ABSTRACT & COMMENTARY

Migraines: Much More Complicated Than Just a Headache

By Dara Jamieson, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Jamieson reports no financial relationships relevant to this field of study.

SYNOPSIS: Migraine is associated with multiple disorders, including irritable bowel syndrome, restless legs syndrome, and non-alcoholic fatty liver disease. Understanding how these disparate disorders link to migraine may lead to an increased understanding of the pathogenesis of this complex neurological condition.

SOURCES: Lau CI, et al. Association between migraine and irritable bowel syndrome: A population-based retrospective cohort study. Eur J Neurol 2014;21:1198-1204.

Zanigni S, et al. Association between restless legs syndrome and migraine: A population-based study. Eur J Neurol 2014;21:1205-1210.

Celikbilek A, et al. Non-alcoholic fatty liver disease in patients with migraine. Neurol Sci 2014; Apr 23. DOI 10.1007/s10072-014-1798-1.

Migraine is multifaceted with many different presentations of pain and associated neurological symptoms. Multiple disparate neurologic and non-neurologic disorders without an intuitive association appear linked to migraine. Migraine and irritable bowel syndrome (IBS) both have triggered episodic pain in an overlapping population. In a retrospective, case-control study, the association between migraine and IBS was investigated using data from the National Health Insurance Research Database of Taiwan, with 14,117 newly diagnosed migraine cases and 56,468 migraine-free individuals as the comparison cohort. Every patient with newly diagnosed migraine was observed until a diagnosis of IBS was made. Using the multivariate Cox proportional hazards regression model, the incidence of IBS was 1.95-fold higher in the migraine cohort than in the comparison cohort (73.87 vs 30.14 per 10,000 person-years). The adjusted cumulative incidence of IBS was also higher in the migraine group than in the control group in the follow-up years, with the risk found to be most prominent in the youngest group (< 30 years old), who exhibited a 3.36-fold increased risk of IBS. The incidence of IBS in migraine sufferers tended to increase with the frequency of migraine-related outpatient visits or hospital admissions per year. This retrospective, cohort, population-based study demonstrated that migraine is associated with an increased risk of IBS after adjusting for comorbidities, particularly in the young population. The authors invoke a genetically predisposed hyperexcitable nervous system, with a serotonergic mechanism, to explain a shared pathophysiology of migraine and IBS.

Restless legs syndrome (RLS) has been noted with increased prevalence in migraineurs. Zanigni et al assessed the association using a computer-assisted personal interview and self-administered questionnaires with 1567 adults living in South Tyrol, Italy. The questionnaires were based on the International Classification of Headache Disorders 2nd edition (ICHD-II), which was used to define the headache type (e.g., migraine with and without aura; tension-type headache). Migraineurs (with and without aura) had an increased risk of having RLS after adjustment for well-known headache confounding factors such as age, sex, major depression, anxiety, and sleep quality (odds ratio 1.79; 95% confidence interval, 1.00-3.19; P = 0.049). RLS was not significantly associated with tension-type headache. The association between RLS and migraine may be explained by overlapping dopaminergic pathogenic pathways. However, disturbed sleep, a major trigger for migraine attacks, could factor into the association with RLS.

Migraine may be linked to metabolic syndrome (MetS), which is associated with hypertension, dyslipidemia, obesity, and insulin resistance. Non-alcoholic fatty liver disease (NAFLD) is regarded as the liver manifestation of MetS, but the relationship between migraine and NAFLD is unknown. In a cross-sectional study by Celikbilek et al, 90 consecutive migraine patients had abdominal ultrasonography and blood work for markers of MetS. The measurements of body mass index, waist circumference, serum insulin level, and insulin resistance were significantly higher in migraine patients with NAFLD than in migraine patients without NAFLD. The incidence of migraine with aura was higher and the disease and attack durations were significantly longer in migraineurs with NAFLD than in those without NAFLD. However, the headache characteristics did not correlate with either the hepatosteatosis grade or degree of insulin resistance in migraine patients. The results showed that NAFLD may be found in migraine patients with

higher frequency of auras and longer disease and attack durations.

COMMENTARY

The comprehensive pathophysiological basis for migraine and its associated findings remains elusive. Multiple different cerebral and brainstem pathways and neurotransmitters have been invoked to explain this very complicated neurological disease. Many systemic disorders have been associated with migraines without clear mechanistic explanations for what appears to be an incomprehensible linkage. The more-likely-than-not linkage between migraine with aura and patent foramen ovale may be the strongest, albeit obscure, association. However, there are many other less prevalent migraine-associated diseases and syndromes. The authors of the cited articles emphasize different pathophysiological pathways to explain the associations between migraine and IBS, RLS, and NAFLD. Lau et al noted that serotonin (5-HT) is abundant in the gastrointestinal system and acts as a mediator between the central nervous system and the enteric nervous system. Both 5-HT agonists and antagonists have been proved to be effective in reducing abnormal motility and visceral hypersensitivity in IBS patients and are used in the acute and preventive treatment of migraine. Zanigni et al hypothesized that dysfunction in the hypothalamic dopaminergic A11 nucleus, as well as disorders of iron metabolism, may link migraine and RLS pathogenesis. Celikbilek et al noted that hepatocyte damage in NAFLD is accompanied by the release of proinflammatory cytokines. The "neurogenic inflammation" with neurogenic plasma extravasation and vascular meningeal inflammation noted in migraine may link these two seemingly disparate conditions. The three blind men describing different parts of an elephant seemed to be encountering different animals, until their findings were combined and synthesized. As odd as these epidemiological associations may be, unraveling their mechanistic explanations may lead to a greater understanding of the widely prevalent and very complicated disease, migraine.