研究者詳細 - 滝沢　翼

論文 - 滝沢　翼

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Real-world use of over-the-counter medications by patients with migraine in Japan: results from the OVERCOME (Japan) 2nd study

Ishii R., Takizawa T., Suzuki S., Danno D., Miura M., Tanizawa Y., Osaga S., Hashimoto C., Komori M.

Journal of Headache and Pain 26 （ 1 ） 107 2025年12月

ISSN 11292369

Background: People with migraine may prefer over-the-counter (OTC) drugs because of multiple reasons, but their overuse can cause medication overuse headaches. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) 2nd study describes the real-world use of OTC headache drugs and the challenges that potentially prevent people with migraine from accessing appropriate medical management in Japan. Methods: This analysis of the cross-sectional, population-based, nationwide online survey included adults with migraine. Respondents reported their experiences with prescription and OTC drugs for migraine, migraine-specific drug awareness, and attitude towards migraine. Subgroup analyses were performed based on the number of monthly headache days (MHD) and the frequency of OTC drug use/month. Results: The 19,590 respondents with migraine (68.8% female; mean [SD] age 40.5 [13.1] years) had mean (SD) 3.5 (5.2) MHDs; 29.0% consulted doctors in the past year for migraine. OTC drug use in the past year was common (≥ 62.1%) regardless of doctor consultation or number of MHDs. Among respondents who answered that they would usually use prescribed drugs when they have a migraine attack, 35.2% reported that they would typically use OTC drugs too. The frequency of OTC drug use was the same or higher than that of prescribed drugs in 51.3% of the respondents who consulted doctors in the past year. Only 14.6% of respondents discussed OTC drugs with doctors during consultations in the past year. Migraine-specific drug access and awareness were limited even among frequent OTC drug users (≥ 10 days/month); 18.2% used triptans, but 65.5% never heard of it. Among 37.1% of respondents who had hesitated to visit a doctor, ‘I could handle it myself with OTC medicine’ was the most common reason for hesitation (34.9%). Conclusion: OTC drug use is common among people with migraine; however, it is not frequently discussed with doctors. Many respondents, even those with frequent OTC drug use, did not have access or awareness of migraine-specific drugs. To prevent medication overuse for migraine, the use of OTC drugs should also be discussed and managed.

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Correction: Vertebral artery dissection in a patient with migraine treated with calcitonin gene-related peptide monoclonal antibody: a case report and FAERS database analysis.

Tokuyasu D, Imai S, Chen SP, Ihara K, Watanabe N, Izawa Y, Nakahara J, Hori S, Takizawa T

BMC neurology 25 （ 1 ） 40 2025年01月

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Vertebral artery dissection in a patient with migraine treated with calcitonin gene-related peptide monoclonal antibody: a case report and FAERS database analysis

Tokuyasu D., Imai S., Chen S.P., Ihara K., Watanabe N., Izawa Y., Nakahara J., Hori S., Takizawa T.

BMC neurology （Springer Science and Business Media LLC） 25 （ 1 ） 1 - 1 2025年01月

BACKGROUND: Migraine is associated with cervical artery dissection (CeAD). Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide with vasodilatory effects. The use of anti-CGRP monoclonal antibodies (CGRP mAb) may affect cerebrovascular disease risk; however, no reports have associated CGRP mAb with CeAD. CASE PRESENTATION AND FAERS DATABASE ANALYSIS: We report a case of vertebral artery dissection in a 39-year-old woman with migraine treated with galcanezumab. We searched the number of cases where cerebral and cervical artery dissection were reported as adverse effects of CGRP mAb using the FDA Adverse Event Reporting System (FAERS) database. Six and ten such cases were reported regarding galcanezumab and CGRP mAbs use, respectively. The reporting odds ratios for galcanezumab and CGRP mAbs were elevated. CONCLUSION: Although migraine is reported to be associated with CeAD, the use of CGRP mAb might be related to CeAD and warrant further investigation.

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片頭痛の発作間欠期の負担とその評価の現状について　文献レビュー

滝沢翼, 竹村亮, 五十嵐久佳, 松森保彦, 佐藤美奈子, 植田要

臨床神経学（(一社)日本神経学会） 65 （ 1 ） 8 - 15 2025年01月

ISSN 0009-918X

片頭痛の発作間欠期の患者負担に関するtargeted literature reviewを実施した.文献レビューの結果,(1)片頭痛の随伴症状や患者負担は発作時のみではなく,発作間欠期にも存在すること,(2)発作間欠期には,繰り返し出現する頭痛発作に対する恐怖や不安などが日常活動への支障や生活の質(Quality of Life:QOL)の低下をもたらすこと,(3)カルシトニン遺伝子関連ペプチド(calcitonin gene-related peptide:CGRP)関連抗体薬による予防治療は,発作間欠期の負担を軽減する可能性があることなどが明らかとなった.これらのことから,片頭痛治療では,発作間欠期の負担を含めた患者のアンメットニーズを確認したうえで,患者個人の負担に合わせた適切な治療法を選択することが重要である.(著者抄録)

Efficacy and Safety of Switching Between Anti-CGRP Monoclonal Antibodies: A Detailed Monthly and Long-term Follow-up Study and Literature Review.

Oshima K, Ihara K, Watanabe N, Takemura R, Ishizuchi K, Takahashi N, Shibata M, Nakahara J, Takizawa T

Internal medicine (Tokyo, Japan) （一般社団法人日本内科学会） advpub （ 0 ） 2025年

ISSN 09182918

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.

Treatment patterns and characteristics of patients with migraine: results from a retrospective database study in Japan

Takizawa T., Kitano T., Iijima M., Togo K., Yonemoto N.

Journal of Headache and Pain （Journal of Headache and Pain） 25 （ 1 ） 19 - 19 2024年12月

ISSN 11292369

Background: Clinical characteristics and treatment practice of patients with migraine in Japan in real-world setting have not been fully investigated. We conducted a retrospective cohort study using claims database to understand the clinical practice of migraine in recent years and to characterize patients potentially not managed well by current treatment options. Methods: Our study used data from the large claims database maintained by JMDC Inc. Patients with diagnosis of headache or migraine between January 1, 2018, and July 31, 2022, were defined as the headache cohort, and those with migraine diagnosis and prescription of migraine treatments among the headache cohort were included in the migraine cohort. In the headache cohort, characteristics of medical facilities and status of imaging tests to distinguish secondary headache were examined. Treatment patterns and characteristics of patients potentially not managed well by acute/preventive treatment were described in migraine cohort. Results: In the headache cohort, 989,514 patients were included with 57.0% females and mean age of 40.3 years; 77.0% patients visited clinics (with ≤ 19 bed capacities) for their primary diagnosis, and 30.3% patients underwent imaging tests (computed tomography and/or magnetic resonance imaging). In the migraine cohort, 165,339 patients were included with 65.0% females and mean age of 38.8 years. In the migraine cohort, 95.6% received acute treatment while 20.8% received preventive treatment. Acetaminophen/non-steroidal anti-inflammatory drugs were most common (54.8%) as the initial prescription for migraine treatment followed by triptan (51.4%). First treatment prescription included preventive treatment in 15.6%, while the proportion increased to 82.2% in the fourth treatment prescription. Among patients with more than 12 months of follow-up, 3.7% had prescription patterns suggestive of risk of medication-overuse headache, and these patients were characterized by a higher percentage of females and a higher prevalence of comorbidities. Conclusions: This study revealed that approximately one-fifth of the patients with migraine visiting medical facilities use preventive drugs. The presence of potential patients at risk of medication-overuse headache and the role of clinics in migraine treatment were also described.

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

Takizawa T., Ihara K., Watanabe N., Takemura R., Takahashi N., Miyazaki N., Shibata M., Suzuki K., Imai N., Suzuki N., Hirata K., Takeshima T., Nakahara J.

Journal of Headache and Pain （Journal of Headache and Pain） 25 （ 1 ） 39 - 39 2024年12月

ISSN 11292369

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.

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The impact of primary headaches on disability outcomes: a literature review and meta-analysis to inform future iterations of the Global Burden of Disease study

Waliszewska-Prosół M., Montisano D.A., Antolak M., Bighiani F., Cammarota F., Cetta I., Corrado M., Ihara K., Kartamysheva R., Petrušić I., Pocora M.M., Takizawa T., Vaghi G., Martelletti P., Corso B., Raggi A.

Journal of Headache and Pain （Journal of Headache and Pain） 25 （ 1 ） 27 - 27 2024年12月

ISSN 11292369

Background: The burden and disability associated with headaches are conceptualized and measured differently at patients’ and populations’ levels. At the patients’ level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0–1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients’ disability which might inform future GBD definitions of DW for headache disorders. Methods: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females’ percentage in the sample, and age). We developed a 0–1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. Results: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. Conclusions: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

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Effects of passive smoking on cortical spreading depolarization in male and female mice

Takizawa T., Ihara K., Unekawa M., Iba C., Kagawa S., Watanabe N., Nakayama S., Sakurai K., Miyazaki N., Ishida N., Takemura R., Shibata M., Izawa Y., Chubachi S., Fukunaga K., Nakahara J.

Journal of Headache and Pain 25 （ 1 ） 162 - 162 2024年12月

ISSN 11292369

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.

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Hallmarks of primary headache: part 1 – migraine

Raggi A., Leonardi M., Arruda M., Caponnetto V., Castaldo M., Coppola G., Della Pietra A., Fan X., Garcia-Azorin D., Gazerani P., Grangeon L., Grazzi L., Hsiao F.J., Ihara K., Labastida-Ramirez A., Lange K.S., Lisicki M., Marcassoli A., Montisano D.A., Onan D., Onofri A., Pellesi L., Peres M., Petrušić I., Raffaelli B., Rubio-Beltran E., Straube A., Straube S., Takizawa T., Tana C., Tinelli M., Valeriani M., Vigneri S., Vuralli D., Waliszewska-Prosół M., Wang W., Wang Y., Wells-Gatnik W., Wijeratne T., Martelletti P.

Journal of Headache and Pain 25 （ 1 ） 189 - 189 2024年12月

ISSN 11292369

Background and aim: Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features. Main results: The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities. Conclusions: Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

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Clinical practice for migraine treatment and characteristics of medical facilities and physicians treating migraine: Insights from a retrospective cohort study using a Japanese claims database

Takizawa T., Kitano T., Togo K., Yoshikawa R., Iijima M.

PLoS ONE 19 （ 12 December ） e0315610 2024年12月

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.

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Clinical characteristics of 2378 patients presenting with headache disorders to headache clinics in Japan: A clinic-based multicenter study

Imai N., Takizawa T., Watanabe N., Matsumori Y.

Clinical Neurology and Neurosurgery 246 108588 - 108588 2024年11月

ISSN 03038467

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.

