Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

Purpose: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Results: Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). Conclusions: AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. Translational Relevance: This systematic review will help to inform and guide future clinical trials.

Acute annular outer retinopathy preceded by invasive ductal breast carcinoma: a case report.

BACKGROUND: Acute annular outer retinopathy (AAOR) is an uncommon disease. To date, there are few documented cases in the literature. Our case report is the first to describe a case of acute annular outer retinopathy in a patient with invasive ductal breast carcinoma. CASE PRESENTATION: The patient presented with photopsias and visual loss approximately 3 weeks prior to a diagnosis of invasive ductal breast carcinoma. We have documented the outer annular white ring seen in the acute phase of this disease and correlate it anatomically with Spectral-domain optical coherence tomography (SD-OCT) imaging. We identified RPE atrophy with nodular hyperreflectivity and loss of ellipsoid layer within the white annular ring with corresponding visual field loss. Fundus autofluorescence correlated with structural alterations seen on SD-OCT and showed both presumed active hyperautofluorescent zones with patchy hypoautofluorescent zones of atrophy and a classic annular hyperautofluorescent border. This case provides additional information about the natural history of this rare entity and its prognosis and varied presentation. CONCLUSIONS: The authors report a single case of acute annular outer retinopathy in a patient with invasive ductal breast carcinoma with the corresponding SD-OCT, fundus autofluorescence and visual field findings, during the acute phase of the disease. These findings provide new insight into the characteristic features, etiology and progression of this rare disease.

Inner Retinal Morphology and Visual Outcomes in Idiopathic Epiretinal Membrane Surgery: A Retrospective Optical Coherence Tomography Study.

Purpose: Epiretinal membrane (ERM) is a common retinal finding for patients older than 50 years. Disorganization of the retinal inner layers (DRIL) has emerged as a novel predictor of poor visual acuity (VA) in eyes with inner retinal pathology. The aim of our study is to correlate preoperative DRIL with visual outcomes after ERM surgery. Methods: Medical records and optical coherence tomography (OCT) images of 81 pseudophakic patients who underwent treatment of idiopathic ERM were reviewed. Preoperative DRIL on OCT was correlated with VA at baseline and at 3 and 6 months after ERM surgery. DRIL was defined as the loss of distinction between the ganglion cell-inner plexiform layer complex, inner nuclear layer, and outer plexiform layer. DRIL severity was based on its extent within the central 2-mm region of a transfoveal B-scan (absent/mild: one-third horizontal width). Results: Review of preoperative OCT showed severe DRIL in 41% and absent/mild DRIL in 59%. Severe DRIL was associated with worse baseline VA (P < .001). Preoperative VA and DRIL status at baseline were both predictors of postoperative VA at follow-up time points (P < .001). Severe DRIL was associated with significantly less improvement in VA at 6 months (-0.23 logMAR for absent/mild vs -0.14 for severe DRIL). Conclusions: Presence of severe preoperative DRIL correlates with worse baseline VA in patients with ERM and reduced VA improvement at 6 months. DRIL can be a strong predictor of long-term poor visual outcomes in ERM surgery.

OPACIFICATION OF SCLERAL-SUTURED AKREOS AO60 INTRAOCULAR LENS AFTER VITRECTOMY WITH GAS TAMPONADE: CASE SERIES.

BACKGROUND/PURPOSE: We report the first two cases of postoperative opacification of scleral-sutured Akreos AO60 intraocular lens after vitrectomy with the gas tamponade. METHODS: Two patients with ectopia lentis underwent pars plana vitrectomy, pars plana lensectomy, and scleral fixation of an Akreos AO60 intraocular lens with Gore-Tex suture. Retinal breaks were noted during vitrectomy and consequently intravitreal gas tamponade was used after endolaser retinopexy. Postoperatively, both patients developed intraocular lens opacification but maintained excellent visual acuity; however, one patient developed bothersome though tolerable photophobia. CONCLUSION: Although still an excellent option for the management of surgical aphakia in the absence of capsular support, caution should be taken when using a hydrophilic secondary intraocular lens, such as Akreos AO60, during vitreoretinal surgery if gas is required.

