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.     

CHANGES IN BLOOD CLOTTING SYSTEMS DURING MIGRAINE ATTACKS

SYNOPSIS
The activity of various blood clotting systems was measured during attacks of migraine complicated by prolonged focal cerebral dysfunction and contrasted with those observed when the same and other patients had uncomplicated migraine. Results differed in the two groups.
In patients with complicated migraine, plasma coagulability rose during both complicated and uncomplicated attacks. During a complicated migraine attack, platelet aggregability to ADP also rose in all but one patient. Platelet aggregability fell in the same patients when they had uncomplicated migraine. Plasma coagulability consistently increased more when the headache was associated with focal cerebral dysfunction.
In patients with uncomplicated migraine, plasma coagulability dropped during the later phase of their attacks. This finding may reflect the release of endogenous heparin from mast cells and basophilic leucocytes. Platelet aggregability to ADP decreased in some but rose in others.
The results support the hypothesis that prolonged focal cerebral dysfunction may reflect thromboembolic phenomena. The influence of estrogens and genetic factors on clotting systems is reviewed.     

Migraine and cerebrovascular disease

Migraine and cerebrovascular disease are linked in different ways: migraine may be a potential cause of stroke as in migrainous infarction, headache may be a symptom of cerebrovascular disease and also a risk factor for stroke, the association of migraine and stroke may constitute specific syndromes such as CADASIL and MELAS. The new IHS 2003 criteria, though preserving their main structure, have changed the terminology regarding secondary headaches, now described as “attributed to” another disease rather than “associated with” it. The more detailed knowledge of causal links between the underlying disorder and headache, has allowed to strengthen the terminology. Many cerebrovascular disorders as cerebral haemorrhage, venous sinus thrombosis, carotid or vertebral dissections and ischaemic stroke may present with a headache or be followed by it. In subarachnoid haemorrhage (SAH) headache may constitute an important warning sign before the bleeding. An interesting issue is the hypothesis that migraine may be a potential risk factor for stroke. Recent studies have underlined the increased relative risk of ischemic stroke in female migraineurs. Many potential mechanisms have been hypothesized: (1) alterations of vasoreactivity due to vessel wall dysfunction, (2) release of vasoactive substances during migraine, (3) platelet hyperactivity as expression of serotoninergic dysfunction in migraineurs, (4) intriguing studies have described a high prevalence of migraine with aura in stroke patients with patent foramen ovale (PFO). Differential diagnosis between migraine and stroke remains fundamental: some types of migraine can mimic cerebrovascular disease such as familial hemiplegic migraine, and basilar migraine. Migraine and stroke may be part of syndromic complexes as in CADASIL and MELAS. In conclusion migraine is a risk factor for cerebrovascular disease, it may be the cause of stroke as in migrainous infarctions, stroke may induce headache which may be a relevant symptom of cerebrovascular disease, yet migraine remains an essentially benign condition.     

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.     

Risque vasculaire et migraine : données acquises et nouveautés

It is well established that migraine is associated with an increased relative risk of ischemic stroke. This relative risk is dramatically increased when migraine with aura is associated with tobacco consumption or contraceptive pill with oestrogen. Migraine is also associated with an increased relative risk of subcortical white matter hypersignals and with patent foramen ovale. Recent Dutch population survey has suggested an increased relative risk of silent infarcts in migraine, especially in cerebellum. Migrainous infarct could not explain these facts: this diagnosis is extremely rare and required a complete and totally negative diagnostic work-up. Recent US epidemiological data suggests an increased risk of coronary artery diseases in migraine with aura in women older than 45. The increased risk of ischemic events is probably multifactorial with more traditional vascular risk factors in migrainers, endothelial dysfunction, decreased level of circulating progenitor cells, prothrombotic circulating factors, and venous thromboembolic disease. Up to now, it is not established that prophylactic treatment of migraine could modify the vascular risk associated with migraine.     

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.     

