Multifocal Choroidopathy Syndromes

Updated: Oct 05, 2015
  • Author: Sam E Mansour, MD, MSc, FACS, FRCSC; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Overview

This group of rare disorders involves a primary pathologic process occurring at or near the level of the retinal pigment epithelium (RPE) with or without photoreceptor outer segment and choriocapillaris involvement. Ultimately, the etiology is presumed to be either a vasculitic obstruction of the choriocapillaris with secondary infarction of the overlying RPE or, possibly, an immunologic response directed at the RPE itself. Many clinical features of these individual entities overlap, causing much confusion. Whether these conditions represent distinct entities or whether some may be parts of a spectrum of the same basic disease is still unknown.

Other conditions of choroiditis with overlying RPE involvement are not described in this article; yet, they are important to consider in the differential diagnosis of these more atypical choroiditides, such as tuberculosis, histoplasmosis, syphilis, posterior scleritis, reticulum cell sarcoma, lymphoid neoplasia, diffuse unilateral subacute neuroretinitis (DUSN), and Lyme disease, or the more common idiopathic syndromes, such as central serous retinochoroidopathy, sarcoidosis, Vogt-Koyanagi-Harada syndrome, and sympathetic ophthalmia.

Classification

Attempts at grouping these myriad disorders, especially by Gass, have resulted in inclusion of multiple evanescent white dot syndrome (MEWDS), acute idiopathic blind spot enlargement syndrome (AIBSES), acute macular neuroretinopathy (AMN), and multifocal choroiditis (MFC) or pseudo–presumed ocular histoplasmosis (pseudo-POHS) under the term acute zonal occult outer retinopathy (AZOOR). [1] This inclusion group arose primarily from the observation of a few case reports where 2 or 3 of these entities had coincident manifestation in the same patient. [2]

AZOOR is characterized by the following common clinical features: minimal initial ophthalmoscopic changes, followed later by signs of retinochoroidal degeneration, rapid reduction in one or more parameters of the visual field, photopsia, and abnormalities on electrophysiologic testing. [3]

More recently, AIBSES has been characterized to have sufficiently unique clinical features, such that, despite some similarities to MEWDS, treating it as a distinct and separate entity may be wise. [4, 5, 6, 7, 8] AMN, a bilateral condition affecting otherwise healthy young adults, appears to involve a pathologic process occurring more in the middle and outer retinal layers rather than in the RPE and choriocapillaris. [9] As such, both AIBSES and AMN will not be discussed in this article.

There remains the conviction that the aforementioned entities are sufficiently distinct as to preclude any effective single inclusion group. [10] In the absence of any significant histopathologic and serologic findings, these conditions not only continue to present a problem as far as classification, but also remain poorly understood with regards to etiology or pathogenesis. The discussion of the various multifocal choroidopathy syndromes in this article will consider each entity separately and, in so doing, will avoid the thorny issue of endorsing any one classification.

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Multifocal Choroiditis

Multifocal Choroiditis and Panuveitis

Since the initial description of the disease by Nozik and Dorsch in 1973, hundreds of patients have been reported in the literature with multifocal choroiditis and panuveitis (MCP). [11] As mentioned earlier, many investigators have lately suspected that MCP is one and the same with several other disorders, all representing various stages of the same basic clinical entity (ie, AZOOR). With further follow-up of some of these patients, hopefully, this spectrum of clinical manifestations of multifocal choroiditis will become better defined.

The disease affects otherwise healthy young patients in their third decade (average age, 34 y; range, 6-74 y), with an incidence of bilateral involvement of 80%. [12] A moderate racial and gender predisposition exists, with approximately 66% of patients being white and 80% of patients being female. [12] As well, myopia is present in more than 85% of these individuals.

Signs and symptoms

The principle presenting symptom is usually blurry vision with or without photophobia. Mild ocular pain may occur, accompanied by complaints of metamorphopsia, floaters, scotomas, and photopsia.

Presenting visual acuity may vary from 20/20 to light perception, with an average of 20/100. Clinical examination reveals a mild-to-moderate aqueous inflammation with cell and flare in approximately 50-60% of patients. Small- to medium-sized keratic precipitates may be present, as well as posterior synechiae and iris atrophy with nodule formation. Vitreous cellular infiltrates are present in more than 90% of patients.

As demonstrated in the image below, fundus examination reveals multiple, small, discrete yellow/gray-white spots that are typically round and may be polygon or oval in shape.

Multifocal choroiditis and panuveitis. Multiple, d Multifocal choroiditis and panuveitis. Multiple, discreet lesions appearing in the early stage of the disease.

These lesions are approximately 200 µm in diameter, but they can vary in size (50-1000 µm). The lesions tend to scatter predominantly in the periphery rather than in the macula and are located at the level of the RPE and choriocapillaris. Multiple active lesions may occur at any one time.

During the late stage of the disease, seen in the image below, the spots may become atrophic, with a rim of hyperpigmentation. These can assume the classic punched-out appearance with bands of subretinal fibrosis at their margins.

Multifocal choroiditis and panuveitis. Late stage Multifocal choroiditis and panuveitis. Late stage of disease manifesting atrophic, punched-out lesions.

During the acute phase, optic disc edema may occur, which later develops to peripapillary scarring assuming a characteristic "napkin ring" subretinal fibrosis. [13] Periphlebitis is often present with resultant retinal vasculature narrowing. [14] Cystoid macular edema is present in approximately 10-20% of patients, and the incidence of choroidal neovascular membrane formation varies from 25-40%. [12, 15]

Diagnostic imaging: fluorescein angiography

During the early stage, the active lesions exhibit blockage of the early fluorescence followed by late staining. A rim of hyperfluorescence may or may not be present around the lesions. With the late stage of the disease, the most predominant feature is that of RPE window defects corresponding to the areas of the lesions. (See the images below.)

Multifocal choroiditis and panuveitis. Fluorescein Multifocal choroiditis and panuveitis. Fluorescein angiogram demonstrating punctate hyperfluorescence due to staining of the lesions.
Multifocal choroiditis and panuveitis. Fluorescein Multifocal choroiditis and panuveitis. Fluorescein angiogram demonstrating late phase transmission hyperfluorescence of lesions.

Diagnostic imaging: indocyanine green angiography

Similar to findings on fluorescein angiography, early lesions of MCP are hypofluorescent on indocyanine green (ICG) angiography. In contrast, early lesions of POHS tend to be hyperfluorescent. [16, 17, 18]

Electrophysiologic and psychophysical studies

The electroretinogram (ERG) is normal in approximately 50% of patients with MCP. However, a report by Jacobson and coworkers looking at ERG testing in patients with AZOOR, which included patients with MCP, revealed interocular asymmetry in all patients tested with full field ERGs. [2] In addition, moderate abnormalities in the a-wave suggest that there is dysfunction at the level of the photoreceptor outer segment. Similar findings have been noted in MEWDS and AMN using both the a-wave and the early receptor potential recordings. [19, 20] Serial multifocal ERG (MERG) testing reveals a diffuse loss of function over the entire test field that is often permanent. [21]

The electrooculographic (EOG) findings are abnormal in approximately 60% of patients studied. Visual field testing sometimes demonstrates increased blind spot size. [22] Scotomata are associated with clinical retinal lesions. Visual field pattern abnormalities correlate well with ERG a-wave amplitude. [2] In addition, large temporal field defects that do not correspond to clinical lesions have also been noted. [21]

Etiology

The etiology of MCP remains unknown. Extensive systemic medical evaluations have not yet identified a single common cause for MCP. Unlike POHS, where 90% of patients exhibit positive reactions to the histoplasmin skin test, only 25% of patients with MCP exhibit positive reactions to this skin test. [23] Positive treponemal serology is evident in up to 27% of patients with MCP, yet no modification of the disease with penicillin treatments has been achieved to date.

Radiologic investigations of patients with MCP have demonstrated hilar adenopathy in a small minority of patients (approximately 4%) along with pulmonary calcification (approximately 10%). In conjunction with this, approximately 20% of patients with MCP have a positive Mantoux test. Half of those patients, when treated with antituberculous medications, have a decrease in the ocular inflammation. Sarcoidosis has also been diagnosed in more than one third of patients with MCP.

