White Dot Syndromes Delhi J Ophthalmol 2015; 25 (4):

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1 E-ISSN White Dot Syndromes Delhi J Ophthalmol 2015; 25 (4): DOI: * Jyotirmay Biswas, ** Sachin B Shetty, *** Swetha Palla * Vision Research Founda on, 18, College Road, Nungambakkam, Chennai , Tamil Nadu, India ** Sadguru Netra Chikitsalaya, Jankikund Post, Chitrakoot, U.P *** Sankara Nethralaya, Chennai, India *Address for correspondence Jyotirmay Biswas MS, FAMS, FIC Path, FAICO Director - Uvei s & Ocular Pathology Department, Vision Research Founda on, 18, College Road, Nungambakkam, Chennai , Tamil Nadu, India -drjb@snmail.org The White Dot Syndromes (WDS) comprise of a hetereogenous group of disorders characterized by mul ple whi sh-yellow inflammatory lesions affec ng the outer re na, re nal pigment epithelium, and choroid. It comprises of : Birdshot re nochoroidopathy, Acute posterior mul focal placoid pigment epitheliopathy (APMPPE), Geographic Helicoid peripapillary choroidopathy (GHPC), Mul focal choroidi s (MFC) & panuvei s syndrome, Punctate inner choroidopathy (PIC), Sub-re nal fibrosis and uvei s syndrome (SFU), Mul ple evanescent white dot syndrome (MEWDS), Diffuse unilateral subacute neurore ni s (DUSN), Re nal pigment epitheli s (Krill s disease), Acute zonal occult outer re nopathy (AZOOR). E ology of WDS is unknown. Both Infec ous cause & autoimmune e ology has been hypothesized. Treatment varies according to the individual disease condi on. Keywords : idiopathic Inflammatory chorioretinopathies (White Dot Syndromes) Birdshot retinochoroidopathy Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) Geographic Helicoid peripapillary choroidopathy (GHPC) Multifocal choroiditis (MFC) & panuveitis syndrome Punctate inner choroidopathy (PIC) Sub-retinal fibrosis and uveitis syndrome (SFU) Multiple evanescent white dot syndrome (MEWDS) The White Dot Syndromes (WDS) comprise of a heterogeneous group of disorders characterized by multiple whitish-yellow inflammatory lesions affecting the outer retina, retinal pigment epithelium, and choroid. They consist of predominantly noninfectious ocular syndromes listed in the table below (Table 1). Other entities like sarcoidosis, histoplasmosis, Behcet s disease, toxoplasmosis, sympathetic ophthalmia, syphilis and intraocular lymphoma should be considered in the differential diagnosis of WDS and must be rule out. Etiology of WDS is unknown. Infectious cause & autoimmune etiology has been hypothesized 1 and it appears that WDS occurs in families with inherited immune dysregulation that predisposes to autoimmunity 2 triggered by some exogenous agent. Few believe WDS represent a clinical spectrum of a single disease entity & not discrete diseases. Common presenting symptoms include photopsia, blurred vision, nyctalopia, floaters, and field loss contiguous with a blind spot. ln many cases, a prodromal viral syndrome can be identified thus supporting an infectious etiology. Bilateral involvement, although asymmetrical (with the exception of multiple evanescent White dot syndrome [MEWDS]), is the rule. Other than patients with birdshot retinochoroidopathy and serpiginous choroidopathy the majority of individuals are younger than 50 years of age. A female predominance is more commonly observed in patients with MEWDS, birdshot retinochoroidopathy, multifocal choroiditis and panuveitis (MCP), punctate inner choroiditis (PIC), and acute zonal occult outer retinopathy (AZOOR) Birdshot Retinochoroidopathy It has also has been called vitiliginous chorioretinitis and and is not common in India. This syndrome affects healthy Table 1: Idiopathic Inflammatory chorioretinopathies (White Dot Syndromes) Birdshot retinochoroidopathy (APMPPE) Acute posterior multifocal placoid pigment epitheliopathy Geographic Helicoid peripapillary choroidopathy (GHPC) Multifocal choroiditis (MFC) & panuveitis syndrome Punctate inner choroidopathy (PIC) Sub-retinal fibrosis and uveitis syndrome (SFU) Multiple evanescent white dot syndrome (MEWD) Diffuse unilateral subacute neuroretinitis (DUSN) Retinal pigment epithelitis (Krill s disease) Acute zonal occult outer retinopathy (AZOOR) 223

