Inflammatory Chorioretinopathies of Unknown Etiology
The inflammatory chorioretinopathies, or white dot syndromes, are a heterogeneous group of inflammatory disorders with overlapping clinical features that share the presence of discrete, multiple, well-circumscribed, yellow-white lesions at the level of the retina, outer retina, RPE, choriocapillaris, and/or choroid during some phase of their course. The white dot syndromes consist of the predominantly noninfectious ocular syndromes listed in Table 9-1.
Their differential diagnosis includes systemic and ocular infectious entities such as syphilis, diffuse unilateral subacute neuroretinitis (DUSN), and ocular histoplasmosis syndrome (OHS), as well as noninfectious entities such as sarcoidosis, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, and intraocular lymphoma. Common presenting symptoms include photopsias, blurred vision, nyctalopia, floaters, and visual field loss contiguous with the blind spot. In many cases, a prodromal viral syndrome can be identified. Bilateral involvement, albeit asymmetrically (with the exception of multiple evanescent white dot syndrome [MEWDS]), is the rule. Excepting patients with birdshot chorioretinopathy or serpiginous choroiditis, most individuals are younger than 50 years of age. A female predominance is observed in patients with MEWDS, birdshot chorioretinopathy, multifocal choroiditis and panuveitis, punctate inner choroiditis (PIC), subretinal fibrosis and uveitis syndrome, and acute zonal occult outer retinopathy.
The etiology of the white dot syndromes is unknown. Some investigators have postulated an infectious cause; others have suggested an autoimmune/inflammatory pathogenesis arising in individuals with common non–disease-specific genetics, triggered by some exogenous agent. An increased prevalence of systemic autoimmune disease, both in patients with white dot syndromes and in their first- and second-degree relatives, suggests that inflammatory chorioretinopathies may occur in families with inherited immune dysregulation that predisposes to autoimmunity. It is also unclear whether the white dot syndromes represent a clinical spectrum of a single disease entity or are discrete diseases. Although they share common features, the white dot syndromes can be differentiated by their variable lesion morphology and evolution, distinct natural histories, and appearance with multimodal imaging. This differentiation has important implications with respect to disease-specific treatments and visual prognosis.
Table 9-1 Inflammatory Chorioretinopathies
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Abu-Yaghi NE, Hartono SP, Hodge DO, Pulido JS, Bakri SJ. White dot syndromes: a 20-year study of incidence, clinical features, and outcomes. Ocul Immunol Inflamm. 2011;19(6):426–430.
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Gass JD. Are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR complex) specific autoimmune diseases? Am J Ophthalmol. 2003;135(3):380–381.
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Jampol LM, Becker KG. White spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol. 2003;135(3):376–379.
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Pearlman RB, Golchet PR, Feldmann MG, et al. Increased prevalence of autoimmunity in patients with white spot syndromes and their family members. Arch Ophthalmol. 2009;127(7):869–874.
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Quillen DA, Davis JB, Gottlieb JL, et al. The white dot syndromes. Am J Ophthalmol. 2004;137(3):538–550.
Birdshot chorioretinopathy
Birdshot chorioretinopathy (also known as birdshot uveitis, birdshot retinochoroidopathy, and vitiliginous chorioretinitis) is an uncommon disease presenting predominantly in white women of northern European descent past the fourth decade of life. Although no consistent systemic disease association has been identified, birdshot chorioretinopathy is highly correlated with the HLA-A29 gene, with a sensitivity of 96% and a specificity of 93%. The presence of the haplotype confers considerably increased relative risk (224-fold) for the development of this disease. HLA-A29 is confirmatory rather than diagnostic, as 7% of the general population carries this haplotype, and in the absence of characteristic clinical features, an alternative diagnosis should be considered.
Manifestations Presenting symptoms include blurred vision, floaters, nyctalopia, and disturbance of color vision. Visual complaints may be out of proportion to the measured Snellen visual acuity, reflecting the diffuse retinal dysfunction that occurs in this disease. Patients may also report unusual peripheral visual phenomena, such as pinwheels, sparkles, or flickering lights, and these symptoms may be indicators of subtle disease activity. Anterior segment inflammation may be minimal or absent; however, varying degrees of vitritis are commonly noted.
Funduscopy reveals characteristic multifocal, hypopigmented, ovoid, cream-colored lesions (50–1500 μm) at the level of the choroid and RPE in the postequatorial fundus. Typically, these lesions show a nasal and radial distribution, emanating from the optic nerve, and frequently they follow the underlying choroidal vessels (Fig 9-7). The lesions do not become pigmented over time and are best appreciated by indirect ophthalmoscopy, although they may not be readily apparent at presentation. Retinal vasculitis, uveitic macular edema, and optic nerve head inflammation are important components of active disease. Late complications include optic atrophy, epiretinal membrane (ERM) formation, and, rarely, CNV.
Fluorescein angiography (FA) findings are variable, depending on duration of disease and clinical activity. Although early birdshot chorioretinopathy lesions may show initial hypofluorescence with subtle late staining, in general, FA is more useful in identifying more subtle indices of active inflammation, such as retinal vasculitis, macular edema, and optic nerve head leakage (Fig 9-8). Indocyanine green (ICG) angiography discloses multiple hypocyanescent spots, which are typically more numerous than those apparent on clinical examination or FA (Fig 9-9).
