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.

Choroidal Changes After Anti-VEGF Therapy in AMD Eyes With Different Types of Macular Neovascularization Using Swept-Source OCT Angiography.

Purpose: Choroidal changes before and after anti-VEGF therapy were investigated in eyes with exudative AMD to determine if there was a difference between eyes with macular neovascularization (MNV) that arises from the choroid (type 1 or 2) versus the retinal circulation (type 3). Methods: Patients with treatment-naïve AMD were imaged with swept-source optical coherence tomography angiography using a 12 × 12-mm scan pattern. The mean choroidal thickness and choroidal vascularity index (CVI) were measured within 5-mm and 11-mm fovea-centered circles before, at the onset of, and after anti-VEGF therapy. Results: Forty-one eyes of 37 patients were included; 24 eyes with type 1 MNV, 4 eyes with type 2 MNV, and 13 eyes with type 3 MNV. Within the 5-mm and 11-mm circles, the mean choroidal thickness and CVI measurements increased from pretreatment to the onset of exudation (P ≤ 0.03). The mean choroidal thickness and CVI measurements decreased from the onset of exudation to after treatment (P < 0.001). No significant changes in mean choroidal thickness or CVI were observed when comparing measurements before or after treatment (P ≥ 0.38). No significant differences in mean choroidal thickness or CVI measurements were observed between eyes with type 1 or 2 MNV and type 3 MNV. Conclusions: In treatment-naïve AMD eyes with MNV, the choroidal thickness and vascularity increased at the onset of exudation and then decreased after anti-VEGF therapy. This finding suggests that these choroidal changes develop in response to the proangiogenic milieu before treatment and in response to treatment, regardless of the site of origin for the MNV.

Automated identification and quantification of activated dendritic cells in central cornea using artificial intelligence.

PURPOSE: To validate an algorithm quantifying activated dendritic cells (aDCs) using in-vivo confocal microscopy (IVCM) images. METHODS: IVCM images obtained at the Miami Veterans Affairs Hospital were retrospectively analyzed. ADCs were quantified both with an automated algorithm and manually. Intra-class-correlation (ICC) and a Bland-Altman plot were used to compare automated and manual counts. As a secondary analysis, individuals were grouped by Dry Eye (DE) subtype: 1) aqueous-tear deficiency (ATD; Schirmer's test ≤5 mm); 2) evaporative DE (EDE; TBUT≤5s); or 3) control (Schirmer's test>5 mm; TBUT>5s) and ICCs were re-examined. RESULTS: 173 non-overlapping images from 86 individuals were included in this study. The mean age was 55.2 ± 16.7 years; 77.9% were male; 20 had ATD; 18 EDE and 37 were controls. The mean number of aDCs in the central cornea quantified automatically was 0.83 ± 1.33 cells/image and manually was 1.03 ± 1.65 cells/image. A total of 143 aDCs were identified by the automated algorithm and 178 aDCs were identified manually. While a Bland-Altman plot indicated a small difference between the two methods (0.19, p < 0.01), the ICC of 0.80 (p = 0.01) demonstrated excellent agreement. Secondarily, similar results were found by DE type with an ICC of 0.75 (p = 0.01) for the ATD group, 0.80 (p = 0.01) for EDE, and 0.82 (p = 0.01) for controls. CONCLUSIONS: Quantification of aDCs within the central cornea may be successfully estimated using an automated machine learning based algorithm. While this study suggests that analysis using artificial intelligence has comparable results with manual quantification, further longitudinal research to validate our findings in more diverse populations may be warranted.

Clinical Factors Impacting Outcomes From Failed Trabeculectomy Leading to Glaucoma Drainage Device Implantation and Subsequent Penetrating Keratoplasty.

