Systemic and Ocular Adverse Events with Intravitreal Anti-VEGF Therapy Used in the Treatment of Diabetic Retinopathy: a Review.

PURPOSE OF REVIEW: Intravitreal anti-vascular endothelial growth factor (VEGF) agents are used routinely in the management of neovascular conditions including proliferative diabetic retinopathy and diabetic macular edema. While the efficacy of anti-VEGF agents has been well-validated, their ocular and systemic adverse events should always be considered and discussed with patients. The aim of this review is to discuss the most recent literature reports regarding the various ocular and systemic adverse events associated with intravitreal anti-VEGF treatment in diabetic retinopathy. RECENT FINDINGS: The most frequently reported adverse ocular events include subconjunctival hemorrhage, vitreous hemorrhage, increased intraocular pressure, uveitis, endophthalmitis, ocular surface disease, and traumatic cataract. Subconjunctival hemorrhage and vitreous hemorrhage are the most common ocular adverse events reported with intravitreal anti-VEGF treatment. The most serious (though rare) ocular adverse events include endophthalmitis and rhegmatogenous retinal detachment. A consensus regarding the association of systemic adverse events (such as myocardial infarction, stroke, and death) with intravitreal anti-VEGF treatments has not been established. Intravitreal anti-VEGF therapy is used in the treatment of diabetic retinopathy, macular degeneration, and other diseases. These agents are associated with a variety of ocular and systemic adverse events that ophthalmologists should always consider.

The Evaluation of Cases with Ocular Complications due to Bacillus Calmette-Guerin (BCG) Treatment using the Pool Analysis Method.

OBJECTIVE: The aim of this study was to investigate cases with ocular complications associated with intravesical BCG therapy in terms of clinical features, demographic features and type of ocular involvement. METHODS: PubMed database was scanned for relevant publications using the keywords. Thirty-seven publications and 147 reported cases were identified related to the development of ocular complications due to intravesical BCG treatment. RESULTS: As a result of the analysis performed according to eye involvement, there were 17 cases of conjunctivitis, 7 uveitis, and 5 endophthalmitis. Only 27 (18.3%) cases were of primary ocular involvement and Reiter's syndrome was present in 120 (81.6%) of all cases. CONCLUSIONS: Most of the side-effects of BCG therapy are minor and of short duration. Although rare, it has been reported that potentially serious ocular complications can develop after treatment. Physicians must keep these facts in mind and be alert to the development of ocular symptoms following BCG therapy.

Safety of Receiving Anti-Vascular Endothelial Growth Factor Intravitreal Injection in Office-Based vs Operating Room Settings: A Meta-analysis.

IMPORTANCE: Compared with the operating room (OR), office-based intravitreal injection (IVI) is considered a more cost-effective and convenient approach, yet clinical outcomes of IVIs with anti-vascular endothelial growth factor (VEGF) agents in different settings (office-based vs OR) have not been systematically evaluated. OBJECTIVE: To evaluate the safety outcomes of IVI with anti-VEGF agents in the OR vs office-based setting. DATA SOURCES: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to July 2020. STUDY SELECTION: Eligible studies reporting on patients who received IVIs with anti-VEGF drugs with a clearly stated injection setting of the office or OR. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened studies, extracted data, and assessed risk of bias. A meta-analysis was conducted to determine the rates of endophthalmitis (EO) and culture-positive EO. MAIN OUTCOMES AND MEASURES: Rates of EO and culture-positive EO following anti-VEGF IVIs in the OR and office-based setting. RESULTS: Thirty-one studies with a total of 1 275 815 injections were included. Comparative analysis suggested no difference between rates of EO after IVIs performed in the office and OR settings (odds ratio, 3.06; 95% CI, 0.07-139.75; P = .57; I2 = 80%) were identified, yet a higher rate of culture-positive EO was found in the office setting (odds ratio, 21.52; 95% CI, 2.39-193.55; P = .006; I2 = 0%). The pooled rates of EO following anti-VEGF IVIs were 0.03% (95% CI, 0.03-0.04) and 0.02% (95% CI, 0.01-0.04) in office and OR settings, respectively, and the pooled rates of culture-positive EO were 0.01% (95% CI, 0.01-0.02) and 0.01% (95% CI, 0-0.02). The pooled rates of other ocular and systemic adverse events were low. CONCLUSIONS AND RELEVANCE: The rate of clinically suspected or culture-positive EO following anti-VEGF IVIs was low whether the procedure was performed in the office or OR setting. Bacterial spectrum could differ between the 2 settings. This meta-analysis could not determine if it is more appropriate to give treatment in the OR for safety reasons in low-income compared with higher-income regions in the world.

