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Complications of Migraine: Migrainous Infarction
Giorgio Bono
a
; Giorgio Minonzio
b
; Marco Mauri
a
; Angelo Maurizio Clerici
a
a
Universitary Center for Adaptive Disorders and Headache, Dipartimento di Medicina Clinica, Universit degli
Studi dell'Insubria, Varese, Italy
b
Servizio di Neuroradiologia, Ospedale di Circolo, Varese, Italy
Online Publication Date: 01 July 2006
To cite this Article Bono, Giorgio, Minonzio, Giorgio, Mauri, Marco and Clerici, Angelo Maurizio(2006)'Complications of Migraine:
Migrainous Infarction',Clinical and Experimental Hypertension,28:3,233 242
To link to this Article: DOI: 10.1080/10641960600549116
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Clinical and Experimental Hypertension, 28:233242, 2006
Copyright Taylor & Francis Group, LLC
ISSN: 1064-1963 print / 1525-6006 online
DOI: 10.1080/10641960600549116
233
LCEH 1064-1963 1525-6006 Clinical and Experimental Hypertension, Vol. 28, No. 3-4, February 2006: pp. 00 Clinical and Experimental Hypertension
Complications of Migraine: Migrainous Infarction
Migrainous Infarction G. Bono et al.
GIORGIO BONO,
1
GIORGIO MINONZIO,
2
MARCO MAURI,
1

AND ANGELO MAURIZIO CLERICI
1
1
Universitary Center for Adaptive Disorders and Headache, Dipartimento di
Medicina Clinica, Universit degli Studi dellInsubria, Varese, Italy
2
Servizio di Neuroradiologia, Ospedale di Circolo, Varese, Italy
Migraine and cerebrovascular disorders are comorbid diseases and the overlap of their
clinical symptoms has relevant diagnostic and therapeutic implications. The prototypic
condition of this relationship is reproduced by a clinical event named migrainous
infarction (MI), listed by the ICHD-II among the complication of migraine. We
discuss the diagnostic criteria proposed for this rare condition with regard to the
epidemiological studies and the clinicopathogenetic implications. In the clinical set-
ting therefore, possible cases of migrainous infarction should undergo an extended
diagnostic workup to rule out symptomatic migraine due to extra/intra-cranial vascular
pathology (artery dissection/malformations, venous thrombosis) and to exclude a
causal role for other conditions. These include patent foramen ovale and thrombophylic
status that may become critical risk factors for stroke, particularly among migraineurs,
in coincidence with precipitating factors that should be more accurately considered
in each single case.
Keywords cerebrovascular disorders, ischemic stroke, migraine
Introduction
The term migrainous infarction (MI) refers to a rare condition, now better defined by new
structured clinical and neuroimaging criteria (ICHD-II), that can be identified within the
overlap that exists between the clinical syndromes associated with migraine headaches
and the symptomatology accompanying ischemic strokes and other cerebrovascular events
(1). Although rare, MI warrants considerable attention in view of the possibility, implicit
in its name, that neuronal and vascular phenomena producing migraine with aura, when
repeated and long-lasting, may become a source of focal ischemic damage (cerebral
lesions). Considerable care must be exercised when considering this possible pathogenetic
link in the clinical setting, given the risk of overestimating the number of ischemic strokes
possibly related (attributed) to migraine mechanisms. This is ture primarily among
younger patients with transient ischemic attacks (TIAs)/minor strokes presenting without
evidence of arterial disease or of other common causes of stroke.
Address correspondence to Giorgio Bono, U.O. Neurologia Ospedale di Circolo e Fondazione
Macchi, V.le L. Borri n 57, 21100 Varese, Italy, 0332-393184. E-mail: neurova@tin.it
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234 G. Bono et al.
However, it is mandatory, particularly in patients presenting with typical/atypical
forms of migraine with aura or with one of the so-called migraine complications, having
first ruled out other major organic causes, also to consider the less common risk factors
(RFs) for stroke, as well as other vascular/nonvascular comorbid conditions that may play
a copathogenetic role in the production of complicated migraine pictures. The phenotypic
complexity of migraine disorders should be addressed through adoption of a multifactorial
approach essential to decide appropriate and tailored therapeutic interventions (2).
As a result of the genetic heterogeneity of the migraine trait, and of the trait-modifiers,
(associated/concomitant conditions and disorders, and various internal and environmental
trigger factors that influence the mode of development, evolution, and course of the dis-
ease), the clinical expression of migraine too is heterogeneous, both between and within
individuals.
