J Headache Pain (2002) 3:15–20
`© Springer-Verlag 2002
`
`R E V I E W
`
`Lucilla Parnetti
`Maurizio Paciaroni
`Virgilio Gallai
`
`Headache and ischemic stroke
`
`Received: 27 September 2001
`Accepted in revised form: 27 December 2001
`
`L. Parnetti (쾷) • M. Paciaroni • V. Gallai
`Department of Neuroscience,
`University of Perugia,
`Via Enrico dal Pozzo, I-06126 Perugia, Italy
`e-mail: parnetti@unipg.it
`Tel.: +39-075-5783564
`Fax: +39-075-5783583
`
`Abstract Migraine is a common neu-
`rological condition affecting yearly
`1%–10% of all men and 3%–20% of
`all women. Focal neurological symp-
`toms (auras), most commonly visual
`and sensory, occur in 4% of migraine
`attacks. Migraine with and without
`aura seems to be associated with an
`increased stroke risk. Migraine with
`aura may mimic transient ischemic
`attacks and may induce stroke
`(migrainous stroke). Headache is also
`a common symptom during ischemic
`stroke In this review, we present the
`evidence about each of these circum-
`stances to better understand the rela-
`tionship between headache, especial-
`ly migraine, and ischemic stroke
`
`Key words Headache • Stroke •
`Migraine • Cerebrovascular diseases
`
`Migraine and subsequent risk of ischemic stroke
`
`Large-scale prospective epidemiological studies have iden-
`tified major risk factors for stroke, including advanced age,
`race, family history of stroke, hypertension, diabetes melli-
`tus, heart disease, elevated cholesterol levels, current smok-
`ing, obesity, heavy alcohol intake, sedentary lifestyle, use of
`exogenous hormones, and hyperhomocysteinemia [1, 2].
`Although several clinical reports claim the existence of an
`association between migraine and stroke, only a few epi-
`demiological studies have addressed this specific issue. The
`U.S. Physicians’ Health Study showed that physicians aged
`
`40–84 years with a history of migraine had increased risk of
`stroke; after adjustment for age and other cardiovascular
`risk factors, the relative risk was 1.84 (95% CI, 1.06 to 3.20)
`for total strokes and 2.0 (95% CI, 1.10 to 3.64) for ischemic
`strokes [3]. Merikangas et al. [4] also found that, after con-
`trolling for established risk factors for stroke (e.g. hyperten-
`sion, diabetes, heart disease, gender), both migraine and
`severe nonspecific headache were associated with a signifi-
`cantly increased risk for stroke (RR, 1.5) that was higher in
`young patients: at the age of 40 years, the relative risk was
`2.81 (95% CI, 1.45–5.43), at 50 years it was 2.07 (95% CI,
`1.30–3.30), at 60 years it was 1.69 (95% CI, 1.10–2.60), and
`at 90 years it was 1.16 (95% CI, 0.63–2.11). Therefore,
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`16
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`migraine plays a more critical role in stroke of the young. In
`other studies the risk of ischemic stroke was not excessive
`among migraineurs aged ≥60 years [5, 6].
`In recent years, several studies have been published on
`the association between migraine and stroke in young
`women under 45 years of age. Tzourio et al. [7] found that
`stroke was strongly associated with migraine, both without
`aura (odds ratio, 3.0; 95% CI, 1.5–5.8) and with aura (odds
`ratio, 6.2; 95% CI, 2.1–1.80). In another study [8], a history
`of migraine was more frequent in stroke patients than in
`controls (odds ratio, 1.9; 95% CI, 1.1–1.3). In the prospec-
`tively designed subgroup analyses, a history of migraine
`reached the highest odds ratio (3.7; 95% CI, 1.5–9.0) and
`was the only significant risk factor in women below age 35
`years. Chang et al. [9] reported that in young women (20–44
`years of age) a personal history of migraine was strongly
`associated with stroke (for all stroke: adjusted OR, 1.78;
`95% CI, 1.14–2.77; for ischemic stroke: OR, 3.54; 95% CI,
`1.30–9.61). In agreement with previous studies [5, 10],
`ischemic stroke was associated with both migraine with aura
`(OR, 3.81; 95% CI, 1.26–1.15) and migraine without aura
`(OR, 2.97; 95% CI, 0.66–1.35).
`The risk of stroke in young migrainous women seems to
`apply not only to ischemic stroke, but also to hemorrhagic
`stroke, although hemorragic stroke has been not extensively
`studied and the results are less consistent [11].
