Ophthalmology Residents' Experience in Cataract Surgery: Preoperative Risk Factors, Intraoperative Complications, and Surgical Outcomes.

INTRODUCTION: This retrospective study explores the connection between preoperative patient risk factors, the experience of ophthalmology residents, and the outcomes of cataract surgeries performed at Hadassah Medical Center. It is hypothesized that with increased experience, residents may demonstrate greater proficiency in handling surgeries on higher-risk patients, potentially leading to improved surgical outcomes overall. METHODS: Data were examined from 691 consecutive cataract surgeries in 590 patients, conducted by ophthalmology residents at Hadassah Medical Center (January 2018 to February 2022). Demographics, surgeon experience, preoperative cataract risk assessment score, and pre- and postoperative corrected distance visual acuity (CDVA) were analyzed. The risk score was based on cataract density, previous vitrectomy, presence of phacodonesis, small pupil, extreme axial length (> 30 mm or < 21.5 mm) or abnormal axial length (26-30 mm), shallow anterior chamber (< 2.5 mm), poor patient cooperation, oral alpha-1 blocker use, diabetic retinopathy (DR), Fuchs endothelial dystrophy, and having one functioning eye. This study focused on the correlation of risk scores with residents' surgical experience and surgical outcomes. RESULTS: As residents gained experience, surgeries on patients with at least one risk factor increased from 54% (first year) to 75% (second year; p < 0.001) and fluctuated between 75%, 82%, and 77% (third, fourth, and fifth years, respectively), with initial preoperative CDVA declining progressively. Despite handling more complex cases over time, the percentage of intraoperative complications per patient decreased with each year of residents' experience (17%, 13%, 11%, 17%, 6%; respectively). Patients without any risk factor had higher postoperative CDVA than those with one or more risk factors (mean ± standard deviation [SD] in logMAR, 0.16 ± 0.26 vs. 0.27 ± 0.35; p < 0.001) and a higher percentage of CDVA improvement (63% vs. 57%, p = 0.016). CONCLUSIONS: The use of a preoperative risk assessment scoring system to allocate surgeries to residents at varying experience levels may reduce the risk for surgical complications, thereby ensuring patient safety and providing residents with a gradual learning experience.

Effect of mydriasis on chord mu value in cataract surgery candidates.

PURPOSE: This study investigates the relationship between pupil size during biometry examinations and the chord mu value in candidates for cataract surgery. METHODS: Retrospective analysis of ocular biometry measurements was performed on consecutive cataract surgery candidates above 50 years of age, examined between 2018 and 2020 at a single tertiary referral center. Statistical analysis assessed the association between pupil size and the chord mu value. The population was categorized into groups based on pupil size, and an analysis was conducted on the barycenter positions of the iris and pupil center for each group. RESULTS: The analysis included 2877 patients. A weak positive correlation was observed between the chord mu value and pupil size using Pearson's test (r = 0.160, p < 0.01). Group stratification by pupil size indicated temporal and inferior shifts in pupil center barycenter as pupil size increased, reflecting asymmetrical pupil dilation during mydriasis. A moderate positive correlation between the chord mu value and chord alpha value was identified (Pearson's test, r = 0.641, p < 0.01). As expected, no correlation was found between chord alpha value and pupil size. CONCLUSIONS: Chord mu values were higher in patients with mydriatic pupils, likely due to asymmetric pupil dilation and center displacement. Evaluating chord mu values requires considering pupil status and conducting biometry under standardized lighting to prevent misinterpretation caused by pharmacological dilation. This caution is crucial to avoid erroneously excluding eligible patients from multifocal IOL implants. Alternatively, the chord alpha value could serve as a more appropriate alternative in such scenarios.

Incidence and Risk Factors of Visual Impairment in Patients with Angioid Streaks and Macular Neovascularization.

