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.

Migraine and its association with pubertal maturation and behavioral traits among adolescent girls.

OBJECTIVE: To determine if the ages at pubertal milestones are associated with the prevalence of adolescent migraine. BACKGROUND: Migraine headaches are a common disease in adolescent girls. Past studies have evaluated the relationship between age of onset of menarche and migraine headache, but none have studied earlier pubertal milestones such as thelarche and pubarche. METHODS: In this cross-sectional study, a previously validated questionnaire was administered to girls (15-18 years) in Breast Cancer and the Environment Research Program puberty cohort to ascertain if they met criteria for migraine over the past year. Ages of pubertal development were ascertained by serial examinations beginning at 6-8 years of age and ending in late puberty. Logistic regression analyses determined if age of onset of each pubertal milestone (thelarche, pubarche, menarche separately) was associated with adolescent migraine after adjusting for other risk factors. RESULTS: Of 761girls, 222 (29.2%) met the criteria for migraine. Later thelarche was associated with a lower odds of adolescent migraine (OR 0.83; 95% CI 0.72-0.97, p = 0.019). In models further adjusted for BASC-2 internalizing problems (n = 490), both later thelarche (OR 0.78; 95% CI 0.64-0.96, p = 0.016) and later menarche (OR 0.81; 95%CI 0.67-0.98, p = 0.026) were associated with a lower migraine prevalence. Internalizing problems (OR 1.05; 95% CI 1.03-1.07) externalizing problems (OR 1.05; 95% CI 1.02-1.07) and behavioral symptoms (OR 1.05; 95% CI 1.03-1.08) were associated with increased prevalence of migraine in separate models. CONCLUSIONS: Age of onset of thelarche and menarche, and internalizing, externalizing, and behavioral symptoms were all associated with adolescent migraine.

Predictors of treatment-response to acute prescription medications in migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study.

OBJECTIVE: To identify predictors of acute treatment optimization with prescription drugs among people with episodic migraine. METHODS: A total of 2896 individuals from the American Migraine Prevalence and Prevention study were included in this study. The primary outcome measures of treatment optimization were 2-h pain freedom (2hPF) and 24-h pain relief (24hPR), which were defined by responses to the Migraine Treatment Optimization Questionnaire-6 (mTOQ-6). We identified predictors of 2hPF and 24hPR in response to triptans, butalbital combination medications (BCMs), and opioids. RESULTS: PARTICIPANTS: were on average 47.3 years old (SD=12.0), 85.6 % were female, and 88.4 % were white, 46.9 % of participants reported 2hPF and 49.5 % reported 24hPR with their "usual acute treatment". The odds of adequate 2hPF response were reduced in men and those with higher average headache pain intensity, higher migraine symptom severity scores, presence of cutaneous allodynia, and depression. Adequate 24hPR was associated with being married, but declined in those with higher-than-average average headache pain intensity and frequency, greater disability, presence of cutaneous allodynia, and depression. Among participants reporting acute monotherapy, individuals taking triptans were more likely to have adequate treatment response in comparison with those taking BCMs (2hPF: OR=1.86, 95 %CI 1.42-2.42; 24hPR: OR=2.26, 95 %CI 1.73-2.96) and opioids (2hPF: OR=2.39, 95 %CI 1.94-2.96; 24hPR: OR=2.78, 95 %CI 2.24-3.44). There was no significant difference in response to treatment between the subsample taking BCMs and opioid users. CONCLUSION: Almost half of study respondents were not optimized on their usual prescription acute migraine treatment(s). Predictive models identified several features associated with treatment optimization.

Predictive models for determining treatment response to nonprescription acute medications in migraine: Results from the American Migraine Prevalence and Prevention Study.