2 J Biswas et al ISSN patients, usually women, between the third and sixth decades of life. Nearly 90% of patients have HLA-A29 allele, the highest association of any HLA antigen with a human disease. Research criteria for the diagnosis of birdshot chorioretinopathy formulated by an International Consensus Conference. 3 Anterior segment inflammation may be minimal or quiet. Varying degrees of vitritis is common. Fundoscopy reveals characteristic multifocal, hypopigmented, ovoid, cream-coloured lesions at the level of the choroid and RPE in the post equatorial fundus, typically nasally & inferiorly to the disc. The term birdshot is given by Ryan & Maumenee because lesions radiate from the optic nerve and follow the larger choroidal vessels in a pattern similar to a shotgun scatter of a birdshot (Figure 1a and 1b). Retinal vasculitis, optic disk edema, and CME may be present. Late complications include optic atrophy, epiretinal membrane (ERM) formation, and, rarely, choroidal 1 (a) 1 (b) Figure 1 a-b: Showing fundus photo montage of a case of Birdshot retinohoroidopathy (courtesy Dr. Anita Agarwal, USA) neovascular membrane. Fundus fluorescein angiography is useful in identifying subtle features of active lnflammation such as retinal vasculitis, optic nerve head leakage and CME. Progressive visual field loss and abnormal electroretinogram (ERG) results are commonly seen with extended followup, suggesting that a more diffuse retinal dysfunction not fully explained by the presence of CME or other structural abnormalities contributes to visual loss. For this reason fullfield ERGs and visual fields are more useful parameters in following disease course and response to therapy than only changes in funduscopic examination results or visual acuity. The disease course is generally marked by multiple exacerbations and remissions. Hence the long term visual prognosis is guarded. Treatment of an active disease consists of the initial administration of systemic corticosteroids, with early introduction & extended treatment with corticosteroidsparing immunosuppressants. Periocular corticosteroid injections are useful as adjunctive therapy in managing CME and inflammatory recurrences. Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) It affects healthy young adults. It is typically preceded with an influenza-like illness (50%). There is no gender predilection. A genetic predisposition may be present as there is association of HLA-B7 and HLA-OR2. Various autoimmune conditions like erythema nodosum, Wegener granulomatosis, polyarteritis nodosa, cerebral vasculitis, scleritis and episcleritis, sarcoidosis and ulcerative colitis have also been associated with APMPPE suggesting an immune related vascular alteration. Young adults typically present with a sudden onset of bilateral, asymmetric diminution of vision. The fellow eye is affected within few days or weeks. Anterior segment is quiet with mild to moderate vitritis. Funduscopic findings include multiple, large, flat, yellow creamy to placoid lesions at RPE level. They are I-2 disc diameters in size and are located throughout the posterior pole. New lesions may appear in a linear or radial pattern extending to the equator over a month (Figure 2a).Atypical findings include papillitis, retinal vasculitis, retinal vascular occlusive disease, retinal neovascularization, and exudative retinal detachment. Acute lesions heal over a period of 2-6 weeks with RPE pigmentary alterations & resultant chorioretinal atrophy. Visual outcome is usually good with visual acuity returning to 20/40 or better within 6 months. 20 % are left with some residual visual dysfunction. FFA in the acute phase of the disease shows early hypofluorescent lesions (which correspond to the fundus lesions but are typically more numerous) with late hyperfluorescent staining. (Figure 2 a - c) Healed lesions reveal transmission window defects. The diagnosis of APMPPE is based on the characteristic clinical presentation and FFA findings. Imaging findings suggest choroidal choriocapillary perfusion abnormalities with secondary involvement of the RPE & photoreceptors. APMPPE needs to be differentiated from serpiginous choroiditis. While 224 Del J Ophthalmol 2015;25(4)

3 E-ISSN White Dot Syndromes 2 (a) 2 (b) 2 (c) Figure 2 a: showing fundus photo withcreamy placoid lesions of APMPPE 2 b: FFA of APMPPE early staged showing hypofluorescence the lesions 2 c: FFA of APMPPE lakstage showing hypofluorescence the lesions APMPPE is an acute condition which does not usually recur, serpiginous choroiditis is recurrent & is relentlessly progressive. APMPPE is a self limiting condition which needs no treatment. There are no convincing data to suggest that treatment with systemic corticosteroids is beneficial in altering the visual outcome. It may be used in patients with extensive macular involvement, CNS vasculitis & other associated autoimmune conditions. Serpiginous