You are in: eMedicine Specialties > Ophthalmology > CHOROID Multifocal Choroidopathy SyndromesArticle Last Updated: Jul 13, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
 
Author: Sam E Mansour, MD, FRCS(C), FACS, Medical Director: The Virginia Retina Center, Associate Clinical Professor of Ophthalmology, Ophthalmology, George Washington University Editors: Brian A Phillpotts, MD, Former Vitreo-Retinal Service Director, Former Program Director, Clinical Assistant Professor, Department of Ophthalmology, Howard University College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences Author and Editor Disclosure Synonyms and related keywords: multifocal choroiditis, acute posterior multifocal placoid pigment epitheliopathy, acute retinal pigment epithelitis, Krill disease, multiple evanescent white dot syndrome, birdshot retinochoroidopathy, serpiginous choroiditis, diffuse unilateral subacute neuroretinitis INTRODUCTIONSection 2 of 11
 
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 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) (Gass, 1993). 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 (Jacobson et al, 1995). 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 (Francis et al, 2005). 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 (Volpe et al, 2001; Machida et al, 2004; Watzke et al, 2002; Gass, 2001; Kondo et al, 2001). 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 (Turbeville et al, 2003). 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 (Jampol et al, 1995). 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. MULTIFOCAL CHOROIDITISSection 3 of 11
Multifocal choroiditis and panuveitisSince 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). 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% (Quillen et al, 2004). A moderate racial and gender predisposition exists, with approximately 66% of patients being white and 80% of patients being female (Quillen et al, 2004). 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. Fundus examination reveals multiple, small, discrete yellow/gray-white spots that are typically round and may be polygon or oval in shape (see Image 1). 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, 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 (see Image 3). During the acute phase, optic disc edema may occur, which later develops to peripapillary scarring assuming a characteristic "napkin ring" subretinal fibrosis (Buerk et al, 2005). Periphlebitis is often present with resultant retinal vasculature narrowing (Schenck et al, 1990). Cystoid macular edema is present in approximately 10-20% of patients, and the incidence of choroidal neovascular membrane formation varies from 25-40% (Quillen et al, 2004; Krill et al, 1970). Fluorescein angiography During the early stage, the active lesions exhibit blockage of the early fluorescence followed by late staining (see Image 2). 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 Image 4). Similar findings are noted on indocyanine green (ICG) angiography where early lesions of MCP are hypofluorescent, in contrast with those of presumed ocular histoplasmosis (POHS), which tend to be hyperfluorescent (Cimino et al, 2000; Parnell et al, 2001; Vadala et al, 2001). 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 (Jacobson et al, 1995). 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 (Sieving et al, 1984). Serial multifocal ERG (MERG) testing reveals a diffuse loss of function over the entire test field that is often permanent (Oh et al, 2001). 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 (Dreyer et al, 1984). 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 (Bloom et al, 1989; Bodine et al, 1992; Frau et al, 1990; Spaide et al, 1991; Tiedeman, 1987). 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 (Palestine et al, 1985). 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 (Palestine et al, 1985). Disease course and prognosis Unfortunately, recurrence is very high in MCP, and the visual prognosis remains poor (Vianna et al, 2004; Joondeph et al, 1991; Morgan et al, 1986). Peripapillary atrophy with progressive subretinal fibrosis results in enlargement of a blind spot in approximately 43% of patients (Khorram et al, 1991; Reddy et al, 1996). 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%) (Watzke et al, 1981). 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 (Vianna et al, 2004). 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 (Michel et al, 2002). In some instances, amelioration of the subretinal neovascular membrane has been noted with corticosteroid therapy (Morgan et al, 1986). Specific laser therapies, both conventional laser therapy and photodynamic therapy (PDT), have been used with moderate success in managing subretinal neovascular membranes (Coquelet et al, 2002; Gebka et al, 2005; Gerth et al, 2006). Surgical treatment of subretinal neovascular membranes involving limited macular translocation has also been reported (Fujii et al, 2001). Diffuse subretinal fibrosis syndromeThis very rare and incompletely characterized entity was first described in 1982 (Doran et al, 1982). 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 (Gandorfer et al, 2000). 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 (see Image 5). 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. In the macula, the lesions tend to coalesce, forming broad zones of subretinal fibrosis. Later complications can include serous and hemorrhagic macular detachment. 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 is present at these sites that, in some cases, may suggest subretinal neovascularization (see Images 6-7) (Doran et al, 1982). 