Published papers

We present the case of a patient who began experiencing cognitive decline in her 30 s and was diagnosed with duplication of the amyloid precursor protein (Dup-APP) associated early-onset Alzheimer's disease (EOAD). The diagnosis was supported by the presence of amyloid and tau biomarkers. The clinical course, neuroimaging findings, and genetic testing excluded other diseases known to cause early-onset cognitive impairment. Our case exhibited a markedly large duplication of 19 Mb and did not present with cerebral amyloid angiopathy. Our findings suggest a potential association between the size of the duplication and the clinical phenotype.

BACKGROUND: Recent pharmacovigilance studies suggested that cluster headache could be a potential adverse effect after coronavirus disease-2019 (COVID-19) vaccination; however, the possibility of coincidence could not be excluded. Detailed case studies might help elucidate their potential link and implicate potential pathogenic mechanisms. METHODS: Patients who developed cluster headache in close temporal relationship to COVID-19 vaccination were identified from two tertiary medical centers in Japan and Taiwan respectively through 2021-2022. Detailed characteristics of the headaches and time between the onset of the index cluster episode and antecedent COVID-19 vaccination were reported. In patients with previous cluster headaches, the duration from previous bout was also recorded. RESULTS: Six patients with new cluster headache bout 3-17 days after COVID-19 vaccination were identified. Two of them were de novo cases. The others either had been attack-free for a long time or developed new cluster bout in seasons atypical to prior bouts. The vaccines included mRNA, viral vector, or protein subunit vaccines. CONCLUSIONS: COVID-19 vaccines, regardless of vaccine types, may elicit de novo or relapse of cluster headache. Future studies are needed to confirm the potential causality and explore the potential pathogenic mechanism.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Goreisan, a traditional Japanese Kampo medicine, is often used to treat headaches, including migraines; however, the underlying mechanisms remain unknown. Therefore, we investigated whether chronic treatment with Goreisan affects cortical spreading depolarization (CSD) in migraines. CSD susceptibility was assessed in male and female C57BL/6 mice by comparing CSD threshold, propagation velocity, and CSD frequency between animals treated with Goreisan for approximately 3 weeks and the corresponding controls with a potassium-induced CSD model. No significant differences were observed in CSD susceptibility between mice that were chronically treated with Goreisan and the control mice. Additionally, no significant differences were observed in other physiological parameters, including body weight, blood gases, and blood pressure. CSD susceptibility was not affected by chronic treatment with Goreisan, which suggests that the drug treats headaches via mechanisms that do not involve CSD modulation.

BACKGROUND: Noninvasive vagus nerve stimulation (nVNS) has recently emerged as a promising therapy for migraine. We previously demonstrated that vagus nerve stimulation inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and triggering headache; however, the optimal nVNS paradigm has not been defined. METHODS: Various intensities and doses of nVNS were tested to improve efficacy on KCl-evoked CSD frequency and electrical threshold of CSD in a validated rat model. Chronic efficacy was evaluated by daily nVNS delivery for four weeks. We also examined the effects of nVNS on neuroinflammation and trigeminovascular activation by western blot and immunohistochemistry. RESULTS: nVNS suppressed susceptibility to CSD in an intensity-dependent manner. Two 2-minute nVNS 5 min apart afforded the highest efficacy on electrical CSD threshold and frequency of KCl-evoked CSD. Daily nVNS for four weeks did not further enhance efficacy over a single nVNS 20 min prior to CSD. The optimal nVNS also attenuated CSD-induced upregulation of cortical cyclooxygenase-2, calcitonin gene-related peptide in trigeminal ganglia, and c-Fos expression in trigeminal nucleus caudalis. CONCLUSIONS: Our study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.

