Best vitelliform macular dystrophy is an autosomal-dominantly inherited disorder whose familial occurrence was first described in 1905 by Friedrich Best in a family of German ancestry.⁶ Previously, in 1883, Adams had described a single patient with this disease.¹ In 1950, the Belgian ophthalmologists Zanen and Rausin⁵³ first used the description vitelliform when referring to the macular lesion that they observed in patients with this disease. The term vitelliform (“egg-yolk-like”) has its origin from the Latin word vitellus meaning “egg-yolk.”

The fundus findings include a spectrum of phenotypic expressions. The most distinctive macular lesion, which is most often initially discovered between the ages of 3 and 15 years, demonstrates a sharply circumscribed, bilateral, yellow, “egg-yolk-like” sunny-side-up appearance (figure 66.1). This clinical phenotype has been observed as early as 1 week and 3 weeks of age^3,13 and as late as age 74 years.¹¹ It is generally between 1 and 2 disk diameters in size, although its size may vary from as small as approximately one half to as large as three or four times the diameter of the optic disk.²⁹ The presence of this macular lesion is still consistent with visual acuity that is most frequently 20/25 or better. Although only a single isolated foveal lesion is usually present, multiple nonfoveal foci of yellow, egg-yolk-like lesions may also be seen, and patients with unilateral lesions have also been described.^11,25,29,34 A vitelliform lesion can develop in a previously normal-appearing macula.^4,11 Of historical interest, none of the eight patients described by Best showed the classic vitelliform macular lesion.⁶

Figure 66.1.  

Fundus photographs representing various stages of macular lesions that can be observed in patients with Best macular dystrophy. Top left, Stage I: mild degree of foveal pigment mottling and nonspecific hypopigmentation. Top right, Stage II: typical vitelliform or egg-yolk-like lesion. Second row left, Stage IIIa: scrambled or “fried egg” phase as the vitelliform lesion becomes diffusely more amorphous and diluted in appearance. Second row right, Stage IIIb: pseudohypopyon phase in which the yellow substance in the vitelliform cyst develops a layered appearance as a consequence of partial resorption. Third row left, Stage IIIc: only a sparse amount of yellowish substance remains as resorption of the vitelliform lesion is almost complete. Third row right, Stage IIId shows atrophic changes of both the retinal pigment epithelium and choriocapillaris vessels. Bottom, Stage IV: both less and more extensive examples are depicted. Characteristic feature is a fibrotic-gliotic-appearing scar in addition resorption of the vitelliform material.

The initial and primary pathogenetic changes in this disease involve the retinal pigment epithelial (RPE) cells. Consistent with this, Weingeist et al.⁵² histologically observed an abnormal accumulation of a lipofuscinlike material in all RPE cells of a patient with Best macular dystrophy, a finding also noted by O’Gorman et al.³⁹ in another patient.

Progressive impairment of visual acuity tends to parallel a subsequent course in which the yellow egg-yolk-like material appears to rupture or become fragmented into a “scrambled-egg” appearance, the so-called vitelliruptive stage.³⁰ Eventually, in turn, this lesion can be replaced by a fibrotic (gliotic) hypertrophic-appearing scar.^16,36 In some patients, the yellow material may resorb and subsequently be resecreted. Infrequently, in other patients, subretinal hemorrhage with identifiable or unidentified choroidal neovascular membranes may develop.^3,5,7,35,38 Variability in phenotypic expression of the macular lesion can occur between different families and within the same family.^25,32 Approaches to classifying the various stages of macular changes observed in patients with Best dystrophy have been published.^11,16,29,36

Most patients are visually asymptomatic or show only slight-to-moderate visual loss bilaterally until between 40 and 50 years of age.^11,29 In one study of 47 patients, 30 of 39 (76%) younger than 30 years of age had a visual acuity of 20/40 or better in at least one eye.¹⁶ Peripheral visual field remains normal. Patients are characteristically hypermetropic and esotropia is commonly observed.^11,27 Astigmatism and amblyopia are also often found.^11,27 ERG cone and rod a- and b-wave amplitudes are typically normal, as is the dark adaptation recovery time, in patients with Best vitelliform macular dystrophy.^2,10,11,30 However, Nilsson and Skoog³⁷ as well as Rover et al.⁴³ reported either absent or small ERG c-wave amplitudes in patients with this disorder (indicative of diffuse RPE cell dysfunction). Using a Siles-Crawford test to determine the directional sensitivity of the fovea in a patient with a vitelliform macular lesion and 20/20 vision, Benson et al.⁵ showed the foveal receptor orientation to be normal. This finding is most consistent with the conclusion that the egg-yolk-like changes reside within, and also probably below, the RPE cells.

