Search

The aim of this study was to determine the short-term compliance with regular home monitoring of macular retinal sensitivity (RS) in intermediate age-related macular degeneration (iAMD). Home-based outcomes were compared with in-clinic outcomes determined using (1) the same tablet device under supervision, and (2) the Macular Integrity Assessment (MaIA) microperimeter.Single-center longitudinal compliance and reliability study.A total of 73 participants with iAMD were trained to perform macular field testing with the Melbourne Rapid Fields-macular (MRF-m) iPad application. Volunteers were asked to return 6 weekly tests from home, guided by audio instructions. We determined compliance with weekly testing and surveyed for factors that limited compliance. Test reliability (false positive, false negative) and RS were compared to in-clinic assays (MaIA). Data are given as mean ± SD or as median [quartile 1-3 range]. Group comparisons were achieved with bootstrap to define the 95% confidence limits.A total of 59 participants submitted 6 home examinations with a median intertest interval of 8.0 [7.0-17] days. Compliance with weekly testing (7 days ±24 hours) was 55%. The main barrier to compliance was information technology (IT) logistic reasons. Of 694 home examinations submitted, 96% were reliable (false-positive results25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P.05) compared to the MaIA.Home monitoring produces reliable results that differ from in-clinic tests because of test design. This should not affect self-monitoring once an at-home baseline is established, but these differences will affect comparisons with in-clinic outcomes. Reasonable compliance with weekly testing was achieved. Improved IT support might lead to better compliance.

Background Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. Objectives The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM. Methods Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed. Results Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21–85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p < 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: − 9.99 vs. − 0.34 points; p < 0.001). Results were similar for MSIS-29 psychological impact. Conclusion No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported. Trial Registration ClinicalTrials.gov: NCT01480063. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00840-x.

PURPOSE: To evaluate the 12-month outcomes of a novel posterior small incision sub-tenon ab interno technique of XEN stent insertion (‘Semi-open’). METHOD: Consecutive eyes underwent XEN stent insertion with the Semi-open technique by two surgeons between 1st July 2018 and 30th September 2019. All cases received subconjunctival injection of 0.1 mL of mitomycin C 0.2 mg/mL. Eyes with primary open angle glaucoma (OAG), secondary OAG or pseudophakic primary angle closure glaucoma (PACG) were included. Exclusion criteria were phakic PACG, uveitic or neovascular glaucoma and postoperative follow-up

Purpose This study examines the short-term uptake, compliance, and performance of a tablet device used for home monitoring of visual field (VF-Home) by glaucoma patients. Design Single-center, observational, longitudinal, compliance study. Methods Participants who were glaucoma suspects or had stable glaucoma in at least one eye were recruited during a regular clinic review. Baseline in-clinic visual field (VF) was recorded with the Humphrey Field Analyser (HFA, SITA standard) and repeated at 6 months. Participants were tasked with performing 6 VF examinations from home, at weekly intervals, using a loaned iPad tablet. Uptake was defined as returning at least 1 test from home. Reliability and global indices from VF-Home were compared to in-clinic outcomes. Data are shown as either mean ± [standard deviation] or median [quartile 1-3 range], and group comparisons were achieved with bootstrap. Results We recruited 186 eyes of 101 participants. VF-Home uptake was excellent, with 88% of participants successfully completing ≥1 home examination and 69% completing all 6 examinations. The median duration between tests was 7.0 [7.0-8.0] days. Barriers to uptake and compliance involved information technology (IT) logistical reasons, lack of motivation, or competing life demands. VF-Home gave greater fixation loss but a similar level of False Positives (FP) as the HFA. A high correlation was found for the mean defect between in-clinic and at-home outcomes (R = 0.85). Conclusions VF-Home can return a high level of short-term compliance and results comparable to those found by in-clinic testing. IT logistical reasons and lack of motivation are barriers to uptake and compliance.

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen.

