A study to investigate the prevalence of headache disorders and migraine conducted using medical claims data and linked results from online surveys: post-hoc analysis of other headache disorders.

BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.

Effectiveness of fremanezumab treatment in patients with migraine headache.

OBJECTIVE: To evaluate the efficacy and safety of fremanezumab for migraine prevention. DESIGN: Retrospective, single-center, real-world study. SETTING: Regional tertiary headache center in Japan. SUBJECTS: Adult individuals with migraine (n = 165, male = 17, female = 148; average age = 45.5 ± 16.0 years) who received fremanezumab between September 2021 and August 2022. METHODS: Fremanezumab was administered subcutaneously at a monthly dose of 225 mg or quarterly dose of 675 mg based on patient preferences. Patients received fremanezumab treatment for up to 1 year unless it was discontinued. Monthly data were collected on migraine days, headache days, and days requiring acute medication. RESULTS: Of the 165 patients, 125 (75.7%) received fremanezumab as their first anti-calcitonin gene-related peptide-related antibody drug. Significant reductions in monthly migraine days, headache days, and days requiring acute medication were observed in those with episodic and chronic migraines. The baseline monthly headache days was 8.1 ± 4.0 in the episodic migraine group, which reduced to 6.1 ± 4.8, 5.8 ± 4.4, 4.7 ± 3.6, and 4.6 ± 3.3 days at 1, 3, 6, and 12 months, respectively; in the chronic migraine group, the baseline monthly headache days was 20.9 ± 6.1, which reduced to 17.0 ± 8.9, 15.0 ± 9.2, 13.0 ± 7.7, and 12.0 ± 9.1 days at 1, 3, 6, and 12 months, respectively. Treatment benefits were enhanced after 6 months of administering fremanezumab in the chronic migraine group. CONCLUSIONS: In this real-world study of patients with migraine, fremanezumab appears to be effective and safe. Further studies are required to identify additional predictors of treatment success and failure with fremanezumab.

Long-term treatment with lasmiditan in patients with migraine: post hoc analysis of treatment patterns and outcomes from the open-label extension of the CENTURION randomized trial.

BACKGROUND: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting. METHODS: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses. RESULTS: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change - Migraine Headache Condition (56.5% vs 33.4%-52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%-83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency. CONCLUSIONS: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018-001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018.

CGRP-monoclonal antibodies in Japan: insights from an online survey of physician members of the Japanese headache society.

BACKGROUND: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown. METHODS: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use. RESULTS: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%). CONCLUSIONS: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Small vessel platelet thrombosis in the peripheral nerves in POEMS syndrome.

INTRODUCTION/AIMS: Vascular thrombosis is prevalent among patients with polyneuropathy, organomegaly, endocrinopathy M-protein, and skin changes (POEMS) syndrome. The endothelial cells in the endoneurium are often hypertrophied and the lumen is frequently occluded. Consequent local hypoxia may increase vascular endothelial growth factor (VEGF), which induces hypercoagulation and vascular permeability. METHODS: This study presents two patients in the fifth decade of life, who had rare nerve biopsy findings of vascular occlusion mainly by platelets. Before the cases presented here, we encountered nine confirmed POEMS patients whose nerve biopsies did not show similar findings. RESULTS: A small artery and a vein were occluded, but no atherosclerotic changes were observed. The endothelial cells that adhered to the packed platelets lost their junctions. DISCUSSION: Platelet aggregation, degranulation, and ischemia may cause a loose endothelial barrier and leak proinflammatory cytokines, such as interleukin-12. This may increase production of VEGF and may cause nerve demyelination. Small vessel platelet thrombosis may contribute to the pathogenesis of this disorder.

Developing an artificial intelligence-based headache diagnostic model and its utility for non-specialists' diagnostic accuracy.

