Published papers

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.

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.

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.

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.

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.

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. 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.

Background and objective Musculoskeletal factors, such as myofascial pain, are often overlooked in chronic headaches. This study aimed to evaluate the effectiveness of a structured self-care program, myofascial pain management (MPM), for patients with chronic headaches. Methods This single-arm observational study involved 37 patients with chronic headaches who were referred from a neurology clinic. The patients were categorized into two groups: suspected myofascial pain (n=19) and medication-refractory (n=18). All patients underwent the MPM program, which included instructions for self-massage and stretching techniques. Treatment effectiveness was evaluated using the pain item in the Integrated Palliative Care Outcome Scale (IPOS), with a score of ≤1 indicating improvement. Results The overall improvement rate in the patients was 76%, with significant improvements observed in the myofascial (84%; p=0.00017) and refractory (67%; p=0.00038) groups. Of the 28 patients who demonstrated improvements, 25 (89%) achieved this outcome without changing their prescribed headache medications. Conclusions The MPM program was effective for patients with chronic headache, including those with medication-refractory headache. Evaluation of the masticatory and pericranial muscles, along with the introduction of a structured self-care program, could prove to be a valuable nonpharmacological strategy for headache management.

INTRODUCTION: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are effective in clinical trials and real-world settings. However, data other than headache frequency remains limited in East Asia. Thus, we investigated long-term efficacy, tolerability, and patient-reported satisfaction of CGRP mAbs in clinical practice. METHODS: This single-center observational study included patients with migraine who were administered one of three CGRP mAbs (erenumab, galcanezumab, and fremanezumab) between August 2021 and February 2023. Baseline demographic and headache characteristics were recorded, and treatment outcomes, adverse events, migraine-associated symptoms, and satisfaction levels were assessed over time. RESULTS: We enrolled 150 patients with episodic (n = 81) or chronic migraine (n = 69), including 40 with migraine aura. At six and twelve months, 36/67 (54%) and 22/42 (52%) patients achieved at least 50% reduction in monthly migraine days. Multivariate logistic regression showed that among differences in demographic and headache characteristics between responders and non-responders, the response rate at 3 months was associated with the 6-month response. Migraine-associated symptoms and aura showed improving trends until 5 months after CGRP mAbs initiation. As for safety, injection site reaction was seen in 35/146 (24%), 14/57 (25%), and 4/37 (11%) at 1, 6, and 12 months, respectively. Regarding satisfaction, 74%, 92%, and 94% answered "very satisfied" or "somewhat satisfied" at 1, 6, and 12 months, respectively. CONCLUSION: This study highlighted the role of early response in predicting the long-term response to CGRP mAbs. We also emphasized the importance of documenting satisfaction, migraine aura frequency, in addition to migraine frequency, for deeper insights into migraine pathophysiology.

Purpose: Recent advances in imaging techniques have significantly enhanced the diagnosis of spontaneous intracranial hypotension (SIH). However, these developments have been reported mostly in Europe and the United States. This study aimed to evaluate the availability and utilization of diagnostic and treatment modalities for SIH in Asia, through a survey of regional headache specialists.Methods: A literature search was conducted using PubMed, and members of the Asian Regional Consortium for Headache were contacted. Participants completed a two-step survey evaluating the availability, accessibility, and frequency of SIH diagnostic and treatment methods in their countries and institutions. Descriptive statistics were used to analyze the data.Results: Twenty physicians from eight countries completed both rounds of the survey. Lumbar puncture, brain magnetic resonance imaging (MRI), and spinal MRI are widely available across Asia, but real-time imaging techniques—such as dynamic computed tomography myelography and digital subtraction myelography—that precisely localize cerebrospinal fluid leaks are less accessible. Blind or semi-targeted epidural blood patches (EBPs) are available at most centers, but are easily accessible in only about half of cases. Surgical interventions are rarely available.Conclusion: Most diagnostic methods for SIH are available in Asia, despite some regional disparities. The utilization of EBP and surgical interventions remains somewhat limited. This highlights the need for greater awareness and standardization of diagnostic methods in Asia.