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 (Salvador et al, 1994). In view of the clinical and angiographic findings, this condition's clinical appearance is likely secondary to a primary RPE hyperplastic process (Cantrill et al, 1986). Histologic evidence of immunoglobulin and complement deposition on the internal side of the Bruch membrane also suggests a focal inflammation of the RPE (Palestine et al, 1985). Disease course and prognosis This condition is characterized by recurrent episodes with the fellow eye becoming involved within a 6-month period. Management of DSFS involves the use of corticosteroids early in the disease (Gandorfer et al, 2000). 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 choroidopathyFirst 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 (Morgan et al, 1986; Watzke et al, 1984). This rare condition is also one of the entities grouped under AZOOR (Taira et al, 2005). 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 (Gass, 1987). 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 Image 8). These lesions tend to assume a linear branching pattern. During the late stage of the disease, the spots become atrophic and pigmented. 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%. Fluorescein angiography Again, paralleling the findings in ocular histoplasmosis, the early phase of the angiogram demonstrates hyperfluorescence of the lesions, and the late phase is marked by leakage at the lesions (see Image 10). Electrophysiologic and psychophysical studies The ERG findings are occasionally subnormal in patients with PIC. The EOG 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 (Morgan et al, 1986). 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. A variable response to systemic corticosteroids occurs depending on the stage of the disease (Brueggeman et al, 2002; Holekamp et al, 2005; Levy et al, 2005). Both conventional laser therapy and PDT have been used for the management of subretinal neovascular membranes with increasing success (Chatterjee et al, 2003; Leslie et al, 2005; Lim et al, 2006; Wachtlin et al, 2003; Postelmans et al, 2005). ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHYSection 4 of 11
In 1968, Gass first described acute posterior multifocal placoid pigment epitheliopathy (APMPPE). This condition typically afflicts young or middle-aged, otherwise healthy, adults (average age is 25 y; range is 8-57 y) who experience an acute loss of visual acuity in one or both eyes. Neither a racial nor gender predilection exists for this condition. A slight preponderance of bilateral involvement does exist. The condition tends to resolve after approximately 7-11 weeks with near normal return of visual function. Although the RPE changes remain visible, no other ocular or systemic disturbances are evident. The typical course of the disease suggests an underlying viral inflammatory disorder. Signs and symptoms Typically, a rapid reduction initially occurs in visual acuity with or without a history of a preceding flulike illness or respiratory infection, often treated with systemic antibiotics. Clinically, APMPPE presents as multiple, well-circumscribed, flat subretinal lesions at the level of the RPE and choriocapillaris (see Image 14). These lesions are approximately 0.125- to 1-disc diameter in size and may be confluent. These typically scatter in the midperiphery and the posterior pole. Initially, they appear cream colored or grayish white in color. There is minimal evidence of anterior segment inflammation, although vitreous cells are present in as many as 50% of the patients. This is likely the result of a mild periphlebitis with exudation. In addition to vascular inflammation, mild optic disc edema also is noted. Very rarely, the condition can result in retinal edema, retinal hemorrhage, and subretinal neovascular membrane formationwith hemorrhage. Fluorescein angiography The initial phase of the angiogram sometimes demonstrates prolonged filling of the choroidal vasculature. An early hypofluorescence often is attributed to a combination of both incomplete and irregular filling of the choriocapillaris in conjunction with a masking effect produced by the edematous, swollen RPE cells. This is followed in a late phase with evidence of leakage and staining at the lesion sites (see Images 15-16). 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 ERGs. Permanent scotomata on visual field testing often are present that may or may not be coincident with the observable clinical lesions. Etiology Deutman and Van Buskirk believed that APMPPE represents a primary obstruction of the choroidal circulation with secondary RPE degeneration. This view is supported by more recent ICG angiographic evidence. However, others, especially Gass, believe this to be a primary disease of the RPE. 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. APMPPE, of all the conditions described in this article, has the greatest variety of associations with other systemic conditions, as follows:
Disease course and prognosis Fortunately, the prognosis for visual recovery is good, and many patients (>80%) experience better than 20/30 vision. Over a 2- to 6-week period, the lesions begin to fade, leaving 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. Recurrences, unlike other conditions in these syndromes, are rare and usually occur within the first 6 months. If there is initial unilateral presentation, the second eye often lags from the first eye within a few days or weeks. Treatment with corticosteroids has not been demonstrated to influence the outcome of this condition. ACUTE RETINAL PIGMENT EPITHELITIS (KRILL DISEASE)Section 5 of 11
