Formation dynamics of branching structure in the slippery DLCA model.

We numerically investigated the aggregation dynamics and resulting network structures of colloidal gels using the slippery diffusion-limited cluster aggregation (DLCA) model. In this model, bonds are irreversibly formed upon the particle contacts, but the angles among them are not fixed, unlike the conventional DLCA. This allows clusters to be deformed in the process of aggregation. By characterizing the aggregation dynamics and using a reduced network scheme, our simulation revealed two distinct branching structure formation routes depending on the particle volume fraction ϕ. In lower volume fraction systems (ϕ ≤ 8%), the deformations of small-size clusters proceed prior to the percolation. When the Maxwell criterion is satisfied and the clusters become mechanically stable, the formation of the branching structure is nearly completed. After forming the branching structures, they aggregate and form a larger percolating network. Then, the aggregation proceeds through the elongation and straightening of the chain parts of the network. In higher volume fraction systems (ϕ > 8%), on the other hand, the clusters percolate, and a fine and homogeneous branching structure is formed at the early stage of the aggregation. In the aging stage, it collapses into a denser and more heterogeneous structure and becomes more stable. Our quantitative analyses of the branching structure will shed light on a new strategy for describing the network formation and elasticity of colloidal gels.

A study to investigate the prevalence of headache disorders and migraine conducted using medical claims data and linked results from online surveys: post-hoc analysis of other headache disorders.

BACKGROUND: Surveys using questionnaires to collect epidemiologic data may be subject to misclassification. Here, we analyzed a headache questionnaire to evaluate which questions led to a classification other than migraine. METHODS: Anonymized surveys coupled with medical claims data from individuals 19-74 years old were obtained from DeSC Healthcare Inc. to examine proportions of patients with primary headache disorders (i.e.; migraine, tension-type headache, cluster headache, and "other headache disorders"). Six criteria that determined migraine were used to explore how people with other headache disorders responded to these questions. RESULTS: Among the 21480 respondents, 7331 (34.0%) reported having headaches. 691 (3.2%) respondents reported migraine, 1441 (6.7%) had tension-type headache, 21 (0.1%) had cluster headache, and 5208 (24.2%) reported other headache disorders. Responses of participants with other headache disorders were analyzed, and the top 3 criteria combined with "Symptoms associated with headache" were "Site of pain" (7.3%), "Headache changes in severity during daily activities" (6.4%), and the 3 criteria combined (8.8%). The symptoms associated with headache were "Stiff shoulders" (13.6%), "Stiff neck" (9.4%), or "Nausea or vomiting" (8.7%), Photophobia" (3.3%) and "Phonophobia" (2.5%). CONCLUSIONS: Prevalence of migraine as diagnosed by questionnaire was much lower than expected while the prevalence of "other headache" was higher than expected. We believe the reason for this observation was due to misclassification, and resulted from the failure of the questionnaire to identify some features of migraine that would have been revealed by clinical history taking. Questionnaires should, therefore, be carefully designed, and doctors should be educated, on how to ask questions and record information when conducting semi-structured interviews with patients, to obtain more precise information about their symptoms, including photophobia and phonophobia.

Associations between the burdens of comorbid sleep problems, central sensitization, and headache-related disability in patients with migraine.

Objective: Sleep disturbances are common in migraine patients and affect quality of life. Central sensitization (CS) is likely to play a role in the increased severity and chronicity of migraine. We hypothesized that the number of comorbid sleep problems would affect headache-related disability through the effects of central sensitization (CS). Methods: We performed a cross-sectional study including 215 consecutive patients with migraine. Insomnia was defined as a Pittsburgh Sleep Quality Index (PSQI) global score greater than 5. Probable REM sleep behavior disorder (pRBD) was defined as an RBD screening score of 5 or greater. Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of 10 or higher. Suspected sleep apnea (SA) was defined as patients with snoring or sleep apnea witnessed 3 or more nights a week. CS was assessed by the Central Sensitization Inventory (CSI). Results: Restless legs syndrome, insomnia, EDS, SA and pRBD were observed in 25.6%, 71.6%, 34.4%, 10.2%, and 21.4%, respectively, of the patients. At least one sleep problem was present in 87.0% of the patients. According to the results of the multinomial logistic regression analysis with no sleep problems as a reference, after we corrected for adjustment factors, the Migraine Disability Assessment (MIDAS) score significantly increased when three or more comorbid sleep problems were present. According to our mediation analysis, an increased number of sleep problems had a direct effect on the MIDAS score after we adjusted for other variables, and the CSI score was indirectly involved in this association. Conclusion: The present study showed an association between migraine-related disability and the burden of multiple sleep problems, which was partially mediated by CS.