BACKGROUND: Misdiagnoses of headache disorders are a serious issue. Therefore, we developed an artificial intelligence-based headache diagnosis model using a large questionnaire database in a specialized headache hospital. METHODS: Phase 1: We developed an artificial intelligence model based on a retrospective investigation of 4000 patients (2800 training and 1200 test dataset) diagnosed by headache specialists. Phase 2: The model's efficacy and accuracy were validated. Five non-headache specialists first diagnosed headaches in 50 patients, who were then re-diagnosed using AI. The ground truth was the diagnosis by headache specialists. The diagnostic performance and concordance rates between headache specialists and non-specialists with or without artificial intelligence were evaluated. RESULTS: Phase 1: The model's macro-average accuracy, sensitivity (recall), specificity, precision, and F values were 76.25%, 56.26%, 92.16%, 61.24%, and 56.88%, respectively, for the test dataset. Phase 2: Five non-specialists diagnosed headaches without artificial intelligence with 46% overall accuracy and 0.212 kappa for the ground truth. The statistically improved values with artificial intelligence were 83.20% and 0.678, respectively. Other diagnostic indexes were also improved. CONCLUSIONS: Artificial intelligence improved the non-specialist diagnostic performance. Given the model's limitations based on the data from a single center and the low diagnostic accuracy for secondary headaches, further data collection and validation are needed.

Treatment of hemiplegic migraine with anti-calcitonin gene-related peptide monoclonal antibodies: A case series in a tertiary-care headache center.

Hemiplegic migraine (HM) is a subtype of migraine with aura that includes motor weakness; such headaches can be excruciating. The presence of not only headache but also aura symptoms of HM increase the burden on patients, and the treatment of HM is sometimes challenging. Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway are novel migraine preventive treatments that have shown promising efficacy in patients with migraine; however, there have been no reports regarding their efficacy in HM to date. Six patients with HM were treated with galcanezumab in a tertiary-care headache center. After 3 months of treatment, the number of monthly days with headache of at least moderate severity was reduced in three patients. The number of days each month with weakness was also reduced in four patients. Furthermore, the Patient's Global Impression of Change and change in Migraine Disability Assessment total score, were improved in five of the six patients after the treatment; however, the change from baseline in days with bothersome symptoms did not show any specific trends in our patients. Notably, no adverse events were reported during the treatments. The mechanism underlying the improvement in aura symptoms in our patients is not clear; however, we speculate that a small amount of CGRP mAbs have a direct mode of action in the central nervous system; alternatively, blocking the CGRP pathway in the periphery may secondarily inhibit cortical spreading depression. While prudence must be practiced, galcanezumab was still generally effective in HM and well tolerated. Further prospective clinical studies will more clearly elucidate the effects of CGRP mAbs in patients with HM.

Cranial autonomic symptoms in migraine are related to central sensitization: a prospective study of 164 migraine patients at a tertiary headache center.

BACKGROUND: Cranial autonomic symptoms (CASs) during migraine attacks are reported to be quite common regardless of ethnicity. In our previous study investigating 373 migraineurs, we found that 42.4% of them had CASs. The patients with CASs more frequently had cutaneous allodynia than did those without CASs, and we speculated that CASs were associated with central sensitization. The present study searched for substantial evidence on the relationship between CASs and central sensitization in migraine patients. METHODS: This was a prospective cross-sectional study. We studied a new independent cohort of 164 migraineurs who presented to the Tominaga Hospital Headache Center from July 2018 until December 2019. The clinical features of CASs according to the criteria in ICHD-3 (beta) were investigated. We also evaluated central sensitization based on the 25 health-related symptoms utilizing the validated central sensitization inventory (CSI), and each symptom was rated from 0 to 4 resulting a total score of 0-100. RESULTS: The mean age was 41.8 (range: 20 to 77) years old. One hundred and thirty-one patients (78.9%) were women. Eighty-six of the 164 (52.4%) patients had at least 1 cranial autonomic symptom. The CSI score of the patients with ≥3 CASs reflected a moderate severity and was significantly higher than in those without CASs (41.9 vs. 30.7, p = 0.0005). The score of the patients with ≥1 conspicuous CAS also reflected a moderate severity and was significantly higher than in those without CASs (40.7 vs. 33.2, p = 0.013). The patients in the CSI ≥40 group had lacrimation, aural fullness, nasal blockage, and rhinorrhea, which are cranial autonomic parasympathetic symptoms, significantly more frequently than those in the CSI < 40 group. CONCLUSIONS: Migraine patients with CASs showed significantly greater central sensitization than those without such symptoms. In particular, cranial parasympathetic symptoms were more frequent in centrally sensitized patients than in nonsensitized patients, suggesting that cranial parasympathetic activation may contribute to the maintenance of central sensitization. TRIAL REGISTRATION: This study was retrospectively registered with UMIN-CTR on 29 Aug 2020 ( UMIN000041603 ).

Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients.

BACKGROUND: Early onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action. METHODS: This subanalysis of primary endpoints of two separate phase 2b/3 studies sought to determine the onset of action of fremanezumab in Japanese and Korean patients with episodic migraine (EM) and chronic migraine (CM). RESULTS: In EM patients (n = 357), both fremanezumab quarterly and fremanezumab monthly led to greater reductions in weekly migraine days (days/week) than placebo from the first week after the initial injection and thereafter during the remainder of the study period. Similarly, CM patients (n = 571) had a greater reduction in headache days of at least moderate severity (days/week) with fremanezumab (total) than placebo. The percentage of patients with a migraine day (EM) or headache day at least moderate severity (CM) was lower in those treated with fremanezumab than placebo and this effect was apparent from as early as Day 2 (1 day after first injection). CONCLUSIONS: These results suggest that fremanezumab has an early onset of action, as noted in previous post hoc analyses of anti-CGRP monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov. NCT03303092 , Registered 5 October 2017, NCT03303079 , Registered 5 October 2017.

A study to investigate the prevalence of headache disorders and migraine among people registered in a health insurance association in Japan.

BACKGROUND: Migraine is a chronic disease characterized by episodic headache attacks. No recent studies have, however been conducted on the epidemiology of migraine or the treatment landscape in Japan. This study was conducted as a fact-finding survey using medical claims data and an online survey on migraine and headaches, conducted among members of health insurance associations with the objective of gaining an understanding of migraine prevalence and the treatment status in Japan. METHODS: The study methodology utilized a unique approach of combined data sources. The data sources used in this study are medical claims data and linked online survey data provided by DeSC Healthcare Inc (DeSC). The primary outcomes (from survey responses) were: the overall number and proportion of migraine patients; and the overall prevalence of migraine, stratified by age and sex. The secondary outcomes (from survey responses) were use of medical care; and clinical features/headache symptoms. The analysis population included all individuals who had response data for surveys conducted by DeSC. The online survey data and medical claims data were summarized. RESULTS: The data population comprised 21,480 individuals. On the basis of the survey results, including probable cases, the overall prevalence of migraine was 3.2%. The highest prevalence of migraine was observed in patients aged 30-39 years. The prevalence of migraine in women was 4.4 times higher than in men. The percentage of migraine patients who had not been seen by a doctor was 81.0%. More than 80% of patients were taking over-the-counter drugs and 4.8% took prescription medicines only. Approximately 52.9% of patients considered that the intensity of pain symptoms was severe. Moreover, the majority of patients (72.9%) considered that the impairment of daily life activities was of moderate or severe degree. CONCLUSIONS: In Japan, the percentage of people with migraine who did not receive medical attention is as high as 80%. Additionally, the majority of patients tend to endure symptoms and continue with everyday activities. With innovative treatment approaches becoming available it is necessary to disseminate information that migraine is not a simple headache but an illness that requires medical treatment and consultation.

Phase 2 randomized placebo-controlled study of lasmiditan for the acute treatment of migraine in Japanese patients.