Even within the strictly circumscribed limits of the rare prototypical form of migraine,
so-called familial hemiplegic migraine (FHM), an internal genetic heterogeneity may be
observed; equally, it is also possible for homogeneous patients (i.e., patients carrying the
same FHM mutation) to present nonhemiplegic attacks; this heterogeneity also may emerge
within a single family that may include members with and without hemiplegic migraine (24).
FHM, being the only form of migraine to show a Mendelian pattern of inheritance, is
still seen as a model; other more common types of migraine (nonhemiplegic and forms
without aura) instead are likely to show complex genetic traits, characterized by the
involvement of multiple genes. Each gene way have alleles that may be common in the
general population and have only relatively weak effects on the trait, produce more than
one effect, or interact with one another giving rise to variable clinical pictures (3,4).
In view of this, the interaction between migraine and cerebral infarction should be considered
from the perspective of cosegregation, as in the case of FHM and hereditary basilar
migraine, and (possibly) benign epilepsy of childhood. In fact, epileptic seizures related
to migraine attacks also have been described in some FHM-II families.
In the area of cerebrovascular diseases (CVDs) there is evidence of association of
migraine with cerebral autosomic dominant arteriopathy with subcortical infacts and
leukoencephalopathy (CADASIL), and also with some cerebral forms of hereditary
amyloid angiopathy (5). Further studies have investigated the possible association between
migraine and genetic factors linked to prothrombotic risk, with positive results emerging
in relation to the 677 mutation of the MTHFR-gene (hyperhomocysteinaemia), the
angiotensin-conventing enzyme gene (correlated with hypertension), and the endothelin-A
and low density lipoprotein receptor genes (2). Associations of this type probably represent
the biological/genetic background to the noncoincidental relationship between migraine
and some other diseases, particularly CVDs, and also may account for the increased lifetime
risk, conferred by migraine, of clinical manifestations of these disorders.
Definition of Migrainous Infarction
In the new, revised IHS Classification of Headache Disorders (ICHD-II), the condition
commonly referred to as migrainous infarction and also as migraine-induced stroke
to use Welchs original definition is listed among the Complications of Migraine
(1,6). For an attack to qualify as MI, the following picture must be present: a properly
defined aura and a migraine (or nonmigraine) headache, similar to previous attacks, but
with persistence of one or more of the aura symptoms for hours or days (or incomplete
recovery after 7 days), in association with neuroimaging evidence of focal ischemia in a
relevant (symptom-related) territory. Accordingly, the condition described as persistent
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Migrainous Infarction 235
aura without infarction demands normal magnetic rescunance imaging (MRI) findings in
the presence of one or more aura symptoms lasting over 1 week.
For a definite diagnosis of MI, other causes of stroke must be ruled out and cases
must present migraine with aura as a background diagnosis. Adherence to these
requirements (1) is likely to reduce the reliability of at least some previous epidemiological
studies that may have included migraine without aura patients and probably patients in
which risks of cardiac or systemic embolism, hematological disorders, coagulopathies,
connective-tissue and other vascular systemic, or cerebral disorders were not properly
excluded. The incidence of MI (7) is estimated to be 3.36 per 100,000/year (1.44 when
excluding other RFs for stroke): MI (8,9) should therefore account for about 0.8% of total
strokes and for 4% of the events occurring under the age of 50 years (6.522.8/100,000).
Migraine and Stroke Risk
Comorbid conditions associated with migraine include cardiovascular (hypertension,
Raynauds phenomenon, mitral valve prolapse, angina, myocardial infarction, stroke),
psychiatric (depression, anxiety), neurological (epilepsy), gastrointestinal, and other dis-
orders (asthma, allergies). Data from the U.S. Physicians Health Study (10) demonstrate
that in a population aged 4084 years, migraine increases the total and the ischemic stroke
risk by factors of 1.84 (95% CI, 1.06 to 3.20) and 2.0 (1.10 to 3.64), respectively.
Stroke risk among migraineurs (11) seems to be age-related and has been found to be
significantly raised at the age of 40 years versus older ages: RR = 2.81, 95% CI, 1.455.43).
More recently, prospective studies have calculated the Odds ratio (OR) for migraine
(3.7, 95% CI, 1.59), which emerged as the only significant RF for stroke in women under
35 years of age (12). In case-control studies recruiting large populations, a stronger associ-
ation between ischemic stroke and migraine has emerged in migraine with aura compared
with migraine without aura patients (1314).