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International Headache Society Global Practice Recommendations for Preventive Pharmacological Treatment of Migraine

Puledda F., Sacco S., Diener H.C., Ashina M., Al-Khazali H.M., Ashina S., Burstein R., Liebler E., Cipriani A., Chu M.K., Cocores A., Dodd-Glover F., Ekizoğlu E., Garcia-Azorin D., Göbel C.H., Goicochea M.T., Hassan A., Hirata K., Hoffmann J., Jenkins B., Kamm K., Lee M.J., Ling Y.H., Lisicki M., Martinelli D., Monteith T.S., Ornello R., Özge A., Peres M.F.P., Pozo-Rosich P., Romanenko V., Schwedt T.J., Souza M.N.P., Takizawa T., Terwindt G.M., Thuraiaiyah J., Togha M., Vandenbussche N., Wang S.J., Yu S., Tassorelli C.

Cephalalgia : an international journal of headache 44 （ 9 ） 3331024241269735 - 3331024241269735 2024年09月

ISSN 0333-1024

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International Headache Society global practice recommendations for the acute pharmacological treatment of migraine.

Puledda F, Sacco S, Diener HC, Ashina M, Al-Khazali HM, Ashina S, Burstein R, Liebler E, Cipriani A, Chu MK, Cocores A, Dodd-Glover F, Ekizoğlu E, Garcia-Azorin D, Göbel C, Goicochea MT, Hassan A, Hirata K, Hoffmann J, Jenkins B, Kamm K, Lee MJ, Ling YH, Lisicki M, Martinelli D, Monteith TS, Ornello R, Ozge A, Peres M, Pozo-Rosich P, Romanenko V, Schwedt TJ, Souza MNP, Takizawa T, Terwindt GM, Thuraiaiyah J, Togha M, Vandenbussche N, Wang SJ, Yu S, Tassorelli C

Cephalalgia : an international journal of headache 44 （ 8 ） 3331024241252666 - 3331024241252666 2024年08月

ISSN 0333-1024

BACKGROUND: In an effort to improve migraine management around the world, the International Headache Society (IHS) has here developed a list of practical recommendations for the acute pharmacological treatment of migraine. The recommendations are categorized into optimal and essential, in order to provide treatment options for all possible settings, including those with limited access to migraine medications. METHODS: An IHS steering committee developed a list of clinical questions based on practical issues in the management of migraine. A selected group of international senior and junior headache experts developed the recommendations, following expert consensus and the review of available national and international headache guidelines and guidance documents. Following the initial search, a bibliography of twenty-one national and international guidelines was created and reviewed by the working group. RESULTS: A total of seventeen questions addressing different aspects of acute migraine treatment have been outlined. For each of them we provide an optimal recommendation, to be used whenever possible, and an essential recommendation to be used when the optimal level cannot be attained. CONCLUSION: Adoption of these international recommendations will improve the quality of acute migraine treatment around the world, even where pharmacological options remain limited.

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Application of Artificial Intelligence in the Headache Field.

Ihara K, Dumkrieger G, Zhang P, Takizawa T, Schwedt TJ, Chiang CC

Current pain and headache reports 28 （ 10 ） 1049 - 1057 2024年07月

ISSN 15313433

Purpose of Review: Headache disorders are highly prevalent worldwide. Rapidly advancing capabilities in artificial intelligence (AI) have expanded headache-related research with the potential to solve unmet needs in the headache field. We provide an overview of AI in headache research in this article. Recent Findings: We briefly introduce machine learning models and commonly used evaluation metrics. We then review studies that have utilized AI in the field to advance diagnostic accuracy and classification, predict treatment responses, gather insights from various data sources, and forecast migraine attacks. Furthermore, given the emergence of ChatGPT, a type of large language model (LLM), and the popularity it has gained, we also discuss how LLMs could be used to advance the field. Finally, we discuss the potential pitfalls, bias, and future directions of employing AI in headache medicine. Summary: Many recent studies on headache medicine incorporated machine learning, generative AI and LLMs. A comprehensive understanding of potential pitfalls and biases is crucial to using these novel techniques with minimum harm. When used appropriately, AI has the potential to revolutionize headache medicine.

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Efficacy and tolerability of 100 mg of lasmiditan for migraine: A multi-center, prospective observational real-world study in Japan

Ishii R., Ishizuchi K., Watanabe N., Fukazawa R., Trivedi M., Nakahara J., Takizawa T.

Cephalalgia : an international journal of headache （Cephalalgia : an international journal of headache） 44 （ 6 ） 3331024241258695 - 3331024241258695 2024年06月

ISSN 0333-1024

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.

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特集患者さんからよく尋ねられる内科診療のQuestion 第9章　神経 [23歳女性,片頭痛]5年くらい前から片頭痛と言われていますが,最近薬を飲んでもあまり効かなくなってきて毎日のように頭が痛くなってしまいます.治療・生活では何に気をつけたらよいでしょうか?

加納裕也, 滝沢翼

内科（南江堂） 133 （ 4 ） 902 - 904 2024年04月

ISSN 00221961

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

Harada S, Iida M, Miyagawa N, Hirata A, Kuwabara K, Matsumoto M, Okamura T, Edagawa S, Kawada Y, Miyake A, Toki R, Akiyama M, Kawai A, Sugiyama D, Sato Y, Takemura R, Fukai K, Ishibashi Y, Kato S, Kurihara A, Sata M, Shibuki T, Takeuchi A, Kohsaka S, Sawano M, Shoji S, Izawa Y, Katsumata M, Oki K, Takahashi S, Takizawa T, Maruya H, Nishiwaki Y, Kawasaki R, Hirayama A, Ishikawa T, Saito R, Sato A, Soga T, Sugimoto M, Tomita M, Komaki S, Ohmomo H, Ono K, Otsuka-Yamasaki Y, Shimizu A, Sutoh Y, Hozawa A, Kinoshita K, Koshiba S, Kumada K, Ogishima S, Sakurai-Yageta M, Tamiya G, Takebayashi T

Ｊｏｕｒｎａｌ　ｏｆ　Ｅｐｉｄｅｍｉｏｌｏｇｙ（日本疫学会） advpub （ 0 ） 393 - 401 2024年

ISSN 09175040

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Striatal Blood Flow Changes by Middle Cerebral Artery Occlusion and Its Effect on Neurological Deficits in Mice

Unekawa M., Tsukada N., Takizawa T., Tomita Y., Nakahara J., Izawa Y.

Microcirculation （Microcirculation） 31 （ 6 ） e12861 2024年

ISSN 10739688

Objective: We attempted to record the regional cerebral blood flow (CBF) simultaneously at various regions of the cerebral cortex and the striatum during middle cerebral artery (MCA) occlusion and to evaluate neurological deficits and infarct formation. Methods: In male C57BL/6J mice, CBF was recorded in three regions including the ipsilateral cerebral cortex and the striatum with laser Doppler flowmeters, and the origin of MCA was occluded with a monofilament suture for 15–90 min. After 48 h, neurological deficits were evaluated, and infarct was examined by triphenyltetrazolium chloride (TTC) staining. Results: CBF decrease in the striatum was approximately two-thirds of the MCA-dominant region of the cortex during MCA occlusion. The characteristic CBF fluctuation because of spontaneously occurred spreading depolarization observed throughout the cortex was not found in the striatum. Ischemic foci with slight lower staining to TTC were found in the ipsilateral striatum in MCA-occluded mice for longer than 30 min (n = 54). Twenty-nine among 64 MCA-occluded mice exhibited neurological deficits even in the absence of apparent infarct with minimum staining to TTC in the cortex, and the severity of neurological deficits was not correlated with the size of the cortical infarct. Conclusion: Neurological deficits might be associated with the ischemic striatum rather than with cortical infarction.

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Repeated Intravenous Methylprednisolone May Prevent Deterioration of Hypertrophic Pachymeningitis in Rosai-Dorfman Disease.

Tezuka T, Nukariya T, Takahashi N, Kufukihara K, Tsuyama N, Terui Y, Kameyama K, Nakahara J, Takizawa T

Internal medicine (Tokyo, Japan) （一般社団法人日本内科学会） advpub （ 0 ） 459 - 462 2024年

ISSN 09182918

Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytosis. Although 20% of patients with RDD have spontaneous remission, some cases with central nervous system (CNS) involvement require surgery or systemic treatment. We encountered a case of RDD in which hypertrophic pachymeningitis was diffuse, eliminating the need for surgical intervention. A 72-year-old Japanese man was diagnosed with RDD based on pathological lymph node findings. Repeated intravenous methylprednisolone (IVMP) administration resolved and stabilized the hypertrophic pachymeningitis without any sequelae. If surgery or anticancer medications are contraindicated, repeated IVMP may be a good therapeutic option for CNS-associated RDD.

Real-world Efficacy of Erenumab on Migraine-associated Symptoms and Patient-reported Satisfaction Levels: A Retrospective Study in Japan.

Ihara K, Takahashi N, Ohtani S, Watanabe N, Ishizuchi K, Takemura R, Tokuyasu D, Sekiguchi K, Miyazaki N, Imai S, Hori S, Nakahara J, Takizawa T

Internal medicine (Tokyo, Japan) （一般社団法人日本内科学会） advpub （ 0 ） 825 - 831 2024年

ISSN 09182918

Objective In randomized clinical trials and real-world studies, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), including erenumab, have demonstrated efficacy for migraine prevention. However, there have been no real-world studies focusing on erenumab in East Asia that investigated its efficacy on migraine-associated symptoms and patient-reported satisfaction levels. Methods This single-center, observational, retrospective, real-world study examined patients who received at least three doses of erenumab at Keio University Hospital, Tokyo, Japan, between December 2021 and March 2023 as their first CGRP mAb treatment in a real-world setting. The patients were administered 70 mg of erenumab monthly. We assessed changes in monthly migraine days (MMDs), responder rates, migraine-associated symptoms including photophobia, phonophobia, nausea/vomiting, and patient-reported satisfaction levels. In addition, injection site reactions and other adverse events were recorded to investigate safety. Results Nineteen patients were considered eligible for the analysis. At 3 months, erenumab decreased MMDs by 6.6 (95% confidence interval, 2.3-10.8; p<0.01). The 50% responder rate was 42%. A total of 83% (n=15), 56% (n=10), and 71% (n=10) of patients reported either improvement in or disappearance of photophobia, phonophobia, and nausea/vomiting, respectively, and 44% (n=8) and 28% (n=5) answered “very satisfied” and “somewhat satisfied”, respectively, with erenumab treatment, leaving only 28% (n=5) as “unsatisfied”. Injection site reactions (n=6, 32%) and constipation (n=4, 21%) were frequent adverse events. Conclusion In a real-world setting in Japan, erenumab proved to be effective in not only reducing migraine and headache frequency but also improving migraine-associated symptoms and satisfying the majority of patients.

Optogenetic Functional Activation Is Detrimental During Acute Ischemic Stroke in Mice

Sugimoto K., Chung D.Y., Fischer P., Takizawa T., Qin T., Yaseen M.A., Sakadžić S., Ayata C.