BACKGROUND: Real-world data on the effectiveness and safety of lasmiditan, a new medication for acute migraine attacks, is necessary. METHODS: We performed a prospective, observational, multi-center, real-world study. A total of 48 patients with migraine (44 females, 44.6 ± 12.9 years old) were included in this study. RESULTS: Twenty-three patients (47.9%) reported they were headache-free two hours after taking lasmiditan and were categorized into the responder group. In total, 44 patients (91.7%) experienced at least one side effect within two hours of taking the medication. Dizziness, somnolence, malaise, nausea, and palpitations were reported by 56.3% (n = 27), 45.8% (n = 22), 37.5% (n = 18), 20.8% (n = 10), and 14.6% (n = 7) of patients respectively. Of 48 patients, 20 (41.7%) indicated that they preferred lasmiditan to their previous acute treatment. There were no predictive factors for efficacy. CONCLUSION: This real-world study demonstrated the efficacy and safety of lasmiditan. More than 90% of patients experienced side effects from lasmiditan. Approximately 40% of patients preferred lasmiditan despite the occurrence of side effects.

BACKGROUND: There are reports from single-center studies on patients visiting headache clinics; however, few multicenter studies have been conducted in Japan. This study aims to address this gap by conducting a multicenter analysis of the clinical characteristics, headache types, severity, and psychiatric comorbidities of patients attending headache clinics. METHODS: We prospectively evaluated the clinical characteristics of 2378 patients with headache disorders visiting three headache clinics. Baseline demographics, such as the visual analog scale (VAS), and psychiatric assessments, such as the Generalized Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9), were evaluated. Headache types were classified as migraine, tension-type headache (TTH), trigeminal autonomic cephalalgias (TACs), other primary headache disorders (OPHDs), and secondary headache. Parameters were compared between headache types using the Kruskal-Wallis test or analysis of covariance, as appropriate. RESULTS: The most common headache type was migraine (78.8 %), followed by TTH (12.2 %), secondary headache (5.5 %), OPHDs (2.1 %), and TACs (1.6 %). Patients with migraine were significantly younger at first consultation (median age 32.0) than those with other headache types (TTH; 47.0, TACs; 39.0, OPHDs; 49.5, and secondary headache; 47.0). Patients with TACs exhibited the highest severity and psychiatric symptoms, with VAS (median 90.0), GAD-7 (7.0), and PHQ-9 (7.5) scores significantly higher than those of other headache type (migraine; 70.0, 5.0, 5.0, TTH; 50.0, 4.0, 4.0, OPHDs; 65.0, 4.0, 3.5, and secondary headache; 60.0, 3.0, 3.5: p<0.001, p=0.019, p<0.001). CONCLUSION: Most patients visiting headache clinics had migraine; patients with TACs showed significantly higher headache severity and psychiatric symptoms than those with other headache types.

BACKGROUND: Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura. FINDINGS: Fifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex. CONCLUSIONS: Female mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

The real-world treatment patterns at medical facilities and their physicians' specialties treating migraine have not been fully investigated in Japan. Therefore, a retrospective cohort study aimed to describe real-world clinical practice and treatment patterns in Japanese patients with migraine according to medical facilities and physicians' specialties. Anonymized claims data of patients with migraine was obtained from JMDC Inc (January 2018-June 2023). Patient characteristics and treatment pattern according to medical facilities and physicians' specialties treating migraine were evaluated. Of 231,156 patients with migraine (mean age [SD], 38.8 [11.8] years; females, 65.3%), 81.8% had the first prescription at clinics (CPs), 42.5% underwent imaging tests, 44.4% visited general internal medicine, and 25.9% consulted neurosurgery at initial diagnosis. Imaging tests were carried out at CPs with specialists (59.4%), hospitals (HPs) with specialists (59.1%), HPs (32.9%), and CPs (26.9%) without specialists. Overall, 95.6% received acute treatment while 21.8% received preventive treatment. At facilities with specialists compared to without specialists, triptans were more frequently prescribed (67.9% vs 44.9%) whereas acetaminophen and nonsteroidal anti-inflammatory drugs were less frequently prescribed (52.4% vs 69.2%). Preventive treatment use was higher at facilities with specialists (27.4%) than without specialists (15.7%) and increased annually regardless of the type of medical institution. In Japan, only half of patients with migraine visited facilities with specialists at their first diagnosis, and specialists are more likely use migraine-specific and preventive drugs than nonspecialists. Therefore, there is a need for awareness among migraine patients that they should consult specialists and for enhancement of medical collaboration between specialists and nonspecialists.