Can calcitonin gene-related peptide monoclonal antibodies ameliorate writer's cramp and migraine?

Recently, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have become available as a prophylactic treatment for migraine and have shown high efficacy and safety in clinical practice. CGRP mAbs have been reported to be effective not only for migraine but also for other comorbidities, such as psychiatric complications in patients with migraine. However, there are no reports examining the effect of CGRP mAbs on dystonia. We treated a patient with comorbid migraine and focal task-specific dystonia (writer's cramp) with a CGRP mAb (erenumab) because of an increase in monthly migraine days despite the addition of migraine prophylaxis. In this patient, erenumab treatment for 3 months led to improvements in symptoms of both focal dystonia and migraine, suggesting a role for CGRP in the pathophysiology of both conditions.

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

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.

Real-world effectiveness of erenumab in Japanese patients with migraine.

Background: Real-world evidence of erenumab effectiveness in migraine patients in Asia with various comorbidities and multiple previous medication failures is still limited. Methods: A 6-month single-center cohort study of 45 patients with episodic or chronic migraine (CM) treated with erenumab was conducted. In the cohort, 60.0% were switching from other calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), and 66.7% had ≥4 prophylaxis failures. The change in monthly migraine days (MMDs) from baseline and percentages of responders after treatment were calculated. Weekly migraine days (WMDs) were obtained at baseline and at months 1, 2 and 3 and were compared between weeks 2 and 4. Results: In total, 36%, 47%, and 63% of patients had a ≥30% response at 1, 3, and 6 months, respectively. The cumulative percentage of patients achieving a ≥30% response over 6 months was 85%. Early responders (average ≥ 30% response at 1-3 months) accounted for 37.8%, 55.6%, and 25.9% of the total, CGRP mAb-naïve, and CGRP mAb-switching groups, respectively. Late responders (average < 30% response at 1-3 months and average ≥ 30% response at 4-6 months) accounted for 46.4%, 37.5%, and 58.8% of nonearly responders in the total, CGRP mAb-naïve, and CGRP mAb-switching groups, respectively. Mild adverse reactions were observed in 5 patients (11.1%). Wearing-off, defined as an increase in the number of WMDs ≥2 between week 2 and week 4, was observed in 2.4-12.5% at months 1-3. Conclusion: Erenumab was effective in migraine patients. At least 4-6 months may be preferable for efficacy evaluation in patients switching to erenumab from other CGRP mAbs.

Impact of Migraine on Daily Life: Results of the Observational survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME [Japan]) Study.

INTRODUCTION: The impacts of migraine on daily life, including daily activities and fundamental health indicators (sleep and mental health), have not been described in detail for people with migraine in Japan. METHODS: The cross-sectional ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) study was conducted between July and September 2020. Impacts of migraine on housework, family/social/leisure activities, driving, and sleep were assessed using questions from the Migraine Disability Assessment (MIDAS), Migraine-Specific Quality-of-Life Questionnaire, and Impact of Migraine on Partners and Adolescent Children scales and questions developed for OVERCOME (Japan). The Migraine Interictal Burden Scale (MIBS-4) evaluated burden on days without headaches. Depression and anxiety were assessed with the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder (GAD-7) scales, respectively. Impacts on daily life were also described across MIDAS/MIBS-4 categories. RESULTS: Among 17,071 respondents with migraine, 24.8% required assistance with housework at least sometimes. Migraine interfered with relationships, leisure, and social activities at least sometimes for 31.8%, 41.6%, and 18.0% of respondents, respectively. Between headache days, 26.8% of respondents worried about planning social/leisure activities at least sometimes. Among respondents living with family (N = 13,548), migraine also had impacts on participation in and enjoyment of family activities. Among respondents who drove (N = 10,921), 43.9% reported that symptoms interfered with driving at least sometimes. Migraine interfered with sleep and mood at least sometimes for 52.7% and 70.7% of respondents, respectively. PHQ-8 and GAD-7 thresholds for clinical depression and anxiety were met by 28.6% and 22.0% of respondents, respectively. Impact of migraine on daily life increased with increasing severity of MIDAS/MIBS-4 categories. CONCLUSION: The burden of migraine on daily activities, sleep, and mental health is substantial for people with migraine in Japan. In clinical practice, it is important to evaluate the impact of migraine on daily life in addition to migraine symptoms.

