White-Dot Syndromes






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 Chapter 13, Chapter 22, Chapter 23, Chapter 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 entity and that the underlying histopathologic lesion is a microgranuloma. 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. Most occur acutely, sometimes leaving minimal or no permanent long-term visual loss. An infectious cause has been suggested for some, 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.




Multiple evanescent white-dot syndrome


Clinical findings


Jampol and colleagues 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. 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. 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.




Figure 29-1.


Fundus photograph showing alterations noted in MEWDS.


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 usually do not report a preceding flu-like episode. The mean age at onset of symptoms is about 28 years, , but Lim and coworkers 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. , Aaberg and colleagues 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. Asano and colleagues 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 associates reported fundus lesions as seen in MEWDS after murine typhus, and Stangos et al. reported similar fundus changes in a 50-year-old after hepatitis A and yellow fever vaccination. An interesting observation was made by Landolfi and coworkers 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 colleagues 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. Indeed, during the acute phase a wave of the ERG and the ERP amplitudes were markedly affected. Feigl and colleagues performed multifocal ERGs on four patients with MEWDS. Although results were varied, first-order kernel amplitudes seemed to reflect early disturbances of the photoreceptors. van Meel and colleagues 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) will show areas of hyperfluorescence. Yeneral et al. 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 colleagues 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, which are more visible on the ICG angiogram than is apparent on clinical examination and appear to be seen longer on the ICG angiogram than with clinical examination.


High-resolution optical coherence tomography (OCT) repeatedly show changes in the outer retina. 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 colleagues found these changes in patients with various acute zonal occult outer retinopathy-complex diseases. Sikorski and colleagues 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.




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 retinopathy-complex diseases. Am J Ophthalmol 2008; 146: 111–120.


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, can be distinguished from MEWDS by the more severe inflammatory response in the vitreous, long-standing lesions, and cystoid edema in the former, as well as the different evolution of the spots and probable normal electrophysiologic results in the latter. Birdshot retinochoroidopathy causes ERG and electrooculogram (EOG) changes that do not improve with time, and the involvement of the retinal vasculature with cystoid edema is quite striking (see Chapter 25 ). Sarcoidosis should be ruled out in patients with MEWDS, because lesions similar to those in this disorder can be seen. Usually, however, the lesions of sarcoidosis are bilateral, have more vitreous involvement, and can cause far more RPE alterations than are seen in MEWDS. As mentioned above, some researchers, including Callanan and Gass, have stressed the notion that there may be an overlap of symptoms in the white-dot syndromes. To confuse matters, Bryan and colleagues reported MEWDS to have occurred in the eyes of four patients with multifocal choroiditis. Gass and Hamed reported MEWDS in an eye that 5 years previously had acute macular neuroretinopathy; with lesions in this entity being red-orange and some appearing in the central macula. Table 29-1 describes three white dot syndromes. Please see comments below.



Table 29-1

Comparison of three white-dot syndromes

(From Golchet PR, et al. Persistent placoid maculopathy: a new clinical entity. Ophthalmology 2007; 114(8): 1530–40)

















































Persistent Placoid Maculopathy Macular Serpiginous choroiditis Acute Posterior Multifocal Placoid Pigment Epitheliopathy
Lesion characteristics Long-standing geographic central whitish plaques involving the fovea Variable sizes and shapes, heal to scars and atrophy in weeks Multiple postequatorial cream-colored placoid lesions of varying sizes, fade in 1–2 wks
Visual acuity Normal to mildly affected (20/20–20/60) with good prognosis for recovery unless complicated by CNV Rapid decrease in central vision to counting fingers with poor prognosis for recovery Sudden onset of moderate vision loss, photopsia, and scotomas with excellent prognosis for recovery
Gender Only 6 patients Male = female Male = female
Laterality Bilateral, symmetric (6/6 patients) Eventually all bilateral, usually asymmetric Usually bilateral and symmetric
FA characteristics Early hypofluorescence followed by partial filling-in in the late phase Early hypofluorescence of the central portion of the lesion surrounded by progressive hyperfluorescence at the margins with eventual late staining Early hypofluorescence followed by late hyperfluorescence and staining; window defects appear in the quiescent stage
ICG angiography characteristics Persistent hypofluorescence throughout the angiogram Early hypofluorescence with some resolution in the late phase; no staining of lesion borders Hypofluorescence of the active and healed lesions
Complications CNV in 11/12 eyes, with 9 resulting in disciform mascular scars so far, RPE mottling in 1/12 eyes CNV and disciform macular scars in up to 35%; RPE mottling and subretinal scar formation common; RPE detachments, vein and artery occlusions described Most patients spontaneously recover; rare cases of permanent loss of vision secondary to RPE alterations or CNV; also, reports of CME, papillitis, bilateral central vein occlusions, and associated CNS vasculitis
Clinical course Persistent lesions with mild decrease in VA unless complicated by CNV or RPE damage Multiple discrete recurrences usually adjacent to old lesions, variably spaced over many years Acute transient decrease in VA associated with a viral prodrome and rare recurrences

