Published papers

INTRODUCTION: Despite the availability of effective treatments, some patients with migraine in Japan do not receive appropriate medical management and treatment for migraine, potentially due to the lack of effective patient-doctor communication. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan)] 2nd study described the current state and challenges of patient-doctor communication in migraine treatment in Japan. METHODS: This analysis included adults with migraine who consulted doctors for headaches/migraine and reported details of their first consultation: their experiences with doctors regarding migraine diagnosis and treatments, migraine-related topics, and treatment goals discussed, and challenges in communication. RESULTS: Among the 6762 included respondents, 55.1% (3729/6762) consulted a general practitioner (GP) first for headaches. Of the 3192 respondents diagnosed with migraine and reported the diagnosing doctor's specialty (as GP, specialist, or non-headache specialist), specialists (64.0%; 2044/3192), followed by GPs (31.4%; 1001/3192), mostly commonly diagnosed migraine. In the first consultation, doctors told 48.0% (3249/6762) of respondents they had migraine. In the past year, 3854 respondents discussed migraine-related topics with doctors; most commonly, the use and effectiveness of prescription drugs, and headache symptoms, severity, and frequency [48.9% (1885/3854) to 67.8% (2612/3854)]. Specialists most commonly discussed migraine-related topics with respondents, but non-headache specialists, i.e., obstetricians and gynecologists, most commonly discussed menstrual-related migraine. A total of 1978 respondents had migraine-related topics they wanted to but could not discuss with doctors in the past year. Among them, 32.9% (651/1978) of respondents did not discuss the topics because the doctor did not ask. Although 96.6% (3724/3854) of respondents had treatment goals in mind, 36.0% (1388/3854) never discussed it with doctors. CONCLUSION: Open and considerate patient-doctor communication and appropriate medical judgment are needed for timely and adequate medical management of migraine. Training doctors in effective communication techniques and considering a migraine diagnosis during consultations may be associated with better patient outcomes.

INTRODUCTION: Understanding real-world calcitonin gene-related peptide monoclonal antibodies' (CGRP mAbs) use in patients with migraine is necessary to potentially guide treatment strategies. METHODS: This retrospective cohort study analyzed administrative claims data from the IQVIA claims data for Japan. It included CGRP mAb-naïve individuals with confirmed migraine diagnosis and ≥ 1 CGRP mAb prescription (January 2021-June 2023). Index date was the first CGRP mAb prescription. Patient characteristics, treatment patterns, adherence (proportion of days covered ≥ 0.80), persistence, and migraine-related direct costs were assessed. Persistence was measured as the proportion of patients continuing treatment for ≥ 3 or ≥ 6 months (≤ 90-day gap between fills). Factors predicting adherence to CGRP mAb treatment were assessed using multivariate logistic regression. Subgroup analyses were conducted for galcanezumab users. RESULTS: Of the 1781 patients included (mean age 41.8 years [standard deviation, SD 10.3]; 79.3% female patients), 55.0% received galcanezumab, followed by fremanezumab (29.7%), and erenumab (15.3%). The prescription rates of concomitant acute and oral preventive medications were 86.1% and 51.3%, respectively, in the first 3 months after initiating CGRP mAb treatment but numerically decreased to 49.8% and 22.5%, respectively, in the fourth to sixth month. The index CGRP mAb persistence rates were 91.9% for ≥ 3 months and 76.9% for ≥ 6 months, and adherence rate was 51.7%. Multiple positive and negative predictors of adherence to CGRP mAbs were observed. Index to 3 months after initiating index CGRP mAbs, the median average monthly migraine-related costs were JPY 75,320 (Q1, Q3 61,593, 89,843) (USD 592), and non-CGRP mAb migraine-related costs were JPY 15,702 (Q1, Q3 8845, 27,848) (USD 123). These costs tended to reduce or plateau for up to 12 months thereafter. The galcanezumab subgroup showed a similar trend. CONCLUSIONS: CGRP mAb adherence and ≥ 6 months persistence rates were 51.7% and 76.9%, respectively, in CGRP mAb-initiating adults with migraine in Japan. During CGRP mAb treatment, acute and oral preventive medication prescription rates appeared to reduce, while direct costs initially increased but appeared to reduce from the post-initiation peak and plateau over time, although the underlying reasons could not be determined from claims data.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 hours later. RESULTS: Optogenetic stimulation of the penumbra was associated with more than 2-fold larger infarcts than stimulation of the contralateral homotopic region and the sham stimulation group (n=10, 7, and 9; 11.0±5.6 versus 5.1±4.3 versus 4.1±3.7 mm3; P=0.008, 1-way ANOVA). Identical stimulation in wild-type mice that do not express channelrhodopsin-2 did not have an effect. Optogenetic stimulation was associated with a small increase in penumbral perfusion that did not explain enlarged infarcts. CONCLUSIONS: Our data suggest that increased neuronal activity during acute focal arterial occlusions can be detrimental, presumably due to increased metabolic demand, and may have implications for the clinical management of hyperacute stroke patients.

