- Open Access
Stroke and migraine is there a possible comorbidity?
© Spalice et al. 2016
- Received: 5 January 2016
- Accepted: 12 April 2016
- Published: 26 April 2016
The association between migraine and stroke is still a dilemma for neurologists. Migraine is associated with an increased stroke risk and it is considered an independent risk factor for ischaemic stroke in a particular subgroup of patients. The pathogenesis is still unknown even if several studies report some common biochemical mechanisms between these two diseases. A classification of migraine-related stroke that encompasses the full spectrum of the possible relationship between migraine and stroke includes three main entities: coexisting stroke and migraine, stroke with clinical features of migraine, and migraine-induced stroke. The concept of migraine-induced stroke is well represented by migrainous infarction and it is described in the revised classification of the International Headache Society (IHS), representing the strongest demonstration of the relationship between ischaemic stroke and migraine. A very interesting common condition in stroke and migraine is patent foramen ovale (PFO) which could play a pathogenetic role in both disorders. The neuroradiological evidence of subclinical lesions most typical in the white matter and in the posterior artery territories in patients with migraine, opens a new field of research. In conclusion the association between migraine and stroke remains an open question. Solving the above mentioned issues is fundamental to understand the epidemiologic, pathogenetic and clinical aspects of migraine-related stroke.
Migraine is a common, chronic, multifactorial neurovascular disease, characterized by severe attacks of headache and autonomic nervous system dysfunction. Migraine is common among children and adolescents. Its prevalence has a documented range from 0.5 to 13.6 % and increases with age. Sex distribution is almost equal between ages of 7 and 11. During puberty, the balance shifts to a 3:1 ratio between females and males, which extends into adulthood. The two most common types of migraine in children are migraine without aura (MO) and migraine with aura (MA). Childhood periodic syndromes (cyclical vomiting, abdominal migraine and benign paroxysmal vertigo of childhood) frequently precede migraine and occur exclusively in the pediatric population [1–4].
Migraine without aura, previously known as “common migraine”, is the most frequent type of migraine, accounting for 60–80 % of all migrainous headaches. Children experiencing migraine without aura have often prodromal symptoms such as behavioral changes (e.g. irritability or decrease in energy) and appearance abnormalities (e.g. pallor, pigmented macules in the infraorbital region or “dark rings under the eyes”). Migraine with aura is characterized by occurrence of one or more fully reversible auras before the onset of headache. Children may complain of visual disturbances (visual auras) and hallucinations. Somatosensory aura, though uncommon, consists of perioral paresthesias and/or numbness and tingling of hands or feet (or both) [1–5].
Although migraine attacks may be acutely disabling, they do not result in long-term brain consequences.
Against this assumption, new data have emerged emphasizing migraine high prevalence among young individuals with stroke, dysfunction of cerebral arteries during migraine attacks and incidence of silent infarct-like brain lesions in migraineurs. It suggests thus that it might exists a comorbidity between migraine and cerebral ischemia [6–8].
The mechanism of IS increased risk in migraine is unknown and numerous hypotheses have been raised.
Migraine is considered a neurovascular disorder with arterial constriction and posterior circulation decreased blood flow as consequences of spreading wave of neuronal depression in the cerebral cortex. In this regard, Cortical Spreading Depression (CSD) may induce cerebral blood flow short-lived increases and tissue hyperoxia, followed by deeper oligoemia and consequent increased intraparenchymal vascular resistance. Thus, low flow in major intracerebral vessels may be due to increased downstream resistance and not to major intracranial arterial vasospasm. A low cerebral blood flow and neuronally mediated vasodilatation could then cause sluggish flow in large intracerebral vessels during migraine auras. When combined with coagulopathy predisposing factors, as dehydration hyperviscosity or intravascular thrombosis, migraine-induced cerebral infarction may occur, even if rarely [11–15].
CSD is accompanied by vasodilatation of extrapaenchymal vesels and release of neuronal inflammatory mediators. Releasing of vasoactive peptides and nitic oxide, activation of cytokines, and adhesion molecules upregulation also predispose to intravascular thrombosis. This could explain why migraine-induced stroke usually respects intracranial arterial territories whereas aura involves more widespread brain regions. Moreover, frequent aura due to CSD, could induce cytotoxic cell damage and gliosis based on glutamate release or excessive intracellular calcium accumulation. Thus, a persistent neurologic deficit could be due to selective neuronal necrosis.
Vasospasm was previously thought to be implied in migraine aura, resulting from releasing of vasoconstrictive molecules as endothelin and serotonin. In rare documented cases it was involved in migrainous infarction [15–18].
Experimental data point toward activation of the thrombotic cascade during a migraine attack. Indeed, platelets and mast cells showed to release platelet activating factor (PAF), a potent inducer of platelet activation and aggregation. PAF is also involved in the release of von Willebrand factor, and indirectly in the activation of the platelet IIb/IIIa receptor, crucial for binding fibrinogen thus leading to primary hemostasis.
However, these mechanisms apply only for the so called migrainous strokes, which, as defined by the IHS criteria, are a rare event. This low incidence cannot explain then the increased risk of stroke in migraine [11–17].
Migraine and patent foramen ovale
Patent foramen ovale (PFO), an interatrial communication remnant of the fetal circulation, is due to a failure in the fusion between septum primum and septum secundum. The prevalence of PFO in healthy adult population is around 25 %. Several case–control studies observed that patent foramen ovale (PFO) is significantly more common in patients who suffered MA than those without migraine. Right-to-left cardiac shunt at rest through a PFO is more common in migraineurs with aura than in non-migraineurs control patients with PFO and patients with migraine tend to have greater right-to-left shunts as compared to the non-migrainous population. This suggests that interatrial communication may play a role in the pathogenesis of migraine. The mechanisms underlying this possible association was postulated but never demonstrated. Paradoxical embolism is suggested to be the causal link between migraine and PFO, but data available are insufficient to substantiate the hypothesis that migraine frequency (and, indirectly, ischemic stroke risk) is reduced by PFO closure. A variable proportion of patients who underwent PFO closure for non-migraine indications however reported cessation or improvement of their migraine attacks after the procedure. On the basis of these findings, the possibility of a PFO–migraine– ischemic stroke triangular association remains a matter of speculation [15–18].
In the last years, some observations have suggested migraine as a predisposing condition for sCAD, one of the most common causes of stroke in young patients. The mechanism by which migraine may affect the risk of sCAD is unknown. A generalized vascular disorder is hypothesized to be a predisposing condition for both diseases. Recent observations in migraineurs of increased activity of serum elastase, a metallopeptidase that degrades specific elastin-type amino acid sequences, suggest a possible extracellular matrix degradation facilitating sCAD occurrence. In line with previous observations of altered common carotid artery distensibility in patients with sCAD, it was recently reported that an endothelium-dependent vasodilatation assessed in the brachial artery is significantly impaired in these subjects. Similar vascular changes were observed in migraine patients during interictal periods and replicated in a recent cross-sectional study in migraineurs of recent onset, excluding the possibility of a bias due to longstanding history of migraine and repeated exposure to vasoconstrictor drugs. Finally, the analysis of small families has shown that the structural abnormalities related to sCAD might be familial and follow an autosomal-dominant pattern of inheritance. This suggests that genetically determined alterations of the extracellular matrix may play a crucial pathogenic role and that candidate genes involved in endothelial and vessel wall functions regulation might increase susceptibility to both conditions [18, 19].
Inconsistent results have been found for the various biologic or clinical markers of thrombotic risk studied so far, such as platelet activation, factor V Leiden mutation, von Willebrand factor, prothrombin factor 1.2, platelet leukocyte aggregation, antiphospholipid antibodies, and livedo reticularis. In contrast, there is mounting evidence that migraine may be a risk factor for endothelial dysfunction, a possible link to ischemic stroke and heart disease.
Endothelial dysfunction is characterized by reduction in bioavailability of vasodilators (such as nitric oxide), increase in endothelial derived contracting factors, and consequent impairment of vessels reactivity, including the microvascular system. It represents the first step in the development of atherothrombosis finally leading to vascular events. It also comprises endothelial activation, characterized by a procoagulant, proinflammatory and proliferative state, which in turn predisposes to ischemia. Endothelial dysfunction is mediated by increased oxidative stress, an important promotor of the inflammatory process, that might have a role in the pathogenesis of migraine. Clinical investigation of markers of oxidative stress in a migraine population during, after, and between migraine attacks yielded support for the association. In fact, compared with migraine-free controls, oxidative stress markers were found higher in migraineurs, even during the interictal period, yielding support to the association [12–14].
