Asymmetric preservation of choroidal pigmentation simulating choroidal nevus in two siblings with Waardenburg syndrome type 2A.

INTRODUCTION: In addition to sensorineural hearing loss, Waardenburg Syndrome (WS) may present with variable pigmentation of skin and choroid, which may simulate other life-threating conditions (e.g. melanoma). CASE REPORT: Two siblings ostensibly presented with unilateral choroidal pigmentary abnormalities concerning for choroidal tumour. Serial ophthalmic examination documented no lesion growth (base or height) whilst the apparent syndromic features (i.e. iris hypochromia, profound sensorineural hearing loss, SNHL), family history (autosomal dominant inheritance) and positive genetic testing (pathogenic MITF variant) led to a revised diagnosis of Waardenburg Syndrome type 2A. CONCLUSION: Sectoral preservation of choroidal pigmentation in WS is rarely associated with choroidal malignancy. Awareness of syndromic features (e.g. SNHL) and access to genetic testing may facilitate early accurate diagnosis (i.e. allay concern for malignancy), enable treatment of modifiable features (e.g. SNHL) and identify other affected relatives.

Peripapillary retinal nerve fibre layer thinning, perfusion changes and optic neuropathy in carriers of Leber hereditary optic neuropathy-associated mitochondrial variants.

BACKGROUND: We investigated Leber hereditary optic neuropathy (LHON) families for variation in peripapillary retinal nerve fibre layer thickness and perfusion, and associated optic nerve dysfunction. METHOD: A group of LHON-affected patients (n=12) and their asymptomatic maternal relatives (n=16) underwent examination including visual acuity (VA), visual-evoked-potential and optic nerve imaging including optical coherence tomography (OCT) and OCT angiography of the peripapillary retinal nerve fibre layer (RNFL). A control sample was also examined (n=10). The software imageJ was used to measure perfusion by assessing vessel density (VD), and statistical software 'R' was used to analyse data. RESULTS: The LHON-affected group (n=12) had significantly reduced peripapillary VD (median 7.9%, p=0.046). Overall, the LHON asymptomatic relatives (n=16) had no significant change in peripapillary VD (p=0.166), though three eyes had VD which fell below the derived normal range at 6% each, with variable VA from normal to blindness; LogMAR median 0, range 0-2.4. In contrast, RNFL thickness was significantly reduced in the LHON-affected group (median 51 µm, p=0.003), and in asymptomatic relatives (median 90 µm, p=0.01), compared with controls (median 101 µm). RNFL thinning had greater specificity compared with reduced perfusion for optic nerve dysfunction in asymptomatic carriers (92% vs 66%). CONCLUSION: Overall, reduced peripapillary retinal nerve fibre layer perfusion was observed in those affected by LHON but was not reduced in their asymptomatic relatives, unlike RNFL thinning which was significantly reduced in both groups versus controls. The presence of RNFL changes was associated with signs of optic neuropathy in asymptomatic relatives.

The Role of the Ophthalmic Genetics Multidisciplinary Team in the Management of Inherited Retinal Degenerations-A Case-Based Review.

(1) Background: Inherited retinal degenertions are rare conditions which may have a dramatic impact on the daily life of those affected and how they interact with their environment. Coordination of clinical services via an ophthalmic genetics multidisciplinary team (OG-MDT) allows better efficiency of time and resources to reach diagnoses and facilitate patient needs. (2) Methods: This clinical case series was conducted by a retrospective review of patient records for patients enrolled in the Target 5000 programme and managed by the OG-MDT, at the Mater Hospital Dublin, Ireland (n = 865) (3) Results: Herein we describe clinical cases and how the use of the OG-MDT optimizes care for isolated and syndromic IRD pedigrees. (4) Conclusions: this paper demonstrates the benefits of an OG-MDT to patients with IRDs resulting in the holistic resolution of complex and syndromic cases. Furthermore, we demonstrate that this format can be adopted/developed by similar centres around the world, bringing with it the myriad benefits.

Long-term anatomical and functional findings of solar maculopathy.

BACKGROUND: Solar maculopathy (SM) is a rare cause of acquired maculopathy related to direct viewing of the sun. Primary symptoms include central scotomata, blurred vision and/or metamorphopsia due to thermal/photochemical damage to foveal photoreceptors. METHODS: Patients were identified from clinic records surrounding a solar eclipse. Clinical examination and multimodal retinal imaging were performed at each follow-up visit. Informed consent was provided by each patient for publication of anonymized data. RESULTS: Seven affected eyes of 4 patients (mean 21.75 years, all female) were identified with mean presenting visual acuity (VA) of LogMAR 0.18. Well-defined photoreceptor ellipsoid zone (EZ) defects were identified on optical coherence tomography (OCT) for all eyes. VA improved for all eyes (median 12 letter improvement) over a mean 5.7-year follow-up (range 5 months to 11 years). CONCLUSIONS: While no effective treatment has been identified for SM, VA can significantly improve in some cases, but persistent scotomata are reported and may be debilitating; thus, prevention by public health measures remains critical.

