Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials. METHODS AND ANALYSIS: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape. ETHICS AND DISSEMINATION: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.

Respiratory issues and current management in neuromuscular diseases: a narrative review.

Background and Objective: Respiratory care is often embedded as a component of the overlapping management strategies in many patients with neuromuscular disease (NMD). Implementation of respiratory care strategies requires a sensitivity to the nature of the disease, the vulnerability during rapid eye movement (REM) sleep and complicating comorbidities specific to each patient. Care must adjust to progression of the disease as well as the comfort and preferences of the patient. Clinical presentations are usually heterogenous based on the specific NMD and overall course of the disease making diagnosis and respiratory care challenging. The aim of this review was to review the state-of-the-art evidence-based clinical practices and updates in the management of respiratory complications in patients with NMDs. Methods: We conducted a search on the PubMed and Medline databases using these keywords: secretions, neuromuscular disease, neuromuscular disorders, non-invasive ventilator, neuromuscular respiratory weakness, respiratory failure. The specified timeframe began from 1980 to 2024. Key Content and Findings: Timely use of non-invasive ventilation and overall respiratory care is most important as emerging evidence shows some benefits with improved mortality in this group of patients. In some settings, comorbid complications that dictate need for airway management and oral diversion may have a more profound impact on mortality than the effectiveness of ventilatory support that are chosen. A multidisciplinary team approach to care has been shown to improve the quality of life and survival in these patients in centers of excellence. Patients should have the ability to access services provided by neurology, pulmonology, speech pathology, sleep medicine, cardiology and respiratory therapy services. Conclusions: The cornerstone for management of respiratory failure and sleep disordered breathing in NMD is non-invasive ventilation (NIV). Initiation of this support and other respiratory cares need to be timely, and patients may have very subtle symptoms during the early stages of the disease which makes it challenging in recognizing the onset of respiratory muscle stress and fatigue. Close attention to these symptoms as well as respiratory and radiologic parameters is essential for appropriate incorporation of these cares.

Acceptability, validity and responsiveness of inertial measurement units for assessing motor recovery after gene therapy in infants with early onset spinal muscular atrophy: a prospective cohort study.

BACKGROUND: Onasemnogene abeparvovec gene replacement therapy (GT) has changed the prognosis of patients with spinal muscular atrophy (SMA) with variable outcome regarding motor development in symptomatic patients. This pilot study evaluates acceptability, validity and clinical relevance of Inertial Measurement Units (IMU) to monitor spontaneous movement recovery in early onset SMA patients after GT. METHODS: Clinical assessments including CHOPINTEND score (the gold standard motor score for infants with SMA) and IMU measurements were performed before (M0) and repeatedly after GT. Inertial data was recorded during a 25-min spontaneous movement task, the child lying on the back, without (10 min) and with a playset (15 min) wearing IMUs. Two commonly used parameters, norm acceleration 95th centile (||A||_95) and counts per minute (||A||_CPM) were computed for each wrist, elbow and foot sensors. RESULTS: 23 SMA-patients were included (mean age at diagnosis 8 months [min 2, max 20], 19 SMA type 1, three type 2 and one presymptomatic) and 104 IMU-measurements were performed, all well accepted by families and 84/104 with a good child participation (evaluated with Brazelton scale). ||A||_95 and ||A||_CPM showed high internal consistency (without versus with a playset) with interclass correlation coefficient for the wrist sensors of 0.88 and 0.85 respectively and for the foot sensors of 0.93 and 0.91 respectively. ||A||_95 and ||A||_CPM were strongly correlated with CHOPINTEND (r for wrist sensors 0.74 and 0.67 respectively and for foot sensors 0.61 and 0.68 respectively, p-values < 0.001). ||A||_95 for the foot, the wrist, the elbow sensors and ||A||_CPM for the foot, the wrist, the elbow sensors increased significantly between baseline and the 12 months follow-up visit (respective p-values: 0.004, < 0.001, < 0.001, 0.006, < 0.001, < 0.001). CONCLUSION: IMUs were well accepted, consistent, concurrently valid, responsive and associated with unaided sitting acquisition especially for the elbow sensors. This study is the first reporting a large set of inertial sensor derived data after GT in SMA patients and paves the way for IMU-based follow-up of SMA patients after treatment.

