Migraine and Obesity: Epidemiology,Mechanisms, and Implications

(Headache 2010;50:631‐648) Adipose tissue is a dynamic neuroendocrine organ that is involved in multiple physiological and pathological processes, and when excessive, results in obesity. Clinical and population‐based data suggest that migraine and chronic daily headache are associated with obesity, as estimated by anthropometric indices. In addition, translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. In this article, we first review the definition and ascertainment of obesity. This is followed by a review of the clinical and population‐based studies evaluating the associations between obesity and chronic daily headache and migraine. We then discuss the central and peripheral pathways involved in the regulation of feeding, where it overlaps with migraine pathophysiology, and where future research may be headed in light of these data.     

Migraine in the Pediatric Population—Evolving Concepts

(Headache 2010;50:1130‐1143) Studying the prevalence of headaches at age extremes is of important clinical relevance. Pediatric studies inform us about determinants of incident disease; studies of elderly populations inform us about the long‐term consequences of headaches, as well as about determinants of headache remission. As with other subspecialties of headache research, research on pediatric headache is an evolving field. However, although substantial advances have been achieved in understanding headaches in adolescents, knowledge of early childhood headaches is not as advanced conceptually. This review provides a theoretical framework for our current understanding, then summarize the results of a large, ongoing, epidemiological study in pre‐adolescent children. It is clear that both in adolescents and in pre‐adolescents, migraine is frequent. Diagnostic criteria for migraine and chronic migraine are certainly over‐restrictive for young children. Migraine often lasts less than 1 hour in young children. A vulnerable population at risk of migraine progression also exists, likely reflecting increased biological predisposition, but also early life exposures. Indeed, it seems that even prenatal exposures of certain substances may increase the risk of migraine progression. Of relevance is the frequency of headaches within a family. Finally, migraine seems to be associated with behavioral hyperactivity, but is not comorbid with attention‐deficit disorder and hyperactivity.     

Obesity and Chronic Daily Headache

Obesity may be the greatest epidemic of modern times. It leads to diabetes and heart disease and shortens lifespan. Although not a risk factor for migraine, it is associated with an increased frequency and intensity of migraine. Obesity is also comorbid with chronic daily headache and is a major risk factor for chronification of episodic migraine in adults and children. Although obesity is not a factor in the effectiveness of migraine treatment, it does increase the peripheral and central events in migraine, ultimately increasing the neurologic potential for migraine. Although evidence suggests that obesity is a modifiable risk factor for migraine progression, it is unknown if weight loss is related to decrease in headache frequency. Recent surgical results suggest that this is true. We suggest all possible effective techniques aimed at weight loss be undertaken for migraineurs, especially obese migraineurs, and that carefully monitoring weight changes should be routinely done as part of their migraine care.     

Migraine and the hypothalamus

Migraine is a complex brain disorder where several neuronal pathways and neurotransmitters are involved in the pathophysiology. To search for a specific anatomical or physiological defect in migraine may be futile, but the hypothalamus, with its widespread connections with other parts of the central nervous system and its paramount control of the hypophysis and the autonomic nervous system, is a suspected locus in quo. Several lines of evidence support involvement of this small brain structure in migraine. However, whether it plays a major or minor role is unclear. The most convincing support for a pivotal role so far is the activation of the hypothalamus shown by positron emission tomography (PET) scanning during spontaneous migraine attacks. A well-known theory is that the joint effect of several triggers may cause temporary hypothalamic dysfunction, resulting in a migraine attack. If PET scanning had consistently confirmed hypothalamic activation prior to migraine headache, this hypothesis would have been supported. However, such evidence has not been provided, and the role of the hypothalamus in migraine remains puzzling. This review summarizes and discusses some of the clues.     

Efficacy of sumatriptan in the treatment of migraine: a review of the literature.

Advanced practice nurses treat many patients, including children and adolescents, with migraine headaches. Management of headache episodes requires a delicate balance of prophylactic and abortive therapies. Sumatriptan has been used effectively to treat adult patients with migraine headaches, but its efficacy in children has not been established. Results of a literature review provide strong evidence supporting the use of sumatriptan in treating adults with migraine headaches. Some evidence also exists for using sumatriptan to treat migraines in pediatric patients. Open prospective studies used small convenience samples, thus limiting the external validity of the research findings. Two randomized, double-blind, placebo-controlled, crossover trials found conflicting results for the efficacy of sumatriptan in the treatment of pediatric migraine. Further research is needed to determine its efficacy in children.     

Obesity and Migraine in Childhood

Purpose of Review

The purpose of this work was to review the current literature on the epidemiology and pathophysiology of pediatric obesity and migraine, underlying pathogenic mechanisms that may explain the association between the two disorders, and the effects of treatment.

Recent Findings

In children and adolescents, the bulk of the available data support an association between obesity and headache disorders in general, though a small number of studies contradict these findings. Relative to the adult population, however, few studies have focused specifically on migraine, and no wide-ranging meta-analyses have been conducted to date. It seems that the pathophysiology of obesity and migraine in adults holds true for the pediatric population as well. The association between obesity and migraine in the pediatric population is likely to be multifactorial and to involve both central and peripheral mechanisms. More attention is currently being addressed to the role of the hypothalamus and the bioactive neurotransmitters and neuropeptides that modulate energy homeostasis, namely serotonin, orexin, and the adiponectins, in migraine. A few innovative studies have demonstrated some benefit for migraine from weight reduction treatments such as exercise and lifestyle management.

Summary

Many open questions remain regarding the modifiable nature of the obesity–migraine relationship and its implications in clinical practice. Further studies of these issues are needed.

     

Pharmacoprophylaxis of tension-type headache

Although tension-type headache typically is not as disabling as migraine, its chronic form may significantly impair patients’ functional ability. The pathogenesis of tension-type headache remains largely unknown. Compared with migraine, tension-type headache is the object of much less research. For a number of years, research on headache therapy has vastly emphasized migraine. Even cluster headache, which is far less frequent than tension-type headache, has been subject to more therapeutic trials than tensiontype headache. Therefore, it is not surprising that since the advent of studies (as early as 1964) on amitriptyline, which remains a pivotal treatment choice, the number of emerging treatments for this condition remains scarce, even in 2005. This emphasizes the need for renewed interest in this field. However, alternate treatment approaches, such as botulinum toxin injections, albeit controversial, have renewed hopes lately. In addition, recent progress in the understanding of tension-type headache pathophysiology, such as the role of peripheral and central sensitization, has revived interest in the field. This is a review of available, proven, or suspected prophylactic therapies for tensiontype headache.     

Genomic abnormalities in patients with migraine and chronic migraine: preliminary blood gene expression suggests platelet abnormalities

BACKGROUND: Migraine has strong genetic and environmental components and may also be a significant contributor to chronic migraine (CM). It is hypothesized that gene expression changes in peripheral blood cells can be used to detect the interaction of these influences. OBJECTIVE: Distinct genomic expression patterns for migraine and CM will be present. These genomic profiles will help clarify the interactions of inheritance and environment. This initial study begins to examine the feasibility of peripheral blood cell genomic analysis to assist in the understanding of the pathophysiology of migraine and CM. METHODS: Blood samples from patients were obtained either during an acute migraine or CM. Genomic expression patterns were analyzed using Affymetrix U95A microarrays. RESULTS: Expression patterns of 7 migraine and 15 CM patients were compared to four distinct control groups (total patients, n=56) including healthy subjects. A group of platelet genes were upregulated in both migraine and CM samples. Different gene expression patterns were also seen between migraine and CM. A group of immediate early genes including c-fos and cox-2 were expressed at higher levels in migraine, whereas specific mitochondrial genes were expressed at higher levels in CM. CONCLUSIONS: Increased expression of platelet genes in patients with migraine and CM suggests similar underlying pathophysiology. The differences seen between migraine and CM in other genes suggest an overlapping but not identical pathophysiology. Further genomic profiling studies will help define these relationships and provide further insights into headache pathogenesis.     