Choroiditis It is also known as geographical helicoid peripapillary choroidopathy (GHPC)). It affects healthy patients from the second to seventh decades of life. Men and women are affected equally. It is usually bilateral, chronic, and progressive inflammatory condition. Its etiology is unknown. The increased frequency of HLA-B7 and retinal S-antigen and reports of various autoimmune vasculitides suggests it to be an immune-mediated occlusive vasculitis. Patients present with painless, unilateral, paracentral scotomata and decreased vision. Anterior segment is quiet with mild vitritis. Fundus shows asymmetric bilateral disease with characteristic gray white lesions at the level of the RPE with a pseudopodial or geographic extension from the peripapillary area into the posterior fundus (Figure 3 a-d). Typically both healed & active lesions are seen with activity confined to the leading edge. Recurrent attacks are typical with a progressive centrifugal extension. The healed inactive chorioretinal lesions appear as well-demarcated geographic atrophic areas with or without pigment epithelial hyperplasia. Visual acuity frequently drops to 20/200 and even counting fingers when fovea is involved. Late complications include subretinal fibrosis and CNV usually occurring at the border of an old scar. More commonly in tuberculosis endemic areas, macular or peripheral lesions may be present without peripapillary involvement (fig 3d). The term multifocal serpiginoid choroiditis (MSC) has been recently proposed 4 for this infective variant to distinguish it from the typical peripapillary serpiginous choroiditis (SC) believed to be autoimmune related. Fluorescein angiography (FA) shows early hypofluorescence and then late staining of the active edge of the lesion (Fig 3 b - c). Indocyanine green angiography reveals hypofluorescence throughout all phases of the study for both acute and old lesions. It may be useful in distinguishing active new lesions, which are hypofluorescent, from choroidal nevascular membrane which may appear as localized areas of hyperfluorescence in the mid to late phases. Fundus autofluorescence (FAF) is useful in monitoring the disease activity with new lesions appearing hyperautofluorescent, at the edge of an old lesion which is hypoautofluorescent. Because of the relapsing and progressive nature of the disease, treatment is aimed at treating acute episodes with steroids and preventing recurrences with the use of immuno-modulatory therapy. Since the disease is bilateral, systemic steroids (oral) are preferred for active lesions. Macular or foveal involvement may warrant use of intravenous methylprednisolone followed by tapering oral steroids. Periocular, intravitreal corticosteroids or intravitreal (fluocinolone acetonide) implants may also be used. Long term management involves prolonged use of immunosuppressants most commonly cyclosporine or azathioprine under supervision of internist. The multifocal serpiginoid choroiditis variant is usually infective with tuberculosis being the most common association. These should be investigated for TB & may need treatment with 225

4 J Biswas et al ISSN (a) 3 (d) 3 (b) 3 (c) Figure 3 a,b, c: Showing colour photo of the fundus & serial FFA photos. FFA shows early hypofluorescence with late staining from active areas in serpiginous choroiditis Figure 3 d: Fundus photo of multifocal serpiginoid choroiditis anti-tubercular therapy (ATT) for at least 9 months with a short course of oral steroids. ATT has shown to decrease number of recurrences in such cases. Immunosuppressives are preferably avoided. Intravitreal anti-vegf agents and photodynamic therapy are important therapeutic modalities for the treatment of associated CNV. Multifocal Choroiditis and Panuveitis Multifocal choroiditis and panuveitis (MCP) is an idiopathic inflammatory disorder of unknown etiology affecting the choroid & retina. It is most often seen in myopic women between second and sixth decade of life 6 presenting with photopsia and decreased vision. It is usually bilateral but may be asymmetric, with delayed development in the fellow eye. 7,8 though it is a form of panuveitis, it is classified as a WDS due to its characteristic appearance. The etiology is not known but may be due to sensitization of antigens within photoreceptors & retinal pigment epithelial cells by an exogenous pathogen. 9 A viral etiology involving herpes simplex and Epstein -Barr virus has been postulated but not proved. Acute MFC lesions are yellow-white and primarily involve the choroid and outer retina. 