Objective Switching from one anti-calcitonin gene-related peptide monoclonal antibody (CGRP mAb) to another can be beneficial for treating patients with migraine who do not respond well to the first CGRP mAb. However, detailed and long-term follow-up reports of both efficacy and safety remain insufficient. We conducted a case-series analysis of patients with migraine who switched from galcanezumab to erenumab, both belonging to the class of CGRP mAbs. Methods We conducted a single-center retrospective real-world study. Patients with migraine who first received galcanezumab for ≥3 months and then switched to erenumab at Keio University Hospital were enrolled to investigate changes in monthly migraine days (MMD), response rate, and adverse effects (e.g., injection-site reactions). Additionally, we performed a narrative review of the literature on switching CGRP mAbs. Results Among the nine patients enrolled, the 50% response rate for MMD was 33% at 3 months after switching. Two patients (22%) initially responded at the 3-month assessment, but later reverted to baseline MMD levels. Switching from galcanezumab to erenumab increased the frequency of constipation, which was typically managed using laxatives. Participants who experienced injection-site reactions tended to exhibit similar reactions regardless of the type of CGRP mAb used. Five patients (56%) demonstrated an improvement in satisfaction after erenumab initiation at least once. A literature review revealed that the characteristics of the cohorts varied among studies. Conclusions Switching from galcanezumab to erenumab was effective in some patients, while it was associated with some tolerable side effects, and it improved patient satisfaction in approximately half of the patients, despite interindividual diversity in responses and fluctuating responses after switching, which warrants further investigation.

BACKGROUND: Antiseizure medications are often used as preventive treatment of migraine in appropriate cases; however, the efficacy of lacosamide (LCM), a sodium channel blocker, in preventing migraine attacks remains unclear. Cortical spreading depolarization (CSD) refers to a wave of slowly propagating depolarization across the cerebral cortex. CSD animal models have been extensively used to investigate migraine attacks and evaluate the effects of migraine medication. Herein, we examined the effects of single dose LCM (40 mg/kg) on CSD sensitivity in a mouse model. FINDINGS: Thirty-two C57BL/6 mice (male, n = 16; female, n = 16) were intraperitoneally injected with either LCM (40 mg/kg) or saline before CSD sensitivity testing. Potassium chloride (KCl) was administered to induce CSD, and the CSD threshold, frequency, and propagation velocity were determined. The average CSD frequency induced by 1 M KCl was significantly lower (p = 0.030) and the CSD propagation velocity tended to be lower in the female LCM group than in the saline group. However, no significant differences were observed in any of the three CSD parameters in male mice. CONCLUSIONS: In female mice, single dose LCM treatment significantly reduced CSD frequency induced by KCl. Further investigations are warranted to assess the clinical potential of LCM in preventing migraine.

Objective Patients with migraine are at increased risk of developing psychiatric comorbidities, particularly depression and anxiety. Recently, anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) have been suggested to be effective not only for migraine but also for comorbid depression. However, their effectiveness in depression and anxiety remains inconclusive, particularly in Asian populations. This study evaluated the effect of galcanezumab on depressive and anxiety symptoms in patients with migraine. Methods We conducted a single-center, retrospective, real-world study of 27 Japanese patients with migraine who received galcanezumab at Keio University Hospital, using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores at two time points (baseline and 3-5 months after initiating galcanezumab) to evaluate depressive and anxiety symptoms. Results During galcanezumab treatment, the mean monthly migraine days (MMD) significantly decreased from 13.6±8.2 to 8.5±9.3 (p<0.001). PHQ-9 scores significantly decreased from 5.8±4.4 to 4.5±4.2 (p=0.010) and GAD-7 scores from 4.0±3.9 to 3.1±3.5 (p=0.030). No significant correlation was observed between changes in PHQ-9/GAD-7 scores and changes in MMD, numerical rating scale scores, or associated symptoms. Furthermore, Fisher's exact tests showed no significant association between improvements in PHQ-9/GAD-7 scores and MMD reduction. Conclusion Galcanezumab improved PHQ-9 and GAD-7 scores in Japanese patients with migraine. These improvements may be partly attributable to the direct effects of galcanezumab, independent of its effect on migraine frequency.