Tension-type headache in children and adolescents

Although tension-type headache is at least as prevalent as migraine in children and adolescents, in contrast to migraine, childhood tension-type headache has received limited research attention. Follow-up studies have shown that migraine may reverse in tension-type headache and vice versa. In addition, children with frequent episodic tension-type headache may be at increased risk of chronic tension-type headache. It is very important to recognize these children and to intervene. Further studies are needed to clarify the pathophysiology of pediatric tension-type headache.     

Migraine and ischaemic vascular events

An association between migraine and ischaemic vascular events, particularly ischaemic stroke, has been debated for many years. The pathophysiology of migraine has been explored in detail, and it is known that a dysfunction of brain cells and arteries is a major component of this disorder. The involvement of cerebral arteries during the migraine attack as well as the high prevalence of migraine among young individuals with ischaemic stroke has led to the hypothesis that migraine may be a risk factor for ischaemic stroke. Furthermore, there is evidence that the vascular nature of migraine is not limited to meningeal blood vessels and that migraine and overall cardiovascular disease may share aetiological pathways. The aim of this review is to summarize the epidemiological evidence that links migraine with ischaemic stroke and ischaemic heart disease and to discuss potential biological mechanisms.     

Mast cell activation in children with migraine before and after training in self-regulation

Migraine may affect as many as 9% of all schoolchildren and often presents with abdominal symptoms of pain, nausea, and vomiting. Even though the pathophysiology of migraine remains unknown, self-regulation techniques appear to be more effective in prevention of childhood migraine than conventional pharmacotherapy which is often associated with adverse effects. Mast cells have been implicated in the pathogenesis of migraine in adults, but have not been previously studied in children with migraine.
Mast cells are found close to the vessels and nerves in the meninges where they can release multiple vasoactive, neurosensitizing, and pro-inflammatory mediators. Therefore, we investigated whether children with migraine may have increased urinary levels of mast cell mediators and whether practicing relaxation imagery exercises has an effect on the frequency of headache, as well as on mast cell activation.
Urine was collected for 24 hours from children with and without migraine after a 5-day amine-restricted diet. Children with migraine also collected urine during migraine episodes. The mean levels of urinary histamine, its main metabolite, methylhistamine, and the mast cell enzyme, tryptase, were higher in children than generally found in adults, but they did not differ statistically in any of the categories studied. However, in 8 of 10 children who practiced relaxation imagery techniques and successfully reduced the number of migraines, the urine tryptase levels were also significantly lower. There was no relationship between successful practice and sex or age of the child. These results suggest that stress may activate mast cells which could be involved in the pathophysiology of migraine.     

Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract

OBJECTIVE: To explore the role of a special butterbur root extract for migraine prevention in children and adolescents with severe migraines. BACKGROUND: Two randomized and placebo-controlled trials with a total of 289 migraine patients have demonstrated the efficacy and safety of a special butterbur root extract in the reduction of migraine attacks in adults. We studied whether butterbur had the potential as an efficient and well-tolerated migraine preventive in children and adolescents. DESIGN/METHODS: 108 children and adolescents between the ages of 6 and 17 were included in a multicenter prospective open-label study. Participants suffered from migraines diagnosed according to IHS classifications for at least 1 year. Patients were treated with 50 to 150 mg of the butterbur root extract depending on age for a period of 4 months. Treatment progression was recorded in migraine journals especially designed for children and adolescents. RESULTS: 77% of all patients reported a reduction in the frequency of migraine attacks of at least 50%. Attack frequency was reduced by 63%. 91% of patients felt substantially or at least slightly improved after 4 months of treatment. About 90% of each, doctors and patients, reported well-being or even improved well-being. Undesired effects (7.4%) included mostly eructation. No serious adverse events occurred and no adverse event caused a premature termination. CONCLUSIONS: The results and low rate of adverse events in this open prospective migraine prevention study in children and adolescents are similar to the results of two multicenter placebo-controlled butterbur studies in adults. Butterbur root extract shows a potential as an effective and well-tolerated migraine prophylaxis also for children and teenagers.     