6 The presence of vitritis as well as anterior chamber inflammation differentiates it from presumed ocular histoplasmosis & PIC. Later punched-out chorioretinal scars with pigmented borders measuring μm are seen at the posterior pole and periphery similar to those found in presumed ocular histoplasmosis. The lesions are smaller than those seen in birdshot retinochoroidopathy or APMPPE but larger and more pigmented than PIC. Causes of decreased vision include floaters and vitritis in the acute stage, cystoid macular edema (CME), exudation due to choroidal neovascularization, ERM formation & fibrotic macular scars in the atrophic stage. 10 Peripheral visual field loss not corresponding to the extent of choroiditis may also develop. 11 Some may develop Diffuse Subretinal Fibrosis (DSF) characterized by a coalescence of lesions and broad 226 Del J Ophthalmol 2015;25(4)

5 E-ISSN White Dot Syndromes zones of subretinal fibrosis. 12,13 Hence many consider MFC, PIC, and DSF to be a continuum of severity of a single syndrome. FA in the acute stage show early hypofluorescence & late staining on Fluorescein angiography (Figure 4 b). In the healed phase, the atrophic lesions show window defect (early hyperfluorescence fading in the late phase). Peripapillary or subfoveal CNV may show classic or late leakage. CME when present shows a petalloid leakage in late phases of the angiogram. 14 Indocyanine green angiography shows hypofluorescent lesions suggestive of active choroiditis commonly clustered around disc far more numerous than those seen on flurorescein angiography or clinical exam. This explains the enlarged blind spot seen on visual field testing. These resolve on treatment. Fundus autofluorescence shows acute lesions as hyperautofluorescent which turns hypoautofluorescent indicating resolution of activity it therefore may be useful in monitoring response to treatment. Punched out lesions appear hypoautofluorescent and may gradually enlarge with time. Visual fields may reveal an enlarged blind spot & peripheral visual field loss out of proportion to the fundus involvement. They not only decrease inflammation but also reduce risk of complications like CME, ERM, fibrosis, CNV. Intravitreal anti-vegf agents and laser modalities (thermal photocoagulation and photodynamic therapy) are important adjuncts to the treatment of CNV. A study comparing bevacizumab with photodynamic therapy for CNV in MCP showed greater beneficial effects in the bevacizumab group. 15 The intravitreal fluocinolone acetonide implant is a possible treatment option for patients unable to tolerate systemic therapy. The disease has a waxing & waning course. Progressive visual loss occurs & visual prognosis is guarded with permanent visual loss in at least 1 eye occurring in up to 75% of patients as a result of the complications associated with chronic recurrent inflammation. Systemic and periocular corticosteroids are useful for the treatment of macular edema and induce regression of CNV in some patients. Corticosteroid sparing therapy with immunosuppressant is frequently required. Ampiginous choroiditis has been recently described as a clinical entity involving features of both acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and serpiginous choroiditis in relatively young patients, occurring predominantly in males It is a disease with multiple relapses which can be effectively controlled with a combination of immunosuppressive therapy and maintain a good visual acuity on long term follow-up. (Figure 4 a-b) showing fundus & flourescein angiogram photograph of ampiginous choroiditis. Punctate Inner Choroidopathy Punctate inner choroidopathy (PIC) is an idiopathic inflammatory disease of the choroid. It was first described by Watzke et al. in an association with Epstein-Barr virus 17 and with HLA-DR 2 positivity 18 has been reported. It affects 4 (a) 4 (b) Figure 4 (a-b) : showing fundus & FA photograph of ampiginous choroiditis, a conditioning mimicking serpiginous choroiditis young healthy myopic women bilaterally. Patients present with complains of blurred vision, photopsias, or paracentral scotomas. 19 Lesions are bilateral, multiple, small, welldefined, yellow-white, usually microns diameter and are limited to the posterior pole. Cells and flare in the anterior chamber or vitreous cavity 20 are typically absent. The lack of vitreous inflammation is a hallmark of PIC. 21 Serous retinal detachment may occur overlying an active lesion. These lesions advance forming punched out atrophic scars leaving depigmented halo. Choroidal neovascular membranes occur in between 40 to 75% of patients from healed scars. 