Headache

Abstract Objective This study aimed to evaluate the discriminative performance of venous asymmetry and index vein sign on susceptibility‐weighted images (SWI) and to construct a preliminary, derivation‐stage score for distinguishing migraine with aura (MA) from transient ischemic attack (TIA) in diffusion weighted imaging (DWI)‐negative patients exhibiting lateralizable hemispheric deficits, defined by symptom‐concordant clinico‐radiologic features. Background Distinguishing migraine with aura from transient ischemic attack in patients with acute neurological deficits remains diagnostically challenging. Imaging biomarkers may aid this differentiation. Methods This study was designed as a retrospective, single‐center, single‐gate hypothesis‐generating study with embedded preliminary score derivation and prospective blinded imaging assessment. Patients presenting with acute stroke‐like symptoms between January 2023 and December 2024 to Hacettepe University Faculty of Medicine Hospitals were enrolled. Reference diagnoses had been assigned during routine clinical care using American Heart Association/American Stroke Association (AHA/ASA) criteria for transient ischemic attack (TIA) and the final International Classification of Headache Disorders, 3rd edition (ICHD‐3) (2018) criteria for MA, without independent adjudication; retrospective per‐patient tabulation of criterion C followed the ICHD‐3 (2018) formulation. Clinical and demographic data were extracted retrospectively, and SWI images were evaluated prospectively. Clinico‐radiologic characteristics of venous asymmetry and index vein sign (IVS) were examined in primary analyses along with their associations. From these analyses, a preliminary score named SVI (the symptom‐concordant venous imaging) was derived. Results Of 290 DWI‐negative patients, only 21 had MA (TIA = 269). Marked or mild venous asymmetry was observed in 19/21 (90.5%) of MA and in 44/269 (16.4%) of patients with TIA (predominantly mild). The IVS was observed in 18/21 (85.7%) of MA versus 28/269 (10.4%) of patients with TIA. In a small follow‐up subset, venous signs tended to resolve interictally in MA, representing a hypothesis‐generating observation. Symptom‐concordant venous asymmetry and the IVS, together with younger age, hypoesthesia, and speech impairment, were independently associated with MA. As derivation‐cohort estimates, the SVI score yielded an area under the receiver operating characteristic curve (AUC) = 0.97 (95% confidence interval [CI] 0.94–0.99); at a data‐derived cutoff of eight or more points, selected to prioritize specificity, sensitivity was 15/21 (71.4%, 95% CI 47.8–88.7%), and specificity 258/269 (95.9%, 95% CI 92.8–97.9%). Conclusion In this single derivation cohort, venous imaging findings were associated with MA and are potentially informative but merit further study. The preliminary SVI score requires independent prospective validation and should not presently guide diagnosis or treatment. image

