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.

LONGITUDINAL ANALYSIS OF DIABETIC CHOROIDOPATHY IN PROLIFERATIVE DIABETIC RETINOPATHY TREATED WITH PANRETINAL PHOTOCOAGULATION USING WIDEFIELD SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Widefield swept-source optical coherence tomography (OCT) imaging was used to characterize choroidal thickness and vascularity at baseline in proliferative diabetic retinopathy (PDR) and longitudinally after panretinal photocoagulation (PRP). METHODS: Patients with treatment-naive PDR were imaged at baseline and at 1 week, 1 month, and 3 months after PRP. Previously validated algorithms were used to calculate the mean choroidal thickness (MCT) and choroidal vascularity index (CVI) in 5 regions of 12 mm × 12 mm scans. RESULTS: Fourteen PDR eyes were included. Baseline MCT in PDR eyes did not differ significantly from normal eyes, but CVI measurements in PDR eyes were lower in all regions (P < 0.001-0.008). After PRP, MCT measurements in PDR eyes were significantly lower at 1 month and 3 months in all regions (P < 0.001-0.005) except the fovea (P = 0.074). However, CVI measurements did not change over time in any region after PRP. CONCLUSION: The choroid in PDR eyes has a smaller CVI than that in normal eyes. After PRP, the choroidal thickness decreases outside the fovea, but the CVI remains constant, which suggests that a relative decrease in choroidal vascularity persists. These widefield swept-source OCT results are consistent with choroidal alterations found in histopathological reports of diabetic choroidopathy.

Visual Field Outcomes in the Tube Versus Trabeculectomy Study.

PURPOSE: To describe visual field (VF) outcomes in the Tube Versus Trabeculectomy (TVT) Study. DESIGN: Cohort analysis of patients in a multicenter randomized clinical trial. PARTICIPANTS: A total of 122 eyes of 122 patients, with 61 eyes in both the tube shunt and trabeculectomy groups. METHODS: The TVT Study is a multicenter randomized clinical trial comparing the safety and efficacy of tube shunt surgery (350-mm2 Baerveldt implant) and trabeculectomy with mitomycin C (MMC) (0.4 mg/ml for 4 minutes) in patients with previous cataract or glaucoma surgery. Enrolled patients underwent perimetry at baseline and annual follow-up visits. The VFs were included if the false-positive rate was ≤20% and false-negative rate was ≤35%. The VFs were excluded if visual acuity <20/400 or loss of ≥2 Snellen lines from baseline was attributed to an etiology other than glaucoma. Longitudinal linear mixed-effects models with best linear unbiased predictions (BLUPs) were applied to estimate rates of change in mean deviation (MD) for each treatment group. MAIN OUTCOME MEASURE: Rate of MD change during follow-up period. RESULTS: A total of 436 reliable VFs were analyzed, with an average of 3.6 VFs per eye. Baseline MD was -13.07 ± 8.4 decibels (dB) in the tube shunt group and -13.18 ± 8.2 dB in the trabeculectomy group (P = 0.99). The rate of change in MD was -0.60 dB/year in the tube group and -0.38 dB/year in the trabeculectomy group (P = 0.34). The 95% confidence intervals for the rates of MD change were -0.77 to -0.44 dB/year in the tube group and -0.56 to -0.20 dB/year in the trabeculectomy group. No significant difference in MD slope was seen when patients were categorized by percentage of visits with intraocular pressure (IOP) <18 mmHg or by average IOP. Univariable and multivariable risk factor analyses identified history of diabetes, elevated IOP, and worse MD as baseline factors associated with more rapid VF loss. CONCLUSIONS: Slow rates of VF loss were observed after randomized surgical treatment in the TVT Study, but no significant difference in the rate of VF loss was seen after tube shunt implantation and trabeculectomy with MMC. Patients with diabetes, higher IOP, and more severe VF loss at baseline were at higher risk for VF progression.

Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 3 Years of Follow-up.

