Best Disease 

Updated: Oct 01, 2018
Author: Michael Altaweel, MD, FRCSC; Chief Editor: Donny W Suh, MD, FAAP 

Overview

Background

Best disease, also termed vitelliform macular dystrophy, is typically an autosomal dominant disorder, which classically presents in childhood with the striking appearance of a yellow or orange yolklike lesion in the macula. Dr Franz Best, a German ophthalmologist, described the first pedigree in 1905.[1]

The lesion evolves through several stages over many years, with increasing potential for adverse visual outcome. A hallmark of the disease is a markedly abnormal electro-oculogram (EOG) in all stages of progression and in phenotypically normal carriers.[2] The adult form varies, as described and shown in the image below.

Adult vitelliform macular dystrophy resembles Best Adult vitelliform macular dystrophy resembles Best disease, but it can be differentiated by its later age of onset, smaller lesion, and normal electro-oculogram testing.

Pathophysiology

Lesions in Best disease are restricted to the eye. No systemic associations exist. Abnormalities in the eye result from a disorder in the retinal pigment epithelium (RPE). A dysfunction of the protein bestrophin results in abnormal fluid and ion transport by the RPE.[3] Lipofuscin (periodic acid-Schiff [PAS] positive) accumulates within the RPE cells and in the sub-RPE space, particularly in the foveal area. The RPE appears to have degenerative changes in some cases, and secondary loss of photoreceptor cells has been noted.[4] Breakdown of RPE/Bruchs membrane can allow choroidal neovascularization to develop as a late complication.

Epidemiology

Frequency

United States

Best disease is rare.

International

Best disease is rare.

Mortality/Morbidity

Visual acuity is good in the previtelliform stage. Even with the egg-yolk appearance, visual acuity is maintained in the range of 20/20 to 20/50 (6/6 to 6/15) for many years. The breakup of the vitelliform stage, leading to the scrambled egg stage, may be accompanied by visual acuity deterioration. It is the final stages of geographic RPE atrophy with possible development of choroidal neovascular membrane that is associated with further deterioration in acuity.[5, 6] These changes usually occur in individuals older than 40 years. Various studies have shown that most individuals retain reading and driving vision in at least 1 eye into adulthood (88% have 20/40 or better vision). Only 4% of these individuals develop vision less than 20/200 in the better eye.

Race

Best disease is most common in individuals of European ancestry but can also be found in individuals of African and Hispanic ancestry.

Sex

No known gender predilection exists.

Age

Usual onset of Best disease is from 3-15 years, with an average age of 6 years. The condition often is not detected until much later in the disease because visual acuity may remain good for many years. The atrophic stage usually occurs after age 40 years.

Prognosis

Prognosis for Best disease is mixed. Some carriers will never phenotypically express the disorder. Some individuals will never have progression beyond the earliest stages of the disease and will maintain better than 20/40 vision in both eyes. In general, most people will maintain reading vision in at least 1 eye throughout life. In one study, 88% of patients retained 20/40 or better visual acuity, and only 4% of them had 20/200 or worse visual acuity in the better eye. The deterioration of vision usually is very slow and is not significant in most individuals until after age 40 years.[7, 8, 9]

Patient Education

Genetic inheritance: Provide an explanation of autosomal dominant inheritance to the patient and family members. In genetic counseling, discuss carrier state, variable penetrance and expressivity, and implications for offspring. Recommend familial evaluation.

Occupational counseling: Discuss the patient's prognosis and the possible implications on career direction.

Routine examination: Emphasize regular examinations because changes in fundus appearance over time may elucidate the eventual prognosis. Conduct evaluation for choroidal neovascularization.

Amsler grid: Teach use of this tool to identify central visual field changes.

Low vision aids: Assistive devices may be necessary if visual acuity deteriorates. Refer to a low vision specialist or organization.

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article Macular Degeneration.

 

Presentation

History

Many individuals with Best disease initially are asymptomatic, with fundus lesions noted on examination. Visual symptoms can include decreased acuity (blurring) and metamorphopsia. These symptoms may worsen if the disease progresses to the atrophic stage.

Physical

Best disease has variable clinical expression. Some carriers have a normal examination and remain asymptomatic. Findings are usually bilateral and can be asymmetric, but unilateral presentations have been reported.[10] Hyperopia is common.[11, 7, 12, 13]

Visual acuity

Visual acuity varies by stage, as follows:

  • Previtelliform stage - 20/20

  • Vitelliform stage - 20/20 to 20/50

  • Pseudohypopyon stage - 20/20 to 20/50

  • Vitelliruptive stage - 20/20 to 20/100

  • Atrophic stage - Acuity may reduce to less than 20/200

Fundus appearance

Several stages of fundus appearance are described.[14, 15] Not all individuals progress beyond the early stages.[16] Other individuals can skip from the earliest stages to an atrophic-appearing macula. Unilateral findings and multifocal lesions have been described.[17, 13]

  • Stage 1 (previtelliform) - Normal macula or subtle RPE pigment changes, EOG abnormal

  • Stage 2 (vitelliform), shown below - Well-circumscribed, 0.5-5 mm round, elevated, yellow or orange lesion; described as an egg-yolk appearance; usually centered on the fovea; can be multifocal; the rest of the fundus has a normal appearance.

