White Dot Syndromes
The term white dot syndromes has been used to refer to the following conditions (Table 11-1):
acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
multiple evanescent white dot syndrome (MEWDS)
multifocal choroiditis (MFC)
multifocal choroiditis and panuveitis syndrome (MCP)
punctate inner choroidopathy (PIC)
Table 11-1 White Dot Syndromes: Comparative Findings and Course
Many authorities now believe that MFC and PIC are part of a spectrum of the same condition; in this chapter, both of these entities are referred to as MFC (discussed in the section “Multifocal choroiditis”). Acute zonal occult outer retinopathy (AZOOR), acute macular neuroretinopathy (AMN), and acute idiopathic maculopathy (AIM), also discussed in this chapter, are often included in discussions of the more classic white dot syndromes listed above because of their presumed inflammatory etiology and the frequently shared symptoms of decreased vision, scotomas, and photopsias.
Acute posterior multifocal placoid pigment epitheliopathy
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE; also known as AMPPPE or AMPPE) is an uncommon, bilateral inflammatory disorder characterized by the acute onset of blurred vision, scotomas, and, in some patients, photopsias. Approximately one-third of patients describe an antecedent flulike illness. Men and woman are affected equally; onset usually occurs in youth to middle age. Mild anterior chamber and vitreous inflammation may be present. The lesions, which are typically multiple, yellow-white, placoid, and variable in size, occur at the level of the outer retina (retinal pigment epithelium, RPE) and inner choroid (choriocapillaris) (Fig 11-1). Recurrences are uncommon. The etiology is unknown, although the condition is characterized by hypoperfusion of the choriocapillaris that results in injury to the overlying RPE. Systemic involvement—especially cerebral vasculitis—can occur, although it is uncommon. APMPPE-like lesions can be present in patients with sarcoidosis, syphilis, and tuberculosis; therefore, testing to exclude these conditions should be considered.
Figure 11-1 Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). A, Color fundus photograph of the right eye of a 19-year-old male patient shows multiple yellowish placoid lesions in the posterior pole. The left eye (not pictured) was also involved. Early (B) and late-phase (C) fluorescein angiography demonstrate hypofluorescence (due to decreased choriocapillaris perfusion and/or thickening of the retinal pigment epithelium [RPE]), and hyperfluorescence, respectively. D, Vertical optical coherence tomography (OCT) scan demonstrates outer retinal involvement of lesions.
(Courtesy of Stephen J. Kim, MD.)
Acutely, fluorescein angiography (FA) of active lesions shows early blockage followed by progressive late leakage and staining. Indocyanine green (ICG) angiography shows early and late (persistent) hypofluorescence, corresponding to and often extending beyond those lesions identified clinically and on FA. Optical coherence tomography (OCT) images taken through active lesions reveal outer retinal lesions associated with disruption of the outer retinal hyperreflective bands. Autofluorescence in and around active lesions varies over time and may be either increased or decreased at presentation; it tends to decrease as disease activity subsides. With time, hypoautofluorescence develops in areas of RPE disruption. The fundus appearance and visual symptoms typically improve within weeks. The long-term prognosis tends to be good, but severe vision loss can result from RPE and/or photoreceptor injury.
Treatment for APMPPE is not typically indicated, although systemic corticosteroids may be considered in cases with central macular involvement and are required in cases with cerebral vasculitis. Severe APMPPE may be difficult to distinguish from serpiginous choroidopathy (discussed in the following section); that difficulty led to the introduction of the term ampiginous to characterize the APMPPE–serpiginous choroidopathy disease continuum. Other, related placoid disorders include persistent placoid maculopathy, which is characterized by central macular involvement, a longer healing time, and a high risk of choroidal neovascularization (CNV) formation, as well as relentless placoid chorioretinitis, which is characterized by the frequent occurrence of smaller, geographically distributed lesions that typically require immunosuppressive treatment.
Serpiginous choroidopathy, also known as geographic choroiditis or helicoid peripapillary choroidopathy, is an uncommon, often vision-threatening, recurring inflammatory disorder involving the outer retina (the RPE) and inner choroid (the choriocapillaris). Classically, lesions first appear at or near the optic nerve head and extend centrifugally in a serpentine pattern. With numerous recurrences, a serpiginous (pseudopodial) or geographic (maplike) pattern of chorioretinal scarring develops (Fig 11-2). Findings on clinical examination and through multimodal imaging of active serpiginous lesions resemble those of acute APMPPE. Lesions tend to occur near or adjacent to inactive scars from prior episodes of inflammation. Persistent scotomas and decreased central vision are common symptoms. Serpiginous choroidopathy tends to affect men and women equally; onset typically occurs in middle age.
