Cardiovascular safety of dihydroergotamine mesylate delivered by precision olfactory delivery (INP104) for the acute treatment of migraine.

OBJECTIVE: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. BACKGROUND: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). METHODS: The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. RESULTS: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. CONCLUSION: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications.

Adult Moyamoya Disease and Syndrome: Current Perspectives and Future Directions: A Scientific Statement From the American Heart Association/American Stroke Association.

Adult moyamoya disease and syndrome are rare disorders with significant morbidity and mortality. A writing group of experts was selected to conduct a literature search, summarize the current knowledge on the topic, and provide a road map for future investigation. The document presents an update in the definitions of moyamoya disease and syndrome, modern methods for diagnosis, and updated information on pathophysiology, epidemiology, and both medical and surgical treatment. Despite recent advancements, there are still many unresolved questions about moyamoya disease and syndrome, including lack of unified diagnostic criteria, reliable biomarkers, better understanding of the underlying pathophysiology, and stronger evidence for treatment guidelines. To advance progress in this area, it is crucial to acknowledge the limitations and weaknesses of current studies and explore new approaches, which are outlined in this scientific statement for future research strategies.

Evaluation and treatment of headache associated with moyamoya disease - a narrative review.

BACKGROUND: Headache in patients with moyamoya disease is an under-addressed topic in the medical literature. Delay in the diagnosis of moyamoya disease or inappropriate treatment of headache could lead to devastating cerebrovascular outcome. With the evolving understanding of moyamoya disease, migraine pathophysiology, and various migraine-specific medications that have become available, it is crucial to provide an updated overview on this topic. METHODS: We searched PubMed for keywords including moyamoya disease, moyamoya syndrome, headache in moyamoya, surgical revascularization, surgical bypass, migraine and moyamoya, and calcitonin gene-related peptide (CGRP). We summarized the literature and provide a comprehensive review of the headache presentation, possible mechanisms, the impact of various surgical revascularizations on headache in patients with moyamoya disease, and the medical management of headache incorporating novel migraine-specific treatments.Results and conclusion: The most common headache phenotype is migraine; tension-type headache, hemiplegic migraine, and cluster headache have also been reported. Most patients experience improvement of headache after surgical revascularization, though some patients report worsening, or new-onset headache after surgery. Given the complexity of moyamoya disease, careful consideration of different types of medical therapy for headache is necessary to improve the quality of life while not increasing the risk of adverse cerebrovascular events. More prospective studies are warranted to better understand and manage headache in patients with moyamoya disease.

Migraine and Ischemic Stroke in Women. A Narrative Review.

OBJECTIVE/BACKGROUND: Migraine is associated with ischemic stroke. Women are 3-fold as likely as men to have migraine, and high estrogen states increase the risk of migraine with aura (MWA), venous thromboembolism (VTE), and of stroke. We review the epidemiological and mechanistic evidence of the migraine-stroke relationship and its risk factors, with a focus on women and conditions that exclusively or predominantly affect them.  METHODS: We performed a search of MEDLINE/PubMed database, then a narrative review of the epidemiological evidence of the migraine-stroke relationship as well as the evidence for arterial, thrombophilic, and cardiac mechanisms to explain this connection. We examine the implications of this evidence for the diagnostic evaluation and treatment of MWA. RESULTS: MWA is associated with multiple stroke risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking, atrial fibrillation, and patent foramen ovale. In women, MWA is also associated with biomarkers of endothelial activation, hormonal contraceptive use, pregnancy, and VTE. This suggests that a subset of auras may be secondary, that is, induced by ischemia related to microemboli or in situ thrombosis. MWA-associated ischemic stroke is more common in young (<45 years old) women with high frequency of migraine attacks, hormonal contraception use, and with pregnancy and preeclampsia. There is increasing evidence that cardioembolism, often in conjunction with thrombophilia, plays a prominent role in MWA-associated cerebral infarction. CONCLUSION: The commonality of factors associated with MWA and with MWA-associated stroke suggest that persons with secondary, ischemia-induced aura may be at elevated risk of stroke. Although further research is needed, we recommend consideration of a diagnostic evaluation of MWA that mirrors the evaluation of transient ischemic attack, given that prophylactic treatment targeting the ischemic origin of secondary aura may prevent migraine as well as stroke.

