"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.

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.

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.

Multidisciplinary Treatment in Patients with Craniofacial, Neurocognitive, and Neuromuscular Disorders with Obstructive Sleep Apnea: A Systematic Review of the Literature.

Obstructive sleep apnea (OSA) is a respiratory disorder that has a high prevalence in patients with craniofacial, neurocognitive, and neuromuscular disorders. Currently, the treatments for this population are diverse and depend on the individual conditions of the patient and the severity of the case. However, there are no multidisciplinary dental treatment guidelines. The aim of the present study was to determine the multidisciplinary dental treatment alternatives in patients with craniofacial, neurocognitive, and neuromuscular disorders with a diagnosis of OSA through evidence-based medicine. A systematic review of the literature has been performed by searching scientific articles in the PubMed, Cochrane, Ovid, ScienceDirect and Scopus databases, through controlled and uncontrolled language. Articles were classified according to the level of evidence and grades of recommendation through the Scottish Intercollegiate Guidelines Network. A total of 19,439 references were identified, of which 15 articles met the predetermined requirements to be included in the investigation. The articles included for this systematic review showed that mandibular distraction osteogenesis and adenotonsilectomy are the first-choice therapies for craniofacial and neurocognitive disorders. However, for neuromuscular disorders, the findings reported were not enough to provide information about surgical or nonsurgical alternatives. Despite the reported high frequency of OSA in those children with craniofacial, neurocognitive, and neuromuscular disorders, the evidence on the surgical and nonsurgical therapeutic success for OSA in these patients is scarce. It is necessary to perform future studies to investigate successful therapies for OSA in children. [Pediatr Ann. 2024;53(2):e62-e69.].

Haplotype information of large neuromuscular disease genes provided by linked-read sequencing has a potential to increase diagnostic yield.

Rare or novel missense variants in large genes such as TTN and NEB are frequent in the general population, which hampers the interpretation of putative disease-causing biallelic variants in patients with sporadic neuromuscular disorders. Often, when the first initial genetic analysis is performed, the reconstructed haplotype, i.e. phasing information of the variants is missing. Segregation analysis increases the diagnostic turnaround time and is not always possible if samples from family members are lacking. To overcome this difficulty, we investigated how well the linked-read technology succeeded to phase variants in these large genes, and whether it improved the identification of structural variants. Linked-read sequencing data of nemaline myopathy, distal myopathy, and proximal myopathy patients were analyzed for phasing, single nucleotide variants, and structural variants. Variant phasing was successful in the large muscle genes studied. The longest continuous phase blocks were gained using high-quality DNA samples with long DNA fragments. Homozygosity increased the number of phase blocks, especially in exome sequencing samples lacking intronic variation. In our cohort, linked-read sequencing added more information about the structural variation but did not lead to a molecular genetic diagnosis. The linked-read technology can support the clinical diagnosis of neuromuscular and other genetic disorders.

Complement and MHC patterns can provide the diagnostic framework for inflammatory neuromuscular diseases.

Histopathological analysis stands as the gold standard for the identification and differentiation of inflammatory neuromuscular diseases. These disorders continue to constitute a diagnostic challenge due to their clinical heterogeneity, rarity and overlapping features. To establish standardized protocols for the diagnosis of inflammatory neuromuscular diseases, the development of cost-effective and widely applicable tools is crucial, especially in settings constrained by limited resources. The focus of this review is to emphasize the diagnostic value of major histocompatibility complex (MHC) and complement patterns in the immunohistochemical analysis of these diseases. We explore the immunological background of MHC and complement signatures that characterize inflammatory features, with a specific focus on idiopathic inflammatory myopathies. With this approach, we aim to provide a diagnostic algorithm that may improve and simplify the diagnostic workup based on a limited panel of stainings. Our approach acknowledges the current limitations in the field of inflammatory neuromuscular diseases, particularly the scarcity of large-scale, prospective studies that validate the diagnostic potential of these markers. Further efforts are needed to establish a consensus on the diagnostic protocol to effectively distinguish these diseases.

