Noriko Isobe

Background: Baló's concentric sclerosis (BCS) is a rare demyelinating disorder defined by alternating rings of demyelinated and preserved myelin. Methods: We retrospectively reviewed the medical records of 15 Japanese patients with BCS lesions seen at our institution over a 15-year period. Results: The median age at onset was 29 years, with a female predominance (67%). All patients fulfilled the 2024 McDonald criteria for multiple sclerosis (MS), and 83% exhibited cerebrospinal fluid oligoclonal bands (OCBs). In patients who underwent susceptibility-weighted imaging, peripheral hypointensity was frequently observed, whereas classic lamellar architecture was not clearly visualized. Over long-term follow-up, new BCS lesions were detected during treatment with interferon beta, dimethyl fumarate, fingolimod, or siponimod, whereas no new BCS lesions were observed during natalizumab or ofatumumab exposure, except shortly after switching to natalizumab. Conclusions: These findings support the concept that BCS constitutes a clinical variant within the MS spectrum. Some patients appeared to benefit from natalizumab or ofatumumab, although the optimal DMT remains uncertain. The frequent presence of OCBs and MS-like radiological features may indicate overlap with classical MS. BCS may thus represent a common and distinct immune-mediated demyelinating phenotype at the interface between classical MS and atypical demyelination.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4⁺ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities.

Objective: Cognitive difficulties in juvenile myoclonic epilepsy (JME) are part of the clinical phenotype alongside epileptic seizures; however, the underlying neurophysiological mechanisms remain unclear. Auditory steady‐state responses (ASSRs) to repetitive 40‐ and 80‐Hz stimuli are widely used measures of gamma‐band oscillations (GBOs) relevant to cognition, but have not yet been investigated in JME. To address this gap, we examined 40‐ and 80‐Hz ASSRs using magnetoencephalography and their relationship with cognitive function in JME. Methods: In this cross‐sectional case–control study, we recorded ASSRs in 16 patients with JME and 16 age‐ and sex‐matched healthy controls (HC). Evoked power and phase‐locking factor (PLF) were quantified from magnetic resonance imaging‐based source estimates in the bilateral primary auditory cortices and compared between groups using linear mixed‐effects models (LMMs). Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Within the JME group, associations between RBANS indices and ASSR measures were examined using age‐ and sex‐adjusted linear regression. Where applicable, p values were adjusted using the Benjamini–Hochberg false discovery rate (FDR) procedure. Results: LMMs showed lower evoked power and PLF in JME than in HC (both group effects p < 0.001). Among the five RBANS indices, only the Attention Index was lower in JME (FDR‐adjusted p = 0.02). Within the JME group, the Attention Index was positively associated with both measures (evoked power: B = 16.65, 95% confidence interval [CI], 5.81 to 27.49; PLF: B = 38.82, 95% CI, 13.82 to 63.83; both FDR‐adjusted p = 0.03), whereas other indices showed no significant associations. Significance: Gamma‐band ASSRs were reduced in JME and were consistently associated with attentional performance across evoked power and PLF. These exploratory findings suggest that gamma‐band ASSRs may help investigate network‐level mechanisms, potentially involving thalamocortical dysfunction that link gamma synchronization to attentional performance in JME. Plain Language Summary: Juvenile myoclonic epilepsy (JME) is associated with cognitive difficulties beyond seizures, but the underlying brain physiology is not fully understood. Using magnetoencephalography, we found that patients with JME showed weaker gamma‐band auditory steady‐state responses (ASSRs) than healthy participants. Within the JME group, stronger and more synchronized responses were associated with better attention scores, suggesting that gamma‐band brain activity may be linked to attentional performance in JME. Together, these findings indicate that ASSRs may provide a useful window into brain mechanisms related to cognitive difficulties, particularly those involving attention, in JME.

Objective: Needle electromyography (nEMG) is essential for diagnosing neuromuscular disorders but is invasive and often painful. We employed single-channel bipolar surface EMG (sEMG) analyzed with a novel wavelet-based analytical approach, “Detecting and Extracting Elemental Wave Components based on a Wavelet Coefficient Set (DEWCS)” and investigated whether fasciculation-related activity could be identified. Methods: In this prospective study, 28 patients undergoing nEMG for suspected neuromuscular disorders and 13 healthy controls were included. Resting-state sEMG was recorded from selected muscles using single-channel bipolar active electrodes at a high sampling rate. DEWCS was used to extract indices reflecting fast- and slow-type motor unit (MU)-related activity. These standardized indices were evaluated against nEMG-detected fasciculation potentials using generalized estimating equation logistic regression to account for within-subject clustering. Diagnostic performance was assessed by receiver operating characteristic analysis. Results: A total of 67 muscles from 38 participants were analyzed. Indices of fast- and slow-type MU-related activity were significantly associated with fasciculation potentials (slow: OR 5.10, p = 0.0041; fast: OR 2.38, p = 0.0162). The combined model showed excellent discrimination (area under the curve = 0.97), outperforming either index alone. Muscle region had no significant effect. Conclusions: A single-channel bipolar sEMG setup combined with DEWCS detected fasciculation-related activity with promising accuracy. This method may serve as a non-invasive surrogate marker of lower motor neuron involvement. Further validation in larger cohorts is warranted. Significance: This non-invasive sEMG approach may help detect fasciculation-related activity and complement nEMG in neuromuscular diagnostics.

