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ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Background and ObjectivesPompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.MethodsNEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of −0.473 per year (−1.188 to 0.242) and −0.648 per year (−1.061 to −0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of −0.701 per year (−1.571 to 0.169) and −0.846 per year (−1.567 to −0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.Trial Registration InformationNCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1—August 19, 2013; NEO-EXT—February 27, 2014.

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

Background and Objectives We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada. Methods All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine. Results GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic. Discussion The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles. Trial Registration Information Clinical trial registration number: NCT02838368.

Contains fulltext : 229739.pdf (Publisher’s version ) (Closed access) 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.

ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. These disorders cause lifetime disability and impact quality of life. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis, therapeutic, genetic counseling, and research planning. Electrodiagnostic testing is useful in directing the diagnosis, but has several limitations: patient discomfort, time consuming, and significant overlap of findings in muscle channelopathies. Although genetic testing is the gold standard in making a definitive diagnosis, a mutation might not be identified in many patients with a well-supported clinical diagnosis of periodic paralysis. In the recent past, there have been landmark clinical trials in non-dystrophic myotonia and periodic paralysis which are encouraging as they demonstrate the ability of robust clinical research consortia to conduct well-controlled trials of rare diseases.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen‐Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522–530, 2018

Importance Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment’s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration ClinicalTrials.gov Identifier:NCT02260388

To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis and therapeutics. These disorders can cause lifetime disability and affect quality of life. There is no treatment of these disorders approved by the US Food and Drug Administration at this time. Recognition and treatment of symptoms might reduce morbidity and improve quality of life. This article summarizes the clinical manifestations, diagnostic studies, pathophysiology, and treatment options in nondystrophic myotonia, congenital myasthenic syndrome, and periodic paralyses.

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

Background: Chronic, excess zinc intake can result in copper deficiency and profound neurologic disease. However, when hyperzincemia is identified, the source often remains elusive. We identified four patients, one previously reported, with various neurologic abnormalities in the setting of hypocupremia and hyperzincemia. Each of these patients wore dentures and used very large amounts of denture cream chronically. Objective: To determine zinc concentration in the denture creams used by the patients as a possible source of excess zinc ingestion. Methods: Detailed clinical and laboratory data for each patient were compiled. Tubes of denture adhesives were analyzed for zinc content using dynamic reaction cell-inductively coupled plasma-mass spectrometry. Patients received copper supplementation. Copper and zinc levels were obtained post-treatment at varying intervals. Results: Zinc concentrations ranging from about 17,000 to 34,000 μg/g were identified in Fixodent and Poli-Grip denture creams. Serum zinc levels improved in three patients following cessation of denture cream use. Copper supplementation resulted in mild neurologic improvement in two patients who stopped using denture cream. No alternative source of excess zinc ingestion or explanation for hypocupremia was identified. Conclusion: Denture cream contains zinc, and chronic excessive use may result in hypocupremia and serious neurologic disease.

Antibodies to muscle-specific receptor tyrosine kinase (MuSK-Ab) are detected in approximately 40% of generalized acetylcholine receptor antibody (AChR-Ab)-negative myasthenia gravis (MG). Based on a growing number of clinical series, a MuSK-Ab-positive phenotype is emerging. Although these clinical patterns are not wholly distinct from either AChR-Ab-positive or seronegative (both AChR-Ab- and MuSK-Ab-negative) MG, they are still helpful in identifying these patients. Patients with MuSK-Ab-positive MG are predominantly female with more prominent cranial and bulbar involvement and more frequent crises than other populations of people with MG. Disease onset tends to be earlier, generally by the third or fourth decade. The yield of repetitive nerve stimulation with conventional limb muscles is lower in these patients, but at least three-fourths demonstrate decrements in facial-innervated muscles. Similarly, single-fiber electromyography of distal limb muscles tends to have a lower yield of abnormality in patients who are MuSK-Ab-positive than either AChR-Ab-positive or seronegative MG, whereas jitter is increased in nearly all patients who are MuSK-Ab-positive when proximal limb or cranial musculature is studied. Patients who are MuSK-Ab-positive are more likely to display poor tolerance of or a lack of improvement with anticholinesterase agents. Most are managed successfully with immunomodulatory therapies, although a higher proportion of patients with MuSK MG have a refractory course when compared to other generalized populations.