Rates of Suspected Endophthalmitis Following Intravitreal Injections in Clinical Practices in the United States.

BACKGROUND AND OBJECTIVE: To evaluate rates of suspected endophthalmitis following intravitreal injections of aflibercept, bevacizumab, ranibizumab (vial and pre-filled), dexamethasone implant, and triamcinolone in clinical practice. PATIENTS AND METHODS: Retrospective study of aggregated electronic medical records from the Vestrum Health Database. Eyes with a diagnosis of suspected endophthalmitis based on billing codes between January 2013 and June 2019 were included. RESULTS: Total number of injections, suspected endophthalmitis cases, and medication rate, respectively, were: aflibercept (1,412,699; 687; 0.049%); bevacizumab (1,467,722; 379; 0.026%); ranibizumab vial (884,061; 233; 0.026%), ranibizumab pre-filled (427,763; 96; 0.022%); dexamethasone implant (49,464; 53; 0.107%); and triamcinolone (75,038; 110; 0.147%). Rates were lower for bevacizumab and ranibizumab (vial and pre-filled) compared to aflibercept, dexamethasone implant, and triamcinolone (P < .05). Triamcinolone had a higher rate compared to all of the other medications (P < .05). CONCLUSIONS: Suspected endophthalmitis rates following anti-vascular endothelial growth factor injections in clinical practice were similar to reported rates in clinical trials. Rates of suspected endophthalmitis following steroid injections trended higher with significantly higher rates with triamcinolone. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:312-318.].

Trends in Endophthalmitis Associated With Intravitreal Injection of Anti-VEGF Agentsat a Tertiary Referral Center.

BACKGROUND AND OBJECTIVE: To report the incidence and clinical features of infectious endophthalmitis after intravitreal (IV) injection of anti-vascular endothelial growth factor inhibitors (VEGF) between 2018 and 2020 and to compare to prior rates. PATIENTS AND METHODS: Retrospective analysis of patients with endophthalmitis after anti-VEGF IV injections treated at Bascom Palmer Eye Institute between January 1, 2018, and December 31, 2020. RESULTS: Between 2018 and 2020, the rate of clinically diagnosed endophthalmitis was 0.014% (10/71,858) and of culture-positive was 0.008% (6/71,858). Clinically diagnosed endophthalmitis rates per injection were: aflibercept (0.022%); ranibizumab (0.019%); bevacizumab (0%); and brolucizumab (0%). Clinically diagnosed endophthalmitis rates were similar in the present study compared to those from 2005 to 2017 (P = .84). Fifteen eyes were diagnosed with endophthalmitis (10 in-house, five external referrals). Of culture-positive eyes, the organisms were coagulase-negative Staphylococcus (8/11), Streptococcus species (2/11), and Abiotrophia defectiva (1/11). A universal face-masking policy in 2020 did not lower infection rates (P = .73). CONCLUSION: Endophthalmitis rates after IV anti-VEGF remain low and are similar to prior reports. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:319-326.].

Efficacy and safety of intravitreal methotrexate for vitreo-retinal lymphoma - 20 years of experience.

