Surgical Observations From the First 120 Cases of Subretinal Gene Therapy for Inherited Retinal Diseases.

PURPOSE: To report surgical observations formulated during the first 120 cases of subretinal gene therapy in patients with inherited retinal degenerations (IRDs). METHODS: A two-surgeon team compiled surgical observations and formulated surgical pearls based on the consecutive cases of subretinal viral vector injection in patients enrolled in clinical trials focusing on choroideremia, achromatopsia, and RP GTPase regulator associated retinitis pigmentosa, as well as patients with retinal pigment epithelium-specific-65-kDa (RPE65) associated Leber congenital amaurosis receiving Food and Drug Administration-approved voretigene neparvovec-rzyl therapy. RESULTS: One hundred twenty subretinal surgeries were performed by a two-surgeon team. Key anatomical features pertinent to surgical management were noted and are described in this article. Surgical decision making for successful subretinal administration of viral vectors and management of potential surgical challenges were formulated. CONCLUSION: Lessons learned during subretinal gene therapy cases may be helpful to other surgeons entering clinical trials or performing postapproval gene therapy administration. Surgical pearls outlined in this article may also be helpful for other targeted subretinal therapies, such as cellular transplantation or retinal prosthesis implantation.

Bilateral radiation therapy followed by methotrexate-based chemotherapy for primary vitreoretinal lymphoma.

Primary vitreoretinal lymphoma (PVRL) is a subset of primary CNS lymphoma that presents as isolated ocular disease without brain involvement. Although ocular radiotherapy (RT) is an effective treatment for PVRL, the optimal treatment is uncertain. PVRL may later involve the brain in 56%-85% of patients. We report on 12 PVRL patients treated with a combination of bilateral RT and a systemic chemotherapy (CT) regimen containing high-dose methotrexate (M). Ten received RT (30-40 Gy) followed by CT, one received RT, and one was treated with intravitreal M; all achieved a complete response (CR). Three patients had tumor recurrence in the brain and received CT and one patient relapsed in the eye with a second recurrence in the brain. Three patients achieved CR-2 remain alive and one died of dementia. One died from recurrent CNS disease. With a median follow of 68 months (range, 17-154 months), median progression-free and overall survival have not been reached. Bilateral RT followed by M-based CT is an effective treatment for reducing CNS progression and prolonging survival.

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative.

TOPIC: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. CLINICAL RELEVANCE: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. METHODS: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. RESULTS: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. CONCLUSIONS: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents.

RETINAL DETACHMENT SURGERY IN A PEDIATRIC POPULATION: Visual and Anatomic Outcomes.

PURPOSE: Pediatric retinal detachments (RDs) are unique in etiology, anatomy, and prognosis compared with the adult population. The mechanisms of pediatric RD include tractional (TRD), rhegmatogenous retinal detachment, traumatic, and other types, such as exudative or hemorrhagic. This study examined visual and anatomical outcomes of pediatric RD undergoing surgical repair at a single university referral center. METHODS: A retrospective consecutive case series of patients clinically diagnosed and undergoing surgery for RD between birth and 15 years of age from 2002 to 2013 at a single academic institution. RESULTS: A total of 206 patients (231 eyes) were included in this study, of which 25 (12%) had bilateral RD. Of those patients, 67 (29%) had TRD (retinopathy of prematurity, persistent fetal vasculature, or familial exudative vitreoretinopathy), 51 (22%) had rhegmatogenous retinal detachment (myopia, X-linked retinoschisis, or Stickler syndrome), 60 (26%) had traumatic RD, and 53 (23%) were due to other types of RD, such as Coats disease or coloboma. Presenting best-corrected visual acuity better than 20/200 correlated with better final best-corrected visual acuity (P < 0.0001). Anatomical success was strongly correlated with visual acuity outcome (P < 0.00001) and was significantly more likely in rhegmatogenous retinal detachment versus TRD (78% vs. 39%, P < 0.05). The rates of obtaining a final best-corrected visual acuity > 20/200 were poorer in TRD (10%) compared with rhegmatogenous retinal detachment (39%, P < 0.01) or traumatic RD (28%, P < 0.05). CONCLUSION: Visual and anatomical outcomes varied among categories of RD. Rhegmatogenous retinal detachments were associated with the best outcomes (anatomical success and globe conservation), whereas TRDs generally had poorer visual and anatomical outcomes.

Hard choices, better outcomes: a review of shared decision-making and patient decision aids around dialysis initiation and conservative kidney management.

