Faculty Bibliography

BACKGROUND:Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening-minimum rim width (BMO-MRW) thickness in MS remains unclear. METHODS:Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships. RESULTS:The MS cohort exhibited significantly lower BMO-MRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P < 0.001 for all), and GCIPL (P < 0.001) thicknesses than HCs. BMO-MRW thickness was associated with 100%-VA (P < 0.001, R = 0.08), 2.5%-LA (P < 0.001; R = 0.13), and 1.25%-LA (P = 0.002; R = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P < 0.001). GCIPL thickness was more strongly associated with 100%-VA (P < 0.001; R = 0.23), 2.5%-LA (P < 0.001; R = 0.27), and 1.25%-LA (P < 0.001; R = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores. CONCLUSIONS:BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process.

OBJECTIVE:To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS:Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established post-mortem. RESULTS:Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post-mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION/CONCLUSIONS:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies. This article is protected by copyright. All rights reserved.

Introduction: Natalizumab treatment in patients with early relapsing-remitting multiple sclerosis (RRMS) may improve clinical outcomes. STRIVE is a completed, 4-year, multicentre, observational, open-label, single-arm study of anti-JC virus antibody negative patients starting natalizumab < 3 years after RRMS diagnosis.
Objective(s): To examine 4-year, end-of-study no evidence of disease activity (NEDA) status, disability worsening and improvement, and cognitive performance of natalizumab-treated patients with early RRMS.
Method(s): Clinical NEDA, the primary endpoint, was defined as no relapses or Expanded Disability Status Scale (EDSS) worsening (score increase of >=1.5 from a baseline [BL] of 0.0, >=1.0 from a BL of 1.0-5.5, or >=0.5 from a BL >=6.0, confirmed over 24 weeks). MRI NEDA was defined as no gadolinium-enhancing or new/enlarging T2-hyperintense lesions. Overall NEDA encompassed both clinical and MRI NEDA. Annualised relapse rates (ARRs) were analysed with a negative binomial regression model. The Kaplan-Meier method estimated time to 24-week-confirmed EDSS worsening or improvement (score decrease of >=1.0 from a BL >=2.0). The Symbol Digit Modalities Test (SDMT) change from BL to year 4 was analysed via a Wilcoxon signed-rank test.
Result(s): At BL (N=222), patients had active disease, a mean (standard deviation [SD]) of 1.4 (1.2) relapses in the prior year, and a mean (SD) EDSS score of 2.04 (1.13). At study end, 100 of 169 patients (59.2%) achieved cumulative clinical NEDA, and 72 of 143 (50.4%) and 45 of 163 (27.6%) had MRI and overall NEDA, respectively. In year 4, 101 of 134 patients (75.4%) had overall NEDA. ARRs decreased by 90.2%, from 1.43 in the year before natalizumab to 0.14 on natalizumab (P< 0.0001). Cumulative probabilities of EDSS worsening and improvement over 4 years were 19.3% and 43.9%, respectively. At study end, the mean (SD) EDSS score was 1.77 (1.55). From BL to year 4, patients had significant improvement in SDMT score (n=174; mean change from BL: 4.6 [95% confidence interval: 2.9-6.2]; P< 0.0001). Serious adverse events were reported in 25 of 222 patients (11.3%), with no cases of progressive multifocal leukoencephalopathy.
Conclusion(s): Natalizumab treatment over 4 years was associated with NEDA achievement, a 43.9% probability of disability improvement, a 19.3% probability of disability worsening, and significantly improved cognitive performance. These results support natalizumab's long-term effectiveness in early RRMS patients

BACKGROUND:STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS:Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS:The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS:These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT01485003 , registered 5 December 2011.