Muscle & Nerve

ObjectiveDegeneration of motor endplates (MEPs) in denervated muscle is thought to be a key factor limiting functional regeneration after peripheral nerve injury (PNI) in humans. However, there is currently no paradigm to determine MEP status in denervated human muscle to estimate likelihood of reinnervation success. Here, we present a quantitative analysis of MEP status in biopsies of denervated muscles taken during nerve repair surgery and ensuing functional recovery. MethodsThis is a retrospective single-surgeon cohort study of patients (n=22) with upper extremity PNI confirmed with electromyography (EMG), treated with nerve transfers. Muscle biopsies were obtained intra-operatively from 10 patients for MEP morphometric analysis. Age at time of surgery ranged from 22-77 years and time from injury to surgery ranged from 2.5 -163 months. Shoulder range of motion (ROM) and Medical Research Council (MRC) scores were recorded pre-op and at final follow-up. ResultsSurviving MEPs were observed in biopsies of denervated muscles from all patients, even those greater than six months from injury. Average postoperative ROM improvement (assessed between 6-9 months post-surgery) was: forward flexion 84.3 {+/-} 51.8{degrees}, abduction 62.5 {+/-} 47.9{degrees}, and external rotation 25.3 {+/-} 28.0{degrees}. InterpretationWhile it is believed that MEP degeneration 6 months post-injury prevents reinnervation, this data details MEP persistence beyond this timepoint along with significant functional recovery after nerve surgery. Accordingly, persistence of MEPs in denervated muscles may predict the extent of functional recovery from nerve repair surgery.

The health of the infralesional lower motor neuron (LMN) has received little attention in individuals with traumatic cervical spinal cord injuries (SCI). Infralesional LMN health is clinically relevant in the context of nerve transfer surgery to restore critical upper limb functions, as those demonstrating LMN damage below the neurological level of injury may experience irreversible sequelae of denervation (e.g., atrophy, fibrosis) without timely intervention. In this two-centre retrospective cohort study, we examined the health of the infralesional LMN in individuals with traumatic cervical SCI, using data derived from the clinical electrodiagnostic examination performed early after SCI. We assessed 66 limbs in 42 individuals with traumatic cervical SCI (40 males, mean age = 43.6{+/-}17.2, mean duration from injury = 3.3{+/-}1.5 months, 25 with motor complete injuries). Analysis was stratified by injury level as 1) C4 and above, 2) C5 and 3) C6-7. EMG performed on representative muscles from C5-6, C6-7, C7-8 and C8-T1, were included in analysis. LMN abnormality was dichotomized as present (abnormal spontaneous activity) or absent. Data were pooled for the most caudal infralesional segment (C8-T1). Overall, a high frequency of denervation potentials was seen in all infralesional segments for all injury levels. The pooled frequency of denervation potentials at C8-T1 was 74.6% of limbs tested. There was also evidence of denervation potentials at the rostral border of the neurological level of injury, as high as 64.3% of C5-6 muscles for C5 injuries. These data support a high prevalence of infralesional LMN abnormality following SCI, which has implications to candidacy, timing of the intervention, donor nerve options and motor prognosis following SCI.

BackgroundSpinal cord injuries (SCI) can affect muscle control, often resulting in significant functional impairments. Damage to sensorimotor pathways in the spinal cord can lead to muscle weakness, which may gradually recover during the first year post-injury. Functional electrical stimulation therapy (FEST) aims to enhance muscle strength, particularly when natural recovery diminishes. However, the recovery profiles of individual muscles treated with FEST during the chronic phase are still not well understood. The primary objective of this study was to characterize the timing and magnitude of gains in individual muscle strength during FEST. The secondary objective was to identify factors predictive of the response. MethodsIn this cohort study, we examined the strength recovery profiles of 136 muscles treated with FEST, from 17 participants with cervical SCI at the chronic phase of the injury. Electrophysiology was conducted at baseline to assess corticospinal tract (CST) integrity and the excitability of the lower motor neuron pools using surface electromyography (sEMG). ResultsOur findings reveal that 69 muscles did not respond to the treatment, while 67 muscles showed a median strength increase of one muscle motor score (MMS). Among responder muscles, achieving a 1 MMS increase required approximately 59 days (19.2 FEST sessions). A prediction model highlighted key predictors of responsiveness to FEST, including baseline MMS, characteristics of lesion location/severity, and neurophysiological indicators of CST integrity. ConclusionOur findings underscore the need for refined guidelines in rehabilitation medicine, particularly for FEST in cervical SCI. The data demonstrates that achieving a 1-point increase in muscle strength requires {approx}59 days and 19 FEST sessions. Further evidence also suggest that CST integrity and the responsiveness of lower motor neuron pools may influence FEST outcomes. These insights will enable more personalized and effective rehabilitation strategies, optimizing outcomes and resource allocation for individuals living with cervical SCI.