Fundus autofluorescence (FAF) imaging reveals hypoautofluorescence in areas of RPE atrophy that are more numerous and not uniformly correspondent with lesions on examination, suggesting that the choroid and RPE may be affected independently (Fig 9-10). Macular hypoautofluorescence has been associated with vision loss and disease severity. Optical coherence tomography (OCT) may show macular edema or demonstrate patchy or diffuse loss of photoreceptors (inner/outer segment line or ellipsoid zone) and macular atrophy, especially with long-standing disease (Fig 9-11). Enhanced-depth OCT imaging may be useful to evaluate choroidal thickening early in the disease course and thinning in advanced disease.
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Böni C, Thorne JE, Spaide RF, et al. Choroidal findings in eyes with birdshot chorioretinitis using enhanced-depth optical coherence tomography. Invest Ophthalmol Vis Sci. 2016;57(9):591–599.
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Piffer AL, Boissonnot M, Gobert F, et al. Relevance of wide-field autofluorescence imaging in birdshot retinochoroidopathy: descriptive analysis of 76 eyes. Acta Ophthalmol. 2014;92(6):e463–469.
Differential diagnosis Important differential diagnostic considerations include pars planitis, VKH syndrome, sympathetic ophthalmia, OHS, intraocular lymphoma, and especially sarcoidosis, which may present with chorioretinal lesions of similar morphology and distribution as those present in birdshot chorioretinopathy.
Disease course Birdshot chorioretinopathy can be insidious, and simply monitoring visual acuity and clinical examination findings is insufficient to protect patients from vision loss. Progressive worsening of the visual field and abnormal electroretinogram (ERG) results are commonly found with extended follow-up. This suggests a more diffuse retinal dysfunction not fully explained by the presence of uveitic macular edema or other structural abnormality. For this reason, full-field ERGs (with attention to the 30-Hz flicker implicit time and scotopic b-wave amplitudes) and Goldmann and automated visual field (30-2 with attention to the mean deviation) testing are more useful parameters for monitoring disease course and response to therapy than are changes in funduscopic examination or visual acuity.
A small subset of patients with birdshot chorioretinopathy may have self-limited disease and do well without treatment. However, there is no way to determine which patients will have disease progression, so close monitoring with the testing modalities discussed earlier is critical. Studies have shown that early and aggressive control of inflammation in this disease results in better visual outcomes.
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Gordon LK, Monnet D, Holland GN, Brézin AP, Yu F, Levinson RD. Longitudinal cohort study of patients with birdshot chorioretinopathy. IV. Visual field results at baseline. Am J Ophthalmol. 2007;144(6):829–837.
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Holder GE, Robson AG, Pavesio C, Graham EM. Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy. Br J Ophthalmol. 2005;89(6):709–718.
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Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH. Birdshot retinochoroidopathy: ocular complications and visual impairment. Am J Ophthalmol. 2005;140(1):45–51.
Treatment Treatment consists of the initial administration of systemic and/or local corticosteroids, with early introduction of corticosteroid-sparing IMT. Birdshot chorioretinopathy is typically incompletely responsive to corticosteroid monotherapy. Extended IMT is anticipated in most patients, given the chronic nature of the disease. Treatment with IMT may include cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, and tumor necrosis factor α (TNF-α) inhibitors. This approach is effective in reducing intraocular inflammation, inflammatory recurrences, and the risk of developing uveitic macular edema, as well as in preserving visual acuity and visual field. Periocular or intravitreal corticosteroid injections are useful as adjunctive therapy in managing macular edema and inflammatory recurrences. The intravitreal fluocinolone acetonide implant is an option for patients who cannot tolerate systemic therapy, or in whom systemic therapy is insufficient, although multiple implants may be necessary to maintain inflammation control over time.
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Kiss S, Ahmed M, Letko E, Foster CS. Long-term follow-up of patients with birdshot retinochoroidopathy treated with corticosteroid-sparing systemic immunomodulatory therapy. Ophthalmology. 2005;112(6):1066–1071.
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Menezo V, Taylor SR. Birdshot uveitis: current and emerging treatment options. Clin Ophthalmol. 2014;8:73–81.
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Tomkins-Netzer O, Taylor SR, Lightman S. Long-term clinical and anatomic outcome of birdshot chorioretinopathy. JAMA Ophthalmol. 2014;132(1):57–62.
Acute posterior multifocal placoid pigment epitheliopathy
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an uncommon condition presenting in otherwise healthy young adults, affecting men and women equally. It may be associated with an influenza-like illness (50%) and may have a genetic predisposition, given the association of HLA-B7 and HLA-DR2 with this entity.
Several noninfectious systemic conditions have been reported in connection with APMPPE, including erythema nodosum, GPA, PAN, cerebral vasculitis, scleritis and episcleritis, sarcoidosis, and ulcerative colitis. Infectious etiologies, including group A streptococcus, adenovirus type 5, tuberculosis, Lyme disease, and mumps virus have also been associated with APMPPE, as has hepatitis B vaccination. It has been postulated that APMPPE is an immune-driven vasculitis. Of greatest concern is the rare but potentially life-threatening association of APMPPE with cerebral vasculitis. Patients presenting with symptoms suggestive of CNS disease should undergo urgent neurologic evaluation.
