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Mutations that reduce the function of KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. These channels are present in nodes of Ranvier in rat brain and nerve and have been proposed to mediate the slow nodal potassium current IKs. We have used immunocytochemistry, electrophysiology and pharmacology to test this hypothesis and to determine the contribution of KCNQ channels to nerve excitability in the rat. When myelinated nerve fibres of the sciatic nerve were examined by immunofluorescence microscopy using antibodies against KCNQ2 and KCNQ3, all nodes showed strong immunoreactivity for KCNQ2. The nodes of about half the small and intermediate sized fibres showed labelling for both KCNQ2 and KCNQ3, but nodes of large fibres were labelled by KCNQ2 antibodies only. In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 and linopirdine completely inhibited IKs, as did TEA . The KCNQ channel opener retigabine (10 μm) shifted the activation curve to more negative membrane potentials by −24 mV, thereby increasing IKs. In isotonic KCl 50% of IKs was activated at −62 mV. The activation curve shifted to more positive potentials as [K+]o was reduced, so that the pharmacological and biophysical properties of IKs were consistent with those of heterologously expressed homomeric KCNQ2 channels. The ability of XE991 to selectively block IKs was further exploited to study IKs function in vivo. In anaesthetized rats, the excitability of tail motor axons was indicated by the stimulus current required to elicit a 40% of maximal compound muscle action potential. XE991 (2.5 mg kg−1i.p.) eliminated all nerve excitability functions previously attributed to IKs: accommodation to 100 ms subthreshold depolarizing currents, the post-depolarization undershoot in excitability, and the late subexcitability after a single impulse or short trains of impulses. Due to reduced spike-frequency adaptation after XE991 treatment, 100 ms suprathreshold current injections generated long trains of action potentials. We conclude that the nodal IKs current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

Introduction/aims: Reliable neurophysiological markers in amyotrophic lateral sclerosis (ALS) are of great interest. The compound muscle action potential (CMAP) amplitude has been a conventional marker, although it is greatly influenced by the electrode position. We propose the far-field potential of the CMAP (FFP-CMAP) as a new neurophysiological marker in ALS., Methods: Patients with ALS and age-matched healthy controls were enrolled. We used a proximal reference (pref) in addition to the conventional distal reference (dref). Routine CMAP was recorded from the belly-dref lead and FFP-CMAP from the dref-pref lead for the ulnar and tibial nerves. Multiple point stimulation motor unit number estimation (MUNE) was also examined in the ulnar nerve. Inter-rater reproducibility was evaluated by two examiners, and some patients were followed up every 3 mo for 1 y., Results: We tested 17 patients with ALS and 10 controls. The amplitudes of routine CMAP and FFP-CMAP in the ulnar and tibial nerves, and hypothenar MUNE value in the ulnar nerve were significantly decreased in ALS compared to controls. Ulnar FFP-CMAP achieved the highest inter-rater intraclass correlation coefficient (ICC) value (0.942) when compared with routine CMAP (0.880) and MUNE (0.839). The tibial FFP-CMAP had a higher ICC value (0.986) than the routine CMAP (0.697). In this way, the FFP-CMAP showed high inter-rater reproducibility because its shape was not much influenced by the electrode position. During 1-y follow-up, decline of CMAP, FFP, and MUNE showed significant correlations with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R)., Discussion: The FFP-CMAP shows promise as a reliable marker for ALS., (© 2023 Wiley Periodicals LLC.)

Antinociceptive therapy for chronic neuropathic pain is anecdotal in nature based on a physician's preference. However, evidence-based therapy is expected, following the chronic pain guideline established in 2021, supported by 10 pain-associated Japanese medical societies. The guideline strongly recommends the use of Ca 2+ -channel α2δ ligands (pregabalin, gabapentin, and mirogabalin) and duloxetine for pain relief. International guidelines also recommend administration of tricyclic antidepressants as first-line agents. Recent studies have described three classes of medicines that show comparable antinociceptive effects in painful diabetic neuropathy. Furthermore, a combination of first-line agents can improve efficacy. Antinociceptive medical therapy should be individualized based on the patient's condition and adverse effect profile of each medication.

