A 36-year-old Hispanic female previously diagnosed with central serous chorioretinopathy of both eyes presents for evaluation of decreased vision in both eyes. The patient reported a history of progressive vision loss OU for the past month. Her past medical history was unremarkable. BCVA was 20/25 OD and 20/30 OS. Anterior segment examination was unremarkable apart from anatomically narrow angles OU. Undilated fundus exam was remarkable for only the presence of neurosensory detachments of both maculae (Fig 1).  SDOCT revealed hyporeflective subretinal fluid encompassing the macula, as well as hyperreflective mottling on the RPE and hyperreflective deposits both above the retinal pigment epithelium (RPE) and underlying the neurosensory detachment (Fig 2). Fundus autofluorescence (FAF) revealed a macular lesion with hyperfluorescence settling below an area of hypofluorescece (Fig 3). Additionally, increase autofluorescence was denoted surrounding the lesion (Fig 3). Given the clinical presentation, the patient was diagnosed with Best’s Disease (vitelliruptive stage) and was also referred to our comprehensive ophthalmologists for bilateral LPI. Genetic testing was offered to the patient to confirm a potential BEST 1 gene mutation.

BEST’S DISEASE

Best’s disease is an autosomal dominant macular dystrophy characterized by bilateral yellowish egg yolk-like lesions within the maculae. This accumulation of lipofuscin at the level of the RPE is associated with variable manifestations, as the disease progresses.   Best’s disease typically progresses through stages, which are associated with variable ophthalmoscopic findings and degree of visual impairment. The initial classic vitelliform stage is associated with an egg yolk-like lesion, which presents in early childhood to late teens. This stage is followed by the pseudo-vitelliform stage, characterized by a half-moon-shaped “pseudo-hypopyon” lesion. This stage represents a disruption of the lesion within the RPE, with part of the lesion’s material dissipating into the sub-retinal space and the remaining material of the lesion settling down within the RPE cell. The vitelliruptive stage, depicted in our case, is described as a “scrambled egg-like” appearance. This disruption is associated with decreased vision and/or visual distortion. The final stage, known as the atrophic stage, reveals scarring associated with more severe vision loss. Although Best’s disease may be initially asymptomatic, like in our case, decreased visual acuity and associated symptomology may ensue with progression.

Diagnostic Modalities

Variable diagnostic tests, including OCT, FAF, fluorescein angiography (FA), electro-oculogram (EOG), and genetic testing, have been used in the evaluation of patients with Best’s disease, helping to confirm the diagnosis and monitor the progression.

Historically, the most valuable clinical diagnostic test used to confirm Best’s disease was EOG. The EOG measures the standing potential of the RPE and thus, it is an indirect measurement of RPE function. A severely reduced light peak/dark trough (known as an Arden ratio) of <1.5 is associated with Best’s disease. 

The use of OCT, while not definitive can be helpful and is easily accessible for the diagnosis and monitoring of the disease progression. During the initial vitelliform stage, hyperflective-filled lesion is typically denoted within the RPE, correlating to the vitelliform material. The vitelliruptive stage (as seen in our case) may show hyporeflective fluid area with loss of the PIL, as well hyperreflective deposits seen above the RPE and below the neurosensory retina. As the material is resorbed throughout the vitelliruptive and into the atrophic stages; the final atrophic stage on the OCT will show deterioration of the macular region with associated outer retina and RPE disruption.

Another helpful test in the diagnosis of Best’s is the FAF. Early in the FAF the examiner would appreciate areas of hyperfluorescence located in the fovea region associated with increased lipofusion material of the lesion. This hyperfluorescent area tends to settle inferiorly during the psuedohypopyon stage of the disease. During the vitelliruptive stage, the FAF will show a mottled area of hypoautofluorescence, which becomes hypofluorescence during the atrophic stage. These changes in the FAF translate to the progressive dysfunction of the RPE.

Recently, given the fact that testing is easy and accessible, genetic testing has been used as the method of choice to confirm the disease. Best’s disease has an autosomal dominant inheritance pattern with mutations occurring on the long arm of chromosome 11q12, which encodes for the BEST1 gene. The BEST1 gene encodes for trans-membrane protein bestropin-1, which is localized within RPE cells. Of note, an autosomal recessive form of Best’s disease has been described with associated subretinal deposits outside the macula, diminished ERG findings, and may even be associated with glaucoma.

Management

Since there is no treatment for Best’s disease, the condition is simply monitored for progression. Intervention is only initiated in the unlikely development of an associated choroidal neovascular membrane (CNVM).

Summary

Best’s disease is an autosomal inherited maculopathy with variable stages presenting through the course of the disease. Although the egg yolk stage is classic for the disease, the distinct stages show variable clinical presentation and thus, cause a diagnostic challenge in an adult patient. The use of multi-modal diagnostic modalities can help confirm the diagnosis. When presenting with any maculopathy a full clinical exam including the use of various diagnostic modalities is imperative to derive the proper diagnosis and management.  

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Authors: Diana Shechtman OD FAAO, Manar Doughouz BS, Daniel Montenegro MD, Jose Danny Diaz MD