25-GAUGE TROCAR CANNULA FOR ACUTE ENDOPHTHALMITIS-RELATED IN-OFFICE VITREOUS TAP AND INJECTION: Patient Comfort and Physician Ease of Use.

PURPOSE: To assess comfort and procedural facility using a 25-gauge trocar cannula as a port to diagnose and treat acute endophthalmitis compared with a standard vitreous tap and injection technique. METHODS: Eighteen consecutive patients with acute endophthalmitis were randomized into two treatment arms: 1) Standard vitreous tap and injection technique, and 2) A technique where a valved 25-gauge trocar cannula is inserted through the pars plana as done in sutureless vitrectomy surgery and subsequent vitreous sampling and injections are performed through the port. A standardized anesthetic protocol was used and subjects were masked to the technique performed. Primary outcomes measured were patient comfort using a Wong-Baker pain scale and standardized physician ease-of-use scoring scale. Secondary outcomes included vitreous sampling success rate and volume of vitreous sample. RESULTS: No significant differences were found when comparing patient comfort (P = 0.340), physician ease-of-use scores (P = 0.796), vitreous sample volume (P = 0.149), successful vitreous taps (P = 0.620), and microbiologic yield (P = 1.000) between treatment arms. There were no adverse events. CONCLUSION: The 25-gauge trocar technique provides a safe, well-tolerated, and equally effective alternative to the standard vitreous tap and injection technique for delivery of intravitreal antibiotics, and procuring of vitreous sample, requiring a single sharp penetration.

Trends in subspecialty training by Canadian ophthalmology graduates.

OBJECTIVE: To evaluate the trends in subspecialty fellowship training by Canadian ophthalmology graduates over the last 25 years. DESIGN: Cross-sectional study. PARTICIPANTS: Canadian-funded, Royal College-certified graduates from 1990 to 2014 who completed a full residency in an English-language Canadian ophthalmology postgraduate training program. METHODS: Data were obtained by contacting all 11 English-language ophthalmology residency programs across Canada for demographic and fellowship information regarding their graduates. Society web sites were then used to corroborate and complement the data set, including those of the Canadian Ophthalmology Society, American Academy of Ophthalmology, and Provincial Colleges of Physicians and Surgeons. Data were organized by demographic variables, and analysis was performed using SPSS v22.0. RESULTS: Of the 528 graduates from 1990 to 2014, 63.5% pursued fellowship training. Males and females were equally likely to undertake fellowship training. The proportion of graduates obtaining fellowship training did not change significantly during this 25-year period. The most popular subspecialty choices were vitreoretinal surgery (24.5%), glaucoma (16.7%), and anterior segment (16.7%). Significantly more males than females pursued vitreoretinal surgery and oculoplastics fellowships (p = 0.001, χ(2) test), whereas females were more likely to train in a paediatric ophthalmology and strabismus fellowship (p = 0.001, χ(2) test). CONCLUSIONS: The majority of ophthalmology graduates from English-language residency programs pursue subspecialty fellowship training. An understanding of trends in fellowship training may be helpful for both workforce planning and career decision making.

The effect of prophylactic topical antibiotics on bacterial resistance patterns in endophthalmitis following intravitreal injection.

PURPOSE: The purpose of this study was to evaluate the effect of prophylactic topical antibiotics on bacterial resistance patterns in endophthalmitis following intravitreal injection of anti-vascular endothelial growth factor (VEGF) medications. METHODS: In this retrospective case-control study, billing records and an infection log were used to identify all cases of endophthalmitis following intravitreal injection of ranibizumab, bevacizumab, or aflibercept between January 1, 2009 and September 30, 2013 at a single retina practice. A 28-month period when topical antibiotic drops were prescribed for use four times a day for 4 days following intravitreal injection was compared to a 21-month period when topical antibiotics were not prescribed. Patients treated during an 8-month transition period were excluded as prescription practices were changed. RESULTS: During the study period, a total of 172,096 anti-VEGF injections were performed. During the period when antibiotics were prescribed, 28 cases of suspected infectious endophthalmitis occurred from a total of 57,654 injections, ten of which were culture-positive. During the period when antibiotics were not used, 24 cases of suspected endophthalmitis occurred from a total of 89,825 injections, six of which were culture-positive. During the antibiotic period, four of the ten (40 %) culture-positive cases grew bacteria resistant to the prescribed prophylactic antibiotics. In contrast, none of the six culture-positive cases grew bacteria resistant to those antibiotics during the period when antibiotics were not used (odds ratio = 9.0; 95 % confidence interval = 0.40-203.3; p = 0.17). CONCLUSIONS: The use of prophylactic topical antibiotics following intravitreal injection may lead to higher rates of antibiotic-resistant bacteria in culture-positive endophthalmitis cases.

