Visual fields in glaucoma: Where are we now?

Visual fields are an integral part of glaucoma diagnosis and management. COVID has heightened the awareness of the potential for viral spread with the practice of visual fields modified. Mask artefacts can occur due to fogging of the inferior rim of the trail lens. Fortunately, the risk of airborne transmission when field testing is low. The 24-2c may be useful to detect early disease and the 10-2 more sensitive to detect advanced loss. The SITA faster test algorithm is able to reduce testing time thereby improving clinic efficiency, however, may show milder results for moderate or severe glaucoma. The technician has an important role of supervising the visual field performance to achieve reliable output. Home monitoring can provide earlier detection of progression and thus improve monitoring of glaucoma as well as reduce the burden of in-clinic assessments. Artificial Intelligence has been found to have high sensitivity and specificity compared to expert observers in detecting field abnormalities and progression as well as integrating structure with function. Although these advances will improve efficiency and guide accuracy, there will remain a need for clinicians to interpret the results and instigate management.

Tablets at the bedside - iPad-based visual field test used in the diagnosis of Intrasellar Haemangiopericytoma: a case report.

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.

Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial.

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.

Daclatasvir and Peginterferon/Ribavirin for Black/African-American and Latino Patients with HCV infection.

 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% CIs 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.

Wound-related complications and clinical outcomes following open globe injury repair.

BACKGROUND: Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound-related issues. DESIGN: Retrospective, cohort study of consecutive open globe injuries presenting to a tertiary referral eye hospital from 1 January 2009 to 31 December 2011. PARTICIPANTS: A total of 267 eyes of 263 patients, mainly male (82.5%) with a mean age of 44.8 (range: 4-97) years. Average follow up was 6.9 months. METHODS: All cases classified according to Ocular Trauma Classification Group. MAIN OUTCOME MEASURES: Visual outcomes, risk factors for and rates of postoperative complications and endophthalmitis. RESULTS: There were 83 globe ruptures, 182 penetrating and 2 perforating eye injuries, of which 43 cases had intraocular foreign body. Factors contributing to final visual acuity (VA) <6/60 were poor presenting VA (odds ratio [OR] = 16.0, 95% confidence interval [CI]: 4.81-53.1), globe rupture (OR = 4.64, [1.99-10.8]), retinal detachment (OR = 3.40, [1.19-9.74]) and age ≥50 (OR = 2.45, [1.05-5.74]). Wound leak occurred in 44 eyes (16%). Of these, 18 (41%) proceeded to re-suturing. Factors contributing to wound leak were stellate-shaped wound (OR = 3.28, [1.39-7.73]) and delayed presentation (OR = 2.80, [1.02-7.71]). Ten eyes (3.7%) developed endophthalmitis. Factors associated with endophthalmitis were delayed presentation (OR = 8.91, [1.71-46.6]), microbial keratitis (OR = 12.5, [1.85-85.0]) and lens capsule breach (OR = 12.4, [1.85-83.1]). CONCLUSIONS: Wound leak is an important postoperative complication of open globe injury repair. Delayed presentation is an important risk factor for postoperative wound leak and endophthalmitis. Prompt and meticulous wound management of open globe injury may reduce these complications.

Measuring Visual Fields in Children With Glaucoma Using a Portable Tablet.