Other infections that have been associated with MCP include herpes simplex, herpes zoster, Epstein-Barr virus, Lyme disease, Toxocara canis, and West Nile virus. [24, 25, 26, 27, 28] Despite this, many investigators still believe that MCP results from an underlying autoimmune mechanism, possibly triggered by an infectious agent. Histopathologic studies of ocular specimens from patients with MCP have revealed a predominant B-lymphocyte and plasma cell infiltrate of the choroid and choriocapillaris. [29] In addition, a deposition of compliment and immunoglobulins at or above the Bruch membrane has been noted. A proliferation occurs of the pigment epithelium with hyperplastic changes and migration into the neurosensory retina. [29]

Disease course and prognosis

Unfortunately, recurrence is very high in MCP, and the visual prognosis remains poor. [30, 31, 32] Peripapillary atrophy with progressive subretinal fibrosis results in enlargement of a blind spot in approximately 43% of patients. [22, 33] Unlike the aforementioned conditions, the major cause of central visual loss is due to subretinal neovascular membrane formation (approximately 45%) and is not due to cystoid macular edema (approximately 13%). [34] Rarely, MCP may lead to serous retinal detachments. Approximately one third of patients with MCP maintain their initial visual acuity at onset, while another one third lose, on average, at least 2 or more Snellen lines. [30]

Treatment

Treatment of MCP remains problematic. In a few cases, a prompt response occurs in the acute phase to high systemic corticosteroids with subsequent improvement in visual acuity. However, with each recurrence of the disease, a progressive diminution in the effect of corticosteroid treatment occurs.

Immunomodulatory therapy, using azathioprine, cyclosporine, or methotrexate, has often resulted in good control of the inflammation and in subsequent preservation of vision. [35] In some instances, amelioration of the subretinal neovascular membrane has been noted with corticosteroid therapy. [32] Specific laser therapies, both conventional laser therapy and photodynamic therapy (PDT), have been used with moderate success in managing subretinal neovascular membranes. [36, 37, 38] Surgical treatment of subretinal neovascular membranes involving limited macular translocation has also been reported. [39]

Diffuse Subretinal Fibrosis Syndrome

This very rare and incompletely characterized entity was first described in 1982. [40] Many investigators have long suspected that diffuse subretinal fibrosis syndrome (DSFS) represents a variation of MCP. As well, this condition shares many features of punctate inner choroidopathy and other similar diseases in the AZOOR group. [41] DSFS typically affects otherwise healthy individuals in their second decade (average age, approximately 20 y; range, 14-34 y). The condition is often bilateral. The association with axial myopia is questionable.

Signs and symptoms

Patients typically present with central visual loss and complaints of metamorphopsia. Clinical examination during the acute phase reveals multiple, small, yellow stellate lesions scattered throughout the posterior pole. Mild vitritis may be present with isolated pockets of subretinal fluid. In the chronic phase, the lesions become discrete with sharply angulated subretinal scar formation, as in the image below. In the macula, the lesions tend to coalesce, forming broad zones of subretinal fibrosis. Later complications can include serous and hemorrhagic macular detachment. See the image below.

Diffuse subretinal fibrosis syndrome. This patient Diffuse subretinal fibrosis syndrome. This patient's right eye shows the typical subretinal angulated scar formation.

Diagnostic imaging: fluorescein angiography

As mentioned earlier, this condition shares many clinical features with that of MCP. This is also reflected in the fluorescein angiogram. The distinct features of DSFS on angiography are an early phase hypofluorescence in the areas of subretinal fluid loculation. During the late phase of the angiogram, extensive leakage (seen in the images below) is present at these sites that, in some cases, may suggest subretinal neovascularization. [40]

Diffuse subretinal fibrosis syndrome. Midphase of Diffuse subretinal fibrosis syndrome. Midphase of fluorescein angiogram demonstrating progressive leakage hyperfluorescence.
Diffuse subretinal fibrosis syndrome. Late phase o Diffuse subretinal fibrosis syndrome. Late phase of the fluorescein angiogram demonstrating progressive leakage as hyperfluorescence.

Electrophysiologic and psychophysical studies

The findings on the ERG and the EOG are notoriously variable in this condition, with surprisingly intact studies in individuals with both acute and chronic involvement. Visual field testing reveals constriction peripherally with central scotomata that often correlate with the clinical lesions.

Etiology

As with MFC, no systemic associations with DSFS exist. Earlier suggestions that this condition may be due to as yet unknown hormonal irregularities in young women has not developed into any trend of significance. [42] In view of the clinical and angiographic findings, this condition's clinical appearance is likely secondary to a primary RPE hyperplastic process. [43]

Histologic evidence of immunoglobulin and complement deposition on the internal side of the Bruch membrane also suggests a focal inflammation of the RPE. [29]

Disease course and prognosis

This condition is characterized by recurrent episodes with the fellow eye becoming involved within a 6-month period.

Treatment

Management of DSFS involves the use of corticosteroids early in the disease. [41] This treatment is useful in sparing visual loss largely in the contralateral eye. Cyclosporin may be useful in those cases where steroid has failed to control the disease.

Punctate Inner Choroidopathy

First described by Watzke and associates in 1984, punctate inner choroidopathy (PIC) typically affects young, moderately myopic women who present with typical signs of ocular histoplasmosis but have negative serology or skin test for histoplasmosis. [32, 44] This rare condition is also one of the entities grouped under AZOOR. [45] Other terms used to describe this condition include multifocal inner choroiditis and pseudohistoplasmosis. The average age of patients with PIC is 27 years with a range of 16-40 years. Females represent 90% of the patients with PIC and usually have bilateral ocular involvement. [46]

Signs and symptoms

Patients present with blurred vision, photopsia, and central and peripheral scotomata; however, no history exists of any viral prodrome. PIC differs from POHS because patients with the latter tend to be more asymptomatic with regard to scotomata. Chronic chorioretinal scars also tend to be more stable in POHS than in PIC.

The initial visual acuity at presentation varies from 20/50 to 20/400. No anterior segment or external ocular signs of inflammation is evident. The characteristic lesion of PIC is essentially identical to that seen in ocular histoplasmosis with multiple (approximately 2-6) yellow-white spots (100-300 µm) of the inner choroid and retina largely confined to the posterior pole (see the image below). These lesions tend to assume a linear branching pattern. During the late stage of the disease, the spots become atrophic and pigmented.

Punctate inner choroidopathy. Pigmented central le Punctate inner choroidopathy. Pigmented central lesions in association with peripapillary scarring.

The classic triad of punched-out peripheral lesions in association with peripapillary atrophic scar formation and disciform macular scar seen in POHS is often present in patients with PIC. Small serous retinal detachments may form; however, they resolve spontaneously and usually require no treatment. Both optic disc edema and the presence of vitreous cells appear to be a variable finding in patients with PIC. The occurrence of subretinal neovascular membranes in this condition is 25-40%.

Diagnostic imaging: fluorescein angiography

Again, paralleling the findings in ocular histoplasmosis, the early phase of the angiogram demonstrates hyperfluorescence of the lesions, and the late phase (seen in the image below) is marked by leakage at the lesions.

Punctate inner choroidopathy. Late phase fluoresce Punctate inner choroidopathy. Late phase fluorescein angiogram of same patient as in Image 9 demonstrating halo hyperfluorescence of both peripapillary and inferior macular scars, which are more chronic relative to the more active superior macular lesion demonstrating leakage hyperfluorescence.

Electrophysiologic and psychophysical studies

The ERG findings are occasionally subnormal in patients with PIC. The electrooculogram demonstrates very mild abnormalities of the Arden ratio. Visual field testing demonstrates central and paracentral scotomas. An enlarged blind spot may or may not be present.

Etiology

PIC likely represents a variant of MFC. This condition may represent either an inflammatory or infectious thrombosis of the choriocapillary layer by as of yet an unidentified organism that behaves very similarly to histoplasmosis.

Disease course and prognosis

Recurrences are common in PIC, usually occurring within the first 3 months. [32] Despite this, visual outcome is good with approximately 50-75% of eyes having vision better than 20/25, especially if uncomplicated with choroidal neovascular membrane formation.

Treatment

A variable response to systemic corticosteroids occurs depending on the stage of the disease. [47, 48, 49] Both conventional laser therapy and PDT have been used for the management of subretinal neovascular membranes with increasing success. [50, 51, 52, 53]

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Acute Posterior Multifocal Placoid Pigment Epitheliopathy

In 1968, Gass first described acute posterior multifocal placoid pigment epitheliopathy (APMPPE). [54] This condition typically affects young or middle-aged, otherwise healthy, adults (average age, 25 y; range, 7-57 y) who experience an acute decrease in visual acuity in one or both eyes. [55, 56]

While neither a racial nor sex predilection is generally though to exist for this condition, a recent 20-year study of the incidence of white dot syndromes in Olmstead County Minnesota found that multiple evanescent white dot syndrome (MEWDS) occurred more commonly in females, and APMPPE occurred more often in males. [57] Bilateral involvement is generally the rule, although the second eye involvement may be delayed for several weeks.

