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Objective: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men. Background: Women report longer migraine attacks and more accompanying symptoms than men in cross-sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general. Methods: This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was “attack” duration. Differences between perimenstrual (Days −2 to +3 of the menstrual cycle) and non-perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache. Results: A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1−Q3]) attack duration in men was 32.1 [17.7–53.6] h, compared to 36.7 [21.9–62.4] h for non-perimenstrual migraine attacks and 44.4 [17.9–79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47–1.79; p < 0.001) and non-perimenstrual 1.15 (95% CI 1.05–1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non-perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93–2.95; p < 0.001), but not for non-perimenstrual (OR 1.18, 95% CI 0.97–1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura. Conclusion: Compared to attacks in men, both perimenstrual and non-perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex-specific approach to migraine treatment and research is needed.

Background and ObjectivesEndogenous and exogenous female sex hormones are considered important contributors to migraine pathophysiology. Previous studies have cautiously suggested that perimenstrual migraine attacks have a longer duration and are associated with higher disability compared to nonperimenstrual attacks, but they showed conflicting results on acute therapy efficacy, pain intensity, and associated symptoms. We compared perimenstrual and nonperimenstrual migraine attack characteristics and assessed premenstrual syndrome (PMS) in women with migraine.MethodsWomen with migraine were invited to complete a headache e-diary. Characteristics of perimenstrual attacks and nonperimenstrual attacks were compared. The primary outcome was attack duration. Secondary outcomes were headache intensity, accompanying symptoms, acute medication intake, and pain coping. Mixed effects models were used to account for multiple attacks within patients. PMS was assessed in patients without hormonal contraceptives. Subgroup analyses were performed for women with menstrually related migraine (MRM) and nonmenstrually related migraine (non-MRM) and women with a natural menstrual cycle and women using hormonal contraceptives.ResultsA representative group of 500 participants completed the e-diary for at least 1 month. Perimenstrual migraine attacks (n = 998) compared with nonperimenstrual attacks (n = 4097) were associated with longer duration (20.0 vs 16.1 hours, 95% confidence interval 0.2–0.4), higher recurrence risk (odds ratio [OR] 2.4 [2.0–2.9]), increased triptan intake (OR 1.2 [1.1–1.4]), higher headache intensity (OR 1.4 [1.2–1.7]), less pain coping (mean difference −0.2 [−0.3 to −0.1]), more pronounced photophobia (OR 1.3 [1.2–1.4]) and phonophobia (OR 1.2 [1.1–1.4]), and less aura (OR 0.8 [0.6–1.0]). In total, 396/500 women completed the diary for ≥3 consecutive menstrual cycles, of whom 56% (221/396) fulfilled MRM criteria. Differences in attack characteristics became more pronounced when focusing on women with MRM and women using hormonal contraceptives. Prevalence of PMS was not different for women with MRM compared to non-MRM (11% vs 15%).DiscussionThe longer duration of perimenstrual migraine attacks in women (with MRM) is associated with higher recurrence risk and increased triptan use. This may increase the risk of medication overuse and emphasizes the need to develop female-specific prophylactic treatment.

Background Cyclic hormonal fluctuations influence migraine incidence and severity. Previously, we described reduced menstrual cyclicity in estradiol levels and dermal blood flow reaction to capsaicin in female migraineurs. It is unclear whether pain perception in women with migraine is influenced by the menstrual cycle. Methods Women with menstrually-related migraine (n = 14), healthy age-matched controls (n = 10) and postmenopausal women (n = 15) were asked to grade trigeminal and non-trigeminal painful stimuli on a numeric pain rating scale on menstrual cycle day 19–21 (mid-luteal) and day 1–2 (early follicular). Results In women with menstrually-related migraine, trigeminal pain remained low throughout the cycle. Controls showed increased trigeminal pain during the mid-luteal phase compared to the early follicular phase. Changes throughout the cycle were significantly different between women with MRM and controls. Conclusion The compromised menstrual cyclicity of pain perception in women with menstrually-related migraine parallels our earlier findings on estradiol levels and dermal blood flow.