Purpose: To compare perimetric outcomes of an iPad perimetry app (Melbourne Rapid Fields [MRF]) with those of the Humphrey Field Analyser (HFA) testing children with glaucoma. Methods: Sixteen children diagnosed and treated for glaucoma were recruited to evaluate their perimetric performance over two visits. At each visit, they undertook visual field assessment using the MRF application as well as the HFA. The HFA test was part of their usual clinical work up and a clinical assistant judged which test format (24-2 SITA standard or SITA fast) might be suited to the testing of that child. The primary outcome measure was the association and repeatability of mean deviation (MD) for the MRF and HFA tests, by way of regression, intraclass correlation coefficient and Bland-Altman analysis. Secondary measures were comparisons of pattern deviation indices, test times as well as an indication of participant test preference. Summary data show means ± standard deviation. Results: The age for our cohort was 7 to 15 years of age (mean, 10.0 ± 2.4 years of age). The MRF MD was in close concordance to HFA MD with an intraclass correlation coefficient of 0.91 (95% confidence interval, 0.82-0.95). Bland-Altman analysis found little bias (-0.6 dB) and a 95% coefficient of repeatability of 2.1 dB in eyes having a normal HFA MD. In eyes with glaucomatous visual field defects the 95% coefficient of repeatability at retest was much larger for both the MRF (10.5 dB) as well as for the HFA (10.0 dB). Average MRF test times (5.6 ± 1.2 minutes) were similar to SITA Fast (5.4 ± 1.9 minutes) with both being significantly faster than SITA standard (8.6 ± 1.4 minutes; P < 0.001). All children chose testing with the MRF as their preference. Conclusions: MRF correlated strongly with HFA and was preferred by the children over the HFA. MRF is suitable for perimetric evaluation of children with glaucoma. Translational Relevance: This study finds that an iPad based visual field test can be used with children having glaucoma to yield outcomes similar to SITA-fast. Children indicate a preference for such testing.

Prospective, Randomized Controlled Trial of Cataract Surgery vs Combined Cataract Surgery With Insertion of iStent Inject.

PURPOSE: To evaluate the efficacy and safety of combined cataract surgery with insertion of an ab interno trabecular microbypass device (iStent Inject, Glaukos Corporation) compared to cataract surgery alone in patients with mild-to-moderate glaucoma. DESIGN: Prospective, randomized, assessor-masked controlled trial at a single centre. PARTICIPANTS: Eyes with visually-significant cataract and mild-to-moderate glaucoma with preoperative intraocular pressure (IOP) of 12 to 30 mmHg on 0 to 3 ocular hypotensive medications. METHODS: Participants eyes were randomized (2017-2020) 1:1 to combined cataract surgery with iStent Inject (treatment group, n = 56) or cataract surgery alone (control group, n = 48), and followed up for 2 years. MAIN OUTCOME MEASURES: The co-primary effectiveness endpoints were the number of ocular hypotensive medications and IOP at 24-months post-surgery. The secondary effectiveness endpoints were ocular comfort as measured by the Ocular Surface Disease Index (OSDI) and vision-related quality of life as measured by the Glaucoma Activity Limitation Questionnaire (GAL-9) at 24-months. Safety measures included postoperative visual acuity, any unplanned return to the operating theatre, adverse events, and complications. RESULTS: Participants (67.3% male) were aged 53 to 85 years, and treatment groups were similar in terms of mean medicated IOP (treatment group 17.7 mmHg ± 4.0; control group 17.1 mmHg ± 3.1), and number of ocular hypotensive medications (treatment group 1.69 ± 1.05; control group 1.80 ± 1.22) at baseline. At 24 months, the number of ocular hypotensive medications were 0.7 ± 0.9 in the treatment groups compared to 1.5 ± 1.9 in the control group, with an adjusted difference of 0.6 fewer medications per eye in the treatment group (95% CI 0.2-1.1, P = 0.008). In the treatment group, 57% of eyes were on no glaucoma medications compared to 36% in the control group. There was no significant difference in IOP between the 2 groups beyond the 4-weeks. There were no differences in patient-reported outcomes between the 2 groups. The visual outcomes and safety profiles were similar between the 2 groups. CONCLUSIONS: Combined cataract surgery with iStent Inject achieved a clinically- and statistically-significantly greater reduction in ocular hypotensive medication usage at 24-months compared to cataract surgery alone, with no significant difference in IOP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Two-year outcomes of Xen 45 gel stent implantation in patients with open-angle glaucoma: real-world data from the Fight Glaucoma Blindness registry.

