CURRENT REVIEW: CLINICAL SCIENCE

Headache Currents

Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment implications
Gretchen E, Tietjen, MD
5 mm/min. The brief phase of excitation of the neuronal and astroglial network is immediately followed by prolonged nerve cell depression. This process induces an efux of excitatory amino acids from nerve cells, enhanced energy metabolism, and changes in genes, growth factors, neurotransmitters, neuromodulators and inammatory mediators. CSD also generates microvascular changes, which are marked by a brief cortical spreading hyperemia (3), followed by a longer lasting cortical spreading oligemia (4). There are functional imaging data to suggest that CSD also occurs in migraine without aura (5). Whereas recognition of the association of migraine and cardiac disease is recent (6,7), migraine and cerebral ischaemia have been linked for over 30 years (8), with reports of ischaemic stroke occurring during (migrainous infarction) and between migraine attacks, particularly in those with aura (918). Potential mechanisms of migraine-related stroke, and implications for treatment, are described in the following paragraphs. POTENTIAL MECHANISMS OF MIGRAINOUS INFARCTION In addition to the central role in headache, the vasculature may also play a key role in migraine-related infarction. Among a variety of putative ischaemic stroke mechanisms, microcirculatory vasoconconstriction (CSD-related oligemia) (19,20) and intracerebral large vessel spasm (21) involve the vasculature. Migraine-associated cerebral ischaemia has also been ascribed to vascular endothelial-related hypercoagulability. Cortical spreading depression Functional neuroimaging with PET and MRI suggests that cerebral blood ow during the oligemic phase of CSD remains above the range associated with ischaemic injury (5,22). Animal models of CSD demonstrate depolarization-initiated release of matrix metalloprotease 9 with consequent disruption of the blood brain barrier (23), suggesting the potential for direct tissue injury and cell death. Vasospasm Vasospasm, once thought to be the mechanism of migraine aura, putatively results from the ictal release of potent vasoconstrictive substances such as endothelin and serotonin, and from the use of vasoconstrictive drugs, including the migraine-specic ergotamines (21), triptans (24), and isometheptene (24). Vasospasm has been implicated in migrainous infarction, although
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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.

Key words: ischaemia, migraine, stroke INTRODUCTION This paper explores the potential mechanisms by which migraine is related to cerebral infarction and to ischaemic heart disease. The migraine-ischaemia relationship is best understood within the context of the pathophysiology underlying migraine. The widely accepted neurovascular theory of migraine integrates the phenomena of head pain and aura, the focal neurological symptoms that precede or accompany headache in a sizable minority. Migraine pain has been ascribed to vascular dilatation and perivascular inammation and nociceptor activation (1). The trigeminal nerves play a prominent role, emanating from the brainstem and innervating the vasculature, although the exact nature of the coupling of aura and pain remains elusive. Migraine aura, once attributed to intracranial vasospasm, is now generally accepted as a consequence of cortical spreading depression of Leao (2). Cortical spreading depression (CSD) is a short-lasting depolarization wave that moves across the cortex at a rate of 3
Address correspondence to Gretchen E. Tietjen, 3120 Glendale Avenue, RHC 1450, Department of Neurology, The University of Toledo-Health Science Campus, Toledo, OH 43614, USA. Tel. +1 419 383 6187; fax +1 419 383 3093; e-mail gretchen.tietjen@utoledo.edu

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migraineurs, or serve as a marker of endothelial perturbation. Oral contraceptive pills increase both the likelihood of migraine (45), and also the risk of ischaemic stroke in migraineurs (10,11,15). Oral contraceptive pill use has been associated with increased levels of brinogen (46), the protein that binds activated platelets, and thereby may lead to a synergy of risk in migraineurs on OCP. MIGRAINE AS A RISK FACTOR FOR ISCHAEMIA Arterial dissection Arterial dissection, a well-recognized cause of stroke in the young, has been found to be more common in migraineurs (47). The association with dissection and intimal tears is postulated to be due to elevations of serum elastase activity, as has been documented in older migraineurs (48). Endothelial dysfunction The endothelium is a mechanical and biological barrier between the blood and vacular wall. Endothelial dysfunction is characterized by reduction in bioavailablility of vasodilator (such as NO), increase in endothelial-derived contracting factors, and consequent impairment of the reactivity of the vasculature, including the microvasculature (49). It also comprises endothelial activation, characterized by a procoagulatory, proinammatory and proliferative state, which, in turn, predisposes to atherogenesis. In this context, endothelial dysfunction is associated with, and predicts, an increased rate of cerebro- and cardiovascular ischaemic events, in essence representing the ultimate risk of the risk factors (49). Traditional risk factors are known to have a signicant impact on endothelial dysfunction. There is also increasing evidence that migraine may be a non-traditional risk factor for endothelial dysfunction, which links it to ischaemic stroke and heart disease (Figure 1). Evidence of enothelial dysfunction in migraine is mounting. One of the most widely accepted biomarkers of endothelial dysfunction is VWF (50). In two previous studies, levels of VWF antigen and VWF activity were signicantly higher in

