Search

Background and purpose: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS. Methods: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters. Results: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre‐baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] −5.6, 14.2) across all follow‐up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], −6.9 pg/mL, IQR −20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR −1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course. Conclusion: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis‐generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors. [ABSTRACT FROM AUTHOR]

Background and purpose: Data on maintenance therapy with subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG) are limited. We report on transitioning acetylcholine receptor (AChR) antibody‐positive (Ab+) MG patients on stable intravenous immunoglobulin (IVIg) regimens as part of routine clinical care to SCIg 1:1.2. Methods: This multicenter North American open‐label prospective investigator‐initiated study had two components: the IVIg Stabilization Period (ISP) enrolling patients already on IVIg as part of routine clinical care (Weeks −10 to −1), followed by transition of stable MG subjects to SCIg in the Experimental Treatment Period (ETP; Weeks 0 to 12). We hypothesized that >65% of patients entering the ETP would have a stable Quantitative Myasthenia Gravis (QMG) score from Week 0 to Week 12. Secondary outcome measures included other efficacy measures, safety, tolerability, IgG levels, and treatment satisfaction. Results: We recruited 23 patients in the ISP, and 22 entered the ETP. A total of 12 subjects (54.5%) were female, and 18 (81.8%) were White, with mean age 51.4 ± 17 years. We obtained Week 12 ETP QMG data on 19 of 22; one subject withdrew from ETP owing to clinical deterioration, and two subjects withdrew due to dislike of needles. On primary analysis, 19 of 22 participants (86.4%, 95% confidence interval = 0.72–1.00) were treatment successes using last observation carried forward (p = 0.018). Secondary efficacy measures supported MG stability. SCIg was safe and well tolerated, and IgG levels were stable. Treatment satisfaction was comparable between ISP and ETP. Conclusions: MG patients on IVIg as part of their routine clinical care remained stable on monthly IVIg dosage, and most maintained similar disease stability on SCIg. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN). Methods: We implemented a Bayesian adaptive design to perform a 12‐wk multisite, randomized, prospective, open‐label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)‐12, pain interference, fatigue, and sleep disturbance, were collected. Results: Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF‐12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy. Discussion: Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence‐based treatment strategies. See Editorial on pages 380‐381 in this issue [ABSTRACT FROM AUTHOR]

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 two 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 score, 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% confidence interval [CI], 39%‐70.8%) and severity decreased by 46.3% (95% CI, 29.5‐63.3%), 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/day, 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. [ABSTRACT FROM AUTHOR]

Introduction/Aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Methods: Twenty‐two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double‐blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358Ala polymorphism of the interleukin 6 receptor (IL‐6R) gene. Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C‐reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (−3.0‐fold relative change, P <.001). CSF CRP reduction (−1.8‐fold relative change, P =.01) was associated with IL‐6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups. Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL‐6R Asp358Ala genotype. IL‐6 trans‐signaling may mediate a distinct central nervous system response in individuals inheriting the IL‐6R C allele. These results warrant further study in ALS patients where IL‐6R genotype and CRP levels may be useful enrichment biomarkers. [ABSTRACT FROM AUTHOR]

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications. [ABSTRACT FROM AUTHOR]

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 (ρ = -0.71, P < .001) and FF (ρ = -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. [ABSTRACT FROM AUTHOR]

While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed. [ABSTRACT FROM AUTHOR]

Immunosuppressive and immunomodulatory therapies have had a major effect on the treatment of immune-mediated neuromuscular diseases. After the landmark introduction of synthetic corticosteroids, other therapies have become available, including plasma exchange (PLEX), immunoglobulin G (IgG), and steroid-sparing immunosuppressive drugs. More recently, novel biologically derived and antigen-specific pharmaceuticals have entered neuromuscular practice. Various levels of evidence guide the use of these treatments. This article reviews current immune-based therapies in neuromuscular diseases and is divided into two parts. Part I provides an update on the evidence and use of traditional therapies, such as corticosteroids, PLEX, intravenously delivered IgG (IVIG), and steroid-sparing immunosuppressive drugs. Part II focuses on the recently US Food and Drug Administration-approved therapies eculizumab and subcutaneous IgG (SCIG), the current indications for rituximab in neuromuscular disease, and on novel immunosuppressive therapeutic approaches under development. [ABSTRACT FROM AUTHOR]

