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Introduction/aims: Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN)., Methods: We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected., Results: Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy., Discussion: Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies., (© 2022 Wiley Periodicals LLC.)

Introduction/aims: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C-reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial., Methods: The phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs-CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS-R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS-R score over 6 mo (non-progressor)., Results: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS-R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40- to 65-y-old subset in which NP001-treated patients demonstrated slower declines in ALSFRS-R score by 36% and VC loss by 51% compared with placebo. A greater number of non-progressors were NP001-treated compared with placebo (p = .004)., Discussion: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS-R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Introduction/aims: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics., Methods: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity., Results: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change., Discussion: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial., (© 2022 Wiley Periodicals LLC.)

Introduction/aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients., Methods: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp 358 Ala polymorphism of the interleukin 6 receptor (IL-6R) gene., Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups., Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp 358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers., (© 2021 Wiley Periodicals LLC.)

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., (© 2020 Wiley Periodicals, Inc.)

Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG)., Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected., Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years., Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Introduction: Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM variables with muscle structure measured by MRI., Methods: We evaluated 20 patients with FSHD at two centers, comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHZ) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF)., Results: While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (ρ = -0.71, P < .001) and FF (ρ = -0.74, P < .001)., Discussion: This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials., (© 2019 Wiley Periodicals, Inc.)

Immunosuppressive and immunomodulatory therapies have had a major effect on the treatment of immune-mediated neuromuscular diseases. After the landmark introduction of synthetic corticosteroids, other therapies have become available, including plasma exchange (PLEX), immunoglobulin G (IgG), and steroid-sparing immunosuppressive drugs. More recently, novel biologically derived and antigen-specific pharmaceuticals have entered neuromuscular practice. Various levels of evidence guide the use of these treatments. This article reviews current immune-based therapies in neuromuscular diseases and is divided into two parts. Part I provides an update on the evidence and use of traditional therapies, such as corticosteroids, PLEX, intravenously delivered IgG (IVIG), and steroid-sparing immunosuppressive drugs. Part II focuses on the recently US Food and Drug Administration-approved therapies eculizumab and subcutaneous IgG (SCIG), the current indications for rituximab in neuromuscular disease, and on novel immunosuppressive therapeutic approaches under development., (© 2019 Wiley Periodicals, Inc.)

While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed., (© 2019 Wiley Periodicals, Inc.)

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

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

Introduction: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG., Methods: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG., Results: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19)., Discussion: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019., (© 2019 Wiley Periodicals, Inc.)

Introduction: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS)., Methods: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting., Results: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events., Discussion: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019., (© 2018 Wiley Periodicals, Inc.)

Introduction: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction., Methods: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test-retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient-reported functional disability., Results: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84-0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures., Discussion: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. Muscle Nerve 57: 503-506, 2018., (© 2017 Wiley Periodicals, Inc.)

Introduction: In this study we evaluated the safety, tolerability, and efficacy of prednisone in patients with ocular myasthenia gravis (OMG) concurrently treated with pyridostigmine., Methods: This investigation was a randomized, double-blind, placebo-controlled trial. Participants whose symptoms failed to remit on pyridostigmine were randomized to receive placebo or prednisone, initiated at 10 mg every other day, and titrated to a maximum of 40 mg/day over 16 weeks. The primary outcome measure was treatment failure., Results: Fewer subjects were randomized than the 88 planned. Of the 11 randomized, 9 completed 16 weeks of double-blind therapy. Treatment failure incidence was 100% (95% CI 48%-100%) in the placebo group (n = 5) vs. 17% (95% CI 0%-64%) in the prednisone group, P = 0.02 (n = 6). Median time to sustained minimal manifestation status (MMS) was 14 weeks, requiring an average prednisone dose of 15 mg/day. Adverse events were infrequent and generally mild in both groups., Conclusions: A strategy of low-dose prednisone with gradual escalation appears to be safe, well-tolerated, and effective in treating OMG., (© 2015 Wiley Periodicals, Inc.)

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders., Methods: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48., Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo., Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need., (Copyright © 2014 Wiley Periodicals, Inc.)

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

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., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders., Methods: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease., Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken., Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued., (Copyright © 2011 Wiley Periodicals, Inc.)

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

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.

To evaluate the effect of SMN2 copy number on disease severity in spinal muscular atrophy (SMA), we stratified 45 adult SMA patients based on SMN2 copy number (3 vs. 4 copies). Patients with 3 copies had an earlier age of onset and lower spinal muscular atrophy functional rating scale (SMAFRS) scores and were more likely to be non-ambulatory. There was, however, no difference between the groups in quantitative muscle strength or pulmonary function testing. Functional scale may be a more discriminating outcome measure for SMA clinical trials.

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

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

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

Miyoshi myopathy, caused by mutations in the membrane protein dysferlin, is the most common muscular dystrophy that presents in the posterior calves. Its onset is before the age of 30 years and it is associated with marked elevations of serum creatine kinase (CK). In contrast, little is known about calf myopathies with onset after the age of 30, and it is not clear whether such patients have a dysferlinopathy. We describe five patients with a myopathy predominantly affecting the calf muscles, with onset after the age of 30. Muscle tissue was analyzed by immunoblot for dystrophin and dysferlin. All five had normal dysferlin but one had a dystrophinopathy. Serum CK levels ranged from 3 to 15 times the upper limit of normal. In contrast, all of 13 patients presenting before age 30 with calf weakness had a dysferlinopathy. Thus, isolated calf atrophy and weakness with onset after age 30, and associated with serum CK levels that are only moderately elevated, represents a distinct myopathy phenotype. Most of these cases are sporadic, although the overall phenotype appears genetically heterogeneous and dysferlinopathy is uncommon.

We initiated a randomized, double-blinded, placebo-controlled trial of intravenous immunoglobulin (IVIG) treatment in myasthenia gravis (MG). Patients received IVIG 2 gm/kg at induction and 1 gm/kg after 3 weeks vs. 5% albumin placebo. The primary efficacy measurement was the change in the quantitative MG Score (QMG) at day 42. Fifteen patients were enrolled (6 to IVIG; 9 to placebo) before the study was terminated because of insufficient IVIG inventories. At day 42, there was no significant difference in primary or secondary outcome measurements between the two groups. In a subsequent 6-week open-label study of IVIG, positive trends were observed., (Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 549-552, 2002)