Migraine as a systemic vasculopathy

Epidemiological studies suggests that migraine is associated with disorders of the cerebral, coronary, retinal, dermal and peripheral vasculature. There is evidence that migraine is associated with endothelial dysfunction, both as a cause and a consequence. Endothelial dysfunction, a vascular risk factor, is characterized by endothelial activation and impaired vascular reactivity. Plasma and genetic biomarkers for these conditions have been identified. The clinical significance lies in the potential for the rapid identification of migraineurs at increased risk of ischaemic stroke and vascular disease through ascertainment of endothelial dysfunction biomarkers. It is uncertain whether stroke, myocardial infarction and other vasculopathies can be prevented by migraine prophylaxis, endothelial repair, platelet inhibition or a combination of these strategies.     

Spreading Depolarization May Link Migraine and Stroke

Migraine increases the risk of stroke, particularly in young and otherwise healthy adults. Being the most frequent neurological condition, migraine prevalence is on a par with that of other common stroke risk factors, such as diabetes or hypertension. Several patterns of association have emerged: (1) migraine and stroke share a common association (eg, vasculopathies, patent foramen ovale, or pulmonary A‐V malformations); (2) injury to the arterial wall such as acute arterial dissections can present as migraine aura attacks or stroke; (3) strokes rarely develop during a migraine attack, as described for “migrainous stroke.” Increasing experimental evidence suggests that cerebral hyperexcitability and enhanced susceptibility to spreading depolarization, the electrophysiologic event underlying migraine, may serve as a mechanism underlying the migraine‐stroke association. Mice carrying human vascular or neuronal migraine mutations exhibit an enhanced susceptibility to spreading depolarization while being particularly vulnerable to cerebral ischemia. The severe stroke phenotype in migraine mutant mice can be prevented by suppressing spreading depolarization. If confirmed in the clinical setting, inhibiting spreading depolarization might protect migraineurs at stroke risk as well as decrease attacks of migraine.     

PET and Doppler sonography in headaches

Whether the primary mechanisms of migraine are vascular or neurogenic is, as yet unresolved. Early studies using Doppler sonography prompted heterogeneous results, mainly due to methodological differences. However, blood flow measurements using single photon emission tomography (SPECT) or positron emission tomography (PET) have not revealed any differences in cerebral blood flow in migraine without aura. Moreover, specific migraine compounds do not alter cortical blood flow. During attacks, increased blood flow is found in the cerebral hemispheres in cingulate, auditory and visual association cortices and the brain stem. Altogether, these findings suggest that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control, rather than in primary vessel diameter changes.     

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.     

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.     

Retinal vascular caliber and migraine: the Blue Mountains Eye Study

OBJECTIVE: To assess whether migraine is associated with retinal microvascular caliber. BACKGROUND: Migraine is believed to be associated with vascular disease, but few studies have investigated the relationship between structural microvascular changes and migraine. DESIGN: Population-based cross-sectional study. METHODS: Participants in the Blue Mountains Eye Study follow-up (1997 to 1999, n = 2,335, aged 54+) had retinal photographs taken. A computer-assisted method was used to measure average retinal arteriolar and venular diameters and calculate the arteriole-to-venule ratio. History of migraine was recorded by interview using International Headache Society criteria (1988). RESULTS: Subjects giving a history of migraine without aura (n = 128) had narrower retinal arterioles than subjects giving a history of migraine with aura (n = 182) or subjects with no migraine history (n = 1619). After multivariate adjustment, mean retinal arteriolar diameter was 4.3 microm (95% confidence interval 0.5, 8.1) narrower in subjects reporting migraine without aura as compared to subjects with no migraine. CONCLUSIONS: Individuals with a history of migraine without aura were more likely to have slightly narrower retinal arteriolar caliber than individuals without migraine. This relationship was not present for migraine with aura. These data support the hypothesis that microvascular disease may be associated with certain types of migraine.     

偏头痛相关性脑卒中发病中抗磷脂抗体的作用

目的研究和探讨偏头痛与缺血性卒中的相关性以及抗磷脂抗体在偏头痛相关性卒中发病中的作用. 方法运用问卷调查方式统计普通人群及脑梗死患者偏头痛的患病率,将脑梗死患者按有否偏头痛病史分为两组,用 ELISA方法分别测定其血清抗心磷脂抗体( anticardiolipin antibodies , ACA)水平. 结果①脑梗死患者偏头痛的患病率与普通人群偏头痛的患病率分别为 20.0 %和 6.0%,二者之间差异有显著性意义(χ2=13.2671,P< 0.01).②脑梗死伴有偏头痛史者和无偏头痛史者,其 ACA阳性率分别为 41.7 %和 19.5 %,二者差异具有显著性意义(χ 2=5.0133,P< 0.05). 结论偏头痛病史与脑梗死具有明显相关性.抗磷脂抗体可能参与偏头痛所相关的脑梗死的发病机制.     