Neuromuscular disorders in the omics era.

Neuromuscular disorders encompass a spectrum of conditions characterized by primary lesions within the peripheral nervous system, which include the anterior horn cell, peripheral nerve, neuromuscular junction, and muscle. In pediatrics, most of these disorders are linked to genetic causes. Despite the considerable progress, the diagnosis of these disorders remains a challenging due to wide clinical presentation, disease heterogeneity and rarity. It is noteworthy that certain neuromuscular disorders, once deemed untreatable, can now be effectively managed through novel therapies. Biomarkers emerge as indispensable tools, serving as objective measures that not only refine diagnostic accuracy but also provide guidance for therapeutic decision-making and the ongoing monitoring of long-term outcomes. Herein a comprehensive review of biomarkers in neuromuscular disorders is provided. We highlight the role of omics-based technologies that further characterize neuromuscular pathophysiology as well as identify potential therapeutic targets to guide treatment strategies.

Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.

BACKGROUND: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes. METHODS: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis. RESULTS: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21-0.82), while a positive family history (OR 5.46; 95%CI 2.60-11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11-7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies. CONCLUSION: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence.

Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.

Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.

Sleep in pediatric neuromuscular disorders.

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD.

¿Se puede utilizar la determinación del pico flujo de tos para valorar la capacidad tusígena en enfermedades respiratorias obstructivas graves? / Can cough peak flow be used to assess cough capacity in severe obstructive respiratory diseases?

Introducción: La valoración de la capacidad tusígena se realiza con la medición del flujo espiratorio máximo durante la tos (peak-flow tos [PFT]). Sin embargo, esta valoración podría alterarse por enfermedades con obstrucción espiratoria de la vía aérea. El objetivo fue valorar la medición de la capacidad tusígena mediante PFT en pacientes con enfermedad pulmonar obstructiva crónica (EPOC), así como las correlaciones con la función pulmonar, muscular respiratoria y orofaríngea. Métodos: Se seleccionaron los pacientes con EPOC y con enfermedad neuromuscular, así como los sujetos sanos a los que se había realizado una medición de la fuerza de los músculos respiratorios de forma asistencial. De esta población, se analizaron los valores de la función respiratoria, así como la fuerza muscular orofaríngea. En un subgrupo de pacientes con EPOC se realizó el estudio de deglución por videofluoroscopia. Resultados: Se incluyeron 307 sujetos (59,3% EPOC, 38,4% enfermedades neuromusculares y 2,3% sanos). En el grupo EPOC, el PFT se encontraba disminuido de forma estadísticamente significativa comparado tanto con el grupo de los sanos como con los enfermos neuromusculares. El 70% de los EPOC tenían una disminución patológica del PFT. Solamente, existía una correlación directa entre el PFT con el grado de obstrucción bronquial y la fuerza de los músculos espiratorios. No se encontró alteración de la función de los músculos inspiratorios ni orofaríngeos. Conclusiones: La utilización del PFT en los pacientes con EPOC no refleja la capacidad tusígena ya que se ve influenciada por el grado de obstrucción bronquial. Por tanto, se deberían valorar nuevas pruebas diagnósticas para la medición de la capacidad tusígena, fundamentalmente, en los pacientes que coexistan enfermedades neuromusculares y patología obstructiva bronquial grave.(AU)