The risk of ischemic stroke in young women with migraine is substantially increased
by the use of oral contraceptives (OR = 13.9), in which a dose-effect relationship (estro-
gens) and a further OR increase in the event of association of estrogen use with high blood
pressure and smoking (15,16) have been found. Therefore, even though the incidence of
stroke in young women is relatively low (10/100,000), the risk of ischemic stroke among
female migraineurs is as high as 1719/100,000 per year.
Migraine Headaches Associated with Stroke
Migraine and other headaches are, above all, syndromes, and their symptoms and signs
may be reproduced under different circumstances and in association with a wide variety of
somatic and extra/intracranial pathologies, both vascular and nonvascular (see ICDH-II,
Part Two The Secondary Headaches) (1). In most secondary headaches, the clinical
features of the cephalic pain attacks and associated symptoms are poorly defined in the
literature, particularly in early epidemiological studies.
Moreover, in clinical practice, mode of onset, evolution, and severity of pain attacks
seem to be considered more important than the complex of specific characteristics that
allow attacks of different migraine subtypes to be distinguished from attacks of other
primary headache forms. Furthermore, clinical features of newly occurring (symptomatic)
headaches, with a few exceptions, contribute very little to attempts to establish the cause
of the headache. Another factor contributing to the variability of symptomatological
pictures and, as a consequence, to their lack of specificity may be host-related: a
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236 G. Bono et al.
higher frequency of migraine-like symptomatic headaches, for example, might occur in
migraineurs, or at least in some subgroups of migraineurs, namely those with CVDs.
Headache attributed to ischemic stroke or to a TIA is defined as any new acute head-
ache developing simultaneously with or in a very close temporal relation to signs or other
evidence (neuroimaging) of ischaemic stroke and its estimated frequency ranges from
17% to 34%, being higher in the case of basilar- versus carotid-territory events (1). In a
series of 104 consecutive patients (17), headache was reported in 35.6% and was more
common in hemorrhagic pictures than in ischemic stroke or TIAs (p < 0.05). Headache
symptoms associated with ischemic events were present in 26.8% of the patients with
anterior circulation stroke and in 62.5% of those with involvement of the posterior circulation;
no relationship was found between lesion size and the presence of head pain. Unilateral
pain symptoms ipsilateral to stroke were found in 21.6% of cases.
Despite the lack of relevant data, ischemia-induced migraine attacks are probably
more frequent than true MIs. On the basis of case reports in the literature, migraine-
like headaches may be more frequent than other headache forms (tension-type, cluster-
like), particularly in association with cerebral vasculitis, fibromuscular dysplasia, artery
dissection, venous sinus thrombosis, and CADASIL. In first-ever migraine attacks, as in
attacks occurring sporadically or showing an atypical temporal pattern, the differential
diagnosis should include stroke or because in a considerable proportion of cases (24%),
headache attacks can precede stroke (on average by 2 days), an imminent vascular
event (18).
Finally, considering that other intracranial vascular disorders such as CADASIL,
MELAS, and benign (or reversible) angiopathy of the ceatral nervous system are now
listed (1) among the causes of secondary headaches (see ICDH-II, Section 6.7), a reduction
in the number of reported migraine syndromes mimicking stroke is to be expected. There
also should be an increase in the number of genetically-identified forms of familial and
sporadic hemiplegic and nonhemiplegic migraine.
Systematic Approach to the Migraine-Stroke Relationship
Large-scale epidemiological studies investigating migraine comorbidity have demonstrated
significant associations with heart attack, angina, hypertension, stroke, and other disorders
(neuropsychiatric and somatic) (2). Recent advances in research on the genetic bases of
migraine also have identified alterations in P/Q neuronal calcium channels and in Na/K-
pump subunits traits specific to autosomal dominant forms of FHM and other neurological
disorders presenting with a wide spectrum of clinical manifestations, none strictly related
to CVDs or cerebral ischemia (3,4). Thus, information regarding the genetic background
of migraine and ischemic CVD comorbidity remains limited to the results of association
studies on common RFs (hypertension, endothelial, and circulating factors), and on rare
inherited syndromes and disorders within the spectrum of CVDs with both hemorrhagic
and/or ischemic consequences (19,20).
Migraine, as confirmed by prospective studies, may confer an increased risk of stroke
in women under 45 years of age and probably in men affected by migraine with aura.