Manifestations Patients typically present with a sudden onset of unilateral vision loss associated with central and paracentral scotomata; the fellow eye becomes involved within days to weeks. Photopsias may precede loss of vision. There is minimal or no anterior segment inflammation; vitritis may be present but is usually mild. Funduscopic examination demonstrates multiple large, flat, yellow-white placoid lesions at the level of the RPE. The lesions vary in size from 1 to 2 disc areas and are scattered throughout the posterior pole (Fig 9-12). New peripheral lesions may appear in a linear or radial array over the next few weeks. Papillitis may be observed, but macular edema is uncommon. Atypical findings include retinal vasculitis, retinal vascular occlusive disease, retinal neovascularization, and exudative retinal detachment. The lesions resolve over a period of 2–6 weeks, leaving a permanent, well-defined alteration in the RPE, consisting of alternating areas of depigmentation and pigment clumping. Rapid evolution of the pigmentary changes, often over days, is a typical feature of the disease.
Diagnosis The diagnosis of APMPPE is based on the characteristic clinical presentation and FA findings during the acute phase of the disease: early hypofluorescent lesions (Fig 9-13A) corresponding to, but typically more numerous than, those apparent on funduscopy and late hyperfluorescent staining (Fig 9-13B). Subacute lesions may show increased central hyperfluorescence with late staining; with resolution, transmission defects are typically observed.
Indocyanine green angiography reveals choroidal hypocyanescence with hypervisualization of the underlying choroidal vessels in both the acute and inactive stages of the disease; these lesions become smaller in the inactive stages (Fig 9-14). Choroidal perfusion abnormalities revealed early on FA and ICG angiography are more numerous than the overlying placoid lesions.
Abnormalities noted on FAF imaging lag the clinical appearance of these lesions and are fewer in number. Typically, lesions are initially hyperautofluorescent and may evolve into areas of hypoautofluorescence over time (Fig 9-15). RPE alterations observed during recovery appear well after the choroid is affected.
It remains controversial whether the lesions of APMPPE are due primarily to involvement of the RPE or represent choroidal/choriocapillary perfusion abnormalities with secondary involvement of the RPE and photoreceptors; however, taken together, the FA, ICG, and FAF imaging findings suggest a primary choroidal process. OCT of acute lesions demonstrates hyperreflectivity of the outer retinal layers; subretinal or intraretinal fluid may also be present (Fig 9-16). As the lesions resolve, outer retinal and photoreceptor loss may be observed.
An important differential diagnostic consideration—in addition to choroidal metastasis, viral retinitis, sarcoidosis, VKH syndrome, and pneumocystis choroiditis—is serpiginous choroiditis. APMPPE is an acute, usually nonrecurring disease, whereas serpiginous choroiditis is insidious and progressive.
Prognosis In most patients with APMPPE, visual acuity returns to 20/40 or better within 6 months, although 20% are left with residual visual dysfunction. Risk factors for loss of vision include foveal involvement at presentation, older age at presentation, unilateral disease, a longer interval between initial and fellow eye involvement, and recurrence. No convincing data suggest that treatment with systemic corticosteroids is beneficial in altering the visual outcome, although some authorities advocate such treatment in patients presenting with extensive macular involvement in an effort to limit subsequent RPE derangement of the foveal center. Systemic corticosteroids are also indicated in individuals with an associated CNS vasculitis.
Relentless placoid chorioretinitis An uncommon variant termed relentless placoid chorioretinitis or ampiginous choroiditis has features of both serpiginous choroiditis and APMPPE. Men or women between the second and sixth decades of life present with floaters, photopsias, paracentral scotomata, and decreased vision, as well as variable degrees of anterior segment inflammation and vitritis. The acute retinal lesions are similar to those of APMPPE or serpiginous choroiditis, both clinically and angiographically, but the clinical course is atypical for both entities. Patients have numerous posterior and peripheral lesions predating or occurring simultaneously with macular involvement (Fig 9-17). Acute lesions heal over a period of weeks, with resultant chorioretinal atrophy. Older pigmented areas are observed together with new, active, white placoid lesions that are not necessarily extensions of previous areas of activity. Prolonged periods of disease activity occur, with the appearance of numerous (>50) multifocal lesions scattered throughout the fundus. Relapses are common, and new lesions may appear and progress for up to 2 years after the initial presentation. FA demonstrates early hypofluorescence and late staining of these lesions. Although macular involvement can result in vision loss, metamorphopsia, or scotomata, visual acuity is preserved in most patients upon healing of the lesions.
The precise roles of systemic steroids, antiviral drugs, and IMT in the treatment of relentless placoid chorioretinitis are incompletely understood. Systemic corticosteroids are commonly employed, but the disease may recur despite their use. It is important to rule out the presence of tuberculosis-associated serpiginous-like choroiditis.
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Jones BE, Jampol LM, Yannuzzi LA, et al. Relentless placoid chorioretinitis: a new entity or an unusual variant of serpiginous chorioretinitis? Arch Ophthalmol. 2000;118(7):931–938.
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Pagliarini S, Piguet B, Ffytche TJ, Bird AC. Foveal involvement and lack of visual recovery in APMPPE associated with uncommon features. Eye (Lond). 1995;9(Pt. 1):42–47.
Serpiginous choroiditis
Serpiginous choroiditis, also known as geographic or helicoid choroidopathy, is an uncommon, chronic, progressive inflammatory condition affecting adult men and women equally in the second to seventh decades of life. Its etiology is unknown, but it is thought to represent an immune-mediated occlusive vasculitis. With the exception of tuberculosis, which can cause a serpiginous-like choroidopathy, no other infectious organisms have been definitively implicated in this disease. Serpiginous choroiditis has been reported to occur in patients with Crohn disease, sarcoidosis, and PAN, but no consistent systemic disease associations have been identified.