Pathophysiologische mechanismen des Migränekopfschmerzes unter klinischen Gesichtspunkten

Migraine is more than the pain involved in the "migraine attack." Before the onset of pain many clinical symptoms can be observed. These symptoms may be classified as vegetative, affective, and vascular. Brain perfusion is altered during migraine attacks as well as during the intervals between attacks. These "more recent" findings are important because brain perfusion is controlled by metabolic and by neurotransmission mediated pathways: 750 ml blood/min is available in brain perfusion. The skull, on the other hand, limits the volume of blood in the brain to 130 ml. Control of the shift of blood inside the brain, with a chance of maximal blood flow or strictly limited blood volume, may be one of the most important problems in neurotransmission mediated cerebral perfusion control. The most important neurotransmission systems of cerebral perfusion control are those that are believed to be involved in affective and vegetative symptoms. It must be assumed that platelets are involved in migraine. Platelet reactivity is enhanced in migraine patients during the interval between attacks. When a migraine attack occurs a release of platelet serotonin and a further increase of platelet reactivity can be observed. Platelet activation in these cases is comparable to the situation in transient ischemic attacks. During transient ischemic attacks, platelet serotonin has been found to be enhanced in the area of transient ischemia. Serotonin is a neurotransmitter, low concentrations of which induce vasodilation, while higher concentrations induce vasoconstriction. It may be assumed that platelet serotonin is a potent vasoregulating substance that may interact in the brain vessels with the neurotransmission controlled perfusion. The hypothesis of an (inborn) instability of the interaction of cerebral neurotransmission systems in patients suffering from migraine is in accordance with the vegetative and affective symptoms in migraine, the observed imbalance of neurotransmission mediated cerebrovascular autoregulation and the irritation of platelets in migraine attacks, as well as in the interval between attacks. The "modern" treatments of migraine with acetylsalicylic acid, ergotamin and/or beta blockers are discussed in relation to this proposed hypothesis of a migraine pathophysiology.     

Migraine and cerebrovascular diseases: Epidemiology,pathophysiological, and clinical considerations

Migraine and cerebrovascular diseases are disabling disorders, which are possibly closely interrelated. Heterogeneous and scattered evidence in literature remains a challenge. We searched for systematic reviews including diverse cerebrovascular events in migraineurs and reported relevant original studies to update the evidence when necessary. The studies show that migraine is associated with increased risk of transient ischemic attacks, any stroke, and possibly hemorrhagic stroke. In addition, migraine with aura increases the risk of ischemic stroke and white matter abnormalities. Migraine without aura increases the risk of cervical artery dissection as a cause of ischemic stroke. Groups with specific risk profiles are women, young people, smokers, and oral contraceptive users. The pathophysiology of the association remains uncertain. However, genetic and environmental factors may be involved in intricate mechanisms responsible for oxidative stress, vascular dysfunction and, ultimately, vascular events. In conclusion, migraine is a potential risk factor for cerebrovascular diseases. Migraineurs should be carefully evaluated considering their vascular risk assessment based on current evidence, so that healthcare professionals can provide appropriate and individualized management of other cardiovascular risk factors, notably quitting smoking and restricting use of oral contraceptives.     

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.     

Cerebrovascular risk factors in migraine with prolonged aura and without aura

The role of cerebrovascular risk factors such as mitral valve prolapse, platelet aggregation, platelet activation and cardiac arrythmias in migraine was investigated in a total of 44 migraineurs (32 migraineurs without aura and 12 with prolonged aura) and 32 controls. Comparing the total of migraineurs and the two subgroups with controls, mitral valve prolapse, a raised thromboxane B2 level, at least one platelet aggregation dysfunction or an abnormality in 24-h ECG was statistically seen no more often than in the control group. Neither did combinations of the variables occur more frequently. Altogether, this study showed no increased coincidence of migraine with prolonged aura and migraine without aura with the above parameters. The absence of cardiac and haematological abnormalities in migraine with prolonged aura focuses attention on the control of the cortical microcirculation.     