Reduced endothelial repair capacity has emerged as another possible connection between migraine and vascular disease. Levels of endothelial progenitor cells, measured using flow cytometry, were found lower in migraineurs – particularly in those with aura – if compared to healthy controls and to patients with tension-type headache. Patients with migraine presented also increased markers of senescence and decreased migratory capacity of endothelial progenitor cells. Endothelial progenitor cells derive from bone marrow, circulate in peripheral blood, are capable of proliferation and differentiation into endothelial cells and play a role in neoangiogenesis after ischemia. Although it is not known if the reduction of endothelial progenitor cells represents a primary alteration in migraine or the consequence of migraine attacks itself, it is possible that their alteration mediates an increased vascular risk [12–19].
Raised risk due to migraine treatments , particularly vasoconstrictors, is supported by an increase in white matter abnormalities and in mortality found in patients taking ergotamine, though recent studies found no increase in severe vascular events treated with triptans. Furthermore, drugs widely used in migraine, such as non-steroidal inflammatory drugs, decrease the risk of cerebral ischemic events .
Over the past years, evidence from twins and family history studies, although not entirely consistent, has supported the notion that genetic predisposition plays a major role in the occurrence of both migraine and ischemic stroke.
Monogenic forms of migraine
FHM1 is caused by mutations in the CACNA1A gene, located on chromosome 19p13, encoding the pore-forming a1A subunit of Cav2.1 (P/Q type) voltage-gated neuronal calcium channels;
FHM2 is caused by mutations in the ATP1A2 gene, located on chromosome 1q23, encoding the a2 subunit of sodium–potassium pump ATPases;
FHM3 is caused by mutations in the SCN1A gene, located on chromosome 2q24 encoding the a1 subunit of the neuronal voltage-gated sodium channel Nav1.1,crucial in action potentials generation and propagation.
Overall, the common consequence of FHM1, FHM2, and FHM3 mutations seems to be to increased levels of glutamate and potassium in the synaptic cleft causing an increased propensity to CSD. Whether this might also increase the propensity to cerebral ischemia is unknown. Similarly, the contribution of FHM genes in common forms of migraine (MO and MA) remains unclear. A recent study showed no linkage to the CACNA1A and ATP1A2 genes in families with apparently autosomal – dominant mode of inheritance of MA, whereas a case – control study investigating the role of the ATP1A2 gene in MA found no evidence of association [11, 12].
Polygenic forms of migraine
The first group includes genes involved in neurotransmitter-related pathway, such as genes encoding for dopamine D2 receptor (DRD2), human serotonin transporter (HSERT), catechol-O-methyltransferase (COMT), and dopamine b-hydroxylase (DBH).
The second group includes genes involved in vascular function, such as 5,10-methylenetetrahydrofolate reductase (MTHFR), angiotensin I-converting enzyme (ACE), and endothelin type A (ETA) receptor.
The third group includes genes involved in hormonal function, such as estrogen receptor 1 (ESR1), progesterone receptor (PGR) and androgen receptor (AR).
Several genes candidate for migraine are also good candidate for cerebral ischemia. Among them, in spite of inconsistent results of some studies hypothesizing a link between this marker and migraine, C677T polymorphism of MTHFR gene looks particularly promising, due to its probable independent effect on ischemic stroke risk. This enzyme catalyzes the reduction of 5,10-MTHF to 5-MTHF, the circulatory form of folate and carbon donor for re-methylation of homocysteine (Hcy), a reactive thiol amino acid, to methionine. It was found that with low dietary folate, patients with migraine and MTHFR C677T variant homozygosis have a higher risk for elevated Hcy (hyperhomocysteinemia or HHcy) levels. HHcy is defined as Hcy level above 5–15_mol/L. Elevated Hcy levels were reported in patients with MA. Animal studies suggest that Hcy may increase migraine susceptibility by heightening cerebral artery sensitivity. Hcy-related endothelial dysfunction seems involved in migraine beginning and maintenance of. Endothelial dysfunction may result from direct damaging effect of Hcy on endothelium and altered oxidative status. Hcy is indeed a risk factor for endothelial cell injury, atherosclerotic vascular diseases, independent of the long-recognized identified common risks. Autooxidation of Hcy promotes the production of hydroxyl radicals, thiolactone and known lipid peroxidation initiators with creation of a prothrombotic environment. It is possible that HHcy may result in temporary cerebral thrombosis and/or altered blood flow, allowing less oxygen into the brain and manifesting the common symptoms to MA and ischemic stroke [12, 13].