OBJECTIVE: To evaluate efficacy and safety outcomes of the Xen 45 gel stent implant over 24 months of follow-up. METHODS: A retrospective analysis of prospectively collected data from the Fight Glaucoma Blindness observational registry. Complete success (CS) was defined as intraocular pressure (IOP) reduction ≥20% from preoperative and an IOP ≤18 mm Hg and ≥6 mm Hg with no secondary procedure at 2 years and without IOP-lowering medications. Qualified success (QS) was defined similarly, allowing the use of IOP-lowering medications. RESULTS: The Xen 45 gel stent implant was implanted in 646 eyes of 515 patients. Preoperative IOP was 21.4±7.6 (mean±SD) mm Hg on 2.7±1.3 IOP-lowering medication and mean deviation was -10.2±8.4 dB. After 24-month follow-up, IOP was 16.8±7.3 mm Hg (mean reduction of 21.7%) on 1.2±1.4 IOP-lowering medications. CS and QS rates at 24 months were 26% and 48%, respectively. CS and QS were higher in the Xen stand-alone group (33% and 52%, respectively) than in the Xen+cataract group (16% and 42%, respectively). Bleb needling was performed in 28.4% of cases, and 18% underwent a secondary procedure. CONCLUSIONS: The Xen 45 gel stent implant offers acceptable long-term efficacy for the treatment of open-angle glaucoma. However, there is a significant rate of reoperation and needling, and outcomes are less effective if combined with cataract surgery.

Independent radiologic review of the Gynecologic Oncology Group Study 0218, a phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer.

OBJECTIVES: Gynecologic Oncology Group Study 0218 (GOG-0218), a phase III, placebo-controlled trial in newly diagnosed stage III/IV ovarian cancer (OC), demonstrated a benefit in investigator (INV)-assessed progression-free survival (PFS) with bevacizumab (BEV) administered with and following carboplatin/paclitaxel (CP) for up to 15 months vs. CP alone. To determine the reliability of Response Evaluation Criteria in Solid Tumors (RECIST) in assessing disease progression (PD) in GOG-0218, an independent review of radiologic and clinical data (IRC) was conducted. METHODS: Blinded reviews followed RECIST 1.0 in accordance with the study protocol; PFS was analyzed in the intent-to-treat population. RESULTS: CP+BEV→BEV achieved a significant PFS improvement in both assessments. Hazard ratios for PFS (IRC: 0.623; 95% confidence interval [CI]: 0.503-0.772; p<0.0001 vs. INV: 0.624; 95% CI: 0.520-0.749; p<0.0001) and the improvement in median PFS (IRC: 19.1 and 13.1 months vs. INV: 18.2 and 12 months) were similar between IRC and INV assessments. There was high concordance between IRC- and INV-determined PD status (77%) and date (73%). Subgroup analyses were consistent with the primary IRC findings. Early and late discontinuation discordance measures showed no evidence of INV bias. CONCLUSION: IRC analysis confirmed a significant PFS improvement with CP+BEV→BEV vs. CP alone. Concordance was not influenced by extent of residual disease after cytoreductive surgery or initial stage. The IRC size, high participation rate, and strong concordance between IRC and INV assessments suggest that RECIST can be applied objectively in OC studies.

Performance of a Smart Device over 12-Months for Home Monitoring of Patients with Intermediate Age-Related Macular Degeneration.

