THE LONG-TERM RECOVERY OF VISION IN PSEUDOPHAKIC MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENTS.

PURPOSE: To assess the long-term visual recovery in uncomplicated macula-off pseudophakic rhegmatogenous retinal detachment treated with pars plana vitrectomy and gas tamponade in the absence of other visual comorbidities. METHODS: Single-center retrospective longitudinal study on eyes with macula-off pseudophakic rhegmatogenous retinal detachment successfully treated with pars plana vitrectomy between 2011 and 2020 and with at least 2 follow-ups (FU), first gas-free FU (first-FU) and a final-FU, were included. Patients with subsequent ocular surgery or comorbidities affecting best-corrected visual acuity were excluded. The duration between operation date and final-FU was calculated (total days FU) and split into total days quintiles-1: ≤57, 2: >57 and ≤77, 3: >77 and ≤152, 4: >152 and ≤508, and 5: >508 days. Multivariable regression was performed with logMAR gain between the first and the final-FU as the dependent variable. RESULTS: In 209 eyes, the authors report association with increase of logMAR gain between the first and the final-FU, with reducing clock hours of pseudophakic rhegmatogenous retinal detachment ( P = 0.041) and relative to the total days Quintile 1. Mean (SD) logMAR gain between the first and the final-FU was 0.02 (0.07) in the first quintile, increasing to 0.14 (0.13) ( P < 0.001) by the fifth quintile on multivariable regression. For patients not achieving 0.30 logMAR at the first-FU, this was attained at the final-FU with a sensitivity of 51.9% and specificity of 95.5% at a cut off ≤0.58 logMAR at the first-FU (area under the curve 0.756 [95% confidence interval 0.664-0.848], P < 0.001). CONCLUSION: The authors report a significant time-dependent visual improvement after uncomplicated pars plana vitrectomy with gas tamponade for macula-off pseudophakic rhegmatogenous retinal detachment without visual confounders and provide important quantitative data for counselling patients with macula-off repair.

SF 6 COMPARED WITH C 2 F 6 FOR INFERIOR RHEGMATOGENOUS RETINAL REPAIR : The Manchester Pseudophakic Retinal Detachment Study.

PURPOSE: To compare SF 6 relative with C 2 F 6 in the anatomical and functional outcomes following pars plana vitrectomy for uncomplicated primary pseudophakic rhegmatogenous retinal detachment with inferior causative breaks. METHODS: This is a retrospective, comparative study on eyes with pseudophakic rhegmatogenous retinal detachment with inferior causative breaks that had small-gauge pars plana vitrectomy repair using SF 6 and C 2 F 6 tamponade between 2011 and 2020 at a tertiary centre in the United Kingdom. Primary outcome was single surgery anatomical success, and the secondary outcome was best-corrected visual acuity. Propensity score matching, using preoperative findings as covariates to account for relevant confounders, was performed. RESULTS: From 162 pseudophakic rhegmatogenous retinal detachment eyes with inferior causative breaks, the median (interquartile range) follow-up was 82 (52-182) days. The single surgery anatomical success was 156 (96.3%) overall: 47 of 47 (100.0%) and 109 of 115 (94.8%) in the SF 6 and C 2 F 6 groups, respectively ( P = 0.182). Relative to the SF 6 group, the C 2 F 6 group had a higher mean number of tears (SF 6 : 3.1[2.0], C 2 F 6 : 4.5[2.7], P = 0.002) and greater retinal detachment extent (SF 6 : 5.3[2.9], C 2 F 6 : 6.2[2.6] clock hours, P = 0.025). Following propensity score matching analysis, 80 eyes were matched with 40 in each group to homogenize preoperative factors. No significant difference was found in single surgery anatomical success and best-corrected visual acuity between the groups following propensity score matching. CONCLUSION: Primary pars plana vitrectomy with gas tamponade leads to a high single surgery anatomical success rate in uncomplicated pseudophakic rhegmatogenous retinal detachment with inferior causative breaks with no additional benefit associated with long-acting tamponade when comparing C 2 F 6 with SF 6 .