Near fibre electromyography (NFEMG) is the use of specifically high-pass filtered motor unit potential (MUPs) (i.e. near fibre MUPs (NFMs)) extracted from needle-detected EMG signals for the examination of changes in motor unit (MU) morphology and electrophysiology caused by neuromuscular disorders or ageing. The concepts of NFEMG, the parameters used, including NFM duration and dispersion, which relates to fibre diameter variability and/or endplate scatter, and a new measure of neuromuscular junction transmission (NMJ) instability, NFM segment jitter, and the methods for obtaining their values are explained. Evaluations using simulated needle-detected EMG data and exemplary human data are presented, described and discussed. The data presented demonstrate the ability of using NFEMG parameters to detect changes in MU fibre diameter variability, end plate scatter, and neuromuscular transmission time variability. These changes can be detected prior to alterations of MU size, numbers or muscle recruitment patterns.

ObjectiveReverse end-to-side (RETS) nerve transfer is a recent surgical technique to augment injured nerve function by supplying a dispensable donor motor nerve to the side of the distal injured nerve. Although clinical studies have suggested advantages of RETS transfer for upper extremity repairs, uncertainties remain regarding its underlying mechanism. Furthermore, our recent clinical studies using electrophysiological examinations revealed no contribution from the donor nerve. Given that most experimental studies were conducted on acutely injured nerves, our objective is to 1) reassess the effectiveness RETS nerve transfer in a rat model of chronic nerve injury and repair; 2) investigate the potential nerve-babysitting effect; and 3) investigate how availability of regenerating tracks, i.e. bands of Bungner, of recipient nerve affects donor nerve regeneration. MethodsObturator and femoral nerve were used as donor and recipient nerves, respectively. Electromyogram, retrograde labeling of regenerated motoneurons and neuromuscular junction (NMJ) formation were used to compare regenerative ability of donor nerve in acute and delayed RETS transfer where the femoral nerve in the latter group was injured by double ligations 8 weeks prior. Nerve-babysitting effect on injured nerve was investigated by 1) no intervention; 2) perineurial window creation; and 3) RETS transfer to femoral nerve in delayed repair model. The effects of availability of regeneration tracks were investigated by severing proximal femoral nerve, allowing complete denervation compared partial denervation in double ligations, followed by acute and delayed repairs. ResultsEMG and motoneuron quantification confirmed inferiority of donor nerve regeneration into recipient nerve in delayed RETS transfer compared to acute repair, yet donor axons reached target muscle and formed NMJs in both conditions. Same functional assessments revealed nerve baby-sitting effects did not significantly contribute to repair success but availability of regeneration tracks in the recipient nerve may influence the final outcomes. ConclusionsOur study offered insights into the effectiveness of RETS nerve transfer in clinically relevant settings, underscoring the compounded impact of delayed intervention and native nerve regeneration which both negatively affect the efficacy of RETS nerve transfer.

BackgroundDuchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease caused by mutations in the DMD gene, leading to the absence or dysfunction of dystrophin. While cardiac and skeletal muscles are both affected, tissue-specific differences in disease manifestation and dystrophin regulation remain poorly understood. MethodsTo investigate these differences, we established a human induced pluripotent stem cell (hiPSC) model of DMD from peripheral blood mononuclear cells (PBMC) of a patient carrying a splice-site mutation in intron 68 (c.9975-1G>T). An isogenic control line was generated via CRISPR/Cas9 correction. Both repaired and DMD hiPSCs were differentiated into cardiomyocytes (hiPSC-CMs) and skeletal muscle cells (hiPSC-SMs). Transcript and protein analyses were performed, along with functional assessment using microelectrode array. ResultsTranscript analysis revealed an in-frame deletion of two amino acids (Tyr3325 and Arg3326) due to skipping of the first six nucleotides of exon 69. Despite this, near full-length Dp427 was detected by western blot, along with expression of Dp116 in hiPSC-CMs. Dystrophin levels were preserved in DMD hiPSC-CMs but markedly reduced in hiPSC-SMs, suggesting tissue-specific regulation. Functional analysis showed altered {beta}-adrenergic responsiveness in DMD hiPSC-CMs, with increased beating frequency and accelerated repolarization upon isoproterenol stimulation. ConclusionsOur study identifies a splice-site mutation that preserves high level of dystrophin expression in cardiac but reduced in skeletal muscle and reveals Dp116 expression in cardiomyocytes. These findings highlight the importance of tissue context in DMD and demonstrate the power of hiPSC-based systems for dissecting mutation-specific effects.

Motor unit number index (MUNIX) of the upper trapezius is a candidate biomarker for lower motor neuron function of the bulbar region; however, only a few studies have explored this measure in neuromuscular diseases and reliability data is incomplete. We conducted a systematic review and meta-analysis of this measure in control participants and assessed its reliability in twenty healthy volunteers. Four studies were included with heterogeneous mean-MUNIX estimates, moderated by variability in the populations age and MUNIX sampling technique. We demonstrated an inter- and intra-rater intraclass correlation of 0.86 and 0.94, respectively. Upper trapezius MUNIX is a reliable measure with in-between study variability moderated by age and MUNIX technique.

Electromyography is a valuable diagnostic procedure for diagnosing patients with neuromuscular diseases; however, it has some drawbacks. First, diagnosis using electromyography is subjective, and in some cases, there is the potential for inter-individual discrepancies. Second, it is a time- and effort-intensive process that requires expertise to yield accurate results. Recently, a deep learning algorithm shows effectiveness for the analysis of waveform data such as electrocardiography. To overcome limitations of electromyography, we developed a deep learning-based electromyography classification system and compared the performance of our deep learning model with that of six physicians. This study included 58 subjects who underwent electromyography and were finally confirmed as having myopathy or neuropathy, or to be in a normal state between June 2015 and July 2020 at Seoul National University Hospital. We developed a one-dimensional convolutional neural network algorithm and divide-and-vote system for diagnosing subjects. Diagnosis results with our deep learning model were compared with those of six physicians with experience in performing and interpreting electromyography. The accuracy, sensitivity, specificity, and positive predictive value of the deep learning model for diagnosis as to whether subjects have myopathy or neuropathy or normal were 0.875, 0.820, 0.904, and 0.820, respectively, whereas those for the physicians were 0.694, 0.537, 0.773, and 0.524, respectively. The area under the receiver operating characteristic curves of the deep learning model for predicting myopathy, neuropathy, and normal states was better than the averaged results of six physicians. Our study showed that deep learning could play a key role in reading electromyography and diagnosing patients with neuromuscular diseases. In the future, large prospective cohort studies incorporating diverse neuromuscular diseases can enable deep learning-based electrodiagnosis on behalf of physicians.