documented cases are rare (21,24,25). One can hypothesize that ictal release of vasoconstrictive substances into the systemic circulation could also cause coronary artery spasm, accounting for the association of Rose angina and migraine (26). Hypercoagulability When challenged by hypoxia, and calcitonin gene-related peptide (released by activated trigeminal endings during migraine), cerebral endothelial cells, platelets and mast cells have been shown to release platelet-activating factor (PAF) (27), which in turn targets neurones, glial and microglial cells, endothelial cells, monocytes and macrophages. PAF has been implicated in nervous tissue ischaemia and in apoptosis. A potent inducer of platelet activation and aggregation, PAF also prompts the release of von Willebrand Factor (VWF), which similarly affects platelets. Von Willebrand factor, a large endothelial-derived glycoprotein, indirectly activates the platelet IIb/IIIa receptor, crucial for binding brinogen, and leading to primary haemostasis (28). Small clinical studies in migraineurs, have demonstrated ictal platelet aggregation (2932), and increased levels of PAF (27) and of VWF (33) compared with the interictal measurements. One can hypothesize a scenario in which, during the course of a migraine attack, thrombosis occurs within a focally constricted vessel. In an alternate scenario, hypercoagulability-related cerebral ischaemia may induce CSD, i.e. symptomatic migraine (34 36). Attacks of migraine with aura have, for example, been associated with thrombocytosis (37) and with polycythemia vera (PCV) (38), both conditions associated with increased ischaemic risk (39,40). A causative relationship between hypercoagulability and migraine is suggested by reports that migraine attacks are controlled by use of antiplatelet agents and agrylin in the case of thrombocytosis (41), and by periodic phlebotomy in the case of PCV (42,43). Underlying genetic reasons for hypercoagulability in migraineurs have not been identied (43). The acquired antiphospholipid antibodies, which predispose to clotting through an unknown mechanism, are probably not associated with migraine per se (44), but may increase clotting risk in

MIGRAINE ACE-DD Oxidative stress MTHFR C677TT Endothelial dysfunction

Thrombosis

Inflammation

Vascular reactivity

STROKE

ISCHAEMIC HEART DISEASE

Fig 1.Potential Mechanism of Ischemia in Migraine. Migraine is associated with endothelial dysfunction, a process: 1) mediated by oxidative stress, 2) causing thrombosis, inammation, and vascular reactivity, 3) and associated with vascular disease.

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independently linked to lacunar infarction (79) in the absence of carotid atheroma (80), and to leaukoariosis (81). It has also been linked to deep white matter hyperintensities in persons with vascular dementia (82). The ACE-DD polymorphism has been associated with migraine, both with (83) and without aura (84). In the migraine without aura population, ACE-DD was associated with increased frequency of attacks (84). One study reported that the ACE DD genotype acts in combination with the MTHFR T/T genotype to increase migraine susceptibility, with the greatest effect in those with aura (85). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine. The most common mutation, C677T, has been implicated as a genetic stroke risk factor (86). The TT polymorphism is also associated with an increased risk of migraine with aura, independent of other cardiovascular risk factors (87). Cardioembolism Patent foramen ovale (PFO), a risk factor for ischaemic stroke in the young (88), has been found to be more common in young ischaemic stroke patients with migraine (16,89). Patent foramen ovale and isolated atrial septal aneurysm have also been associated with migraine with aura in non-stroke individuals (9093). The basis for the association of PFO and migraine with aura is uncertain, but there is evidence that both migraine and PFO have a genetic predisposition (90,94). A recent intriguing nding that PFO closure reduced or abolished migraine suggests a causal relationship (9597). It has been hypothesized that shunted microbubbles trigger migraine, possibly by creating a surface for coagulation and platelet activation, or by liberation of vasoactive substances (95). There is, however, recent evidence that in persons with migraine with aura, there was no association of white matter lesions (presumed silent strokes) and PFO (98). The presence of PFO would not explain the migraineCHD association. IMPLICATIONS FOR TREATMENT Understanding the mechanism of stroke in migraineurs may be useful in determining effective strategies for stroke prevention and for acute and preventive treatment of migraine. Migraineurs, like other individuals, should avoid cigarette smoking and manage stroke risk factors such as hypertension, hyperlipidemia and diabetes mellitus. Those with prior cerebral or cardiac ischaemia, as well as those with vascular risk factors, or hemiplegic or basilar migraine, should be cautioned to avoid the use of vasoconstrictive drugs, including the migraine-specic triptans, ergotamines and isometheptene. Women with migraine should avoid oestrogen-containing OCP, particularly if they have migraine with aura, have vascular risk factors (hypertension, increased cholesterol, smoking), are over the age of 35, or have a personal or family history of thrombosis (99). With regard to acute migraine treatment, triptans, the selective serotonin agonists, have been widely used since their introduction in the early 1990s. Triptans have three main

