New Daily Persistent Headache in the Pediatric and Adolescent Population: An Updated Review.

PURPOSE OF REVIEW: New daily persistent headache (NDPH) is a primary headache disorder characterized by the sudden onset of continuous pain and its intractability to treatment. It is more prevalent in the pediatric population than the adult population, but remains understudied and underdiagnosed. The purpose of the current article is to provide a current overview of new daily persistent headache in the pediatric and adolescent population, including history, pathophysiology, clinical findings, current and emerging treatment options, and the results of recent studies and meta-analyses. RECENT FINDINGS: Despite recent studies and meta-analyses showing significant phenotypic overlap between chronic migraine and NDPH in the pediatric population, multiple recent studies have come to conflicting conclusions about the overlap of medication overuse in headache and pediatric NDPH. Recent studies reveal alterations in neuroimaging, particularly in functional connectivity, in patients with NDPH. Patients frequently remain treatment-refractory even to medications that have historically proven helpful in this population; however, new treatment options, including calcitonin gene-related peptide (CGRP) monoclonal antibodies, may be more effective. SUMMARY: NPDH remains a perplexing and difficult-to-manage condition for both children and adults. Despite a higher prevalence in the pediatric population, there are relatively few studies to guide the evaluation and treatment of NDPH in pediatric and adolescent patients. Early treatment, both pharmacological and non-pharmacological, should be employed to reduce disability. Overall, further studies are needed to better understand pathogenesis and to identify more effective therapeutic strategies, both pharmacological and non-pharmacological.

Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Remote electrical neuromodulation (REN) wearable device for adolescents with migraine: a real-world study of high-frequency abortive treatment suggests preventive effects.

Introduction: Migraine is a chronic neurological disease manifesting as attacks of disabling head pain and associated symptoms. Remote electrical neuromodulation (REN) is a non-pharmacological, prescribed, wearable device (Nerivio®). This device has been certified by the FDA for the acute and/or preventive treatment of migraine with or without aura in patients 12 years of age or older. The device is affixed to the user's arm during 45-min treatment sessions and is operated using a smartphone app. This study (NCT05769322) aims to evaluate whether frequent use of REN for the acute treatment of migraine in adolescents resulted in a reduction in monthly migraine treatment days (MMTD), as previously demonstrated in adults through a dedicated prevention clinical trial (NCT04828707). Methods: The study included real-world prospective data from adolescent patients who used REN on at least 10 days every 28-day month, following the REN migraine prevention guideline of an every-other-day pattern. Additional requirements were at least three REN treatment days in each of the two subsequent months. The number of MMTD was used as a proxy measure for the number of monthly migraine days (MMD). The change in MMTD from the first month, taken as a "baseline," to each of the following months was used to evaluate the presence and size of potential migraine preventive benefits of REN in adolescents. Results: A total of 83 adolescents were eligible for analysis. The users were 15.9 ± 1.3 years of age (mean ± SD), and 89% of them were female. The results demonstrated a substantial month-to-month reduction in the mean (±SD) number of REN treatment days from 12.6 (±3.2) MMTD in the first month to 9.0 (±4.8) MMTD in the second month (p < 0.001), and a further decrease to 7.4 (±4.2) MMTD in the third month (p < 0.001). This indicates an accumulative reduction of 5.2 (±4.8) mean REN MMTD from the first month to the third month of consecutive REN treatment. The users also reported consistent 2-h acute pain responses in at least 50% of their treated attacks, with 61.9% of the users reported experiencing pain relief, 24.5% reported pain freedom, 67.4% indicated relief in functional disability, and 41.3% reported complete freedom from functional disability. Conclusion: The frequent use of REN among adolescents as an acute treatment for migraine attacks resulted in a decrease in the mean number of monthly treatment days in the subsequent months, suggesting that REN may have potential preventive benefits for migraine in this subpopulation.

Alopecia as an emerging adverse event to CGRP monoclonal antibodies: Cases Series, evaluation of FAERS, and literature review.