The condition tends to resolve spontaneously in approximately 7-11 weeks with near-normal return of visual acuity and visual function in the majority of cases. Although some RPE changes may remain visible and small paracentral scotomas may persist, usually no other ocular disturbances are evident. The typical course of the disease suggests an underlying viral inflammatory disorder [1, 58] or a delayed type IV hypersensitivity reaction to multiple stimuli. [59]

Signs and symptoms

A rapid reduction in visual acuity typically occurs with or without a history of a preceding flulike illness or upper respiratory tract infection. APMPPE presents clinically as multiple, well-circumscribed, flat lesions deep to the retina at the level of the RPE and choriocapillaris. The retina overlying the lesions appears normal. Subretinal fluid or neurosensory detachment over the lesions is very rare and should cause one to consider the diagnosis of Vogt-Koyanagi-Harada syndrome. These lesions are variable (approximately 0.125- to 1-disc diameter) in size, generally larger than those seen in retinal pigment epitheliitis, and are usually isolated but may be confluent. They are typically scattered throughout the posterior pole, including the macula, and in the postequatorial midperiphery. Initially, they appear cream-colored or grayish-white in color, as seen in the image below.

Acute posterior multifocal placoid pigment epithel Acute posterior multifocal placoid pigment epitheliopathy. Lesions are typically creamy white and are scattered throughout the posterior pole. Courtesy of Everett Ai, MD, San Francisco, Calif.

There is usually no evidence of anterior segment inflammation, although vitreous cells are present in as many as 50% of the patients. This may be the result of a mild periphlebitis with exudation. In addition to vascular inflammation, mild optic disc edema may also be noted. Very rarely, the condition can result in retinal edema, retinal hemorrhage, and choroidal neovascular membrane formation. [60]

Diagnostic imaging: fundus autofluorescence (FAF)

Initially, the lesions demonstrate hyperautofluorescence with hypoautofluorescent margins. [61, 62, 63, 64] Hypoautofluorescence of the fovea on FAF may correlate with visual acuity impairment in the white dot syndromes, including APMPPE. [65]

Diagnostic imaging: fluorescein angiography

The initial phase of the angiogram sometimes demonstrates prolonged filling of the choroidal vasculature. The acute phase lesions are hypofluorescent. This early hypofluorescence is often attributed to a combination of incomplete and irregular filling of the choriocapillaris in conjunction with a masking effect produced by the edematous, swollen RPE cells. This is followed in the late phase with evidence of leakage and staining at the lesion sites. See the images below.

Acute posterior multifocal placoid pigment epithel Acute posterior multifocal placoid pigment epitheliopathy. The lesions here are more peripheral than those in the previous image.
Midphase of fluorescein angiogram of the same pati Midphase of fluorescein angiogram of the same patient as in the image directly above, demonstrating typical light leakage and staining of the lesions.

The healed lesions of APMPPE demonstrate mottled hyperfluorescence and window-type defects due to alterations in the RPE in areas corresponding to the acute lesions.

Diagnostic imaging: indocyanine green angiography

The typical ICG pattern for both active and inactive lesions consists of hypofluorescent areas up to the late phase, suggesting choriocapillaris nonperfusion. [66, 67, 68, 69]

Diagnostic imaging: optical coherence tomography (OCT) scanning

Initially, the active phase of the disease demonstrates an anterior displacement and hyperreflectivity of neuroretina and outer reflective bands in areas overlying affected RPE.

With resolution, there is an accompanying regression of the prior displacement, increased reflectance of the outer reflective band, and mild disruption of the outer retinal layers. Quiescent lesions display a nodular, hyperreflective lesion on the plane of the RPE, with mild underlying backscattering from the choroidal layer, consistent with RPE atrophy. [62, 64, 70, 71, 72]

A recent SD-OCT study of a case of acute APMPPE lesions, however, revealed a hyperreflective area located between the outer nuclear layer and the inner and outer photoreceptor segments (IS/OS junction) corresponding to the placoid lesions seen clinically and angiographically. [73] This finding suggests that the whitish placoid lesions seen clinically in APMPPE may represent edema between the outer nuclear layer and the IS/OS junction rather than swelling or opacification of the RPE cells.

Goldenberg and colleagues have proposed a 4-stage classification system for APMPPE based on Spectralis SD-OCT findings in a study of 12 eyes of 6 patients. [74]

In stage 1a, the hyperacute phase of the placoid lesions, there is a well-demarcated dome-shaped elevation of the IS/OS junction with hyperreflective intertwined material and variable amounts of subretinal fluid present beneath the IS/OS junction and the RPE. In Stage 1b, the acute phase lesion, there is a fairly rapid flattening of the well-demarcated dome-shaped lesion accompanied by thickening of the IS/OS junction and hyperreflectivity of the outer nuclear layer.

Within about 2 weeks, the lesion evolves into stage 2, a subacute phase, with a distinct separation of the IS/OS junction and RPE layer visible with mild subretinal fluid accumulation present. The hyperreflectivity of the outer nuclear layer begins to fade and the layer thins at this stage.

In Stage 3, the late phase, which occurs approximately 6 weeks post disease onset, there is partial disappearance of the IS/OS junction and accentuated hyperreflectivity of the RPE is seen.

At 3 months post onset, stage 4, or resolution phase, is visible. In it, 2 hyperreflective bands indicative of the IS/OS junction and the RPE reappear as separate and distinct bands.

Montero et al reported a case of APMPPE with severe intraretinal edema with large cysts present in the outer nuclear layer and disruption of the IS/OS junction on SD-OCT. [75] The intraretinal edema and structural abnormalities normalized with disease resolution. Others have demonstrated photoreceptor layer changes in both the acute and resolved stages of APMPPE on SD-OCT. [76]

Electrophysiologic and psychophysical studies

Most patients with APMPPE have normal EOG findings. However, some patients may have diminished, subnormal EOG findings during the acute phase of the disease. Some may exhibit subnormal cone and rod ERG findings. Scotomata on visual-field testing often are present during the acute phase of the disease that may or may not be coincident with the observable clinical lesions. These scotomata can persist and be permanent.

Etiology

The underlying etiology of APMPPE is unknown. Deutman and Van Buskirk believed that APMPPE represents a primary obstruction of the choroidal circulation with secondary RPE degeneration. [77, 78] This view is supported by ICG angiographic and OCT scan evidence. [66, 67, 68, 69, 64, 70] However, others, especially Gass, believe this to be a primary disease of the RPE. [1, 54] In view of this condition's association with a viral flulike illness, it is possible that an immune reaction to shared viral and RPE antigens with or without modification by the use of antibiotics might be underlying any primary RPE involvement. Krey has been able to experimentally reproduce APMPPE-like lesions in the posterior poles of rabbits and rhesus monkeys infected with Borna disease virus (BDV). [79]

APMPPE, of all the conditions described in this article, has the greatest variety of associations with other systemic conditions and complications, as follows [63, 80, 81, 82, 83, 84, 85, 86, 87, 88] :

  • Thyroiditis [83, 89]
  • Platelet aggregation abnormalities
  • Lymphadenopathy
  • Renal cell carcinoma [82]
  • Systemic mycobacterial infections [90]
  • Hepatomegaly
  • Erythema nodosum [78, 91]
  • Regional enteritis
  • Cerebrovasculitis [85, 87, 91, 92, 93, 94]
  • Recurrent stroke [94]
  • Juvenile pontine infarction [95, 96]
  • Recurring meningoencephalitis [97]
  • Cranial nerve VI paralysis [98]
  • Vitamin B-12 deficiency [85]
  • Homocysteinemia [85]
  • Sarcoidosis [91, 99]
  • Lyme disease [63, 100]
  • Microvascular nephropathy [101]
  • DRESS syndrome [102]
  • Hemophagocytic syndrome [88]
  • Dysacusis [103]
  • Adenovirus type V [84]
  • Reaction to Swine Flu Vaccine [80]
  • Following influenza vaccination [104]
  • Spinal fluid pleocytosis and elevated cerebral spinal fluid (CSF) protein

The association between APMPPE and cerebral vasculitis is well known. Gass suggested that APMPPE may be the initial manifestation of primary CNS angiitis. [105] Mortality from the later condition is high, especially when associated with a rapid taper of systemic steroids. [73, 106, 107] A case of recurring meningoencephalitis has also been reported with APMPPE with prednisone tapering. [97] Because of the CNS associations with APMPPE, neurologic symptoms and signs in these patients should be investigated appropriately.