CME, cystoid macular edema; CNV, choroidal neovascularization; FA, fluorescein angiography; ICG, indocyanine green; RPE, retinal pigment epithelium; VA, visual acuity.


Therapy


To date, patients with MEWDS who have been reported have rarely needed to be treated. 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 have recurrences. Figueroa and colleagues used ciclosporin to treat one such patient who had multiple recurrences. The recurrences stopped while the patient was taking a therapeutic dose of the medication.




Multifocal choroiditis and panuveitis


Several investigators reported a fundic condition with the characteristics of presumed ocular histoplasmosis syndrome. This began with the report of Nozik and Dorsch of two patients with bilateral uveitis associated with a distinctive chorioretinopathy. The identification of these patients is relevant because of the associated sequelae that may lead to irreversible visual handicap.


Clinical findings


Patients have a multifocal choroiditis that strongly suggests the ocular histoplasmosis syndrome ( Fig. 29-3 ). However, they also have a significant vitreitis and often an anterior uveitis. The lesions, 50–200 mm in diameter, can be strewn throughout the fundus, but in our experience are posterior to the equator. They have a punched-out appearance and appear to be at the level of the RPE or inner choroid. At times pigment is heaped around the edge of the lesion. The pigmentary changes around the disc that are associated with the histoplasmosis syndrome can be seen here as well. The disorder is bilateral and occurs more frequently in women. In the review of Dreyer and Gass the median age of 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) came to us after having had a long, chronic course of inflammation and averaged 52 years of age. Morgan and Schatz found that all but one of the patients they examined had myopia. Patients with this disorder do not necessary come from an area that is endemic for histoplasmosis, and a relatively low percentage show a response to the histoplasmin skin test.




Figure 29-3.


A and B, Multiple histoplasmosis-like lesions in periphery of patients with focal choroiditis and uveitis. These eyes, unlike those with ocular histoplasmosis syndrome, have a profound vitreous inflammatory response and cystoid macular edema. Both conditions carry the risk of subretinal neovascularization of the fovea.


The inflammatory activity in the vitreous is marked, and retinal involvement can be noted on close examination. Cystoid macular edema has been 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 net in the macula. Nets from these patients are similar to others removed from eyes with other entities; many have the extradomain B-containing fibronectin. Mild disc edema can also be seen. However, acute and symptomatic blind-spot enlargements with no signs of optic nerve abnormalities have been reported by Khorram and coworkers, who conjectured that this is a manifestation of peripapillary retinal dysfunction. 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 of MEWDS were transiently noted, suggesting a similar cause for these two disorders. Peripheral chorioretinal streaks, once thought to be seen only in the ocular histoplasmosis syndrome, were noted in three of 47 eyes with multifocal choroiditis.


