The incidence, monitoring coverage and clinical characteristics of hydroxychloroquine retinopathy in the United Kingdom

Background: Retinal monitoring is recommended for hydroxychloroquine users to detect pre-symptomatic retinopathy and preserve visual function. However, the incidence of hydroxychloroquine retinopathy and monitoring coverage in the U.K. are incompletely characterised. Moreover, the visual benefits of monitoring for retinopathy – recommended for over 70,000 long-term hydroxychloroquine users in the U.K. - remain unproven. Methods: A national, prospective observational study was undertaken with the British Ophthalmological Surveillance Unit (BOSU). Newly diagnosed cases of hydroxychloroquine retinopathy in the U.K. were reported and data captured using a standardised questionnaire over 3.5 years (July 2018–Dec 2021). The frequency of retinopathy and coverage of monitoring amongst long-term users was estimated. Visual function was compared between asymptomatic individuals detected on monitoring and those presenting with visual symptoms. The clinical characteristics, dosing and management of reported cases were captured. Results: The annualised number of incident cases of hydroxychloroquine retinopathy was 29–57, with an annualised frequency of 0.04–0.08% amongst long-term users (~1 in 1247–2625). The coverage of monitoring was approximately 2.6–5.5%. Visual acuity (0.1 vs. 0.22 logMAR; p = 0.007) and visual field mean deviation (−3.73 dB vs. −8.69 dB; p = 0.017) were better preserved in asymptomatic individuals compared to those presenting with visual symptoms. Conclusion: These data support the efficacy of monitoring in the preservation of visual function in patients with hydroxychloroquine retinopathy at diagnosis. The overall population coverage of monitoring was low, consistent with the high proportion of symptomatic patients at diagnosis. This study presents a method for evaluating the yield of monitoring for hydroxychloroquine retinopathy in the U.K

An audit of the use of hydroxychloroquine in rheumatology clinics

Objectives To audit the use, indications, complications and patient information regarding hydroxychloroquine (HCQ) treatment in rheumatology clinics in a tertiary referral centre. Methods During a 9-month period, we identified all patients prescribed HCQ and attending rheumatology clinics in one hospital. We established: (1) the indication for HCQ (2) the prevalence of HCQ overdosing based on absolute body weight (ABW) (3) documentation of warning of risk of retinal toxicity (4) systemic and ocular co-morbidities (5) ocular symptoms during treatment (6) reasons for stopping HCQ. Results We identified 427 patients (104 male, 323 female). The cumulative dose of HCQ was lower in rheumatoid arthritis (RA; median 365 g; range 6-1752 g) compared to systemic lupus erythematosus (SLE; 450 g; 66-1788 g) (p = 0.105). The median duration of HCQ therapy was four years (range 0.1-13); 28% of patients with RA and 29% with SLE continued HCQ beyond five years. After adjusting for ABW and renal function, 10% (31/312) had been prescribed doses exceeding recommendations. Formal documentation of counselling on ocular complications was only found in one third of patients. Three cases of HCQ retinopathy were identified (all of whom had RA). Conclusion HCQ therapy is being used for more than five years in 29% of patients with rheumatic diseases, with higher than recommended doses in approximately 10% of patients. We recommend more rigorous scrutiny of the use of HCQ to reduce the risk of retinopathy

Age-related macular degeneration: suitability of optogenetic therapy for geographic atrophy

Age-related macular degeneration (AMD) is a growing public health concern given the aging population and it is the leading cause of blindness in developed countries, affecting individuals over the age of 55 years. AMD affects the retinal pigment epithelium (RPE) and Bruch’s membrane in the macula, leading to secondary photoreceptor degeneration and eventual loss of central vision. Late AMD is divided into two forms: neovascular AMD and geographic atrophy (GA). GA accounts for around 60% of late AMD and has been the most challenging subtype to treat. Recent advances include approval of new intravitreally administered therapeutics, pegcetacoplan (Syfovre) and avacincaptad pegol (Iveric Bio), which target complement factors C3 and C5, respectively, which slow down the rate of enlargement of the area of atrophy. However, there is currently no treatment to reverse the central vision loss associated with GA. Optogenetics may provide a strategy for rescuing visual function in GA by imparting light-sensitivity to the surviving inner retina (i.e., retinal ganglion cells or bipolar cells). It takes advantage of residual inner retinal architecture to transmit visual stimuli along the visual pathway, while a wide range of photosensitive proteins are available for consideration. Herein, we review the anatomical changes in GA, discuss the suitability of optogenetic therapeutic sensors in different target cells in pre-clinical models, and consider the advantages and disadvantages of different routes of administration of therapeutic vectors