OBJECTIVE: To identify predictors of acute treatment response for nonprescription (over-the-counter [OTC]) medications among people with migraine and develop improved models for predicting treatment response. BACKGROUND: Pain freedom and sustained pain relief are important priorities in the acute treatment of migraine. OTC medications are widely used for migraine; however, it is not clear which treatment works best for each patient without going through the trial and error process. METHODS: A prediction model development study was completed using the 2006 American Migraine Prevalence and Prevention Study survey, from participants who were aged ≥18, met criteria and headache day frequency for episodic migraine, did not take prescription medication for migraine, and used ≥1 of the following acute migraine medication classes: acetaminophen, aspirin, NSAIDs, or caffeine containing combination products (CCP). Two items from the Migraine Treatment Optimization Questionnaire were used to evaluate treatment response, adequate 2-h pain freedom (2hPF) and 24-h pain relief (24hPR), which were defined by a response to treatment ≥half the time at 2 h and 24 h post treatment, respectively. We identified predictors of adequate treatment response and developed models to predict probability of treatment response to each medication class. RESULTS: The sample included 3852 participants (3038 [79.0%] females) with an average age of 45.0 years (SD = 12.8). Only 1602/3852 (41.6%) and 1718/3852 (44.6%) of the participants reported adequate 2hPF and 24hPR, respectively. Adequate treatment-response was significantly predicted by lower average headache pain intensity, less cutaneous allodynia, and lower depressive symptom scores. Lower migraine symptom severity was predictive of adequate 2hPF and fewer monthly headache days was predictive of adequate 24hPR. Among participants reporting OTC monotherapy (n = 2168, 56.3%) individuals taking CCP were more likely to have adequate 2hPF (OR = 1.55, 95% CI 1.23-1.95) and 24hPR (OR = 1.79, 95% CI 1.18-1.88) in comparison with those taking acetaminophen. Predictive models were modestly predictive of responders to OTC medications (c-statistics = 0.65; 95% CI 0.62-0.68). CONCLUSION: These results show that response to acute migraine treatments is not optimized in the majority of people with migraine treating with OTC medications. Predictive models can improve our ability to choose the best therapeutic option for individuals with episodic migraine and increase the proportion of patients with optimized response to treatments.

Patient-Centered Treatment of Chronic Migraine With Medication Overuse: A Prospective, Randomized, Pragmatic Clinical Trial.

BACKGROUND AND OBJECTIVES: Overuse of symptomatic (i.e., acute) medications is common among those with chronic migraine. It is associated with developing frequent headaches, medication side effects, and reduced quality of life. The optimal treatment strategy for patients who have chronic migraine with medication overuse (CMMO) has long been debated. The study objective was to determine whether migraine preventive therapy without switching or limiting the frequency of the overused medication was noninferior to migraine preventive therapy with switching from the overused medication to an alternative medication that could be used on ≤2 d/wk. METHODS: The Medication Overuse Treatment Strategy (MOTS) trial was an open-label, pragmatic clinical trial, randomizing adult participants 1:1 to migraine preventive medication and (1) switching from the overused medication to an alternative used ≤2 d/wk or (2) continuation of the overused medication with no maximum limit. Participants were enrolled between February 2017 and December 2020 from 34 clinics in the United States, including headache specialty, general neurology, and primary care clinics. The primary outcome was moderate to severe headache day frequency during weeks 9 to 12 and subsequently during weeks 1 to 2 after randomization. RESULTS: Seven hundred twenty participants were randomized; average age was 44 (SD 13) years; and 87.5% were female. At baseline, participants averaged 22.5 (SD 5.1) headache days over 4 weeks, including 12.8 (SD 6.7) moderate to severe headache days and 21.4 (SD 5.8) days of symptomatic medication use. Migraine preventive medication without switching of the overused medication was not inferior to preventive medication with switching for moderate to severe headache day frequency during weeks 9 to 12 (switching 9.3 [SD 7.2] vs no switching 9.1 [SD 6.8]; p = 0.75, 95% CI -1.0 to 1.3). The treatment strategies also provided similar outcomes during the first 2 weeks (switching 6.6 [SD 3.7] moderate to severe headaches days vs no switching 6.4 [SD 3.6]; p = 0.57, 95% CI -0.4 to 0.7). DISCUSSION: When reduction in moderate to severe headache days was used as the outcome of interest for the management of CMMO, migraine preventive medication without switching or limiting symptomatic medication is not inferior to migraine preventive medication with switching to a different symptomatic medication with a maximum limit of 2 treatment days per week. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT02764320. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients who have CMMO, migraine preventive medication without switching or limiting the overused medication is noninferior to migraine preventive medication with switching and limiting symptomatic medication.

A rational approach to migraine diagnosis and management in primary care.

Migraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.Key messagesMigraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

PURPOSE: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population. METHODS: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing). FINDINGS: Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period. IMPLICATIONS: The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial.

OBJECTIVE: "Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. METHODS: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. RESULTS: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. CONCLUSIONS: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Headache characteristics and burden from chronic migraine with medication overuse headache: Cross-sectional observations from the Medication Overuse Treatment Strategy trial.