    Classic egg-yolk appearance in the second (vitelli Classic egg-yolk appearance in the second (vitelliform) stage of vitelliform macular dystrophy. The 0.5-6 mm diameter yellow or orange lesion results from an accumulation of lipofuscin beneath and within the retinal pigment epithelium. This lesion is usually noted in individuals aged 3-15 years. Visual acuity is most often preserved in the 20/20 to 20/40 range.
  • Stage 3 (pseudohypopyon), shown below - Yellow material can break through the RPE and accumulate in the subretinal space in a cyst with a fluid level formed. The yellow material will shift with extended changes in position (60-90 min). This stage most often is found in the teenage years, but it has been described in individuals aged 8-38 years.

    The pseudohypopyon (stage 3) lesion is found in th The pseudohypopyon (stage 3) lesion is found in the teenage or later years. It results from a break in the retinal pigment epithelium, allowing accumulation of the yellow substance in the subretinal space with the formation of a fluid level. This fluid can shift over 60-90 minutes with positioning.
  • Stage 4 (vitelliruptive), shown below - Scrambled egg appearance is due to the breakup of the uniform vitelliform lesion. Pigment clumping and early atrophic changes may be noted. Visual acuity may deteriorate moderately.

    The scrambled egg appearance of stage 4 results fr The scrambled egg appearance of stage 4 results from a deterioration of the uniform cystic lesion noted in stage 2 (egg-yolk appearance). At this point, the visual acuity can begin to worsen.
  • Stage 5 (atrophic), shown below - As the yellow material disappears over time, an area of RPE atrophy remains. This appearance is difficult to distinguish from other causes of macular degeneration. Visual acuity can deteriorate more markedly at this stage.

    The atrophic stage (stage 5) may be accompanied by The atrophic stage (stage 5) may be accompanied by the deposition of pigment or choroidal neovascularization, both of which can lead to visual deterioration.
  • Stage 6 (choroidal neovascular/cicatricial) - Following the atrophic stage, choroidal neovascularization can develop,[6] leading to a whitish subretinal fibrous scar.

Causes

Best disease is generally autosomal dominant with variable penetrance. Genetic linkage has mapped the disease to the long arm of chromosome 11 (11q12-q13). The gene responsible has been named bestrophin1 (BEST1). The abnormality is in the RPE, as noted on histopathology and electrophysiology testing. An autosomal recessive form of Best disease has been described.[18]

Complications

Although uncommon, choroidal neovascularization can occur following the atrophic stage, and it can be responsible for further deterioration in visual acuity. A disciform scar may result.

Plaques of white subretinal fibrous tissue can develop in conjunction with the atrophic stage. Visual acuity is often reduced to 20/100 or worse with this appearance.

 

DDx

Diagnostic Considerations

Autosomal-recessive bestrophinopathy

Autosomal-recessive bestrophinopathy results from a homozygous or compound heterozygous BEST1 mutation. The age of onset is between 4 and 40 years, and the condition results in vision deterioration to below 20/70 within a few years. Fundus examination reveals irregular RPE and white subretinal deposits in the macula and midperiphery. Affected individuals may not have vitelliform lesions. EOG is severely reduced, and the pattern ERG is markedly abnormal.[18]

Autosomal-recessive bestrophinopathy: Atrophic cen Autosomal-recessive bestrophinopathy: Atrophic central lesion and white subretinal deposits along the vascular arcades in a 14-year-old female with 20/70 vision and no family history of Best macular dystrophy.

Differential Diagnoses

  • Adult-Onset Vitelliform Macular Dystrophy (Pattern Dystrophy)

  • Autosomal-Recessive Bestrophinopathy

  • Basal Laminar Drusen

  • Central Serous Chorioretinopathy With Subretinal Fibrin

  • Fundus Flavimaculatus (Stargardt Disease)

  • Resolving Subretinal Hematoma

 

Workup

Laboratory Studies

Genetic testing: This disorder has been mapped to a genetic defect in chromosome 11 (region q12-q13.1).[19, 20, 21, 9] A mutation in BEST1 is more probable when a vitelliform lesion is accompanied by a reduced Arden ratio on EOG testing.[22] Although most individuals with Best disease have an autosomal dominant defect, there are individuals with autosomal recessive inheritance.[13]

Imaging Studies

Fluorescein angiogram reveals blockage of choroidal fluorescence by the vitelliform lesion. The angiogram is otherwise normal at this stage. In the atrophic stage, a transmission defect is noted; this is shown in the image below. If a choroidal neovascular membrane develops, then a corresponding area of hyperfluorescence with leakage will be found in fluorescein or indocyanine green angiography.[6, 23]

The fluorescein angiogram of the latter lesion rev The fluorescein angiogram of the latter lesion reveals a transmission defect consistent with atrophic changes in the retinal pigment epithelium. This appearance also can be found in the later stages of Best disease.