Punctate inner choroidopathy


Watzke and colleagues described a group of patients with a condition they termed punctate inner choroidopathy (PIC), which we consider to be a variant of multifocal choroiditis until proved otherwise. In their report of 10 moderately myopic women the ocular changes noted were essentially the same as those already described, except that there were no signs of ocular inflammation. The women had blurred vision associated with light flashes and paracentral scotomas. The lesions were 100–300 mm in diameter and initially appeared yellow. Reddy and Folk believe that PIC and multifocal choroiditis, although quite similar, can be distinguished. In multifocal choroiditis there is vitreous inflammation and the retinal lesions are less discrete and shallower, whereas PIC lesions are deep, punched out, and cylindric. Also, new lesions can appear with multifocal choroiditis, which is unusual in PIC. In our mind these distinctions are blurred, and thus we generally consider PIC as a subgroup of multifocal choroiditis. Although macular edema may be somewhat less common with PIC, both PIC and multifocal choroiditis are associated with the real risk of subretinal membranes. A recent comparison of 66 patients with multifocal choroiditis and 13 with PIC does suggest some differences clinically. Those with PIC presented earlier with sympotoms (29 years versus 45 years). At presentation, in the comparison reported, PIC patients presented more frequently with CNV (76.9% versus 27.7%); however they appeared to have fewer structural complications due to the intraocular inflammation, such as cataract, CME, and epiretinal membrances. Those with PIC also tended not to have as great a decrease in visual acutiy. A questionnaire sent to members of the PIC society essentially corroborated those clinical findings. Those who responded confirmed the impression that the typical patient was a young, myopic Caucasian woman. Self-reporting, they said that most had the development of CNV and subretinal fibrosis within the first year of diagnosis. Often observers are intoning a dual diagnosis, i.e. an initial diagnosis of PIC but then with time and findings of unexplained visual field changes, sometimes elecetrophysiologic alterations, a diagnosis of AZOOR is then made. , This blurring of diagnoses can sometimes be a bit confusing unless one is convinced these clinical disorders are really the same, which yet needs to be proved.


Laboratory findings


Patients with multifocal choroiditis do not appear to originate from areas that are endemic for histoplasmosis. However, some give a history of an antecedent febrile illness.


Fluorescein angiographic evaluation of the punched-out lesions shows early hyperfluorescence, typical of a RPE window defect. Morgan and Schatz noted a fuzzy hyperfluorescent leakage late in the angiogram in some lesions. ICG angiography , tends to show more presumptive lesions than are noted on a clinical examination or on fluorescein angiography. Electrophysiologic testing does not demonstrate typical findings in multifocal choroiditis. Indeed, the results of the ERG will tend to be normal or borderline in most patients.


The disorders that need to be excluded when diagnosing this condition include many of those mentioned for MEWDS. One to note in particular is birdshot retinochoroidopathy (see Chapter 25 ). 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 25 ). 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 and color discrimination. The presence of cystoid macular edema appears to be as common in both entities in our experience, but the incidence of subretinal foveal nets is higher in this condition. In ocular histoplasmosis vitreous cells should not be present, and the lesions are generally larger. The incidence of subfoveal neovascular nets is higher in ocular histoplasmosis. Deutsch and Tessler reported their observations in 28 patients with a pseudohistoplasmosis syndrome; 43% were African-American and 32% had disciform scars. Further, 32% of the patients were presumed to have sarcoidosis, 29% tuberculosis, and 11% syphilis. Multifocal, creamy choroidal infiltrates in older patients can be due to a masquerade syndrome (see Chapter 30 ). Patients with familial juvenile systemic granulomatosis (Blau syndrome) have been shown to have multifocal choroiditis lesions ( Fig. 29-4 ). MEWDS patients will more often have unlateral disease, with yellow lesions at the level of outer retina, and often with spontaneous resolution.




Figure 29-4.


Multifocal choroiditis in patient from family with familial juvenile systemic granulomatosis (Blau syndrome).

(From Latkany PA, Jabs DA, Smith JR et al. Multifocal choroiditis in patients with familial juvenile systemic granulomatosis. Am J Ophthalmol 2002; 134: 897–904.)


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, i.e. the field defects were larger than the spots. This could be used as evidence that both multifocal choroiditis and PIC are just one manifestion of 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 RPE.


A provocative hypothesis is that this disorder is virally induced. Grutzmacher and coworkers ascribed RPE punched-out lesions to herpes retinitis in an otherwise healthy patient. Tiedeman evaluated 10 patients with the multifocal choroiditis and panuveitis syndrome for evidence of Epstein–Barr virus-specific antibodies. These patients were noted to have antibodies directed against the viral capsid antigen (immunoglobulin [Ig] M) or the Epstein–Barr early antigen. None of the control subjects tested was found to have these antibodies, but most did have viral capsid antigen IgG or Epstein–Barr 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 of developing the systemic complications of Epstein–Barr virus, an association not so far made. Further, chronic Epstein–Barr infection has been reported by Wong and coworkers to manifest a different intraocular inflammatory disease picture that responds to treatment with aciclovir. More recent studies have not borne out these observations. Spaide and colleagues evaluated 11 patients with multifocal choroiditis whom they compared with 11 gender- and age-matched control subjects for the presence of anti-Epstein–Barr virus antibodies. They found that neither the antiviral capsid antigen IgG nor the antinuclear antigen antibody titers were significantly different 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.


