Showing papers in "Muscle & Nerve in 2016"

Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment

Abstract: In this review we provide a current overview of the clinical features, pathophysiology, epidemiology, and diagnostic and therapeutic strategies in neuralgic amyotrophy (NA). The disorder has several phenotypic variations, with a classic form in 70% of the patients. It is not rare, with an incidence of 1 per 1,000 individuals, but it is still often missed. Recurrences are common, yet the proposed multifactorial etiology, which includes genetic, biomechanical, and immunologic factors, limits our capacity to predict or prevent them. NA is a clinical diagnosis, and ancillary studies serve to exclude infectious or malignant causes or to assess a differential diagnosis. If patients are seen early and are still in pain, a short trial of high-dose oral corticosteroids is advised, and adequate analgesia may require opioids and non-steroidal anti-inflammatory drugs. Persistent complaints are common, and a multidisciplinary rehabilitation approach focusing on scapular coordination, energy distribution strategies, and self-management is indicated.

Influence of relative blood flow restriction pressure on muscle activation and muscle adaptation

Abstract: Introduction The aim of this study was to investigate the acute and chronic skeletal muscle response to differing levels of blood flow restriction (BFR) pressure. Methods Fourteen participants completed elbow flexion exercise with pressures from 40% to 90% of arterial occlusion. Pre/post torque measurements and electromyographic (EMG) amplitude of each set were quantified for each condition. This was followed by a separate 8-week training study of the effect of high (90% arterial occlusion) and low (40% arterial occlusion) pressure on muscle size and function. Results For the acute study, decreases in torque were similar between pressures [-15.5 (5.9) Nm, P = 0.344]. For amplitude of the first 3 and last 3 reps there was a time effect. After training, increases in muscle size (10%), peak isotonic strength (18%), peak isokinetic torque (180°/s = 23%, 60°/s = 11%), and muscular endurance (62%) changed similarly between pressures. Conclusion We suggest that higher relative pressures may not be necessary when exercising under BFR.

Electrodiagnostic reference values for upper and lower limb nerve conduction studies in adult populations.

Abstract: Introduction To address the need for greater standardization within the field of electrodiagnostic medicine, the Normative Data Task Force (NDTF) was formed to identify nerve conduction studies (NCS) in the literature, evaluate them using consensus-based methodological criteria derived by the NDTF, and identify those suitable as a resource for NCS metrics. Methods A comprehensive literature search was conducted of published peer-reviewed scientific articles for 11 routinely performed sensory and motor NCS from 1990 to 2012. Results Over 7,500 articles were found. After review using consensus-based methodological criteria, only 1 study each met all quality criteria for 10 nerves. Conclusion The NDTF selected only those studies that met all quality criteria and were considered suitable as a clinical resource for NCS metrics. The literature is, however, limited and these findings should be confirmed by larger, multicenter collaborative efforts. Muscle Nerve 54: 371-377, 2016.

Small fiber neuropathy: Getting bigger!

Abstract: Etiological and clinical heterogeneity of small fiber neuropathy (SFN) precludes a unifying approach and necessitates reliance on recognizable clinical syndromes. Symptoms of SFN arise from dysfunction in nociception, temperature, and autonomic modalities. This review focuses on SFN involving nociception and temperature, examining epidemiology, etiology, clinical presentation, diagnosis, pathophysiology, and management. Prevalence of SFN is 52.95 per 100,000 population, and diabetes and idiopathic are the most common etiologies. Dysesthesia, allodynia, pain, burning, and coldness sensations frequently present in a length-dependent pattern. Additional autonomic features in gastrointestinal, urinary, or cardiovascular systems are frequent but poorly objectified. SFN is diagnosed by intraepidermal nerve fiber density and quantitative sensory and autonomic tests in combination with normal nerve conduction. Pathophysiological understanding centers on sodium channel dysfunction, and genetic forms are beginning to be understood. Treatment is directed at the underlying etiology supported by symptomatic treatment using antidepressants and anticonvulsants. Little is known about long-term outcomes, and systematic cohort studies are needed.

Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized, controlled trial

Abstract: 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. Muscle Nerve 53: 363–369, 2016

Six-minute walk test is reliable and valid in spinal muscular atrophy.

Abstract: Introduction The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. Methods Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. Results Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. Conclusions This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016.

Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab.