Purpose Recent developments in electronic technology are making it possible to home monitor the sensitivity of the central visual field using portable devices. We used simulations to investigate whether the higher test frequency afforded by home monitoring improves the early detection of rapid visual field loss in glaucoma and how any benefits might be affected by imperfect compliance or increased variability in the home-monitoring test. Design Computer simulation, with parameter selection confirmed with a cohort study. Participants A total of 43 patients with treated glaucoma (both open-angle and closed-angle), ocular hypertension or glaucoma suspects (mean age, 71 years; range, 37–89 years), were followed in the cohort study. Methods We simulated series (n = 100 000) of visual fields for patients with stable glaucoma and patients with progressing glaucoma for 2 in-clinic (yearly and 6-monthly) and 3 home-monitoring (monthly, fortnightly, and weekly) schedules, each running over a 5-year period. Various percentages of home-monitored fields were omitted at random to simulate reduced compliance, and the variability of the home monitored fields also was manipulated. We used previously published variability characteristics for perimetry and confirmed their appropriateness for a home-monitoring device by measuring the device's retest variability at 2 months in a cohort of 43 patients. The criterion for flagging progression in our simulation was a significant slope of the ordinary least squares regression of a simulated patient's mean deviation (MD) data. Main Outcome Measures The sensitivity for identifying rapid visual field loss (−2 decibels [dB]/year loss of MD). Results Although a sensitivity of 0.8 for rapid field loss was achieved after 2.5 years of 6-monthly testing in the clinic, weekly home monitoring achieved this by 0.9 years despite moderate test compliance of 63%. The improved performance of weekly home monitoring over 6-monthly clinical testing was retained even when home monitoring was assumed to produce more variable test results or be associated with low patient compliance. Conclusions Detecting rapid visual field progression may be improved using a home-monitoring strategy, even when compliance is imperfect. The cost-benefit of such an approach is yet to be demonstrated, however.

Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection.Material and methods. In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate.Results. Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (aEs) occurred in 9 black/AA and 6 Latino patients.Conclusion. SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% Cls were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.

PURPOSE: To establish the medium-term repeatability of the iPad perimetry app Melbourne Rapid Fields (MRF) compared to Humphrey Field Analyzer (HFA) 24-2 SITA-standard and SITA-fast programs. DESIGN: Multicenter longitudinal observational clinical study. METHODS: Sixty patients (stable glaucoma/ocular hypertension/glaucoma suspects) were recruited into a 6-month longitudinal clinical study with visits planned at baseline and at 2, 4, and 6 months. At each visit patients undertook visual field assessment using the MRF perimetry application and either HFA SITA-fast (n = 21) or SITA-standard (n = 39). The primary outcome measure was the association and repeatability of mean deviation (MD) for the MRF and HFA tests. Secondary measures were the point-wise threshold and repeatability for each test, as well as test time. RESULTS: MRF was similar to SITA-fast in speed and significantly faster than SITA-standard (MRF 4.6 ± 0.1 minutes vs SITA-fast 4.3 ± 0.2 minutes vs SITA-standard 6.2 ± 0.1 minutes, P < .001). Intraclass correlation coefficients (ICC) between MRF and SITA-fast for MD at the 4 visits ranged from 0.71 to 0.88. ICC values between MRF and SITA-standard for MD ranged from 0.81 to 0.90. Repeatability of MRF MD outcomes was excellent, with ICC for baseline and the 6-month visit being 0.98 (95% confidence interval: 0.96-0.99). In comparison, ICC at 6-month retest for SITA-fast was 0.95 and SITA-standard 0.93. Fewer points changed with the MRF, although for those that did, the MRF gave greater point-wise variability than did the SITA tests. CONCLUSIONS: MRF correlated strongly with HFA across 4 visits over a 6-month period, and has good test-retest reliability. MRF is suitable for monitoring visual fields in settings where conventional perimetry is not readily accessible.

Background In the assessment of a pituitary mass, objective visual field testing represents a valuable means of evaluating mass effect, and thus in deciding whether surgical management is warranted. Case presentation In this vignette, we describe a 73 year-old lady who presented with a three-week history of frontal headache, and ‘blurriness’ in the left side of her vision, due to a WHO grade III anaplastic haemangiopericytoma compressing the optic chiasm. We report how timely investigations, including an iPad-based visual field test (Melbourne Rapid Field, (MRF)) conducted at the bedside aided swift and appropriate management of the patient. Conclusions We envisage such a test having a role in assessing bed-bound patients in hospital where access to formal visual field testing is difficult, or indeed in rapid testing of visual fields at the bedside to screen for post-operative complications, such as haematoma.

