RetINal Toxicity And HydroxyChloroquine Therapy (INTACT): protocol for a prospective population-based cohort study.

PURPOSE: Hydroxychloroquine (HCQ) is an important medication for patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other rheumatic diseases. Although it is well-tolerated and cost-effective, the risk of HCQ retinal toxicity is of increasing concern. The aim of this study is to re-examine the HCQ retinal toxicity incidence rate, risk factors and clinical course after discontinuation. METHODS: We designed a prospective population-based cohort study in adult patients with SLE or RA, currently receiving HCQ for five or more years, who are residents of British Columbia (BC), Canada. Based on administrative data, we identified 5508 eligible participants (1346 SLE and 4162 RA). They will participate in annual or biannual retinal screening over 5 years in alignment with the recently revised American Academy of Ophthalmology guidelines. To standardise procedures for retinal screening, imaging, diagnostic criteria, severity staging and data transfer, a consensus meeting was convened in December 2019 with participation of BC retinal specialists and the research team. Agreement was attained on: use of spectral domain-optical coherence tomography as the primary objective screening modality; classification of images into categories of normal, equivocal or abnormal; and transferring the equivocal and abnormal images plus corresponding subjective test results via cloud-based server from each clinic to a reading centre. Confirmation of HCQ retinal toxicity diagnoses and severity staging will be performed by three independent and masked reviewers. The incidence of HCQ retinal toxicity will be calculated, accounting for the competing risk of death. Hazard ratios for each risk factor will be calculated for the risk of HCQ retinopathy, after adjusting for confounders. We will also estimate the risk of HCQ retinal toxicity progression over 5 years. ETHICS AND DISSEMINATION: This study has received approval from the University of British Columbia Clinical Research Ethics Board (H20-00736) and the Vancouver Coastal Health Research Institute.

Evaluating Signs of Microangiopathy Secondary to Diabetes in Different Areas of the Retina with Swept Source OCTA.

Purpose: The purpose of this study was to compare perfusion parameters of the parafovea with scans outside the parafovea to find an area most susceptible to changes secondary to diabetic retinopathy (DR). Methods: Patients with different DR severity levels as well as controls were included in this cross-sectional clinical trial. Seven standardized 3 × 3 mm areas were recorded with Swept Source Optical Coherence Tomography Angiography: one centered on the fovea, three were temporal to the fovea, and three nasally to the optic disc. The capillary perfusion density (PD) of the superficial capillary complex (SCC) and deep capillary complex (DCC) as well as the fractal dimension (FD) were generated. Statistical analyses were done with R software. Results: One hundred ninety-two eyes (33 controls, 51 no-DR, 41 mild DR, 37 moderate/severe DR, and 30 proliferative DR), of which 105 patients with diabetes and 25 healthy controls were included (59 ± 15 years; 62 women). Mean PD of the DCC was significantly less in patients without DR (parafovea = 0.48 ± 0.03; temporal = 0.48 ± 0.02; and nasal = 0.48 ± 0.03) compared to controls (parafovea = 0.49 ± 0.02; temporal = 0.50 ± 0.02; and nasal = 0.50 ± 0.03). With increasing DR severity, PD and FD of the SCC and DCC further decreased. Conclusions: Capillary perfusion of the retina is affected early by diabetes. PD of the DCC was significantly reduced in patients with diabetes who did not have any clinical signs of DR. The capillary network outside the parafovea was more susceptible to capillary perfusion deficits compared to the capillaries close to the fovea. Trial Registration: clinicaltrial.gov, NCT03765112, https://clinicaltrials.gov/ct2/show/NCT03765112?term=NCT03765112&rank=1.

A comparison of robotic and manual surgery for internal limiting membrane peeling.

