tiny crystalline dot-like deposits at the level of the outer retina or RPE. No yellow flecks are present. The dark choroid sign is absent. There is an associated history of systemic findings or drug exposure. Alport’s syndrome. Hereditary nephritis in association with deafness may associate with tiny white yellow lesions at the inner retinal level in the macula and in the outer retinal level (RPE) in the periphery. The macular lesions do not cause any IVFA changes and the dark choroid sign is not present. Vitamin A deficiency. Tiny white dots appear at the level of the RPE throughout the retina often sparing the macula. The fundus appearance can be similar to fundus albipunctatus except that the dots are generally smaller. Nyctalopia is a prominent symptom, the dark choroid sign is absent, and the findings and symptoms disappear with vitamin A therapy if therapy is instituted before rod photoreceptors die.

11.1.1.4  Inherited Forms: STGD

While autosomal recessive patterns of STGD/FF are well established, autosomal dominant patterns of the disease are rare. Many new cases appear with isolate or simplex inheritance patterns. Molecular studies have

a

Fig. 11.2  Fundus appearance in BMD. (a) The vitelliform phase of the disease is shown for the OD of an individual from an established autosomal dominant pedigree with a visual acuity of

20/60 OU and EOG Arden ratios of 1.36 (OD) and 1.24 (OS), and with Humphrey visual fields and mfERG measures that showed reduced central sensitivity. A Heidelberg OCT image is also shown demonstrating the foveal vitelliform eruption. (b) The posterior fundus photo of the OS of the same patient shows the vitelliform eruption which is successfully imaged by OCT.

(c) A postvitelliform stage of the disease is shown for a different patient with Best disease. Note the atrophic changes in the RPE as a result of the lesion

more recently shown that autosomal recessive forms of FF, STGD (STGD1), and some more widespread forms of CRD and RP are all associated with mutations in the ABCA4 (formerly ABCR) gene [14–16, 193]. One rare dominant form of macular disease with phenotypic similarity to STGD (STGD3) has been related to mutations in ELOVL4, a gene believed to be related to long-chain fatty acid metabolism [6, 7, 17]. More recently, mutations PROM1, a gene involved in specifying outer segment disc structure in rods and cones, has been causally associated with a second rare autosomal dominant form of STGD (STGD4) [18]. There is a broad genotypic and phenotypic heterogeneity in STGD that depends upon the gene, the mutation in that gene, and the impact on the cells in which the mutant gene(s) are expressed.

11.1.2  Best Macular Dystrophy

BMD was first described by Best [19] as an inherited bilateral juvenile macular degeneration associated with an egg-like cyst in the foveal region. In BMD, patients show characteristic lesions at different stages of the disease (Fig. 11.2) but typically do not lose visual acuity until the later stages. While an abnormal EOG may

be diagnostic for this disease, the EOG is of little use for following patients over time. An adult-onset variant of the disease is known as adult-onset vitelliform macular dystrophy (AVMD) and typically has multiple smaller lesions that are present in the macular and extramacular regions.

11.1.2.1  Clinical Features: BMD

In BMD, the fundus is normal at birth. The vitelliform lesion begins to appear as early as 3 years of age. The initial symptoms generally occur in a school age child with the appearance of decreased central visual acuity

(uncorrectable to 20/20) and/or central visual distortion (metamorphopsia). The time of presentation depends strongly on the temporal emergence and the state of the vitelliform lesions. Children may also be identified as part of a routine screening in a family where other individuals have been diagnosed with BMD. After the diagnosis of the presence of BMD, there is commonly a loss of vision by at least two lines over a period of around 5 years. Surprisingly, many BMD patients maintain good central visual acuity despite the presence of foveal lesions in various stages of disease progression. The prevalence of BMD is estimated to be around 1 in 10,000 people.

