AimRimegepant is an effective acute migraine treatment, with limited evidence regarding its consistency across multiple migraine attacks. The primary aim is to assess rimegepant effectiveness across multiple migraine attacks.MethodsIn this real-world, prospective, multicentric study we assessed participants who treated up to four different migraine attacks with rimegepant 75 mg orally disintegrating tablet. Data was collected every 30 min from migraine onset up to 2 h post dose using an electronic diary. Our primary outcome was 2-h pain freedom across all-treated attacks; secondary outcomes were: consistency of response (percentage of participants who achieved 2-h pain freedom in at least two treated attacks), safety and tolerability.ResultsWe enrolled 191 participants (80.1% females, age 44.8 [43.2-46.5] years, disease duration 28.4 [25.0-31.8] years, 27.7% with chronic migraine, 9.6 [8.9-10.9] baseline monthly migraine days-MMDs). We collected data from 377 migraine attacks (191 first-treated, 110 s-treated, 46 third-treated and 30 fourth-treated). Two-hour pain freedom was achieved in 44.6% (168/377) of treated attacks [39.3-49.6]. After correction for age, timing of rimegepant intake, baseline pain intensity, ongoing preventive treatment, and number of preventive drug classes that previously proved ineffective, 2-h pain freedom was associated with female sex (odds ratio (OR) = 2.3 [1.2-4.3], p = 0.012), no ongoing mAbs treatment (OR = 3.2 [1.6-6.4], p = 0.001), and lower MMDs (OR = 1.05 [1.0-1.1], p = 0.002). Consistency of response was 36.4% [27.3-45.5] (40/110). Participants reporting at least one adverse event were 11.5% (22/191).ConclusionOur study confirms the effectiveness of rimegepant in nearly half of treated attacks and describe the consistency of response in a relatively large real-world population where one out of five participants achieved 2-h pain freedom in all-treated migraine attacks. No new safety signals were identified.

AimMigraine is associated with increased odds of hypertensive disorders of pregnancy (HDP). Elevated soluble Fms-like tyrosine kinase-1 (sFlt-1), decreased placental growth factor (PlGF), and upregulated sFlt-1/PlGF ratios are biomarkers of preeclampsia-related complications. Our primary objective was to examine the effect of migraine on sFlt-1, PlGF, and their ratio within subgroups of women with different HDP diagnoses. Our secondary objective was to evaluate the interrelationship between migraine and these biomarkers in the overall cohort with suspected or confirmed HDP.MethodsWe evaluated pregnant women with suspected or confirmed HDP in whom sFlt-1, PlGF and their ratio were measured during index pregnancy. Migraine diagnoses before/during index pregnancy were retrospectively assessed according to ICHD-3 criteria. Both, descriptive and adjusted analyses were performed, comparing women with and without migraine. For the latter analyses, linear regression analyses were conducted for the log-transformed sFlt-1 levels, PlGF levels and their ratio, while adjusting for gestational age, maternal age, and smoking status.ResultsAmong 234 women (mean age 32 years, SD = 5), 91 had (a history of) migraine. No significant association between migraine and the log-transformed biomarkers was observed in women with and without migraine across HDP groups, also when adjusting for confounding factors (adjusted estimates of the sFlt-1/PlGF ratio: β = -0.2 [95% CI: -1.0-0.6] for women with preeclampsia or hemolysis, elevated liver enzyme levels, and low platelet levels syndrome, β = -0.8 [95% CI: -2.0-0.4] for gestational hypertension, and β = -0.1 [95% CI: -0.7-0.4] for those without HDP). Secondary analyses showed that, when pooling the overall study population, women with migraine had lower sFlt-1 levels and sFlt-1/PlGF ratios compared to women without migraine. Adjusted analyses in the overall study population instead showed that migraine was not associated with significant changes in log sFlt-1 levels (β = -0.2 [95% CI: -0.5-0.04]), but rather with higher log PlGFs levels (β = 0.3 [95% CI: 0.03-0.6]) and lower log sFlt-1/PlGF ratios (β = -0.5 [95% CI: -1.0 - -0.08]).ConclusionsResults of this study do not support enhanced angiogenic imbalance by migraine status within HDP groups. As a consequence, interpretation of sFlt-1 and PlGF might not require modification according to migraine status within different HDP diagnoses. The findings observed in the overall cohort require cautious interpretation; whether migraine influences magnitude of angiogenic dysregulation warrants prospective investigation.