OBJECTIVE: To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH). METHODS: In all, 610 adult patients were enrolled into the Medication Overuse Treatment Strategy trial from 34 healthcare clinics, including headache specialty, general neurology, and primary care clinics. Descriptive statistics characterize baseline demographics, headache characteristics, medication use, disability (Headache Impact Test 6 [HIT-6] and Migraine Functional Impact Questionnaire [MFIQ]), pain interference (PROMIS Pain Interference), and quality of life (EQ-5D-5L). Relationships with headache frequency were assessed. RESULTS: Mean age was 45 years (SD 13) and 531/608 (87.3%) were females. Mean headache days per 30 was 24.3 (SD 5.5), including 13.6 (SD 7.1) with moderate to severe headache. Daily headaches were reported by 36.1% (219/607) of patients. Acute headache medications were used on 21.5 (SD 7.5) per 30 days. The most commonly overused medications were simple analgesics (378/607, 62% of patients), combination analgesics (246/607, 41%), and triptans (128/607, 21%). HIT-6, MFIQ, PROMIS Pain Interference, and EQ-5D-5L scores demonstrated substantial negative impact from CM with MOH on patient functioning and quality of life. Higher headache frequency was associated with more moderate-severe headache days, more frequent acute headache medication use, greater headache-related disability, and lower quality of life. Only 272/606 (44.9%) were taking migraine preventive medication. CONCLUSIONS: CM with MOH is associated with a large burden on patients in the United States. Higher headache frequency is associated with greater impact on functioning, pain interference, and quality of life.

Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study.

OBJECTIVE: To test the hypothesis that statistically defined subgroups of migraine (based on constellations of comorbidities and concomitant conditions; henceforth comorbidities), previously identified using Chronic Migraine Epidemiology and Outcomes (CaMEO) Study data, differ in prognosis, as measured by rates of progression from episodic migraine (EM) to chronic migraine (CM). METHODS: The onset of CM was assessed up to 4 times over 12 months in individuals with EM and ≥1 comorbidity at baseline, based on constellations of comorbidities (comorbidity classes). The "fewest comorbidities" class served as reference. Individuals completing ≥1 follow-up survey from the web-based CaMEO Study were included. Covariates included sociodemographic variables and headache characteristics. Sex, income, cutaneous allodynia, and medication overuse were modeled as binary variables; age, body mass index, headache-related disability (Migraine Disability Assessment [MIDAS]), and Migraine Symptom Severity Scale as continuous variables. CM onset was assessed using discrete time analysis. RESULTS: In the final sociodemographic model, all comorbidity classes had significantly elevated hazard ratios (HRs) for risk of progression to CM from EM, relative to fewest comorbidities. HRs for CM onset ranged from 5.34 (95% confidence interval [CI] 3.89-7.33; p ≤ 0.001) for most comorbidities to 1.53 (95% CI 1.17-2.01; p < 0.05) for the respiratory class. After adjusting for headache covariates independently, each comorbidity class significantly predicted CM onset, although HRs were attenuated. CONCLUSIONS: Subgroups of migraine identified by comorbidity classes at cross-section predicted progression from EM (with ≥1 comorbidity at baseline) to CM. The relationship of comorbidity group to CM onset remained after adjusting for indicators of migraine severity, such as MIDAS. CLINICALTRIALSGOV IDENTIFIER: NCT01648530.

Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To identify natural subgroups of people with migraine based on profiles of comorbidities and concomitant conditions, hereafter referred to as comorbidities. BACKGROUND: Migraine is a heterogeneous disease. Identifying natural subgroups (endophenotypes) may facilitate biological and genetic characterization and the development of personalized treatment. METHODS: The Chronic Migraine Epidemiology and Outcomes Study is a prospective web-based survey study designed to characterize the course of migraine and related comorbidities in a systematic US sample of people with migraine. Respondents were asked if they ever had a specific comorbidity and, if present, whether the comorbidity was confirmed/diagnosed by a "doctor"; 62 comorbidities were available for analysis. Latent class analysis (LCA) modeling determined the optimal number of classes and a parsimonious set of comorbidities. RESULTS: Of the 12,810 respondents with migraine, 11,837 reported ≥1 comorbidity and were included in this analysis. After statistical analysis and clinical judgment reduced the number of comorbidities, we selected an 8-class model based on 22 comorbidities. Each class had a distinct pattern summarized as follows: Class 1, Most Comorbidities; Class 2, Respiratory/Psychiatric; Class 3, Respiratory/Pain; Class 4, Respiratory; Class 5, Psychiatric; Class 6, Cardiovascular; Class 7, Pain; Class 8, Fewest Comorbidities. The distribution of individuals across models was variable, with one-third of respondents in Class 8 (Fewest Comorbidities) and <10% in Class 1 (Most Comorbidities). Demographic and headache characteristics, not used in assigning class membership, varied across classes. For example, comparing Class 1 (Most Comorbidities) and Class 8 (Fewest Comorbidities), Class 1 had a greater proportion of individuals with severe disability (Migraine Disability Assessment grade IV; 48.1% vs 22.3% of overall individuals) and higher rates of allodynia (67.6% vs 47.0%), medication overuse (36.4% vs 15.0%), chronic migraine (23.1% vs 9.1%), and aura (40.1% vs 28.8%). CONCLUSIONS: LCA modeling identified 8 natural subgroups of persons with migraine based on comorbidity profiles. These classes show differences in demographic and headache features not used to form the classes. Subsequent research will assess prognostic and biologic differences among the classes.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Forecasting Individual Headache Attacks Using Perceived Stress: Development of a Multivariable Prediction Model for Persons With Episodic Migraine.

OBJECTIVE: To develop and validate a prediction model that forecasts future migraine attacks for an individual headache sufferer. BACKGROUND: Many headache patients and physicians believe that precipitants of headache can be identified and avoided or managed to reduce the frequency of headache attacks. Of the numerous candidate triggers, perceived stress has received considerable attention for its association with the onset of headache in episodic and chronic headache sufferers. However, no evidence is available to support forecasting headache attacks within individuals using any of the candidate headache triggers. METHODS: This longitudinal cohort with forecasting model development study enrolled 100 participants with episodic migraine with or without aura, and N = 95 contributed 4626 days of electronic diary data and were included in the analysis. Individual headache forecasts were derived from current headache state and current levels of stress using several aspects of the Daily Stress Inventory, a measure of daily hassles that is completed at the end of each day. The primary outcome measure was the presence/absence of any headache attack (head pain > 0 on a numerical rating scale of 0-10) over the next 24 h period. RESULTS: After removing missing data (n = 431 days), participants in the study experienced a headache attack on 1613/4195 (38.5%) days. A generalized linear mixed-effects forecast model using either the frequency of stressful events or the perceived intensity of these events fit the data well. This simple forecasting model possessed promising predictive utility with an AUC of 0.73 (95% CI 0.71-0.75) in the training sample and an AUC of 0.65 (95% CI 0.6-0.67) in a leave-one-out validation sample. This forecasting model had a Brier score of 0.202 and possessed good calibration between forecasted probabilities and observed frequencies but had only low levels of resolution (ie, sharpness). CONCLUSIONS: This study demonstrates that future headache attacks can be forecasted for a diverse group of individuals over time. Future work will enhance prediction through improvements in the assessment of stress as well as the development of other candidate domains to use in the models.

Headache Disorders May Be a Risk Factor for the Development of New Onset Hypothyroidism.

OBJECTIVE: To determine whether headache disorders are a risk factor for the development of new onset hypothyroidism. BACKGROUND: Past studies have reported associations between headache disorders and hypothyroidism, but the directionality of the association is unknown. METHODS: This was a longitudinal retrospective cohort study using data from the Fernald Medical Monitoring Program (FMMP). Residents received physical examinations and thyroid function testing every 3 years during the 20 year program. Residents were excluded from the cohort if there was evidence of past thyroid disease or abnormal thyroid function tests at the first office visit. A diagnosis of a headache disorder was established by self-report of "frequent headaches," use of any headache-specific medication, or a physician diagnosis of a headache disorder. The primary outcome measure was new onset hypothyroidism defined as the initiation of thyroid replacement therapy or TSH ≥ 10 without thyroid medication. A Cox survival analysis with time dependent variables were used for the model. Headache disorders, age, sex, body mass index, income, smoking, narcotic use, and hypothyroidism-producing medications were independent variables in the model. RESULTS: Data from 8412 residents enrolled in the FMMP were used in the current study. Headache disorders were present in about 26% of the residents and new onset hypothyroidism developed in ∼7%. The hazard ratio for the development of new onset hypothyroidism was 1.21 (95% CI = 1.001, 1.462) for those with headache disorders. CONCLUSIONS: Headache disorders may be associated with an increased risk for the development of new onset hypothyroidism.