Role of dopaminergic system in migraine

The theory that hypersensitivity of dopamine (DA) system is involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and, recently, genetic evidence. Apomorphine, a selective and specific DA agonist, has a cerebral vasodilatatory effect and increases blood flow significantly in the middle cerebral artery in migraineurs. Processes from central DA neurons terminate in close contact with penetrating arterioles and cerebral capillaries in the cerebral cortex. This finding reaffirms the role of central neurogenic mechanisms in the regulation of the cerebral circulation and, we believe, further supports the major role of dopamine in the neurogenic mechanisms of migraine. Various studies have been carried out to verify the involvement of DA in migraine pathogenesis using molecular genetics as a tool. A positive association between the “dopaminergic” phenotype of migraine without aura and the D2 receptor gene has been found. To explain dopaminergic hypersensitivity in migraine without aura, we will study the genes encoding proteins involved in the signal transduction system.     

Brain hypoxia: the turning-point in the genesis of the migraine attack?

The hypothesis postulates that a brief episode of focal cerebral hypoxia occurs in every attack of migraine. Clinical, biochemical and technical (EEG and CT scans) evidence is summarized suggesting that cerebral hypoxia may indeed occur in the course of a migraine attack. Focal hypoxia is seen as the turning-point in the pathogenesis of the attack. It may be provoked by different mechanisms in different patients; the potential role of decreased oxygen supply and of increased oxygen need are reviewed and excess sympathetic drive is considered a potential key mechanism in a majority of patients. Whether or not focal hypoxia leads to a genuine migraine attack, depends largely upon the quality of the whirlpool of biochemical, vascular and hematological changes that follow the hypoxic episode. These changes are discussed and it is concluded that those which have been reported to occur during migraine attacks could be due to a preceding hypoxic event. Finally, the hypoxia viewpoint is confronted with some popular theories about the pathogenesis of migraine. It is found that the other points of view are compatible with the hypoxia hypothesis.     

How Imaging Can Help Us Better Understand the Migraine-Stroke Connection

Migraine and stroke are among the most prevalent and disabling neurological diseases. Epidemiologic studies showed that there is an association between migraine and stroke. Migraineurs, especially those with aura, are more likely to develop subclinical infarct-like lesions in the brain and are at risk for cryptogenic or cardioembolic stroke. Migrainous headache can be found at the onset of acute ischemic stroke in some patients, and in rare instances, an infarction can be directly attributed to a prolonged migraine aura, ie, migrainous infarction. Importantly, recent studies suggest that in the event of cerebral artery occlusion, even a history of migraine is sufficient to accelerate infarct progression and worsen outcomes. The mechanisms underlying the migraine-stroke connection are multifactorial, with genetic predisposition, aura-related electrophysiological mechanisms (cortical spreading depolarization), and cerebral microembolism being the most convincing ones at this point. Here, we provide a comprehensive overview on recent imaging studies that have helped us better understand the complex association between migraine and stroke.     

Platelet dysfunction and stroke in the female migraineur

Some studies suggest that platelet activation and aggregation are associated with migraine, likely secondary to changes occurring during the acute attack. Evidence also suggests that platelet clots can lodge in small cerebral vessels, and that the resultant is chemia and inflammation can induce cortical spreading depression with aura-like symptoms and pulsatile headache. Endothelial dysfunction, a result of numerous vascular, genetic, and environmental risk factors, is more common in women with migraine and leads to altered hemostasis. When associated with other factors, such as oral contraceptive use, there may be an increased tendency for thrombus formation, secondary migraine with aura, transient ischemic attacks, and stroke. Identifying those migraineurs at highest risk of developing endothelial dysfunction and platelet disorders may allow for preventive strategies to avoid the cerebral consequences.     

Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment implications

The migraine-ischemia relationship is best understood in the context of the pathophysiology of migraine. Potential mechanisms of migrainous infarction (stroke occurring during migraine) include vasospasm, hypercoagulability, and vascular changes related to cortical spreading depression. Stroke occurring remote for the migraine attack may be related to arterial dissection, cardioembolism, and endothelial dysfunction. Endothelial dysfunction, a process mediated by oxidative stress, may be a cause or a consequence of migraine, and explain the relationship of migraine to vascular factors and ischemic heart disease. It remains uncertain whether stroke or myocardial infarction can be prevented by migraine prophylaxis, endothelial repair, platelet inhibition, or a combination of these strategies. Although triptans are generally considered safe for use in migraine, caution is warranted in those with multiple vascular risk factors. Known vascular disease is a contraindication to triptan use.     

Basilar and middle cerebral artery reactivity in patients with migraine

BACKGROUND: Migraine has been reported as a possible risk factor for ischemic stroke. The mechanisms underlying this association are unknown. OBJECTIVES: To evaluate cerebrovascular reactivity to hypercapnia in the anterior and posterior circulation of patients with migraine, as reduced cerebrovascular reactivity is associated with a predisposition to stroke in various clinical conditions. METHODS: Using transcranial Doppler ultrasonography, changes in flow velocity during apnea were measured in both middle cerebral arteries and in the basilar artery of 15 control subjects and 30 patients with migraine (15 with aura and 15 without aura) during an attack-free period. Cerebrovascular reactivity was evaluated using the breath-holding index, which is calculated by dividing the percent increase in mean flow velocity recorded during a breath-holding episode by its duration (in seconds) after a normal inspiration. RESULTS: Vascular reactivity in the middle cerebral arteries was similar in patients and controls and significantly lower in the basilar artery of patients with migraine with aura compared with the other 2 groups (P <.0001). CONCLUSIONS: These findings show that in patients with migraine with aura, there is an impairment in the adaptive cerebral hemodynamic mechanisms in the posterior circulation. This fact could have pathogenetic implications since the association between migraine and stroke frequently regards patients with migraine with aura, and cerebral infarcts occur more commonly in the vertebrobasilar district.     

Are vascular disorders more prevalent in the relatives of children and adolescents with migraine?

The objective of the study was to assess whether a family history of vascular disorders is more common in children and adolescents with migraine than in the general population. Family history of stroke, arterial hypertension, myocardial infarction and diabetes was investigated by history taking in relatives of ambulatory children and young adults with migraine and in a control group. The odds ratios (ORs) with 95% confidence intervals (95% CI) were used as a risk measure. Using univariate and multivariate (logistic regression) analysis, family history was assessed in the whole sample and in subgroups by sex and age, degree of relationship (parents and grandparents vs. relatives), disease type (migraine with and without aura), and type of vascular disorder. The sample included 143 cases (migraine with aura 35, migraine without aura 108) and 164 controls aged 3-24 years (mean 12 +/- 3.8 years). Patients with migraine were at increased risk of vascular disorders in parents and grandparents but not in all relatives. Multivariate analysis indicated family history of stroke as most common only in boys. In conclusion, our study provides some clues to the assumption that migraine and vascular disorders have common pathogenic mechanisms and that genetic susceptibility plays a role in increasing the risk of migraine in the offspring of families with one or more cerebrovascular or cardiovascular conditions.     

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome‐wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.     

Physiopathologie de la migraine

A migraine attack is due to the development of a vasomotor storm within the brain and overlying meninges. The crisis is initiated in the hypothalamus and in the adrenergic and serotonergic nuclei situated in the midbrain and pons. Activation of these nuclei results in arteriolar vasoconstriction in the cerebral cortex and also disturbs the inhibitory mechanisms involved in pain regulation. In order for the crisis to develop, there has to be a genetic predisposition (migraine susceptibility). In a rare migraine variant, familial hemiplegic migraine (FHM), various genetic mutations have been described. These affect the functioning of ionic channels located within the neuronal and astrocyte membranes, thus producing abnormal excitability of the cerebral cortex and increasing the susceptibility to cortical spreading depression (CSD). The neurological symptoms of the migrainous aura result from the passage of one or more CSDs over the corresponding zone of the cortex. The CSD spreads through the cortex slowly (3–4 mm/min), which accords with the progressive development of the symptoms of the aura (aura progression). The headache derives from activation of the trigemino-vascular system (TVS). These sensory fibres travel in the 1^stbranch of the trigeminal nerve (V₁) and innervate the meningeal veins and arteries on the cortical surface. Their main mediator is CGRP (calcitonin gene-related peptide). Release of this causes sterile inflammation around the blood vessels with vasodilation, extravasation of plasma proteins, degranulation of mast cells and activation of platelets. Thus, a substantial quantity of serotonin is released into cerebral venous blood during migraine attack. Activation of the TVS might either arise from “peripheral” initiation due to the passage of a CSD in the cortex (migraine with aura) or result from a “central” phenomenon of disturbance of mechanisms of pain regulation in the brain stem (migraine without aura).     