Efficacy of Galcanezumab for Migraine Prevention in Patients With a Medical History of Anxiety and/or Depression: A Post Hoc Analysis of the Phase 3, Randomized, Double-Blind, Placebo-Controlled REGAIN, and Pooled EVOLVE-1 and EVOLVE-2 Studies.

OBJECTIVE: This post hoc analysis evaluated the efficacy of galcanezumab for the prevention of migraine in patients with and without comorbid anxiety and/or depression. BACKGROUND: Patients with migraine have a higher risk of anxiety and/or depression. Given the high prevalence of psychiatric symptoms and their potential negative prognostic impact, determining the efficacy of migraine treatments in patients with these comorbidities is important. METHODS: The results of 2 phase 3 episodic migraine studies of patients with 4-14 migraine headache days (MHD) per month were pooled. A third chronic migraine study, which was evaluated separately, enrolled patients with ≥15 headache days per month, of which ≥8 had migraine-like features. Patients in all 3 studies were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. The efficacy of galcanezumab on migraine was measured in subgroups of patients with anxiety and/or depression (current or past) and patients without. A repeated measures model was used to compare treatment groups within each subgroup and to test for consistency of treatment effect across the anxiety/depression subgroups (subgroup-by-treatment interaction) during the double-blind treatment phases. RESULTS: Among 1773 intent-to-treat patients with episodic migraine, both doses of galcanezumab demonstrated statistically significant improvements relative to placebo in overall number of MHD for the subgroups of patients with anxiety and/or depression (mean change difference from placebo [95% CI]: -2.07 [-2.81, -1.33] for galcanezumab 120 mg [P < .001], -1.91 [-2.78, -1.04] for 240 mg [P < .001]) and without anxiety and/or depression (mean change difference from placebo [95% CI]: -1.92 [-2.36, -1.47] for 120 mg [P < .001], -1.77 [-2.20, -1.33] for 240 mg [P < .001]), as was observed for the secondary outcomes of MHD with acute medication use and functional impairment. Among 1113 intent-to-treat patients with chronic migraine, those with anxiety and/or depression had significant reductions in overall MHD frequency with the 240-mg dose (mean change difference from placebo [95% CI]: -1.92 [-3.52, -0.33]; P = .018), whereas significant reductions were observed at both the 120-mg (mean change difference from placebo [95% CI]: -2.29 [-3.26, -1.31]; P < .001) and 240-mg (-1.85 [-2.83, -0.87]; P < .001) doses in patients without anxiety and/or depressions. Significant reductions (P < .01) in MHD with acute medication use were observed at both doses within both anxiety/depression subgroups and for overall functional impairment for patients without anxiety and/or depression, though neither dose significantly reduced overall functional impairment beyond placebo in the subgroup with anxiety and/or depression. In the episodic and chronic migraine studies, the subgroup-by-treatment interaction was not statistically significant for MHD, MHD with acute medication use, or functional impairment (chronic study only), suggesting a lack of evidence of differential effect between subgroups. Furthermore, differences between subgroups in the mean change differences from placebo, as well as overlapping 95% confidence intervals for the subgroups, indicated lack of a clinical or statistical difference between subgroups for these outcome variables. There was a significantly higher percentage of patients with episodic migraine attaining ≥50%, ≥75%, and 100% reductions, and a higher percentage of patients with chronic migraine attaining ≥50% and ≥75% reductions from baseline with galcanezumab compared with placebo, regardless of medical history of anxiety and/or depression. CONCLUSIONS: A medical history of anxiety and/or depression does not seem to interfere with response to galcanezumab among patients with episodic migraine, and both doses of galcanezumab appear efficacious for these individuals regardless of this psychiatric history. Among patients with chronic migraine and comorbid anxiety and/or depression, the 240-mg dose, but not the 120-mg dose, significantly decreased overall MHD, but neither dose resulted in significantly greater functional improvement. Patients with migraine and comorbid anxiety and/or depression often require additional interventions, and this may be more important in chronic migraine.