OBJECTIVE: To estimate the incidence and risk factors of visual impairment and complications in eyes with macular neovascularization (MNV) because of angioid streaks (ASs). DESIGN: Longitudinal multicenter retrospective cohort study. SUBJECTS: Patients with AS-associated MNV treated with anti-VEGF agents and a follow-up of > 3 months. METHODS: Clinical and MNV characteristics were collected at baseline. Visual acuity (VA) values and the presence of atrophy or fibrosis were collected at each visit. MAIN OUTCOME MEASURES: Rate of VA change over time and associated factors; the incidence rate of moderate-to-severe visual impairment (MSVI) and blindness and hazard ratio (HR) of candidate risk factors for MSVI; the incidence rate of fibrosis and macular atrophy. RESULTS: Overall, 84 eyes of 66 patients (39 men, 58%) with a mean (standard deviation) age of 55.7 (13.8) years were followed for a mean (standard deviation) of 67.7 (48.5) months. The median number of anti-VEGF doses per eye was 13. The average rate (95% confidence interval [CI]) of visual loss was +0.04 (0.02-0.06) logarithm of the minimum angle of resolution/year (P < 0.001); the visual loss was faster in nonnaive eyes (P = 0.007) and those with better baseline VA (P < 0.001); it was slower in eyes with pattern dystrophy-like features (P = 0.04). The incidence rates (95% CI) of MSVI and blindness were 10.4 (6.88-15)/100-eye-years and 2.33 (1.12-4.29)/100-eye-years. A higher number of injections (HR [95% CI] = 0.45 [0.19-0.94] for receiving ≥ 13 injections vs. < 13; P = 0.03) was protective against MSVI. The incidence rates (95% CI) of fibrosis and macular atrophy were 24.1 (17.5-32.3)/100-eye-years and 14.3 (10.1-19.6)/100-eye-years. CONCLUSIONS: Eyes with MNV-related AS had a high rate of visual impairment and propensity to macular fibrosis and atrophy. A higher number of injections yielded better chances of maintaining good VA, suggesting the need for intensive treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Evaluation of three biometric devices: ocular parameters and calculated intraocular lens power.

Cataract surgery is among the most common medical procedures, and accurate ocular biometry measurements are key for successful visual outcome. The current study evaluated data obtained by the Eyestar 900, Anterion, IOLMaster700 biometers and the Pentacam corneal topographer. Compared values were axial length (AL), anterior chamber depth (ACD), steep- and flat-K, cylinder and axis. Clinical impact was assessed by calculating intraocular lens (IOL) power using the mean values of every parameter and the Barrett and Kane formulas, stratified by device and amount of cylinder. IOL was re-calculated for each device substituting Pentacam K-values. This study included 196 eyes (98 participants) of cataract surgery candidates. When comparing the IOLMaster to the Eyestar (157 eyes), no difference was found in mean AL or ACD measurements (P > 0.05). Steep-K measurements differed between these devices and the Pentacam (P = 0.01). AL and ACD measurements differed between the IOLMaster and Anterion (38 eyes; P < 0.05). Strong correlations (range 0.72-0.99) were found between all four devices. Bland-Altman analysis demonstrated excellent agreement between biometry devices other than ACD between the IOLMaster and Eyestar. Calculated IOL power was 0.50-1.00 diopter (D) lower with the IOLMaster. Cylinder power was 0.75D higher in all biometers when Pentacam K-values were substituted.

Clinical impact of the worldwide shortage of verteporfin (Visudyne®) on ophthalmic care.

INTRODUCTION: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option. MATERIALS AND METHODS: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. RESULTS: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. CONCLUSION: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships.

Cystoid macular edema secondary to ibrutinib.

PURPOSE: To describe a unique case of cystoid macular edema associated with Ibrutinib treatment for Chronic Lymphocytic Leukemia (CLL). OBSERVATIONS: A 73-year-old male patient presented to the ophthalmology clinic complaining of decreased vision in his seeing-eye ('only eye', left). Further clinal examination and imaging revealed the presence of a cystoid macular edema (CME). With no apparent cause to this condition, topical treatment with NSAIDS and steroids continued over two years with only partial response and persistent macular edema, resulting in decreased vision. Cessation of Ibrutinib treatment resulted in resolution of the macular edema and improvement in visual acuity over 6 months. CONCLUSIONS AND IMPORTANCE: Several novel oncologic therapies have been associated with CME in recent years. This case demonstrates an association between Ibrutinib an oral, irreversible inhibitor of Bruton's Tyrosine Kinase (BTK), and the development of CME. CME was resistant to topical treatment but resolved after treatment cessation. Along with two previous cases reported, this case suggests that CME is a rare adverse event of Ibrutinib therapy. Screening for CME in Ibrutinib treated patients who report visual symptoms should be considered.

