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Inherited Retinal Degenerations

Rachel Patel, MD; Simon S. Gao, PhD; Paul Yang, MD, PhD; Richard G. Weleber, MD; David J. Wilson, MD; and Mark Pennesi, MD, PhD

BACKGROUND

Inherited retinal dystrophies (IRDs) are a diverse spectrum of diseases with overlapping and heterogeneous presentations. The plethora of genes linked to IRDs, along with the variety of mutations of each gene, present diagnostic challenges that cannot always be resolved by current genetic testing. Multimodal imaging is highly useful for diagnosis and tracking progression in patients with IRDs. With the advent of gene therapy trials for various IRDs,¹ these modalities will be of even greater significance in monitoring response or progression.

Optical coherence tomography angiography (OCTA) offers a novel method of observing both retinal and choroidal circulation in patients with suspected or confirmed IRD. Many IRDs involve degeneration of the outer retinal layers and retinal pigment epithelium (RPE), as well as atrophy of the retinal vessels and choriocapillaris.^2,3 The temporal relationship between retinal degeneration and vascular atrophy, however, has been difficult to establish using current clinical imaging techniques. OCTA may be useful in this regard by permitting assessment of the retinal and choroidal vasculature and quantification of capillary density. Furthermore, in combination with structural en face OCT, degeneration of the retina and RPE may be compared to retinal and choroidal vascular changes.

Animal models of retinitis pigmentosa (RP) (with dogs heterozygous for the T4R mutation in the RHO gene) and Stargardt dystrophy (with ABCA4 knockout mice) have demonstrated that light exposure at the levels employed in routine clinical practice may be deleterious to the retina and suggest that use of traditional fundus photography, short-wavelength fundus autofluorescence, and fluorescein angiography (FA) should be used with caution.^4,5 An attractive feature of OCTA is that it relies solely on stimuli in the infrared spectrum, and thus minimizes any potential light toxicity in IRD patients.

IMAGING CHOROIDAL NEOVASCULARIZATION IN INHERITED RETINAL DYSTROPHIES

Choroidal neovascularization (CNV) is a known complication of multiple IRDs. Current diagnosis relies on FA with the identification of early-phase hyper-fluorescence and late-phase leakage or pooling. Interpretation of FA may be complicated by the distorted retinal architecture or pigmentary changes often present in IRDs. Figure 25-1 illustrates such a case of EFEMP1-related retinopathy, in which diffuse confluent drusen at the macula present a mottled hypo- and hyper-fluorescent pattern on FA. The early hyper-fluorescence (Figure 25-1A) is therefore more difficult to isolate, while late leakage is difficult to distinguish from staining in later frames (Figure 25-1B). Automated segmentation of OCT angiograms is capable of delineating angiographic flow in the outer retina despite distorted architecture, thereby highlighting the CNV (yellow; Figures 25-1C and 25-1D). Furthermore, OCTA is capable of quantifying the area of the neovascular lesion, which may aid in monitoring progression and response to therapy.^6,7

Detection of CNV by OCTA can also be useful in vitelliform dystrophies such as Best vitelliform dystrophy or adult-onset vitelliform dystrophy (AOVD). Best disease is most commonly due to an autosomal dominant mutation in the BEST1 gene, while AOVD may be linked to mutations in PRPH2, BEST1, IMPG1, or IMPG2.8 Both are characterized by subretinal yellowish lesions at the posterior pole. A subset of patients with vitelliform dystrophies will develop CNV, precipitating further loss of visual acuity if not treated. The vitelliform lesions frequently demonstrate intense staining patterns on FA, which may obscure CNV detection.⁹ In one study investigating cases of AOVD, OCTA correlated well with FA in diagnosing CNV, demonstrating a sensitivity of 80%, and specificity of 100%.¹⁰ Figure 25-2 illustrates one such case of AOVD in which detection of CNV corresponded with diagnosis by FA (Figures 25-2A to 25-2E). In such genetically predisposed patients, OCTA may offer a safe and noninvasive method of screening for CNV.

There are limitations, however, on the use of OCTA in Best disease or AOVD, for while OCTA readily visualizes retinal circulation (Figures 25-2F and 25-2G) and may assess for the presence of CNV, the accumulation of vitelliform material is highly reflective, obscuring angiographic signal posterior to the lesion (Figures 25-2H to 25-2J). Thus evaluation of choroidal flow is limited in patients with large vitelliform lesions.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY TO EXAMINE PATHOLOGY IN CHOROIDEREMIA

OCTA has demonstrated potential utility in IRDs that involve pathologic alterations of the vasculature. Choroideremia is an X-linked recessive chorioretinal dystrophy due to mutations in the CHM gene encoding Rab escort protein 1. The disease manifests as nyctalopia followed by progressive loss of peripheral vision due to severe progressive atrophy of the RPE, photoreceptors, and choriocapillaris.¹¹ Severe visual acuity loss does not typically occur until the seventh decade,¹¹ so most affected individuals retain central fixation sufficient to undergo OCTA testing. In characterizing the progression of disease, it is not yet known if the degeneration of the retina, RPE, and choroid are independent or sequential events; OCTA and en face OCT provide the opportunity to study this relationship further.¹²

Eyes affected by choroideremia tend to have normalcaliber retinal vessels until late in the disease, suggesting that choroidal circulation is more significantly affected (Figure 25-3A).¹² Indeed, the choriocapillaris is diffusely atrophied to absent on OCTA, with the area of choriocapillaris nonperfusion exceeding the area of retinal nonperfusion (Figures 25-3B to 25-3E). In most cases of choroideremia, choriocapillaris is preserved in an irregular island at the macula, while deep choroidal vessels are easily visualized in the periphery because of atrophy of the overlaying RPE and choriocapillaris. Correlation with fundus auto-fluorescence (Figures 25-3F) further indicates that the RPE loss is greater than that of the choriocapillaris, suggesting that the primary event may be RPE degeneration, although further longitudinal study is needed.¹³ The utility of OCTA in diagnosing and monitoring choroideremia indicates that its capacity to map and quantify retinal and choriocapillaris perfusion may play a role in deciphering the temporal progression of other retinal degenerative disorders.

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