PURPOSE: To report 3-year results of the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Unmasked multicenter randomized clinical trial. PARTICIPANTS: Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. METHODS: Patients were enrolled at 16 clinical centers and were assigned randomly 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) of more than 21 mmHg or reduced less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures included IOP, glaucoma medical therapy, visual acuity, and surgical complications. RESULTS: The cumulative probability of failure after 3 years of follow-up was 33% in the tube group and 28% in the trabeculectomy group (P = 0.17; hazard ratio, 1.39; 95% confidence interval, 0.9-2.2). Mean ± standard deviation IOP was 14.0±4.2 mmHg in the tube group and 12.1±4.8 mmHg in the trabeculectomy group at 3 years (P = 0.008), and the number of glaucoma medications was 2.1±1.4 in the tube group and 1.2±1.5 in the trabeculectomy group (P < 0.001). Serious complications requiring reoperation or producing loss of 2 or more Snellen lines developed in 3 patients (2%) in the tube group and 9 patients (8%) in the trabeculectomy group (P = 0.11). CONCLUSIONS: There was no significant difference in the rate of surgical failure between the 2 surgical procedures at 3 years. Trabeculectomy with MMC achieved lower IOP with use of fewer glaucoma medications compared with tube shunt surgery after 3 years of follow-up in the PTVT Study. Serious complications producing vision loss or requiring reoperation occurred with similar frequency after both surgical procedures.

Long-term PERG monitoring of untreated and treated glaucoma suspects.

PURPOSE: To investigate long-term structural and functional progression of untreated and treated glaucoma suspects (UGS and TGS). METHODS: Retrospective analysis of serial steady-state pattern electroretinogram (PERG), mean retinal nerve fiber layer thickness (RNFLT), and standard automated perimetry mean deviation (SAP-MD) in UGS (N = 20) and TGS (N = 18). Outcome measures were the rates of change (linear regression slopes) of PERG amplitude, PERG phase, mean RNFLT, and SAP-MD over 9.8 ± 1.3 years (15.6 ± 4.2 visits). RESULTS: The number of patients with significant (P < 0.05) progression slopes for PERG amplitude, PERG phase, RNFLT, and SAP-MD was, respectively, UGS: 5, 0, 4, 2; TGS: 8, 2, 6, 5. In UGS, outcome measures were not correlated with each other. In TGS, both PERG amplitude and RNFLT were significantly (P < 0.05) correlated with SAP-MD (R ≥ 0.58), while PERG amplitude and RNFLT were not correlated with each other (R = 0.43, P = 0.064). The rate of change of SAP-MD was predicted (P < 0.05) by a linear combination of RNFLT slope and PERG amplitude slope. CONCLUSIONS: Results substantiate and extend previous results showing that steady-state PERG amplitude progressively decreased over time in a proportion of glaucoma suspects, with relatively steeper slope in TGS compared to UGS. RNFLT progression also had a steeper slope in TGS compared to UGS; however, progressions of PERG amplitude and RNFLT were not significantly correlated. Both PERG progression and RNFLT progression independently contribute to prediction of visual field progression.

Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 1 Year of Follow-up.

PURPOSE: To report 1-year treatment outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. METHODS: Patients were enrolled at 16 clinical centers and assigned randomly 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: Intraocular pressure (IOP), glaucoma medical therapy, visual acuity, visual fields, surgical complications, and failure (IOP of more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision). RESULTS: The cumulative probability of failure during the first year of follow-up was 17.3% in the tube group and 7.9% in the trabeculectomy group (P = 0.01; hazard ratio, 2.59; 95% confidence interval, 1.20-5.60). Mean ± standard deviation IOP was 13.8±4.1 mmHg in the tube group and 12.4±4.4 mmHg in the trabeculectomy group at 1 year (P = 0.01), and the number of glaucoma medications was 2.1±1.4 in the tube group and 0.9±1.4 in the trabeculectomy group (P < 0.001). Postoperative complications developed in 36 patients (29%) in the tube group and 48 patients (41%) in the trabeculectomy group (P = 0.06). Serious complications requiring reoperation or producing a loss of 2 Snellen lines or more occurred in 1 patient (1%) in the tube group and 8 patients (7%) in the trabeculectomy group (P = 0.03). CONCLUSIONS: Trabeculectomy with MMC had a higher surgical success rate than tube shunt implantation after 1 year in the PTVT Study. Lower IOP with use of fewer glaucoma medications was achieved after trabeculectomy with MMC compared with tube shunt surgery during the first year of follow-up. The frequency of serious complications producing vision loss or requiring reoperation was lower after tube shunt surgery relative to trabeculectomy with MMC.