OBJECTIVE: To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine. BACKGROUND: Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study in Japan (NCT03962738), which enrolled adults with migraine with or without aura. Participants were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg to be self-administered orally within 4 h of onset of a single moderate-to-severe migraine attack. Participants recorded their response to treatment prior to dosing and for 48 h postdose. The primary endpoint was headache pain freedom at 2 h postdose. RESULTS: Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent-to-treat). At 2 h postdose, a significantly higher proportion of participants were headache pain-free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain-free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose-response relationship for pain freedom was achieved at 2 h by a Cochran-Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment-emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported. CONCLUSIONS: Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies.

Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study.

OBJECTIVES: Erenumab is a human anti-calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. Global studies have demonstrated its efficacy in chronic and episodic migraine (EM). Here we report the outcomes from a Phase 3 study of erenumab in Japanese patients with chronic migraine (CM) or EM. METHODS: Japanese patients with EM (<15 headache days/month, including ≥4 migraine days/month) or CM (≥15 headache days/month, including ≥8 migraine days/month) were randomized 1:1 to placebo or erenumab 70 mg once monthly for a 24-week double-blind treatment phase (DBTP). The primary endpoint of change from baseline in mean monthly migraine days (MMD) over months 4, 5, and 6 of the DBTP was compared between erenumab and placebo groups. Secondary efficacy and safety endpoints were also assessed. RESULTS: A total of 261 patients were randomized to placebo (n = 131) or erenumab 70 mg (n = 130); all patients were included in the efficacy and safety analyses. The mean (standard deviation) MMD at baseline was 11.84 (5.70) for the placebo group and 12.40 (5.99) for erenumab 70 mg. The mean (standard error) change in MMD was -1.98 (0.38) for the placebo group (n = 131) and -3.60 (0.38) for erenumab 70 mg (n = 130). The difference in MMD reduction between groups was -1.67 (95% CI: -2.56, -0.78, p < 0.001) for EM and -1.57 (95% CI: -3.39, 0.24, p = 0.089) for CM. Adverse events (AEs) were consistent with earlier studies. The most frequent AEs (placebo, erenumab) were nasopharyngitis (28.2% and 26.9%, respectively), back pain (4.6% and 5.4%), and constipation (0.8% and 4.6%). CONCLUSION: Treatment with erenumab 70 mg once monthly demonstrated favorable efficacy and safety findings in Japanese patients with EM or CM.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

OBJECTIVE: To assess long-term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients. BACKGROUND: Previously published results from the double-blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM. METHODS: Patients completing the 24-week placebo-controlled DBTP could continue into the 76-week open-label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine-specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6-item Headache Impact Test (HIT-6™) score, and safety (exposure-adjusted patient-incidence of adverse events [AEs], calculated as number of patients per 100 patient-years). RESULTS: Of 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of -2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of -1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT-6™ score was 58.4 (5.4) at baseline with a change of -6.4 (8.2) at week 100. The exposure-adjusted patient-incidence of AEs during the OLTP was 207.1/100 patient-years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient-years) or placebo (257.3/100 patient-years) during the DBTP, and no new safety signals were detected during the OLTP. CONCLUSION: Long-term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.

Quantitative arterial spin labeling magnetic resonance imaging analysis of reversible cerebral vasoconstriction syndrome: A case series.

OBJECTIVE: This study aimed to quantify chronological cerebral blood flow (CBF) changes using arterial spin labeling (ASL) magnetic resonance imaging in patients with reversible cerebral vasoconstriction syndrome (RCVS). BACKGROUND: Quantitative ASL analyses in RCVS have not been well described in the literature. METHODS: Quantification of ASL using an automated region-of-interest placement software and a 5-point visual scale of vasoconstriction severity was performed in five RCVS patients. The association between CBF changes and RCVS-related complications was evaluated. RESULTS: Quantitative ASL revealed variable patterns of decreasing CBF in the first week, followed by subsequent increases. Notably, arterial vasoconstriction paradoxically progressed despite an increase in CBF from the first to the second week; this increase was relatively higher in patients with both cortical subarachnoid hemorrhage and posterior reversible encephalopathy syndrome. CONCLUSIONS: Quantitative ASL revealed that CBF initially decreased and subsequently increased, especially in the second week. These changes may serve as surrogate imaging markers for RCVS-related complications, and could further contribute to understanding the pathology of RCVS.

