White-Dot Syndromes

Clinical Findings

Jampol et al. 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 μm), discrete white lesions are noted deep in the retina or at the level of the retinal pigment epithelium (RPE) ( Fig. 30.1 ). 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, often the macula has a granular appearance. The granularity may take the appearance of tiny white or orange specks, which do not approach the size of the deeper circular lesions, and the lesions are sometimes described as wreath-like. The macular changes cause irregularity of the internal limiting membrane reflex. Other ocular findings include mild vitreous cells and occasional sheathing of the retinal venules ( Box 30.1 ). There is usually no significant anterior chamber reaction. Although the lesions appear to fade with time, hence the term multiple evanescent white-dot syndrome (MEWDS), they can evolve into pigmented RPE stippling and scars.

Approximately 50% of patients with MEWDS report a preceding flu-like episode, but this historical information is not completely reliable. The mean age at onset of symptoms is about 28 years, ^, but Lim et al. 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, and 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. ^, Aaberg et al. reported recurrence in a previously affected eye 3 years after the initial visual loss and recurrences in the contralateral eye. Although most reports are from North America, this disorder has been seen in Europe. Asano et al. 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 et al. reported fundus lesions as seen in MEWDS after murine typhus, and Stangos et al. reported similar fundus changes in a 50-year-old individual after vaccination for hepatitis A and yellow fever. An interesting observation was made by Landolfi et al. in reporting a case of sympathetic ophthalmia that appeared to mimic MEWDS. In a patient whose eye was promptly repaired after a ruptured globe, a decrease in vision and 100- to 500-mm gray-white lesions developed in the other eye. MEWDS-like lesions have been described in a cohort of patients with pseudoxanthoma elasticum, further raising the possibility that clinical appearance may not totally reflect pathogenesis. There is overlap between MEWDS and acute idiopathic blind spot enlargement (AIBSE), and the patient with AIBSE may also have subretinal spots and foveal granularity, but the visual field defect in AIBSE may not improve. However, others have reported blind spot improvement, and these two syndromes may be variants of one disease process.

Laboratory Findings

There appear to be neither systemic manifestations of MEWDS nor characteristic blood test abnormalities. Jampol et al. reported collecting acute and convalescent sera for viral titers from one patient, but no antibody to a specific virus was identified.

Findings on electroretinography (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. Indeed, during the acute phase, a wave of ERG and ERP amplitudes were markedly affected. Feigl et al. performed multifocal ERG on four patients with MEWDS. Although the results were varied, first-order kernel amplitudes seemed to reflect early disturbances of the photoreceptors. Van Meel et al. 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. Fundus autofluorescence (FAF) shows areas of hyperfluorescence. Yenerel et al. reported that in their study, FAF showed the lesions before the clinical examination 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 disk. Gross et al. reported recognizing new angiographic features, that is, dots and spots, in a subgroup of patients with MEWDS. 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 sub-RPE level. These findings would suggest varying degrees of choroidal and retinal involvement in this disorder. Indocyanine green (ICG) angiography shows hypofluorescent lesions throughout the posterior pole, which are more visible on ICG angiography than is apparent on clinical examination and appear to be seen longer on ICG angiography than on clinical examination.

Optical coherence tomography (OCT) consistently shows changes in the outer retina. What appears to be most often reported is loss of retinal photoreceptor inner and outer segments, which can return to a more normal appearance after the acute episode ( Fig 30.2 ). There is disruption of the ellipsoid zone hyperreflective material in the RPE, ellipsoid zone, and outer nuclear layer in most cases. It should be noted that Spaide et al. found these changes in patients with various acute zonal occult outer retinopathy-complex diseases. Sikorski et al. have suggested that spectral mapping indicates that the alterations noted are better explained by alterations in the RPE/photoreceptor juncture rather than sites of active inflammatory disease. These outer retinal abnormalities distinguish MEWDS from many of the other white-dot syndromes and suggest that the primary involved tissue is the outer retina.