migraineurs than in non-headache controls during the interictal phase (51,52). In one, the differences from the control group were most robust in those migrainuers with a history of prior stroke (50), and in the other in those migraineurs with livedo reticularis (52), a putative cutaneous marker of endothelial damage, which has been associated with both migraine (53), and with stroke (54). Levels of VWF have also been shown to increase during the course of the migraine attack (33), suggesting that migraine may be causative in the development of endothelial dysfunction. In addition to biomarkers there have been studies in migraineurs demonstrating impaired vascular reactivity, both cerebral (55) and systemic (56). In an hereditary condition, CADASIL, notable for small vessel stroke and migraine, cutaneous laser Doppler owmetry demonstrates impairment of endothelial dependent vasodilation (57). Whether or not small cerebral infarcts, including clinically silent lesions in the white matter, which have been demonstrated in migraineurs without CADASIL (58), are associated with endothelial dysfunction is uncertain. Increases in platelet function (28,59,60) and thrombin markers (61) have been documented in persons with migraine, and considered either the origin of, or an epiphenomenon of, the attacks. The contribution of hypercoagulability to migrainerelated ischaemic disease is uncertain. There is, however, evidence that aCL, a group of prothrombotic circulating serum immunoglobulins, while not related to migraine per se (44), are associated with silent white matter lesions in migraineurs (44), and with stroke (62). Endothelial dysfunction is mediated by increased oxidative stress, an important promotor of inammatory processes (49). Inammation, a recognized consequence of endothelial dysfunction, has been proposed in the pathogenesis of migraine (63). There is a paucity of studies demonstrating the association of migraine with inamatory markers (64), but much evidence of the efcacy of anti-inammatory agents (anaprox, aspirin, ibuprofen, solumderol, Cox-2) (6569). Clinical investigation of markers of oxidative stress in a migraine population during, after and between migraine attacks has yielded support for the association (70). Compared with migraine-free controls, oxidative stress markers were higher in the migraineurs, even during the interictal period. Within the migraine cohort, oxidative stress markers were higher during than between attacks. Genetic factors that increase susceptibility to oxidative stress, endothelial dysfunction and, possibly, stroke include the angiotensin-converting enzyme gene deletion polymorphism (ACEDD), and the methylenetetrahydrofolate reductase (MTHFR) C677-TT polymorphism. In hypertensive populations, VWF has been associated with ACE-DD (71,72), which mediates oxidative stress and is associated with endothelial dysfunction (73). This polymorphism has also been tied to venous thrombophilia (74), hypercoagulability (75), decreased vasomotion, increased vascular smooth muscle tone, and decreased bradykinin (76). The relationship of ACE-DD genotype to ischaemic stroke and cardiovascular disease is controversial (7578), but it has been
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with regard to ischaemic stroke and heart disease, but contraindicated in the presence of known vascular disease or of multiple vascular risk factors. Treatments with dopamaine antagonists (e.g. metoclopramide, prochlorperazine), non-steroidal antiinammatory drugs, or combination analgesics (containing caffeine, acetaminophen, aspirin or butalbital) are options under these circumstances. References
1 Moskowitz MA. Pathophysiology of headache past and present. Headache 2007; 47 (Suppl. 1):S5863. 2 Leao APP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7:35990. 3 Cao Y, Welch KM, Aurora S, Vikingstad EM. Functional MRIBOLD of visually triggered headache in patients with migraine. Arch Neurol 1999; 56:54854. 4 Friberg L, Olesen J, Lassen NA, Olsen TS, Karle A. Cerebral oxygen extraction, oxygen consumption, and regional cerebral blood ow during the aura phase of migraine. Stroke 1994; 25:9749. 5 Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331:168992. 6 Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Migraine and risk of cardiovascular disease in women. JAMA 2006; 296:28391. 7 Kurth T, Gaziano JM, Cook NR, Bubes V, Logroscino G, Diener HC, Buring JE. Migraine and risk of cardiovascular disease in men. Arch Intern Med 2007; 167:795801. 8 Oral contraceptives and stroke in young women. Associated risk factors. JAMA 1975; 231:71822. 9 Tzourio C, Iglesias S, Hubert JB, Visy JM, Alperovitch A, Tehindrazanarivelo A et al. Migraine and risk of ischaemic stroke: a casecontrol study. BMJ 1993; 307:28992. 10 Tzourio C, Tehindrazanarivelo A, Iglesias S, Alperovitch A, Chedru F, dAnglejan-Chatillon J et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995; 310:8303. 11 Lidegaard O. Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the inuence of diabetes, hypertension, migraine and previous thrombotic disease. Br J Obstet Gynaecol 1995; 102:1539. 12 Buring JE, Hebert P, Romero J, Kittross A, Cook N, Manson J et al. Migraine and subsequent risk of stroke in the Physicians Health Study. Arch Neurol 1995; 52:12934. 13 Carolei A, Marini C, De Matteis G. History of migraine and risk of cerebral ischaemia in young adults. The Italian National Research Council Study Group on Stroke in the Young. Lancet 1996; 347:15036. 14 Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, Risch N. Association between migraine and stroke in a large-scale epidemiological study of the United States. Arch Neurol 1997; 54:3628. 15 Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318:138. 16 Milhaud D, Bogousslavsky J, Van Melle G, Liot P. Ischemic stroke and active migraine. Neurology 2001; 57:180511.

