The motor unit and quantitative electromyography.

Electromyography (EMG) assesses the anatomic motor unit (A-MU), but knowledge of its anatomy, physiology, and changes with pathology is limited. The electrophysiological motor unit (E-MU) and its motor unit potential (E-MUP) represents a fraction of the A-MU. Routine EMG assesses a limited number of E-MUP waveform characteristics (metrics) and their magnitudes qualitatively scaled in a nonlinear manner. Another approach is quantitative EMG (QEMG), whereby 20+ E-MUPs are extracted and both basic and derived metrics obtained and values expressed quantitatively. In diseased muscle, many E-MUP metrics may be normal, which complicates diagnostic interpretation. In QEMG, E-MUP metrics can be clustered and statistical analyses performed to assign probabilities that E-MUPs (and the muscle) are normal, neuropathic, or myopathic. In this article we review what is known about the A-MU, the restricted E-MU, E-MUP metrics, and what QEMG offers currently and in the future.

Patient demographics and health plan paid costs in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: We determined health plan paid costs and healthcare resource usage of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: CIDP patients from 9 U.S. commercial health plans with claims in 2011 were identified from the Accordant Health Services claims database. We examined demographics, prevalence of comorbidities, prescribed drugs, place of service, and mean annual health plan paid costs per patient. RESULTS: From 6.5 million covered lives, 73 (56% men; mean age 47) met study entry criteria. The most prescribed therapies were intravenous immunoglobulin (IVIg) (26% of patients), gabapentin (26%), and prednisone (16%). The annual health plan paid cost was $56,953. Pharmacy cost was the major cost driver (57% of the total), and IVIg totaled 90% of the pharmacy costs. CONCLUSIONS: Healthcare costs for CIDP patients are substantial, with a large burden in pharmacy usage. Studies are needed to determine optimal long-term treatment strategies for CIDP, particularly related to IVIg.

Motor unit number estimation: a technology and literature review.

INTRODUCTION: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility. METHODS: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed. RESULTS: The most commonly reported MUNE methods are the incremental, multiple-point stimulation, spike-triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging. CONCLUSIONS: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.

What Is in the Literature.

ABSTRACT: This issue of What is in the Literature focuses on the Guillain-Barré syndrome. Guillain-Barré syndrome is a monophasic illness, and there is new information about precipitating factors, changes in nerve conduction studies over time, potential biomarkers, optimal treatment, and features in uncommon patient populations.

Quantitative electrodiagnosis of the motor unit.

Electromyography (EMG) focuses on assessment of the motor unit (MU), and a given muscle has several hundred MUs, each innervating hundreds of muscle fibers. Assessment is limited by the recording radius of electrodes, 1-2 fibers with single-fiber electrodes and 7-15 fibers with concentric or monopolar electrodes. Routine qualitative EMG studies rely on observing MUs in free-run mode and qualitatively estimating common metrics. In contrast, quantitative EMG (QEMG) applied to routine studies includes assessment of individual MUs by software available in modern EMG machines with extraction of discrete values for common metrics, and also derived metrics. This results in greater precision and statistical interpretation. Other QEMG techniques assess muscle fiber density within the MU and time variability at the neuromuscular junction. The interference pattern can also be assessed. The number of MUs innervating a muscle can be estimated. Advanced signal processing, called near-fiber EMG, allows for extraction of underlying muscle fiber contributions to MU waveforms. It is also possible to use QEMG to make statistical probabilities of the state of a muscle as to whether normal, myopathic, or neuropathic. Time to acquire QEMG data is minimal. QEMG is most useful in situations where pathology is uncertain.

ALSUntangled #63: ketogenic diets.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

The role of a clinical pharmacist in a multidisciplinary amyotrophic lateral sclerosis clinic.