Expansile gas concentration in primary pseudophakic retinal detachment repair, effect on intraocular pressure and outcomes; the Manchester Pseudophakic Retinal Detachment Study.

PURPOSE: To investigate the effect of isovolumetric and expansile gas tamponade concentrations on single surgery anatomical success (SSAS) and day 1 intraocular pressure (IOPD1) following pars plana vitrectomy (PPV) for mild-moderate complexity primary pseudophakic rhegmatogenous retinal detachment (PRD). METHODS: We conducted a single-centre retrospective continuous and comparative study on eyes that had undergone small-gauge PPV using isovolumetric versus expansile gas for PRD repair between 2011 and 2020 at a single tertiary vitreoretinal centre in UK. We performed propensity score matching (PSM) using preoperative findings as covariates to account for relevant confounders. Significant risk factors such as proliferative vitreoretinopathy C or giant retinal tears were excluded. RESULTS: From 456 eyes, PSM analysis matched 240 eyes with 120 in each group. The median (interquartile range) follow-up was 96 (59 to 218) days. The SSAS was 229/240 (95.8%) overall; 115/120 (95.8%) and 114/120 (95.0%) in isovolumetric and expansile groups, respectively (p = 1.000). Relative to the isovolumetric group, the expansile group had lower proportion of eyes with IOP ≤ 21 mmHg (odds ratio, 95% confidence interval, 0.40 [0.23-0.68], p < 0.001); but significantly higher number of eyes with IOP ≥ 22 mmHg (2.53 [1.48-4.34], p < 0.001), ≥ 25 mmHg (2.77 [1.43-5.33], p < 0.001), ≥ 30 mmHg (2.90 [1.28-6.58], p = 0.006) and ≥ 40 mmHg (p = 0.029, isovolumetric: 0 [0%] vs expansile group: 6 [5%]). There was only one case of hypotony (≤ 5 mmHg) 1/240 (0.4%) which occurred in the expansile group. CONCLUSIONS: Expansile gas concentration does not impact SSAS but is associated with significantly raised IOPD1 with no reduction in hypotony rates following PPV for primary PRD.

LASER PROPHYLAXIS IN STICKLER SYNDROME: The Manchester Protocol.

PURPOSE: Patients with Stickler syndrome are at high risk of giant retinal tears (GRTs) and detachments. Vitreoretinal interventions can reduce this risk, but there is presently no consensus about the optimal prophylactic approach. The aim of our study was to determine whether 360° laser prophylaxis is a safe and effective procedure to prevent GRT detachments in patients with Stickler syndrome. METHODS: Study subjects were recruited retrospectively through the databases of the vitreoretinal and ophthalmic genetic tertiary services in Manchester, United Kingdom. Clinical data were collected including on prophylactic intervention, the occurrence of retinal detachment, and the presence/type of retinal breaks. RESULTS: One hundred thirteen eyes from 63 patients with Stickler syndrome were studied; 72.6% (82/113) of these eyes received 360° laser prophylaxis. Of these, 9% had a retinal detachment, but no GRTs occurred. Among the 27.4% (31/113) of eyes that had no prophylactic treatment, 23% suffered a retinal detachment and 42.9% of these were associated with a GRT. CONCLUSION: Patients who underwent laser prophylaxis had fewer retinal detachments and no GRTs during an average of 6.1 years of follow-up (median 5 years), suggesting that this is a safe and effective approach for individuals with Stickler syndrome.

PREDICTION OF MACULAR HOLE SIZE PROGRESSION BASED ON BASELINE OPTICAL COHERENCE TOMOGRAPHY FINDINGS.

