Management of traumatic globe subluxation with optic nerve and extraocular muscle transection.

A care algorithm for partial globe subluxation cases with optic nerve and at least one extraocular muscle (EOM) transection is presented after a literature review was performed using key term variations of globe, ocular, subluxation, optic nerve evulsion or transection, and trauma. Partial globe subluxation cases with transection of the optic nerve and at least 1 EOM were included. Exclusion criteria included globe rupture, complete enucleation defined by a globe without at least 1 EOM attachment, or unclear details confirming optic nerve transection. Including the patient presented herein, a total of 24 patients with 26 eyes were analyzed. About 73.08% of cases underwent initial repositioning (n = 19), with 11.54% of those requiring secondary enucleation or evisceration (n = 3). Of the secondarily managed cases, 2 of the 3 cases listed pain (n = 2) and inadequate cosmesis (n = 1) as rationale. We found that 26.92% of cases underwent initial enucleation (n = 7), citing lack of visual potential and limiting later complications. Most cases favored repositioning, which was typically sustainable. Initial repositioning can improve cosmetic outcome and psychological impact. Given the low risk of later management, cases of traumatic partial subluxation with EOM and optic nerve transections should attempt initial repositioning.

Phenotypic Variability of Retinal Disease Among a Cohort of Patients With Variants in the CLN Genes.

Purpose: To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature. Methods: Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes. Results: Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele. Conclusions: Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling.

Effects of medications on hypoxia-inducible factor in the retina: A review.

Hypoxia-inducible factor (HIF) plays a critical role in the mechanisms that allow cells to adapt to various oxygen levels in the environment. Specifically, HIF-1⍺ has shown to be widely involved in cellular repair, survival, and energy metabolism. HIF-1⍺ has also been found in increased levels in cancer cells, highlighting the importance of balance in the hypoxic response. Promoting HIF-1⍺ activity as a potential therapy for degenerative diseases and inhibiting HIF-1⍺ as a therapy for pathologies with overactive cell proliferation are actively being explored. Digoxin and metformin, HIF-1⍺ inhibitors, and deferoxamine and ⍺-ketoglutarate analogues, HIF-1⍺ activators, are being studied for application in age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. However, these same medications have retinal toxicities that must be assessed before implementation of therapeutic care. Herein, we highlight the duality of therapeutic and toxic potential of HIF-1⍺ that must be carefully assessed prior to its clinical application in retinal disorders.

Phenotypic variability in PRPH2 as demonstrated by a family with incomplete penetrance of autosomal dominant cone-rod dystrophy.

INTRODUCTION: Mutations in the peripherin-2 gene (PRPH2) are a common cause of inherited retinal dystrophies well known for their phenotypic diversity. We describe a novel presentation of the c.623G > A; p.(Gly208Asp) variant in association with cone-rod dystrophy and reduced penetrance. CASE DESCRIPTION: A 39-year-old man presents with a history of decreased visual acuity, photophobia, and dyschromatopsia. Fundus examination was largely unremarkable while spectral-domain optical coherence tomography (SD-OCT) demonstrated diffuse granularity at the ellipsoid zone. Full-field electroretinogram (ffERG) revealed a cone-rod dystrophy. Genetic testing revealed a heterozygous pathogenic variant, c.623G > A; p.(Gly208Asp), in the PRPH2 gene, also found in an unaffected brother. The 50-year-old brother had no visual symptoms and no findings on fundus examination. SD-OCT showed normal retinal architecture and ffERG was within normal limits bilaterally. CONCLUSION: This case report broadens the known phenotypic presentations of PRPH2-associated retinopathy and suggests that the PRPH2 variant c.623G > A; p.(Gly208Asp) may be associated with reduced penetrance.

Clinical characteristics of high myopia in female carriers of pathogenic RPGR mutations: a case series and review of the literature.

BACKGROUND: RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described. MATERIALS AND METHODS: Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected. RESULTS: Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium. CONCLUSION: RPGR-related high myopia has been associated with mutations in exons 1-14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers.

Correlations of Full-Field Stimulus Threshold With Functional and Anatomical Outcome Measurements in Advanced Retinitis Pigmentosa.

PURPOSE: To compare full-field stimulus (FST) threshold values to conventional functional and anatomical measures commonly used in clinical practice. DESIGN: Cross-sectional study. METHODS: Patients with retinitis pigmentosa with nondetectable electroretinogram rod-mediated responses and light-adapted 3.0 cd·s·m2 30-Hz flicker (LA 3.0 flicker) amplitudes of 15 mV or less were included in this study. The threshold values for blue, white, and red stimuli on FST were correlated with best-corrected visual acuity, LA 3.0 flicker amplitude and implicit times, length of the ellipsoid zone (EZ) band and thickness of outer nuclear layer measurements on optical coherence tomography, and the vertical and horizontal diameters of the autofluorescent ring on autofluorescence imaging. RESULTS: Forty-two eyes of 21 patients were included in the study. The mean FST thresholds were -22.5 ± 15.5 dB, -17.6 ± 11.5 dB, and -12.7 ± 6.0 dB for the blue, white, and red stimuli, respectively. The threshold values for the 3 FST stimuli were significantly correlated with selected functional and anatomical outcome measures. Specifically, they were strongly correlated with LA 3.0 flicker amplitude and EZ band length measured on optical coherence tomography. Using linear regression, blue and white stimulus values on FST were found to be predictive of EZ band length (R2 = 0.579 and 0.491, respectively), and the vertical (R2 = 0.694 and 0.532, respectively) and horizontal (R2 = 0.626 and 0.400, respectively) diameters of the hyperautofluorescent ring. CONCLUSIONS: The significant correlations between FST and other clinical outcome measures highlight its potential as an adjunct outcome measure.

