Key concepts

•These entities comprise disorders that are usually transient compared to those that cause long-term visual handicap.

•Nuances of these disorders, such as ‘ampiginous’, can take on the characteristics of two entities.

•It is not yet clear whether these clinical entities are manifestations of the same disease process.

Localized, well-circumscribed areas of inflammatory disease in the fundus are a common manifestation of many intraocular inflammatory disorders (see Chapters 13, 22, 23, and 25). In addition, several entities have been noted to occur with multiple white dots in the fundus, usually in the deeper layers of the posterior segment. They are grouped here because of their sometimes overlapping features and the belief by some that these disorders may represent the broad spectrum of one underlying entity1 and that the underlying histopathologic lesion is a microgranuloma.2 Recently, we are seeing that many investigators appear to be ‘lumpers,’ suggesting that all these are really the expression of one disease, as suggested many years ago by Gass.3 Most occur acutely, sometimes leaving minimal or no permanent long-term visual loss. An infectious cause has been suggested for some,3 although more recent evidence does not support this theory, and other disorders due to presumed infectious causes may not easily fit into the better-defined entities.4

Multiple evanescent white-dot syndrome

Clinical findings

Jampol and colleagues5 reported on 11 patients in whom similar funduscopic changes were noted. The alterations are unilateral and are predominantly seen in young women. Numerous small (100–200 m), discrete white lesions are noted deep in the retina or at the level of the retinal pigment epithelium (RPE) (Fig. 29-1) – hence the term multiple evanescent white-dot syndrome (MEWDS). The lesions appear in the posterior pole and extend to the midperiphery. They tend to be concentrated in the perifoveal region, but seem usually to spare the fovea itself. In addition, there is often a granular appearance to the macula. The granularity may take the appearance of tiny white or orange specks, which do not approach the size of the deeper circular lesions.

White-Dot Syndromes

Robert B. Nussenblatt

The macular changes cause an irregularity to the internal limiting membrane reflex. Other ocular findings include vitreous cells and occasional sheathing of the retinal venules (Box 29-1). There is usually no significant anterior chamber reaction. Although the lesions appear to fade with time, they can evolve into chorioretinal scars.6

Patients with MEWDS usually do not report a preceding flu-like episode. The mean age at onset of symptoms is about 28 years,5,7 but Lim and coworkers8 reported two patients in their seventh decade. The decrease in visual acuity is usually quite sudden. The disease may cause a marked drop in visual acuity even to the level of 20/200, and an afferent pupillary defect may be noted. The disease runs its course over an average of 7 weeks, after which a return to a visual acuity of between 20/20 and 20/40 usually ensues. The white lesions and macular granularity will fade with time, but subtle RPE alterations can be noted. Recurrences of the disorder are seen rarely.9,10 Aaberg and colleagues9 reported a recurrence in a previously affected eye 3 years after the initial visual loss, as well as recurrences in the contralateral eye. Although most reports have come from North America, this disorder has been seen in Europe.11 Asano and colleagues12 found that the degree of myopia was statistically higher in Japanese patients than that seen in controls. It is usually not associated with systemic disease. Lu and associates13 reported fundus lesions as seen in MEWDS after murine typhus, and Stangos et al.14 reported similar fundus changes in a 50-year- old after hepatitis A and yellow fever vaccination. An interesting observation was made by Landolfi and coworkers15 in reporting that sympathetic ophthalmia appeared to mimic MEWDS. A patient whose eye was promptly repaired after a ruptured globe developed in the other eye a decrease in vision and 100–500 mm grey-white lesions.

Laboratory findings

Although no formal evaluation of these patients has been undertaken, there appear to be neither systemic manifestations of this disorder nor characteristic blood test results. Jampol and colleagues5 reported collecting acute and convalescent sera for viral titers from one patient, but no antibody to a specific virus was identified.

Findings on the electroretinogram (ERG), early receptor potential (ERP), and visual pigment regeneration tests have been noted to be abnormal in these patients during the acute phase of the disease, with a return to normal during the recovery phase.16 Indeed, during the acute phase a wave of the ERG and the ERP amplitudes were markedly affected. Feigl and colleagues17 performed multifocal ERGs on four

Box 29-1  Clinical findings in multiple evanescent

white-dot syndrome

Sudden drop in visual acuity Patients are mostly young females Small discrete white dots at RPE level ‘Grainy’ macula

ERG changes that reverse after episode Minimal RPE pertubation after episode Condition rarely recurs

Vision returns without medication

patients with MEWDS. Although results were varied, firstorder kernel amplitudes seemed to reflect early disturbances of the photoreceptors. van Meel and colleagues18 performed scanning laser densitometry on a patient with MEWDS and noted small areas of absent visual pigment that did not correspond to the white fundic spots. Even with recovery, these abnormal areas of pigment loss were still faintly seen. The authors believed that their study supported the notion that this disorder is the result of a metabolic disturbance at the level of the RPE. MP1 mapping areas of retinal sensitivity can show enlarged blind spots in these patients.19 Fundus autofluorescence (FAF) will show areas of hyperfluorescence. Yeneral et al.20 reported that FAF showed lesions before the clinical exam became apparent.

Fluorescein angiography frequently shows early hyperfluorescence with late staining. This is unlike the angiographic findings associated with acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (see later discussion). There is staining also of the macula and late staining of the disc. Gross and colleagues21 reported recognizing new angiographic features in a subgroup of patients with MEWDS

– dots and spots. Small dots noted on fluorescein angiography were interpreted to be at the level of the inner retina or the RPE, whereas larger spots were more external, in the subpigment epithelial level. These findings would suggest varying degrees of choroidal and retinal involvment in this disorder. Indocyanine green (ICG) angiography shows hypofluorescent lesions throughout the posterior pole,

B

Figure 29-2  A, Case of MEWDS with initial loss of inner segment/outer segment boundary. B, Spontaneous resolution with segment boundary restored. (From Spaide RF, Koizumi H, Bailey Freund K. Photoreceptor outer segment abnormalities as a cause of blind spot enlargement in acute zonal occult outer retinopathycomplex diseases. Am J Ophthalmol 2008; 146: 111–120. © 2008, Elsevier Inc.)

which are more visible on the ICG angiogram than is apparent on clinical examination22 and appear to be seen longer on the ICG angiogram than with clinical examination.23

High-resolution optical coherence tomography (OCT) repeatedly show changes in the outer retina.24–26 What appears to be most often reported is the loss of the retinal photoreceptor inner and outer segments, which can return to a more normal apppearance after the acute episode (Fig 29-2). It should be noted that Spaide and colleagues26 found these changes in patients with various acute zonal occult outer retinopathy-complex diseases. Sikorski and colleagues24 suggest that the spectral mapping they performed suggests that the alterations noted are better explained by alterations in the RPE/photoreceptor juncture rather than sites of active inflammatory disease.

Several entities have ocular manifestations similar to those seen in MEWDS. APMPPE is usually a bilateral disease with considerably larger lesions. With resolution there is often considerable RPE perturbation in this disorder, whereas in MEWDS the changes are more subtle. In APMPPE, the fluorescein angiographic picture is one of initial blockage with late staining, unlike that seen in MEWDS. Multifocal choroiditis, as first reported by Nozik and Dorsch,27 can be