PURPOSE: To quantify the rate of idiopathic macular hole progression from presentation and identify factors that may influence stratification and urgency for surgical listing based on the initial optical coherence tomography scans. METHODS: The minimal linear diameter (MLD), base diameter (BD), and hole height on nasal and temporal sides of idiopathic macular hole were measured on spectral domain optical coherence tomographies, on initial presentation and just before surgery. Mean hole height, hole height asymmetry (absolute difference between nasal and temporal height), MLD/BD, and MLD change per day (MLD/day) were calculated for each patient. Multivariable linear regression analysis with MLD/day as the dependent variable was performed to identify significant risk factors for MLD progression. Minimal linear diameter was grouped to quintiles: 1: ≤290 µ m, 2: >290 µ m and ≤385 µ m, 3: >385 µ m and ≤490 µ m, 4: >490 µ m and ≤623 µ m, and 5: >623 µ m. RESULTS: In 161 eyes (157 patients), we report significant associations with MLD/day: 1) MLD/BD ( P = 0.039) (i.e., wide BD relative to MLD lead to faster progression of MLD), 2) hole height asymmetry ( P = 0.006) (larger absolute difference between nasal and temporal hole height lead to faster progression), and 3) days between scans ( P < 0.001) (longer duration between scans had reduced MLD/day, indicating more rapid increase initially then plateaux), and relative to MLD Quintile 1, MLD Quintile 3 ( P = 0.002) and MLD Quintile 4 ( P = 0,008), and MLD Quintile 5 ( P < 0.001) all lead to a reduced MLD/day rate on multivariable regression. CONCLUSION: In addition to finding that the previously reported initial smaller MLD is a risk factor for rapid MLD progression, we report two novel findings, large hole height asymmetry and a low MLD/BD (wide base relative to MLD), that represent significant risk factors. These factors should be taken into consideration on presentation to stratify timing of surgery.

The Role of Subretinal Injection in Ophthalmic Surgery: Therapeutic Agent Delivery and Other Indications.

Subretinal injection is performed in vitreoretinal surgery with two main aims, namely, the subretinal delivery of therapeutic agents and subretinal injection of fluid to induce a controlled and localized macular detachment. The growing interest in this technique is mainly related to its suitability to deliver gene therapy in direct contact with target tissues. However, subretinal injection has been also used for the surgical management of submacular hemorrhage through the subretinal delivery of tissue plasminogen activator, and for the repair of full-thickness macular holes, in particular refractory ones. In the light of the increasing importance of this maneuver in vitreoretinal surgery as well as of the lack of a standardized surgical approach, we conducted a comprehensive overview on the current indications for subretinal injection, surgical technique with the available variations, and the potential complications.

STEP-WISE APPROACH TO THE MANAGEMENT OF SUBMACULAR HEMORRHAGE USING PNEUMATIC DISPLACEMENT AND VITRECTOMY: The Manchester Protocol.

PURPOSE: To evaluate a sequential approach of pneumatic displacement followed by vitrectomy (pars plana vitrectomy) in failed cases to deal with submacular hemorrhage (SMH) of various etiologies. METHODS: Retrospective, nonrandomized interventional case series of consecutive patients with SMH of up to 2 weeks' duration, who were treated with a stepwise approach. Step 1 involved intravitreal injection of 0.3 mL 100% C3F8 and recombinant tissue plasminogen activator 50 µg/0.1 mL. If unsuccessful, a prompt pars plana vitrectomy with subretinal recombinant tissue plasminogen activator 50 µg/0.1 mL and 20% SF6 gas tamponade was performed as a second attempt to displace the SMH. RESULTS: Thirty-one patients with SMH underwent pneumatic displacement; 24 (77.4%) had a successful outcome without further intervention. The mean presenting visual acuity of the "successful cohort" was 1.34 logMAR (20/440 Snellen), improving to 0.83 logMAR (20/135 Snellen) 1 month after treatment. Five of the seven patients with failed pneumatic displacement underwent pars plana vitrectomy with subretinal recombinant tissue plasminogen activator at an average of 5 days poststep 1, with successful SMH displacement in 3 patients, giving an overall success of 87.1% for this treatment protocol. CONCLUSION: A sequential approach of expansile gas injection followed by prompt pars plana vitrectomy, aided by recombinant tissue plasminogen activator at both steps, is a coherent, logical pathway to treat SMH with high anatomical and functional success.

OUTCOME OF REVISION PROCEDURES FOR FAILED PRIMARY MACULAR HOLE SURGERY.