Objective To assess validity of ICHD-3 diagnostic criteria for menstrual migraine. Methods We performed a longitudinal E-diary study in premenopausal women with migraine. Menstrual migraine diagnosis was self-reported at baseline, and verified according to diary based ICHD-3 criteria and a previous proposed statistical model. Validity of self-reported menstrual migraine was compared to diary based diagnosis and statistical diagnosis. Test-retest reliability and concordance between both methods were determined. Clinical characteristics of perimenstrual and non-perimenstrual migraine attacks were compared in women with and without menstrual migraine. Results We included 607 women. Both women who did and women who did not self-report to suffer from menstrual migraine fulfilled ICHD-3 criteria in the E-diary in two thirds of cases. Pure menstrual migraine was extremely rare (Conclusion Self-reported menstrual migraine diagnosis has extremely poor accuracy. Two thirds of women suffer from menstrual migraine, independent of self-reports. Pure menstrual migraine is rare. Women with menstrual migraine have longer attack duration and increased triptan intake during perimenstrual attacks, in contrast to women without menstrual migraine. Prospective headache (E-)diaries are required for a menstrual migraine diagnosis, also in clinical practice.

Background There is a need for standardization of the definition of a migraine day for clinical and research purposes. Methods We prospectively compared different definitions of a migraine day with E-diary data of n = 1494 patients with migraine. We used a baseline definition based on migraine characteristics with a duration of ≥4 hours OR triptan intake (independently from its effect) OR (visual) aura lasting 5–60 minutes. Results Of all migraine days defined by triptan intake only, 66.2% had a duration Conclusion We propose to define a migraine day as follows: 1) (a) headache duration ≥30 minutes; (b) matching ≥2 of four characteristics: unilateral, pulsating, moderate to severe pain, aggravation by or causing avoidance of routine physical activity; and (c) during headache ≥1 of the following: nausea and/or vomiting, photophobia and phonophobia or 2) (visual) aura duration 5–60 minutes or 3) a day with headache for which acute migraine-specific medication is used irrespective of its effect.

Background The objective of this study was to assess whether migraine-related outcomes changed during intelligent lockdown when compared with the prior period. Methods This was a cohort study evaluating the first month of intelligent lockdown in the Netherlands (12 March to 8 April 2020) compared with one baseline month (13 February to 11 March 2020). We identified 870 migraine patients treated at the Leiden Headache Center with headache e-diaries during the period of interest. Adherence to the e-diary had to be ≥80%, yielding 592 enrolled patients. Results Intelligent lockdown led to a decrease in monthly migraine days (−0.48; 95% CI: −0.78 to −0.18, p = 0.002) and acute medication days (−0.48; 95% CI: −0.76 to −0.20, p Conclusions Our findings imply that intelligent lockdown measures can improve migraine disability despite of the potential negative effects of COVID-19 and lockdown. We hypothesise that this effect is a combined result of working from home, scaling down demanding social lives, and freedom to choose how to organise one’s time.

Aim To determine whether our E-diary can be used to diagnose migraine and provide more reliable migraine-related frequency numbers compared to patients’ self-reported estimates. Methods We introduced a self-developed E-diary including automated algorithms differentiating headache and migraine days, indicating whether a patient has migraine. Reliability of the E-diary diagnosis in combination with two previously validated E-questionnaires was compared to a physician’s diagnosis as gold standard in headache patients referred to the Leiden Headache Clinic (n = 596). In a subset of patients with migraine (n = 484), self-estimated migraine-related frequencies were compared to diary-based results. Results The first migraine screening approach including an E-headache questionnaire, and the E-diary revealed a sensitivity of 98% and specificity of 17%. In the second approach, an E-migraine questionnaire was added, resulting in a sensitivity of 79% and specificity of 69%. Mean self-estimated monthly migraine days, non-migrainous headache days and days with acute medication use were different from E-diary-based results (absolute mean difference ± standard deviation respectively 4.7 ± 5.0, 6.2 ± 6.6 and 4.3 ± 4.8). Conclusion The E-diary including algorithms differentiating headache and migraine days showed usefulness in diagnosing migraine. The use emphasised the need for E-diaries to obtain reliable information, as patients do not reliably recall numbers of migraine days and acute medication intake. Adding E-diaries will be helpful in future headache telemedicine.