BACKGROUND: To determine the 12-month compliance with and retention of home monitoring (HM) with Melbourne Rapid Fields (MRFh) for patients with intermediate age-related macular degeneration (iAMD) and compare visual acuity (VA) and retinal sensitivity (RS) results to clinical measures. METHODS: Participants were recruited to a 12-month HM study with weekly testing of vision with MRFh. Inclusion criteria were a diagnosis of iAMD, understand English instructions, VA ≥ 20/40, and access to an iPad. Supervised in-clinic testing of high contrast VA (HVA, ETDRS), low-luminance VA (LLVA, ETDRS with ND2 filter), and RS (Macular Integrity Assessment, MAIA, and MRF in-clinic, MRFc) was conducted every 6-months. RESULTS: A total of 54 participants (67 ± 6.8 years) were enrolled. Compliance to weekly HM was 61% and study retention at 12-months was 50% of those with uptake (n = 46). No difference was observed between MRFc and MRFh across all RS and VA outcomes (p > 0.05). MRFh RS was higher than MAIA (29.1 vs. 27.1 dB, p < 0.001). MRFh HVA was not different from ETDRS (p = 0.08), but LLVA was 9 letters better (81.5 vs. 72.4 letters, p < 0.001). CONCLUSIONS: Over 12-months, MRFh yields a moderate level of compliance with (61%) and retention (50%) of weekly testing. Further studies are required to assess the ability of MRFh to detect early progression to nAMD.

Progressive multifocal leukoencephalopathy with natalizumab extended or standard interval dosing in the United States and the rest of the world.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited. RESEARCH DESIGN AND METHODS: A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems. RESULTS: Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis. CONCLUSIONS: This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Test Reliability and Compliance to a Twelve-Month Visual Field Telemedicine Study in Glaucoma Patients.

Background: Our primary aim is to quantify test reliability and compliance of glaucoma patients to a weekly visual field telemedicine (VFTM) schedule. A secondary aim is to determine concordance of the VFTM results to in-clinic outcomes. Methods: Participants with stable glaucoma in one eye were recruited for a 12 month VFTM trial using the Melbourne Rapid Fields (MRF-home, MRFh) iPad application. Participants attended routine 6 month clinical reviews and were tasked with weekly home monitoring with the MRFh over this period. We determined compliance to weekly VFTM (7 + 1 days) and test reliability (false positives (FPs) and fixation loss (FL) <33%). A secondary aim considered concordance to in-clinic measures of visual field (MRF-clinic (MRFc) and the Humphrey Field Analyzer (HFA)) in active participants (≥10 home examinations and 5 reliable HFA examinations). The linear trend in the MRFh mean deviation (MD) was compared to the HFA guided progression analysis (GPA) using Bland−Altman methods. Data are shown as the mean ± standard deviation. Results: Forty-seven participants with a mean age of 64 ± 14.6 years were recruited for the trial. The VFTM uptake was 85% and compliance to weekly home monitoring was 75% in the presence of weekly text reminders in the analysed group (n = 20). The analysed group was composed of test subjects with five reliable in-clinic HFA examinations (GPA analysis available) and who submitted a minimum of 10 MRFh examinations from home. Of the 757 home examinations returned, approximately two-thirds were reliable, which was significantly lower than the test reliability of the HFA in-clinic (MRFh: 65% vs. HFA: 85%, p < 0.001). The HFA-GPA analysis gave little bias from the MRFh slope (bias: 0.05 dB/yr, p > 0.05). Two eyes were found to have clinical progression during the 12 month period, and both were detected by VFTM. Conclusions: VFTM over 12 months returned good compliance (75%) to weekly testing with good concordance to in-clinic assays. VFTM is a viable option for monitoring patients with glaucoma for visual field progression in between clinical visits.

The Short-Term Compliance and Concordance to in Clinic Testing for Tablet-Based Home Monitoring in Age-Related Macular Degeneration.

PURPOSE: 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. DESIGN: Single-center longitudinal compliance and reliability study. METHODS: 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. RESULTS: 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 results <25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P < .05) compared to the MaIA. CONCLUSIONS: 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.

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial.

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.

Optic disc evaluation in optic neuropathies: the optic disc assessment project.