In endemic areas, such as India, tuberculosis is recognized as producing serpiginouslike lesions, leading some clinicians to describe such lesions as tubercular serpiginous-like choroiditis. In patients with serpiginous-like lesions, evaluation for tuberculosis, sarcoidosis, and syphilis should be considered. Standard autoimmune disease treatment options are typically needed to stabilize the condition and prevent recurrences.
Figure 11-2 Serpiginous choroidopathy. A, Color fundus photograph shows an old peripapillary chorioretinal scar with an active serpentine lesion extending centrifugally into the fovea. B, Early-phase fluorescein angiogram demonstrates classic hypofluorescence, with hyperfluorescence of the edge of the older peripapillary chorioretinal scar. C, Late-phase angiogram demonstrates hyperfluorescence of involved areas. D, Autofluorescence image demonstrates a complete absence of autofluorescence in the area of older chorioretinal scarring, but not in the area of active extension. E, OCT image demonstrates disorganization of outer retinal layers and choroid nasal to and underneath the fovea that corresponds to the involved areas.
(Courtesy of Stephen J. Kim, MD.)
Multiple evanescent white dot syndrome
Multiple evanescent white dot syndrome (MEWDS) is an acute-onset syndrome characterized by multiple small gray, white, or yellow-white dots at the level of the outer retina (RPE level) in and around the posterior pole (Fig 11-3). In some patients, an unusual transient foveal granularity consisting of tiny yellow-orange flecks at the level of the RPE also develops; this is highly suggestive of the condition. Abnormalities on ICG angiography suggest simultaneous choroidal involvement. Mild anterior chamber cell reaction or vitritis may be present. Affected individuals are typically young to middle aged; women are affected more often than men. Symptoms tend to be unilateral and include decreased vision, scotomas, and sometimes photopsias. Temporal visual field abnormalities and an enlarged blind spot are common, and an afferent pupillary defect is often present. The etiology of MEWDS is unknown, although one-third of patients describe a flulike prodrome.
FA reveals multiple, punctate, hyperfluorescent dots associated with the spots observed clinically, typically in a wreath-like cluster. Mild, late leakage and staining of the optic nerve head is often observed. ICG angiography shows hypofluorescence around the optic nerve head as well as multiple hypofluorescent dots, which are typically more numerous than those observed either clinically or on FA. OCT images taken through active lesions reveal dome-shaped outer retinal lesions associated with disruption of the outer retinal hyperreflective bands. Fundus autofluorescence imaging often shows focal hyperautofluorescence in the area of the white dots. On electroretinogram (ERG) testing, some patients show delayed 30-Hz flicker responses and decreased bright-flash, dark-adapted a-wave amplitudes. The symptoms and fundus findings start to improve in most patients in 2–6 weeks without treatment. In rare cases, MEWDS can be recurrent or bilateral, cause persistent scotomas or visual field defects, or be associated with the late development of CNV.
Figure 11-3 Multiple evanescent white dot syndrome (MEWDS). A, Color fundus photograph demonstrates foveal granularity consisting of tiny yellow-orange flecks that can be easily visualized in a red-free image (B). C, Angiography image demonstrates classic hyperfluorescent punctate lesions in a wreath-like cluster. D, OCT image demonstrates disruption of the outer retina and RPE.
(Courtesy of Shriji N. Patel, MD.)
Birdshot uveitis, or vitiliginous chorioretinitis, is bilateral and affects women more often than men, typically in late middle age. Early symptoms include floaters and blurred or decreased vision. Later in the course of disease, nyctalopia, diminished contrast sensitivity, and decreased color vision may occur. Examination reveals vitreous inflammation, which is typically mild and is associated with multiple yellow-white choroiditis spots that are often most prominent inferonasal to the optic nerve head (Fig 11-4). Fluorescein angiography often shows leakage from the retinal vessels and optic nerve head, frequently producing cystoid macular edema (CME). Variable amounts of outer retinal atrophy can also be present, resulting in window defects. Choroidal lesions are best visualized using ICG angiography. OCT and fundus autofluorescence can be used to assess the extent of outer retinal atrophy.