The detrimental effects of delayed intravitreal anti-VEGF therapy for treating retinal pathology: lessons from a forced test-case.

PURPOSE: Determine the anatomical consequences of delaying intravitreal injection (IVI) therapy with anti-vascular endothelial growth factor (anti-VEGF) in patients using treat-and-extend (T&E) protocol. METHODS: Retrospective medical record review of consecutive patients receiving intravitreal anti-VEGF therapy using T&E protocol prior to and during the COVID-19 pandemic. RESULTS: The study included 923 eyes of 691patients; 58.8% (543 eyes), 25% (231 eyes), and 16.2% (149 eyes) had nvAMD, DME, and RVO, respectively. Mean (± SD) patient age was 74.5 ± 11.7 years. Overall, 56.3% of cases had a delay in therapy of ≥ 7 days; specifically, 56.2%, 61.5%, and 49.0% of nvAMD, DME, and RVO cases, respectively, had a delay. The median delay in days, among cases ≥ 7 days late was 21 (IQR 7 to 42) days, with 21(IQR 7 to 45), 22.5(IQR 8 to 42), and 14(IQR 7 to 33.5) days of delay among patients with nvAMD, DME, and RVO, respectively. Delaying therapy by ≥ 7 days resulted in increased CST in 47.5%, 58.5%, and 58.9% of nvAMD, DME, and RVO cases, respectively, with a significant correlation between the length of treatment delay and the increase in CST (Spearman's rho: 0.196; p < 0.001). CONCLUSIONS: Delayed IVI treatment in eyes treated with T&E protocol was associated with increased macular thickness with potential consequences with respect to visual outcome.

Long-term outcome of neovascular age-related macular degeneration: association between treatment outcome and major risk alleles.

AIMS: To evaluate the long-term functional and anatomical outcomes of neovascular age-related macular degeneration (nvAMD) treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) for up to 10 years, and to identify associated risk factors. METHODS: Clinical and optical coherence tomography findings were retrieved for nvAMD cases treated with intravitreal anti-VEGF compounds using a treat-and-extend protocol. In addition, the major risk alleles for AMD in the CFH (rs1061170), HTRA1 (rs1200638) and C3 (rs2230199) genes were genotyped. RESULTS: From 276 eligible eyes in 206 patients, 80 eyes (29%) in 66 patients (32.0%) had a follow-up period of ≥8 years and were included in this study. Over a 10-year period, 73.3±28.0 (mean±SD) anti-VEGF injections were administered. Best-corrected visual acuity (BCVA; LogMAR) deteriorated from 0.55±0.53 at baseline to 1.00±0.73 at 10 years (p<0.0005). Central subfield thickness (CST) decreased from 415.8±162.1 µm at baseline to 323±113.6 µm (p<0.0005) after three monthly injections and remained lower than baseline throughout the follow-up period. Visual outcome was associated with BCVA and intraretinal fluid (IRF) at baseline, macular atrophy, and macular thinning at follow-up. The decrease in CST was inversely correlated with the number of CFH and/or C3 risk alleles carried by the patient (Pearson's r: -0.608; p=0.003). CONCLUSIONS: Patients with nvAMD who received anti-VEGF therapy for 10 years developed substantial vision loss associated with the presence of IRF at baseline and macular atrophy. Major risk alleles for AMD in two complement genes were associated with a reduced long-term reduction in macular thickness.

Correlation of response to intravitreal bevacizumab treatment between the first and second treated eyes in diabetic macular edema.

