Muscle & Nerve最新文献

The electrodiagnostic instrument is foundational to the acquisition of electrophysiologic data and its subsequent interpretation and diagnostic implications. The initiation of data acquisition occurs at the three recording electrodes which consist of: E-1 (the noninverting amplifier port), E-2 (the inverting amplifier port), and E-0 (the so-called ground electrode). All three electrodes are essential in forming the recording montage. They must have similar, high-quality impedance and be properly connected to the amplifier. Their recording surfaces and the tissues from which they record must have low impedance and be properly prepared and applied at the recording site to ensure an accurate representation of the electrophysiologic signal. Both surface and needle electrodes can be used, contingent on the technique and data required (i.e., nerve conduction studies or needle electromyography, respectively). These biologic signals are small, ranging from millivolts to microvolts, depending on the generator source (e.g., muscle and nerve). Therefore, they must be amplified and subsequently filtered. Artifacts, distorted signal amplification, or inappropriate filtration will result in waveform distortion leading to erroneous interpretation (i.e., false positives or negatives). The electrodiagnostic medicine consultant (EMC) has other tools to deal with this, such as averaging. The signal is then digitized and displayed visually and acoustically through an analog-to-digital converter/loudspeaker requiring appropriate amplification and time scale to avoid any signal distortion. The EMC can then visually as well as auditorily analyze the signal of interest and store or print out the data for further interpretation. Current technology in instrumentation permits greater precision and accuracy in data analysis. Failure at any one of the above sequential processing steps can lead to data misinterpretation. It is incumbent upon the EMC to be thoroughly familiar with all of the steps in this process, including potential shortcomings.

Introduction/aims: Glycosylation defects are a recognized cause of congenital myasthenic syndrome (CMS), affecting the stability and functions of the neuromuscular junction proteins. Mutations in five genes (GFPT1, DPAGT1, GMPPB, ALG2, and ALG14) are currently associated with glycosylation-related CMS. This cohort describes Iranian patients with CMS and variants in these genes.

Methods: A retrospective study was conducted to examine demographic, clinical, genetic, and histological data from Iranian patients with confirmed CMS-glycosylation defects. Patients were identified and recruited through the Neuromuscular Clinics of Tehran University of Medical Sciences. Only patients with complete clinical and genetic data available were included.

Results: Twenty-three genetically confirmed patients with glycosylation-related CMS were enrolled. Genetic analysis revealed the mutations in the GFPT1, GMPPB, and ALG2 genes, with those in GFPT1 and GMPPB being the most common. The median age of onset and diagnosis was 6 and 16 years, respectively. Common clinical features were limb-girdle muscle weakness with minimal ocular involvement. Consanguinity and a positive family history were common, identified in 21 and 14 patients, respectively. Muscle biopsies revealed tubular aggregates in patients with GFPT1 and GMPPB variants. In addition, novel genetic variants were identified, and phenotypic variability was observed even within families sharing identical mutations.

Discussion: This study identifies novel variants and phenotypic variability in glycosylation-related CMS, with GFPT1 and GMPPB as the predominant subtypes in Iran. These findings expand the genotypic and phenotypic spectrum and underscore the importance of early genetic testing in high-consanguinity populations to improve diagnosis and management.

Introduction/aims: Lipid storage myopathies (LSM) are rare disorders characterized by abnormal lipid accumulation in muscle fibers, commonly resulting in proximal muscle weakness and elevated creatine kinase (CK) levels. Within the category of LSM, there are various subtypes categorized by biochemical markers and genetic mutations. While LSM often is hereditary, there are ways that these myopathies can be acquired. Multiple acyl-CoA dehydrogenase deficiency (MADD) is a subtype of lipid storage myopathy associated with sertraline use. Sertraline has been linked to respiratory chain inhibition. The mainstay of treatment for MADD is high-dose riboflavin supplementation. We present two patients with acquired, sertraline-associated MADD who experienced full clinical recovery with riboflavin treatment before discontinuation of sertraline.

Methods: We describe two adult-onset patients with an acquired, sertraline-associated MADD-like disorder.

Results: Both patients showed clinical and serological improvement with riboflavin supplementation, even prior to sertraline discontinuation. Clinically, strength in the affected muscles returned to baseline (5/5) within 2 months. Serologically, the patients saw a 650-700 U/L decrease in CK levels (to baseline or near baseline) within 1 month and acylcarnitine profiles showed a marked decrease in medium and long-chain fatty acids within 6 months of initiating therapy.