The definitive diagnostic test in this disease is the electro-oculogram (EOG), which is markedly abnormal in affected patients. Appreciably reduced EOG light-peak to dark-trough ratios are observed at all stages of clinically evident disease,^{9,20,21,25,30,45,49} as well as in those who inherit the gene yet show no clinically apparent fundus changes.^10,11,19,49 In instances when only one eye manifests a clinically apparent retinal lesion, both eyes show reduced EOG ratios.^11,20,21 Since the EOG is regarded as a functional test of the entire retina, an abnormal EOG recording implies overall retinal dysfunction. The large interindividual variation of the EOG standing potential limits it diagnostic usefulness. However, the mean baseline values of the EOG standing potential in patients with Best disease for both those expressing and those not expressing clinically apparent retinal changes have been reported as below the mean of a control population.⁴⁹ Weleber⁵¹ found that not only was the EOG slow-oscillation light peak subnormal, but also it was delayed in reaching its peak in patients with Best dystrophy. He additionally observed that the EOG fast oscillations were preserved in patients with this disease.

On occasion, a patient with Best macular dystrophy can have bilateral atrophic-appearing foveal lesions that may show some phenotypic similarities to other hereditary macular lesions, such as those seen in Stargardt macular dystrophy or cone dystrophy. However, the absence of fundus flecks in Best disease, the presence of a dark choroid in Stargardt macular dystrophy, and a markedly abnormal EOG in patients with Best dystrophy help to distinguish patients with Best disease from those with Stargardt disease. The normal ERG and abnormal EOG in patients with Best macular dystrophy differentiate these patients who show an atrophic foveal lesion from patients with cone dystrophy. Additionally, with few exceptions, patients with cone dystrophy manifest abnormal cone ERG a- and b-wave amplitudes but a normal EOG response.^14,15 Unlike a number of patients with cone dystrophy, those with Best disease, as a rule, do not complain of photoaversion or impairment of color vision. In addition to Stargardt disease and cone dystrophy, some patients with Best macular dystrophy with an atrophic-appearing foveal lesion may present with a phenotype having certain clinical similarities to lesions that are observed in patients with North Carolina macular dystrophy. Normal EOG ratios in this disorder are distinct from the EOG abnormality found in Best disease.¹⁷

There are a group of macular disorders other than Best vitelliform macular dystrophy that may present with a vitelliform lesion. They include (1) those described as either a peculiar foveomacular dystrophy,²² adult foveomacular vitelliform dystrophy,^8,40 dominant slowly progressive macular dystrophy,⁴⁷ or adult-onset foveomacular pigment epithelial dystrophy;⁵⁰ (2) those associated with leakage from retinal perifoveal capillaries;¹⁸ (3) those observed as a spectrum of age-related macular degeneration associated with an elevation of the retinal pigment epithelium;^23,33,48 (4) those unassociated with any of the above descriptions or clinical findings;^12,28,33,44 and (5) a variant expression of pattern dystrophy.^24,26 The macular lesions within the first four categories can collectively be considered forms of adult-onset foveomacular vitelliform dystrophies/degenerations (AOFVD). Table 66.1 summarizes the differential diagnosis of vitelliform macular lesions. In general, a normal EOG light-peak to dark-trough ratio helps to distinguish these disorders from Best dystrophy. However, there are reports of both slightly subnormal and even more substantially subnormal EOG findings in some patients with vitelliform lesions unassociated with Best disease. The use of optical coherence tomography has been reported to be of possible value in differentiating at least some patients with AOFVD from those with Best vitelliform macular dystrophy.⁴²

In addition to the aforementioned hereditary, or likely hereditary, disorders with either a vitelliform phenotype or atrophic-appearing macular changes with phenotypic similarity to some patients with Best dystrophy, certain acquired disorders may also show changes that might resemble atypical presentations of Best dystrophy. These include inflammatory macular lesions associated with chorioretinitis or central serous choroidopathy. Normal EOG light-peak to dark-trough ratios in these latter disorders can resolve any lingering diagnostic uncertainty.

Mutations in a novel retina-specific gene on the long arm of chromosome 11 (11q13) have been identified in patients affected with Best macular dystrophy.^31,41 This gene encodes a 585-amino-acid protein known as bestrophin, which is selectively expressed in the RPE cells of the retina.⁴¹