Multimodal imaging analysis of autosomal recessive bestrophinopathy: Case series.

RATIONALE: Autosomal recessive bestrophinopathy (ARB) is a subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene, which affect the retinal pigment epithelium (RPE). Studying RPE abnormalities through imaging is essential for understanding ARB. This case series involved the use of multimodal imaging techniques, namely autofluorescence (AF) imaging at 488 nm [short-wavelength AF] and 785 nm [near-infrared AF (NIR-AF)] and polarization-sensitive optical coherence tomography (PS-OCT), to investigate RPE changes in 2 siblings with ARB. PATIENT CONCERNS: Two Japanese siblings (Case 1: male, followed for 20-23 years; Case 2: female, followed for 13-17 years) carried compound heterozygous mutations of the BEST1 gene. DIAGNOSIS: Both siblings were diagnosed with ARB. INTERVENTIONS AND OUTCOMES: Multimodal imaging techniques were used to evaluate RPE changes. Both siblings had funduscopic changes similar to those seen in the vitelliruptive stage of Best vitelliform macular dystrophy during the follow-up period. NIR-AF imaging showed hypo-AF of the entire macular lesion in both cases, and this hypo-AF remained stable over time. PS-OCT confirmed reduced RPE melanin content in these hypo-AF areas. Additionally, hyper-NIR-AF dots were observed within hypo-NIR-AF areas. Concomitant identification of focally thickened RPE melanin on PS-OCT imaging and hyper-AF on short-wavelength AF imaging at the sites containing hyper-NIR-AF dots indicated that the hyper-NIR-AF dots had originated from either stacked RPE cells or RPE dysmorphia. LESSONS: We confirmed RPE abnormalities in ARB, including diffuse RPE melanin damage in the macula alongside evidence of RPE activity-related changes. This case series demonstrates that multimodal imaging, particularly NIR-AF and PS-OCT, provides detailed insights into RPE alterations in ARB.

Optic Atrophy and Inner Retinal Thinning in CACNA1F-related Congenital Stationary Night Blindness.

Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from retinal photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness in humans. Although the primary defect is at the terminal end of first-order neurons (photoreceptors), there is limited knowledge of higher-order neuronal changes (inner retinal) in this disorder. This study aimed to investigate inner retinal changes in CACNA1F-retinopathy by analyzing macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor in 22 subjects with molecularly confirmed CACNA1F-retinopathy. Detailed ocular phenotypic data including distance and color vision, refraction and electroretinogram (ERG) were collected. Distance vision was universally reduced (mean: 0.42 LogMAR), six had abnormal color vision and myopia was common (n = 15; mean: -6.32 diopters). Mean GCL-IPL thickness was significantly lower in patients (55.00 µm) compared to age-matched controls (n = 87; 84.57 µm; p << 0.001). The GCL-IPL thickness correlated with scotopic standard (p = 0.04) and bright-flash (p = 0.014) ERG b/a ratios and photopic b-wave amplitudes (p = 0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). Fifteen putative disease-causing, including five novel variants were identified. This study establishes macular inner retinal thinning and optic atrophy as characteristic features of CACNA1F-retinopathy, which are independent of myopia and could impact potential future treatment strategies.

Optical Coherence Tomography Neuro-Toolbox for the Diagnosis and Management of Papilledema, Optic Disc Edema, and Pseudopapilledema.

BACKGROUND: Distinguishing optic disc edema from pseudopapilledema is a common, sometimes challenging clinical problem. Advances in spectral-domain optical coherence tomography (SD-OCT) of the optic nerve head (ONH) has proven to be a cost effective, noninvasive, outpatient procedure that may help. At its core are tools that quantify the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL). The SD-OCT also provides a set of tools that may be qualitatively interpreted in the same way that we read an MRI. They include the transverse axial, en face, and circular tomogram. Our goal is to describe a practical office-based set of tools using SD-OCT in the diagnosis and monitoring of papilledema, optic disc edema, and pseudopapilledema. EVIDENCE ACQUISITION: Searches on PubMed were performed using combinations of the following key words: OCT, papilledema, pseudopapilledema, optic disc drusen, retinal folds (RF), and choroidal folds (CF). RESULTS: The principal elements of SD-OCT analysis of the ONH are the RNFL and GC-IPL thickness; however, these metrics have limitations when swelling is severe. Qualitative interpretation of the transverse axial SD-OCT aids in assessing peripapillary shape that may help distinguish papilledema from pseudopapilledema, evaluate atypical optic neuropathies, diagnose shunt failures, and identify outer RF and CF. There is a consensus that the SD-OCT is the most sensitive way of identifying buried optic disc drusen. En face SD-OCT is especially effective at detecting peripapillary wrinkles and outer retinal creases, both of which are common and distinctive signs of optic disc edema that rule out pseudopapilledema. Mechanically stressing the ONH in the adducted eye position, in patients with papilledema, may expose folds and peripapillary deformations that may not be evident in primary position. We also discuss how to optimize the acquisition and registration of SD-OCT images. CONCLUSIONS: The SD-OCT is not a substitute for a complete history and a careful examination. It is, however, a convenient ancillary test that aids in the diagnosis and management of papilledema, optic disc edema, and pseudopapilledema. It is particularly helpful in monitoring changes over the course of time and distinguishing low-grade papilledema from buried drusen. The application of the SD-OCT toolbox depends on optimizing the acquisition of images, understanding its limitations, recognizing common artifacts, and accurately interpreting images in the context of both history and clinical findings.

Novel compound heterozygous variants of tyrosinase gene in an isolated foveal hypoplasia patient without nystagmus.

