Search

Importance: Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated., Objective: To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4)., Design, Setting, and Participants: This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye., Interventions: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing., Main Outcomes and Measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers)., Results: The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers., Conclusions and Relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

Importance: Despite the unquestionable effectiveness of anti-vascular endothelial growth factor therapy (VEGF), there is ongoing controversy about potential systemic adverse effects. Besides the direct adverse effects of anti-VEGF agents, other factors associated with the injection itself, such as perioperative blood pressure fluctuations, may contribute to adverse events., Objective: To determine blood pressure fluctuations during intravitreal injections., Design, Setting, and Participants: Prospective observational study at a tertiary referral center (Department of Ophthalmology, University Hospital Bern, Bern, Switzerland). Consecutive patients scheduled for intravitreal injections were recruited. Data were analyzed between October 2017 and January 2018., Main Outcomes and Measures: Systolic and diastolic blood pressure, pulse rate, and oxygen saturation were recorded before, during, and after the intravitreal injection. An anxiety questionnaire was completed by all participants. Multivariate regression analysis was used to investigate potential factors associated with blood pressure rise during injections., Results: Two hundred one patients (92 women and 109 men) were included in this study, with a mean age of 68 years (range, 18-93 years). Mean (SD) systolic blood pressure increased from a baseline of 150 (20) mm Hg to 162 (24) mm Hg following the preparation procedure to 168 (24) mm Hg during the injection (P < .001). Mean (SD) diastolic blood pressure increased from 78 (14) mm Hg to 83 (37) mm Hg to 83 (16) mm Hg, respectively (P = .009). Mean (SD) pulse frequency increased from 76 (13) bpm to 80 (13) bpm (P = .005). In total, 23 patients (11%) had a systolic blood pressure greater than 200 mm Hg. This subgroup of patients had a mean (SD) perioperative systolic blood pressure increase from 182 (19) mm Hg to 214 (12) mm Hg, resulting in an increase of 32 (20) mm Hg (P < .001). Age and anxiety were to be next associated with systolic blood pressure rise., Conclusions and Relevance: The intravitreal injection process is associated with a transient increase in blood pressure. Most of the increase occurs following the preparation before the injection itself. This may constitute a risk factor for cardiovascular or cerebrovascular complications during treatment and could be of particular relevance in patients at high risk for such events and those receiving frequent injections. Future work may be needed to determine whether, in patients at risk for cardiovascular or cerebrovascular events, perioperative blood pressure monitoring or antihypertensive therapy needs to be considered.

Importance: Patients with birdshot chorioretinopathy (BSCR) can experience a delay in diagnosis owing to the challenges of identifying the condition prior to evolution of characteristic choroidal scars. An objective, noninvasive method for detecting early lesions in BSCR might have an effect on preventing vision loss in these patients., Objective: To test the feasibility of swept-source optical coherence tomography angiography (SS-OCTA) in the detection of BSCR choroidal lesions and to use en face image analysis of choroidal layers to localize lesion depth., Design, Setting, and Participants: Prospective, longitudinal, observational case series of 3 patients diagnosed as having BSCR at 1 of 2 tertiary care uveitis centers between August 2017 and October 2017., Exposures: Widefield SS-OCTA and indocyanine green angiography (ICGA)., Main Outcomes and Measures: En face SS-OCTA slabs through the choroid were evaluated for the presence of flow voids corresponding to hypocyanescent lesions by ICGA. Baseline and posttreatment images were compared., Results: Six eyes of 3 patients with previously undiagnosed and untreated BSCR were imaged at baseline and after initiation of immune modulation treatment. Two patients had a history of recent-onset BSCR, and the third patient had a history of chronic untreated disease of at least 5 years' duration. All patients were white and between the ages of 50 and 67 years. All eyes demonstrated multiple flow voids on en face SS-OCTA images that corresponded with hypocyanescent lesions by ICGA. Analysis of serial depth en face SS-OCTA flow images identified that in the acute-onset patients, flow voids were located adjacent to large vessels in the Haller layer and regressed with treatment. In the patient with chronic, untreated disease, full-thickness choroidal flow voids were identified that did not regress with treatment., Conclusions and Relevance: For these 3 patients, SS-OCTA provided a noninvasive method for identifying early BSCR lesions previously visible only with ICGA. The depth information provided by SS-OCTA suggests acute lesions originate in the Haller layer, and that in the absence of treatment, damage extends up thorough the superficial choroid, and ultimately to the retinal pigment epithelium and retina. Swept-source OCTA may represent a new and noninvasive method for detecting and monitoring disease activity in BSCR.