Objective: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. Methods: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. Results: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form–36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant ( p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). Conclusions: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. Classification of evidence: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

Neuromuscular channelopathies are heterogeneous disorders with marked phenotypic and genotypic variability. These include non-dystrophic myotonia (NDM), periodic paralysis (PP), and congenital myasthenic syndrome (CMS). Their diverse clinical manifestations remain a challenge in diagnosis and management to this date. These disorders impact quality of life and cause lifelong disabling symptoms. Treatment options are few and not FDA-approved. This is largely due to a paucity of large, randomized clinical trials in these rare diseases. Challenges of conducting such trials include the rarity of these disorders and the genetic heterogeneity. Physicians rely on off-label use of drugs to treat muscle channelopathies to reduce morbidity and improve quality of life. Besides pharmacological treatment, dietary modifications, lifestyle changes, awareness of triggers, and genetic counseling also play an important role in long-term disease management. This article reviews the current management strategies for neuromuscular channelopathies.

Von Hippel-Lindau (VHL) disease is an autosomal-dominant disorder characterized by central nervous system hemangioblastomas, retinal angioma, and renal cell carcinoma. Thymoma and autoimmune neurologic disorders have not been reported in association with VHL disease. We report a unique concurrence of antibody-positive myasthenia gravis and thymoma in a patient with VHL disease. Although this may be coincidental, a possible genetic link between thymoma and VHL is described.

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

Neuropathic pain management is an important aspect in the management of painful peripheral neuropathy. Anticonvulsants and antidepressants have been studied extensively and are often used as first-line agents in the management of neuropathic pain. In this article, data from multiple randomized controlled studies on painful peripheral neuropathies are summarized to guide physicians in treating neuropathic pain. Treatment is a challenge given the diverse mechanisms of pain and variable responses in individuals. However, most patients derive pain relief from a well-chosen monotherapy or well-designed polypharmacy that combines agents with different mechanisms of action.

To evaluate the disparity in authorship based on gender and nationality of institutional affiliation among journals from developed and developing countries.Original articles from two neuroscience journals, with a 5 year impact factor15 (Neuron and Nature Neuroscience) and from two neurology journals from a developing country (Neurology India and Annals of Indian Academy of Neurology) were categorized by gender and institutional affiliation of first and senior authors. Articles were further divided by the type of research (basic/translational/clinical), study/target population (adult/pediatrics/both) and field of neurology. Data was collected for the years 2002 and 2012.There are large disparities in authorship by women and from developing countries in high impact factor neuroscience journals. However, there was a non-statistical rise in female first and senior authorship over a 10 year period. Additionally there was a significant increase in first authorship from institutions based in developing countries in the two neuroscience journals examined (P0.05). In the two neurology journals based in India there was a significant increase in the number of articles published by international investigators between 2002 and 2012 (P0.05).Over the last decade, there has been a non-statistical increase in proportion of female first and senior authors, and a significant increase in authors from developing countries in high impact factor neuroscience journals. However they continue to constitute a minority. The disparity in authorship based on gender also exists in neurology journals based in a developing country (India).

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

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.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.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.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.

Background There have been a few case reports of motor neuron disease in association with Huntington disease (HD). Objective To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation. Design Case report. Setting University of Texas Southwestern Medical Center, Dallas. Patient A 69-year-old man with chorea and fasciculations. Interventions Genetic and electrophysiologic testing. Main Outcome Measures Genetic test result, electrophysiologic test result, and physical examination. Results A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination. Electrophysiologic studies revealed evidence of motor neuron disease. Genetic test showed CAG repeat of 40 on chromosome 4, confirming the diagnosis of HD. Conclusion Motor neuron disease can rarely occur in patients with HD and could be one of its presenting features.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). Methods: One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex®]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by ≥1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36® (SF-36) and the Rotterdam Handicap Scale (RHS). Results: In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7–8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role–physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4–5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Conclusions: Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy.

Objective : The objective of this study was to characterize the clinical features and natural history of primary lateral sclerosis (PLS). Background : PLS is a motor neuron disorder defined by corticospinal and corticobulbar tract dysfunction without clinically significant lower motor neuron involvement. Methods : We collected data from 25 patients with PLS seen in 2 academic neurology departments over a 5-year period. Results : The PLS population represented approximately 3% of acquired motor neuron disease cases seen during that period. Twenty-three patients (92%) presented with lower limb weakness, spasticity, or difficulty with ambulation. None presented with upper limb symptoms. Eleven patients (44%) developed bulbar symptoms. All patients had hyperreflexia and increased muscle tone. Muscle weakness was observed in 15 patients (60%) and tended to be mild and asymmetric. Needle electromyography (EMG) was normal or showed only fasciculations in 15 patients (60%); 10 patients had features of mild active denervation, consisting of fibrillation or positive sharp wave potentials, but the extent of these findings did not satisfy World Federation of Neurology electrophysiological criteria for the diagnosis of amyotrophic lateral sclerosis. Fourteen patients (52%) continued independent ambulation. Of the 10 patients with active denervation on EMG, 6 (60%) required a walker, scooter, or wheelchair at a mean follow up of 6.2 years. There were no fatalities over the 5-year period. Conclusions : Our experience supports the observation that PLS progresses more slowly than other forms of acquired motor neuron disease, particularly amyotrophic lateral sclerosis. Follow-up data suggest that patients with active denervation changes develop greater disability.

