Neuro-ophthalmic complications of modern anti-cancer drugs.

PURPOSE: Targeted cancer therapies have been responsible for a dramatic shift in treatment strategies for cancer, and the number of drugs, classes, and indications are continually growing. Neuro-ophthalmic complications of these medications are an uncommon but important subset of adverse events which profoundly impact vision. This review aims to collate studies and reports of known neuro-ophthalmic complications of targeted therapies and describe their management. METHODS: The anti-cancer drugs included in the review were any drugs targeting specific molecules involved in the cancer disease process. PubMed, EMBASE, and Web of Science were searched using the generic names of each drug and keywords of neuro-ophthalmic conditions. The prescribing information published by the US Food and Drug Administration (FDA) for each drug was also reviewed. RESULTS: Several classes of targeted anti-cancer drugs were found to cause neuro-ophthalmic adverse effects. Immune checkpoint inhibitors are responsible for a raft of immune-related adverse events such as optic neuritis, ischemic optic neuropathy, PRES, and myasthenia gravis. Therapies with anti-VEGF activity can provoke posterior reversible leukoencephalopathy, which commonly presents with visual loss and can be fatal if not treated promptly. Inhibitors of BCR-ABL1, VEGF, ALK, and proteasomes have all been linked to optic nerve disorders which can have debilitating consequences for vision. CONCLUSION: The neuro-ophthalmic complications of modern anti-cancer drugs can limit or necessitate the withdrawal of these life-prolonging medications. Ophthalmologists should be alert for neuro-ophthalmic complications in these medications to facilitate prompt diagnosis and treatment and reduce the risk of severe and permanent consequences.

Nonarteritic Anterior Ischemic Optic Neuropathy After Cataract Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported to occur after cataract surgery. It is not clearly established whether cataract surgery increases the risk of NAION over baseline. EVIDENCE ACQUISITION: Medline, PubMed, Embase, and Cochrane Central registers were systematically searched for eligible studies reporting on postcataract surgery NAION (psNAION) within 1 year. All peer-reviewed publications with events n ≥ 10 were included. Pooled incidence and odds/hazard ratios and 95% confidence intervals (CIs) were extracted and calculated using random effect models for early and delayed psNAION. Time to event data were pooled for temporal analysis of psNAION events within the first year. This systematic review was registered (PROSPERO CRD42021274383). RESULTS: Nine articles met the selection criteria with five studies suitable for meta-analysis. A total of 320 psNAION cases, 1,307 spontaneous NAION (sNAION) cases, 1,587,691 cataract surgeries, and 1,538,897 noncataract surgery controls were included. Pooling of 63,823 cataract surgeries and 161,643 controls showed a hazard ratio of 4.6 (95% CI 2.7-7.8) of psNAION within 1 year of surgery. Pooled unadjusted incidence of psNAION within 2 months was 99.92 (95% CI 38.64-161.19) per 100,000/year, psNAION within 1 year was 32.36 (95% CI 9.38-55.34) per 100,000/year, and sNAION was 8.87 (95% CI 2.12-15.62) per 100,000/year. psNAION cases were older by a mean of 7.6 years; otherwise, pooled odds ratios for baseline risk factors in psNAION vs. sNAION cases were not statistically significant. psNAION within the first year peaked within 72 hrs and at 6 weeks after the surgery with 73% of cases occurring within 6 months. CONCLUSION: The risk of NAION after cataract surgery is four times greater within the first year and usually occurs within 6 months. However, the absolute risk remains low at 1 in 1,000-3,100 surgeries and is unlikely to warrant extra mention for consenting.

Gender differences in surgical case volume among ophthalmology trainees.

