The Migraine-Ischemic Stroke Connection: Potential ...

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(familial or sporadic hemiplegic migraine; FHM or. SHM). The International Headache Society (IHS) has established criteria for the diagnosis and classification.
Current Molecular Medicine 2009, 9, ???-???

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The Migraine-Ischemic Stroke Connection: Potential Pathogenic Mechanisms Alessandro Pezzini*,1, Elisabetta Del Zotto2, Alessia Giossi1, Irene Volonghi1, Mario Grassi3 and Alessandro Padovani1 1

Dipartimento di Scienze Mediche e Chirurgiche, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia 2

Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi di Brescia, Brescia, Italia

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Dipartimento di Scienze Sanitarie Applicate, Sezione di Statistica Medica e Epidemiologia, Università di Pavia, Pavia, Italia Abstract: Strong epidemiological evidence indicates that migraine, especially migraine with aura, is associated with increased risk of ischemic stroke. However, the precise mechanisms of such a relation are currently not fully elucidated and are still a matter of speculation. Migraine may directly cause an ischemic event (i.e, migrainous infarct), by inducing cerebral microcirculatory vasoconstriction (cortical spreading depression-related oligemia), intracerebral large vessel spasm, and vascular endothelium-related hypercoagulability. On the other hand, migraine may predispose to cerebral ischemia outside of a migraine attack by affecting endothelial function, alone or in combination with traditional vascular risk factors, or by interacting with pre-existent stroke susceptibility conditions (i.e, patent foramen ovale). At least theoretically, the migraine-stroke link may be the consequence of the unfavourable effect of migraine-specific drugs (i.e, triptans or ergot alkaloids). Finally, migraine and ischemic vascular events may be linked via genetic pathways, certain genes playing a role on both diseases and influencing their relation. The coexistence of ischemic stroke and migraine in the context of specific syndromes (i.e, CADASIL) characterized by peculiar phenotype, proven inherited background and chronic alterations of the wall of cerebral small vessel arteries suggests that migraine and ischemic stroke may end the phenotype of common pathogenic mechanisms. How to identify those migraineurs at highest risk of ischemic stroke and whether stroke can be prevented by specific therapeutic strategies are the goals of future research.

Keywords: Migraine, ischemic stroke, migrainous infarction.

INTRODUCTION Migraine is a common disorder characterized by recurrent disabling attacks of headache associated with nausea, vomiting, hypersensitivity to light, sound, and smell (migraine without aura; MO) and, in a third of patients, neurological aura symptoms (migraine with aura; MA) [1]. These aura symptoms generally include visual disturbances and last for up to one hour or sometimes for several days. The underlying neurobiological mechanism for aura is cortical spreading depression (CSD) [2]. More severe neurological symptoms, such as hemiparesis, are part of the clinical aura spectrum (familial or sporadic hemiplegic migraine; FHM or SHM). The International Headache Society (IHS) has established criteria for the diagnosis and classification of migraine symptoms [1]. The diagnosis relies on a combination of traits or symptoms, and the individual traits are not completely independent of each other. Migraine affects about 15% of people in developed countries [3] and is three times more common in women than in men. Patients have a median of one attack per month and 25% have at least two attacks *Address correspondence to this author at the Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, 25100 Brescia, Italia; Tel: +39.030.399 5631 – 5632; Fax: +39.030.399 5027; E-mail: [email protected] 1566-5240/09 $55.00+.00

per month [4]. Patients with more than one attack per month are at increased risk of brain lesions [5].

MIGRAINE AND ISCHEMIC EVIDENCE OF ASSOCIATION

STROKE:

Although migraine attacks may be acutely disabling, the traditional view is that they do not result in longterm consequences to the brain. Against this assumption, new data have emerged which emphasize the high prevalence of migraine among young individuals with stroke as well as a dysfunction of cerebral arteries during migraine attacks and the finding of silent infarctlike brain lesions in migraineurs, thus leading to the hypothesis that a co-morbidity between migraine and cerebral ischemia exists [6]. Over the last decade, several retrospective casecontrol, three prospective, as well as one crosssectional cohort study have been published on the association between migraine and stroke risk. Three of the case-control studies found increased risk of ischemic stroke among women < 45 years of age who reported a history of MA, with risk estimates ranging from 3.8 to 8.4, and two additional case-control studies found increased risk for migraineurs with aura among both genders. In one case-control study, MO was associated with increased risk of ischemic stroke [7]. © 2009 Bentham Science Publishers Ltd.

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Current Molecular Medicine, 2009, Vol. 9, No. 2

A meta-analysis of 11 case-control and three cohort studies published before 2004 indicated that the risk of stroke is increased in people with migraine (pooled relative risk 2.16; 95% CI, 1.89 to 2.48). This risk was consistent in people who had MA (relative risk, 2.27; 95% CI, 1.61 to 3.19) and MO (relative risk, 1.83; 95% CI, 1.06 to 3.15) [8]. Since the publication of the metaanalysis, two large-scale prospective cohort studies [9, 10] and one population-based case-control study [11] were published whose results reinforced the epidemiological assumption of a relation between migraine and risk of stroke. In particular, at least from prospective data, there is no evidence that MO, as opposed to MA, is associated with increased risk of ischemic cerebral events. The risk is apparently more than tripled by smoking (OR, 10), and quadrupled by oral contraceptives (OCs) use (OR, 13.9 – 16.9). The combination of migraine, OCs and smoking further increases such a risk. Overall, there is strong epidemiological evidence that migraine, particularly MA, is associated with increased risk of cerebral ischemic events, which appears to be stronger among the young but may persist in the elderly. Recent findings from two large-scale prospective cohort studies suggesting an association between migraine and ischemic heart disease [12, 13], indirectly strengthen this assumption and lead to the hypothesis that MA is associated with a systemic vascular disorder.

