The White Dot Syndromes

Yoko Matsumoto, MD, PHD; Sebastian P. Haen, MD; Richard F. Spaide, MD

Disclosures

Compr Ophthalmol Update. 2007;8(4):179-200. 

In This Article

Acute Posterior Multifocal Placoid Pigment Epitheliopathy

In 1968, Gass described three young women who developed a rapid, but transient, loss of visual acuity associated with multiple yellow-white placoid lesions at the level of the RPE.[2] The disorder was presumed to primarily involve the RPE and was named with the descriptive term, acute posterior multifocal placoid pigment epitheliopathy. Van Buskirk et al, and Deutman et al hypothesized that an acute inflammation of the choriocapillaris was the main etiologic problem in APMPPE.[3,4] The disease shows no gender preference, most commonly affects people between the ages of 20 and 50 years old,[5] and Caucasians may be affected more than other races.[6]acute posterior multifocal placoid pigment epitheliopathy is a rare entity, and as such, estimates of the prevalence and incidence of APMPPE are not available; however, there is no indication that APMPPE appears in endemic or epidemic clusters.[7]

Acute posterior multifocal placoid pigment epitheliopathy is often preceded by flu-like symptoms, such as fever, malaise, and headaches,[8] followed by sudden, painless loss of vision associated with central and paracentral scotomas. Approximately one-third of the patients report an antecedent viral illness;[2,5] however, the report of viral illness is usually based on patient recall and not on acute and convalescing viral titers.[9] On occasion, APMPPE can be related to an identifiable systemic disorder, including Graves-Basedow disease, necrotizing vasculitis, ulcerative colitis, nephritis, renal cell carcinoma, Wegener granulomatosis, Lyme disease, mumps, cerebral involvements, and to a postvaccination complication of the hepatitis B vaccine.[8,10,11,12,13,14,15,16,17,18,19,20,21,22,23] An elevated prevalence of the human leukocyte antigens HLA-DR2 and HLA-B7 has been reported.[7]

Most cases of APMPPE do not appear to be related to currently identified systemic disorders. However, after healing, patients complain about fever, malaise, and, not infrequently, neck stiffness occurring prior to the onset of APMPPE. We began testing patients by looking at the acute and convalescing titers for enteroviruses, but we have yet to find one patient with signs of this infection. It seems likely that some infectious agent is involved in at least some of the patients, although the agent has not yet been identified. Variations in immune response among certain patients at risk may predispose them to develop APMPPE in the face of an infection that would not cause ocular problems in patients with differing immune responses.

The fundus changes are usually bilateral, but may be asymmetrical or even unilateral.[24] Each discrete lesion is round, yellowish-white, and nearly the same size as the optic disk. Large lesions appear as groups of confluent smaller lesions. Most of the lesions are found in the posterior pole, and lesions can be seen peripheral to the arcades only occasionally. The lesions do not appear all at once; they may appear over a period of days or even weeks. There may be cells in the vitreous, retinal vasculitis, choroidal vasculitis, and subtle papillitis concurrent with the appearance of the lesions. Additional sequelae, which are more severe but less common, include central retinal vein occlusion, CNV, neovascularization from the optic disk, and subhyaloid hemorrhage. Atypical findings include papillitis, central retinal vein occlusion, neovascularization of the optic disk, choroidal neovascularization, exudative neurosensory retinal detachment, and subhyaloid hemorrhage.[25,26,27,28,29,30] Although cystoid macular edema (CME) is frequently seen in patients with ocular inflammatory diseases, patients with APMPPE rarely get significant CME, even if there are subfoveal lesions.

The APMPPE lesions have a stereotypical resolution over a period of 1 to 2 months. In the first 1 or 2 weeks, the lesions start to become more transparent, so that large choroidal vessels can be seen during fluorescein angiography, particularly in the center of the lesion. The pigmentation at the level of the RPE adopts a more granular appearance within the lesion. The visual acuity usually begins to improve, but often does not reach a peak until 2 months or so after infection.

In the acute stages, the early phase fluorescein angiography and indocyanine green angiography (ICG) reveal hypofluorescence of the lesions[31] (Figure 1).[32,33,34] There are more lesions that are hypofluorescent in the early phases of angiography than there are yellow-white lesions visible by ophthalmoscopy (Figure 1). In the subacute phase, starting 1 or 2 weeks after the onset of the disease, the lesions have increasing fluorescence within the central lesion early in the angiogram, with intense staining later in the angiogram, the characteristic central fluorescence suggested by some investigators indicates the recurrence of blood flow into the central portion of the lesion earlier than into the peripheral parts.

However, this central hyper- fluorescence is seen at different time points in fluorescein angiography compared to ICG angiography, suggesting the early central fluorescence may be related to intrinsic characteristics of the lesion. With further resolution of the lesion, there is an increasing transmission defect seen in which the larger underlying choroidal vessels can be seen; this implies that the obstruction of view ordinarily caused by both the RPE and choriocapillaris is diminished in healing APMPPE. After resolution of the inflammatory phases, patients may have areas of poor perfusion, but these areas are usually not ischemic. Broader areas of choroidal perfusion defects suggest an alternate diagnosis, usually serpiginous choroidopathy.

Autofluorescence imaging in APMPPE shows several interesting findings. Early lesions show almost no changes, but the subacute lesions have autofluorescence abnormalities that mirror those found in fluorescein angiography. The regions staining intensively in fluorescein angiography show no autofluorescence, but the areas showing blocking of fluorescein fluorescence are hyperautofluorescent. The early angiographic findings show more choroidal perfusion abnormalities than there are overlying visible yellowish-white fundus lesions. In addition, the autofluorescence changes are fewer in number and lack the perfusion changes seen during angiography. This implies that the choroidal changes are primary in this condition.[35]

Optical coherence tomography (OCT) shows a nonspecific increase in reflectivity from the normally lucent area corresponding to the outer nuclear layer. With the healing process, these changes resolve.[36] Visual field testing can show the whole spectrum from normal findings to dense scotomata. Although Gass reported that most patients with acute APMPPE have normal electroretinograms (ERGs) and electro-oculograms (EOGs),[37] electrophysiologic testing can reveal abnormal ERG and EOG findings.

After resolution, the lesions have varying degrees of granularity of pigmentation, with flecks of pigment interspersed by areas of depigmentation. There are usually early transmission defects early on in the fluorescein angiogram. Some patients have increased fluorescence around the outer borders of healed lesions with somewhat decreased fluorescence centrally, which may indicate a decrease in the perfusion centrally as a consequence of the inflammation.

There is no evidence that treatment, in particular corticosteroid therapy,[14,19,24] alters the natural course of the disease. This is not to say that corticosteroid treatment does not work; rather, there have not been any controlled trials. Some patients with APMPPE experience concurrent vasculitis of the central nervous system.[38] Aggressive treatment of cerebral vasculitis is a medical emergency. If a patient with findings consistent with APMPPE presents with severe headaches, a neuroophthalmologic workup is required.

Visual recovery is common and expected in APMPPE (over 90%);[39] however, some patients with severe foveal involvement may have permanent visual acuity of 20/40 or less. Recurrences of the disease are rare. Long-term loss of vision is related to complications, such as extensive RPE changes, choroidal neovascularization, or the atypical finding as described above. Risk factors for poor visual prognosis include foveal involvement at initial presentation, older age at onset, unilateral disease, an interval before involvement of the second eye of at least 6 months, recurrence of the disease, and leakage from choroidal veins.[40,41]

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