal). ERG abnormalities can be detected before symptoms or clinical features develop.

• Treatment: No effective treatment.

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FIGURE 10-181 Central atrophy in a patient with central areolar choroidal dystrophy.

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FIGURE 10-182 Left eye of same patient as Figure 10-181 demonstrating similar central atrophy.

Choroideremia

Progressive, bilateral, diffuse atrophy of the choriocapillaris and overlying retinal pigment epithelium/photoreceptors with scalloped edges and large choroidal vessels visible underneath; spares macula until late. Visual loss starts in second to third decades. Affected males have nyctalopia, photophobia, and constricted visual fields in late childhood; female carriers have normal vision, visual fields, color vision, and ERG, but may show subtle pigmentary retinal changes. Central vision is maintained until late in the disease. Poor prognosis with legal blindness by 50–60 years of age.

• Prevalence: 1 in 50,000.

• Inheritance: X-linked recessive.

• Genetics: Caused by a mutation in the CHM gene mapped to chromosome Xq21 (encodes the Rab escort protein (REP-1), which is involved with post-translational isoprenyl modification of Rab proteins).

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FIGURE 10-183 Choroideremia demonstrating late stage with complete atrophy of the RPE and visible choroidal vessels.

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FIGURE 10-184 Choroideremia demonstrating scalloped border of atrophic changes near macula. Radial choroidal vessels are easily seen inferiorly.

• Color vision: Variable color deficits seen in most affected males and female carriers; normal until late in the disease.

• Visual fields: Constricted (peripheral ring scotoma).

• Fundus autofluorescence: Reveals areas of RPE loss and remaining islands of RPE. Female carriers demonstrate mixed hypoautofluorescent and hyperautofluorescent spots.

• Fluorescein angiogram: Absent choroidal flush with large choroidal vessels visible underneath with scalloped borders (hypofluorescent scalloped areas of absent choriocapillaris adjacent to hyperfluorescent intact choriocapillaris); window defects in the RPE are seen in female carriers.

• Optical coherence tomography: Retinal thickening with normal laminae occurs in the early phase. Shortening of the inner and outer segments, reduced thickness of the outer nuclear layer, and depigmentation of the RPE are demonstrated in later phases. Inner and outer segment loss can be seen in carriers.

• Electrophysiologic testing: ERG (markedly reduced); full-field ERG is normal in carriers. Multifocal ERG reveals focal areas of retinal dysfunction in carriers.

• Treatment: No effective treatment.

Congenital Stationary Night Blindness

Group of bilateral (inherited), non-progressive disorders with reduced night vision (rods) and normal day vision (cones). Patients have normal acuity, color vision, and full visual fields, but have reduced acuity with low light levels (nyctalopia), paradoxical pupillary response, absent Purkinje shift, and reduced rod ERG by first decade. Two categories: without fundus changes (further subdivided based on ERG findings into Schubert–Bornschein and Riggs) and with fundus changes.

• Prevalence: Rare.

Without Fundus Changes

Nougaret disease

Night blindness, but no reduction in central vision; onset at birth. Normal retinal examination and no significant refractive error.

• Inheritance: Autosomal dominant [AD].

• Genetics: Caused by mutations in the GNAT1 gene (encodes the alpha subunit of rod transducin) on chromosome 3p21. Autosomal dominant CSNB has also been associated with mutations in RHO and PDE6B, and mutations in the rod cAMP phosphodiesterase beta subunit on 4p16.3 and in the rhodopsin gene on 3q21-q24.

• Visual fields: Full.

• Electrophysiologic testing: Photopic ERG (normal), scotopic ERG (subnormal, no rod a-wave), EOG (normal). ERG is of the Riggs type.

Riggs type

Rare; there is some residual rod function, no myopia. Usually has visual acuity within the normal range and doesn’t exhibit nystagmus; normal retinal appearance.

• Inheritance: Autosomal recessive (AR).

• Electrophysiologic testing: Photopic ERG (normal), scotopic ERG (subnormal, some rod a-detectable; scotopic a-wave: normal to subnormal; scotopic b-wave: near-normal or reduced; larger than a-wave), EOG (normal).

Schubert–Bornschein type

May have some residual rod function (type 2, incomplete form) or no recordable rod function (type 1, complete form); nonprogressive. Cone function is also affected in type 2, which may lead to reduced visual acuity compared with type 2. May have nystagmus and reduced visual acuity; distinguished from dominant Nougaret type by presence of myopia and by mode of inheritance (more myopic in type 1 compared with type 2); carriers are asymptomatic. Night blindness more common in type 1. Type 1 usually has high myopia with typical myopic changes (chorioretinal fundus changes, macular hypoplasia, and tilted myopic discs with temporal chorioretinal atrophy). Type 2 is mildly myopic or even hyperopic.

• Inheritance: X-linked recessive or autosomal recessive.

• Genetics: Type 1 (complete) linked to NYX gene (encodes a-nyctalopin, a leucine-rich proteoglycan without a known function) on chromosome Xp11.4; Type 2 (incomplete) linked to CACNA1F gene (encodes the alpha-1 subunit of a retina-specific L-type calcium channel that is involved in the release of glutamate from photoreceptor presynaptic terminals) on chromosome Xp11.23. Type 1 is associated with the following genes: NYX (X-linked; most commonly identified), GRM6 (autosomal recessive), TRPM1 (autosomal recessive; next most common), and GPR179 (autosomal recessive). Type 2 is associated with the CACNA1F gene (X-linked; most commonly identified), the CABP4 gene (autosomal recessive), and the CACNA2D4 gene (autosomal recessive).

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• Fluorescein angiogram: Usually normal but may show minor window transmission defects.

• Electrophysiologic testing: Photopic ERG (normal; in the photopic ERG, type 1 is within the normal range but shows a square-wave appearance, while type 2 shows a decreased b-wave), scotopic ERG (minimal to no rod function depending on type; a recordable scotopic ERG is usually not seen in type 1, while in type 2 a recordable ERG is usually seen with a reduced b-wave or a b-wave in the low normal range), and dark adaptation (may be abnormal). A double peak in the 30 Hz flicker ERG is usually seen in type 1. An “electronegative” ERG is seen in dark adaptation in response to standard flash (b-wave amplitude reduced to smaller than the a-wave). Type 1 is characterized by an absent or reduced rod b-wave response and normal cone b-wave amplitudes. In type 2, on the other hand, reduced rod b-wave and greatly reduced cone responses are seen. Normal or near-normal a-wave, but reduced b-wave on the dark-adapted bright flash ERG. No scotopic threshold response (STR) in type 1, but recordable STR in type 2.

With Fundus Changes

Fundus albipunctatus

Distinctive, discreet, yellow-white (50 μm) deep dots located in the midperipheral retina, sparing the macula. Not all lesions fluoresce on fluorescein angiogram (unlike drusen); stationary, unlike retinitis punctata albescens.

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FIGURE 10-185 Fundus albipunctatus demonstrating small white spots in the posterior pole sparing the central macula.

• Inheritance: Autosomal recessive (AR).

• Genetics: Caused by mutations in the RDH5 gene on chromosome 12q13-q14; gene encodes 11-cis retinol dehydrogenase 5, an RPE microsomal enzyme involved in photoreceptor transduction.

• Electrophysiologic testing: Delayed cone and rod adaptation; a- and b-wave amplitudes increase slowly with dark adaptation and reach normal levels after about 3 hours (impaired scotopic response that improves following prolonged dark adaptation).

• Treatment: Oral therapy with 9-cis-beta-carotene improves visual function.

Flecked retina of Kandori

Irregularly shaped, deep-yellow spots are usually found in the equatorial region; fewer and larger spots than fundus albipunctatus (may be variant).

• Prevalence: Very rare.

• Inheritance: Autosomal recessive (AR).

• Genetics: Unknown.

• Electrophysiologic testing: Dark-adaptation thresholds are delayed, but normalize after about 40 minutes of dark adaptation. ERG scotopic responses delayed, but the b-wave amplitudes progressively normalize with prolonged dark adaptation.

Oguchi disease

Diffuse golden-brown /yellow or gray retinal discoloration in light that returns to normal retinal color (orange-red) with prolonged (2–12 hours) dark adaptation (Mizuo–Nakamura phenomenon); onset at birth; night blindness, but normal visual acuity and color vision.

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FIGURE 10-186 Oguchi disease demonstrating characteristic golden retinal sheen.

• Inheritance: Autosomal recessive (AR).

• Genetics: Mapped to Oguchi1/Arrestin / SAG gene on chromosome 2q37.1 (Oguchi disease 1) and Oguchi2 / GRK1 gene on chromosome 13q34 encoding rhodopsin kinase (RHOK) (Oguchi disease 2).

• Fluorescein angiogram: Normal.

• Electrophysiologic testing: Photopic ERG (normal), scotopic ERG (reduced, no b-wave, a-wave increases with dark adaptation time; after long dark adaptation the a- and b-waves increase), and dark adaptation (no rod phase).

• Treatment: No effective treatment.

Crystalline Retinopathy of Bietti

Glittering, yellow-white, refractile spots are scattered throughout fundus (located in inner and outer layers of retina) with multiple areas of geographic atrophy and choroidal sclerosis. Associated with crystals in the perilimbal anterior corneal stroma. Histopathology reveals crystals located in conjunctiva, skin, and circulating lymphocytes, suggesting the disease may result from systemic lipid metabolism abnormality; in addition, it is associated with hypercholesterolemia, which further supports this observation. Patients have slowly progressive decreased vision, night blindness, and paracentral scotoma beginning in fifth decade; most common in Asia. Two types: one type with corneal crystalline deposits present (½ to ⅓ of Bietti patients) and a second type without any corneal or limbal crystalline deposits.

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FIGURE 10-187 Crystalline retinopathy of Bietti demonstrating refractile fundus lesions.

• Inheritance: Autosomal recessive (AR).

• Genetics: Caused by mutations in the CYP4V2 (cytochrome P450, family 4, subfamily V, polypeptide 2) gene on chromosome 4q35.1, which encodes a fatty acid omega hydroxylase.

• Fundus autofluorescence: Hypoautofluorescence corresponding to atrophic retinal areas and hyperautofluorescence corresponding to crystalline deposits.

• Fluorescein angiogram: Progressively enlarging patches of blocked fluorescence and window defects corresponding to the areas of atrophy; crystals hyperfluorescence early.

• Optical coherence tomography: Intraretinal crystals, diffuse hyperreflectivity, and disruption of IS/OS junction.

• Electrophysiologic testing: ERG (reduced).

• Treatment: No effective treatment.

Gyrate Atrophy

Progressive retinal degeneration with well-circumscribed, scalloped areas of chorioretinal atrophy that enlarge and coalesce, starting anteriorly and spreading posteriorly. The macula is spared until late in the disease. Patients develop nyctalopia, constricted visual fields, progressive myopia, and decreased vision in the first decade of life. The entire retina is atrophic by the fourth to fifth decades if not treated. Abnormal laboratory studies include hypolysinemia, hyperornithinuria, and increased urine and plasma ornithine levels (the latter being 10–20 times normal) due to deficiency of the mitochondrial matrix enzyme, and ornithine aminotransferase (OAT), which converts ornithine to glutamate and proline. Associated with posterior subcapsular cataracts, which appear by the second or third decades of life. Mild proximal muscle weakness and fine sparse hair in some patients; approximately ⅓ of patients have slow waves on electroencephalography.

• Prevalence: Rare.

• Inheritance: Autosomal recessive (most common).

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FIGURE 10-188 Gyrate atrophy demonstrating coalescence of well-circumscribed atrophic patches.

• Genetics: Associated with numerous mutations in OAT gene on chromosome 10q26 that encodes (OAT)

• Lab tests: Plasma ornithine levels, also consider urine ornithine levels and plasma lysine levels.

• Fundus autofluorescence: Reveals sharply demarcated areas of increased or preserved signal.

• Fluorescein angiogram: Window defects corresponding to the areas of atrophy (hyperfluorescence in atrophic areas with staining at the edges of normal-appearing retina).

• Optical coherence tomography: Hyperreflective deposits in the ganglion cell layer and multiple intraretinal cystic spaces have been reported. Outer retinal tubulation has been noted in advanced disease; also, foveal thickening noted in early stages of disease despite relatively normal-appearing fundus.

• Electrophysiologic testing: ERG (reduced late in the disease course, but before atrophy is complete) and dark adaptation (elevated threshold).

• Treatment: Restrict dietary arginine (a precursor of ornithine) and protein (less than 15 g protein per day); vitamin B6 (pyridoxine 300–750 mg po qd) therapy may be helpful (in patients who carry alleles V332M, A226V, T181M, E318K, and G237D). Pyridoxine-responsive patients constitute less than 5% of patients with gyrate atrophy. Most patients with Finnish founder L402P mutation do not respond to supplementation.

Progressive Cone–Rod Dystrophy

Profound cone dysfunction with normal rod function. Often develop “bull’s eye” macular pigment changes (bull’s-eye maculopathy in AD type; salt-and-pepper maculopathy in AR type), patchy atrophy in the posterior pole, vascular attenuation, and temporal pallor or optic atrophy. Patients have slowly progressive loss of central vision (worse during day), dyschromatopsia, and photophobia that develops in the first to third decades (+ / − fine pendular nystagmus). Called cone degeneration when not inherited. Poor prognosis with vision deteriorating to the 20 / 200 level by fourth decade.