Stroke 55 （ 10 ） 2502 - 2509 2024年

ISSN 00392499

BACKGROUND: Functional activation of the focal ischemic brain has been reported to improve outcomes by augmenting collateral blood flow. However, functional activation also increases metabolic demand and might thereby worsen outcomes. Indeed, preclinical and clinical reports have been conflicting. Here, we tested the effect of functional activation during acute ischemic stroke using distal middle cerebral artery occlusion in anesthetized mice. METHODS: Using transgenic mice expressing channelrhodopsin-2 in neurons, we delivered functional activation using physiological levels of transcranial optogenetic stimulation of the moderately ischemic cortex (ie, penumbra), identified using real-time full-field laser speckle perfusion imaging during a 1-hour distal microvascular clip of the middle cerebral artery. Neuronal activation was confirmed using evoked field potentials, and infarct volumes were measured in tissue slices 48

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片頭痛の誘発因子についての最新の知見

滝沢翼, 渡邊成美, 伊庭知里, 石川直樹, 梅田聡, 中原仁

日本頭痛学会誌（一般社団法人日本頭痛学会） 51 （ 1 ） 110 - 111 2024年

ISSN 13456547

片頭痛の発作間欠期の負担とその評価の現状について：文献レビュー

滝沢翼, 竹村亮, 五十嵐久佳, 松森保彦, 佐藤美奈子, 植田要

臨床神経学（日本神経学会） advpub （ 0 ） 8 - 15 2024年

ISSN 0009918X

片頭痛の発作間欠期の患者負担に関するtargeted literature reviewを実施した．文献レビューの結果，①片頭痛の随伴症状や患者負担は発作時のみではなく，発作間欠期にも存在すること，②発作間欠期には，繰り返し出現する頭痛発作に対する恐怖や不安などが日常活動への支障や生活の質（Quality of Life：QOL）の低下をもたらすこと，③カルシトニン遺伝子関連ペプチド（calcitonin gene-related peptide：CGRP）関連抗体薬による予防治療は，発作間欠期の負担を軽減する可能性があることなどが明らかとなった．これらのことから，片頭痛治療では，発作間欠期の負担を含めた患者のアンメットニーズを確認したうえで，患者個人の負担に合わせた適切な治療法を選択することが重要である．

The Impact of Migraine on the Whole Life Course of Patients: Results from the OVERCOME (Japan) 2nd Study

Danno D., Suzuki S., Takizawa T., Ishii R., Hamakawa M., Tanizawa Y., Osaga S., Komori M.

Neurology and Therapy 14 （ 1 ） 335 - 356 2024年

ISSN 21938253

Introduction: The impact of migraine on patients’ lives, including challenges they face before getting access to appropriate medical management, is not well understood. The ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE [OVERCOME (Japan)] 2nd study was conducted to provide information regarding burden and experience with migraine throughout the life course. Methods: This cross-sectional, population-based, nationwide online survey was conducted in adults with or without migraine. The migraine group reported their headache features and experiences in medical management since headache onset. Migraine’s burden and impact were assessed with various PRO instruments. Migraine and non-migraine groups reported their experiences in life events and answered questions on self-esteem. Subgroup analyses by the number of monthly headache days (MHD) were performed. Results: The migraine group (n = 19,590) was numerically younger [mean (SD) age 40.5 (13.1) years vs. 53.1 (17.8) years] and included more females (68.8% vs. 52.1%) than the non-migraine group (n = 2219). The migraine group had mean (SD) 3.5 (5.2) MHDs; 24.2–56.7% had moderate-to-very severe disease burden per various PRO instruments. Headaches started when respondents with migraine were 17.8 years old; 86.7% started over-the-counter medications at 19.4 years of age. Only 46.4% self-reported migraine diagnosis by a physician and 25.1% received an oral preventive drug, almost a decade after headache onset. Up to 16.8% reported poor support/lack of understanding from either teachers or parents during school life. The migraine group had numerically more frequent job changes and divorce, and lower self-esteem, than the non-migraine group. Across assessments, increased MHDs tended to worsen outcomes. Conclusion: Migraine affected many individuals from an early stage, but timely support and medical intervention were insufficient. This may negatively impact important life events, cause long-term impairment, and decrease self-esteem. Hence, improving the social understanding and medical environment for migraine to provide timely support is essential.

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Predicting response to CGRP-monoclonal antibodies in patients with migraine in Japan: a single-centre retrospective observational study

Ihara K., Ohtani S., Watanabe N., Takahashi N., Miyazaki N., Ishizuchi K., Hori S., Takemura R., Nakahara J., Takizawa T.

Journal of Headache and Pain （Journal of Headache and Pain） 24 （ 1 ） 23 - 23 2023年12月

ISSN 11292369

Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are a favourable option for patients with migraine who experience distressful headache disability and fail to respond to traditional preventive treatment options. However, since CGRPmAb has been available for only 2 years in Japan, the difference between good and poor responders remains unknown. We aimed to investigate the clinical characteristics of patients with migraine in Japan who responded well to CGRPmAb based on real-world data. Methods: We analysed patients who visited Keio University Hospital, Tokyo, Japan, between the 12th of August 2021 and 31st of August 2022, and were prescribed one of three CGRPmAbs (erenumab, galcanezumab, and fremanezumab) for more than 3 months. We recorded the patients’ basic migraine characteristics, such as pain quality, monthly migraine days (MMD)/monthly headache days (MHD), and the number of prior treatment failures. We defined good responders as patients whose MMDs decreased by more than 50% after 3 months of treatment and other patients as poor responders. We compared the baseline migraine characteristics between the two groups and performed logistic regression analysis based on the items that showed statistically significant differences. Results: In total, 101 patients were considered eligible for the responder analysis (galcanezumab: 57 (56%), fremanezumab: 31 (31%), and erenumab: 13 (13%)). After 3 months of treatment, 55 (54%) patients achieved ≥ 50% reduction in MMDs. Comparisons between ≥ 50% responders and non-responders revealed that age was significantly higher (p = 0.003), and MHD and total prior treatment failures were significantly lower (p = 0.027, 0.040, respectively), in responders than in non-responders. Age was a positive predictive factor, and the total number of prior treatment failures and past medical history of immuno-rheumatologic diseases were negative predictive factors of CGRPmAb responsiveness in Japanese patients with migraine. Conclusions: Patients with migraine who are older, with fewer prior treatment failures and no past history of immuno-rheumatologic disease, may respond well to CGRPmAbs.

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Real-world evidence of fremanezumab for treating migraine in Japan: a retrospective study

Ohtani S., Watanabe N., Ihara K., Takahashi N., Miyazaki N., Ishizuchi K., Takemura R., Hori S., Nakahara J., Takizawa T.

BMC Neurology （BMC Neurology） 23 （ 1 ） 404 - 404 2023年12月

Background: There have been very few real-world studies reported in the literature solely focusing on fremanezumab in Asia. This study aimed to evaluate the efficacy and safety of fremanezumab in a real-world setting in Japan. Method: This single-centered, observational, retrospective study examined patients with migraines who received four doses of fremanezumab between December 2021 and August 2022 at Keio University Hospital. We assessed the changes in monthly migraine days, responder rates, and migraine-associated symptoms, as well as injection site reactions and adverse events. Result: Twenty-nine patients were enrolled, wherein 79.3% were women. Compared with those at baseline, the monthly migraine days decreased by 5.9 days at 4 months. The 50% responder rate was 55.2% at 4 months. A total of 57.9%, 47.8%, and 65.0% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Moreover, injection site reactions were the most common adverse events (55.2%). Conclusion: Fremanezumab is effective and safe for migraine prevention in Japan. Fremanezumab also improved migraine-associated symptoms in half of the patients.

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Systemic lupus erythematosus mimicking retinal migraine: a case report

Tezuka T., Shibata M., Hanaoka H., Izawa Y., Kikuchi T., Akino K., Ozawa Y., Saito M., Kaneko Y., Nakahara J., Takizawa T.

Cephalalgia （Cephalalgia） 43 （ 12 ） 3331024231219477 - 3331024231219477 2023年12月

ISSN 03331024

Background: Retinal migraine is a diagnosis of exclusion and is characterized by repeated episodes of transient monocular blindness associated with migraine. We report a case of systemic lupus erythematosus with acute episodes mimicking retinal migraines. Case report: A 46-year-old woman with a history of migraine with aura since her 20s and Evans syndrome presented with episodic transient monocular blindness. Retinal migraine was considered as the cause, and migraine prophylaxis initially reduced its frequency. After 5 months, the frequency increased, with chilblain-like lupus lesions on her extremities. Laboratory testing revealed lymphopenia and hypocomplementemia, fulfilling the diagnostic criteria for systemic lupus erythematosus, which may have caused Evans syndrome and transient monocular blindness, mimicking retinal migraines. After intravenous methylprednisolone and rituximab therapy, the transient monocular blindness episodes did not recur. Conclusion: Given the clinical presentation, systemic lupus erythematosus should be considered as a cause of transient monocular blindness and should be distinguished from retinal migraine.

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Switching between anti-calcitonin gene-related peptide monoclonal antibodies: A comparison of monthly and quarterly dosing

Ihara K., Ohtani S., Watanabe N., Takahashi N., Miyazaki N., Takemura R., Hori S., Nakahara J., Takizawa T.

Journal of the Neurological Sciences （Journal of the Neurological Sciences） 453 120811 - 120811 2023年10月

ISSN 0022510X

Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have dramatically changed preventive treatment options for patients with migraine. Although there is emerging real-world evidence on the use of CGRPmAbs globally, the change in efficacy and safety after switching between CGRPmAbs owing to patients' frequency of hospital visits preference remains unknown. Methods: We conducted a single-centre, retrospective, real-world study of patients with migraine who first received galcanezumab for 3 or 4 months and then switched to fremanezumab at Keio University Hospital. We investigated changes in monthly migraine days (MMD), responder rate, and adverse effects such as injection site reactions. Results: MMD increased only by 0.7 (95% CI, −4.1-5.5; p = 0.748) after 4 months of treatment with fremanezumab (6.1, 95% CI, 2.3–9.9) compared to before switching (5.4, 95% CI, 2.2–8.6). Furthermore, switching from galcanezumab to fremanezumab produced only minor adverse events, such as injection site reactions. Conclusions: After switching from galcanezumab to fremanezumab out of the desire to visit the hospital less often, the reduction in MMD compared to baseline was sustained, and no serious adverse effects were observed.

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Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice

Fischer P., Tamim I., Sugimoto K., Morais A., Imai T., Takizawa T., Qin T., Schlunk F., Endres M., Yaseen M.A., Chung D.Y., Sakadzic S., Ayata C.