22 Unlike MCP, PIC lesions are more localized to the posterior pole. PIC by definition does not have peripheral lesions. 23 Vitritis, subretinal fibrous metaplasia, and bridging tissue are more characteristic of MFC. 21 MFC is more likely to develop complications of inflammation such as cataract, CME, and ERM. 22 Some studies show that PIC is more likely to develop CNV compared to MFC. 22 Diagnosis is based on typical ocular finding. FA of acute lesions reveals early hyperfluorescence and late staining. Leakage into the subretinal space occurs if an overlying serous detachment is present. Choroidal neovascularization also shows late leakage. In the healed phase, atrophic 227

6 J Biswas et al ISSN lesions reveal window defects. FFA shows more lesions than seen clinically. ICG shows numerous hypofluorescent spots in the middle and late phases of ICG. 24 ICG reveals even more lesions than FA. OCT is useful when a CNVM & CME is present. Fundus autofluorescence findings resemble MFC & are useful in monitoring disease activity. Visual prognosis is guarded. If subfoveal lesions and choroidal neovascularization do not occur, visual acuity is usually better than 20/40 (6/12). Recurrences are common. Treatment aims to control inflammation during its active stage and manage complications (CME and CNV). Systemic Corticosteroids are used in the active stages. Steroid sparing immunosuppressants become necessary when steroids are not tolerated or recurrence is frequent. CNV can be managed with thermal laser if extrafoveal, PDT, or anti- VEGF injections in combination with oral steriods. 25 Spontaneous regression of choroidal neovascularization can occur. No treatment may be necessary if the lesions are not sight threatening. Submacular translocation surgery in have been tried in submacular diseases including PIC but recurrence of CNVM has been reported. 26 Sub-Retinal Fibrosis and Uveitis Syndrome Subretinal fibrosis and uveitis syndrome (SFU) is a rare form of panuveitis of unknown etiology affecting otherwise healthy myopic women between the ages of 14 and 34 years (same demographics as MFC and PIC). MFC also has a variable amount of fibrosis 27 and hence many authors consider these entities as part of the same disease spectrum. SFU patients present with unilateral symptoms despite bilateral involvement detected on clinical examination. Significant anterior segment inflammation and mild to moderate vitritis are typically present bilaterally, with whiteyellow lesions ( μm) located in the posterior pole to midperiphery at the level of the RPE. Many authors 28,29 believe these lesions are accompanied by the appearance of turbid subretinal exudation & this differentiates SFU from others like MFC & PIC. Meanwhile the active lesions may fade without RPE alterations, get atrophic, or become chorioretinal scars. Over the next several months to years, the subretinal fibrin and turbid exudates coalesce into large, white, stellate zones of subretinal fibrosis to involve most of the retina and choroid. Serous neurosensory retinal detachment, CME, and CNV may also be observed. On FFA, the acute lesions show early hyperfluorescence followed by late leakage. As fibrosis sets in, there is staining in late phases of FFA. CNV is not common and is difficult to differentiate from fibrosis. 31 Laboratory evaluation is typically unrewarding. 30 The differential diagnosis of SFU is similar to that of MFC and PIC and includes conditions producing panuveitis. Sarcoidosis (Figure 5), ocular histoplasmosis syndrome, APMPPE, syphilis, tuberculosis, birdshot retinochoroidopathy, pathologic myopia, sympathetic ophthalmia, and toxoplasmosis must be ruled out. Often the diagnosis of SFU is made only with disease progression and development of end stage fibrosis. Auto - immune mechanisms have been implicated with Figure 5: showing fundus photo of a case of sarcoidosis with sarcoid nodules the demonstration of local antibodies & B lymphocytes 31, plasma cells, and subretinal fibrotic tissues with islands of RPE and Muller cells in histopathologic specimens. The disease course is marked by chronic recurrent inflammation and the visual prognosis is guarded. Treatment of this entity with systemic glucocorticoids has been reported to be unsuccessful, with eventual progression to complete subretinal fibrosis of the macula. 