PRCIS: We evaluated the factors that impacted time from glaucoma drainage implant (GDI) surgery to penetrating keratoplasty (PK) in eyes with previously clear corneas (ie, GDI-first sequence), and that specifically underwent a trabeculectomy before GDI surgery for intraocular pressure (IOP) control. PURPOSE: To describe through an event-triggered data collection method the clinical course and the long-term outcomes of 2 procedures that are commonly performed sequentially in complex clinical situations: GDI surgery and PK. The study investigates the clinical factors associated with the progression to PK and determines the GDI success rate and graft survival. METHODS: A single, tertiary-care center retrospective interventional cases series including patients with a sequential history of trabeculectomy, GDI surgery, and PK from 1999 to 2009. Outcome measures included IOP, visual acuity, graft failure, GDI failure, and time from GDI to PK. RESULTS: Of the eyes, 56% had primary open angle glaucoma. The time from the last trabeculectomy to GDI was 66.5 ± 66.7 months. Of the eyes, 84% received a Baerveldt GDI. Time from GDI to PK was 36.4 ± 28.4 months. IOP at the time of PK was between 5 mm Hg and 21 mm Hg in 90% of eyes. At the last follow-up, 48% of grafts were clear. At 5 years post-PK, 33% of corneal grafts remained clear, whereas 81% of tubes remained functional. CONCLUSIONS: Nearly half of the corneal grafts are clear at the last long-term follow-up. Graft failure occurs at a higher rate than tube failure suggesting that IOP control is only one and possibly not the most important factor in graft survival in eyes with prior glaucoma surgery.

Decreased Central Macular Choriocapillaris Perfusion Correlates With Increased Low Luminance Visual Acuity Deficits.

PURPOSE: Correlations between low luminance visual acuity deficits (LLVADs) and central choriocapillaris perfusion deficits were investigated to help explain how increases in LLVAD scores at baseline predict annual growth rates of geographic atrophy (GA). DESIGN: Prospective cross-sectional study. METHODS: Photopic luminance best-corrected visual acuity (PL-BCVA) and low luminance BCVA (LL-BCVA) were measured using the Early Treatment Diabetic Retinopathy Study chart. LL-BCVA was measured using a 2.0-log unit neutral density filter. LLVADs were calculated as the difference between PL-BCVA and LL-BCVA. Within a fovea-centered 1-mm circle, the percentage of choriocapillaris flow deficits (CC FD%), drusen volume, optical attenuation coefficient (OAC) elevation volume, and outer retinal layer (ORL) thickness were assessed. RESULTS: In all 90 eyes (30 normal eyes; 31 drusen-only eyes; 29 non-foveal GA eyes), significant correlations were found between the central CC FD% and PL-BCVA (r = -0.393, P < .001), LL-BCVA (r = -0.534, P < .001), and the LLVAD (r = 0.439, P < .001). Central cube root (cubrt) drusen volume, cubrt OAC elevation volume, and ORL thickness were correlated with PL-BCVA, LL-BCVA, and LLVADs (all P < .05). Stepwise regression models showed that central cubrt OAC elevation volume and ORL thickness were associated with PL-BCVA (R2 = 0.24, P < .05); central CC FD%, cubrt OAC elevation volume, and ORL thickness were associated with LL-BCVA (R2 = 0.44, P < .01); and central CC FD% and ORL thickness were associated with LLVAD (R2 = 0.24, P < .01). CONCLUSIONS: The significant correlations between central CC FD% and LLVAD support the hypothesis that the ability of LLVAD to predict the growth of GA is mediated through a decrease in macular choriocapillaris perfusion.

Symmetry of Macular Fundus Features in Age-Related Macular Degeneration.

