Muscle & Nerve最新文献

Introduction: Motor recovery following nerve injury is dependent on time required for muscle reinnervation. This process is imperfect, however, and recovery is often incomplete. At the neuromuscular junction (NMJ), macrophage signaling aids muscle reinnervation. Tacrolimus (FK506) treatment speeds functional recovery through unknown mechanisms. This study investigated whether macrophages were required for FK506 neuroenhancing effects.

Methods: Wildtype (WT) mice and mice with impaired macrophage recruitment to injury sites (Ccr2 ^-/- ) were injected subcutaneously with either saline or FK506 for 3 days prior to sciatic nerve transection and immediate repair and then daily for 4 weeks. Functional recovery was assessed by grid walk and muscle force. Morphometric NMJ and macrophage analyses were conducted in extensor digitorum longus muscles.

Results: FK506-injected WT mice showed increased proportions of fully reinnervated NMJs and terminal Schwann cells/NMJ (p < 0.05), improved recovery of tetanic muscle force (p < 0.05), and improved grid walking (p < 0.05) relative to controls. Ccr2 ^-/- mice showed no enhancements in recovery; Ccr2 ^-/- mice treated with FK506 did not differ from controls on any tested metric. We also observed at the NMJ of WT mice increased macrophage numbers with FK506 treatment and increased macrophages expressing FK506 binding protein, FKBP52, after nerve injury.

Discussion: These results show that macrophages are required for FK506-mediated improvements in NMJ reinnervation and muscle function. These data implicate macrophages in the mechanism underlying FK506-mediated enhancement of motor recovery after nerve injury. Enhanced knowledge of the neuroenhancing mechanism of FK506 may identify new clinically relevant therapeutic targets.

Introduction/aims: Literature on the role of gastrostomy and noninvasive ventilation (NIV) in primary lateral sclerosis (PLS) is limited. We aim to investigate whether PLS patients develop dysphagia requiring feeding tubes or respiratory failure necessitating NIV.

Methods: We conducted a retrospective study of PLS patients with a definite diagnosis followed at our center (1994-2024). Patients with marked dysphagia (score < 3 on Question 3 of the ALSFRS-R) received a recommendation for gastrostomy and were divided into two groups: G1/G2 (accepted/declined gastrostomy). We investigated NIV indications due to respiratory failure and compared these patients (G3) to those without respiratory impairment (G4). Demographic, clinical, and neurophysiological data were collected and compared.

Results: Forty-eight patients had a definite diagnosis of PLS. Gastrostomy was recommended to 18 (37.5%), yet only 7 patients (38.9%-G1) consented. The median time to gastrostomy was 77 months. Total survival and survival post-gastrostomy recommendation were not different between G1 and G2. Six PLS patients (12.5%-G3) developed respiratory failure and initiated NIV (median of 63 months). At 63 months, G3 had significantly lower median forced vital capacity (65% vs. 99%; p < 0.001) and phrenic nerve amplitude (0.43 vs. 0.75 mV; p = 0.039), but a greater ALSFRS-R slope (0.34 vs. 0.14; p = 0.046) and shorter survival (35 vs. 94.9 months; p = 0.009) compared to G4.

Discussion: Dysphagia requiring gastrostomy was common in our PLS cohort, but survival after gastrostomy recommendation did not differ between groups. Patients who developed respiratory impairment may represent a distinct group with faster disease progression and shorter survival. Our findings may contribute to a deeper understanding and improved management of PLS.

Introduction/aims: Neuromuscular ultrasound (NMUS) is gaining prominence as a valuable tool for diagnosing neuromuscular disorders at the point of care. Neuromuscular disorder diagnostic criteria guidelines have begun incorporating NMUS findings. As interest grows, fellowship programs must consider incorporating training into their curricula. This study evaluated the current state of NMUS training, potential barriers, and interest in training across Canadian neuromuscular fellowship programs.

Methods: A 23-question online survey was developed and distributed via email to all 10 neuromuscular fellowship program directors across Canada.

Results: Seven (70%) programs responded to the survey. There was general agreement among programs on the value of NMUS, however, only one (14.3%) program reported they would consider recent graduates to be competent in NMUS. Critical barriers to incorporation of NMUS training included lack of a formalized curriculum, faculty expertise and time, and equipment. Two (28.6%) programs reported that accessibility of equipment and one (14.3%) that faculty expertise was not a barrier to NMUS training. Two (28.6%) programs have local NMUS training options available to fellows (in only one program is NMUS training mandatory). All programs expressed interest in additional training opportunities, and three (43%) programs reported taking steps toward incorporating NMUS training into their curricula.

Discussion: NMUS training is in its infancy in Canada, with several common barriers identified across programs. There is universal interest in further NMUS training opportunities for fellows, highlighting the importance of a common approach to addressing the educational gap to support development of formalized NMUS training mechanisms in Canada.

