Autoimmune Neuromuscular Disorders Associated With Neural Antibodies.

OBJECTIVE: This article reviews autoimmune neuromuscular disorders and includes an overview of the diagnostic approach, especially the role of antibody testing in a variety of neuropathies and some other neuromuscular disorders. LATEST DEVELOPMENTS: In the past few decades, multiple antibody biomarkers associated with immune-mediated neuromuscular disorders have been reported. These biomarkers are not only useful for better understanding of disease pathogenesis and allowing more timely diagnosis but may also aid in the selection of an optimal treatment strategy. ESSENTIAL POINTS: Recognition of autoimmune neuromuscular conditions encountered in inpatient or outpatient neurologic practice is very important because many of these disorders are reversible with prompt diagnosis and early treatment. Antibodies are often helpful in making this diagnosis. However, the clinical phenotype and electrodiagnostic testing should be taken into account when ordering antibody tests or panels and interpreting the subsequent results. Similar to other laboratory investigations, understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists.

[Clinical characteristics analysis of 4 cases with acute flaccid myelitis in children].

Objective: To summarize the clinical manifestations, diagnosis, treatment and prognosis of acute flaccid myelitis (AFM) in children. Methods: Clinical characteristics of 4 AFM cases from Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, from September 2018 to November 2022, were analyzed retrospectively. Results: The age of 4 children with AFM was 7 years, 4 years and 3 months, 7 years and 1 month, 6 years and 5 months, respectively. There were 2 boys and 2 girls. Prodromal infection status showed 3 children of respiratory tract infection and 1 child of digestive tract infection. The main manifestation was asymmetrical limb weakness after infection, and the affected limb range was from monoplegia to quadriplegia. Cranial nerve injury was involved in 1 child, no encephalopathy. Magnetic resonance imaging in the spinal cord of all 4 children showed long T1 and T2 signals, mainly involving gray matter. Cerebrospinal fluid cell-protein separation was observed in 2 children. Pathogen detected in 1 child pharyngeal swab was enterovirus D68. Antibody IgM to adenovirus was positive in the blood of 1 child. Antibody IgG against Echo and Coxsackie B virus were positive in the blood of another child. After glucocorticoid, human immunoglobulin or simple symptomatic treatment and at the same time under later rehabilitation training, muscle strength recovered to different degrees, but there were disabilities left in 3 children. Conclusions: AFM should be considered in children with acute and asymmetrical flaccid paralysis accompanied by abnormal magnetic resonance imaging signal in the central region of spinal cord, especially post-infection. The effective treatment is limited and the prognosis is poor.

Neuromuscular Disorders in Pediatric Respiratory Disease.

Respiratory sequelae are a frequent cause of morbidity and mortality in children with NMD. Impaired cough strength and resulting airway clearance as well as sleep disordered breathing are the two main categories of respiratory sequelae. Routine clinical evaluation and diagnostic testing by pulmonologists is an important pillar of the multidisciplinary care required for children with NMD. Regular surveillance for respiratory disease and timely implementation of treatment including pulmonary clearance techniques as well as ventilation can prevent respiratory related morbidity including hospital admissions and improve survival. Additionally, novel disease modifying therapies for some NMDs are now available which has significantly improved the clinical trajectories of patients resulting in a paradigm shift in clinical care. Pulmonologists are 'learning' the new natural history for these diseases and adjusting clinical management accordingly.

Neuromuscular Emergencies.

OBJECTIVE: This article aims to familiarize the reader with the clinical approach, diagnostic considerations, and treatment strategies for patients presenting with abrupt-onset or acutely worsening weakness due to neuromuscular disorders. LATEST DEVELOPMENTS: Neuromuscular weakness is often the result of an inflammatory process. In recent years, there has been growing recognition of pathologic antibodies that cause neuromuscular injury. This has allowed clinicians to make a more accurate diagnosis. Additionally, neuromuscular junction disorders and myopathies are increasingly identified as the adverse effects of novel anticancer therapies, namely immune checkpoint inhibitors. More data are being incorporated into frameworks for neuroprognostication after neuromuscular emergencies, especially for commonly encountered disorders such as Guillain-Barré syndrome. ESSENTIAL POINTS: Care of patients with neuromuscular emergencies requires prompt attention to respiratory status. Once supportive measures are in place to protect the airway and facilitate effective ventilation, diagnostic considerations should hinge on appropriate neurologic localization. Aggressive immunosuppression is often required for immune-mediated neuromuscular disorders, and clinicians must be thoughtful in selecting a strategy that best aligns with each patient's risk factors and comorbidities.