Abnormalities of uncertain clinical significance are frequent findings on brain MRI scans in patients with migraine. The most common abnormality is white matter lesions (WMLs), typically multiple, small, punctate hyperintensities, occurring in the deep or periventricular white matter and often seen on T2-weighted or Fluid-Attenuated Inversion Recovery (FLAIR) images. In a small minority of cases, number, distribution, and location of WMLs may lead to the diagnosis of an underlying disease of which migraine may be but one symptomatic manifestation. Some authors hypothesized that white-matter abnormalities are due to ischaemic insults which leed to the suggestion that migraine could be a progressive brain disorder .
Emphasis on identification and treatment of modifiable vascular risk factors, such as smoking, hypertension, diabetes, and hypercholesterolemia, is warranted in migraineurs, especially those with MA.
Because of the potential synergistic effect of several migraine-specific drugs with vasoconstrictive action, including triptans, and traditional predisposing conditions in increasing the risk of ischemic stroke, subjects with major cardiovascular risk factors should be encouraged to adopt migraine prophylactic strategies. This approach should be also recommended to subjects with a personal history of prior ischemic disease (cerebral and/or myocardial).
There is no direct evidence that PFO closure is effective for MA prophylaxis and, indirectly, for primary prevention of stroke, and, this procedure cannot thus be recommended for MA prophylaxis.
Patients with migrainous stroke should undergo the same diagnostic workup and receive the same pharmacological treatment of any ischemic stroke in the young, both during the acute phase and follow-up.
Preventing disease progression in migraine has already been added to traditional goals of relieving pain and restoring patients’ ability to function. If migraineurs brain lesions of have a significant clinical correlation, preventing brain lesions accumulation may become an additional goal of treatment. The association of stroke with frequency of migraine attacks suggests that migraine prophylaxis, especially MA, may actually reduce migraine-related stroke risk. It opens then issues of whether prophylactic drugs decreasing such a risk (i.e., antihypertensives) might be the best choice in these cases [17–20].
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Agostoni E, Fumagalli L, Santoro P, Ferrarese C. Migraine and stroke. Neurol Sci. 2004;25 Suppl 3:S123–5.View ArticlePubMedGoogle Scholar
- Welch KM. Relationship of stroke and migraine. Neurology. 1994;44(10 Suppl 7):S33–6. Review.PubMedGoogle Scholar
- Olesen J, Friberg L, Olsen TS, Andersen AR, Lassen NA, Hansen PE, Karle A. Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-inducedischaemic insults. Brain. 1993;116(Pt 1):187–202.View ArticlePubMedGoogle Scholar
- Welch KM, Levine SR. Migraine-related stroke in the context of the International Headache Society classification of head pain. Arch Neurol. 1990;47(4):458–62. Review.View ArticlePubMedGoogle Scholar
- Galimi R. Migraine and ischemic stroke: possible pathogenic relation. Recenti Prog Med. 2012;103(9):319–27. doi:10.1701/1136.12525.Review.Italian.PubMedGoogle Scholar
- Larrosa-Campo D, Ramón-Carbajo C, Para-Prieto M, Calleja-Puerta S, Cernuda-Morollón E, Pascual J. Migraine as a vascular risk factor. Rev Neurol. 2012;55(6):349–58. Review. Spanish.PubMedGoogle Scholar