The Relationship Between Migraine or Severe Headache and Chronic Health Conditions: A Cross-Sectional Study from the National Health Interview Survey 2013-2015.

OBJECTIVE: To estimate the prevalence of having at least one or two or more chronic health conditions among US adults with self-reported migraine or severe headaches. DESIGN: Cross-sectional study. METHODS: Using data collected from the 2013-2015 National Health Interview Survey, we examined adults with and without migraine or severe headache and associations with chronic obstructive pulmonary disease, cancer, heart disease, stroke, diabetes, and hypertension. We calculated point estimates, variances, and 95% confidence intervals and conducted bivariate and multivariable logistic regression modeling to examine the relationships between migraine or severe headache and each of the chronic health conditions, as well as multinomial modeling, to examine the relationship between migraine or severe headache and having one or more chronic health conditions. RESULTS: A total of 104,926 people were in the study. Adults aged 18 to 44 years (18.2%), women (20.1%), and those with some college education (17.6%) had the greatest proportion with migraine or severe headache (P < 0.0001). Using multinomial modeling with the number of chronic health conditions as the dependent variable, adults reporting migraine had an increased odds of reporting a single chronic health condition (adjusted odds ratio [aOR] = 1.7, 95% confidence interval [CI] = 1.6-1.8) and more than double the odds of reporting two or more chronic health conditions (aOR = 2.5, 95% CI = 2.3-2.8) compared with adults who did not have migraine or severe headache. CONCLUSIONS: Our study confirms observed relationships between migraine or severe headache and chronic health conditions and supports the need for further research to uncover the shared biological pathways.

Emergent carotid endarterectomy versus stenting in acute stroke patients with tandem occlusion.

OBJECTIVE: Acute stroke due to tandem cervical internal carotid artery (ICA) and intracranial large-vessel occlusion (ILVO) has a high rate of morbidity and mortality. The most appropriate treatment strategy for the extracranial culprit lesion remains unclear. In this study, we report our institutional outcomes with two approaches: emergent carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: Patients with tandem ICA-ILVO were identified in a prospective mechanical thrombectomy (MT) database between July 2012 and April 2016. Patients had a concomitant complete ICA origin occlusion and occlusion of the intracranial ICA or M1 or M2 middle cerebral artery segment. Baseline characteristics, procedural data, and treatment times were reviewed. End points included good recanalization of both ICA and ILVO, symptomatic intracerebral hemorrhage (defined by clinical decline of >4 points on the National Institutes of Health Stroke Scale), and functional outcome at 90 days. RESULTS: Forty-five patients had tandem ICA-ILVO occlusion; 27 patients underwent emergent CAS and 12 patients underwent emergent CEA after MT. Successful Thrombolysis in Cerebral Infarction grade 2B/3 recanalization was achieved in 92% of the CEA and 96% of the CAS patients (P = .53). Three CAS patients (11%) and none of the CEA patients had symptomatic intracerebral hemorrhage (P = .54). At 90 days, 75% (9/12) of the CEA patients were functionally independent compared with 70% (19/27) in the CAS group (P = 1.0). No deaths were noted in the CEA group compared with five (18.5%) in the CAS arm (P = .30). CONCLUSIONS: Our study indicates that early recanalization with MT followed by emergent CEA is safe and feasible, which suggests that both CAS and CEA should be considered in the emergent treatment of patients with tandem occlusion.

Migraine and vascular disease biomarkers: A population-based case-control study.

Background The underpinnings of the migraine-stroke association remain uncertain, but endothelial activation is a potential mechanism. We evaluated the association of migraine and vascular disease biomarkers in a community-based population. Methods Participants (300 women, 117 men) were recruited as a part of the Dutch CAMERA 1 (Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis) study. Participants were aged 30-60 (mean 48) years, 155 migraine had with aura (MA), 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Results Fibrinogen and hs-CRP were elevated in migraineurs compared to controls. In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP. Fibrinogen and Factor II were associated with MA in women but not men. In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II. Conclusions Elevated vascular biomarkers were associated with migraine, particularly MA, as well as with years of aura and number of aura attacks.