Polarization-Diversity Optical Coherence Tomography Assessment of Choroidal Nevi.

Purpose: The purpose of this study was to demonstrate the utility of polarization-diversity optical coherence tomography (PD-OCT), a noninvasive imaging technique with melanin-specific contrast, in the quantitative and qualitative assessment of choroidal nevi. Methods: Nevi were imaged with a custom-built 55-degree field-of-view (FOV) 400 kHz PD-OCT system. Imaging features on PD-OCT were compared to those on fundus photography, auto-fluorescence, ultrasound, and non-PD-OCT images. Lesions were manually segmented for size measurement and metrics for objective assessment of melanin distributions were calculated, including degree of polarization uniformity (DOPU), attenuation coefficient, and melanin occupancy rate (MOR). Results: We imaged 17 patients (mean age = 69.5 years, range = 37-90) with 11 pigmented, 3 non-pigmented, and 3 mixed pigmentation nevi. Nevi with full margin acquisition had an average longest basal diameter of 5.1 mm (range = 2.99-8.72 mm) and average height of 0.72 mm (range = 0.37 mm-2.09 mm). PD-OCT provided clear contrast of choroidal melanin content, distribution, and delineation of nevus margins for melanotic nevi. Pigmented nevi were found to have lower DOPU, higher attenuation coefficient, and higher MOR than non-pigmented lesions. Melanin content on PD-OCT was consistent with pigmentation on fundus in 15 of 17 nevi (88%). Conclusions: PD-OCT allows objective assessment of choroidal nevi melanin content and distribution. In addition, melanin-specific contrast by PD-OCT enables clear nevus margin delineation and may improve serial growth surveillance. Further investigation is needed to determine the clinical significance and prognostic value of melanin characterization by PD-OCT in the evaluation of choroidal nevi.

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.

Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients.

Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Presentations to eye emergency departments with flashes and floaters differ dependent on incident solar radiation.

AIM: The aim of this retrospective review was to analyse the frequency of patients presenting with flashes and/or floaters (F/F) on bright versus dark days to the eye emergency department of a tertiary referral hospital (the Mater Misericordiae University Hospital) over a 3-year period. The diagnostic and clinical outcomes of F/F presentations were also analysed. METHODS: This retrospective study assessed eye casualty attendances between January 2018 and December 2020. Solar irradiation (j/cm2) at ground level was retrieved from the records of Met Eireann (Irish National Meteorological Service) via their open access records. A review of electronic patient medical records using the in-house database patient centre was carried out of all patients who attended EED of during the study timeline on the 5 'brightest' and 5 'darkest' days of each year. RESULTS: Seven hundred forty patient presentations were analysed in total. Overall, 16% (n = 119) of all patients that attended EED during the timeframe of the study presented with F/F. One hundred six patients (89%) presented with floaters, 40 patients (34%) presented with flashing lights/photopsia, and 35 patients (29%) presented with both F/F. More patients presented to EED with F/F on bright days when compared with dark days (74 vs 45, p < 0.05). Eighty-nine percent of all patients with F/F presented with monocular floaters. There were more floater presentations during bright when compared with dark days (70 vs 36, p < 0.05). More patients were diagnosed with PVD on bright days when compared with those diagnosed with PVD on dark days (43vs 15, p < 0.05). More RDs were diagnosed on dark days compared with bright days (7 vs 3, p < 0.05). CONCLUSION: This study established that F/F presentations were more likely to present during bright days when compared with dark days. The diagnosis of PVD was more common during bright days, and RDs were diagnosed significantly more frequently on dark days. Although incident solar radiation was correlated with greater floaters/PVD presentation, causation is unlikely, and the duration of PVD may have been longer in patients presenting on bright days (i.e. pseudo-sudden symptoms).

Risk of Neurotoxicity with Multiple General Anaesthetics for Examination Under Anaesthesia in Paediatric Ophthalmology - A Cause for Concern?