BACKGROUND: The number of females in ophthalmology has steadily increased over recent decades. The aim of this study was to evaluate whether there is a difference in procedural volume and cataract surgery between male and female trainees in the Royal Australian and New Zealand College of Ophthalmologists (RANZCO). METHODS: A longitudinal retrospective review of de-identified surgical RANZCO trainee logbook data from 2008 to 2020 was undertaken. Data from 241 trainee logbooks were analysed for: location of training, gender, date of commencement of training, maternity/paternity leave status, number of surgeries observed, assisted, supervised and unsupervised. Surgical cases were grouped as: (1) all surgical cases; (2) complete cataract cases and (3) partial cataract cases. RESULTS: Among 241 trainees (40.7% females), 197 263 procedures were performed. Total surgical volume was 21.1% lower at 4 years for females (median 665.5 vs. 843.5; p = 0.036). Completed cataract surgery was 21.5% lower at 18 months (median 87.5 vs. 111.5; p = 0.022) and 41.7% lower at 4 years (median 216 vs. 369; p < 0.001). Interrupted training was significantly more common in females (30.6% vs. 0.7%; p < 0.001). However, linear regression analysis did not identify parental leave or duration as a significant predictor for number of completed cataracts (p = 0.206). Complication rate was not different between males and females (p = 0.35). CONCLUSIONS: Female trainees completed 41.7% fewer cataract operations at the end of their training compared to male counterparts with the gap widening between years 1 and 4 of training. The current data demonstrates that female and male RANZCO trainees are not receiving equivalent operating experiences.

Neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein IgG associated disorder: A comprehensive neuro-ophthalmic review.

Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system that involves the optic nerves, spinal cord, and often other specific brain regions such as area postrema of the medulla. NMOSD was formerly classified as a variant of multiple sclerosis (MS), given the similar symptomatology and relapsing course but is now considered to have distinct clinical, paraclinical, immunological and prognostic features. The discovery of aquaporin 4 (AQP4) immunoglobulin G (IgG) has improved the ability to diagnose NMOSD. AQP4-IgG targets the astrocytic AQP4 water channel leading to complement activation and increased blood-brain barrier permeability. Accurate and early diagnosis is crucial as timely treatment may result in mitigation of long-term disability. Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorder (MOGAD) is a distinct nosologic entity, which has been more recently described. Its clinical spectrum partly overlaps that of seronegative NMOSD and MS. Although it is considered to have fewer relapses and better prognosis than NMOSD, the clinical course and outcome of MOGAD has not been fully characterized.

Bullying, harassment and sexual discrimination among ophthalmologists in Australia and New Zealand.

BACKGROUND: Discrimination, bullying and sexual harassment (DBSH) impact the psychological well-being of doctors and contribute to poor health outcomes. The Royal Australian and New Zealand College of Ophthalmologists (RANZCO) commissioned independent surveys to evaluate DBSH among members/trainees. METHODS: Anonymous online surveys by Best Practice Australia were undertaken in 2015 and 2018. Cross-sectional analysis was prevalence of perceived DBSH, rates of reporting, intervention and resolution undertaken. Response rate was 50% (658/1319) in 2015 and 40% (557/1401) in 2018. In both surveys, 29% were female. This is representative of the distribution of the RANZCO members. RESULTS: In a 2015 survey, 37.6% of respondents experienced DBSH, with prevalence being the highest for females (62.3%; N = 104 cf males 27.7%; N = 167) and trainees (49.2%; N = 61). In 2018, 49.2% of respondents reported DBSH with rates low for all forms of DBSH (22%-29%). Sexual harassment was reported by 12% and the least discussed or reported. Respondents strategy for taking action included draw on personal support network (25-43%), official complaints to supervisors (16-22%), human resources (2%-10%) and RANZCO (0%-6%). Reasons for not taking action included fear of impact of future career options (54.1%-60.7%), fear of victimization (35.7%-50.4%) and afraid of not being believed (31.9%-52.4%). Satisfactory resolution rates were 6% to 25%. A majority of respondents (77%) were positive about RANZCO initiatives. CONCLUSIONS: DBSH is commonly reported by RANZCO members with female ophthalmologists more than two times more likely to experience any one of the four behaviours, three times more likely to experience discrimination and six times for sexual harassment. Fear of compromising personal and career progression contribute to low levels of reporting.

Microdroplet and spatter contamination during phacoemulsification cataract surgery in the era of COVID-19.