Purpose To evaluate the accuracy and efficiency of Visual Fields Easy (VFE), a free iPad app, for performing suprathreshold perimetric screening. Design Prospective, cross-sectional validation study. Methods We performed screening visual fields using a calibrated iPad 2 with the VFE application on 206 subjects (411 eyes): 210 normal (NL), 183 glaucoma (GL), and 18 diabetic retinopathy (DR) at Tilganga Institute of Ophthalmology, Kathmandu, Nepal. We correlated the results with a Humphrey Field Analyzer using 24-2 SITA Standard tests on 373 of these eyes (198 NL, 160 GL, 15 DR). Results The number of missed locations on the VFE correlated with mean deviation (MD, r = 0.79), pattern standard deviation (PSD, r = 0.60), and number of locations that were worse than the 95% confidence limits for total deviation (r = 0.51) and pattern deviation (r = 0.68) using SITA Standard. iPad suprathreshold perimetry was able to detect most visual field deficits with moderate (MD of −6 to −12 dB) and advanced (MD worse than −12 dB) loss, but had greater difficulty in detecting early (MD better than −6 dB) loss, primarily owing to an elevated false-positive response rate. The average time to perform the Visual Fields Easy test was 3 minutes, 18 seconds (standard deviation = 16.88 seconds). Discussion The Visual Fields Easy test procedure is a portable, fast, effective procedure for detecting moderate and advanced visual field loss. Improvements are currently underway to monitor eye and head tracking during testing, reduce testing time, improve performance, and eliminate the need to touch the video screen surface.

The exponential distribution is frequently used to model the survival time of a patient population, which assumes the hazard rate to be a constant over time. This assumption is often violated as the hazard function may vary over time and exhibit one or more change points in its values. Several methods exist in the literature for detecting a single change point in a piecewise constant hazard function for right-censored data. A sequential testing approach to detecting multiple change points in the hazard function using likelihood ratio statistics and resampling is proposed, which is applicable to both right-censored and interval-censored data. Numerical results based on simulated survival data and a real example show that the proposed approach can accurately detect the change points in the hazard function for both right-censored and interval-censored data.

This study provides ophthalmologists who manage uveitic glaucoma with important information on factors that can affect the success of surgical management of this challenging disease.This study examines surgical outcomes of trabeculectomy and glaucoma device implant (GDI) surgery for uveitic glaucoma, in particular the effect of uveitis activity on surgical outcomes.Retrospective chart review at a tertiary institution.Eighty-two cases with uveitic glaucoma (54 trabeculectomies and 28 (GDI) surgeries) performed between 1 December 2006 and 30 November 2014.Associations of factors with surgical outcomes were examined using univariate and multivariate analysis.Surgical outcomes as defined in Guidelines from World Glaucoma Association.Average follow up was 26.4 ± 21.5 months. Overall qualified success rate of the trabeculectomies was not statistically different from GDI, being 67% and 75%, respectively (P = 0.60). Primary and secondary GDI operations showed similar success rates. The most common postoperative complication was hypotony (~30%). Active uveitis at the time of operation was higher in trabeculectomy compared with GDI group (35% vs. 14%). Active uveitis at the time of surgery did not significantly increase risk of failure for trabeculectomies. Recurrence of uveitis was significantly associated with surgical failure in trabeculectomy group (odds ratio 4.8, P = 0.02) but not in GDI group.Surgical success rate of GDI was not significantly different from trabeculectomy for uveitic glaucoma in this study. Regular monitoring, early and prolonged intensive treatment of ocular inflammation is important for surgical success particularly following trabeculectomy.

Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6–62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1–55·3] of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4–53·8] vs 14 [20%; 11·4–31·3]). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 [95% CI 0·29–0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Interpretation Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Funding Bristol-Myers Squibb.