`In this category of patients, the risk of ischemic stroke
`was substantially increased by the use of oral contraceptives
`(OR, 13.9), for which a dose-effect relationship between risk
`of stroke and dose of estrogen was found (for pills contain-
`ing 50 µg estrogen: OR, 4.8; for pills with 30–40 µg: OR, 2.7;
`pills with 20 µg: OR, 1.7; pills with progesterone; OR, 1) [7];
`the risk of ischemic stroke was also elevated in heavy smok-
`ers (≥20 cigarettes per day: OR, 10.2). In migrainous women,
`coexistent use of oral contraceptives, history of high blood
`pressure and smoking habit had greater than multiplicative
`effects on the odds ratio for ischemic stroke (OR, 34.4; 95%
`CI, 3.27–3.61). However, this dramatic increase was based
`on only nine cases and two controls [9]. Other conditions
`predisposing to stroke, namely minor cardiac abnormalities
`like patent foramen ovale [12] and mitral valve prolapse [13]
`or the presence of anti-cardiolipin antibodies [14], may cause
`a stroke when combined with migraine, but this has not been
`definitely established [11].
`Several hypotheses have been raised to explain the asso-
`ciation between migraine and stroke: vasospasm, endothe-
`lial dysfunction, congenital thrombophilia, platelet hyperag-
`gregability, and association with cardiac abnormalities pre-
`disposing to ischemic stroke. However, no fully convincing
`evidence has been produced [11].
`The strength of the association should not, however, lead
`to the conclusion that all young women with migraine are at
`high risk of stroke. The incidence of ischemic stroke in
`
`young women is low (approximately 10 cases in 100 000
`women/years) [15, 16], and the risk of ischemic stroke is
`only 17–19 per 100 000 women with migraine per year [7].
`Furthermore, it is not known whether this increased risk
`relates to all young migrainous women or only to a subgroup
`of them (i.e. patients with MELAS, cardiac abnormalities or
`antiphospholipid antibodies syndrome) [17–19]. However,
`young women, especially those <35 years of age, should be
`firmly advised to avoid smoking, and if they use oral con-
`traceptives, to choose pills with a low estrogen content or
`only progesterone [11].
`
`Migrainous stroke
`
`Stroke is a rare but potentially devastating complication of
`migraine. In 1988, the International Headache Society [20]
`classified migrainous infarction under the complications of
`migraine with aura (IHS 1.6.2), where the diagnosis of
`migraine-induced stroke in patients with migraine without
`aura is not allowed. To meet this definition, patients must
`have: (i) neurological symptoms and signs that are identical
`or similar to those of other migraine attacks and not com-
`pletely reversible within 7 days and/or neuroimaging evi-
`dence of ischemic infarction in a relevant area; (ii) the stroke
`must have occurred during a typical migraine attack; (iii)
`other causes of stroke must be excluded, although stroke
`risk factors may be present. Several authors [21, 22] pro-
`posed that migrainous infarction should be redefined in the
`IHS classification as a possible complication of both
`migraine with and without aura because they described
`patients who had an ischemic stroke during a typical
`migraine attack (even if migraine with aura is substantially
`present (80%) in patients with migrainous stroke) [23]. In
`the WHO study [9], migrainous stroke was defined as any
`stroke occurring in presence of headaches in the 3 days
`before the stroke; following this rule, up to 40% of the
`strokes in migrainous women can be considered migrainous
`stroke.
`The incidence of migrainous infarction has been esti-
`mated to be 3.36 per 100 000 persons per year, but in the
`absence of other stroke risk factors, this was reduced to 1.44
`per 100 000 persons per year [24]. Migraine-induced stroke
`accounts for 0.8% of all strokes and accounts for as few as
`4% [25] to as many as 20% of ischemic strokes in the young
`[26, 27].
`Bogousslavsky et al. [28] found a marked female pre-
`ponderance in the migrainous stroke group with respect to
`controls, and Iglesias et al. [29] claimed that the combina-
`tion of smoking and migraine was highly associated with
`stroke. Oral contraceptives are also recognized to increase
`stroke risk in migraine sufferers [7]. Usually, headache fre-
`
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`

`

`quency and severity decrease after stroke, probably due to
`reduced nociceptive transmission as a result of loss in
`vasoreactivity of the affected cerebral blood vessel [30].