• Prevalence: Cone dystrophy and cone–rod dystrophy: 1 in 30,000 to 40,000.

• Inheritance: Autosomal recessive (AR) (most prevalent mode of inheritance in cone dystrophy, autosomal dominant, and X-linked. In one study, autosomal recessive inheritance was found in 92% of cone dystrophy and 90% of cone–rod dystrophy patients.

• Genetics: Cone dystrophy mapped to several loci including: COD1 / RPGR gene on chromosome Xp21.1 encoding retinitis pigmentosa GTPase regulator; COD2 gene linked to chromosome Xq27; COD3 / GUCA1A / GCAP1 gene on chromosome 6p21.1 encoding guanylate cyclase activating protein. Genes for dominant, recessive, and X-linked forms of cone–rod dystrophy (CORD) that have been identified by linkage and mutation analyses include:

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• Color vision: Severe deutan–tritan defect out of proportion to visual acuity; some patients have no color perception.

• Visual fields: Central scotomas common; peripheral fields are usually intact; may get midperipheral relative scotomas late.

• Fluorescein angiogram: Hypofluorescence with ring of hyperfluorescence corresponding to the “bull’s eye” lesion; diffuse, irregular window defects throughout posterior pole and often midperiphery.

• Optical coherence tomography: Altered or absent photoreceptors in the fovea; peripheral photoreceptors are grossly intact. Reduced retinal thickness has been noted in the macula. Retinal atrophy was most prominent in the ONL, photoreceptor IS / OS junction, and RPE. OCT may be of great utility in the early stages of the disease, at which time diagnosis can be difficult.

• Electrophysiologic testing: Photopic ERG (markedly reduced to nonrecordable), scotopic ERG (can be normal, often subnormal), and EOG (normal to subnormal), dark adaptation (cone segment: abnormal; rod segment: normal [may be subnormal to abnormal later in disease]); flicker fusion frequency is reduced.

• Treatment: No effective treatment; tinted spectacles or contact lenses may help photophobia.

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FIGURE 10-189 Progressive cone dystrophy with bull’s eye appearance and temporal optic atrophy.

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FIGURE 10-190 Progressive cone dystrophy with patchy atrophy in the posterior pole.

Rod Monochromatism (Achromatopsia)

Total absence of cone function, with normal rod function. Patients have poor central vision (< 20 / 200 in complete form; as high as 20 / 80 in incomplete form), achromatopsia (no color perception), congenital nystagmus, and photophobia from birth; patients may have some degree of color perception. Based on this difference, rod monochromatism can be broken down into the complete/typical form (no color perception) and the less common incomplete/atypical form (some degree of abnormal color perception). May have normal macula, but often develop similar pigmentary changes as progressive cone dystrophy with granular changes and “bull’s eye” maculopathy. Nonprogressive; poor prognosis with vision deteriorating to the 20 / 200 level by fourth decade. Patients with the complete form are usually hyperopic.

• Prevalence: 1 in 20,000 to 50,000.

• Inheritance: Autosomal recessive (AR).

• Genetics: Linked to five genes: CNGA3/ACHM2 (2q11), CNGB3/ACHM3 (8q21), GNAT2/ACHM4 (1p13), PDE6C/ACHM5/COD4 (10q24), and PDE6H (12p12) (24, 33, 34). Most cases are due to mutations in the CNGB3 gene (50%).

• Color vision: No color perception; all colors appear as shades of gray. Incomplete form exhibits some degree of abnormal color perception.

• Visual fields: Central scotomas; peripheral fields are intact.

• Fluorescein angiogram: Normal or may show window defects in areas of pigmentary changes.

• Optical coherence tomography: Loss of IS / OS junction, disruption of the RPE layer, foveal hypoplasia, and an optically empty cavity in the fovea is often observed.

• Electrophysiologic testing: Photopic ERG (absent, nonrecordable), scotopic ERG (usually normal, may be subnormal), flicker fusion frequency (generally below 20 Hz), EOG (normal), dark adaptation (cone segment: abnormal and may be absent; rod segment: normal).

• Treatment: No effective treatment; dark glasses may help photophobia.

Hereditary Macular Dystrophies

Adult Foveomacular Vitelliform Dystrophy

• Bilateral, symmetric, round, slightly elevated, yellow-orange lesions with surrounding darker border and pigment clumping. Onset between 30 and 50 years of age with minimally affected vision and metamorphopsia (often unilateral symptoms, but bilateral disease). Smaller lesions than Best disease, no disruption or layering of the yellow pigment, and occurs in older patients; good prognosis. CNV may pccur (5–15%).

• Prevalence: Rare.

• Inheritance: Autosomal dominant (AD) with variable expression and incomplete penetrance.

• Genetics: Mutations in BEST1 have been identified (but may actually be milder cases of Best disease. Causal mutations have also been identified in the peripherin 2 gene (PRPH2).

• Visual fields: Relative central scotoma (corresponding to central lesion).

• Fundus autofluorescence: Various abnormal patterns are often observed. A commonly observed pattern is patchy with a central area of hypoAF and irregularly positioned hyperAF signals close to the central area. A focal pattern with a central hyperAF lesion is also commonly seen.

• Fluorescein angiogram: Central hypofluorescence of macular vitelliform lesion with surrounding area of hyperfluorescence. Later in the disease, the vitelliform lesion may develop areas of hyperfluorescence centrally corresponding to atrophy.

• Optical coherence tomography: Subretinal thickening of the RPE without a serous detachment (as seen in Best disease); overlying neurosensory retina is thin; dome-shaped lesion present between RPE and sensory retina; hyper-reflective material (lipofuscin) separates RPE and photoreceptor layers.

• Electrophysiologic testing: EOG (normal or slightly subnormal).

• Treatment: Intravitreal anti-VEGF injections have been reported to help in the treatment of choroidal neovascularization associated with adult-onset foveomacular vitelliform dystrophy (experimental).

Best Disease (Best Vitelliform Dystrophy)

Macular dystrophy due to abnormality of the RPE with high phenotypic variability first described by Best in 1905. Usually starts asymptomatically (75% better than 20 / 40) with yellow, round, subretinal vitelliform macular lesion (“egg-yolk” lesion) in early childhood (5–10 years), but age of onset is variable. Various stages:

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FIGURE 10-191 Adult foveomacular vitelliform dystrophy demonstrating central round yellow lesion.

Stage 0 (Previtelliform)

Average age at onset is 6 years old, normal macula, abnormal EOG, normal vision.

Stage 1 (Previtelliform)

Normal clinically, normal vision, fluorescein angiogram shows RPE window defects.

Stage 2 (Vitelliform)

Age 3–15 years old, classic “egg yolk” appearance clinically, mild visual loss, fluorescein angiogram shows blocking defects.

Stage 2a (Vitelliruptive)

“Scrambled-egg” stage as the cysts break apart with irregular subretinal spots, mild visual loss, fluorescein angiogram shows nonhomogenous blocking and hyperfluorescence.

Stage 3 (Pseudohypopyon)

Age 8–38 years old, fluid level with yellow vitelline material as the subretinal material layers, mild visual loss, fluorescein angiogram blocks in area of pseudohypopyon, hyperfluorescent above it.

Stage 4a (Atrophic)

Age > 40 years old, greater visual loss (> 20 / 100), atrophy of RPE.

Stage 4b (Cicatricial)

Macular scarring.

Stage 4c (Neovascular)

CNV develops.

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FIGURE 10-192 Small egg-yolk lesion in a 7-year-old boy with Best disease.

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FIGURE 10-193 Left eye of same patient as Figure 10-192 demonstrating characteristic “sunny side up” egg-yolk lesion.

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FIGURE 10-194 Spectral domain OCT of vitelliform lesion.

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FIGURE 10-195 Best disease demonstrating “scrambled egg” lesion in the macula.

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FIGURE 10-196 Same patient as Figure 10-195, 5 years later demonstrating atrophic lesion in central macula.

Usually bilateral, slowly progressive, and occurs in Caucasians who are slightly hyperopic. Variable vision loss, deteriorates slowly and may be stable for years (75–88% have > 20 / 40 vision in one eye up to age 50 years old); cannot predict visual function from fundus appearance; tritan color deficiency; incidental trauma can lead to visual loss. Good prognosis with vision ranging from 20 / 30 to 20 / 100 unless CNV develops.

• Inheritance: Autosomal dominant (AD) (variable expressivity, generally complete penetrance).

• Genetics: Caused by mutations in the BEST1 gene (previously known as VMD2) on chromosome 11q12–q13.1. It encodes bestrophin-1, which is a protein localized to the basolateral RPE surface, where it likely forms calcium-gated chloride channels.

• Color vision: Significant proportion of cases has abnormal color discrimination (often in the proton axis). Color defects proportional to degree of visual loss.

• Visual fields: Relative central scotoma early; more dense scotomas may be noted following degeneration and organization of lesion.

• Fundus autofluorescence: Early in the disease hyperautofluorescent areas are observed that correspond to the areas of hypofluorescence seen on FA. In contrast as the disease progresses towards the vitelliruptive phase, these areas of hyperautofluorescent overlap with areas of hyperfluorescence on FA.

• Fluorescein angiogram: Blockage by vitelliform lesion due to lipofuscin accumulation; transmission defects when cyst ruptures; irregular RPE transmission and staining depending on presence of pigmentary disturbance, choroidal neovascularization and scarring.

• Optical coherence tomography: In pre-vitelliform lesions, there is a thicker layer between the photoreceptor IS / OS junction and the RPE; in the pseudo-hypopyon stage, there is accumulation of material in the sub-RPE space; in the atrophic stage, there are diffuse RPE changes with overlying photoreceptor disruption.

• Electrophysiologic testing: ERG (normal, but foveal or multifocal ERG may have reduced amplitudes), EOG (markedly abnormal in all stages even in otherwise normal appearing carriers) Arden (light-peak/dark-trough) ratio < 1.5, and dark adaptation (normal).

• Treatment: No effective treatment unless CNV forms.

Butterfly Pattern Dystrophy

Bilateral, subtle RPE mottling in younger patients; symmetric, gray-yellow, butterfly-shaped lesions in central macula with surrounding halo of depigmentation in older patients; may develop choroidal neovascular membrane. Onset between 20 and 50 years of age with mild decrease in vision (20 / 25 to 20 / 40) and slow progression. Relatively good prognosis unless CNV develops.

• Inheritance: Autosomal dominant (AD).

• Genetics: Linked to PRPH2 gene on chromosome 6p21.1-cen encoding peripherin.

• Color vision: Normal.

• Visual fields: Relative central scotoma; normal peripheral fields.

• Fluorescein angiogram: Hypofluorescent blocking defects by pigment and lipofuscin, window defects corresponding to the areas of the atrophy; hyperfluorescent leakage from CNV if present.

• Optical coherence tomography: Variable hyper reflectivity between the RPE/Bruch’s complex and interface of the IS/OS junction.

• Electrophysiologic testing: ERG (photopic: normal to subnormal; scotopic: normal to subnormal), EOG (usually normal, but can be markedly subnormal), and dark adaptation (normal).

• Treatment: No effective treatment unless CNV forms.

Dominant Drusen (Doyne’s Honeycomb Dystrophy, Malattia Leventinese)

Asymptomatic, unless degenerative changes occur in the macula. Bilateral, symmetric, round, yellow-white deposits (nodular thickening of the retinal pigment epithelium basement membrane) scattered throughout the posterior pole and nasal to the optic disc. Occurs by age 20–30 years old. The lesions coalesce (forming a honeycomb appearance), enlarge, or disappear. May be associated with pigment clumping, RPE pigmentary disturbance, RPE detachment, chorioretinal atrophy, and choroidal neovascular membrane.

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FIGURE 10-197 Dominant drusen demonstrating abundant yellow lesions in the posterior pole.

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FIGURE 10-198 Left eye of same patient as Figure 10-197.

• Inheritance: Autosomal dominant (AD).

• Genetics: Mapped to EFEMP1 (epidermal growth factor-containing fibrillin-like extracellular matrix protein 1) gene on chromosome 2p16-p21 that encodes fibulin, an extracellular matrix protein expressed in the RPE and accumulates within and beneath RPE overlying drusen.

• Color vision: Normal.

• Visual fields: Normal; central scotoma if macular degeneration present.

• Fundus autofluorescence: Areas of increased and decreased signal corresponding spatially to drusen.

• Fluorescein angiogram: Early blockage and late hyperfluorescent staining of drusen; irregular dye transmission, leakage and pooling within macula depending on degree of associated degenerative change; hyperfluorescent leakage from CNV if present.

• Optical coherence tomography: Accumulation of drusen at the level of RPE-Bruch membrane and thickening of this complex.

• Electrophysiologic testing: ERG (normal), EOG (subnormal in late stages), and dark adaptation (normal).