Manifestations Patients present with painless, paracentral scotomata and decreased vision, with minimal vitreous involvement and a quiet anterior chamber. Although patients may present with unilateral symptoms, funduscopy usually reveals asymmetric bilateral scarring. Active areas appear as gray-white lesions at the level of the RPE that project in a pseudopodial or geographic manner from the optic nerve in the posterior fundus (Fig 9-18). Far less commonly, macular or peripheral lesions may present without peripapillary involvement. Disease activity is typically confined to the leading edge of the advancing lesion and may be associated with shallow subretinal fluid. Occasionally, vascular sheathing has been reported along with RPE detachment and neovascularization of the disc. Late findings include atrophy of the choriocapillaris, RPE, and retina, with extensive RPE hyperpigmentation and subretinal fibrosis. CNV may occur at the border of an old scar in up to 25% of patients.
Disease course The disease course is marked by progressive centrifugal extension, with marked asymmetry between the 2 eyes. New lesions and recurrent attacks are typical; up to 38% of affected eyes deteriorate to a visual acuity of 20/200 or worse. Fluorescein angiography may show blockage of the choroidal flush in the early phase and staining of the active edge of the lesion in the later stage of the angiogram (Fig 9-19). In contrast, early hyperfluorescence with late leakage is indicative of the presence of CNV. Indocyanine green angiography reveals hypocyanescence throughout all phases of both acute and old lesions. It may reveal more extensive involvement than FA or clinical examination and may be useful in distinguishing active new serpiginous lesions, which are hypofluorescent, from CNV, which may appear as localized areas of hyperfluorescence during the middle to late phases.
Fundus autofluorescence imaging may be an exquisitely sensitive modality for detecting damage to the RPE and monitoring the clinical course of serpiginous choroiditis. Characteristic hypoautofluorescence corresponds closely to areas of regressed disease activity, and hyperfluorescence highlights areas of active disease (Fig 9-20A). OCT can show increased outer retinal reflectivity and disruption and thickening of the underlying choroid in active disease (Fig 9-20B), and atrophic changes in the retina and RPE in quiescent areas.
Treatment Given the small number of patients with serpiginous choroiditis, no consensus has evolved regarding the optimal treatment regimen or its efficacy. Treatments include the following:
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Systemic, periocular, and intravitreal corticosteroids may be used in the treatment of active lesions, particularly lesions threatening the fovea.
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The addition of systemic IMT at the outset has been suggested, as corticosteroids alone are typically insufficient, and patients require prolonged anti-inflammatory therapy.
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Combination therapy with an antimetabolite and a T-cell inhibitor may be effective.
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Cytotoxic therapy with cyclophosphamide or chlorambucil has been shown to induce long, drug-free remissions.
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Intravitreal steroid implants, including the fluocinolone acetonide and dexamethasone implants, may be used in patients intolerant of systemic therapy.
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Intravitreal anti-VEGF drugs, focal laser photocoagulation, and photodynamic therapy are important adjuvant therapies for the treatment of associated CNV.
It is important to distinguish presumed immune-mediated serpiginous choroiditis from infectious entities that can simulate the disease. Although herpetic and syphilitic choroiditis can occasionally mimic serpiginous choroiditis, much more commonly, Mycobacterium tuberculosis can cause inflammation in a pattern that simulates typical serpiginous choroiditis. Tuberculosis (TB)-associated disease has been called multifocal serpiginoid choroiditis or serpiginous-like choroiditis (see Chapter 13).
Patients with serpiginous-like choroiditis tend to be from countries where TB is endemic or have been exposed to active pulmonary TB. In such cases, results of tuberculin skin testing and the interferon-gamma release assay are usually positive for TB, although the chest x-ray often appears normal. The ocular involvement in TB-related serpiginous-like choroiditis is mostly unilateral, with serpiginoid lesions involving the posterior pole, midperiphery, and periphery but usually sparing the juxtapapillary area until late in the disease. The lesions tend to appear and progress in multiple areas rather than to spread out centrifugally as they do in serpiginous choroiditis. Patients with serpiginous-like choroiditis exhibit a more prominent inflammatory cellular reaction in the vitreous than do patients with serpiginous choroiditis. The disease usually responds to anti-TB treatment, although complete control may take months and corticosteroids may also be needed to control inflammation. (See Chapter 9 for a full discussion of TB-associated uveitis.)
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Akpek EK, Jabs DA, Tessler HH, Joondeph BC, Foster CS. Successful treatment of serpiginous choroiditis with alkylating agents. Ophthalmology. 2002;109(8):1506–1513.
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Bansal R, Gupta A, Gupta V, Dogra MR, Sharma A, Bambery P. Tubercular serpiginous-like choroiditis presenting as multifocal serpiginoid choroiditis. Ophthalmology. 2012;119(11):2334–2342.
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Christmas NJ, Oh KT, Oh DM, Folk JC. Long-term follow-up of patients with serpiginous choroiditis. Retina. 2002;22(5):550–556.
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Nazari Khanamiri H, Rao NA. Serpiginous choroiditis and infectious multifocal serpiginoid choroiditis. Surv Ophthalmol.2013;58(3):203–232.
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Rao NA. Serpiginous choroiditis: autoimmune, herpes, or tuberculosis. [American Academy of Ophthalmology Annual Meeting Video Program.] San Francisco: American Academy of Ophthalmology; 2012. Available at www.aao.org/annual-meeting-video/serpiginous-choroiditis-autoimmune-herpes-tubercul. Accessed September 20, 2018.