Hypercoagulability and Migraine.

BACKGROUND: A growing body of literature suggests that migraineurs, particularly those with aura, have an increased risk for ischemic stroke, but not via enhanced atherosclerosis. The theory that micro-emboli induced ischemia provokes cortical spreading depression (ie, symptomatic aura) in migraineurs but transient ischemic attacks in others highlights a potential role for hypercoagulability as a link between migraine (with aura) and stroke. AIM: Our objective is to summarize the literature evaluating the association of migraine with various acquired or inheritable thrombophilic states, including those related to elevated estrogen levels, endothelial activation and dysfunction, antiphospholipid antibodies (aPL), deficiency of coagulation inhibitors, and presence of certain genetic polymorphisms. FINDINGS: Although definitive studies are lacking, a preponderance of available evidence links migraine, and especially aura, to increased levels of estradiol (eg, oral contraceptive pill [OCP] use, pregnancy), thrombo- and erythrocytosis, von Willebrand factor (vWF) antigen, fibrinogen, tissue plasminogen activator (tPA) antigen, and endothelial microparticles. Studies of a link to migraine are conflicting for aPL, homocysteine, Protein S, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. No association with migraine was found in meta-analyses of Factor V Leiden, and of prothrombin gene mutation. Within a large, young ischemic stroke sample, migraine with aura was associated with a thrombophilic state and with patent foramen ovale (PFO). In the non-stroke population, meta-analyses show an association of PFO and migraine with aura (MA), but two population-based studies do not support the link. RECOMMENDATIONS: For persons with MA and (1) a personal history or family history of thrombosis, or (2) MRI evidence of micro-vascular ischemia or of stroke, an evaluation for hypercoagulability is warranted. In cases of MA alone, consider screening for markers of endothelial activation (eg, vWF, high sensitivity c-reactive protein [hs CRP], and fibrinogen). Rigorous management of other stroke risk factors is paramount, but efficacy of anti-thrombotic agents in the treatment of migraine is unproven. Closure of PFO is not routinely recommended based on negative randomized trials.

Do Personality Traits Mediate the Relationship Between Childhood Abuse and Migraine? An Exploration of the Relationships in Young Adults Using the Add Health Dataset.

BACKGROUND: Personality traits (especially neuroticism) and childhood maltreatment have been independently related to many negative health outcomes later in life, including migraine. Studies have also shown the association between childhood maltreatment and maladaptive personality traits. The mediating role of personality traits on the relationship between childhood maltreatment and depression, psychological distress, and alcohol dependence has been extensively studied. However, this type of mediation has not been studied in the case of the development of migraine. This study investigated (1) the main effects of childhood abuse on personality traits, and of personality traits on migraine, and (2) the mediating role of neuroticism, on the relationship between childhood abuse and migraine in young adults. METHOD: We analyzed retrospective, cross-sectional data from 13,493 adults aged 24-32 years in Wave 4 of the National Longitudinal Survey of Adolescent Health ("Add Health") data set. Participants were queried regarding maltreatment (emotional, physical, and sexual) during childhood, current Big Five personality traits (using mini International Personality Item Pool), current depression (using Center for Epidemiologic Studies-Depression Scale), perceived stress (Using Cohen's Perceived Stress Scale), and diagnosis of migraine by a health care provider. Linear and logistic regressions were used to assess the main effects of childhood maltreatment on the five personality traits (openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism) and the main effect of the personality traits on self-reported provider diagnosis of migraine. A structural equation model (SEM) was used to examine the mediating role of neuroticism on the relationship between childhood maltreatment and migraine. RESULTS: Linear regression models showed that childhood abuse independently predicted increased neuroticism (ß = 0.338, SE=±0.05, P < .001), and increased openness to experiences (ß = 0.341, SE = ±0.06, P < .001) after adjusting for socio-demographic characteristics, current depression, and perceived stress. Logistic regression to examine the main effect of personality traits on migraine revealed that only neuroticism had a significant effect (OR = 1.07, 95%CI = 1.04-1.10) after controlling for childhood abuse, socio-demographic characteristics, current depression, and perceived stress. Our regression analyses showed that neuroticism, but not openness to experience, was a potential mediator for the relationship between childhood abuse and migraine. SEM confirmed significant mediation of the relationship between childhood abuse and migraine through neurotic personality traits (goodness of fit indices: CFI = 0.992, TLI = 0.979, RMSEA = 0.025), unadjusted for socio-demographic variables, depression, and stress. In addition to the indirect effect (ß = 0.039, P < .01) of childhood abuse on migraine through neuroticism, there was also a significant direct effect (ß = 0.143, P < .01) of childhood abuse on migraine. After adjusting for socio-demographic variables, other personality types, depression, and stress, both the direct effect (ß = 0.127; P < .01) of childhood abuse on migraine and the indirect effect (ß = 0.09; P < .01) of childhood abuse on migraine through neuroticism were attenuated, but remained significant. CONCLUSION: Childhood abuse is associated with personality and migraine. An estimated 21% of the total effect of childhood abuse on migraine could be explained by mediation through neuroticism in the unadjusted model. In the fully adjusted model, an estimated 8.7% of the total effect could be explained by mediation, although, self-reported data limit the ability to draw firm conclusions.

