114 Chapter 5 Table 5. Recommendations for future editions of the ICHD criteria for menstrual migraine. Diagnostic criteria A. Attacks fulfilling criteria for migraine without aura1. B. In a menstruating woman with migraine1. C. Starting on day 1 ± 2 (i.e., days −2 to +3)2 of menstruation3 in at least two out of three4 menstrual cycles. D. Attacks may occur additionally at other times of the cycle. Notes 1. On a patient level the diagnosis can be migraine with aura, but with additional migraine attacks without aura. Only the migraine attacks without aura are related to menstruation, and should be counted as perimenstrual migraine attacks. 2. The first day of menstruation is day 1 and the preceding day is day −1; there is no day 0. 3. Menstruation is considered to be endometrial bleeding resulting either from the natural menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of combined oral contraceptives or cyclical hormone replacement therapy. 4. A prospective (E-)diary is required for both research purposes and clinical practice. Estrogens have excitatory properties and can alter neuronal excitability.15, 16 One possible theory behind different effects of estradiol on the trigeminovascular system and the initiation of cortical spreading depolarization (CSD) may lie in the long-term effects from nuclear estradiol receptors and short-term effects via transmembrane receptors.17, 18 After a rapid drop in estradiol levels, an imbalance between these effects may predispose a woman to migraine headaches, while long-term elevated estradiol levels may be necessary to predispose a woman to migraine aura. Migraine auras are thought to originate from CSD, a short-term depolarizing wave that slowly expands from the occipital cortex and is followed by a sustained hyperpolarization of neurons.19 In a CACNA1A knockin migraine mouse model, the susceptibility to CSD was studied and found to be higher in female mice compared to males.20, 21 This sex difference disappeared after ovariectomy in females and partially reappeared after treatment with 17β-estradiol.21 Other in vitro studies have shown similar results.22-24 Increased estradiol levels during pregnancy and breastfeeding are therefore hypothesized to increase the susceptibility to CSD and thereby initiate migraine attacks with aura in women.3, 21, 22, 25-27 Extrapolating these findings directly to humans is however complicated, as mice have a 4-day ovarian cycle, which is hardly comparable to the menstrual cycle in humans.28 This underlines the necessity of clinical studies with E-diary data on the menstrual cycle in humans. In a small study estradiol levels were found to be elevated prior to ovulation in women with MA compared to headache-free controls and women with MO, but no differences were found prior to menstruation.29 Clinically, ovulation has not been
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