White Dot Syndromes
ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY
Céline Terrada
Bahram Bodaghi
Don Gass, MD, first described acute posterior multifocal placoid pigment epitheliopathy (APMPPE or AMPPE) in 1968. The clinical presentation is usually characterized by multiple, bilateral, cream-colored, placoid lesions at the level of the outer retina/retinal pigment epithelium (RPE). It is caused by ischemic changes occurring within the choriocapillaris.
Epidemiology and Etiology
• It predominantly occurs in young individuals that are in the second to fourth decades of life.
• It affects both men and women equally.
• APMPPE is usually bilateral, but it can be quite asymmetric, and the second eye may not become involved for several weeks after the first eye.
• APMPPE is idiopathic, but it has been associated with mumps, secondary syphilis, Lyme disease, streptococcal group A infection, and hepatitis B virus vaccination.
• The disease has also been called acute multifocal ischemic choroidopathy.
Symptoms
• Patients complain of visual disturbances, blurred vision, photopsias, and scotomas.
• The degree of visual impairment can be variable, depending upon the location of the lesions.
• Visual loss is caused by macular involvement, and there is usually a gradual improvement in vision over the course of a few weeks.
Signs
• Systemic signs include a flu-like syndrome and headache.
• Episcleritis, scleritis, anterior uveitis, vitreous haze, papillitis, and retinal vasculitis can occur.
• On fundus examination during the acute phase, the lesions are characterized by multiple yellow-white deep plaques, ranging from one-half to one optic disc diameter in size (Figs. 8-1 and 8-2).
• Lesions appear to be at the level of the outer retina and the RPE, even though the ischemic alterations involve the choriocapillaris.
• After a few days, healing starts at the center of the plaques, leaving a pigmented scar or mottled RPE.
• New lesions can appear in the posterior pole within the first 3 weeks of disease onset.
• APMPPE may be associated with serous retinal detachments, mimicking Vogt-Koyanagi-Harada (VKH) disease.
Differential Diagnosis
• White dot syndromes: presumed ocular histoplasmosis syndrome (OHS), punctate inner choroidopathy (PIC), multifocal choroiditis (MFC), subretinal fibrosis/uveitis syndrome
• Sarcoidosis, syphilis, tuberculosis (TB)
• VKH syndrome
• Sympathetic ophthalmia
• Serpiginous choroiditis
• Birdshot chorioretinopathy
Diagnostic Evaluation
• Fluorescein angiography (FA)
Acute stage: Early and intermediate hypofluorescence followed by staining and pooling in the late frames
Late Stage
▶ Delay in choriocapillaris circulation, hyperfluorescence in early and late frames without leakage (window defect)
• Indocyanine green angiography (ICGA) shows hypofluorescence during the intermediate and late transit frames.
• Optical coherence tomography (OCT) demonstrates nodular hyperreflectivity at the level of the photoreceptors and RPE.
• Visual field testing objectively identifies the scotomata the patients’ report.
• Interestingly, the electroretinogram (ERG) and electrooculogram (EOG) are normal.
Treatment
• Usually no treatment is required.
• For patients with macular involvement, systemic corticosteroids can be initiated to hasten visual recovery, and immunosuppressive agents are rarely required.
Prognosis
• The prognosis is good with a visual acuity of 20/25 after 6 months although small scotomas may persist.
• Recurrences or exacerbations are rare.
• Macular localization may be more aggressive.
• Subretinal neovascularization remains a rare complication.
REFERENCES
Gass JD. Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1968;80:177-185.
Jones BE, Jampol LM, Yannuzzi LA, et al. Relentless placoid chorioretinitis: a new entity or an unusual variant of serpiginous chorioretinitis? Arch Ophthalmol. 2000;118:931-938.
Scarinci F, Fawzi AA, Shaarawy A, Simonett JM, Jampol LM. Longitudinal quantitative evaluation of outer retinal lesions in acute posterior multifocal placoid pigment epitheliopathy using optical coherence tomography. Retina. 2017;37:851-857.
Souka AA, Hillenkamp J, Gora F, Gabel VP, Framme C. Correlation between optical coherence tomography and autofluorescence in acute posterior multifocal placoid pigment epitheliopathy. Graefes Arch Clin Exp Ophthalmol. 2006;244:1219-1223.