Efficacy and safety of fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

OBJECTIVE: To determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with chronic migraine (CM). BACKGROUND: Available preventive treatments for CM are limited by various efficacy and safety issues. Fremanezumab, a monoclonal antibody that targets the calcitonin gene-related peptide pathway involved in migraine pathogenesis, has been shown to be effective and well tolerated in large-scale, international Phase 3 trials. METHODS: Randomized, placebo-controlled trial of patients with CM who received subcutaneous fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. Primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12 weeks after the first dose. RESULTS: Among 571 patients randomized (safety set, n = 569; full analysis set, n = 566), the least-squares mean (±standard error [SE]) reduction in the average number of headache days of at least moderate severity per month during 12 weeks was significantly greater with fremanezumab monthly (-4.1 ± 0.4) and fremanezumab quarterly (-4.1 ± 0.4) than with placebo (-2.4 ± 0.4). The difference from the placebo group in the mean change (95% confidence interval [CI]) was -1.7 days (-2.54, -0.80) for the fremanezumab monthly group and -1.7 days (-2.55, -0.82) for the fremanezumab quarterly group (p < 0.001 vs. placebo for both fremanezumab groups). The percentage of patients with a ≥50% reduction in the average number of headache days of at least moderate severity per month (response rate) was higher with fremanezumab monthly (29.0%) and fremanezumab quarterly (29.1%) than with placebo (13.2%) in addition to other improvements in secondary endpoints, including reduction of acute medication use (mean change from baseline during 12-week period ± SE: fremanezumab monthly, -3.7 ± 0.4; fremanezumab quarterly, -3.9 ± 0.4; placebo, -2.4 ± 0.4) and improvements in disability scores (mean change from baseline in six-item Headache Impact Test score at 4 weeks after third injection ± SE: fremanezumab monthly, -8.1 ± 0.7; fremanezumab quarterly, -8.0 ± 0.7; placebo, -6.5 ± 0.7). Fremanezumab was well tolerated with a similar incidence of adverse events including injection-site reactions as placebo (patients with at least one treatment-emergent adverse event: fremanezumab total, n = 232 [61.4%]; placebo, n = 118 [61.8%]). CONCLUSION: Fremanezumab effectively prevents CM in Japanese and Korean patients and was well tolerated. No safety signal was detected.

Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial.

BACKGROUND: These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) ("failed-yes" and "failed-no" subgroups) and with/without concomitant preventive treatment ("concomitant preventive-yes" and "concomitant preventive-no" subgroups). METHODS: Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4-6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. RESULTS: Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4-6 (treatment difference versus placebo [95% CI], failed-yes: - 1.9 [- 3.3, - 0.4]; failed-no: - 1.4 [- 2.6, - 0.3]; concomitant preventive-yes: - 1.7 [- 3.3, 0.0]; concomitant preventive-no: - 1.6 [- 2.6, - 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. CONCLUSION: Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. TRIAL REGISTRATION: Clinicaltrials.gov . NCT03812224. Registered January 23, 2019.

Impact of the COVID-19 pandemic on migraine in Japan: a multicentre cross-sectional study.