Emotional Abuse History and Migraine Among Young Adults: A Retrospective Cross-Sectional Analysis of the Add Health Dataset.

OBJECTIVES: To define and examine the relationship between self-reported childhood abuse and migraine among young adults. BACKGROUND: Headache and migraine have been linked to childhood abuse in numerous studies, but there is incomplete characterization of headache types, and limited assessment of abuse types and frequency. Only one population-based study has examined the relationship between emotional abuse and migraine. None have investigated the temporal relationship between onset of abuse and of migraine. METHODS: We analyzed data from 14,356 adults aged 24-32 years in Wave 4, which is a cross-sectional subset of the longitudinal Add Health study. Participants were queried regarding abuse (emotional, physical and sexual) during childhood, diagnosis of migraine, depression and anxiety by healthcare providers, and symptoms of current depression. We used logistic regression to estimate the association between childhood abuse and migraine, controlling for socio-demographic factors, current depression, and lifetime diagnosis of anxiety and depression. RESULTS: About 14% (n = 2040) of respondents reported migraine. Participants with migraine (vs no migraine) reported significantly higher rates of childhood abuse overall (60.6% vs 48.9%), including emotional (57.8% vs 45.4%), sexual (8.4% vs 4.6%) and physical (22.4% vs 17.9%) abuse. Emotional abuse had a stronger association with migraine (odds ratio [OR] 1.62; 95% confidence interval [CI] 1.43-1.85) when compared with physical (OR 1.06; 95% CI 0.89-1.68) and sexual abuse (OR 1.06; 95% CI 0.93-1.68), adjusting for socio-demographic factors. The emotional abuse-migraine association remained even when controlling for lifetime diagnosis of depression and anxiety (OR 1.37; 95% CI 1.19-1.57) and for current depression (OR 1.47; 95% CI 1.30-1.67). The odds of migraine increased with increasing number of abuse types reported. There was a U-shaped distribution of odds of migraine associated with frequency of occurrences of emotional abuse, peaking at one time (OR 1.65; 95% CI 1.34-2.03) and ≥ six times (OR 1.77; 95% CI 1.49-2.10). CONCLUSIONS: Emotional abuse during childhood contributed more than physical or sexual abuse to the development of migraine. There is a dose-response relationship with increasing number of abuse types associated with rising odds of migraine. In addition, the relationship between the frequency of emotional abuse and the odds of migraine follows a U-shape pattern.

Childhood Maltreatment and Headache Disorders.

Childhood maltreatment is substantiated in 12 % of children, but nearly 50 % adults recall having been neglected or abused as children. Maltreatment, especially emotional abuse, is associated with migraine. Dysregulation of the HPA axis, autonomic, immune, and metabolic systems appears to be a consequence of maltreatment, and is also reported in migraine. Areas of the brain structurally and functionally affected by childhood abuse and by migraine are also similar, and include the limbic system structures, which connect to pain regions in the brainstem. Putative mechanisms by which early life stress increases the likelihood of developing migraine include gene x environment interactions, in addition to epigenetic modifications via DNA methylation. These modifications are stable and may be transferred across generations, but they may also be reversed by some medications commonly used in migraine, including valproic acid and topiramate.