Aim: Several studies have reported a higher prevalence of migraine in patients with multiple sclerosis (MS) than in healthy controls (HCs). The aim of this study was to elucidate the headache prevalence in patients with MS or other neuroimmunological disorders, as well as to investigate the associations between headache characteristics and disease activity. Methods: In this multicenter study in Japan, a headache questionnaire was distributed to patients with MS (n = 338), aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (NMOSD; n = 106), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD; n = 51) or acetylcholine receptor antibody-positive myasthenia gravis (MG; n = 104), and healthy controls (HCs; n = 407). We included only participants aged 18–65 years in this study. The questionnaire responses were classified according to the International Classification of Headache Disorders, 3rd edition. The questionnaire was designed to systematically capture headache characteristics based on established diagnostic criteria. Results: In total, any type of headache was found for 54.1% in MS, 63.2% in NMOSD, 43.1% in MOGAD, 43.3% in MG and 43.5% in HCs. After Holm–Bonferroni correction for comparisons among the five groups, the MS ( p = 0.015) and NMOSD ( p < 0.001) groups had significantly higher odds of any headache compared to the HC group. No difference was observed for migraine (MS 16.0%, NMOSD 16.0%, MOGAD 9.8%, MG 12.5%, HCs 17.0%). In contrast, patients with MS (24.0%) and NMOSD (37.7%) showed a significantly higher frequency of tension-type headache (TTH) than HCs (16.7%) even after adjusting for age and sex. Neither disease activity nor disease-modifying therapy displayed any association with headache severity in patients with MS, NMOSD, or MOGAD. Conclusions: Our study showed no increased prevalence of migraine in MS and other neuroimmunological disorders, whereas TTH comorbidity was higher in MS and NMOSD than in controls.

Purpose: To evaluate the real-world effectiveness and safety of satralizumab over 2.5 years using medical data charts of satralizumab-treated Japanese patients with aquaporin-4 immunoglobulin-G seropositive neuromyelitis optica spectrum disorder (AQP4[+] NMOSD). Major findings: Overall, 124 patients were evaluated (mean ± standard deviation: age, 51.1 ± 14.0 years; disease duration, 7.0 [6.0] years). At baseline, 72.6%, 16.9%, and 35.5% of patients received oral glucocorticoids (GCs), azathioprine (AZA), and tacrolimus (TAC), respectively. The annualized relapse rate (ARR [95% confidence interval]) decreased from 0.45 (0.34–0.58) within 52 weeks before satralizumab initiation to 0.03 (0.02–0.07) after 130 weeks of satralizumab initiation; relapse-free rate was 91.8% at 130 weeks. Nine patients had nine relapses; seven were re-administered satralizumab after relapse. At 130 weeks, 48.8% of relapse-free patients were not receiving oral GCs (89.3% received ⩽5 mg/day); mean oral GC dose reduced from 10.3 to 2.5 mg/day. In patients receiving AZA and TAC at baseline, 80.0% and 47.1% were no longer receiving AZA and TAC at 130 weeks, respectively. Serious drug reactions occurred in 9.7% of patients (serious infections, 6.5%). Conclusion: The real-world relapse-free rate at 2.5 years was 91.8% (ARR = 0.03) in satralizumab-treated patients with AQP4[+] NMOSD, supporting the relapse-preventive effect of satralizumab without new safety concerns. Registration number: UMIN000050027

Interictal epileptiform discharges (IEDs) are crucial for epilepsy diagnosis but are often undetectable on scalp EEG (scEEG). This study aims to develop a Support Vector Machine classifier to detect mesial temporal lobe (MTL) IEDs invisible on scEEG using simultaneous intracranial EEG (iEEG) and scEEG recordings and to identify contributing scEEG features. Data from 17 patients with epilepsy were analyzed. IED epochs were extracted where IEDs were present on iEEG but absent on scEEG. Control epochs were selected from periods without IEDs on both Electroencephalographies (EEGs). Feature selection was performed, and a classifier was developed and validated with external data from 35 MTL epilepsy (MTLE) and 33 nonepileptic patients. The classifier used 58 selected features and achieved an accuracy of 0.70 and an area under the receiver operating characteristic curve of 0.78 on holdout validation. External validation revealed significant differences in IED-classified epoch frequencies before and after drug withdrawal in patients with MTLE, and between MTLE and nonepileptic groups. Feature analysis identified high-frequency power suppression, increased ipsilateral connectivity, and enhanced cross-frequency coupling as markers of IEDs that were undetectable in scEEG. This study shows that machine learning can detect MTL IEDs invisible to scEEG, revealing related scEEG changes and aiding EEG analysis.