PURPOSE: To analyze the outcomes of revision surgery for idiopathic full-thickness macular holes that have failed to close after primary surgery, and also to assess factors predicting success and to review the relative effect of adjunctive surgical techniques. METHODS: A multicenter retrospective study. Anatomical closure rates and visual acuity change between pre and postrevision surgery were assessed. Hole size, age, symptom duration, surgical interval, and reduced hole size were analyzed as predictive factors for success. Effectiveness of adjunctive surgical techniques was reviewed. RESULTS: Seventy-seven eyes were included in the study. Anatomical closure was achieved in 71% (55/77) cases. There was a median gain of 11 Early Treatment of Diabetic Retinopathy Score letters in all holes and 14 letters in closed holes. Full-thickness macular holes that increased in size by more than 10% following primary surgery had a closure rate of 50% compared with 80% in holes that reduced by 10% or stayed the same (P = 0.015). Increasing hole size is associated with a modest reduction in odds of closure (odds ratio = 0.99; P = 0.04). Surgical interval <2 months is not associated with better outcomes compared with >2 months (P = 0.14). CONCLUSION: Revision surgery for full-thickness macular holes that have failed to close after primary surgery is associated with high closure rates and significant visual gains.

MANCHESTER REVISIONAL MACULAR HOLE STUDY: Predictive Value of Optical Coherence Tomography Parameters on Outcomes of Repeat Vitrectomy, Extension of Internal Limiting Membrane Peel, and Gas Tamponade for Persistent Macular Holes.

PURPOSE: To evaluate the efficacy of repeat pars plana vitrectomy and gas tamponade for persistent macular holes (MHs), especially looking at a predictive value of optical coherence tomography parameters in revisional surgery. METHODS: Retrospective, nonrandomized interventional case series of consecutive patients with a persistent MH that underwent revisional pars plana vitrectomy and gas tamponade. The primary outcome measure was anatomical closure of the MH after revisional surgery. The secondary outcome measure was a functional outcome of the MH closure based on the best-corrected visual acuity. The changes of minimum linear diameter and MH index after the primary surgery were evaluated to see if they were prognostic markers of success for the revisional surgery. RESULTS: A total of 27 patients with a persistent MH after primary MH surgery were identified, all of whom underwent a second operation with pars plana vitrectomy and gas tamponade with an internal limiting membrane peel extension in 20 cases. The MH closure rate after revisional surgery was 89% (24/27). Twenty-two cases were included in the optical coherence tomography analysis, of which 14 MHs that showed both a reduction of the minimum linear diameter and an increase in the MH index after the primary repair closed after revisional surgery. The mean best-corrected visual acuity before revisional surgery was 0.86 logMAR (20/145 Snellen) but increased significantly postoperatively to 0.69 (±0.15) logMAR (20/98 Snellen) at 3 months and to 0.49 logMAR (20/62 Snellen) at 12 months. CONCLUSION: For a persistent idiopathic MH, simple repeat pars plana vitrectomy with gas tamponade has a good anatomical and functional success rate in selected cases. The minimum linear diameter and MH index can be useful optical coherence tomography markers for prognostic guidance.

Antiplatelets and anticoagulants in vitreoretinal surgery, with a special emphasis on novel anticoagulants: a national survey and review.

PURPOSE: To survey current practice and opinion regarding the cessation of antiplatelet and anticoagulant agents prior to vitreoretinal surgery, with special emphasis on novel anticoagulants, and to provide an overview of current literature. METHODS: An online survey was sent to 167 members of the British and Eire Association of Vitreoretinal Surgeons (BEAVRS). A literature search and analysis was conducted on studies that reviewed the bleeding risk of antiplatelet and anticoagulant agents. RESULTS: The majority (93% for aspirin, 82% for clopidogrel) of respondents would not suspend antiplatelet administration, and 79% would not stop warfarin before vitreoretinal surgery. Regarding the novel anticoagulants (factor Xa inhibitors), 58% would not stop them, and 24% were unsure. Eighty-three percent of the surgeons were not confident regarding the management of factor Xa inhibitors preoperatively. Thirty-one percent of the respondents felt that anticoagulation cessation was independent of the type of vitreoretinal surgery, whereas 9% each felt that they would stop anticoagulation if possible for diabetic vitrectomy and retinectomy. Published evidence suggests that antiplatelet agents and warfarin do not confer a significantly greater risk of intra- or perioperative bleeding. Evidence regarding the novel anticoagulants is sparse. CONCLUSIONS: Further evaluation of novel anticoagulants in vitreoretinal surgery is required in order to provide evidence-based recommendations and address variations in practice.

Iatrogenic retinal breaks in 20-G versus 23-G pars plana vitrectomy.

BACKGROUND: The purpose of this study was to compare the incidence of iatrogenic anterior retinal breaks in 20-G vitrectomy (PPV) with transconjunctival 23-G PPV. METHODS: Retrospective, observational review study involving consecutive patients undergoing PPV in a single center in the UK during a 2-year period. RESULTS: Sclerotomy-related entry-site breaks (ESB) were found in 50/628 (7.9 %) 20-G PPV cases and 5/296 (1.7 %) 23-G PPV eyes (p<0.0001*). Anterior non-sclerotomy iatrogenic breaks (ANSB) were present in 55/628 (8.7 %) 20-G PPV cases and 18/296 (6.1 %) 23-G PPV eyes (p=0.19). The incidence of total anterior iatrogenic breaks (ANSB + ESB) was 105/628 (16.7 %) for 20-G PPV and 23/296 (7.8 %) for 23-G PPV (p=0.002*). Univariate analysis showed that posterior vitreous detachment induction was the only risk factor significantly associated with the development of anterior retinal breaks for both 20-G and 23-G PPV. Multivariate logistic model of risk factors for development of iatrogenic retinal breaks demonstrated that 23-G PPV was the most important factor reducing the risk of anterior breaks (p<0.0001*). CONCLUSIONS: We report the largest series of patients undergoing 20-G and 23-G vitrectomy, where 23-G vitrectomy was associated with a significantly lower incidence of anterior iatrogenic retinal breaks.

Bilateral paediatric optic neuropathy precipitated by vitamin B12 deficiency and a novel mitochondrial DNA mutation.

We present an 11-year-old girl with sudden, severe, sequential optic neuropathy. Investigations revealed severe vitamin B12 deficiency, and identified a novel mitochondrial ND5 variant. She was treated with steroids followed by plasma exchange, but the vision continued to deteriorate to eventual bilateral blindness over the next few months. Vitamin B12 deficiency can rarely cause severe irreversible visual loss secondary to optic neuropathy. The significance of the concurrent mitochondrial ND5 variant remains undetermined.

AUTOLOGOUS RETINAL TRANSPLANT FOR REFRACTORY SEROUS RETINAL DETACHMENT SECONDARY TO OPTIC DISK PIT: A NOVEL SURGICAL APPROACH.

PURPOSE: To present a new technique to treat refractory retinal detachment secondary to optic disk pit. METHODS: An interventional case report. RESULTS: A 25-year-old man with congenital optic disk pit had two failed vitrectomies involving laser around the optic disk, internal limiting membrane peel and flap to plug the disk pit, and gas tamponade to reattach the retina. With all options running out, a further vitrectomy with autologous retinal transplant and silicone oil tamponade was performed to treat the refractory serous retinal detachment; the silicone oil was removed at 6 weeks after the last procedure. The retina remained successfully attached at 6 months postsurgery with the patient maintaining his baseline visual acuity. CONCLUSION: The use of autologous retinal transplant is a new approach to treat refractory retinal detachment secondary to congenital optic disk anomalies, and adds to our options of dealing with this complex condition when first-line approaches have failed.

Unilateral retinal neovascularization associated with recurrent vitreous hemorrhage in a patient with gyrate atrophy.