AimsAlthough depression commonly co-occurs with migraine, data on the combined humanistic and economic burden outside the US are limited. This study aimed to evaluate the global impact of migraine and comorbid depression.MethodsThis observational, cross-sectional study analyzed data from adults with migraine, with or without comorbid depression, across three regions (4 EU countries + UK [EU4+UK], Brazil [BR], and South Korea [SK]) from the National Health and Wellness Survey (NHWS). Sociodemographic and clinical characteristics, health-related quality of life, work productivity and activity impairment, healthcare resource utilization, and (in)direct costs were compared within each region using descriptive, bivariate, and multivariate analyses.ResultsOverall, 1623 adults with migraine were identified in the NHWS; 35.7%, 32.9%, and 36.5% had comorbid depression in EU4+UK (N = 1073), BR (N = 331), and SK (N = 219), respectively. Across all cohorts, a higher proportion of individuals with comorbid depression experienced severe disability (Migraine Disability Assessment ≥21) compared with those without depression: EU4+UK: 60.8% vs 30.1%; BR: 65.1% vs 35.6%; SK: 48.8% vs 20.9%. Individuals with comorbid depression also had a greater overall work productivity loss (average number of days missed of work in the past 6 months) versus those with no comorbid depression (EU4+UK: 7.8 vs 2.5 days; BR: 6.1 vs 3.5 days; SK: data not available). Multivariate analyses revealed higher estimated marginal mean number of physician visits among individuals with migraine and comorbid depression versus those with no comorbid depression: EU4+UK: 12.0 vs 5.3; BR: 11.1 vs 5.1; SK: 15.0 vs 9.6. Mean total annualized direct costs (EU4+UK: €1427.7 vs €712.6; BR: $99.5 vs $60.6; SK: $1314.5 vs $729.0) and mean total annualized indirect costs (EU4+UK: €8064.9 vs €4487.5; BR: $4354.1 vs $2745.5; SK: $31,550.0 vs $19,894.0) were higher for those with comorbid depression versus those with migraine alone.ConclusionAcross all regions, individuals with migraine and comorbid depression reported more substantial humanistic and economic burden versus individuals with migraine alone emphasizing the importance of providing appropriate treatment to mitigate the impact of migraine and comorbid depression on individuals and healthcare systems.

AimLong-term risk stratification for cryptogenic ischemic stroke (CIS) remains uncertain in patients with migraine and contrast-enhanced transcranial Doppler ultrasound-confirmed right-to-left shunting (RLS). Therefore, we aimed to develop and externally validate a simple baseline score for identifying individuals at low risk.MethodsThis 10-year study included 978 and 237 patients in the development and external validation cohorts, respectively. Internal validation involved a five-fold cross-validation strategy. Multivariable Cox proportional hazards modeling was used to develop the Migraine Risk Stratification Score (MRSS). Model performance was comprehensively evaluated using time-dependent receiver operating characteristic (ROC) curves at 3, 5, and 7 years, calibration plots, and decision curve analysis. Model interpretation was based on the Cox regression coefficients, hazard ratios, and integer points assigned to each predictor. Survival divergence was assessed by Kaplan-Meier analysis.ResultsAge ≥50 years (1 point), migraine with aura (2 points), and permanent and large RLS (2 points each) were identified as predictors. Patients were stratified into low- (0-4 points) and high-risk (5-7 points) groups based on total score. The high-risk group exhibited a significantly higher 10-year CIS risk (21.77% vs. 4.68%; hazard ratio: 5.06; 95% confidence interval: 3.31-7.74). The areas under the curve (AUCs) at 3, 5, and 7 years were 0.771, 0.777, and 0.751 in the development cohort; 0.753, 0.768, and 0.744 after five-fold cross-validation; and 0.917, 0.863, and 0.808 in external validation, respectively. The 3-year external AUC was based on only five events; therefore, it should be interpreted cautiously. Across evaluated horizons, the negative-predictive value was high (0.96-0.99), whereas the positive-predictive value (0.05-0.19) and F1 score (0.10-0.30) were low. Kaplan-Meier curves confirmed significant long-term stroke-free survival stratification (log-rank P < 0·001).ConclusionMRSS exhibited characteristics consistent with a rule-out-oriented baseline risk stratification tool rather than a precise individualized absolute risk assessment for treatment selection. Further prospective validation and recalibration are required.