PURPOSE OF REVIEW: Patients reaching end-stage kidney disease face difficult decisions, including choosing among renal replacement therapies (RRTs). With an increasingly elderly and frail population, there is growing interest in conservative kidney management (CKM) as a viable alternative to dialysis. Shared decision-making (SDM) is a patient-centered approach to these decisions, in which choices are viewed within the explicitly discussed values and preferences of the patient. Patient decision aids (PDAs) are tools designed to facilitate these discussions. The choice between dialysis and CKM is particularly complex, given the poor prognostication data for CKM. This is an emerging area for PDAs in nephrology. This review highlights care gaps around SDM for dialysis versus CKM, presents current PDAs for making choices about RRTs and CKM and discusses exciting new work around the development of novel PDAs. RECENT FINDINGS: Many PDAs have been created recently, primarily to help with decisions about RRTs. Three new PDAs are in testing phases to aid with the more complex decision of choosing between dialysis and CKM. SUMMARY: International nephrology communities are moving toward improved SDM with their patients and PDAs are being developed to facilitate this process.

Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results.

PURPOSE: To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). DESIGN: Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. PARTICIPANTS: Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. METHODS: Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. MAIN OUTCOME MEASURE: Loss of visual acuity. RESULTS: For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P < 0.001). Two patients demonstrated asymptomatic uveitis that resolved without treatment. Optical coherence tomography of treated eyes showed an average temporal retinal nerve fiber layer thickness of 54 µm before injection and 55 µm at month 12. For fellow eyes before injection, it was 56 µm, decreasing to 50 µm at month 12 (P = 0.013). Generalized estimating equations suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by approximately 0.05 µV (P = 0.009 exchangeable). No difference between eyes in outcomes of other visual function measures was evident. CONCLUSIONS: Allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer, opening the door next for testing of the high dose.

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies.

BACKGROUND: Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS: In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS: There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardt's macular dystrophy. INTERPRETATION: The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING: Advanced Cell Technology.

Epidemiology of Herpes Zoster Ophthalmicus: Recurrence and Chronicity.

PURPOSE: A hospital-based epidemiology study to describe herpes zoster ophthalmicus (HZO) prevalence and risk factors for recurrent and chronic disease. DESIGN: Retrospective, hospital-based cohort study. PARTICIPANTS: All patients evaluated in the Broward and Miami Veterans Administration Healthcare System (MIAVHS) during the study period. METHODS: Retrospective medical record review of patients seen in the MIAVHS from January 1, 2010, through December 31, 2014, with a HZO clinical diagnosis. Assessment of the patient's clinical course was defined by the following: an acute episode of HZO was defined as quiescence of disease within 90 days of initial presentation, HZO recurrence was defined as any recurrent eye disease or rash 90 days or more after quiescence of disease was noted off therapy, and chronic HZO was defined as active disease persisting more than 90 days from initial presentation. MAIN OUTCOME MEASURES: Main outcome measures included the frequency of HZO with and without eye involvement, HZO recurrence rates, and risk factors for recurrent or chronic HZO. RESULTS: Ninety patients with HZO were included in the study. The mean age at incident episode of HZO was 68±13.8 years (range, 27-95 years). Most patients were white (73%), immune competent (79%), and did not receive zoster vaccination at any point during the follow-up (82%). Patients were followed for a mean of 3.9±5.9 years (range, 0-33 years). The period prevalence of HZ in any dermatome was 1.1%, the frequency of HZ involving V1 (HZO) was 0.07%, and the frequency of HZO with eye involvement was 0.05%. The overall 1-, 3-, and 5-year recurrence rates for either recurrent eye disease or rash were 8%, 17%, and 25%, respectively. Ocular hypertension (hazard ratio [HR], 4.6; 95% confidence interval [CI], 1.3-16.5; odds ratio [OR], 6.7; 95% CI, 1.5-31.2) and uveitis (HR, 5.7; 95% CI, 1.7-19.0; OR, 6.7; 95% CI, 1.5-31.2) increased the risk of recurrent and chronic disease. CONCLUSIONS: This study supports newer data indicating that a significant proportion of patients experience recurrent and chronic HZO. Further study is needed to guide preventative and therapeutic approaches to recurrent and chronic HZO.

Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

PURPOSE: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS: Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES: Loss of visual acuity. RESULTS: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS: No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.

SYMPATHETIC OPHTHALMIA: Clinicopathologic Correlation in a Consecutive Case Series.