A history of migraine was found, by Carolei et al. (12), to be more frequent in patients
with TIA/strokes versus controls (adjusted OR 1.9, 95% CI, 1.13.1). The highest OR
(3.7, 1.59) was recorded in women under the age of 35, in whom migraine emerged as
the only significant RF (p = 0.003). In this study, atherogenic factors were more significant
in men and in patients over 35, whereas previous attacks of migraine with aura were more
frequent among stroke patients.
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Migrainous Infarction 237
Another case-control study (9) investigating the role of atherogenic vs nonatherogenic
RFs for cerebral ischemia in young adults has identified migraine as an independent RF
for cerebral ischemia, in a manner probably unrelated to carotid and cardiac abnormalities.
Within this population, a higher incidence of cerebral ischemia also was reported in
women <35 years, possibly due to an interaction among migraine status, oral contraceptives,
and other as yet unidentified RFs. With regard to these factors, platelet activation,
antiphospholipid antibodies, and congenital thrombophilia have been considered, whereas
the role of homocysteine, vitamin B
12
, and apo-LpA remains controversial. Careful review
of the various contributions on these topics underlines the need for more systematic clinical
and laboratory investigations (21).
A role for activated coagulation, on the other hand, has been stressed (22) as a
cofactor in the pathogenesis of paradoxical embolism in migraine patients harboring a
patent foramen ovale (PFO) (7% migraine with aura versus 1.8% without aura). In some
cases, a combination of factors (PFO or mitrol valve prolapse [MVP], sustained platelet
activation, contraceptive use) added to trigger factors (stress/exercise, metabolic imbal-
ance, and/or inflammatory status, others) could explain the unexpected occurrence of
ischemia during attacks of migraine with aura in young patients. Convergence of the
above conditions (in various combinations) with other migraine-trait associated and
nonassociated RFs for CVDs could, finally, account for the general aspects of migraine
and stroke comorbidity.
A systematic approach to the relationship between the two disorders therefore should
address the three different situations that can be defined comorbidity: the possibility that
one condition causes the other (symptomatic migraine and, possibly, MI); that the two
conditions may share genetic or environmental risk factors; or as a further alternative that
genetic or environmental risk factors may converge to produce a situation that gives rise to
both conditions (another possible explanation for MI). Stroke and migraine share certain
features: clinical phenomena, focal neurological deficits, cerebral blood flow alterations,
and head pain. On the other hand, while aura symptoms, crossing arterial territories, show
a slow, march-like progression and most frequently consist of positive phenomena, the
opposite is true of stroke symptoms.
The ICHD-II provides definitions and diagnostic criteria for MI, but to cover the
more general aspects of the problem, it is necessary to refer to a broader definition and to
a structured classification of migraine-related strokes, as originally proposed by Welch
(1,6). From this perspective it is possible to see that stroke can occur in the course of
migraine attacks (true migraine-induced cerebral infarction) and that four categories of
relationship between migraine and strokes may be considered.
Four Categories of Relationship
Category I coexisting stroke and migraine. The two conditions may coexist without
migraine being a contributory factor to stroke, which can be, temporally, distinct from attacks.
The true cause of stroke in young migraineurs may be difficult to demonstrate: in some cases
it may be linked to underlying RFs such as MVP, PFO, or antiphospholipid syndrome.
Category II includes symptomatic migraine-stroke and migraine with common
cause and migraine mimic stroke that masquerades as migraine. In the former,
certain conditions related to CVDs (for example, arteriovenous malformations) or to
certain Central Nervous System disorders (mitochondrial myopathy, encephalopathy,
lactic acidosis and stroke-like episodes [MELAS], CADASIL) episodically can cause
symptoms typical of migraine with aura.
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238 G. Bono et al.
The case illustrated in Figure 1 and 2 may be an example of a symptomatic migraine
attack (migraine mimic) against the background of a typical migraine without aura history.
The onset of attacks with typical and prolonged aura is signalled by a first, remote (and
undiagnosed) episode of partial or total venous sinus thrombosis, occurring over 10 years
before the present observation, while the patient was still using oral contraceptives. Note
that the MRI abnormalities shown in the first MRI investigation had previously (when
the patient was examined following a minor head trauma) been judged to be a possible
consequence of the migraine history.
A common cause (venous thrombosis) may have subtended or at least modulated the
clinical picture, characterized for years by a combination of mainly (i.e., with incidental
exceptions) absolutely typical attacks, without and with aura, and also by responsiveness
to symptomatic drugs, including most recently the triptans.