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 angiography picture is one of initial blockage with late staining, unlike that seen in MEWDS. Multifocal choroiditis, as first reported by Nozik and Dorsch, can be distinguished from MEWDS on the basis of the more severe inflammatory response in the vitreous in some cases, cystoid macular edema (CME), and persistent lesions, which are often punched out and pigmented in appearance as they evolve. Birdshot retinochoroidopathy causes ERG and electrooculography (EOG) changes that do not improve with time, and the involvement of the retinal vasculature with CME is common (see Chapter 26 ). Sarcoidosis should be ruled out in all patients with posterior uveitis, including patients with MEWDS, because lesions that appear similar can be seen; however, sarcoid lesions tend to involve the choroid rather than the outer retina. Usually, the lesions of sarcoidosis are bilateral, have more associated vitritis, and cause more permanent RPE alterations compared with those seen in MEWDS. As mentioned earlier, some researchers, including Callanan and Gass, have stressed the notion that there may be an overlap of symptoms in the white-dot syndromes. Furthermore, Bryan et al. reported MEWDS occurring in the eyes of four patients with multifocal choroiditis. Gass and Hamed reported MEWDS in an eye that had acute macular neuroretinopathy 5 years ago, with lesions in this entity being red-orange and some appearing in the central macula.

Therapy

To date, in cases of MEWDS, treatment has rarely been necessary. Sequelae to the acute episode seem to be minimal, with an expected return to near-preattack vision in about 7 weeks, on average. However, some patients may experience recurrences. Figueroa et al. used cyclosporin to treat one such patient who had multiple recurrences. The recurrences stopped while the patient was taking a therapeutic dose of the medication.

Clinical Findings

Patients have multifocal choroiditis that shares some clinical aspects of POHS ( Fig. 30.3 ). However, they also can have significant vitritis and often anterior uveitis. Anterior and vitreous inflammation need not be present to make the diagnosis of MFCPU. The lesions, 150 to 400 micron in diameter, can be distributed throughout the fundus but, in our experience, are posterior to the equator. They often have a punched-out appearance with white centers and pigmented borders and appear to be at the level of the RPE or the inner choroid. At times, pigment is heaped around the edge of the lesion. The pigmentary changes around the disk that are associated with POHS can be seen here as well. The disorder is usually bilateral and occurs more frequently in women. In a review by Dreyer and Gass, the median age at onset was 33 years, and in the group reported by Morgan and Schatz, 28 years. Most of our group of 24 patients (19 females and five males; average age 52 years) were evaluated after they had had a long, chronic course of inflammation. Morgan and Schatz found that all but one of the patients they examined had myopia. Patients with this disorder do not necessarily come from an area that is endemic for histoplasmosis, and a relatively low percentage show a response to the histoplasmin skin test or have calcific nodules on chest x-ray. Notably, patients with POHS are usually diagnosed in regions that are endemic for histoplasmosis, whereas MFCPU is seen worldwide.

The inflammatory activity in the vitreous may be marked, and chorioretinal involvement can be noted on detailed examination. CME was found in 14% of the eyes studied by Dreyer and Gass, whereas 41% of our patients had sequelae of this disorder. At least one-third of the eyes will ultimately have a subretinal neovascular membrane in the macula. These choroidal neovascular membranes are similar to others removed from eyes with other entities and represent an end-stage response to inflammatory disruption of the choroid–RPE barrier; many have extradomain B-containing fibronectin. Mild disk edema can also be seen. However, acute and symptomatic blind-spot enlargements with no signs of optic nerve abnormalities have been reported by Khorran et al., who hypothesized that this could be a manifestation of peripapillary retinal dysfunction similar to the process in MEWDS and AIBSE. Callanan and Gass also reported an acutely enlarged blind spot in seven of their patients. Also, in four of these, white dots similar to those in MEWDS were transiently noted, suggesting a similar cause for these two disorders. Peripheral chorioretinal streaks, once thought to be seen only in the POHS, were noted in three of 47 eyes with multifocal choroiditis.

Laboratory Findings

Patients with multifocal choroiditis do not appear to originate from areas that are endemic for histoplasmosis. However, some provide a history of an antecedent febrile illness as is commonly reported in many cases of posterior uveitides.

Fluorescein angiography of the punched-out lesions shows early hyperfluorescence, typical of an RPE window defect. Morgan and Schatz noted fuzzy hyperfluorescent leakage in the late phase of angiography in some lesions, and this may represent active choroidal lesions appearing to block fluorescence early and stain later. ICG angiography ^, tends to show more spots that appear as blockage of the fluorescence and are considered to be presumptive lesions that are not noted on a clinical examination or on fluorescein angiography. Electrophysiologic testing does not demonstrate typical findings in multifocal choroiditis. Indeed, the results of ERG will tend to be normal or borderline in most patients, suggesting that MFCPU does not diffusely involve the posterior segment.