Abstract: INTRODUCTION While anticancer immunotherapies have traditionally focused on activation of the immune system, there is recent interest in disinhibition of the natural antitumor immune response by targeting immune checkpoints such as cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). One humanized monoclonal antibody against PD-1, pembrolizumab, was recently approved for treatment of metastatic malignant melanoma. METHODS We report exacerbation of myasthenia gravis (MG) after treatment with pembrolizumab and provide a brief literature review. RESULTS We describe a 75-year-old man with stable MG who experienced myasthenic crisis in the setting of pembrolizumab treatment. A concurrent azathioprine taper was a possible although unlikely contributor given the short time interval between taper and exacerbation. CONCLUSIONS As long-term data become available regarding the adverse immune effects of novel checkpoint inhibitors, clinicians should be mindful of their risks/benefits and of possible autoimmune disease exacerbation. Muscle Nerve 54: 157-161, 2016.

Heterogeneity of muscle sizes in the lower limbs of children with cerebral palsy.

Abstract: INTRODUCTION Cerebral palsy (CP) is associated with reduced muscle volumes, but previous studies have reported deficits in only a small number of muscles. The extent of volume deficits across lower limb muscles is not known. This study presents an imaging-based assessment of muscle volume and length deficits in 35 lower limb muscles. METHODS We imaged and segmented 35 muscles in 10 subjects with CP and 8 typically developing (TD) controls using MRI. Muscle volumes were normalized, and Z-scores were computed using TD data. Volume Z-scores and percent deficits in volume, length, and cross-sectional area are reported. RESULTS Muscle volumes are 20% lower, on average, for subjects with CP. Volume deficits differ significantly between muscles (12%-43%) and display significant heterogeneity across subjects. Distal muscles, especially the soleus, are commonly and severely small. CONCLUSIONS Heterogeneity across muscles and across subjects reinforces the subject specificity of CP and the need for individualized treatment planning. Muscle Nerve 53: 933-945, 2016.

ALS biomarkers for therapy development: State of the field and future directions.

Abstract: Biomarkers have become the focus of intense research in the field of amyotrophic lateral sclerosis (ALS), with the hope that they might aid therapy development efforts. Notwithstanding the discovery of many candidate biomarkers, none have yet emerged as validated tools for drug development. In this review we present a nuanced view of biomarkers based on the perspective of the Food and Drug Administration; highlight the distinction between discovery and validation; describe existing and emerging resources; review leading biological fluid-based, electrophysiological, and neuroimaging candidates relevant to therapy development efforts; discuss lessons learned from biomarker initiatives in related neurodegenerative diseases; and outline specific steps that we, as a field, might take to hasten the development and validation of biomarkers that will prove useful in enhancing efforts to develop effective treatments for ALS patients. Most important among these is the proposal to establish a federated ALS Biomarker Consortium in which all interested and willing stakeholders may participate with equal opportunity to contribute to the broader mission of biomarker development and validation.

Estimating motor unit numbers from a CMAP scan

Abstract: INTRODUCTION: Compound muscle action potential (CMAP) scans are detailed stimulus-response curves which provide information about motor unit properties in neuromuscular disorders. This study assessed a method of automatic motor unit number estimation (MUNE) from 5-min CMAP scans. METHODS: A preliminary model, derived from the variance and slope of the scan, is refined to fit the CMAP scan more closely. The method was tested by application to 60 simulated scans, generated from between 5 and 160 motor unit potentials. RESULTS: The fitting procedure took an average of 1.5 min on a standard personal computer. Small unit numbers (5-20) were on average correctly estimated, but large unit numbers (>40) were slightly underestimated. Overall, the absolute MUNE error averaged 6.9%. CONCLUSIONS: This new MUNE method takes all excitable motor units into account and provides realistic estimates of unit numbers over the range 5 to 160. Validation as a clinical tool awaits further study.

P/Q- and N-type calcium-channel antibodies: Oncological, neurological, and serological accompaniments.