The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors

Midlife diagnosis of Refsum Disease in siblings with Retinitis Pigmentosa – the footprint is the clue: a case report

<p>Abstract</p> <p>Introduction</p> <p>Refsum disease is a potentially lethal and disabling condition associated with retinitis pigmentosa in which early treatment can prevent some of the systemic manifestations.</p> <p>Case presentation</p> <p>We present the cases of two brothers with a diagnosis of retinitis pigmentosa from childhood in whom Refsum disease was subsequently diagnosed midlife, after routine enquiry into hand and feet abnormalities. Subsequent treatment through dietary modification stabilised visual impairment and has prevented development of neurological complications to date.</p> <p>Conclusion</p> <p>It is therefore important to consider the diagnosis of Refsum disease in any patient with autosomal recessive or simplex retinitis pigmentosa, and to enquire about the presence of "unusual" feet or hands in such patients.</p

Clinical features of the pathogenic m.5540G>A mitochondrial transfer RNA tryptophan gene mutation

AbstractMitochondrial DNA disease is one of the most common groups of inherited neuromuscular disorders and frequently associated with marked phenotypic and genotypic heterogeneity. We describe an adult patient who initially presented with childhood-onset ataxia without a family history and an unremarkable diagnostic muscle biopsy. Subsequent multi-system manifestations included basal ganglia calcification, proteinuria, cataract and retinitis pigmentosa, prompting a repeat muscle biopsy that showed features consistent with mitochondrial myopathy 13 years later. She had a stroke with restricted diffusion change in the basal ganglia and internal capsule at age 44 years. Molecular genetic testing identified a previously-reported pathogenic, heteroplasmic mutation in the mitochondrial-encoded transfer RNA tryptophan (MT-TW) gene which based on family studies was likely to have arisen de novo in our patient. Interestingly, we documented an increase in the mutant mtDNA heteroplasmy level in her second biopsy (72% compared to 56%), reflecting the progression of clinical disease

Improving Mobility Performance in Low Vision With a Distance-Based Representation of the Visual Scene

Citation: van Rheede JJ, Wilson IR, Qian RI, Downes SM, Kennard C, Hicks SL. Improving mobility performance in low vision with a distancebased representation of the visual scene. Invest Ophthalmol Vis Sci. 2015;56:4802-4809. DOI:10.1167/ iovs.14-16311 PURPOSE. Severe visual impairment can have a profound impact on personal independence through its effect on mobility. We investigated whether the mobility of people with vision low enough to be registered as blind could be improved by presenting the visual environment in a distance-based manner for easier detection of obstacles. METHODS. We accomplished this by developing a pair of &apos;&apos;residual vision glasses&apos;&apos; (RVGs) that use a head-mounted depth camera and displays to present information about the distance of obstacles to the wearer as brightness, such that obstacles closer to the wearer are represented more brightly. We assessed the impact of the RVGs on the mobility performance of visually impaired participants during the completion of a set of obstacle courses. Participant position was monitored continuously, which enabled us to capture the temporal dynamics of mobility performance. This allowed us to find correlates of obstacle detection and hesitations in walking behavior, in addition to the more commonly used measures of trial completion time and number of collisions. RESULTS. All participants were able to use the smart glasses to navigate the course, and mobility performance improved for those visually impaired participants with the worst prior mobility performance. However, walking speed was slower and hesitations increased with the altered visual representation. CONCLUSIONS. A depth-based representation of the visual environment may offer low vision patients improvements in independent mobility. It is important for further work to explore whether practice can overcome the reductions in speed and increased hesitation that were observed in our trial

Age-related macular degeneration: suitability of optogenetic therapy for geographic atrophy