BACKGROUND: Alopecia is associated with erenumab post-marketing, but no cases have been described. METHODS: We describe two patients that reported temporary hair loss and review the FDA Adverse Event Reporting System (FAERS). RESULTS: The first patient experienced alopecia within three months of starting erenumab, which did not improve with ongoing use or transition to fremanezumab. The second patient reported alopecia within two weeks of starting erenumab, which continued after transition to galcanezumab; months later, there was also recurrent hair loss within one month of starting fremanzeumab. According to FAERS (last accessed 18 August 2022), alopecia was reported most with erenumab (1158), followed by galcanezumab (554), fremanezumab (175), eptinezumab (23), rimegepant (26), ubrogepant (4), and atogepant (3). CONCLUSION: Most events were reported in women and non-serious. The potential mechanism of alopecia with drugs targeting calcitonin gene-related peptide or its receptor possibly includes disruptions in the microvascular circulation and other homeostatic mechanisms.

Post-vaccination headache reporting: Trends according to the Vaccine Adverse Events Reporting System.

OBJECTIVE: To assess the characteristics and associated disability of headache as an adverse event following vaccination. BACKGROUND: According to clinical trials and post-licensure surveillance, headache is a common symptom of vaccines, yet systematic investigations of post-licensure reports of this adverse event are lacking. METHODS: This was a retrospective database analysis study. We searched the Vaccine Adverse Events Reporting System (VAERS) database completed from July 1990 to June 2020 (a 30-year period prior to the start of COVID-19 pandemic) to identify reports of headache. We evaluated epidemiological features, including event characteristics, patient demographics, and vaccine type. RESULTS: In those aged 3 years or older, headache was the fifth most reported adverse symptom, present in 8.1% (43,218/536,120) of all reports. Of headache reports, 96.3% (41,635/43,218) included the code "headache" not further specified. Migraine was coded in 1973 cases, although almost one-third (12,467/41,808; 29.8%) of headache reports without a migraine code mention nausea or vomiting. The onset of symptoms was within 1 day of vaccination in over two-thirds of cases. The majority of reports were classified as not serious; about one-third involved emergency room or office visits. Of the 43,218 total headache reports, only a minority involved hospitalizations (2624; 6.1%) or permanent disability (1091; 2.5%), females accounted for 68.9% (29,771) and males for 29.5% (12,725), patients aged 6 to 59 years represented 67.3% (29,112), and over one-third of cases were reported after herpes zoster (8665; 20.1%) and influenza (6748; 15.6%) vaccinations. CONCLUSION: In a national surveillance system, headache was a commonly reported post-vaccination adverse event; a small subset of reports was considered serious. The development of standardized vaccine-related case definitions could be useful for better evaluating headache as an adverse event during vaccine development, and may reduce vaccine hesitancy especially in headache-prone individuals.

Headache After Vaccination: An Update on Recent Clinical Trials and Real-World Reporting.

PURPOSE OF REVIEW: The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials. RECENT FINDINGS: Of the recent phase III vaccine RCTs (non-COVID-19), 53 studies reported on headache (13 infectious agents). The median rate (interquartile range) of headache was 15.6% (IQR: 9.6-37.6%). Of these, 24.5% of the RCTs reported headache greater in the vaccine group compared to the placebo/control group. In the herpes zoster vaccination trials, headache was more common in all active groups: median rate 33.9% (IQR: 29.7-40.5%) as compared to placebo: median rate 17.7% (IQR: 15.4-23.8%). Influenza and HPV vaccination trials were the 2nd and 3rd most common to have headache as a VAE. Of the 6 widely distributed COVID-19 vaccinations, median rate of post-vaccination headache was 39% (IQR: 28-50%). Headache is a common VAE in vaccine trials. Standardized grading methods, predictors of persistence, and treatment regimens are warranted.

Advocacy for Migraine Relief: Strategic Planning to Eliminate the Burden.

PURPOSE OF REVIEW: The goal of this article is to describe migraine advocacy as an essential means to advance the field of headache medicine. Special attention is spent outlining advocacy initiatives and priorities. RECENT FINDINGS: There is little written about "migraine advocacy" in the literature. However, organizational and expert priorities include advocating for policies that improve systems of care, telemedicine, education, research, and public initiatives that reduce health disparities and the stigma of migraine. This summary includes the latest advocacy efforts to support policies that may improve migraine care, strengthen the field of headache medicine, and eliminate the burden of migraine.

Equity and Disparities in Diagnosis, Management, and Research of Post-Traumatic Headache.