PURPOSE: The symmetry of major macular fundus features in both eyes of the same patient with age-related macular degeneration (AMD) was investigated using swept-source(SS)-OCT. DESIGN: Retrospective review of a prospective study. PARTICIPANTS: Patients with AMD. METHODS: Grading was performed on the first SS-OCT images obtained on the patients. Two graders diagnosed the presence of drusen, geographic atrophy (GA), and exudative AMD (eAMD) in each eye. Medical records were reviewed to assess prior exudation. To assess symmetry, 1 eye of each patient was randomly selected as the index eye and compared with the fellow eye. The kappa statistic (κ) was used to assess the symmetry of diagnosis. The intraclass correlation coefficient (ICC) was used to assess the symmetry of drusen area and volume. MAIN OUTCOME MEASURES: Interocular symmetry of the AMD stages: drusen, GA, and eAMD. RESULTS: A total of 1310 patients with AMD were included. The average age was 78 years (range, 50-102; 60% women). Of the 1310 subjects, 54% (701) presented with symmetric disease: 20% with bilateral drusen, 11% with bilateral GA, and 22% with bilateral eAMD. Only 0.5% of the subjects had both GA and eAMD in both eyes. Of the randomly selected index eyes, 825 (47%) were right eyes. Overall, limited interocular agreement was observed between the index and fellow eyes (54%; κ = 0.29). Kappa coefficients were poor (< 0.4) for index eyes diagnosed with drusen (κ = 0.27), eAMD (κ = 0.17), and mixed disease (κ = 0.03). There was moderate agreement between the index and fellow eyes for GA (κ = 0.50). Of the 265 patients with bilateral drusen, the symmetry of drusen area measurements had moderate ICC values of 0.70, 0.71, and 0.70 in the 3- and 5-mm diameter foveal-centered circles and in the total scan area, respectively. The ICC values for the drusen volumes were 0.65, 0.66, and 0.64, respectively. CONCLUSIONS: Interocular symmetry was poor for eyes with drusen, eAMD, and mixed disease, but moderate for GA. Although the diagnosis of drusen was not very symmetric between eyes, when present in both eyes, the drusen area and volume measurements were moderately symmetric. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Detection of Nonexudative Macular Neovascularization on Structural OCT Images Using Vision Transformers.

Purpose: A deep learning model was developed to detect nonexudative macular neovascularization (neMNV) using OCT B-scans. Design: Retrospective review of a prospective, observational study. Participants: Normal control eyes and patients with age-related macular degeneration (AMD) with and without neMNV. Methods: Swept-source OCT angiography (SS-OCTA) imaging (PLEX Elite 9000, Carl Zeiss Meditec, Inc) was performed using the 6 × 6-mm scan pattern. Individual B-scans were annotated to distinguish between drusen and the double-layer sign (DLS) associated with the neMNV. The machine learning model was tested on a dataset graded by humans, and model performance was compared with the human graders. Main Outcome Measures: Intersection over Union (IoU) score was measured to evaluate segmentation network performance. Area under the receiver operating characteristic curve values, sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) were measured to assess the performance of the final classification performance. Chance-corrected agreement between the algorithm and the human grader determinations was measured with Cohen's kappa. Results: A total of 251 eyes from 210 patients, including 182 eyes with DLS and 115 eyes with drusen, were used for model training. Of 125 500 B-scans, 6879 B-scans were manually annotated. A vision transformer segmentation model was built to extract DLS and drusen from B-scans. The extracted prediction masks from all B-scans in a volume were projected to an en face image, and an eye-level projection map was obtained for each eye. A binary classification algorithm was established to identify eyes with neMNV from the projection map. The algorithm achieved 82%, 90%, 79%, and 91% sensitivity, specificity, PPV, and NPV, respectively, on a separate test set of 100 eyes that were evaluated by human graders in a previous study. The area under the curve value was calculated as 0.91 (95% confidence interval, 0.85-0.98). The results of the algorithm showed excellent agreement with the senior human grader (kappa = 0.83, P < 0.001) and moderate agreement with the junior grader consensus (kappa = 0.54, P < 0.001). Conclusions: Our network (code is available at https://github.com/uw-biomedical-ml/double_layer_vit) was able to detect the presence of neMNV from structural B-scans alone by applying a purely transformer-based model.

Impact of Cataract Surgery on Low Luminance Visual Acuity Deficit Measurements.