Disease course and prognosis

Over a 2- to 6-week period, the acute lesions begin to fade, leaving pigment mottling and atrophic, geographic-shaped lesions at the level of the RPE. Improvement in visual acuity often lags the resolution of the RPE lesions, which can take from weeks to months. Fortunately, the prognosis for visual recovery is very good, and many patients (75-80%) experience better than 20/40 vision. [108, 109] Some eyes remain symptomatic, however, and visual acuity remains reduced in up to 40% if there is foveal involvement at presentation. [109] Recurrences, unlike other conditions in this section, are rare, and usually occur within the first 6 months. [110] If there is initial unilateral presentation, the second eye often lags the first eye by a few days or weeks. A variant of APMPPE occurring in older patients and complicated by subsequent geographic atrophy and choroidal neovascular membrane formation has been described. [111]

Treatment

Treatment of the acute phase of APMPPE with corticosteroids is common but has shown limited benefit. Treatment with the tumor necrosis factor (TNF) blocker infliximab has been reported to show improvement in visual acuity and prevention of recurrences during the follow-up period. [112] However, treatment with infliximab did not prevent disease spread to the contralateral eye. Sub-Tenon and intravitreal triamcinolone has been used for associated complications, such as macular edema and choroidal neovascularization. [113, 114] Sporadic treatments with antituberculous and systemic antibiotics have also been reported but have not, as of yet, been proven to be effective. [115]

Photodynamic laser therapy has also been used to manage choroidal neovascularization in this condition, as has the anti-VEGF agent ranibizumab. [113, 116] Immunosuppressive therapy with azathioprine [97] and with mitoxantrone [93] have been used successfully in the treatment of meningoencephalitis and the cerebral vasculitis associated with APMPPE, respectively.

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Acute Retinal Pigment Epitheliitis (Krill Disease)

This very rare condition was first described by Krill and Deutman in 1972. [117] Acute retinal pigment epitheliitis (ARPE) is a self-limited disease of the RPE that typically occurs in young, otherwise healthy adults. It has a median age of onset of approximately 45 years, with a range of 16-75 years. A preponderance of involvement is evident in males (approximately two thirds). No racial predilection exists, and the condition is bilateral in approximately 40% of patients.

Signs and symptoms

Approximately half the patients are asymptomatic at the time of presentation, with the symptomatic patients describing a sudden, usually mild, decrease in vision with or without central or paracentral scotomata and metamorphopsia. Unlike APMPPE, many patients (approximately 75%) have visual acuities around 20/30. The lesions appear dark gray to black in color, with a surrounding yellow-white halo, and are typically between 50-100 µm in size. Often, 1-4 golden-colored spots are arranged in discrete clusters around the macula. With resolution, the spots may either darken or lighten, but the halos remain. Extramacular lesions are rare, and, with time, a pattern of RPE migration may develop at the sites of the spots. Very rarely, this condition is associated with macular edema or vitreitis. [118, 119] See the image below.

Acute retinal pigment epitheliitis. Acute retinal pigment epitheliitis.

Diagnostic imaging: fluorescein angiography

During the acute phase of the disease, the centers of the spots are hypofluorescent owing to blockage. The surrounding halos typically demonstrate light hyperfluorescence early, which is due to a window-type defect rather than dye leakage. [120, 121]

Late phase fluorescein angiogram in a patient with Late phase fluorescein angiogram in a patient with acute retinal pigment epitheliitis displaying transmission hyperfluorescence.

Diagnostic imaging: ICG angiography

Early and midphase ICG angiography shows patchy hyperfluorescence in the macula, and late-phase frames show hyperfluorescent halos around the individual lesions, with a cockadelike appearance of the macula. [121] These angiographic abnormalities tend to resolve over time.

Diagnostic imaging: OCT scanning

Limited time-domain OCT scanning studies of acute retinal pigment epitheliitis have demonstrated an abnormal foveal hyperreflectivity involving the outer nuclear layer and photoreceptors, with variable disruption of the retinal pigment epithelium and moderate backscattering. [122]

SD-OCT shows disruption of the IS/OS junction of the photoreceptors and a wider disruption of the inner band of the RPE layer. [121] SD-OCT in the acute phase may also show undulation of the RPE and backscattering, similar to TD-OCT. [123] The inner segment and outer segment layers and RPE inner band typically show restoration of normal anatomy with disease resolution, and restoration of the foveal IS/OS junction may be of prognostic value for visual recovery. [123] Whether the outer retinal involvement seen in these OCT studies is a primary or secondary response is unknown.

Electrophysiologic and psychophysical studies

On Amsler grid testing, these patients sometimes describe variable central or paracentral scotomas. [119] Mild color vision abnormalities also have been described with this condition. ERG testing is generally normal, while EOG testing has yielded various results, from normal to subnormal depending on the extent of RPE involvement. With resolution of the disease, there is a high rate of conversion back to normal in all tests.

Etiology

To date, systemic investigations of patients with this rare condition have failed to yield any conclusive etiology, although a viral etiology is generally suspected in this condition. Associations with rubella, Borrelia burgdorferi (Lyme disease), influenza, and hepatitis C infections have been made. [12, 124, 125, 126] In some instances, this condition is a harbinger of central serous retinal choroidopathy (CSR). [127] A case of ARPE has been reported following the administration of intravenous bisphosphonate. [128]

Disease course and prognosis

ARPE has a self-limited course, usually with complete resolution over a 6- to 12-week period. [129] Recurrences have been reported to occur but are rare. [130]

Treatment

Given the generally benign and self-limited course of this condition, no specific treatment is recommended.

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Multiple Evanescent White Dot Syndrome

First described in 1984 by Jampol et al, [131, 19] MEWDS is a self-limited condition that afflicts young, otherwise-healthy patients, usually in their second decade (average age is 28 y; range is 14-57 y), although cases involving children and elderly patients have been described. [132, 131] Its incidence in one 20-year study of white dot syndromes was approximately 0.45 case per 100,000 population per year. [57]

MEWDS shares many clinical and electrophysiologic features with acute idiopathic blind spot enlargement syndrome (AIBES) and other entities in the acute zonal occult outer retinopathy (AZOOR) group. [4, 7] Despite that commonality, MEWDS is believed to be uniquely distinguishable, warranting its own separate identification. [10, 133]

The condition usually presents unilaterally, with few instances of later contralateral ocular involvement. [134] There is a preponderance of the condition in women (approximately 75% of patients) and in patients who are highly myopic. [135] No racial predilection exists.

Signs and symptoms

In addition to presenting with blurred vision, photopsia, and multiple paracentral scotomata, patients may also report symptoms of a flulike illness (approximately 25-50%). Initial visual acuities on presentation vary from 20/25 to 20/300 (average 20/100). Vitreous cells are noted in approximately 50% of patients, despite the absence of any anterior segment or external ocular signs of inflammation.

The characteristic lesions in MEWDS consist of multiple, small (approximately 100-200 µm in diameter), gray-white patches, with each patch being made up of smaller white to light orange-colored dots. These lesions clinically appear to be at the level of the outer retina or RPE and typically are distributed in the perifoveal and peripapillary regions with rare involvement of the fovea itself. (See the image below.)

Multiple evanescent white dot syndrome. Acute mani Multiple evanescent white dot syndrome. Acute manifestation of deep, white spots scattered throughout the posterior pole.

A circumpapillary presentation of MEWDS with corresponding blind spot enlargement can mimic the appearance of presumed ocular histoplasmosis syndrome. [136, 137, 138] In the periphery, the dots become sparse and assume a somewhat radial pattern, in some instances paralleling the retinal vasculature. Later, the macula often exhibits a fine, granular, white- or orange-speckled appearance, as demonstrated in the image below. [139, 140] These specks are much smaller than the white dots and often are associated with an irregular light reflex of the internal limiting membrane.

Multiple evanescent white dot syndrome. This patie Multiple evanescent white dot syndrome. This patient has spots similar to those seen in the patient in the previous image, but this patient also displays the almost pathognomonic granular changes in the macula.

Other reported posterior pole findings include splinter hemorrhages, venous sheathing, panuveitis, hyperemia or edema of the optic nerve head, and, rarely, choroidal neovascularization. [141, 142, 143] Choroidal neovascularization can, in fact, be an initial presenting or early manifestation of MEWDS. [144, 145]

Diagnostic imaging: fundus autofluorescence

Fundus autofluorescence (FAF) has shown both hyperautofluorescence and hypoautofluorescence of the spots, corresponding to the hypofluorescent lesions seen on ICG angiography. [139, 146, 147, 148] The FAF lesions generally appear less numerous than the focal hypofluorescent spots seen on ICG angiography. [146, 148] With disease resolution, the spots usually evolve into areas of decreased autofluorescence or disappear altogether. [146, 147]

Diagnostic imaging: fluorescein angiography

In the early phase of the fluorescein angiogram, there is a punctate hyperfluorescence of the gray-white patches that often displays a wreath-shaped pattern. Leakage of dye at the optic disc is present in approximately 60% of patients. During the late phase of the angiogram, represented in the image below, a patchy, mottled pattern of hyperfluorescence is observed throughout the posterior pole, with staining of the optic nerve head. With resolution of the acute episode, the angiographic findings become much less prominent; however, subtle RPE window defects usually persist. [149] See the image below.