Stroke （Stroke） 54 （ 10 ） 2640 - 2651 2023年10月

査読有り, ISSN 00392499

BACKGROUND: Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While rapid hematoma growth during intracerebral hemorrhage triggers SDs, their role in intracerebral hemorrhage is unknown. METHODS: We used intrinsic optical signal and laser speckle imaging, combined with electrocorticography, to investigate the effects of SD on hematoma growth during the hyperacute phase (0-4 hours) after intracortical collagenase injection in mice. Hematoma expansion, SDs, and cerebral blood flow were simultaneously monitored under normotensive and hypertensive conditions. RESULTS: Spontaneous SDs erupted from the vicinity of the hematoma during rapid hematoma growth. We found that hematoma growth slowed down by >60% immediately after an SD. This effect was even stronger in hypertensive animals with faster hematoma growth. To establish causation, we exogenously induced SDs (every 30 minutes) at a remote site by topical potassium chloride application and found reduced hematoma growth rate and final hemorrhage volume (18.2±5.8 versus 10.7±4.1 mm3). Analysis of cerebral blood flow using laser speckle flowmetry revealed that suppression of hematoma growth by spontaneous or induced SDs coincided and correlated with the characteristic oligemia in the wake of SD, implicating the vasoconstrictive effect of SD as one potential mechanism of action. CONCLUSIONS: Our findings reveal that SDs limit hematoma growth during the early hours of intracerebral hemorrhage and decrease final hematoma volume.

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IV．一次性頭痛：片頭痛，その診断と治療

滝沢翼

日本内科学会雑誌（一般社団法人日本内科学会） 112 （ 8 ） 1350 - 1358 2023年08月

ISSN 00215384

片頭痛は，Quality of life（QOL）を著しく低下させ得る「脳の病気」であり，我が国では約1,000万人もの患者がいる．急性期治療薬としてはトリプタン製剤が従来使用されており，2022年からはラスミジタンも加わった．予防療法については，2021年に登場したカルシトニン遺伝子関連ペプチド（calcitonin gene-related peptide：CGRP）関連抗体薬が著効し「人生が変わる」ような症例も経験する．片頭痛は緊張型頭痛と誤診されているケースも多いが，片頭痛と適切に診断し，片頭痛に特化した治療を提供していくことが重要である．

Calcitonin Gene-Related Peptide mRNA Synthesis in Trigeminal Ganglion Neurons after Cortical Spreading Depolarization

Shibata M., Kitagawa S., Unekawa M., Takizawa T., Nakahara J.

International journal of molecular sciences （International journal of molecular sciences） 24 （ 14 ） 2023年07月

ISSN 16616596

Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, activates the trigeminovascular system. In the present study, we investigated CGRP mRNA expression in TG neurons in a CSD-based mouse migraine model. Our in situ hybridization analysis showed that CGRP mRNA expression was observed in smaller-sized neuronal populations. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral TG. However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger in the 48 h and 72 h post-CSD groups than in the control group. The proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters less than 14 μm became significantly less at several time points after CSD. In contrast, we found significantly greater proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters of 14-18 μm at 24 h, 48, and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift in CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy.

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Dysautonomia associated with immune checkpoint inhibitors

Tezuka T., Okuzumi S., Nakashima C., Ide T., Imai S., Mitsuboshi S., Kuwahara Y., Takizawa T., Seki M., Minematsu N., Aragane N., Nakahara J., Hori S., Nakane S., Suzuki S.

Journal of Neurology （Journal of Neurology） 270 （ 7 ） 3413 - 3423 2023年07月

ISSN 03405354

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.

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Anti-N-methyl-D-aspartate receptor encephalitis with concurrent human herpes virus-6A deoxyribonucleic acid detection: An autopsy case

Shimohama S., Iizuka T., Takizawa T., Watanabe N., Tezuka T., Matsuda K., Yamanoi K., Kanazawa N., Kawamura Y., Yoshikawa T., Suzuki T., Takao M., Nakahara J., Izawa Y.

Neuropathology （Neuropathology） 43 （ 3 ） 257 - 261 2023年06月

ISSN 09196544

We report an autopsy case of anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis with concurrent human herpes virus-6 (HHV-6) A deoxyribonucleic acid (DNA) detection in cerebrospinal fluid (CSF). A 38-year-old previously healthy Japanese man presented with a generalized seizure. Brain magnetic resonance imaging (MRI) findings were unremarkable, but CSF revealed pleocytosis. On Day 11, HHV-6 DNA was detected in CSF, and IgG antibodies against the NR1 subunit of the NMDAR (GluN1) were subsequently detected. Since HHV-6 encephalitis was initially suspected, the patient was treated with foscarnet and ganciclovir, but the HHV-6A copy number increased from 200 (Day 22) to 2000 copies/mL (Day 47), and the therapy was ineffective. As typical symptoms of anti-NMDAR encephalitis developed, we changed the patient's treatment to combat anti-NMDAR encephalitis. He was repeatedly treated with first-line immunotherapy, and GluN1 antibody titer decreased. He was not treated with second-line immunotherapy because of recurrent infections; he died on Day 310. Postmortem examinations did not show systemic tumors. Microscopic examination of the brain revealed only severe neuronal rarefaction in the hippocampal cornu ammonis (CA) 3–4 areas with gliosis. Early initiation of aggressive immunotherapy may be required in a refractory case of anti-NMDAR encephalitis, even with HHV-6A DNA detection, because the significance of this concurrent detection in autoimmune encephalitis remains unclear.

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COVID-19 vaccination elicited de novo and recurrence of cluster headache: A case series

Chen S.P., Takizawa T., Sekiguchi K., Nakahara J., Wang S.J.

Cephalalgia （Cephalalgia） 43 （ 5 ） 3331024231173354 - 3331024231173354 2023年05月

ISSN 03331024

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.

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Optogenetic Spreading Depolarizations Do Not Worsen Acute Ischemic Stroke Outcome

Sugimoto K., Yang J., Fischer P., Takizawa T., Mulder I.A., Qin T., Erdogan T.D., Yaseen M.A., Sakadžić S., Chung D.Y., Ayata C.

Stroke （Stroke） 54 （ 4 ） 1110 - 1119 2023年04月

ISSN 00392499

Background: Spreading depolarizations (SDs) are believed to contribute to injury progression and worsen outcomes in focal cerebral ischemia because exogenously induced SDs have been associated with enlarged infarct volumes. However, previous studies used highly invasive methods to trigger SDs that can directly cause tissue injury (eg, topical KCl) and confound the interpretation. Here, we tested whether SDs indeed enlarge infarcts when induced via a novel, noninjurious method using optogenetics. Methods: Using transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP), we induced 8 optogenetic SDs to trigger SDs noninvasively at a remote cortical location in a noninjurious manner during 1-hour distal microvascular clip or proximal an endovascular filament occlusion of the middle cerebral artery. Laser speckle imaging was used to monitor cerebral blood flow. Infarct volumes were then quantified at 24 or 48 hours. Results: Infarct volumes in the optogenetic SD arm did not differ from the control arm in either distal or proximal middle cerebral artery occlusion, despite a 6-fold and 4-fold higher number of SDs, respectively. Identical optogenetic illumination in wild-type mice did not affect the infarct volume. Full-field laser speckle imaging showed that optogenetic stimulation did not affect the perfusion in the peri-infarct cortex. Conclusions: Altogether, these data show that SDs induced noninvasively using optogenetics do not worsen tissue outcomes. Our findings compel a careful reexamination of the notion that SDs are causally linked to infarct expansion.

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Long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine attacks

Begasse de Dhaem O., Takizawa T., Dodick D.W.

Cephalalgia （Cephalalgia） 43 （ 2 ） 3331024221137092 - 3331024221137092 2023年02月

ISSN 03331024

Background: Long-term data helps assess the consistency of efficacy, tolerability, and safety of acute treatment over repeated use for different attacks. Real-world studies help assess tolerability, safety, and efficacy in patients with possibly refractory chronic migraine, more comorbidities, other diseases such as cardiovascular diseases, and polypharmacy. Methods: This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine. Both manuscripts and abstracts were reviewed. Results: The efficacy and tolerability of lasmiditan, ubrogepant, and rimegepant are maintained over time. No significant cardiovascular adverse events were thought to be related to any of these medications. The rare instances of palpitations and/or tachycardia occurred within 48 hours of lasmiditan. One participant with a history of supraventricular tachycardia had sinus tachycardia thought to be related to ubrogepant which did not recur despite continued use. One case of thrombocytopenia and two cases of increased aspartate aminotransferase and alanine transaminase were thought to be possibly related, but the alanine transaminase and aspartate aminotransferase levels normalized despite continued use of ubrogepant. A case of first-degree atrioventricular block was considered possibly related to rimegepant. Acute use of rimegepant was associated with a decrease in monthly migraine days over time. The three medications were associated with improvement in function and/or productivity. Conclusion: Long-term and real-world data of tolerability, safety and efficacy of lasmiditan, ubrogepant, and rimegepant is thus far consistent with prior studies, but more longitudinal data that clarifies long-term safety as well as consistency and predictors of response is needed.

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Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review

Caronna E., van den Hoek T.C., Bolay H., Garcia-Azorin D., Gago-Veiga A.B., Valeriani M., Takizawa T., Messlinger K., Shapiro R.E., Goadsby P.J., Ashina M., Tassorelli C., Diener H.C., Terwindt G.M., Pozo-Rosich P.

Cephalalgia （Cephalalgia） 43 （ 1 ） 3331024221131337 - 3331024221131337 2023年01月

ISSN 03331024

Objective: The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. Methods: This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review. Results: Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. Conclusions: The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

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日本のリアルワールドにおけるCGRP関連抗体薬の動向

大谷星也, 井原慶子, 堀里子, 中原仁, 滝沢翼

日本頭痛学会誌（一般社団法人日本頭痛学会） 49 （ 3 ） 578 - 583 2023年

査読有り, ISSN 13456547

片頭痛は生活の質を著しく低下させるコモンディジーズの1つである．片頭痛の発症機序に基づいてcalcitonin gene-related peptide (CGRP) 関連抗体薬が開発され，わが国においては2021年に上市された．2022年8月現在，リアルワールド (real-world, RW) における有効性，安全性についてはまだ情報が十分でない．そこで本総説では，第49回日本頭痛学会総会 (2021年11月) ，第63回日本神経学会学術大会 (2022年5月) の一般演題抄録より，CGRP関連抗体薬にかかわる研究報告を抽出した．有効性や安全性を1ヵ月以上観察していた13件の報告について結果を要約する．

Reversible Splenial Lesion Triggered by Hyperthyroidism

Okusa S., Nakahara J., Takizawa T.

Japanese Journal of Medicine （一般社団法人日本内科学会） advpub （ 0 ） 2925 - 2926 2023年

ISSN 09182918

Migraine triggers in Asian countries: a narrative review

Iba C., Ohtani S., Lee M.J., Huh S., Watanabe N., Nakahara J., Peng K.P., Takizawa T.

