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Background: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. Methods: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18?74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0?3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period?study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. Findings: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (?15?1% [IQR ?31?1 to 3?2] in the zilucoplan group vs ?16?3% [?43?8 to 5?9] in the placebo group; p=0?46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). Interpretation: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. Funding: Ra Pharmaceuticals (now part of UCB Pharma).

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.

Introduction/aims The Midwest has the highest regional prevalence of self-reported amyotrophic lateral sclerosis (ALS) in the US, but with limited epidemiological studies. We aimed to explore the characteristics of patients with ALS in the Midwest. Methods This was a retrospective cohort study of participants with ALS deceased between January, 2010 and September, 2020, registered with the ALS Association Mid-America Chapter. Demographics and clinical variables included gender, race/ethnicity, military status, site of onset, interventions (gastrostomy, non-invasive ventilation, tracheostomy), and visits to ALS Association-registered clinics. Disease characteristics were compared to the National ALS Registry, and survival analysis was performed followed by sample augmentation with historical data to estimate survival with hypothetical censoring. Results The database included 1447 participants with a mean age at diagnosis of 65.7±11.9 years ( >60 years at diagnosis: 72%). The median survival from symptom onset was 28.0 months [95% confidence limit: 26.3, 29.7]; sample augmentation increased this to 41.0 months [38.5, 43.5]. Bulbar onset disease and older age at diagnosis were associated with shorter survival. Participants not followed in ALS-Association registered clinics were more frequently male, had familial onset and tracheostomy. Veterans (N=298) were older at diagnosis but had similar survival after adjustment for age. Discussions Our cohort had an older age at onset and more frequent bulbar onset than the National ALS Registry, perhaps reflecting ascertainment biases in each registry. Prospective cohort studies with more clinical and functional data are needed to better characterize ALS in Midwest, veterans, and non-clinic populations, and to optimize care.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies characterized by considerable variability in severity, rates of progression and functional outcomes. Few studies follow FSHD cohorts long enough to understand predictors of disease progression and functional outcomes, creating gaps in our understanding, which impacts clinical care and the design of clinical trials. Efforts to identify molecularly targeted therapies create a need to better understand disease characteristics with predictive value to help refine clinical trial strategies and understand trial outcomes. Here we analysed a prospective cohort from a large, longitudinally followed registry of patients with FSHD in the USA to determine predictors of outcomes such as need for wheelchair use. This study analysed de-identified data from 578 individuals with confirmed FSHD type 1 enrolled in the United States National Registry for FSHD Patients and Family members. Data were collected from January 2002 to September 2019 and included an average of 9 years (range 0–18) of follow-up surveys. Data were analysed using descriptive epidemiological techniques, and risk of wheelchair use was determined using Cox proportional hazards models. Supervised machine learning analysis was completed using Random Forest modelling and included all 189 unique features collected from registry questionnaires. A separate medications-only model was created that included 359 unique medications reported by participants. Here we show that smaller allele sizes were predictive of earlier age at onset, diagnosis and likelihood of wheelchair use. Additionally, we show that females were more likely overall to progress to wheelchair use and at a faster rate as compared to males, independent of genetics. Use of machine learning models that included all reported clinical features showed that the effect of allele size on progression to wheelchair use is small compared to disease duration, which may be important to consider in trial design. Medical comorbidities and medication use add to the risk for need for wheelchair dependence, raising the possibility for better medical management impacting outcomes in FSHD. The findings in this study will require further validation in additional, larger datasets but could have implications for clinical care, and inclusion criteria for future clinical trials in FSHD.

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). Objective: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 –

INTRODUCTION/AIM Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP). METHODS Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies. RESULTS Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], -1.00 [P

Introduction/Aims In this study, we examined the social and health impacts of the coronavirus disease 2019 (COVID‐19) pandemic and social guidelines on people with muscular dystrophies. Methods A prospective de‐identified electronic survey was distributed to adults with self‐reported facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM), and limb‐girdle muscular dystrophy (LGMD) enrolled in national registries or with patient advocacy groups. The COVID‐19 Impact Survey was developed by muscular dystrophy experts in association with patient collaborators and advocacy groups. The Perceived Stress Scale was used to measure perceived stress. Results Respondents (n = 774: 56% FSHD; 35% DM, and 9% LGMD) were mostly women and middle‐aged (range 19–87 y). Rates of COVID‐19 infections were low (