• Treatment: No effective treatment. Experimental treatment of the RPE anterior to drusen with Argon green laser results in improved visual acuity.

North Carolina Macular Dystrophy (Lefler–Wadsworth–Sidbury Dystrophy)

Yellow spots (drusen) appear in early childhood (first decade) and progress to chorioretinal atrophy, macular staphyloma or “colobomas,” and peripheral drusen. Normal central vision early unless atrophic macular “coloboma” forms; possible progression to 20 / 200 or worse vision late in patients who develop choroidal neovascular membranes; typically nonprogressive. Three grades:

Grade I

Drusen-like lesions and pigment dispersion in fovea.

Grade II

Confluent drusen-like lesions in fovea.

Grade III

Atrophy of RPE and choriocapillaris within central macula.

• Prevalence: Rare.

• Inheritance: Autosomal dominant (AD).

• Genetics: Linked to MCDR1 gene on chromosome 6q14-q16.2 at same location as clinically distinct dominant progressive bifocal chorioretinal atrophy. Actual gene not identified yet.

• Color vision: Normal.

• Visual fields: Central scotoma occasionally; normal peripheral fields.

• Fluorescein angiogram: Grades I and II: RPE transmission defects and late staining of drusen-like lesions; Grade III: nonperfusion of choriocapillaris.

• Optical coherence tomography: In grade III lesions, there are deep chorioretinal excavations that don’t involve the sclera.

• Electrophysiologic testing: ERG (normal), EOG (normal), dark adaptation (normal).

• Treatment: No effective treatment.

Pseudo–inflammatory Macular Dystrophy (Sorsby Fundus Dystrophy)

Bilateral, symmetric, choroidal atrophy with decreased vision, nyctalopia, and tritone dyschromatopsia; occurs in 40–50 year-old patients. Three early patterns seen: disciform maculopathy with drusenoid deposits, disciform maculopathy without deposits, and chorioretinal atrophy. All patterns lead to end-stage pattern of progressively enlarging chorioretinal atrophy from the macula outward. May develop choroidal neovascular membrane. Poor prognosis with final vision in hand motion range.

• Inheritance: Autosomal dominant (AD).

• Genetics: Linked to TIMP-3 gene cloned on chromosome 22q12.1-q13.2 encoding tissue inhibitor of metalloproteinase-3 (TIMP-3).

• Color vision: Can be abnormal.

• Visual fields: Relative central and paracentral scotomas are common.

• Fluorescein angiogram: Hyperfluorescent window defects in areas of atrophy and hyperfluorescent leakage from CNV if present.

• Electrophysiologic testing: ERG (subnormal in advanced stages), EOG (subnormal in advanced stages), and dark adaptation (delayed).

• Treatment: No effective treatment.

Sjögren Reticular Pigment Dystrophy

Hyperpigmented fishnet/reticular pattern at the level of the retinal pigment epithelium that starts centrally and spreads peripherally. The disease is thought to appear in infancy and may be fully developed by the teenage years. Bilateral and symmetric; usually asymptomatic with good vision.

• Prevalence: Very rare.

• Inheritance: Unclear, both autosomal recessive and dominant transmission occur.

• Genetics: No related genes identified.

• Fundus autofluorescence: May have hyperautofluorescence of the net.

• Fluorescein angiogram: Hypofluorescence of the fishnet /reticulum over normal background fluorescence in early views.

• Optical coherence tomography: May have abnormalities of the RPE-Bruch membrane complex, photoreceptor outer segments, and photoreceptor IS/OS junction.

• Electrophysiologic testing: ERG (normal), EOG (lower limit of normal), and dark adaptation (normal).

• Treatment: No effective treatment.

Stargardt Disease / Fundus Flavimaculatus

Most common hereditary macular dystrophy; onset is in first to second decade. Bilateral, deep, symmetric, yellow pisciform (fish-tail shaped) flecks (yellow flecks are groups of enlarged RPE cells packed with a granular substance with ultrastructural, autofluorescent and histochemical properties consistent with lipofuscin) at the level of the retinal pigment epithelium and scattered throughout the posterior pole. Spectrum of disease: fundus flavimaculatus (no macular dystrophy; occurs in adults) to Stargardt disease (“bull’s eye” atrophic maculopathy with “beaten-bronze” appearance, patchy areas of atrophy; occurs in late childhood /adolescence). “Salt-and-pepper” pigmentary changes in periphery may develop late; no sex predilection; patients have bilateral decreased vision even before fundus changes appear. Poor prognosis with vision deteriorating to the 20 / 200 level by third decade and stable or continued slowly progressive loss of vision thereafter. Autosomal dominant form has more benign course with milder color and night vision changes, no photophobia, later onset, and generally less severe clinical course.

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FIGURE 10-199 Stargardt disease demonstrating pisciform flecks along the vascular arcades and pigmentary changes in the fovea.

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FIGURE 10-200 Fluorescein angiogram of same patient as Figure 10-199 demonstrating hyperfluorescence of the lesions and the characteristic “silent” choroid.

• Prevalence: 1 in 10,000.

• Inheritance: Autosomal recessive > autosomal dominant.

• Genetics: Recessive Stargardt disease is caused by mutations in the ABCA4 gene on chromosome 1p21-p22. ABCA4 encodes the retina-specific adenosine triphosphate-(ATP) binding cassette transporter (ABCR) that is localized in the rims of rod and cone outer segments and is involved in the transport of all-trans-retinol produced in light-exposed photoreceptor outer segments to the extracellular space. Autosomal dominant Stargardt disease results from mutations in the ELOVL4 (elongation of a very long-chain fatty acids-like 4) gene on chromosome 6q14 encoding a photoreceptor-specific component of a polyunsaturated fatty acid elongation system. Fundus flavimaculatus is considered a form of Stargardt disease and results from mutations in the ABCA4 gene on chromosome 1p21-p13.

• Color vision: May be abnormal with mild to moderate deutan–tritan defects as disease progresses.

• Visual fields: May be normal, or develop central scotoma late (most with visual acuity < 20 / 40 have a central scotoma). Normal in early stages and with time develop a relative central scotoma that often becomes absolute.

• Fundus autofluorescence: Areas of hypoautofluorescence correlate with RPE loss, yellowish flecks correspond to hyperautofluorescent areas. Mottled areas of hypoautofluorescence may be seen in macula or the macula may show a relatively preserved autofluorescence signal.

• Fluorescein angiogram: Generalized decreased choroidal fluorescence (dark or “silent” choroid sign), hyperfluorescent spots that do not correspond to the flecks seen clinically, flecks demonstrate early blockage and late hyperfluorescent staining, and window defects corresponding to the areas of the macular atrophy.

• Optical coherence tomography: Loss of photoreceptor layers (absent IS / OS junction) corresponding to macular atrophic areas (reduced foveal thickness). Presence of intact photoreceptor layer in the context of inner retinal atrophy correlates with better visual acuity

• Electrophysiologic testing: ERG (usually normal, but ⅓ may have photopic abnormalities), multifocal ERG subnormal in macula; EOG (normal to subnormal; abnormal in up to ¾ of cases), and dark adaptation (usually normal, mildly elevated in late stages).

• Treatment: No effective treatment. Targeting the vitamin A cycle may potentially lower lipofuscin levels and A2E accumulation. Vitamin A should be avoided due to accelerated lipofuscin accumulation. DHA supplementation may slow the progression of photoreceptor and RPE cell death in STGD3 as a result of the inverse relationship between functional ELOVL4 activity and DHA levels in red blood cell lipids.

Hereditary Vitreoretinal Degenerations

Familial Exudative Vitreoretinopathy

Rare, slowly progressive, bilateral, peripheral vascular developmental disorder; similar in appearance to retinopathy of prematurity, but without premature birth, low birth weight, and supplemental oxygen; asymmetric with no associated systemic diseases. Premature arrest of retinal angiogenesis or retinal vascular differentiation with incomplete peripheral retinal vasculature. Defective platelet function (rare). In 20–40% of affected eyes, the vision is less than or equal to 20 / 200. However, due to the asymmetric nature of the disease, this poor visual acuity in both eyes occurs in only 12–17% of affected individuals. Three stages:

Stage 1

Starts with peripheral avascularity, white with / without pressure (virtually all cases of stage 1), vitreous bands, peripheral cystoid degeneration, microaneurysms, telangiectasia, straightened vessels, and vascular engorgement especially in the temporal periphery. Asymptomatic in 73% of cases, but may have strabismus and nystagmus. Good visual acuity is present. Progression to stage 2 may or may not occur.

Stage 2

Dilated, tortuous peripheral vessels, neovascularization, fibrovascular proliferation, subretinal /intraretinal exudation, dragging of disc and macula (“dragged disc” and ectopic macula), falciform retinal folds, and localized retinal detachments. Visual loss after second to third decades is rare unless degeneration progresses to stage 3.

Stage 3

Cicatrization causes traction (rare) and / or rhegmatogenous retinal detachments (10–20%); retinal folds, fibrotic scaffolding and massive subretinal exudates; secondary findings include vitreous hemorrhage, subretinal exudates (10–15% of eyes; the massive exudation may resemble Coat’s disease), band keratopathy, posterior synechiae, iris atrophy, secondary cataract, and neovascular glaucoma, myopia, microphthalmia, amblyopia; positive angle kappa (pseudostrabismus) or strabismus is common; retinal detachments common in third to fourth decades; retinal detachments difficult to repair (recurrent retinal detachments and proliferative vitreoretinopathy).

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FIGURE 10-201 Familial exudative vitreoretinopathy demonstrating fibrovascular proliferation, exudates, and cicatrization.

• Inheritance: Autosomal dominant > autosomal recessive.

• Genetics: Most commonly autosomal dominant with 100% penetrance and wide variability in expression; X-linked and autosomal recessive rarer.

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• Fluorescein angiogram: Peripheral nonperfusion past vascularized retina; at border area, arteriovenous anastomoses form and leak fluorescein.

• Electrophysiologic testing: Normal (mildly affected individuals) to abnormal (in proportion to disease severity in more advanced cases)

• Treatment: Prophylactic laser treatment of the avascular retina is controversial; most retina specialists laser-treat avascular retinal periphery when extraretinal vascularization occurs. Retinal surgery for retinal detachments; should be performed by a retina specialist.

Enhanced S-cone Syndrome / Goldmann–Favre Syndrome

Extremely rare, bilateral vitreotapetoretinal degeneration with foveal and peripheral retinoschisis (similar to juvenile retinoschisis), “optically empty” vitreous cavity, condensed vitreous veils, attenuation of retinal vessels, peripheral pigmentary (bone spicules) changes, subretinal dot-like flecks in peripheral retina, lattice degeneration, progressive cataracts, and waxy optic disc pallor. May have anterior chamber inflammation and late-onset optic atrophy. Dendritic, whitish retinal vessels, which are diagnostic, may be present in the posterior pole and in areas of retinoschisis. No sex predilection (unlike juvenile retinoschisis). Patients have nyctalopia and constricted visual fields from early childhood. Reduced vision becomes evident with age. The condition is characterized by increased sensitivity of photoreceptors (cones) to blue light. Goldmann–Favre refers to the severe end of the very wide disease spectrum.

• Prevalence: 1 in 56,000 to 164,000.

• Inheritance: Autosomal recessive (AR).

• Genetics: Caused by mutations in nuclear receptor gene NR2E3 or PNR on chromosome 15q23. NR2E3 encodes a ligand-dependent transcription factor that is involved in retinal progenitor cell fate and is expressed in rod photoreceptors.

• Color vision: Abnormal with blue-yellow and red-green defects.

• Visual fields: May have absolute scotomas corresponding to peripheral retinoschisis.

• Fluorescein angiogram: No leakage from foveal schisis. Leaking retinal capillary abnormalities and areas of non-perfusion can be seen. Multiple punctate hyperfluorescent areas corresponding to RPE window defects are observed primarily along the arcades. Punctate areas of blockage corresponding to RPE hyperpigmentation are also observed.

• Optical coherence tomography: Retinoschisis with inner retinal layer loss, formation of inner and outer retinal holes, and confluent macular cystoid changes

• Electrophysiologic testing: ERG (usually profoundly abnormal; scotopic does not reveal any rod-driven responses; large, slow waveforms are detected in response to bright flashes; photopic is more sensitive to blue than to red or white stimuli; pathognomonic: similar waveforms are seen in photopic and scotopic responses to the same stimulus and are dominated by short-wavelength-sensitive responses with higher amplitudes than the normal population; non-recordable ERG develops in later phases) and EOG (flat or severely abnormal, reduced light peak and light-to-dark ratio; Note: helps differentiate from juvenile retinoschisis). The pathognomonic ERG findings allow the diagnosis to be determined by standard ERG recording.

• Treatment: Consider prophylactic treatment of any retinal breaks /tears; avoid prophylactic treatment of outer layer breaks because this may lead to a retinal detachment. Retinal detachments can usually be repaired with a standard scleral buckle. However, when significant traction or posterior retinal breaks are present, a vitrectomy may be performed. Cyclosporin A has been reported to cause macular edema regression and retinoschisis cavity flattening, but its role as a treatment remains unknown. It has also been reported that grid laser photocoagulation causes macular retinoschisis cavity collapse and moderate visual acuity improvement. The use of topical dorzolamide in the treatment of enhanced S-cone syndrome has been reported to improve visual acuity and decrease macular edema.