Validation and comparison of the coding algorithms to identify people with migraine using Japanese claims data.

Purpose: The study aimed to validate and compare coding algorithms for identifying people with migraine within the Japanese claims database. Methods: This study used the administrative claim database provided by DeSC Healthcare, Inc., that was linked to the results of an online survey administered to adult users of the health app "kencom®." The ability of the 12 algorithms to detect migraines using diagnostic records alone or with prescription records was evaluated based on sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs). We used a migraine diagnosis judged based on respondents' self-reported symptoms according to the diagnostic criteria of the International Classification of Headache Disorders, version 3 (ICHD-3), as true. Results: Of the 21,480 individuals, 691 had migraine according to the ICHD-3 criteria. The 12 algorithms had a sensitivity of 5.4-8.8%, specificity of 98.8-99.6%, PPVs of 19.2-32.5%, and NPVs of 96.9-97.0%. Algorithm 9 (migraine diagnostic records more than once AND at least one prescription record for migraine prophylaxis or triptans in the same month as diagnosis) produced the highest PPV, whereas Algorithm 2 (at least one diagnostic record of migraine or tension-type headache) had the highest sensitivity. Similar trends were observed when using the ID-Migraine or 4-item migraine screener, instead of the ICHD-3 criteria, for case ascertainment. Conclusion: Strict algorithms, such as Algorithm 9, yielded a higher PPV but a lower sensitivity, and such algorithms may be suitable for studies estimating the relative risk. Conversely, algorithms based on a single diagnostic record, such as Algorithm 2, had a higher sensitivity and may be suitable for studies estimating the prevalence/incidence of disease. Our findings will help select a desirable algorithm for migraine studies using a Japanese claim database.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Long-term efficacy and safety of erenumab in Japanese patients with episodic and chronic migraine: results from a 28-week open-label treatment period of a randomised trial.

OBJECTIVES: To evaluate the 1-year efficacy and safety of once-monthly erenumab 70 mg following a 24-week double-blind treatment period (DBTP) of a phase III randomised study of Japanese patients with episodic migraine (EM) or chronic migraine (CM). DESIGN: Multicentre open-label study. SETTING: A total of 41 centres in Japan. PARTICIPANTS: Patients completing the DBTP continued into the 28-week open-label treatment period (OLTP). 254 of 261 (97.3%) randomised patients continued into the OLTP; 244 (93.5%) completed treatment. INTERVENTIONS: Once-monthly subcutaneous erenumab 70 mg. MAIN OUTCOME MEASURES: Changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication treatment days (MSMD) reported via patient eDiary; proportion of ≥50% and ≥75% responders in MMD reduction from baseline; incidence and exposure-adjusted incidence of treatment-emergent adverse events (TEAEs). RESULTS: At week 24 of the DBTP, the mean (SE) change from baseline in MMD for the erenumab group was -3.8 (0.4) days (EM, -3.0 (0.4); CM, -5.2 (0.8)); in MSMD, -2.6 (0.4) days (EM, -2.1 (0.4); CM, -3.4 (0.7)). At the end of the OLTP (52 weeks postbaseline), the mean (SE) change from baseline in MMD was -4.7 (0.3) days (EM, -3.4 (0.3); CM, -6.9 (0.6)); in MSMD, -3.3 (0.3) days (EM, -2.4 (0.3); CM, -4.6 (0.5)). The proportion of ≥50% responders for MMD reduction in the erenumab group was 34.1% at week 24; 44.4% at week 52. The exposure-adjusted incidence of TEAEs was 219.7 per 100 patient-years during the OLTP (DBTP, 251.0 for the erenumab group). The most common TEAEs during the OLTP were nasopharyngitis, constipation and influenza. No new safety concerns were identified. CONCLUSIONS: Erenumab treatment was associated with reduced migraine frequency in Japanese patients with EM or CM for up to 1 year. Overall safety results from the OLTP were consistent with DBTP results. TRIAL REGISTRATION NUMBER: NCT03812224.

