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Purpose: The purpose of this study was to determine the natural history of the photoreceptor disease in a large group of pediatric patients with RHD12-associated Leber congenital amaurosis (RDH12-LCA), to estimate the changes expected over the duration of a clinical trial, and to define the relationship between the photoreceptor loss and visual dysfunction., Methods: Forty-six patients representing 36 families were included. The great majority of patients were under the age of 18 years. Patients underwent complete ophthalmic examinations and imaging with various modalities including adaptive optics scanning laser ophthalmoscopy. Visual function was assessed with static and kinetic perimetry, and full-field stimulus test (FST) under dark- and light-adapted conditions., Results: Patients had a severe and early onset retinal degeneration (EORD). Visual acuity losses showed a progression rate of 0.04 logMAR per year. A small foveal island could be retained but showed degeneration over time. Foveal cone sensitivity losses were predictable by the loss of photoreceptors. Peripapillary retina could be retained with no significant progression detectable. Peripapillary rod sensitivity was substantially less than expected from photoreceptor structure pointing to a large improvement potential. FST sensitivities were reliably recordable in pediatric patients and showed a small but significant improvement with age. Locally and globally, loss of rod sensitivity tended to be larger than loss of cone sensitivity., Conclusions: Foveal cones of RDH12-LCA should be targeted with treatments aimed to slow progression, whereas peripapillary rod photoreceptors should be targeted with treatments aimed to improve night vision. Pediatric FST testing may be complicated by age-related maturation of decision making regarding threshold criteria.

Background/aaims: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F , NYX and TRPM1 . High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression., Methods: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F , NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated., Results: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F , NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F , NYX and TRPM1 , respectively., Conclusions: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To describe the retinal phenotype of an unusual case of anti-TRPM1 autoantibody-positive unilateral melanoma-associated retinopathy (MAR) triggered by nivolumab therapy and compare with the phenotype of TRPM1 -associated Congenital Stationary Night Blindness ( TRPM1 -CSNB)., Observations: Unilateral MAR was diagnosed 3 months after starting nivolumab therapy for consolidation of a successfully treated melanoma. Retinal autoantibodies against TRPM1 were identified. ffERG, microperimetry and static chromatic perimetry confirmed unilateral ON-Bipolar Cell (ON-BPC) dysfunction and central rod sensitivity losses in the left eye; the contralateral eye was normal. There was borderline ganglion cell (GCL) and inner nuclear layer (INL) thinning, but a significantly thinner inner plexiform layer (IPL) in the affected compared to the unaffected eye. Longitudinal reflectivity profiles (LRPs) demonstrated an abnormal inner plexiform layer (IPL) lamination in the involved eye. Nearly identical changes were documented in two cases of TRMP1 -cCSNB and in a case of anti-TRPM1 autoantibody-negative MAR. The functional changes partially recovered with discontinuation of the medication without added immunosuppression., Conclusions and Importance: Comparisons between the affected and unaffected eye in this unilateral MAR case revealed inner retinal abnormalities and abnormal lamination of the IPL associated with the classical retina-wide ON-BPC dysfunction, and localized central rod-mediated sensitivity losses. A nearly identical structural phenotype in two cases of cCSNB and a case of anti-TRPM1 autoantibody-negative MAR supports a specific structural-functional phenotype for these conditions with ON-BPC dysfunction., Competing Interests: The authors have no financial disclosures., (© 2024 The Authors.)

Purpose: To describe in detail the structural and functional phenotypes of a patient with cone-rod dystrophy associated with a full deletion of the NPHP1 gene., Methods: A 30-year-old man with a history of end-stage renal disease presented with progressive vision loss in early adulthood prompting evaluation for retinal disease. Ophthalmic evaluation was performed including visual fields, electroretinography, spectral domain optical coherence tomography and short-wavelength and near-infrared fundus autofluorescence imaging., Results: The visual acuity was 20/60 in each eye. Fundus examination revealed a subtle bull's-eye maculopathy confirmed with fundus autofluorescence. Spectral domain optical coherence tomography demonstrated perifoveal loss of the outer retinal layers with structural preservation further peripherally. Static perimetry confirmed the loss of cone greater than rod sensitivities in a manner that colocalized to structural findings. Electroretinography revealed decreased cone- and rod-mediated responses. Genetic testing confirmed a homozygous whole-gene deletion of the NPHP1 gene., Conclusion: NPHP1 -associated retinal degeneration may present as a cone-rod dystrophy in addition to the previously reported rod-predominant phenotypes and can notably be associated with systemic abnormalities, including renal disease. Our work further expands on the growing literature describing the retinal disease associated with systemic ciliopathies.

Background: To describe the clinical presentation with a focus on ocular manifestations and response to riboflavin supplementation of 3 patients with riboflavin transporter deficiency (RTD) caused by mutations in SLC52A2 ( SLC52A2- RTD)., Methods: This is a retrospective review of records of 3 children (aged 18, n = 2 and age = 8, n = 1) with SLC52A2- RTD. Patients underwent comprehensive ophthalmic evaluations including color vision testing, pattern visual-evoked potentials (pVEPs, 1 patient) and spectral domain optical coherence tomography (SD-OCT) imaging. Patients received riboflavin supplements from the time of the molecular diagnosis of RTD., Results: Two unrelated 18-year-old patients with SLC52A2- RTD had a symptomatic onset with sensorineural hearing loss and auditory neuropathy/dys-synchrony since age 3 and 11, respectively. On examination 7 years after symptomatic onset, they showed subnormal visual acuities (20/30 and 20/60, both eyes, respectively), preserved color vision, and a thin but measurable retinal ganglion cell layer (GCL) and nerve fiber (RNFL). The inner and outer nuclear layers were normal. The asymptomatic SLC52A2- positive brother of one of these patients started riboflavin supplementation right after the molecular diagnosis and had normal vision and SD-OCTs 7 years later. Onset of riboflavin supplementation in one of the 2 symptomatic cases resulted in acute improvement of the pattern visual-evoked potential and vision., Conclusions: Retinal ganglion cells and their axons are uniquely susceptible to RTD compared with other highly energy-dependent retinal neurons, such as photoreceptors, raising the possibility for alternative mechanisms of disease or protection. Riboflavin supplementation results in acute functional improvement of vision and long-term preservation of GCL and RNFL if initiated early., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs)., Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ)., Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects)., Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly., Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

