Sex differences in migraine attack characteristics:A longitudinal E-diary study

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 &lt; 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 &lt; 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.</p

Continuous combined oral contraceptive use versus vitamin E in the treatment of menstrual migraine:rationale and protocol of a randomized controlled trial (WHAT!)

Background: Currently, there is no evidence-based hormonal treatment for migraine in women. Several small studies suggest a beneficial effect of combined oral contraceptives, but no large randomized controlled trial has been performed. As proof of efficacy is lacking and usage may be accompanied by potentially severe side effects, there is a great need for clarity on this topic. Methods: Women with menstrual migraine (n = 180) are randomly assigned (1:1) to ethinylestradiol/levonorgestrel 30/150 μg or vitamin E 400 IU. Participants start with a baseline period of 4 weeks, which is followed by a 12-week treatment period. During the study period, a E-headache diary will be used, which is time-locked and includes an automated algorithm differentiating headache and migraine days. Results: The primary outcome will be change in monthly migraine days (MMD) from baseline (weeks − 4 to 0) to the last 4 weeks of treatment (weeks 9 to 12). Secondary outcomes will be change in monthly headache days (MHD) and 50% responder rates of MMD and MHD. Conclusions: The WHAT! trial aims to investigate effectivity and safety of continuous combined oral contraceptive treatment for menstrual migraine. Immediate implementation of results in clinical practice is possible. Trial registration: Clinical trials.gov NCT04007874. Registered 28 June 2019.</p

Sex differences in prevalence of migraine trigger factors: A cross-sectional study

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 < 0.001), skipping a meal (1.24 [1.09–1.42]; p = 0.015), sleep deprivation (1.37 [1.20–1.57]; p < 0.001), high altitudes (1.70 [1.40–2.09]; p < 0.001), and weather changes (1.35 [1.18–1.55]; p < 0.001). Women reported more triggers than men, even when menstruation was disregarded (mean ± SD: 4.6 ± 2.3 and 4.3 ± 2.3; p < 0.001). Conclusion: Women report migraine trigger factors to be provocative of their attacks more frequently than men, which may be related to a lower migraine threshold due to sex hormonal changes

Pain perception in women with menstrually-related migraine

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

Validation of diagnostic ICHD-3 criteria for menstrual migraine

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 (<1%). Concordance between statistical and diary based diagnosis was minimal (κ = 0.28, 95% CI:0.23–0.33). Women diagnosed with menstrual migraine showed 37–50% longer attack duration and increased triptan intake (OR 1.19–1.22, p < 0.001) during perimenstrual attacks. 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

Migraine with and without aura in relation to the menstrual cycle and other hormonal milestones: A prospective cohort study

BACKGROUND: Previous studies showed that the perimenstrual window is associated with an increased susceptibility to migraine attacks without aura, but had conflicting results regarding attacks with aura. METHODS: We performed a longitudinal E-diary study among 526 premenopausal women with migraine. Differences in occurrence of perimenstrual migraine attacks between women with migraine with aura and without aura were assessed using a mixed effects logistic regression model. Additionally, participants completed a questionnaire about the influence of hormonal milestones on migraine frequency. RESULTS: Prevalence of menstrual migraine did not differ between women with migraine without aura and migraine with aura (59% versus 53%, p  =  0.176). The increased risk of migraine attacks without aura during the perimenstrual window was similar for women with migraine without aura (OR[95%CI]:1.53 [1.44-1.62]) and those with migraine with aura (1.53 [1.44-1.62]). The perimenstrual window was not associated with increased risk of migraine aura attacks (1.08 [0.93-1.26], p = 0.314). Women with migraine with aura more often reported increased migraine frequency during pregnancy and breastfeeding compared to women with migraine without aura, but not during hormonal contraception use. CONCLUSION: Sex hormone levels seem to differently affect the trigeminovascular system (migraine headache) and the susceptibility to cortical spreading depolarization (aura). Exclusively migraine attacks without aura should be interpreted as perimenstrual attacks