Marshall Syndrome

Rare degeneration with pronounced facial dysmorphism; less frequent risk of retinal detachments than Stickler syndrome (phenotypically similar, but with prominent midfacial hypoplasia, short stature, a thick calvarium, abnormal frontal sinuses, intracranial calcifications, early sensorineural hearing loss, progressive myopia, cataracts, and a liquefied vitreous). May develop spontaneous lens subluxation causing secondary glaucoma, membranous vitreous veils, and radial lattice.

• Inheritance: Autosomal dominant [AD].

• Genetics: Caused by mutations in the COL11A1 gene mapped to chromosome 1p21 (allelic to Stickler type 2, STL2); linked to a defect in collagen XI.

Snowflake Degeneration

Extremely rare degeneration characterized by yellow–white deposits in peripheral retina associated with white without pressure, sheathing of retinal vessels, fibrillar vitreous degeneration, and early-onset cataracts; increased risk of retinal detachments. Four stages:

Stage 1

White-without-pressure is present in the peripheral retina with associated small, punctate yellow opacities; may have early fibrillar vitreous degeneration.

Stage 2

Thickening of the midperipheral and peripheral retina due to numerous yellow-white granular or crystalline-appearing “snowflake” deposits (100–200 um in size), may have a predilection for the inferior retina and be less defined posteriorly than anteriorly. The post-equatorial snowflakes are often radially oriented along retinal vessels. Fibrillar vitreous condensation is more apparent.

Stage 3

More advanced changes, prominent lens changes, peripheral pigment deposition and clumping, and vascular sheathing. Fibrillar strands of condensed vitreous are easily seen.

Stage 4

Snowflake deposits not as easily identified, peripheral retinal vessels appear obliterated, and round-to-oval pigment deposits are present; retinal tears and detachments are common and may lead to severe visual loss; may have retinal neovascularization. The optic nerve is characterized by waxy pallor, flat appearance with or without a dysmorphic shape, and situs inversus of the central retinal vessels. May be association with corneal guttae. Systemic abnormalities are absent.

• Inheritance: Autosomal dominant (AD).

• Genetics: Linked to the R162W mutation on the KCNJ13 gene that mapped to chromosome 2q36. It encodes Kir7.1, an inwardly rectifying potassium channel localizing to the ILM and RPE.

• Visual fields: May have peripheral defects (may not correspond to visible lesions) more pronounced superiorly, corresponding to inferior predilection of the snowflake lesions.

• Fluorescein angiogram: May have areas of capillary nonperfusion bordering abnormal retinal vessels.

• Electrophysiologic testing: Retinal function progressively declines and marked abnormalities may be observed in late disease. Dark adaptation reveals elevated rod thresholds in late stages. In all stages, decreased scotopic b-wave amplitudes in response to dim white light. May have decreased photopic b-wave amplitudes and photopic flicker responses.

• Treatment: No treatment recommended. Retinal surgery for retinal detachments; should be performed by a retina specialist. Prophylactic treatment of all retinal breaks with photocoagulation is recommended due to the high incidence of retinal detachment. Retinal detachments may be treated with scleral buckling, however due to the high failure rate and continued vitreous traction, pars plana vitrectomy may be considered. Scatter laser photocoagulation for peripheral neovascularization associated with nonperfusion may also be considered.

Wagner / Jansen / Stickler Vitreoretinal Dystrophies

All have “optically empty” vitreous cavity with thick, transvitreal and preretinal membranes/ strands, retinal perivascular pigmentary changes (60%), and lattice-like degeneration; associated with myopia, glaucoma, and posterior subcapsular cataracts.

• Prevalence: 1 in 10,000.

• Inheritance: Autosomal dominant (AD).

Wagner Disease

No systemic associations. Most consistent finding is optically empty vitreous cavity, containing avascular strands or veils. Chorioretinal atrophy and cataracts increase with age and are observed in all patients older than 45 years. Cataracts begin as dot-like opacities in anterior and posterior cortex and are often visually significant by the fourth decade. Peripheral tractional retinal detachments occur in 55% of eyes among those over age 45, and glaucoma in 18%, with nearly half being neovascular. Peripheral vascular sheathing, retinal arteriolar attenuation, and perivascular pigmentary clumping like that seen in RP may be prominent; also have peripheral cystoid degeneration, myopia (3 to 4 diopters), abnormal retinal vessel architecture (inverted papilla), ectopic fovea, lattice degeneration, and a peripheral preretinal membrane. Rhegmatogenous retinal detachments are less common in Wagner disease (15%) than in Stickler syndrome (50%). Visual acuity and lens are usually normal at 30 years of age. After the age of 50, only 25% of eyes have better than 20 / 100 vision.

• Genetics: Linked to WGN1 gene on chromosome 5q13-q14; additional phenotype linked to mutation in exon 2 of COL2A1 gene on chromosome 12q13.11-q13.2, the candidate gene for Stickler syndrome. This exon is present in vitreous collagen mRNAs, but absent in cartilage mRNAs, thus accounting for the lack of systemic manifestations associated with Stickler.

• Visual fields: May have peripheral constriction and ring scotomas corresponding to peripheral chorioretinal degeneration.

• Electrophysiologic testing: Normal in the early stages. Progressive rod and cone dysfunction occurs. With dark adaptation, elevated rod and cone thresholds may occur in later disease (63%). The majority (87%) show subnormal rod and cone b-wave amplitudes. The EOG is depressed early.

• Treatment: Prophylactic treatment of retinal breaks.

Jansen Disease

No systemic associations, but patients do have an increased risk of retinal detachments; often bilateral retinal detachments.

Stickler Syndrome

Also known as progressive hereditary arthro-ophthalmopathy; associated with systemic abnormalities and connective tissue disorders including Marfanoid habitus, mid-facial hypoplasia, glossoptosis, micrognathia, flat nasal bridge, anteverted nares, midline clefting (ranges in severity from a cleft palate to Pierre-Robin sequence), neurosensory hearing loss (severity worse in non-ocular types), skeletal abnormalities (90%) including hyperextensible joints, degenerative joint disease (that typically develops in the third or fourth decades), scoliosis, kyphosis, and spondyloepiphyseal dysplasia of vertebrae (which is often apparent radiographically), hip, and shoulder. Slender extremities and arachnodactyly are occasionally seen, thus leading to a clinical appearance similar to Marfan syndrome in some patients. An association with mitral valve prolapse has been reported. Stature and intelligence are usually normal. Ocular abnormalities include congenital, nonprogressive, high myopia (75–90%; in the range of 8 to 18 D; associated with increased axial length) in the first decade, congenital megalophthalmos, optically empty, liquefied vitreous with associated vitreous veils inserting into the equatorial retina, lattice-like degeneration with retinal holes in the regions of the vitreoretinal adhesions, radial perivascular lattice degeneration, depigmented punched-out lesions, posterior vitreous detachment, cataract (30–80%) often with wedge- or fleck-shaped cortical opacities, angle abnormalities (26%) including prominent iris processes, hypoplastic iris root, and chronic open-angle glaucoma (5-10%); and increased risk of retinal breaks (75%; most occur in the superotemporal quadrant; most have multiple breaks) and retinal detachments (present in 50% by the second decade; 50% bilateral). Giant tears, often located posteriorly, are common. Most common cause of inherited rhegmatogenous retinal detachment. Staphylomata, choroidal neovascularization, lacquer cracks, congenital glaucoma and lens subluxation are rarely seen. Premature vitreous syneresis is seen at the slit-lamp by age 3 to 4 years. Six types:

Type 1

Most common (75% of patients); membranous congenital vitreous, congenital megalophthalmos, deafness, arthropathy, and cleft palate. Particularly high risk of giant retinal tears and retinal detachment (70%)

Type 2

Severe hearing loss; beaded congenital vitreous, congenital high myopia, deafness, arthropathy, and cleft palate; lower risk than type 1 of retinal detachment (40–50%)

Type 3

Least common; normal vitreous and ocular phenotype, deafness, arthropathy, and cleft palate.

Type 4

Recessive inheritance; myopia, vitreoretinopathy, sensorineural deafness, and epiphyseal dysplasia.

Ocular only (COL2A1)

Membranous congenital vitreous and congenital megalophthalmos; no systemic features.

Other

Hypoplastic vitreous, deafness, arthropathy, and cleft palate.

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FIGURE 10-202 Stickler syndrome with pigmented demarcation lines from a chronic retinal detachment.

• Prevalence: 1 in 10,000; the most common connective tissue disorder in the United States.

• Inheritance: Majority autosomal dominant with variable expressivity and nearly 100% penetrance (types 1–3). Autosomal recessive inheritance seen in Type 4.

• Genetics: Linked to genes encoding collagen type II and XI precursors; type 1 linked to COL2A1 gene on chromosome 12q13.11-q13.2 for collagen type II alpha1 chain; type 2 linked to COL11A1 gene on chromosome 1p21 for collagen type XI alpha1; type 3 linked to COL11A2 gene on chromosome 6p21.3 for collagen type XI alpha2 chain.

• Electrophysiologic testing: ERG (normal) and EOG (normal).

• Genetic counseling.

• ENT or orthopedic evaluation (cleft palate repair, hearing aids, joint replacement).

• Treatment: Retinal surgery for retinal detachments (increased risk of PVR from abnormal adherence between vitreous and retina); prophylactic laser photocoagulation controversial; should be performed by a retina specialist.

Leber’s Congenital Amaurosis

Group of hereditary disorders with onset at birth or early childhood of severe visual impairment (visual acuity ranges between 20 / 40 and NLP, but most have around 20 / 200 to CF vision), sluggish pupils, nyctalopia, light sensitivity (50%), and nystagmus. May have range of fundus abnormalities from no fundus changes (most common especially early in life) to progressive retinal pigment epithelial granularity, vascular attenuation, tapetal sheen, yellow flecks, “salt-and-pepper” fundus, macular “colobomas,” chorioretinal atrophy, or a retinitis pigmentosa appearance. Associated with high hyperopia, oculodigital sign, mental retardation (37%), deafness, seizures, skeletal abnormalities, posterior subcapsular cataracts, keratoconus, and renal /muscular abnormalities.

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FIGURE 10-203 Leber’s congenital amaurosis demonstrating granular and RP-like pigmentary changes, attenuated vessels, and a macular scar.

• Prevalence: 1 in 30,000 to 80,000.

• Inheritance: Autosomal recessive (AR).

• Genetics:

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• Color vision: Abnormal.

• Visual fields: Severely constricted.

• Fundus autofluorescence: Macular hypoautofluorescence.

• Optical coherence tomography: Retinal thinning with loss of outer nuclear layers, photoreceptors, and outer segments.

• Electrophysiologic testing: ERG (markedly reduced, absent); nonrecordable before the age of 1; EOG (abnormal).

• Treatment: No effective treatment. Gene replacement therapy currently in trials for patients with RPE65 mutations.

Retinitis Pigmentosa (RP)

Definition

Group of hereditary, progressive retinal degenerations (rod–cone dystrophies) that result from abnormal production of photoreceptor proteins. Prevalence is 1 in 5,000 worldwide (most common retinal dystrophy); 1 in 3,000 to 5,000 in the United States; 1 in 1,878 in Navajo Indians. There are more than 29 loci associated with various phenotypes of RP with more being discovered daily.

Atypical forms

Retinitis Pigmentosa Inversus

Macula and posterior pole are affected differentially; confused with hereditary macular disorders. Central and color vision are reduced earlier than normal, and pericentral ring/central scotomas occur.

Retinitis Pigmentosa Sine Pigmento

Descriptive term to describe patients with symptoms of retinitis pigmentosa, but who fail to show pigmentary fundus changes. Occurs in up to 20% of cases; associated with more pronounced cone dysfunction. More representative of the early stages of RP, when fundus appears normal or nearly normal, rather than a subtype of RP. Many cases have autoimmune retinopathy.

Retinitis Punctata Albescens

Multiple, punctate white (50–100 μm) spots at the level of the retinal pigment epithelium scattered in the midperiphery with attenuated vessels and bone spicules. Slowly progressive (differentiates from fundus albipunctatus).

• Inheritance: Autosomal recessive (AR).

Sector Retinitis Pigmentosa

Subtype with pigmentary changes limited to one retinal area that generally does not enlarge; usually inferonasal quadrants; relatively good ERG responses. Associated with particular mutations in rhodopsin.

Forms Associated with Systemic Abnormalities

Abetalipoproteinemia (Bassen–Kornzweig Syndrome)

Development of nyctalopia and an atypical pigmentary retinopathy in the early teens secondary to vitamin A deficiency; white dots present throughout the fundus are most numerous in the periphery; RP-like picture eventually results; less commonly seen are ptosis, strabismus, ophthalmoplegia, and nystagmus; associated with steatorrhea, abdominal distension, failure to thrive, malnutrition, spinal curvature (beginning in the first few months of life), spinocerebellar ataxia, areflexia, weakness, erythrocyte acanthocytosis, growth retardation, neuropathy, and lack of serum beta-lipoprotein causing intestinal malabsorption of fat-soluble vitamins (A, D, E, K), triglycerides, and cholesterol; minimal pigmentary changes early; reduced life expectancy; death often occurs from cardiac arrhythmias; most cases reported in Eastern European (Ashkenazi) Jews.

