Faculty Bibliography

OBJECTIVE: To determine the predictors of longitudinal changes in fatigue based on pain, mood, and neurological impairment across multiple sclerosis (MS) subtypes. BACKGROUND: Fatigue is the most common symptom of MS but remains poorly understood. The New York State Multiple Sclerosis Consortium (NYSMSC) database offers a unique opportunity to longitudinally assess a variety of potential fatigue correlates in a very large and diverse MS sample. DESIGN/METHODS: This study examined baseline and 1-year follow-up data on 2768 patients drawn from the NYSMSC database regarding fatigability, pain, depressive symptoms, MS subtype, and expanded disability status scale (EDSS). Correlates and predictors of fatigue were assessed in correlational and multiple regression analyses. RESULTS: Baseline fatigue, pain, and depression accounted for 34.6% of the variance in 1-year follow-up fatigue scores. Fatigue was lower in relapsing-remitting subjects than in other MS subtypes. Fatigue consistently correlated at baseline and follow-up with depressive symptoms, pain severity, and EDSS. Changes in fatigue correlated with changes in other variables. CONCLUSIONS: Predictors of fatigue at 1 year include baseline fatigue, pain, mood, and EDSS. These symptoms are also correlated at baseline, follow-up, and in change scores. Identifying predictors of fatigue may facilitate patient management.

The diagnosis of pediatric multiple sclerosis (MS) is challenging due to its low frequency and the overlap with other acquired childhood demyelinating disorders of the central nervous system. To identify potential protein biomarkers which could facilitate the diagnosis, we used two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry to identify proteins associated with pediatric MS. Plasma samples from nine children with MS and nine healthy subjects, matched in aggregate by age and gender, were analyzed for differences in their patterns of protein expression. We found 12 proteins that were significantly up regulated in the pediatric MS group: alpha-1-acid-glycoprotein 1, alpha-1-B-glycoprotein, transthyretin, apoliprotein-C-III, serum amyloid P component, complement factor-I, clusterin, gelsolin, hemopexin, kininogen-1, hCG1993037-isoform, and vitamin D-binding protein. These results show that 2-DE in combination with mass spectrometry is a highly sensitive technique for the identification of blood-based biomarkers. This proteomic approach could lead to a new panel of diagnostic and prognostic markers in pediatric MS.

Baseline predictors of cognitive change were explored in a sample of persons with multiple sclerosis (MS). Potential predictors included demographic features, baseline clinical characteristics, and psychological state. Participants were 38 individuals diagnosed with either relapsing remitting or secondary progressive MS who did not meet criteria for a current major depressive episode. Subjects were tested at baseline and approximately 1 year in an ongoing longitudinal study of cognition in MS. Participants completed neuropsychological tests sensitive to impairment in MS. They also completed self-report measures of depression, anxiety, fatigue, apathy, and positive and negative affect. Baseline measures of negative affect (e.g., depressed mood, state anxiety, and negative affective state) consistently predicted cognitive change over the course of the study. Higher baseline levels of negative affect were associated with greater relative declines in cognitive performance. This longitudinal relation occurred in the absence of a cross-sectional relation between negative affect and overall cognition. High baseline negative affect particularly predicted a relative decline in episodic memory for newly learned verbal and visuospatial information. The negative affect measures were unique in their predictive value among all the baseline measures assessed. (JINS, 2009, 15, 53-61.)

Fatigue and quality of life are significant concerns in adult multiple sclerosis (MS) but little is known about these factors in pediatric MS. The present investigation evaluates fatigue and quality of life in 51 pediatric MS patients to determine the rate of fatigue and reduced quality of life and assesses the relations between these variables and clinical factors. Fatigue and quality of life were assessed by self- and parent-report via the PedsQL Multidimensional Fatigue Scale and the PedsQL Quality of Life Scale. One-sample t-tests determined if scores were below published data for healthy individuals. Moreover, scores falling one standard deviation from norms were considered mildly affected, with severe difficulties being defined as scores falling two or more standard deviations from norms. Associations between self- and parent-reported difficulties and clinical factors were examined via Pearson correlation analyses. In comparison with healthy samples, pediatric MS patients reported greater difficulties with respect to fatigue, sleep, cognition, physical limitations, and academics. In addition to significant difficulties on these factors, parents reported problems with respect to emotional functioning, and tended to report greater fatigue, sleep, and cognitive difficulties than were self-reported. Expanded Disability Status Scale score was the only neurologic variable significantly related to fatigue or quality of life scores. Fatigue was significantly correlated with reports of sleep difficulties, cognitive problems, and quality of life variables. These findings suggest that fatigue and poorer quality of life is a clear concern in pediatric MS, and is related to overall physical disability

BACKGROUND: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. METHODS: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit