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.

Vogt-Koyanagi-Harada disease in a Native American population in Oklahoma.

PURPOSE: To describe the presentation, features, and outcomes of patients with Vogt-Koyanagi-Harada disease (VKH) seen by uveitis specialists in Oklahoma. METHODS: Clinical data were collected for 26 patients (52 eyes) diagnosed with VKH and seen between 1992 and 2018. Main outcome measures included rates of visual loss, ocular complications, and remission. RESULTS: There were 11 Native American (NA) patients (11/26, 42.3%) and 15 non-Natives (n-NA). NA VKH patients were significantly more likely to present at a younger age (18.6 years) than n-NA VKH patients (30.1 years) (p = 0.023). NA patients were less likely to have meningismus (0.00 vs. 42.9%; 0.048) or systemic symptoms (50.0% vs. 93.3%; p = 0.023) than n-NA patients, but more likely to develop cataracts (100.0% vs. 66.7%; p = 0.003). There were similar rates of macular edema, epiretinal membrane, subretinal fibrosis, and recurrent uveitis between the two groups. Oral corticosteroid use was similar between both groups (72.7% vs. 86.7%; p = 0.61). CONCLUSIONS: VKH may manifest with earlier disease course in NA patients than n-NA patients, particularly regarding ocular findings. However, NA patients were less likely to have systemic symptoms than n-NA patients.

Endophthalmitis: a bibliographic review.

PURPOSE: To analyze the 100 most cited articles pertaining to endophthalmitis using bibliometric analysis. METHODS: An all-time Web of Science literature search and refined to peer-reviewed articles in the field of ophthalmology with the keyword "endophthalmitis" was completed. Total citation count of articles published pertaining to endophthalmitis, topic, incidence rate, publishing journals, year published, language, country of origin, number of authors, names of the first and last authors, study type, and number of patients/eyes studied. RESULTS: The top 100 most cited articles pertaining to endophthalmitis had a mean citation count of 362.92, with a range of 175 to 3583. They were published in 20 peer-reviewed journals, with Ophthalmology publishing the most (n = 42). Thirteen different countries were represented, with the majority (n = 77) originating from the USA. The most common study type was clinical experiences (n = 52), though eight of the top ten were clinical trials. The number of patients varied widely, represented by a mean of 9680, but with a median of only 229. The majority (n = 67) examined the incidence of endophthalmitis which included 24 articles after anti-vascular endothelial growth factor injections, 18 after ocular surgeries/procedures, 15 after intraocular steroid injections, eight after chemotoxic drug use, and three after ocular injuries. CONCLUSION: This bibliographic study serves as a unique historical analysis of the top 100 cited scholarly articles pertaining to endophthalmitis with many of the articles related to post-procedural endophthalmitis.

A comprehensive review of diagnostic imaging technologies to evaluate the retina and the optic disk.

Ophthalmic imaging has undergone a revolution over the past 20 years with increasingly efficient and high-definition modalities now available. The use of wide-field retinal angiography, fundus autofluorescence, state-of-the-art spectral domain, and enhanced depth imaging optical coherence tomography has proven to be effective in this field. This comprehensive review is devoted to retinal and optic disk imaging modalities and their clinical implications. It is based on the published literature in the field of ophthalmic imaging with a focus on recent advances. Ophthalmic imaging plays a crucial role in the management of patients with both isolated retinal disease and systemic diseases with ocular manifestations. Evolving technology enables imaging of ocular disease in vivo, facilitating objective assessment of disease progression and response to treatment. These latest technical improvements in ophthalmic imaging are now a part of standard ophthalmic assessment in academic centers and most private practices. In the coming years, further advances may improve diagnostic sensitivity and enable cost-effective screening of large populations.

Optical coherence tomography-guided ranibizumab injection for cystoid macular edema in well-controlled uveitis: twelve-month outcomes.

PURPOSE: To determine whether serial ranibizumab injections are effective in the treatment of cystoid macular edema in patients with chronic controlled noninfectious uveitis. METHODS: Five eyes of 5 patients were included in a prospective noncomparative therapeutic trial. They received intravitreal injections of ranibizumab at Day 0 and were followed monthly for 1 year. Injections were repeated monthly if persistent or new cystic edema manifested on optical coherence tomography. The primary outcome measure was the mean change in best-corrected visual acuity from baseline at 12 months. Secondary outcome measures included mean percentage change in central subfield retinal thickness (CST) and incidence of adverse events through Month 24. RESULTS: Thirty-two injections were performed over the study period. At 1 year, the mean increase in acuity was 12.2 Early Treatment for Diabetic Retinopathy Study letters (P = 0.015). There was a statistically significant increase in visual acuity over time (P = 0.002). The CST decreased by 31.4%, 46.0%, 37.6%, and 45.4% relative to baseline at 3, 6, 9, and 12 months, respectively (P = 0.003). One patient experienced recurrence of uveitis with subsequent cataract and glaucoma progression. CONCLUSION: Optical coherence tomography-guided monthly intravitreal ranibizumab injections delivered over the course of 1 year resulted in improved vision and reduced central retinal thickness.