The disorders that need to be excluded when diagnosing MFCPU include many of those mentioned for MEWDS. One to note in particular is birdshot retinochoroidopathy (see Chapter 26 ). Human leukocyte antigen (HLA) typing has not been performed on many of these patients, and no information, to date, suggests any linkage, whereas HLA-A29 is strongly associated with birdshot retinochoroidopathy (see Chapter 26 ). In addition, the lesions in this entity tend to be smaller and more punched out or discrete in appearance than those in birdshot retinochoroidopathy. Birdshot retinochoroidopathy tends to occur in older persons who have less anterior segment inflammatory disease, more optic nerve involvement, and problems with night vision, photopsia, and color discrimination. The presence of CME appears to be as common in both entities in our experience, but the incidence of subretinal foveal neovascularization is higher in this condition. In presumed ocular histoplasmosis, vitreous cells should not be present, and the lesions may extend more peripherally. The incidence of subfoveal neovascular nets is higher in ocular histoplasmosis. Deutsch and Tessler reported their observations in 28 patients with pseudohistoplasmosis syndrome; 43% of these patients were African Americans, and 32% had disciform scars. Furthermore, 32% of the patients were presumed to have sarcoidosis, 29% tuberculosis, and 11% syphilis. Multifocal, creamy choroidal infiltrates in older patients can be caused by masquerade syndromes including intraocular lymphoma (see Chapter 31 ). Patients with familial juvenile systemic granulomatosis (Blau syndrome) have been shown to have multifocal choroiditis lesions ( Fig. 30.4 ). Patients with MEWDS will more often have unilateral disease, with yellow lesions at the level of the outer retina, and often experience spontaneous resolution.

Visual field changes need to be documented. Holz et al., in an early description of these patients, noted the presence of an enlarged blind spot and that the visual field alterations could not be explained on the basis of the fundus changes—that is, the field defects were larger than the spots. This could be used as evidence that both multifocal choroiditis and PIC are just one manifestation of acute zonal occult outer retinopathy (AZOOR), as has been suggested by some. However, one could argue that the spots are simply the tip of the iceberg, reflective of changes surrounding these funduscopically apparent lesions that disrupt the neighboring photoreceptors and the RPE.

A provocative hypothesis was that MFCPU is virally induced. Grutzmacher et al. ascribed the RPE punched-out lesions to herpes retinitis in an otherwise healthy patient. Tiedeman evaluated 10 patients with MFCPU for evidence of Epstein-Barr virus (EBV)–specific antibodies. These patients were noted to have antibodies directed against the viral capsid antigen (immunoglobulin [Ig] M) or the EBV early antigen. None of the control subjects tested was found to have these antibodies, but most did have viral capsid antigen IgG or EBV nuclear antigen antibodies, indicating previous exposure to this virus. Although none of the patients had overt systemic disease, it was hypothesized that these responses suggested an active or persistent state of viral infection and that the patients might be immunologically unable to clear the virus. Because we know that the ocular disease can continue for years, this hypothesis suggests that such persons would, in theory, have a higher risk for the systemic complications of EBV infection, an association that has not been made so far. Furthermore, chronic EBV infection has been reported by Wong et al. to manifest as a different intraocular inflammatory disease that responds to treatment with acyclovir. However, acyclovir is not usually an active therapy for EBV infection. More studies have not borne out these observations. Spaide et al. evaluated 11 patients with multifocal choroiditis and compared them with 11 sex- and age-matched control subjects for the presence of anti-EBV antibodies. They found no significant differences in the antiviral capsid antigen IgG and in the antinuclear antigen antibody titers between the two groups. None of the patients in either group had IgM antibodies to the antiviral capsid antigen. One patient with multifocal choroiditis and three control subjects had positive anti–early antigen antibody titers.

There is still debate as to whether PIC (discussed later) is a variant of MFCPU or a separate disease. This is, in part, an issue with defining disease by phenotypic clinical findings rather than etiologic mechanisms. For patients with the PIC subgroup of the disease, a novel, but unproven, mechanistic explanation was offered by Scheider. He hypothesized that young women with myopia are more prone to this syndrome because of their tendency to have bacteremia, which, coupled with the attenuated choroidal vessels of myopia, would increase their risk of infectious thromboses.