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a non-invasive biomarker approach to phenotype (fine-)motor skills, speech production and cognition in adults with ADSS1 myopathy. Five individuals with ADSS1 myopathy and five age-sex-matched healthy controls (HCs) underwent a comprehensive multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI) and (vi) plasma proteomics. ADSS1 participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Speech production analysis revealed asthenia (p=0.02), lower intelligibility (p=0.008), and worse voice quality during the sustained vowel task (p=0.03) in the ADSS1 cohort. Cognitive functioning remained unaffected in patients with ADSS1. On EIM, ADSS1 participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliffs 8=0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p=0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival and differentiation) levels in the ADSS1 cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1 myopathy. Take-home messageThis multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and non-invasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1 myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0-97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

BackgroundSarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca2+ homeostasis. The transcript SERCA2a is predominantly expressed in cardiac muscle and in type I myofibers, while SERCA2b is ubiquitously expressed including in skin cells. To date, variants in this gene were reported to be the cause of Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to primary skeletal muscle disease. We describe four patients suffering from a novel hereditary myopathy caused by a homozygous missense variant in ATP2A2. MethodsWe studied a family with four affected individuals suffering from an adult-onset progressive skeletal myopathy. We performed a comprehensive evaluation of the clinical phenotype, serum CK levels, muscle MRI, and muscle biopsy, with genetic workup by means of gene panel sequencing followed by whole genome sequencing and segregation analysis. Immunohistochemistry and western blot (WB) to evaluate SERCA2 and SERCA1 expression in skeletal muscle was performed. We evaluated kinetics of Ca2+handling following caffeine exposure or voltage-induced sarcolemma depolarization in patient myoblasts and myotubes, compared to healthy controls. ResultsFour siblings in their fifties developed in early adulthood symmetric proximal weakness in lower limbs, which was slowly progressive over time. They had no skin or cardiac involvement. Biopsy findings in two affected individuals showed small vacuoles restricted to type I myofibers. Ultrastructural analysis showed dilation and proliferation of T-tubules, swelling of sarcoplasmic reticulum and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G>A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested SERCA2 mislocalization in patient myofibers compared to controls. WB did not show changes in the amount or molecular weight of the protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca2+reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation with caffeine or depolarization. ConclusionsWe report a novel adult-onset vacuolar myopathy caused by a homozygous variant in ATP2A2, resulting in a pure skeletal muscle phenotype with a limb-girdle distribution. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca2+ dysregulation in slow-twitch skeletal myofibers highly support the pathogenicity of the variant.

BackgroundWeakness of facial, ocular, and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. MethodsWe analysed exome and genome sequencing data from three unrelated individuals with congenital myopathy characterised by striking facial, ocular, and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-seq data of one proband and performed gene expression outlier analysis in 129 samples. ResultsThe three probands had remarkably similar clinical presentation with prominent facial, ocular, and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but most prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatiguability. While muscle biopsy on light microscopy did not show any obvious morphological abnormalities, ultrastructural analysis showed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified three unique homozygous loss of function variants in JPH1, encoding junctophilin-1 in the three families; a stop-gain (c.354C>A; p.Tyr118*) and two frameshift (c.373del p.Asp125Thrfs*30 and c.1738del; p.Leu580Trpfs*16) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. ConclusionsJunctophilin-1 is critical to the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement. Key messageThis study identified novel homozygous loss-of-function variants in the JPH1 gene, linking them to a unique form of congenital myopathy characterised by severe facial and ocular symptoms. Our research sheds light on the critical impact on junctophilin-1 function in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype. What is already known on this topicPrevious studies have shown that pathogenic variants in genes encoding triad proteins lead to various myopathic phenotypes, with clinical presentations often involving muscle weakness and myopathic facies. The triad structure is essential for excitation-contraction (EC) coupling and calcium homeostasis and is a key element in muscle physiology. What this study adds and how this study might affect research, practice or policyThis study establishes that homozygous loss-of-function mutations in JPH1 cause a congenital myopathy predominantly affecting facial and ocular muscles. This study also provides clinical insights that may aid the clinicians in diagnosing similar genetically unresolved cases.