Purpose: The impact of cataract surgery on low luminance visual acuity deficit (LLVAD) measurements was investigated by measuring the LLVAD before and after cataract surgery. Design: Prospective, longitudinal study. Participants: Patients undergoing cataract surgery. Methods: Photopic luminance (PL)-best-corrected visual acuity (BCVA) and low luminance (LL)-BCVA were obtained using the ETDRS chart. Low luminance visual acuity deficit scores were calculated by subtracting the LL-BCVA letter score from the PL-BCVA letter score. To demonstrate the reproducibility of these visual acuity measurements, we used data from drusen-only eyes previously published in the Complement Inhibition with Eculizumab for the Treatment of Nonexudative Age-Related Macular Degeneration (COMPLETE) study. The PL-BCVA, LL-BCVA, and LLVAD measurements obtained at an interval of 3 months in this cohort were used for comparison. In the current study, the impact of cataract surgery on LLVAD measurements was analyzed by comparing the PL-BCVA, LL-BCVA, and LLVAD measurements before and after cataract surgery. Main Outcome Measures: The reproducibility of the visual acuity measurements and the changes in LLVAD measurement after cataract surgery. Results: In the COMPLETE study, no clinically significant differences were found in the PL-BCVA, LL-BCVA, or LLVAD measurements between baseline and the 3-month follow-up visits with a change of -1.1 letters, -1.3 letters, and 0.1 letters, respectively (P = 0.02, P = 0.11, and P = 0.88, respectively). In the current study, significant increases were found in the PL-BCVA and LL-BCVA measurements, with a change of 7.3 letters and 10.2 letters after cataract surgery (P < 0.001 for both), and a statistically significant decrease in LLVAD measurements was found, with a change of -3.0 letters after cataract surgery (P = 0.002). Conclusions: Because of the variable effect of cataracts on LL-BCVA measurements and the significant change in LLVAD measurements after cataract surgery, investigators should be aware that cataract surgery during a trial will have an unpredictable impact on LLVAD measurements, and pseudophakic and phakic patients should be analyzed separately.

CHANGE IN CHORIOCAPILLARIS FLOW DEFICITS WITHIN TEARS OF THE RETINAL PIGMENT EPITHELIUM IMAGED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: Choriocapillaris (CC) flow deficits (FDs) were measured in the areas exposed by tears of the retinal pigment epithelium (RPE) before and after their onset to determine their change over time. METHODS: Patients enrolled in a prospective, swept-source optical coherence tomography angiography (SS-OCTA) study were retrospectively reviewed for RPE tears, and scans were evaluated before and after RPE tear formation. Choriocapillaris flow deficits were measured within the bed of the tear and within a symmetric control region. RESULTS: Three patients with RPE tears were imaged before tear formation and for at least 16 months afterward. When the baseline and first posttear visit were compared, CC FDs decreased by 1.0% in the tear region and 1.7% in the control region ( P = 0.84). When the 16-month follow-up visits were compared with the first post-RPE tear visits, CC FDs decreased by 1.9% in tear regions and increased by 1.3% in control regions ( P = 0.37). CONCLUSION: No significant changes in CC FDs were observed before and after RPE tear formation and for 16 months afterward, suggesting that CC FDs can be reliably detected in the presence of an intact RPE and the absence of the RPE did not affect CC perfusion for at least 16 months.

Does the Outer Retinal Thickness Around Geographic Atrophy Represent Another Clinical Biomarker for Predicting Growth?

PURPOSE: To determine whether the outer retinal layer (ORL) thickness around geographic atrophy (GA) could serve as a clinical biomarker to predict the annual enlargement rate (ER) of GA. DESIGN: Retrospective analysis of a prospective, observational case series. METHODS: Eyes with GA were imaged with a swept-source OCT 6 × 6 mm scan pattern. GA lesions were measured from customized en face OCT images and the annual ERs were calculated. The ORL was defined and segmented from the inner boundary of outer plexiform layer (OPL) to the inner boundary of retinal pigment epithelium (RPE) layer. The ORL thickness was measured at different subregions around GA. RESULTS: A total of 38 eyes from 27 participants were included. The same eyes were used for the choriocapillaris (CC) flow deficit (FD) analysis and the RPE to the Bruch membrane (RPE-BM) distance measurements. A negative correlation was observed between the ORL thickness and the GA growth. The ORL thickness in a 300-µm rim around GA showed the strongest correlation with the GA growth (r = -0.457, P = .004). No correlations were found between the ORL thickness and the CC FDs; however, a significant correlation was found between the ORL thickness and the RPE-BM distances around GA (r = -0.398, P = .013). CONCLUSIONS: ORL thickness showed a significant negative correlation with annual GA growth, but also showed a significant correlation with the RPE-BM distances, suggesting that they were dependently correlated with GA growth. This finding suggests that the loss of photoreceptors was associated with the formation of basal laminar deposits around GA.