 FIGURE 8-1. Acute posterior multifocal placoid pigment epitheliopathy. Color (A) and red-free (B) fundus photographs showing multiple, deep yellow-white placoid lesions. Fluorescein angiography (FA). The early frame shows hypofluorescence (C), and the late frame shows staining and pooling (D). ICGA demonstrating hypofluorescence in both the intermediate (E) and the late (F) frames and shows more lesions than are visible clinically. ICGA, indocyanine green angiography. |
 FIGURE 8-2. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Color fundus photographs in a case of APMPPE with bilateral involvement. APMPPE, acute posterior multifocal placoid pigment epitheliopathy. |
SERPIGINOUS CHORIORETINOPATHY
Céline Terrada
Bahram Bodaghi
Serpiginous choroidopathy, also known as serpiginous choroiditis, geographic choroidopathy, or geographic helicoid peripapillary choroidopathy, is an inflammatory disorder involving the choroid, the choriocapillaris, and the RPE. It gets its name because of the serpentine pattern it develops as it progresses from the optic disc.
Epidemiology and Etiology
• Serpiginous choroiditis is a rare cause of posterior uveitis (<5% of cases in uveitis clinics), and usually occurs in the fourth to seventh decades of life.
• The disease is a chronic, progressive, recurrent inflammatory or infectious condition.
• Most patients present with unilateral vision loss, but on examination usually have bilateral disease.
• Males are affected slightly more often than females.
• The geographic distribution is worldwide.
• The etiology is unknown, but autoimmune and infectious hypothesis have been proposed (herpes viruses and TB).
• There is no human leukocyte antigen (HLA) association.
Symptoms
• Patients without macular alterations and choroidal neovascularization (CNV) present with photopsias and decreased vision.
• Patients with macular involvement or CNV are usually symptomatic and may have metamorphopsia, scotoma, and sudden vision loss.
Signs
• The main finding is a peripapillary choroiditis that has a characteristic serpentine appearance. In some cases, it involves the macula while sparing the peripapillary region (Figs. 8-3, 8-4 and 8-5).
• The lesions are typically not multifocal in contrast to ampiginous or tuberculous serpiginous-like choroiditis (TB-SLC).
• The areas of active choroiditis appear gray or white-yellow. They often appear to elevate the overlying retina.
• The active lesions spontaneously resolve after 6 to 8 weeks and result in atrophy of the RPE and choriocapillaris. Inactive lesions appear as pigmented and atrophic scars that are usually connected to the optic disc.
• Patients may have recurrences months to years after the initial lesions, and the reactivation occurs at the edges of the previous lesions.
• One-third of affected individuals have mild inflammatory cells in the posterior vitreous. Rarely is anterior segment inflammation seen.
• CNV may occur in up to 35% of cases.
• Occasionally, patients may have RPE and serous retinal detachments.
Differential Diagnosis
• White dot syndromes: APMPPE or ampiginous choroiditis (which have a multifocal presentation of lesions)
• Tuberculosis-Serpiginous-like Choroiditis TB-SLC: Patients with TB-SLC come from areas in which TB is endemic, have significant vitritis, and usually have multifocal lesions in the periphery and posterior pole. Patients with serpiginous choroiditis have little to no vitritis, have bilateral involvement, and have a larger, more confluent lesion, which extends mainly from the disc and usually is confined to the posterior pole.
• Sarcoidosis
• Sympathetic ophthalmia
• Syphilis
• Subretinal fibrosis/uveitis syndrome
• VKH syndrome
Diagnostic Evaluation
• Fundus photography is helpful to follow disease progression.
• FA
If no CNV is present:
▶ Areas of acute choroiditis demonstrate early hypofluorescence with blockage and diffuse late staining and leakage of dye.
▶ Inactive, atrophic lesions appear as a window effect with a late hyperfluorescent border. Disappearance of the hyperfluorescent border suggests disease recurrence.
CNV in these cases shows the typical signs of a classic CNV: well-defined early hyperfluorescence with leakage in the late phase.
• ICGA
Hypoperfusion of the choroid is more extensive than shown by FA. It appears as a primary inflammatory choriocapillaropathy.
Lesions not seen on FA can be apparent on ICGA.
• OCT can identify:
Macular edema in rare cases
Areas of retinal atrophy (which appears to be secondary to atrophy of the RPE and choriocapillaris)
Visual fields can be useful to identify scotomas, which can be absolute and/or relative. The visual field deficit can vary over time.
• It is important to exclude TB with a tuberculin skin test (purified protein derivative), chest radiograph, and/or interferon-gamma release assays (e.g., QuantiFERON-TB Gold), especially before any immunosuppressive therapy is instituted.
Treatment
• Patients with an active inflammatory component benefit from treatment.
Corticosteroids: High-dose systemic steroids, as well as periocular steroids, can be used to control acute inflammation.