Vitreo-retinal lymphoma (VRL) is the most common intraocular lymphoma and is highly associated with central nervous system (CNS) lymphoma (CNSL), both posing a therapeutic challenge. We investigated patients' characteristics, efficacy and safety of intravitreal methotrexate (MTX) injections and their outcomes over 20 years. The records of 129 patients diagnosed between 1997 and 2018 were retrospectively reviewed. Lymphoma involved both the CNS and vitreo-retina (49%), solely the CNS (37%) or solely the vitreo-retina (14%). In all, 45·5% of the patients with CNSL either presented with VRL or developed it after a mean (±SE) of 85·7 (7·3) months. In all, 66·0% of the patients diagnosed with VRL either presented with CNSL or developed it after a mean (±SE) 42·6 (7·6) months. The 81 patients with VRL (134 eyes) received a mean (±SD) of 19 (7) injections; however, only 5 (4) injections were needed to reach complete remission. Local recurrence occurred in two of the 81 patients. Overall, 80·2% of eyes had an initial moderate-severe visual loss, and >50% of them improved. Reversible keratopathy was the most prevalent side-effect. A total of 18·5% developed intraocular pressure (IOP) elevation due to angle neovascularisation after 16 injections, which could be reversed with prompt intravitreal injection of bevacizumab. Intravitreal MTX injections are a safe and effective treatment for VRL. Fewer injections (15) may offer similar results with fewer side-effects.

Clinical features, management and outcomes of patients with sterile endophthalmitis associated with intravitreal injection of antivascular endothelial growth factor. / Características clínicas, manejo y resultados de los pacientes con endoftalmitis estéril asociados con la inyección intravítrea de factores de crecimiento endotelial antivascular.

PURPOSE: Analyze clinical features, management and outcomes of patients with sterile endophthalmitis associated with intravitreal antivascular endothelial growth factor. METHODS: Observational retrospective case series of patients with sterile endophthalmitis following anti-VEGF intravitreal injections. Clinical data of patients treated with intravitreal anti-VEGFs during one year have been revised. Those who have presented an episode of sterile endophthalmitis are analyzed and their causality and management are studied. RESULTS: Seven patients have had a sterile endophthalmitis onset within 4days after intravitreal injection (aflibercept n=5 and ranibizumab n=2). These patients have some active neovascular condition: age related macular degeneration (n=4), myopic choroidal neovascularization (n=1) or macular edema: diabetic macular edema (n=1), branch retinal vein occlusion (n=1). Shared signs and symptoms included painless vision loss, anterior chamber and vitreous cell and lack of hypopyon. In all patients, visual acuity returned to within one line of baseline acuity. CONCLUSION: Differentiating cases of sterile from infectious endophthalmitis may be challenging. It is crucial to differentiate both entities as a good diagnosis determines the visual prognosis. We should be aware of minimal inflammation after repeated intravitreal injections in order to establish the adequate treatment.

Illicit drugs: Effects on eye.

There is a myriad of changes that can be produced in the eye by toxic drugs ranging from mild/no symptoms to severe loss of vision from endophthalmitis. The routes of administration include oral ingestion, smoking, nasal inhalation, intravenous injection, topical application or application to other mucosal surfaces. It is important to recognize certain clinical signs and symptoms in the eye produced by these toxins. This article describes in brief some of the ocular effects of commonly abused drugs. For identification of a particular poisoning, in addition to the clinical presentation, pulse, blood pressure, respiration and body temperature, pupillary size, pupillary reaction to light, ocular convergence and nystagmus can be useful indicators of the type of drug the patient is exposed to. Unmasking these features help the clinician in an early and accurate diagnosis of the offending drug as well as timely management.

Leftover mitomycin-c sponge causing blebitis.

Trabeculectomy is the commonest surgical intervention performed worldwide for the treatment of open-angle glaucoma. However, the use of antimetabolites during trabeculectomy has been associated with various bleb related complications. We report this interesting case to highlight unique clinical presentation and management of a leftover mitomycin-C sponge causing blebitis.