27,30 Immunosuppressive agents may be helpful. Treatment is directed towards early diagnosis and aggressive management to prevent fibrosis setting in the other eye. Once severe subretinal fibrosis develops, treatment has little benefit. Multiple Evanescent White Dot Syndrome (MEWDS) Multiple Evanescent White Dot Syndrome (MEWDS) is an idiopathic inflammatory disorder of the retina. It usually affects otherwise healthy, young, moderately myopic females in their second to fourth decades of life. There are no known racial or hereditary associations. Patients present with acute, painless, unilateral (80%) blurred or decreased vision, photopsias, and central or paracentral scotoma corresponding to an enlarged physiologic blind spot. Rare bilateral cases have also been reported, which are asymmetric. 32 An antecedent viral prodrome occurs in approximately one-third of cases. A relative afferent pupillary defect may be present. The anterior segment appears normal, without signs of inflammation. Mild vitritis may be present with disc edema and, in rare cases isolated vascular sheathing results. Funduscopy during the acute phase reveals multiple, discrete, perifoveal white to orange spots ( m) at the level of the RPE or deep retina. These spots fade away and are frequently missed but leave behind a granular macular pigmentary change which is pathognomonic (Figure 6 a). Choroidal scarring may ensue in some patients. Rarely CNV may develop & may be the presenting sign. Diagnosis is clinical based on the typical fundus appearance. Fluorescein angiography may reveal disc capillary leakage and late punctate staining, characteristically in a wreath like pattern 33,34 Leakage in the macula in a non cystoid pattern may be seen. ICG 228 Del J Ophthalmol 2015;25(4)

7 E-ISSN White Dot Syndromes angiography shows multiple hypofluorescent lesions that are more numerous than those seen clinically or FA and that typically fade with resolution of the disease. Fundus autofluorescence shows hypofluorescent spots in greater number than clinically seen lesions (Figure 6 b-c). 6 (a) 6 (b) 6 (c) Figure 6 (a-c): showing colour fundus photographs, FFA & ICG photographs of a case of MEWDS OCT shows dome shaped reflective lesions corresponding to the clinical white dot at the level of the photoreceptors. These lesions ultimately disappear. 35 There is also a disturbance in the photoreceptor inner/ outer segment junction. Although lesions typically seen unilaterally, photoreceptors can have abnormalities bilaterally. 36 Visual field defects are variable and range from generalized depression, paracentral or temporal scotoma to enlargement of the blind spot ERG may reveal profoundly decreased a wave amplitude and early receptor potential amplitudes in the acute phase of the disease, which suggests widespread photoreceptor dysfunction. 37 During the recovery, these amplitudes return to normal. The multifocal ERG (mferg), electro-oculogram (EOG) and the changes in microperimetry sensitivity localize the disease process to the RPE-photoreceptor complex rather than to the choroid. The prognosis is excellent with visual recovery in 2-10 weeks without treatment. However, residual symptoms including photopsias and enlargement of the blind spot may persist for months. Recurrences are uncommon (10-15 % of patients) and have a similarly good prognosis. Treatment is not needed in view of the favorable natural course. Acute Zonal Occult Outer Retinopathy (AZOOR) AZOOR is a syndrome consisting of one or more zones of outer retinal dysfunction that occurs in young to middle age patients that progresses to develop retinal cell death. 38 Two pathogenic mechanisms have been proposed - the common genetic hypothesis of autoimmune/inflammatory diseases by Jampol and Becker & primary infection of retinal photoreceptors by Gass. 39 But none has been proven. Patients are typically young, myopic women. The early symptoms of AZOOR are acute visual field loss and photopsias in one or both eyes. The photopsias in AZOOR can be very distinctive with patients describing them as movement of colors or lights within the area of visual field loss. Patients typically have an apparently normal fundus on initial examination, making the diagnosis all the more difficult. There may be an associated mild vitritis (50%) with moderate diminution of vision in the 20/40 range. Unilateral disease is more common at first, but eventually both eyes may be affected. During the early stages of the disease, FA findings may be entirely normal, showing only a prolonged retinal circulation time. However, with disease progression, diffuse areas of RPE changes appear. These have been described variously 40 as areas of hyperfluorescence, salt & pepper, granularity, or patchy hyper - and hyofluorescence and window defects corresponding to zones of RPE derangement. FAF imaging is useful in following up patients with AZOOR. It shows areas of central hypoautofluorescence corresponding to areas of chorioretinal atrophy with peripheral hyperautofluorescence seen at the border of an expanding lesion due to the presence of lipofuscin-laden cells that predicts RPE cell death. 40 OCT shows an irregularity of the inner segment outer segment (IS OS) photoreceptor line in the areas of retinal involvement. The RPE and outer retina 229