Introduction: The Inclusion Body Myositis Functional Rating Scale (IBMRFS) is a 10-item clinician-rated ordinal scale developed for people with inclusion body myositis.Methods: Single observations of the IBMFRS were collected from 132 patients. After Rasch analysis, modifications were made to the scale to optimize fit to the Rasch model while maintaining clinical validity and utility.Results: The original IBMFRS did not fit the assumptions of the Rasch model because of multidimensionality of the scale. Items assessed local dependence, disordered step thresholds, and differential item functioning. Deconstructing the scale into upper limb (IBMFRS-UL) and lower limb (IBMFRS-LL) scales improved fit to the Rasch model. A 9-item scale with the swallowing item removed (IBMFRS-9) remained multidimensional but demonstrated the ability to discriminate patients along the severity continuum. IBMFRS-UL, IBMFRS-LL, and IBMFRS-9 scores were transformed to a 0-100 scale for comparability.Discussion: This analysis has led to the development of 3 optimized versions of the IBMFRS. Muscle Nerve 60: 161-168, 2019. [ABSTRACT FROM AUTHOR]

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy.Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients.Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019. [ABSTRACT FROM AUTHOR]

Introduction: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS).Methods: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting.Results: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events.Discussion: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019. [ABSTRACT FROM AUTHOR]

Objective To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. Results Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) 'probable IIM,' had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to 'definite IIM.' A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as 'possible IIM.' Conclusion The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of 'definite,' 'probable,' and 'possible' IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria. [ABSTRACT FROM AUTHOR]

Objective Myasthenia gravis ( MG) is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors ( AChR) or, in a minority of patients, to muscle specific kinase (Mu SK). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two MG subtypes ( AChR or Mu SK). The antibodies are thought to be T-cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of MG. Methods An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors ( BCR) in naive populations was applied to specimens collected from patients with either AChR or Mu SK MG and healthy controls. Radioimmuno- and cell-based assays were used to measure BCR binding to AChR and Mu SK. Results The frequency of polyreactive and autoreactive BCRs ( n = 262) was higher in both AChR and Mu SK MG patients than in healthy controls. None of the MG-derived BCRs bound AChR or Mu SK. Interpretation The results indicate that both these MG subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in MG and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells. [ABSTRACT FROM AUTHOR]

Introduction: In this study we evaluated the safety, tolerability, and efficacy of prednisone in patients with ocular myasthenia gravis (OMG) concurrently treated with pyridostigmine.Methods: This investigation was a randomized, double-blind, placebo-controlled trial. Participants whose symptoms failed to remit on pyridostigmine were randomized to receive placebo or prednisone, initiated at 10 mg every other day, and titrated to a maximum of 40 mg/day over 16 weeks. The primary outcome measure was treatment failure.Results: Fewer subjects were randomized than the 88 planned. Of the 11 randomized, 9 completed 16 weeks of double-blind therapy. Treatment failure incidence was 100% (95% CI 48%-100%) in the placebo group (n = 5) vs. 17% (95% CI 0%-64%) in the prednisone group, P = 0.02 (n = 6). Median time to sustained minimal manifestation status (MMS) was 14 weeks, requiring an average prednisone dose of 15 mg/day. Adverse events were infrequent and generally mild in both groups.Conclusions: A strategy of low-dose prednisone with gradual escalation appears to be safe, well-tolerated, and effective in treating OMG. [ABSTRACT FROM AUTHOR]