Real-world experience with monthly and quarterly dosing of fremanezumab for the treatment of patients with migraine in Japan.

Background: The effectiveness of fremanezumab in treating migraine has been demonstrated in randomized controlled trials. However, real-world study results are still limited. Methods: We conducted a single-center, observational study that included patients with episodic migraine (EM) and chronic migraine (CM) who received fremanezumab monthly or quarterly over 6-month periods. The primary outcome of this study was to evaluate changes in monthly migraine days (MMD) and responder achievement after treatment with fremanezumab. The secondary aim was to characterize the predictors of responder at 6 months. We also evaluated the effectiveness of fremanezumab in the patients who switched from other calcitonin gene-related peptide (CGRP) monoclonal antibodies, and compared the effectiveness of fremanezumab between the monthly and quarterly dosing groups. One hundred twenty-seven patients with migraine (age, 45.2 ± 12.6 years; 96 women) who received at least one dose of fremanezumab with ≥3 months of follow-up were included. The number of MMD was assessed by headache diary. Results: The changes in MMD from baseline at 1, 3, and 6 months were -6.1 ± 4.7, -7.7 ± 4.4, and - 8.5 ± 4.5 days in the total cohort, respectively (p < 0.001). The ≥50%, ≥ 75 and 100% responder rates at 6 months were 67.6, 22.5, and 5.4% in the total cohort, 90.4, 36.5, and 9.6% in the EM group, and 52.2, 14.9, and 1.5% in the CM group, respectively. Fremanezumab was also effective in 35 patients who switched from other CGRP monoclonal antibodies. Quarterly and monthly fremanezumab doses were equally effective in MMD reduction in the EM and CM groups. In the CM group, 65.1% experienced remission to EM after 6 months. Adverse reactions were mild and occurred in 9.5% of total patients. An at least ≥50% reduction in MMD from months 1 to 3 better predicted a ≥ 50% reduction in MMD at 6 months with 90.5% sensitivity and 80.6% specificity (p < 0.001). Conclusion: In our real-world study, quarterly and monthly fremanezumab dosing showed both favorable effectiveness and tolerability in patients with migraine.

Outcomes and Factors Associated with Insufficient Effectiveness of Acute Treatments of Migraine in Japan: Results of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) Study.

BACKGROUND: Knowledge of patient outcomes and treatment effectiveness associated with acute migraine treatments in Japan is lacking. OBJECTIVE: To describe patient-reported outcomes (PROs) and treatment effectiveness in three acute treatment groups from OVERCOME (Japan): over-the-counter (OTC) only, prescription nonsteroidal anti-inflammatory drugs/acetaminophen (Rx-NSAIDs/ACE) only, and triptans. METHODS: OVERCOME (Japan) was an observational, cross-sectional, population-based web survey of people with migraine (July-September 2020). PROs, including the Migraine-Specific Quality of Life Questionnaire (MSQ), Migraine Interictal Burden Scale (MIBS-4), Migraine Disability Assessment (MIDAS), and Work Productivity and Activity Impairment Questionnaire: Migraine (WPAI-M), were compared pairwise between treatment groups. Logistic regression was used to examine treatment effectiveness. RESULTS: The analysis included 9075 survey respondents (OTC only: n = 5791; Rx-NSAIDs/ACE only: n = 751; triptans: n = 2533). Triptan users reported the lowest MSQ scores, most severe disability (MIDAS: 20.7% versus 6.3% and 11.6%) and severe interictal burden (MIBS-4: 50.1% versus 21.2% and 19.8%), and greatest work impairment (WPAI-M: 50.4% versus 32.2% and 30.8%) compared with the OTC and Rx-NSAIDs/ACE groups, respectively. Treatment effectiveness was very poor-to-poor for 60.9%, 43.1%, and 47.6% of the triptan, OTC, and Rx-NSAIDs/ACE groups, respectively. Severe interictal burden was significantly associated with insufficient treatment effectiveness (odds ratios, severe versus no burden: 0.47 [95% confidence interval: 0.40-0.54], 0.56 [0.35-0.89], and 0.41 [0.32-0.52], for the OTC, Rx-NSAIDs/ACE, and triptan groups, respectively). CONCLUSION: People with high migraine burden used triptans for acute treatment, but many reported poor treatment effectiveness. Education may be required to promote better treatments, including earlier introduction of migraine-specific acute and preventive medications.