Treatment of neuropathic pain is the primary focus of management for many patients with painful peripheral neuropathy. Antidepressants and anticonvulsants are the two pharmacological classes most widely studied and represent first-line agents in the management of neuropathic pain. The number of pharmacological agents that have demonstrated effectiveness for neuropathic pain continues to expand. In the current review, we summarize data from randomized, controlled pharmacological trials in painful peripheral neuropathies. Although neuropathic pain management remains challenging because the response to therapy varies considerably between patients, and pain relief is rarely complete, a majority of patients can benefit from monotherapy using a well-chosen agent or polypharmacy that combines medications with different mechanisms of action.

Background Adult polyglucosan body disease (PGBD) is rare and typically presents with upper and lower motor neuron involvement and neurogenic bladder. Extrapyramidal features are unusual in PGBD and are presumed secondary to widespread pathology that includes the basal ganglia. There are no prior reports of Lewy bodies in PGBD. Objective To report a unique finding of Lewy bodies in a patient with PGBD. Report of a Case A 46-year-old woman initially presented with a 4-year history of resting tremor. The tremor responded to levodopa therapy. Several months later, she developed upper and lower motor neuron involvement and other clinical features of PGBD. A sural nerve biopsy specimen revealed intra-axonal polyglucosan bodies that confirmed the clinical diagnosis. Bulbar and limb weakness progressed, and she developed dementia. She died 6 years after onset. At autopsy, extensive polyglucosan body formation was found in many regions of the central nervous system. In addition, numerous α-synuclein staining Lewy bodies were observed in the substantia nigra, accompanied by marked neuron depopulation. Conclusions To our knowledge, this is the first report of adult PGBD associated with Lewy bodies and levodopa-responsive tremor. Although polyglucosan bodies were seen in substantia nigra, it is most likely that our patient had coexisting Parkinson disease.

Objective: To assess the outcome of chronic and critical ischemic monomelic neuropathy after revascularization. Background Chronic and critical limb ischemia is a known cause of monomelic neuropathy. Although revascularization improves rest pain, objective neuropathic improvement has not been adequately studied in prospective studies. Design/Methods: A prospective study was performed in 9 patients with critical limb ischemia. The contralateral limb was used as a control. Neurologic Symptom Score (NSS – range 0-15, sensory/motor), Neurologic Examination Score (NES – range 0-52, sensory/reflexes/motor), and electrophysiologic data were available for 5 patients at baseline and 6 months post revascularization. Results: The mean improvement in NSS was 6.6/15 (44%) in the revascularized limbs compared to 1.4/15 (9%) in the control limbs (p = 0.052). The mean improvement in NES was 3/52 (6%) in the revascularized limbs compared to 0/52 (0.3%) in the control limbs (p = 0.266). The sural sensory amplitude in the revascularized limbs was unchanged in 2, worsened in 2, and improved in 1 (absent to 7.8 µV). In the control limbs, this response worsened in 2, improved in 2, and was unchanged in 1. Improvement in conduction velocities of the peroneal and tibial motor responses were greater in revascularized than control limbs. Sympathetic skin response (SSR) was absent in three affected limbs at baseline, but were recordable post revascularization in two of these limbs. In the control limbs, SSR was present in 5/5 at baseline and 4/5 at 6 months. Conclusions: Improvement of symptoms, neurologic exam findings, and sympathetic function can be seen following revascularization in patients with chronic critical ischemic monomelic neuropathy. Disclosure: Dr. Absalom has nothing to disclose. Dr. Wolfe has received personal compensation for activities with Eli Lilly & Company, Talecris and Genzyme Corporation as a speaker and/or participant on an advisory board. Dr. Nations has received personal compensation for activities with Hilton Pharmaceuticals. Dr. Nations has received research support from Genzyme Corporation. Dr. Trivedi has nothing to disclose. Dr. Muppidi has nothing to disclose.