PURPOSE OF REVIEW: There are notable health disparities and inequities in individuals with traumatic brain injury (TBI) and concussion by race, ethnicity, gender, socioeconomic status, and geography. This review will evaluate these disparities and inequities and assess the social determinants of health that drive outcomes for post-traumatic headache. Interventions for achieving this are also discussed. RECENT FINDINGS: Significant disparities and inequities exist in TBI and concussion among people of different races, socioeconomic status, and geographic locations. Migraine is a common symptom post-concussion, for which disparities and social determinants of health are also discussed. Overall, multi-level interventions to reduce these disparities and inequities are reviewed for post-traumatic headache but require further investigation. Interventions are needed to reduce disparities and inequities including public health initiatives, improvements in clinical care, diversity/inclusion training, and research efforts. As literature expands, we can form guidance to identify solutions for eliminating disparities in care of diverse populations.

Headache as a Neurologic Manifestation of Systemic Disease.

Purpose of Review: This is an update of headache attributed to systemic disease and current therapeutic strategies. Clinical scenarios are discussed. Recent Findings: The diagnosis of headache attributed to metabolic or systemic disorder appears in the Appendix of International Classification of Headache Disorders, Third Edition, and requires further evaluation and validation. However, recent studies characterizing headache appear in the literature. Specific treatment includes addressing underlying systemic disorders, managing concurrent primary headache, and treating comorbidities that may exacerbate headache. Evidence for specific treatment trials for headache as a symptom is lacking, including headaches post-COVID19 infection. Calcitonin gene-related peptide receptor antagonists and 5-HT1F receptor agonists are attractive options for migraine with vascular comorbidities, but long-term studies are needed. Summary: Headache is commonly encountered as a manifestation or complication of systemic disease. Further research is needed to validate headache associated with systemic disorders and to determine optimal treatment strategies.

Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FUNDING: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411.

Development of an Equity, Diversity, Inclusion, and Anti-racism Pledge as the Foundation for Action in an Academic Department of Neurology.

Racial inequities as illustrated by the health disparities in COVID19 infections and deaths, the recent killings of Black men and women by law enforcement, and the widening socioeconomic inequality and have brought systemic racism into a national conversation. These unprecedented times may have deleterious consequences, increasing stress, and trauma for many members of the neurology workforce. The Equity, Diversity, Inclusion and Anti-Racism Committee within our Department of Neurology provides infrastructure and guidance to foster a culture of belonging and addresses the well-being of faculty, staff, and trainees. Here, we present the creation and implementation of our Equity, Diversity, Inclusion, and Anti-Racism (EDIA) Pledge which was central to our committee's response to these unprecedented times. We outline the process of developing this unique EDIA Pledge and provide a roadmap for approaching these important topics through a CME Neurology Grand Rounds aimed at fostering a diverse, inclusive, equitable and antiracist work environment. Through the lived experiences of 4 faculty members, we identify the impact of bias and microaggressions, and encourage allyship and personal development for cultural intelligence. We hope these efforts will inspire Neurology departments and other academic institutions across the globe to make a similar pledge.

Factors Associated With, and Mitigation Strategies for, Health Care Disparities Faced by Patients With Headache Disorders.

OBJECTIVE: To review contemporary issues of health care disparities in headache medicine with regard to race/ethnicity, socioeconomic status (SES), and geography and propose solutions for addressing these disparities. METHODS: An Internet and PubMed search was performed and literature was reviewed for key concepts underpinning disparities in headache medicine. Content was refined to areas most salient to our goal of informing the provision of equitable care in headache treatment through discussions with a group of 16 experts from a range of headache subspecialties. RESULTS: Taken together, a multitude of factors, including racism, SES, insurance status, and geographical disparities, contribute to the inequities that exist within the health care system when treating headache disorders. Interventions such as improving public education, advocacy, optimizing telemedicine, engaging in community outreach to educate primary care providers, training providers in cultural sensitivity and competence and implicit bias, addressing health literacy, and developing recruitment strategies to increase representation of underserved groups within headache research are proposed as solutions to ameliorate disparities. CONCLUSION: Neurologists have a responsibility to provide and deliver equitable care to all. It is important that disparities in the management of headache disorders are identified and addressed.

Drug profile: galcanezumab for prevention of cluster headache.