Multifocal choroiditis and panuveitis
Multifocal choroiditis and panuveitis (MCP), PIC, and the subretinal fibrosis and uveitis syndrome represent a subset of the white dot syndromes. Some authorities regard them as discrete entities, whereas others view them as a single disease with a variable severity continuum. When the disorders are considered a continuum, the term multifocal choroiditis may be used to describe all the entities, and the presence of fibrosis or panuveitis is then described separately. For this discussion, the traditional nomenclature is used to discuss the three related diseases as discrete entities.
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Essex RW, Wong J, Jampol LM, Dowler J, Bird AC. Idiopathic multifocal choroiditis: a comment on present and past nomenclature. Retina. 2013;33(1):1–4.
Manifestations MCP is an idiopathic inflammatory disorder affecting the choroid, retina, and vitreous. It presents asymmetrically, most often in young women with myopia. Symptoms include floaters, photopsias, enlargement of the physiologic blind spot, and decreased vision. The ophthalmoscopic hallmarks include the presence of multiple old, atrophic lesions that appear as punched-out, white-yellow dots (50–200 μm) in a peripapillary, midperipheral, and anterior equatorial distribution (Fig 9-21).
Acute lesions have a creamier, opaque appearance and develop more discrete borders over time. Varying degrees of anterior segment inflammation and vitritis are uniformly present, which differentiate this condition from OHS or PIC. The lesions are smaller than those present in birdshot chorioretinopathy or APMPPE, are larger than those found in PIC, and evolve into atrophic scars with varying degrees of hyperpigmentation. New lesions may appear, and peripheral chorioretinal streaks and peripapillary pigment changes similar to those present in OHS have been observed. Subretinal fibrosis with RPE clumping is much more common in MCP than in OHS. Structural complications noted at presentation may include cataract, uveitis macular edema, ERM, and CNV and are frequent causes of visual impairment.
Fluorescein angiography shows early hypofluorescence with late staining of acute active lesions, whereas atrophic lesions produce transmission defects (early hyperfluorescence that fades in the late phases of the angiogram). Early hyperfluorescence and late leakage are observed in the presence of macular edema and CNV (Fig 9-22).
As in birdshot chorioretinopathy, ICG angiography reveals multiple midphase hypocyanescent lesions compatible with active choroiditis that are more numerous than those apparent on clinical examination or FA; they are frequently clustered around the optic nerve. This finding may correlate with an enlarged blind spot on visual field testing. The hypofluorescent spots may fade with resolution of the intraocular inflammation.
The most common findings on FAF imaging are punctate hypoautofluorescent spots (≥125 μm) corresponding to multiple areas of chorioretinal atrophy; however, smaller (<125 μm) spots numbering in the hundreds may be seen in the macular and peripapillary regions that are not visible on fundus examination. Some of these lesions will later develop into clinically evident chorioretinal scars (Fig 9-23). Active MCP lesions display hyperautofluorescence that disappears with minimal RPE disruption following antiinflammatory treatment. Fundus autofluorescence findings in MCP suggest that patients have more widespread involvement of the RPE than indicated by other imaging modalities; therefore, FAF may be useful in monitoring response to treatment.
Optical coherence tomography may show drusenlike material beneath the RPE at the site of visible spots that can be associated with more widespread disruption of the overlying outer retina (Fig 9-24). There is also choroidal hyperreflectivity beneath these deposits.
The herpes simplex and Epstein-Barr viruses have been implicated in this disease process; however, a viral etiology has not been proven. Pathologic specimens obtained from eyes with MCP have shown variable findings, ranging from large numbers of B lymphocytes in the choroid to a predominance of T lymphocytes, suggesting that different immune mechanisms may produce a similar clinical picture, and that an initial viral infection may trigger an autoimmune process.
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Yeh S, Forooghian F, Wong WT, et al. Fundus autofluorescence imaging of the white dot syndromes. Arch Ophthalmol. 2010;128(1):46–56.
Diagnosis The diagnosis is one of exclusion, as many other conditions—such as sarcoidosis, syphilis, and TB—may produce lesions similar in appearance to those of MCP.
Treatment Systemic and periocular corticosteroids may be effective for the treatment of macular edema and have been shown to induce regression of CNV in some patients. Corticosteroid-sparing strategies with IMT are frequently required because of the chronic, recurrent nature of the inflammation; these treatments have been successful in achieving not only inflammatory quiescence but also an 83% reduction in the risk of posterior pole complications (macular edema, ERM, and CNV) and a 92% reduction in the risk of vision loss to 20/200 or worse in affected eyes. The intravitreal fluocinolone acetonide implant is also a potential treatment option for patients who cannot tolerate systemic therapy. Intravitreal anti-VEGF drugs are important adjuncts for the treatment of CNV. However, active inflammation can stimulate neovascularization and blunt the effectiveness of these treatments, so it is important that inflammation also be well controlled. This concept applies to any uveitic entity complicated by CNV.
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Haen SP, Spaide RF. Fundus autofluorescence in multifocal choroiditis and panuveitis. Am J Ophthalmol. 2008;145(5):847–853.
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Michel SS, Ekong A, Baltatzis S, Foster CS. Multifocal choroiditis and panuveitis: immunomodulatory therapy. Ophthalmology. 2002;109(2):378–383.
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Spaide RF, Goldberg N, Freund KB. Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging. Retina. 2013;33(7):1315–1324.