Foveal hypoplasia is the major cause of visual loss. Here we report an isolated foveal hypoplasia patient without nystagmus. It is very rare, and its etiology is not completely understood. Using whole-exome sequencing and foveal hypoplasia-related gene filtering from a family with two generations, we identified a novel variant c.859T>C (p.S287P) and a rare non-frameshift variant c.229_230insGGG (p.Arg77_Glu78insGly) in the tyrosinase (TYR) gene that co-segregated in the affected member of this family. The compound heterozygous variants inherited in the proband were confirmed by Sanger sequencing and predicted from in silico studies to have an effect on protein function. In conclusion, our finding extends the spectrum of TYR variants and supports the important role of TYR in the development of eyes.

ENHANCED S-CONE SYNDROME: VISUAL FUNCTION, CROSS-SECTIONAL IMAGING, AND CELLULAR STRUCTURE WITH ADAPTIVE OPTICS OPHTHALMOSCOPY.

PURPOSE: To describe in detail the phenotype of a patient with enhanced S-cone syndrome. METHODS: We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory to steroid treatment, and a negative uveitic workup. The patient underwent a complete ophthalmic examination, full-field electroretinograms (ffERG), automatic static perimetry and multimodal imaging with spectral domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy (AOSLO). RESULTS: Spectral domain optical coherence tomography demonstrated cystoid macular edema and a hyperthick, delaminated midperipheral retina. Fluorescein angiography did not demonstrate macular leakage. Rod-mediated ffERGs were undetectable, and there was a supernormal response to short-wavelength stimuli compared with photopically matched longer wavelengths of light consistent with enhanced S-cone syndrome. Gene screening was positive for compound heterozygous mutations NR2E3: a known (c.119-2 A>C) and a novel (c.119-1G>A) mutation. By perimetry, sensitivities were normal or above normal for short-wavelength stimuli; there was no detectable rod-mediated vision. AOSLO demonstrated higher than normal cone densities in the perifoveal retina and evidence for smaller outer segment cone diameters. CONCLUSION: Evidence for supernumerary cones (at least twice the normal complement) by AOSLO and spectral domain optical coherence tomography was associated with supernormal S-cone sensitivities and electroretinogram responses confirming previous in vivo findings in postmortem human specimens. Smaller than normal cones in enhanced S-cone syndrome may represent "hybrid" photoreceptors analogous to the rd7/rd7 murine model of the disease.

MULTIMODAL EVIDENCE OF TYPE 3 NEOVASCULARIZATION IN ENHANCED S-CONE SYNDROME.

PURPOSE: To investigate, using multimodal imaging, the anatomy of neovascularization in eyes with enhanced S-cone syndrome. METHODS: Three eyes with neovascularization, from two patients with enhanced S-cone syndrome, were analyzed using fluorescein angiography, indocyanine-green and optical coherence tomography angiography imaging. RESULTS: The eyes reported had a demonstrable Type 3 neovascularization with evidence of retinal-retinal anastomoses on fluorescein angiography, indocyanine-green and optical coherence tomography angiography imaging. One eye that was initially without neovascularization, but with chronic macular edema developed a macular hemorrhage. This eye was treated with 8 injections of intravitreal bevacizumab over 29-months resulting in a final fibrovascular lesion. The characteristics of this final lesion share similarities to the two other eyes described. In all eyes and all exams, retinal vessels are observed to communicate with the subretinal fibrovascular lesion. CONCLUSION: We provide evidence of retinal arteriovenous anastomosis of the superficial retinal plexus to a subretinal neovascular complex in patients with enhanced S-cone syndrome and point to similarities with Type 3 neovascularization in macular telengiectasia Type 2 (MacTel2) and age-related macular degeneration. These findings provide insights into the anatomy of neovascularization in these pathologies and may lead to hypotheses of their etiologies.

Peripapillary hyperreflective ovoid mass-like structures-a novel entity as frequent cause of pseudopapilloedema in children.

BACKGROUND: Optic nerve head drusen (ONHD) are considered the most common cause for pseudopapilloedema in children. We aimed to investigate and further characterize a new type of optic nerve head lesion on enhanced depth imaging optical coherence tomography (EDI-OCT) named peripapillary hyperreflective ovoid mass-like structures (PHOMS), and ONHD in asymptomatic children with pseudopapilloedema. METHODS: Retrospective cohort study including 64 eyes from 32 patients with pseudopapilloedema due to PHOMS and/or ONHD. Mean age was 9.0 ± 3.1 years. PHOMS and ONHD were identified and classified on EDI-OCT and infrared images. Ultrasound images were classified for the presence of hyperechogenic structures of the optic nerve head. RESULTS: On EDI-OCT, PHOMS were detected in 63 out of 64 eyes (98.4%). In 60 eyes (93.8%), small hyperreflective foci inside the PHOMS were present. In all cases, we identified a new ring sign visible on infrared images, corresponding clearly to the edge of the PHOMS as seen on EDI-OCT. On ultrasound, we describe a new feature of PHOMS appearing as small hyperechogenic structures without posterior shadowing. In 13 eyes (20.3%), ONHD were present on EDI-OCT and ultrasound. CONCLUSION: This is the first study showing that PHOMS are the most common cause for pseudopapilloedema in children. PHOMS is a new entity of optic nerve head lesions. It might be a precursor of buried optic nerve head drusen, which can lead to visual field defects, haemorrhages and CNV. This study offers new tools to identify and follow-up these lesions early in childhood using EDI-OCT.

Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene.

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.