Congenital Stationary Night Blindness: Clinical and Genetic Features.

Congenital stationary night blindness (CSNB) is an inherited retinal disease (IRD) that causes night blindness in childhood with heterogeneous genetic, electrophysical, and clinical characteristics. The development of sequencing technologies and gene therapy have increased the ease and urgency of diagnosing IRDs. This study describes seven Taiwanese patients from six unrelated families examined at a tertiary referral center, diagnosed with CSNB, and confirmed by genetic testing. Complete ophthalmic exams included best corrected visual acuity, retinal imaging, and an electroretinogram. The effects of identified novel variants were predicted using clinical details, protein prediction tools, and conservation scores. One patient had an autosomal dominant CSNB with a RHO variant; five patients had complete CSNB with variants in GRM6, TRPM1, and NYX; and one patient had incomplete CSNB with variants in CACNA1F. The patients had Riggs and Schubert-Bornschein types of CSNB with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. This is the first report of CSNB patients in Taiwan with confirmed genetic testing, providing novel perspectives on molecular etiology and genotype-phenotype correlation of CSNB. Particularly, variants in TRPM1, NYX, and CACNA1F in our patient cohort have not previously been described, although their clinical significance needs further study. Additional study is needed for the genotype-phenotype correlation of different mutations causing CSNB. In addition to genetic etiology, the future of gene therapy for CSNB patients is reviewed and discussed.

Case report: novel PCDH15 variant causes usher syndrome type 1F with congenital hearing loss and syndromic retinitis pigmentosa.

BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder primarily responsible for deaf-blindness. Patients with subtype Usher syndrome type 1 (USH1) typically experience congenital sensorineural hearing loss, abnormal vestibular function, and retinitis pigmentosa (RP). Here we present a case of Usher syndrome type 1F (USH1F) with a novel homozygous variant in the calcium-dependent cell-cell adhesion protocadherin-15 (PCDH15) gene. CASE PRESENTATION: Ophthalmic examinations were evaluated over a course of 10 years and the disease-causing variant was identified by whole exome sequencing (WES). Initial and follow-up examination of color fundus photos after 10 years revealed an increase in bone spicule pigment deposits in both eyes. A parafoveal hyper-AF ring in both eyes was shown in fundus autofluorescence (FAF) with a progressive diameter-wise constriction observed over 8 years. Outer nuclear layer (ONL) loss was observed in parafoveal and perifoveal regions of both eyes on spectral domain-optical coherence tomography (SD-OCT). Full-field electroretinography (ffERG) showed extinguished global retinal function. WES identified a novel two-base-pair deletion, c.60_61del (p.Phe21Ter), in the PCDH15 gene, confirming the diagnosis of USH1F. CONCLUSIONS: We report a novel homozygous PCDH15 pathogenic variant expected to lead to nonsense-mediated decay (NMD) of PCDH15 mRNA. The patient exhibits a loss of function with USH1F, experiencing congenital hearing loss and syndromic RP.

Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence.

INTRODUCTION: Leber congenital amaurosis (LCA) type 2, due to disease-causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec-rzyl (VN) for RPE65-associated LCA. Herein, we present the long-term follow-up of a patient treated with VN using quantitative autofluorescence (488 nm excitation). CASE REPORT: A 9-year-old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6- and 8-year follow-up revealed a central area of fundus autofluorescence. DISCUSSION: This case report demonstrates acquisition of fundus autofluorescence at 6- and 8-year follow-up despite the development of chorioretinal atrophy.

A pathogenic in-frame deletion-insertion variant in BEST1 phenocopies Stargardt disease.

Here, we describe affected members of a 2-generation family with a Stargardt disease-like phenotype caused by a 2-base pair deletion insertion, c.1014_1015delGAinsCT;p.(Trp338_Asn339delinsCysTyr), in BEST1. The variant was identified by whole-exome sequencing, and its pathogenicity was verified through chloride channel recording using WT and transfected mutant HEK293 cells. Clinical examination of both patients revealed similar phenotypes at 2 different disease stages that were attributable to differences in their age at presentation. Hyperautofluorescent flecks along the arcades were observed in the proband, while the affected mother exhibited more advanced retinal pigment epithelium (RPE) loss in the central macula. Full-field electroretinogram testing was unremarkable in the daughter; however, moderate attenuation of generalized cone function was detected in the mother. Results from electrooculogram testing in the daughter were consistent with widespread dysfunction of the RPE characteristic of Best disease. Whole-cell patch-clamp recordings revealed a statistically significant decrease in chloride conductance of the mutant compared with WT cells. This report on a mother and daughter with a BEST1 genotype that phenocopies Stargardt disease broadens the clinical spectrum of BEST1-associated retinopathy.

Foveolar thickness as potential standardized structural outcome measurement in studies of Bietti crystalline dystrophy.

Bietti crystalline dystrophy (BCD) is an ultra-rare orphan disorder that can lead to blindness. Because of the variable rates of progression of the disease, it is necessary to identify suitable outcome measurements for tracking progression in BCD. A retrospective analysis of patients with a clinical and genetic diagnosis of BCD was conducted. Four measurements of spectral domain-optical coherence tomography were compared to patients' best corrected visual acuity. We observed that patients with higher measurements of foveolar thickness, choroidal thickness in the foveolar region, ellipsoid zone band length and the outer nuclear layer + area, had on average better visual acuity. Future studies are needed to validate the structural-functional correlations we observed in BCD and to propose a sensitive and clinically meaningful outcome measurement for tracking this rare, variable disease.

Neurological toxicities associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.