PURPOSE: To compare the Preceyes Surgical Robotic System (Eindhoven, Netherlands) to manual internal limiting membrane (ILM) peeling using the Eyesi surgical simulator (VRmagic, Mannheim, Germany) as the operative platform. METHODS: A comparative study was carried out with surgeons initially performing ILM peeling manually and then with the robot. Twenty-three vitreoretinal surgeons agreed to participate and all consented to the use of their surgical data from the Eyesi surgical simulator. Surgeons were given a 5-min demonstration of the devices and were allowed to practice for 10 min before attempting the membrane peel. Initially, the peel was performed manually and afterwards, this was repeated using the robot-controlled forceps. Surgical simulator outcome measures were compared between approaches. RESULTS: The average time required for the procedure was 5 min for the manual approach and 9 min with the robot (paired t test, p = 0.002). Intraocular instrument movement was reduced by half with the robot. On average 344 mm was required to complete the ILM peeling with the robot compared with 600 mm using the manual approach (paired t test, p = 0.002). There were fewer macular retinal hemorrhages with the robot: 53 with manual surgery, 32 with the robot (Mann-Whitney U test, p = 0.035). Retinal injuries were eliminated with the robot. CONCLUSIONS: Intraocular robotic surgery is still in its infancy and validation work is needed to understand the potential benefits and limitations of emerging technologies. Safety enhancements over current techniques may be possible and could lead to the broader adoption of robotic intraocular surgery in the future.

Ocular adverse events with immune checkpoint inhibitors.

PURPOSE: To quantify the risk of ocular adverse events with immune checkpoint inhibitors (ICIs) as reported to the Food and Drug Administration (FDA). METHODS: Disproportionality analysis using data from U.S. FDA's Adverse Events Reporting System (FAERS) database 2003 to 2018. Data from pharmaceutical manufacturers, healthcare providers, consumers in the U.S., and post-marketing clinical trial reports from U.S. and non-U.S. studies. All cases of uveitis, dry eye syndrome, ocular myasthenia and eye inflammation with use of the following ICIs: atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab and pembrolizumab. Reported odds ratios (RORs) and corresponding 95% confidence intervals (CIs) were computed for all drugs as a group or as individual agents. RESULTS: We identified 113 ocular adverse events for all ICIs of interest including uveitis, dry eye, ocular myasthenia and eye inflammation. Nivolumab had the highest number of adverse events (N = 68) associated with use of the ICI. Nivolumab had the highest association with ocular myasthenia [ROR = 22.82, 95% CI (7.18-72.50)] followed by pembrolizumab [ROR = 20.17, 95% CI (2.80-145.20)]. Among all ICIs approved in North America, atezolizumab had the highest association with eye inflammation [ROR = 18.89, 95% CI (6.07-58.81)] and ipilmumab had the highest association with uveitis [ROR = 10.54, 95% CI (7.30-15.22)]. CONCLUSION: The results of this disproportionality analysis suggest use of ICIs is associated with an increase risk for ocular adverse reactions. Future epidemiologic studies are needed to better quantify these adverse events.

One-year effectiveness study of intravitreous bevacizumab in neovascular age-related macular degeneration: a population-based retrospective cohort study.

OBJECTIVE: To assess effectiveness of intravitreous bevacizumab in a cohort of patients with neovascular age-related macular degeneration (nAMD) in British Columbia, Canada. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with new-onset AMD who completed 1 year of bevacizumab treatment. METHODS: A cohort of 4507 patients with nAMD (5174 eyes) aged 50 years and older treated on an as-needed basis with bevacizumab was followed from June 1, 2010, to May 31, 2014, and then evaluated after completing a follow-up treatment at 1 year. Descriptive statistics were used to characterize eyes treated with bevacizumab. Multivariable regression models were used to quantify visual acuity (VA) changes over time, adjusting for baseline prognostic variables. RESULTS: On average, patients received 8.6 injections (SD 2.4) per eye during the year of treatment. There was an average gain of 5.2 letters over the 1-year study period. Among eyes treated with bevacizumab, improvement in VA was greater for eyes with poorer baseline VA and for eyes receiving more injections. The odds ratio for VA at 1 year was 9.35 (95% CI 6.00-14.6) for eyes with VA 20/50-20/80 versus 20/20-20/40 and increased to 74.5 (95% CI 47.7-116.4) for eyes 20/400 or worse versus 20/20-20/40. CONCLUSION: Intravitreous bevacizumab is effective in treating nAMD, especially for eyes with poor baseline VA. Gains in VA were greatest by month 3 and were generally maintained thereafter.

One-Year Effectiveness Study of Intravitreous Ranibizumab in Wet (Neovascular) Age-Related Macular Degeneration: A Meta-Analysis.

