In light of important new information reported on menstrual migraine (MM) in recent years, including evidence that has led to a revision of the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria for MM, a narrative review aimed to summarize recent data on pathophysiology, epidemiology, burden of disease and treatment of MM was published in the Journal of Neurology.
The goal of this review was to provide an updated overview on the topic of MM. Researchers conducted a literature search to identify relevant studies, reviews and abstracts from MEDLINE, PubMed, Cochrane Library and EMBASE databases published between 1972 and October 2019.
According to the ICHD-3 classification, a diagnosis of MM includes both migraine related to menstruation (MRM) and pure menstrual migraine (PMM) and there are criteria for PMM and MRM with and without aura. In both cases, women reported that migraines occur more frequently during menses, and that those are more severe than other migraines. The diagnostic criteria included migraine attacks in a menstruating woman that occur in a range of 2 days before to 3 days after menstruation in ≥2 of 3 menstrual cycles.
Estrogens play multiple actions in migraine when intense hormonal fluctuations occur leading up to and immediately after menstruation. The “estrogen withdrawal hypothesis,” described more than 40 years ago, relates to estrogen fluctuations across the menstrual cycle and has been implicated in the initiation of migraine attack. The drop in estrogen levels mid-cycle can lead to a significant increase in prostaglandins, resulting in neurogenic inflammation, release of various neuropeptides, including substance P, neurokinins and calcitonin gene-related peptide (CGRP). Furthermore, estrogens and estrogen receptors are widely expressed in the brain and in
the trigeminovascular system. A clear association between progesterone fluctuations and migraine attacks was not appreciated.
As for the genetic aspects of MM, polymorphisms in tumor necrosis factor alpha (TNFα), Spectrin Repeat Containing Nuclear Envelope 1 (SYNE1), and neurophilin 1 (NRP1) gene were found to be associated with MM.
MRM is more common than PMM and studies have reported wide variations in the prevalence MM, with one Norwegian study reporting a prevalence of 7.6%. Of note, a higher occurrence of MM along with menstrual cycle synchrony was evident among women living together, compared with those living alone.
It is noted that MM may change over a woman’s reproductive life. Higher headache intensity was reported among women with MM during early pregnancy and postpartum period, compared with those without MM. Although serum estradiol levels are low during the perimenopausal period, MM can appear during menopausal transition.
Compared with nonmenstrual migraine, attacks of MM are frequently more debilitating with longer duration, higher recurrence rate and lower response rate to acute treatment. However, there are no specific treatment options for MM approved by the United States Food and Drug Administration or the European Medicine Agency.
The available treatment options for acute migraine including triptans, nonsteroidal anti-inflammatory drugs (NSAID) and ergot derivatives. Triptans have the strongest evidence for acute MM treatment, with positive reports on the use of almotriptan, naratriptan, sumatriptan, and zolmitriptan.
Preventive treatment may be important as the response to acute treatment is frequently limited. Short-term prophylactic therapies administered only during the perimenstrual period include triptans, estrogen, and naproxen. Triptans also have the strongest evidence for preventive MM treatment, including frovatriptan, naratriptan, and zomitriptan.
Continuous prophylactic treatment with hormonal contraceptives may be effective, but there are concerns regarding the risk for vascular disease and stroke associated with these agents. Furthermore, oral contraceptives should not be used for MM with aura, as they may further increase the vascular risk. Limited data are available on the use of phytoestrogens, Vagus Nerve Simulation and Onabotulinium A for MM prophylaxis.
Additional studies have suggested a potential benefit for perimenstrual use of telcagepant, a CGRP receptor antagonist. Several additional antibodies directed against CGRP or CGRP receptor may prove to be useful in these cases. The development of ditans and gepants might represent a major progress, not only in the treatment of migraine, but also in the treatment of MM.
“Understanding the mechanisms that contribute to neuroendocrine vulnerability in some women and some menstrual cycles may yield possible marker of the disease opening treatment options specifically targeting MM, concluded the study authors. They also note that, “An increased interest for future research on the subject will further elucidate how to manage this debilitating type of migraine.”
Cupini LM, Corbelli I, Sarchelli P. Menstrual migraine: what it is and does it matter? [published online January 28, 2020]. J Neurol. doi:10.1007/s00415-020-09726-2