IMPORTANCE: Determine phacoemulsification cataract surgery risk in a Covid-19 era. BACKGROUND: SARS-CoV-2 (Covid-19) transmission via microdroplet and aerosol-generating procedures presents risk to medical professionals. As the most common elective surgical procedure performed globally; determining contamination risk from phacoemulsification cataract surgery may guide personal protection equipment use. DESIGN: Pilot study involving phacoemulsification cataract surgery on enucleated porcine eyes by experienced ophthalmologists in an ophthalmic operating theatre. PARTICIPANTS: Two ophthalmic surgical teams. METHODS: Standardized phacoemulsification of porcine eyes by two ophthalmologists accompanied by an assistant. Fluorescein incorporated into phacoemulsification irrigation fluid identifying microdroplets and spatter. Contamination documented using a single-lens reflex camera with a 532 nm narrow bandpass (fluorescein) filter, in-conjunction with a wide-field blue light and flat horizontal laser beam (wavelength 532 nm). Quantitative image analysis using Image-J software. MAIN OUTCOME MEASURES: Microdroplet and spatter contamination from cataract phacoemulsification. RESULTS: With phacoemulsification instruments fully within the eye, spatter contamination was limited to <10 cm. Insertion and removal of the phacoemulsification needle and bimanual irrigation/aspiration, with irrigation active generated spatter on the surgeons' gloves and gown extending to >16 cm below the neckline in surgeon 1 and > 5.5 cm below the neckline of surgeon 2. A small tear in the phacoemulsification irrigation sleeve, presented a worse-case scenario the greatest spatter. No contamination above the surgeons' neckline nor contamination of assistant occurred. CONCLUSIONS AND RELEVANCE: Cataract phacoemulsification generates microdroplets and spatter. Until further studies on SARS-CoV-2 transmission via microdroplets or aerosolisation of ocular fluid are reported, this pilot study only supports standard personal protective equipment.

Gender differences in Australasian ophthalmologists' experiences of the workplace.

IMPORTANCE: Gender differences were identified in experiences of the workplace and family responsibilities amongst Australian and New Zealand ophthalmologists. BACKGROUND: To survey ophthalmologists regarding their balance of career, family and workplace experiences and to identify gender differences. DESIGN: Online questionnaire sent to 1000 randomly selected Royal Australian and New Zealand College of Ophthalmologists (RANZCO) Fellows in 2017. PARTICIPANTS: The response rate was 28% (n = 282) with 192 males. METHODS: Confidential questionnaire. MAIN OUTCOME MEASURES: Questionnaire responses. RESULTS: Gender differences were noted in working hours (59% of males worked greater than 40 hours a week vs 26% of females, P < 0.001) and frequency of private practice work (mean of 6.6 half-day sessions per week for men vs 4.9 sessions for women, P < 0.001). Female ophthalmologists reported additional obstacles to career advancement including difficulty receiving mentorship (57% vs 40%, P = 0.027), travel difficulties due to family responsibilities (59% vs 34%, P < 0.001) and rigid timelines for promotion/tenure (38% vs 19%, P = 0.005). Female ophthalmologists delayed child-bearing, with 59% becoming parents after fellowship training. Women spent more time child-rearing (67% vs 8% of men cared for children >20 hours per week, P < 0.001). Female ophthalmologists were more likely to report experiencing discrimination (31% vs 8% of men, P < 0.001). CONCLUSIONS AND RELEVANCE: Female ophthalmologists worked fewer hours, mainly in the private sector, to fulfil their greater family commitments. Female ophthalmologists reported additional obstacles to career advancement and were more likely to report experiencing discrimination in the workplace.

Variations in optic nerve head morphology by intraocular pressure in open-angle glaucoma.

PURPOSE: To compare optic disc topography in eyes in three intraocular pressure (IOP) groups of <15 mmHg, 15-20 mmHg, and ≥21 mmHg using spectral domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy, adjusting for the degree of damage, as measured by retinal nerve fiber layer (RNFL) thickness and average visual field loss. METHODS: A total of 184 eyes of 112 patients with primary open-angle glaucoma were recruited into groups based on baseline untreated intraocular pressure (IOP) of <15 mmHg (normal-tension glaucoma [NTG], very low), 15-20 mmHg (NTG, medium), or ≥21 mmHg (high-tension glaucoma [HTG]). Patients underwent scanning laser ophthalmoscopy, SD-OCT, and Humphrey visual field testing. Univariate and multivariate models were created, accounting for degree of retinal ganglion cell (RGC) loss by either OCT RNFL thickness or visual field mean deviation (MD). RESULTS: Univariate and multivariate analyses demonstrated no morphological differences in HRT or OCT parameters among IOP groups that met Bonferroni-corrected statistical significance when using either MD or OCT RNFL as the damage criterion (p < 0.0063). The mean cup depth was shallower for the IOP <15 mmHg group than the IOP ≥21 mmHg group (p < 0.05) for both MD (p < 0.011) and OCT RNFL (p < 0.014). CONCLUSION: Normal-tension and high-tension glaucoma are not distinguishable by optic nerve head topography with HRT and OCT when the degree of damage by Humphrey visual field testing is taken into account.

Glaucoma as a neurodegenerative disease.

BACKGROUND: The primary pathophysiological feature of glaucoma is a progressive optic neuropathy with characteristic morphological changes of the optic disc and risk factors of age and intraocular pressure. Recently, involvement of other areas of the central nervous system (CNS) beyond the optic nerve has been demonstrated. This article addresses the proposition that glaucoma shares mechanistic and pathophysiologic features with neurodegenerations in the CNS. METHODS: The literature on CNS alterations in patients with glaucoma is reviewed with particular focus on neuroimaging and pathological studies. A theoretical framework for assessing whether glaucoma is truly a neurodegenerative disease is developed based on the comparison with neurodegenerative and nonneurodegenerative diseases. RESULTS: Although there is convincing evidence of abnormalities in CNS regions distal to the optic nerve in glaucoma, these are similar to those seen in other disorders of the proximal visual pathways, such as other optic neuropathies or retinal diseases. Similarly, features of glaucoma that are similar to neurodegenerations are also seen in nonneurodegenerative diseases. CONCLUSIONS: Glaucoma is less likely a primary neurodegeneration affecting the CNS and more likely a primary optic neuropathy with secondary effects in the CNS.

Functional effects of unilateral open-angle glaucoma on the primary and extrastriate visual cortex.

The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate the response of the visual cortex to unilateral primary open-angle glaucoma (POAG). Specifically, we assessed whether regions of V1 and V2 with lost input from the glaucomatous eye had a greater response to input from the nonaffected fellow eye. Nine participants with unilateral POAG causing paracentral visual field defects and four controls participated in the study. We found no evidence for an increased response to the fellow eye in glaucoma-affected regions of the visual cortex; however, in agreement with previous studies, there was a pronounced, retinotopically localized reduction of activation in both the primary (V1) and extrastriate visual cortex (V2), when participants viewed through their glaucomatous eye. Our results suggest a remarkable level of stability within the adult primary and extrastriate visual cortex in response to unilateral neurodegeneration of the optic nerve.

Gap junction proteins in the light-damaged albino rat.

PURPOSE: Changes in connexin expression are associated with many pathological conditions seen in animal models and in humans. We hypothesized that gap junctions are important mediators in tissue dysfunction and injury processes in the retina, and therefore, we investigated the pattern of connexin protein expression in the light-damaged albino rat eye. METHODS: Adult Sprague-Dawley rats were exposed to intense light for 24 h. The animals were euthanized, and ocular tissue was harvested at 0 h, 6 h, 24 h, 48 h, and 7 days after light damage. The tissues were processed for immunohistochemistry and western blotting to analyze the expression of the gap junction proteins in the light-damaged condition compared to the non-light-damaged condition. Cell death was detected using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique. RESULTS: Intense light exposure caused increased TUNEL labeling of photoreceptor cells. Immunocytochemistry revealed that connexin 36 (Cx36) was significantly increased in the inner plexiform layer and Cx45 was significantly decreased in the light-damaged retina. The pattern of Cx36 and Cx45 labeling returned to normal 7 days after light damage. Cx43 significantly increased in the RPE and the choroid in the light-damaged tissue, and decreased but not significantly in the retina. This elevated Cx43 expression in the choroid colocalized with markers of nitration-related oxidative stress (nitrotyrosine) and inflammation (CD45 and ionized calcium-binding adaptor molecule-1) in the choroid. CONCLUSIONS: The results suggest that connexins are regulated differently in the retina than in the choroid in response to photoreceptor damage. Changes in connexins, including Cx36, Cx43, and Cx45, may contribute to the damage process. Specifically, Cx43 was associated with inflammatory damage. Therefore, connexins may be candidate targets for treatment for ameliorating disease progression.