Systemic Diseases and Heart Block.

Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (<60) with heart block should be evaluated for an underlying systemic disease. These disorders are classified into infiltrative, rheumatologic, endocrine, and hereditary neuromuscular degenerative diseases. Cardiac amyloidosis owing to amyloid fibrils and cardiac sarcoidosis owing to noncaseating granulomas can infiltrate the conduction system leading to heart block. Accelerated atherosclerosis, vasculitis, myocarditis, and interstitial inflammation contribute to heart block in rheumatologic disorders. Myotonic, Becker, and Duchenne muscular dystrophies are neuromuscular diseases involving the myocardium skeletal muscles and can cause heart block.

Muscle excitability testing.

Conventional electrophysiological methods, i.e. nerve conduction studies and electromyography are suitable methods for the diagnosis of neuromuscular disorders, however, they provide limited information about muscle fibre membrane properties and underlying disease mechanisms. Muscle excitability testing is a technique that provides in vivo information about muscle fibre membrane properties such as membrane potential and ion channel function. Since the 1960s, various methodologies have been suggested to examine muscle membrane properties but technical difficulties have limited its use. In 2009, an automated, fast and simple application, the so-called multi-fibre muscle velocity recovery cycles (MVRC) has accelerated the use of muscle excitability testing. Later, frequency ramp and repetitive stimulation protocols have been developed. Though this method has been used mainly in research for revealing disease mechanisms across a broad range of neuromuscular disorders, it may have additional diagnostic uses; value has been shown particularly in muscle channelopathies. This review will provide a description of the state-of-the art of methodological and clinical studies for muscle excitability testing.

Rasch analysis of the Unidimensional Self-Efficacy Scale in Neuromuscular Disorders and comparison between sex, age, and diagnoses.

INTRODUCTION/AIMS: Self-efficacy reflects a person's perceptions of their capabilities for specific tasks and influences motivation and performance. The Unidimensional Self-Efficacy in Neuromuscular Disorders (USE-NM) was modified from the Multiple Sclerosis (MS) USE-MS scale and administered to patients attending a specialist neuromuscular clinic. The aim was to investigate this measure in neuromuscular disorders and to compare between patient sex, age, and diagnosis. METHODS: The USE-NM was posted to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis using RUMM2030 software and descriptive statistics were performed using SPSS version 28. RESULTS: One hundred and ninety-eight patients (56.1% male) grouped by age (<50; 50-59; 60-69; and >69 years) and with varied NM disorders returned the USE-NM. It did not meet the Rasch model expectations due to disordered thresholds of items 6 and 8 ("Sometimes I feel inadequate as a person because of my neuromuscular disorder" and "I feel that my social life would be better if I did not have a neuromuscular disorder"). Following item re-scoring, the modified USE-NM satisfied the Rasch model with a unidimensional scale free from differential item functioning and an overall chi-square probability of 0.146 with good reliability and validity. Post hoc nonparametric testing showed no significant difference in fatigue between sex, age, and neuromuscular diagnoses. DISCUSSION: The Rasch-modified USE-NM offers a measure of self-efficacy for neuromuscular disorders encountered in a typical specialist clinic. Future considerations could be given to assessing any benefits of multidisciplinary team input, across a specialist neuromuscular service.

[Neuromuscular Ultrasound: Diagnosis and Evaluation in Neuromuscular Diseases].

Neuromuscular ultrasound has become an integral part of the diagnostic workup of neuromuscular diseases in neurology. Neuromuscular ultrasound can detect nerve enlargement, selective muscle damage, and fasciculation easily and non-invasively, which allows differentiation between auto-immune/inflammatory and degenerative/hereditary diseases. It is significant and essential for all neurologists to master the neuromuscular ultrasound technique.

[Enhancing Neuromuscular Disease Diagnosis through Electrophysiology].