Figure 1. A female patient aged 51 years, with a clinical history of migraine and prolonged clusters
of migraine without and with aura (right motor symptoms) from the age of 32, smoker, with nonre-
cent use of contraceptives has an MRI after minor head trauma: axial T2-weighted image showed
multiple left frontal hyperintensities. The same patient, after 2 years with lower frequency of attacks,
developed a new migraine-like attack with aura symptoms (sensory motor and speech): digital
subtraction angiography (DSA) showed (A) thrombosis of the left lateral sinus and (B) deep venous
system including the inferior sagittal sinus.
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Migrainous Infarction 239
Category III includes true MI, or better migraine-induced stroke. The author (6,23)
considers the possibility of using criteria expanded to encompass migraine without aura, a
possibility excluded by the ICHD-II definition of MI (1). Exclusion of other causes also is
by definition, mandatory for MI diagnosis, but the possible presence of a causal factor or
other potential RFs and concurring conditions must be considered in all cases.
Figures 3 and 4 refer to a case of migraine-induced stroke producing lateral homonymous
hemianopsia and right-arm numbness. The patient, aged 49 years, is a heavy smoker with
active migraine and previous attacks with visual or visual plus hemisensory (alternating
side) aura; she also presents Raynauds phenomenon, livedo reticularis (legs and trunk),
increased levels of Ig-G-type anticardiolipin antibodies (ACAG = 24.77 versus normal
values, <19 GPL unit/ml), suggesting a diagnosis of Sneddon syndrome. Despite the clinical
picture suggesting MI, this case should more properly be classed as migraine mimic.
Figure 2. Two years later, the same patient, off treatment and after strong exercise, developed a
cluster of partial motor seizures (right side), followed by a migraine-like headache lasting 48 hr. A
postacute MRI showed a lesion in the afferent territory to the inferior sagittal sinus, located in the
perivenous territory due to isolated thrombosis of the inferior sagittal sinus, as a re-recurrence after
venous thrombosis episodes. After 30 days under anticoagulant treatment, MRI (A) shows full clini-
cal recovery with resolution of focal oedema. At MRI angiography (B), inferior sagittal sinus is still
absent.
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Category IV, according to Welch (6,23), could include complex cases, particularly
those with convergence of multiple factors of as-yet-unidentified pathogenetic relevance,
factors including drug hypersensitivity generally and possibly the effects of symptomatic
migraine drugs (ergot alkaloids). Certainly, the tentative allocation of cases observed in
the clinical setting to one of the above categories will not only help us to be more critical
Figure 3. MRI axial FLAIR (A) image showing multifocal subcortical areas of probable microan-
giopathic origin. MRI T2-weighted section shows remnant left occipital ischemia (B).
Figure 4. DSA image of the right internal carotid artery (A, B): absence of lesions in the proximal
major branches of the Willis circle. During the capillary phase, a weak (abnormal) peripheral reticu-
lum is evident. An elongated aneurysm of the internal carotid artery also is visible with superior
hypophyseal location.
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Migrainous Infarction 241
in our approach to the problem of defining MI cases, but also raise our awareness of the
increased stroke risk in young migraineurs.
Conclusion
In the new version of the International Classification of Headaches Disorders-II, the category
of migrainous infarction has been reviewed and given diagnostic criteria based on objective
findings (neuroimaging) and strict clinical parameters. This will further contribute to narrow
the space left to the subgroup of true migraine-induced infarction while increasing the
number of cases identified as symptomatic migraine.
In the clinical setting, some particular aspects remain of crucial importance for
orienting and eventually expanding the diagnostic procedures: the clinical picture and
temporal pattern of aura and headache symptoms, type and respective history of migraine
or nonmigraine pre-existing headaches, eventual association of migraine comorbid
conditions that increase the risk for cerebrovascular disorders, co-occurrence of factors
and events capable to interact with constitutional or acquired conditions of vascular risk in
each single case.
Among these, coagulopathies, valvular abnormalities, contraceptive use, even subclinical
connective tissue disorders, and drug interactions should be considered, particularly in the
presence of other predisposing or triggering factors (nutritional and metabolic imbalance,
substance abuse, unstable hypertension, endocrine abnormalities, immunological alterations,
and incidental infectious disease).
Each of the conditions listed above require consideration also among those patients
suffering from migraine without aura and presenting with asymptomatic ischemic lesions
characterized by occasional MRI findings.
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