Vascular biomarkers in migraine.

AIM: Migraine has been associated with stroke as well as with several non-atherosclerotic vascular conditions leading to discussions about the potential role of endothelium in the etiopathogenesis of migraine and migraine-associated stroke. We present a systematic review of the literature on vascular biomarkers in migraine, including those suggesting endothelial activation and damage. METHODS: We conducted a systematic literature search from 1990 to 2013 using multiple research databases with the keywords "migraine," "headache," "vascular," and "biomarkers." We used selected inclusion and exclusion criteria to create a final pool of studies for this review. RESULTS: The literature search identified a total of 639 citations of which 129 were included in our review. The final pool of clinical- and population-based studies assessed the level of various biomarkers (e.g. inflammatory, prothrombotic, endothelial activation, endothelial repair) in migraineurs of varying ages, gender, and demographic characteristics. Although for each biomarker there is at least one study suggesting an association with migraine, in many cases the quality of evidence is poor and there are conflicting studies showing no relationship. The results were, therefore, in each case inconclusive. CONCLUSION: This systematic review indicated that in migraine populations there are a number of positive vascular biomarker studies, including some involving novel biomarkers such as endothelial microparticles and endothelial precursor cells. These lend insight into possible pathophysiological mechanisms by which migraine may be associated with stroke. More high-quality studies are needed to establish whether a true association between promising vascular biomarkers and migraine exists.

Ictal adiponectin levels in episodic migraineurs: a randomized pilot trial.

OBJECTIVE: To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs. METHODS: Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity. Paired t-tests and random intercept longitudinal models were utilized to assess the mean changes in T-ADP, ADP oligomers, and ratios over time in treatment responders and nonresponders. RESULTS: Twenty participants (11 responders, 9 nonresponders) have been studied to date. In all participants, increases in the HMW : LMW ADP ratio were associated with an increase in pain severity. For every 1 point increase in the HMW : LMW ratio, pain severity increased by 0.22 (Confidence Interval [CI]: 0.07, 0.37; P = .004). In contrast, for every 0.25 µg/mL increase in LMW-ADP, pain severity decreased by 0.20 (CI: -0.41, -0.002; P = .047). In treatment responders, T-ADP levels were reduced at 30 minutes (12.52 ± 3.4; P = .03), 60 minutes (12.32 ± 3.2; P = .017), and 120 minutes (12.65 ± 3.2; P = .016) after treatment as compared with onset (13.48 ± 3.8). Additionally, in responders, the HMW : LMW ratio level was greater at pain onset (3.70 ± 1.9 µg/mL) as compared with nonresponders (2.29 ± 0.71 µg/mL), P = .050. Responders also showed a decrease in the HMW : LMW ratio at 60 minutes (2.37 ± 1.1; P = .002) and 120 minutes (2.76 ± 1.4; P = .02) after treatment as compared with onset (3.70 ± 1.9). These changes in responders remained significant after adjusting for covariates, including measured body mass index (m-BMI). Although nonresponders showed no significant changes in unadjusted T-ADP or ADP oligomer or ratio levels, the HMW : LMW ratio was increased in nonresponders after adjustments (P = .025). CONCLUSION: In this pilot study of women episodic migraineurs, the HMW : LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW : LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine.

Risk factors for migraine disease progression: a narrative review for a patient-centered approach.