Background: Extensive use of polyethylene glycol (PEG) in consumer products necessitates the assessment of anti-PEG antibodies (APAb). Methods: In clinical trials comparing PEG-IFN-λ to PEG-IFN-α, conventional bridge and direct assays were assessed. Results & Conclusion: The bridge assay detected IgM and IgG APAb reactive with common PEG sizes and derivatives at sufficient sensitivity, 15–500 ng/ml. Of subjects evaluated, 6% of PEG-IFN-λ and 9% of PEG-IFN-α subjects had persistent APAb while 60% of PEG-IFN-λ and 33% of PEG-IFN-α subjects had persistent anti-interferon antibodies (AIAb). Pre-existing APAb and AIAb prevalence was comparable (approximately 10% of subjects). APAb were earlier onset, less frequent, less persistent and lower titer than AIAb. No associated hypersensitivity events were reported.

To determine whether monoscopic vs stereoscopic viewing impacts evaluation of optic disc photographs for glaucoma diagnosis in an expert population.Prospective observational study.Twenty pairs of high-quality monoscopic and stereoscopic photographs of similar size and magnification (ie, 40 images), were selected to demonstrate a range of optic disc features from a total of 197 eyes of 197 patients with glaucoma and normal subjects recruited from a tertiary clinic. These were presented in randomized order via an interactive platform (http://stereo.gone-project.com/). Participants assessed 9 topographic features and estimated glaucoma likelihood for each photograph. Main outcome measures were intra- and inter-observer agreement.There was good intra-observer agreement between monoscopic and stereoscopic assessments of glaucoma likelihood (κw = 0.56). There was also good to substantial agreement for peripapillary atrophy (κw = 0.65), cup shape (κw = 0.65), retinal nerve fiber layer loss (κw = 0.69), vertical cup-to-disc ratio (κw = 0.58), and disc shape (κw = 0.57). However, intra-observer agreement was only fair to moderate for disc tilt, cup depth, and disc size (κw = 0.46-0.49). Inter-observer agreement for glaucoma likelihood in monoscopic photographs (κw = 0.61, 95% confidence interval [CI] = 0.55-0.67) was substantial and not lower than in stereoscopic photographs (κw = 0.59, CI = 0.54-0.65). Monoscopic photographs did not lead to lower levels of inter-observer agreement compared to stereoscopic photographs in the assessment of any optic disc characteristics, for example disc size (mono κw = 0.65, stereo κw = 0.52) and cup-to-disc ratio (mono κw = 0.72, stereo κw = 0.62).For expert observers in the evaluation of optic disc photographs for glaucoma likelihood, monoscopic optic disc photographs did not appear to represent a significant disadvantage compared to stereoscopic photographs.

Purpose Following the recent demonstration of increased mitochondrial DNA mutations in lymphocytes of POAG patients, the authors sought to characterize mitochondrial function in a separate cohort of POAG. Methods Using similar methodology to that previous applied to Leber's hereditary optic neuropathy (LHON) patients, maximal adenosine triphosphate (ATP) synthesis and cellular respiration rates, as well as cell growth rates in glucose and galactose media, were assessed in transformed lymphocytes from POAG patients (n = 15) and a group of age- and sex-matched controls (n = 15). Results POAG lymphoblasts had significantly lower rates of complex-I-driven ATP synthesis, with preserved complex-II-driven ATP synthesis. Complex-I driven maximal respiration was also significantly decreased in patient cells. Growth in galactose media, where cells are forced to rely on mitochondrial ATP production, revealed no significant differences between the control and POAG cohort. Conclusions POAG lymphoblasts in the study cohort exhibited a defect in complex-I of the oxidative phosphorylation pathway, leading to decreased rates of respiration and ATP production. Studies in LHON and other diseases have established that lymphocyte oxidative phosphorylation measurement is a reliable indicator of systemic dysfunction of this pathway. While these defects did not impact lymphoblast growth when the cells were forced to rely on oxidative ATP supply, the authors suggest that in the presence of a multitude of cellular stressors as seen in the early stages of POAG, these defects may lead to a bioenergetic crisis in retinal ganglion cells and an increased susceptibility to cell death.