Objective: To describe genotype-phenotype correlations in non-dystrophic myotonia (NDM). Background NDM are heterogeneous disorders caused by mutations in skeletal muscle sodium (SCN4A) and chloride channel (CLCN1) genes. Although NDMs are distinct, it is at times difficult to distinguish them clinically. Design/Methods: 95 participants with NDM were recruited from 6 centers across the United States, England, and Canada. Mutational and clinical analyses were performed in 93. They were categorized into chloride channel (CLCN1), sodium channel (SCN4A), myotonic dystrophy type 2 (DM2), and unknown mutations. We included DM2 since they clinically present as NDM. We quantitated symptoms and myotonia measurements. Results: Of the 93 subjects reviewed, 29 had CLCN1, 31 SCN4A, and 7 DM2 mutations with 26 as yet unknown. Stiffness was the most prominent symptom in all subtypes and occurred earlier in the SCN (median-5 yrs) vs CLCN (10 yrs) and DM2 (35 yrs) (p=0.0001). Painful myotonia was reported in SCN (25/31), CLCN (16/29), and DM2 (5/7) (p=0.19). Episodic weakness was reported in all subtypes: 23/31 SCN, 12/29 CLCN, and 4/7 DM2. Frequency of fixed weakness was higher in DM2 (6/7) compared to SCN (7/30) and CLCN (9/29) (p=0.012). Muscle hypertrophy was most common in CLCN (21/29) followed by SCN (13/31). DM2 patients did not have hypertrophy. Eye closure myotonia was observed more in SCN (23/31) compared to CLCN (7/29) or DM2 (2/7) (p=0.0005). Grip myotonia warm-up was noted in 20/29 CLCN, 8/31 SCN, and 1/7 DM2 subjects. Paradoxical hand grip & eye closure myotonia was seen in 16/31 SCN. Conclusions: While clinical features can help differentiate various NDM subtypes, mutational analysis is required due to an overlap in the clinical findings in NDM patients. Supported by: NIH/Office of Rare Disease Research Network sponsored Consortium for Clinical Investigations of Neurological Channelopathies (CINCH). Disclosure: Dr. Trivedi has nothing to disclose. Dr. Bundy has nothing to disclose. Dr. Raja Rayan has nothing to disclose. Dr. Salajegheh has nothing to disclose. Dr. Statland has nothing to disclose. Dr. Venance has received personal compensation for activities with Genzyme Corporation. Dr. Wang has nothing to disclose. Dr. Fialho has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Gorham has nothing to disclose. Dr. Herbelin has nothing to disclose. Dr. Amato has received personal compensation for activities with MedImmune, Amgen, and Biogen Idec as a medical advisory board member. Dr. Hanna has nothing to disclose. Dr. Griggs has nothing to disclose. Dr. Barohn has received personal compensation for activities with Talecris Biotherapeutics, Genzyme Corporation and Speakers Bureau. Dr. Barohn has received research support from Alexion Pharmaceuticals.

The Non-Dystrophic Myotonias (NDM) are a group of skeletal muscle channelopathies caused by mutations in the chloride channel gene, CLCN1 or sodium channel gene, SCN4A. They can cause disabling stiffness, fatigue and weakness. There is anecdotal evidence that mexiletine may reduce stiffness but no randomised, double-blind, placebo-controlled trials have been done to date. We conducted an international, randomised, double-blind, placebo-controlled, crossover trial of 59 subjects with NDM. Participants were randomised to mexiletine 200 mg tds or placebo for 4 weeks, followed by a 1-week wash out, and then crossover to the alternate treatment for 4 weeks. Efficacy of the drug was monitored by daily patient reported symptom severity (stiffness, pain, weakness, tiredness) on a scale of 1–9. Improvement in stiffness was the primary outcome measure. Secondary outcome measures included a clinical assessment, quality of life, quantitative grip myotonia assessment and neurophysiological measurements of short and long exercise testing and myotonia on needle EMG. Mexiletine was found to significantly improve stiffness compared with placebo with a mean difference of 2.73 (p

Background Neurological involvement occurs rarely with systemic sclerosis (SSc). Only a few cases of transverse myelopathy have been reported in the setting of SSc. Objective To describe a patient with SSc who developed transverse myelitis that improved during a course of immunosuppression. Results A 30-year-old woman with SSc presented with subacute onset of bilateral lower extremity weakness and numbness. Results of magnetic resonance imaging and cerebrospinal fluid studies supported a diagnosis of transverse myelitis. The patient responded favorably to a course of corticosteroids and cyclophosphamide. No overlapping autoimmune disorders were evident. Clinical follow-up showed significant recovery, with resolution of radiological abnormalities. Conclusion Transverse myelitis can occur as a rare manifestation of SSc and may respond favorably to immunosuppressive therapy.