Post-Ranibizumab injection endophthalmitis in aggressive posterior retinopathy of prematurity.

A preterm infant with zone 1 aggressive posterior retinopathy of prematurity developed infectious endophthalmitis after intravitreal injection of ranibizumab. Urgent empirical intravitreal therapy with vancomycin, ceftazidime, and dexamethasone along with intravenous therapy with amikacin and meropenem helped in early resolution. Vascularization/activity of disease subsided on follow-up, media cleared, and laser photocoagulation was completed. Later the disease reactivated, developed vitreous membranes and central retinal traction, for which 25-gauge lens-sparing vitrectomy was performed. Emergent treatment helped in salvaging the eye from both aggressive ROP disease and devastating endophthalmitis. Rationale approach to such a case is being discussed.

Same-Day Bilateral Intravitreal Anti-Vascular Endothelial Growth Factor Injections: Experience of a Large Canadian Retina Center.

OBJECTIVE: To evaluate the outcomes and complications of bilateral same-day intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. METHODS: This is a single-center, retrospective study that included 524 eyes of 262 patients who received concomitant bilateral intravitreal anti-VEGF injections in 2016 at St. Michael's Hospital, Toronto. If any of the patients were receiving simultaneous bilateral injections on a regular basis prior to 2016, data pertaining to previous injections were also reviewed. Everyone received bevacizumab, ranibizumab, or aflibercept in an office setting. RESULTS: A total of 9,798 intravitreal anti-VEGF injections (4,899 bilateral injection sessions) were performed in 524 eyes of 262 patients. The average number of bilateral injection sessions per patient was 18.7 ± 14.1. Ranibizumab was the most commonly used anti-VEGF drug (83.8%). The incidence of endophthalmitis was 0.01%, and there were 2 episodes of acute intraocular inflammation among the 9,798 injections (0.02%). All 3 cases occurred after treatment with ranibizumab. There were 2 deaths (0.76%) due to nonvascular causes but no vascular related systemic adverse events were reported. CONCLUSIONS: Same-day bilateral intravitreal anti-VEGF injections present a low rate of complications and are well tolerated by patients. This safe practice may reduce the burden on the health-care system and on the patients.

Association of Acute Endophthalmitis With Intravitreal Injections of Corticosteroids or Anti-Vascular Growth Factor Agents in a Nationwide Study in France.

Importance: The number of patients affected by retinal diseases treated with intravitreal injections (IVTs) has resulted in a rapidly growing number of procedures. One of the worst complications after these injections is endophthalmitis. Objective: To evaluate the incidence of acute endophthalmitis after IVTs of corticosteroids or anti-vascular endothelial growth factor (anti-VEGF) agents. Design, Setting, and Participants: This population-based cohort study included patients undergoing IVTs from January 1, 2012, through December 31, 2015, in France. Data were acquired from the French medical-administrative database (Système National d'Information Inter-Régime de l'Assurance Maladie), which collects hospitalization discharge abstracts and out-of-hospital care information for the whole country. Data were analyzed from March through July 2017. Exposures: Intravitreal injections of corticosteroid or anti-VEGF agents. Main Outcomes and Measures: Incidence of acute endophthalmitis within 6 weeks after IVT by means of billing codes from a national database. Results: During the study period, 1 811 977 IVTs of corticosteroids or anti-VEGF agents performed on 254 927 patients (60.4% female; median age, 79 years [interquartile range, 70-85 years]) were analyzed. A total of 444 acute endophthalmitis cases (crude incidence, 0.0245%) were recorded. In multivariable analysis, which did not include adjustment for when the endophthalmitis occurred during the study period, the risk of endophthalmitis was lower in male patients (incidence rate ratio [IRR], 0.78; 95% CI, 0.63-0.96; P = .02), higher for corticosteroids than for anti-VEGF agents (IRR, 3.21; 95% CI, 2.33-4.44; P < .001), and higher for nonprefilled syringes of anti-VEGF medications than prefilled syringes for ranibizumab (IRR, 1.63; 95% CI, 1.15-2.30) and aflibercept (IRR, 1.82; 95% CI, 1.25-2.66; P < .001). Conclusions and Relevance: The findings from this study of a nationwide database appear to have confirmed the low incidence rate of acute endophthalmitis after IVTs of corticosteroids or anti-VEGF agents. Although an association may not necessarily indicate a cause and effect, the risk for acute endophthalmitis after IVTs appeared to be higher for corticosteroids compared with anti-VEGF agents, while a lower risk of endophthalmitis appeared to be found with prefilled syringes of anti-VEGF medications.