Could efficacy at 1 week after galcanezumab administration for patients with migraine predict responders at 3 months? A real world study.

BACKGROUND: In real-world studies, it is unclear whether galcanezumab has a significant effect in the first week after administration. METHODS: We retrospectively assessed 55 high-frequency episodic migraine (HFEM) and chronic migraine patients who received three galcanezumab doses. Mean changes in the numbers of weekly migraine days (WMDs) during month 1 and migraine days per month (MMDs) after 1-3 months of treatment were obtained. Clinical factors related to a ≥ 50% response rate (RR) at month 3 were analyzed. The prediction of ≥ 50% responders at month 3 using different weekly RRs at week 1 (W1) was evaluated. The RR at W1 was calculated with the following formula: RR (%) = 100 - [(WMDs at W1/baseline WMD) × 100]. RESULTS: The number of MMDs significantly improved from baseline to 1, 2 and 3 months. The ≥ 50% RR was 50.9% at 3 months. The number of WMDs decreased significantly from baseline to week 1 (- 1.6 ± 1.7 days), week 2 (- 1.2 ± 1.6 days), week 3 (- 1.0 ± 1.3 days), and week 4 (- 1.1 ± 1.6 days) during month 1. The RR at W1 was largest (44.6 ± 42.2%). The ≥ 30%, ≥ 50% and ≥ 75% RRs at W1 were significantly predictive of a ≥ 50% RR at 3 months. Logistic regression analysis predicting a ≥ 50% RR at month 3 showed that the RR at W1 was the sole contributing factor. CONCLUSION: In our study, galcanezumab showed a significant effect in the first week after administration, and the RR at W1 could predict the RR at 3 months.

Effectiveness of three calcitonin gene-related peptide monoclonal antibodies for migraine: A 12-month, single-center, observational real-world study in Japan.

BACKGROUND: Real-world data on the effectiveness of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) in migraine patients are needed. METHODS: We performed a single-center, real-world study with an observation period of up to 12 months (mean 7.5 ± 3.4 months) after CGRP mAb administration. A total of 228 Japanese patients with episodic or chronic migraine (age, 45.9 ± 13.2 years; 184F; 45 erenumab; 60 galcanezumab; 123 fremanezumab) who were treated with CGRP mAbs for at least three months were ultimately included in this study. RESULTS: In the total cohort, after CGRP mAb treatment, mean monthly migraine days decreased by 7.2 ± 4.8, 8.3 ± 4.7, and 9.5 ± 5.0 at three, six and 12 months, respectively. The ≥50% monthly migraine day reduction rates at three, six and 12 months were 48.2%, 61.0% and 73.7%, respectively. In the logistic regression analysis, the presence of osmophobia and fewer baseline monthly migraine days contributed to ≥50% responders at three, six and 12 months. The ≥50% responders at three or six months were useful in predicting ≥50% responders at 12 months. In subgroups of patients with difficult-to-treat migraine (those with medication overuse headache or psychiatric comorbidities) and previous CGRP mAb users, monthly migraine days were substantially reduced over 12 months. There was no difference in monthly migraine day reduction over 12 months among three different CGRP mAbs. Adverse reactions were observed in 28 (12.3%) patients, with injection site reactions being the most common (n = 22) though generally mild in severity. CONCLUSION: This real-world study confirmed the efficacy and safety of three different CGRP mAbs for prophylactic treatment of patients with migraine.

[Pharmacological Treatment for Restless Legs Syndrome].

Restless legs syndrome (RLS) is a neurological disorder that causes insomnia and daytime functional disability due to an urge to move the legs usually accompanied by uncomfortable sensations. Non-pharmacologic treatment includes regular sleep habits and exercise. Iron supplementation is indicated for patients with low serum ferritin levels. Antidepressants, antihistaminergics, and dopamine antagonists should be reduced or discontinued because they induce RLS symptoms. Dopamine agonists and alpha 2-delta ligands are the first-line pharmacological treatments for RLS.