Introduction: Cough capacity is assessed by measuring cough peak flow (CPF). However, this assessment could be altered by obstructive airway diseases. The aim was to assess measurement of cough capacity by CPF in patients with chronic obstructive pulmonary disease (COPD), as well as correlations with pulmonary, respiratory muscle, and oropharyngeal function. Methods: Patients with COPD, and with neuromuscular disease, were selected as well as healthy subjects who had undergone respiratory muscle strength measurement in a healthcare setting. From this population, respiratory function values and lung and oropharyngeal muscle function were analysed. A subgroup of COPD patients underwent a videofluoroscopic swallow study. Results: Three hundred and seven subjects were included (59.3% COPD, 38.4% neuromuscular diseases, and 2.3% healthy). CPF was found to be statistically significantly decreased in the COPD group compared to both the healthy and neuromuscular disease groups. Of the COPD patients, 70% had a pathological decrease in CPF. There was only a direct correlation between CPF with the degree of bronchial obstruction and expiratory muscle strength. No alteration of inspiratory or oropharyngeal muscle function was found. Conclusions: The use of CPF in COPD patients does not reflect cough capacity as it is influenced by the degree of bronchial obstruction. Therefore, new diagnostic tests to measure cough capacity should be considered, especially in patients with coexisting neuromuscular diseases and severe bronchial obstructive disease.(AU)

Ventilatory failure in chronic neuromuscular disease.

Patients with neuromuscular diseases (NMD) can present to the neurologist with symptoms and signs of respiratory failure, either acutely or as an insidious process in the outpatient setting. Since the advent of non-invasive ventilation, the outcomes of patients with ventilatory failure due to NMD have dramatically improved. However, the natural history of different NMDs requires a nuanced approach to respiratory investigation and management. Respiratory failure dictates the prognosis of many NMDs and timing the most appropriate investigation and referral to ventilation services is crucial in optimising care.

Recurrent atraumatic compartment syndrome as a manifestation of genetic neuromuscular disease.

Compartment syndrome (CS) is a medical emergency that occurs secondary to excessively high pressures within a confined fibro-osseous space, resulting in reduced perfusion and subsequent tissue injury. CS can be divided into acute forms, most commonly due to trauma and considered an orthopaedic emergency, and chronic forms, most commonly presenting in athletes with recurrent exercise-induced pain. Downstream pathophysiological mechanisms are complex but do share commonalities with mechanisms implicated in genetic neuromuscular disorders. Here we present 3 patients with recurrent CS in the context of a RYR1-related disorder (n = 1) and PYGM-related McArdle disease (n = 2), two of whom presented many years before the diagnosis of an underlying neuromuscular disorder was suspected. We also summarize the literature on previously published cases with CS in the context of a genetically confirmed neuromuscular disorder and outline how the calcium signalling alterations in RYR1-related disorders and the metabolic abnormalities in McArdle disease may feed into CS-causative mechanisms. These findings expand the phenotypical spectrum of RYR1-related disorders and McArdle disease; whilst most forms of recurrent CS will be sporadic, above and other genetic backgrounds ought to be considered in particular in patients where other suggestive clinical features are present.

Respiratory Insufficiency in Neuromuscular Disease (RIND): A Delphi Study to Establish Consensus Criteria to Define and Diagnose Hypoventilation in Pediatric Neuromuscular Disease.

Chronic respiratory failure is a common endpoint in the loss of respiratory muscle function in patients with progressive neuromuscular disease (NMD). Identifying the onset of hypoventilation is critical to allow for the timely introduction of ventilator support and effectively manage respiratory failure [1-3]. While there are accepted criteria governing the diagnosis of hypoventilation during polysomnography (PSG) [4], there is concern that criteria are insufficient for identifying hypoventilation in the earlier stages of respiratory insufficiency related to NMD. The purpose of this project was to identify more sensitive criteria for identifying hypoventilation. METHODS: Fifteen pediatric pulmonologists with broad experience in managing patients with NMD, 10 of whom were board certified in and practice sleep medicine, were assembled and performed a review of the pertinent literature and a two-round Delphi process with 6 domains (Table 1). RESULTS: Within the 6 domains there were three pertinent items per domain (Table 2). There was clear agreement on findings on history (morning headaches) and pulmonary function testing (FVC < 50% or awake TcCO2 > 45 mmHg) indicating a high concern for nocturnal hypoventilation. There was close agreement on the definitions for nocturnal hypercapnia and hypoxemia. PSG criteria were identified that indicate a patient is likely in the transitional phase from adequate ventilation to hypoventilation. DISCUSSION: We identified a set of clinical criteria that may allow for more sensitive diagnosis of hypoventilation in NMD and earlier initiation of non-invasive ventilation leading to a reduction in the respiratory morbidity in progressive NMD. These criteria need to be further and more broadly validated prospectively to confirm their utility.