• Inheritance: Autosomal recessive (AR).

• Genetics: MTP gene mapped to chromosome 4q24, produces microsomal triglyceride transfer protein.

• Lab tests: Crenated or “thorny” red cells on blood smear (ancanthocytosis; “burr-cell” malformation); plasma cholesterol < 100 mg / dL; absence of plasma apolioprotein (apo) B and apo-LDL.

• Treatment: Treat with vitamin A (100–400 IU / kg po QD), vitamin E (2,400–12,000 IU / kg po QD), vitamin K (5 mg po QD), omega-3 fatty acids (0.10 g /kg po QD), iron, folic acid supplementation, and dietary fat restriction.

Alstrom’s Disease

Photophobia and nystagmus are present early in life. Early and profound visual loss (visual acuity < 20 / 200 by age 10 and NLP by age 20). Associated with cataracts, deafness, obesity, diabetes mellitus (due to insulin resistance), diabetes insipidus, dilated cardiomyopathy (even in infancy), liver failure, cirrhosis, renal failure (slowly progressive chronic nephropathy), acanthosis nigricans, baldness, and hypogenitalism. More common among French Acadians of Yarmouth County, Nova Scotia, and Louisiana.

• Inheritance: Autosomal recessive (AR).

• Genetics: ALMS1 gene mapped to chromosome 2p13.

• Electrophysiologic testing: ERG (severe cone impairment with mild or no rod involvement early on; progresses to more severe rod dysfunction).

Cockayne’s Syndrome

Characterized by early onset (type I) and sometimes congenital (type II) growth retardation. Also have progeroid faces with small head, disproportionately long limbs, photodermatitis, horseback-riding stance resulting from skeletal malformations and knee contracture, progressive sensorineural deafness, progressive neural degeneration with mental deficiency, cerebellar ataxia, choreoathetosis, epilepsy, extrapyramidal signs, intracranial calcifications, and peripheral neuropathy; may have hyperbetaglobulinemia, hyperinsulinemia, and hyperlipoproteinemia may be observed. Visual acuity preserved in most patients despite advanced optic atrophy and retinal dystrophy; severe visual loss occurs late; also have enophthalmos (secondary to subcutaneous and orbital fat loss), hypoplasia of the dilator muscle with iris transillumination and poor pupillary dilation, strabismus, high hyperopia (+ 10 D) and astigmatism; pigmentary retinopathy is often present with a salt-and-pepper appearance, optic atrophy, and arteriolar attenuation. Denser black pigmentation in the posterior pole is sometimes seen instead of the typical salt-and-pepper retinopathy. May have extreme photophobia, nystagmus, raised inferior corneal lesions, band keratopathy, recurrent erosions, and cataracts in 15% (may be congenital). MRI of the brain reveals hypomyelination, cerebellar atrophy, and basal ganglia calcification. Cultured fibroblasts are very sensitive to UVC light. A defect in UV-induced DNA damage is present. There is no increased risk of skin cancer (as seen with xeroderma pigmentosum). Normal development may occur in the first year of life with later deterioration. Death usually occurs in the second to fourth decades.

• Inheritance: Autosomal recessive (AR).

• Genetics: Type I mapped to chromosome 5; type II mapped to chromosome 10q11; type III unmapped.

• Electrophysiologic testing: ERG (decreased or extinguished).

Kearns–Sayre Syndrome

Onset prior to age 20 with diffuse pigmentary retinopathy most pronounced in the macula; may have peripapillary atrophy; associated with chronic, progressive external ophthalmoplegia, bilateral ptosis, cardiac conduction defects (arrhythmias, heart block, cardiomyopathy), cerebellar ataxia, CSF protein > 1 g / L; growth retardation, delayed sexual maturation, and mental deterioration are often present; pharyngeal and facial weakness, skeletal muscle weakness, and deafness are less commonly seen; and other abnormalities. “Ragged red” fibers found histologically on muscle biopsy; CT may show diffuse leukoencephalopathy or cerebellar/brainstem atrophy with basal ganglia calcification; abnormal pyruvate and lactate metabolism are observed on biochemistry; death usually occurs in the 3rd or 4th decades due to heart disease (see Chapter 2).

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FIGURE 10-204 Kearns–Sayre syndrome with pigmentary retinopathy.

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FIGURE 10-205 Same patient as Figure 10-204 demonstrating chronic progressive external ophthalmoplegia with ptosis. This patient also could not move her eyes.

• Inheritance: Most cases are sporadic (with the abnormality occurring in the oocyte or zygote), but autosomal recessive inheritance and maternal transmission has been reported; deletions of mitochondrial DNA are usually present.

• Electrophysiologic testing: ERG (decreased).

• Treatment: Coenzyme Q may improve AV block, eye movements, and fatigue.

Bardet–Biedl Syndrome (BBS)

Characterized by pigmentary retinopathy (80%) with early macular involvement (often bull’s eye); salt-and-pepper appearance to frank bone spicules. Two syndromes: Bardet–Biedl (polydactyly in 75% and syndactyly in 14%) and Laurence–Moon (spastic paraplegia, no polydactyly/syndactyly). Both include short stature, congenital obesity (above 95th percentile), hypogenitalism (74–96%; sterility in males), partial deafness (5%), renal abnormalities (46–95%), and mental retardation (41–85%); minimal pigmentary changes early; severe vision loss in almost all patients by age 30 years old (with more than 90% being legally blind by this age). Nystagmus is present in 5% of BBS patients. Patients may also have posterior cortical and precapsular cataracts, myopia, gaze limitation, short and narrow palpebral fissures, pigmentary vitreous syneresis, macular edema, and diffuse secondary optic atrophy. BBS is associated with anosmia resulting from a generalized ciliated epithelia defect.

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FIGURE 10-206 Diffuse pigmentary changes in a patient with Laurence–Moon syndrome.

• Inheritance: Autosomal recessive (AR).

• Genetics:

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• Color vision: Severe abnormalities.

• Visual fields: Severely constricted.

• Electrophysiologic testing: ERG (non-recordable or substantially reduced); dark adaptation (elevated thresholds).

Neuronal Ceroid Lipofuscinosis (Batten Disease)

Associated with seizures, dementia, ataxia, and mental retardation; infantile (Hagberg–Santavuori syndrome; usually death occurs in infancy or early childhood), late-infantile (Jansky–Bielschowsky; usually death occurs in the first decade of life or early teenage years), juvenile (Vogt–Spielmeyer and Batten; most die in the third decade of life), or adult (Kufs) onset. Pigmentary retinopathy with progressive vision loss is seen in all patients (except those with Kufs disease). Optic atrophy is also seen in the infantile, late-infantile, and juvenile forms. Macular pigmentary mottling and granularity in addition to retinal vascular attenuation are seen in the late-infantile form. Cataracts have been reported in those with the infantile form. Amaurotic pupils, bull’s-eye macular lesion, and retinal vessel attenuation are seen in patients with the juvenile form. No ocular manifestations are seen in patients with the adult form. Conjunctival biopsy shows granular inclusions with autofluorescent lipopigments that also accumulate in neurons causing the retinal and CNS degeneration.

• Prevalence: 1 in 13,000 newborns in Finland; and approximately 300 affected newborns each year in the US (most with juvenile form).

• Inheritance: Autosomal recessive (AR).

• Genetics:

Locus

Gene

Gene Product

1p32

CLN1

Palmitoyl-protein thioesterase (PPT)

11p15.5

CLN2

Protease

*16p12.1

CLN3

Protein with unknown function

• Electrophysiologic testing: ERG (reduced in amplitude or nonrecordable [infantile type]).

Refsum’s Disease

The infantile form is characterized by dysmorphic facies, mental retardation, hepatomegaly, severe progressive neurosensory deafness, nystagmus with progressive pigmentary retinopathy (100%), optic nerve pallor, macular atrophic changes, arteriolar narrowing, and late-onset cataracts (7%). The adult form is characterized by cerebellar ataxia, polyneuropathy, retinitis pigmentosa, anosmia, deafness, ichthyosis, cardiac myopathy, and arrhythmias; night blindness may be an early symptom, while atrophic maculopathy and pigmentary retinal changes occur with advancing disease; may also have cataracts, pupillary abnormalities (miosis and poor pupillary dilation), and optic atrophy. Defect in fatty acid metabolism due to phytanic acid oxidase deficiency; causes elevated plasma phytanic acid, pipecolic acid, and very long-chain fatty acid levels.

• Inheritance: Autosomal recessive (AR).

• Genetics: Associated with PNYH gene mapped to chromosome 10p15.3-p12.2 that encodes phytanoyl-CoA hydroxylase; infantile Refsum’s associated with PEX1 gene on chromosome 7q21-q22 encoding peroxisome biogenesis factor 1.

• Electrophysiologic testing: ERG (abnormal or virtually unrecordable).

• Treatment: Treat by restricting dietary phytanic acid to less than 10 mg / day (animal fats and milk products) and phytol (leafy green vegetables); this can prevent progression or allow improvement in some features of the adult-type (ichthyosis, peripheral neuropathy, and cardiac conduction defects), but not in the visual or auditory symptoms; no conclusive beneficial effect has been proved in the infantile-type; plasmapheresis may be needed to rapidly reduce phytanic acid levels and prevent death from cardiac arrhythmias; follow serum phytanic acid levels.

Usher Syndrome

Associated with congenital, sensorineural hearing loss. Retinal dystrophy with typical findings of retinitis pigmentosa is seen (may be very mild, especially early in disease course); central vision is decreased late in type 1 (stays better longer in types 2 and 3); nyctalopia in childhood or early teens in type 1 and later in types 2 and 3. Most develop cataracts by age 40, 25% have mental retardation or psychosis, the majority have gait disturbances secondary to labyrinthine dysfunction. Delayed walking and vestibular dysfunction are characteristic. Due to structural abnormality of the axoneme, which is a component of ciliated cells. Four types:

Type I (75%)

Profound, congenital deafness with no vestibular function; ataxia may develop; visual loss in the first decade; retinal changes are not noticeable until 24 to 36 months; may develop psychosis and mental retardation.

Type II (23%)

Mild, later-onset hearing loss with normal vestibular function; retinal dystrophy with visual loss in teens.

Type III (2%, Hallgren’s syndrome)

Progressive hearing loss and vestibular ataxia; retinal dystrophy; accounts for 2% of all cases of Usher syndrome except in Finland, where accounts for 42%.

Type IV

Deafness and mental retardation.

Note: controversial if types III and IV are forms of Usher’s syndrome or separate genetic entities.

• Prevalence: 1.8 to 6.2 in 100,000 in the United States; 3 in 100,000 in Scandinavia; constitute 2.5% of families with retinitis pigmentosa; 30% of deaf French Acadians in Louisiana have type 1C Usher syndrome.

• Inheritance: Autosomal recessive (AR).

• Genetics:

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• Electrophysiologic testing: ERG (unrecordable in type 1, but a waveform may be present in type 2; substantial timing differences of implicit time measurements between types 1 and 2 have been demonstrated).

• Treatment: Protect ears against loud noises; avoid ototoxic medications, such as aminoglycosides. Many patients with total deafness receive cochlear implants.

Epidemiology

Most common hereditary degeneration (1 : 5000); can have any inheritance pattern: AR (25%), AD (20%, usually with variable penetrance, later onset, milder course), X-linked (9%, more severe, carriers also affected), isolated (38%), and undetermined (8%).

Symptoms

Nyctalopia, dark adaptation problems, photophobia, progressive constriction of visual fields (“tunnel vision”), dyschromatopsia, photopsias, and slowly progressive decreased central vision starting at approximately age 20 years old.

Signs

Decreased visual acuity, constricted visual fields, decreased color vision (tritanopic); classic fundus appearance with dark pigmentary clumps in the midperiphery and perivenous areas (bone spicules), attenuated retinal vessels, cystoid macular edema, fine pigmented vitreous cells, and waxy optic disc pallor; associated with posterior subcapsular cataracts (39–72%), high myopia, astigmatism, keratoconus, and mild hearing loss (30%, excluding Usher’s patients). Fifty percent of female carriers with X-linked form have golden reflex in posterior pole.

Differential Diagnosis

Congenital rubella syndrome, syphilis, thioridazine/chloroquine drug toxicity, carcinoma-associated retinopathy, congenital stationary night blindness, vitamin A deficiency, atypical cytomegalovirus or herpes virus chorioretinitis, trauma, diffuse unilateral subacute neuroretinitis, gyrate atrophy, bear tracks, and congenital hypertrophy of the retinal pigment epithelium (CHRPE).

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FIGURE 10-207 Retinitis pigmentosa demonstrating characteristic bone-spicule pigmentary changes.

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FIGURE 10-208 Retinitis pigmentosa demonstrating dense retinal pigment epithelium changes, optic disc pallor, and attenuated retinal vessels.