Introduction: In this study, we examined the long-term social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic on people with muscular dystrophy. Methods: We modified our prior COVID-19 Impact Survey to assess impacts from the continuing pandemic using feedback from muscular dystrophy experts, patients, and advocacy group/registry representatives. The survey assessed COVID-19 medical history, and the effects of the pandemic on social aspects, muscle disease, and medical care. We also used the validated 10-item Perceived Stress Scale. The de-identified, electronic survey was distributed to adults with muscular dystrophy via international patient registries and advocacy group websites from February 8, 2021 to March 22, 2021. Results: Respondents (n = 1243 : 49% Facioscapulohumeral Muscular Dystrophy (FSHD); 43% Myotonic Dystrophy (DM), and 8% Limb-Girdle Muscular Dystrophy (LGMD)) were mostly women and middle-aged (range 18–90 years). Rates of COVID-19 infections were low at 8% with zero deaths. Reported recovery times were also short with only 9% reporting a recovery period greater than eight weeks, and 7% requiring hospitalization with one individual requiring a ventilator. Major challenges reported during the pandemic included stress management, particularly for those with LGMD (27%), and wearing a mask (24%). The majority reported a slight worsening of their disease state. Respondents reported moderate stress levels (stress score = 16.4; range = 0–39), with higher stress levels reported by women and those under age 30 years. Seventy-percent of participants who had telemedicine visits were satisfied with the encounters; however, most reported a preference for in-person visits. Conclusions: People with muscular dystrophy found ways to manage their stress and overcome obstacles during the COVID-19 pandemic. COVID-19 infection rates and medical complications were similar to a general population. Telemedicine visits may have a more permanent role in care.

Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD., This paper presents the development and validation of a patient‐reported Rasch‐built interval scale on activity and participation for facioscapulohumeral muscular dystrophy (FSHD‐RODS). The final 38‐inquiry scale met Rasch model expectations and showed adequate discriminative power, test‐retest reliability and validity. The use of this scale is recommended in the near future to determine the functional deterioration slope in facioscapulohumeral muscular dystrophy (FSHD) per year as a preparation for the upcoming clinical intervention trials in FSHD.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

Background: A decrement >10% detected during repetitive nerve stimulation (RNS) is supportive of considering a diagnosis of myasthenia gravis (MG). Several studies have found that most of this decrement is seen between 4 to 6 min post-exercise. However, there are not available studies analyzing if shorter timing would be sufficient. Objective: The objective of this study was to evaluate if RNS up to 2 min post-exercise is sufficient to detect a decrement response >10%. Methods: We performed a retrospective chart review study of patients referred to our neuromuscular clinic at The University of Kansas Medical Center with symptoms suggestive of MG from 2013 to 2017. Results: A total of 76 patients with MG and 100 controls were identified. A significant decrement was detected in 95% of MG patients with abnormal RNS within 2 minutes post-exercise. Conclusion: RNS up to 2 min post-exercise might be sufficient to detect a significant decrement in MG patients.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

Introduction: Amyloid myopathy is a rare presentation of systemic amyloidosis. Amyloid myopathy can be initially misdiagnosed as sporadic inclusion body myositis (IBM). Methods: We report 4 cases of amyloid myopathy clinically mimicking inclusion body myositis and initially thought to be phenotypically IBM by neuromuscular experts. Results: Case 1 is an 81-year-old woman who presented with distal arm and proximal leg asymmetric weakness (myopathy pattern 4). Case 2 is a 76-year-old man with primary systemic amyloidosis who presented with myopathy pattern 4 and progressive dysphagia for four years. Case 3 is an 82-year-old man with progressive myopathy pattern 4 weakness and swallowing difficulty. Case 4 is a 62-year-old man with progressive bilateral finger flexor weakness. Muscle biopsies in all 4 cases showed perivascular amyloid deposits Discussion: Amyloid myopathy may be clinically indistinguishable from IBM. Muscle biopsy is of critical importance in the evaluation of patients suspected to have IBM.