PURPOSE: To correlate the clinical course of sympathetic ophthalmia with the histological and immunohistochemical characteristics of the enucleated inciting eye. METHODS: A consecutive case series with baseline clinical features and subsequent histopathologic findings. RESULTS: Evaluation of the 16 enucleated inciting eyes (blind and painful) disclosed that 9 of the 16 had typical histology, fulfilling the criteria for sympathetic ophthalmia of diffuse granulomatous inflammation. Among the 16, 11 sustained previous penetrating trauma, 4 underwent previous eye surgery, and 1 patient presented with an unknown etiology. Patients with atypical histology (7 of 7) were taking corticosteroids at the time of enucleation. Only 2 of 9 patients with typical histology were taking corticosteroids at the time of enucleation. At 6 months after enucleation of the inciting eye, 4 of the 7 patients with atypical histology had a visual acuity of ≥20/40 compared with 8 of 8 patients (100%) with typical histology. On a 4-point scale (0-3+), the choroidal infiltrate of the 9 histopathologically typical eyes showed an average of 2.5+ CD68 (macrophages), 2.5+ CD20 (B cells), and 1.5+ CD3 (T cells). CONCLUSION: Histopathologic findings had minimal correlation with the clinical course of sympathetic ophthalmia. Corticosteroid treatment before enucleation may influence the pathologic confirmation of sympathetic ophthalmia. The predominance of B lymphocytes and macrophages over T lymphocytes may represent different stages of the disease process.

Interobserver agreement in clinical grading of vitreous haze using alternative grading scales.

PURPOSE: To evaluate the reliability of clinical grading of vitreous haze using a new 9-step ordinal scale versus the existing 6-step ordinal scale. DESIGN: Evaluation of diagnostic test (interobserver agreement study). PARTICIPANTS: A total of 119 consecutive patients (204 uveitic eyes) presenting for uveitis subspecialty care on the study day at 1 of 3 large uveitis centers. METHODS: Five pairs of uveitis specialists clinically graded vitreous haze in the same eyes, one after the other using the same equipment, using the 6- and 9-step scales. MAIN OUTCOME MEASURES: Agreement in vitreous haze grade between each pair of specialists was evaluated by the κ statistic (exact agreement and agreement within 1 or 2 grades). RESULTS: The scales correlated well (Spearman's ρ = 0.84). Exact agreement was modest using both the 6-step and 9-step scales: average κ = 0.46 (range, 0.28-0.81) and κ = 0.40 (range, 0.15-0.63), respectively. Within 1-grade agreement was slightly more favorable for the scale with fewer steps, but values were excellent for both scales: κ = 0.75 (range, 0.66-0.96) and κ = 0.62 (range, 0.38-0.87), respectively. Within 2-grade agreement for the 9-step scale also was excellent (κ = 0.85; range, 0.79-0.92). Two-fold more cases were potentially clinical trial eligible on the basis of the 9-step than the 6-step scale (P<0.001). CONCLUSIONS: Both scales are sufficiently reproducible using clinical grading for clinical and research use with the appropriate threshold (≥ 2- and ≥ 3-step differences for the 6- and 9-step scales, respectively). The results suggest that more eyes are likely to meet eligibility criteria for trials using the 9-step scale. The 9-step scale appears to have higher reproducibility with Reading Center grading than clinical grading, suggesting that Reading Center grading may be preferable for clinical trials.

Ocular syphilis.

PURPOSE OF REVIEW: Review current literature relevant to syphilitic uveitis utilizing Medline search and online governmental resources relevant to the diagnosis and management of syphilis presenting with ocular manifestations. RECENT FINDINGS: There is a trend for increasing frequency of primary and secondary syphilis in developed countries, especially in young men. Ocular manifestations of syphilis are rare, occurring in less than one in 1 million persons in the United Kingdom. Distinctive patterns of syphilitic uveitis include white, focal preretinal opacities, and acute posterior placoid uveitis. Enhanced imaging can facilitate clinical diagnosis. Definitive diagnosis remains serologic. The Centers for Disease Control currently recommends reverse sequence testing with initial treponemal antibodies, followed by a quantitative nontreponemal test, which, if negative, triggers a confirmatory treponemal pallidum agglutination test. Persons testing positive for syphilis should also be tested for HIV. Recommendations of the Centers for Disease Control for treatment are unchanged: all ocular syphilis should be treated according to neurosyphilis regimens and should receive cerebrospinal fluid testing. SUMMARY: Increased case numbers of syphilitic uveitis have stimulated interest in this old disease. This locally destructive ocular inflammation with the potential for severe systemic complications is curable with treatment and should have the highest priority for prompt recognition and treatment.

