Best Disease

Etiology

The cause of the disease is a mutation in the VMD2 or BEST1 gene at chromosome 11q12-q13.[5][6] The product of this gene is a transmembrane protein called Bestrophin 1, located predominantly at the basolateral membrane of the RPE.[7] Bestrophin 1 acts as both a regulator of intracellular Ca++ signaling and a pentameric anion channel.[7] Bestrophin 1 functions as a calcium-activated chloride channel and also may work as a channel for other anions, including bicarbonate.[7] Also, it plays a significant role in the calcium homeostasis of the RPE.[7] In effect, bestrophin plays a crucial part in the regulation of the ionic environment of the RPE and/or subretinal space. The ionic balance of the RPE is an important factor for adhesion between the retina and the RPE. Also, the mutation causes reduced Arden ratio in EOG in Best vitelliform macular dystrophy both in the carrier and the affected individuals.

Approximately 5% of individuals with BEST1 mutation will have normal or near-normal macular findings.[8]

The mutation BEST1 causes multiple diseases, including:

• Vitelliform macular dystrophy 2 or BVMD (Phenotype MIM No. 153700)
• Autosomal recessive bestrophinopathy (Phenotype MIM No. 611809)
• Retinitis pigmentosa 50 (RP50)/concentric retinitis pigmentosa (Phenotype MIM No. 613194)
• Autosomal dominant microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 193220 (Phenotype MIM No. 193220)
• Autosomal dominant vitreoretinochoroidopathy (Phenotype MIM No. 193220)
• Adult-onset vitelliform macular dystrophy[7]

Epidemiology

The prevalence of Best vitelliform macular dystrophy was noted to be between 1 in 16,500 to 1 in 21,000 in a study conducted at Olmsted County, Minnesota.[9] Both males and females are affected. The usual age at presentation is within the first two decades, and detection is usually incidental. The macular lesion may be noted for the first time as late as at 75 years of age.[8]

Pathophysiology

There is deposition of yellow material within the retinal pigment epithelium (RPE), the subretinal space, and the photoreceptor zone.[10] A break/disturbance in the RPE/Bruch's membrane[11] results in a late complication of a choroidal neovascular membrane (CNVM).

Histopathology

Only a few reports have investigated the histopathological features of Best vitelliform macular dystrophy.

Histopathology of a 69-year-old male with BVMD showed[12]:

• Accumulation of lipofuscin within the RPE, particularly at the fovea. Lipofuscin was confirmed by staining, ultrastructural appearance, and autofluorescence properties.
• Other features included:
  • Accumulation of heterogeneous material between RPE and Bruch's membrane, which likely derived from degenerating RPE cells containing lipofuscin
  • Loss of foveal photoreceptors above the lesion
  • Photoreceptor outer segment debris and phagocytic cells in the subretinal space

Histology of another eye showed 'well-circumscribed area of RPE hyperplasia, accumulation of lipofuscin in the RPE, deposition of granular material in the photoreceptors, macrophages, and drusen.'[13]

Mullin and colleagues reported a male who was noted to have small macular vitelliform lesions and extramacular subretinal flecks in both eyes for the first time at 75 years of age.[8] On histopathology at 93 years, the eye showed attenuated outer nuclear layer (ONL) usually associated with normal RPE, degeneration of photoreceptors with loss of RPE at the central macula, and drusen and basal laminar deposits at the peripheral flecks. Bestrophin was noted to be present at the basolateral and apical membrane of RPE.

Histopathological evaluation of a 28-year-old male with vitelliruptive stage 'with some features of a pseudohypopyon' revealed diffuse RPE abnormality with an accumulation of lipofuscin. Lipopigment was noted 'within the RPE, within macrophages in the subretinal space, and within the choroid.'[14]

Frangieh and colleagues suggested that the changes in the neurosensory retina were primary, and RPE changes were secondary.[15] The choriocapillaris was normal, and they noted abnormal fibrillar material underneath RPE cells at the area of photoreceptor loss. Disruption in Bruch's membrane with CNVM was also noted. They found lipofuscin and melanolipofuscin deposit in RPE, and 'PAS-positive, acid-mucopolysaccharide-negative, electron-dense, finely granular material was deposited in the inner segments of the degenerating photoreceptors and the Mueller cells.'[15] This material corresponds mainly to A2E.[16]

Also, the brilliant autofluorescence of the vitelliform lesion might suggest the deposited material to be A2E or lipofuscin. However, angiographic evidence of generalized deposition of lipofuscin in RPE causing block fluorescence (dark choroid in fluorescein angiogram as seen in Stargardt disease) is not a feature in BVMD.