Introduction: Diagnostic criteria for CIDP have been proven useful for clinical trials. However, use of these criteria in clinics has been limited by time constraints and unknown usefulness in predicting outcomes. Methods: A retrospective chart review of CIDP patients at the University of Kansas seen between 2008 and 2014 was performed. We determined the diagnostic criteria fulfilled by each patient and assessed treatment responses. A positive response was defined by improvement sensory or motor examination as determined by a neuromuscular physician.Results: There were 38 total patients included in the study. The response rate to IVIG in patients who fulfilled EFNS/PNS criteria was 20/22 (90.1%). Among patients who fulfilled AAN criteria, 8/9 (88.9%) responded positively to IVIG. Slightly lower response rates were seen in patients fulfilling INCAT criteria and Saperstein criteria at 10/15 (66.7%) and 12/17 (70.6%), respectively.Discussion: EFNS/PNS and AAN criteria can similarly predict IVIG treatment response.

Introduction. Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods.xAn analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion. There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes.

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes—composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes—that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.

Background and ObjectivesTo perform a systematic review of published N-of-1 trials (e.g., single patient crossover trials) in neurologic disorders, including an assessment of methodologic quality and reporting.MethodsWe searched PubMed, MEDLINE, and Embase from inception date to the December 1, 2019, for reports on N-of-1 trials in neurologic disorders. Basic trial information on design, disease, intervention, analysis, and treatment success was extracted. Strengths and weaknesses of the N-of-1 trials were assessed with the Consolidated Standards of Reporting Trials extension for N-of-1 trials (CENT) 2015 criteria checklist and the Jadad score as measures of quality and reporting.ResultsWe retrieved 40 reports of N-of-1 trials in neurologic disorders (19 individual N-of-1 trials, 21 series of N-of-1 trials). Most N-of-1 trials were performed in neuromuscular and neurodegenerative/movement disorders. Unlike the majority of trials that studied the main symptom(s) of a chronic stable condition, 9 N-of-1 trials studied a stable chronic symptom of a progressive or acute neurologic disorder. Besides pharmacologic interventions, electric stimulation protocols and nutritional products were studied. A mean total CENT score of 20.88 (SD 9.10, range 0–43) and mean total Jadad score of 2.90 (SD 2.15, range 0–5) were found as methodologic measures of quality and reporting across all N-of-1 trials.DiscussionN-of-1 trials have been reported in numerous neurologic disorders, not only in chronic stable disorders, but also in progressive or acute disorders with a stable symptom. This indicates the emerging therapeutic area of N-of-1 trials in neurology. Methodologic quality and reporting of N-of-1 trials were found to be suboptimal and can easily be improved in future trials by appropriately describing the methods of blinding and randomization and following CENT guidelines. Because most N-of-1 trials remain unreported in medical literature, this systematic review probably represents only the tip of the iceberg of conducted N-of-1 trials in neurologic disorders. In addition to conventional trial designs, N-of-1 trials can help to bridge the gap between research and clinical care by providing an alternative, personalized level 1 evidence base for suitable treatments.

This study determined the frequency and impact of symptoms on quality of life (QoL) in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings.

Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

Background: Isolated bulbar amyotrophic lateral sclerosis (IBALS) is a regional variant of amyotrophic lateral sclerosis (ALS) with weakness restricted to the bulbar muscles for at least 2 years, and slower progression than generalized ALS. Bulbar-onset generalized ALS, by contrast, typically has a more rapid progression than limb-onset ALS.Objective: To characterize patients with IBALS and compare them to patients with isolated bulbar disease at presentation who progress to generalized ALS.Methods: We performed a retrospective chart review of patients seen in our ALS specialty clinic at the University of Kansas Medical Center between 2001-2011. Results: Of 543 patients seen in the ALS clinic, 150 presented with bulbar symptoms at disease onset: 28 (18.7%) had bulbar signs and no evidence of extremity involvement on exam or electrodiagnostic testing at their initial visit; and 14 (9.3%) had weakness restricted to the bulbar muscles after 2 years of follow up (IBALS). IBALS patients were 57.1% male, with a mean age of symptom onset of 60.8 years (range 39-77 years). The mean disease duration was 3.1 years (range of 2-8 years), with 50% mortality at a mean follow up of 3.5 years. Minimal denervation changes were seen in at least one limb in 6 subjects (42.9%). Other clinical features included: 4 subjects (28.6%) had cognitive impairment, 4 (28.6%) had pseudo-bulbar affect, and 5 subjects (35.7%) had impaired eye movements on smooth pursuit.Conclusion: Isolatred bulbar ALS IBALS is an identifiable restricted regional ALS pattern if there is no clinical limb weakness 2 years after symptom onset. It may have a slower progression from typical ALS. The biologic factors that account for the IBALS restricted pattern are unknown.