Surface electrode EMG is an established method for studying biomechanical activity. It has not been well studied in detecting laryngeal biomechanical activity of pre-phonatory onset. Our aims were to compare the sensitivity of surface EMG in identifying pre-phonatory laryngeal activity to needle electrode laryngeal EMG and to compare the pre-phonatory period in patients with adductor laryngeal dystonia (ADLD) with that in controls. ADLD patients (n = 10) undergoing needle LEMG prior to Botox(R) injection and participants with normal voices (n = 6) were recruited. Surface EMG electrodes were placed over the cricoid ring and thyrohyoid membrane. Needle EMG electrodes were inserted into the thyroarytenoid muscle. EMG and auditory output samples were collected during phonation onset. Tracings were de-identified and evaluated. Measurements of time from onset in change of the amplitude and motor unit frequency on the interference pattern to onset of phonation were calculated by two blinded raters. 42 of 71 patient and 40 of 50 control tracings were available for analysis. Correlation for pre-phonatory time between electrode configuration was 0.70 for patients, 0.64 for controls and 0.79 for all the data combined. Interrater correlation was 0.97 for needle and 0.96 for surface electrodes. ADLD patients had a longer pre-phonatory time than control subjects by 169.48ms with surface electrode and 140.23ms with needle electrode (p < 0.001). Surface EMG demonstrates equal reliability as Needle EMG in detecting pre-phonatory activity in controls and subjects. Patients with ADLD have a significantly prolonged pre-phonatory period when compared with controls.

IntroductionSpinal muscular atrophy (SMA) is a monogenic neuromuscular disorder due to survival motor neuron 1 mutation. Onasemnogene abeparvovec is a US FDA approved single-dose gene therapy for SMA, but is priced at USD 2.1 million per patient which severely limit its accessibility in low-and-middle-income countries (LMIC). We conducted a Phase 1 trial on vesemnogene lantuparvovec, an affordably priced substitute to onasemnogene intended for use in LMICs. MethodsSixteen patients with SMA (eight SMA Type 1 and Type 2 each) received a single dose of intrathecal vesemnogene lantuparvovec. Eleven patients received a low dose (1.5 x 1014 vg) and five received high dose (3.0 x 1014 vg). The primary outcomes were safety, and efficacy with the change from baseline in the developmental gross motor milestones achieved according to World Health Organization (WHO) criteria. ResultsAs of the data cutoff in August 2025, 16 patients enrolled have been followed-up to at least three-month post-treatment. The median ages at diagnosis and dosing were 5 months (0.1, 18) and 12 months (3, 22), respectively. The commonest adverse event (AE) was transiently increased aspartate amino-transaminase which occurred in 11 patients (69%), with one patient having a level twice the upper limit of normal. No patient had required prolonged prednisolone prophylaxis. The most serious AEs were respiratory tract infections which occurred in four (50%) of eight patients with Type 1 SMA, leading to invasive ventilation in 2 and one of them eventually died. Among the eight patients with SMA Type 1, two had gained one WHO milestone at 3-month post-treatment. Among the eight patients with SMA Type 2, at 3-month post treatment, all patients had gained at least one WHO milestone while 2 had gained four milestones and could walk with assistance. ConclusionsIn patients with Type 1 and Type 2 SMA below 24 months, a single intrathecal dose of vesemnogene lantuparvovec was safe and well-tolerated, resulting in improved developmental gross motor milestones which contrast with patients referred to the trial but were untreated. Further studies are necessary to confirm this gene therapys long term safety and efficacy. (ClinicalTrials.gov number NCT06288230.)