Postoperative Complications in the Primary Tube Versus Trabeculectomy Study During 5 Years of Follow-up.

PURPOSE: To describe postoperative complications encountered in the Primary Tube Versus Trabeculectomy (PTVT) Study during 5 years of follow-up. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: A total of 242 eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 patients in the tube group and 117 patients in the trabeculectomy group. METHODS: Patients were enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC, 0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: Surgical complications, reoperations for complications, visual acuity, and cataract progression. RESULTS: Early postoperative complications occurred in 24 patients (19%) in the tube group and 40 patients (34%) in the trabeculectomy group (P = 0.013). Late postoperative complications developed in 27 patients (22%) in the tube group and 32 patients (27%) in the trabeculectomy group (P = 0.37). Serious complications producing vision loss and/or requiring a reoperation were observed in 3 patients (2%) in the tube group and 9 patients (8%) in the trabeculectomy group (P = 0.11). Cataract progression was seen in 65 patients (52%) in the tube group and 52 patients (44%) in the trabeculectomy group (P = 0.30). Surgical complications were not associated with a higher rate of treatment failure (P = 0.61), vision loss (P = 1.00), or cataract progression (P = 0.77) CONCLUSIONS: A large number of surgical complications were observed in the PTVT Study, but most were transient and self-limited. The incidence of early postoperative complications was higher following trabeculectomy with MMC than with tube shunt surgery. The rates of late postoperative complications, serious complications, and cataract progression were similar with both surgical procedures after 5 years of follow-up. Surgical complications did not increase the risk of treatment failure, vision loss, or cataract progression.

Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 5 Years of Follow-up.

PURPOSE: To report 5-year treatment outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: A total of 242 eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 patients in the tube group and 117 patients in the trabeculectomy group. METHODS: Patients were enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC) (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: The primary outcome measure was the rate of surgical failure, defined as intraocular pressure (IOP) > 21 mmHg or reduced < 20% from baseline, IOP ≤ 5 mmHg, reoperation for glaucoma, or loss of light perception. Secondary outcome measures included IOP, glaucoma medical therapy, and visual acuity. RESULTS: The cumulative probability of failure after 5 years of follow-up was 42% in the tube group and 35% in the trabeculectomy group (P = 0.21; hazard ratio = 1.31; 95% confidence interval = 0.86-2.01). At 5 years, IOP (mean ± standard deviation) was 13.4 ± 3.5 mmHg in the tube group and 13.0 ± 5.2 mmHg in the trabeculectomy group (P = 0.52), and the number of glaucoma medications (mean ± standard deviation) was 2.2 ± 1.3 in the tube group and 1.3 ± 1.4 in the trabeculectomy group (P < 0.001). CONCLUSIONS: Trabeculectomy with MMC and tube shunt surgery produced similar IOPs after 5 years of follow-up in the PTVT Study, but fewer glaucoma medications were required after trabeculectomy. No significant difference in the rate of surgical failure was observed between the 2 surgical procedures at 5 years.

Neoadjuvant Intra-Arterial Cytoreductive Chemotherapy for Lacrimal Gland Adenoid Cystic Carcinoma: A Long-Term Follow-up Study of a Trimodal Strategy.