Introduction Limb-girdle muscular dystrophy (LGMD) consists of over 30 genetic conditions with varying clinical phenotypes primarily affecting pelvic girdle, shoulder girdle, and other proximal limb muscles. Studies focusing on the physical, mental, and social effects of this disease from the patient's perspective are limited. Methods Adults with LGMD were interviewed and asked to identify issues that have the greatest impact on their quality of life. Each interview was recorded, transcribed, coded, and analyzed. Results Participants provided 1385 direct quotes. One hundred sixty-five potential symptoms of importance were identified and grouped into 15 larger themes. The most frequently reported themes included limitations with mobility, difficulty performing activities, social role limitations, and emotional distress. Discussion There are multiple symptoms that alter the lives of adults with LGMD. These affect their physical, emotional, and social health, and may be amenable to medical intervention.

Limited resources are a challenge when planning comparative effectiveness studies of multiple promising treatments, often prompting study planners to reduce the sample size to meet the financial constraints. The practical solution is often to increase the efficiency of this sample size by selecting a pair of treatments among the pool of promising treatments before the clinical trial begins. The problem with this approach is that the investigator may inadvertently leave out the most beneficial treatment. This paper demonstrates a possible solution to this problem by using Bayesian adaptive designs. We use a planned comparative effectiveness clinical trial of treatments for sialorrhea in amyotrophic lateral sclerosis as an example of the approach. Rather than having to guess at the two best treatments to compare based on limited data, we suggest putting more arms in the trial and letting response adaptive randomization (RAR) determine better arms. To ground this study relative to previous literature we first compare RAR, adaptive equal randomization (ER), arm(s) dropping, and a fixed design. Given the goals of this trial we demonstrate that we may avoid 'type III errors' - inadvertently leaving out the best treatment - with little loss in power compared to a two-arm design, even when choosing the correct two arms for the two-armed design. There are appreciable gains in power when the two arms are prescreened at random.

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

Background To assess the feasibility of using automated capture of Electronic Medical Record (EMR) data to build predictive models for amyotrophic lateral sclerosis (ALS) outcomes. Methods We used an Informatics for Integrating Biology and the Bedside search discovery tool to identify and extract data from 354 ALS patients from the University of Kansas Medical Center EMR. The completeness and integrity of the data extraction were verified by manual chart review. A linear mixed model was used to model disease progression. Cox proportional hazards models were used to investigate the effects of BMI, gender, and age on survival. Results Data extracted from the EMR was sufficient to create simple models of disease progression and survival. Several key variables of interest were unavailable without including a manual chart review. The average ALS Functional Rating Scale – Revised (ALSFRS-R) baseline score at first clinical visit was 34.08, and average decline was − 0.64 per month. Median survival was 27 months after first visit. Higher baseline ALSFRS-R score and BMI were associated with improved survival, higher baseline age was associated with decreased survival. Conclusions This study serves to show that EMR-captured data can be extracted and used to track outcomes in an ALS clinic setting, potentially important for post-marketing research of new drugs, or as historical controls for future studies. However, as automated EMR-based data extraction becomes more widely used there will be a need to standardize ALS data elements and clinical forms for data capture so data can be pooled across academic centers. Electronic supplementary material The online version of this article (10.1186/s12883-018-1208-z) contains supplementary material, which is available to authorized users.