`The prognosis of cerebral infarction associated with
`migraine is generally good. Hoekstra-van Dalen et al. [31]
`found that no patient had recurrent stroke during an average
`follow-up period of 5.8 years. Strokes related to migraine
`are commonly found in the territory of the posterior cerebral
`artery [27, 32]. The mechanism by which migraine causes a
`cerebral infarction is unknown; it has been proposed that
`during migraine attack there is a reduction of cerebral blood
`flow secondary to arteriolar vasoconstriction [33–35]. A
`slowly spreading wave of cortical neuronal depression with
`spreading oligoemia is also possible. Prolonged vasocon-
`striction and oligoemia may lead to hemostasis and predis-
`pose to intravascular thrombosis and migraine-induced cere-
`bral infarction Increased platelet aggregability, presence of
`antiphospholipid antibodies and use of oral contraceptives
`may contribute to the risk of enhanced coagulation [36–38].
`The increase in procoagulant effects, the decrease in antico-
`agulant effects, and the hyperactivation of the antifibrinolyt-
`ic system indicate that oral contraceptives do have a net pro-
`thrombotic effect [39]. In his model of neurogenic inflam-
`mation due to pathological activation of the trigeminovas-
`cular system during migraine attack, Moskowitz [40]
`showed that platelet aggregation occurs in the lumen of
`blood vessels. Another hypothesis suggests that repeated
`episodes of migraine-induced vasoconstriction may weaken
`the internal elastic lamina of cerebral vessels and predispose
`to arterial dissection [41]. Paradoxical embolism is another
`postuled cause [42]. Both migraine and stroke may also
`result from underlying genetic disorders such as MELAS or
`CADASIL [43, 44].
`
`Headache during ischemic stroke
`
`Headache occurs frequently in acute ischemic stroke (IHS
`6.1.2) or during a transient ischemic attack (IHS 6.1.1), but
`its frequency varies widely among different studies, ranging
`from 18% to 41% [45–55]. Overall, an underestimation of
`the frequency of headache in ischemic stroke patients can be
`claimed, as patients with language dysfunction, altered men-
`tal status or other factors impeding reliable determination of
`a headache complaint are excluded from most studies. In our
`series, headache was present in more than one-third of the
`patients with ischemic stroke and was much more common
`among patients with infarct in the posterior circulation
`(73.3%) than in those in whom the anterior circulation was
`involved (25.8%) [55]; this finding has also been described
`in other reports and may be due to the rich innervation by
`nociceptive afferents of vessels in the posterior circulation
`
`17
`
`[40, 51]. Stroke-related headache was frequently associated
`with large artery disease (40.7%) and was higher in patients
`with carotid artery occlusion. Similar results have been
`obtained by other authors, who reported headache frequen-
`cies ranging from 26% to 35% in patients with symptomatic
`carotid artery disease [46, 48]. Gorelick et al. [48] reported
`that there is no significant difference in the frequency of
`onset headache between patients with extracranial carotid
`artery disease, disease of the carotid siphon, middle cerebral
`artery, or carotid siphon and middle cerebral artery in tan-
`dem. As already reported, in the great majority of papers,
`headache is less common in lacunar infarction. In our series,
`the frequency of headache in lacunar infarction was 12.9%;
`similar frequencies have been observed by others [47, 49,
`51, 56]. A history of headache, was present only in stroke
`patients with headache, and headache anticipated (on aver-
`age by 2 days) the stroke in 24% of subjects. This observa-
`tion is in agreement with previous studies and demonstrates
`that stroke in many cases is the result of a long-lasting
`pathological vascular process, in which headache merely
`serves as a warning sign of ischemic stroke [48, 51]. In sev-
`eral series, a higher frequency of onset headache was pre-
`sent in women and young people [57, 58], who generally
`have a higher frequency of headaches. The mechanisms
`underlying headache are not known. Several studies have
`suggested that headache is associated with dilation of some
`arteries at the base of the brain [59]. Headache is probably
`related to activation of nociceptive trigeminovascular affer-
`ents; pain ensues when a sufficient amount of nociceptors
`have been recruited [60]. The release of amino-acid neuro-
`transmitters [61] and platelet activation [62] may also play a
`role in the pathogenesis of headache occurring at the onset
`of ischemic stroke.
`Headache is also common in patients with cervical artery
`dissection [63]. Unilateral facial or orbital pain is present in
`half of patients with internal carotid artery dissection. The
`characteristic unilateral headache develops in two-thirds of
`patients, most commonly in the frontotemporal area, but it
`occasionally involves the hemicranium or the occipital area
`[64]. The onset of headache is usually gradual, but it may be
`an instantaneous, excruciating, “thunderclap” headache that
`mimics a subarachnoid hemorrhage [64, 65]. The headache
`is most commonly described as a constant steady aching, but
`it may also be throbbing or steady and sharp [63, 64]. About
`one-fourth of patients with a history of migraine claim that
`the headache is similar to a migraine attack. In case of ver-
`tebral artery dissection, headache occurs in two-thirds of
`patients, almost always in the occipital area, but in rare cases
`it involves the hemicranium or the frontal area or is bilater-
`al [64]. Pain is usually the initial manifestation of cervical
`artery dissection and the mean time to the appearance of
`other symptoms is four days for carotid dissection and 15
`hours for vertebral dissection [63]. In our experience [66],
`
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`18
`
`headache was present in 10% of patients with cervical artery
`dissection before the focal neurological deficits, while
`66.7% of the patients had headache during the dissection-
`related stroke.
