Noboru Imai

Aim: Although ergotamine is administered before bedtime as a preventive therapy, recent studies have suggested that morning administration is more effective. Lasmiditan, a selective 5-HT _1F receptor agonist, does not have vasoconstrictive properties and can be used in combination with ergotamine or triptan. A combination therapy with ergotamine and lasmiditan may be effective as a preventive strategy for patients with cluster headache who do not respond to standard treatment. Methods: We report a case of a 27-year-old man with chronic cluster headache who experienced chest tightness and palpitations after subcutaneous sumatriptan and showed an inadequate response to verapamil, lithium, topiramate, and galcanezumab. Oxygen therapy was only partially effective, and short corticosteroid courses resulted in transient remission. We administered ergotamine (1 mg) in the morning and lasmiditan (100 mg) at bedtime. Results: Within 7 days, the attack frequency declined from daily (3–4/day) to once every 3–4 days, and pain intensity decreased from NRS 8/10 to 3/10. Benefits persisted for over 3 months without reported adverse effects, enabling a return to full-time work. Conclusion: This case demonstrates that a combination therapy with ergotamine and lasmiditan may be a preventive option for cluster headaches that are difficult to manage with standard treatment.

Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Migraine is a multifactorial brain disorder characterized by recurrent disabling headaches and their associated features. Several studies have suggested that these features are related to headache impact, pain intensity, and psychiatric conditions. However, differences in the relationship between each associated feature and headache impact, pain intensity, or psychiatric conditions remain unclear. This study aimed to assess the impact of migraine-associated features on headache impact, pain intensity, and psychiatric conditions in patients with migraine. In this two-centered study, patients with migraine without aura (MwoA) were enrolled to exclude those without headaches and avoid the influence of medication overuse, which is commonly associated with chronic migraine. We used multiple logistic regression to analyze the headache impact, pain intensity, and psychiatric conditions measured using the Headache Impact Test (HIT-6), Visual Analog Scale (VAS), Generalized Anxiety Disorder 7-item scale (GAD-7), and Patient Health Questionnaire-9 (PHQ-9). Patients’ likelihood of experiencing symptoms such as nausea, vomiting, photophobia, phonophobia, osmophobia, and allodynia were also recorded. A total of 1103 patients with MwoA were enrolled in this study, and 164 patients were excluded from the study because of missing data. Finally, 939 patients with MwoAs were included. On multiple logistic regression analyses, nausea (odd ratios [OR] 1.87, confidence interval [CI]: 1.37–2.54), vomiting (OR 1.57, CI: 1.11–2.23), photophobia (OR 1.67, CI: 1.18–2.35), and allodynia (OR 1.56, CI: 1.06–2.28) were independent positive predictors of higher HIT-6 scores, and nausea (OR 1.72, CI: 1.22–2.43), vomiting (OR 1.84, CI: 1.29–2.63), phonophobia (OR 1.58, CI: 1.10–2.25), photophobia (OR 1.49, CI: 1.07–2.08), and allodynia (OR 1.81, CI: 1.24–2.66) were independent positive predictors of higher VAS score. Nausea (OR 1.49, CI: 1.09–2.02), phonophobia (OR 2.00, CI: 1.42–2.82), and allodynia (OR 1.81, CI: 1.24–2.63) were independent positive predictors of GAD-7 score. Nausea (OR 1.66, CI: 1.21–2.28), phonophobia (OR 1.49, CI: 1.05–2.11), and allodynia (OR 1.68, CI: 1.16–2.45) were independent positive predictors and vomiting (OR 0.54, CI: 0.37–0.78) was an independent negative predictor of PHQ-9 score. Our results suggest that nausea, vomiting, photophobia, phonophobia, and osmophobia have distinct effects on headache impact, pain intensity, and psychiatric conditions. Understanding these differences can aid in the personalized management of patients with MwoA.

Background: We have previously shown that static and dynamic resting-state functional connectivity differ between migraineurs with and without photophobia, phonophobia, or osmophobia. Furthermore, some patients with photophobia also experience phonophobia or osmophobia. To investigate the functional connectivity specific to migraineurs with photophobia, we examined the differences in static and dynamic resting-state functional connectivity between patients with and without photophobia, with no phonophobia or osmophobia. Methods: Fifteen migraineurs with photophobia but without phonophobia or osmophobia, as well as 15 sex- and age-matched migraineurs without photophobia, phonophobia, or osmophobia, underwent 3-T functional magnetic resonance imaging during the interictal phase. Static and dynamic resting-state functional connectivity were compared using region-of-interest analyses of 91 cortical, 15 subcortical, and 26 cerebellar areas. Results: Static resting-state functional connectivity analysis revealed ten significant connectivity pairs in patients with photophobia, while dynamic resting-state functional connectivity analysis revealed six significant connectivity pairs in patients with photophobia. Migraineurs with photophobia had significantly lower connectivity between the cerebellar hemisphere and the temporal region than those without photophobia in both static and dynamic studies. Conclusions: Our results show that lower resting-state functional connectivity between the cerebellar hemisphere and the temporal region is specific to migraineurs with photophobia.