OBJECTIVE: Optic nerve morphology is affected by genetic and acquired disease. Glaucoma is the most common optic neuropathy; autosomal-dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON) are the most prevalent hereditary optic neuropathies. These 3 entities can exhibit similar topographical changes at the optic nerve head. Both ADOA and LHON have been reported to be misdiagnosed as glaucoma. Our aim was to determine whether glaucoma subspecialists and neuro-ophthalmologists can distinguish these diagnoses on optic disc assessment alone. DESIGN: Observational study. PARTICIPANTS: Twenty-three optic nerve experts. METHODS: We randomized and masked 60 high-resolution stereoscopic optic disc photographs (15 ADOA images, 15 LHON, 15 glaucoma, and 15 normal controls). Experts were asked to assess the discs on 12 conventional topographic features and assign a presumptive diagnosis. Intra- and interanalysis was performed using the index of qualitative variation and absolute deviation. MAIN OUTCOME MEASURES: Can glaucoma specialists and neuro-ophthalmologists distinguish among the disease entities by optic nerve head phenotype. RESULTS: The correct diagnosis was identified in 85%, 75%, 27%, and 16% of the normal, glaucoma, ADOA, and LHON disc groups, respectively. The proportion of correct diagnoses within the ADOA and LHON groups was significantly lower than both normal and glaucomatous (P<0.001). Where glaucoma was chosen as the most likely diagnosis, 61% were glaucomatous, 34% were pathologic but nonglaucomatous discs, and 5% were normal. There was greater agreement for individual parameters assessed within the normal disc set when compared with pathologic discs (P<0.05). The only parameter to have a significantly greater agreement within the glaucomatous disc set when compared with ADOA or LHON disc sets was pallor, whereby experts agreed on is absence in the glaucomatous discs but were not in agreement on its presence or its absence in the ADOA and LHON discs (P<0.01). CONCLUSIONS: Optic neuropathies can result in similar topographic changes at the optic disc, particularly in late-stage disease, making it difficult to differentiate ADOA and LHON from glaucoma based on disc assessment alone. Other clinical parameters such as acuity, color vision, history of visual loss, and family history are required to make an accurate diagnosis.

Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies.

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.

Uptake, Persistence, and Performance of Weekly Home Monitoring of Visual Field in a Large Cohort of Patients With Glaucoma.

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.

Screening for Glaucomatous Visual Field Defects in Rural Australia with an iPad.

AIM AND OBJECTIVE: Developing improved methods for early detection of visual field defects is pivotal to reducing glaucoma-related vision loss. The Melbourne Rapid Fields screening module (MRF-S) is an iPad-based test, which allows suprathreshold screening with zone-based analysis to rapidly assess the risk of manifest glaucoma. The versatility of MRF-S has potential utility in rural areas and during infectious pandemics. This study evaluates the utility of MRF-S for detecting field defects in non-metropolitan settings. MATERIALS AND METHODS: This was a prospective, multicenter, cross-sectional validation study. Two hundred and fifty-two eyes of 142 participants were recruited from rural sites through two outreach eye services in Australia. Participants were tested using MRF-S and compared with a reference standard; either Zeiss Humphrey Field Analyzer or Haag-Streit Octopus performed at the same visit. Standardized questionnaires were used to assess user acceptability. Major outcome measures were the area under the curve (AUC) for detecting mild and moderate field defects defined by the reference tests, along with corresponding performance characteristics (sensitivity, specificity). RESULTS: The mean test duration for MRF-S was 1.88 minutes compared with 5.92 minutes for reference tests. The AUCs for mild and moderate field defects were 0.81 [95% confidence interval (CI): 0.75-0.87] and 0.87 (95% CI: 0.83-0.92), respectively, indicating very good diagnostic accuracy. Using a risk criterion of 55%, MRF-S identified moderate field defects with a sensitivity and specificity of 88.4 and 81.0%, respectively. CONCLUSION AND CLINICAL SIGNIFICANCE: The MRF-S iPad module can identify patients with mild and moderate field defects while delivering favorable user acceptability and short test duration. This has potential application within rural locations and amidst infectious pandemics. HOW TO CITE THIS ARTICLE: Chia MA, Trang E, Agar A, et al. Screening for Glaucomatous Visual Field Defects in Rural Australia with an iPad. J Curr Glaucoma Pract 2021;15(3):125-131.

Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study.

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.