Title Eyelid myotonia and face stiffness in skeletal muscle sodium channelopathy Video Legend Video 1. Notice the delayed relaxation of the eyelids after forced eye closure (eyelid myotonia). Also, notice the full facial hair to prevent facial muscle stiffening exacerbation with cold weather. AuthorsSrijan Adhikari, MBBS, Jeffrey Statland, MD, Constantine Farmakidis, MD Authors information: Srijan Adhikari, MBBS, ORCID ID: 0000-0001-9653-3079, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAJeffrey Statland, MD, ORCID ID: 0000-0003-0790-5315 University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAConstantine Farmakidis, MD, ORCID ID: 0000-0002-4688-9224, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USA Corresponding Author Srijan Adhikari, MBBS,Department of Neurology,University of Kansas Medical Center,3901 Rainbow Boulevard., MS 2012,Kansas City, KS 66160sadhikari@kumc.edu Author Conflict of Interests Dr Adhikari has nothing to disclose.Dr. Statland reports grants from NIH, grants from MDA, grants from FSHD Society, grants from Friends of FSH Research, personal fees from Dyne, personal fees from Fulcrum, personal fees from Avidity, personal fees from MT Pharma, personal fees from Acceleron, personal fees from Sarepta, personal fees from Strongbridge, outside the submitted work. Dr. Farmakidis reports personal fees from Argnex, personal fees from Momenta, personal fees from Terumo BCT, outside the submitted work.

ObjectiveTo evaluate facial weakness in patients with FSHD to better define clinical signs, and pilot a facial weakness severity score.Methods87 FSHD patients and 55 controls were video recorded while performing seven facial tasks. The videos were assessed by three independent examiners to compile an overview of signs of facial weakness. Next, videos were semi-quantitatively assessed using a newly developed 4-point facial weakness score (FWS). This score was evaluated and correlated to other FSHD disease characteristics.ResultsPatients had lower scores on the total FWS than controls (mean score 43 ± 28, range 4–118, vs 14 ± 9, range 0–35,p p ConclusionThis study provides an overview of the clinical spectrum of facial weakness and its relation to other disease characteristics. The 4-point scale we introduced to grade the severity of facial weakness enables correlation of facial weakness to disease characteristics, but is not suited as clinical outcome measure for longitudinal studies.

Background: Motor neuron disorders are rare, progressive neurodegenerative diseases which affect multiple domains of motor function. The ability to assess function from home using an electronic medical record (EMR) would facilitate pragmatic studies. Objective: To develop a Patient Activity of Daily Living scale for Amyotrophic Lateral Sclerosis and other motor neuron disorders (PADL-ALS) to support large pragmatic trials. Methods: The Greater Plains Collaborative Clinical Data Research Network (GPC) developed and tested the feasibility of using the PADL-ALS. We convened patient and caregiver focus groups and in-person meetings to recommend changes to the ALS Functional Rating Scale-Revised (ALSFRS-R), which clarified language and added questions about pseudobulbar affect, pain, and faith. Feasibility was determined by conducting a survey of participants identified using EMR-computable phenotypes and returned via patient-preferred modalities. Results: Surveys were distributed to 1079 participants at nine GPC health systems. The survey response rate was 44.4% (range 12.9-57.66%): male to female ratio 1.56; 84% self-identified as a patient with ALS. Patient respondents used computers or tablets more frequently than caregivers responding on their behalf. The PADL-ALS correlated to clinic-performed ALSFRS-R within 4 weeks of survey completion (n=33, rho=0.93, Kansas only). The pseudobulbar affect question correlated to functional motor burden. Over 80% agreed to be contacted for future research opportunities. Conclusion: We demonstrated the feasibility of determining functional burden with the PADL-ALS using an EMR-computable phenotype. Future directions include implementing the PADL-ALS to answer pragmatic questions about ALS care.

Amyotrophic lateral sclerosis (ALS) is a multi‐system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine‐learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post‐mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS., Single nucleotide polymorphisms (SNPs) previously identified through genome‐wide association studies as risk factors for amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) further associate in a polygenic manner with risk for cognitive dysfunction in ALS and related disorders.

Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.

Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by a European investigator. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.

We describe our efforts to overcome barriers to patient engagement in facioscapulohumeral muscular dystrophy (FSHD) and offer a roadmap that can be replicated in other rare neurologic disorders. We implemented an engagement plan during Clinical Trial Readiness to Solve Barriers to Drug Development for FSHD (ReSolve), an 18-month, multisite, observational study of individuals with FSHD. Elements of our engagement plan included conducting focus groups during protocol development, patient involvement on the ReSolve external advisory committee, creation of a patient advisory committee, and collaboration with patient advocacy groups. Patient feedback led to adaptations in the study protocol and to changes in recruitment and retention methods. Patient engagement ensures that the patient voice contributes to multiple aspects of trial design and implementation. Our engagement efforts exemplify how collaboration with patients and families can be accomplished in FSHD and the resultant roadmap process may be replicable in other rare neurologic diseases.