Immunomodulatory or immunosuppressive agents
▶ Should be considered in refractory cases or for individuals intolerant to corticosteroids
▶ Mycophenolate mofetil, azathioprine, cyclosporine A, and cyclophosphamide have been used in severe cases, and some investigators have recommended triple therapy with azathioprine, cyclosporine, and oral prednisone.
▶ Treatment must be adapted to the severity of each situation and must take into account the potential side effects.
• Active disease with CNV: Corticosteroids and immunosuppressive agents are usually used along with other adjunctive measures.
Extrafoveal: focal laser, anti-vascular endothelial growth factor (VEGF) therapy
Juxtafoveal: anti-VEGF therapy, photodynamic therapy, focal laser
Subfoveal: anti-VEGF therapy, photodynamic therapy
Peripapillary: focal laser for small lesions, anti-VEGF therapy
Prognosis
• The prognosis depends on macular involvement and complications, including CNV formation.
• Unilateral or bilateral severe visual loss may be observed in 25% of cases.
REFERENCES
Akpek EK, Jabs DA, Tessler HH, Joondeph BC, Foster CS. Successful treatment of serpiginous choroiditis with alkylating agents. Ophthalmology. 2002;109:1506-1513.
Cardillo-Piccolino F, Grosso A, Savini E. Fundus auto-fluorescence in serpiginous choroiditis. Graefes Arch Clin Exp Ophthalmol. 2009;247:179-185.
Gupta V, Gupta A, Rao NA. Intraocular tuberculosis: an update. Surv Ophthalmol. 2007;52:561-587.
Song MH, Roh YJ. Intravitreal ranibizumab for choroidal neovascularization in serpiginous choroiditis. Eye (Lond). 2009;23(9):1873-1875.
Vasconcelos-Santos DV, Rao PK, Davies JB, Sohn EH, Rao NA. Clinical features of tuberculous serpiginouslike choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol. 2010;128:853-858.
Venkatesh P, Tayade A, Gogia V, Gupta S, Shah BM, Vohra R. Short-term intensive immunosuppression: a randomized, three-arm study of intravenous pulse methylprednisolone and cyclophosphamide in macular serpiginous choroiditis. Ocul Immunol Inflamm. 2016:1-8.
 FIGURE 8-3. Serpiginous chorioretinopathy. Color fundus photograph (A) and red-free photo (B) showing the sequelae of choroiditis. Note the geographic pigmented and atrophic scars connected to the optic disc. C. The early frame of the fluorescein angiogram showing hypofluorescence likely because of limited perfusion. D. The late frame demonstrating staining with a hyperfluorescent border, characteristic of inactive serpiginous. |
 FIGURE 8-4. Serpiginous chorioretinopathy. This patient with a previous diagnosis of serpiginous chorioretinopathy came in with further vision changes. A. The color photograph reveals darker areas consistent with previous scarring, as well as yellow areas of active chorioretinitis. B. The early frame of the fluorescein angiogram shows RPE window defects in the area of previous scarring. The new lesions block early. C. The new lesions stain in the late frames of the angiogram. RPE, retinal pigment epithelium. (Courtesy of MidAtlantic Retina, the Retina Service of Wills Eye Hospital.) |
 FIGURE 8-5. A 27-year-old woman had serpiginous choroiditis that progressed despite numerous immunosuppressive agents. Her vision was 20/400 in this eye. (Courtesy of Sunir Garg, MD.) |
MULTIPLE EVANESCENT WHITE DOT SYNDROME
Céline Terrada
Bahram Bodaghi
Multiple evanescent white dot syndrome (MEWDS) is a rare, acute, multifocal inflammatory retinochoroidopathy. It spontaneously resolves with an excellent visual outcome.
Epidemiology and Etiology
• It occurs mainly in young, healthy young women in the second to fourth decades of life.
• The etiology remains unknown; however, an infectious etiology has been suspected because one-third of patients have a viral prodrome.
• Patients often have mild myopia.
Symptoms
• Photopsias, often in the temporal visual field
• Blurry vision, with visual acuity ranging from 20/20 to 20/400
• Central microscotoma
Signs
• Multiple small dots in the fundus at the level of the outer retina and the RPE (Figs. 8-6, 8-7 and 8-8)
• An orange granularity of the fovea
• No anterior segment inflammation, but some patients have a mild vitritis.
• A mild afferent pupillary defect may occur.
• Optic disc edema
• Usually monophasic, unilateral, and self-limited
Differential Diagnosis
• Inflammatory white dot syndromes
• Acute idiopathic blind spot enlargement syndrome (AIBSES)
• Acute zonal occult outer retinopathy (AZOOR)
Diagnostic Evaluation
• White dots
FA demonstrates both early and late hyperfluorescence of the dots and late staining of the optic disc.