AimThis prospective real-world study aimed to evaluate the effectiveness of escalating eptinezumab to 300 mg in difficult-to-treat migraine patients with a partial response after two 100 mg cycles.MethodsWe included adults with high-frequency episodic or chronic migraine who achieved a partial response (30% to < 50% reduction in monthly headache days (MHD)) after two 100 mg eptinezumab cycles and escalated to 300 mg for two consecutive quarterly cycles. The primary outcome was the proportion of patients achieving a ≥ 50% MHD reduction from baseline after each 300 mg cycle. Secondary outcomes evaluated changes in MHDs with peak intensity > 4, monthly acute medication intake, Migraine Disability Assessment (i.e. MIDAS), and Headache Impact Test-6 (i.e. HIT-6) scores. Logistic regression assessed predictors of response.ResultsWe analyzed 57 patients (87.7% female, mean ± SD age of 48.2 ± 10.8 years). Following dose escalation, 57.9% and 64.9% of partial responders achieved ≥ 50% MHD reduction after the first and second 300 mg cycles, respectively. Using generalized estimating equations models, estimated marginal mean MHDs (95% confidence interval) dropped from a baseline of 18.65 (16.93-20.37) days/month to 13.33 (11.76-14.91) days/month after two 100 mg cycles, 10.02 (8.15-11.88) days/month after one 300 mg cycle, and 8.84 (6.77-10.91) days/month after two 300 mg cycles (all p < 0.05 vs baseline). Across all secondary outcomes, significant cumulative improvements occurred. Multivariable analysis showed that greater MHD reduction during the 100 mg phase (odds ratio = 0.920, p = 0.008) and no prior erenumab exposure (odds ratio = 0.145, p = 0.012) independently predicted a ≥ 50% response.ConclusionsEscalation to eptinezumab 300 mg was associated with improved population-averaged outcomes in this selected cohort of difficult-to-treat partial responders to 100 mg, supporting, as such, dose escalation over switching therapy.

AimIdiopathic intracranial hypertension (IIH) may involve bidirectional interactions between elevated intracranial pressure (ICP) and sympathetic nervous system activity along an ICP-sympathetic axis. We hypothesized that superior cervical sympathetic ganglion (SCG) volume is increased in IIH and investigated whether SCG enlargement on MRI may serve as a potential imaging covariate of disease severity associated with cerebrospinal fluid opening pressure (OP).MethodsIn this retrospective case control study, we selected IIH patients with a brain MRI within six weeks prior to lumbar puncture, and control participants with normal MRIs. We measured bilateral SCG volumes on MRI, and performed group comparisons and linear regression analyses.ResultsThirty-six IIH patients and 36 controls were included. Median OP in IIH was 24.5 cmH2O. Right, but not left, SCG volume was greater in IIH than controls (281 vs. 208 mm[3], P = 0.038; BMI-adjusted P = 0.032). Combined bilateral SCG volume was also increased (631 vs. 381 mm[3], P = 0.030; BMI-adjusted P = 0.026). A right SCG cutoff of ≥442 mm[3] discriminated elevated OP (AUC = 0.713, optimal point for OP = 37.5 cmH2O) and was associated with increased odds of elevated OP (12.11, P = 0.016).ConclusionSCG enlargement may provide a potential imaging covariate for disease severity. However, given the exploratory nature of this investigation, future validation studies will determine its value in clinical decision-making and longitudinal assessment.

AimProcesses related to glymphatic function and fluid exchange may contribute to migraine pathophysiology. We used multimodal diffusion MRI to investigate perivascular diffusivity and the interstitial microenvironment in migraine and to assess differences across migraine phases and clinical phenotypes.MethodsWe enrolled 120 migraine participants and 52 healthy controls (HC) who underwent 3 T MRI. Participants were classified as episodic migraine (EM, n = 93) or chronic migraine with medication-overuse headache (CM-MOH, n = 25), and by headache status as migraine with headache (MwH, n = 25) or headache-free migraine (MwoH, n = 95). Two CM participants without MOH were excluded from phenotype analyses. Diffusion-derived metrics included diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) and neurite orientation dispersion and density imaging-derived white matter intracellular (IVF) and extracellular volume fractions (EVF). Group comparisons and correlations were assessed using pBonferroni-corrected < 0.05. Voxel-wise IVF and EVF analyses were performed using tract-based spatial statistics with threshold-free cluster enhancement (pFWE-corrected < 0.05).ResultsNo DTI-ALPS differences were observed between migraine and HC or across subgroups. No significant IVF or EVF differences emerged between the migraine group and HC, between EM and HC, or between EM and CM-MOH. In contrast, CM-MOH participants showed reduced EVF and increased IVF versus HC (pFWE-corrected < 0.05). Similar alterations were observed in MwH versus HC and MwoH (pFWE-corrected < 0.05). Changes involved the corpus callosum, anterior thalamic radiation, cingulum, and optic radiations. No significant associations with clinical variables emerged, except a weak association between longer disease duration and lower EVF (r = -0.3, pBonferroni-corrected=0.04).ConclusionsMultimodal diffusion MRI revealed subgroup-specific differences in compartmental volume fractions, with reduced EVF and increased IVF, in individuals with migraine. These findings suggest possible alterations in the interstitial microenvironment that vary with headache phase and disease burden, rather than representing a stable trait. Whether such compartmental shifts influence interstitial transport or glymphatic-related processes remains speculative and warrants further investigation.