PURPOSE: The clinical efficacy of ranibizumab has been examined by a large number of prospective and retrospective studies to date. This meta-analysis was conducted to summarize the current body of evidence on visual acuity (VA) changes with use of ranibizumab in the treatment of wet (neovascular) age-related macular degeneration (wAMD). METHODS: A literature review of multiple electronic databases (EMBASE, MEDLINE, MedMEME) was conducted to find randomized controlled trials (RCTs) and observational studies that reported changes in VA while patients with wAMD were on ranibizumab. Study factors analyzed were baseline patient characteristics, study type, sample size, and 12-month change in VA. Data were pooled in a meta-analysis with VA change as the main outcome. Data were then stratified by study design and a meta-regression was conducted to assess 12-month VA change against baseline VA and age. RESULTS: A total of 42 studies were included for analysis. An overall increase of 5.58 letters (95% confidence interval [CI]: 4.42-6.75; p heterogeneity, < 0.001) was shown with use of ranibizumab compared to baseline. Improvements in VA were larger for RCTs, at 7.71 letters (95% CI: 6.66-8.76; p heterogeneity, 0.013), compared to observational studies, at 4.85 letters (95% CI: 3.32-6.38; p heterogeneity, < 0.001). The meta-regression showed a significant decrease in effect size between baseline VA and 12-month VA change. CONCLUSION: This meta-analysis suggests visual improvements at 12 months of 0.5-mg ranibizumab use in patients with wAMD. A higher gain in VA was observed when pooling results from RCTs compared to those in observational studies.

Association of Repeated Intravitreous Bevacizumab Injections With Risk for Glaucoma Surgery.

Importance: Intravitreous injections of anti-vascular endothelial growth factor (VEGF) agents are associated with a sustained increase in intraocular pressure. This sustained elevated intraocular pressure could lead to higher rates of glaucoma surgery to lower this pressure. Objective: To determine the risk of glaucoma surgery following repeated intravitreous bevacizumab injections. Design, Setting, Participants: This nested, case-control study acquired and analyzed data from large, population-based, linked health databases supported by the British Columbia Ministry of Health in Canada. Study participants included all patients with ophthalmic issues in British Columbia, such as those of the Provincial Retinal Diseases Treatment Program, who had received intravitreous bevacizumab injections for exudative age-related macular degeneration between January 1, 2009, and December 31, 2013. Cases were identified using glaucoma surgical codes for trabeculectomy, complicated trabeculectomy, glaucoma drainage device, and cycloablative procedure. For each case, 10 controls were identified and matched for age, preexisting glaucoma, calendar time, and follow-up time. The number of intravitreous bevacizumab injections received per year-3 or fewer, 4 to 6, or 7 or more-was determined for both cases and controls. Data analysis was performed from February 23, 2016, to November 14, 2016. Main Outcomes and Measures: Risk of glaucoma surgery compared with the number of intravitreous bevacizumab injections per year in cases and controls. Rate ratios were adjusted for covariates (diabetes mellitus, myocardial infarction, stroke, and verteporfin use). Results: Seventy-four cases of glaucoma surgery and 740 controls were identified, with a mean (SD) age of 81.3 (8.4) years for cases and 81.4 (7.9) for controls. The case group had more males than the control group (38 [51.4%] vs 272 [36.8%]). The adjusted rate ratio of glaucoma surgery among those who received 7 or more injections per year was 2.48 (95% CI, 1.25-4.93). There was a 10.3% higher number of 7 or more injections among cases compared with controls. The adjusted rate ratio for those who received 4 to 6 injections per year compared with those who received 3 or fewer was 1.65% (95% CI, 0.84-3.23). Conclusions and Relevance: Findings from this large, pharmacoepidemiologic study suggest that 7 or more intravitreous injections of bevacizumab annually is associated with a higher risk of glaucoma surgery and that 4 to 6 injections per year show a nonstatistically significant rate ratio in the same direction.

LAMELLAR HOLE-ASSOCIATED EPIRETINAL PROLIFERATION: A Clinicopathologic Correlation.