Objectives: To evaluate the efficacy of ultrasound (US) as a diagnostic tool for sarcopenia in patients with rheumatoid arthritis (RA)., Methods: Female RA patients aged >50 years and matched controls were cross-sectionally assessed. Sarcopenia was diagnosed based on the 2019-updated Asian Working Group for Sarcopenia definition. The cross-sectional area (CSA) and echo intensity (EI) of the biceps brachii, rectus femoris, and EI of the vastus lateralis were examined bilaterally. Correction for subcutaneous fat and calculation of the recorrected EI (rcEI) were performed. We performed logistic regression using both muscle rcEI and CSA with receiver operating curve analysis to evaluate the discriminative performance per muscle group., Results: Seventy-eight consecutive RA patients and 15 age-and sex-matched controls were assessed. Sarcopenia was diagnosed in 34 RA patients (43.6%). The rcEI of examined muscles were significantly higher, whereas CSA were significantly lower in sarcopenic RA patients than in non-sarcopenic patients and matched controls. The combined discriminative performance of rcEI and CSA was superior to those of rcEI or CSA alone., Conclusions: This study suggests the use of US for the diagnosis of sarcopenia in RA patients. The diagnostic performance increases when both echogenicity and CSA are considered together rather than individually., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent., Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset., Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo., Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks., Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set., Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups., Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period., Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Waveform analysis of compound muscle action potential (CMAP) is important in the detailed analysis of conduction velocities of each axon as seen in temporal dispersion. This understanding is limited because conduction velocity distribution cannot be easily available from a CMAP waveform. Given the recent advent of artificial intelligence, this study aimed to assess whether conduction velocity (CV) distribution can be inferred from CMAP by the use of deep learning algorithms. Simulated CMAP waveforms were constructed from a single motor unit potential and randomly created CV histograms ( n = 12,000). After training the data with various recurrent neural networks (RNNs), CV inference was tested by the network. Among simple RNNs, long short-term memory (LSTM) and gated recurrent unit, the best accuracy and loss profiles, were shown by two-layer bidirectional LSTM, with training and validation accuracies of 0.954 and 0.975, respectively. Training with the use of a recurrent neural network can accurately infer conduction velocity distribution in a wide variety of simulated demyelinating neuropathies. Using deep learning techniques, CV distribution can be assessed in a non-invasive manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nodera and Matsui.)

Objectives: We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren's syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD)., Methods: We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control., Results: We included 11 patients with pSS-PSN (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7). Sural nerve CSA were significantly increased in pSS-PSN group (3.48 ± 1.0 mm 2 vs 2.05 ± 0.65 mm 2 , p  = .001). US of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 - 1). Sural nerve CSA and IENFD of lower leg showed positive correlation. Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers., Conclusion: US was useful in discriminating pSS patients with PSN from those without. Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM)., Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety., Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively)., Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint., Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467., Classification of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2., (© 2021 American Academy of Neurology.)

Background: Diagnosing cervical radiculopathy (CR) can be difficult because of symptomatic overlap with peripheral neuropathies. In this retrospective observational study, we aimed to determine whether short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) sequences are useful for detecting signs of denervation in the multifidus muscles in patients with CR., Methods: We analyzed the data of 18 patients with CR who developed arm weakness within 1 year. We also included 10 patients with sensorimotor symptoms involving the upper extremities who did not have intervertebral foraminal stenosis on MRI as controls. For each patient with CR, the signal intensity (SI) of the affected multifidus muscles was measured and compared to that on the contralateral side (signal intensity ratio: SIR)., Results: Control patients without CR did not exhibit STIR signal abnormalities in the multifidus muscles. Most of the 18 patients with CR were male (83.3%), and the mean age was 59.4 years. Thirteen of 18 CR patients (72.2%) were determined to have STIR signal abnormalities by a radiologist. The mean SIR in the 13 patients with increased SI was significantly higher than that in the five patients without signal abnormalities (1.23 vs 0.97, P = .004), supporting the radiologist's diagnosis. The distribution of signal abnormalities closely followed those identified via clinical and electrophysiological tests, especially severe weakness (P = .044)., Conclusions: Denervation edema of the multifidus muscles can be detected in CR and correlates with clinical/electrophysiological tests and weakness severity, which may aid in CR diagnostics., (© 2020 Wiley Periodicals LLC.)