Clinical characteristics, medication use, and impact of primary headache on daily activities: an observational study using linked online survey and medical claims data in Japan.

BACKGROUND: Limited epidemiological data are available for headache disorders in Japan, and no recent studies have reported the impact of several primary headache disorders in Japan. This study aimed to report the up-to-date epidemiological data and impact of primary headaches on daily activities as well as the use of medical care, clinical features, and pain severity/activity impairment using nationwide data in Japan. METHODS: We used anonymized online survey data coupled with medical claims data, from individuals aged 19-74 years old, that were provided by DeSC Healthcare Inc. The outcomes included the prevalence of migraine, tension-type headache, cluster headache, and other headache types stratified by age and sex, use of medical care, clinical features, medication use, and severity of pain/activity impairment. All outcomes were examined separately for each headache type. This is the second paper reported concurrently with this research. RESULTS: The study population comprised 691/1,441/21/5,208 individuals with migraine/tension-type headache/cluster headache/other headache types, respectively. The prevalence of migraine and tension-type headache was higher in women than in men but was similar for cluster headache (male vs. female, 1.7% vs. 7.4%, 5.3% vs. 10.8%, and 0.1% vs. 0.1%, respectively). The percentage of individuals with migraine, tension-type headache, cluster headache who had not seen a doctor was 81.0%, 92.0%, 57.1%, respectively. The common headache triggers were fatigue in migraine and tension-type headache, and weather-related phenomena and turning of the seasons in migraine. Common activities refrained from or reduced by headaches were "operating a computer or smartphone", "drinking alcohol", and "going to crowded places" in all three headache types and housework-related activities in women. Among individuals taking medicines, 16.8%, 15.8%, 47.6% with migraine, tension-type headache, and cluster headache reported moderate to severe pain, respectively, and 12.6%, 7.7%, 19.0% reported moderate to severe disability, respectively. CONCLUSIONS: This study found various triggers of headache attacks, and daily activities refrained from or reduced by headaches. Additionally, this study suggested that the disease burden in people possibly experiencing tension-type headaches, many of whom had not seen a doctor. The study findings are of clinical value for the diagnosis and treatment of primary headaches.

Evaluating the Potential Pathology and Short-Term Outcomes of Cryptogenic Stroke Using the Etiological Classification System.

AIM: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system. METHODS: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge. RESULTS: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P =0.012), body mass index (OR, 0.93 [0.88-0.99]; P =0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P＜0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01-1.08]; P =0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P =0.009), and S＋C score (OR, 1.26 [1.03-1.56]; P =0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3. CONCLUSIONS: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

Safety profile of lasmiditan in patients with migraine in an Asian population.

BACKGROUND: MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management. RESEARCH DESIGN AND METHODS: Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE-efficacy associations. RESULTS: Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy. CONCLUSIONS: In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m2) patients and Asian patients with migraine.

A multicenter, open-label, phase 3 study to evaluate the safety of fremanezumab for migraine, subcutaneously self-administered with an auto-injection device at institutional sites and at home.

BACKGROUND: Fremanezumab is a humanized monoclonal antibody against calcitonin gene-related peptide for subcutaneous use to suppress migraine attacks. A phase 3 study was conducted to investigate the safety of autoinjector (AI)-assisted self-injection of fremanezumab 225 mg. RESEARCH DESIGN AND METHODS: The multicenter, open-label study involving 71 patients with migraine was conducted between June 2020 and November 2020 at ten institutions in Japan. The study consisted of a 4-week (28-day) screening period and an 8-week (57-day) treatment period. According to the investigator's instructions, all patients successfully performed self-injection for 4 weeks at the institutional site and at home and maintained eDiaries of their headaches. The primary endpoint was safety of the drug based on treatment-emergent adverse events (TEAEs). RESULTS: Treatment-emergent adverse events were more frequent after at-home injection than after at-site injection, but they were mainly injection site reactions and mostly mild. The safety profile was comparable, raising no concerns compared with what has been reported in previous studies. Both migraine days and headache days were decreased considerably. CONCLUSIONS: Overall, AI-assisted, at-home self-injection of fremanezumab was found to be generally safe and well-tolerated. This injection strategy is considered clinically meaningful in view of improved utility of and adherence to the drug.