Inflammatory Diseases

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is one of the inflammatory white dot syndromes. It is characterized by acute, bilateral loss of vision in young healthy men or women between

the ages of 20 and 50 years. Approximately one third of individuals report an antecedent viral illness.

Symptoms

Symptoms of APMPPE include a rapid onset of blurred vision often associated with central and paracentral scotomas. Visual loss is usually bilateral but may be asymmetric. Individuals may complain of photopsia,

a symptom reported by persons with other inflammatory white dot disorders as well.

Clinical Features

Pathology/Pathogenesis

The etiology of APMPPE is not well understood. An abnormal immune response to an inciting agent— possibly viral—has been postulated. The early hypofluorescence of the acute lesions demonstrated by IVFA and ICG angiography suggests that nonperfusion or infarction of the choroid, perhaps secondary to vasculitis, may be the primary disorder; the multifocal placoid lesions may be related to RPE ischemia or infarction.

Acute posterior multifocal placoid pigment epitheliopathy has been described in association with mumps, Wegener’s granulomatosis, ulcerative colitis, group A streptococcal infection, tuberculosis, previous hepatitis B vaccination, and Lyme disease; however, the nature of these associations is unclear. Associations with HLA-B7 and HLA-DR2 also have been reported.

In APMPPE, the anterior segment usually appears normal, although episcleritis, iritis, and bilateral perilimbal anterior stromal corneal infiltrates have been reported.

Mild vitreous cells usually are present. The ophthalmoscopic examination is characterized by bilateral, multifocal yellowish white placoid lesions located primarily in the posterior pole at the level of the retinal pigment epithelium (RPE). The lesions fade over the course of

1 to 2 weeks. The acute lesions are replaced by varying degrees of RPE abnormalities including atrophy and hyperpigmentation. Atypical findings include papillitis, periphlebitis, central retinal vein occlusion, disc neovascularization, and subhyaloid hemorrhage.

Ancillary Testing

Treatment/Prognosis

In general, no treatment is required for APMPPE. Most individuals have an excellent prognosis, with spontaneous recovery of visual acuity to 20/40 or better within 3 to 6 weeks. Recurrences are rare. Long-term loss of vision may be related to extensive RPE alterations, choroidal neovascularization, or the atypical features described herein.

Systemic corticosteroid treatment has been suggested in cases with foveal involvement and/or associated central nervous system (CNS) vasculitis. Although extremely rare, there are reports of death associated with CNS vasculitis that developed within several weeks after the onset of APMPPE.

Intravenous fluorescein angiography (IVFA) reveals a characteristic “block early, stain late” pattern. In the early phase of the angiogram, the acute lesions are hypofluorescent. The hypofluorescence is related to both the gray-white opacification of the RPE and choroidal nonperfusion. The lesions become hyperfluorescent in

the late phase of the study. In the quiescent stage of APMPPE, varying degrees of hypofluorescence and hyperfluorescence are revealed by IVFA, depending on the extent of the RPE derangement.

Indocyanine green (ICG) angiography reveals hypofluorescence of the active and healed lesions, highlighting the role of choroidal nonperfusion in APMPPE. Electrophysiologic testing may demonstrate an abnormal electro-oculogram.

Systemic Evaluation

No systemic investigation is necessary for typical APMPPE. A neurology workup including magnetic resonance imaging is indicated in individuals with evidence of CNS vasculitis, including severe headache or other neurological signs or symptoms.

Acute posterior multifocal placoid pigment epitheliopathy is characterized by sudden onset of multifocal yellowish white placoid lesions located at the level of the retinal pigment epithelium.

Fluorescein angiography is important in the diagnosis of acute posterior multifocal placoid pigment epitheliopathy. It is characterized by a “block early, stain late” pattern. The lesions are hypofluorescent

in the early phase of the angiogram.

The fellow eye of the same patient demonstrates the bilateral, symmetric nature of acute posterior multifocal placoid pigment epitheliopathy.

In the late phase of the angiogram, the lesions become hyperfluorescent.

Another example of acute posterior multifocal placoid pigment epitheliopathy shows that the macular lesions are beginning to fade.

The fluorescein angiogram of the same patient reveals prominent hypofluorescence corresponding to the lesions observed clinically. The hypofluorescence is believed to result from choroidal nonperfusion.

ACUTE RETINAL NECROSIS

Acute retinal necrosis (ARN) is a syndrome of rapidly spreading retinal necrosis, occlusive arteriolar vasculitis, and vitritis that affects both healthy and immunocompromised individuals. In immunocompromised patients ARN is particularly virulent and is designated progressive outer retinal necrosis.

Symptoms

Acute retinal necrosis may present with mild ocular discomfort due to inflammation. Vitritis usually causes floaters or decreased vision due to vitreous haze. A rapid deterioration of vision may occur due to spread of necrosis, optic neuropathy, or retinal vascular occlusion.