Acute Endophthalmitis after Intravitreal Bevacizumab Injections at The Tertiary Centre in Nepal.

INTRODUCTION: There are many reports of endophthalmitis following Anti- VEG F use in developed countries and from India, but there are none from Nepal yet. Therefore, the aim of this study was to report the prevalence and management of acute endophthalmitis after intravitreal injection of bevacizumab. METHODS: This is a clinical, retrospective, non-comparative study, performed in Tilganga Institute of Ophthalmology, Kathmandu, Nepal from Jan 2015 till Dec 2016. All consecutive cases of intravitreal 1.25 mg of bevacizumab injections during the study period were collected from Bevacizumab registry of the operation theatre. A total number of endophthalmitis, following intravitreal bevacizumab injections were collected from Endophthalmitis registry. The statistical analysis was carried out by SPSS for percentage calculation and its 95% Confidence Interval (CI) calculation. RESULTS: There were 4182 injections performed during the study period for various retinal conditions. Two eyes of two patients with acute postoperative endophthalmitis were identified in the first week following intravitreal injections of 1.25 mg bevacizumab among a total of 4128 injections with a prevalence of 0.048% (95% CI: 0.00 to 0.12.). CONCLUSIONS: The prevalence of acute endophthalmitis following intravitreal Bevacizumab in our retrospective series was 0.048% and was comparable with the other studies conducted elsewhere. Acute post-injection endophthalmitis following intravitreal bevacizumab can result in severe loss of vision. Therefore prompt recognition and treatment are important part of its management in such patients.

Generic trypan blue as possible cause of a cluster of toxic anterior segment syndrome cases after uneventful cataract surgery.

Five of 16 patients having uneventful cataract surgery over 2 consecutive days presented on the first postoperative day with painless, unexpected blurry vision; marked limbus-to-limbus corneal edema; and severe anterior chamber inflammation with hypopyon and fibrin formation. Review of the records showed the 5 patients had received an intracameral injection of generic trypan blue solution 0.06% to facilitate the capsulorhexis. Patients who had not received the trypan blue injection had an uneventful first-day check and subsequent course. Management comprised intense topical steroids and close follow-up, which led to gradual improvement in all cases. The batch of trypan blue vials was withdrawn, and there were no additional cases of toxic anterior segment syndrome (TASS). This TASS cluster highlights a rarely reported cause of the syndrome, underscoring the need for thorough documentation of solutions and/or medications used intraoperatively and surgeon awareness of possible adverse events.

Presumed Sterile Endophthalmitis Afer Intravitreal Triamcinolone (Kenalog)-More Common and Less Benign Than We Thought?

