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.

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.

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.

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.

Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients.

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.

Clinical manifestations of cuticular drusen in Korean patients.

Cuticular drusen show some similarities to and differences from soft drusen in age-related macular degeneration (AMD) and might thus be a unique AMD subtype. Previous studies on cuticular drusen were performed mainly in white ethnic groups, but AMD shows ethnic differences. We investigated clinical manifestations of cuticular drusen in Korean patients to evaluate possible ethnic differences. Clinical records of Korean patients with cuticular drusen were retrospectively reviewed. Fundus distribution pattern, imaging features, and presence of large drusen, drusenoid pigment epithelial detachment (PED), and macular complications, including geographic atrophy (GA), choroidal neovascularization (CNV), and acquired vitelliform lesion (AVL), were assessed via multimodal imaging in 162 eyes with cuticular drusen (n = 81 patients; 67 females; mean age: 66.6 ± 9.1 years). Diffuse distribution was found in 61.7% and peripapillary involvement in 75.3% of eyes. Large drusen, drusenoid PED, GA, CNV, and AVL were observed in 59.3%, 26.5%, 18.5%, 3.7%, and 1.2% of eyes, respectively. The macular complication prevalence was similar between patients ≤ 60 and those > 60 years old. In Korean patients, cuticular drusen were less frequently associated with macular complications than in white patients, and the proportion of macular complications differed significantly, with AVL representing an uncommon complication.

The recurrent TUBB3 Gly98Ser substitution is the first described to inconsistently result in CFEOM3.

Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G>A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of TUBB3 syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype-specific to the TUBB3 Gly98Ser substitution.

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals. Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated. Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30. Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).

Coexistence of papilledema and pseudopapilledema after remission of idiopathic intracranial hypertension by bariatric surgery / Coexistência de papiledema e pseudopapiledema após remissão de hipertensão intracraniana idiopática por cirurgia bariátrica

ABSTRACT A 37-year-old woman complained of headaches following bilateral visual loss in the past two years. She was obese and had undergone bariatric surgery three months earlier, followed by a considerable weight loss. Neuro-ophthalmic examination revealed a bilateral swollen optic disk. After a computerized analysis of the visual fields and magnetic resonance imaging of the brain and orbits, a diagnosis of idiopathic intracranial hypertension was made. At six months after the bariatric surgery, the patient reported no further headaches and exhibited better findings on computerized analysis of visual fields. However, fundus examination revealed persistent mild papilledema in both eyes. Ocular B-scan ultrasonography showed bilateral optic disk drusen. This report highlights the coexistence of true papilledema and pseudopapilledema due to optic disk drusen, following remission of idiopathic intracranial hypertension after a bariatric surgery.

RESUMO Uma mulher de 37 anos queixou-se de cefaleia após perda visual bilateral nos últimos dois anos. Apresentava história de obesidade e havia sido submetida à cirurgia bariátrica três meses antes, seguida de considerável perda de peso. O exame neuro-oftálmico revelou um disco óptico inchado bilateral. Após uma análise computadorizada dos campos visuais e ressonância magnética do crânio e órbitas, foi feito um diagnóstico de hiper tensão intracraniana idiopática. Após seis meses da cirurgia bariátrica, a paciente não relatou mais cefaleia e foram descobertas melhoras na análise computadorizada dos campos visuais. No entanto, o exame de fundo de olho revelou papiledema leve persistente em ambos os olhos. A ultrassonografia ocular B-scan mostrou drusas do disco óptico bilateralmente. Este relato destaca a coexistência de papiledema verdadeiro e pseudopapiledema devido à drusa de disco óptico após remissão da hipertensão intracraniana idiopática após uma cirurgia bariátrica.

Coexistence of papilledema and pseudopapilledema after remission of idiopathic intracranial hypertension by bariatric surgery.

A 37-year-old woman complained of headaches following bilateral visual loss in the past two years. She was obese and had undergone bariatric surgery three months earlier, followed by a considerable weight loss. Neuro-ophthalmic examination revealed a bilateral swollen optic disk. After a computerized analysis of the visual fields and magnetic resonance imaging of the brain and orbits, a diagnosis of idiopathic intracranial hypertension was made. At six months after the bariatric surgery, the patient reported no further headaches and exhibited better findings on computerized analysis of visual fields. However, fundus examination revealed persistent mild papilledema in both eyes. Ocular B-scan ultrasonography showed bilateral optic disk drusen. This report highlights the coexistence of true papilledema and pseudopapilledema due to optic disk drusen, following remission of idiopathic intracranial hypertension after a bariatric surgery.

Wide-field true-colour imaging and clinical characterization of a novel GRK1 mutation in Oguchi disease.

PURPOSE: The available literature regarding Oguchi disease is limited, with around 50 cases described to date. Caused by mutations to either the SAG gene coding for arrestin (Hayashi et al. in Ophthalmic Res 46:175-180, 2011) or the GRK1 gene coding for rhodopsin kinase (Yamamoto et al. in Nat Genet 15:175-178. https://doi.org/10.1038/ng0297-175 , 1997), Oguchi disease is an autosomal recessive condition with a good visual prognosis. The clinical diagnosis of the condition is based on the presence of night blindness (nyctalopia), as well as fundoscopic observation of the Mizuo-Nakamura phenomenon. The Mizuo-Nakamura phenomenon refers to a fundus discolouration described as a golden-brown colour with a yellow-grey metallic sheen most prominent in the peripheral retina; after prolonged dark adaptation, the fundus appears normal. The prevalence of Oguchi disease is highest in Japan, particularly with SAG mutations (Nakazawa et al. in Retina 17:17-22, 1997), although patients from Europe, Pakistan and India have also been described. Formal diagnosis requires genetic testing. METHODS: Wide-field fundus images were obtained in both dark-adapted and light-adapted retina. Optical coherence tomography and dark-adapted electroretinography responses were used to further characterize the clinical phenotype. RESULTS: Existing descriptions of Oguchi disease have been limited by available technology. The flashes required for 45°-montage photographs in a dark-adapted eye quickly cause light adaptation. Recent advances in technology enable the capture of larger retinal areas in a single image. Wide-field 133° images were obtained of the native and dark-adapted fundus in natural colour. To our knowledge, these represent the first reported single-wide-field images of Oguchi disease, showing the characteristic Mizuo-Nakamura phenomenon in true colour. Genetic testing revealed a novel homozygous mutation in GRK1. CONCLUSIONS: Here, we demonstrate how characterizing this condition with single-shot true-colour wide-field imaging has distinct advantages over scanning laser technology, which applies artificial colouration, or stitched true-colour images. Images captured with wide-field systems create a much better representation of the native and dark-adapted fundus than can be observed by the ophthalmologist using direct fundoscopy and are essential in the clinical characterization of new mutations.