Chorioretinal biopsies of the lesions in multifocal choroiditis have shown the presence not of a virus (see Case 30.2) but of a large number of B cells in the choroid. Shimada et al. reported the histopathology of choroidal neovascular lesions removed from 14 eyes with multifocal choroiditis and PIC. Vascular endothelial growth factor (VEGF) was seen in all the specimens (no surprise), and in three of the eight multifocal choroiditis specimens, CD20+ B cells were noted. Overall, there appeared to be no real histopathologic differences between the specimens from the eyes with multifocal choroiditis and the eyes with PIC. These findings are in contrast to the report of Nölle and Eckardt that in nine vitrectomy specimens from patients with multifocal choroiditis there were a large number of T cells—about one-third of the cell population being macrophages—and only rare B cells. Charteris and Lee reported the necropsy results of eyes from a 59-year-old woman with this disorder. They noted that 70% to 80% of the lymphocytes were identified as T cells; less than 20% were B cells. In situ hybridization for identification of herpes simplex virus showed negative results. The finding of a large number of T cells, presumably in the choroid, in this study reflects the fact that different underlying mechanisms will result in similar clinical entities, which we had also seen with this entity (see Case 30.2). An eye that was evaluated showed B cells and substantial numbers of CD3+ lymphocytes. No microgranulomas were noted.

Therapy for multifocal choroiditis has centered on the use of immunosuppressive agents (see later discussion), with varying success. An interesting hypothesis is that an initial viral disorder may have triggered an immune response that no longer requires the presence of the virus but rather needs immunosuppressive therapy to be controlled.

Therapy

Periocular or systemic corticosteroids have been used to treat multifocal choroiditis during initial presentation. In the report by Dreyer and Gass, six of 18 patients had improvement of vision with steroid therapy, whereas nine had no change, and in two, it was thought that this form of therapy halted a rapid decline in vision. Morgan and Schatz reported that in their patients, the inflammatory disease responded very well to steroid therapy and that most patients were left with good vision, as reported by Levy et al. as well. We studied 24 patients, and 10 of the 17 who needed steroid therapy had CME. We have seen a moderately good response to steroid therapy, but the disorder can become chronic, requiring consideration of the addition of other immunosuppressive agents. In our experience, the visual prognosis is guardedly optimistic. Of great interest was the report by Morgan and Schatz that subretinal neovascular lesions regressed with steroid therapy. This was not seen by Dreyer and Gass in one patient. We have not observed regression in our patients but have observed that the neovascular lesions remain quiet on immunosuppressive therapy once the patients have initially been treated with anti-VEGF injections. Michel et al. reported their experience in treating 19 patients with multifocal choroiditis. In their series, no patient experienced visual loss after they were given immunosuppressive therapy. Laser ablation of the subretinal net may be indicated in extrafoveal lesions; however, several caveats apply. The first is that there is risk of an increase in the inflammatory response after such an intervention—something to avoid if we theorize that the inflammatory response is the underlying “initiator” of the neovascular net. Second, the experience of Dreyer and Gass suggests that laser ablation has not been particularly successful in preventing further deterioration of vision. The combination of photodynamic therapy (PDT) and intravitreal injection of triamcinolone has been reported to yield a positive therapeutic result. Cirino et al. reported resolution of a choroidal neovascularization (CNV) lesion secondary to PIC when a patient with multiple sclerosis began receiving regular therapy with interferon (IFN)-β _1A . It would seem reasonable to suppose that the CNV is driven by the inflammation in part, and therefore treating the inflammation and giving some agent directed against the neovascular component would be a good approach. Intravitreal anti-VEGF agents are also effective in treating subretinal neovascularization and are the preferred treatment in most cases. Unlike with age-related macular degeneration, these drugs can often be stopped once the inflammation is controlled.

Nölle and Eckardt saw no impressive therapeutic effect of vitrectomy in nine patients with multifocal choroiditis. We have limited experience with the removal of submacular neovascular nets in these patients, who often, unlike those with histoplasmosis syndrome, have a great deal of fibrosis associated with the net, making removal difficult, if at all possible. Spaide et al. used PDT to treat seven patients with multifocal choroiditis with subretinal neovascular membranes. All had myopia, and in four of the seven, corticosteroid therapy was unsuccessful. The mean improvement in visual acuity was 0.86 line.