Suprachoroidal CLS-TA with and without Systemic Corticosteroid and/or Steroid-Sparing Therapy: A Post-Hoc Analysis of the Phase 3 PEACHTREE Clinical Trial.

PURPOSE: To study the efficacy and safety of suprachoroidal CLS-TA (proprietary suspension of triamcinolone acetonide) in uveitic macular edema (UME) with and without concurrent systemic corticosteroid or steroid-sparing therapy (ST). METHODS: Post hoc analysis of the PEACHTREE phase 3 randomized trial. RESULTS: Among UME patients receiving no ST, at week 24, mean BCVA change was +15.6 letters in 68 CLS-TA patients versus +4.9 letters in 49 sham-control patients (p < .001), while mean CST change was -169.8 µm versus -10.3 µm, respectively (p < .001). Among patients receiving ST, at week 24, mean BCVA change was +9.4 letters in 28 CLS-TA patients versus -3.2 letters in 15 sham-control patients (p = .019), while mean CST change was -108.3 µm versus -43.5 µm, respectively (p = .190). No SAEs related to treatment were reported. CONCLUSIONS: A clinically meaningful benefit of CLS-TA was noted in UME patients, regardless of concurrent ST usage.Abbreviation and AcronymsCST = central subfield thickness; BCVA = best corrected visual acuity; ME = macular edemaI; IVT = intravitreal; AE = adverse event; FA = fluocinolone acetonide; SD-OCT = spectral-domain optical coherence tomography; NIU = noninfectious uveitis; SAE = serious adverse event; TEAE = treatment emergent adverse event; ITT = intent to treat; CI = confidence interval.

Representation of Women in Ophthalmology Receiving Private Industry Funding 2015-2018.

PURPOSE: To report the representation of female ophthalmologists receiving private industry funding from 2015 through 2018, and to compare to previously observed trends. DESIGN: Retrospective, comparative trend study METHODS: The study population consisted of US ophthalmologists listed in CMS Open Payments Database. Data were reviewed for payments for research, consulting, honoraria, industry grants, faculty and speakers, royalties, and services other than consulting. The primary outcome measure was percentage of female representation compared to male in each sub-category of payment. RESULTS: The percentage of female, board-certified ophthalmologists who practiced in the United States ranged from 21.3% to 24.1%. The total number of reported ophthalmologists with industry ties ranged from 1629 to 1873, of whom between 17.2% and 19.4% were women. Women received significantly less industry compensation by than men in 2015 (median average $3273 vs $4825, P = .003), 2016 ($3600 vs $4750, P = .023), 2017 ($2493 vs $3500, P = .013), and 2018 ($2000 vs $3000, P = .011). Women remained underrepresented in receiving payments for research (ranging from 5.4% of total paid for research to 8.0%), consulting (11%-17.4%), honoraria (6%-14.9%), industry grants (4%-41.2%), royalties and licenses (0.1%-10.2%), faculty and speakers (11.6%-16.4%), and services other than consulting (8.4%-28.9%). Compared to 2013-2014, an increasing proportion of women received industry payments for consulting (P = .012), honoraria (P = .007), royalties and licenses (P = .019), faculty and speakers (P = .007), and services other than consulting (P = .007). CONCLUSIONS: Female ophthalmologists remain underrepresented in terms of the percentage of women who receive private industry funding and dollar value of the funding.

CHALLENGES IN THE MANAGEMENT OF PRESUMED FUNGAL ENDOPHTHALMITIS IN PREGNANCY.

PURPOSE: To report a rare case of endogenous endophthalmitis in pregnancy and the challenges of managing culture-negative fungal infection. METHODS: Retrospective case report. A 30-year-old woman presented with a subfoveal chorioretinal lesion with vitritis and anterior chamber inflammation in the context of intravenous drug use. Spectral domain optical coherence tomography and fluorescein angiography were used for documentation and monitoring. RESULTS: After 2 months of systemic and intravitreal injections of amphotericin, the patient had clinical improvement in visual acuity, degree of inflammation, and in the size and activity of the chorioretinal lesion, which was presumed to be fungal in origin. CONCLUSION: Among limited cases of endophthalmitis in pregnancy, we report a challenging case of presumed fungal endogenous endophthalmitis. The patient responded favorably to intravitreal and systemic antifungal medications.