PURPOSE: To correlate clinical and optical coherence tomographic features with histopathological and immunohistochemical findings in an eye undergoing surgical excision of lamellar hole-associated epiretinal proliferation (LHEP). METHODS: An eye with a lamellar macular hole and LHEP without a tractional epiretinal membrane component was identified with spectral-domain optical coherence tomographic imaging and underwent pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. The surgically excised LHEP specimen was analyzed with histopathological and immunohistochemical staining using flat-mount preparation techniques. Postsurgical outcomes including visual acuity and optical coherence tomographic imaging were reviewed. RESULTS: With spectral-domain optical coherence tomography, the lamellar macular hole was found to be closed with no residual LHEP after the surgery. Visual acuity improved from 20/200 preoperatively to 20/40 at 6 months after the surgery. Histopathological and immunohistochemical analyses of the LHEP specimen revealed retinal glial cells that reacted positively with anti-glial fibrillary acidic protein and anti-glutamine synthetase, a Müller cell-specific antibody. CONCLUSION: Lamellar macular hole with LHEP may demonstrate closure after pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. There was considerable improvement in visual acuity. It is possible that LHEP originates from middle retinal layers of the lamellar hole defect because it contains retinal glial cells, specifically Müller cells.

Risk of Myocardial Infarction and Stroke With Single or Repeated Doses of Intravitreal Bevacizumab in Age-Related Macular Degeneration.

PURPOSE: To examine the risk of myocardial infarction and stroke with single and repeated doses of intravitreal bevacizumab in wet age-related macular degeneration (AMD). DESIGN: Nested case-control study and retrospective cohort study. METHODS: setting: Two patient cohorts from British Columbia, Canada. STUDY POPULATION: Patients with wet AMD. INTERVENTION: For the cohort study, patients who received the first intravitreal bevacizumab; for the nested case-control study, repeated injections of intravitreal bevacizumab. MAIN OUTCOME MEASURES: Myocardial infarction for the retrospective cohort study; myocardial infarction and stroke for the nested case-control study. RESULTS: In the cohort analysis, there were 2564 AMD subjects not on a vascular endothelial growth factor (VEGF) inhibitor and 5644 subjects receiving intravitreal bevacizumab. The rate of myocardial infarction (MI) among bevacizumab users was 11/1000 person-years, compared to 14.9/1000 person-years in nonusers. The adjusted rate ratio (RR) for MI was 0.70 (95% confidence interval [CI]: 0.50-1.00) and 0.74 (0.46-1.20) for the propensity score-adjusted analysis. In the nested case-control analysis there were 7452 new users of VEGF inhibitors, within which there were 313 cases of MI with 3130 matched controls. The adjusted RR for MI among those receiving 3 or more injections compared to those receiving fewer than 3 was 0.71 (95% CI: 0.41-1.22). Also in the nested case-control analysis, the adjusted RR for stroke was 0.81 (95% CI: 0.39-1.65) for those receiving ≥4 injections vs those receiving fewer than 4 injections. CONCLUSION: Single or repeated doses of intravitreal bevacizumab were not shown to increase the risk of myocardial infarction or stroke in patients with wet AMD.

ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR PROLIFERATIVE DIABETIC RETINOPATHY: A Systematic Review and Meta-Analysis.

PURPOSE: To systematically review and perform meta-analysis on the available randomized controlled trial data for anti-vascular endothelial growth factor (anti-VEGF) agents in the management of proliferative diabetic retinopathy and its complications. METHODS: The authors identified randomized controlled trials using anti-VEGF agents, either as stand-alone therapy or combined with other interventions, in the management of proliferative diabetic retinopathy. The primary outcome measures were change in best-corrected visual acuity and (in the context of vitrectomy) duration of surgery and postoperative vitreous hemorrhage. Secondary outcomes were change in central retinal thickness and (in the context of vitrectomy) intraoperative variables suggestive of complex surgery (retinal breaks, intraoperative bleeding, and endodiathermy applications). The quality of evidence for all outcomes was appraised using the GRADE criteria. RESULTS: Twenty-two studies involving 1,397 subjects met the criteria for inclusion in this study. One study compared intravitreal ranibizumab with saline, one compared intravitreal pegaptanib to pan-retinal photocoagulation (PRP), one compared intravitreal bevacizumab to PRP, 3 compared combined intravitreal ranibizumab/PRP to PRP, 5 compared combined intravitreal bevacizumab/PRP to PRP alone, and 11 compared combined intravitreal bevacizumab/PPV to PPV alone. When used in conjunction with PRP, there is a high-quality evidence to suggest that intravitreal ranibizumab is associated with superior visual acuity and central retinal thickness outcomes at 3 months to 4 months. In the context of PPV, there is moderate quality evidence to suggest that preoperative intravitreal bevacizumab results in a significant reduction in the duration of surgery, fewer retinal breaks, less intraoperative bleeding, and fewer endodiathermy applications. Although there is evidence to suggest occurrence of early postoperative vitreous hemorrhage is reduced, the quality of evidence in support of this finding is low. CONCLUSION: The use of anti-VEGF agents before PRP results in superior functional and structural outcomes at 3 months to 4 months. The use of anti-VEGF agents before PPV results in decreased duration of surgery, fewer breaks, and less intra-operative bleeding. Although there is evidence for a decreased incidence of early postoperative vitreous hemorrhage, the quality of evidence is low. The available data therefore support the use of anti-VEGF agents as adjuncts to PRP and PPV in patients with complicated proliferative diabetic retinopathy primarily as a means of facilitating, and potentially minimizing the iatrogenic damage resulting from, these procedures.