Introduction: Cluster headache [CH] is a severely disabling trigeminal autonomic cephalalgia [TAC]. Approximately 1 in 1,000 adults are affected by CH. Calcitonin gene-related peptide [CGRP] is an important mediator in the pathophysiology of CH. Galcanezumab is a monoclonal antibody with an affinity for the CGRP peptide, FDA approved for the prevention of episodic CH. Areas covered: Search words queried were 'cluster headache,' 'cluster headache, and CGRP,' 'cluster headache, and galcanezumab.' Over 99 articles in Pubmed and prescribing information for galcanezumab were reviewed. Some of the data pertaining to CH trials with fremanezumab were reviewed using clinical trials.org. Expert opinion: Galcanezumab has shown benefit in decreasing the weekly frequency of CH attacks across week 1 through week 3 in patients with CH; 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (95% confidence interval, 0.2 to 6.7; P = 0.04). It has a favorable risk-benefit ratio. The prevention of CH with CGRP inhibition represents a novel advance for a condition with a significant unmet need. The negative trial results of galcanezumab for chronic cluster headache [CCH] may be due to the refractory nature and sheds light on the critical need to investigate the underlying biology and therapeutic options.

Head injury and neuropsychiatric sequelae in asylum seekers.

OBJECTIVE: Asylum seekers experience a high burden of physical and psychological trauma, yet there is a scarcity of literature regarding the epidemiology and sequelae of head injury (HI) in asylum seekers. We examined HI prevalence and association with neuropsychiatric comorbidities in asylum seekers. METHODS: A retrospective cross-sectional study was performed through review of 139 medical affidavits from an affidavit database. Affidavits written from 2010 to 2018 were included. Demographic and case-related data were collected and classified based on the presence of HI. For neuropsychiatric sequelae, the primary study outcome was headache and the secondary outcomes were depression, posttraumatic stress disorder, and anxiety. Multivariable logistic regression was performed to examine the association between HI and neuropsychiatric sequelae, adjusted for demographic and clinical characteristics. RESULTS: A total of 139 medical affidavits of asylum seekers were included. The mean age was 27.4 ± 12.1 years, 56.8% were female, and 38.8% were <19 years. Almost half (42.5%) explicitly self-reported history of HI. Compared to clients who did not report HI, clients with HI were older and more likely to report a history of headache, physical abuse, physical trauma, concussion, and loss of consciousness. After adjustment for demographic and clinical characteristics, clients with HI had greater odds for neuropsychological sequelae such as headache (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0-8.7) and depression (OR 2.5, 95% CI 1.1-5.7). CONCLUSIONS: We observed a high prevalence of HI in asylum seekers. Comprehensive screening for HI and neuropsychiatric comorbidities is encouraged when evaluating asylum seekers.

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 2.

OBJECTIVE: To review the challenges and potential solutions in treatment options for quality migraine care in adult patients who are under or uninsured. BACKGROUND: The Affordable Care Act has improved access to health care for many; however, those who are underserved continue to face treatment disparities and have inadequate access to appropriate migraine management. METHODS: This manuscript is the second of a 2-part narrative review which was performed after a series of discussions within the Underserved Populations in Headache Medicine Special Interest Section meetings of the American Headache Society. Literature was reviewed for key concepts underpinning conceptual boundaries and a broad overview of the subject matter. Published guidelines, state-specific Medicaid websites, headache quality measurement sets, literature review, and expert opinion were used to tailor suggested treatment options and therapeutic strategies. In this second part of our narrative review, we explored migraine care strategies and considerations for underserved and vulnerable adult populations with migraine. RESULTS: Although common, migraine remains untreated, particularly among those of low socioeconomic status. Low socioeconomic status may play an important role in the disease progression, prescription of hazardous medications such as opioids, outcomes, and quality of life of patients with migraine and other headache disorders. There are some evidence-based and guideline supported treatment options available at low cost that include prescription medications and supplements, though approved devices are costly. Resources available online and simple nonpharmacological strategies may be particularly useful in the underserved migraine population. CONCLUSIONS: We identified and discussed migraine treatment barriers that affect underserved populations in the US and summarized practical, cost-effective strategies to surmount them. However, more research is needed to identify the best cost-effective measures for migraine management in underserved and vulnerable patients who are uninsured or underinsured.

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 1.

