Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review.

Purpose: Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive (AR) syndromic inherited retinal degenerations (IRDs) representing 50% of deaf-blindness. All subtypes include retinitis pigmentosa, sensorineural hearing loss, and vestibular abnormalities. Thorough phenotyping may facilitate genetic diagnosis and intervention. Here we report the clinical/genetic features of an Irish USH cohort. Methods: USH patients were selected from the Irish IRD registry (Target 5000). Patients were examined clinically (deep-phenotyping) and genetically using a 254 IRD-associated gene target capture sequencing panel, USH2A exon, and whole genome sequencing. Results: The study identified 145 patients (24.1% USH1 [n = 35], 73.8% USH2 [n = 107], 1.4% USH3 [n = 2], and 0.7% USH4 [n = 1]). A genetic diagnosis was reached in 82.1%, the majority (80.7%) being MYO7A or USH2A genotypes. Mean visual acuity and visual field (VF) were 0.47 ± 0.58 LogMAR and 31.3° ± 32.8°, respectively, at a mean age of 43 years. Legal blindness criteria were met in 40.7%. Cataract was present in 77.4%. ADGRV1 genotypes had the most VF loss, whereas USH2A patients had greater myopia and CDH23 had the most astigmatism. Variants absent from gnomAD non-Finnish Europeans and ClinVar represented more than 20% of the variants identified and were detected in ADGRV1, ARSG, CDH23, MYO7A, and USH2A. Conclusions: USH is a genetically diverse group of AR IRDs that have a profound impact on affected individuals and their families. The prevalence and phenotype/genotype characteristics of USH in Ireland have, as yet, gone unreported. Understanding the genotype of Irish USH patients may guide clinical and genetic characterization facilitating access to existing/novel therapeutics.

CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History.

PURPOSE: To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date. DESIGN: Multicenter retrospective cohort study. SUBJECTS: Forty-seven patients (37 families) with likely disease-causing CERKL variants. METHODS: Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers. MAIN OUTCOME MEASURES: Visual function, retinal imaging, and characteristics were evaluated and correlated. RESULTS: The mean age at the first visit was 29.6 ± 13.9 years, and the mean follow-up time was 9.1 ± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up. CONCLUSIONS: The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Direct Exchange of PerfluoroCarbon Liquid for Silicone Oil: A Surgical Technique to Control Pressure and Avoid Retinal Slippage.

BACKGROUND/PURPOSE: Perfluorocarbon heavy liquid (PFCL) is used in vitreoretinal surgery to flatten the unsupported detached retina before insertion of silicone oil in cases of giant retinal tear or relaxing retinectomy. Direct exchange of PFCL for silicone oil is recommended to reduce retinal slippage when compared with fluid-air exchange, but it is commonly regarded as a difficult procedure. We describe our technique for direct PFCL-silicone oil exchange using a 20-gauge drainage cannula, reliably avoiding the complications of retinal slippage and high intraoperative intraocular pressure. METHODS: We present a consecutive case series of patients undergoing PFCL-oil exchange and explain, using Poiseuille's equation for laminar fluid flow through a cannula, the rationale for using a 20-gauge drainage cannula rather than smaller gauges to avoid high intraocular pressure. RESULTS: Twenty-six patients underwent PFCL-oil exchange from February 1, 2019, to September 30, 2019. There was no intraoperative retinal slippage or pressure-related complications. Postoperatively 20 patients underwent oil removal. Six suffered retinal redetachment, and 14 remained attached. The vision postoil removal ranged from 6/6 to hand movements. CONCLUSION: We are confident that the PFCL-oil exchange technique described here is reliable and safe. The use of a 20-gauge drainage cannula is recommended regardless of vitrectomy gauge.

Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases.

Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30-40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy.

PURPOSE: To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports. METHODS: The clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG). RESULTS: Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5-6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases. CONCLUSIONS: This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.

Iris-fixated phakic intraocular lens explantation.

BACKGROUND/AIMS: To evaluate the visual outcomes and indication for surgery in a series of patients who underwent explantation of a phakic intraocular lens (PIOL). METHODS: A retrospective case series of patients who underwent PIOL explantation in our institution was performed. The indication for explantation and visual and refractive outcomes were examined. The method of explantation is described. RESULTS: Twenty-two eyes of 16 patients underwent PIOL explantation with a mean time to explantation of 7 ± 3 years (range 3-11.4). The mean age at explantation was 50.3 ± 9.3 years. Sixteen Artisan PIOLs and six Artiflex PIOLs were explanted. The indications for explanation were cataract development (17/22), endothelial cell loss (4/22) and synechiae formation (1/22). All patients with cataract underwent a combined procedure with explantation and phacoemulsification and the placement of a posterior chamber IOL. Mean corrected vision after explantation was 0.22 ± 0.10 logMAR (range 0.1-0.3 logMAR). One patient with endothelial cell loss required a Descemet's Stripping Endothelial Keratoplasty (DSEK). CONCLUSION: Removal of PIOLs was necessitated most frequently by cataract followed by endothelial cell loss. Both explantation alone and explantation with concurrent phacoemulsification are safe procedures with good visual outcomes and will become more frequent in the future as more patients with PIOLs reach cataractous age.

Investigating the Role of Optometrists in Teleophthalmology and the Implications of Increasing Access to Advanced Imaging Techniques and Digital Referral: A Systematic Search and Review.