Patients with ALS have complicated medication regimens and many questions about medications. Our multidisciplinary ALS clinic includes a clinical pharmacist, and the purpose of this study was to assess the types and outcomes of consultative interactions. This was a prospective, data collection study of patients seen by the pharmacist at a single ALS clinic visit. The following data were obtained: 1) current medications; 2) number and types of pharmacy interventions; 3) amount of time spent by the pharmacist with each patient. Thirty-seven patients were included. The average number of prescriptions used per patient was 3.59 (0-10) with 1.75 (0-9) used for ALS related indications. The average number of pharmacist interventions was two per patient, with the majority related to medication monitoring and optimizing drug therapy for ALS symptoms. The pharmacist provided education on an average of 2.5 topics per patient. The pharmacist spent an average of 21 (5-50) min with each patient. In conclusion, a clinical pharmacist contributes to the team by: 1) optimizing drug therapy for ALS symptoms; 2) providing medication-related education to patients; 3) allowing more time for the neurologist to attend to neurologic issues; and 4) discussing general medicine issues.

Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside.

Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.

What Is in the Literature.

ABSTRACT: This issue of What Is in the Literature focuses on articles on amyotrophic lateral sclerosis over the past year. Amyotrophic lateral sclerosis remains a challenging disorder with progression to death. Within the past year, a phase 2 trial of a drug combination showed slowing in the rate of progression. While awaiting a phase 3 trial or approval by the Food and Drug Administration, selected articles that aid the diagnosis, contribute to care, or add to general knowledge about the disease are reviewed.

What Is in the Literature.

ABSTRACT: What is in the Literature focuses on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a neuropathy with challenges in diagnosis and treatment. A recent revision of diagnostic criteria (EFN/PNS criteria) has helped define clinical features of typical and atypical variants and what is not considered CIDP. Initiating pathologic factors is not known for typical CIDP or variants. New treatment approaches are based on immunologic mechanisms. Rare patients with a CIDP-like clinical pattern are found to have antibodies to proteins at and around the node of Ranvier and are not considered to be CIDP but a nodal-paranodopathy. Although occurring mainly in adults, CIDP also occurs in children. CIDP may have clinical and electrodiagnostic features that overlap with hereditary neuropathies, and the latter might show some response to treatment. Articles published in the past year that address these issues are discussed in this review.

Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene.

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.

Review of the evolution of electrodiagnostic criteria for chronic inflammatory demyelinating polyradicoloneuropathy.

Chronic inflammatory demyelinating polyradicoloneuropathy (CIDP) is a treatable form of neuropathy. Efforts to devise sets of electrodiagnostic (nerve conduction) criteria to distinguish primary demyelination from primary axonal neuropathies have been elusive, and at least 16 criteria have been proposed. Modifications to criteria frequently represent minor changes based on applying a set to a small number of patients with the clinical diagnosis of CIDP, whereas others are based on physiological changes related to demyelination and other pathophysiological features. The various modifications continue to result in limited sensitivity, likely related to the wide range of nerve conduction abnormalities among CIDP patients. Although some sets are appropriate for formal clinical drug trials, their complexity makes them difficult to apply in the clinic or electromyography laboratory. This study considers the evolution of the criteria, discusses their limitations, and ends with a simplified set of guidelines that can be applied in the clinic or laboratory.

A survey of stress among amyotrophic lateral sclerosis care providers.

Amyotrophic lateral sclerosis (ALS) is a uniformly fatal disease. In the US, care is concentrated in specialized clinics. ALS health care providers likely experience stress, but levels and associated factors and methods to manage them are not known. A questionnaire was designed to assess levels of emotional stress among ALS clinic providers (neurologists and clinic managers) at time of diagnosis, during care of the patient, and at time of the patient's death. Also included were questions about diagnostic practice patterns. Sixty-eight Muscular Dystrophy Association and ALS Association certified clinics were surveyed with a 47% response rate. Stress levels ranged from very severe to none at the various clinical stages but did not differ significantly between neurologists and managers. Stress tended to be lower in more experienced providers, although not uniformly so for all situations and time-points. Stress reduction techniques were rated as more effective for managers than for neurologists. Providers reported high levels of job satisfaction but a significant number gave consideration to leaving their positions due to stress and operational issues. In conclusion, stress is experienced by ALS clinic providers and managed by a variety of methods but with limited success.