Clinical Features

Patients with ARN may present with conjunctival injection, mild to moderate anterior chamber inflammation with keratic precipitates, and normal to elevated intraocular pressure. Vitritis is usually substantial, with dense cellular and protein exudation. Acute retinal necrosis is characterized by peripheral multifocal areas of retinal whitening that rapidly become confluent with full-thick- ness retinal necrosis. Retinal opacification usually spreads posteriorly and may spare the macula. The whitened retina is replaced with thinned retina and pigmentary scarring. The retinal arterioles often demonstrate perivascular infiltrate, which may cause occlusion and retinal hemorrhage. Optic neuropathy may be a cause of significant visual loss. Retinal detachment is a frequent outcome due to the development of large irregular holes in necrotic retina and severe proliferative vitreoretinopathy. Less common findings are optic neuritis, retinal vascular occlusion, and ocular neovascularization.

Ancillary Testing

Fluorescein angiography demonstrates decreased perfusion to areas of retinal necrosis. Arterial occlusion may be demonstrated posterior to necrotic retina. Inflammation and breakdown of the blood-retinal barrier cause fluorescein leakage from retinal capillaries. Laboratory testing may rule out other causes of retinal whitening.

Pathology/Pathogenesis

Reports have linked ARN with varicella-zoster virus, herpes simplex virus, cytomegalovirus, and toxoplasmosis. Polymerase chain reaction demonstration of herpesvirus family DNA in the vitreous of patients with ARN as well as the positive response to intravenous acyclovir suggests that herpesvirus family is the cause of ARN.

Histopathologic examination shows sharply defined zones of full-thickness necrotizing retinitis associated with replicating herpesvirus along with occlusive vasculitis of the choroid and retina.

Treatment/Prognosis

Early studies indicate that the natural course of untreated eyes is poor, with less than 28% of eyes obtaining a final visual acuity better than 20/200 because of retinal detachment. Antiviral therapy and advanced vitreoretinal techniques have decreased this degree of visual loss to less than 30% of cases. The percentage of bilateral disease has also been decreased by the early recognition of disease and immediate use of intravenous acyclovir. Anticoagulation with aspirin as well as corticosteroids has been recommended to prevent severe visual loss due to ischemic optic neuropathy. Corticosteroids may also serve to decrease the chorioretinal and vitreous inflammation.

Prophylactic confluent laser photocoagulation applied posterior to the areas of retinitis has been used to reduce the risk of retinal detachment. Surgery for retinal detachment following ARN invariably uses silicone oil because of the atrophic nature of the retina.

Systemic Evaluation

It is important to assess the patient’s level of systemic immunocompetence, as this may influence the treatment regimen. Intravitreal antiviral medications have been suggested for immunocompromised patients.

Acute retinal necrosis with areas of yellowish white, full-thickness retinitis with perivascular sheathing of the inferonasal retinal arteriole.

Fundus photograph of the same patient following treatment with acyclovir. Necrosis is replaced with retinal atrophy and retinal pigmentary alterations. The arteriole is sclerotic.

The areas of retinal necrosis may become confluent. This finding is most notable in the peripheral retina.

Retinal detachment is a common cause of visual loss in patients with acute retinal necrosis. The retina becomes atrophic, with multiple holes leading to retinal detachment.

Fundus photograph of an otherwise healthy man who developed acute retinal necrosis is characterized by widespread peripheral retinal necrosis and arteritis.

Fluorescein angiogram of the same patient demonstrates multifocal branch retinal artery occlusions as a result of arteritis.

BEHÇET’S DISEASE

Behçet’s disease is an immune complex disease with occlusive vasculitis as the main pathologic feature. The disease is found worldwide but predominantly in the Middle and Far East.

Symptoms

The symptoms of Behçet’s disease are primarily those of iridocyclitis—periorbital pain, erythema, photophobia, and blurred vision. The vitritis, vaculitis, and retinal infiltrates of posterior disease may lead to visual loss.

Clinical Features

The diagnosis of Behçet’s disease is based on the presence of various clinical features. The diagnosis requires recurrent oral ulcerations plus two of the following: recurrent genital ulcerations, eye lesions, skin lesions, and a positive pathergy test. The eye findings are observed in most patients, usually occurring 3 to 4 years after buccal and genital lesions. There may be asymmetric and nonconcurrent disease, but it is nearly always bilateral.

The anterior segment disease is classically iridocyclitis with hypopyon. The anterior uveitis may have a rapid, “explosive” onset. Without treatment, the iridocyclitis may resolve in 3 to 4 weeks, but usually recurs.

The characteristic posterior segment lesion is retinal vasculitis, which may involve both the arteries and veins, with arterial occlusion and retinal necrosis. Perivascular sheathing and retinal exudation are observed. Vitritis is always present acutely. Papillitis is present acutely in 25% of cases.

Recurrences are the rule, and visual loss is associated with iris atrophy and posterior synechiae; cataract; vitreous cells; narrowed, occluded retinal vessels; and optic atrophy. Retinal neovascularization may be seen in late disease due to ischemic retinopathy.