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.

We conducted a targeted literature review on patient burden during the interictal period of migraine. The results of the literature review revealed that: (1) migraine-associated burden persists into the interictal period and is not confined to the headache episodes themselves; (2) anxiety over the possible recurrence of headache episodes is a factor that reduces daily activities and quality of life (QOL); and (3) prophylactic treatment with calcitonin gene-related peptide (CGRP) antibody drugs may reduce the burden during the interictal period. From these findings, it is considered important in migraine treatment to identify the unmet needs of patients, including the burden during the interictal period, and to select an appropriate treatment method based on the burden experienced by individual patients.

BACKGROUND AND AIM: Tension-type headache is the most prevalent primary headache disorder. While the episodic subtype is more common, chronic tension-type headache significantly impacts health-related quality of life and contribute to increased healthcare utilization and disability. Despite considerable advances in the understanding of tension-type headache, critical gaps persist. This paper aims to provide a comprehensive review of the hallmarks of tension-type headache, from its pathophysiology, comorbidities, treatment options, to psychosocial impact. MAIN RESULTS: Multiple factors are associated with tension-type headache, including peripheral mechanisms (increased muscle tenderness and myofascial trigger points), central sensitization, genetic predisposition, and psychological comorbidities such as anxiety and depression. Neuroimaging and neurophysiological studies demonstrated altered pain processing in cortical and subcortical regions in patients with tension-type headache. Regarding treatment strategy, in addition to pharmacological treatment, novel insights into non-pharmacological interventions such as cognitive behavioral therapy, neuromodulation techniques, physical therapy, mindfulness, lifestyle management, and patient education were highlighted as valuable components of comprehensive management strategies. CONCLUSIONS: A complex interplay between peripheral and central mechanisms and psychosocial stressors underpins tension-type headache. Integrated multidisciplinary approaches combining pharmacological and non-pharmacological interventions are critical for optimal patient outcomes. Further research should continue to refine the understanding of these mechanisms to improve targeted therapeutic strategies and reduce the global burden of tension-type headache.

BACKGROUND: Cluster headache (CH) is a rare primary headache disorder characterized by recurrent episodes of strictly unilateral excruciating pain accompanied by trigemino-autonomic signs, which significantly impacts the quality of life, social interactions, and occupational functioning of those who are affected. To promote a better understanding of this disabling condition and to foster research on the topic, this review provides a comprehensive description of the hallmarks of CH, including its clinical presentation, diagnostic challenges, pathophysiology, and current and novel therapeutic targets. It concludes by describing the disease burden and advocating for significant improvements in healthcare systems, and promoting health equity, as well as reducing stigma. PRINCIPAL FINDINGS: Despite its distinctive clinical and chronobiological features, CH may be mistaken for other primary headache disorders or different types of orofacial pain. Key pathogenic characteristics include the activation of the trigeminal-autonomic system with the release of several neuropeptides, the involvement of the hypothalamus in regulating the circadian rhythm, genetic variants, and the mesolimbic system. Both invasive and non-invasive neuromodulation treatments have been used to target the trigemino-cervical, parasympathetic, and hypothalamic systems. Additionally, novel therapeutic targets are currently being study. Alongside canonical therapies, several complementary approaches have been explored over the years, with most evidence deriving from uncontrolled research involving individuals who do not respond to standard pharmacological treatments. Despite advancements in our understanding of this complex disease, CH continues to pose considerable social, economic, and psychological challenges. Advocacy is essential and should prioritize early diagnosis, alleviate stigma, provide specialized training for healthcare professionals, and offer support to and through patient associations. CONCLUSIONS: CH is characterised by a complex, multifactorial, pathophysiology that is still not fully understood. Precise diagnosis, additional research studies, and robust psychosocial and institutional support are necessary to improve the quality of life for individuals affected by this debilitating condition.

Hemiplegic migraine is a rare subtype of migraine characterized by reversible hemiplegia/hemiparesis as an aura symptom. Visual, sensory, and/or speech symptoms typically accompany the motor aura, followed by throbbing headache. Because motor symptoms may last for up to several weeks, this unique clinical entity can markedly impair quality of life. Familial hemiplegic migraine is caused by autosomal dominant mutations in the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes. These mutations are thought to induce neuronal hyperexcitability with resultant enhanced synaptic transmission and increased susceptibility to cortical spreading depolarization/depression. Therapeutic options remain limited, owing to the contraindication of triptans for acute treatment and the lack of established preventive therapies. However, recent evidence supports the potential efficacy of calcitonin gene–related peptide–targeting monoclonal antibodies.