Prognosis The visual prognosis is guarded, with permanent vision loss in at least 1 eye occurring in up to 75% of patients as a result of the complications associated with chronic, recurrent inflammation. In one study, the incidence of vision loss to 20/200 or worse was 12% per eye-year in the affected eye.
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Thorne JE, Wittenberg S, Jabs DA, et al. Multifocal choroiditis with panuveitis: incidence of ocular complications and loss of visual acuity. Ophthalmology. 2006;113(12):2310–2316.
Punctate inner choroiditis
Punctate inner choroiditis is an idiopathic inflammatory disorder that, like MCP, predominantly occurs in otherwise healthy myopic white women, but it presents at a younger median age (29 vs 45 years, respectively).
Manifestations Patients with PIC can present with metamorphopsia, paracentral scotomata, photopsias, and asymmetric loss of central acuity. In contrast to the lesions of MCP, those of PIC are smaller (100–200 μm), rarely extend to the midperiphery, and are never associated with vitritis (Fig 9-25). They progress to atrophic scars, sometimes leaving a halo of pigmentation, and appear deeper and more punched-out than those of MCP. Macular edema is rarely seen in this condition, although serous retinal detachments may be found over confluent PIC lesions. With the exception of CNV, patients with PIC have few structural complications (cataract, macular edema, or ERM) at presentation, unlike patients with MCP, a difference undoubtedly related to the presence of chronic intraocular inflammation in MCP. Choroidal neovascularization, a common vision-threatening complication in both entities, may be more frequent at presentation in patients with PIC (79%) than with MCP (28%), but patients with MCP are more likely to have bilateral visual impairment of visual acuity 20/50 or worse.
Fluorescein angiography studies in patients with PIC show early hypofluorescence of the inflammatory lesions with late staining, although early hyperfluorescence can also occur, especially if CNV is present (Figs 9-26, 9-27). Indocyanine green angiography displays midphase hypocyanescence throughout the posterior pole in a peripapillary distribution that may exceed the lesions apparent on FA and clinical examination (Fig 9-28); these imaging studies may be employed to delineate disease extent and monitor its activity. OCT findings are similar to those seen in MCP and may be useful in identifying CNV (Fig 9-29).
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Kedhar SR, Thorne JE, Wittenberg S, Dunn JP, Jabs DA. Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation. Retina. 2007;27(9):1174–1179.
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Leung TG, Moradi A, Liu D, et al. Clinical features and incidence rate of ocular complications in punctate inner choroidopathy. Retina. 2014;34(8):1666–1674.
Treatment Treatment should target both inflammation and its complications. Options include local and systemic corticosteroids and IMT. Depending on disease severity, some eyes may be carefully observed without treatment. Intravitreal anti-VEGF drugs may be considered in eyes with CNV. The visual prognosis is favorable in eyes without CNV involving the foveal center.
Subretinal fibrosis and uveitis syndrome
Subretinal fibrosis and uveitis syndrome is an extremely uncommon panuveitis of unknown etiology affecting otherwise healthy myopic females between the ages of 20 and 40 years.
Manifestations and differential diagnosis Significant anterior segment inflammation and mild to moderate vitritis are typically present bilaterally, with white-yellow lesions (50–500 μm) located in the posterior pole to midperiphery at the level of the RPE. These lesions may fade without RPE alterations, become atrophic, or enlarge and coalesce into large, white, stellate zones of subretinal fibrosis (Figs 9-30, 9-31). Serous neurosensory retinal detachment, macular edema, and CNV may also be observed.
Histopathologic studies of eyes with this disease reveal a lymphocytic granulomatous infiltration of the choroid with marked gliosis of the retina and subretinal fibrosis. It has been theorized that this is an immune-driven destruction of RPE, which is replaced by fibrotic tissue.
Fluorescein angiography shows multiple areas of blocked choroidal fluorescence and hyperfluorescence in the early stages of the study; in the late phase, staining of the lesions without leakage is observed. Optical coherence tomography shows variable retinal edema, subretinal fluid, and subretinal fibrosis. The differential diagnosis includes sarcoidosis, OHS, APMPPE, syphilis, TB, birdshot chorioretinopathy, pathologic myopia, sympathetic ophthalmia, and toxoplasmosis.
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Kim MK, Chan CC, Belfort R Jr, et al. Histopathologic and immunohistopathologic features of subretinal fibrosis and uveitis syndrome. Am J Ophthalmol. 1987;104(1):15–23.
Disease course and treatment The course of the disease is marked by chronic recurrent inflammation, and the visual prognosis is guarded. Treatment with systemic corticosteroids and IMT has shown variable success. Recent reports suggest that biologic agents may have some efficacy.
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Adán A, Sanmarti R, Burés A, Casaroli-Marano RP. Successful treatment with infliximab in a patient with diffuse subretinal fibrosis syndrome. Am J Ophthalmol. 2007;143(3):533–534.
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Brown J Jr, Folk JC, Reddy CV, Kimura AE. Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome. Ophthalmology. 1996;103(7):1100–1105.
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Cornish KS, Kuffova L, Forrester JV. Treatment of diffuse subretinal fibrosis uveitis with rituximab. Br J Ophthalmol. 2015;99(2):153–154.
Multiple evanescent white dot syndrome
Multiple evanescent white dot syndrome (MEWDS) is an uncommon idiopathic inflammatory condition of the retina that typically affects otherwise healthy, young, moderately myopic females in the second to fourth decades of life.