8 J Biswas et al ISSN eventually atrophy. The outer retinal dysfunction can be documented by visual fields which shows large, superior, temporal and, occasionally, central zones of visual field loss. The scotomas often increase in size within a few days to weeks and then stabilize. Visual field loss often occurs in both eyes, but can be asymmetric. An abnormal ERG is observed in the vast majority of cases, and the diagnosis of AZOOR should be questioned if an individual has a normal ERG. 41 ERG shows abnormality not only at the photoreceptor-rpe complex but also at the inner retinal level. Typically a delayed 30-Hz-flicker ERG and a reduction in the EOG light rise 42 has been described, which when present with classic symptomatology may be helpful in the diagnosis, obviating extensive neurologic evaluation. With extended follow-up, the majority of patients develop bilateral disease, with recurrences in approximately one-third. Visual field abnormalities typically stabilize in approximately three-quarters of patients and partially improve in about 25%. Visual acuity remains in the 20/40 range in 68% of patients. Legal blindness has been reported in as many as 18% with long-term follow-up. It is unclear whether treatment with systemic corticosteroids or immunomodulators alters the disease course or visual outcome. The considerable similarities between AZOOR and other WDS like- MEWDS, MCP, OHS, PIC, acute macular neuroretinopathy, and acute idiopathic blind spot enlargement syndrome have led some investigators to group these entities together in the so-called AZOOR complex of diseases. Diffuse Unilateral Sub acute Neuroretinitis (DUSN) This term was coined by Gass 43,44 in 1978 to describe the inflammatory changes in the optic nerve and retina caused by the movement of a single parasite in the subretinal space. It is an uncommon disease caused by nematode infection occurring in healthy, young patients (mean age 14 years. 44 It is commonly caused by solitary nematodes of 2 different sizes, as per the geographic region. The smaller worm, measuring μm in length, has been proposed to be either Ancylostoma caninum (the dog hookworm) or T. canis, the latter being endemic to the parts of United States, Caribbean islands, and Brazil. The larger worm is believed to be Baylisasearis proeyonis (the raccoon roundworm), which measures μm in length and has been found in parts of United States and Canada. It is characterized by the insidious onset of unilateral visual loss from recurrent episodes of inflammation of the retina, RPE, and optic nerve. Though highly unusual, bilateral cases 44,45 have been reported, as have cases of DUSN associated with neurologic disease (neural larvae migrans). The early stage of the disease is marked by moderate to severe vitritis, disc edema and relative afferent papillary defect. 44 Recurrent clusters of multiple gray-white or yellow-white lesions in the deep retina that fade within days are seen. These lesions are evanescent and may be associated with overlying serous retinal detachment. It is at this stage that the worms are most easily visualized in the subretinal space. The later stages are characterized by retinal arteriolar narrowing, sheathing of vessels, optic atrophy, diffuse pigment epithelial degeneration, and abnormal electroretinographic results. Few differential diagnoses are posttraumatic chorioretinopathy, occlusive vascular disease, toxic retinopathy, and retinitis pigmentosa. Later choroidal neovascularization, hypertrophy of the retinal pigment epithelium, and subretinal fibrosis can occur. The diagnosis is mainly clinically with direct visualization of the nematode. Examination with scanning laser ophthalmoscopy (SLO) provides a high contrast & facilitates visualization of the nematode. 