PURPOSE: To evaluate whether outcome of bevacizumab treatment in the first treated eye can guide the selection of compound for the second treated eye in patients with bilateral diabetic macular edema. METHODS: Demographic, clinical, and optical coherence tomography data were retrospectively collected from consecutive patients who underwent bevacizumab therapy for bilateral diabetic macular edema. Change in central subfield thickness and visual acuity were evaluated and compared between the first treated eye and second treated eye. RESULTS: A total of 66 eyes of 33 patients were included in the study. The mean ± SD follow-up time was 13 ± 5 months. The mean ± SD central subfield thickness at baseline was 464 ± 30 µm in the first treated eye and 461 ± 29 µm in the second treated eye (p = 0.91). Final central subfield thickness was reduced to 392 ± 27 µm in the first treated eye (p = 0.01 compared with baseline) and 416 ± 25 µm in the second treated eye (p = 0.03 compared with baseline). Using ≥5% or ≥10% reduction of central subfield thickness as diagnostic criteria to predict similar magnitude of thickness reduction in the first treated eye yielded a positive and negative predictive value ranging from 46% to 81%, and sensitivity and specificity ranging from 54% to 84%. Regression models did not show correlation between central subfield thickness reduction in first treated eye and the second treated eye at the end of follow-up. CONCLUSIONS: Bevacizumab therapy reduced macular thickness in both eyes in bilateral diabetic macular edema. Treatment outcome of the first treated eye could not predict the outcome of the second treated eye. Particularly, failure to reduce central subfield thickness in the first treated eye does not preclude a favorable response to bevacizumab therapy in the second eye.

Autoimmune retinopathy: clinical, electrophysiological, and immunological features in nine patients with long-term follow-up.

PURPOSE: We aim to report on the clinical, imaging, immunological, and electrophysiological features of patients with autoimmune retinopathy (AIR) with long-term follow-up. METHODS: Single-center, retrospective study of a consecutive group of AIR patients treated in a tertiary academic medical center. RESULTS: Included were nine patients with a mean ± SD age at presentation of 65 ± 13 years and a median follow-up of 63 months (range 18-120). Five patients were known to have cancer. Median interval between onset of ocular symptoms and diagnosis of AIR was 36 months. Mean baseline and final LogMAR visual acuity were 0.72 ± 0.9 and 1.1 ± 1.2, respectively (p = 0.17). The most common funduscopic findings included optic atrophy and bone-spicule-like pigmentation. Thinning of the nerve fiber layer was the most frequent optical coherence tomographic abnormality. Electroretinographic (ERG) recordings demonstrated variably reduced cone- and rod-derived amplitudes in the majority of eyes at presentation. The most commonly detected anti-retinal antibody was anti-α-enolase. Treatment included immunomodulatory therapy and plasmapheresis. ERG tests showed stability in 64% of eyes throughout the treatment period. CONCLUSION: This study highlights the importance of maintaining a high index of suspicion of AIR, particularly in late middle-aged and elderly patients with "unexplained" visual loss, in light of the non-specific posterior segment signs and the inconsistency of the routinely used ancillary tests.

Anti-tumor necrosis factor alpha reduces the proangiogenic effects of activated macrophages derived from patients with age-related macular degeneration.

Purpose: Macrophages are believed to promote choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nvAMD); however, the underlying proangiogenic mechanism is poorly understood. Therefore, we examined this mechanism in proinflammatory macrophages derived from patients with nvAMD. Methods: Monocytes were isolated from patients with nvAMD and polarized to form an M1 proangiogenic phenotype. We then screened for the role of proangiogenic cytokines expressed by these macrophages, including TNF-α, VEGF, IL-6, IL-8, and IL-1ß, using an ex vivo choroid sprouting assay and an in vivo rodent model of laser-induced CNV (LI-CNV). We also examined the value of inhibiting TNF-α inhibition with respect to reducing the proangiogenic effects of M1 macrophages. Finally, we analyzed the macrophage cytokine expression database to evaluate the feasibility of modulating the expression of TNF-α. Results: The cytokines above are expressed at high levels in patient-derived M1 macrophages. However, among the cytokines tested only TNF-α significantly increased choroid sprouting. Moreover, adoptive intravitreal transfer of M1 macrophages significantly increased LI-CNV, and blocking TNF-α abolished the proangiogenic effects of M1 macrophages in both models. An analysis of cytokine expression revealed that >50% of TNF-α expression is determined by modifiable factors. Conclusions: Blocking TNF-α can reduce the proangiogenic effects of M1 macrophages in nvAMD. Thus, activated macrophages may represent a potential therapeutic target for altering TNF-α expression in nvAMD.