Introduction/aims: Tofacitinib, a first-generation Janus kinase (JAK) 1/3 inhibitor, is commonly used for treating ulcerative colitis and rheumatoid arthritis. However, its role in myasthenia gravis (MG) remains unclear. This study aimed to evaluate the immunomodulatory effects of tofacitinib on experimental autoimmune myasthenia gravis (EAMG) and peripheral blood mononuclear cells (PBMCs) from patients with MG.

Methods: Flow cytometry, enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot were used to evaluate the effects of tofacitinib on T helper (Th) cell profiles, humoral immune responses, and the JAK-signal transducer and activator of transcription (STAT) pathway proteins.

Results: In vivo, tofacitinib significantly ameliorated EAMG severity in rats, reducing the proportions of Th1, Th17 and memory B cells, and anti-acetylcholine receptor (AChR) antibodies levels, while increasing the proportions of regulatory T (Treg) cells. In vitro, tofacitinib administration resulted in a significant decrease in the proportions of Th1 and IgG-secreting B cell, and a significant upregulation of Treg cells in mononuclear cells (MNCs) from EAMG rats, which was consistent with findings in PBMCs from MG patients. Further analysis revealed that tofacitinib inhibited CD4⁺ T cell differentiation into Th1 by decreasing phosphorylated STAT1 levels, while promoting Treg differentiation via increased phosphorylated STAT5 levels in MNCs from EAMG rats.

Discussion: Tofacitinib modulates Th cell profiles and humoral immune responses by targeting the JAK-STAT pathway, suggesting its potential as a therapeutic candidate for MG. Further clinical studies are warranted to evaluate the efficacy and safety of tofacitinib in MG patients.

Introduction/aims: A previous randomized controlled trial showed that guided self-help acceptance and commitment therapy plus standard medical care (ACT+SMC) was superior to standard medical care alone (SMC) for improving quality of life (QoL) and mood at 9-weeks post randomization in a sample of people with muscle disorders (MD). This follow-up study evaluated whether these effects were maintained in the longer term alongside individual patterns of response.

Methods: The original study was a two-arm parallel group randomized controlled trial, which compared ACT+SMC to SMC. The primary outcome of QoL was assessed with the Individualized Neuromuscular Quality of Life Questionnaire. We recruited people with different MDs from UK National Health Service clinics and patient registries. In this follow-up study, we re-administered all outcome measures to participants at 6 months post randomization.

Results: Questionnaires were completed by 109 participants (70.3% of the original sample). At six months, the adjusted group difference in QoL continued to favor ACT+SMC, which was significant with moderate effect size. Improvements in secondary outcomes of mood and aspects of psychological flexibility also favored ACT+SMC. Reliable improvement was evident in 33.9% of the ACT+SMC group and 5.7% of the SMC group. Reliable deterioration was uncommon following ACT+SMC (1.8% of participants.) DISCUSSION: The beneficial impacts of guided self-help ACT for QoL and mood were maintained in the longer-term. A third of participants showed response to this brief intervention, and negative individual outcomes were very rare. As is common in psychological interventions, there was a considerable group of non-responders.

Introduction: Extrapolated reference values (E-Ref) procedure is a new method for determining the cutoff value without collecting the control data. We tried to apply this method to determine the cutoff value for the distal motor latency of the median nerve (median DML). During this process, we found two pitfalls of the E-Ref method. First, the E-Ref procedure did not correctly work when the DML values measured with 0.1 ms accuracy frequently took on tie values. Second, the result was influenced by the proportion of abnormal values. This study investigated these issues.

Methods: Data of the median DML were extracted from our laboratory database. To solve the problem of tie values, we tried a wider post-smoothing window in the original E-Ref method. We also devised a modified method conducting pre-smoothing. To see the effect of the proportion of abnormal data, we simulated many datasets having different proportion of abnormal data.

Results: In total, 1016 DML values were identified. False deflections due to tie values were often identified as the E-Ref point using the original methods even using a wider window, resulting in unrealistically low values. Modified method was free from this drawback. For all methods, the E-Ref value increased as the proportion of abnormal values increased.

Discussion: The problem of tie values, a pitfall of the E-Ref method, might be solved by pre-smoothing the data. The E-Ref value is influenced by the proportion of the normal data, and datasets containing less than 20% abnormal data may achieve appropriate results.

Introduction/aims: Glucocorticoid (GC)-related adverse reactions and risks are commonly seen during the treatment of immune-mediated and inflammatory neuromuscular disorders. There is wide variation in the management of associated complications. The aim of this study is to develop international consensus guidance on the management of GC-related complications in neuromuscular disorders.

Methods: Through the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), an international task force of 15 experts was convened to develop clinical guidance for the management of GC-related complications in neuromuscular patients. The RAND/UCLA appropriateness method (RAM) was used to develop consensus guidance statements. Initial guidance statements were crafted after a thorough literature review and were modified after anonymous panel input, with up to three rounds of voting via email to achieve consensus.

Results: Statements were developed and achieved consensus for general care, monitoring of patients while on GC, osteoporosis prevention, vaccinations, infection screening, and Pneumocystis jiroveci pneumonia prophylaxis. A multidisciplinary approach to the management of GC-related complications was emphasized.