Multiple evanescent white dot syndrome. Fluorescei Multiple evanescent white dot syndrome. Fluorescein angiogram of the same patient as in the image directly previous to this one, demonstrating the characteristic late phase mottled hyperfluorescence and staining of the optic disc.

Diagnostic imaging: indocyanine green angiography

ICG angiography studies have demonstrated multiple deep, small, round, hypofluorescent choroidal lesions appearing early and persisting into the late phases [150] of the disease. In some instances, the late phase hypofluorescence can appear as a series of small dots overlying larger spots. Many more lesions usually are observed on ICG angiography than are visible by clinical examination or fluorescein angiography. [151, 152, 153] The hypofluorescent lesions in the ICG angiogram persist for a longer time than do those lesions displayed during fluorescein angiography. [154, 155] The ICG-defined lesions also closely correlate with visual function. [16] ICG angiography in MEWDS can be helpful in establishing the diagnosis in cases with subtle fundus findings, and may also provide some useful guidance for therapy. [156, 149]

Diagnostic imaging: optical coherence tomography scanning

OCT scanning performed during the acute phase of MEWDS demonstrates moderately reflective focal lesions in the outer photoreceptor layer and a disruption of the foveal photoreceptor outer segments and the inner segment–outer segment (IS/OS) junction. [149, 157, 158, 159, 160] SD-OCT also demonstrates increased retinal pigment granularity in the affected eye in MEWDS. [161] One SD-OCT study showed decreased photoreceptor outer segment length in the acute phase of the disease with restoration to normal as the disease resolved. [162]

Reflectivity maps created from 3-dimensional SD-OCT data analysis have shown that disruptions of the IS/OS junction correspond to the hypofluorescent spots seen on ICG in the acute phase of MEWDS. [158] Line scans obtained through active white spot lesions show a dome-shaped, hyperreflective region in the subretinal space, with increased hyperreflectivity in the underlying choroidal space.

With resolution of the spots, the OCT scan abnormalities gradually reverse. [163] OCT scans obtained through the enlarged blind spot region show thinning of the outer nuclear layer in addition to IS/OS junction defects. [133, 149, 159] The information obtained from OCT scanning suggests that the principal defect in MEWDS occurs in the photoreceptor-RPE complex.

Electrophysiologic and psychophysical studies

Despite clinical evidence of prominent RPE involvement in MEWDS, there is surprisingly only a brief manifestation of RPE dysfunction on electrophysiologic testing throughout most of the disease course. ERG performed during the acute phase demonstrates marked reduction in a-wave and early receptor potential (ERP) amplitudes, suggesting not only photoreceptor malfunction but also abnormal visual pigment regeneration kinetics. [19, 164] Selective cone ERG testing demonstrates predominantly more impairment of the S-cone system than of the L- and M-cone systems in the acute stage of MEWDS. [165]

Likewise, multifocal ERG testing has demonstrated not only reduction of amplitudes in areas corresponding to clinically visible lesions, but also in the remainder of normal-appearing retina. [21, 166, 167] It has also demonstrated abnormalities in asymptomatic and clinically normal-appearing fellow eyes. [149] Oscillatory potentials are reduced throughout the retina in patients with MEWDS, even in areas with normal multifocal ERG readings. [168] The reduced amplitudes on multifocal ERG testing persist for many months after normalization of both the fundus appearance and the psychophysical tests. [149, 169]

EOG testing demonstrates only mild abnormalities of the Arden ratio, again suggesting that the abnormalities in MEWDS occur mainly at the level of the photoreceptors and the cycling of visual pigments.

Visual field testing demonstrates not only paracentral and central scotomas but also enlarged blind spots. [133, 170, 171] Similarly, mapping regions of retinal sensitivity using microperimetry during the active phase of the condition demonstrates an enlarged blind spot. [172] Visual evoked potentials (VEP) have demonstrated prolongation of the P100 latency persisting for many months after resolution of symptoms, suggesting more significant optic nerve involvement than previously thought. [173]

Etiology

The etiology of MEWDS remains unknown. The possibility of a viral cause has been considered in view of a history of a flu-like illness in a significant proportion of patients. MEWDS has been associated with hepatitis A and B vaccine, yellow fever vaccine, and human papilloma virus and meningococcus vaccines. further suggesting either a direct viral role or indirect viral antigen–induced response in the disease. [174, 175, 176, 177, 178]

The high prevalence of MEWDS in female patients also suggests that hormonal factors may play a role in this condition. Despite a report of increased serum immunoglobulins (IgM and IgG) in MEWDS, workups for systemic disease in MEWDS are usually negative. [179] An association between human leukocyte antigen B51 (HLA-B51) and MEWDS has been previously reported, possibly implicating a genetic predisposition for this disease. [180]

As has been suggested, MEWDS might also share a similar etiology with multifocal choroiditis. [133, 181] In addition, cases of primary intraocular lymphoma and sympathetic ophthalmia have been described as presenting with an MEWDS-type appearance. [182, 183, 184] This is important in differentiating true etiologic factors from other conditions that mimic MEWDS.

Disease course and prognosis

The disease usually has a self-limited course with good visual recovery, typically occurring within a 2-month period from the onset of symptoms (varies 2-16 wk). Approximately 90% of patients have better than 20/30 final visual acuity. Although late recurrences occasionally may occur, MEWDS is characterized by recovery of visual function and normalization of OCT and ERG findings. [163, 185] There is a return of normal peripheral funduscopic appearance, although macular changes (ie, foveal granularity) may persist. Long-term follow-up of patients is critical, because in rare cases, choroidal neovascularization can develop. [186, 144] Spaide et al report that AZOOR may develop in patients with MEWDS and that the subsequent development of AZOOR in these patients may be associated with a poorer visual prognosis. [133]

Treatment

In general, due to its self-limited course, no treatment for MEWDS is generally needed or indicated. Systemic therapy with cyclosporine and corticosteroids have been described for isolated cases, with moderately good results. [187, 188] The use of photodynamic lasers and of the anti-vascular endothelial growth factor (anti-VEGF) agent ranibizumab has been effective in treating MEWDS cases complicated by macular edema or choroidal neovascularization. [189, 190]

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Birdshot (Vitiliginous) Retinochoroidopathy

Franceschetti and Babel may have incompletely described this chronic condition as early as 1949. [191] First named by Ryan and Maumenee in 1980 to describe a rare, acquired, bilateral intraocular inflammatory disease, the condition also has been called vitiliginous chorioretinitis partly because of its fundus appearance and its loose association with cutaneous vitiligo in earlier reports. [192] It typically involves middle- to late-aged patients (average age is approximately 52 y; range is 23-70 y). The disease primarily affects Caucasians, and, in the older age groups, especially beyond the fourth decade, females outnumber males.

Signs and symptoms

Patients typically present with not only decreased visual acuity but also symptoms of nyctalopia and dyschromatopsia. Rarely, patients may complain of photophobia and a reduction in visual field. The condition is painless. On clinical examination, minimal to no anterior segment inflammation is present. Visual acuities may vary at onset from 20/20 to 20/800, with most patients having a visual acuity of approximately 20/50.

The characteristic appearance of lesions in birdshot consists of multifocal patches of RPE and choroidal depigmentation seen below.

Birdshot (vitiliginous) retinochoroidopathy. Multi Birdshot (vitiliginous) retinochoroidopathy. Multiple, uniformly hypopigmented lesions with mild disc swelling.

Unlike other conditions in these syndromes, a halo of hyperpigmentation is absent within or at the lesion margins. Individual lesions are typically 0.25-disc diameter in size and have certain uniformity in appearance. They can be cream-colored or depigmented and round to oval in appearance and typically do not have a well-defined border. Hyperpigmentation may occur in some lesions in the late stages of the disease.