Introduction/AimsDuchenne muscular dystrophy (DMD) is a progressive genetic muscle disease. Quantitative muscle ultrasound (MUS), muscle MRI, and functional tools are important to delineate characteristics of muscle involvement. We aimed to establish correlations between clinical/functional and above-named imaging tools respecting their diagnostic and prognostic role in DMD children. MethodsA Prognostic cross-sectional retrospective study of 27 steroid-naive, ambulant male children/adolescents with genetically-confirmed DMD (mean age, 8.8 {+/-} 3.3 years). Functional performance was assessed using motor function measure (MFM) which assess standing/transfer (D1), proximal (D2) and distal (D3) motor function. And six-minute-walk test (6MWT). Imaging evaluation included quantitative muscle MRI which measured muscle fat content in a specific location of right rectus femoris by mDixon sequence. Quantitative MUS measured muscle brightness in standardized US image as an indicator of muscle fat content. ResultsWe found a highly significant positive correlation between the mean MFM total score and 6MWT (R=0.537, P=0.007). And a highly significant negative correlation between fat content by MUS and MFM total score (R=-0.603, P=0.006) and its D1 subscore (R=-0.712, P=0.001). And a significant negative correlation between fat content by US and 6MWT (R=-0.529, P=0.02). And a significant positive correlation between muscle fat content by mDixon MRI and patients age (R=0.617, P=0.01). DiscussionQuantitative MUS correlates significantly with clinical/functional assessment tools as MFM and 6MWT, and augments their role in disease-tracking of DMD. Quantitative MUS has the potential to act as a substitute to functional assessment tools. The role for quantitative muscle MRI in disease-tracking should be further explored after elimination of confounding factors. Graphical abstractDivergent arrows represent negative correlations, while convergent the arrow represents a positive correlation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/21262119v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1c40baborg.highwire.dtl.DTLVardef@1da4708org.highwire.dtl.DTLVardef@16d6031org.highwire.dtl.DTLVardef@1c66a1d_HPS_FORMAT_FIGEXP M_FIG C_FIG

Amyotrophic Lateral Sclerosis (ALS) is a terminal condition with accelerated loss of motor neurons (MN), resulting in the progressive paralysis of affected patients. ALS is either sporadic (90%) or genetically transmitted (10%) and affects cortical (pyramidal) and spinal cord (lower) MN, axons, and respective muscle endplates. ALS research has focused on MN survival, and current FDA-approved therapies provide only small patient survival benefits. This study reports the intravenous (IV) delivery of serial infusions of allogenic Schwann cell-derived extracellular vesicles (SCEV). The recipient had transient clinical stabilization during treatment but deteriorated rapidly during a pause in the infusions. There were no SCEV infusion-related adverse events observed. Allogeneic SCEV appeared safe for IV delivery in this case and may have therapeutic potential.

AimTo test sensitivity of the Segmental Assessment of Trunk Control (SATCo) to changes in neutral vertical (NV) head and trunk control in children with neuromuscular disorders (NMD) and compared with typically developing (TD) children. MethodsIn this observational cross-sectional study, SATCo was applied in 19 children with NMD (10y6m(3y7m), 2 female) and 19 TD children (7y10m(4y12m), 6 female). Statistical differences between condition (NMD and TD), segment (seven trunk segments), and control type (static, active, and reactive control), and relationship between age and SATCo outcomes were analysed with linear mixed-effects models (LME). ResultsSATCo scores were measurably different between conditions (F(1,39.6)=151.0,p<.001), segments (F(6,138.3)=23.3,p<.001), control type (F(2,33.0)=6.3,p=.005), and interactions condition segment (F(6,138.3)=23.3,p<.001) and condition control type (F(2,33.0)=6.3,p=.005). A significant relationship between decreasing active control and increasing age in 10 children with Duchenne muscular dystrophy confirmed measurable decline in trunk control following diagnosis. InterpretationThe results showed that SATCo is sensitive to differences in trunk control status in NMD. While still ambulatory, children with NMD presented already a measurable trunk control deficit at varying segments. SATCo has potential as an outcome measure for therapeutic interventions or effectiveness of treatments promoting NV trunk control in children with NMD and needs further study. What this paper addsO_LINeutral vertical head/trunk control was different between NMD and TD children C_LIO_LISATCo is sensitive to head/trunk control differences between NMD and TD children C_LIO_LIAmbulant children with NMD showed measurable head/trunk control deficit at various segments C_LIO_LISATCo detected subtle head/trunk control changes in early disease stages of NMD C_LIO_LIActive segmental trunk control declines with increasing age in Duchenne muscular dystrophy C_LI