Fundus photography is useful for documentation and follow-up of fundus lesions.

Spectral-domain optical coherence tomography (SD-OCT) demonstrates abnormality in the region between the RPE and the inner segment/outer segment line visualized on high resolution studies. Disruption of the outer retina is noted in stages 2-4, while absence is seen in stage 5 (atrophic).[24] Enhanced depth imaging reveals choroidal thinning in advanced disease, correlating to a decline in visual acuity.[25] Cystoid macular edema and choroidal neovascularization can be identified on OCT (see image below).[26] Subretinal fluid is associated with worse visual acuity.[24]

Spectral domain optical coherence tomography demon Spectral domain optical coherence tomography demonstrates subretinal lesion with adjacent cystoid macular edema.

Adaptive optics demonstrates disruption of photoreceptor integrity with some retention of function,[27] consistent with the retention of visual function found through the earlier stages of Best disease.

Other Tests

Electro-oculogram

The EOG, which reflects RPE function, is the most diagnostic test for evaluating vitelliform macular dystrophy. In the majority of such individuals, a severe decrease occurs in light response, reflected by an Arden (light-peak/dark-trough) ratio of 1.1-1.5. (The normal Arden ratio is 1.8.) Carriers will also have an abnormal EOG result.[28] No correlation exists between EOG result and disease stage, visual acuity, or patient age. EOG results are usually symmetric for both eyes.[29]

The EOG is very useful for distinguishing this diagnosis from its differential. The EOG result is usually normal in adult foveomacular dystrophy.

Electroretinogram

The full-field electroretinogram (ERG) result is normal in this condition. A focal ERG or multifocal ERG, concentrating on macular function, reveals abnormal function corresponding to the area of anatomical disruption.[30]

Histologic Findings

This disease primarily affects the RPE. Lipofuscin accumulates within RPE cells and in the sub-RPE space. This material stains PAS-positive. The RPE can degenerate, and macrophages containing PAS-positive material have been found to migrate into the outer retina. The choriocapillaris is normal. Choroidal neovascularization has been demonstrated.[31, 4]

Staging

See Physical.

 

Treatment

Medical Care

No treatment exists for vitelliform macular dystrophy (Best disease). Secondary choroidal neovascularization (CNVM) can be managed with direct laser treatment or photodynamic therapy[32, 33] ; however, treatment with anti–vascular endothelial growth factor (VEGF) therapy, including intravitreal injection of bevacizumab, has been reported more recently.[34, 5] CNVMs may spontaneously resolve without treatment, but vision outcomes are better with anti-VEGF than with observation alone.[34]

Evaluation of family members is important to identify carriers and individuals with vitelliform macular dystrophy. Both genetic counseling and career counseling are provided.

Future directions for research may include gene therapy targeting BEST1.[35]

Consultations

Consult a vitreoretinal disease specialist for the initial diagnosis, electrophysiology testing, and family assessment, as well as for the long-term follow-up care of patients to monitor disease progression and choroidal neovascularization.

Consult a low vision specialist who can provide specialized equipment to assist individuals who have significant deterioration in visual acuity in both eyes.

Occupational counseling is important. Although most patients retain reading vision in at least 1 eye throughout life, visual deterioration can occur, particularly beyond age 40 years. This knowledge may influence the choice of career.

Diet

Diet is not known to influence the progression of Best disease.

Activity

Physical activity does not influence the progression of Best disease.

Long-Term Monitoring

Examination of visual acuity and fundus lesions should be performed on a schedule dictated by the current stage of the disease. If visual changes occur at any stage, then an earlier visit should be scheduled, as follows:

  • Previtelliform stage - Yearly

  • Vitelliform/pseudohypopyon stage - Every 6 months

  • Scrambled egg stage - Every 6 months

  • Atrophic stage - Every 6 months to yearly

Patients in the atrophic stage should routinely use an Amsler grid. Changes in the central visual field should prompt an early visit to evaluate for choroidal neovascularization.

The electrophysiology test is usually only necessary once to establish the diagnosis. Initial results remain fairly stable during disease progression.

Fluorescein angiography should be performed at any visit if choroidal neovascularization is suspected.

 

Medication

Medication Summary

No medications are used to treat Best disease. Docosahexaenoic acid supplementation has been studied in a small clinical trial; no benefit in retinal or retinal pigment epithelial function was found.[36]