BACKGROUND: Menstrual migraine (MM) is a distinct and burdensome subtype of migraine; however, comprehensive data on its clinical and social impact among Japanese females remain limited. Therefore, we aimed to clarify the clinical characteristics and social burden of MM in Japan. METHODS: A cross-sectional, population-based web survey was conducted among Japanese females (≥ 18 years) with regular menstruation who were diagnosed with migraine. Participants were classified into MM and non-MM groups. Clinical parameters assessed between MM and non-MM included pain intensity, pain duration, and headache frequency during the perimenstrual period (-2 days to + 2 days of menstruation onset). Social burden was evaluated using the Migraine Disability Assessment (MIDAS), Migraine Interictal Burden Scale (MIBS-4), Migraine-Specific Quality of Life Questionnaire (MSQ), and Work Productivity and Activity Impairment for Migraine (WPAI-M). These were compared between MM and non-MM, adjusting for potential confounders through inverse probability of treatment weighting using propensity scores. RESULTS: Of 266,392 screened patients, 4,592 were included in MM and 5,174 in non-MM. The mean age was 36.8 ± 8.0 years in MM and 35.5 ± 8.3 years in non-MM. MM patients experienced higher pain intensity and longer pain duration than non-MM during both perimenstrual and non-perimenstrual periods (perimenstrual periods: -2 days to + 1 day of menstruation onset: all p < 0.001 for both, +2 days of menstruation onset: intensity, p = 0.003, duration, p = 0.046; non-perimenstrual period: intensity, p < 0.001, duration, p = 0.005). MM exhibited higher MIDAS and MIBS-4 scores (both p < 0.001) and lower MSQ scores (restriction, interference, emotion: all p < 0.001), indicating greater disability and reduced quality of life. Among WPAI-M scores, presenteeism, overall work and activity impairment, were also higher in MM vs non-MM (all p < 0.001). MM demonstrated increased usage (MM: 54.0% [1,088/2,015]; non-MM: 24.0% [169/705]) and broader type of medications (MM: 13.2% [265/2,015]; non-MM: 7.1% [50/705]) during the perimenstrual period, particularly non-steroidal anti-inflammatory drugs (MM: 51.4% [801/1,557]; non-MM: 45.4% [636/1,402]). CONCLUSIONS: This study highlights the significant burden of MM, demonstrating increased pain intensity, longer pain duration and higher headache frequency during perimenstrual period, accompanied by a concurrent increase in social burden compared to non-MM. These findings underscore the impact of clinical severity and social burden of MM in Japanese females.

INTRODUCTION: The burden of migraine on an individual's life is associated with an individual's background. However, limited evidence in Japan exists on the association of age, sex, employment, income, and family caregiving with patient-reported outcomes (PROs) and migraine treatment patterns. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) 2nd study describes the migraine burden and treatment usage of individuals with migraine across these demographic subgroups. METHODS: Participants self-reported demographic and clinical characteristics, and PRO instrument responses, such as Headache Impact Test-6, Migraine Disability Assessment Scale (MIDAS), Migraine-Specific Quality of Life Questionnaire version 2.1, Migraine Interictal Burden Scale-4 (MIBS-4), and Impact of Migraine on Partners and Adolescent Children Scale. They also reported use of over-the-counter and prescription drugs for migraine, and headache-related expenses. Descriptive statistics were reported according to sex, employment status, menstrual-related migraine status and frequency, annual personal and family income, age, and family caregiving status for the elderly. RESULTS: Female sex, unemployment, presence of menstrual-related migraine, low personal or family income, and family caregiving for elders appeared to increase migraine burden and impact prescription drug use. Specifically, men tended to have higher triptan (11.7% vs. 8.7%) and preventive medication use (18.3% vs. 11.2%) than women; unemployed women had the highest proportion of MIDAS grade IV (14.1%); women with menstrual-related migraine appeared to have greater MIBS-4 severe burden (36.3% vs. 27.8%) than those without; and family caregivers tended to have higher MIBS-4 severe burden (39.2% vs. 26.0%) and prescription drug use than non-caregivers. Respondent sex further appeared to influence migraine burden and treatment patterns within the employment and income subgroups. CONCLUSION: These data suggest certain sociodemographic groups may suffer from greater migraine burden and have reduced access to effective treatment and care. We hope this study's results will help healthcare providers and societies identify such populations with migraine and address potential clinical care gaps.