The misdiagnosis of headache disorders is a serious issue, and AI-based headache model diagnoses with external validation are scarce. We previously developed an artificial intelligence (AI)-based headache diagnosis model using a database of 4000 patients’ questionnaires in a headache-specializing clinic and herein performed external validation prospectively. The validation cohort of 59 headache patients was prospectively collected from August 2023 to February 2024 at our or collaborating multicenter institutions. The ground truth was specialists’ diagnoses based on the initial questionnaire and at least a one-month headache diary after the initial consultation. The diagnostic performance of the AI model was evaluated. The mean age was 42.55 ± 12.74 years, and 51/59 (86.67%) of the patients were female. No missing values were reported. Of the 59 patients, 56 (89.83%) had migraines or medication-overuse headaches, and 3 (5.08%) had tension-type headaches. No one had trigeminal autonomic cephalalgias or other headaches. The models’ overall accuracy and kappa for the ground truth were 94.92% and 0.65 (95%CI 0.21–1.00), respectively. The sensitivity, specificity, precision, and F values for migraines were 98.21%, 66.67%, 98.21%, and 98.21%, respectively. There was disagreement between the AI diagnosis and the ground truth by headache specialists in two patients. This is the first external validation of the AI headache diagnosis model. Further data collection and external validation are required to strengthen and improve its performance in real-world settings.

Introduction: Giant cell arteritis (GCA) is characterized by headaches, but few studies have examined the detailed characteristics of pathologically confirmed cases. We investigated the characteristics of GCA patients, particularly headache, and their correlation with pathological findings.

Giant cell arteritis (GCA) is characterised by headache, but few studies have examined detailed characteristics in pathologically confirmed cases. We aimed to investigate the characteristics of GCA, particularly headache, and their correlation with pathologic findings. We retrospectively analysed 26 patients (median age: 77.5 years, male: 38.4%) with GCA who underwent superficial temporal artery (STA) biopsy at the Japanese Red Cross Shizuoka Hospital between May 2001 and February 2022. All patients fulfilled the American College of Rheumatology and European League Against Rheumatism diagnostic criteria for GCA. We focused on the relationship between clinical features, especially headache, and pathologic findings. Twenty-four patients had unilateral, non-pulsating, intermittent headaches. Transmural inflammation (TMI), a characteristic pathology of GCA, was present in 14 patients. Bivariate analysis revealed significant associations between TMI and STA tenderness (odds ratio [OR]=11, 95% confidence interval [CI] 1.14 to 106.43, p=0.046) and between TMI and STA chordal thickening (OR=0.19, 95% CI 0.068 to 0.52, p=0.021). Headache in GCA patients was often unilateral, non-pulsatile, and intermittent. This study highlights the significant association of TMI with STA tenderness and ligamentous thickening, which has not been reported previously. Abnormal STA findings were significantly associated with pathologic changes in GCA, emphasising their importance in suspecting GCA.

Migraine—a primary headache—has circadian and circannual rhythms in the onset of attacks. The circadian and circannual rhythms involve the hypothalamus, which is strongly associated with pain processing in migraines. Moreover, the role of melatonin in circadian rhythms has been implied in the pathophysiology of migraines. However, the prophylactic effect of melatonin in migraines is controversial. Calcitonin gene-related peptide (CGRP) has recently attracted attention in the pathophysiology and treatment of migraines. Pituitary adenylate cyclase-activating peptide (PACAP)—a neuropeptide identical to CGRP—is a potential therapeutic target after CGRP. PACAP is involved in the regulation of circadian entrainment to light. This review provides an overview of circadian and circannual rhythms in the hypothalamus and describes the relationship between migraines and the molecular and cellular neurobiology of circadian and circannual rhythms. Furthermore, the potential clinical applications of PACAP are presented.

Background: Headache is an important clinical feature of giant cell arteritis (GCA), and biopsy is important for diagnosing GCA. However, no report has examined the clinical features of pathologically confirmed GCA, including headaches, in detail. Thus, we aimed to investigate detailed characteristics of GCA, including headache, and the relationship between pathological findings and clinical symptoms. Methods: We retrospectively identified 26 patients (median age; 77.5 years, male; 38.4%) with GCA who underwent superficial temporal artery (STA) biopsy at the Japanese Red Cross Shizuoka Hospital between May 2001 and February 2022. All patients met the GCA diagnostic criteria of the American College of Rheumatology and the European League Against Rheumatism. We focused on the relationship between clinical features, such as headaches, and pathological findings. Results: Twenty-four patients had a headache that tended to be unilateral, non-pulsatile, and intermittent. Transmural inflammation (TMI), a characteristic pathological finding of GCA, was observed in 14 patients. Bivariate analysis showed a significant association between TMI and STA tenderness (p=0.046) and between TMI and STA chordal thickening (p=0.021). Conclusions: Headaches in patients with GCA were often unilateral, non-pulsatile, and intermittent. Furthermore, this study is the first to report that TMI is significantly associated with STA tenderness and ligamentous thickening. We showed that abnormal STA findings were significantly related to GCA pathological findings; thus, it is necessary to pay attention to abnormal STA findings when suspecting GCA.