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.

Defining Retinal Vasculitis.

PURPOSE: To assess the validity of retinal vasculitis as the preferred diagnostic term for multiple conditions. DESIGN: Perspective METHODS: Expert opinion and review of literature focused on the current nosology and pathology of retinal vasculitis. Interpretation of the subset of intraocular inflammation named retinal vasculitis based on fundamental knowledge of the blood-retinal barrier, the neurovascular unit and pathological and functional responses to a variety of stimuli. Correlation with multimodal imaging and known mechanisms of immunologically mediated disease. RESULTS: A search of Medline in early 2024 for the phrase "retinal vasculitis" resulted in 2041 citations encompassing immunologic, genetic, neoplastic, infectious, drug- and ischemia-related disorders. Classification schemes and angiographic grading systems are descriptive and do not address pathologic mechanisms adequately, in part due to lack of histologic confirmation. Although OCT angiography holds promise for better imaging of retinal vascular changes, it does not reveal the key feature of leakage and only partially improves understanding of pathophysiology. Diagnosing catastrophic retinal vascular occlusion after intravitreal injections as a retinal vasculitis is the most recent example of speculative application of the term to complex and rare disorders. CONCLUSIONS: Retinal vasculitis is a diagnostic term that is over-used and imprecise. Revised nosology should limit the term to primary inflammation of the retinal vasculature itself that results in opening of the blood-retinal barrier with or without retinal vascular occlusions. Pending new histologic or mechanistic evidence, the provisional term of retinal vascular inflammation or retinal vasculopathy should be used for leakage or occlusion occurring in the context of intraocular inflammation.

Occlusive Retinal Vasculitis After a Single Injection of Pegcetacoplan.

Purpose: To describe a patient with retinal vasculitis after a single intravitreal injection (IVI) of pegcetacoplan. Methods: A case and its findings were analyzed. Results: An 80-year-old woman was treated with pegcetacoplan for subfoveal geographic atrophy. Ten days later, the patient noted "purple iridescent waves" but did not immediately report it. On day 18, she presented with pain and decreased visual acuity from 20/80 (pinhole) preinjection to 20/150 postinjection. No signs of inflammation were observed, and she was treated for high intraocular pressure (30 mm Hg). On day 23, iritis was noted. The fluorescein angiogram showed severe occlusive vasculitis involving all quadrants and the macula. The vasculitis/neuroretinitis laboratory panels were negative, and no contributing systemic features were identified other than well-controlled diabetes. Conclusions: In this patient, occlusive retinal vasculitis occurred shortly after a single IVI of pegcetacoplan.

Retinal Vasculitis After Intravitreal Pegcetacoplan: Report From the ASRS Research and Safety in Therapeutics (ReST) Committee.

Purpose: To analyze post-marketing cases of retinal vasculitis after intravitreal pegcetacoplan. Methods: The American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee as well as an expert panel performed a retrospective review of cases of retinal vasculitis reported to the ASRS. Clinical and imaging characteristics were reviewed for evidence of retinal vasculitis and analyzed. Results: Fourteen eyes of 13 patients were confirmed to have retinal vasculitis by review of imaging studies. All cases occurred after the first pegcetacoplan injection. Occlusive retinal vasculopathy was confirmed in 11 eyes (79%). Patients presented a median of 10.5 days (range, 8-23 days) after pegcetacoplan injection. All eyes had anterior chamber inflammation, and 12 eyes (86%) had vitritis. Vasculopathy involved retinal veins (100%) more than arteries (73%), and 12 eyes (86%) had retinal hemorrhages. The median visual acuity (VA) was 20/60 (range, 20/30-5/200) at baseline, 20/300 (range, 20/100-no light perception [NLP]) at vasculitis presentation, and 20/200 (range 20/70-NLP) at the last follow-up. Eight eyes (57%) had more than a 3-line decrease in VA, and 6 eyes (43%) had more than a 6-line decrease in VA from baseline to the final follow-up, including 2 eyes that were enucleated. Six eyes (43%) developed signs of anterior segment neovascularization. Conclusions: There is currently no known etiology for vasculitis in this series. Optimum treatment strategies remain unknown. Infectious etiologies should be considered, and corticosteroid treatments may hasten resolution of inflammatory findings. Continued treatment of affected patients with pegcetacoplan should be avoided.

Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures.

PURPOSE: To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). DESIGN: Phase 1 clinical trial. METHODS: This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range = 18-36 months). RESULTS: Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P = .023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.