Outcomes of primary rhegmatogenous retinal detachment repair among young adult patients.

PURPOSE: To evaluate the functional and anatomical outcomes of primary rhegmatogenous retinal detachment (RRD) repair in young adults. METHODS: A retrospective, comparative case series study. Patients between the ages of 18 and 40 years who underwent surgical repair of primary RRD between the years 2006 and 2013 were included. Patients were divided into three groups according to the surgical technique used: scleral buckle (SB), pars plana vitrectomy (PPV) or combined surgery (SB-PPV). RESULTS: Ninety eyes (90 patients) were included. The mean age (SD) was 31.5 ± 5.1 years (range 22-40). Sixty-seven patients underwent SB, 10 had PPV and 13 had SB-PPV. Anatomical success rates were similar between the three groups (87%, 90% and 85% for SB, PPV and SB-PPV groups, respectively; p-value = 0.9). Mean (SD) preoperative LogMAR visual acuity (VA) was 0.46 ± 0.6, 1.73 ± 1.1, 1.1 ± 1.1 for SB, PPV and SB-PPV groups, respectively (p < 0.0001). The VA improved at last follow-up to 0.23 ± 0.4, 0.7 ± 1.5 and 1.09 ± 1.08 in SB, PPV and SB-PPV groups, respectively (p < 0.0001). Macula-off was diagnosed in 19.4% of SB, 80% of PPV and 53.9% of SB-PPV groups (p < 0.0001). In the SB group one phakic patient (1.5%) needed cataract extraction, while following PPV, all phakic eyes (100%) underwent cataract extraction eventually (p-value < 0.0001). CONCLUSIONS: The study emphasizes the efficacy of SB as a primary procedure for the repair of retinal detachment in young adults in terms of anatomical and functional success. Furthermore, preservation of the lens as a result of using SB rather than PPV when possible is of great importance in this age group.

A 12-month prospective study to evaluate the efficacy of using the treat-and-extend regimen with intravitreal aflibercept as a Second-Line Treatment for Diabetic Macular Oedema (the TADI Study).

PURPOSE: To evaluate the efficacy of intravitreal aflibercept as a second-line therapy in eyes with persistent diabetic macular oedema (DMO) despite receiving initial bevacizumab treatment. METHODS: A prospective multicentre study was conducted in nine academic clinics in Israel. Starting from the first follow-up visit, a treat-and-extend regimen was applied in which the treatment intervals were extended by 2 weeks based on macular thickness using SD-OCT. The primary outcome was central subfield thickness (CST) at week 52. RESULTS: Forty-four patients (n = 48 eyes) were recruited to the study, and 43 eyes completed 52 weeks of follow-up. Patients received a mean (±SD) of 7.9 ± 3.5 bevacizumab injections before enrolment. The mean (±SD) CST under aflibercept therapy decreased from 468 ± 131 µm at baseline to 303 ± 67 µm at 52 weeks (p = 0.002), and best corrected visual acuity improved from 64 ± 15 ETDRS letters at baseline to 75 ± 8 letters at week 52 (p = 0.001). Twenty (46%) eyes met the treat-and-extend criteria and received a mean (±SD) of 10.9 ± 2 aflibercept injections. CONCLUSIONS: Eyes with persistent DMO following initial bevacizumab therapy had a marked reduction in macular thickness and improved visual acuity following 1 year of treatment with intravitreal aflibercept. Less than half of the patients met eligibility criteria for extension of the treatment interval; for these patients, the treat-and-extend regimen resulted in a maximum treatment interval of 10 weeks during the first year.

Socioeconomic status and visual outcome in patients with neovascular age-related macular degeneration.

