研究者詳細 - 滝沢　翼

論文 - 滝沢　翼

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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

<p>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．</p>

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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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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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

<p> 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．</p>

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

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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