Figure 11-4 Color fundus photograph montage of the right (A) and left (B) eyes of a patient with birdshot uveitis demonstrate multiple creamy, yellow-white choroiditis lesions scattered around the posterior pole. The images are slightly hazy due to vitritis.
(Courtesy of Stephen J. Kim, MD.)
The disease is chronic, progressive, and prone to recurrent episodes of inflammation. Vision loss may be caused by CME, epiretinal membrane formation, and/or outer retinal atrophy, which can be extensive and is associated with optic atrophy in advanced cases. Most patients with birdshot uveitis are white and test positive for HLA-A29 (> 90%); birdshot uveitis has the strongest association documented between a disease and HLA class I. Disease activity and progression may be assessed in the office using multimodal imaging (FA, ICG angiography, spectral-domain OCT, enhanced depth OCT, and fundus autofluorescence) and through periodic electrophysiologic (ERG), color vision, and visual field testing—each of which may show a degree of dysfunction far greater than that suggested by Snellen visual acuity assessments. Standard autoimmune disease treatment options are employed.
Use of the terms idiopathic multifocal choroiditis, multifocal choroiditis with panuveitis (MFCPU), recurrent multifocal choroiditis (RMC), punctate inner choroiditis or choroidopathy (PIC), and pseudo-presumed ocular histoplasmosis syndrome (pseudo-POHS), among others, is both inconsistent and confusing in the literature. Current recommendations suggest that only the term multifocal choroiditis (MFC) should be used to refer to the occurrence of discrete chorioretinitis lesions in the absence of an identifiable underlying infection (such as tuberculosis or histoplasmosis) or systemic inflammation (such as sarcoidosis). In MFC, lesions are commonly clustered in the macula and around the optic nerve head, although they can also occur in the mid- and far periphery (Fig 11-5), and are frequently aligned in a curvilinear manner—configurations that are sometimes referred to as Schlaegel lines. Affected individuals are typically young, myopic, and female. Clinical examination usually reveals little or no anterior chamber or vitreous inflammation, although patients can have mild to moderate vitreous inflammation—a presentation some clinicians mean when using the term MFCPU. Blurred or decreased vision and scotomas are the most common symptoms. Decreased central vision results most frequently from direct central macular involvement or from the development of CNV, which occurs in one-third of patients (Fig 11-6). Subretinal fibrosis can occur in and around lesions and, when the central macula is involved, can also limit vision. Standard treatment options for autoimmune disease are employed.
Figure 11-5 Color fundus photograph montage of the right (A) and left (B) eyes showing multifocal chorioretinal scars, some with a punched-out appearance, in a patient with end-stage multifocal choroiditis (MFC) with panuveitis.
(Courtesy of Stephen J. Kim, MD.)
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.
Acute zonal occult outer retinopathy
Acute zonal occult outer retinopathy (AZOOR), a presumed inflammatory disorder, damages broad zones of the outer retina in 1 or both eyes. AZOOR typically occurs in young women with myopia, and onset is acute and unilateral. Three-fourths of cases progress to bilateral involvement. Initial symptoms include photopsia, nasal visual field loss, and sometimes an enlarged blind spot; visual acuity is affected in rare instances. On initial presentation, the fundus may appear normal or show evidence of mild vitritis (Fig 11-7). Nearly 25% of patients have an afferent pupillary defect. Angiographic findings may include retinal and optic nerve head capillary leakage, especially in patients with evidence of vitritis. On ERG, a delayed 30-Hz flicker response is common; multifocal ERG (mfERG) shows decreased responses in areas of the visual field defect. Visual field testing may show scotomas, which can enlarge over weeks or months.
Figure 11-6 Choroidal neovascularization (CNV). A, Fundus photograph of a patient with MFC with panuveitis with central subfoveal fibrosis. B, After resolution of CNV, subretinal fibrosis is present.
(Courtesy of Stephen J. Kim, MD.)