Abstract: Introduction Voltage-gated calcium-channel autoimmunity (VGCC-P/Q and VGCC-N types) occurs beyond Lambert–Eaton syndrome and lung cancer. Methods We reviewed records for 236 Mayo Clinic patients with VGCC antibodies found in evaluation for paraneoplastic neurological autoimmunity (generally without myasthenic syndromes). Results VGCC autoantibodies were detected in 3.4% of neurological patients, 1.7% of healthy controls, and 4% of neurologically asymptomatic lung cancer controls. Fifty neurological patients (21%) had ≥ 1 neoplasm, historically (46) or detected prospectively [small-cell lung carcinoma (2), breast adenocarcinoma (2), lymphoma (1), and suspected tonsillar carcinoma (1)]. Autoimmune neurological diagnosis frequencies (encephalopathy, ataxia, myelopathy, neuropathy, neuromuscular junction disorder, and myopathy) among patients with medium values (24%; 0.10–0.99 nmol/L) or low values (19%; 0.03–0.10 nmol/L) were fewer than among patients with antibody values exceeding 1.00 nmol/L (71%; P = 0.02 and 0.004, respectively). Conclusions Among neuronal VGCC-autoantibody–seropositive patients, autoimmune neurological phenotypes and cancer types are diverse. Cautious interpretation of results (particularly medium and low values) is advised. Muscle Nerve, 2016 Muscle Nerve 54: 220–227, 2016

Reference values for ultrasonograpy of peripheral nerves.

Abstract: Introduction: High-resolution ultrasonography (HRU) is a novel method that provides morphological information about peripheral nerves. We aimed to determine reference values for nerve cross-sectional area (CSA) on HRU. Methods: One hundred healthy volunteers had HRU of median, radial, ulnar, fibular, tibial, sural, and superficial fibular nerves at defined sites. The CSA was measured and the effects of age, gender, and body mass index (BMI) were evaluated. Results: CSA values in healthy subjects are described. CSA is larger in lower limb motor nerves than in sensory nerves at similar sites, and the CSA tends to be symmetrical. The strongest effect on CSA was for age, although gender and BMI had some effects. Conclusions: This study provides normative values for HRU, and it suggests that further research with age- and gender-specific distributions must be a key priority in the development of HRU for use as a diagnostic test for peripheral nerve diseases. Muscle Nerve 53: 538–544, 2016

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

Abstract: Introduction The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. Methods We first performed Rasch analysis on >1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG-QOL15r scales. Results The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. Conclusions The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Sensory neuronopathies: Sensory Neuronopathies

Abstract: The sensory neuronopathies (or ganglionopathies) are a small subcategory of neuropathies characterized by primary degeneration of the dorsal root ganglia and trigeminal ganglion sensory neurons, resulting in a distinctive clinical presentation. Patients typically have subacute onset of asymmetric, non–length‐dependent sensory impairment and early ataxia. The etiologies of acquired sensory neuronopathies are rather limited. Early identification is imperative, as they may herald an underlying malignancy or an autoimmune condition such as Sjögren syndrome. This review addresses the various causes of acquired sensory neuronopathies, the recommended diagnostic approach, and treatment options. Finally, I will briefly discuss a select few hereditary and degenerative sensory neuronopathies, which, in contrast to the acquired disorders, are slowly progressive and are usually associated with additional neurological symptoms. Muscle Nerve 53: 8–19, 2016

Causes of neuropathy in patients referred as "idiopathic neuropathy".

Abstract: Introduction: The etiology of neuropathy was idiopathic in 20%–30% of patients despite thorough investigation, based on results from the 1980s and 1990s. Since then, new etiologies have been recognized, and skin biopsy has been used to confirm small-fiber neuropathy. Methods: The authors reviewed the charts of 373 patients with idiopathic neuropathy who were referred to a neuropathy center between 2002 and 2012. Results: Among the 284 eligible patients, 93 (32.7%) remained idiopathic. The most common cause was impaired glucose metabolism (72 patients, 25.3%), including diabetes in 26 and prediabetes in 46. Other etiologies were chronic inflammatory demyelinating polyneuropathy (CIDP) in 57 (20%) and monoclonal gammopathy in 20 (7%), as well as toxic, Sjogren disease, celiac disease, other immune-mediated diseases, vitamin B12 deficiency, amyloidosis, vitamin B1 and B6 deficiency, vasculitis, hypothyroidism, hereditary, Lyme disease, and anti-sulfatide antibody. Conclusions: The major causes of undiagnosed neuropathies were impaired glucose metabolism, CIDP, and monoclonal gammopathies. Despite thorough evaluation 32.7% remained idiopathic. Muscle Nerve 53: 856–861, 2016

Impact of expiratory strength training in amyotrophic lateral sclerosis

Abstract: Introduction We evaluated the feasibility and impact of Expiratory Muscle Strength Training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS).

Median and ulnar nerve anastomoses in the upper limb: A meta-analysis.