What is in the Literature.

ABSTRACT: This edition of What is in the Literature focuses on chronic immune neuropathies as they represent treatable conditions. There are formal criteria to solidify the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but patients are encountered who have clinical and electrodiagnostic features of CIDP but do not fulfill diagnostic criteria. These patients are addressed in recent publications. CIDP (and variants) and other forms of immune-mediated neuropathies (multifocal motor neuropathy) are responsive early on to treatment, but long-term factors are less well described, and a number of publications focus on extended consequences. Acute immune neuropathies have been described in the setting of viral illness, and recent publications look at the question as to whether they are associated with the COVID-19 pandemic. Finally, idiopathic sensory neuropathies are the most common polyneuropathy, and consensus efforts to codify features into subtypes can be used clinically for a more precise diagnosis.

I Want to Row Across the Atlantic. But You Have Amyotrophic Lateral Sclerosis!

ABSTRACT: We describe an individual with slowly progressive amyotrophic lateral sclerosis who decided to enter the Talisker Whisky Atlantic Challenge, a rowing event across the Atlantic Ocean, and completes it in 51 days in a 5-man boat.

Pathogenic effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis.

OBJECTIVE: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we utilized sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in TP73. METHODS: We analyzed exome sequences of 87 sporadic ALS patients and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit, TP73, a regulator of apoptosis, differentiation, and a binding partner as well as homolog of the tumor suppressor gene TP53, we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were perform in vitro. In vivo, we used CRISPR/Cas9 targeting of zebrafish tp73 to assay motor neuron number and axon morphology. RESULTS: Five heterozygous rare, nonsynonymous mutations in TP73 were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in TP73. Patient TP73 mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder ΔN-p73's ability to bind p53. CRISPR/Cas9 knockout of tp73 in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. CONCLUSION: Together, these results strongly suggest that variants in TP73 correlate with risk for ALS and indicate a novel role for apoptosis in ALS disease pathology.

A timeline for predicting durable medical equipment needs and interventions for amyotrophic lateral sclerosis patients.

ALS is progressive with increasing patient needs for durable medical equipment (DME) and interventions (gastric feeding tube - PEG, and non-invasive ventilation - NIV). We performed a chart review of deceased patients to determine the time-course of needs and their estimated costs. A timeline of needs was based on when clinic personnel felt an item was necessary. The point in time when an item or intervention was needed was expressed as a percentage of a patient's total disease duration. A wide range of DME and interventions was needed irrespective of site of ALS symptom onset (bulbar, upper, lower extremity), beginning at 10% of disease duration of lower extremity onset and increasing thereafter for all sites. The cumulative probability of costs of items and interventions began at 25%-50% of disease duration and increased to between $18,000 and $32,000 (USD), highest for lower extremity onset due to the cost of wheelchairs. We conclude that a high percentage of ALS patients will need a full spectrum of major DME items and interventions during the second half of disease duration. This results in a linear rise in costs over the second half of the disease duration.

An approach to the evaluation of peripheral neuropathies.

Requests for an evaluation for a peripheral neuropathy are common in the clinic and electrodiagnostic laboratory. Lists of types of neuropathies are long as are diagnostic tests. An approach to the evaluation of peripheral neuropathies is valuable as it permits full characterization of the neuropathy after which the lists of possible types and tests becomes much shorter and manageable. In this article, the author presents such an approach, focusing on the clinical aspects.

Nerve conduction pitfalls and pearls in the diagnosis of peripheral neuropathies.

Nerve conduction studies are an integral component of the evaluation of a peripheral neuropathy. While routine in nature, they require attention to detail. This article focuses on operator and machine errors that can affect the correct interpretation of nerve conduction data and the nature of a neuropathy.