BackgroundMany migraine sufferers report difficulties in managing their attacks, leading to missed workdays, impaired cognitive function and reduced participation in social activities. This challenge underscores the importance of identifying reliable indicators of an impending attack. The present study aimed to develop and evaluate machine learning models for predicting migraine attacks based on continuous, non-invasive monitoring of autonomic nervous system activity.MethodsData from a wrist-worn biosensor device the Empatica EmbracePlus (Empatica Inc., Boston, MA, USA) capturing electrodermal activity, heart rate, skin temperature and metabolic equivalent of task were analysed using machine learning models to detect prodromal autonomic nervous system alterations and predict impending migraine headaches. Personalised models were developed using participant-specific model selection, whereas generalised transferability was assessed using a leave-one-participant-out approach.ResultsData from 27 participants were analysed, with an average monitoring period of 30.8 ± 12.9 days, during which 96 migraine attacks were recorded, corresponding to 3.6 ± 1.0 episodes per individual. Personalised prediction models, each reflecting a participant-specific best-selected configuration, achieved good overall predictive performance, with mean values of 0.82 ± 0.10 for accuracy, 0.75 ± 0.16 for precision, 0.72 ± 0.12 for recall and 0.73 ± 0.12 for the F1-score. The mean area under the receiver operating characteristic curve was 0.84 ± 0.10. Gaussian Naive Bayes was most frequently selected, accounting for 44% of valid participant-specific configurations. Generalised models provided above-chance performance in only one-third of participants.ConclusionsThis study supports the feasibility of migraine attack prediction using continuous physiological data from a wrist-worn biosensor analysed with personalised machine learning approaches.

BackgroundExploring the pathogenesis of chronic migraine (CM) remains a formidable challenge. While 7T MRI enables precise detection of microstructural alterations in subcortical nuclei and subregions in CM, comprehensive multimodal imaging studies are few. We therefore conducted a 7T multimodal imaging study to characterize subcortical nuclei and limbic subregions within the hypothalamus, thalamus, hippocampus, and amygdala alterations associated with migraine chronification and to determine the impact of medication-overuse headache (MOH) on CM brain changes.MethodsWe performed multimodal 7T MRI in 62 healthy controls (HCs), 62 episodic migraine (EM) patients, and 62 CM patients (31 with MOH). MRI measures included volumes, functional indicators (fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo)), quantitative susceptibility mapping (QSM), and diffusion tensor imaging analysis along the perivascular space, choroid plexus volume, and basal ganglia perivascular space (PVS) metrics for glymphatic function. Group differences and associations with clinical measures were assessed.ResultsAfter false discovery rate (FDR) correction, fALFF in the accumbens area (L) and mean individual PVS volume differed significantly among the three groups (q < 0.05). Both EM and CM showed lower left accumbens fALFF and greater PVS volume than HCs, whereas no significant difference was detected between EM and CM. No group effects survived FDR correction for regional volume, ReHo, QSM, or other PVS metrics. No significant differences were found between CM patients with and without MOH. Left accumbens fALFF was negatively correlated with the headache duration, whereas PVS volume was positively correlated with headache duration.ConclusionsMigraine was associated with reduced spontaneous activity in the left accumbens area and increased basal ganglia PVS volume. The absence of detectable differences between EM and CM suggests that these abnormalities may represent shared migraine-related features rather than changes that increase linearly with chronification. The findings implicate altered pain-reward processing and perivascular morphology, while indicating that the transition to CM may depend on changes that static regional measures do not capture.