The authors have developed an MG activities of daily living (ADL) profile (MG-ADL)-a simple eight-question survey of MG symptoms. In 254 consecutive encounters with established MG patients, the authors compared scores from the MG-ADL to the quantitative MG score (QMG)-a standardized, reliable scale used in clinical trials. The mean MG-ADL score was 4.89+/-3.63. The mean QMG score was 10.80+/-5.70. Pearson's correlation coefficient was 0.583 (p < 0.001). The MG-ADL is an easy-to-administer survey of MG that correlates well with the QMG and can serve as a secondary efficacy measurement in clinical trials.

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Context Non-dystrophic myotonias (NDM) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally-limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in case studies and one single blind trial. As is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective To determine the effects of mexiletine for symptoms and signs of myotonia in NDM. Design, Setting, and Participation Fifty-nine patients with NDM participated in a randomized, double-blind, placebo-controlled two-period crossover study conducted between December 23, 2008 and March 30, 2011 at 7 neuromuscular referral centers in 4 countries, as part of the NIH-funded Rare Disease Clinical Research Network. Intervention Oral 200 mg mexiletine or placebo capsules three times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1 week wash-out between periods. Main Outcome Measures Patient-reported stiffness recorded on an interactive voice response diary (IVR) was the primary endpoint (1 ‘minimal’ to 9 ‘worst ever experienced’). Secondary endpoints included IVR-reported changes in pain, weakness, and tiredness, clinical myotonia assessment, quantitative grip myotonia, Individualized Neuromuscular Quality of Life (INQoL, percent of maximal detrimental impact), SF-36, electrophysiological exercise testing, and needle EMG. Results Mexiletine significantly improved patient-reported stiffness on the IVR. Because of a statistically significant interaction between treatment and period for this outcome, primary endpoint is presented by period (period 1 means were mexiletine 2.53 versus placebo 4.21, difference −1.68, 95% Confidence Interval [CI] −2.66, −0.706, P<0.001; period 2 means were mexiletine 1.60 versus placebo 5.27, difference −3.68, 95% CI −3.85, −0.139, P=0.04). Mexiletine improved the INQoL QOL score (mexiletine 14.0, placebo 16.7, difference −2.69, 95% CI −4.07, −1.30, P<0.001) and decreased handgrip myotonia on clinical exam (seconds: mexiletine 0.164, placebo 0.494, difference −0.330, 95% CI −0.633, −0.142, P<0.001). The most common adverse effect was gastrointestinal (9 mexiletine, 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 placebo, 1 mexiletine). One serious adverse event was determined to be not study-related. Conclusion In this preliminary study of patients with NDM, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration Clinicaltrials.gov identifier: NCT 00832000

We performed a retrospective chart review on 53 muscle-specific kinase antibody (MuSK-Ab)-positive myasthenia gravis (MG) patients at nine university-based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9-79 years. Twenty-seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long-term (> or =3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG-related death. This survey reinforces several cardinal features of MuSK-Ab-positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long-term outcome is favorable in about 60% of cases.

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

Using 42 strength and functional assessments recorded monthly, the natural history of amyotrophic lateral sclerosis (ALS) is described in 167 patients (98 men, 67 women) followed in five medical centers in the western United States. The mean age at onset was 57.4 years, and symptoms were present for 2.64 years before study entry. Although there was a highly variable rate of decline within the group of patients, there were no differences in rate of decline by age or gender. Older patients and women were weaker on entry. Forty-eight patients died during the study. The median survival was 4.0 years for the study cohort but 2.1 years for newly diagnosed cases. Decline in pulmonary function most closely correlated with death. Our results emphasize the importance of considering clinical variability in planning clinical trials. One possible strategy is to identify and stratify patients by rate of decline in pulmonary function since prospectively identifying homogeneous subgroups allows investigators to substantially reduce sample size in therapeutic trials.

We developed a disease-specific, 10-point functional rating scale for patients with inclusion body myositis (IBMFRS). The IBMFRS was utilized as a secondary outcome measure in a multicenter pilot trial of the clinical safety and tolerability of high-dose beta interferon-1a. In this trial, 28 IBM patients completed the IBMFRS at baseline and monthly for 6 months. The IBMFRS showed statistically significant correlations (P < 0.001) with maximal voluntary isometric contraction, manual muscle testing, handgrip dynamometry, and the amyotrophic lateral sclerosis (ALS) functional rating scale (ALSPRS). Compared to these other outcome measures, the IBMFRS was also the most sensitive measure of change over the course of the study.