MICROBIAL SPECTRUM AND OUTCOMES OF ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION VERSUS PARS PLANA VITRECTOMY.

PURPOSE: To compare infectious organisms and visual outcomes of endophthalmitis after intravitreal injection (IVI) with endophthalmitis after pars plana vitrectomy (PPV). METHODS: Retrospective, comparative, consecutive case series of patients diagnosed with presumed infectious endophthalmitis after IVI of an anti-vascular endothelial growth factor medication or PPV between January 1, 2009, and October 1, 2012, from one center. Main outcome measures were infectious organism and final visual acuity. RESULTS: Forty-four cases of presumed infectious endophthalmitis (17 culture positive) occurred after IVI and 19 cases (9 culture positive) occurred after PPV. Of note, 56.3% of culture-positive IVI cases were due to bacteria associated with oral flora, primarily Streptococcus species, compared with none in the PPV group (P = 0.01). There was a trend approaching significance for IVI patients to have lost ≥3 lines of visual acuity compared with PPV patients at final follow-up (P = 0.07). Within the IVI group, patients were more likely to have lost ≥6 lines of visual acuity at final follow-up when endophthalmitis was due to an organism associated with oral flora (P = 0.007). CONCLUSION: Endophthalmitis after IVI has a higher likelihood of being due to oral flora compared with endophthalmitis after PPV. Among IVI patients, worse visual outcomes occurred when endophthalmitis was due to oral flora.

Effect of a Strict 'No-Talking' Policy During Intravitreal Injection on Post-Injection Endophthalmitis.

BACKGROUND AND OBJECTIVE: To report the effect of a "no-talking" policy during intravitreal injection (IVI) on post-injection endophthalmitis. PATIENTS AND METHODS: Retrospective, comparative, consecutive case series of patients receiving IVI between Jan. 1, 2009, and Dec. 31, 2012. A 24-month "usual care" period was compared to a 24-month no-talking period, during which a strategy to further minimize speech during IVI was implemented. RESULTS: During the usual care period, 47,155 IVIs were performed, with nine culture-positive cases (0.019%), including seven due to oral pathogens (0.015%). During the no-talking period, 82,658 IVIs were performed, with eight culture-positive cases (0.010%), including two due to oral pathogens (0.002%). The no-talking policy was associated with a decreased endophthalmitis risk (P = .004), including oral pathogen-associated endophthalmitis (P = .02). CONCLUSION: This study demonstrates that a more stringent no-talking policy during IVI may reduce the risk of post-injection endophthalmitis.

Contemporary Management of Rhegmatogenous Retinal Detachment Due to Giant Retinal Tears: A Consecutive Case Series.

BACKGROUND AND OBJECTIVE: To investigate outcomes of contemporary surgical techniques for repair of rhegmatogenous retinal detachments (RRD) associated with giant retinal tears (GRT). PATIENTS AND METHODS: Retrospective, consecutive case series including 58 eyes of 58 patients. Mean age was 52 years (range: 16 to 83 years). All patients underwent 23-gauge pars plana vitrectomy with use of perfluorocarbon liquid and intravitreal tamponade (28 with silicone oil, 25 with octafluoropropane gas, and five with sulfur hexafluoride gas). Scleral buckle (SB) was placed in 30 eyes (52%). RESULTS: At a mean follow-up of 17 months, mean visual acuity improved from 20/500 preoperatively to 20/88 at final follow-up. Fifty-one patients (88%) had single-surgery anatomic success, and all patients achieved final retinal reattachment. Use of SB (P = 1.0), silicone oil (P = .1), or 360° endophotocoagulation (P = .7) did not correlate with higher rates of successful repair. CONCLUSION: Contemporary vitreoretinal surgery techniques achieve high rates of primary anatomic success in GRT-related RRDs.