Abstract Objectives/Background Migraine is one of the leading causes of neurological disability globally, and conventional prophylactic pharmacotherapy may be limited by incomplete efficacy, poor tolerability, contraindications, and concerns about long‐term safety. Vitamins and nutraceuticals including riboflavin, coenzyme Q10 (CoQ10), magnesium, and vitamin D3 are increasingly used as adjunctive or alternative preventive strategies, yet their comparative efficacy within a single evidence synthesis remains uncertain. Our objective was to evaluate and rank the comparative efficacy and safety of vitamins and nutraceutical interventions for migraine prevention using a network meta‐analysis (NMA) of randomized controlled trials (RCTs). Methods We conducted a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses‐compliant systematic review and NMA International Prospective Register of Systematic Reviews (PROSPERO: CRD420261389392). PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar were searched from inception to March 2026 for double‐blind RCTs evaluating vitamins or nutraceuticals for migraine prevention in adults or children. The primary outcome was monthly attack frequency; achievement of ≥50% responder status was a secondary outcome. Secondary outcomes included attack duration, pain severity, and migraine days. The primary network was restricted to adults; pediatric trials were summarized separately. Shared‐unit outcomes (attack frequency, migraine days, attack duration) were reported as mean differences (MDs) and pain severity as standardized MDs; responder status was reported as odds ratios, all with 95% confidence intervals (CIs). Certainty of evidence was assessed using the Confidence in Network Meta‐Analysis (CINeMA) (Grading of Recommendations Assessment, Development and Evaluation‐NMA) framework. Results Twenty unique double‐blind RCTs (reported in 21 publications; n = 1829 randomized; 1600 analyzed) were included; 10 adult trials informed the primary attack‐frequency network. For attack frequency, riboflavin 400 mg showed the most reliable reduction in adults (MD = −1.95 attacks per month, 95% CI = −2.42 to −1.49; moderate certainty); larger point estimates were observed for vitamin B12 500 μg (MD = −2.50, 95% CI = −4.35 to −0.65), vitamin B6 80 mg (MD = −2.33, 95% CI = −4.19 to −0.48), and vitamin D3 (MD = −2.29, 95% CI = −3.03 to −1.54). The vitamin B12 and B6 estimates were derived from single small trials and the vitamin D3 estimate from two small trials, all of low to very low certainty. Riboflavin 100 mg and 200 mg contributed no adult attack‐frequency data (all estimates versus placebo). For ≥50% responder status, CoQ10 300 mg was the only intervention with a statistically significant advantage in adults (odds ratio = 4.83, 95% CI = 1.17–19.89; very low certainty). The previously reported riboflavin 200 mg signal was derived from a pediatric trial. CoQ10 400 mg significantly reduced attack duration (MD = −3.30 h, 95% CI = −5.72 to −0.88; low certainty, downgraded for imprecision) and pain severity (standardized MD = −0.70, 95% CI = −1.12 to −0.27; low certainty). However, responder‐status findings were limited by network sparsity and imprecision and should be interpreted cautiously. Magnesium showed no detected benefit across outcomes; adverse‐event proportions were highest for magnesium but are reported descriptively only and are not comparative evidence. Conclusion In this systematic review and NMA, in adults, riboflavin 400 mg showed the most consistent, moderate‐certainty reduction in migraine attack frequency, whereas CoQ10 400 mg showed potential benefit for reducing attack duration and pain severity. Vitamin D3 and selected B vitamins also demonstrated frequency‐lowering effects, although estimates were limited by sparse evidence and imprecision. Magnesium showed no detected benefit; adverse‐event proportions were descriptive only and not comparative evidence. Because several treatment nodes were informed by few studies and responder estimates were imprecise, these findings should be interpreted cautiously. Larger, standardized, and adequately powered trials are needed to confirm comparative efficacy and safety.

Abstract Objectives/Background Our objective was to gain a better understanding of how Black patients in the Greater Toronto Area experience barriers and facilitators of headache care. Headache is a common, potentially serious neurological condition. Migraine specifically, can lead to emergency room visits, missed workdays, and a reduction in overall quality of life. Black and Indigenous communities experience worse headache outcomes compared to other communities. We engaged Black patients with headache in the Greater Toronto Area to learn from their perspectives on barriers they face in accessing headache care. Methods This study deployed an intersectional, community‐informed qualitative research methodology. We included patients between 18 and 65 years of age who self‐identified as Black and live in the Greater Toronto Area. We conducted semistructured interviews between July 2022 and September 2023. Interviews were deidentified and transcribed prior to inductive thematic analysis to reveal emerging themes and subthemes. Results We conducted a total of 12 interviews. Ten were included for analysis. Multiple themes and subthemes were identified, including the impact of headache on personal and family quality of life, negative experiences in emergency departments, as well as challenges navigating primary and specialist care. Patients specifically noted delays in receiving a diagnosis, lack of headache education, and difficulty accessing appropriate pharmacological therapies. Barriers to headache specialist care included difficulty getting time off work, cost of transportation, lack of access to referrals, and wait time to see a specialist. Conclusion This is the first study to document the experiences of Black patients seeking headache care in Toronto, Ontario, Canada. Patients with headaches face barriers to care regardless of race, ethnicity, or socioeconomic status. This was not a comparative study; rather, we specifically sought to hear the voices of patients from historically marginalized Black communities who have not been reflected in research and for whom headache outcomes are poor relative to other communities. The participants provided key insights into areas for improvement. Participant recommendations include location of specialist clinics in Black communities, use of social media and other community news networks to promote migraine and headache education in communities, and ongoing use of virtual care models to increase scheduling flexibility and reduce financial burdens of seeking care. Physicians and clinic staff who reflect communities they serve were recommended as a way of improving physician–patient respect and communication.