Introduction: The objective of this systematic search and review was to investigate the role of optometrists in teleophthalmology and digital referral. We examine the implications of the optometric communities' increasing access to advanced imaging, such as optical coherence tomography (OCT), in ophthalmic telemedicine schemes. Methods: A systematic search was conducted, using PubMed and Embase, in April of 2019. Eight hundred eight (n = 808) texts were retrieved and 99 articles were deemed eligible for full-text review. Twenty-six (n = 26) studies were included in the qualitative synthesis. All studies involved optometrists as principal service providers. Results: Findings demonstrate that optometrist-facilitated teleophthalmology results in consistent reductions in hospital referrals and waiting times, as well as high patient satisfaction. Optometrists are identified as crucial to the success of many projects and their access to advanced imaging technology is observed to position optometry practices as the most convenient location to establish a teleophthalmology program. OCT imaging demonstrated the potential to increase diagnostic accuracy and is increasingly prevalent in optometry practice. The importance of additional training for optometrists participating in teleophthalmology schemes is highlighted, as is the need for appropriate remuneration for those involved. Conclusion: The role of community-based ophthalmic care in reducing demands on hospital eye services (HES) is highlighted by our results, demonstrating that optometrist-facilitated teleophthalmology can dramatically reduce referrals and streamline care. In addition, the increasing prevalence of OCT in optometric practice represents an underutilized resource for HES.

Persistent pseudomyopia following a whiplash injury in a previously emmetropic woman.

PURPOSE: Accommodative spasm, which manifests as ciliary muscle spasm, convergent strabismus or miosis, is a recognised consequence of head trauma. In whiplash cases, cervical spine hyperextension poses a risk of contra-coup injury and brainstem trauma, and is known to affect the visual system. However, to date, no cases of accommodative spasm due to whiplash injury have been reported. OBSERVATIONS: We present the case of a 34-year-old female who developed sudden onset blurred distance vision after a rear impact car crash, having previously been emmetropic. Her unaided distance visual acuity was 20/70 in the right eye and 20/20 in the left. Best-corrected visual acuity in the right eye was 20/20 with a correction that progressed from -1.75 to -3.50 DS over the 12 months following the accident.This patient's sudden unilateral myopia, with unilaterally increased amplitude of accommodation suggests pseudomyopia due to accommodative spasm. Magnetic resonance imaging showed no evidence of injury to her brain stem, frontal lobes or oculomotor nerve. The patient is now well adjusted with a -3.50DS corrective lens for the right eye. CONCLUSIONS AND IMPORTANCE: The accommodation reflex is susceptible to injury at the occipital lobe, frontal eye fields, Edinger-Westphal nuclei and oculomotor nerves. As such it should be examined in patients who present with visual disturbances following whiplash injury.It is important that such cases are identified at presentation, as early intervention can improve outcomes in accommodative spasm and reduce the long term psychological effects often associated with whiplash injuries.

Corneal inlay implantation complicated by infectious keratitis.

BACKGROUND/AIMS: To report five cases of infectious keratitis following corneal inlay implantation for the surgical correction of presbyopia. METHODS: This was a retrospective, observational case series. Five eyes of five patients were identified consecutively in two emergency departments during a 1-year period, from November 2013 to November 2014. Patients' demographics, clinical features, treatment and outcomes are described. RESULTS: There were four female patients and one male, aged 52-64 years. Three patients had the KAMRA inlay (AcuFocus) and two had the Flexivue Microlens inlay (Presbia Coöperatief U.A.) inserted for the treatment of presbyopia and they presented from 6 days to 4 months postoperatively. Presenting uncorrected vision ranged from 6/38 to counting fingers. One patient's corneal scrapings were positive for a putatively causative organism, Corynebacterium pseudodiphtheriticum, and all patients responded to broad-spectrum fortified topical antibiotics. All patients lost vision with final uncorrected visual acuity ranging from 6/12 to 6/60 and best-corrected vision ranging from 6/7.5 to 6/12. Two patients' corneal inlays were explanted and three remained in situ at last follow-up. CONCLUSIONS: Infectious keratitis can occur at an early or late stage following corneal inlay implantation. Final visual acuity can be limited by stromal scarring; in the cases where the infiltrate was small and off the visual axis at the time of presentation, the final visual acuity was better than those patients who presented with larger lesions affecting the visual axis. Though infection may necessitate removal of the inlay, early positive response to treatment may enable the inlay to be left in situ.

Long-term heavy silicone oil intraocular tamponade.

Heavy silicone oil tamponade is intended to be temporary, but may occasionally be indefinite in patients who refuse, or are deemed unsuitable for, further surgery. The aim of this study is to compare the outcomes of patients with temporary versus indefinite heavy silicone oil intraocular tamponade. This retrospective, comparative case series identified 75 patients who underwent heavy silicone oil instillation (Oxane HD) over a 6 year period (2006-2012) in one institution. Thirty-nine patients had temporary heavy oil tamponade and 36 patients had indefinite tamponade. The majority (68 %) of patients had a history of previous vitreoretinal surgery prior to oil instillation and 66.7 % had pre-existing proliferative vitreoretinopathy (PVR). The mean final logMAR best corrected visual acuity (BCVA) was significantly better in the temporary tamponade group (1.34 ± 0.66) than the indefinite tamponade group 1.82 ± 0.64 (p = 0.003). Ambulatory BCVA (≥ 4/200) was retained in 76.3 % of temporary tamponade patients versus 54.3 % of indefinite tamponade patients (p = 0.093). Successful retinal reattachment was significantly more likely in temporary tamponade patients (92.3 %) than indefinite tamponade patients (75 %; p = 0.04). Complications in the patients with indefinite heavy silicone oil tamponade included redetachment (38.9 %), corneal pathology (13.8 %), secondary glaucoma (11.1 %) and anterior segment emulsification (8.3 %).While temporary tamponade patients had better outcomes than those with indefinite tamponade, the majority of indefinite tamponade patients still retained ambulatory vision in the affected eye. Indefinite heavy silicone oil tamponade remains a viable option for those who cannot undergo removal of oil surgery.