Genetic Panel Reveals Coexisting Neuromuscular Disorders in Patients With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy is a genetically based neuromuscular disorder characterized by progressive physical impairment and cardiomyopathy in children, leading to fatal cardiac or respiratory failure. Duchenne muscular dystrophy shares some overlapping clinical features with other disorders, complicating clinical differentiation. We hypothesized that some Duchenne muscular dystrophy patients may have a secondary neuromuscular disorders that could negatively skew data during pharmaceutical clinical trials and lead to incomplete treatment plans. Consecutive genetic panels on 353 patients were reviewed. Thirty-two (32; 9.1%) patients with Duchenne muscular dystrophy were identified. Three (3; 9.4%) were found to have at least 1 genetically confirmed secondary neuromuscular disorder. Overlooking these coexisting disorders could lead to unexpected treatment failures, potentially affecting medication efficacy in trials or commercial use. Secondary neuromuscular disorders should be considered in Duchenne muscular dystrophy patients before clinical trial enrollment or treatment planning, with expanded genetic testing, such as whole exome sequencing or whole genome sequencing, likely to reveal even more secondary disorders.

Role of Magnesium in Skeletal Muscle Health and Neuromuscular Diseases: A Scoping Review.

Magnesium (Mg) is a vital element for various metabolic and physiological functions in the human body, including its crucial role in skeletal muscle health. Hypomagnesaemia is frequently reported in many muscle diseases, and it also seems to contribute to the pathogenesis of skeletal muscle impairment in patients with neuromuscular diseases. The aim of this scoping review is to analyze the role of Mg in skeletal muscle, particularly its biological effects on muscle tissue in neuromuscular diseases (NMDs) in terms of biological effects and clinical implications. This scoping review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines. From the 305 studies identified, 20 studies were included: 4 preclinical and 16 clinical studies. Preclinical research has demonstrated that Mg plays a critical role in modulating pathways affecting skeletal muscle homeostasis and oxidative stress in muscles. Clinical studies have shown that Mg supplementation can improve muscle mass, respiratory muscle strength, and exercise recovery and reduce muscle soreness and inflammation in athletes and patients with various conditions. Despite the significant role of Mg in muscle health, there is a lack of research on Mg supplementation in NMDs. Given the potential similarities in pathogenic mechanisms between NMDs and Mg deficiency, further studies on the effects of Mg supplementation in NMDs are warranted. Overall, maintaining optimal Mg levels through dietary intake or supplementation may have important implications for improving muscle health and function, particularly in conditions associated with muscle weakness and atrophy.

Longitudinal management in Duchenne muscular dystrophy with exon 63 duplication.

A boy with nonambulatory Duchenne muscular dystrophy (DMD) tested positive for exon 63 duplication and exhibited intellectual disability, overweight and dyslipidaemia. The patient underwent a comprehensive multidisciplinary approach involving pharmacological and non-pharmacological interventions. Despite challenges, such as socioeconomic constraints and limited access to advanced therapies, the patient received tailored care. The management included prednisone medication, dietary modifications and psychological support. The patient's journey highlighted the complex interplay of medical and psychosocial factors affecting DMD patients in resource-limited settings. Regular monitoring and the involvement of the patient's family in a peer group were arranged to improve overall quality of life. The case underscores the need for accessible and holistic care for DMD patients, addressing both medical and psychosocial challenges.

Seroprevalence of binding and neutralizing antibodies against 18 adeno-associated virus types in patients with neuromuscular disorders.

High levels of pre-existing antibodies are a major challenge for the application of viral vectors since they can severely limit their efficacy. To identify promising candidates among adeno-associated virus (AAV) based vectors for future gene therapies for the treatment of hereditary neuromuscular disorders (NMDs), we investigated the antibody levels in sera from patients with NMDs against 18 AAV types, including 11 AAVs with wild-type capsids, 5 AAVs with peptide-modified capsids and 2 AAVs with shuffled capsids. With regard to the wild-type capsid AAVs, the lowest binding antibody levels were detected against AAV6, AAV5, AAV12 and AAV9, whereas the highest binding antibody levels were detected against AAV10, AAV8, AAV1, and AAV2. The lowest neutralizing antibody levels against wild-type AAVs were detected against AAV12, AAV5, AAV9, AAV7, AAV8 and AAV10, and the highest neutralizing antibody levels were detected against AAV13, AAV2 and AAV3. Interestingly, the influence of peptide modifications or shuffling of AAV capsids on antibody binding and AAV neutralization seemed to depend on the parental AAV. While the sex of the serum donors had no significant impact on binding or neutralizing antibody levels, we observed a trend to higher binding antibodies in older serum donors against some AAV types and a clear positive correlation of neutralizing antibody titers with the age of the serum donors. The disease status on the other hand did not have a meaningful impact on antibody levels, with no changes in AAV neutralization. Our data indicate that several wild-type or peptide-modified AAV may be good candidates for therapeutic application due to low pre-existing antibody levels, and that the age of potential recipients rather than their health status with regard to NMDs has the biggest impact on vector applicability.