Discussion: Although riboflavin therapy is often reserved for genetically confirmed patients, our findings support its efficacy in sertraline-associated, genetically negative MADD. These cases underscore the importance of recognizing medication-associated metabolic myopathies and the potential for targeted riboflavin therapy.

While randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of therapies in amyotrophic lateral sclerosis (ALS), post hoc analyses can provide critical insights into clinical effectiveness, treatment durability, and subpopulation responses. Several post hoc analyses of Study MCI186-19 (Study 19), the pivotal phase 3 RCT that supported the United States Food and Drug Administration approval of intravenous edaravone, have been performed to explore the broader clinical impact of this therapy. These analyses assessed the long-term treatment efficacy, changes in individual ALS Functional Rating Scale-Revised item scores, survival and additional milestone events, and the impact of edaravone in patient subgroups defined by disease progression trajectories using latent class analysis. Collectively, these findings reinforce the long-term clinical benefit of edaravone and demonstrate that edaravone may offer benefits across a spectrum of ALS disease trajectories, beyond those defined in the original study criteria. These studies help address questions not captured in the original RCT and may inform future trial design and treatment decisions.

Randomized controlled trials remain the cornerstone of evidence generation in amyotrophic lateral sclerosis (ALS), yet their inherent challenges, including disease rarity, heterogeneity, and limited validated biomarkers, highlight the need for complementary clinical evidence. This exploratory, retrospective study assessed overall survival in patients with ALS treated with intravenous (IV) edaravone using data from a large United States administrative claims database of patients enrolled from August 2017 to March 2020. Patients receiving IV edaravone (n = 318) were propensity score matched 1:1 with controls not treated with IV edaravone (n = 318), adjusting for 11 covariates. Median overall survival was 29.5 versus 23.5 months for the edaravone-treated group compared to controls, with a 27% reduced risk of death observed in the treated cohort (p = 0.005). These findings, together with existing data from the pivotal phase 3 Study MCI186-19 of IV edaravone, contribute to the growing body of literature suggesting a dual benefit of edaravone on both function and survival in ALS, offering critical insights for clinicians, patients, and payers navigating ALS treatment decisions.

This article summarizes the post-marketing pharmacovigilance safety data of intravenous (IV) edaravone during the 1- and 3-year periods following its launch for amyotrophic lateral sclerosis (ALS) in the United States. The most frequently reported adverse events (AEs) and serious AEs (SAEs) included those consistent with ALS disease progression, such as fatigue and muscular weakness, and were not qualitatively different from those reported in previous ALS trials. There were AEs and SAEs associated with IV administration, such as administration site reactions, and five non-fatal anaphylaxis SAEs were reported. No new safety signals were identified, and IV edaravone continues to demonstrate a favorable safety profile. These insights are especially useful as treatment transitions to edaravone oral suspension, which avoids IV-related complications. These findings underscore the importance of ongoing clinical safety assessments in informing ALS treatment decisions.

The pivotal phase 3 trial MCI186-19 (Study 19) demonstrated the efficacy of intravenous edaravone in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS), leading to United States Food and Drug Administration approval. Study 19 utilized a targeted enrollment enrichment strategy based on post hoc analyses from earlier trials, selecting patients with higher baseline function, more rapid disease progression, and better respiratory status. To evaluate the generalizability of Study 19 results, subsequent post hoc analyses assessed the efficacy of edaravone in broader ALS populations. One machine learning-based analysis retrospectively applied a validated model to Study 16 data, stratifying patients by predicted risk of respiratory decline. This detectable effect cluster analysis suggested that up to 70% of Study 16 participants may have benefited from edaravone. A second analysis investigated edaravone efficacy in patients from Study 19 with forced vital capacity (FVC) < 80% predicted (%p) at the start of treatment, since FVC ≥ 80%p was one of the Study 19 inclusion criteria. Both high- and low-FVC subgroups demonstrated reduced ALS functional rating scale-revised decline at 48 weeks when treated continuously with edaravone. These findings support the potential benefit of edaravone in a wider range of patients with ALS than those enrolled in Study 19, providing important insights into how clinical trial enrichment strategies may influence perceived efficacy, and underscoring the need for future prospective studies in more diverse ALS populations.

Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real-world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high-quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision-making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient-reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.