Aim To examine the effect of sex on migraine trigger factors. Methods Prevalence of 11 frequently reported trigger factors was determined in a cross-sectional study among migraine patients from a validated migraine database (n = 5725 females and n = 1061 males). Female-to-male odds ratios were calculated for each trigger, using a logistic regression model with attack frequency and migraine subtype (with or without aura) as covariates. Additionally, the effect of sex on total number of triggers per individual was determined. Results The top three most reported triggers in women were menstruation (78%), stress (77%), and bright light (69%). Men reported stress (69%), bright light (63%), and sleep deprivation (60%) most frequently as provoking factors. The following triggers were more often reported by women than men: Bright light (odds ratio 1.29 [95% CI 1.12–1.48]; p = 0.003), stress (1.47 [1.27–1.69]; p

Migraine prevalence is three times higher in women than in men during fertile years, which is mainly due to sex hormone differences. The majority of women suffering from migraine without aura report improvement of their migraine attacks during pregnancy. Migraine attacks with aura can also improve during pregnancy, but more often remain the same or worsen. Anovulation caused by lactation is generally associated with a decrease in migraine attacks in breastfeeding women. This chapter describes the current knowledge on acute and prophylactic treatment options of migraine and other primary headache disorders during pregnancy and lactation. Further, clinical profiles of secondary headaches during pregnancy and the postpartum period are summarized.

ObjectiveTo examine the effect of sex on clinical response to triptans in migraine and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis.MethodsWe searched clinical trials distinguishing clinical response to or pharmacokinetic parameters of triptans between sexes in PubMed, MEDLINE, Cochrane Library, Embase, and Web of Science up to Dec 12, 2019. Analysis was based on data extracted from published reports. Male-to-female pooled risk ratios (RR) were calculated for clinical outcomes and pooled ratio of means (RoM) for pharmacokinetic outcomes using random-effects models.ResultsOf 1,188 publications on clinical trials with triptans, 244 were identified with sex-related search terms. Only 19 publications presented sex-specific results, comprising n = 2,280 men and n = 13,899 women. No sex differences were revealed for 2-hour headache and pain-free responses, but men had a lower risk for headache recurrence (male-to-female RR 0.64, 95% confidence interval [CI]: 0.55–0.76, Q = 0.81) and adverse events (RR 0.82, 95% CI: 0.72–0.93, Q = 4.93). Men had lower drug exposure with lower area under the curve (RoM 0.69, 95% CI: 0.60–0.81, Q = 18.06) and peak drug concentration (RoM 0.72, 95% CI: 0.64–0.82, Q = 8.24) than women.ConclusionsRemarkably few publications about sex differences in triptan response are available. The limited number of eligible studies show sex differences in adverse event frequency, which may be partly because of drug exposure differences. This higher drug exposure in women is not reflected in different response rates. Despite higher exposure, women have higher headache recurrence rates possibly because of longer attack duration related to sex hormonal changes.

Migraine prevalence is three times higher in women than in men, which is mainly due to sex hormone differences. Hormonal fluctuations related to the menstruation and menopausal transition phase are associated with increased incidence of migraine attacks. Especially migraine attacks triggered by hormonal changes are more resistant to pharmacological treatment. This chapter describes the current knowledge on the role of hormonal fluctuations throughout the menstrual cycle in migraine patients. Further, specific treatments for pure menstrual migraine, menstrually related migraine, and perimenopausal migraine are discussed.