Safety and efficacy of viltolarsen in ambulatory and nonambulatory males with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by mutations in the dystrophin gene, causing motor and pulmonary function decline. Viltolarsen is indicated for patients with dystrophin gene mutations amenable to exon 53 skipping. Here, we report safety, motor function, and the first pulmonary function results from the open-label, phase II Galactic53 trial of viltolarsen (NCT04956289). Male participants aged ≥ 8 years with DMD received 80 mg/kg intravenous viltolarsen once weekly for 48 weeks. Results from participants receiving viltolarsen were compared with an external control cohort group-matched for multiple variables. All treatment-emergent adverse events were mild or moderate, 4 were considered treatment-related, and no participants discontinued. Participants receiving viltolarsen experienced clinically meaningful benefits in pulmonary function with higher percent predicted forced vital capacity and higher peak cough flow at Week 49 compared with the control cohort for both ambulatory and nonambulatory participants. Viltolarsen also stabilized upper limb motor function over the Treatment Period. These results support viltolarsen as an important part of the treatment armamentarium for both ambulatory as well as nonambulatory patients with DMD.

Longitudinal relationships between free-living activities, fatigue, and symptom severity in myasthenia gravis using cohort and individualized models.

INTRODUCTION/AIMS: Fluctuating symptoms and fatigue are common issues in myasthenia gravis (MG), but it is unclear if these symptoms are related to physical activity or sleep patterns. This study sought to determine the day-to-day relationship between patient-reported symptoms and physical activity and sleep over 12 weeks. METHODS: Sixteen participants with generalized MG wore a wrist-mounted accelerometer continuously for the study duration and reported their symptoms and fatigue each evening. Cumulative link mixed models were used to analyze whether clinical and demographic characteristics, physical activity, and sleep were related to symptom severity and fatigue over the study period. Three types of models were constructed: a cohort model, a model in which data was scaled to each participant, and individual models. RESULTS: The cohort model indicated that higher disease severity, female sex, more comorbidities, less physical activity, more inactive time, and lower quantity of sleep were significantly associated with increased symptom severity and fatigue (p < .05). However, in the within-participant scaled model, there were almost no significant associations with physical activity or sleep. In the individual models, some participants showed similar results to the cohort model, but others showed no associations or the opposite response in some variables. DISCUSSION: While physical activity and sleep were associated with self-reported symptoms and fatigue within this population, this was not necessarily applicable to individuals. This demonstrates the importance of an individualized analysis for determining how physical activity and sleep may impact outcomes in MG, with implications for clinical and self-management.

Tubular Aggregates as a Marker of Aging in Skeletal Muscle.

Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.

Atypical Presentations of Myasthenia Gravis as Acute Respiratory Failure: A Rare Case.

Myasthenia gravis (MG) is a chronic neuromuscular disease characterized by the progressive weakness of voluntary muscles, which encompass those in the face, throat, diaphragm, and those attached to bones. Patients commonly present with specific muscle weakness, such as difficulty in eye movement, facial expression, or swallowing, rather than generalized fatigue. However, as the disease advances, the majority of patients develop respiratory symptoms, which can significantly impact their quality of life. This makes the management of respiratory comorbidities essential, as respiratory tract infections can lead to exacerbations of MG and trigger a myasthenic crisis, necessitating immediate medical intervention. This report highlights a patient who initially presented with acute respiratory distress and was subsequently diagnosed with MG, underscoring the importance of recognizing respiratory symptoms in the context of this condition.

Magnetic Resonance Imaging Biomarkers of Muscle.

This review is focused on the current status of quantitative MRI (qMRI) of skeletal muscle. The first section covers the techniques of qMRI in muscle with the focus on each quantitative parameter, the corresponding imaging sequence, discussion of the relation of the measured parameter to underlying physiology/pathophysiology, the image processing and analysis approaches, and studies on normal subjects. We cover the more established parametric mapping from T1-weighted imaging for morphometrics including image segmentation, proton density fat fraction, T2 mapping, and diffusion tensor imaging to emerging qMRI features such as magnetization transfer including ultralow TE imaging for macromolecular fraction, and strain mapping. The second section is a summary of current clinical applications of qMRI of muscle; the intent is to demonstrate the utility of qMRI in different disease states of the muscle rather than a complete comprehensive survey.

Social Participation Restrictions and Explanatory Factors in Adults with Oculopharyngeal Muscular Dystrophy.