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FIGURE 10-209 Retinitis pigmentosa with diffuse chorioretinal atrophy and early optic disc pallor.

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FIGURE 10-210 Fluorescein angiogram of same patient as Figure 10-209 demonstrating the diffuse chorioretinal atrophy.

Evaluation

• Complete ophthalmic history with attention to consanguinity, family history, and hearing.

• Complete eye exam with attention to refraction, pupils, cornea, lens, vitreous cells, and ophthalmoscopy.

• Lab tests: Plasma ornithine levels, fat-soluble vitamin levels (especially vitamin A), serum lipoprotein electrophoresis (Bassen–Kornzweig syndrome), serum cholesterol/triglycerides, VDRL, FTA-ABS, peripheral blood smears (acanthocytosis), serum phytanic acid levels (Refsum’s disease).

• Color vision (Farnsworth panel D15): Normal except very late in the disease.

• Visual fields: Midperipheral ring scotoma; progresses to total loss except for central islands that disappear at the very end of the disease process.

• Electrophysiologic testing: ERG (markedly reduced /absent; decreases 10% per year, abnormal in 90% of female carriers in X-linked, subnormal scotopic amplitudes precede reduction of photopic amplitudes), EOG (abnormal), dark adaptation (elevated rod and cone thresholds).

Management

• No effective treatment except in forms with treatable systemic diseases (abetalipoproteinemia, Refsum’s disease).

• Correct any refractive error; prescribe dark glasses.

• Low-vision consultation for visual aids.

• For common forms of retinitis pigmentosa (age > 18 years old): vitamin A (15,000 IU po qd of palmitate form) slows reduction of ERG amplitudes and avoid vitamin E; follow liver function tests and serum retinol levels annually. Note: controversial and not tested in atypical forms of RP. The use of vitamin A in younger patients is even more controversial: age 6–10 years old, vitamin A (5000 IU po qd of palmitate form), 10–15 years, vitamin A (10,000 IU po qd of palmitate form); check with pediatrician before starting high-dose vitamin A therapy.

• Systemic acetazolamide (Diamox 500 mg IV or po) for cystoid macular edema is controversial.

• Cataract surgery may be indicated depending on retinal function; check potential acuity meter (PAM) when considering cataract extraction.

Prognosis

Poor, usually legally blind by fourth decade.

Albinism

Ocular Albinism

Congenital disorder of melanogenesis with clinical manifestations limited to the eye; decreased number of melanosomes (although each melanosome is fully pigmented). Patients have decreased vision, reduced or absent stereoacuity, and photophobia; signs include congenital nystagmus, strabismus, high myopia, diffuse iris transillumination, foveal hypoplasia, fundus hypopigmentation, lack of retinal vessels wreathing the fovea, and abnormal decussation of optic nerve fibers at the chiasm (only 10–20% remain uncrossed). Visual acuity ranges from 20 / 80 to 20 / 400. Female carriers of the X-linked form often (87–92%) have a “mud-splattered” fundus appearance (mottled hyperpigmentation in the posterior pole merges with peripheral linear streaks of hypopigmentation and normal pigmentation), and may have partial iris translucency. It is preferred to restrict the term ocular albinism to the X-linked form of the disease and refer to all others as oculo-cutaneous.

• Inheritance: X-linked /autosomal recessive (XLR/AR).

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FIGURE 10-211 Fundus hypopigmentation in a patient with albinism. The deep choroidal vasculature is clearly visible.

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FIGURE 10-212 Albinism demonstrating diffuse iris transillumination. Note that the equator of the crystalline lens is visible as a dark line near the peripheral iris.

Oculocutaneous Albinism

Systemic disorder with decreased melanin in all melanosomes. Patients lack pigmentation of the hair, skin, and eyes, have an increased risk for skin cancer and should avoid direct prolonged sun exposure, use sunscreens, and have regular dermatologic exams. Two forms: tyrosinase-positive/ OCA Type 2 (little pigmentation at birth that increases with age) and tyrosinase-negative / OCA Type 1 A (no pigmentation). Those with the tyrosinase-negative form have visual acuity around 20 / 200, while those that are tyrosinase-positive have vision in the 20 / 40 to 20 / 200 range. Potentially lethal variants of oculocutaneous albinism include Chédiak–Higashi (reticuloendothelial incompetence with neutropenia, anemia, thrombocytopenia, recurrent infections (pyogenic), leukemia, and lymphoma; decreased lifespan) and Hermansky–Pudlak (clotting disorders and bleeding tendencies secondary to platelet abnormalities; pulmonary fibrosis; visual acuity between 20 / 100 to 20 / 300; occurs in 1 in 1,800 Puerto Ricans.

• Inheritance: Autosomal recessive (AR).

• Genetics:

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• Treatment: No effective treatment. Medical and hematology consultation to rule out potentially lethal variants. Tinted glasses help with light sensitivity. Treatment of congenital nystagmus with large rectus muscle recessions, the Anderson-Kestenbaum procedure, or an artificial divergence procedure remains controversial.

Phakomatoses

Group of congenital, mainly heritable, syndromes with multiple tumorous growths both ocular and systemic; commonly have incomplete penetrance and variable expressivity. (Phako = “motherspot” [birthmark].)

Angiomatosis Retinae (von Hippel–Lindau Disease)

VHL type 1 (no pheochromocytomas) and VHL type 2 (pheochromocytomas present; type 2A have a low risk of renal cell carcinomas (RCC), type 2B have a high risk of RCC, and type 2C have isolated pheochromocytoma). Retinal capillary hemangioblastomas (45–60%; most common presenting feature; mean age of diagnosis is 25 years; usually seen in peripheral retina, most commonly in superotemporal quadrant; up to 15% are on or within one disc diameter of the optic nerve; often bilateral and multiple; globular, orange-red, vascular lesion; dilated feeding artery and vein typically present; lipid exudates may develop around the lesion or distantly around the disc or in the macula; histologically, consist of vascular endothelial-lined channels separated by vacuolated “foam” cells), cystic cerebellar hemangioblastoma (60%; may become calcified), clear renal cell carcinoma (clinically evident in ⅓; most common cause of death; account for 50% of deaths), pheochromocytoma (10%), polycythemia (25%), liver, pancreas, and epididymis cysts (if only retinal findings = von Hippel disease), cherry hemangiomas of the face, liver, lung, and adrenal gland, seizures, ataxia, paroxysmal hypertension. Earliest manifestations are retinal (95% by age 10 years old); bilateral in 50%; 20% have visual acuity < 20 / 100 in at least one eye; visual loss results from exudative or tractional retinal detachment, vitreous hemorrhage, macular edema, epiretinal membrane, or macular holes; very small peripheral angiomas may also be present. Individuals with an isolated retinal hemangioblastoma have a 30% risk of developing VHL disease.

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FIGURE 10-213 Angiomatosis retinae (von Hippel–Lindau disease) demonstrating retinal capillary hemangioma with feeder and draining vessels, and surrounding exudates.

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FIGURE 10-214 Fluorescein angiogram of a patient with retinal angioma demonstrating fluorescein filling from feeder vessel and drainage via drainage vessel.

• Prevalence: 1 in 36,000.

• Inheritance: Autosomal dominant (AD).

• Genetics: Linked to chromosome 3p25-p26; mutation in the VHL tumor suppressor gene that regulates cell growth and controls VEGF expression.

• Fluorescein angiogram: Hyperfluorescence of feeder vessel to retinal hemangioblastoma during the arterial phase, while draining vein is most prominent in the venous phase. Hyperfluorescence of the tumor itself is seen also with leakage in the later phases. Ultrawide field angiography can aid in the detection of small peripheral angiomas.

• Head, upper cervical spinal cord, and abdominal CT scan or MRI (gadolinium-enhanced MRI in two separate sessions is best way to screen for brain and spinal cord hemangioblastomas).

• Medical consultation.

• Treatment: Small lesions ( < 500 microns) without exudate or subretinal fluid may be observed. Photocoagulation (up to 4.5 mm in size), cryotherapy, and diathermy may be used to treat small retinal lesions. Argon laser may be applied directly to lesions less that 2.5 disc diameters in size. Cryotherapy is used in slightly larger tumors (larger than 3 mm), those that anteriorly located, and in semiopaque media. For larger tumors, combined laser therapy and cryopexy may be needed. Diathermy with or without a scleral buckle can be used for large tumors. Plaque radiotherapy or low-dose external beam radiotherapy can be used for larger tumors ( > 4.5 mm) or those that have been resistant to prior photocoagulation or cryotherapy. Anti-VEGF has been described as a potential treatment also. In severe case, surgical excision may be performed, however a high rate of recurrences and complications has been reported

Ataxia Telangiectasia (Louis–Bar Syndrome)

Progressive cerebellar ataxia (first symptom; onset as the infant begins to walk), dysarthria, telangiectasia (noted by age of 10 years) of the skin (especially around face, ears, and neck) and bulbar conjunctiva (91%; most common ocular finding; the interpalpebral region is the first and most prominent location), ocular motility abnormalities (strabismus, abnormalities in saccades/pursuits, OKN abnormalities, head thrusting movements, nystagmus, and impaired convergence/accommodation), swallowing incoordination, facial hypomimia, peripheral neuropathy, elevated serum alpha-fetoprotein (AFP), spontaneous X-irradiation-induced chromosomal breakage; also associated with seborrheic dermatitis, mental retardation, thymus gland hypoplasia with reduced T-cell immunity. High incidence of malignancies (33%) including lymphoma and leukemia, and humoral/cellular immunodeficiency with increased risk of infections especially chronic respiratory infections. Visual acuity is reported to be 20 / 50 or better in 96% of individuals. Poor prognosis with death by adolescence.

• Inheritance: Autosomal recessive (AR).

• Genetics: Linked to ATM gene on chromosome 11q22-q23; thought to encode protein vital to DNA repair.

• Color vision: Normal.

• Visual fields: Normal.

• Medical consultation.

Encephalotrigeminal Angiomatosis (Sturge–Weber Syndrome)

Classic triad of isolated or diffuse, flat, dark red, “tomato catsup” choroidal cavernous hemangioma (40–50%; most often located temporal to the disc and are most elevated in the macula; does not cause visual disturbances early in life, but may lead to the late development of overlying retinal cystoid changes or exudative retinal detachment), congenital facial angioma (nevus flammeus or “port-wine stain” = essential for diagnosis; often occurs in the distribution of the ophthalmic and maxillary divisions of the trigeminal nerve; usually does not cross the midline; does not regress), and ipsilateral leptomeninges angiomatosis with cerebral gyriform calcifications; nevus flammeus involving the eyelid (suspect glaucoma if upper eyelid involved), episcleral hemangiomas (69%), conjunctival angioma, dilated episcleral vessels, congenital, ipsilateral glaucoma (30%), heterochromia iridis, retinal aneurysms associated with an arteriovenous angioma of the thalamus and midbrain, amblyopia, anisometropia, exudative retinal detachment. The majority have intracranial calcifications. May have mental retardation (54%), seizures (80%), contralateral hemiplegia (31%), headaches, growth hormone deficiency, and central hypothyroidism. No associated malignancies. Variable prognosis depending on CNS involvement.

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FIGURE 10-215 Encephalotrigeminal angiomatosis (Sturge–Weber syndrome) demonstrating nevus flammeus.

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FIGURE 10-216 Encephalotrigeminal angiomatosis demonstrating tomato-catsup fundus appearance of a diffuse choroidal hemangioma.

• Prevalence: 1 in 200 individuals in the US are born with a port-wine stain (8–15% of those have the syndrome).

• Inheritance: Sporadic, no hereditary pattern.

• Visual fields: Often shows homonymous hemianopsia contralateral to the cerebral and facial lesions.

• Fluorescein angiogram: Diffuse early hyperfluorescence of choroidal hemangioma with no leakage.

• Head and orbital MRI with contrast.

• Neurology consultation if intracranial lesions exist.

• Treatment: The facial angioma is not responsive to sclerosing agents or corticosteroids, but may be treated with pulsed dye laser with some success. Argon laser photocoagulation has been used to treat localized choroidal hemangiomas. Low-dose lens-sparing radiotherapy or proton beam irradiation can be used to treat subretinal fluid and induce regression of diffuse choroidal hemangiomas. Photodynamic therapy has been reported in the treatment of diffuse choroidal hemangiomas.

• May require treatment of increased intraocular pressure (see Primary Open-Angle Glaucoma section in Chapter 11).

Neurofibromatosis (von Recklinghausen’s Disease)

Disorder of the neuroectodermal system; there are two forms (see Chapter 3).

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FIGURE 10-217 Neurofibromatosis (von Recklinghausen’s disease) demonstrating facial neurofibromas.