The Primary Tube Versus Trabeculectomy Study: Methodology of a Multicenter Randomized Clinical Trial Comparing Tube Shunt Surgery and Trabeculectomy with Mitomycin C.

PURPOSE: To describe the methodology of the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Patients with medically uncontrolled glaucoma and no prior incisional ocular surgery. METHODS: Patients are being enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: The primary outcome measure is the rate of surgical failure, defined as intraocular pressure (IOP) more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures include IOP, glaucoma medical therapy, visual acuity, visual fields, and surgical complications. CONCLUSIONS: Practice patterns vary in the surgical management of glaucoma, and opinions differ among surgeons regarding the preferred primary operation for glaucoma. The PTVT Study will provide valuable information comparing the 2 most commonly performed glaucoma surgical procedures.

INTRAVITREAL OCRIPLASMIN IN CLINICAL PRACTICE: Predictors of Success, Visual Outcomes, and Complications.

PURPOSE: To investigate predictors of success, visual outcomes, and complications of intravitreal ocriplasmin for the treatment of symptomatic vitreomacular adhesion in a clinical care setting. METHODS: Retrospective chart review of 49 consecutive eyes of 47 patients who received intravitreal ocriplasmin. Spectral domain optical coherence tomography scans were examined for vitreomacular traction (VMT) release, full-thickness macular hole (FTMH) closure, and other changes in retinal anatomy. RESULTS: Pharmacologic VMT release occurred in 41% of eyes; positive predictors included age ≤75 years (P = 0.001), phakic status (P = 0.016), VMT width ≤750 µm (P = 0.001), and absence of retinal comorbidities (P = 0.035). Pharmacologic FTMH closure occurred in 25% of cases; positive predictors included successful VMT release (P = 0.042), better preinjection best-corrected visual acuity (P = 0.036), and smaller FTMH aperture width (P = 0.033). Eyes that achieved VMT release and did not undergo surgery attained significant improvement in best-corrected visual acuity (P = 0.015). Complications included subfoveal lucency (33%), ellipsoid zone disruption (33%), and FTMH base enlargement (75%). Only FTMH base enlargement resulted in worse visual outcomes (P = 0.024). Subgroup analysis of 14 eyes with ideal characteristics (all positive predictors listed above) yielded a 93% VMT release rate. CONCLUSION: Proper case selection may facilitate successful pharmacologic vitreolysis with ocriplasmin, improve visual outcomes, and minimize potential complications.

The Association of Dry Eye Symptom Severity and Comorbid Insomnia in US Veterans.