Pars Plana Lensectomy After Femtosecond Laser-Assisted Cataract Surgery.

The use of femtosecond laser during cataract surgery is increasing, as it may potentially improve accuracy, safety and refractive outcomes. However, posterior capsule rupture with retained lens material can occur, necessitating vitreoretinal intervention. The authors report the first videographically documented case of removal of retained lens material after femtosecond laser-assisted cataract surgery.

Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion.

PURPOSE: To better characterize a novel spectral-domain optical coherence tomography (OCT) presentation, termed paracentral acute middle maculopathy, to describe this finding in patients with nonischemic central retinal vein occlusion (CRVO), and to support a proposed pathogenesis of intermediate and deep retinal capillary ischemia. DESIGN: Retrospective observational case series. METHODS: Clinical histories, high-resolution digital color imaging, red-free photography, fluorescein angiography, near-infrared reflectance, and spectral-domain OCT images of 484 patients with acute CRVO from 2 centers were evaluated for the presence of coexisting paracentral acute middle maculopathy. RESULTS: Of 484 patients diagnosed with CRVO, 25 (5.2%) demonstrated evidence of concurrent paracentral acute middle maculopathy. Patients averaged 51 years of age and presented with complaints of paracentral scotomas. All patients demonstrated hyper-reflective plaquelike lesions at the level of the inner nuclear layer by spectral-domain OCT and showed corresponding dark-gray lesions on near-infrared reflectance and perivenular deep retinal whitening on color fundus photography. There was no fluorescein angiographic correlate to these lesions. On follow-up spectral-domain OCT imaging, the lesions had resolved into areas of inner nuclear layer atrophy with persistence of scotomas. CONCLUSIONS: Paracentral acute middle maculopathy refers to characteristic hyper-reflective spectral-domain OCT lesions involving the middle layers of the retina at the level of the inner nuclear layer that may develop in response to ischemia of the intermediate and deep capillary plexuses. This series is the largest to describe this spectral-domain OCT finding to date, and it is the first to associate it with nonischemic CRVO.

The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection.

OBJECTIVE: To compare the incidence of endophthalmitis after intravitreal injection with and without topical postinjection antibiotic prophylaxis. DESIGN: Retrospective case-control study. PARTICIPANTS: All patients treated with intravitreal injection of ranibizumab, bevacizumab, or aflibercept for a variety of retinal vascular diseases at a single, large retina practice between January 1, 2009, and October 1, 2012, were included. METHODS: The total numbers of patients and injections were determined from a review of billing code and practice management records. Endophthalmitis cases were determined from billing records and from an infection log. All cases of endophthalmitis were confirmed with chart review. A 28-month period when topical antibiotics were prescribed after intravitreal injection was compared with a 9-month period when topical antibiotics were not prescribed. Patients treated during an 8-month transition period were excluded to allow for the conversion of antibiotic prescription practices. MAIN OUTCOME MEASURES: Incidence of endophthalmitis, visual acuity outcomes, and microbial spectrum. RESULTS: During the study period, a total of 117 171 intravitreal injections were performed (57 654 injections during the topical antibiotic period, 24 617 during the transition period, and 34 900 during the no-antibiotic period), with a total of 44 cases of suspected endophthalmitis (0.038%; 1 in 2663 injections), 17 of which showed culture-positive results (0.015%; 1 in 6892 injections). During the 28-month topical antibiotic period, there were 28 cases of suspected endophthalmitis (0.049%; 1 in 2059 injections), 10 of which showed culture-positive results (0.017%; 1 in 5765 injections). During the 9-month no-antibiotic period, there were 11 cases of suspected endophthalmitis (0.032%; 1 in 3173 injections), 4 of which showed culture-positive results (0.011%; 1 in 8725 injections). Topical antibiotic use was associated with a trend toward increased risk of suspected endophthalmitis (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.77-3.10) and culture-positive endophthalmitis (OR, 1.51; 95% CI, 0.47-4.83). CONCLUSIONS: The incidence of endophthalmitis after intravitreal injection is low. Using postinjection topical antibiotic drops does not reduce the risk of endophthalmitis developing and is associated with a trend toward higher incidence of endophthalmitis.