PURPOSE: To report the therapeutic efficacy of integrating neoadjuvant chemotherapy with conventional bimodal therapies for lacrimal gland adenoid cystic carcinoma by providing an additional 8 years of follow-up data on the same cohort of patients whose cumulative 10-year disease-free survival outcomes were reported in 2013. DESIGN: Non-randomized, retrospective, interventional case series. METHODS: Nineteen consecutive patients treated with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC), orbital exenteration, chemoradiotherapy, and adjuvant intravenous chemotherapy at a single institution were included. Analyses were undertaken of locoregional recurrences and distant metastases, disease-free survival time, TNM tumor stage at presentation, response to IACC, and prognostic impact of positive resection margins. The main outcome measures were overall survival, disease-free survival, disease relapse, positive tumor resection margins, and tumor stage at presentation. RESULTS: Eight patients with an intact lacrimal artery (group 1), 7 with AJCC stage T4a-c, had significantly better overall survival (87.5% versus 14.3% at 15 years), disease-specific mortality, and recurrences (all < .001, log-rank test) than prior conventionally treated patients from the Bascom Palmer Eye Institute. Group 1 was superior to group 2, patients lacking an intact lacrimal artery, concerning overall survival (P = .042) and recurrence (P = .017), but with no significant difference in disease-specific mortality (P = .23). Group 2 was associated with a significantly lower cause-specific mortality than the institutional comparator group (P = .039). Prior tumor resection with lateral wall osteotomy and failure to adhere to all protocol elements were adverse prognostic factors for suboptimal outcomes. Positive tumor margins increased the risk of all-cause mortality 4.1 times (P = .036, stratified Cox proportional hazards regression) and disease-specific mortality 8.0 times (P = .043, stratified Cox proportional hazards regression) than a patient with negative margins. CONCLUSIONS: Extended follow-up supplemented with AJCC staging data supports neoadjuvant IACC as an integral component of a trimodal treatment strategy in patients with an intact lacrimal artery. Protocol elements implemented as designed appear to have improved overall survival and decreased disease relapse in this cohort. This extended long-term IACC dataset suggests that a critical bar of at least 15 years of follow-up is appropriate for assessing the efficacy of current conventional and future globe-sparing bimodal therapies.

Risk Factors for Failure of Tube Shunt Surgery: A Pooled Data Analysis.

PURPOSE: To identify the risk factors associated with failure of tube shunt surgery. DESIGN: Pooled analysis of 3 prospective multicenter, randomized clinical trials. METHODS: A total of 621 patients with medically uncontrolled glaucoma were enrolled, including 276 from the Ahmed Baerveldt Comparison Study, 238 from the Ahmed Versus Baerveldt Study, and 107 from the tube group of the Tube Versus Trabeculectomy Study. Patients were randomized to treatment with an Ahmed glaucoma valve (model FP7) or Baerveldt glaucoma implant (model 101-350). The associations between baseline risk factors and tube shunt failure were assessed using a Cox proportional hazards regression model. The primary outcome measure was the rate of surgical failure defined as intraocular pressure (IOP) > 21 mmHg or reduced < 20% from baseline, IOP ≤ 5 mmHg, loss of light perception vision, reoperation for glaucoma, or removal of implant. RESULTS: The cumulative probability of failure after tube shunt surgery was 38.3% after 5 years. In multivariable analyses, baseline factors that predicted tube shunt failure included preoperative IOP (≤ 21 mmHg compared to IOP > 21 and ≤ 25 mmHg; HR, 2.34; 95% CI, 1.52-3.61; P < .001), neovascular glaucoma (HR, 1.79; 95% CI, 1.28-2.52; P = .001), randomized treatment (for Ahmed glaucoma valve; HR, 1.36; 95% CI, 1.04-1.78; P = .025), and age (for 10 year decrease in age; HR, 1.19; 95% CI, 1.09-1.31; P < .001). CONCLUSIONS: Lower preoperative IOP, neovascular glaucoma, Ahmed implantation, and younger age were predictors of tube shunt failure. This Study provides the largest prospectively collected dataset on tube shunt surgery.

The Relationship Between Stage of Leber's Hereditary Optic Neuropathy and Pattern Electroretinogram Latency.