BIOLOGICAL MECHANISMS The relation between migraine and ischemic stroke can be better understood within the context of the pathophysiology underlying migraine.

MIGRAINE PATHOPHYSIOLOGY Migraine is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels, which, in turn, results in pain and further nerve activation [14]. Migraine is not caused by a primary vascular event [15]. Furthermore, it seems possible that the aura of migraine is separate from the headache. Migraine probably results from a dysfunction of brain-stem or diencephalic nuclei that are involved in the nociceptive modulation of craniovascular afferents. Activation in the brain stem during attacks of migraine has been detected with the use of positron-emission tomography (PET) [16, 17]. The aura of migraine is likely to be the human counterpart of the animal phenomenon of Leão’s spreading depression, and represents the response to depressed neuronal function that is still clearly present when the headache starts [18,19]. These findings, together with direct evidence that the local oxygen supply is more than adequate [20], make the notion that migraine is simply a vascular headache untenable. As to the pathogenesis of pain in migraine, three key factors merit consideration: the cranial blood ves-

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sels, the trigeminal innervation of the vessels, and the reflex connections of the trigeminal system with the cranial parasympathetic outflow. Pain can be generated by large cranial vessels, proximal intracranial vessels, or by the dura mater [21]. These vessels are innervated by branches of the ophthalmic division of the trigeminal nerve, whereas the structures of the posterior fossa are innervated by branches of the C2 nerve roots. In nonhuman primates, stimulation of vascular afferents leads to the activation of neurons in the superficial layers of the trigeminal nucleus caudalis in the region of the cervico-medullary junction and the superficial layers of the dorsal horns of the C1 and C2 levels of the spinal cord, the trigeminocervical complex. Similarly, stimulation of branches of C2 activates neurons in the same regions of the brain [22]. The involvement of the ophthalmic division of the trigeminal nerve and the overlap with structures innervated by C2 explain the common distribution of migraine pain over the frontal and temporal regions, as well as the involvement of parietal, occipital, and high cervical regions by what is, in essence, referred pain. Stimulation of the trigeminal ganglion results in plasma protein extravasation (PPE) in the dura mater [23], cerebral vasodilation [24], and local nerve stimulation in dural vasodilation [25]. PPE has two important components: vasodilation and leakage of plasma proteins. The extravasation component relies on the substance P (neurokinin-1) receptor [26], which is highly effective in blocking dural PPE [27]. CSD can activate trigeminal neurons in the rat [28] and matrix metalloproteinase (MMP)-9, which leads to increased vascular permeability [29]. Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both calcitonin gene-related peptide (CGRP) and substance P (SP) [30]. In the cat, trigeminal ganglion stimulation also increases cerebral blood flow (CBF) by a pathway traversing the greater superficial petrosal branch of the facial nerve [24], releasing a powerful vasodilator peptide, vasoactive intestinal polypeptide (VIP) [31]. Stimulation of the morespecifically vascular painproducing superior sagittal sinus increases CBF and jugular vein CGRP levels. Evidence from humans that CGRP level is elevated in the headache phase of migraine [32] supports the view that the trigeminovascular system might be activated for a protective role in these conditions.

MIGRAINE-ISCHEMIC STROKE PATHWAYS The exact mechanisms by which migraine may lead to ischemic stroke are currently unknown and likely to be complex. The observation that stroke may occur during migraine attacks prompts to speculation that migraine may directly cause an ischemic event (i.e, migrainous infarct). Alternatively, as stroke occurs more frequently during the interictal phase of migraine, an indirect relation between the two diseases might exist. In this regard, several hypotheses have been envisioned: 1) migraine pathophysiology may affect endothelial function and by this alone or in combination with existing local vascular pathologies increase the

The Migraine-Ischemic Stroke Connection

risk of stroke outside of a migraine attack (that is, migraine is a risk factor for ischemic stroke); 2) migraine is associated with an increased prevalence of risk factors for ischemic vascular events; 3) the link is caused by migraine-specific drugs; and 4) migraine and ischemic vascular events are linked via a genetic component [7].

MIGRAINE-INDUCED STROKE: THE MIGRAINOUS INFARCTION It has long been recognized that, although a rare event, stroke may occur during the course of a migraine attack with aura. This phenomenon suggests a causal relationship between migraine and stroke. According to the IHS migraine classification, “migrainous infarction” is defined as a stroke occurring during a typical attack of MA. Patients have a history of MA and the neurological deficits occur in the same vascular distribution as the aura, persist for more than 60 minutes, and are associated with an ischemic brain lesion in a suitable territory demonstrated by neuroimaging. A major criterion of this cause of infarction is that other possible causes are excluded by appropriate investigations [1]. Although the exact incidence of migrainous infarction is difficult to estimate, because of the limitations inherent in the diagnostic criteria and the consequent weakness of the epidemiologic studies, it seems reasonable to assume that migrainous infarction does not account for all strokes occurring during migraine attacks, and, overall, it is responsible for only a minority of migraine-related infarcts. In spite of its small epidemiologic impact, migrainous infarction represents a useful model to understand the potential mechanisms underlying the relation between migraine and stroke. These might include microcirculatory vasoconstriction (CSD-related oligemia), intracerebral large vessel spasm, and vascular endothelium-related hypercoagulability. Cortical Spreading Depression CSD is associated with depressed neuronal bioelectrical activity and transient loss of membrane ionic gradients, with massive surges of extracellular potassium (