Background and ObjectivesSporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals over age 50. The disorder is slowly progressive and while many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM is limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort, as well as prognostic factors for disease progression. MethodsClinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003-2018. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in IBM patients. ResultsAmong the 335 IBM patients meeting inclusion criteria, 64% were male with an average age of disease onset of 58.7 years and a delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients but were less likely to develop dysphagia. Female patients had stronger finger flexors and knee extensors compared to their male counterparts but were more likely to develop dysphagia. A significant number (20%) of patients had an age of onset less than 50 years. This group of younger patients was weaker at their first visit; however, this may be accounted for by a longer disease duration at first visit. DiscussionAlthough IBM has long been considered a disorder predominately of older, White men, female, and non-White patients comprise a significant proportion of the IBM population. Our study demonstrates that female and Black patients have distinct clinical phenotypes within the overarching IBM clinical phenotype.

ObjectivesAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, affecting both upper and lower motor neurons. High-density surface electromyography is a non-invasive measure of muscle fasciculations, a phenomenon prevalent early in the disease. Previous studies highlighted the clinical importance of these measures from the biceps brachii muscle. Our study aimed to investigate the diagnostic and prognostic value of the medial gastrocnemius muscle. MethodsWe performed a retrospective study of 49 ALS and 25 control participants. Means comparisons, logistic regression, receiver operating characteristic analysis, Kaplan-Meier analysis, and a multilevel Cox model were used to determine the predictive utility of fasciculation potential (FP) parameters including FP frequency, median amplitude, and amplitude dispersion. ResultsFP parameters demonstrated a poor ability to differentiate between ALS and controls, with ROC analysis producing areas under the curve between 0.58 and 0.63. Furthermore, there was no association between FP parameters and ALS prognosis in the Cox model. ConclusionsFP parameters from the medial gastrocnemius muscle are not useful for the diagnosis or prognosis of ALS patients. SignificanceOur results highlight the poor clinical utility of fasciculation quantification in the medial gastrocnemius muscle. Future studies should focus on recordings from more clinically relevant muscles earlier in the disease. HighlightsO_LIFasciculation parameters from the medial gastrocnemius muscle have poor ability to differentiate ALS patients from controls. C_LIO_LIFasciculation parameters from the medial gastrocnemius muscle cannot reliably predict the prognosis of ALS patients. C_LIO_LIFuture studies should measure more clinically relevant muscles at an earlier stage in the disease course over a protracted period. C_LI

BackgroundAcute intermittent hypoxia (AIH) is an emerging technique for facilitating neural plasticity in individuals with major neurological deficits. In people with chronic incomplete spinal cord injury (iSCI), a single sequence of AIH enhances motor function such as hand grip strength and ankle plantarflexion torque, but the underlying mechanisms are not yet clear. ObjectiveTo examine how AIH-induced changes in magnitude and spatial distribution of electromyography (EMG) activity over the surface of the biceps and triceps brachii muscles contributes to improved strength. MethodsSeven individuals with iSCI visited the laboratory on two occasions, at least a week apart, and received either AIH or Sham AIH intervention in a randomized order. AIH consisted of 15 brief ([~]60s) periods of low oxygen (fraction of inspired O2 = 0.09) alternating with 60s of normoxia, whereas Sham AIH consisted of repeated exposures to normoxic gas mixtures. Muscle activity of biceps and triceps brachii was recorded with high-density surface EMG during maximal elbow flexion and extension contractions. We used these EMG recordings to generate spatial maps which distinguished active muscle regions prior to and 60 minutes after AIH or Sham AIH. ResultsAfter an AIH sequence, elbow flexion and extension forces increased by 91.7 {+/-} 33.5% and 51.7 {+/-} 21.9% from baseline, respectively, whereas there was no difference after Sham AIH exposure. Changes in strength were associated with an altered spatial distribution of EMG activity and increased root mean squared EMG amplitude in both biceps and triceps brachii muscles. ConclusionsThese data suggest that altered motor unit activation profiles may underlie improved volitional strength after a single dose of AIH and warrant further investigation using single motor unit analysis techniques to further elucidate mechanisms of AIH-induced plasticity.