Acute retinal pigment epithelitis (ARPE) is an extremely rare, self-limited RPE disease 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. In 1972, Krill and Deutman first described this condition. 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 one half of patients are asymptomatic at the time of presentation, with other patients describing a sudden decrease in vision with or without central 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 yellow-white halo and are typically between 50-100 µm in size (see Image 17). 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 can result in macular edema or vitritis. Fluorescein angiography During the active phase of the disease, hyperfluorescence is present in the center of the spots with normal halos. With time, the center of the spots may either remain hyperfluorescent or become hypofluorescent, while the halos might demonstrate hyperfluorescence, which is largely due to window defect pattern rather than any leakage (see Image 18). Electrophysiologic and psychophysical studies On Amsler grid testing, these patients sometimes describe variable central scotomas. Mild color vision abnormalities also have been described with this condition. EOG testing has yielded various results, from essentially normal to subnormal depending on the extent of RPE involvement in the macula. 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 viral etiology, although that clearly is suspected in this condition. Associations with rubella, Borrelia burgdorferi (Lyme disease), and hepatitis C infections have been made. Interestingly, in some instances, this condition is believed to be a harbinger of central serous retinal choroidopathy (CSR). Disease course and prognosis ARPE has a self-limited course, usually with complete resolution over a 6- to 12-week period. Fortunately, recurrences are rare. Currently, no therapeutic modalities are available that are recommended specifically for this condition. MULTIPLE EVANESCENT WHITE DOT SYNDROMESection 6 of 11
Recently described in 1984, MEWDS is a self-limited condition that afflicts otherwise healthy, young patients, usually in their second decade (average age is 28 y; range is 14-57 y). MEWDS shares many clinical and electrophysiologic features with AIBES and other entities in the AZOOR group. Despite that commonality, MEWDS is believed to be uniquely distinguishable, warranting its own separate identification. The condition usually presents unilaterally with few instances of later contralateral ocular involvement. Many patients appear to be women (approximately 75%). No racial predilection exists. Signs and symptoms In addition to presenting with blurred vision and multiple paracentral scotomata, patients also have symptoms of 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, each patch being comprised of smaller white to light orange dots (see Image 11). These lesions appear to be at the level of the RPE and outer retina and typically are distributed in the perifoveal and peripapillary regions with rare involvement of the fovea itself. Peripapillary involvement with corresponding blind spot enlargement often can mimic the appearance of POHS. 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 (see Image 12). These specks are much smaller than the white dots and often are associated with an irregular light reflex of the internal limiting membrane. Other posterior pole findings include splinter hemorrhages; venous sheathing; hyperemia or edema of the optic nerve head; and, very rarely, subretinal neovascular membrane. Angiography In the early phase of the fluorescein angiogram, there is a punctate hyperfluorescence of the gray-white patches that often display a wreath-shaped pattern. Leakage of dye at the optic disc is present in approximately 60% of patients (see Image 13). During the late phase of the angiogram, a patchy, mottled pattern of hyperfluorescence is observed throughout the posterior pole with staining of the optic nerve head (see Image 13). With resolution of the acute episode, the angiographic findings become much less prominent; but usually, subtle RPE window defects persist. Recent ICG angiography studies demonstrate multiple deep, small, round, hypofluorescent choroidal lesions appearing early and persisting into the late phases. Many more lesions usually are observed on ICG angiography than are visible by clinical examination or fluorescein angiography. Electrophysiologic and psychophysical studies Despite clinical evidence of prominent RPE involvement in MEWDS, there is surprisingly only a brief manifestation of RPE dysfunction on electrophysiological 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. 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. The reduced amplitudes on multifocal ERG testing persist for many months after normalization of both the fundus appearance and the psychophysical tests. EOG testing demonstrates only mild abnormalities of the Arden ration, again suggesting that abnormalities in MEWDS occur mainly at the level of the photoreceptors and visual pigments. Visual field testing demonstrates not only paracentral and central scotomas but also enlarged blind spots. 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 known. Etiology The etiology of MEWDS remains unknown. The possibility of a viral cause has been entertained in view of the elicitation of a history of a flulike illness in a significant proportion of patients. More recently, MEWDS has been associated with hepatitis B vaccine, further suggesting either a direct viral role or indirect viral antigen-induced response in the disease. 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, immunoglobulin M (IgM) and immunoglobulin G (IgG), in MEWDS, workup for systemic disease in MEWDS is usually negative. However, an association between human leukocyte antigen B51 (HLA-B51) and MEWDS recently has been reported, possibly implicating a genetic predisposition for this disease. 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 ERG findings. There is a return of normal peripheral funduscopic appearance, although macular changes may persist. Because of its self-limited course, no treatment for MEWDS currently is indicated. BIRDSHOT (VITILIGINOUS) RETINOCHOROIDOPATHYSection 7 of 11