Purpose: To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 ( CEP290-LCA ) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition., Methods: This is a retrospective review of records of five patients with CEP290-LCA . Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths., Results: All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals., Conclusions: We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.

Purpose: To describe in detail the retinal phenotype of LAMP2-associated Danon disease., Methods: Three LAMP2-positive patients from two unrelated families were studied with spectral-domain optical coherence tomography and with short-wavelength and near-infrared fundus autofluorescence (FAF) imaging. Visual function was measured with full-field electroretinography and chromatic perimetry. A patient with choroideremia was also studied for comparison., Results: A 45-year-old LAMP2-heterozygous woman, her 21-year-old hemizygous son, and an unrelated heterozygous 60-year-old woman had normal visual acuities. Central spectral-domain optical coherence tomographies were grossly normal in the younger two patients (mother and son). The oldest patient showed a tenuous interdigitation signal, interruptions of the inner segment ellipsoid zone band, and parafoveal outer nuclear layer thinning. Quantitatively, all patients had shorter than normal ellipsoid zone to retinal pigment epithelium distance in pericentral retina, normal at the foveola. A speckled hypoautofluorescence pattern on short-wavelength FAF contrasted with grossly abnormal near-infrared FAF in the heterozygous carriers. The oldest patient had reduced full-field electroretinography amplitudes (to ∼50% of normal) for rod- and cone-mediated responses and her perimetry showed severe rod dysfunction but substantial cone function. A disproportionate loss of the near-infrared FAF compared with the short-wavelength FAF, predominantly outer segment changes, and severe rod dysfunction with preserved cone function was similarly documented in a 9-year-old choroideremia hemizygous patient., Conclusion: A disproportionate loss of the near-infrared FAF signal compared with the short-wavelength FAF signal, outer segment abnormalities, and severe rod dysfunction but relatively preserved cone vision suggests a stereotypical pattern of primary retinal pigment epithelial or parallel retinal pigment epithelial + photoreceptor disease in Danon disease.

Background: We report on a patient with a juvenile-onset inherited retinal degeneration (IRD) associated with homozygous RP1 mutations inherited by uniparental disomy (UPD)., Material and Methods: A 6-year-old healthy girl failed school vision screening and was diagnosed with a bull's eye maculopathy. She underwent complete ophthalmic examination, full-field electroretinograms (ERG), kinetic fields, full-field sensitivity testing (FST), and retinal imaging with spectral domain optical coherence tomography (SD-OCT) and near-infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF)., Results: Visual acuities were relatively preserved (20/30+). There was subtle foveal depigmentation but an otherwise normal fundus examination. SD-OCT revealed a relatively preserved fovea with thinning of the photoreceptor outer nuclear layer with increasing distance from the foveal center coinciding with marked attenuation of the NIR and less marked loss of the SW-FAF signal. ERGs were non-detectable. Kinetic visual fields were generally full to large (V-4e) target but constricted to ~10°of eccentricity to I-4e stimuli. Dark-adapted thresholds by FST were rod-mediated and elevated by ~2 log units. Homozygous pathogenic mutations in RP1 (c.1720_1721del; p.Ser574Asnfs*8) were identified. Family member testing revealed father and siblings to be unaffected carriers; the mother carried wild-type alleles. Further testing suggested UPD of chromosome 8., Conclusion: This report adds support to UPD as a mechanism of inheritance in IRDs and stresses the importance of familial testing for genetic diagnosis and counseling. Consistent with earlier descriptions of autosomal recessive RP1 -IRDs our patient showed an early rod and cone photoreceptor degeneration.

Purpose: To characterize vision-related malpractice litigation involving prisoners., Methods: Retrospective legal database review using the Westlaw database was performed to identify vision-related malpractice lawsuits involving prisoners in the United States from 1914 to 2020. Main outcomes and measurements were allegations of malpractice, verdicts, and settlements., Results: Sixty-four vision-related malpractice lawsuits involving prisoners were identified. Mean defendant age was 49 years (range, 28-74 years). Fifty-seven percent of the defendants were ophthalmologists and 43% were optometrists. The cases were most commonly from the South and Midwest (n = 19 [30%] for each). Allegations of malpractice included inadequate medical care or treatment refusal (n = 21 [33%]), failure to treat fully leading to continued suffering (n = 18 [28%]), and delay in treatment or referral (n = 17 [27%]). Retina-related diagnoses were most common (n = 18 [28%]). Forty-six (72%) cases were closed, 14 (22%) were open, and four (6.3%) were partially closed. Only two (3.1%) cases were decided in favor of the plaintiff. The most common reason for an unsuccessful suit was lack of deliberate indifference by the eye care professional (n = 21 [46%])., Conclusion: The most common reasons for vision-related malpractice brought forth by prisoners were inadequate or incomplete eye care and treatment refusal. Retina was the most commonly involved subspecialty. However, the success rate of these suits was extremely low.