Frontiers in Neurology （Frontiers in Neurology） 14 1169795 - 1169795 2023年

ISSN 1664-2295

Background: Migraine is one of the most common neurological disorders worldwide. Clinical characteristics of migraine may be somewhat different across ethnic groups. Although factors such as stress, lack of sleep, and fasting are known as migraine triggers, the discussion about geographical differences of migraine triggers in Asia is lacking. Methods: In this study, we performed a narrative review on migraine triggers in Asia. We searched PubMed for relevant papers published between January 2000 and February 2022. Results: Forty-two papers from 13 Asian countries were included. Stress and sleep are the most frequently reported migraine triggers in Asia. There were some differences in migraine triggers in Asian countries: fatigue and weather common in Eastern Asia and fasting common in Western Asia. Conclusion: Majority of the common triggers reported by patients with migraine in Asia were stress and sleep, similar to those reported globally, thus showing they are universally important. Some triggers linked to internal homeostasis are influenced by culture (e.g., alcohol, food/eating habit), and triggers related to environmental homeostasis, such as weather, are highly heterogenous between regions.

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私の留学体験談　～Massachusetts General Hospital～

滝沢翼

日本頭痛学会誌（一般社団法人日本頭痛学会） 50 （ 1 ） 117 - 119 2023年

ISSN 13456547

ガルカネズマブ，フレマネズマブ，エレヌマブ : リアルワールドデータ

滝沢翼, 大谷星也, 井原慶子

日本頭痛学会誌（一般社団法人日本頭痛学会） 50 （ 1 ） 33 - 37 2023年

ISSN 13456547

TACsの疫学，症状の特徴について～群発頭痛を中心に～

滝沢翼, 石鎚啓

日本頭痛学会誌（一般社団法人日本頭痛学会） 50 （ 1 ） 59 - 63 2023年

ISSN 13456547

Serious Bacterial Infections Associated with Eculizumab: A Pharmacovigilance Study

Shohei Okusa, Tsubasa Takizawa, Shungo Imai, Munenori Oyama, Kei Ishizuchi, Jin Nakahara, Satoko Hori, Shigeaki Suzuki

Internal Medicine （Japanese Society of Internal Medicine） 2023年

ISSN 0918-2918

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Prevalence of Primary Headache in Nurses in Japan: A Cross-sectional Single-center Study

Sekiguchi K., Huh S., Watanabe N., Miyazaki N., Ishizuchi K., Iba C., Tagashira Y., Shibata M., Takemura R., Nakahara J., Takizawa T.

Internal Medicine （一般社団法人日本内科学会） advpub （ 0 ） 1217 - 1222 2023年

ISSN 09182918

Objective This study examined the prevalence of migraine in nurses in Japan, which, to our knowledge, has not been documented in English. Methods From April to May 2021, we administered a questionnaire to 229 nurses working at Keio University Hospital to investigate the prevalence and characteristics of headache among nurses in Japan. Headaches were classified as migraine or tension-type headache (TTH) based on the International Classification of Headache Disorders 3rd edition (ICHD-3). Results In total, 80 patients (34.9%) had primary headaches, including 47 (20.5%) with migraine and probable migraine and 33 (14.4%) with TTH and probable TTH. We found a significant difference in the Numerical Rating Scale score, nausea and vomiting, photophobia, phonophobia, and aggravation by routine physical activity between migraine and TTH. The specificities for a migraine diagnosis were 100% and 93.9% for nausea/vomiting and photophobia, respectively. Only 8.8% of patients had their headaches diagnosed by a physician. Conclusion Migraines have a high prevalence (>20%) among nurses and are often under-diagnosed. In many cases, headache-associated symptoms are more important than laterality or other characteristics for the diagnosis. Many nurses are treated for headaches without a correct diagnosis. Further education regarding primary headaches may be necessary for health practitioners as well as society.

Cerebral Venous Thrombosis Mimicking Limbic Encephalitis

Tezuka T., Takahashi N., Tokuyasu D., Azami S., Sekiguchi K., Takizawa T., Izawa Y., Nakahara J., Katsumata M.

Internal Medicine （一般社団法人日本内科学会） advpub （ 0 ） 1277 - 1280 2023年

ISSN 09182918

Cerebral venous thrombosis (CVT) is challenging to diagnose, as it presents with variable symptoms. We encountered a complicated case of CVT that mimicked limbic encephalitis due to sensory aphasia. Based on the characteristic magnetic resonance imaging findings, this 72-year-old Japanese man was later confirmed to have CVT, the cause of which was periodontitis due to Eikenella corrodens, a Gram-negative facultative anaerobic that is part of the mouth’s normal flora. The symptoms improved without sequelae following anticoagulation treatment and antibiotics. Clinicians should consider CVT as a differential diagnosis when unexplainable neurological symptoms suggesting limbic encephalitis are observed.

Metabolic and toxicological considerations regarding CGRP mAbs and CGRP antagonists to treat migraine in COVID-19 patients: a narrative review

Takizawa T., Ihara K., Uno S., Ohtani S., Watanabe N., Imai N., Nakahara J., Hori S., Garcia-Azorin D., Martelletti P.

Expert Opinion on Drug Metabolism and Toxicology （Expert Opinion on Drug Metabolism and Toxicology） 19 （ 12 ） 951 - 967 2023年

ISSN 17425255

Introduction: Migraine pharmacological therapies targeting calcitonin gene-related peptide (CGRP), including monoclonal antibodies and gepants, have shown clinical effect and optimal tolerability. Interactions between treatments of COVID-19 and CGRP-related drugs have not been reviewed. Areas covered: An overview of CGRP, a description of the characteristics of each CGRP-related drug and its response predictors, COVID-19 and its treatment, the interactions between CGRP-related drugs and COVID-19 treatment, COVID-19 and vaccination-induced headache, and the neurological consequences of Covid-19. Expert opinion: Clinicians should be careful about using gepants for COVID-19 patients, due to the potential drug interactions with drugs metabolized via CYP3A4 cytochrome. In particular, COVID-19 treatment (especially nirmatrelvir packaged with ritonavir, as Paxlovid) should be considered cautiously. It is advisable to stop or adjust the dose (10 mg atogepant when used for episodic migraine) of gepants when using Paxlovid (except for zavegepant). CGRP moncolconal antibodies (CGRP-mAbs) do not have drug–drug interactions, but a few days’ interval between a COVID-19 vaccination and the use of CGRP mAbs is recommended to allow the accurate identification of the possible adverse effects, such as injection site reaction. Covid-19- and vaccination-related headache are known to occur. Whether CGRP-related drugs would be of benefit in these circumstances is not yet known.

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特集令和の頭痛診療-プライマリ・ケア医のためのガイド頭痛診療Start-Up 頭痛患者の問診と身体診察のコツ

石鎚啓, 滝沢翼

medicina （株式会社医学書院） 59 （ 13 ） 2350 - 2353 2022年12月

ISSN 00257699

Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

Liu T.T., Morais A., Takizawa T., Mulder I., Simon B.J., Chen S.P., Wang S.J., Ayata C., Yen J.C.

Journal of Headache and Pain （Journal of Headache and Pain） 23 （ 1 ） 12 - 12 2022年12月

ISSN 11292369

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.

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Real-world evidence of galcanezumab for migraine treatment in Japan: a retrospective analysis

Takizawa T., Ohtani S., Watanabe N., Miyazaki N., Ishizuchi K., Sekiguchi K., Iba C., Shibata M., Takemura R., Hori S., Nakahara J.

BMC Neurology （BMC Neurology） 22 （ 1 ） 512 - 512 2022年12月

Objective: To evaluate the efficacy and safety of galcanezumab in patients with migraine in a real-world setting in Japan. Background: Galcanezumab is the first anti-calcitonin gene-related peptide monoclonal antibody approved in Japan. To the best of our knowledge, no real-world studies on galcanezumab have been published in any international journal from Japan. Methods: We retrospectively examined patients with migraine who received three doses of galcanezumab between August 2021 and February 2022 at the Keio University Hospital. We assessed changes in monthly migraine days, responder rate, and migraine-associated and premonitory symptoms. We also investigated injection site reactions and adverse events. Results: Fifty-two patients received three doses of galcanezumab during the study period. Compared with those at baseline, the monthly migraine days decreased by 5.9 days (95% confidence interval, 4.2–7.7) at 3 months. The 50% responder rate was 61.5% at 3 months. A total of 64.9%, 50.0%, and 63.9% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Premonitory symptoms without subsequent headache were reported in 62.5% of patients. Moreover, injection site reaction was the most common adverse event (34.6%). Conclusion: This study revealed the efficacy and safety of galcanezumab for migraineurs in Japan. Galcanezumab also improved migraine-associated symptoms. However, despite a reduction in headaches, premonitory symptoms without subsequent headache were reported in > 50% of the patients at 3 months.

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Effect of Goreisan, a Japanese Traditional Medicine, on Cortical Spreading Depolarization in Mice

Iba C., Unekawa M., Izawa Y., Nakahara J., Takizawa T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 23 （ 22 ） 2022年11月

ISSN 16616596

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.

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Immunodeficiency in patients with thymoma-associated myasthenia gravis

Ishizuchi K., Takizawa T., Ohnuki Y., Sekiguchi K., Motegi H., Oyama M., Nakahara J., Shiina T., Suzuki S.

Journal of Neuroimmunology （Journal of Neuroimmunology） 371 577950 - 577950 2022年10月

ISSN 01655728

Thymoma with immunodeficiency is sometimes accompanied by myasthenia gravis (MG), but the clinical characteristics have not been elucidated. This study aimed to characterize its clinical and immunological features. Of the 132 thymoma-associated MG patients, 9 patients presented with immunodeficiency. All suffered from severe pneumonia, and most had invasive thymoma and autoimmune disorders. DRB1*08:03 and DQB1*06:01 alleles were frequently detected. Compared to group without immunodeficiency, they showed no significant differences in the severity of MG, significantly lower IgG concentrations and higher mortality rate. Thymoma-associated MG with immunodeficiency is a distinct subset requiring special attention to prevent infection during the follow-up period.

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Anemia in female patients with myasthenia gravis

Sekiguchi K., Ishizuchi K., Takizawa T., Motegi H., Oyama M., Nakahara J., Suzuki S.

PLoS ONE （PLoS ONE） 17 （ 9 September ） e0273720 2022年09月

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.

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早朝頭痛を認めた片頭痛患者における閉塞性睡眠時無呼吸症候群の検討

関口耕史, 渡邊成美, 渡辺理沙, 臼田頌, 山澤稚子, 柴田護, 福永興壱, 中原仁, 滝沢翼

日本頭痛学会誌（(一社)日本頭痛学会） 48 （ 3 ） 566 - 570 2022年04月

ISSN 1345-6547

早朝に頭痛が集中している片頭痛患者を臨床において経験することがある.慶應義塾大学病院神経内科頭痛外来を通院している片頭痛患者のうち,頭痛ダイアリーや問診上,早朝頭痛が目立った8例について,特徴および閉塞性睡眠時無呼吸症候群(OSAS)との関連を検討した.8例中7例においてOSAS(6例が軽症,1例が中等症)を認めた.Apnea hypopnea indexと頭痛が早朝に生じる割合には正の相関傾向を示していた.OSASは片頭痛増悪因子となっている可能性もあり,早朝頭痛を認める片頭痛患者でOSAS合併例に対しての治療は今後の研究課題である.(著者抄録)

Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study

Sekiguchi K., Watanabe N., Miyazaki N., Ishizuchi K., Iba C., Tagashira Y., Uno S., Shibata M., Hasegawa N., Takemura R., Nakahara J., Takizawa T.

