Cone dystrophy is a category of inherited retinal degenerations that is characterized by primary degeneration of the cone photoreceptors with or without secondary involvement of the rod photoreceptors, which are typically affected in more severe or advanced disease. In these cases, cone-rod dystrophy is a more accurate description; however, for the purposes of this chapter, cone dystrophy will be used as an all-inclusive term. In addition, the progressive nature of cone dystrophy differentiates it from the stationary cone dysfunction syndromes (e.g., achromatopsia, oligocone trichromacy, blue cone monochromatism), which will not be discussed here.
37.1.1 Common Symptoms
Typically presents between childhood and young adulthood. Slowly progressive loss of visual acuity over many years and decades, central scotoma, dyschromatopsia, hemeralopia, and photoaversion are common. Nystagmus is rare given that patients typically have good vision early in life. However, with advanced disease and severe loss of central vision, patients may develop strabismus and even nyctalopia.
37.1.2 Exam Findings
The most notable finding is bilateral decreased visual acuity and color discrimination deficits that accompany a spectrum of macular changes that may include blunted macula with loss of foveal reflex, mild pigment mottling, bull’s eye pigment changes, or well-demarcated area of macular atrophy (▶ Fig. 37.1). The presence of yellow subretinal fleck deposits in the macula or posterior pole may be suggestive of Stargardt fundus dystrophy from mutations in ABCA4 gene. In severe and advanced disease, there may be waxy disc pallor, vascular attenuation, diffuse confluent nummular atrophy, and pigment changes throughout the posterior pole and fundus with residual preservation of the far periphery.
Fig. 37.1 Spectrum of cone dystrophy. (a–c) Milder disease with pigment mottling of the macula, which appear as mottled macular hypo-autofluorescence on fundus autofluorescence, and perifoveal attenuation of the ellipsoid zone (EZ or inner segment/outer segment) layer (white arrowheads show the transition zones) on OCT. (d–f) More advanced disease with macular atrophy, macular hypo-autofluorescence with hyper-autofluorescent ring, and macular attenuation of the ellipsoid zone (white arrowheads) and RPE (red arrowheads show the resulting hyperreflective appearance of the underlying choroid). (g–i) More severe disease with findings similar to B, except with the addition of perimacular ring of atrophy and mottled hypo-autofluorescence, and diffuse attenuation of the ellipsoid zone. (j–l) Different phenotype with generalized mottling of pigment and hypo-autofluorescence of the macula with perifoveal attenuation of the ellipsoid zone (white arrowheads).
37.2 Key Diagnostic Tests and Findings
37.2.1 Optical Coherence Tomography
Spectral domain optical coherence tomography (SD-OCT) is an increasingly important imaging modality for the diagnosis and monitoring of cone dystrophy. Common findings are outer retina layer attenuation with a pattern of foveal and/or perifoveal loss of the ellipsoid zone (EZ) (i.e., inner segment/outer segment junction; ▶ Fig. 37.1). In more advanced cases, there is atrophy of the retinal pigment epithelium (RPE), wherein the transition zones between preserved and atrophic macular RPE are often marked by a section of hyperreflective choroid due to differences in the OCT signal penetration (▶ Fig. 37.1). When yellow fleck deposits are evident, they are seen as scattered focal spots of subretinal hyperreflective thickening with or without adjacent EZ attenuation. The integrity of the foveolar EZ island is typically correlated with the visual acuity. Thus, the extent of foveolar involvement can be monitored as a marker of disease progression.
37.2.2 Fluorescein Angiography or Ultra-Widefield Fluorescein Angiography
Commonly, a window defect from RPE atrophy and staining of fleck deposits (also easily observable on OCT and fundus autofluorescence [FAF]) may be present. With the advent of OCT, fluorescein angiography (FA) is less commonly used in the diagnosis of cone dystrophy. Historically, a dark choroid was a useful tool in the diagnosis of Stargardt fundus dystrophy; however, modern FA imaging systems often utilize automatic exposure settings that may diminish the prominence of a dark choroid. FA is still used for the evaluation of choroidal neovascularization which can be a rare complication of cone dystrophy.
37.2.3 Fundus Autofluorescence
Intense hyper-autofluorescent flecks that correlate with yellow deposits on examination in cases of suspected Stargardt fundus dystrophy. Less specific hyper-autofluorescent findings include a perifoveal ring (▶ Fig. 37.1b), which can also be seen in rod-cone dystrophy or autoimmune retinopathy. The spectrum of macular and fundus hypo-autofluorescence include a mottled (▶ Fig. 37.1a,d), discrete round (▶ Fig. 37.1b), or diffuse nummular pattern, which is generally correlated with RPE atrophy as seen on OCT. Some patients exhibit both a discrete round macular and mottled perimacular hypo-autofluorescence pattern (▶ Fig. 37.1c). The overall hypo-autofluorescent pattern is more specific for cone dystrophy using ultra-widefield FAF, wherein it is readily apparent that the macular or posterior pole is predominantly affected compared to the mid and far peripheral retina. In addition, areas of hypo-autofluorescence on ultra-wide FAF are usually well correlated with scotomas on visual field (▶ Fig. 37.2).
Fig. 37.2 Ultra-widefield fundus autofluorescence and widefield perimetry. (a) Mild-moderate disease with macular hypo-autofluorescence and normal autofluorescence of the mid and far peripheral retina on ultra-wide fundus autofluorescence, which correlate with an eccentrically located central scotoma (due to eccentric fixation) and intact peripheral isopters on widefield kinetic perimetry. (b) Severe advanced disease with hypo-autofluorescence concentrated in the macula and widespread throughout the fundus with residual normal autofluorescence only in the far peripheral retina. Widefield kinetic perimetry shows large scotoma affecting the central and midperipheral visual fields with residual far peripheral islands of response that correlate with the preserved far peripheral retina.