PURPOSE: The authors compared the visual gaze behaviors of glaucoma subspecialists with those of ophthalmology trainees during optic disc and retinal nerve fiber layer (RNFL) examination. METHODS: Seven glaucoma subspecialists and 23 ophthalmology trainees participated in the project. Participants were shown eight glaucomatous optic disc images with varied morphology. Eye movements during examination of the optic disc photographs were tracked. For each disc image, graders were asked to assign a presumptive diagnosis for probability of glaucoma. There was no time restriction. RESULTS: Overall, trainees spent more time looking at disc images than glaucoma subspecialists (21.3 [13.9-37.7] vs. 16.6 [12.7-19.7]) seconds; median [interquartile range (IQR)], respectively; P < 0.01) and had no systematic patterns of gaze behavior, and gaze behavior was unaltered by disc morphology or topographic cues of pathology. Experienced viewers demonstrated more systematic and ordered gaze behavior patterns and spent longer times observing areas with the greatest likelihood of pathology (superior and inferior poles of the optic nerve head and adjacent RNFL) compared with the trainees. For discs with focal pathology, the proportion of total time spent examining definite areas of pathology was 28.9% (22.4%-33.6%) for glaucoma subspecialists and 13.5% (12.2%-19.2%) for trainees (median [IQR]; P < 0.05). Furthermore, experts adapted their viewing habits according to disc morphology. CONCLUSIONS: Glaucoma subspecialists adopt systematic gaze behavior when examining the optic nerve and RNFL, whereas trainees do not. It remains to be elucidated whether incorporating systematic viewing behavior of the optic disc and RNFL into teaching programs for trainees may expedite their acquisition of accurate and efficient glaucoma diagnosis skills.

The similarities between glaucoma and mitochondrial optic neuropathies have driven a growing interest in exploring mitochondrial function in glaucoma. The specific loss of retinal ganglion cells is a common feature of mitochondrial diseases - not only the classic mitochondrial optic neuropathies of Leber's Hereditary Optic Neuropathy and Autosomal Dominant Optic Atrophy - but also occurring together with more severe central nervous system involvement in many other syndromic mitochondrial diseases. The retinal ganglion cell, due to peculiar structural and energetic constraints, appears acutely susceptible to mitochondrial dysfunction. Mitochondrial function is also well known to decline with aging in post-mitotic tissues including neurons. Because age is a risk factor for glaucoma this adds another impetus to investigating mitochondria in this common and heterogeneous neurodegenerative disease. Mitochondrial function may be impaired by either nuclear gene or mitochondrial DNA genetic risk factors, by mechanical stress or chronic hypoperfusion consequent to the commonly raised intraocular pressure in glaucomatous eyes, or by toxic xenobiotic or even light-induced oxidative stress. If primary or secondary mitochondrial dysfunction is further established as contributing to glaucoma pathogenesis, emerging therapies aimed at optimizing mitochondrial function represent potentially exciting new clinical treatments that may slow retinal ganglion cell and vision loss in glaucoma.

PURPOSE. To prospectively evaluate the effect of 1.25 mg and 2.5 mg intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma (NVG), with primary outcome measures being the regression of neovascularization of iris (NVI) and reduction of intraocular pressure (IOP). METHODS. Consecutive patients with neovascular glaucoma from December 2006 to March 2007 were randomized into two cohorts assigned to receive 1.25 mg (Group 1) or 2.5 mg (Group 2) intracameral bevacizumab prior to undergoing mitomycin C (MMC) trabeculectomy. Surgical outcome measures were evaluated following initial injection and during follow-up post-surgery. RESULTS. The most common causes for iris neovascularization were central retinal vein occlusion (47.3%) and proliferative diabetic retinopathy (36.8%). Following intracameral bevacizumab, there was a reduction in IOP compared to baseline in both treatment groups (Group 1, n=9: –10.4±4.5 mmHg, p=0.57; Group 2, n=10: –12.1±5.5 mmHg, p=0.1). The reduction in IOP was not statistically significant between the two groups (p=0.55). None of the eyes underwent further retinal ablation post trabeculectomy. Reappearance of NVI was seen in three eyes (Group 1, n=2; Group 2, n=1) after 3 months. There was no statistically significant difference in regression of NVI grade between the treatment groups (p=0.1). CONCLUSIONS. The efficacy of an intracameral dose of 2.5 mg of bevacizumab prior to trabeculectomy for eyes with NVG is not significantly different from a 1.25 mg dose. Intracameral bevacizumab followed by trabeculectomy results in good surgical outcomes. Longer follow-up would be needed to evaluate differences in recurrence rates of iris neovascularization using different dosages. (Eur J Ophthalmol 2009; 19: 435-41)