Purpose: To evaluate the impact of clinical protocol change via active minimisation on the number of general anaesthetic (GA)/sedation episodes for diagnostic ophthalmic purposes at Children's Health Ireland at Temple Street (CHI-TS), Dublin, Ireland, from 2016 to 2019, inclusive. Change was implemented following published cautionary principles in 2016 by the FDA regarding the potential neurotoxic risk from multiple GA exposure in children. Methods: Retrospective analysis of electronic operating theatre records was completed using procedure codes "Ophthalmological examination" and "Examination of fundi". Available records for patients undergoing multiple examination under anaesthesia (EUA) procedures were assessed for demographics, indication. Comparison was made regarding overall EUA numbers and breakdown for each year, before and after the new departmental approach. From 2018 onward, a patient-centred, departmental strategy of active minimisation of EUA was adopted, using strategies of "training, technology and patience". A literature review was conducted using online databases. Results: A total of 450 EUAs were performed over the 4 years investigated. In the former 2 years of the study period, prior to departmental policy change, EUAs represented 32% (304 of 948 total theatre episodes) of the ophthalmic theatre caseload. In the latter 2 years of this study period, this proportion fell to 19% (146 EUAs of 783 theatre episodes). Total theatre case numbers were comparable in both time periods. Eighteen children had multiple EUAs (ie, ≥2 EUAs, mean 6.5, SD 2.9) for life/sight threatening indications, totalling 116 EUAs (25.7%). Conclusion: A significant reduction in diagnostic EUA volume was accomplished resulting in reduced individual patient risk and increased capacity for surgical interventions. A detailed description of this methodology is included for the purposes of replication at comparable units. EUA will continue to play a crucial role in the management of life/sight threatening conditions but the application of a cautionary principle to reduce EUA, where possible, is appropriate to reduce potential for neurotoxicity.

Optic Nerve Structural and Functional Changes in LHON-Affected and Asymptomatic Maternal Relatives: Association with H and HV Mitochondrial Haplogroups.

Leber Hereditary Optic Neuropathy (LHON) affects a minority of carriers of causative mitochondrial DNA mutations. We investigated a cohort of patients with LHON, including m.11778G>A, m.3460G>A, m.14484T>C and DNAJC30 c.152A>G variants, and their asymptomatic maternal carrier relatives for additional potential associations with vision loss. We assessed visual acuity, optical coherence tomography (OCT) of the peripapillary retinal nerve fibre layer (RNFL), visually evoked potential including P-100 latency, and full mitochondrial genome sequencing. Comparison was made with a reference standard for OCT; European Descent, Heidelberg Engineering ©; and electrophysiology measurements with in-house normative ranges. RNFL was thinned overall in LHON patients (n = 12); median global RNFL −54 µm in the right eye (RE) and −50 µm in the left eye (LE) versus normal, and was found to be normal overall in asymptomatic carriers at +1 µm RE and −2 µm LE (n = 16). In four asymptomatic carriers there was RNFL thinning found either unilaterally or bilaterally; these cases were associated with isolated delay in P-100 latency (25%), delay and reduced visual acuity (50%), or reduced visual acuity without P-100 latency delay (25%). Optic nerve dysfunction was associated with mitochondrial haplogroup H and HV, versus non-H haplogroups, in the asymptomatic carriers (Fisher's exact test, p = 0.05). Our findings suggest that optic nerve abnormalities may be identified in asymptomatic LHON mitochondrial mutation carriers, which may be associated with optic nerve dysfunction. For asymptomatic carriers these findings were associated with mitochondrial haplogroup H and HV.

Differentiating primary dry eye disease from ocular neuropathic pain: implications for symptom management.

CLINICAL RELEVANCE: Eyecare practitioners' management of ocular surface disease is essential in managing increasing dry eye disease (DED) presentations including ocular neuropathic pain (ONP). Topical Proxymetacaine offers a simple, readily available and practical method of detecting ONP in practice and can be used to differentiate ONP from DED by eyecare practitioners, when accompanied with an anterior segment examination. BACKGROUND: Differentiating DED from ONP presents a significant opportunity to eyecare providers, allowing appropriate treatment choices for more adequate symptom control, greater patient satisfaction, and reduced emergent re-presentations. This study aims to differentiate patients presenting with DED symptoms into DED or ONP using a simple diagnostic tool, which can be used in practice to allocate appropriate treatment options for the patient's respective condition. A comparison of the prevalence of presentations of ONP presenting with DED symptoms in hospital ophthalmology settings and in optometric primary care settings will also be made. METHODS: Patients with symptoms of DED were opportunistically recruited as they presented to ophthalmology outpatient clinics and primary care optometric services. Patients were then categorised as DED, ONP, or mixed DED/ONP based on their subjective response 30 seconds post-Proxymetacaine Hydrochloride 2% instillation. RESULTS: Twenty-one patients were recruited, including 12 patients from ophthalmologic outpatient clinics and nine patients from primary care optometric services. Twelve patients were identified to have primary DED, while nine patients were identified to have ONP. 43% of patients presenting with DED symptoms had features of neuropathic pain in ophthalmologic outpatient presentations compared to 44% of patients in primary care optometric services. CONCLUSION: Categorising DED and ONP patients by their response to Proxymetacaine can be used as a simple diagnostic tool in guiding future patient management and can be indicative of their potential response to topical therapies. The use of topical Proxymetacaine and the resultant change in ocular pain score can facilitate selection of patients who may benefit from centrally acting neuropathic pain agents over topical ocular therapy.