OBJECTIVES: To assess the impacts of social situation changes due to the coronavirus disease 2019 (COVID-19) pandemic on headache-related disability and other symptoms in patients with migraine in Japan. METHODS: We conducted a multicentre, cross-sectional study including 659 outpatients with migraine diagnosed by headache specialists. The participants were asked about the impacts of the first wave of the COVID-19 pandemic on headache-related disability, headache days, headache intensity, stress, physical activity, hospital access and their work and home lives. For headache-related disability, the total Migraine Disability Assessment (MIDAS) score and part A and B scores were analysed. Multivariate stepwise linear regression analysis was performed to identify the clinical predictors of changes in the total MIDAS score before and during the COVID-19 pandemic. Logistic regression analysis was performed to determine the factors related to new-onset headache during the COVID-19 pandemic. RESULTS: Finally, 606 migraine patients (73 M/533 F; age, 45.2 ± 12.0 years) were included in the study, excluding those with incomplete data. Increased stress, substantial concern about COVID-19 and negative impacts of the first wave of the COVID-19 pandemic on daily life were reported in 56.8 %, 55.1 and 45.0 % of the participants, respectively. The total MIDAS and A and B scores did not significantly change after the first wave of the COVID-19 pandemic. New-onset headache, which was observed in 95 patients (15.7 %), was associated with younger age and worsened mood and sleep in the logistic regression analysis. The multivariate stepwise linear regression analysis of changes in the total MIDAS score before and during the first wave of COVID-19 pandemic identified worsened sleep, increased acute medication use, increased stress, medication shortages, comorbidities, the absence of an aura and new-onset headache were determinants of an increased total MIDAS score during the first wave of the COVID-19 pandemic. CONCLUSIONS: In this multicentre study, clinical factors relevant to headache-related disability, such as new-onset headache, stress and sleep disturbances, were identified, highlighting the importance of symptom management in migraine patients during the first wave of the COVID-19 pandemic.

The relation between emotion regulation and migraine: A cross-cultural study on the moderating effect of culture.

BACKGROUND: Effects of emotion suppression on physical health might be contingent on culture. Existing research on emotion regulation has mainly included western participants. Herewith the question arises, whether this gained expertise is transferable to an Asian culture. OBJECTIVES: This cross-sectional study evaluated to what extent the regulation of emotions is related to migraine and if the relation between emotion regulation and migraine complaints differs between a Western and an Asian population. Therefore, the main characteristics and symptoms of patients with migraine from both Germany and Japan are compared. METHODS: 261 Japanese and 347 German headache patients participated in this online study and completed self-report measures of emotion regulation (suppression and reappraisal) and headache complaints. RESULTS: Cultural groups did not differ regarding their demographic data, intake of medication and number of days with headache. German participants showed significantly higher levels of anxiety and lower levels of emotion suppression compared to Japanese patients. Emotion regulation is not correlated with headache complaints either in the Japanese or in the German patient group. CONCLUSION: Although group differences were found with respect to anxiety and emotion suppression, subsequent regression analysis revealed these differences were unrelated to headache complaints. As our baseline analysis focused on group means, approaches that examine individual reaction patterns to stress and accompanying sensory stimulus processing may prove to be more fruitful and illuminating.

Cranial Autonomic Symptoms of Migraine in Japan: Prospective Study of 373 Migraine Patients at a Tertiary Headache Center.

OBJECTIVE: To clarify the detailed clinical characteristics of cranial autonomic symptoms (CAS) of Japanese patients with migraine and to get insight into the pathophysiological implications. BACKGROUND: Recent studies reported that CAS in migraine is causing diagnostic confusion with cluster headache or sinus headache; however, most reports have concerned Caucasians, and Asian data are scarce. The regional differences in the clinical characteristics of primary headaches between Caucasians and Asians have also been revealed recently. METHOD: This was a cross-sectional study. We investigated 373 patients with migraine in a tertiary headache center with face-to-face interviews. RESULTS: According to our findings, 158/373 (42.4%) patients with migraine had CAS and were characterized by more frequent cutaneous allodynia than those without CAS, suggesting the contribution of central sensitization; however, there were no statistically significant differences in pulsating pain or motion sensitivity as signs of peripheral sensitization. In contrast to the previous study, osmophobia was found to be significantly related to CAS. CONCLUSION: CAS in patients with migraine is common not only in Caucasians but also in Asians. Central sensitization seems to contribute more than peripheral sensitization to CAS manifestation, and osmophobia might be noteworthy among Asian patients with migraine. To avoid a misdiagnosis, we emphasize the need for comments on CAS in the international classification of headache disorders migraine criteria.