Discussion: These formal consensus statements provide guidance to clinicians who use GC in the treatment of neuromuscular diseases regarding prevention and management of the more common associated adverse events and risks that arise with long and short-term GC use and serve as a springboard for investigation and updates.

Introduction/aims: Electrophysiological investigations in early Guillain-Barré Syndrome (GBS) can be nondiagnostic. Improved testing for facial weakness in the early phase of GBS may improve diagnostic processes, as such weakness is found in approximately 50% of patients with GBS. This work pilots the utility of high-speed video analysis to complement blink reflex testing in early GBS.

Methods: This work prospectively evaluated consecutive patients admitted to a metropolitan teaching hospital in Melbourne, Australia, with suspected acute GBS within the first 14 days of neurological symptoms and compared them to a cohort of healthy controls. Blink reflex testing, mechanically-activated masseter reflexes, and analysis of high-speed video recordings of the evoked blinks were performed at admission (day 0), day 7, and day 21 (±2 days).

Results: 19 suspected GBS patients (12 GBS and 7 mimics) were compared to 22 healthy controls. At the first test, 83% of GBS patients and 29% of mimics demonstrated blink reflex abnormalities. 50% of GBS manifested video abnormalities (14% mimics), but abnormalities preceded electrophysiological changes in two GBS patients. The calculated reference values for peak lid velocity and lid excursion by video analysis were ~160 mm/s and 7-8 mm, respectively, with slightly different values for ipsilateral versus contralateral responses.

Discussion: Combining high-speed video analysis and blink reflex testing improves the detection of facial involvement in early GBS and helps discriminate from mimic disorders. Further work in a larger cohort is required to validate the sensitivity and specificity of this technique.

Background: Nusinersen and risdiplam are U.S. Food and Drug Administration (FDA)-approved treatments for spinal muscular atrophy (SMA). No head-to-head clinical trials to assess efficacy exist. Observational studies are needed to determine if transitioning to risdiplam is safe and efficacious.

Methods: This retrospective study at Nationwide Children's Hospital included individuals with SMA treated with nusinersen who switched to risdiplam. Motor, pulmonary and bulbar function were assessed before and 2 years after nusinersen and risdiplam initiation.

Results: Forty-four individuals were included: 11 with SMA type 1, 25 with SMA type 2 and 8 with SMA type 3. Motor function improved after initiation of nusinersen treatment with the most significant improvements seen in the first year. After transition to risdiplam, motor function remained largely stable. Need for noninvasive ventilation (NIV) overnight occurred in both groups. Cough peak flow significantly improved in the risdiplam group. Hospitalizations were the same in both groups. One individual in the nusinersen group gained the ability to take some food by mouth; two individuals in the risdiplam group achieved some oral feeding and two became exclusively orally fed.

Conclusions: As expected, motor function was most improved in treatment naïve individuals in the first year after nusinersen initiation. Over half of our study population had posterior spinal fusion surgery (57%) which significantly impacted motor and respiratory outcomes, though slightly less so in the risdiplam group. Overall, our data demonstrates that transitioning from nusinersen to risdiplam is associated with a favorable safety profile and stable motor outcomes.

Introduction/aims: Skeletal muscle magnetic resonance imaging (MRI) is a validated noninvasive tool to assess Duchenne muscular dystrophy (DMD) progression. There is interest in finding DMD biomarkers that decrease the burden of clinical trial participation, such as wearable devices. Our aim was to evaluate the relationship between activity, via accelerometry, and skeletal muscle MRI, particularly T₂ mapping.

Methods: DMD children and young adults completed skeletal muscle MRI and were asked to wear an accelerometer on the dominant wrist for 7 days. MRI data included fat-suppressed transverse relaxation time (T₂) mapping of the calves and longitudinal relaxation time (T₁) mapping. Activity was assessed as vector magnitudes (VMs) and fraction of time (FOT) in activity groups (sedentary 1 or 2, low 1 or 2, moderate-to-vigorous physical activity (MVPA)).

Results: Participants (n = 22; median age 11.4 years, 41% ambulatory) wore the accelerometer for a median of 7 days. Longer T₂ in multiple lower extremity muscles was negatively correlated with VMs per minute (tibialis posterior Spearman's rho = -0.68, p < 0.001), even when accounting for age, ambulatory status, or glucocorticoid use. Longer T₂ of the tibialis posterior was positively correlated with FOT in sedentary 1 (rho = 0.49, p = 0.02) and negatively correlated with FOT in higher activity levels (low 1 (rho = -0.58, p = 0.004), low 2 (rho = -0.67, p = 0.002), MVPA (rho = -0.7, p < 0.001)).

Discussion: In individuals with DMD, longer T₂ on skeletal muscle MRI of the calves moderately correlated with lower activity levels indicating the potential use of home accelerometry as a future clinical trial biomarker of skeletal muscle health and progression in DMD.