Purpose: The purpose of this study was to compare the baseline steady-state pattern electroretinogram (SS-PERG) of patients with G11778A Leber hereditary optic neuropathy (LHON) with different stages of visual acuity (VA) loss before allotopic gene therapy (GT). Methods: Patients (n = 28) were enrolled into groups (GT I: chronic bilateral VA ≤35 Early Treatment Diabetic Retinopathy Study [ETDRS]; GT II: acute bilateral VA ≤35 ETDRS; GT III: acute unilateral, VA ≤35 ETDRS, and better eye VA ≥70 ETDRS) and tested with SS-PERG together with 210 age-matched normal controls (NCs). SS-PERG amplitude (nV) and latency (ms) of each eye were averaged for groups GT I, GT II, and NC. Symptomatic eyes (GT III-S) and asymptomatic eyes (GT III-A) of group GT III were included separately and accounted for by using generalized estimating equation (GEE) methods. Results: Compared to NC, SS-PERG amplitudes were reduced similarly by approximately 50% (P < 0.001) among all GT groups (NC > GT I, GT II, GT III-S, and GT III-A). SS-PERG latencies were shorter by ≥3.5 ms in all LHON groups and differed by disease stage (G III-A < NC, P = 0.002; GT III-S < GT III-A, P = 0.01; GT II < GT III-S, P = 0.03; GT I < NC, P < 0.001, but not different from other GT groups, all P > 0.1). Conclusions: Although SS-PERG amplitude reduction did not distinguish between disease stages, SS-PERG latency shortening occurred in asymptomatic eyes and symptomatic eyes and distinguished between disease stages. Translational Relevance: SS-PERG latency shortening is consistent with primary damage of smaller/slower axons and sparing of larger/faster axons and may provide an objective staging of LHON, which may be helpful to determine efficacy in LHON trials.

Optical coherence tomography angiography in the evaluation of vascular patterns of ocular surface squamous neoplasia during topical medical treatment.

PURPOSE: Optical coherence tomography angiography (OCTA) was utilized to examine changes in ocular surface squamous neoplasia (OSSN) vascular patterns over time in individuals treated with topical medical therapy. METHODS: Ten individuals with OSSN diagnosed by clinical examination and high resolution (HR)-optical coherence tomography (OCT) were recruited. All individuals received topical immuno- or chemotherapy. OCTA images were obtained and analyzed at three points: presentation, mid-treatment and tumor resolution. Tumor metrics including tumor area (TA), tumor volume (TV), tumor depth (TD), and total tumor density (TTD) were calculated. Vessel area density (VAD) was also quantified within the OSSN, the subepithelium under and adjacent to the OSSN and the subepithelium of the uninvolved, contralateral eye. Vascular network changes were also subjectively evaluated. RESULTS: TA, TV, TD and TTD all significantly decreased with time (p < 0.001). The mean VAD within the OSSN significantly decreased (p < 0.001) between visits (presentation: 26.52 ± 6.8%, mid-treatment: 7.19 ± 5.88%, tumor resolution: 0.11 ± 0.34%). The mean subepithelial VAD under the OSSN also decreased with time (23.22 ± 11.03%, 20.99 ± 5.99% and 19.58 ± 7.08%), and after resolution the sub-tumor VAD (19.58 ± 7.08%) was comparable to the subepithelial VAD in the contralateral eye (15.47 ± 4.37%, p > 0.05). The mean VAD in the subepithelium adjacent to the OSSN increased with treatment, then decreased significantly between mid-treatment and resolution (23.26 ± 4.54, 28.30 ± 7.43% and 21.68 ± 6.10%, p = 0.009). Qualitatively, the tumor subepithelial vascular network was complex and dense but with tumor resolution appeared less tortuous and similar to the uninvolved eye. CONCLUSION: OCTA provided insight into the pathophysiology of tumor angiogenesis, showing decreased vascular density and normalization of vascular networks associated with tumor resolution.

Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups.

PURPOSE: To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). DESIGN: Phase 1 clinical trial. METHODS: Setting: single institution. PARTICIPANTS: Patients with G11778A LHON and 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). INTERVENTION: 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. OUTCOME MEASURES: Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes. RESULTS: Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P < .001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment. CONCLUSIONS: G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye.