History and Physical

The lesions are usually detected incidentally, but symptoms may include dimness of vision, metamorphopsia or scotoma.

Evaluation

The disease usually involves the eye only with no systemic manifestations.

Refractive error (usually hypermetropia) may be present. The fundus appearance is drastic and shows a single egg-yolk like symmetrical subretinal deposit at the macula bilaterally, but the visual acuity is usually normal. However, there are reports of unilateral cases in patients with BEST1 mutation and bilateral reduced EOG Arden ratio with normal electroretinogram.[17] Best vitelliform macular dystrophy with affected EOG may have multifocal vitelliform lesions.[18] 

Typically, the optic nerve and retinal vessels are normal, and bony spicules are not seen.

The vitelliform macular lesion may progress through the typical stages, may regress with time, or may be associated with newer extramacular lesions. 

Visual field - Usually, there is no peripheral visual field defect. Central scotoma may be present.

Autofluorescence - The vitelliform material is typically brilliantly autofluorescent and has a round or oval shape in the vitelliform stage. In pseudohypopyon stage, the autofluorescence is visible in the inferiorly deposited yellow material. Vitelliruptive disease shows speckled autofluorescence. The atrophic stage shows hypo-autofluorescence. Peripheral ring/small circumferential dots of hyper-autofluorescence may be noted in the vitelliruptive stage.[19] Late stages characteristically show central hypo autofluorescence and peripheral hyper-autofluorescence.[20] Retinal dysfunction and autofluorescence revealed a centrifugal pattern of loss from center to periphery in a study.[20] The central area of atrophy correlates with low visual acuity, reduced autofluorescence, central scotoma, reduced color vision, and reduced pattern ERG (PERG) response.[20] 

Fundus fluorescein angiogram (FFA)- FFA is crucial to rule out choroidal neovascular membrane (CNVM), which shows fluorescence that increases in size and intensity with time. The vitelliform deposit usually causes hypofluorescence secondary to blocked fluorescence. The atrophic stage reveals a window defect. There is no 'black choroid' appearance on FFA, as seen in Stargardt disease. 

Optical coherence tomography (OCT) - In the vitelliform stage, the OCT reveals the deposit of homogenous hyperreflective material.[21] In the pseudohypopyon stage, the vertical OCT scan shows clear fluid superiorly and a sharp margin of the deposited vitelliform material. In the atrophic phase, retinal thinning may be noted similar to geographic atrophy in age-related macular degeneration. Subretinal/intraretinal fluid, and/or subretinal hemorrhage may characterize the CNVM stage. The location of vitelliform material has undergone study with both time-domain and spectral-domain OCT.

In the subclinical stage, the middle highly reflective layer or middle HRL (interdigitation zone or IZ/cone outer segment tip line or COST) showed notable thickening throughout the macula, especially at the fovea.[22] The location of this middle HRL is between inner HRL (inner-segment outer segment junction/ellipsoid zone or EZ) and the outer HRL (RPE-Bruch's membrane complex). There was thinning of ONL. In the vitelliform stage, the hyper-reflective vitelliform material exists between middle HRL and outer HRL. The middle HRL showed thickening at areas of the macula not involved with a vitelliform deposit, and there was thinning of ONL. Pseudohypopyon characteristically shows as optically clear space between the neurosensory retina and outer HRL, some disruptions in the inner HRL, lengthening of the outer segment of photoreceptors, small hyperreflective mounds over the outer HRL, and thinning of ONL. The OCT in vitelliruptive stage showed disruption in both inner and middle HRL, shortening of outer segments, and hyperreflective deposits over the outer HRL.[22]  OCT may show fibrotic pillars.

In another study, the outer retinal layers were noted to be disrupted in stage 2 through 4 disease (vitelliform, pseudohypopyon, and vitelliruptive stage), and absent outer retinal layers were noted in the atrophic or cicatricial stage.[23] Poor visual acuity is associated with subretinal fluid and disruptions of EZ.[21][23]

EOG - The normal light peak to dark trough ratio (Arden ratio) is at least 1.85. In BVMD (all stages, even with no apparent fundus lesion, all patients, and carriers with normal fundus), the light peak is universally reduced, resulting in an Arden ratio of 1.50 or less usually.

The diagnosis of BVMD needs the following criteria

• Presence of one of the typical lesions of BVMD
• Abnormal EOG
• Dominant mode of inheritance
• Typical natural course and onset of the disease as in BVMD

ERG - Typically, the ERG is normal.

Dark adaptometry is normal. 

Color vision and contrast sensitivity may be affected.