The lesions typically are scattered throughout the post-equatorial fundus in 1 of 4 patterns: (1) diffuse, (2) macular sparing, (3) macular predominance, and (4) asymmetrical. [193] Often, the pattern is analogous to the splattering of birdshot from a shotgun. Initial foveal sparing is present. Birdshot can be associated with other retinal and ocular abnormalities, as follows: [194, 195]

  • Cystoid macular edema
  • Retinovascular attenuation
  • Retinovascular sheathing
  • Retinal and vitreous hemorrhages
  • Epiretinal membrane formation
  • Glaucoma optic atrophy
  • Rhegmatogenous retinal detachment
  • Subretinal neovascularization
  • Optic disc edema (very rare)
  • Retinal neovascularization (very rare)
  • Serous macular degeneration (very rare)

Diagnostic imaging: fundus autofluorescence

The fundus lesions of birdshot retinochoroidopathy generally appear more numerous and are more readily visible with fundus autofluorescence imaging compared with color fundus photographs, especially in eyes with blonde fundi. [196] The FAF findings usually consist of a circumferential hypoautofluorescence around the optic nerve head; multifocal hypoautofluorescent areas in the posterior pole, which may or may not correspond to the hypopigmented birdshot lesions; and linear hypoautofluorescent streaks along the retinal vessels. [197] Some eyes also show placoid hypoautofluorescence in the macula, indicating RPE atrophy, and this may be an explanation for the decreased visual acuity in patients with birdshot retinochoroidopathy. [197]

Diagnostic imaging: fluorescein angiography

The key fluorescein angiographic findings in birdshot result from vascular leakage. This is quite pronounced in the perifoveal region with resultant cystoid macular edema. Acutely, the patches in birdshot are surprisingly silent, showing no fluorescein abnormalities. With time and subsequent atrophy of the RPE, the individual lesions behave as window defects transmitting underlying fluorescence from the choroid.

In the early phase of the angiogram, there is a delay in retinal arteriole filling and circulation time, although retinal capillary nonperfusion typically is not seen with this disease. During this phase, the lesions are either not evident or are hypofluorescent. Choroidal vessels are often visible through the hypofluorescent lesions. With the late phase, the patches become hyperfluorescent, as demonstrated in the image below, with staining of the larger retinal veins and pooling of dye, particularly in the setting of cystoid macular edema. Prolonged retinal circulation time has been noted in birdshot. [198]

Birdshot (vitiliginous) retinochoroidopathy. Late Birdshot (vitiliginous) retinochoroidopathy. Late phase fluorescein angiogram that demonstrates patchy hyperfluorescence.

Diagnostic imaging: indocyanine green angiography

In general, ICG angiography reveals a greater number of lesions than is evident either funduscopically or on fluorescein angiography. [193] During the active phase of the disease, well-demarcated, hypofluorescent, round to oval spots appear throughout the posterior pole with relative sparing of the macula. [66] These spots appear early during the arteriovenous phase and persist unchanged during the late phase of the angiogram.

Progressive diffuse background fluorescence often occurs in the late phase of the angiogram in active disease. In the chronic or burned-out phase of the disease, ICG angiography reveals persistence of the characteristic hypofluorescent spots with absence of diffuse late phase hyperfluorescence. [199] Remarkably, the ICG lesions are preserved despite an improvement in clinical appearance of the fundus lesions.

ICG angiography may be particularly useful in the early diagnosis of birdshot retinochoroidopathy, when the typical birdshot lesions are either absent or poorly seen on clinical examination. [200]

Electrophysiologic and psychophysical studies

The ERG in birdshot typically displays moderate-to-severe abnormalities of both rod and cone function (less than or equal to 80% of patients). A disproportionate decrease occurs in the amplitude of the b-wave compared with the a-wave (as demonstrated in the image below), and some believe that this decrease is the distinguishing feature of the disease. [201]

Birdshot retinochoroidopathy electroretinogram res Birdshot retinochoroidopathy electroretinogram response to a scotopic white light stimulus (arrow). Tracing demonstrates a slight disproportionate reduction of the b-wave response in comparison to the a-wave.

The 30-Hz flicker implicit time is abnormal in up to 70% of patients with birdshot retinochoroidopathy, and normalization of this ERG parameter may be a useful indicator that patients can be successfully tapered from immunomodulatory therapy. [202]

The EOG findings may be either normal or slightly subnormal (70% of patients), and dark adaptation studies may show subnormal rod function. Patients also may exhibit nonspecific color vision defects. The visual field demonstrates a generalized constriction of peripheral fields with central scotomas or enlarged blind spots. These scotomas do not correspond clinically to the birdshot lesion distribution. Serial automated visual-field testing has been found to be useful in the monitoring of the response to therapy. [203] Microperimetry of the macula has been suggested as another means to evaluate disease activity and assess visual impairment in birdshot retinochoroidopathy. [204]

Etiology

Birdshot is believed to result from a pathologic process occurring not only in the receptor-RPE-choroid complex but also a pathologic process occurring more diffusely throughout the neural layers of the retina. A genetic predisposition has been suggested since the incidence of the human leukocyte antigen A29 (HLA-A29) marker is present in approximately 85-96% of patients with birdshot retinochoroidopathy. [205] This incidence rate is to be contrasted with 7% prevalence in the normal population. [206] The HLA-A29:02 subtype is the most predominant in Caucasian patients with the disease. [193, 205]

An autoimmune mechanism as the cause of birdshot is supported by several findings. First, in vitro studies demonstrating lymphocyte-mediated immune responses to retinal S-antigen are present in most patients tested. [207, 206] Second, histologic examination reveals a cell-mediated inflammatory response to the outer retina and focal depigmentation of the choroidal melanocytes. [193] Birdshot also has been associated with cutaneous vitiligo, elevated C4 complement, and elevated soluble interleukin (IL)–2 receptors, [208] as well as elevated intraocular levels of the proinflammatory and T cell–associated cytokines IL-1β, IL-17, tumor necrosis factor-α. [209]

Therefore, an altered immune mechanism likely is responsible for the clinical findings of this disease. As in the case of MEWDS, primary intraocular lymphoma may masquerade as birdshot retinochoroidopathy, and the lack of response to systemic immunosuppression therapy should lead to a reevaluation of the diagnosis. [210]

Disease course and prognosis

Birdshot retinochoroidopathy, unlike the aforementioned conditions, is a fairly chronic disease with slow progression. It can be active for 3-4 years before finally going into remission. [207] Although 73% of eyes have a visual acuity better than 20/60, ultimately, one third of patients have a final visual acuity of less than 20/200. The causes of central visual loss in patients with birdshot are the presence of cystoid macular edema (40-60% of patients) [193] and RPE atrophy in the macula. [197] Rarely, the condition can resemble advanced tapetoretinal degeneration, particularly when untreated. [211, 212]

Treatment

Currently, no single therapy has proven effective for treating patients with this condition. Various nonsteroidal anti-inflammatory drugs, corticosteroids, and systemic immunosuppressive agents have been tried with limited efficacy. Corticosteroid therapy in both local and systemic forms often is tried initially for moderate disease. Good control sometimes can be achieved with an initial induction followed by a slow taper to a maintenance dose. [213] In situations where recurrence and exacerbation of the disease is present, a combination of azathioprine and prednisone may be effective in reducing the relapse rate. [214]

Rush et al reported the use of an intravitreal sustained-release fluocinolone acetonide–containing device in the treatment of 36 eyes of 22 patients with birdshot retinochoroidopathy. [215] That study showed the fluocinolone intravitreal implant can successfully control intraocular inflammation, decrease cystoid macular edema, and reduce or eliminate the need for systemic immunosuppressive therapy, but at the expense of high incidences of intraocular hypertension, glaucoma, and cataract.

Intravenous polyclonal immunoglobulin (IVIG) treatment has been reported in the past to be effective in achieving significant remission without the use of corticosteroids or cytotoxic agents. [216]

Recently, low dose (7.5-25 mg/wk) methotrexate has been reported to be effective in the treatment of birdshot retinochoroidopathy and was associated with a better long-term visual outcome compared with untreated patients and those treated with corticosteroids. [217]

Cyclosporine A has been demonstrated to have an ameliorating effect on birdshot, both as a single agent and in combination with prednisone. [193] A combination of systemic cyclosporine A and mycophenolate mofetil therapy resulted in control of inflammation for at least 1 year in 67% of birdshot retinochoroidopathy patients in one study. [218] Reports using a combination of ketoconazole and cyclosporine therapy have shown it to be effective not only in controlling the disease, but also achieving stability with much lower doses of cyclosporine than conventionally used. [219, 220]

Finally, the newer biologic agents, including infliximab, etanercept, and adalimumab may be considered for use in the treatment of cases of refractory uveitis, although experience with these agents is somewhat limited. [221, 222, 223, 224, 225] Recently, Kruh and coworkers reported obtaining clinical remission in 72 (81.8%) of 88 patients with refractory noninfectious uveitis, including 13 with birdshot chorioretinopathy, using infliximab. [226]

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Serpiginous (Geographic) Choroiditis

Serpiginous choroiditis, geographic choroiditis or choroidopathy, or geographic helicoid peripapillary choroidopathy is a rare, chronic, recurrent, and progressive choroiditis of unknown etiology that manifests a characteristic geographic or snakelike pattern of inner choroidal and RPE, and secondarily outer retinal atrophy. This condition was first described in 1932 by Junius, but it was not until 1974 that Shatz, Maumenee, and Patz characterized the condition more completely. [227, 228] Hamilton and Bird also described this condition in the same year. [229]

The disease typically affects otherwise healthy patients in their fourth to sixth decades. This condition is more prevalent in Caucasians, and no gender predilection exists. The condition may present unilaterally; however, with time, all cases eventually become bilateral. The interval between the primary and contralateral eye involvement may be several years.

