Utility of multimodal imaging in the clinical diagnosis of inherited retinal degenerations

Abstract

Inherited retinal degeneration (IRD) is a heterogeneous group of genetic disorders of variable onset and severity, with vision loss being a common endpoint in most cases. More than 50 distinct IRD phenotypes and over 280 causative genes have been described. Establishing a clinical phenotype for patients with IRD is particularly challenging due to clinical variability even among patients with similar genotypes. Clinical phenotyping provides a foundation for understanding disease progression and informing subsequent genetic investigations. Establishing a clear clinical phenotype for IRD cases is required to corroborate the data obtained from exome and genome sequencing, which often yields numerous variants in genes associated with IRD. In the current work, we review the use of contemporary retinal imaging modalities, including ultra-widefield and autofluorescence imaging, optical coherence tomography, and multispectral imaging, in the diagnosis of IRD.

Keywords: Autofluorescence; imaging; inherited retinal degeneration; inherited retinal disease; optical coherence tomography; retina.

Figure 1

Conventional and ultra-widefield fundus photography. (a) Retinal flecks are prominently seen in this 61-year-old male with ABCA4-associated Stargardt macular dystrophy. (b) Crystalline deposits throughout the macula in a 26-year-old female with Bietti crystalline dystrophy due to biallelic mutations in CYP4V2. (c) Radial spoke-like cysts in a 15-year-old male with X-linked retinoschisis secondary to pathogenic mutations in RS1. (d) Diffuse retinal atrophy mimicking RP with bone spicule-like pigmentation in a 37-year-old female with severe early-onset ABCA4-associated retinal degeneration. (e) UWF pseudocolor imaging (Optos) revealed that atrophy was more prominent at the macula and posterior pole, with sparing of the peripheries. This is typical of ABCA4-associated macular dystrophy but less common in RP

Figure 2

Fundus autofluorescence in cases of IRD. (a) Macular atrophy and flecks in a 13-year-old male with ABCA4-associated macular dystrophy; (b) fundus AF imaging of the same patient highlights the atrophy with a central elliptical focus of hypoautofluorescence surrounded by hyperautofluorescent flecks. (c) Cystoid macular degeneration and peripheral nummular deposits in a 16-year-old male with NR2E3-associated retinopathy; (d) fundus AF imaging highlights the cystic spaces and peripheral hyperautofluorescent nummular lesions in the peripheral macula. (e) A classical pseudohypopyon appearance in a 40-year-old male with autosomal dominant Best disease; (f) macular autofluorescence highlights the vitelliform material with inferior gravitational ‘fluid’ level.

Figure 3

Spectral domain optical coherence tomography imaging in Inherited retinal degeneration. (a) Paracentral ellipsoid zone (EZ) band loss in a 25-year-old male with RHO-associated RP. (b) Subfoveal fluid with elongated photoreceptor outer segments in a 40-year-old male with dominantly inherited Best vitelliform macular dystrophy secondary to a pathogenic BEST1 variant. (c) Diffuse outer retinal losses and prominent retinal thickening in a 7-year-old male with CRB1-associated LCA. (d) Loss of inner retinal laminations, cystoid foveal changes and parafoveal EZ loss in a 26-year-old female with CLN1-associated retinal degeneration

Figure 4

Comparison of the diagnostic utility of retinal imaging modalities in inherited retinal degeneration (IRD). (a) Six common IRD phenotypes are displayed with each of the most widely employed imaging modalities, including standard 40°–50° fundus color photography, macular spectral domain-optical coherence tomography, macular or standard field AF, ultra-widefield (UWF) color, and UWF AF imaging. Diagnostically helpful features for the cases shown include (1) hyper-AF flecks extending into the periphery with peripapillary sparing and macular atrophy in Stargardt disease; (2) subfoveal fluid with a hyper-AF signal in Best disease; (3) nummular or lobular hypo-AF signals extending into the periphery in choroideremia; (4) localized subfoveal outer retinal loss and central hypo-AF signals in cone-rod dystrophy; (5) diffuse peripheral hypo-AF with macular sparing and parafoveal outer retinal loss in RP; and (6) inner retinal macular schisis and peripheral schisis in X-linked retinoschisis. Genotypes are shown inset in the color fundus photographs. (b) Suggested clinical diagnostic utility for each imaging modality, when applied to each IRD phenotype, is shown with a relative ranking applied as a guide to highlight modalities that are helpful when phenotyping patients with suspected IRD

Figure 5

Ultra-widefield fluorescein angiography (Optos, MA, USA) findings in a 12-year-old female with RP and secondary vasoproliferative lesion with vitreous hemorrhage. (a) UWF pseudo-color image showing heavy exudation in the temporal periphery (arrow), accompanied by retinal hemorrhages and vitreous hemorrhage. (b) The fellow eye had bone spicule-like pigmentation and arteriolar attenuation, with a small vascular lesion seen inferotemporally (arrow). (c) UWF FA of the right eye disclosed the presence of multiple areas of temporal leakage (arrow) that were used to guide laser ablation of the vasoproliferative lesion. (d) Minimal dye leakage was seen in the fellow eye lesion

Figure 6

Multispectral imaging in patients with fleck retinal dystrophies. (a) AF imaging of a 66-year-old female with ABCA4-associated macular dystrophy, showing prominent central hypoautofluorescence with peripheral hyperautofluorescent flecks (b) Infrared reflectance shows central atrophy as a stippled hyperreflective area with surrounding hyporeflective foci, with hyperreflective flecks in the periphery. Fine detail is visible in the area of atrophy (arrow) which is less visible in the AF image. (c) Blue reflectance highlights the flecks, with early RPE changes (arrow) seen prior to its appearance in the AF image, while (d) green reflectance prominently highlights central RPE atrophy (arrow) and fleck-associated RPE atrophy as hyperreflectance. (e) AF imaging of a 61-year-old female with PRPH 2-associated macular dystrophy, which flecks highlighted as areas of hyperautofluorescence and fleck-associated RPE atrophy being hypoautofluorescent. (f) Infrared reflectance shows flecks as prominent hyperreflective foci and choroidal vessels (arrow), while (g) blue reflectance imaging highlights the flecks, albeit with lower contrast compared to AF and infrared reflectance. (h) Fine vascular detail is well visualized on green reflectance imaging (arrow) Images were captured using a Spectralis optical coherence tomography instrument (Heidelberg, Lübeck, Germany)