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INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in 2 sequential cohorts: 500 mg (Cohort 1) and 1000 mg (Cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale-revised, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2 respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% CI 39 to 70.8%) and severity decreased by 46.3% (95% CI 29.5 to 63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg daily with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial. more...

Introduction: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. Methods: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants utilizing a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test-retest reliability. Gait parameters in FSHD participants were compared to a normative data base, FSHD clinical severity score, manual muscle testing, and patient-reported functional disability. Results: Gait parameters in FSHD participants were significantly (p more...

Introduction Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM variables with muscle structure measured by MRI. Methods We evaluated 20 patients with FSHD at two centers, comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHZ) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF). Results While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (rho = -0.71, P < .001) and FF (rho = -0.74, P < .001). Discussion This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials. more...

Item does not contain fulltext OBJECTIVE: This study explores the use of quantitative data on strength and fatigability of orofacial muscles in patients with facioscapulohumeral muscular dystrophy (FSHD) and assesses the frequency of swallowing and communication difficulties and their relationship to orofacial muscle involvement. METHODS: We included 43 patients with FSHD and 35 healthy controls and used the Iowa Oral Performance Instrument (IOPI) to obtain quantitative measurements of strength and endurance of lip compression, cheek (buccodental) compression, and tongue elevation. For the assessment of swallowing and communication difficulties, we used the dysphagia-specific quality of life (SWAL-QOL) and Communicative Participation Item Bank questionnaires. RESULTS: Cheek compression strength was reduced in patients with FSHD compared to healthy controls. Dysphagia and difficulty with verbal communication were reported by 25% and 35% of patients, respectively, and correlated to cheek compression strength and endurance and to anterior tongue elevation endurance. Prolonged cheek compression or anterior tongue elevation endurance (decreased fatigability) made swallowing or speech problems less likely to occur. CONCLUSION: Cheek compression strength is the most sensitive IOPI measure for orofacial weakness in FSHD. Orofacial weakness contributes to dysphagia and speech difficulties in FSHD, which are both common, though generally mild. Higher endurance of orofacial muscles was associated with a lower chance of dysphagia or speech problems. More research is required for further refinement of the pattern of facial muscle involvement in FSHD and to provide new insights for improvement of speech and language therapy. more...

INTRODUCTION: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. METHODS: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test–retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient-reported functional disability. RESULTS: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84–0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures. DISCUSSION: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. more...