Differentiation of compressive from glaucomatous optic neuropathy with spectral-domain optical coherence tomography.

PURPOSE: To compare optic disc topography in eyes with compressive optic neuropathy (CON) and open-angle glaucoma (OAG) using spectral-domain (SD) optical coherence tomography (OCT) and Heidelberg retinal tomograph (HRT) (Heidelberg Engineering GmbH, Heidelberg, Germany). DESIGN: Cross-sectional, observational study. PARTICIPANTS: A total of 200 eyes from 123 patients with CON (69 eyes) or OAG (58 eyes) and controls (73 eyes). METHODS: Univariate and multivariate analyses of HRT parameters, SD-OCT circumpapillary retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) parameters. MAIN OUTCOME MEASURES: Circumpapillary RNFL, OCT ONH parameters, and HRT parameters. RESULTS: The univariate analysis of OCT parameters demonstrated significant differences between the temporal and nasal quadrants; clock hours 3 (55 vs. 73 µm), 4, 8 (93.9 vs. 70.7 µm), 9, and 10; vertical cup-to-disc ratio (C:D) (0.6 vs. 0.8) and cup volume (0.2 vs. 0.5) (P<0.001) between patients with CON and OAG, respectively. The CON discs were significantly different from normal discs for all OCT parameters except cup volume. The CON discs were not significantly different from normal discs for HRT parameters, except for mean RNFL thickness and cup shape measure. The OAG discs were significantly different from normal discs in all HRT and OCT parameters (P<0.001). Multivariate analysis demonstrated that the OCT 3 o'clock temporal sector, average C:D ratio, vertical C:D ratio, and cup volume measurements were able to differentiate OAG from CON. CONCLUSIONS: Compressive optic neuropathy is associated with significantly thinner nasal and temporal sectors compared with OAG, whereas OAG results in larger cups and cup volume with OCT measurements. The Heidelberg retinal tomograph is not able to differentiate CON from normal discs.

A review of neuro-ophthalmic sequelae following COVID-19 infection and vaccination.

Background: It has become increasingly clear that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect most organs in the human body, including the neurologic and ophthalmic systems. Vaccination campaigns have been developed at rapid pace around the world to protect the population from the fast-mutating virus. This review seeks to summarise current knowledge of the neuro-ophthalmic manifestations of both COVID-19 infection and vaccination. Evidence acquisition: Electronic searches for published literature were conducted using EMBASE and MEDLINE on the 30th of July 2023. The search strategy comprised of controlled vocabulary and free-text synonyms for the following terms in various combinations: "coronavirus, COVID-19, SARS-CoV-2, 2019-nCoV, vaccination, vaccine, immunisation and neuro-ophthalmology". No time range limits were set for the literature search. Published English abstracts for articles written in a different language were screened if available. Results: A total of 54 case reports and case series were selected for use in the final report. 34 articles documenting neuro-ophthalmic manifestations following COVID-19 infection and 20 articles with neuro-ophthalmic complications following COVID-19 vaccination were included, comprising of 79 patients in total. The most commonly occurring condition was optic neuritis, with 25 cases following COVID-19 infection and 27 cases following vaccination against COVID-19. Conclusions: The various COVID-19 vaccines that are currently available are part of the global effort to protect the most vulnerable of the human population. The incidence of neuro-ophthalmic consequences following infection with COVID-19 is hundred-folds higher and associated with more harrowing systemic effects than vaccination against the virus.