Malpractice Litigation in Glaucoma.

PURPOSE: To analyze and report the causes and outcomes of malpractice litigation for patients with a diagnosis of glaucoma. DESIGN: Retrospective case series. PARTICIPANTS: Malpractice litigation cases. METHODS: The WestLaw database was reviewed for all malpractice litigation with ophthalmologist defendants in the United States between 1930 and 2014. All litigation involving glaucoma was included in this analysis and was compared with litigation in ophthalmology as a whole. MAIN OUTCOME MEASURES: The primary outcomes were the number of cases, jury award amounts, whether the case resolved in favor of the defendant, and the type of glaucomatous disease or procedure with the highest amount of litigation. RESULTS: Sixty-nine glaucoma malpractice cases were included. Overall, 62.3% of cases were resolved in favor of defendants. Twenty-nine cases were resolved via jury trial, 8 of which were associated with plaintiff verdicts with a mean adjusted jury award of $994 260. Ten cases resulted in settlements with mean adjusted indemnity of $1 210 414. Commonly litigated allegations included mismanagement of glaucoma (20.3%), failure to diagnose glaucoma (17.4%), failure to diagnose or mismanagement of angle-closure glaucoma (18.5%), adverse drug effects (14.5%), and trabeculectomy complications (8.7%). Overall, the median plaintiff award for all of glaucoma litigation was $977 476; the median award across all ophthalmic subspecialties was $568 302 (P = 0.25). For jury verdicts alone, the median award in glaucoma was $977 474, compared with $604 352 for all ophthalmology (P = 0.05). For settlements alone, the median indemnity payment in glaucoma was $955 988, compared with $827 051 for all ophthalmology (P = 0.24). CONCLUSIONS: Overall, the rate of plaintiff verdicts was similar in glaucoma and in ophthalmology as a whole; however, the magnitude of plaintiff awards was higher in glaucoma than in ophthalmology overall. Common scenarios leading to litigation included failure to diagnose or mismanagement of glaucomatous disease, as well as adverse drug effects and surgical complications. Many cases could have been avoided with careful examinations, thorough documentation in the patients' charts, and detailed conversations with patients.

A History of Anti-VEGF Inhibitors in the Ophthalmic Literature: A Bibliographic Review.

Purpose: This work aimed to analyze the 100 most-cited articles on antivascular endothelial growth factor (anti-VEGF) inhibitors. Methods: A literature search for anti-VEGF inhibitors using the Web of Science was completed using the bibliographic databases for peer-reviewed literature published in Ophthalmology, the New England Journal of Medicine, Journal of the American Medical Association, and Lancet. Primary outcomes were the most frequently cited articles and journals with the most citations as well as the specific drug and disease process studied. Results: There were 42 696 cumulative citations among the top 100 articles. The articles were published between 2004 to 2016, with most articles published in 2006. Ophthalmology published the greatest number of articles among the top 100 at 48, whereas the New England Journal of Medicine has the most citations per publication at 1714. Ranibizumab was the medication researched in most articles at 56, followed by bevacizumab at 48, aflibercept at 10, and pegaptanib at 9. Forty-two articles investigated treatment of age-related macular degeneration, followed by 24 investigating diabetic macular edema, 10 for retinal vein occlusion, 8 for proliferative diabetic retinopathy, 2 for retinopathy of prematurity and polypoidal choroidal vasculopathy, and 1 for corneal neovascularization. Conclusions: As evidenced by the considerable number of citations accumulated over the past 20 years, anti-VEGF inhibitors have led to significant research in ophthalmology.

Malpractice Litigation in Ophthalmic Trauma.