BACKGROUND: Migraine is globally more prevalent in females; however, the clinical and social burden among males remains insufficiently characterized. This study aimed to describe the clinical features and social burden of migraine in Japanese males to identify sex-specific migraine profiles. METHODS: A cross-sectional, population-based web survey was conducted among Japanese adults aged ≥ 18 years diagnosed with migraine according to modified criteria from the International Classification of Headache Disorders, Third Edition (ICHD-3). Participants were grouped by sex; females diagnosed with menstrual migraine (MM) were excluded to minimize hormonal confounding. Key outcomes included pain intensity (Visual Analog Scale [VAS]), pain duration, and social burden assessed using validated instruments: Migraine Interictal Burden Scale (MIBS-4), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life Questionnaire (MSQ), and Work Productivity and Activity Impairment for Migraine (WPAI-M) scores. RESULTS: Of 266,392 individuals screened, 18,750 completed the survey; 4,161 males and 9,997 females (excluding those with MM) were included in the analysis. Males were older (mean± standard deviation age: 43.9 ± 12.4 vs. 40.9 ± 12.2 years) and reported more lifestyle-related triggers (e.g., alcohol, irregular eating, and overexercise). Males, compared to females, experienced greater pain intensity (VAS: 57.1 ± 16.7 vs. 54.9 ± 19.6; p < 0.001) but shorter pain duration (6.3 ± 9.4 vs. 7.9 ± 12.4 h; p < 0.001). MIDAS scores were comparable (6.3 ± 10.8 vs. 6.0 ± 9.6; p = 0.283), while MIBS-4 scores were higher in males (4.0 ± 3.5 vs. 3.3 ± 3.3; p < 0.001). MSQ scores were lower in males for domains of interference (83.5 ± 20.0 vs. 85.4 ± 18.3; p = 0.001) and emotional function (80.2 ± 20.9 vs. 81.8 ± 20.3; p = 0.007). Work-related impairment was more pronounced in males than in females, with higher absenteeism (4.7 ± 14.1 vs. 3.4 ± 12.7; p = 0.001), presenteeism (31.5 ± 22.9 vs. 29.5 ± 23.1; p = 0.007), and overall work impairment (33.6 ± 24.6 vs. 30.9 ± 24.3; p = 0.001). Preventive medication use was higher in males (oral: 40.8% vs. 34.3%; injectables: 3.3% vs. 1.7%). CONCLUSION: Males with migraine exhibited a greater burden in terms of pain intensity and functional impairment relative to females without MM. These findings support the development of sex-specific and individualized management strategies that incorporate both pharmacological and lifestyle interventions to reduce disease burden and enhance patient-centered care. TRIAL REGISTRATION: Not applicable.