Franceschetti and Babel may have incompletely described this chronic condition as early as 1949. 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. 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 (see Image 22). Unlike other conditions in these syndromes, a halo of hyperpigmentation is absent within or at their 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 thelate stages of the disease. The lesions typically are scattered throughout the postequatorial fundus in 1 of 4 patterns: (1) diffuse, (2) macular sparing, (3) macular predominance, and (4) asymmetric. Often, the pattern is analogous to the splattering of a birdshot from a shotgun. Initial foveal sparing is present. Birdshot can be associated with other retinal and ocular abnormalities, as follows:
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 abnormality. With time and enlargement of the patches, 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 (see Image 23) with staining of the larger retinal veins and pooling, particularly in the setting of cystoid macular edema. Prolonged retinal circulationtime has been noted in birdshot. ICG angiography recently has been performed in birdshot and has demonstrated certain characteristic patterns depending on the stage of the disease. In general, ICG angiography reveals a greater number of lesions than is evident either funduscopically or on fluorescein angiography. 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. 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. Remarkably, the ICG lesions are preserved despite an improvement in clinical appearance of the fundus lesions. 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, and some believe that this decrease is the distinguishing feature of the disease (see Image 24). The EOG findings may be either normal or slightly subnormal (70% of patients), and, similarly, 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. 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% of patients with birdshot retinochoroidopathy. This incidence rate is to be contrasted with 7% prevalence in the normal population. The HLA-A29.2 subtype is the most predominant in Caucasian patients with the disease. 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. Second, histologic examination reveals a cell-mediated inflammatory response to the outer retina and focal depigmentation of the choroidal melanocytes. Birdshot also has been associated with cutaneous vitiligo, elevated C4 complement, and elevated soluble interleukin 2 (IL-2) receptors. Therefore, a sort of altered immune mechanism likely is responsible for the clinical findings of this disease. Disease course and prognosis Birdshot, 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. Birdshot is characterized by exacerbations and remissions. 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. Not surprisingly, the most significant cause of central visual loss in patients with birdshot is the presence of cystoid macular edema (40-60% of patients). Rarely, the condition can resemble advanced tapetoretinal degeneration, particularly if left untreated. Currently, no single therapy has proven effective for treating patients with this condition. Various nonsteroidal anti-inflammatory drugs, immunosuppressives, and corticosteroids, in addition to antibiotics, 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. 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. Cyclosporine has been demonstrated to have an ameliorating effect on birdshot, both as a single agent and in combination with prednisone. Recent 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. Another interesting treatment that recently has been reported for use in this condition is intravenous polyclonal immunoglobulin (IVIG). This treatment was effective in achieving significant remission without the use of corticosteroids or cytotoxic agents. SERPIGINOUS (GEOGRAPHIC) CHOROIDITISSection 8 of 11
Serpiginous or geographic helicoid peripapillary choroidopathy is a rare, progressive choroiditis that manifests a characteristic snakelike or propellerlike pattern of RPE and choriocapillaris atrophy. First described in 1932 by Junius, Shatz, Maumenee, and Patz characterized the condition in 1974. Hamilton and Bird also described this condition in the same year. 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 initially as unilateral; however, with time, eventually all cases 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 scotomas, mostly central or paracentral. 