Objective To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti-Mi-2, anti-signal recognition particle, anti-transcription intermediary factor 1γ [TIF-1γ], anti-MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement. Results In the final multivariable model, the presence of an antisynthetase, primarily anti-Jo-1 (hazard ratio [HR] 3.08, P < 0.01), anti-Mi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations. Conclusion Our findings indicate that the presence of antisynthetase and anti-Mi-2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). Results: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3-point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo ( P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo ( P < 0.0001). Eculizumab was well tolerated. Conclusion: The data suggest that eculizumab may have a role in treating severe, refractory MG. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

Objective To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. Methods Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. Results Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups ( P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. Conclusion Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design. [ABSTRACT FROM AUTHOR]

Prednisone is a frequently used treatment for myasthenia gravis (MG) but it has numerous side effects. Methotrexate is a selective inhibitor of dihydrofolate reductase and lymphocyte proliferation and is an effective immuosuppressive medication for autoimmune diseases. Given the negative results of the mycophenolate mofetil study, search for an effective immunosuppressant drug therapy is ongoing. The objective is to determine if oral methotrexate is safe and effective for MG patients who take prednisone. We have initiated a randomized, double-blind, placebo-controlled multicenter trial of methotrexate versus placebo in patients taking at least 10 mg/day of prednisone at enrollment. The methotrexate dose is increased to 20 mg and the prednisone dose is adjusted per protocol during the study. Clinical and laboratory evaluations are performed monthly for 12 months, with the primary efficacy measure being the nine-month prednisone area under the curve (AUC) from months 3 to 12. Secondary outcome measures include MG outcomes, quality of life measures, and a polyglutamation biomarker assay. A total of 18 U.S. sites and 2 Canadian sites are participating, with 48 screened cases, 42 enrolled, with 19 still active in the study. [ABSTRACT FROM AUTHOR]

Introduction: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. Methods: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. Results: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. Conclusion: QMA is an automated, non-invasive technique for evaluating myotonia in NDM. Muscle Nerve 46: 482-489, 2012 [ABSTRACT FROM AUTHOR]

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Methods: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease. Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

Introduction: Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM. Methods: Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits. Results: We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness. Conclusions: IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM. Muscle Nerve 44: 30-35, 2011 [ABSTRACT FROM AUTHOR]

Defining long-term outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) has been complicated by varying definitions of treatment response and differing scales measuring impairment or disability. An expert panel was convened to devise a CIDP Disease Activity Status (CDAS) and to classify long-term outcome by applying it to 106 patients with a consensus diagnosis of CIDP. Sixty of these cases were graded blindly by three independent reviewers to assess inter-rater reliability. The mean duration of follow-up was 6.4 years (range, 3 months-23 years). Eleven percent of patients were classified as cured (stable examination and off treatment for ≥5 years), 20% were in remission (stable and off treatment for <5 years), 44% had stable active disease but required ongoing therapy for at least 1 year, 7% were improving after recent initiation of therapy, and 18% had unstable active disease (treatment naïve or treatment refractory). Excellent inter-rater reliability was observed (kappa scores: 0.93-0.97; p < 0.0001). The CDAS is considered a simple and reproducible tool to classify patients with CIDP according to disease activity and treatment status that can be applied easily in practice and potentially to select patients for clinical trials. [ABSTRACT FROM AUTHOR]

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 (≥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. Muscle Nerve, 2009 [ABSTRACT FROM AUTHOR]

Objective Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. Methods We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. Results Stage 1 selected the 2,700mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700mg/day and placebo. There were no safety concerns. Interpretation CoQ10 at 2,700mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. Ann Neurol 2009;66:235-244 [ABSTRACT FROM AUTHOR]