PURPOSE: This study aimed to review the incidence and clinical outcome of presumed sterile endophthalmitis after the off-label use of intravitreal Kenalog injections (triamcinolone acetonide with 1.5% benzyl alcohol) and to compare it with the presumed sterile endophthalmitis incidence after intravitreal Kenacort-A (0.99% benzyl alcohol) at our center. DESIGN: This was a single-center, retrospective, consecutive, interventional case series of all patients who underwent intravitreal Kenalog injections at Hong Kong Eye Hospital from November 1, 2009, to July 31, 2012. METHODS: This was a retrospective medical records review. RESULTS: A total of 81 intravitreal Kenalog injections were performed. Ten eyes (12.3%) developed presumed sterile endophthalmitis, presenting clinically with dense anterior chamber cells, fibrin, hypopyon, and vitritis. All cases were treated with topical steroids and antibiotics. Although the inflammation resolved eventually in all cases, 2 eyes developed complications, resulting in eventual loss of best corrected visual acuity: one developed rhegmatogenous retinal detachment with choroidal detachment, and another developed vitreous hemorrhage. CONCLUSIONS: The rate of presumed sterile endophthalmitis after Kenalog injection is much higher than our previous experience with Kenacort-A. To the best of our knowledge, this is the first study reporting the incidence of presumed sterile endophthalmitis using intravitreal Kenalog and Kenacort in the same center using the same injection technique. We believe that it may be due to a difference in the concentration of the preservative. Although sterile endophthalmitis is generally thought to run a benign course, this study has shown that serious complications may occur.

A cluster of presumed, noninfectious endophthalmitis after intravitreal injection of bevacizumab: long-term follow-up.

PURPOSE: To report the outcome of 5 consecutive cases of presumed, noninfectious endopththalmitis following intravitreal injection of bevacizumab (IVB). METHODS: Ten pre-loaded syringes of bevacizumab (1.25 mg/50 µL) furnished by a compounding pharmacy were injected intravitreally. Treatments were performed in the operating room by the same surgeon on 2 consecutive days. RESULTS: Of 10 eyes, 5 showed moderate to severe ocular inflammation within a few days of injection. All patients were treated in the same surgical session. Vitreous tap performed in the patient presenting with the most severe grade of inflammation was negative for bacteria and fungi. At the time of the vitreous biopsy, this patient was injected with vancomycin 1 mg/100 µL in the vitreous cavity. Other eyes with moderate inflammation received topical and systemic antibiotics and topical steroid treatment. Visual acuity returned to pre-endophthalmitis or better levels in all eyes within 1 month. The other 5 patients treated with IVB from the same batch in the other surgical session did not develop inflammation. CONCLUSIONS: IVB can induce noninfectious endophthalmitis. The use of compounded syringes can explain clustering of the inflammation. We were unable to identify the reasons for the variable grade of inflammation we observed in our patients.

Counterfeit Avastin in India: Punish the Criminals, Not the Patients.

PURPOSE: To report the recent controversy surrounding the intraocular use of bevacizumab in India and its relationship to the broader problems of off-label drug use, medication compounding, and drug counterfeiting. DESIGN: Perspective. METHODS: Data for this perspective were obtained from several sources. Literature reviews for compounding-related endophthalmitis and drug counterfeiting were performed. Supplemental information was obtained through targeted Google searches for related published manuscripts. First-hand accounts of negotiations between representatives of the Vitreoretinal Society of India (VRSI) and India's Central Drugs Standards Control Organization (CDSCO) were provided by 2 of the authors (R.N., V.G.). RESULTS: In December, 2015, 15 cases of intraocular inflammation following injections of counterfeit bevacizumab occurred in Gujarat, India. CDSCO reacted by prohibiting the use of intraocular bevacizumab throughout the country. Intense negotiations between the VRSI and CDSCO resulted in the permission to use bevacizumab in accordance with new safety guidelines. These include an enhanced informed consent process, the stamping of the Kezzler code on all bevacizumab vials, a real-time digital verification process between the end user and Roche Pharmaceuticals, and mandatory destruction of empty drug vials. CONCLUSION: Counterfeit bevacizumab has caused outbreaks of sterile and infectious postinjection endophthalmitis in at least 3 countries during the past 5 years and has entered the supply chain in other countries. Physicians and compounding pharmacists need to be aware that international counterfeiters have targeted bevacizumab.