The Lack of Peripheral Pathology in Migraine Headache

This article reviews the baffling problem of the pathophysiology behind a peripheral genesis of migraine pain – or more particularly the baffling problem of its absence. I examine a number of pathophysiological states and the effector mechanisms for these states and find most of them very plausible and that they are all supported by abundant evidence. However, this evidence is mostly indirect; to date the occurrence of any of the presumed pathological states has not been convincingly demonstrated. Furthermore, there is little evidence of increased trigeminal sensory traffic into the central nervous system during a migraine attack. The article also examines a number of observations and experimental programs used to bolster a theory of peripheral pathology and suggests reasons why they may in fact not bolster it. I suggest that a pathology, if one exists, may be in the brain and even that it may not be a pathology at all. Migraine headache might just happen because of random noise in an exquisitely sensitive and complex network. The article suggests an experimental program to resolve these issues.     

Premonitory Symptoms of Migraine in Childhood and Adolescence

Purpose of Review

Premonitory symptoms in migraine; symptoms occurring before the onset of migraine pain or aura, are an increasingly recognised area of interest within headache research. It has been recently documented in the literature that these symptoms also occur in children and adolescents, with a comparable phenotype to adults. This review discusses the wide presentation of premonitory symptoms in migraine in children and adolescents, and the importance of understanding how these early symptoms are mediated in order to ensure that targeted abortive therapies are developed in the future. Recognition of these symptoms by parents, guardians, teachers and carers is of importance in ensuring early and effective attack treatment.

Recent Findings

A previous clinic-based questionnaire study in 103 children found a prevalence of premonitory symptoms in paediatric migraine of 67%, with a mean number of reported symptoms of two. A recent study found that in a clinic population of 100 children or adolescents with a migraine diagnosis who were preselected as having at least one premonitory symptom associated with their attacks, two or more premonitory symptoms were reported by 85% of patients. The most common symptoms were fatigue, mood change and neck stiffness.

Summary

Although the population prevalence of premonitory symptoms in migraine within the paediatric population, or their ability to predict accurately the onset of an impending headache cannot be deduced from the retrospective studies performed to date, premonitory symptoms occur in children as young as 18 months old. Understanding the biological basis of these, and their heterogeneous phenotype may help future targeted therapeutic research, helping the development of drugs that act before the onset of pain, limiting the morbidity associated with the migraine attack.

     

Exteroceptive suppression of masseter muscle activity in juvenile migraineurs

The second exteroceptive suppression period (ES2) of masseter or temporalis muscle activity may be reduced in adults with chronic tension-type headache. In adults with migraine, ES2 was found normal or tended to be protracted. To date, no studies on exteroceptive suppression in children and adolescents with headaches have been published. We investigated the exteroceptive suppression of masseter muscle activity in 14 migraineurs and 19 controls between 6 and 18 years of age. It was elicited by electrical stimulation at the labial commissure. No differences were found regarding the first suppression period, but ES2 was significantly longer in the migraine group than in controls. The results of the migraine group suggest overactivity of the interneurons of the reflex loop due to impaired inhibitory control from superior antinociceptive systems already at the beginning of this headache disorder.     

Neuroendocrine dysfunction in fibromyalgia and migraine

Fibromyalgia (FM) and migraine are common chronic disorders that predominantly affect women. The prevalence of headache in patients with FM is high (35%–88%), with migraine being the most frequent type. A particular subgroup of patients with FM (approximately half) presents with a combined clinical form of these two painful disorders, which may exhibit a different manner of progression regarding symptomatology and impact on daily activities. This article reviews several common aspects of the pathophysiology regarding pain control mechanisms and neuroendocrine dysfunction occurring in FM and migraine, particularly in the chronic form of the latter. We also discuss the participation of hypothalamic and brainstem centers of pain control, the putative role played by neurotransmitters or neuromodulators on central sensitization, and changes in their levels in the cerebrospinal fluid. Understanding their mechanisms will help to establish new treatment strategies for treating these disabling brain disorders.     