Signs and symptoms

Patients typically complain of blurred vision in association with metamorphopsia and central or paracentral scotomas. Clinical examination during the acute phase reveals an initial visual acuity of approximately 20/40 (range 20/20 to counting fingers, dependent on extent of foveal involvement). Although a nongranulomatous uveitis may occasionally be present, both anterior segment and external ocular examinations are usually unremarkable. [230] Vitritis may be present in up to 33% of patients. [231, 232]

The characteristic lesion of serpiginous choroiditis is a yellow-to-gray geographic lesion with a slightly fuzzy appearance, but usually with well-defined borders. The lesion typically arises from the peripapillary region and spreads centrifugally in a geographiclike or, as in the image below, pseudopodlike fashion. Although rare, cases have been reported in which the macula initially is affected. [233, 234] This variant is termed macular serpiginous choroiditis and, not surprisingly, carries a worse visual prognosis compared with typical serpiginous choroiditis. [235, 236, 237] Regions of quiescent atrophy are present in the wake of the advancing, active border of the lesion. Multiple areas of activity can be present in an eye at the same time, and isolated, noncontiguous areas of activity may be present, but both of these are fairly rare.

Serpiginous (geographic) choroiditis. This patient Serpiginous (geographic) choroiditis. This patient shows an old, inactive serpiginous scar extending in a pseudopod-like fashion from the optic disc. Courtesy of Patrick Monahan, MD, San Jose, Calif.

With time, pigment clumping, hypopigmentation of the RPE, and fibrous scar tissue formation occurs, with clear visibility of the underlying larger choroidal vessels within these atrophic patches. [238] Chronic recurrent or untreated disease may result in lesions present out to the equator of the eye, and large areas of the fundus may eventually be involved by the disease. Despite bilateral involvement, a high degree of asymmetry between both eyes is often present.

Unfortunately, this condition has a predilection for the temporal rather than the nasal fundus. Although the retina overlying the active lesion is usually edematous, and may develop a serous detachment, the retinal vessels and the optic nerve head usually appear normal throughout the disease. Choroidal neovascularization develops in approximately 25% of patients. [239, 240] Other reported posterior segment complications of serpiginous choroiditis include retinal periphlebitis, retinal and disc neovascularization, branch retinal vein occlusion, RPE detachment, cystoid macular edema, and bilateral macular holes. [234, 241, 242, 243, 244] Tang and colleagues reported a case of antiphospholipid antibody syndrome mimicking the clinical and angiographic appearance of serpiginous choroiditis. [245] Eales disease and acute retinal necrosis have also been reported in association with serpiginous choroiditis. [246, 247, 248]

Diagnostic imaging: fundus autofluorescence (FAF)

The FAF images of serpiginous choroiditis vary depending on whether the lesion imaged is one of active inflammation, transitional, or old inactive inflammation. [249, 250] New acute lesions show a hypoautofluorescent spot or area along the border of a more hypoautofluorescent old lesion. [250] Within 2-5 days, a new lesion develops hyperautofluorescence and may exhibit a border of hypoautofluorescence, which corresponds to a thin rim of RPE depigmentation that can be seen clinically. [250] Over the next several weeks, the acute lesion evolves from a granular to a speckled hyperautofluorescent pattern. [250] As the lesion heals and becomes inactive, the affected RPE atrophies and degenerates, and the autofluorescence is lost. [250]

Old, inactive lesions are largely hypoautofluorescent. The detection of new areas of hyperautofluorescence along the borders of old, inactive, hypoautofluorescent lesions is reported to be a sensitive, noninvasive method of detecting disease recurrences. [250, 251] The severity of vision impairment in serpiginous choroiditis correlates with the degree of foveal hypoautofluorescence. [251]

Diagnostic imaging: fluorescein angiography (FA)

The angiographic appearance of serpiginous choroiditis also varies according to the state of the disease. The lesions in the acute phase of the disease demonstrate blocked fluorescence during the early transit phase of the angiogram. Light hyperfluorescence and staining as a result of active inflammation occurs during the late phases. This staining typically progresses from the periphery towards the center, similar to that seen with APMPPE. [247] The hypofluorescence during the early phase is attributed to a combination of both RPE cell edema and choriocapillaris nonperfusion. Staining of the vein walls may be demonstrated when focal areas of retinal phlebitis are present. [247]

The inactive stage of the disease is characterized by a patchy diminution of the early choroidal flush due to the destruction of the choriocapillaris, and in some cases of the larger choroidal vessels too. There is unmasking of the underlying choroidal vessel hyperfluorescence in areas of healed lesions, which have become atrophic scars. The staining at the margins of inactive lesions results from leakage of adjacent preserved choriocapillaris. (See the images below.)

Serpiginous (geographic) choroiditis. Chronic atro Serpiginous (geographic) choroiditis. Chronic atrophic lesions that display widespread geographic chorioretinal atrophy with moderate foveal sparing.
Serpiginous (geographic) choroiditis. A transit-ph Serpiginous (geographic) choroiditis. A transit-phase fluorescein angiogram of the same eye as in the above image demonstrates leakage and staining hyperfluorescence at the margins of the atrophic lesions. The underlying large choroidal vessels are seen easily within the atrophic lesions.

In the very late phases of the angiogram, diffuse hyperfluorescence of the lesions occurs due to staining of the sclera and any fibrous tissues.

Diagnostic imaging: indocyanine green angiography (ICGA)

ICGA of acute lesions generally shows a uniformly hypofluorescent geographic area corresponding to the acute lesion throughout all phases of the study. [252] In some cases, the active lesion develops a hyperfluorescent border around the edges of the active lesion in the late phase. [252, 253] ICGA tends to show a larger area of choroidal involvement than either clinical fundus examination or fluorescein angiography. [252] Once healed, the lesions show a heterogeneous pattern of hypofluorescence on ICGA. [252]

Giovannini and coworkers classified serpiginous choroiditis into 4 stages based on a combination of FA and ICGA findings: (1) a subclinical or choroidal stage in which the lesions are hypofluorescent with faint edges detectable only by ICGA; (2) an active or retinal stage with clinical, FA, and ICGA evidence of lesions; (3) a subhealing stage with slight late hyperfluorescence of lesions on ICGA but no evidence of them on FA; and (4) an inactive or healed stage with areas of hypofluorescence with clearly defined margins on ICGA and areas of hyperfluorescence and staining on FA. [253, 254]

Diagnostic imaging: optical coherence tomography (OCT)

The active serpiginous lesion typically demonstrates hyperreflectivity of the outer retina and a "waterfall effect" behind it due to the alterations in the RPE and choriocapillaris layers on time-domain OCT. [255, 256] Spectral-domain OCT typically shows hyperreflectivity of both the outer retina and choroid along with disruption of the IS/OS junction. [257, 258]

Electrophysiologic and psychophysical studies

The degree of ERG and EOG abnormality is correlated closely with the extent of clinically involved retina. [234] Unless there is extensive retinal involvement, as in long-standing or untreated disease, the ERG and EOG studies are usually normal or only mildly subnormal. [259] Visual-field testing reveals absolute or relative scotomata corresponding to clinical retinal lesions. Central, cecocentral, and paracentral scotomata are the predominant feature on visual-field testing. Microperimetry has shown dense scotomas corresponding to all atrophic or inactive lesions and some active lesions, and relative scotomas in clinically normal–appearing areas of the posterior pole and peripapillary areas, indicating possible subclinical inflammation or choroidal perfusion abnormalities. [260] In spite of extensive involvement of the macula in serpiginous choroidits, stable fixation was found in over 60% of eyes by microperimetry. [260]

Etiology

The etiology of serpiginous choroiditis remains elusive, although it is known that the lesions appear to be at the level of the RPE and choriocapillaris. Histopathologic studies reveal that the disease is primarily a nongranulomatous choroiditis with a moderate, diffuse lymphocytic infiltration of the choroid. [261] The suggestion that serpiginous may be caused by immunologic mechanisms is strengthened by its association with the human leukocyte antigen A2 (HLA-A2) and human leukocyte antigen B7 (HLA-B7) histocompatibility and by the occurrence of other inflammatory lesions in the involved eye. [241] Evidence of serologic reaction to retinal S-antigen in affected patients lends further support to alterations in immune responsiveness. [233] Other associations with serpiginous and serpiginouslike choroiditis include sarcoidosis, tuberculosis, extrapyramidal dystonia, and elevated factor VIII-von Willebrand factor. [234, 262, 263, 264]

Disease course and prognosis

The disease is characterized by an episodic, but generally indolent and progressive, course with recurrences often going undetected until there is macular involvement. Reactivation of quiescent borders of single lesions can occur, and new activity may arise from independent foci in the peripheral fundus. Active lesions typically resolve in 6-8 weeks, but reactivations may not occur for months or even years. Fibrous metaplasia of the RPE develops within the area of chorioretinal atrophy in approximately 50% of patients. This is particularly prominent nasally and in the peripapillary region.