For patients with the PIC subgroup of disease, a novel mechanistic explanation was offered by Scheider. He hypothesized that young myopic women are more prone to develop 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 virus (see Case 29-2 ) 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. 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 apeared to no be no real histopathologic differences between the specimens from the multifocal choroiditis and the PIC eyes. These are in contrast to the report of Nölle and Eckardt that in nine vitrectomy specimens from patients with this disorder 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 70–80% 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 29-2 ). An eye that was evaluated showed B cells as well as substantial numbers of CD3+ lymphocytes. No microgranulomas were noted.


Therapy for multifocal choroiditis has centered on the use of immunosuppressive agents (see following 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. 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 did Levy et al. Of our 24 patients to date, 10 of the 17 who needed steroid therapy had cystoid macula edema. We have seen a moderately good response to steroid therapy, but the disorder can be stubbornly chronic, requiring at least consideration of the addition of other immunosuppressive agents. In our experience the visual prognosis is guardedly optimistic. Of great interest was the observation of 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. Foster’s group reported their experience in treating 19 patients with multifocal choroiditis. In their series, no patient had visual loss after they were given immunosuppressive therapy. Laser ablation of the subretinal net appears to be indicated; however, several caveats apply. The first is that there is the potential for 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 a further deterioration of vision. The combination of PDT and an intravitreal injection of triamcinolone has been reported to yield a positive therapeutic result. Cirino and colleagues reported the resolution of a CNV lesion secondary to PIC when a multiple sclerosis patient began receiving regular therapy with interferon (IFN)-β 1A . It would seem reasonable to suppose that the CNV is inflammatorily driven, and therefore treating the inflammation as well as giving some agent directed against the neovascular component, would be a good approach.


Nölle and Eckardt saw no impressive therapeutic effect of vitrectomy in nine patients with this disease. We have limited experience with the removal of submacular neovascular nets in such 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 and colleagues used photodynamic therapy to treat seven patients with multifocal choroiditis with subretinal neovascular membranes. All were myopic, and in four of the seven corticosteroid therapy was unsuccessful. The mean improvement in visual acuity was 0.86 line.




Acute retinal pigment epitheliitis


Clinical findings


Acute retinal pigment epitheliitis was first reported by Krill and Deutman, who described a group of relatively young patients with fairly subtle alterations at the level of the RPE. The condition resulted in an acute drop in visual acuity or metamorphopsia. This appears to be an acute inflammation of the retinal pigment epithelium, with a usually benign course. Some of the changes may be so mild that patients do not see a physician. Clusters of lesions, usually in the posterior pole, are noted. The lesions themselves are deep, fine, dark-gray, or black spots which in their acute stage are surrounded by a yellow halo. With resolution the halo may disappear and the lesions may appear darker in color. Fine subfoveal pigmentary clumping may be present, and could be due to an inflammation of the neurosensory retina. ,


Central serous retinopathy has been noted in this entity, presumably due to the perturbation of the RPE. Retinopathy may be either bilateral or unilateral and can affect both men and women. A gradual resolution with complete or near-complete return to good vision occurs within 6–12 weeks.


This ‘disorder’ seems to be a sign and not a real disease. So many things can affect the RPE, as this chapter suggests. We may see more and more of these RPE alterations as we become better as seeing RPE changes that were not obvious to the naked eye; an example today would be fundus autofluorescence. It may help to better understand the mechanisms. One example is the report by Hsu and Fineman using OCT. They showed outerneurosensory retinal involvement rather than RPE changes, suggesting that RPE alterations may be secondary. One can argue that recognizing the phenomenon is valuable in having some idea about its natural history.


Laboratory findings


The fluorescein angiogram will demonstrate an area of hypofluorescence surrounded by an area of hyperfluorescence. As the disorder progresses it leaves a somewhat depigmented background, and a ‘lacy’ hyperfluorescence may be noted. Central serous retinopathy may also be documented on angiographic examination.