Glaucoma is increasingly recognized as a neurodegenerative disorder, characterized by the accelerated loss of retinal ganglion cells (RGCs) and their axons. Open angle glaucoma prevalence and incidence increase exponentially with increasing age, yet the pathophysiology underlying increasing age as a risk factor for glaucoma is not well understood. Accumulating evidence points to age-related mitochondrial dysfunction playing a key role in the etiology of other neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer and Parkinson disease. The 2 major functions of mitochondria are the generation of ATP through oxidative phosphorylation and the regulation of cell death by apoptosis. This review details evidence to support our hypothesis that age-associated mitochondrial dysfunction renders RGCs susceptible to glaucomatous injury by reducing the energy available for repair processes and predisposing RGCs to apoptosis. Eliciting the role of mitochondria in glaucoma pathogenesis may uncover novel therapeutic targets for protecting the optic nerve and preventing vision loss in glaucoma.

IMPORTANCE: Glaucoma is a significant health problem for which diagnosis remains suboptimal. Optic disc evaluation, which is fundamental to the diagnosis, is a difficult skill to acquire. OBJECTIVES: To determine the optic disc characteristics that most influence decision making in the assessment of glaucoma likelihood and to ascertain the optic disc features associated with overestimation and underestimation of glaucoma likelihood. DESIGN, SETTING, AND PARTICIPANTS: This prospective, observational, Internet-based study with multinational participation included 197 ophthalmic clinicians (37 glaucoma subspecialists, 51 comprehensive ophthalmologists, and 109 ophthalmology trainees) from 22 countries who self-registered for the Glaucomatous Optic Neuropathy Evaluation (GONE) Project from December 1, 2008 through June 30, 2010. INTERVENTIONS: A series of 42 monoscopic optic disc photographs of healthy and glaucomatous eyes were presented to clinicians using the GONE Project Program. Participants were asked to assess each disc according to 9 conventional topographic features and assign a presumptive grade for glaucoma likelihood. MAIN OUTCOMES AND MEASURES: Agreement (κ and weighted κ) among participants for disc signs and glaucoma likelihood and contributions of disc-related factors to overestimation and underestimation of glaucoma likelihood. RESULTS: Ophthalmology trainees and comprehensive ophthalmologists underestimated glaucoma likelihood in a mean (SD) of 22.1% (1.6%) and 23.8% (1.8%) of discs, respectively. Underestimation of vertical cup-disc ratio and failure to identify retinal nerve fiber layer loss, disc hemorrhage, or rim loss were most likely to lead to underestimation of glaucoma. When all 4 features were inaccurately assessed, underestimation of glaucoma likelihood increased to 43.0%. Ophthalmology trainees and comprehensive ophthalmologists overestimated glaucoma likelihood in a mean (SD) of 13.0% (1.2%) and 8.9% (1.3%) of discs, respectively. Overestimation of glaucoma likelihood was associated with overestimation of retinal nerve fiber layer loss, rim loss, vertical cup-disc ratio, disc hemorrhage, and incorrect assessment of disc tilt and was more likely in large discs. CONCLUSIONS AND RELEVANCE: Ophthalmology trainees and comprehensive ophthalmologists underestimated glaucoma likelihood in approximately 1 in 5 disc photographs and were twice as likely to underestimate as overestimate glaucoma likelihood. Underestimating the vertical cup-disc ratio and cup shape and missing retinal nerve fiber layer defects and disc hemorrhage were the key errors that led to underestimation. When all 4 parameters were incorrectly assessed, underestimation increased to almost 1 in 2.