There are several stages to the evolution of the foveal lesions in BMD. In the previtelliform or carrier

phase (Stage 1), the lesion may initially emerge as a blunted foveal light reflex or a fine yellow pigmentary change at the RPE level that may demonstrate a subtle window defect on IVFA. In the vitelliform phase, (Stage 2) the lesion emerges generally late in the first decade as circular yellow sunny-side up egg yolk-like lesion within the foveal region and usually distributed symmetrically with respect to the foveal center. The vitelliform lesions achieve between 0.5 and 2.0 disk diameters in size and have a uniform yellow color. The bilateral lesions are commonly symmetric in size and appearance between the two eyes, although size asymmetry may occur. Additional vitelliform lesions may occur (multifocal BMD). Multifocal BMD appears to be a part of the spectrum of disease including BMD and AVMD, in that BEST1 mutations are also associated with this variant. In the vitelliruptive phases, the vitelliform foveal lesions breakdown and flatten out to create the spatially heterogeneous appearance of a “scrambled egg” (Stage 3a). There is commonly a slight decrease in visual acuity due to this process. There may be a secondary shallow foveal retinal detachment with layering of the yellow cystic material into a pseudohypopyon (Stage 3b). The material at this stage is clearly fluid in nature as it shifts with gravity. It appears that this stage is due to the appearance of liquefied LF-like material in the subretinal space. There is eventually a resorption of yellow LF-like material (Stage 3c). What is left with resorption is the appearance of RPE and choriocapillaris atrophy and increased visibility of the underlying choroidal vasculature (Stage 3d). An area of foveal RPE and choriocapillaris atrophy can result that appears similar to that found in central areolar choroidal dystrophy or the geographic atrophy of late dry age-related macular degeneration (dAMD) (atrophic phase). A late cicatricial phase of fibrotic or gliotic scarring may also occur (Stage 4). Choroidal neovascularization can also be a late consequence in BMD [188].

In BMD, the RPE is diffusely abnormal with large amounts of LF-like material present in cytoplasmic granules of RPE cells throughout the fundus. This material is autofluorescent on fluorescent retinal imaging with a blue excitation source. The vitelliform material (Stage 2) and the residual yellow material in the vitelliruptive and resorptive phases are also autofluorescent. The location of the yellow material in the different phases of the lesion remains to be better understood, although high-resolution optical coherence

tomography (OCT) is contributing rapidly. Recent high-resolution OCT studies suggest that the vitelliform material accumulates between the RPE and the boundary between the inner and outer segments of photoreceptors, and may represent unphagocytized outer segments [20, 21]. The primary cellular defect is a change in chloride transport across the RPE surface. The relationship of alterations in chloride channel function and transport in the RPE (e.g., bestrophin) to LF formation is under active investigation [22]. Vitelliform lesions commonly remain intact until middle or late age and patients often maintain good functional visual acuity (e.g., 20/50 or better) despite the presence of the striking lesions.

11.1.2.2  Diagnostic Features: BMD

Visual acuity varies but is generally good. Color vision is usually normal with the possibility of a protan deficit. Final dark adaptive threshold is normal. Visual fields are normal, except perhaps for a relative central scotoma early in the disease and absolute scotoma if late foveal atrophy occurs. The full-field ERG is normal. The EOG findings are a single pathognomonic feature of BMD with a decrease in the LP/DT ratio representing a significant change in the light-mediated standing potential of the RPE cell surface membrane. The EOG is always abnormal in BMD, likely in largest part, because bestrophin is a basolateral surface membrane transport protein that plays a significant role in establishing and modulating the basolateral membrane potential. In outer retinal degenerations, in general, the EOG is abnormal in an environment of coincident fullfield ERG changes. The EOG can be used to identify individuals who do not yet express the disease, because the physiological changes precede the clinical anatomic lesions. In the IVFA, the vitelliform lesions can block fluorescein excitation or emission from the fovea. As the lesions evolve, the subsequent resorption of LF-like material and the associated RPE changes and atrophy set the stage for the emergence of the transmission window defects on the IVFA. Given that areas of persistent LF-like material and areas of atrophy can coexist in the same lesion, it is possible to have lesions with coincident areas of block and transmission. Emergence of choroidal neovascularization in a field of BMD-related macular atrophy can be diagnosed with the IVFA.