Manifestations In MEWDS, patients present with acute, unilateral decreased vision, photopsias, and central or paracentral scotomata. An antecedent viral prodrome occurs in approximately one-third of cases. Funduscopy during the acute phase of the disease reveals multiple, discrete, white-to-orange spots (100–200 μm) at the level of the RPE or deep retina, typically in a perifoveal location (Fig 9-32), but can be found in the midperiphery and peripheral retina as well. These spots are transitory and frequently missed. A granular macular pigmentary change is usually present—a pathognomonic finding that can be very useful in making the diagnosis when patients present with symptoms after the white dots have faded. Bilateral disease has been reported in rare cases. There may be variable degrees of vitreous inflammation, mild blurring of the optic disc, and, in rare instances, isolated vascular sheathing.
Fluorescein angiography reveals characteristic, late-staining punctate hyperfluorescent lesions in a wreath-like configuration surrounding the fovea (Fig 9-33).
Fundus autofluorescence imaging shows hyperfluorescent spots corresponding to and exceeding those found on clinical examination (Fig 9-34) and may also show small, punctate hypoautofluorescent areas localized around the optic disc and posterior pole. The lesions on FAF may show delayed resolution than clinically apparent lesions. Indocyanine green angiography shows multiple hypocyanescent lesions that are more numerous than those apparent on clinical examination or FA and that typically fade with resolution of the disease (Fig 9-35).
Visual field abnormalities are variable and include generalized depression, paracentral or peripheral scotomata, and enlargement of the blind spot. The ERG reveals diminished a-wave and early receptor potential (ERP) amplitudes, both of which are reversible. Results of the multifocal ERG (mfERG) and electro-oculogram (EOG) localize the disease process to the RPE–photoreceptor complex rather than to the choroid.
Further support for localization of the disease process to the RPE–photoreceptor complex comes from the demonstration of abnormal photoreceptor inner/outer segment line (ellipsoid zone) reflectivity on spectral-domain optical coherence tomography (SD-OCT), the corresponding findings of hypocyanescent spots visualized on ICG angiography, and changes in microperimetry sensitivity (Fig 9-36). These abnormalities completely resolve during the course of the disease.
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Hangai M, Fujimoto M, Yoshimura N. Features and function of multiple evanescent white dot syndrome. Arch Ophthalmol. 2009;127(10):1307–1313.
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Thomas BJ, Albini TA, Flynn HW Jr. Multiple evanescent white dot syndrome: multimodal imaging and correlation with proposed pathophysiology. Ophthalmic Surg Lasers Imaging Retina. 2013;44(6):584–587.
Prognosis The prognosis is excellent, with recovery of vision within 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.
Disease associations The syndrome has been reported in association with MCP, acute zonal occult outer retinopathy, and acute macular neuroretinopathy (AMN). The last is a rare condition that affects otherwise healthy young women. It is characterized by the acute onset of visual impairment and multiple scotomata that correspond to reddish-brown, flat, wedge-shaped lesions in the macula that are best appreciated on infrared imaging. Associated risk factors suggest microvascular etiology. AMN has been associated with nonspecific febrile illness, use of oral contraceptives, and epinephrine/ephedrine use.
Acute retinal pigment epitheliitis
Acute retinal pigment epitheliitis, or Krill disease, is a benign, self-limited inflammatory disorder of the RPE of unknown etiology. It typically presents in otherwise healthy young adults between the ages of 16 and 40 years with acute unilateral vision loss, central metamorphopsia, and scotomata. No treatment is required, as the lesions resolve without sequelae over 6–12 weeks.
Manifestations Ophthalmoscopic findings include clusters of small, discrete, hyperpigmented lesions, typically with a yellow halo, in the posterior pole, without associated vitritis (Fig 9-37A). Fluorescein angiography shows early hyperfluorescence of the pinpoint dots with a surrounding halo of hyperfluorescence and late staining (Fig 9-37B). Fundus autofluorescence results have been variable, with some reports of normal autofluorescence and some with hypoautofluorescent spots, corresponding to the fundus lesions. Visual field testing shows central scotomata. Abnormal EOG findings, in the setting of a normal ERG, localize the disease process to the RPE. Optical coherence tomography shows transient disruption of the ellipsoid zone, along with wider disruption of the RPE inner band.
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Aydoğan T, Güney E, Akçay Bİ, Bozkurt TK, Ünlü C, Ergin A. Acute retinal pigment epitheliitis: spectral domain optical coherence tomography, fluorescein angiography, and autofluorescence findings. Case Rep Med. 2015;2015:149497.
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Baillif S, Wolff B, Paoli V, Gastaud P, Mauget-Faÿsse M. Retinal fluorescein and indocyanine green angiography and spectral-domain optical coherence tomography findings in acute retinal pigment epitheliitis. Retina. 2011;31(6):1156–1163.
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Cho HJ, Han SY, Cho SW, et al. Acute retinal pigment epitheliitis: spectral-domain optical coherence tomography findings in 18 cases. Invest Ophthalmol Vis Sci. 2014;55(5):3314–3319.
Acute zonal occult outer retinopathy
Acute zonal occult outer retinopathy (AZOOR) is typified by acute loss of 1 or more zones of outer retinal function associated with photopsias and visual field loss, often in the setting of a normal-appearing fundus. Patients are typically young, myopic women who present with acute unilateral visual disturbances, sometimes associated with a mild vitritis (50%), and visual acuity in the 20/40 range.