Migraine-related vertigo: Diagnosis and treatment

A comprehensive review of the neurotologic manifestations of migraine is presented, focusing on the most recent publications regarding the epidemiology, clinical presentation, pathophysiology, diagnosis, and management of migraine-related vertigo (MV). A strong association exists between vertigo and migraine, with MV being the most common cause of spontaneous (nonpositional) episodic vertigo. Symptoms can be quite variable among patients and within individual patients over time, creating a diagnostic challenge. MV generally presents with attacks of spontaneous or positional vertigo lasting seconds to days with associated migrainous symptoms. Operational diagnostic criteria have been proposed but are not included in the most recent International Headache Society classification of migraine. Better elucidation of the neurologic linkages between the central vestibular pathways and migraine-related pathways and the discovery of ion channel defects underlying some causes of familial migraine, ataxia, and vertigo have furthered the understanding of MV pathophysiology. Treatment of MV currently parallels that of migraine headache, as proper studies of optimal MV management are just beginning.     

Serotonin and migraine: a reconsideration of the central theory

The 5-hydroxytryptamine (5-HT) has been implicated in migraine pathophysiology for the past 50 years. A low central 5-HT disposition associated with an increase in 5-HT release during attack is the most convincing change of 5-HT metabolism implicated in migraine. Peripheral studies on plasma/platelet have not generally shown low 5-HT levels. Studies on 5-HT reactivity showed hypersensitivity, also expressed as reduced tachyphylaxis (habituation), which successively was evidenced as the most characteristic marker of an altered sensory neurotransmission. Even the gender and seasonal variations of 5-HT parameters seem to agree with a low 5-HT turnover with receptoral hypersensitivity. The interpretation of the effects of some serotonergic drugs and recent neuroimaging studies give major evidence for this cascade of events. Although the exact mechanism that links abnormal 5-HT neurotransmission to the manifestation of head pain has yet to be fully understood, a deficit on 5-HT descending pain inhibitory system is still probably today the most implicated in migraine pathophysiology. This short review focuses and discusses the alteration of peripheral and central 5-HT parameters in migraine patients.     

Migraine in the Triptan Era: Lessons From Epidemiology, Pathophysiology, and Clinical Science

The triptan era has been a time of remarkable progress for migraine diagnosis and treatment. In this paper, we review some of the advances achieved in migraine science during this era focusing on 3 themes: lessons from clinical practice, lessons from epidemiology and lessons from pathophysiology. Science has shown that migraine is a disorder of the brain, and that the key events happen in the the trigeminal neuronal pathways, not on blood vessels. Clinical science has led to the observation that migraine sometimes progresses or remits. This in turn led to longitudinal epidemiologic studies focusing on factors that determine migraine prognosis. In addition, these studies raised questions about the mechanisms of migraine progression, including the role of allodynia, obesity, inflammation, and medications as determinants of progression. This in turn opens a new set of scientific questions about the neurobiologic determinants of migraine, as well as of its clinical course, and exciting opportunities to develop new therapies for this highly disabling brain disorder.     

Pediatric Inpatient Headache Therapy: What is Available

Status migrainosus is defined by the international classification of headache disorders (ICHD) criteria as a debilitating migraine lasting more then 72 hours. The epidemiology of status migrainosus is still unknown in adult and children, and frequently underdiagnosed. Children and adolescents often end up in the emergency room with an intractable headache that failed outpatient therapy. Six to seven percent of these children do not respond to acute infusion therapy and require hospitalization. It is imperative that more aggressive therapy is considered when patients are affected by a severe intractable headache to prevent further disability and returning the child to baseline activity. Multiple therapies are available for adults and children. Studies for acute therapy in the emergency room are available in adults and pediatric groups. Small studies are available for inpatient therapy in children and, along with available therapies for children and adolescents, are described in this review. A review of the literature shows growing evidence regarding the use of dihydroergotamine intravenously once patients are hospitalized. Effectiveness and safety have been proven in the last decades in adults and small studies in the pediatric populations.