OBJECTIVE: To review the scope of the problem facing individuals with migraine who are under- or uninsured. In this first of a 2-part narrative review, we will explore migraine epidemiology and the challenges that face this vulnerable population. BACKGROUND: Implementation of the Affordable Care Act has improved access to health care for many individuals who were previously uninsured, but there are many, particularly those of certain demographics, who are at high risk for worse outcomes. METHODS: A narrative review was performed after a series of discussions within the Underserved Populations in Headache Medicine Special Interest Section meetings of the American Headache Society. Literature was reviewed for key concepts underpinning conceptual boundaries and a broad overview of the subject matter. Published guidelines, state-specific Medicaid websites, headache quality measurement set, literature review, and expert opinion were used to tailor suggested treatment options and therapeutic strategies. RESULTS: Migraine is common, yet remains underdiagnosed and associated with worse outcomes among those of under-represented backgrounds and those who are underinsured or uninsured. Low socioeconomics may play an important role in the disease progression, characteristics, outcome, and quality of life of patients with migraine and other headache disorders. Other barriers to optimal care include time constraints, lack of access to specialty providers, transportation, and financial limitations. CONCLUSION: There are many barriers and challenges that affect people with migraine who are underinsured or uninsured, particularly those of under-represented racial backgrounds and of lower socioeconomic status.

Acute Confusional Migraine: Distinct Clinical Entity or Spectrum of Migraine Biology?

The goal of this review is to explore the literature reports of acute confusional migraine (ACM) including patient characteristics, migraine symptomatology, and proposed diagnostic criteria. A literature review was conducted using PubMed, Scopus and Web of Science using the terms "confusional migraine" and "confusional state in migraine". All the relevant articles from 1970 to 2016 were included. A total of 120 patients were found in the literature. Most of the cases were seen in the pediatric population with a slight male predominance. Personal or family history of migraine was common. Most patients had a headache prior to the confusional state. In addition to confusion and agitation, some developed visual (32.5%) and/or sensory symptoms (19%) and/or speech problems (39%) either prior to or during the confusional state. Data on treatment outcomes is lacking. Patients with most common forms of migraine report attention and cognitive disturbances but awareness remains intact as opposed to patients with ACM. ACM is a distinct entity and should be included as part of the appendix of International Classification of Headache Disoders-3 beta version (ICHD-3ß) criteria. Prospective studies are needed to further study this disorder and its association with other migraine forms.

The utility of radioisotope cisternography in low CSF/volume syndromes compared to myelography.

Objective The objective of this report is to compare computed tomography (CT) and magnetic resonance (MR) myelography with radioisotope cisternography (RC) for detection of spinal cerebrospinal (CSF) leaks. Methods We retrospectively reviewed 12 spontaneous intracranial hypotension (SIH) patients; CT and RC were performed simultaneously. Three patients had MR myelography. Results CT and/or MR myelography identified CSF leaks in four of 12 patients. RC detected spinal leaks in all three patients confirmed by CT myelography; RC identified the CSF leak location in two of three cases, and these were due to osteophytic spicules and/or discs. RC showed only enlarged perineural activity. Only intrathecal gadolinium MR myelography clearly identified a slow leak from a perineural cyst. In eight remaining cases, the leak site was unknown; however, two of these showed indirect signs of CSF leak on RC. CSF slow leaks from perineural cysts were the most common presumed etiology; and the cysts were best visualized on myelography. Conclusion RC is comparable to CT myelography but has spatial limitations and should be limited to atypical cases.

Migraine and risk of stroke in older adults: Northern Manhattan Study.

OBJECTIVE: To examine the association between migraine and stroke/vascular outcomes in a racially/ethnically diverse, older cohort. METHODS: Participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were assessed for migraine symptoms using a self-report questionnaire based on criteria from the International Classification of Headache Disorders, second edition. We estimated the association between migraine and combined vascular events including stroke and stroke only over a mean follow-up of 11 years, using Cox models adjusted for sociodemographic and vascular risk factors. RESULTS: Of 1,292 participants (mean age 68 ± 9 years) with migraine data followed prospectively for vascular events, 262 patients (20%) had migraine and 75 (6%) had migraine with aura. No association was found between migraine (with or without aura) and risk of either stroke or combined cardiovascular events. There was an interaction between migraine and current smoking (p = 0.02 in relation to stroke and p = 0.03 for combined vascular events), such that those with migraine and smoking were at an increased risk. The hazard ratio of stroke for migraine among current smokers was 3.17 (95% confidence interval [CI] 1.13-8.85) and among current nonsmokers was 0.77 (95% CI 0.44-1.35). In relation to combined vascular events, the hazard ratio for migraine vs no migraine among current smokers was 1.83 (95% CI 0.89-3.75) and among current nonsmokers was 0.63 (95% CI 0.43-0.94). CONCLUSION: In our racially/ethnically diverse population-based cohort, migraine was associated with an increased risk of stroke among active smokers but not among nonsmokers.