Comorbid neuropathologies in migraine

The identification of comorbid disorders in migraineurs is important since it may impose therapeutic challenges and limit treatment options. Moreover, the study of comorbidity might lead to improve our knowledge about causes and consequences of migraine. Comorbid neuropathologies in migraine may involve mood disorders (depression, mania, anxiety, panic attacks), epilepsy, essential tremor, stroke, and white matter abnormalities. Particularly, a complex bidirectional relation exists between migraine and stroke, including migraine as a risk factor for cerebral ischemia, migraine caused by cerebral ischemia, migraine as a cause of stroke, migraine mimicking cerebral ischemia, migraine and cerebral ischemia sharing a common cause, and migraine associated with subclinical vascular brain lesions.     

Migraine genes and the relation to gender

Migraine is an episodic brain disorder that is characterized by recurrent attacks of severe unilateral headache that are accompanied by various neurological symptoms. In addition, many patients have what is called an aura with visual and sensory disturbances. The majority of patients are female, suggesting that female hormones play an important role in the pathophysiology of the disorder. The molecular mechanisms, however, underlying this female preponderance are not well understood. It can be expected that the field of genetics that aims at identifying genetic factors that cause migraine by lowering the threshold for attacks will unravel some of these mechanisms. The 3 best known migraine genes encode ion transporters and were identified in families with familial hemiplegic migraine (FHM), a rare subtype of migraine with aura. FHM gene mutations cause alterations in mechanisms that control and modulate the neurotransmitter balance in the brain. Transgenic mice knock-in with human pathogenic mutations that were shown to exhibit some migraine-relevant features were very helpful in dissecting molecular mechanisms of migraine and pointed to a central role for cortical glutamate. In addition, transgenic mice that overexpress human RAMP1 exist and exhibit an increased sensitivity to calcitonin gene-related peptide. Findings from genetic and animal experiments on gender differences in migraine are discussed. Recently, a role for glutamate also came forward from a genome-wide association study in common migraine. By deciphering genetic and pathogenic migraine pathways, it can be expected that in the near future we will better understand mechanisms behind the female preponderance in migraine.     

Migraine to the year 2000

Although migraine is inextricably bound up with 5-hydroxytryptamine and its many receptors, its precise mechanisms continue to elude us and there is still no clear evidence supporting either a vascular or neurogenic hypothesis unequivocally. What appears to distinguish migraine sufferers from normal subjects may be a greater genetic sensitivity to a wide variety of triggering agents-even including nitric oxide and the migraine aura, as well as those more usually recognized. Attention is drawn to a possible role for neurotrophins, such as the hyperalgesia-provoking nerve growth factor (NGF) in particular, as well as basic fibroblast growth factor (bFGF) and brain-derived neurotrophic factor (BDNF).     

The Shared Genetics of Migraine and Anxious Depression

(Headache 2010;50:1549‐1560) Objectives.— To investigate (1) whether shared genetic factors influence migraine and anxious depression; (2) whether the genetic architecture of migraine depends on anxious depression; (3) whether the association between migraine and anxious depression is causal. Background.— Migraine and anxious depression frequently occur together, but little is known about the mechanisms causing this association. Methods.— A twin study was conducted to model the genetic architecture of migraine and anxious depression and the covariance between them. Anxious depression was also added to the model as a moderator variable to examine whether anxious depression affects the genetic architecture of migraine. Causal models were explored with the co‐twin control method. Results.— Modest but significant phenotypic (rP = 0.28), genetic (rG = 0.30), and nonshared environmental (rE = 0.26) correlations were found between the 2 traits. Interestingly, the heritability of migraine depended on the level of anxious depression: the higher the anxious depression score, the lower the relative contribution of genetic factors to the individual differences in migraine susceptibility. The observed risk patterns in discordant twins are most consistent with a bidirectional causal relationship. Conclusions.— These findings confirm the genetic association between migraine and anxious depression and are consistent with a syndromic association between the 2 traits. This highlights the importance of taking comorbidity into account in genetic studies of migraine, especially in the context of selection for large‐scale genotyping efforts. Genetic studies may be most effective when migraine with and without comorbid anxious depression are treated as separate phenotypes.