Some patients recover from AZOOR, whereas others have persistent, large visual field defects, which tend to stabilize over 6 months. Permanent visual field loss is often associated with late development of fundus changes. Depigmentation of large zones of RPE usually corresponds to scotomas (see Fig 11-7); narrowed retinal vessels may be visible within these areas. In some patients, the late fundus appearance may resemble cancer-associated retinopathy or retinitis pigmentosa. FA images tend to appear normal early on but become abnormal in eyes with RPE alterations. ICG angiography may show areas of late hypofluorescence. OCT typically reveals outer retinal atrophy, including disruption of the ellipsoid zone and the outer nuclear layer in involved areas. Confocal near-infrared reflectance imaging shows hyporeflective areas that correspond to areas of lost ellipsoid zone. Autofluorescence is typically decreased in areas of involvement and is occasionally associated with either punctate or a peripheral rim of hyperautofluorescence. Immunosuppression does not alter the course of the disease.
Figure 11-7 Acute zonal occult outer retinopathy (AZOOR). Annular depigmentation of the RPE can be seen around the optic nerve (top left). Autofluorescence (top right) demonstrates areas of hypofluorescence corresponding to RPE loss. The fovea appears normal. OCT images (bottom) demonstrate outer retinal atrophy in the involved area.
(Courtesy of Richard F. Spaide, MD.)
Acute macular neuroretinopathy
Acute macular neuroretinopathy (AMN) is a rare condition characterized by the acute onset of paracentral scotomas in 1 or both eyes in young, otherwise healthy patients. Women outnumber men nearly 6 to 1 in this condition. Clinically, reddish-brown tear-drop or wedge-shaped lesions are observed around the fovea. The tips of these lesions point centrally; the lesions correspond in size and location to the subjective paracentral scotomas. The lesions can be difficult to see on fundus examination or with color photography but are apparent on near-infrared imaging. The retinal vessels and optic nerve are unaffected, and there is no vitreous inflammation. High-resolution OCT is particularly helpful for visualizing the lesions and has revealed 2 patterns: (1) type 1, which is characterized by involvement of the middle retina or inner nuclear layer; and (2) type 2, which is characterized by involvement of the outer retina—including both the outer nuclear layer and the hyperreflective bands associated with the photoreceptors of the ellipsoid zone. Both patterns are believed to result from ischemia of the deep capillary plexus of the central retina.
The lesions typically resolve over several weeks to months with corresponding visual recovery; alternatively, the scotomas persist. The pathogenesis of AMN is unclear. Several associations have been noted, however, including a preceding flulike illness, the use of oral contraceptives or caffeine, and injection of adrenaline or epinephrine. Lesions resembling AMN can occur following mild to moderate, blunt, or whiplash-type trauma. Whether these lesions are AMN or traumatic maculopathy is controversial (Fig 11-8).
Fawzi AA, Pappuru RR, Sarraf D, et al. Acute macular neuroretinopathy: long-term insights revealed by multimodal imaging. Retina. 2012;32(8):1500–1513.
Acute idiopathic maculopathy
Acute idiopathic maculopathy (AIM) is a rare disorder that presents with sudden, severe central or paracentral vision loss, typically in younger individuals following a flulike illness. Men and women are affected equally. Initially, only central unilateral lesions were described, but both bilateral and eccentric macular lesions have since been added to the disease spectrum. The main clinical finding is an exudative neurosensory macular detachment with little or no vitreous inflammation and variable discoloration of the underlying RPE. Mild optic nerve head swelling, retinal hemorrhages, vasculitis, and subretinal infiltrates occur infrequently. Fluorescein angiography typically shows progressive irregular hyperfluorescence at the level of the RPE, followed in the late stages by pooling in the detachment space. ICG angiography shows early and persistent hypofluorescence. High-resolution OCT imaging documents the size and extent of the detachment space and shows loss of the hyperreflective outer retinal bands associated with the photoreceptors and RPE. The lesions resolve spontaneously but leave a bull’s-eye pattern of RPE alteration, which on FA shows central hypofluorescence and surrounding hyperfluorescence. There is typically near-complete recovery of vision over weeks to months. The cause is unknown, although isolated cases have been associated with coxsackievirus infection.
Figure 11-8 Acute macular neuroretinopathy following whiplash-type trauma. Reddish-brown wedge-shaped lesions nasal to the fovea are difficult to see in a color fundus photograph (A), but they are apparent in a near-infrared image (B). C, OCT image demonstrates involvement of the external limiting membrane and ellipsoid zone (arrows).
(Courtesy of Milam A. Brantley, MD, PhD.)
Yannuzzi LA, Jampol LM, Rabb MF, Sorenson JA, Beyrer C, Wilcox LM Jr. Unilateral acute idiopathic maculopathy. Arch Ophthalmol. 1991;109(10):1411–1416.
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