Optic atrophy in prematurity: pathophysiology and clinical features.

Optic atrophy is an important cause of visual impairment in children, and the aetiological profile has changed over time. Technological advancements led by neuroimaging of the visual pathway and imaging of the optic nerve with optical coherence tomography have accelerated the understanding of this condition. In the new millennium, an increasing prevalence of prematurity as a cause of optic atrophy in children has been highlighted. This new shift has been linked with increasing rates of premature births and improved neonatal survival of preterm infants. The available literature is limited to hospital and registry-based cohorts with modest sample sizes, methodological heterogeneity and selection bias limitations. Larger studies that are better designed are required to better understand the contribution of prematurity to the disease burden. In addition to considering other life-threatening aetiologies, screening for premature birth should be covered as part of a comprehensive history when evaluating a child with paediatric optic atrophy.

Neuro-ophthalmic evaluation and management of pituitary disease.

Neuro-ophthalmic evaluation is a crucial component of the diagnostic and prognostic assessment of pituitary disease and compressive chiasmopathy, and can inform the timing of vision-restoring tumour resection surgery. The most common disease affecting the pituitary with neuro-ophthalmic implications are pituitary adenomas. Neuro-ophthalmic manifestations include decreased vision, abnormal colour vision and impaired visual field or diplopia. The recognition of these syndromes is critical to achieve early diagnosis and treatment and to improve prognosis. The pattern of vision loss in chiasmal compression is determined by the anatomical relationship between the pituitary lesion and optic chiasm, and potential visual field defects include bitemporal deficits, junctional scotomas, monocular cecocentral defects, and incongruous homonymous hemianopias. Rarer neuro-ophthalmic manifestations of pituitary disease include ophthalmoplegia, nystagmus, and obstructive hydrocephalus. There is growing evidence that demonstrates the strong diagnostic utility of optical coherence tomography (OCT) parameters in detecting the presence of compressive chiasmopathy, as well as the prognostic ability to predict the rate and degree of visual recovery following decompression surgery. Long-term neuro-ophthalmic monitoring is critical for detecting delayed vision loss following resection surgery, which may represent tumour recurrence or secondary complications.

Herpes zoster ophthalmicus (HZO) recurrence: risk factors and long-term clinical outcomes.

PURPOSE: To examine the frequency of recurrences, risk factors and long-term clinical outcomes in subjects with herpes zoster ophthalmicus (HZO). DESIGN: Retrospective cohort study. METHODS: All subjects with acute HZO seen at a single centre from 2006 to 2016 were included in the study. The primary outcome measure was eye disease recurrence. The secondary outcome measure was moderate vision loss (≤20/50). RESULTS: A total of 869 patients with acute HZO were identified with a median follow-up time of 6.3 years (interquartile range 3.7-8.9 years). 551 recurrences were observed, and at least one recurrence was seen in 200 subjects (23.0%), with uveitis (34.8%) being most common. The median time to first recurrence was 3.5 months. Predictors of disease recurrence included immunosuppression (p=0.026), higher presenting intraocular pressure (p=0.001), corneal involvement (p=0.001), and uveitis (p<0.001) on multivariate analysis. Topical steroids were initiated in the first month of presentation for 437 subjects, and recurrence was observed in 184 (42.1%) of these subjects. Following cessation of topical steroid treatment, recurrence occurred after a median of 1.4 months (90% within 7 months). Moderate vision loss (≤ 20/50) occurred in 15.5%, 28.6%, 31.4%, 50.0% and 57.4% of eyes with zero, one, two, three, and four or more recurrences. CONCLUSIONS: Recurrence of HZO eye disease is common, with an increased risk of vision loss with more recurrences. These findings indicate the need for close monitoring for potential recurrences, especially after cessation of topical steroid treatment, and in those with identified risk factors for recurrence.

Ocular manifestations of COVID-19.