`
`Migraine syndromes that mimic stroke
`
`Migrainous syndromes that may mimic conventional cere-
`brovascular syndromes include hemiplegic migraine and
`basilar artery migraine. The IHS classifies hemiplegic
`migraine under migraine with typical aura (IHS 1.2.1) or
`prolonged aura (IHS 1.2.2). Familial hemiplegic migraine is
`classified as a subgroup of migraine with aura (IHS 1.2.3)
`and the definition includes the criteria for migraine with
`aura with hemiplegic features and at least one first-degree
`relative with identical attacks. Hemiplegic migraine attacks
`are characterized by hemiparesis or hemiplegia. There is an
`autosomal dominant inheritance pattern of the disorder.
`Hemiplegic migraine attacks may also be part of other
`familial disorders, namely mitochondrial encephalomyopa-
`thy with lactic acidosis and stroke-like episodes (MELAS),
`and cerebral autosomal dominant arteriopathy with subcor-
`tical infarcts and leukoencephalopathy (CADASIL). Basilar
`migraine (IHS 1.2.4) is another disorder that may mimic a
`transient cerebrovascular accident. The diagnostic criteria
`include those for migraine with aura plus two or more aura
`symptoms of the following types: visual symptoms in both
`the temporal and nasal fields of both eyes, dysarthria, verti-
`go, tinnitus, decreasing hearing, double vision, ataxia, bilat-
`eral paresthesias, bilateral paresis, and decreased level of
`consciousness. The diagnosis of basilar migraine is support-
`ed by the pattern of evolution of the neurological deficit and
`the accompanying headache, the history of previous similar
`attacks, a positive family history and the often negative
`diagnostic workup [67]. It is not unusual for patients who
`have experienced migraine with aura to suffer identical
`auras at other times, but without headache, particularly as
`they get older [68, 69]. Diagnostic difficulty arises when a
`patient over 40 years of age with no previous history of clas-
`sic migraine presents a first-ever episode of transient symp-
`toms of focal neurological dysfunction that are typical of a
`
`migrainous aura, but without any associated headache [70].
`The differential diagnosis of this circumstance is important
`especially for the prognosis: after 10 years of follow-up, the
`relative risk of a stroke occurring in a patient with a history
`of transient ischemic attack (TIA) compared with that in a
`patient with “migrainous aura without headache” was 7.6
`(95% CI, 0.8–74), and the relative risk of any serious vas-
`cular event (e.g. stroke, myocardial infarction, or vascular
`death) was 3.8 (95% CI, 0.8–19) [71].
`
`Conclusions
`
`Headache is an underemphasized feature of ischemic cere-
`brovascular disease; the thorough evaluation of its clinical
`features can be of help in diagnosing correctly different
`cerebrovascular pathological conditions.
`The relationship between headache, namely migraine,
`and stroke is difficult to disentangle. Epidemiological stud-
`ies indicate that the comorbidity of migraine and stroke in
`the young is an important issue and has implications for
`patient management.
`Migraine is associated with an increased incidence of
`stroke in young migraineur women who smoke or use oral
`contraceptives; these subjects should be strongly advised to
`discontinue smoking and they should be discouraged to use
`oral contraceptives; in any case, only pills with a low (<50
`µg) estrogen content should be used.
`No randomized study of primary stroke prevention in
`migraineurs or of secondary prevention in patients with a
`migraine-associated stroke has been performed. In patients
`who have had a migraine-induced stroke, daily use of an
`antiplatelet agent is reasonable although unproven, while the
`use of vasoconstrictive agents (e.g. ergotamine, triptans) for
`treating migraine attack should be avoided.
`The mechanism by which migraine causes a cerebral
`infarction – i.e. why focal oligoemia sometime progresses to
`cerebral
`infarction –
`is
`substantially unknown.
`Pathophysiological studies aimed at identifying the role
`played by each different component (endothelium, platelets,
`leukocytes, coagulation factors, genetic susceptibility) in the
`ischemic cascade are highly recommended.
`
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`6
`
`

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`The
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`eadache
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