BACKGROUND: This study compared the efficacy and safety/tolerability of atogepant versus rimegepant as preventive migraine treatments in Japanese patients using anchored matching-adjusted indirect comparisons (MAICs). METHODS: Three placebo-controlled trials were included: RELEASE and PROGRESS (atogepant), and BHV3000-309 (rimegepant). Efficacy outcomes included change from baseline in mean monthly migraine days (MMDs) and mean monthly acute medication use days (MUDs). Quality-of-life endpoints included Migraine-Specific Quality-of-Life Questionnaire (MSQ) v2.1 Role Function-Restrictive (RFR) domain score, Migraine Disability Assessment (MIDAS) total score, and EQ visual analog scale (EQ-VAS) score. Safety/tolerability outcomes included treatment-emergent adverse events (AEs) and AEs leading to treatment discontinuation. RESULTS: Atogepant demonstrated a statistically significant greater reduction from baseline in mean MMDs (mean difference [MD]: 1.33; 95% confidence interval [CI]: -2.48, -0.18) and monthly acute MUDs (MD: ‑1.97; 95% CI: -3.06, -0.87) versus rimegepant across 12 weeks; and a statistically significant greater improvement from baseline in MSQ v2.1 RFR domain score at Week 12 (MD: 4.80; 95% CI: 0.15, 9.45). No significant differences were identified for other endpoints. CONCLUSIONS: In these MAICs, atogepant was associated with statistically significant greater reductions in MMDs and monthly acute MUDs, and greater improvements in MSQ v2.1 RFR domain scores versus rimegepant in Japanese patients with migraine.

BACKGROUND: In anti-NMDA receptor (NMDAR) encephalitis, delayed recovery and slow improvement makes it difficult to assess treatment refractoriness, leaving a knowledge gap about prolonged impaired consciousness. We aimed to assess treatment response, long-term outcomes, and their predictors in patients with NMDAR encephalitis and a prolonged vegetative state. METHODS: In this international retrospective cohort study, we included patients with NMDAR encephalitis from Jan 1, 2007 to Sept 30, 2024 who remained in a vegetative state (unresponsive wakefulness) for 9 months or longer in 21 hospitals across Austria, Brazil, Chile, China, Germany, Hong Kong, Japan, the Netherlands, Spain, Switzerland, and the USA. Data on disease presentation and long-term outcomes were collected via medical record review and a structured questionnaire sent to referring physicians. Outcomes were death, ability to follow commands, reaching a modified Rankin Scale (mRS) score of 2, or complete recovery (mRS 0 with return to premorbid activities). Competing risks analysis was used to assess survival and predictors of death, mRS score 2, and recovery. FINDINGS: 45 patients were identified (38 female and seven male; median age 22 [IQR 19-31] years). The patients had impaired consciousness a median of 9 days after symptom onset (IQR 5-16). All 45 patients received first-line immunotherapy; 41 (91%) received second-line, and 18 (40%) received third-line immunotherapies. 21 (47%) of 45 patients had ovarian teratomas, which were removed in 20 patients. Median durations were: vegetative state 399 days (IQR 307-698); intensive care unit stay 275 days (189-354); mechanical ventilation 270 days (195-394); and hospitalisation 474 days (349-715). 13 (28%) patients were resuscitated from dysautonomic cardiac arrest. After a median of 5 years (IQR 3-7), 15 (33%) of 45 patients completely recovered (mRS score ≤1 and returned to all previous activities), 13 (29%) substantially improved (mRS score 2), 11 (24%) had mRS score 3-5, and six (13%) died. Five patients began command-following a median of 11 months (IQR 2-21) after last immunotherapy. Estimated cumulative incidence for reaching an mRS score of 2 was 66% at 5 years and 76% at 10 years, and for recovery was 32% at 5 years and 54% at 10 years. Teratomas were associated with a lower probability of reaching mRS score 2 (sub-distribution hazard ratio 0·39 [95% CI 0·18-0·84], p=0·0160), whereas older age (1·10 per year [1·04-1·23], p=0·0052) and higher NMDAR encephalitis 1-Year Functional Status (NEOS)2 score (1·51 [1·12-2·04], p=0·0072) were associated with increased mortality. INTERPRETATION: In people with NMDAR encephalitis and prolonged impairment of consciousness, full or substantial recovery was reached in approximately two-thirds of cases. Consequently, early assessment of treatment response or refractoriness might underestimate delayed improvement, prolonged therapy needs, or spontaneous recovery. Futility decisions should therefore be individualised with multidisciplinary input and based on extended follow-up. FUNDING: Instituto de Salud Carlos III and Fundació La Caixa.