Manifestations Electrophysiological studies demonstrate abnormality not only at the photoreceptor–RPE complex but also at the inner retinal level. Essentially, this dysfunction consists of a delayed 30-Hz flicker ERG and a reduction in the EOG light rise, which, when present with classic symptomatology, may be helpful diagnostically. Visual field changes include paracentral defects and enlargement of the blind spot, even in the absence of any visible fundus changes.
With disease progression, subtle RPE changes may develop, with depigmentation in areas of vision loss (Fig 9-38). Occasionally a demarcation line can be seen at the edge of active disease expansion. In later stages of disease, vessel attenuation, late pigment migration, and focal perivenous sheathing may be seen.
Optical coherence tomography demonstrates areas of loss or irregularity of the ellipsoid zone, corresponding to the visual field defects, and suggests that photoreceptor outer segment dysfunction and/or degeneration is the primary lesion in AZOOR (Fig 9-39).
During the early disease stages, FA findings may be essentially normal, showing only a prolonged retinal circulation time. With disease progression, however, diffuse areas of hyperfluorescence due to window defects, corresponding to zones of RPE derangement, may develop.
Fundus autofluorescence imaging may be particularly useful in monitoring patients with AZOOR, as it reveals conspicuous areas of central hypoautofluorescence corresponding to RPE and choriocapillary atrophy; peripheral hyperautofluorescence is found at the border of the expanding lesion, due to the presence of lipofuscin-laden cells that presage RPE cell death (Fig 9-40). There may also be diffuse zones of speckled hyperautofluorescence in areas of subacute disease activity. These evolve into areas of speckled hypoautofluorescence as atrophic changes ensue.
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Francis PJ, Marinescu A, Fitzke FW, Bird AC, Holder GE. Acute zonal occult outer retinopathy: towards a set of diagnostic criteria. Br J Ophthalmol. 2005;89(1):70–73.
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Mrejen S, Khan S, Gallego-Pinazo R, Jampol LM, Yannuzzi LA. Acute zonal occult outer retinopathy: a classification based on multimodal imaging. JAMA Ophthalmol. 2014;132(9):1089–1098.
Disease course and differential diagnosis With extended follow-up, most patients are found to develop bilateral disease, with recurrences in approximately one-third. Visual field abnormalities typically stabilize in approximately 75% of patients and partially improve in about 25%. Visual acuity remains in the 20/40 range in 68% of patients; however, legal blindness has been reported in as many as 18% with long-term follow-up.
Cancer-associated retinopathy and retinitis pigmentosa should be considered in the differential diagnosis of AZOOR. It is unclear whether treatment with systemic corticosteroids or IMT alters the disease course or vision outcome.
The considerable similarities between AZOOR and other white dot syndromes—namely, 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. Although an infectious etiology has been postulated, systemic autoimmune disease has been observed in 28% of these patients, supporting the notion that these diseases are of an inflammatory etiology and arise in patients with a common non–disease-specific genetic background, possibly triggered by some exogenous agent.
Autoimmune retinopathy
Autoimmune retinopathy (AIR) can be broadly categorized into paraneoplastic retinopathy and nonparaneoplastic retinopathy. Paraneoplastic retinopathy can be further subdivided into cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). AIR is a rare and poorly understood immune-mediated disease that is characterized by antiretinal antibodies, photoreceptor dysfunction, and resultant visual field loss.
Manifestations AIR typically presents with progressive, bilateral vision loss, scotomata, photopsias, nyctalopia, and dyschromatopsias. About 50% of patients with nonparaneoplastic AIR will have a systemic autoimmune disease. The fundus may initially appear normal, but arteriolar attenuation, RPE mottling, and diffuse retinal and optic nerve atrophy may develop as the disease progresses. Inflammatory cells are rare or absent. Both visual field testing and ERG are typically abnormal, often markedly so. While the ERG in CAR typically demonstrates depressed cone responses, the ERG in MAR most commonly shows a normal photoreceptor response, followed by an attenuated b-wave. Visual prognosis is variable but generally poor.
Pathophysiology and diagnosis The pathophysiology of AIR is thought to be related to an immune response to retinal proteins, some of which have been identified as potential targets. Recoverin, a photoreceptor-specific calcium-binding protein, is the most commonly associated antibody target in paraneoplastic retinopathy but has also been implicated in nonparaneoplastic retinopathy. The role of testing for antiretinal antibodies is unclear at this point, as these antibodies are nonspecific, and it is not well understood which of them cause disease. Additionally, no standardized laboratory detection techniques for antiretinal antibodies exist at this time, so test results between laboratories may vary widely.
The diagnosis is one of exclusion; importantly, workup should include a thorough search for malignancy. The most common malignancy associated with CAR is small cell lung cancer.
Treatment As with many other rare diseases, the treatment for AIR is not well established and based primarily on anecdotal evidence. Corticosteroids and nonbiologic IMT are generally first-line therapy, although randomized, controlled trials are needed to determine whether these treatments are efficacious. Biologic agents and intravenous immunoglobulin have also been used in nonparaneoplastic AIR. Refer also to discussion of paraneoplastic and autoimmune retinopathies in BCSC Section 5, Neuro-Ophthalmology, and BCSC Section 12, Retina and Vitreous.
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Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009;127(4):390–397.
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Fox AR, Gordon LK, Heckenlively JR, et al. Consensus on the diagnosis and management of nonparaneoplastic autoimmune retinopathy using a modified Delphi approach. Am J Ophthalmol. 2016;168:183–190.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.