Racemose Hemangiomatosis (Wyburn–Mason Syndrome)

Anomalous anastomosis between the arterial and venous systems of the retina (usually stable; predilection for superotemporal quadrant), ocular adnexa (including the conjunctiva, lids, face, and oronasopharynx), brain (20–30% have intracranial arteriovenous malformations causing mental status changes or hemiparesis; 80% AVMs are supratentorial and are supplied by the middle cerebral artery), orbit (resulting in proptosis and dilated conjunctival vessels), and facial bones (pterygoid fossa, mandible, and maxilla). Usually unilateral (96%) racemose angiomas that appear as intertwined tangles of dilated vessels; may cause visual loss due to retinal or vitreous hemorrhage, retinal ischemia, vascular occlusive disease, or neovascular glaucoma. Clinical signs and symptoms include headaches, seizures, bruits, intracerebral and subarachnoid hemorrhages, epistaxis (due to nasopharyngeal AVMs), oral hemorrhages, cranial nerve palsies, and a variety of sensory and motor deficits. Early mortality due to intracranial arteriovenous malformations.

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FIGURE 10-218 Racemose hemangiomatosis (Wyburn–Mason syndrome) demonstrating retinal vascular arteriovenous malformation (AVM) with dilated, tortuous vessels.

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FIGURE 10-219 Fluorescein angiogram of same patient as Figure 10-218 demonstrating the retinal vascular arteriovenous malformation filled with fluorescein dye. Note: line points at same vessel in both pictures.

• Inheritance: Sporadic, no hereditary pattern.

• Visual fields: Defects in 30% including homonymous hemianopia.

• Fluorescein angiogram: Anomalous AV communications and the presence or absence of intervening capillaries; no leakage in late phases.

• Head and orbital CT scan.

• Neurology consultation if intracranial lesions exist.

• Treatment: Asymptomatic retinal lesions do not require treatment. Consider laser photocoagulation around lesions (direct treatment dangerous) if symptomatic.

Tuberous Sclerosis (Bourneville’s Disease)

Classic Vogt triad of seizures (60%), mental retardation (50–60%), and adenoma sebaceum (85%, a misnomer for angiofibromas, a red-brown papular malar rash). Major features: forehead plaque or facial angiofibromas (adenoma sebaceum; the nasolabial folds, malar region, and chin are typical locations; two types: seed-like reddish angiofibromatous growths and yellow to brown primary fibromatous nodules; first noted between 3 to 5 years of age), nontraumatic ungula or periungual angiofibromas, shagreen patch (connective tissue nevus), hypomelanotic macule (3 or more), cortical tuber, subependymal nodule, subependymal giant cell astrocytoma, cardiac rhabdomyomas (43%; interventricular septum or ventricular wall; usually asymptomatic), lymphangiomyomatosis, and renal angiomyolipoma (50-80%). Minor features: Multiple randomly distributed pits in dental enamel (71%), bone cysts, hamartomatous rectal polyps, cerebral white matter radial migration lines, gingival fibromas, nonrenal hamartomas, such as retinal hamartomas (½ – ⅔; unilateral in ⅔; most common location is along the arcades; three types: an elevated, nodular, and calcific mulberry-like lesion which is typically in the posterior pole adjacent to the optic nerve [type 2], the more common, relatively flat and translucent, soft-appearing lesion usually located in the posterior fundus [type 1], or combined lesions [type 3]; mostly in type 2 tuberous sclerosis; usually static, but some grow and calcify with time; never undergo malignant degeneration; rarely complicated by vitreous hemorrhage or glaucoma), retinal achromic patch (12%), “confetti” skin lesions, and multiple renal cysts. Other findings include cutaneous shagreen patch (fibromatous skin infiltration especially on lower back, forehead, legs; 25%), ash-leaf spots (hypopigmented skin macules seen best with ultraviolet “Wood’s” lamp; 80%; may be present at birth or appear within the first 2 years of life), skin tags (molluscum fibrosum pendulum), cystic lung disease, calcified CNS astrocytic hamartomas (2%; “brain stones” in cerebellum, basal ganglia, and posterior fossa), or infantile spasms (25%). Some additional ocular findings are optic atrophy, ash-leaf spots of the pigment epithelium, atypical colobomas, eyelid angiofibromas, white patches of the iris or eyelashes, strabismus, papilledema, and CN VI palsy (from hydrocephalus secondary to brain tumors). Those with retinal findings are more likely to have subependymal giant cell astrocytomas, renal angiomyolipomas, cognitive impairment, and epilepsy. Developmental delay is present in 40% of individuals. Poor prognosis with 75% mortality prior to age 20 years old.

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FIGURE 10-220 Tuberous sclerosis (Bourneville’s disease) demonstrating adenoma sebaceum.

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FIGURE 10-221 Tuberous sclerosis demonstrating astrocytic hamartoma with mulberry appearance.

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FIGURE 10-222 Tuberous sclerosis demonstrating astrocytic hamartoma with smooth appearance.

• Prevalence: 1 in 5,800 to 1 in 10,000.

• Inheritance: Autosomal dominant (AD), with a high rate of new mutations (60%) and variable expressivity.

• Genetics: Mapped to TSC1 gene on chromosome 9q34 encoding hamartin and TSC2 gene on chromosome 16p13.3 encoding tuberin (GTP-ase activating protein). TSC2 mutations are more frequent in those with retinal findings. Also mapped to the TSC3 and TSC4 genes that have not been localized.

• Optical coherence tomography: Type 1 lesions appear as dome-shaped hyper reflective elevations of the retinal NFL with normal underlying neurosensory retina and RPE. In type 1 lesions, there is also a gradual transition between the hamartoma and the normal retina. This can help to differentiate from retinoblastomas, which tend to have an abrupt transition.

• Medical and neurology consultation.

• Brain MRI should be performed before the age of 2 years and repeated every year after the age of 21 years.

Tumors

Benign Choroidal Tumors

Choroidal Hemangioma

Vascular tumor. Two forms:

(1) Unilateral, well-circumscribed, solitary; round, slightly elevated (< 6 mm), orange-red lesion located in the posterior pole often with an overlying serous retinal detachment. Occurs in fourth decade. No extraocular associations.

(2) Diffuse, reddish, choroidal thickening described as “tomato-catsup” fundus (reddish thickening overlying dark fundus). Occurs in children with Sturge–Weber syndrome (see Fig. 10-216).

Usually asymptomatic, but both types can cause exudative retinal detachments (50%). Reduced vision, metamorphopsia, micropsia from foveal distortion due to underlying tumor or accumulation of subretinal fluid.

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FIGURE 10-223 Choroidal hemangioma (discrete type) appearing as an elevated orange lesion in the macula.

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FIGURE 10-224 B-scan ultrasound of same patient as Figure 10-223 demonstrating elevated mass with underlying thickened choroid.

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FIGURE 10-225 A-scan ultrasound of same patient as Figure 10-223 with high internal reflectivity.

• B-scan ultrasonography: Mass with moderate elevation, thickened choroid, and high internal reflectivity, often with overlying serous retinal detachment.

• Fluorescein angiogram: Early filling of intrinsic tumor vessels, progressive hyperfluorescence during the transit views, and late leakage (multiloculated pattern); circumscribed lesions have defined vascular pattern.

• Indocyanine green angiogram: Circumscribed hemangiomas: early hyperfluorescence with relative late hypofluorescence, or “washout” phenomenon. Diffuse hemangioma: early hyperfluorescence with late hypofluorescence of the lesion and persistent hot spots of hyperfluorescence along the vascular channels.

• Observe if asymptomatic especially if extrafoveal without subretinal fluid; longstanding subfoveal lesions with poor chance of recovery of vision are also observed.

• Decision to treat is individualized based on extent of symptoms, loss of vision, and potential for visual recovery; aim of treatment is to induce tumor atrophy with resolution of subretinal fluid and tumor-induced foveal distortion without destroying function of overlying retina; goal is not to obliterate tumor.

• Preferred treatment of circumscribed hemangioma is photodynamic therapy (PDT) with verteporfin using standard treatment parameters. Other methods include laser photocoagulation (moderately intense, white reaction on the tumor surface to eliminate serous exudation), transpupillary thermotherapy, or I-125 plaque brachytherapy (all treatments considered experimental).

• Visual loss can be progressive and irreversible; poor visual acuity results may be expected despite resolution of fluid exudates due to chronic macular edema and photoreceptor loss.

Choroidal Nevus

Dark gray-brown pigmented, flat or slightly elevated lesion (< 1 mm); often with overlying drusen and a hypopigmented ring around the base. Prevalence of 6.5% in US population > 49 years old. Usually nonprogressive, but can grow slowly over decades; growth in an adult should be watched carefully. Multiple nevi may occur in patients with neurofibromatosis. Characteristics of suspicious nevi include growth (months), tumor thickness (> 2 mm), presence of visual symptoms, overlying orange pigment, subsensory fluid, and proximity to the optic nerve head. Ten percent of suspicious nevi progress to malignant melanoma.

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FIGURE 10-226 Large choroidal nevus (nevoma) with overlying drusen.

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FIGURE 10-227 Flat choroidal nevus with overlying drusen indicating chronicity.

• B-scan ultrasonography: Flat to slightly elevated lesion, choroidal discontinuity, and medium to high internal reflectivity.

• Follow with serial photographs, ultrasonography, and clinical examination for any growth that would be suspicious for malignant melanoma at 1, 3, 6, 9, and 12 months, and then on an annual or semiannual basis if there is no growth.

Choroidal Osteoma

Slightly elevated, well-circumscribed, peripapillary, orange-red (early) to cream-colored (late) benign tumor with small vascular networks on the surface. Eighty to ninety percent are unilateral; typically occurs in younger patients who may be asymptomatic or have decreased vision, paracentral scotomas, and metamorphopsia, although well documented in older patients; slight female predilection. Consists of mature cancellous bone; growth may occur over years, and may spontaneously resolve. Choroidal neovascular membrane common at tumor margins; variable prognosis.

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FIGURE 10-228 Choroidal osteoma with orange, placoid appearance.

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FIGURE 10-229 Choroidal osteoma with calcification.

• B-scan ultrasonography: Calcification, orbital shadowing, and a high reflective spike from the tumor surface.

• Fluorescein angiogram: Irregular hyperfluorescence and late staining of the tumor; the vascular networks may appear hypofluorescent against the hyperfluorescent tumor.

• Orbital radiographs and CT scan show the calcifications within the tumor.

• Treat CNV with laser photocoagulation for juxta- and extrafoveal lesions, often requires multiple sessions; for subfoveal CNV consider anti-VEGF agents (experimental).

Benign Retinal Tumors

Astrocytic Hamartoma

Yellow-white, well-circumscribed, elevated lesion that may contain nodular areas of calcification and/or clear cystic spaces; classically has mulberry appearance but may have softer, smooth appearance (see Figs 10-221 and 10-222). Multiple lesions common in tuberous sclerosis. Usually do not grow. Rare cases of exudative retinal detachment have been reported.

• Fluorescein angiogram: Variable intrinsic vascularization within tumor that leaks in late views.

• No treatment is necessary.

Capillary Hemangioma

Benign vascular tumor arising from the inner retina and extending toward the retinal surface. Two forms:

(1) Single, sporadic, nonhereditary, and unilateral; no systemic associations; resembles that observed with von Hippel–Lindau syndrome, except being unifocal.

(2) Hereditary, bilateral (50%), multifocal, and associated with multiple systemic abnormalities (von Hippel–Lindau syndrome); classically has dilated feeder and draining vessels.

Both forms initially appear as a red, pink, or gray lesion that later grows as proliferation of capillary channels within the tumor progresses. These new capillaries leak fluid, leading to exudates and serous retinal detachments. Associated with preretinal membranes.

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FIGURE 10-230 Retinal angioma with feeder and draining vessels in patient with von Hippel–Lindau syndrome (see Figure 10-214 for fluorescein angiogram).

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FIGURE 10-231 Capillary hemangioma in a patient with von Hippel disease demonstrating the characteristic pink lesion with a dilated, tortuous, feeder vessel; there is also some surrounding exudate.

• Fluorescein angiogram: Early filling of tumor vasculature in arterial phase with late leakage.

• Some authors recommend treatment even for small asymptomatic hemangioma as they tend to grow and treatment efficacy is lower for larger tumors.

• Consider cryotherapy, photocoagulation, and plaque brachytherapy for hereditary tumors; should be performed by an ophthalmic oncologist.

• Intravitreal injection of anti-VEGF agents reduce exudation transiently; do not induce tumor regression (experimental).

• Medical consultation for hereditary form for evaluation of von Hippel–Lindau syndrome.

Retinal Vasoproliferative Tumor

Benign vascular tumor arising from the peripheral retina. Two forms:

(1) Single, sporadic, nonhereditary, and unilateral; no systemic associations; no feeder vessels.

(2) Primary or secondary to cyclitis, laser scars, retinitis pigmentosa.

Both forms initially appear as a yellow, pink, or gray lesion associated with lipid exudation, subretinal fluid and preretinal membranes.

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FIGURE 10-232 Retinal vasoproliferative tumor.

• Fluorescein angiogram: Early filling of tumor in arterial phase with late leakage.

• Consider cryotherapy or plaque brachytherapy for hereditary tumors; should be performed by an ophthalmic oncologist.

Cavernous Hemangioma

Rare, vascular tumor composed of clumps of saccular, intraretinal aneurysms filled with dark venous blood (“cluster-of-grapes” appearance). Fine, gray epiretinal membranes may cover the tumor. Typically unilateral; occurs in second to third decades, slight female predilection (60%). Usually no exudation occurs, retinal/vitreous hemorrhages are rare; commonly asymptomatic and nonprogressive.