Age-related macular degeneration (AMD) is a growing public health concern given the aging population and it is the leading cause of blindness in developed countries, affecting individuals over the age of 55 years. AMD affects the retinal pigment epithelium (RPE) and Bruch’s membrane in the macula, leading to secondary photoreceptor degeneration and eventual loss of central vision. Late AMD is divided into two forms: neovascular AMD and geographic atrophy (GA). GA accounts for around 60% of late AMD and has been the most challenging subtype to treat. Recent advances include approval of new intravitreally administered therapeutics, pegcetacoplan (Syfovre) and avacincaptad pegol (Iveric Bio), which target complement factors C3 and C5, respectively, which slow down the rate of enlargement of the area of atrophy. However, there is currently no treatment to reverse the central vision loss associated with GA. Optogenetics may provide a strategy for rescuing visual function in GA by imparting light-sensitivity to the surviving inner retina (i.e., retinal ganglion cells or bipolar cells). It takes advantage of residual inner retinal architecture to transmit visual stimuli along the visual pathway, while a wide range of photosensitive proteins are available for consideration. Herein, we review the anatomical changes in GA, discuss the suitability of optogenetic therapeutic sensors in different target cells in pre-clinical models, and consider the advantages and disadvantages of different routes of administration of therapeutic vectors

The m.13051G>A mitochondrial DNA mutation results in variable neurology and activated mitophagy.

Maternally inherited mitochondrial DNA (mtDNA) mutations cause symptoms of Leber hereditary optic neuropathy (LHON) in -1 in 30,000 individuals. Most of the affected individuals lack respiratory chain defects1 and there is no proven prophylactic treatment

Phenotypic and genetic characteristics in a cohort of patients with Usher genes.

Background: This study aimed to compare phenotype–genotype correlation in patients with Usher syndrome (USH) to those with autosomal recessive retinitis pigmentosa (NS-ARRP) caused by genes associated with Usher syndrome. Methods: Case notes of patients with USH or NS-ARRP and a molecularly confirmed diagnosis in genes associated with Usher syndrome were reviewed. Phenotypic information, including the age of ocular symptoms, hearing impairment, visual acuity, Goldmann visual fields, fundus autofluorescence (FAF) imaging and spectral domain optical coherence tomography (OCT) imaging, was reviewed. The patients were divided into three genotype groups based on variant severity for genotype-phenotype correlations. Results: 39 patients with Usher syndrome and 33 patients with NS-ARRP and a molecular diagnosis in an Usher syndrome-related gene were identified. In the 39 patients diagnosed with Usher syndrome, a molecular diagnosis was confirmed as follows: USH2A (28), MYO7A (4), CDH23 (2), USH1C (2), GPR98/VLGR1 (2) and PCDH15 (1). All 33 patients with NS-ARRP had variants in USH2A. Further analysis was performed on the patients with USH2A variants. USH2A patients with syndromic features had an earlier mean age of symptom onset (17.9 vs. 31.7 years, p < 0.001), had more advanced changes on FAF imaging (p = 0.040) and were more likely to have cystoid macular oedema (p = 0.021) when compared to USH2A patients presenting with non-syndromic NS-ARRP. Self-reported late-onset hearing loss was identified in 33.3% of patients with NS-ARRP. Having a syndromic phenotype was associated with more severe USH2A variants (p < 0.001). Eighteen novel variants in genes associated with Usher syndrome were identified in this cohort. Conclusions: Patients with Usher syndrome, whatever the associated gene in this cohort, tended to have an earlier onset of retinal disease (other than GPR98/VLGR1) when compared to patients presenting with NS-ARRP. Analysis of genetic variants in USH2A, the commonest gene in our cohort, showed that patients with a more severe genotype were more likely to be diagnosed with USH compared to NS-ARRP. USH2A patients with syndromic features have an earlier onset of symptoms and more severe features on FAF and OCT imaging. However, a third of patients diagnosed with NS-ARRP developed later onset hearing loss. Eighteen novel variants in genes associated with Usher syndrome were identified in this cohort, thus expanding the genetic spectrum of known pathogenic variants. An accurate molecular diagnosis is important for diagnosis and prognosis and has become particularly relevant with the advent of potential therapies for Usher-related gene