Migraine is a debilitating neurovascular disorder affecting over one billion people globally. While reported prevalence in Asia is lower than in Western countries, significant regional variations and unique clinical presentations necessitate a tailored approach to management. From the Advisory Board Meeting of the East Asian Network for Migraine, expert insights and current literature from China, Japan, South Korea, and Taiwan were synthesized to establish a unified perspective on the epidemiological and sociocultural contexts of the region. Patients in these East Asian countries exhibit distinct clinical features, such as a lower frequency of migraine with aura and photophobia, but a higher incidence of osmophobia compared to Western populations. Despite these clear phenotypic differences, significant gaps in care persist. Acute treatments like triptans remain underutilized, and while emerging CGRP-targeting therapies show promise, their adoption is hindered by high costs and limited accessibility. Furthermore, the region faces critical challenges, including a lack of region-specific clinical trials, culturally appropriate assessment tools, and unified clinical guidelines. Optimizing migraine care in East Asia requires a shift toward personalized, culturally sensitive strategies. Experts reached a consensus on the urgent need for collaborative research to address existing disparities and improve patient outcomes. By aligning clinical practice with the unique sociocultural landscapes of these nations, this statement provides a foundational framework for enhanced policy development and improved migraine management across East Asia.

INTRODUCTION: Galcanezumab, a humanized calcitonin gene-related peptide monoclonal antibody, is approved in Japan for migraine prevention, but real-world effectiveness data are limited. This analysis describes the 3-month treatment outcomes of galcanezumab and traditional oral migraine preventive medications (TOMPs) in the TReatment of mIgraine: oUtcoMes for Patients in real-world Healthcare systems (TRIUMPH) study's Japan subgroup. METHODS: TRIUMPH, an international, prospective, observational, 24-month cohort study, included adults with migraine who initiated or switched to galcanezumab or TOMP. Japan subgroup data were collected from September 2021 to November 2024. Physicians decided on the treatment course in routine clinical practice. The primary outcome was achieving a clinically meaningful response at 3 months, defined as a ≥ 50% reduction in monthly migraine headache days for episodic migraine and ≥ 30% for chronic migraine. Secondary outcomes included changes in migraine headache days and patient-reported outcomes (PROs): Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Interictal Burden Scale-4 (MIBS-4), Migraine-Specific Quality of Life Questionnaire (MSQv2.1), and Work Productivity and Activity Impairment (WPAI). Inverse probability of treatment weighting was used to adjust for baseline differences in the primary analysis. No alpha was allocated for comparative formal testing between treatment groups. RESULTS: Of 846 patients, 469 received galcanezumab and 377 received TOMPs. In the galcanezumab and TOMP groups, the 3-month weighted response rates were 59.4% and 38.3%, and the reduction in mean migraine headache days from baseline was - 6.2 [95% confidence interval (CI): - 6.9, - 5.5] and - 4.2 (95% CI: - 5.0, - 3.4), respectively. Mean change at 3 months from baseline was numerically higher in the galcanezumab group than in the TOMP group for all the PROs. CONCLUSIONS: Patients receiving galcanezumab had numerically greater 3-month response rates and experienced improved PROs after initiating galcanezumab. These real-world findings may help physicians make treatment decisions in clinical settings. TRIAL REGISTRATION: EU PAS Register number-EUPAS33068.

A quinquagenarian woman visited our hospital due to experiencing headache around the right upper eyelid for the previous 2 months. T2-weighted MRI of the head showed multiple high-signal-intensity lesions in the corpus callosum and bilateral corona radiata. She was thought to have an autoimmune disease and was treated with steroid pulse therapy, but the light reflex of the right eye diminished and the patient developed inferior horizontal hemianopsia. T2-weighted orbital MRI showed an enlarged right optic nerve, a high-intensity signal in the superior half of the optic nerve, and an enhancing effect. She also tested positive for anti–aquaporin 4 antibodies, so she was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). This case shows that headache can be an initial symptom of NMOSD and that clinicians should consider NMOSD when attempting to diagnose patients presenting with headaches.