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 occasional nongranulomatous uveitis may be present, both anterior segment and external ocular examinations are usually unremarkable. Vitritis may be present in 25-30% of patients. The characteristic lesion in serpiginous choroiditis is a yellow to gray geographic pattern, usually with well-defined borders (see Image 19). The lesion typically arises from the peripapillary region and spreads centrifugally in pseudopod or a geographiclike fashion. Although rare, cases have been reported where the macula initially is affected. Regions of quiescent atrophy are present in the wake of the advancing, active border of the lesion. Isolated, noncontiguous areas of activity may be present. With time, pigment clumping and hypopigmentation of the RPE occur, with clear visibility of the underlying large choroidal vessels within these atrophic patches. Despite bilateral involvement, a high degree of asymmetry between both eyes often is present. Unfortunately, this condition has a predilection for the temporal rather than the nasal fundus. Although the overlying retina is usually edematous and may progress to serous detachment, the retinal vessels and the optic nerve head usually appear normal throughout the disease. Choroidal neovascularization develops in approximately 25% of patients. Other rare associations with serpiginous choroiditis include retinal periphlebitis, retinal and disc neovascularization, branch retinal vein occlusion, and RPE detachment. Fluorescein angiography Angiographic appearance of serpiginous choroiditis varies according to the state of the disease. The lesions in the acute phase of the disease demonstrate blockage of fluorescence during the early transit phase of the angiogram. Eventually, staining occurs during the late phases. The hypofluorescence during the acute 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. The inactive phase is characterized by a patchy diminution of the early choroidal flush due to the destruction of the choriocapillaris. There is unmasking of the underlying choroidal vessel fluorescence, this occurring in areas of healed lesions, which become atrophic scars (see Images 20-21). The staining at the margins of inactive lesions results from leakage of adjacent preserved choriocapillaris. In the very late phases of the angiogram, diffuse hyperfluorescence of the lesions occurs due to staining of the sclera and fibrous tissues. The staining typically progresses from the peripheral margins toward the center, similar to that seen in APMPPE. Electrophysiologic and psychophysical studies The ERG amplitude and implicit time responses are abnormal in approximately 11% of patients with serpiginous. The EOG findings are likewise abnormal in 25% of patients. The degree of ERG and EOG abnormality is correlated closely with the extent of clinically involved retina. Visual field testing reveals absolute or relative scotomata also corresponding with clinical retinal lesions. Central, cecocentral, and paracentral scotomata are the predominant feature on visual field testing. 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. 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 also by the occurrence of other inflammatory lesions in the involved eye. Evidence of serologic reaction to retinal S-antigen in affected patients lends further support to alterations in immune responsiveness. Other associations with serpiginous choroiditis include sarcoidosis, tuberculosis, extrapyramidal dystonia, and elevated factor VIII-von Willebrand factor. Disease course and prognosis The disease is characterized by an episodic and indolent course with recurrences often going undetected unless 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. 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. The prognosis for retaining good visual acuity is poor. Only 45% of patients are able to maintain normal visual acuity. The contralateral eye may be involved within months or several years following the initial process in the involved eye. Despite that, most patients are able to maintain good central and peripheral function in at least 1 eye. Most investigators currently agree that the efficacy of any therapeutic agent has not yet been established in serpiginous choroiditis. Laser photocoagulation treatment does not appear to slow the progression of this disease. Treatments using systemic corticosteroids (eg, chlorambucil, cyclosporine-A) have variable responses. Combination therapy with azathioprine, cyclosporine-A, and prednisone may hold promise. DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS AND CONCLUSIONSection 9 of 11
Diffuse unilateral subacute neuroretinitisDiffuse 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) can be seen (see Image 25). In the inactive phase, the posterior pole exhibits extensive mottling of the RPE assuming a pseudo–retinitis pigmentosa appearance (see Image 29). 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. 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 (see Image 28). Hyperfluorescence, indicative of RPE atrophy, occurs in the periphery and the peripapillary regions, exhibiting fine, mottled hyperfluorescence, particularly in the macular region. If a worm is present, it can be seen as a hypofluorescent lesion. 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 is the 3 nematodes, Toxocara canis (dog roundworm), Ancylostoma caninum (dog hookworm), and Baylisascaris procyonis (raccoon intestinal nematode). 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. Recent surgical removal of a subretinal nematode in a patient with DUSN identified the causative organism as a third stage T canis larva. 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 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 and in causing minimal inflammatory reaction. Surgical (transvitreal) removal of a subretinal nematode elicits less inflammatory response but is accompanied with 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. ConclusionWith the exception of DUSN, the idiopathic multifocal chorioretinopathy 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. MULTIMEDIASection 10 of 11
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