Electrophysiologic testing may show an abnormal EOG during the acute phase of the disease, which will return toward normal as the disorder wanes. The finding does, however, strongly suggest that the disorder affects the RPE in a far more widespread manner than is recognized on the basis of ophthalmoscopic observations. ERG results and visually evoked cortical responses have been reported as being normal.


Because of the acute nature of the illness, it has been assumed that it is viral in origin. To date, however, no studies have corroborated this hypothesis. It appears to be an adverse event secondary to drug therapy. Zoledronate, a bisophonate used to treat tumor-induced hypercalcemia, was reported to induce acute retinal pigment epitheliitis in a patient (it has also been reported to induce uveitis). Loh et al. reported similar changes in a patients with Dengue fever.


Therapy


No therapy is generally called for because the disease should resolve spontaneously, although one patient was treated with nonsteroidal antiinflammatory drugs and vision returned to normal.




Acute posterior multifocal placoid pigment epitheliopathy


APMPPE is a term first used by Gass in 1968 to describe a syndrome of multiple large plaque-like lesions at the level of the RPE associated with temporary visual loss. Although there is no histologic confirmation that this is an inflammatory disease, the transient nature of the lesions and a possible association with a viral prodrome have led most authors to consider APMPPE as a manifestation of inflammation or infection at the level of the RPE or superficial choroid. It is probable that the clinical entity of benign diffuse external exudative retinitis first described by Scuderi and colleagues in 1948 represents part of the clinical spectrum that we now include in the diagnosis of APMPPE.


Clinical findings


The disease usually manifests with a sudden onset of visual blurring or flashing lights in a patient younger than 30 years of age. There is no gender predilection. Older patients have occasionally been reported. In some patients flashing lights precede the visual loss by several weeks. Most cases are bilateral and appear simultaneously in both eyes. However, unilateral cases and a delay in the appearance of the disease in the second eye by several weeks have also been noted. The anterior segments may have no significant inflammation, or there may be a 1+ to 2+ nongranulomatous inflammation. The vitreous may also have a mild to moderate inflammatory response. The characteristic clinical finding is multiple flat yellow-white (cream-colored) plaques at the level of the RPE ( Fig. 29-5 ). These vary in size and are clearly defined. The placoid lesions typically begin in the macula or posterior pole, with later-developing lesions noted more peripherally. The lesions do not extend beyond the equator. Cystoid macular edema is not a prominent part of this syndrome and is rarely seen, if ever. In the acute phase the vision is often moderately decreased but rarely falls below 20/400. Some patients may have only a mild decrease, with vision in the 20/25 to 20/40 range. Visual field testing will demonstrate a central or pericentral scotoma.




Figure 29-5.


Acute lesions of APMPPE.


Papillitis is occasionally seen in association with this disease. , Characteristically the vision begins to improve spontaneously within a few weeks after the onset of symptoms, but may be somewhat slower in resolving. Usually preceding the visual improvement by a few weeks is the initial resolution of the cream-colored placoid lesions. As the fundus lesions resolve, they lose their cream-colored appearance. Older lesions may resolve while new lesions are still appearing. There is often a residual RPE stippling, mottling, and depigmentation ( Fig. 29-6 ). Vision usually returns to near normal, but some patients may have mild residual visual deficits. Snellen acuity returns rapidly in most patients, but residual defects in visual fields, color vision, and the Stiles–Crawford effect may persist for up to a year. A few patients will have significant residual visual loss.




Figure 29-6.


A, Reparative phase with RPE clumping. B, Late phase of disease, showing a profound amount of RPE perturbation.


Although APMPPE is thought to be a nonrecurrent disorder and the prognosis has been considered favorable, there are reports of recurrences. Of 13 patients in one study, five had late recurrences in previously unaffected eyes. We observed one patient who had recurrent episodes of APMPPE leading to significant visual loss. We have seen disease begin as what appears as a severe form of APMPPE and take on more of a serpiginous character (see Chapter 28 ). We have called this condition ampiginous choroiditis (see Comment 29-2 and Fig. 29-7 ), an entity that seems very similar to that described in the literature as relentless placoid chorioretinitis.


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