- Guillan M, Alonso-Canovas A, Gonzalez-Valcarcel J, Garcia Barragan N, Garcia Caldentey J, Hernandez-Medrano I, Defelipe-Mimbrera A, Sanchez-Gonzalez V, Terecoasa E, Alonso de Leciñana M, Masjuan J. Stroke mimics treated with thrombolysis: further evidence on safety and distinctive clinical features. Cerebrovasc Dis. 2012;34(2):115–20. doi:10.1159/000339676. Epub 2012 Jul 31.View ArticlePubMedGoogle Scholar
- Partap S. Stroke and cerebrovascular complications in childhood cancer survivors. Semin Pediatr Neurol. 2012;19(1):18–24. doi:10.1016/j.spen.2012.02.012. Review.View ArticlePubMedGoogle Scholar
- Cercy SP, Sahler K. Discrete progression of migraine-induced focal cerebral infarction. Neurol Sci. 2013;34(5):781–3. doi:10.1007/s10072-012-1116-8. Epub 2012 May 19. No abstract available.View ArticlePubMedGoogle Scholar
- Santos E, Sánchez-Porras R, Dohmen C, Hertle D, Unterberg AW, Sakowitz OW. Spreading depolarizations in a case of migraine-related stroke. Cephalalgia. 2012;32(5):433–6. doi:10.1177/0333102412441414. Epub 2012 Mar 9.View ArticlePubMedGoogle Scholar
- Eising E, de Vries B, Ferrari MD, Terwindt GM, van den Maagdenberg AM. Pearls and pitfalls in genetic studies of migraine. Cephalalgia. 2013;33(8):614–25. doi:10.1177/0333102413484988. Review.View ArticlePubMedGoogle Scholar
- Ducros A. Genetics of migraine. Rev Neurol (Paris). 2013;169(5):360–71. doi:10.1016/j.neurol.2012.11.010. Epub 2013 Apr 22. Review. French.View ArticleGoogle Scholar
- Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain: a systematic review and meta-analysis. Neurology. 2013;81(14):1260–8. doi:10.1212/WNL.0b013e3182a6cb32. Epub 2013 Aug 28. Review. PMID: 23986301 [PubMed - indexed for MEDLINE].View ArticlePubMedPubMed CentralGoogle Scholar
- Gibson LM, Whiteley W. The differential diagnosis of suspected stroke: a systematic review. J R Coll Phys Edinb. 2013;43(2):114–8. doi:10.4997/JRCPE.2013.205. Review. PMID: 23734351 [PubMed - indexed for MEDLINE].View ArticleGoogle Scholar
- Guegan-Massardier E, Lucas C. Migraine and vascular risk. Rev Neurol (Paris). 2013;169(5):397–405. doi:10.1016/j.neurol.2013.03.004. Epub 2013 Apr 18. Review. French. PMID: 23602119 [PubMed - indexed for MEDLINE].View ArticlePubMedGoogle Scholar
- Tana C, Tafuri E, Tana M, Martelletti P, Negro A, Affaitati G, Fabrizio A, Costantini R, Mezzetti A, Giamberardino MA. New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters? J Headache Pain. 2013;14(1):9. doi:10.1186/1129-2377-14-9.View ArticlePubMedPubMed CentralGoogle Scholar
- Davis D, Gregson J, Willeit P, Stephan B, Al-Shahi Salman R, Brayne C. Patent foramen ovale, ischemic stroke and migraine: systematic review and stratified meta-analysis of association studies. Neuroepidemiology. 2013;40(1):56–67. doi:10.1159/000341924. Epub 2012 Oct 11.View ArticlePubMedGoogle Scholar
- Kurth T, Diener HC. Migraine and stroke: perspectives for stroke physicians. Stroke. 2012;43(12):3421–6. doi:10.1161/STROKEAHA.112.656603. Epub 2012 Sep 20. Review.View ArticlePubMedGoogle Scholar
- Agostoni E, Rigamonti A. Migraine and small vessel diseases. Neurol Sci. 2012;33 Suppl 1:S51–4. doi:10.1007/s10072-012-1041-x. Review.View ArticlePubMedGoogle Scholar
- Laurell K, Lundström E. Migrainous infarction: aspects on risk factors and therapy. Curr Pain Headache Rep. 2012;16(3):255–60. doi:10.1007/s11916-012-0262-2.View ArticlePubMedGoogle Scholar
- Parisi P, Verrotti A, Costa P, Striano P, Zanus C, Carrozzi M, Raucci U, Villa MP, Belcastro V. Diagnostic criteria currently proposed for "ictal epileptic headache": Perspectives on strengths, weaknesses and pitfalls. Seizure. 2015;31:56–63. doi:10.1016/j.seizure.2015.07.005. Epub 2015 Jul 17.View ArticlePubMedGoogle Scholar