BACKGROUND: In individuals with migraine, attacks may increase in frequency, severity, or both. Preventing migraine progression has emerged as a treatment goal in headache subspecialty practice, but there may be less awareness in general neurology or primary care settings where most people with migraine who seek treatment consult. Herein, we review the definition of and risk factors for migraine progression and consider strategies that could reduce its risk. METHODS: A group of headache expert healthcare professionals, clinicians, and researchers reviewed published evidence documenting factors associated with increased or decreased rates of migraine progression and established expert opinions for disease management recommendations. Strength of evidence was rated as good, moderate, or based solely on expert opinion, using modified criteria for causation developed by AB Hill. RESULTS: Migraine progression is commonly operationally defined as the transition from ≤ 15 to ≥ 15 monthly headache days among people with migraine; however, this does not necessarily constitute a fundamental change in migraine biology and other definitions should be considered. Established and theoretical key risk factors for migraine progression were categorized into five domains: migraine disease characteristics, treatment-related factors, comorbidities, lifestyle/exogenous factors, and demographic factors. Within these domains, good evidence supports the following risk factors: poorly optimized acute headache treatment, cutaneous allodynia, acute medication overuse, selected psychiatric symptoms, extra-cephalic chronic pain conditions, metabolism-related comorbidities, sleep disturbances, respiratory conditions, former/current high caffeine intake, physical inactivity, financial constraints, tobacco use, and personal triggers as risk factors. Protective actions that may mitigate migraine progression are sparsely investigated in published literature; our discussion of these factors is primarily based on expert opinion. CONCLUSIONS: Recognizing risk factors for migraine progression will allow healthcare providers to suggest protective actions against migraine progression (Supplementary Fig. 1). Intervention studies are needed to weight the risk factors and test the clinical benefit of hypothesized mitigation strategies that emerge from epidemiological evidence.

Adverse childhood experiences are associated with migraine and vascular biomarkers.

OBJECTIVES: Migraine is a risk factor for stroke in young women. Biomarker studies implicate endothelial activation as a possible mechanism. Emerging relationships of childhood adversity with migraine, and with inflammation, a component of endothelial activation, suggest that it may play a role in the migraine-stroke association. Our objective is to evaluate the relationship between adverse childhood experiences (ACEs), migraine, and vascular biomarker levels in premenopausal women. METHODS: Vascular and metabolic biomarkers from women 18-50 years, including 125 with migraine (interictal) and 50 without migraine, were evaluated. An ACE questionnaire was later collected by mail (response rate 80.6%, 100 migraineurs, 41 controls). RESULTS: Migraineurs and controls were demographically similar. Migraineurs reported adversity more commonly than controls (71% vs 46%, odds ratio [OR] = 1.53, 95% confidence interval 1.07-2.17). Average ACE scores were elevated in migraineurs as compared with controls (2.4 vs 0.76, P < .001). ACE scores correlated with headache frequency (0.37, P = .001) and younger age of headache onset (-0.22, P = .04). It also correlated with body mass index (r = 0.43, P = .0001), von Willebrand factor activity (r = 0.21, P = .009), tissue plasminogen activator antigen (r = 0.28, P = .004), prothrombin activation fragment (r = 0.36, P = .001), high-sensitivity C-reactive protein (r = 0.98, P = .0001), transforming growth factor-beta1 (r = 0.28, P = .003), tissue necrosis factor-alpha (r = 0.20, P = .03), interleukin-6 (r = 0.22, P = .03), adiponectin (r = -0.29, P = .003), and nitrate/nitrite concentration (r = -314, P = .001). Logistic regression analyses (adjusted for vascular risk factors and migraine) demonstrated an association of childhood adversity with inflammatory factors (high-sensitivity C-reactive protein, interleukin-6, and tissue necrosis factor-alpha). CONCLUSIONS: In young women, adverse childhood events are associated with migraine, particularly chronic and transformed migraine, and with vascular biomarkers, especially inflammatory biomarkers. These findings implicate early life stress as a link between migraine and endothelial activation.

Childhood abuse and migraine: epidemiology, sex differences, and potential mechanisms.

Migraine and maltreatment are both common conditions that are more prevalent in women. Epidemiological evidence supports an association between childhood abuse and headache, as well as pain in general, although some controversy exists based on methodological concerns of studying the influence of remote, traumatic, stigmatizing events in an often depressed population. There is a growing scientific body of knowledge regarding the neurobiological effects of abuse on brain function and structure that suggest a possible role of early life stress in the pathogenesis of migraine, and a differential impact based on sex. Advances in our understanding of the basic mechanisms by which an adverse environment interacts with and changes the genome, may suggest new treatment strategies.