PURPOSE: Visual outcome in patients with neovascular age-related macular degeneration is variable. We aimed to evaluate for association between socioeconomic status visual acuity in neovascular age-related macular degeneration. METHODS: A retrospective single-center study of a consecutive group of neovascular age-related macular degeneration patients was performed. Socioeconomic status was determined for each patient based on the 2008 Israeli census. Medical information was extracted from medical records and included visual acuity and optical coherence tomography parameters. Associations between socioeconomic status and clinical outcomes were analyzed. RESULTS: A total of 233 patients were included in the analysis. A correlation was found between low baseline visual acuity of the first eye diagnosed with neovascular age-related macular degeneration and low socioeconomic status (r = -0.13, p = 0.049; n = 233). The difference between the visual acuity of the lowest and the highest socioeconomic status categories at baseline was approximately 3 ETDRS lines (p = 0.048). Socioeconomic status and baseline visual acuity of the second eye of the same individual with neovascular age-related macular degeneration were not correlated (r = -0.05, p = 0.95). Socioeconomic status was not associated with the number of anti-vascular endothelial growth factor injections of the first or second eye, or the visual acuity outcome of the first or second eye after 1 year of therapy (p = 0.421, p = 0.9, respectively). Central subfield thickness of the first eye at presentation as measured by spectral-domain optical coherence tomography was associated with socioeconomic status (r = -0.31 p = 0.001). CONCLUSION: Individuals of lower socioeconomic status presented at more advanced stage of the disease when developing neovascular age-related macular degeneration in the first eye but not in the second eye. The research underscores the importance of improving referral patterns and awareness for the lowest socioeconomic status classes.

Correlation of Response between Both Eyes to First- and Second-Line Anti-VEGF Therapy in Diabetic Macular Edema.

PURPOSE: To evaluate the anatomical correlation between fellow eyes for bilateral second-line anti-VEGF treatment in eyes with bilateral diabetic macular edema (DME) with incomplete response to first-line bevacizumab therapy. METHODS: Seventy-four eyes (n = 37 patients) with bilateral-DME having incomplete response to first-line bevacizumab therapy that were switched for bilateral treatment with ranibizumab were retrospectively evaluated. Data collected included demographics, visual acuity and macular thickness. We evaluate the correlation for the response of both eyes in terms of macular thickness and visual acuity. RESULTS: The mean±SD age was 76 ± 8 years. The mean±SD number of bevacizumab injections prior the switch was 11.03 ± 5.1 in the first eye (FE) and 10.9 ± 5.2 in the second eye (SE). The central subfield thickness (CST) reduced from 472 ± 171 microns at baseline to 418 ± 161 after the last bevacizumab injection and 365 ± 74 after 3 ranibizumab injections in the FE (p = .016, p = .004, respectively), and from 463 ± 145 microns to 446 ± 123, and 421 ± 103 in the SE (p = .112, p = .001, respectively). There was strong positive correlation between the eyes for the CST reduction under bevacizumab and ranibizumab treatments in each visit. BCVA± SD at baseline was 0.41 ± 0.30 LogMAR in the FE, and 0.42 ± 0.29 in the SE (p = .44). After 3 injections of bevacizumab, the BCVA was 0.37 ± 0.26 and 0.42 ± 0.23 in FE and SE respectively (p = .013, p = .132, respectively). CONCLUSIONS: This study demonstrated a strong anatomical correlation responses between the eyes in patients with bilateral DME for both first-line bevacizumab therapy and second-line ranibizumab therapy. Response to second-line therapy was favorable and correlated among eyes regardless they were from the same or different individuals.

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations.

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th-5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.

Risk of SARS-CoV-2 transmission to medical staff and patients from an exposure to a COVID-19-positive ophthalmologist.

PURPOSE: To evaluate the risk of transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after exposure to a COVID-19+ physician in a retina clinic. METHODS: A retrospective observational study. Records of 142 patients and 11 staff members from a single retina clinic that were exposed to a COVID-19+ ophthalmologist were reviewed. All 153 individuals were placed in quarantine for 14 days. They were contacted after the quarantine period to inquire about symptoms consistent with COVID-19, and the results of diagnostic test for SARS-CoV-2 when performed. RESULTS: All patients (n = 142) were contacted successfully. The mean age was 72.8 ± 13.6 years; 54.2% (n = 77) were females. Twenty-three patients (16.2%) were exposed during an ophthalmic exam, 111 (78.2%) during intraocular injection, 4 (2.8%) underwent exam and injection, 3 (2.1%) underwent surgery, and one patient (0.7%) had laser photocoagulation. Half of the patients (50%; n = 71) were in contact with the COVID-19+ physician while he was symptomatic. Forty-four patients (31%) wore a mask on the day of their visit. 11.3% (n = 16) of the patients, and all involved staff had been tested for the virus and all were negative. One patient (0.7%) reported transient cough and sore throat, and the remaining 141 (99.3%) patients and 11 (100%) staff did not develop symptoms. CONCLUSIONS: Low risk for SARS-CoV-2 transmission in the ophthalmic setting was observed when universal safety measures such as social distancing, meticulous hand hygiene, enlarged breath shields, and mask wear during procedures were taken.

Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD.

Purpose: Anti-vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome. Methods: Israeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108). Results: Linear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10-5. The top variant in the gene VWA3A (P = 1.77 × 10-6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was -0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline. Conclusions: An VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.

Evaluation of antioxidant treatments for the modulation of macrophage function in the context of retinal degeneration.

Purpose: Oxidative stress and macrophages have been implicated in the pathogenesis of atrophic and neovascular age-related macular degeneration (aAMD and nvAMD). It is unclear whether oxidative injury mediates macrophage involvement in AMD. We aimed to investigate the effect of antioxidant treatments on human monocyte-derived macrophages (hMDMs) from patients with AMD in models for the disease. Methods: Four antioxidant treatments were evaluated (G1: lutein + zeaxanthin, G2: lutein + zeaxanthin and zinc, G3: lutein + zeaxanthin, zinc, Lyc-O-Mato, and carnosic acid, G4: lutein + zeaxanthin, carnosic acid, and beta-carotene, G5: olive oil as vehicle control). The compounds were added to the culture medium of M1 (interferon-gamma [IFN-Ɣ] and lipopolysaccharide [LPS]) and M2a (interleukin-13 [IL-13] and IL-4) hMDMs from patients with AMD (n=7 and n=8, respectively). Mouse choroidal tissue was cultured with supernatants from treated M1/M2a hMDMs, to evaluate the effect of treatments on the angiogenic properties of macrophages with choroidal sprouting assay (CSA). Mouse retinal explants were cultured with treated hMDMs for 18 h, and evaluated for photoreceptor apoptosis using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) labeling. Adult BALB/c mice (n=8) were exposed to 8,000 lux bright light for 3 h, and treated orally with antioxidant supplements for 7 days that preceded light injury and following it. Oxidative stress was assessed using an anti-4 hydroxynonenal (4-HNE) antibody. Retinal function and the thickness of the outer nuclear layer were evaluated with electroretinography (ERG) and histological analysis, respectively. Results: The G3 treatment reduced M2a hMDMs-associated sprouting in the CSA compared to the untreated group (n=7, -1.52-fold, p=0.05). Conversely, the G2 treatment was associated with an increased neurotoxic effect of M2a hMDMs in the retinal explant assay compared to the control group (n=7, 1.37-fold, p=0.047), as well as compared to the G3 treatment group (1.46-fold, p=0.01). The G4 treatment was also associated with increased cytotoxicity compared to the control group (1.48-fold, p=0.004), and compared to the G3 treatment group (1.58-fold, p=0.001). In the in vivo light damage model, mice (n=8) supplemented with G2, G3, and G4 had decreased levels of oxidative injury assessed using 4-HNE labeling (-2.32-fold, -2.17-fold, and -2.18-fold, respectively, p<0.05 for all comparisons). None of the treatments were associated with reduced photoreceptor cell loss, as shown with histology and ERG. Conclusions: Antioxidant treatment modulates M2a hMDMs at the functional level. In particular, we found that the G3 combination has a beneficial effect on M2a macrophages in reducing their angiogenic and neurotoxic capacity ex vivo. In addition, antioxidant treatments considerably reduced the oxidative stress level in light-damaged retinas. Further research is required to assess whether such therapies may curb macrophage-driven photoreceptor loss and neovascularization in AMD.

Promiscuous Chemokine Antagonist (BKT130) Suppresses Laser-Induced Choroidal Neovascularization by Inhibition of Monocyte Recruitment.

BACKGROUND: Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. METHODS: A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. RESULTS: BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages' proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. CONCLUSIONS: Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.