Infantile Refsum disease in a young adult: case presentation and brief review.

PURPOSE: To review and describe findings, pathophysiology, and management of infantile Refsum disease in a young adult, and to compare with those of classic Refsum Disease. METHODS: Retrospective chart and digital photography review. RESULTS: A 25-year-old woman with a diagnosis of infantile Refsum disease presented with progressively decreasing vision. Findings included a noncorpuscular pigmentary degeneration of both fundi, optic nerve head drusen, attenuated retinal vasculature, cataract, myopia, and esotropia. She was treated with a low phytanic acid diet, resulting in improved metabolic values on laboratory testing. CONCLUSION: Infantile Refsum disease has clinical features and a pathophysiology distinct from classic Refsum disease, despite occasionally presenting for examination later in life. Ophthalmic and systemic distinctions between the two are important to consider for the ophthalmologist, who may be involved in the initial diagnosis of the patient.

All-trans retinoic Acid differentiation syndrome chorioretinopathy: a case of multifocal serous neurosensory detachments in a patient with acute promyelocytic leukemia treated with all-trans retinoic Acid.

PURPOSE: The purpose of this study was to report a case of multifocal serous neurosensory retinal detachments associated with systemic differentiation syndrome (DS) (formerly known as all-trans retinoic acid [ATRA] syndrome) in a patient with acute promyelocytic leukemia. METHODS: In this observational case report, we identify a case of DS because of ATRA induction therapy with associated multiple focal serous neurosensory retinal detachments in a 39-year-old man with acute promyelocytic leukemia. RESULTS: While suffering from a rebound episode of DS secondary to ATRA therapy, the patient experienced deterioration of his vision bilaterally. Within 8 days of discontinuing ATRA and the initiation of dexamethasone, the patient's systemic status and ocular findings resolved completely. Optical coherence tomography and fluorescein angiography confirmed the resolution of the subretinal fluid. CONCLUSION: Given the time of onset of the patient's visual symptoms with associated chorioretinopathy, his concurrent systemic manifestations of DS, along with his concurrent systemic, and ocular response to treatment, we speculate that this is the first reported occurrence of ATRA-associated chorioretinopathy in a patient with ATRA DS.

Intravitreal bevacizumab for iris neovascularization following proton beam irradiation for choroidal melanoma.

OBJECTIVE: To evaluate the safety and efficacy of intravitreal injections of bevacizumab as an eye-sparing treatment for iris neovascularization (NVI) following proton beam irradiation for choroidal melanoma. DESIGN: Retrospective interventional case series. PARTICIPANTS: Four patients who received intravitreal bevacizumab for NVI following proton beam irradiation for choroidal melanoma were identified in the Department of Ophthalmology archives at the University of British Columbia. METHODS: Clinical details were reviewed. Long-term follow-up of more than 2 years was detailed for each case. RESULTS: All 4 patients responded to a single injection of bevacizumab with regression of NVI. Neovascular glaucoma (NVG) was evident in 3 cases, 2 of which had stable intraocular pressure following treatment. NVI recurred following a single injection in all patients after an interval ranging from 1 month to 12 months. A longer period of regression was seen in patients with fewer systemic neovascular risk factors and earlier treatment. CONCLUSIONS: Regression of NVI following proton beam irradiation for choroidal melanoma was seen in all treated patients. Repeated treatments may be required to maintain regression of new vessels. This treatment modality may be a useful eye-sparing adjunct in the prevention and treatment of NVG following proton beam irradiation.