Treatment / Management

Best vitelliform macular dystrophy without a choroidal neovascular membrane (CNVM) needs no treatment. Dilated fundus evaluation of family members, electrophysiological testing (EOG, ERG), and genetic analysis are essential in establishing the diagnosis. Regular follow-up is vital for the early detection of complications, especially CNVM.

The CNVM may respond favorably with anti-vascular endothelial growth factor agents (anti-VEGF agents like bevacizumab, ranibizumab, or aflibercept).[24] Other options include laser and photodynamic therapy.[25] The CNVM may regress spontaneously also, but the visual outcome may be better with anti-VEGF agents.[24] On average, one bevacizumab injection was necessary for BVMD with CNVM in the study by Khan and colleagues.[24](B3)

All patients should receive good refraction.

In patients with significant cataracts, cataract surgery may lead to visual improvement. 

Amsler grid is an important tool for home monitoring and may detect metamorphopsia early.

Low vision aids, including magnifiers and telescopes, may help to rehabilitate patients with atrophic disease with poor vision.

Differential Diagnosis

The differential diagnoses include:

• Central serous chorioretinopathy with fibrin
  • There is the presence of serous pigment epithelial detachment and area of subretinal lucency at the location of the leak[26] 
  • FFA features are typical and show leaks (ink-blot, smoke-stack or diffuse) and pigment epithelial detachment
• Adult-onset vitelliform macular dystrophy (a variant of pattern dystrophy)
  • The patients present at late-middle or old age with visual decline
  • The lesion is smaller and may not pass through the typical stages of BVMD
  • There may be a mutation of the BEST1 or PRPH2 (RDS) gene. Up to one-third of patients have abnormal EOG and the disease is dominantly inherited
• Subretinal granuloma due to choroidal tuberculosis/sarcoidosis
  • There is clinical or angiographic evidence of inflammation
• Wet age-related macular degeneration
  • Distinguishing features are old age and irregular lesion
  • Disciform scar has a whitish appearance rather than the typical yellow, smooth appearance of BVMD
• Acute exudative vitelliform maculopathy
• Fundus flavimaculatus with large flecks
• Large dehemoglobinized subretinal hemorrhage
• Basal laminar drusen

Staging

The disease usually goes through several stages:

1. Previtelliform/subclinical stage - The fundus is normal in an asymptomatic infant or child. However, EOG is abnormal.
2. Vitelliform stage or egg yolk stage - Best vitelliform macular dystrophy gets its name from this stage, and this stage typically presents in infancy or early childhood. An egg-yolk like round or oval yellow smooth elevated lesion with a well-defined margin is seen at the macula. The size is 0.5 to 2 disc diameters, and the lesion usually centers on the fovea but not in every case. The size/site/shape/stage of the lesion may not be very symmetrical. Vision is usually normal or minimally affected despite the drastic fundus appearance. The lesion(s) may be multiple and extramacular and be very large with a geographic shape.
3. Pseudohypopyon stage - The vitelliform deposits gravitate down in the subretinal space with a horizontal upper level, usually at puberty. The fluid above this deposit is clear. One hypothesis is that the retinal pigment epithelium takes up the yellow deposit, and heavier material gravitates down. Vision is usually good at this stage. After a change of head position for 60 to 90 minutes, the pseudohypopyon may shift.
4. Vitelliruptive stage or scrambled egg stage is due to the breakup of the smooth and uniform vitelliform material giving a nonhomogenous look. Visual acuity starts to deteriorate at this stage. A small area or areas of pigmentation/atrophy may be noted.
5. Atrophic stage- The vitelliform material is no longer visible, and there is an area of atrophy and pigmentation which may simulate geographic atrophy due to age-related macular degeneration. Marked visual deterioration is present. This stage usually occurs after 40 years of age.
6. Cicatricial and choroidal neovascularization - Subretinal bleed may be present due to CNVM. This stage is associated with poor vision and may lead to subretinal fibrosis.

Prognosis

The visual prognosis is usually good. Best-corrected visual acuity is:

• 20/20 in the pre-vitelliform stage
• 20/20-20/60 in the vitelliform or pseudohypopyon stage
• 20-20-20/120- in the vitelliruptive stage
• The visual acuity may be worse than 20/200 in the atrophic or cicatricial/CNVM stage

In a large series,[27] 77% of the eyes with Best vitelliform macular dystrophy had at least 20/40. In 8-10 years, 19% of the eyes with atrophic stage or fibrous scar lost at least two lines.

Complications

The complications of the disease include

• Choroidal neovascular membrane leading to disciform scar
• Subretinal fibrosis
• Macular hole (rare)