Diet and Headache: Part 2.

BACKGROUND: Comprehensive diets do not require the exclusion of a specific provocative food or ingredient, but regulate the quantities of core components of foods such as vitamins, ions, proteins, carbohydrates, and fats. OBJECTIVES: To review the evidence supporting the use of comprehensive diets in the prevention of migraine and other headache disorders and to discuss the mechanisms through which food, and ingredients within foods and beverages might trigger attacks of headache METHODS: This represents Part 2 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: "folate," "vitamin D," "low fat diet," "omega-3 and omega-6 fatty acid diet," "ketogenic diet," "Atkins diet," and "sodium." Each of these search terms was then crossreferenced with "headache" and "migraine" to identify relevant studies. Only studies that were written in English were included in this review. RESULTS: Low fat and high omega-3/low omega-6 fatty diets decrease the frequency of attacks of migraine and/or other headache disorders as demonstrated in two separate randomized controlled trials. A ketogenic diet was more effective than a standard diet in reducing the frequency of migraine in a single nonrandomized clinical study. An observation study found that dietary consumption of folate was inversely associated with the frequency of migraine attacks in persons with migraine with aura that have the C variant of the methylene tetrahydrofolate reductase gene. The mechanisms though which diets may precipitate headache include their effects on neuropeptides, neuro-receptors and ion channels, inflammation, sympathetic nervous system, release of nitric oxide, vasodilation, and cerebral glucose metabolism. CONCLUSIONS: Evidence exists to support the use of comprehensive diets in the prevention of migraine and other headache disorders. However, the results of these studies should be considered preliminary until replicated in larger randomized controlled clinical trials.

Diet and Headache: Part 1.

BACKGROUND: The role of diet in the management of the headache patient is a controversial topic in the headache field. OBJECTIVES: To review the evidence supporting the hypothesis that specific foods or ingredients within foods and beverages trigger attacks of headache and/or migraine and to discuss the use of elimination diets in the prevention of headache disorders METHODS: This represents part 1 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: "monosodium glutamate," "caffeine," "aspartame," "sucralose," "histamine intolerance syndrome," "tyramine," "alcohol," "chocolate," "nitrites," "IgG elimination diets," and "gluten." Each of these search terms was then cross-referenced with "headache" and "migraine" to identify relevant studies. Only studies that were written in English were included in this review. RESULTS: Caffeine withdrawal and administration of MSG (dissolved in liquid) has the strongest evidence for triggering attacks of headache as evidenced by multiple positive provocation studies. Aspartame has conflicting evidence with two positive and two negative provocation studies. Observational studies provide modest evidence that gluten- and histamine-containing foods as well as alcohol may precipitate headaches in subgroups of patients. Two of three randomized controlled trials reported that an elimination diet of IgG positive foods significantly decreased frequency of headache/migraine during the treatment as compared to baseline time period. CONCLUSIONS: Certain foods, beverages, and ingredients within foods may trigger attacks of headache and/or migraine in susceptible individuals. Elimination diets can prevent headaches in subgroups of persons with headache disorders.

Perimenopause and Menopause Are Associated With High Frequency Headache in Women With Migraine: Results of the American Migraine Prevalence and Prevention Study.

OBJECTIVES: To examine the relationship of headache frequency to the stages of the menopausal transition in mid-life women with migraine. BACKGROUND: Past studies suggest that the perimenopause is associated with an increased prevalence of migraine, particularly in those with a history of premenstrual syndrome. The effect of the menopausal transition on the frequency of headache attacks in women with migraine has not been explored. METHODS: This was a cross-sectional observational study. Using data from the 2006 American Migraine, Prevalence and Prevention study survey, women meeting modified ICHD-3 beta criteria for migraine between the ages of 35-65 years were included in analyses. Women who had never menstruated or were pregnant, breastfeeding, or using exogenous sex hormones were excluded. The 2006 survey was selected because it included detailed questions on the menstrual cycle. The stages of the menopausal transition were defined based upon the self-reported cycle length and/or duration of amenorrhea. The primary outcome, high vs low headache frequency, was defined using a cut score of ≥10 headache days per month. Binary logistic regression models were used to assess the influence of menopausal stage on headache frequency category using premenopause as the reference group. Adjustments for stage of menopausal transition and sociodemographics (eg, age and income) were included in the first model, while the second model included sociodemographics, depression, body mass index, preventative medications, and medication overuse. RESULTS: The study sample included 3664 women at a mean age of 46 years. Among women who were premenopausal, 8.0% (99/1242) were in the high frequency headache group in comparison with 12.2% (154/1266) of perimenopausal and 12.0% (131/1095) of postmenopausal women. Compared with premenopausal women, the adjusted odds of being in the high frequency headache group was 1.62 (95% CI = 1.23, 2.12) for perimenopausal and 1.76 (95% CI = 1.23, 2.52) for postmenopausal women (Model 1). In model 2, high frequency headache was only increased in perimenopausal women with an OR of 1.42 (95% CI = 1.03, 1.94). CONCLUSIONS: The risk of high frequency headache is increased in women during the perimenopause compared to premenopause in the fully adjusted model. The fact that the increased risk of high frequency headache was not statistically significant for menopause in the fully adjusted models suggests that different mechanisms might account for the increased risk for this stage of the menopausal transition. Recognition of the increased risk of high frequency headache during the menopausal transition suggests a need for optimized preventive treatment of migraine during this time of women's life.

Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study.

OBJECTIVES: To test the hypothesis that in persons with episodic migraine (EM), asthma is a risk factor for the onset of chronic migraine (CM). BACKGROUND: Migraine and asthma are comorbid chronic disorders with episodic attacks thought to involve inflammatory and neurological mechanisms. Herein, we assess the influence of asthma on the clinical course of EM. METHODS: To be eligible for this observational cohort study, AMPP Study participants had to meet criteria for EM in 2008, complete the validated six-item asthma questionnaire from the European Community Respiratory Health Survey (ECRHS) in 2008, and provide follow-up data in 2009. Using the ECRHS, we defined asthma as a binary variable (present or absent) based on an empirical cut score and developed a Respiratory Symptom Severity Score (RSSS) based on the number of positive responses (no severity = 0 positive responses, low severity = 1-2 positive responses, moderate severity = 3-4 positive responses, high severity = 5-6 positive responses). Chronic migraine was the primary outcome measure and was defined as those with ≥15 headache days per month on the 2009 AMPP Study survey. We used logistic regression in separate models to assess the influence of asthma as a binary variable (Model 1) and RSSS score categories (Model 2 using no respiratory symptoms as the reference) on CM onset after adjusting for sociodemographic factors, headache day frequency, migraine preventive medication use, and medication overuse. RESULTS: The eligible sample for this study included 4446 individuals with EM in 2008 of whom 17% had asthma. This group had a mean age of 50.4 and was 80.8% female. In 2009, new onset CM developed in 2.9% (131/4446) of the 2008 EM cohort, including 5.4% (40/746) of the asthma subgroup and 2.5% (91/3700) of the non-asthma subgroup. In comparison to those without asthma, the adjusted odds for individuals with asthma and EM in 2008 to develop CM in 2009 were greater than two (adjusted odds ratio [aOR] 2.1; 95% CI: 1.4-3.1). Using the RSSS, the aOR for CM onset increased with the number of asthma symptoms, but only those in the high RSSS category showed a statistically significant increase in the odds of chronic migraine onset in comparison with the no RSSS reference group (aOR 3.3; 95% CI 1.7-6.2). CONCLUSIONS: Asthma is associated with an increased risk of new onset CM 1 year later among individuals with EM, with the highest risk being among those with the greatest number of respiratory symptoms. The exact mechanisms underlying this association are unknown, but could suggest mast cell degranulation, autonomic dysfunction, or shared genetic or environmental factors.

Joint hypermobility and headache: understanding the glue that binds the two together--part 1.

BACKGROUND: Heritable connective tissue disorders (HCTD) present with a wide array of findings, including headache. Because of their unusual substrate, headaches in HCTD can derive from both common and uncommon circumstances. METHODS: Literature review. RESULTS: Ehlers-Danlos hypermobile type can be recognized by multiple joint findings and its tendency to progress to a multisystem chronic pain syndrome. Ehlers-Danlos classic type also manifests joint laxity and similar pain complaints, but is differentiated by its skin laxity and fragility. Ehlers-Danlos vascular type presents the most severe risk due to blood vessel and hollow organ rupture. Marfan syndrome demonstrates skeletal abnormalities, lens dislocations, and aortic root dilation that can result in dissection. CONCLUSIONS: In a headache patient, recognizing the presence of an HCTD improves the strategy for diagnosis and management. A brief review of findings related to joints, skin, and arteries may prompt further investigation into the HCTDs.