BACKGROUND/PURPOSE: To describe the first case of unilateral peripheral retinal neovasularization associated with recurrent vitreous hemorrhage and localised tractional retinal detachment in a patient with gyrate atrophy (GA). METHODS: Interventional case report. RESULTS: A 23-year-old man with confirmed diagnosis of gyrate atrophy presented with vitreous hemorrhage and history of stable peripheral inferior tractional retinal detachment in the left eye. After three months, the vitreous hemorrhage partially reabsorbed and peripheral retinal vascular abnormalities with focal neovascularization were detected with associated tractional retinal detachment and confirmed on fluorescein angiography. Cryotherapy was performed to prevent any further bleeding. Twelve months later, the left eye remained stable and no further vitreous bleeding occurred. CONCLUSIONS: The combination of peripheral retinal neovascularization, localised tractional retinal detachment and recurrent vitreous hemorrhage can be a unilateral complication of gyrate atrophy. In similar cases, cryotherapy may represent a valuable therapeutic option to prevent recurrent bleeding.

Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy.

BACKGROUND: Voretigene neparvovec (VN) is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. We illustrate, both the benefits and pitfalls associated with ocular gene therapy in the same patient. METHODS: Two eyes of one patient with bi-allelic RPE65 mutations have been treated with VN. The clinical examinations included visual acuity (VA, in normal and low luminance), colour vision, contrast sensitivity, International Society for Clinical Electrophysiology of Vision (ISCEV) standard retinal electrophysiology and dark-adapted full-field stimulus threshold (FST), Goldmann VF analysis and imaging studies, including optical coherence tomography (OCT) and autofluorescence. These were performed at baseline, 2-weeks, 3 and 6-months, 1 and 2-years follow-up. RESULTS: The first eye showed improvement in rod photoreceptor function with increased peripheral and low luminance vision (baseline VA: 0.9 logMAR and 2-years post-operative VA: 0.7 logMAR). The second eye, whilst showing increased light sensitivity, suffered a drop in central vision (at 2-weeks) with loss of foveal photoreceptors as shown by the loss of ellipsoid zone on OCT scan (baseline VA: 0.6, 2-year post-operative VA: 1.2). FST improvements were maintained in both eyes indicating a sustained efficacy of VN with little waning of its effect. CONCLUSIONS: We present a previously unreported adverse complication of subretinal VN therapy in bi-allelic RPE65, indicating a probable immune response in treatment of the second eye, resulting in loss of foveal photoreceptors. This case-series highlights the potential and pitfalls of retinal gene therapy in the same patient. The immune responses of the body to a 'foreign vector', remains a challenge.

The use of fluorinated gases and quantification of carbon emission for common vitreoretinal procedures.

PURPOSE: To report the contribution to carbon dioxide equivalent mass [CO2EM] of various types of VR surgery performed across three tertiary referral centres, according to their indication and fluorinated gas used. We secondarily reported on the difference in tamponade choice, and CO2EM between the different centres. MATERIALS: Retrospective, continuous, comparative multicentre study of all procedures using fluorinated gases between 01/01/17-31/12/20 at the Manchester Royal Eye Hospital and Birmingham and Midland Eye Centre, and between 01/01/19-31/12/2020 at the University Hospitals Coventry and Warwickshire. RESULTS: Across 4877 procedures, the use of fluorinated gases produced 284.2 tonnes (71.2 tonnes annually) CO2EM; an annual consumption of 30,330 l of gasoline. Rhegmatogenous-retinal-detachment (RRD) and macular hole repair had the highest CO2EM by indication, accounting for 191.4 tonnes CO2EM (67.3%) and 28.6 tonnes CO2EM (10.1%); a mean 60.0 kg and 32.0 kg of CO2EM produced per surgery respectively. The use of fluorinated gases and their respective CO2EM contributions were significantly different across all three centres (p < 0.001) for all indications. SF6, despite being used in 1883 procedures (38.6%), contributed to 195.5 tonnes CO2EM (68.8%). Relative to C2F6, procedures using C3F8 and SF6 produced 1.9 and 4.4 times more CO2EM. CONCLUSION: We demonstrated that SF6 causes significantly higher carbon emissions relative to C2F6 and C3F8 with RRD and macular hole repair having the greatest environmental impact. We also reported large variations between different large VR centres in fluorinated gas use, and therefore in carbon emission contributions depending on indications for surgery. Evidence-based protocols might help in making VR surgery "greener".

Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations.

Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss. Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study. Design, Setting, and Participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021. Main Outcomes and Measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months. Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred. Conclusions and Relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials. Trial Registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.