PURPOSE: To investigate the association between dry eye (DE) and insomnia symptom severity. METHODS: Cross-sectional study of 187 individuals seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding insomnia (insomnia severity index [ISI]) and DE symptoms, including ocular pain, followed by a comprehensive ocular surface examination. Using a two-step cluster analysis based on intensity ratings of ocular pain, the patient population was divided into two groups (high and low ocular pain groups: HOP and LOP). A control group was ascertained at the same time from the same clinic as defined by no symptoms of DE (Dry Eye Questionnaire 5 [DEQ5], <6). The main outcome measure was the frequency of moderate or greater insomnia in the DE groups. RESULTS: The mean age of the study sample was 63 years, and 93% were male. All insomnia complaints were rated higher in the HOP group compared with the LOP and control groups (P<0.0005). Most (61%) individuals in the HOP group experienced insomnia of at least moderate severity (ISI≥15) compared with the LOP (41%) and control groups (18%) (P<0.0005). Black race (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2-6.0; P=0.02), depression severity (OR, 1.2; 95% CI, 1.1-1.3; P<0.0005), and DE symptom severity (DEQ5; OR, 1.1; 95% CI, 1.01-1.2; P=0.03) were significantly associated with clinical insomnia (ISI≥15) after controlling for potential confounders. CONCLUSIONS: After adjusting for demographics and medical comorbidities, we show that DE symptom severity is positively associated with insomnia severity.

Comparison of graft survival following penetrating keratoplasty and Descemet's stripping endothelial keratoplasty in eyes with a glaucoma drainage device.

PURPOSE: To compare corneal graft survival rates after penetrating keratoplasty (PK) and Descemet's stripping endothelial keratoplasty (DSEK) in patients with a glaucoma drainage device (GDD) or medically managed glaucoma. METHODS: A retrospective chart review was conducted on consecutive patients who underwent primary PK or primary DSEK. Inclusion criteria consisted of eyes with a diagnosis of glaucoma prior to corneal transplantation and a minimum of 6 months of follow-up. Graft failure was defined as an edematous cornea with failure to maintain deturgescence lasting beyond a period of 1 month of intense steroid therapy or vascularization and scarring resulting in irreversible loss of central graft clarity. Corneal graft survival was calculated using Kaplan-Meier survival analysis. Patients were divided into four groups: GDD-PK, GDD-DSEK, medical-PK and medical-DSEK. RESULTS: Fifty-six eyes of 56 patients were identified as meeting inclusion criteria. Among eyes with a GDD, there was no difference in the proportion of failures between PK grafts (48%) and DSEK grafts (50%) (p = 0.90). Failure occurred earlier in DSEK recipients compared to PK recipients, 5.82 ± 6.77 months versus 14.40 ± 7.70 months, respectively (p = 0.04). A Kaplan-Meier analysis did not identify a difference between the four groups with respect to graft failure (p = 0.52). CONCLUSION: There is no significant difference in graft survival rates between medically and surgically treated glaucoma patients for either PK or DSEK grafts. In patients with GDD, graft failure occurs earlier in DSEK compared to PK.

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

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

Comparison between Widefield En Face Swept-Source OCT and Conventional Multimodal Imaging for the Detection of Reticular Pseudodrusen.

PURPOSE: The ability to detect reticular pseudodrusen (RPD)/subretinal drusenoid deposits (SDDs) using 12×12-mm widefield en face swept-source optical coherence tomography (SS-OCT) imaging was compared with conventional multimodal imaging (color, fundus autofluorescence (FAF), and infrared reflectance [IR] imaging) in eyes with nonexudative age-related macular degeneration (AMD). DESIGN: Cross-sectional study. PARTICIPANTS: Patients with nonexudative AMD were prospectively enrolled in an SS-OCT imaging study at the Bascom Palmer Eye Institute. METHODS: On the same day, all participants underwent color, FAF, and IR fundus imaging, as well as imaging with a prototype Zeiss 100 kHz SS-OCT instrument (Carl Zeiss Meditec Inc, Dublin, CA). Two masked graders assessed the presence, absence, or uncertainty of RPD/SDDs on conventional multimodal images and separately on 4 different SS-OCT en face images derived from the same volumetric dataset. The results from grading the conventional images and the SS-OCT en face images were compared. MAIN OUTCOME MEASURES: Agreement in the detection of RPD/SDDs using different imaging modalities. RESULTS: A total of 307 eyes (209 patients) were graded for the presence or absence of RPD/SDDs. The agreement between SS-OCT and multimodal imaging was 83%. The difference in RPD/SDD detection with either image modality was not statistically significant (P = 0.21). The sensitivity of SS-OCT in RPD/SDD detection was 83%, and when using conventional imaging, the sensitivity was 75%. When using SS-OCT imaging alone, 10% of RPD/SDD cases would be missed, and when using conventional imaging alone, 14% of RPD/SDD cases would be missed. The presence of RPD/SDD was confirmed retrospectively in 48 of 52 cases once the overall grading was unmasked and the graders reevaluated the conventional multimodal images and the widefield SS-OCT en face images. CONCLUSIONS: All 4 imaging modalities used together provided the best strategy for the detection of RPD/SDDs. However, when using widefield en face SS-OCT slab imaging alone, the detection of RPD/SDDs was at least as good as conventional imaging.

Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration.

TOPIC: To review the role of anatomic endpoints in clinical trials for the study of nonexudative age-related macular degeneration (AMD) with an emphasis on a novel composite endpoint for the study of emerging therapies for intermediate AMD (iAMD). CLINICAL RELEVANCE: Unlike clinical trials for exudative AMD, it is impractical to use the change in visual acuity (VA) as a primary endpoint for the study of nonexudative AMD. By the time VA has been lost in nonexudative AMD, proof-of-concept early-stage clinical trials would take years to run, and drug development would be a near impossible task. Surrogate endpoints are needed that reliably predict future vision loss and can be easily measured. Anatomic changes that correlate with disease progression in nonexudative AMD offer the greatest promise as primary endpoints. METHODS: In preparation for this review, the electronic PubMed database was searched for relevant research pertaining to anatomic endpoints for the study of nonexudative AMD. Paper selection was based on our knowledge of the field with the goal to be as inclusive as possible. Whenever possible, recent review articles and results from large clinical trials, preferably with outcomes from many years of follow-up were favored over trials of short duration. RESULTS: The most commonly used anatomic endpoint for the study of late, nonexudative AMD is the growth of geographic atrophy (GA). The advantages of studying GA include the appreciation that its enlargement through the foveal center leads to significant vision loss through the availability of natural history studies, the understanding that prevention of this growth would preserve vision in the future, the ability to reliably measure GA using different imaging strategies, and the development appropriate statistical tools that reliably predict the growth of GA over time. The major disadvantage of using GA is that significant, irreversible disease progression has already occurred. The use of drusen volume as a predictor of disease progression and the use of a composite endpoint that incorporates drusen growth, formation of GA, and formation of neovascularization offers an opportunity to study therapies at an earlier stage of AMD with a greater likelihood of preserving better vision over a lifetime. CONCLUSIONS: Anatomic endpoints for the study of nonexudative AMD are needed to accelerate drug development, and the availability of optical coherence tomography algorithms capable of reliably measuring drusen morphology offer the best opportunity to study therapies for iAMD.

A Retrospective Comparison of Primary Baerveldt Implantation versus Trabeculectomy with Mitomycin C.

PURPOSE: To compare the safety and efficacy of Baerveldt implantation (Abbott Medical Optics, Santa Ana, CA) and trabeculectomy with mitomycin C (MMC) in patients who have not undergone prior incisional ocular surgery. DESIGN: Retrospective, comparative case series. PARTICIPANTS: A total of 125 patients with low-risk glaucoma undergoing primary glaucoma surgery, including 55 patients who received a 350-mm(2) Baerveldt glaucoma implant and 70 patients who underwent trabeculectomy with MMC. METHODS: Eligible patients were identified using Current Procedural Terminology codes, and their medical records were reviewed retrospectively. MAIN OUTCOME MEASURES: The primary outcome measure was surgical success (intraocular pressure [IOP] ≤21 mmHg and reduced ≥20% from baseline, IOP >5 mmHg, no reoperation for glaucoma, no loss of light-perception vision). Secondary outcome measures included visual acuity, IOP, number of glaucoma medications, and complications. RESULTS: The cumulative probability of success at 3 years with or without medical therapy was 87% in the Baerveldt group and 76% in the trabeculectomy group (P = 0.23). Postoperative complications occurred in 11 patients (20%) in the Baerveldt group and 20 patients (29%) in the trabeculectomy group (P = 0.27). Mean follow-up ± standard deviation was 27±19 months in the Baerveldt group and 34±20 months in the trabeculectomy group (P = 0.053). CONCLUSIONS: Similar rates of surgical success and postoperative complications were observed in patients undergoing trabeculectomy with MMC and in those undergoing Baerveldt implantation during 3 years of follow-up. Both are viable primary glaucoma procedures in patients who have not undergone prior ocular surgery.

Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

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

Integrative properties of retinal ganglion cell electrical responsiveness depend on neurotrophic support and genotype in the mouse.

Early stages of glaucoma and optic neuropathies are thought to show inner retina remodeling and functional changes of retinal ganglion cells (RGCs) before they die. To assess RGC functional plasticity, we investigated the contrast-gain control properties of the pattern electroretinogram (PERG), a sensitive measure of RGC function, as an index of spatio-temporal integration occurring in the inner retina circuitry subserving PERG generators. We studied the integrative properties of the PERG in mice exposed to different conditions of neurotrophic support. We also investigated the effect of genotypic differences among mouse strains with different susceptibility to glaucoma (C57BL/6J, DBA/2J, DBA/2.Gpnmb(+)). Results show that the integrative properties of the PERG recorded in the standard C57BL/6J inbred mouse strain are impaired after deficit of neurotrophic support and partially restored after exogenous neurotrophic administration. Changes in PERG amplitude, latency, and contrast-dependent responses differ between mouse strains with different susceptibility to glaucoma. Results represent a proof of concept that the PERG could be used as a tool for in-vivo monitoring of RGC functional plasticity before RGC death, the effect of neuroactive treatments, as well as for high-throughput tool for phenotypic screening of different mouse genotypes.

Impaired retinal microcirculation in multiple sclerosis.

BACKGROUND: The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS). METHODS: A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume. RESULTS: The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04). CONCLUSION: The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.

Cigarette Smoking and Activities of Daily Living in Ocular Myasthenia Gravis.

BACKGROUND: Myasthenia gravis is an autoimmune disease of the neuromuscular junction, commonly affecting the ocular muscles. Cigarette smoking has been shown to influence many autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, but its effect on myasthenia gravis has not been well studied. We sought to determine whether cigarette smoking influenced disease-related symptoms in ocular myasthenia gravis (OMG). METHODS: We performed a prospective, clinic-based cross-sectional study in a single academic neuro-ophthalmology practice. All patients diagnosed with OMG between November 2006 and April 2014 were included. A prospective telephone survey was administered to determine smoking status and myasthenia gravis-related symptom severity. The main outcome measure was the myasthenia gravis-specific activities of daily living (MG-ADL) score, a well-validated marker of symptoms and quality of life in myasthenia gravis. RESULTS: Forty-four patients were included in the analysis. Comparison of MG-ADL ocular subscores between current smokers (3.4 ± 2.6), former smokers (1.8 ± 2.1), and never smokers (1.1 ± 1.5) revealed a statistically significant relationship (P = 0.031) where current smokers had the highest MG-ADL ocular subscores and never smokers the lowest. Comparison of MG-ADL total scores revealed the same relationship (current 5.6 ± 4.5, former 2.9 ± 3.1, never 1.4 ± 2.5, P = 0.003). There were borderline significant correlations of pack years with MG-ADL ocular subscore (r = 0.27, P = 0.074) and MG-ADL total score (r = 0.30, P = 0.051). CONCLUSIONS: Our findings indicate an association between cigarette smoking and symptom severity in OMG. This association suggests that smoking cessation in OMG patients may lead to improved symptom-related quality of life.