Serpiginous lesions in the macula, cystoid macular edema, and choroidal neovascularization can adversely affect central visual acuity. The contralateral eye may be involved within months or several years following the initial process in the involved eye. Christmas and colleagues found that 25% of patients have a visual acuity of 20/200 or worse in one eye on long-term follow-up. [265] Most patients, however, are able to maintain good central and peripheral function in at least 1 eye.

Treatment

The current management of serpiginous choroiditis usually involves combination treatment with high-dose corticosteroids (1 mg/kg/day of oral prednisone or 1 g of pulse intravenous methylprednisolone for 3-5 days, followed by a tapering dose of oral prednisone over 1-3 months) to control the acute inflammatory disease and an immunosuppressive agent or immunomodulator needed to prolong remission and preserve good vision. [266, 267, 268, 269]

The combination of azathioprine, cyclosporine, and prednisone has been reported to provide early remission in 5 patients treated with this combination of three drugs. [270]

Chlorambucil or cyclophosphamide has been reported to be successful in 9 patients with active serpiginous choroiditis. [271]

Intravitreal steroids have been used, as has the fluoroquinolone acetonide intravitreal implant as alternatives to long-term systemic steroid use with its attendant complications. [272, 273, 274, 275, 276]

Sahin has reported a case of serpiginous choroiditis successfully managed with the alkylating agent cyclophosphamide and prednisone for initial control, and cyclophosphamide alone for suppression of recurrences for 1 year. [277]

The immunomodulators adalimumab and infliximab have also been used in the treatment of serpiginous choroiditis, [278, 279] but they are not recommended as first-line treatments. [280]

Both bevacizumab and ranibizumab have been used to successfully manage the complication of choroidal neovascularization in serpiginous choroiditis. [281, 282, 283, 284, 285]

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Diffuse Unilateral Subacute Neuroretinitis

Diffuse unilateral subacute neuroretinitis (DUSN), which is caused by the chronic subretinal migration of 1 of at least 2 species of nematodes, characteristically involves children or young adults with a slight male preponderance among patients. Patients are otherwise healthy and are often asymptomatic at time of presentation.

Signs and symptoms

Patients often present quite late in the disease with typically poor visual acuities, usually less than 20/200. Those few cases that have presented during the acute period have demonstrated a moderate degree of vitritis with optic disc swelling and a variable anterior chamber reaction, with or without hypopyon.

The characteristic posterior pole findings are those of focal, gray-white or yellow-white spots developing in the deep layers of the retina and also at the level of the RPE. These normally develop within several days to weeks from the onset of symptoms. The lesions tend to cluster in the macula or juxtamacular region and typically last several days before fading. Occasionally, a subretinal worm (500-2000 µm length, 25 µm in width), such as that present in the eye below, can be seen.

Diffuse unilateral subacute neuroretinitis. Attemp Diffuse unilateral subacute neuroretinitis. Attempted focal laser photocoagulation of a subretinal nematode suspected of being Baylisascaris procyonis. Courtesy of Everett Ai, MD, San Francisco, Calif.
The worm was only later discovered to have migrate The worm was only later discovered to have migrated from the original site, which initially was targeted for laser treatment.
A second laser treatment was successful at destroy A second laser treatment was successful at destroying the worm.
The same eye immediately after the second laser tr The same eye immediately after the second laser treatment, showing not only the hypofluorescent laser-treated areas but also the characteristic mottled hyperfluorescence of diffuse retinal pigment epithelium and choriocapillaris destruction.

In the inactive phase, the posterior pole exhibits extensive mottling of the RPE, assuming a pseudo–retinitis pigmentosa appearance. There is also extensive retinovascular narrowing and sheathing with optic atrophy. Subretinal neovascularization may develop at this stage. A mild to moderate anterior chamber and vitreous cell reaction may be present even in the inactive stage. The patient often has an afferent pupillary defect. Barbazetto et al reported that the active phase of DUSN can mimic the fundus appearance of a white dot syndrome. [286]

Diagnostic imaging: fluorescein angiography

In the very early stage of the disease, angiogram findings may be entirely normal. If lesions are present, hypofluorescence of the lesions occurs during the early phase of the angiogram, and the lesions typically stain during the late phase. In addition, leakage occurs from the capillaries overlying the optic nerve, in addition to more diffuse perivenous leakage occurring in the retina. In a more typical late stage of the disease, an increase occurs in the background choroidal fluorescence due to extensive RPE dropout and loss of pigmentation. Hyperfluorescence, indicative of RPE atrophy, occurs in the periphery and the peripapillary regions, exhibiting fine, mottled hyperfluorescence, particularly in the macular region. (See the image below.) If a worm is present, it can be seen as a hypofluorescent lesion.

Diffuse unilateral subacute neuroretinitis. Late s Diffuse unilateral subacute neuroretinitis. Late stage of the disease presenting the characteristic pseudo–retinitis pigmentosa features.

Electrophysiologic and psychophysical studies

Often, a moderate-to-severe reduction in the ERG occurs. With later stages of the disease, a disproportionate decrease occurs with the b-wave amplitude relative to the decrease in the a-wave amplitude. In rare instances, the ERG may be extinguished.

Etiology

Leading the list of suspected causative agents in this disease are the nematodes Toxocara canis (dog roundworm), Ancylostoma caninum (dog hookworm), and Baylisascaris procyonis (raccoon intestinal nematode). [46, 287] Clinically, 2 types of worms apparently have been described with this condition. They are differentiated by length. Smaller worms (400-1000 µm) and longer worms (1500-2000 µm) may wander in the subretinal space for many years and cause progressive ocular damage. However, the nematode may be found during any stage of the disease.

The worm often is located in the deep, white retinal exudative lesions. Surgical removal of a subretinal nematode in a patient with DUSN identified the causative organism as a third stage T canis larva. [288] Serologic testing for Toxocara is typically negative in patients with DUSN.

The damage caused by the organisms appears to involve a local toxic tissue reaction to the outer retina caused by the worm's byproducts, in addition to a more diffuse toxic reaction affecting both the inner and the outer retinal tissues that is believed to be due to the host's immunologic defenses. Eosinophilia infrequently is detected, and patients do not manifest evidence of systemic disease.

Histopathologic examination of the few eyes that have been examined with DUSN reveals a largely nongranulomatous vitritis, retinitis, and retinal and optic nerve perivasculitis. Low-grade, patchy, nongranulomatous choroiditis also is present. Extensive degeneration of the peripheral retina occurs, particularly of the posterior region within the arcades. Mild-to-moderate degenerative changes in the RPE also have been described. Not surprisingly, optic atrophy is a common feature of these eyes.

Disease course and prognosis

Following the acute phase of the disease, focal and more diffuse depigmentation of the RPE develops over the ensuing weeks or months. Pigment migration occurs into the overlying retina with a gradual narrowing of the retinal vasculature. Retinal hemorrhages may result from choroidal neovascularization and can result in occasional serous retinal detachments.

Treatment

Treatment of patients with DUSN has not yet been optimized to date. Three modalities of treatment, of which a combination usually is applied, are available. Argon laser photocoagulation is effective in destroying the worm, but can cause an inflammatory reaction. Surgical (transvitreal) removal of a subretinal nematode elicits less inflammatory response but is accompanied with higher risks inherent to this treatment. The use of such medicinals as antihelminthics (eg, thiabendazole, diethylcarbamazine) or antifilarial agents (eg, Ivermectin) may be used as adjunctive treatment.

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Conclusion

With the exception of DUSN, the idiopathic multifocal choroidopathy syndromes discussed remain problematic, not only from an etiologic point of view but also from a classification point of view. Although there is a practical benefit to combine these entities under one group, such as AZOOR or multifocal choroidopathy, sufficiently unique characteristics in each of these conditions still exist that make them distinct from each other. Additionally, many instances occur where the patient's symptomatology and clinical findings overlap between the entities. Similarly, although many findings point toward an infectious and/or immunologic mechanism as the cause of these conditions, no conclusive evidence for either one has yet been demonstrated. Until more clinical and histologic information regarding these entities is available, current attempts at grouping or subgrouping these conditions proves inadequate in the long run.

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