Current Biomarker Strategies in Autoimmune Neuromuscular Diseases.

Inflammatory neuromuscular disorders encompass a diverse group of immune-mediated diseases with varying clinical manifestations and treatment responses. The identification of specific biomarkers has the potential to provide valuable insights into disease pathogenesis, aid in accurate diagnosis, predict disease course, and monitor treatment efficacy. However, the rarity and heterogeneity of these disorders pose significant challenges in the identification and implementation of reliable biomarkers. Here, we aim to provide a comprehensive review of biomarkers currently established in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), and idiopathic inflammatory myopathy (IIM). It highlights the existing biomarkers in these disorders, including diagnostic, prognostic, predictive and monitoring biomarkers, while emphasizing the unmet need for additional specific biomarkers. The limitations and challenges associated with the current biomarkers are discussed, and the potential implications for disease management and personalized treatment strategies are explored. Collectively, biomarkers have the potential to improve the management of inflammatory neuromuscular disorders. However, novel strategies and further research are needed to establish clinically meaningful biomarkers.

Multidisciplinary Clinics in Neuromuscular Medicine.

ABSTRACT: Multidisciplinary care is comprehensive, coordinated clinical care across medical disciplines and allied health professions. Neuromuscular disorders, such as amyotrophic lateral sclerosis and muscular dystrophies, are often associated with disabling weakness and extramuscular symptoms and may benefit from care in a model that consolidates numerous clinic visits into a single more efficient multidisciplinary clinic visit. The goal of the neuromuscular multidisciplinary care model is to improve patient outcomes, patient satisfaction, quality of life, access to medications and equipment, and survival. Although the costs of running a multidisciplinary clinic are high, they are likely associated with cost savings from the patient's perspective. Several barriers to acceptance of multidisciplinary clinics include the distance needed to travel to the clinic and the duration of the clinic visit. Telehealth multidisciplinary clinic visits may address some of these concerns. Further study is needed to understand the value of multidisciplinary clinics and is a necessary step toward creating a sustainable model.

Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions.

INTRODUCTION/AIMS: Exome sequencing (ES) has proven to be a valuable diagnostic tool for neuromuscular disorders, which often pose a diagnostic challenge. The aims of this study were to investigate the clinical outcomes associated with utilization of ES in the pediatric neuromuscular clinic and to determine if specific phenotypic features or abnormal neurodiagnostic tests were predictive of a diagnostic result. METHODS: This was a retrospective medical record review of 76 pediatric neuromuscular clinic patients who underwent ES. Based upon clinical assessment prior to ES, patients were divided into two groups: affected by neuromuscular (n = 53) or non-neuromuscular (n = 23) syndromes. RESULTS: A diagnosis was made in 28/76 (36.8%), with 29 unique disorders identified. In the neuromuscular group, a neuromuscular condition was confirmed in 78% of those receiving a genetic diagnosis. Early age of symptom onset was associated with a significantly higher diagnostic yield. The most common reason neuromuscular diagnoses were not detected on prior testing was due to causative genes not being present on disease-specific panels. Changes to medical care were made in 57% of individuals receiving a diagnosis on ES. DISCUSSION: These data further support ES as a powerful diagnostic tool in the pediatric neuromuscular clinic and highlight the advantages of ES over gene panels, including the ability to identify diagnoses regardless of etiology, identify genes newly associated with disease, and identify multiple confounding diagnoses. Rapid and accurate diagnosis by ES can not only end the patient's diagnostic odyssey, but often impacts patients' medical management and genetic counseling of families.