Faculty Bibliography

BACKGROUND: Neuromyelitis optica (NMO) is an uncommon, life-threatening inflammatory demyelinating disorder. Recently, much has become known about its immunopathogenesis. However, optimal treatments, with expected outcomes, have not been established. OBJECTIVE: To evaluate the use and efficacy of rituximab for treating NMO. DESIGN: Retrospective multicenter case series of NMO patients treated with rituximab. SETTING: Seven tertiary medical centers in the United States and England. PATIENTS: Twenty-five patients (including 2 children), 23 of whom experienced relapses despite use of other drugs before rituximab. Extended follow-up of 7 previously reported patients is included. INTERVENTIONS: Infusions of rituximab at median intervals of 8 months. MAIN OUTCOME MEASURES: Annualized relapse rate and disability (expressed as Expanded Disability Status Scale score). RESULTS: At a median follow-up of 19 months, the median annualized posttreatment relapse rate was lower than the pretreatment rate (0 [range 0-3.2] vs 1.7 [range, 0.5-5] relapses, P < .001). Disability improved or stabilized in 20 of 25 patients (80%, P = .02). Two patients died during the follow-up period, 1 owing to a brainstem relapse and 1 owing to suspected septicemia. Infections were reported in 20% of patients. CONCLUSIONS: In NMO, treatment with rituximab appears to reduce the frequency of attacks, with subsequent stabilization or improvement in disability.

OBJECTIVE: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS). METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. RESULTS: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more 'consistent responders' in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. CONCLUSIONS: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks

BACKGROUND: we sought to assess how impairment (physiological/psychological) and disability (social/environmental) are associated with physical and leisure/recreation activity levels and quality of life (QOL) in people with moderate/severe multiple sclerosis (MS). We conducted a cross-sectional survey at the MS Comprehensive Care Center, Stony Brook University Hospital, Stony Brook, NY, of a convenience sample of 43 people (50 eligible) with MS and Expanded Disability Status Scale scores of 6.0 to 8.0. The main outcome measures were QOL measured by MSQOL-54, physical activity measured by Physical Activity Disability Scale, and leisure/recreation activity measured by Nottingham Leisure Questionnaire. We analyzed the canonical correlations among physical and leisure/recreation activity levels and (1) impairment and (2) QOL. RESULTS: higher levels of physical and leisure/recreation activity were associated with lower levels of apathy and depression and higher levels of cognition, self-efficacy, and QOL (physical and mental). Major barriers reported included fatigue, lack of motivation, and cost. CONCLUSION: impairments and social/environmental disabilities create barriers to physical and leisure/recreation activity. Additional research is needed to determine, for people with MS, what supports might increase participation in physical and leisure/recreation activities and whether this increase yields improved QOL.

OBJECTIVES: Pediatric-onset multiple sclerosis offers a unique window into early targets and mechanisms of immune dysregulation. It is unknown whether heightened T-cell reactivities documented in adult patients, to both target-organ and environmental antigens, emerge in parallel or develop as early or late events. Our objectives were to determine the presence, pattern, and specificity of abnormal T-cell reactivities to such antigens in the earliest stages of the multiple sclerosis process. METHODS: Peripheral T-cell proliferative responses to self-, dietary, and control antigens were blindly evaluated in a large cohort of well-characterized children (n = 172) with central nervous system (CNS) inflammatory demyelination (n = 63), recent-onset type 1 (insulin-dependent) diabetes mellitus (T1D; n = 41), nonautoimmune neurological conditions (n = 39), and healthy children (n = 29). RESULTS: Children with inflammatory demyelination, CNS injury, and T1D exhibited heightened T-cell reactivities to self-antigens, and these responses were not strictly limited to the disease target organs. Children with autoimmune disease and CNS injury also exhibited abnormal T-cell responses against multiple cow-milk proteins. Responses to specific milk epitopes distinguished T1D from inflammatory demyelination and other neurological diseases. INTERPRETATION: Abnormal T-cell reactivities to self- and environmental antigens manifest in the earliest clinical stages of inflammatory demyelination and T1D. The pattern of heightened T-cell reactivities implicates both shared and distinct mechanisms of immune dysregulation in the different autoimmune diseases. Abnormal T-cell responses in children with tissue injury challenge the prevailing view that CNS autoreactive cells inherently mediate the disease in early multiple sclerosis.