The Natural History of Leber's Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers.

In this study we have assessed the clinical and genetic characteristics of an Irish Leber's hereditary optic neuropathy (LHON) cohort and assessed for useful biomarkers of visual prognosis. We carried out a retrospective review of clinical data of patients with genetically confirmed LHON presenting to an Irish tertiary referral ophthalmic hospital. LHON diagnosis was made on classic clinical signs with genetic confirmation. Alternate diagnoses were excluded with serological investigations and neuro-imaging. Serial logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) was stratified into 'on-chart' for logMAR 1.0 or better and 'off-chart' if worse than logMAR 1.0. Serial optical coherence tomography scans of the retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) monitored structure. Idebenone-treated and untreated patients were contrasted. Statistical analyses were performed to assess correlations of presenting characteristics with final VA. Forty-four patients from 34 pedigrees were recruited, of which 87% were male and 75% harboured the 11778 mutation. Legal blindness status was reached in 56.8% of patients by final review (mean 74 months). Preservation of initial nasal RNFL was the best predictor of on-chart final VA. Females had worse final VA than males and patients presenting at < 20 years of age had superior final VA. Idebenone therapy (50% of cohort) yielded no statistically significant benefit to final VA, although study design precludes definitive comment on efficacy. The reported cases represent the calculated majority of LHON pedigrees in Ireland. Visual outcomes were universally poor; however, VA may not be the most appropriate outcome measure and certain patient-reported outcome measures may be of more use when assessing future LHON interventions.

Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population.

Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a "telegenetics" approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.

Insidious ocular surface lesion in an 81-year-old woman.

Ocular surface melanoma (OSM) is rare. An 81-year-old Caucasian woman presented with a 4-month history of right eye pain and reduced vision. Histopathological examination of the excisional biopsy identified invasive amelanotic melanoma of the conjunctiva expressing Melan A and SOX10. X-ray of chest, CT of liver and MRI of the brain and orbit did not identify macroscopic metastases. She was given adjuvant topical mitomycin-C 0.04% for four cycles of 2 weeks. Her vision improved and the cornea was clear at 6 months.

Management of Keratoconus in Down Syndrome and Other Intellectual Disability.

PURPOSE: The purpose of this study was to assess an intellectual disability (ID) cohort with keratoconus (KC) regarding ophthalmic (visual acuity and corneal tomography) and systemic characteristics and to describe an appropriate clinical algorithm for investigation and management of KC in this setting. METHODS: This was the retrospective cohort study of patients with ID (Down syndrome, autism, and other) in the cornea department of a tertiary referral ophthalmic hospital in Dublin, Ireland. Retrospective chart review was conducted on people with ID undergoing examination under anesthesia or crosslinking under general anesthetic. Key outcome data included corneal examination findings, corneal tomography, visual acuity, and examination findings (eg, type of ID, general anesthetic, and cardiac status). RESULTS: Mean age of the 24 patients was 31.9 years (66.7% male). ID type was Down syndrome (66.7%), autism (25%), and other (8.3%). KC was diagnosed in 98% of eyes, with 45.8% having untreatable advanced disease (57.1% of these bilateral), 39.6% amenable to corneal collagen crosslinking (35.7% of these bilateral), and 6.3% having corneal transplantation. Congenital heart defects were present in 37.5% of the Down syndrome group. There were no serious ocular or systemic adverse events. CONCLUSIONS: KC is strikingly prevalent in the ID population. Ireland has the highest rate of Down syndrome in Europe (26.3:10,000 live births). This group is rarely suitable for corneal transplantation, and corneal collagen crosslinking is an effective intervention to prevent progression to advanced KC in this already socially restricted group. We propose an algorithm for investigation/treatment and also recommend uniform pediatric KC screening/treatment in ID populations.