46 Photographic /video documentation of the worm motility in the subretinal space with SLO are supportive. Laboratory tests are typically negative. On FA active lesions show early hypofluorescence and late staining. Mild disc leakage may be present indicating an active inflammation (Figure 7). 44 Later retinal pigment epithelium changes are seen. The electroretinogram is usually moderately to severely affected, but not extinguished. 44 The ERG abnormalities may be present even when the test is performed early in the disease course. Direct laser photocoagulation of the worm should be attempted in all cases. 47,48 In the early phases it is helpful in halting progression and improving visual acuity, & does not cause much inflammation. Corticosteroids provide transient control of the inflammation, but leads to recurrence of symptoms and progression of visual loss. Antihelminthic therapy not only decreases inflammation, it also immobilizes the subretinal nematode & facilitates laser photocoagulation. In cases where worm cannot be initially identified, it maximizes the chances of identifying and treating the offending organism. Also sometimes a second nematode, presumably from reinfection, may be seen in patients who have completed a successful previous photocoagulation. These patients may also benefit from a course of systemic antihelminthic therapy. This is suspected whenever inflammation does not abate promptly following laser photocoagulation. Oral thiabendazole (22 mg/kg twice daily for 2-4 days with a maximum dose of 3 g) is successful Figure 7: showing FFA photo of DUSN with evanescent hypopigmented lesions due to worm migration, scattered all over the retina. Late staining of the lesions is seen here 230 Del J Ophthalmol 2015;25(4)

9 E-ISSN White Dot Syndromes in moderate to severe inflammation. Albendazole (200 mg twice daily for 30 days) may be a better-tolerated alternative. Surgical extraction, either transsclerally 47 or transvitreally 49 may be appropriate in young children who cannot tolerate laser photocoagulation. Retinal pigment epithelitis (Krill s disease) Acute retinal pigment epitheliitis, or Krill s disease, is a benign self-limiting inflammatory disorder of the RPE of unknown etiology. A viral or drug induced etiology has been suspected. It typically presents in otherwise healthy young adults between the ages of 16 and 40 years with acute unilateral visual loss, central metamorphopsia, and scotoma. Visual acuity may range from 20/20 to 20/100 at presentation. Anterior segment is typically quiet. Fundus shows clusters of small, discrete, hyperpigmented lesions, typically surrounded with a yellow halo in the posterior pole unassociated with vitritis or other abnormalities. Amsler grid may show central metamorphopsia or central scotoma. Visual field examinations may show central scotoma. FFA shows hypofluorescence of the gray-black spots (dye blockage due to hyperpigmentation) with surrounding halo of early hyperfluorescence (consistent with a window defect) that fades later. ICG angiography in the early and midphase show a patchy macular hyperfluorescence. In the late phase, a hyperfluorescent halo with a cockade-like appearance of the macula is observed. ICG findings resolve with time. OCT shows disruption of the photoreceptors inner segment and outer segment (IS-OS) junction associated with a wider disruption of the RPE inner band. These are replaced by a dome-shaped highly reflective lesion involving the RPE inner layer & IS-OS layers. As the disease resolves, the IS- OS layers and RPE inner bands get restored and appear continuous. Normal ERG with abnormal results on EOG localizes the disease process to the RPE. No treatment is required, as the lesions resolve without sequelae with excellent visual acuity over 6-12 weeks. Recurrence is very rare. Conclusion The White dot syndromes are a distinctive group of disorders affecting the retina, retinal pigment epithelium, and choroid. They present significant diagnostic and therapeutic challenges both to the clinician & research scientist. Careful observation of signs, documentation of findings, long follow-up of cases & appropriate treatment of reactivation with steroids & immunosuppressives are needed for successful management of a white dot case. Financial & competing interest disclosure The authors do not have any competing interests in any product/ procedure mentioned in this study. The authors do not have any fi nancial interests in any product / procedure mentioned in this study. References 1. Jampol LM, Becker KG: White spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. 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