Interocular asymmetry of choroidal thickness and vascularity index measurements in normal eyes assessed by swept-source optical coherence tomography.

BACKGROUND: To investigate the symmetry of interocular choroidal thickness and vascularity index measurements in normal eyes using swept-source optical coherence tomography (SS-OCT). Cross-sectional and observational study. This study included 244 eyes of 122 normal adults with ages uniformly distributed from 19 to 89 years. METHODS: SS-OCT imaging was performed using a scanning pattern of 12×12 mm. Mean choroidal thickness (MCT) and choroidal vascularity index (CVI) measurements in the entire scanning region were obtained using a validated and published automatic method. The correlation and differences (including signed and absolute differences) between bilateral MCT and CVI measurements were analyzed at the following 6 regions: 3 concentric circles centered on the fovea with diameters of 2.5, 5, and 11 mm; the inner rim from 2.5 to 5 mm circle; the outer rim from 5 to 11 mm circle; and the entire 12×12-mm scan region, respectively. Comparison of interocular MCT and CVI measurements. RESULTS: MCT measurements in right and left eyes were strongly correlated in all regions [all intraclass correlation (ICC) >0.73], but MCT measurements in right eyes were significantly thicker than in left eyes. CVI measurements in right and left eyes were moderately correlated in all regions (all ICC >0.46), but CVI measurements in right eyes were significantly smaller than that in left eyes in the macular subregions (2.5 mm circle, 5 mm circle, and the inner rim). Neither signed nor absolute interocular differences in MCT were correlated with corresponding CVI interocular differences. CONCLUSIONS: Choroidal differences exist between normal fellow eyes in adults in the absence of obvious pathology. This study is useful in assisting clinicians and researchers in distinguishing asymmetric changes that are to be expected in normal eyes versus changes that could be associated with diseases.

Diagnosing Persistent Hypertransmission Defects on En Face OCT Imaging of Age-Related Macular Degeneration.

PURPOSE: A training exercise was performed to study the ability of graders to reliably identify precursor lesions to geographic atrophy (GA), known as persistent choroidal hypertransmission defects (hyperTDs), using en face OCT images from eyes with nonexudative age-related macular degeneration (AMD). DESIGN: Intergrader agreement study. PARTICIPANTS: Eleven graders participated in this exercise. METHODS: Formal training on how to identify persistent hyperTDs on en face OCT images was provided to the graders. A persistent hyperTD was defined as a bright lesion having a greatest linear dimension (GLD) of at least 250 µm. Training consisted of a tutorial session followed by the grading of 3 pretest exercises, each consisting of 3 cases. After all graders scored 100% on the pretest exercises, they performed a final exercise consisting of 30 en face OCT images from 29 eyes with nonexudative AMD containing 107 hyperTDs that each grader needed to evaluate. The cases contained a variety of AMD-related atrophic lesions. MAIN OUTCOME MEASURES: The sensitivity, positive predictive value (PPV), and modified accuracy were assessed for each grader. RESULTS: A total of 1177 hyperTDs from 30 en face OCT images were reviewed by the graders. The mean sensitivity, PPV, and modified accuracy for all the graders were calculated to be 99.0%, 99.2%, and 98.2%, respectively. There was a 97% agreement observed between all the graders (first-order agreement coefficient [AC1] = 0.97). Internal graders from the Bascom Palmer Eye Institute had a slightly higher agreement compared with the external graders (AC1 = 0.98 vs. AC1 = 0.96). The hyperTDs most often incorrectly identified included the following features: (1) hyperTDs containing hypotransmission defect cores, (2) single hyperTDs that were incorrectly graded as 2 separate lesions, and (3) hyperTDs with borderline GLDs that were close to 250 µm. CONCLUSIONS: The accurate detection of persistent hyperTDs on en face OCT images by graders demonstrates the feasibility of using this OCT biomarker to identify disease progression in eyes with nonexudative AMD, especially when used as a clinical trial end point in studies designed to test new therapies that may slow disease progression from intermediate AMD to GA.