Electrophysiologic testing plays an important role in evaluating peripheral nerve, muscle, and neuromuscular junction diseases, aiding in diagnosis and treatment strategies by offering real-time assessment. Demyelination of peripheral nerves results in increased conduction delay, temporal dispersion, conduction block, and stimulation threshold. The localization or diffusion of these changes is crucial in understanding disease pathogenesis, necessitating stimulation at multiple points along nerve pathways. When axonal degeneration occurs, the amplitude is reduced, with mild conduction delay. Acute axonal degeneration may require 1 week to develop into Wallerian degeneration. During this time, conductivity was preserved in the nerve peripheral to the lesion. When MG or LEMS is suspected, repetitive nerve stimulation tests and single-fiber EMG are valuable for the diagnosis and pathophysiological evaluation. Notably, the latter is highly sensitive but not specific. Needle electromyography (EMG) assists in differentiating between myopathies and neurogenic diseases, and in determining whether the patient is in an acute or chronic stage. Integration of these tests contribute to an accurate diagnosis when considering the presenting symptoms.

Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders.

Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.

Neuromuscular problems of the critically Ill neonate and child.

Acute neuromuscular disorders occasionally occur in the Pediatric Neurologic Intensive Care Unit. Many of these are primary disorders of the motor unit that may present acutely or exacerbate during an intercurrent illness. Additionally, acute neuromuscular disorders may develop during an acute systemic illness requiring intensive care management that predispose the child to another set of acute motor unit disorders. This chapter discusses acute neuromuscular crises in the infant, toddler, and adolescent, as well as neuromuscular disorders resulting from critical illness.

Acute Flaccid Myelitis With Human Rhinovirus A19 Detection: Case Report and Literature Review.

Human rhinovirus (HRV) has been sporadically detected in patients with acute flaccid myelitis (AFM). We report a case of AFM in a 2-year-old boy with severe neurologic sequelae, whose nasopharyngeal and stool samples tested positive for HRV-A19. Clinical information related to AFM with HRV is limited. Further study of the association of AFM with HRV is warranted.

Serial electrodiagnostic testing: Utility and indications in adult neurological disorders.

Although existing guidelines address electrodiagnostic (EDX) testing in identifying neuromuscular conditions, guidance regarding the uses and limitations of serial (or repeat) EDX testing is limited. By assessing neurophysiological change longitudinally across time, serial electrodiagnosis can clarify a diagnosis and potentially provide valuable prognostic information. This monograph presents four broad indications for serial electrodiagnosis in adult peripheral neurological disorders. First, where clinical change has raised suspicion for a new or ongoing lesion, EDX reassessment for spatial spread of abnormality, involvement of previously normal muscle or nerve, and/or evolving pathophysiology can clarify a diagnosis. Second, where diagnosis of a progressive neuromuscular condition is uncertain, electrophysiological data from a second time point can confirm or refute suspicion. Third, to establish prognosis after a static nerve injury, a repeat study can assess the presence and extent of reinnervation. Finally, faced with a limited initial study (as when complicated by patient or environmental factors), a repeat EDX study can supplement missing or limited data to provide needed clarity. Repeat EDX studies carry certain limitations, however, such as with prognostication in the setting of remote or chronic lesions, sensory predominant fascicular injury, or mild axonal injury. Nevertheless, serial electrodiagnosis remains a valuable and underused tool in the diagnostic and prognostic evaluation of neuromuscular conditions.

Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.

OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today. INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

"De Novo" Hypercapnic Respiratory Failure Unmasking Neuromuscular Disorders: Experiences From a Tertiary Care Center and Review of Literature.

OBJECTIVES: Neuromuscular disorders could have respiratory involvement early or late into illness. Rarely, patients may present with a hypercapnic respiratory failure (with minimal motor signs) unmasking an underlying disease. There are hardly any studies which have addressed the spectrum and challenges involved in management of this subset, especially in the real-world scenario. METHODS: A retrospective study comprising consecutive patients hospitalized with hypercapnic respiratory failure as the sole/dominant manifestation. The clinical-electrophysiological spectrum, phrenic conductions, diaphragm thickness, and outcomes were analyzed. RESULTS: Twenty-seven patients were included, the mean age was 47.29 (SD 15.22) years, and the median duration of respiratory symptoms was 2 months (interquartile range [IQR] 1-4). Orthopnea was present in 23 patients (85.2%) and encephalopathy in 8 patients (29.6%). Phrenic nerve latencies and amplitudes were abnormal in 83.3% and 95.6%, respectively. Abnormal diaphragm thickness was noted in 78.5%. Based on a comprehensive electrophysiological strategy and paraclinical tests, an etiology was established in all. Reversible etiologies were identified in 17 patients (62.9%). These included myasthenia gravis (anti-AChR and MuSK), inflammatory myopathy, riboflavin transporter deficiency neuronopathy, Pompe disease, bilateral phrenic neuritis, and thyrotoxicosis. Respiratory onset motor neuron disease was diagnosed in 8 patients (29.6%). Despite diaphragmatic involvement, a functional respiratory recovery was noted at discharge (45%) and last follow-up (60%). Predictors for good outcomes included female sex, normal nerve conductions, and recent-onset respiratory symptoms. DISCUSSION: A good functional recovery was noted in most of the patients including respiratory onset motor neuron disease. A systematic algorithmic approach helps in proper triaging, early diagnosis, and treatment. Clinical and electrodiagnostic challenges and observations from a tertiary care referral center are discussed.