Cephalalgia （Cephalalgia） 42 （ 3 ） 266 - 272 2022年03月

ISSN 03331024

Background: Headache is an adverse event of coronavirus 2019 (COVID-19) vaccination. Whether patients with history of headache suffer more from vaccination-induced headaches is unknown. We aimed to uncover if headache patients develop more headaches after COVID-19 mRNA vaccination than healthy controls. Methods: We performed a questionnaire survey for nursing staff in our hospital from April to May 2021. Based on baseline characteristics, we divided the participants into migraine, non-migrainous headache, and healthy control, and examined the occurrence and features of headache after COVID-19 vaccinations. Results: We included 171 participants (15.2% migraine and 24.6% non-migrainous headache). Headache incidence after vaccinations was significantly higher in the migraine (69.2%) and non-migrainous headache (71.4%) groups than in the healthy control (37.9%) group. The incidence of headaches was significantly higher after the second dose compared to the first (45.6% vs. 20.5%). Conclusion: Migraineurs and non-migrainous headache participants developed more headaches compared to the healthy controls after COVID-19 vaccination.

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大学での教育（卒後教育を中心に）

滝沢翼

日本頭痛学会誌（一般社団法人日本頭痛学会） 48 （ 3 ） 506 - 508 2022年

ISSN 13456547

頭痛が視野障害より2ヵ月先行した視神経脊髄炎関連疾患の1例

砂金瑛実, 石鎚啓, 滝沢翼, 藤原広和, 伊澤良兼, 中原仁

臨床神経学（(一社)日本神経学会） 61 （ 11 ） 722 - 726 2021年11月

ISSN 0009-918X

症例は50代女性で,2ヵ月前より持続する右上眼瞼周囲の頭痛のため受診となった.頭部MRI T2強調画像で脳梁,両側放線冠に多発性の高信号病変を認めた.自己免疫疾患を考えステロイドパルス療法を施行したが,右眼に下方水平性半盲と対光反射減弱が出現した.眼窩MRIのT2強調画像で右視神経腫大,視神経上半側の高信号,ガドリニウム造影増強効果を認め,抗AQP4抗体陽性と併せ視神経脊髄炎関連疾患(neuromyelitis opticaspectrum disorders,以下NMOSDと略記)と診断した.NMOSDの初発症状として頭痛がみられることがあるので,鑑別の際に念頭に置く必要がある.(著者抄録)

特集頭痛診療の基本から最新の知見まで最近の話題　片頭痛の最新の知見

滝沢翼, 伊庭知里

小児科診療（(株)診断と治療社） 84 （ 10 ） 1357 - 1362 2021年10月

ISSN 03869806

特集片頭痛　病態の理解と薬物療法の最前線片頭痛薬物療法の新たな潮流!新薬の最新エビデンス　抗CGRP抗体・抗CGRP受容体抗体

滝沢翼, 鈴木則宏

薬局（(株)南山堂） 72 （ 8 ） 2791 - 2797 2021年07月

ISSN 00440035

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Fischer P., Sugimoto K., Chung D.Y., Tamim I., Morais A., Takizawa T., Qin T., Gomez C.A., Schlunk F., Endres M., Yaseen M.A., Sakadzic S., Ayata C.

Journal of Cerebral Blood Flow and Metabolism （Journal of Cerebral Blood Flow and Metabolism） 41 （ 6 ） 1264 - 1276 2021年06月

ISSN 0271678X

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

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Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior

Harriott A.M., Chung D.Y., Uner A., Bozdayi R.O., Morais A., Takizawa T., Qin T., Ayata C.

Annals of Neurology （Annals of Neurology） 89 （ 1 ） 99 - 110 2021年01月

ISSN 03645134

Objective: Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. Methods: Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice. Results: A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point. Interpretation: Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99–110.

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Painless thyroiditis presenting with headache

Takizawa T., Kurihara I., Suzuki N., Nakahara J., Shibata M.

Internal Medicine （Internal Medicine） 60 （ 16 ） 2693 - 2696 2021年

ISSN 09182918

Although headache attributed to hypothyroidism is coded within The International Classification of Headache Disorders, 3rd edition, an association between headache and thyrotoxicosis (hyperthyroidism) is mentioned only in the appendix. Reports on relevant cases are too scarce to establish a causal relationship. A young man with a history of migraine with aura arrived at our headache clinic with a 10-day history of headache and weight loss. Brain MRI revealed normal findings. Blood tests revealed thyrotoxicosis. A test for thyroid-related antibodies was negative. Thus, the patient was diagnosed with painless thyroiditis. The patient's headache resolved as his thyroid hormone levels decreased. To the best of our knowledge, this is the first reported case of headache exaggerated by painless thyrotoxicosis.

A case of neuromyelitis optica spectrum disorder in which headache preceded visual field disturbances by 2 months

Isago E., Ishizuchi K., Takizawa T., Fujiwara H., Izawa Y., Nakahara J.

Clinical Neurology （Clinical Neurology） 61 （ 11 ） 722 - 726 2021年

ISSN 0009918X

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.

[123I]-IMP single-photon emission computed tomography imaging in visual snow syndrome: A case series.

Mamoru Shibata, Kei Tsutsumi, Yu Iwabuchi, Masashi Kameyama, Tsubasa Takizawa, Tadaki Nakahara, Hirokazu Fujiwara, Masahiro Jinzaki, Jin Nakahara, David W Dodick

Cephalalgia : an international journal of headache 40 （ 14 ） 1671 - 1675 2020年12月

BACKGROUND: Visual snow syndrome (VSS) is a neurological condition characterized by persistent flickering dots in the visual fields, palinopsia, enhanced entoptic phenomenon, photophobia, and nyctalopia. Neuroimaging evidence supports the role of the visual association cortex in visual snow syndrome.Case series: We provided clinical care to three patients with visual snow syndrome, in whom [123I]-IMP single-photon emission computed tomography (SPECT) imaging was performed. Case 1 was a 21-year-old male with a past history of migraine with aura who exhibited visual snow and entoptic phenomenon. In this patient, [123I]-IMP SPECT imaging revealed right occipital and temporal hypoperfusion with a distribution matching the ventral visual stream. [123I]-IMP SPECT imaging detected only mild bilateral frontal hypoperfusion in Case 2 and no overt abnormalities in Case 3. CONCLUSION: Although visual snow syndrome seems to be a heterogenous condition, our observations indicate that abnormal visual processing within the ventral visual stream may play a role in the pathogenesis of this condition.

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Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

Takeshi Yanagisawa, Hua Zhang, Tomoaki Suzuki, Yoshinobu Kamio, Tsubasa Takizawa, Andreia Morais, David Y Chung, Tao Qin, Yuichi Murayama, James E Faber, Aman B Patel, Cenk Ayata

Stroke 51 （ 10 ） 3083 - 3094 2020年10月

BACKGROUND AND PURPOSE: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. RESULTS: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. CONCLUSIONS: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

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Cluster headache in Asian populations: Similarities, disparities, and a narrative review of the mechanisms of the chronic subtype.

Kuan-Po Peng, Tsubasa Takizawa, Mi Ji Lee

Cephalalgia : an international journal of headache 40 （ 10 ） 1104 - 1112 2020年09月

OBJECTIVE: Headache disorders like migraine show geographic and ethnic differences between Asian and European/North American countries. In cluster headache, these differences are rarely mentioned and discussed. This article aimed to review the characteristics of cluster headache in Asian countries and compare the clinical features to those in European and North American populations. METHODS: We conducted a narrative literature review on the demographics, clinical presentations, and treatments of cluster headache in Asian countries. RESULTS: Patients with cluster headache in Asian populations showed a stronger male predominance compared to European and North American populations. Chronic cluster headache was rare in Asian countries. The clinical presentation of restlessness was not as common in Asian as it was in European and North American countries, and Asian patients with aura were extremely rare. Patients in Asian countries may have a lower circadian rhythmicity of cluster headache and a lower headache load, as demonstrated by lower attack frequencies per day, bout frequencies, and bout durations. CONCLUSIONS: Regional differences in the presentation of cluster headache exist. Greater awareness for cluster headache should be raised in Asian regions, and further studies are warranted to elucidate the mechanisms behind observed differences.

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Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations.

Kazutaka Sugimoto, David Y Chung, Maximilian Böhm, Paul Fischer, Tsubasa Takizawa, Sanem Aslihan Aykan, Tao Qin, Takeshi Yanagisawa, Andrea Harriott, Fumiaki Oka, Mohammad A Yaseen, Sava Sakadžić, Cenk Ayata

Stroke 51 （ 8 ） 2526 - 2535 2020年08月

BACKGROUND AND PURPOSE: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. METHODS: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. RESULTS: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P=0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. CONCLUSIONS: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.

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Cortical spreading depolarisation-induced facial hyperalgesia, photophobia and hypomotility are ameliorated by sumatriptan and olcegepant.

Chunhua Tang, Miyuki Unekawa, Satoshi Kitagawa, Tsubasa Takizawa, Yohei Kayama, Jin Nakahara, Mamoru Shibata

Scientific reports 10 （ 1 ） 11408 - 11408 2020年07月

Cortical spreading depolarisation (CSD), the neural mechanism underlying migraine aura, may cause headache by sensitising the trigeminal system. Photophobia, the most bothersome accompanying symptom during migraine attacks, is more prevalent in migraine with aura than in migraine without aura. Whether CSD plays a role in developing photophobia remains unknown. Moreover, migraine-induced physical hypoactivity contributes to loss of productivity. We aimed to investigate the development of trigeminal sensitisation, photophobia and locomotive abnormality after KCl-induced CSD using 86 male C57BL/6 mice. Sham-operated mice were used as controls. We confirmed the presence of trigeminal sensitisation and photophobia at 24 h after CSD. CSD-subjected mice also exhibited significantly reduced locomotive activity in both light and dark zones. Hence, the CSD-induced hypomobility was likely to be independent of photophobia. The 5-HT1B/1D agonist, sumatriptan, corrected all these CSD-induced abnormalities. Moreover, dose dependency was demonstrated in the ameliorating effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, olcegepant, on these abnormalities. Sumatriptan and olcegepant improved mouse locomotion with therapeutic lags ranging from 20 to 30 min. Collectively, CSD caused trigeminal sensitisation, photophobia and hypomobility that persisted for at least 24 h by a mechanism involving the 5-HT1B/1D and CGRP activity.

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Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.

Tsubasa Takizawa, Tao Qin, Andreia Lopes de Morais, Kazutaka Sugimoto, Joon Yong Chung, Liza Morsett, Inge Mulder, Paul Fischer, Tomoaki Suzuki, Maryam Anzabi, Maximilian Böhm, Wen-Sheng Qu, Takeshi Yanagisawa, Suzanne Hickman, Joseph El Khoury, Michael J Whalen, Andrea M Harriott, David Y Chung, Cenk Ayata

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 （ 5 ） 1117 - 1131 2020年05月

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.