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FIGURE 10-233 Cavernous hemangioma with “cluster-of-grapes” appearance.

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FIGURE 10-234 Flourescein angiogram of same patient as Figure 10-233 showing fluorescein fluid levels within the aneurysms.

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FIGURE 10-235 OCT of same patient as Figure 10-233 showing irregular retinal surface from the saccular aneurysms that shadow beyond.

• Fluorescein angiogram: Hyperfluorescent saccules with fluid levels; “layering” effect.

• No treatment necessary.

• Uncommon association with CNS cavernous hemangioma.

Congenital Hypertrophy of the Retinal Pigment Epithelium

Flat, round, solitary, dark brown-to-black pigmented lesion with sharp borders, scalloped edges, and hypopigmented lacunae. The vast majority are stationary, although very slow enlargement of basal dimensions (horizontal growth) has been documented. Extremely rare instances of transformation into adenoma are indicated by nodule formation (vertical growth). Bilateral, multifocal CHRPE-like lesions (> 4 lesions) occur in familial adenomatous polyposis (Gardner’s syndrome [AD]: triad of multiple intestinal polyps, skeletal hamartomas, and soft-tissue tumors).

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FIGURE 10-236 Congenital hypertrophy of the retinal pigment epithelium with hypopigmented lacunae.

• No treatment is necessary if no growth.

• For nodular growth within an area of the CHRPE lesion associated with retinal exudates and cystoid macular edema, consider plaque brachytherapy (experimental).

Bear Tracks

Multifocal variant of CHRPE clustered in one quadrant with appearance of animal tracks. Polar bear tracks are another variant in which the lesions are hypopigmented.

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FIGURE 10-237 Bear tracks demonstrating multifocal congenital hypertrophy of the retinal pigment epithelium clusters.

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FIGURE 10-238 Polar bear tracks demonstrating hypopigmented lesions.

• No treatment is necessary.

Combined Hamartoma of Retinal Pigment Epithelium and Retina

Slightly elevated, dark-gray (variable pigmentation) lesion with poorly defined, feathery borders often associated with a fine glial membrane on the surface of the tumor; dilated, tortuous retinal vessels are common. Can occur in a peripapillary location (46%) or in the posterior pole; causes decreased vision, metamorphopsia, and strabismus in children and young adults. Choroidal neovascular membrane and subretinal exudation are late complications. Bilateral cases associated with neurofibromatosis type 2 (NF-2); variable prognosis.

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FIGURE 10-239 Combined hamartoma of retinal pigment epithelium (RPE) and retina demonstrating gray appearance with feathery borders.

• Fluorescein angiogram: Early filling of the dilated, tortuous retinal vessels with late leakage.

• Consider pars plana vitrectomy with membrane peel if epiretinal membrane results in significant visual distortion; should be performed by a retina specialist. Intrinsic involvement of macula may limit visual recovery.

• Laser photocoagulation if CNV develops.

Malignant Tumors

Note: Treatment and workup for tumors of the retina and choroid should be performed by a multidisciplinary team composed of an internist, an oncologist, and an ophthalmic oncology specialist. Therefore, in-depth discussions of management for these tumors are beyond the scope of this book, and treatment is best relegated to the physicians caring for the patient.

Choroidal Melanoma

Most common primary intraocular malignancy in adults; single, darkly pigmented or amelanotic, dome- or collar-button-shaped (break through Bruch’s membrane) tumor usually associated with overlying serous retinal detachment and lipofuscin (orange spots); commonly has episcleral sentinel vessels. Collaborative Ocular Melanoma Study (COMS) classified lesions by size: small, medium, and large (see below). Most common sites of metastasis are: liver, lung, bone, skin, and central nervous system. Factors predictive of metastasis include: presence of epithelioid cells (Callender classification), high number of mitoses, extrascleral extension, increased tumor thickness, ciliary body involvement, tumor growth, and proximity to optic disk.

Collaborative Ocular Melanoma Study (COMS) results:

• Small lesions (1–2.5 mm apical height, 5–16 mm basal diameter): 204 patients with tumors not large enough to be randomized were followed in the COMS trial; 6% all-cause mortality at 5 years; 1% melanoma mortality at 5 years. It must be emphasized that a majority (about two-thirds) of lesions identified as “small melanoma” did not grow and therefore represented nevi.

• Medium lesions (2.5–10 mm apical height and ≤ 16 mm longest basal diameter): 1317 patients with medium tumors were randomized to enucleation versus iodine-125 brachytherapy; equivalent mortality rates; 34% all-cause mortality for enucleation and 34% all-cause mortality for iodine-125 brachytherapy at 10 years; metastatic mortality in 17% after enucleation and 17% after iodine-125 brachytherapy at 10 years.

• Large lesions (apical height ≥ 2 mm and > 16 mm longest basal diameter or > 10 mm apical height, regardless of basal diameter or > 8 mm apical height if < 2 mm from the optic disk): 1003 patients with large tumors all received enucleation and were randomized to pre-enucleation external beam radiation (PERT) or not; equivalent mortality rates: 61% all-cause mortality for enucleation, 61% all-cause mortality for PERT/enucleation at 10 years, metastasis in 62% histologically confirmed at time of death, additional 21% suspected based on imaging and ancillary testing; metastatic mortality in 39% after enucleation and 42% after PERT/enucleation at 10 years.

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FIGURE 10-240 Choroidal malignant melanoma demonstrating elevated dome-shaped tumor.

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FIGURE 10-241 Choroidal amelanotic melanoma demonstrating hypopigmented subretinal mass.

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FIGURE 10-242 B-scan ultrasound of same patient as Figure 10-241 demonstrating dome-shaped choroidal mass.

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FIGURE 10-243 A-scan ultrasound of same patient as Figure 10-241 demonstrating low internal reflectivity.

• B-scan ultrasonography: Collar-button-shaped (27% in COMS) or dome-shaped (60% in COMS) mass > 2.5 mm (95%), low to medium (5–60% spike height) internal reflectivity (84% in COMS), regular internal structure, solid consistency, echo attenuation, acoustic hollowness within the tumor, choroidal excavation, and orbital shadowing.

• Fluorescein angiogram: May demonstrate double circulation due to intrinsic tumor circulation in large tumors, late staining of lesion with multiple pinpoint hyperfluorescent hot spots; not useful unless the intrinsic circulation is documented.

• Medical and oncology consultation for systemic workup.

Choroidal Metastasis

Most common intraocular malignancy in adults; multiple creamy yellow-white lesions with mottled pigment clumping (leopard spots); low to medium elevation; often with overlying serous retinal detachment; predilection for posterior pole; may be bilateral (20%). Two-thirds of metastatic lesions come from a known primary; primary is not detected in 1%. Most common primary tumors for females are breast (metastasis late), lung, gastrointestinal (GI) and pancreas, skin melanoma, and other rare sources; for males they are lung (metastasis early), unknown primary, GI, prostate, renal cell, and skin melanoma. Ocular involvement is by hematogenous spread; rapid growth; very poor prognosis (median survival is 8.5 months from the time of diagnosis).

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FIGURE 10-244 Choroidal metastasis with leopard-spot appearance (lung carcinoma).

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FIGURE 10-245 Metastatic breast carcinoma with yellow, creamy posterior pole lesion.

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FIGURE 10-246 B-scan ultrasound of a patient with choroidal metastasis demonstrating elevated choroidal mass with irregular surface and overlying serous retinal detachment.

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FIGURE 10-247 A-scan ultrasound of same patient as Figure 10-246 demonstrating medium internal reflectivity.

• Lab tests: Liver function tests, serum chemistry analysis.

• Contrast-enhanced CT scans of chest, abdomen, and pelvis.

• B-scan ultrasonography: Flat or mildly elevated mass with irregular surface, medium to high internal reflectivity, serous retinal detachment usually visible, no orbital shadowing or acoustically silent zone.

• Fluorescein angiogram: Early hypofluorescence with pinpoint hyperfluorescence in the venous phase that increases in later views.

• Chemotherapy, hormonal therapy (breast and prostate), targeted therapy (breast and lung), radiation therapy, brachytherapy, enucleation; should be performed by an ophthalmic oncologist; hospice care for very advanced systemic disease.

• Oncology consultation for metastatic workup if no known primary site.

Primary Intraocular Lymphoma (Primary CNS Lymphoma)

Bilateral (80%) anterior uveitis, vitritis, retinal vasculitis, creamy yellow pigment epithelial detachments, hypopigmented retinal pigment epithelial lesions with overlying serous retinal detachments, and disc edema. Cystoid macular edema is uncommon (unlike uveitis). Occurs in sixth to seventh decades; mimics uveitis (see Masquerade syndrome section). Patients have decreased vision and floaters; associated with central nervous system involvement and dementia. Poor prognosis with death occurring within 2 years of diagnosis.

• Fluorescein angiogram: Early staining of pigment epithelial detachments with late pooling; window defects occur in areas of atrophy.

• Consider diagnostic pars plana vitrectomy to obtain vitreous biopsy for histopathologic and cytologic analysis; should be performed by a retina specialist.

• Lumbar puncture for cytology.

• Head MRI.

• Treatment with chemotherapy (systemic, intrathecal, intravitreal) and radiation should be performed by an oncologist.

• Medical and oncology consultation.

Retinoblastoma

Globular, white-yellow, elevated mass or masses with calcifications that may grow toward the vitreous (endophytic) causing vitreous seeding, or toward the choroid (exophytic) causing retinal detachment, or diffusely infiltrating within the retina. Most common primary intraocular malignancy in children (1 in 15–20,000 live births or approximately 300 cases/year in the US). Ninety percent diagnosed by 5 years of age. Seventy percent are unilateral, 40% heritable, 95% sporadic (25% germinal, 75% somatic), and 5% familial (AD). RB1 gene mapped to chromosome 13q14. Children present with leukocoria (50%), strabismus (18%), intraocular inflammation, and decreased vision. Risk factors for poor prognosis include optic nerve invasion, choroidal invasion, extraocular extension, delay in diagnosis, and prior inadvertent surgical intervention (biopsy, vitrectomy). Prognosis is usually good, with long-term survival approaching 85–90%; 25–30% of children with heritable retinoblastoma may develop a secondary malignancy.

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FIGURE 10-248 Retinoblastoma demonstrating discrete round tumor.

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FIGURE 10-249 Retinoblastoma demonstrating exophytic growth with a serous retinal detachment.

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FIGURE 10-250 Retinoblastoma demonstrating endophytic growth with vitreous seeding.

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FIGURE 10-251 Retinoblastoma demonstrating discrete round tumor.

• Examination under anesthesia required for ophthalmoscopy and treatment.

• B-scan ultrasonography and CT scan to detect calcifications (80%).

• Head and orbital MRI to evaluate for optic nerve and extraocular extension and trilateral retinoblastoma (bilateral with pinealblastoma or parasellar mass).

• Enucleation and chemotherapy (intravenous, intra-arterial, peribulbar, intravitreal [experimental]) are most commonly used. Cryotherapy, laser photocoagulation, thermotherapy, and brachytherapy are used in conjunction with chemotherapy. External beam radiation therapy is used only in exceptional circumstances because of concerns for causing second malignant neoplasms later in life; should be performed only by an experienced ophthalmic oncologist.

• Oncology consultation.

Paraneoplastic Syndromes

Bilateral Diffuse Uveal Melanocytic Proliferation Syndrome

Rare paraneoplastic disorder consisting of diffuse uveal thickening with multiple, faint, yellow-orange spots or slightly elevated, pigmented lesions scattered throughout the fundus (“giraffe-skin” fundus). Occurs in elderly patients with a systemic malignancy who have progressive decreased vision; bilateral, shallow serous retinal detachments may occur late. Poor prognosis, with death within 2 years of diagnosis.

• B-scan ultrasonography: Diffuse uveal thickening.

• Fluorescein angiogram: Orange spots appear hyperfluorescent.

• Electrophysiologic testing: ERG (markedly reduced).

• No effective ocular treatment; treat underlying malignancy.

• Oncology consultation.

Carcinoma-Associated Retinopathy

Sudden onset of progressive nyctalopia, decreased vision (can progress to no light perception [NLP] over months to years), dyschromatopsia, and visual field changes in patients > 50 years old who have a systemic malignancy (notably small cell lung carcinoma). Patients develop retinal pigment degeneration with narrowed retinal vessels and vitreous cells; poor prognosis.

• Lab tests: Antibody against recoverin.

• Electrophysiologic testing: ERG (markedly reduced).

• No effective treatment.

• Oncology consultation.

Melanoma-Associated Retinopathy

Subset of carcinoma-associated retinopathy (CAR) with similar symptoms and fundus findings; paraneoplastic syndrome associated with cutaneous melanoma. Antibodies to bipolar cells cause a selective loss of b-wave on ERG.

• Lab tests: Antibody against bipolar cell.

• Electrophysiologic testing: ERG (markedly reduced with selective loss of b-wave).

• No effective treatment.

• Oncology consultation.