OBJECTIVE: To report and analyze the causes and outcomes of malpractice litigation in ophthalmic trauma. METHODS: The Westlaw® database was reviewed for ophthalmology litigation in the United States between 1930 and 2014. All ophthalmic trauma cases were included and compared to non-traumatic ophthalmology malpractice cases. RESULTS: Forty-four ophthalmic trauma cases were included. Of these cases, 90.9% of ophthalmic trauma plaintiffs were male compared to 54.8% of plaintiffs in ophthalmology as a whole (P=<0.001); 34.1% of cases involved minor plaintiffs compared to 6.4% in ophthalmology as a whole (P=<0.001). Cases involving minors were more likely to be resolved in favor of the plaintiff than cases involving adult plaintiffs (53.3% vs 37.9%); however, this was not found to statistically significant (P=0.35). Overall, 54.5% of cases were resolved in favor of defendants; 40.9% of cases were resolved via jury trial with 50.0% resulting in payments to plaintiffs compared to the 29.6% rate of plaintiff verdicts in ophthalmology as a whole. Open globe injuries represented 61.4% of cases; 55.6% of these cases had intraocular foreign bodies and 37.0% developed endophthalmitis. Most cases (63.6%) alleged insufficient intervention. Of these cases, 31.8% of cases involved surgical or procedural claims, and 4.5% involved medical claims only. CONCLUSION: Males and minors were overrepresented among plaintiffs in ocular trauma litigation. Most cases involved open globe injuries, often complicated by retained intraocular foreign bodies and endophthalmitis. Analysis of malpractice litigation in ophthalmic trauma calls attention to commonly litigated scenarios to improve clinical practice and to inform risk management.

Malpractice Litigation in Vitreoretinal Surgery and Medical Retina.

BACKGROUND AND OBJECTIVE: To report and analyze the causes and outcomes of vitreoretinal surgery and medical retina malpractice litigation. PATIENTS AND METHODS: The WestLaw database was reviewed for all vitreoretinal malpractice litigation in the United States between 1930 and 2014. RESULTS: One hundred forty-two retina cases were included. Overall, 64.1% of cases were resolved in favor of defendants. Eighty-three (58.5%) cases were resolved via jury trial, 30.1% of which were associated with plaintiff verdicts with mean adjusted jury award of $5,222,894 (median, $691,974). Eight cases (5.6%) resulted in settlements with mean adjusted indemnity of $726,003 (median: $437,165). Jury awards were higher than settlement awards (P = .04). Commonly litigated scenarios included retinal detachment (46.5%) and retinopathy of prematurity (9.2%). CONCLUSIONS: The complexity of treating vitreoretinal problems and the high potential for vision loss inherent in many diagnoses make treating retinal problems high-risk. Many cases in this series resulted in multi-million-dollar plaintiff awards. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:272-278.].

Association of Cancer Immunotherapy With Acute Macular Neuroretinopathy and Diffuse Retinal Venulitis.

Importance: Checkpoint inhibition in cancer immunotherapy related to T-cell-driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here. Objective: To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab. Design, Setting, and Participants: Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers. Main Outcomes and Measures: Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities. Results: Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab. Conclusions and Relevance: While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.

Dilated superior ophthalmic veins and posterior ischemic optic neuropathy after prolonged spine surgery.

A 55-year-old man developed bilateral posterior ischemic optic neuropathy after prolonged prone position lumbar laminectomy. Brain MRI performed 19 hours after the procedure revealed markedly dilated superior ophthalmic veins, a finding that had disappeared on a comparable study performed 5 months later. This first report of dilated superior ophthalmic veins present in the immediate postoperative period but not later may be important in suggesting that an increase in orbital venous pressure during surgery contributes to the development of postoperative posterior ischemic optic neuropathy (PION).

Dexamethasone implantation in birdshot chorioretinopathy - long-term outcome.

PURPOSE: To evaluate the long-term efficacy of the 0.70 mg dexamethasone (DEX) intravitreal implant in patients with birdshot chorioretinopathy (BSCR). METHODS: Retrospective descriptive case series of BSCR patients treated with DEX implant (DEX implant 0.70 mg, DEX). Patients receiving treatment between September 2013 and November 2016 with a minimum follow-up (FU) of 12 months were included. The outcomes of primary interest were vision-related functioning, Snellen visual acuity, ocular inflammation status, presence or absence of vasculitis, change in central macular thickness, and development of glaucoma and/or cataract. Change in vision-related functioning was evaluated by comparing the National Eye Institute Visual Function Questionnaire-25. The outcomes were assessed at baseline, after DEX implant, at time of relapse, and at last FU. RESULTS: Three patients (six eyes) were included in the study and were followed for 1-3 years. They received 1-4 DEX implants OU. All patients demonstrated improvement in National Eye Institute Visual Function Questionnaire-25 scores. Mean Snellen visual acuity better than or equal to 20/40 was seen in three eyes at baseline and five eyes at last FU. At induction, all of the patients (six eyes) had active vitritis and two (four eyes) had retinal vasculitis. All three patients (six eyes) were quiet at last FU. One patient (two eyes) developed bilateral ocular hypertension requiring topical therapy and discontinuation of DEX implants. Two patients (three eyes) developed posterior subcapsular cataract during therapy. Two patients (four eyes) showed progression of disease while on DEX therapy. All patients were eventually transitioned to systemic immunosuppressive drug therapy. CONCLUSION: BSCR patients receiving DEX implant experienced clinically meaningful improvements in patient-reported visual function as well as ocular inflammation. However, patients in this study required repeat implantation and were unable to be maintained on DEX implant long term due to development of adverse effects or progression of disease. Eventually, it was necessary to transition to systemic immunosuppressive therapy in all patients.