Twenty ALS patients with sialorrhea refractory to medical therapy were enrolled in this double-blind, randomized study to receive either 2,500 U of botulinum toxin type B (BTxb) or placebo into the bilateral parotid and submandibular glands using electromyographic guidance. Patients who received BTxb reported a global impression of improvement of 82% at 2 weeks compared to 38% of those who received placebo ( P < 0.05). This significant effect was sustained at 4 weeks. At 12 weeks, 50% of patients who received BTxb continued to report improvement compared to 14% of those who received placebo. There were no significant adverse events, including dysphagia, in the BTxb group, and there was no significant increase in the rate of decline of vital capacity. Muscle Nerve 39: 137-143, 2009 [ABSTRACT FROM AUTHOR]

We determined the strength of correlation among, and responsiveness of, outcome measures used in a multicenter, double-blind, placebo-controlled trial of mycophenolate mofetil in combination with prednisone in myasthenia gravis (MG). The primary efficacy measure was the change from baseline in the Quantitative MG (QMG) score at week 12. Secondary outcome measures included the MG-Activities of Daily Living profile (MG-ADL) and MG Manual Muscle Test (MMT). The measures were collected at baseline and at weeks 4, 8, and 12 in the blinded study and at weeks 16, 20, 28, and 36 in an optional open-label extension. At baseline, the QMG was moderately correlated with the MG-ADL ( r = 0.55, P < 0.0001) and the MMT ( r = 0.53, P < 0.0001), but the correlation between the MG-ADL and the MMT was lower ( r = 0.30, P = 0.007). These findings were similar at weeks 4, 8, and 12. Similar correlations were found among the changes in scores from baseline at weeks 12 and 36. The MMT and MG-ADL appeared to be the most sensitive measures for changes in MG status at weeks 12 and 36. Although a task force has recommended use of the QMG in prospective MG trials, the MMT and MG-ADL appear to be suitable alternatives and offer potential advantages. No special training or equipment is required, and they take less time. © 2008 Wiley Periodicals, Inc. Muscle Nerve 38: 1429-1433, 2008 [ABSTRACT FROM AUTHOR]

Although once an often fatal illness, myasthenia gravis can now be well managed with relatively safe and effective therapies. Prior to 1960 mortality for myasthenia gravis was approximately 30%. In the current era, mortality should be less than 5%. Major therapeutic advances by decade were: physostigmine and thymectomy (1930s); mechanical ventilation (1950s); corticosteroids and plasmapheresis (1960s); azathioprine (1960s–1970s); cyclosporine (1980s); intravenous gamma globulins (1980s–1990s); and most recently mycophenolate mofetil (1990s–2000s). Modern management involves a graded approach, beginning with cholinesterase inhibitors for mild symptoms and advancing to immunomodulating medications for more severe weakness. We now have several immunomodulating agents from which to choose: selection is based largely on time to clinical effect and adverse effects. The various available treatment modalities all have their limitations. In addition, some controversies remain regarding the effectiveness of some of the commonly used myasthenia gravis treatments. Recently completed and ongoing clinical trials suggest that there is still equipoise regarding the benefit of mycophenolate mofetil and thymectomy. Hopefully, the future will be promising, with clinical trials involving novel immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy). Methods This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1mg/kg; Cohort 2 at 3mg/kg; Cohort 3 at 10mg/kg; Cohort 4 at 30mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic absorptiometry studies, and muscle biopsy. Results MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology. Interpretation This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

The spectrum of motor neuron diseases ranges from disorders that clinically are limited to lower motor neurons to those that exclusively affect upper motor neurons. Primary lateral sclerosis (PLS) is the designation for the syndrome of progressive upper motor neuron dysfunction when no other etiology is identified. Distinction between PLS and the more common amyotrophic lateral sclerosis (ALS) relies primarily on recognition of their symptoms and signs, as well as on ancillary, although non-specific, laboratory data. In this review, we survey the history of PLS from the initial descriptions to the present. We discuss the role of laboratory, electrodiagnostic, and imaging studies in excluding other diagnoses; the findings from major case series of PLS patients; and proposed diagnostic criteria. Consistent differences are evident in patients classified as PLS compared to those with ALS, indicating that, despite its limitations, this clinical designation retains important utility. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]