ICGA
▶ Intermediate/late hypofluorescent spots scattered throughout the posterior pole and midperiphery.
▶ The lesions are more numerous on ICGA than those seen clinically or on FA.
▶ Intermediate transient pinpoints hyperfluorescence.
Fundus autofluorescence
▶ In the acute phase of the disease, there are small areas of hypoautofluorescence around the disc and posterior pole and hyperfluorescent areas corresponding to the white dots. These spots evolve over time and may persist or fade.
▶ The lesions are more numerous than those seen clinically.
OCT demonstrates defects located at the level of the outer retina and RPE. The areas corresponding to the white spots show interruption or signal attenuation of the photoreceptor inner segment/outer segment band.
• Granularity of the macula
FA shows hyperfluorescence throughout the angiogram.
ICGA demonstrates intermediate/late hypofluorescence.
Fundus autofluorescence shows pinpoint areas of increased or decreased autofluorescence.
Treatment
• Observation as MEWDS spontaneously resolves over a period of several weeks to months with return of normal vision in nearly all patients.
Prognosis
• Very good
• Mild pigmentary changes may be seen after recovery, and some patients will have persistent visual field or color deficits.
• Submacular CNV may rarely develop.
 FIGURE 8-6. Multiple evanescent white dot syndrome (MEWDS). Color photograph showing numerous small, yellow-white spots scattered throughout the posterior pole in a patient with MEWDS. |
REFERENCES
Dell’Omo R, Mantovani A, Wong R, Konstantopoulou K, Kulwant S, Pavesio CE. Natural evolution of fundus autofluorescence findings in multiple evanescent white dot syndrome. Retina. 2010;30:1479-1487.
Jampol LM, Sieving PA, Pugh D, Fishman GA, Gilbert H. Multiple evanescent white dot syndrome. I. Clinical findings. Arch Ophthalmol. 1984;102:671-674.
Nguyen MH, Witkin AJ, Reichel E, et al. Microstructural abnormalities in MEWDS demonstrated by ultrahigh resolution optical coherence tomography. Retina. 2007;27:414-418.
Pichi F, Srvivastava SK, Chexal S, et al. En face optical coherence tomography and optical coherence tomography angiography of multiple evanescent white dot syndrome: new insights into pathogenesis. Retina. 2016;36 suppl 1:S178-S188.
 FIGURE 8-7. Multiple evanescent white dot syndrome (MEWDS). FA early (A) and late (B) frames showing hyperfluorescence and disc staining. C. Late frame ICGA showing numerous hypofluorescent spots. Note there are more spots seen on ICGA than on FA. FA, fluorescein angiogram; ICGA, indocyanine green angiography. |
 FIGURE 8-8. Multiple evanescent white dot syndrome (MEWDS). SD-OCT in MEWDS patient illustrating interruption or signal attenuation of the photoreceptor inner segment/outer segment band (arrows). SD-OCT, spectral-domain optical coherence tomography.s |
MULTIFOCAL CHOROIDITIS/SUBRETINAL FIBROSIS AND UVEITIS SYNDROME
Céline Terrada
Bahram Bodaghi
Multifocal choroiditis and panuveitis (MFCP) syndrome was described by Dreyer and Gass in 1984. It is a rare, idiopathic, inflammatory choroidal disease, mimicking presumed OHS that affects otherwise healthy young adults. MFCP, PIC, MEWDS, and AIBSES may constitute different clinical presentations of the same disease, but this hypothesis has not been validated.
Epidemiology and Etiology
• The disease usually affects Caucasian adults (80% of cases).
• MFCP usually occurs in the third to fourth decades of life, and affects women more than men (approximately 3:1), and most patients have some degree of myopia.
• The disease is bilateral in approximately 80% of cases, but it can be asymmetric or unilateral at presentation.
• It occurs worldwide.
• There are usually no other systemic findings.
• There is no well-defined HLA association. It may be virally induced.
Symptoms
• Patients describe photopsias, floaters, and/or an enlarged blind spot; rarely, some patients may remain asymptomatic.
• With macular involvement or submacular CNV membrane (CNVM) formation, patients describe metamorphopsia, subjective scotomas, and/or sudden central vision loss.
Signs
• Anterior chamber flare and cells are variable in intensity but are usually mild.
• Vitreous haze is common and is useful to distinguish MFC from ocular histoplasmosis.
• Multiple choroidal lesions (20 to 100) are randomly distributed throughout the posterior pole and midperiphery. Active lesions have a “creamy” appearance, whereas older lesions appear atrophic and can become pigmented at their edges. The lesions appear to be at the level of the RPE and choroid (Figs. 8-9, 8-10, 8-11 and 8-12).