Paraneoplastic frosted branch angiitis as first sign of relapsed Hodgkin lymphoma.

Frosted branch angiitis (FBA) is a rare form of retinal vasculitis with typical perivascular edema taking the shape of frost on a tree branch. It was reported only twice as the initial presentation of Hodgkin lymphoma (HL). Here, we present the first case of paraneoplastic FBA as the initial sign of HL relapse in an elderly female.

Malpractice Litigation in Cornea and Refractive Surgery: A Review of the WestLaw Database.

PURPOSE: To report and analyze the causes and outcomes of malpractice litigation in cornea and refractive surgery. METHODS: The WestLaw database was reviewed for all malpractice litigation related to ophthalmology in the United States between 1930 and 2014. Search terms included ophthalmology or ophthalmologist and malpractice anywhere in the retrieved results. All cases involving cornea and refractive surgery were included in this analysis, and results were compared with ophthalmology as a whole. RESULTS: One hundred fifty-nine cornea and refractive surgery cases between the years 1964 and 2014 were included. Ninety-three cases (58.5%) were resolved through a jury trial, 21.5% of which were associated with plaintiff verdicts with a median adjusted jury award of $588,896 (mean $1,518,686). Nineteen cases (11.9%) resulted in settlements with a median adjusted indemnity of $782,533 (mean $761,963). Commonly litigated scenarios included laser-assisted in situ keratomileusis (74.2%) and corneal transplantation (8.2%). Overall, 88.7% of cases involved surgical or procedural claims, 8.8% involved noninterventional claims, and 2.5% involved medical claims only. CONCLUSIONS: Cornea and refractive surgery is a high-risk subspecialty of ophthalmology. Laser-assisted in situ keratomileusis and corneal transplant claims were the most commonly litigated entities in this series. Many cases focus on failure to achieve patients' desired expectations after elective refractive procedures or the negligent performance of refractive surgery on patients with contraindications to surgery, both highlighting the importance of detailed informed consent discussions, realistic goal setting with patients, and thorough examinations and preoperative evaluation.

Medical Malpractice in Uveitis: A Review of Clinical Entities and Outcomes.

PURPOSE: To guide risk management in uveitis. METHODS: Retrospective review of malpractice verdicts, rulings, and settlements. RESULTS: The WestLaw® database was reviewed for lawsuits related to uveitis in the United States from 1930-2014. Twenty-five cases met inclusion criteria, and 48% of these were infectious. Overall, 64% of outcomes favored the defendant ophthalmologist. The most common diagnoses were viral retinitis (28%), iritis (12%), syphilis (8%), and toxoplasmosis (8%). Seven suits (28%) were resolved by settlement, with mean adjusted indemnities of $724,302 (median, $409,390; range, $127,837-2,021,887). Two cases (8%) resulted in plaintiff verdict, with adjusted awards of $1,399,800 and $630,799. CONCLUSIONS: Despite being a rare diagnosis, viral retinitis (especially acute retinal necrosis) is the most common clinical entity associated with litigation in uveitis and should be considered early. Educating patients about potential adverse events, early testing for syphilis, and maintaining a positive relationship may also minimize risk.

Inner retinal vasculopathy in Zika virus disease.

PURPOSE: Zika virus infection is associated with vision-threatening ocular complications including uveitis and outer retinopathy. The aim of this report is to describe a case of an adult patient with serologically confirmed Zika infection who presented with retinal vascular abnormalities that coincided with systemic post-viral neurological manifestations of the disease. OBSERVATIONS: A 34-year-old white female presented with symptoms of peripheral neuropathy following serologically confirmed Zika virus infection that was acquired in Puerto Rico four months prior to presentation. Ocular evaluation revealed perifoveal microaneurysms which were not associated with visual symptoms. CONCLUSIONS AND IMPORTANCE: These data potentially expand the phenotypic spectrum of Zika virus retinopathy. In addition to outer retinal abnormalities which are well-described in infants and adults, inner retinal vascular abnormalities may also occur and may be temporally associated with post-viral neurological sequelae of Zika virus infection. Clinicians should be aware of potential retinal involvement in affected patients who present with neurological symptoms after recovery from acute Zika virus infection.