There is an increasing body of knowledge regarding how COVID-19 may be associated with ocular disease of varying severity and duration. This article discusses the literature on the ocular manifestations associated with COVID-19, including appraisal of the current evidence, suggested mechanisms of action, associated comorbidities and risk factors, timing from initial infection to diagnosis and clinical red flags. The current literature primarily comprises case reports and case series which inevitably lack control groups and evidence to support causality. However, these early data have prompted the development of larger population-based and laboratory studies that are emerging. As new data become available, a better appraisal of the true effects of COVID-19 on the eye will be possible. While the COVID-19 pandemic was officially declared no longer a "global health emergency" by the World Health Organization (WHO) in May 2023, case numbers continue to rise. Reinfection with different variants is predicted to lead to a growing cumulative burden of disease, particularly as more chronic, multi-organ sequelae become apparent with potentially significant ocular implications. COVID-19 ocular manifestations are postulated to be due to three main mechanisms: firstly, there is a dysregulated immune response to the initial infection linked to inflammatory eye disease; secondly, patients with COVID-19 have a greater tendency towards a hypercoagulable state, leading to prothrombotic events; thirdly, patients with severe COVID-19 requiring hospitalisation and are immunosuppressed due to administered corticosteroids or comorbidities such as diabetes mellitus are at an increased risk of secondary infections, including endophthalmitis and rhino-orbital-mucormycosis. Reported ophthalmic associations with COVID-19, therefore, include a range of conditions such as conjunctivitis, scleritis, uveitis, endogenous endophthalmitis, corneal graft rejection, retinal artery and vein occlusion, non-arteritic ischaemic optic neuropathy, glaucoma, neurological and orbital sequelae. With the need to consider telemedicine consultation in view of COVID-19's infectivity, understanding the range of ocular conditions that may present during or following infection is essential to ensure patients are appropriately triaged, with prompt in-person ocular examination for management of potentially sight-threatening and life-threatening diseases.

Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia.

Connexin43 gap junction protein is expressed in astrocytes and the vascular endothelium in the central nervous system. It is upregulated following central nervous system injury and is recognized as playing an important role in modulating the extent of damage. Studies that have transiently blocked connexin43 in spinal cord injury and central nervous system epileptic models have reported neuronal rescue. The purpose of this study was to investigate neuronal rescue following retinal ischaemia-reperfusion by transiently blocking connexin43 activity using a connexin43 mimetic peptide. A further aim was to evaluate the effect of transiently blocking connexin43 on vascular permeability as this is known to increase following central nervous system ischaemia. Adult male Wistar rats were exposed to 60 min of retinal ischaemia. Treatment groups consisted of no treatment, connexin43 mimetic peptide and scrambled peptide. Retinas were then evaluated at 1-2, 4, 8 and 24 h, and 7 and 21 days post-ischaemia. Evans blue dye leak from retinal blood vessels was used to assess vascular leakage. Blood vessel integrity was examined using isolectin-B4 labelling. Connexin43 levels and astrocyte activation (glial fibrillary acidic protein) were assessed using immunohistochemistry and western blot analysis. Retinal whole mounts and retinal ganglion cell counts were used to quantify neurodegeneration. An in vitro cell culture model of endothelial cell ischaemia was used to assess the effect of connexin43 mimetic peptide on endothelial cell survival and connexin43 hemichannel opening using propidium iodide dye uptake. We found that retinal ischaemia-reperfusion induced significant vascular leakage and disruption at 1-2, 4 and 24 h following injury with a peak at 4 h. Connexin43 immunoreactivity was significantly increased at 1-2, 4, 8 and 24 h post ischaemia-reperfusion injury co-localizing with activated astrocytes, Muller cells and vascular endothelial cells. Connexin43 mimetic peptide significantly reduced dye leak at 4 and 24 h. In vitro studies on endothelial cells demonstrate that endothelial cell death following hypoxia can be mediated directly by opening of connexin43 hemichannels in endothelial cells. Blocking connexin43 mediated vascular leakage using a connexin43 mimetic peptide led to increased retinal ganglion cell survival at 7 and 21 days to levels of uninjured retinas. Treatment with scrambled peptide did not result in retinal ganglion cell rescue. Pharmacological targeting of connexin43 gap junction protein by transiently blocking gap junction hemichannels following injury provides new opportunities for treatment of central nervous system ischaemia.