• The lesion size ranges from 50 to 350 µm in diameter. They can enlarge and become coalescent.
• CNV is present in 30% of cases. CNV is characterized by the presence of subretinal fluid, subretinal hemorrhage, and subretinal exudate.
• Cystoid macular edema (CME), epiretinal membrane (ERM), optic disc edema, enlarged blind spots, and peripapillary scarring also occur.
• Subretinal fibrosis may link the atrophic scars and is probably because of subclinical progression of the disease.
Differential Diagnosis
• White dot syndromes
Ocular histoplasmosis: Unlike MFC, OHS does not have anterior uveitis or vitritis.
PIC: Many feel that this is a variant of MFC. In PIC, the lesions tend to be deeper and more punched out, and these patients have less vitritis.
Birdshot retinochoroidopathy: These patients are usually HLA-A29 positive, are older, and have larger and less discrete lesions.
• Sarcoidosis, syphilis, TB
• Serpiginous choroiditis
• Subretinal fibrosis/uveitis syndrome
• Sympathetic ophthalmia
• VKH syndrome
Diagnostic Evaluation
• FA
Acute choroiditis appears as early hypofluorescence with staining in the late frames.
Late (chronic) choroiditis has early hyperfluorescence that persists in the late frames (window defect).
Staining of the optic disc and vessels
CME
If a CNV is present, there is well-defined early hyperfluorescence with late leakage.
• ICGA
Large and small hypofluorescent inflammatory lesions may cluster around the disc.
There are more lesions on ICGA than are seen clinically.
• Fundus autofluorescence shows hypoautofluorescent scars.
The larger lesions (>125 µm) appear as atrophic scars.
There are many smaller lesions (<125 µm) that are not clinically apparent.
• OCT demonstrates nodular hyperreflectivity at the level of the photoreceptors and RPE.
• Visual field testing objectively identifies the areas of visual field loss, and periodic testing may help to monitor disease progression.
• ERG findings are often normal or mildly depressed and are nonspecific. Multifocal ERG can show diffuse depression in addition to focal areas of greater depression, which corresponds to the scotomas on the visual field.
Treatment
• Uveitic component
Corticosteroids
▶ Systemic corticosteroids are effective to control acute inflammation.
▶ Periocular and intravitreal injections and sustained-release devices may be useful.
Immunomodulatory therapy (IMT)
▶ Given the chronic nature of MFC, consideration should be given to IMT, especially in cases of inflammation which cannot be controlled with low-dose steroids or for patients who are intolerant to corticosteroids.
▶ Methotrexate, mycophenolate mofetil, and azathioprine have been used with success.
▶ IMT has been found to greatly reduce the risk of macular complications, including CME, ERM, and CNV formation.
• CNV: Corticosteroids and IMT may reduce recurrences by controlling the inflammatory state.
Extrafoveal CVNM can be treated with focal laser.
Juxtafoveal and subfoveal CNVM have been treated with anti-VEGF agents, photodynamic therapy, and intravitreal triamcinolone injection. Submacular surgery may still be useful in cases with vision worse than 20/100 that did not respond to other treatments.
Peripapillary CNV may be treated with focal laser for small lesions as well as anti-VEGF therapy.
Spontaneous resolution of the active neovascularization has been reported.
Prognosis
• Seventy-five percent of patients develop permanent visual loss in at least one eye due to subfoveal lesions, CNVM, chronic CME, or subretinal fibrosis.
• Therapy with systemic corticosteroids and IMT has improved the prognosis:
Eighty-three percent reduction in risk of macular complications
Ninety-two percent reduction in the risk of developing vision loss to less than 20/200 in the affected eye
REFERENCES
Cheng L, Chen X, Weng S, et al. Spectral-domain optical coherence tomography angiography findings in multifocal choroiditis with active lesions. Am J Ophthalmol. 2016;169:145-161.
Fine HF, Zhitomirshy I, Freund KB, et al. Bevacizumab (Avastin) and ranibizumab (Lucentis) for choroidal neovascularization in multifocal choroiditis. Retina. 2009;29:8-12.
Michel SS, Ekong A, Baltazis S, Foster CS. Multifocal choroiditis and panuveitis: immunomodulatory therapy. Ophthalmology. 2002;109:378-383.
Munk MR, Jung JJ, Biggee K, et al. Idiopathic multifocal choroiditis/punctate inner choroidopathy with acute photoreceptor loss or dysfunction out of proportion to clinically visible lesions. Retina. 2015;35(2):334-343.
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