Abstract: Introduction The most frequently described anomalous neural connections between the median and ulnar nerves in the upper limb are: Martin-Gruber anastomosis (MGA), Marinacci anastomosis (MA), Riche-Cannieu anastomosis (RCA), and Berrettini anastomosis (BA). The reported prevalence rates and characteristics of these anastomoses vary significantly between studies. Methods A search of electronic databases was performed to identify all eligible articles. Anatomical data regarding the anastomoses were pooled into a meta-analysis using MetaXL 2.0. Results A total of 58 (n = 10,562 upper limbs) articles were included in the meta-analysis. The pooled prevalences were: MGA, 19.5% (95% confidence interval [CI], 16.2%–23.1%); MA, 0.7% (95% CI, 0.1%–1.7%); RCA, 55.5% (95% CI, 30.6%–79.1%); and BA, 60.9% (95% CI, 36.9%–82.6%). The results also showed that MGA was more commonly found unilaterally (66.8%), on the right side (15.7%), following an oblique course (84.8%), and originating from the anterior interosseous nerve with a prevalence of 57.6%. Conclusions As anastomoses between the median and ulnar nerves occur commonly, detailed anatomical knowledge is essential for accurate interpretation of electrophysiological findings and reducing the risk of iatrogenic injuries during surgical procedures. Muscle Nerve 54: 36–47, 2016

The problem Of muscle hypertrophy: Revisited.

Abstract: In this paper we revisit a topic originally discussed in 1955, namely the lack of direct evidence that muscle hypertrophy from exercise plays an important role in increasing strength. To this day, long-term adaptations in strength are thought to be primarily contingent on changes in muscle size. Given this assumption, there has been considerable attention placed on programs designed to allow for maximization of both muscle size and strength. However, the conclusion that a change in muscle size affects a change in strength is surprisingly based on little evidence. We suggest that these changes may be completely separate phenomena based on: (1) the weak correlation between the change in muscle size and the change in muscle strength after training; (2) the loss of muscle mass with detraining, yet a maintenance of muscle strength; and (3) the similar muscle growth between low-load and high-load resistance training, yet divergent results in strength. Muscle Nerve 54: 1012-1014, 2016.

Increased collagen cross‐linking is a signature of dystrophin‐deficient muscle

Abstract: Author(s): Smith, Lucas R; Hammers, David W; Sweeney, H Lee; Barton, Elisabeth R | Abstract: IntroductionCollagen cross-linking is a key parameter in extracellular matrix (ECM) maturation, turnover, and stiffness. We examined aspects of collagen cross-linking in dystrophin-deficient murine, canine, and human skeletal muscle.MethodsDMD patient biopsies and samples from mdx mice and golden retriever muscular dystrophy dog samples (with appropriate controls) were analyzed. Collagen cross-linking was evaluated using solubility and hydroxyproline assays. Expression of the cross-linking enzyme lysyl oxidase (LOX) was determined by real-time polymerase chain reaction, immunoblotting, and immunofluorescence.ResultsLOX protein levels are increased in dystrophic muscle from all species evaluated. Dystrophic mice and dogs had significantly higher cross-linked collagen than controls, especially in the diaphragm. Distribution of intramuscular LOX was heterogeneous in all samples, but it increased in frequency and intensity in dystrophic muscle.ConclusionThese findings implicate elevated collagen cross-linking as an important component of the disrupted ECM in dystrophic muscles, and heightened cross-linking is evident in mouse, dog, and man. Muscle Nerve 54: 71-78, 2016.

Progress and challenges in diagnosis of dysferlinopathy

Abstract: Dysferlin-deficient limb girdle muscular dystrophy type 2B, distal Miyoshi myopathy, and other less frequent phenotypes are a group of recessive disorders called dysferlinopathies. They are characterized by wide clinical heterogeneity. To diagnose dysferlinopathy, a clinical neuromuscular workup, including electrophysiological and muscle imaging investigations, is essential to support subsequent laboratory testing. Increased serum creatine kinase levels, distal or proximal muscle weakness, and myalgia with onset in the second or third decades are the main clinical features of the disease. In muscle biopsies, severe dysferlin deficiency by immunoblot or its abnormal localization by immunohistochemistry are the gold standard, as they have a high diagnostic value. Dysferlin testing on monocytes is a valuable alternative to muscle immunoblotting. Molecular techniques for gene mutation detection, such as next generation sequencing, have improved the genetic diagnosis, which is crucial for treatment and genetic counselling. Muscle Nerve 54: 821-835, 2016.

Randomized, placebo-controlled trial of incobotulinumtoxina for upper-limb post-stroke spasticity.

Abstract: Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016

Amifampridine phosphate (Firdapse(®)) is effective and safe in a phase 3 clinical trial in LEMS.

Abstract: ObjectiveWe evaluated the efficacy and safety of amifampridine phosphate (Firdapse((R))) for symptomatic treatment in Lambert-Eaton myasthenic syndrome (LEMS). MethodsPhase 3, randomized, double-blind, study. Patients were treated initially with amifampridine phosphate for 7-91 days, followed by randomization to continue amifampridine phosphate for 14 days or placebo (7-day taper, 7-day placebo). The primary efficacy endpoints were changes from baseline at day 14 in Quantitative Myasthenia Gravis and Subject Global Impression scores. ResultsThe coprimary efficacy end points and 1 of the secondary efficacy end points were met, showing a significant benefit of aminfampridine phosphate over placebo at Day 14. All 5 primary, secondary, and tertiary endpoints achieved statistical significance at Day 8. Amifampridine phosphate was well tolerated;the most common adverse events were oral and digital paresthesias, nausea, and headache. ConclusionsThis study provides Class I evidence of efficacy of amifampridine phosphate as a symptomatic treatment for LEMS. Muscle Nerve53: 717-725, 2016

Reference values for jitter recorded by concentric needle electrodes in healthy controls: A multicenter study.

Abstract: Introduction: The aim of this study was to create reference values for jitter measured with concentric needle electrodes. Methods: Operators worldwide contributed recordings from orbicularis oculi (OO), frontalis (FR), and extensor digitorum (ED) muscles in healthy controls. Criteria for acceptable signal quality were agreed upon in advance. Fifteen or 20 recordings of acceptable quality from each muscle were required for voluntary and electrical stimulation recordings, respectively. Results: Recordings from 59 to 92 subjects were obtained for each muscle and activation type. Outlier limits for mean consecutive difference and individual jitter data for voluntary acti- vation were: OO, 31 and 45 ms; FR, 28 and 38 ms; ED, 30 and 43 ms; and for electrical stimulation they were: OO, 27 and 36 ms; FR, 21 and 28 ms; ED, 24 and 35 ms. Conclusion: Reference jitter values from con- centric needle electrode recordings were developed from signals of defined quality while seeking to avoid creating supernormal values. Muscle Nerve 53: 351-362, 2016

Ultrasonographic diaphragm thickness correlates with compound muscle action potential amplitude and forced vital capacity

Abstract: Introduction Noninvasive evaluation of respiratory function in patients with various neuromuscular disorders is important for predicting life expectancy. Methods We performed B-mode ultrasonography (USG) and nerve conduction studies in 37 patients (16 had amyotrophic lateral sclerosis; 11, myopathy; and 10, neuropathy) and 10 controls. USG of the diaphragm was performed in the supine position using a linear probe over the intercostal space at the anterior axillary line. Diaphragm muscle thickness was measured at end-expiration. The amplitude of diaphragm compound muscle action potentials (CMAP) was obtained by phrenic nerve stimulation with a surface electrode. Respiratory function was measured with standard pulmonary function tests including forced vital capacity (FVC). Results Diaphragm thickness was significantly correlated with FVC (r = 0.74) and CMAP amplitude (r = 0.53). Conclusions Diaphragm USG is useful for objective evaluation of pulmonary function in neuromuscular disorders without requiring undue patient effort or cooperation.

Myasthenia gravis induced by nivolumab therapy in a patient with non–small‐cell lung cancer

Abstract: tylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol 2016;46:86–88. 5. Johnson DB, Saranga-Perry V, Lavin PJ, Burnette WB, Clark SW, Uskavitch DR, et al. Myasthenia gravis induced by ipilimumab in patients with metastatic melanoma. See comment in PubMed Commons below J Clin Oncol 2014;32:1–3. 6. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014;16:589–593. 7. Saulat B, Maertens P, Hamilton WJ, Bassam BA. Anti-musk antibody after thymectomy in a previously seropositive myasthenic child. Neurology 2007;69:803–804.

Natural history of muscle cramps in amyotrophic lateral sclerosis

Abstract: Introduction: Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. Methods: We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. Results: Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (P < 0.0001) and younger patients (P < 0.0001). Conclusions: The high variability of the number of cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial. Muscle Nerve 53: 513–517, 2016

Myasthenia gravis exacerbation associated with pembrolizumab

Abstract: A 59-year-old woman presented for neurological evaluation. She suffered from rheumatoid arthritis, and there was a remote history of myasthenia gravis (MG). In her 30s, she developed mild ptosis, hoarseness, and neck flexor weakness. The acetylcholine receptor (AChR) binding antibody assay was positive. Following pyridostigmine treatment for a few months, her symptoms resolved quickly without further treatment. Three months before presentation, she received pembrolizumab infusion once every 3 weeks for metastatic melanoma. After the third infusion, she developed rapidly progressive hoarseness and dysphagia and eventually required placement of a percutaneous endoscopic gastrostomy. Other symptoms included exertional dyspnea and generalized weakness without ptosis or diplopia. Brain MRI, CT scan of soft tissues of the neck, and esophagogastroduodenoscopy were unremarkable. Evaluation by an otolaryngologist showed severe pharyngeal and palatal weakness and vocal fold hypomobility. Neurological exam revealed proximal limb muscle weakness with normal sensation. AChR and muscle-specific tyrosine kinase antibodies were negative. The 3 HZ repetitive stimulation studies of the facial and fibular nerves revealed 13% and 19% postexercise amplitude decrement, respectively, without postexercise facilitation, consistent with a postsynaptic neuromuscular junction disorder such as MG. Treatment with plasmapheresis, intravenous immunoglobulin, and prednisone 40 mg daily led to steady improvement of all symptoms. Her speech became nearly normal, and a regular diet was resumed. Repeat endoscopy showed significant improvement in pharyngeal, palatal, and glottic movement. Pembrolizumab is an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody recently approved for treatment of melanoma and nonsmall cell lung cancer. PD-1 is a cell surface receptor that prevents Tcell activation, reduces autoimmunity, and promotes selftolerance. Pembrolizumab treatment results in enhanced immune responses to tumor cells and normal host tissues. An association of pembrolizumab treatment with inflammatory arthritis has been described, but so far no case of MG has been reported. Two prior case reports described development of MG following the use of another anti-PD-1 monoclonal antibody, nivolumab. One patient received co-administration of nivolumab and ipilimumab, and ipilimumab was believed to be the more likely causative agent based on prior similar reports. In another patient, a retrospective examination of the patient’s serum before nivolumab administration detected anti-AChR antibodies, suggesting nivolumab may have exacerbated previously clinically silent MG. Our patient has 2 significant features. First, there was a remote history of mild MG symptoms, and pembrolizumab use caused an exacerbation of the latent MG. The AChR binding antibody was initially positive in our patient, but it became negative with the recent MG exacerbation. The precise explanation for this observation is unknown, but could be related to possible antigenic spreading or antigenic shifting from AChR to other components of the neuromuscular junction that occurs rarely during the course of MG. The results in our patient and the Shirai et al. patient supports a mechanism that anti-PD-1 therapy allows preexisting autoimmune T-cell clones to escape tolerance by suppressing regulatory T cells. Second, predominantly focal manifestation with prominent palatal and pharyngeal weakness was noted. Whether this is a unique clinical feature of MG in association with anti-PD-1 therapy awaits further study. T-lymphocyte-activating drugs are now used with increasing frequency in cancer treatment. Development of MG symptoms following the use of anti-PD-1 monoclonal antibodies should be recognized promptly. Drug discontinuation and initiation of MG therapy are appropriate treatment strategies that can lead to improved outcome.

Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography.

Abstract: Introduction: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). Methods: In 37 patients, ulnar and median nerve cross-sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow-up was 14.5 months. Linear mixed-effects models were conducted to analyze time effects on CSA. Results: Ulnar nerve CSA declined significantly at a monthly rate of –0.04 mm (forearm) and –0.05 mm (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. Conclusions: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54: 391–397, 2016.

Twenty‐year follow‐up of newborn screening for patients with muscular dystrophy

Abstract: Introduction An opt-out newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) was implemented at 2 hospitals in Pittsburgh, Pennsylvania, between 1987 and 1995. Methods For patients and their parents in families who received a diagnosis of DMD or BMD, either by NBS or by traditional diagnostics after symptom onset, attitudes toward NBS for DMD and BMD were assessed. Results All patients and most parents supported NBS for DMD and BMD. In contrast to the NBS parent cohort, the non-NBS cohort felt that diagnosis by NBS would cause anxiety. Conclusions There was strong support of NBS for DMD and BMD in both patients and their parents in families who received a diagnosis through NBS or through traditional diagnostics. No negative psychosocial impacts of NBS were identified among those families who received a diagnosis through NBS. Muscle Nerve 53: 570–578, 2016