BACKGROUND: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are an effective preventive treatment for migraine. However, their population-level utilization patterns and treatment gaps are underreported in Japan. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) 2nd study, evaluated utilization patterns of CGRP mAbs and treatment gaps, and identified factors associated with CGRP mAb treatment experience among CGRP mAb-eligible individuals with migraine in Japan. METHODS: This analysis of a nationwide, population-based, cross-sectional online survey included adults with migraine. Respondents were further classified according to CGRP mAb eligibility (based on the guidelines for the promotion of optimal use). Both CGRP mAb-eligible and ineligible individuals were stratified by experience with CGRP mAbs. CGRP mAb-experienced respondents were further stratified into "current CGRP mAb" and "discontinued CGRP mAb" subgroups. Respondents reported their CGRP mAb utilization pattern, headache perceptions, attitude, and barriers to treatment initiation. Multivariate logistic regression was performed to identify the factors associated with CGRP mAb treatment experience among CGRP mAb-eligible respondents. RESULTS: Among the 19,590 respondents with migraine, 1484 (7.6%) met the eligibility criteria for CGRP mAbs (78 were current CGRP mAb users, 58 discontinued CGRP mAb, and 1348 never used CGRP mAbs), indicating about 90% of CGRP mAb-eligible individuals had never received CGRP mAb therapy. Among the 18,106 CGRP mAb-ineligible respondents, based on the current symptom status at the time of the survey, 110 were current CGRP mAb users, 176 discontinued CGRP mAbs, and 17,820 never used CGRP mAbs. In both the eligibility groups, more CGRP mAb-experienced respondents visited CGRP mAb-prescribable departments (63.6-88.5%). Among the CGRP mAb-eligible current users, most had consulted headache specialists (40.5%), and the proportion of triptan use (ever and current) was also high in these groups (84.6% and 73.1%). Among eligible nonusers (n = 1348), awareness of CGRP mAbs was markedly low (78.0% had never heard of CGRP mAbs), and only 4.2% had been informed about CGRP mAbs by a physician. Eligible nonusers were less likely to discuss treatment goals with physicians and more likely to perceive migraine as an unavoidable condition. Among the eligible respondents, CGRP mAb treatment experience was strongly associated with prior triptan use (OR 9.38 [95% CI 5.94, 14.80]), and consultation at the CGRP mAb-prescribing department (OR 7.20 [95% CI 3.60, 14.37]). CONCLUSIONS: A substantial treatment gap exists in the use of CGRP mAbs among eligible individuals with migraine in Japan. Improving access to specialist care, enhancing patient-physician communication, and increasing awareness of preventive treatment options are critical to address the unmet treatment needs.

Aims: The association between alcohol consumption and the risk of cardiovascular disease (CVD) varies according to the presence of underlying cardiovascular risk factors. Incorporating such risk factors may be important to effectively reduce harmful alcohol use through health guidance. However, whether the risk of alcohol consumption is affected due to renal impairment remains unclear.Methods: A total of 10,583 community-dwelling Japanese adults (mean age 59.4 (SD 10.1) years; 46% men) were followed for 10 years. Alcohol consumption was categorized into five groups for men: never drinkers, former drinkers, light drinkers (＜20 g/day), moderate drinkers (20-39 g/day), and heavy drinkers (≥ 40 g/day), and four groups for women with moderate and heavy combined. Cox proportional hazards models estimated hazard ratios for incident CVD stratified by the presence or absence of reduced estimated glomerular filtration rate (eGFR) (＜60 mL/min/1.73m2) and proteinuria, with adjustment for confounders.Results: Among men with proteinuria, alcohol consumption was associated with a higher risk of atherosclerotic CVD, whereas an inverse association was observed in men without proteinuria [hazard ratio (95% confidence interval): moderate drinkers without proteinuria, 0.58 (0.34-0.97); moderate drinkers with proteinuria, 3.49 (1.15-10.56)]. Moderate to heavy drinking increased the risk of intracerebral hemorrhage irrespective of the renal status. In women, moderate to heavy drinking was associated with an increased CVD risk only when proteinuria was present. In contrast, a reduced eGFR did not clearly affect the association in either sex.Conclusions: The CVD risk associated with alcohol consumption may differ according to the renal status, particularly depending on the presence or absence of proteinuria.