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Neurovascular coupling during optogenetic functional activation: Local and remote stimulus-response characteristics, and uncoupling by spreading depression.

Maximilian Böhm, David Y Chung, Carlos A Gómez, Tao Qin, Tsubasa Takizawa, Homa Sadeghian, Kazutaka Sugimoto, Sava Sakadžić, Mohammad A Yaseen, Cenk Ayata

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 （ 4 ） 808 - 822 2020年04月

Neurovascular coupling is a fundamental response that links activity to perfusion. Traditional paradigms of neurovascular coupling utilize somatosensory stimulation to activate the primary sensory cortex through subcortical relays. Therefore, examination of neurovascular coupling in disease models can be confounded if the disease process affects these multisynaptic pathways. Optogenetic stimulation is an alternative to directly activate neurons, bypassing the subcortical relays. We employed minimally invasive optogenetic cortical activation through intact skull in Thy1-channelrhodopsin-2 transgenic mice, examined the blood flow changes using laser speckle imaging, and related these to evoked electrophysiological activity. Our data show that optogenetic activation of barrel cortex triggers intensity- and frequency-dependent hyperemia both locally within the barrel cortex (>50% CBF increase), and remotely within the ipsilateral motor cortex (>30% CBF increase). Intriguingly, activation of the barrel cortex causes a small (∼10%) but reproducible hypoperfusion within the contralateral barrel cortex, electrophysiologically linked to transhemispheric inhibition. Cortical spreading depression, known to cause neurovascular uncoupling, diminishes optogenetic hyperemia by more than 50% for up to an hour despite rapid recovery of evoked electrophysiological activity, recapitulating a unique feature of physiological neurovascular coupling. Altogether, these data establish a minimally invasive paradigm to investigate neurovascular coupling for longitudinal characterization of cerebrovascular pathologies.

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Resilience to capsaicin-induced mitochondrial damage in trigeminal ganglion neurons.

Mamoru Shibata, Yohei Kayama, Tsubasa Takizawa, Keiji Ibata, Toshihiko Shimizu, Michisuke Yuzaki, Norihiro Suzuki, Jin Nakahara

Molecular pain 16 1744806920960856 - 1744806920960856 2020年

Capsaicin is an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). Strong TRPV1 stimulation with capsaicin causes mitochondrial damage in primary sensory neurons. However, the effect of repetitive and moderate exposure to capsaicin on the integrity of neuronal mitochondria remains largely unknown. Our electron microscopic analysis revealed that repetitive stimulation of the facial skin of mice with 10 mM capsaicin induced short-term damage to the mitochondria in small-sized trigeminal ganglion neurons. Further, capsaicin-treated mice exhibited decreased sensitivity to noxious heat stimulation, indicating TRPV1 dysfunction, in parallel with the mitochondrial damage in the trigeminal ganglion neurons. To analyze the capsaicin-induced mitochondrial damage and its relevant cellular events in detail, we performed cell-based assays using TRPV1-expressing PC12 cells. Dose-dependent capsaicin-mediated mitochondrial toxicity was observed. High doses of capsaicin caused rapid destruction of mitochondrial internal structure, while low doses induced mitochondrial swelling. Further, capsaicin induced a dose-dependent loss of mitochondria and autophagy-mediated degradation of mitochondria (mitophagy). Concomitantly, transcriptional upregulation of mitochondrial proteins, cytochrome c oxidase subunit IV, Mic60/Mitofilin, and voltage-dependent anion channel 1 was observed, which implied induction of mitochondrial biogenesis to compensate for the loss of mitochondria. Collectively, although trigeminal ganglion neurons transiently exhibit mitochondrial damage and TRPV1 dysfunction following moderate capsaicin exposure, they appear to be resilient to such a challenge. Our in vitro data show a dose-response relationship in capsaicin-mediated mitochondrial toxicity. We postulate that induction of mitophagy and mitochondrial biogenesis in response to capsaicin stimulation play important roles in repairing the damaged mitochondrial system.

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Therapeutic implications of cortical spreading depression models in migraine.

Tsubasa Takizawa, Cenk Ayata, Shih-Pin Chen

Progress in brain research 255 29 - 67 2020年

Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.

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Effects of olcegepant and sumatriptan on locomotive activity after cortical spreading depolarization in mice

Mamoru Shibata, Chunhua Tang, Miyuki Unekawa, Satoshi Kitagawa, Tsubasa Takizawa, Yohei Kayama, Jin Nakahara

CEPHALALGIA （SAGE PUBLICATIONS LTD） 39 144 - 145 2019年09月

査読有り, ISSN 0333-1024

Spreading depression as a preclinical model of migraine.

Andrea M Harriott, Tsubasa Takizawa, David Y Chung, Shih-Pin Chen

The journal of headache and pain 20 （ 1 ） 45 - 45 2019年05月

Spreading depression (SD) is a slowly propagating wave of near-complete depolarization of neurons and glial cells across the cortex. SD is thought to contribute to the underlying pathophysiology of migraine aura, and possibly also an intrinsic brain activity causing migraine headache. Experimental models of SD have recapitulated multiple migraine-related phenomena and are considered highly translational. In this review, we summarize conventional and novel methods to trigger SD, with specific focus on optogenetic methods. We outline physiological triggers that might affect SD susceptibility, review a multitude of physiological, biochemical, and behavioral consequences of SD, and elaborate their relevance to migraine pathophysiology. The possibility of constructing a recurrent episodic or chronic migraine model using SD is also discussed.

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Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice.

Tomoaki Suzuki, Tsubasa Takizawa, Yoshinobu Kamio, Tao Qin, Tomoki Hashimoto, Yukihiko Fujii, Yuichi Murayama, Aman B Patel, Cenk Ayata

Stroke 50 （ 5 ） 1216 - 1223 2019年05月

Background and Purpose- Inflammation is a critical determinant of aneurysmal wall destabilization, growth, and rupture risk. Targeting inflammation may suppress aneurysm rupture. Vagus nerve stimulation (VNS) has been shown to suppress inflammation both systemically and in the central nervous system. Therefore, we tested the effect of a novel noninvasive transcutaneous VNS approach on aneurysm rupture and outcome in a mouse model of intracranial aneurysm formation with wall inflammation. Methods- Aneurysms were induced by a single stereotaxic injection of elastase into the cerebrospinal fluid at the skull base, combined with systemic deoxycorticosterone-salt hypertension, without or with high-salt diet, for mild or severe outcomes, respectively. Cervical VNS (two 2-minute stimulations 5 minutes apart) was delivered once a day starting from the day after elastase injection for the duration of follow-up. Transcutaneous stimulation of the femoral nerve (FNS) served as control. Multiple aneurysms developed in the circle of Willis and its major branches, resulting in spontaneous ruptures and subarachnoid hemorrhage, neurological deficits, and mortality. Results- In the milder model, VNS significantly reduced aneurysm rupture rate compared with FNS (29% versus 80%, respectively). Subarachnoid hemorrhage grades were also lower in the VNS group. In the more severe model, both VNS and FNS arms developed very high rupture rates (77% and 85%, respectively). However, VNS significantly improved the survival rate compared with FNS after rupture (median survival 13 versus 6 days, respectively), without diminishing the subarachnoid hemorrhage grades. Chronic daily VNS reduced MMP-9 (matrix metalloproteinase-9) expression compared with FNS, providing a potential mechanism of action. As an important control, chronic daily VNS did not alter systemic arterial blood pressure compared with FNS. Conclusions- VNS can reduce aneurysm rupture rates and improve the outcome from ruptured aneurysms.

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Real-time non-invasive in vivo visible light detection of cortical spreading depolarizations in mice.

David Y Chung, Kazutaka Sugimoto, Paul Fischer, Maximilian Böhm, Tsubasa Takizawa, Homa Sadeghian, Andreia Morais, Andrea Harriott, Fumiaki Oka, Tao Qin, Nils Henninger, Mohammad A Yaseen, Sava Sakadžić, Cenk Ayata

Journal of neuroscience methods 309 143 - 146 2018年11月

BACKGROUND: Cortical spreading depolarization (CSD) is a phenomenon classically associated with migraine aura. CSDs have also been implicated in secondary injury following ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury; however, most investigations involving these disease processes do not account for the occurrence of CSDs. A major barrier to detection of CSDs in experimental models is that currently validated methods are invasive and require specialized equipment and a high level of expertise to implement. NEW METHOD: We present a low-cost, easy-to-implement approach to the detection of CSDs in the mouse through full-thickness intact skull. Our method uses the optical intrinsic signal from white light illumination (OIS-WL) and allows for real-time in vivo detection of CSDs using readily available USB cameras. RESULTS: OIS-WL detected 100% of CSDs that were seen with simultaneous electrode recording (69 CSDs in 28 mice), laser Doppler flowmetry (82 CSDs in 10 mice), laser speckle flowmetry (68 CSDs in 25 mice), or combined electrode recording plus laser speckle flowmetry (29 CSDs in 20 mice). OIS-WL detected 1 additional CSD that was missed by laser Doppler flowmetry. COMPARISON WITH EXISTING METHODS: OIS-WL is less invasive than electrophysiological recordings and easier to implement than laser speckle flowmetry. Moreover, it provides excellent spatial and temporal resolution for dynamic imaging of CSDs in the setting of brain injury. CONCLUSIONS: Detection of CSDs with an inexpensive USB camera and white light source provides a reliable method for the in vivo and non-invasive detection of CSDs through unaltered mouse skull.

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Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis.

Homa Sadeghian, Baptiste Lacoste, Tao Qin, Xavier Toussay, Roberto Rosa, Fumiaki Oka, David Y Chung, Tsubasa Takizawa, Chenghua Gu, Cenk Ayata

Annals of neurology 84 （ 3 ） 409 - 423 2018年09月

OBJECTIVE: Cortical spreading depolarizations (CSDs) are intense and ubiquitous depolarization waves relevant for the pathophysiology of migraine and brain injury. CSDs disrupt the blood-brain barrier (BBB), but the mechanisms are unknown. METHODS: A total of six CSDs were evoked over 1 hour by topical application of 300 mM of KCl or optogenetically with 470 nm (blue) LED over the right hemisphere in anesthetized mice (C57BL/6 J wild type, Thy1-ChR2-YFP line 18, and cav-1-/- ). BBB disruption was assessed by Evans blue (2% EB, 3 ml/kg, intra-arterial) or dextran (200 mg/kg, fluorescein, 70,000 MW, intra-arterial) extravasation in parietotemporal cortex at 3 to 24 hours after CSD. Endothelial cell ultrastructure was examined using transmission electron microscopy 0 to 24 hours after the same CSD protocol in order to assess vesicular trafficking, endothelial tight junctions, and pericyte integrity. Mice were treated with vehicle, isoform nonselective rho-associated kinase (ROCK) inhibitor fasudil (10 mg/kg, intraperitoneally 30 minutes before CSD), or ROCK-2 selective inhibitor KD025 (200 mg/kg, per oral twice-daily for 5 doses before CSD). RESULTS: We show that CSD-induced BBB opening to water and large molecules is mediated by increased endothelial transcytosis starting between 3 and 6 hours and lasting approximately 24 hours. Endothelial tight junctions, pericytes, and basement membrane remain preserved after CSDs. Moreover, we show that CSD-induced BBB disruption is exclusively caveolin-1-dependent and requires rho-kinase 2 activity. Importantly, hyperoxia failed to prevent CSD-induced BBB breakdown, suggesting that the latter is independent of tissue hypoxia. INTERPRETATION: Our data elucidate the mechanisms by which CSDs lead to transient BBB disruption, with diagnostic and therapeutic implications for migraine and brain injury.