mechanisms: vasoconstriction, peripheral trigeminal inhibition and inhibition of transmission through second order neurones of the trigeminal cervical complex (100). Generally proven to be safe and well tolerated, these medications should not be used by persons with history, symptoms or signs of ischaemic cardiac, cerebrovascular or peripheral vascular syndromes. Cerebrovascular syndromes include strokes of any type as well as transient ischaemic attacks. Triptans are contraindicated in the treatment of patients with hemiplegic and basilar migraine because of concerns over the potential for cerebral vasoconstriction leading to stroke (101). With a theoretical concern that persons with migraine may have predisposition to vasospasm, it is also strongly recommended that triptans not be given to patients with two or more risk factors unless they have undergone an appropriate cardiovascular evaluation (102). There are only a few published reports of stroke associated with the use of triptans. A study of 130 141 migraineurs and an equal number of age, sex and health plan matched non-migraineurs suggests that the use of triptans is not associated with increased risk of myocardial infarction, stroke or overall mortality (103). In this analysis, the rate of myocardial infarction (MI) was identical in migraineurs and non-migraineurs, 1.4 per 1000 person-years, and there was no signicant increase in MI risk based on current or recent triptan use. Neither current nor recent triptan use was associated with risk of stroke. Since the introduction of the triptans, the uses of ergots have declined, in part due to the less attractive side-effect prole, including nausea and emesis. There are reports of ergotrelated stroke (21,104), but in patients without contraindications, data collected over 50 years of clinical experience suggest that ergotamines are safe for clinical use (105). Effective migraine prophylaxis with drugs, which carry no increased risk of stroke or even possibly decrease stroke risk, will reduce the need for acute therapies. The association of stroke with recent occurrence and frequency of migraine attacks suggests that migraine prophylaxis may actually reduce migrainerelated stroke risk. There have been several reports of stroke in migraineurs using beta-blockers (106111). Because propranolol may limit compensatory vasodilator capacitance, some headache specialists avoid its use for those with prolonged aura and basilar migraine (112). ACE inhibitors and angiotensin receptor blockers have demonstrated efcacy in migraine prophylaxis (113,114) and have also been shown to decrease VWF levels, reecting endothelial repair (115). In summary, studies support an independent relationship of ischaemic disease and migraine, and the vasculature has been widely implicated in this link. Identifying migraineurs at highest risk of ischaemic stroke and heart disease is the rst step towards prevention. Aside from controlling traditional vascular risk factors, it remains uncertain, however, whether stroke or myocardial infarction in the migraine population can be prevented by (i) migraine prophylaxis, (ii) endothelial repair, (iii) platelet inhibition, or a combination of these strategies. Treatment of acute migraine attacks with triptans is generally safe
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