Abstract Objectives/Background Our aim was to compare the performance of commercially available enzyme‐linked immunosorbent assay (ELISA) kits for detecting mature α‐ and β‐calcitonin gene‐related peptide (CGRP) isoforms and test the hypothesis of a potential lack of reliability. CGRP is one of the most extensively studied biomarkers in migraine, but the reliability of commercially available ELISA assays for its measurement remains controversial. Methods In this method comparison study, we analyzed serum samples from 19 patients with migraine in Marqués de Valdecilla University Hospital, along with synthetic peptide samples (α‐ and β‐CGRP), including preparations of each isoform at different concentrations. The following ELISA kits were evaluated according to the manufacturers' instructions: one kit theoretically specific for α‐CGRP (abx252189, Abbexa, Kit B); and three kits considered specific for β‐CGRP (CSB‐E08210h, CUSABIO, Kit C; abx151047, Abbexa, Kit D; and abx514274, Abbexa, Kit E). In addition, Bertin assay (A05481.96), Kit A, designed to detect both CGRP isoforms, was assessed. Results Kit A was the only kit capable of detecting the synthetic peptide in both isoforms and demonstrated a measurable positive relationship of nominal versus observed levels. In contrast, the remaining kits, theoretically specific for a single isoform, failed to detect the corresponding synthetic peptide. Quantification of CGRP levels in 19 patient samples showed no significant correlation among the assays. No correlation was found among the three different assays targeting β‐CGRP. Intrakit variability was acceptable for all kits tested. Conclusion These findings indicate that the ELISA assays tested, designed to measure specific isoforms of mature CGRP isoforms, are unable to detect the synthetic peptide. Nevertheless, it is possible that these assays quantify other CALCA/CALCB ‐derived products that may retain biological activity in patients with migraine. The absence of correlation among kits targeting the β‐CGRP isoform further suggests differences among kits, which might be due to differences in calibration, cross‐reactivity, noise, or the use of different antigens, raising the possibility that the kits detect different CGRP‐related forms, including precursor/propeptide and other processed forms.

Abstract Objective This study aimed to evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) on persistent post‐traumatic headache (pPTH) in adults with pPTH and a high burden of persistent post‐concussion symptoms (pPCS) 4–5 months after mild traumatic brain injury (mTBI). Background pPTH is a disabling sequela of mTBI with no established effective treatment. rTMS is a promising treatment modality. Methods This two‐arm parallel‐group, randomized (1:1), single‐blind, sham‐controlled, clinical superiority trial was conducted at Hammel Neurorehabilitation Centre and University Research Clinic, Hammel, Denmark from August 2023 to August 2024. Participants were randomized to receive five sessions of either active high‐frequency rTMS (HF‐rTMS; 2000 pulses, 10 Hz) or sham stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) 4–5 months post‐trauma. The primary outcome was the monthly mean difference in change in headache days of moderate‐to‐severe intensity between the active treatment group and the sham group. This was assessed using daily headache diaries before and after intervention. Secondary outcomes included measures of pPCS burden and headache impact, and pain catastrophizing at 1‐ and 3‐month follow‐up. Results A total of 62 participants were randomized (rTMS, n = 30; sham, n = 32). In the intention‐to‐treat (ITT) population ( n = 62), the adjusted monthly mean difference in change (i.e., the treatment effect) between the active treatment group and the sham group was −1.55 (95% confidence interval [CI]: [−3.10; −0.01], p = 0.049) headache days. The treatment effect in a sensitivity analysis of the modified ITT population ( n = 61) was −1.08 (95% CI: [−2.60; 0.45]), p = 0.166) headache days. No significant adjusted mean difference in change was observed for any secondary outcome between the active rTMS group and the sham group from baseline to 1 month end of treatment (EOT): it was −0.58 (95% CI: [−1.23; 0.08], p = 0.084) for headache intensity on the Numerical Rating Scale; 0.14 days (95% CI: [−1.01; 1.29], p = 0.816) for acute medication use; −4.07 (95% CI: [−8.81; 0.69], p = 0.093) for total Rivermead Post‐Concussion Symptoms Questionnaire score; −1.08 (95% CI: [−4.80; 2.64], p = 0.567) for Headache Impact Test score; −1.36 (95% CI: [−2.91; 0.19], p = 0.085) for Symptom Checklist‐6 subscale depression score; 1.74 (95% CI: [−5.22; 1.73], p = 0.324) for Pain Catastrophizing Scale score. The primary outcome and all secondary outcomes, except acute medication use, showed significant reductions over time in both groups ( p < 0.001). Conclusion High‐frequency rTMS targeting the left DLPFC was associated with a statistically significant reduction in monthly moderate‐to‐severe headache days compared with sham in adults with pPTH 4–5 months post‐trauma; however, the sensitivity analysis did not support the findings. Both groups demonstrated symptom reduction over time, likely reflecting spontaneous recovery and non‐specific treatment effects. Further studies are needed to confirm these findings and to further evaluate the role of rTMC in pPTH, including alternative stimulation targets and treatment protocols.