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Low-signal Intensity Rims along the Cerebral Cortex and U-fibers on Susceptibility-weighted Imaging in Progressive Multifocal Leukoencephalopathy.

Yuki Arita, Hirokazu Fujiwara, Jun Kurasawa, Suketaka Momoshima, Tsubasa Takizawa, Masahiro Jinzaki

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 17 （ 2 ） 109 - 110 2018年04月

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Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology.

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Keiji Ibata, Toshihiko Shimizu, Taeko Ebine, Haruki Toriumi, Michisuke Yuzaki, Norihiro Suzuki

Cephalalgia : an international journal of headache 38 （ 5 ） 833 - 845 2018年04月

Background Recent genome-wide association studies have identified transient receptor potential M8 ( TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.

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Serial changes of corticospinal tract hyperintensity on magnetic resonance imaging from the preclinical stage in amyotrophic lateral sclerosis

Tsubasa Takizawa, Gen Shiihashi, Junki Maehara, Koichi Oki, Mayuko Osaka, Hirokazu Fujiwara, Hidenori Ojima, Yuichi Ichinose, Mamoru Shibata, Shinichi Takahashi, Norihiro Suzuki

NEUROLOGY AND CLINICAL NEUROSCIENCE （WILEY） 6 （ 1 ） 29 - 30 2018年01月

査読有り, ISSN 2049-4173

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Signaling Pathways Relevant to Nerve Growth Factor-induced Upregulation of Transient Receptor Potential M8 Expression.

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Keiji Ibata, Jin Nakahara, Toshihiko Shimizu, Haruki Toriumi, Michisuke Yuzaki, Norihiro Suzuki

Neuroscience 367 178 - 188 2017年12月

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that primarily detects the innocuous cold. In pathological conditions, TRPM8 plays a role in the development of cold hyperalgesia/allodynia. Nerve growth factor (NGF) is an important mediator involved in various pain disorders. In the present study, the NGF-TrkA pathway increased TRPM8 expression by stabilizing TRPM8 mRNA through the actions of phosphatidylinositol 3-kinase and p38 MAP kinase. Moreover, c-Jun N-terminal kinase and Src tyrosine kinase were identified as a positive and negative regulator of TRPM8 expression, respectively, via post-transcriptional mechanisms independent of mRNA stabilization. PTEN activity was found to increase protein TRPM8 expression. Calcium imaging confirmed that NGF induced TRPM8 functional upregulation. Time-lapse fluorescence microscopic analysis and a cell fractionation assay revealed that NGF promoted the trafficking of TRPM8 to the plasma membrane. In the presence of NGF, lysosome-associated membrane protein-2 (LAMP-2) was localized to TRPM8-positive dot-like and linear structures, the latter of which were observed in the periphery of the cytoplasm. It was inferred that LAMP-2 was involved in the vesicular transport of TRPM8. Pharmacological blockade of the proteasome with MG132 led to a further increase in NGF-induced TRPM8 expression, indicating that the proteasome system played a pivotal role in the degradation of TRPM8. Our findings provide novel insight into the signaling pathways involved in NGF-mediated TRPM8 upregulation and its reversion to the normal state.

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New onset of myasthenia gravis after intravesical Bacillus Calmette-Guerin: A case report and literature review.

Tsubasa Takizawa, Marenori Kojima, Shigeaki Suzuki, Takashi Osada, Satoshi Kitagawa, Jin Nakahara, Shinichi Takahashi, Norihiro Suzuki

Medicine 96 （ 46 ） e8757 2017年11月

RATIONALE: Recently, drug-related myasthenia gravis (MG) has received attention, because the number of reported cases involving MG associated with immune checkpoint inhibitors, a new immunotherapy, is increasing. We present a case involving the new onset of MG, in which the symptoms started shortly after intravesical Bacillus Calmette-Guerin (BCG) for bladder cancer. PATIENT CONCERNS: A 69-year-old male with bladder cancer developed ptosis and diplopia 4 days after the completion of a treatment regimen with intravesical BCG weekly for 6 weeks. DIAGNOSES: Ocular MG was confirmed by a positive serum anti-acetylcholine receptor antibody test. INTERVENTIONS: Treatment with high-dose methylprednisolone pulse therapy was given, after insufficient treatment with pyridostigmine bromide and 10 mg/d prednisolone. OUTCOMES: Symptoms resolved completely 12 days after high-dose methylprednisolone pulse therapy. LESSONS: Intravesical BCG could be listed as a novel drug that may induce a new onset of MG along with drugs such as D-penicillamine and immune checkpoint inhibitors.

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Possible Involvement of Hypotension in Postprandial Headache: A Case Series.

Tsubasa Takizawa, Mamoru Shibata, Takahiro Hiraide, Morinobu Seki, Shinichi Takahashi, Norihiro Suzuki

Headache 57 （ 9 ） 1443 - 1448 2017年10月

BACKGROUND: It is commonly known that headaches are induced by intake of specific food, drink, and/or additive. In addition, some patients experience postprandial headache independent of ingestion of specific items. Currently, information on the pathophysiology underlying this particular type of headache is scarce. CASE REPORTS: We report two cases in which headaches were observed after each meal. Postprandial hypotension was demonstrated in both cases. Tonometry-based continuous blood pressure measurement during head-up tilt revealed sympathetic dysfunction. In one patient, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy detected cardiac sympathetic denervation, and diagnosis of pure autonomic failure was made. In both cases, treatment of postprandial hypotension was effective in relieving postprandial headache. DISCUSSION: The possibility of postprandial hypotension should be explored in patients with headache that occurs after meal. To this end, tonometry-based blood pressure measurement and MIBG myocardial scintigraphy may be useful diagnostic investigations. Treating postprandial hypotension may be effective in alleviating the symptoms.

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Facial TRPM8 stimulation ameliorates thermal hyperalgesia in a mouse migraine model

Yohei Kayama, Mamoru Shibata, Tsubasa Takizawa, Toshihiko Shimizu, Haruki Toriumi, Taeko Ebine, Norihiro Suzuki

CEPHALALGIA （SAGE PUBLICATIONS LTD） 37 294 - 294 2017年09月

査読有り, ISSN 0333-1024

High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression.

Tsubasa Takizawa, Mamoru Shibata, Yohei Kayama, Toshihiko Shimizu, Haruki Toriumi, Taeko Ebine, Miyuki Unekawa, Anri Koh, Akihiko Yoshimura, Norihiro Suzuki

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 37 （ 3 ） 890 - 901 2017年03月

Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1-TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

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Alterations in the threshold of the potassium concentration to evoke cortical spreading depression during the natural estrous cycle in mice.

Taeko Ebine, Haruki Toriumi, Toshihiko Shimizu, Miyuki Unekawa, Tsubasa Takizawa, Yohei Kayama, Mamoru Shibata, Norihiro Suzuki

Neuroscience research 112 57 - 62 2016年11月

Cortical spreading depression (CSD) has been implicated in a variety of neurological disorders. However, the relationship between serum sex hormones and susceptibility to the development of CSD in naturally estrous cycling female animals is largely unknown. The natural estrous cycle of mice consists of four stages, namely, proestrus, estrus, metestrus and diestrus. We measured the serum concentration of estradiol and progesterone in estrus and diestrus and compared the minimum potassium concentrations necessary to evoke CSD in each stage and in males. In diestrus, the minimum potassium concentration required to evoke CSD was significantly lower compared to the other three phases and male animals. The serum level of estradiol is significantly higher and serum level of progesterone is significantly lower in diestrus compared to estrus. Furthermore, when we administered an estrogen receptor antagonist, the susceptibility to the development of CSD was decreased. Conversely, the administration of a progesterone receptor antagonist increased the susceptibility to CSD. Our results demonstrated that neuronal excitability related to CSD induction differs among the natural estrous phases in mice.

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Repetitive trigeminal nociceptive stimulation in rats increases their susceptibility to cortical spreading depression.

Haruki Toriumi, Toshihiko Shimizu, Taeko Ebine, Tsubasa Takizawa, Yohei Kayama, Anri Koh, Mamoru Shibata, Norihiro Suzuki

Neuroscience research 106 74 - 8 2016年05月

We examined the ability of trigeminal nerve activation to induce cortical spreading depression in rats. Capsaicin was injected into the bilateral plantar or whisker pad for either 4 or 6 days in rats. The number and duration of cortical spreading depressions induced by potassium were significantly increased in animals injected with capsaicin in the bilateral whisker pad compared with animals injected in the bilateral plantar or in controls, while administration of a GABAA receptor agonist decreased these effects. Repetitive nociceptive stimulation of the trigeminal nerve lowers the threshold for the induction of cortical spreading depression by altering GABAergic neuronal activity.

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Adult-onset recurrent painful ophthalmoplegic neuropathy displaying atypical oculomotor nerve gadolinium-enhancement pattern in the orbit and cavernous sinus.

Tsubasa Takizawa, Mamoru Shibata, Hirokazu Fujiwara, Toshihiko Shimizu, Suketaka Momoshima, Norihiro Suzuki

Cephalalgia : an international journal of headache 36 （ 2 ） 199 - 200 2016年02月

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Temporal profiles of high-mobility group box 1 expression levels after cortical spreading depression in mice.

Tsubasa Takizawa, Mamoru Shibata, Yohei Kayama, Haruki Toriumi, Taeko Ebine, Anri Koh, Toshihiko Shimizu, Norihiro Suzuki

Cephalalgia : an international journal of headache 36 （ 1 ） 44 - 52 2016年01月

INTRODUCTION: Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes. METHODS: Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining. RESULTS: Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, the high-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes. CONCLUSION: Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.

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When do we judge IVIg for myasthenia gravis ineffective?

Tsubasa Takizawa, Shigeaki Suzuki, Norihiro Suzuki

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 36 （ 7 ） 1295 - 7 2015年07月

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Lowering barometric pressure induces c-Fos expression in neurons of rat vestibular nucleus

Megumi Funakubo, Toshihiko Shimizu, Mamoru Shibata, Tatsuo Iwashita, Haruki Toriumi, Taeko Ebine, Youhei Kayama, Tsubasa Takizawa, Jun Sato, Norihiro Suzuki

JOURNAL OF PHYSIOLOGICAL SCIENCES （SPRINGER JAPAN KK） 63 S155 - S155 2013年

ISSN 1880-6546

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