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.     

The platelet and the neuron: Two cells in focus in migraine

Reports of platelet abnormalities in migraine are abundant, and the present paper discusses the role of platelets in the migraine aetiology. Platelets are considered good models for pre- and post-synaptic functions in serotonergic neurons. We propose that migraine is associated with a lowered threshold for stimulus response in both platelets and serotonergic neurons and that the alterations in platelet function reflect central serotonergic disturbances. The platelet abnormalities in migraine approach those found in depression, and there are several links between the two disorders. The clinical significance of platelet hyperactivity in migraineurs for the occurrence of thrombotic disorders is also discussed. Studies of platelet functions in migraine, using platelets as models for serotonergic neurons, may broaden our understanding of the neuronal processes that take place during a migraine attack. The platelet can also be an investigative tool for better understanding of the modes of action of anti-migraine drugs.     

Migraine and prothrombotic genetic risk factors

It has been suggested that during attacks of migraine both platelet activation and plasma coagulability are increased. We investigated the prevalence of several prothrombotic genetic risk factors in patients with migraine: factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion in the factor VII promoter, and the platelet HPA-1 and HPA-2 alloantigenic systems, by genotypic identification in an age- and sex-matched case-control study including 106 patients with migraine (49 with aura, and 57 without aura). The prevalence of all genotypes was similar among case patients and controls. No association in relation to the type of migraine was detected in the factor II, factor VII, HPA-1, or HPA-2 polymorphisms. Our results showed a high prevalence of factor V Leiden in those patients with migraine with aura (6.1%), though that association was not statistically significant. The studied prothrombotic genetic factors do not seem to be associated with the development of migraine and, therefore, are not likely relevant in the previously reported hypercoagulability and platelet hyperaggregability in this disease.     

Phenome-wide analysis highlights putative causal relationships between self-reported migraine and other complex traits

BackgroundMigraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach.MethodsWe leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method.ResultsWe identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine.ConclusionsOverall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01284-w.     

Platelet nitric oxide metabolites in migraine

Nitric oxide (NO) is a candidate as a causative molecule in migraine. We determined nitrite, total nitrate/nitrite, and cyclic guanosine 3',5'-monophosphate (cGMP) concentrations in platelets from 30 migraine without aura (MwoA) patients and 17 migraine with aura (MwA) patients. All migraine patients were studied during their migraine attacks. The control group consisted of 28 healthy volunteers. Concentrations of platelet nitrite and total nitrate/nitrite were determined using simple and sensitive nitrate/nitrite fluorometric assay techniques. High concentrations of platelet nitrite and total nitrate/nitrite were found in patients with MwoA and MwA when compared with healthy controls. High concentrations of platelet cGMP were also found in patients with MwoA and MwA. The levels of platelet total nitrate/nitrite significantly decreased in headache-free periods after treatment with oral propranolol. These findings suggest that NO is produced in platelets during migraine attacks. It may also be related to the migrainous pain and the changes in cerebral blood flow experienced during migraine attacks. These data may provide new strategies for the treatment of migraine.     

Seizures in Migraine: Warning of an Underlying Cerebral Infarction?

SYNOPSIS
Reports of an association between migraine and seizures have existed for a long time. A syndrome of basilar artery migraine, seizures and abnormal EEG's has also been published. We now report four patients with seizures and migraine in whom we feel the seizures were secondary to cerebral infarctions. Migraine was of the classical type in all patients and the auras were predominantly visual, Neurological symptoms associated with the cerebral infarctions were mild or transient and could have easily been dismissed as "complex migraine". CT scans showed cerebral infarctions involving the occipital cortex in all four cases. Two-dimensional echocardiography revealed mitral valve prolapse (MVP) in two cases and a bicuspid aortic valve in one case. In two cases, both with MVP, there were more than one cerebral infarctions.
Seizures may be an early warning of cerebral infarctions in patients with migraine and should alert the physician towards such a possibility.     

Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease

The role of hemostatic elements in stroke has been clearly defined but several prothrombotic polymorphisms of hemostatic factors, important for other thromboembolic disorders, seem not to be very significant in stroke. Recently, the high prevalence of factor V Leiden in patients with stroke and a history of migraine has suggested an association between migraine and prothrombotic genetic risk factors. Stroke being a multifactorial disease, the aim of this study was to test whether prothrombotic tendencies increase the risk of stroke in patients with migraine. We determined the prevalence of four prothrombotic genetic risk factors (factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion in the factor VII promoter, and the platelet HPA-1 alloantigen system) in 17 patients with coexisting ischemic cerebrovascular disease and migraine, 107 patients with ischemic cerebrovascular disease, 106 patients with migraine, and 202 control subjects. Genotyping for all polymorphisms analyzed in our study were performed after specific genomic polymerase chain reaction, and confirmed by single-strain conformation polymorphism analysis. In the group of patients with coexisting ischemic cerebrovascular disease and migraine, the prevalence of prothrombotic genotypes (factor V Leiden, 5.8%; factor II 20210 A, 0%; factor VII A1, 70.6%; and HPA-1b, 35.3%) was similar to that obtained in all other groups. We can conclude that the studied polymorphisms do not seem to be associated with the development of ischemic cerebrovascular disease in those patients with migraine.     

Migraine and genetic and acquired vasculopathies

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.     

Determinants of tension-type headache in children

The objective of this study was to study the prevalence, characteristics and predisposing factors of tension-type headache in children. An unselected population-based questionnaire study was carried out in 1409 Finnish schoolchildren aged 12 years. Of them, 1135 (81%) returned an acceptably completed questionnaire. The prevalence of episodic tension-type headache in children was 12% (138 of 1135). Children with episodic tension-type headache also often reported characteristics of pain typical for migraine. Children with frequent and persistent episodic tension-type headache reported stabbing and severe occipital pain, phonophobia and abdominal pain significantly more often than children with infrequent episodic tension-type headache. Neck-shoulder symptoms, symptoms of depression and oromandibular dysfunction were each independently associated with episodic tension-type headache. The father's occupation of a lower-level white-collar worker put the child at a four-fold risk for episodic tension-type headache. We conclude that episodic tension-type headache is as common as migraine in children. It can be associated with depression, oromandibular dysfunction and muscular stress. Especially children with frequent and persistent episodic tension-type headache report characteristics of pain typical for migraine.     

Antithrombotic Management in Ischemic Stroke with Essential Thrombocythemia: Current Evidence and Dilemmas

Thrombotic diseases like ischemic stroke are common complications of essential thrombocythemia (ET) due to abnormal megakaryopoiesis and platelet dysfunction. Ischemic stroke in ET can occur as a result of both cerebral arterial and venous thrombosis. Management of ET is aimed at preventing vascular complications including thrombosis. Acute management of ischemic stroke in ET is the same as that in the general population without myeloproliferative disorders. However, an ET patient with ischemic stroke is at high risk for rethrombosis and is therefore additionally managed with cytoreductive therapy and antithrombotic agents. Given abnormal platelet production in ET, there is suboptimal suppression of platelets with the standard recommended dose of aspirin for cardiovascular (CV) prevention. Hence, for optimal CV protection in ET, low-dose aspirin is recommended twice daily in an arterial thrombotic disease like atherothrombotic ischemic stroke in presence of the following risk factors: age >60 years, Janus kinase2 V617F gene mutation, and presence of CV risk factors. In the presence of the same risk factors, concurrent antiplatelet and anticoagulant therapy is suggested for venous thrombosis. However, increased risk of bleeding with dual antithrombotic agents poses a significant challenge in their use in cerebral venous thromboembolism or atrial fibrillation in presence of the above-mentioned risk factors. We discuss these dilemmas regarding antithrombotic management in ischemic stroke in ET in this case-based review of literature in the light of current evidence.