Background. Limited knowledge is available regarding the impact of oculopharyngeal muscular dystrophy (OPMD) impairments on participation in daily and social activities, which currently hinders occupational therapy practice in this population. Purpose. To describe social participation and explore influencing factors in individuals with OPMD. Methods. Thirty-four individuals were assessed with outcome measures of social participation restrictions, mobility, dysphagia, and fatigue. Spearman correlations and stepwise multiple regression analyses were used. Findings. Results show a negative impact of OPMD on the social participation level, which was more important in participants aged over 60 years. Walking speed was found to be the main factor influencing participation levels for daily and social activities, with faster walking associated with higher participation. Conclusions. This study emphasizes the impact of OPMD impairments and limitations on social participation level. While dysphagia is obviously an important impairment to consider, interventions for mobility limitations should also be considered during clinical follow-up.

Patient-reported daily functioning after SARS-CoV-2 vaccinations in autoimmune neuromuscular diseases.

BACKGROUND AND PURPOSE: There are concerns for safety regarding SARS-CoV-2 vaccines for patients with autoimmune neuromuscular disease. We compared daily functioning using disease-specific patient-reported outcome measures (PROMs) before and after SARS-CoV-2 vaccinations. METHODS: In this substudy of a prospective observational cohort study (Target-to-B!), patients with myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and idiopathic inflammatory myopathy (IIM) vaccinated against SARS-CoV-2 were included. Surveys of daily functioning (Myasthenia Gravis Activities of Daily Living, Inflammatory Rasch-Built Overall Disability Scale, Multifocal Motor Neuropathy Rasch-Built Overall Disability Scale, and Health Assessment Questionnaire-Disability Index) were sent before first vaccination and every 60 days thereafter for up to 12 months. Regression models were constructed to assess differences in PROM scores related to vaccination, compared to scores unrelated to vaccination. We also assessed the proportion of patients with deterioration of at least the minimal clinically important difference (MCID) between before first vaccination and 60 days thereafter. RESULTS: We included 325 patients (median age = 59 years, interquartile range = 47-67, 156 [48%] female sex), of whom 137 (42%) had MG, 79 (24%) had CIDP, 43 (13%) had MMN, and 66 (20%) had IIM. PROM scores related to vaccination did not differ from scores unrelated to vaccination. In paired PROMs, MCID for deterioration was observed in three of 49 (6%) MG patients, of whom none reported a treatment change. In CIDP, MCID for deterioration was observed in eight of 29 patients (28%), of whom two of eight (25%) reported a treatment change. CONCLUSIONS: SARS-CoV-2 vaccination had no effect on daily functioning in patients with autoimmune neuromuscular diseases, confirming its safety in these patients.

The transition from children to young people living with home mechanical ventilation.

PURPOSE: This study aimed to examine how young people living with Home Mechanical Ventilation experience the transition from childhood to young adulthood in relation to everyday life, perceived health and transition into adult professional healthcare. METHODS: Nine young adults (three females and six males aged 18-31) were interviewed, and data was primary analysed using phenomenological hermeneutics. In the actual study, data was reworked using secondary analysis as described by Beck. Two interviewees were ventilated invasively and six non-invasively, and one was treated with continuous positive airway pressure (CPAP). RESULTS: The results are presented in two main categories. First; moving towards adulthood; and second, To handle changes in health and healthcare contacts. The study highlights the importance of ongoing social relations and being part of a socializing and physically active community. The transfer from paediatric to adult healthcare was solid and worked out well but was a process in which the participants struggled to find their own voice. CONCLUSIONS: The transition into adulthood is a sensitive and challenging time for young people with HMV, but stable, close relationships and a well-organized transfer can enable this group to feel safe and able to find and use their own voice.

Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.

We present a boy in middle childhood with a medical history of arthrochalasiaEhlers-Danlos syndrome who was diagnosed with scoliosis as a toddler. His treatment began at a regional children's hospital, where initial spine radiographs demonstrated a 43.6° dextroscoliosis curve with the apex at L3. He was initially treated with a Boston brace, and the family was informed that MAGEC (Magnetic Expansion Control) growing rods were likely the definitive treatment due to the high likelihood of progression given the patient's large Cobb angle. However, the decision was made by the family and the Ehlers-Danlos syndrome specialist to proceed with the Wood-Rigo-Cheneau derotational brace.

Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure. METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal. RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased. DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.

Predictors of cardiac disease in duchenne muscular dystrophy: a systematic review and evidence grading.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. METHODS: The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS: We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], ß-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45-50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). CONCLUSION: Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research.