Ancillary Testing

Fluorescein angiography shows leakage from retinal vessels before sheathing may be seen clinically. Macular cystic leakage may be found. Decreased fluorescein leakage may serve as a marker of response to therapy.

Pathology/Pathogenesis

The cause of Behçet’s disease remains unknown. It has a strong association with HLA-B5 phenotype and subtype HLA-Bw51, suggesting genetic susceptibility. Behçet’s disease is likely due to a dysregulation of the immune response, resulting in immune complex formation and vasculitis.

Treatment/Prognosis

Immunosuppressive agents are required for effective treatment. These agents suppress inflammation, reduce the frequency and severity of recurrences, and may halt retinal involvement. Along with the acute use of corticosteroids, other immunosuppressive agents include chlorambucil, colchicine, and dapsone. Sustained intraocular drug delivery systems for patients with chronic uveitis are being studied.

The natural course of Behçet’s disease is poor. Most patients will lose most vision within 5 years without treatment. Even with aggressive treatment many patients may experience visual loss.

Systemic Evaluation

The ophthalmologist must follow up patients along with the dermatologist, neurologist, rheumatologist, and others. The greatest mortality arises from central nervous system involvement—untreated neurologic disease is associated with 50% mortality.

Systemic findings in Behçet’s disease include oral aphthous ulcers, recurrent genital ulcerations, and skin lesions.

Retinal findings in patients with Behçet’s disease include retinal vasculitis, retinal vascular occlusions, and focal areas of retinitis. This woman had vasculitis with a branch retinal vein occlusion.

Behçet’s disease may present with iridocyclitis and hypopyon, as seen in this patient.

Fundus photograph of a 40-year-old woman with Behçet’s disease. She had a focal retinal infiltrate, intraretinal hemorrhage, and an epiretinal membrane.

This patient had areas of retinal whitening, with the most notable lesion in the macula. Also present are intraretinal hemorrhage and mild disc edema.

Fluorescein angiogram of the same patient reveals ischemia corresponding to the area of retinal whitening.

BIRDSHOT CHORIORETINOPATHY

Birdshot chorioretinopathy is a rare, bilateral posterior uveitis and chorioretinitis with distinctive fundus lesions and a strong HLA-A29 association. It is a chronic disorder characterized by intermittent exacerbations and remissions. Birdshot chorioretinopathy typically affects healthy individuals in the fifth through seventh decades; women are affected more than men.

Symptoms

Symptoms of birdshot chorioretinopathy include blurred vision, floaters, photopsia, nyctolopia, and dyschromatopsia. Visual loss is insidious, and exacerbations and remissions are common.

Clinical Features

The anterior segment of affected patients is usually normal, although mild iritis and keratic precipitates may be seen. Vitreous cells are prominent. Characteristic fundus lesions are bilateral, cream-colored, oval spots located at the level of the retinal pigment epithelium and choroid.

The lesions vary from one-fourth to three-fourths disc diameter in size and are distributed in the postequatorial fundus (usually, they are most notable nasal to the optic disc). Sequelae include cystoid macular edema (CME), optic disc edema or pallor, epiretinal membrane formation, and choroidal neovascularization. Retinal vascular abnormalities include arteriolar narrowing, vascular tortuosity, and intraretinal hemorrhages.

Ancillary Testing

Intravenous fluorescein angiography demonstrates hypofluorescence of the lesions in the early phase, with or without hyperfluorescence in the late phase. Vascular leakage and CME are common.

Indocyanine green angiography is interesting in that it often reveals more lesions than detected by ophthalmoscopy or fluorescein angiography. Lesions are usually hypofluorescent in the early and mid-phases of the study. They may become isofluorescent or remain hypofluorescent in the late phase.

Electrophysiologic testing may demonstrate an abnormal electroretinogram and a subnormal electrooculogram.

Pathology/Pathogenesis

The etiology of birdshot chorioretinitis is unclear. Because of the strong HLA-A29 association and cellmediated responses to retinal S antigen (approximately 50%), an unspecified immune mechanism is postulated.

Treatment/Prognosis

Treatment for birdshot chorioretinitis is directed mainly at the vitritis and CME. The mainstay of treatment is immunosuppressive agents such as topical, periocular, and systemic corticosteroids and low-dose cyclosporine (2.5 to 5.0 mg/kg/day).

Systemic Evaluation

Birdshot chorioretinitis may be associated with vitiligo and hearing loss. HLA-A29 blood testing is helpful in distinguishing birdshot chorioretinitis from the other inflammatory white dot syndromes.

Birdshot choroidopathy is characterized by bilateral, symmetric, cream-colored, oval spots at the level of the retinal pigment epithelium.

The inflammatory white dots are most notable in the posterior fundus nasal to the optic disc.

Common associations include vitritis, retinal vascular narrowing, disc pallor, and cystoid macular edema.

The inflammatory white dots are usually one-fourth to three-fourths disc diameter in size. They often assume a radiating pattern from the optic disc.