Peripheral nervous system and neuromuscular disorders in the emergency department: A review.

INTRODUCTION: Acute presentations and emergencies in neuromuscular disorders (NMDs) often challenge clinical acumen. The objective of this review is to refine the reader's approach to history taking, clinical localization and early diagnosis, as well as emergency management of neuromuscular emergencies. METHODS: An extensive literature search was performed to identify relevant studies. We prioritized meta-analysis, systematic reviews, and position statements where possible to inform any recommendations. SUMMARY: The spectrum of clinical presentations and etiologies ranges from neurotoxic envenomation or infection to autoimmune disease such as Guillain-Barré Syndrome (GBS) and myasthenia gravis (MG). Delayed diagnosis is not uncommon when presentations occur "de novo," respiratory failure is dominant or isolated, or in the case of atypical scenarios such as GBS variants, severe autonomic dysfunction, or rhabdomyolysis. Diseases of the central nervous system, systemic and musculoskeletal disorders can mimic presentations in neuromuscular disorders. CONCLUSIONS: Fortunately, early diagnosis and management can improve prognosis. This article provides a comprehensive review of acute presentations in neuromuscular disorders relevant for the emergency physician.

Towards a diagnostic tool for neurological gait disorders in childhood combining 3D gait kinematics and deep learning.

Gait abnormalities are frequent in children and can be caused by different pathologies, such as cerebral palsy, neuromuscular disease, toe walker syndrome, etc. Analysis of the "gait pattern" (i.e., the way the person walks) using 3D analysis provides highly relevant clinical information. This information is used to guide therapeutic choices; however, it is underused in diagnostic processes, probably because of the lack of standardization of data collection methods. Therefore, 3D gait analysis is currently used as an assessment rather than a diagnostic tool. In this work, we aimed to determine if deep learning could be combined with 3D gait analysis data to diagnose gait disorders in children. We tested the diagnostic accuracy of deep learning methods combined with 3D gait analysis data from 371 children (148 with unilateral cerebral palsy, 60 with neuromuscular disease, 19 toe walkers, 60 with bilateral cerebral palsy, 25 stroke, and 59 typically developing children), with a total of 6400 gait cycles. We evaluated the accuracy, sensitivity, specificity, F1 score, Area Under the Curve (AUC) score, and confusion matrix of the predictions by ResNet, LSTM, and InceptionTime deep learning architectures for time series data. The deep learning-based models had good to excellent diagnostic accuracy (ranging from 0.77 to 0.99) for discrimination between healthy and pathological gait, discrimination between different etiologies of pathological gait (binary and multi-classification); and determining stroke onset time. LSTM performed best overall. This study revealed that the gait pattern contains specific, pathology-related information. These results open the way for an extension of 3D gait analysis from evaluation to diagnosis. Furthermore, the method we propose is a data-driven diagnostic model that can be trained and used without human intervention or expert knowledge. Furthermore, the method could be used to distinguish gait-related pathologies and their onset times beyond those studied in this research.

The Importance of Early Treatment of Inherited Neuromuscular Conditions.

There has been tremendous progress in treatment of neuromuscular diseases over the last 20 years, which has transformed the natural history of these severely debilitating conditions. Although the factors that determine the response to therapy are many and in some instance remain to be fully elucidated, early treatment clearly has a major impact on patient outcomes across a number of inherited neuromuscular conditions. To improve patient care and outcomes, clinicians should be aware of neuromuscular conditions that require prompt treatment initiation. This review describes data that underscore the importance of early treatment of children with inherited neuromuscular conditions with an emphasis on data resulting from newborn screening efforts.