Nov/2/17

&

Hasan Sjahrir
Department of Neurology
University of North Sumatera
Medan, Indonesia

Contact person : hasansjahrir@gmail.com

http://neurologiusu.id

Is migraine a risk factor for stroke ?

1  
 Nov/2/17  

REVIEW ARTICLE
published: 08 October 2014
doi: 10.3389/fneur.2014.00193

Migraine and stroke: “vascular” comorbidity

Donata Guidetti , Eugenia Rota*, Nicola Morelli and Paolo Immovilli
Neurology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy

Meta-analyses addressing the migraine-stroke association

Edited by: Several comorbidities are associated to migraine. Recent meta-analyses have consis-
Study
Vincenzo Guidetti, Sapienza University
of Rome, Italy
Stroke type Migraine MA
tently demonstrated a relationship between migraine and stroke, which is well-defined MO
for ischemic stroke and migraine with aura (MA), even stronger in females on oral contra-
Etminan Reviewed
M et al. by: 14 ischaemic RR 2.16, (95% CI) RR, 2.27;
ceptives or smokers. However, there seems to be no clear-cut association between stroke
RR 1.83;
Stefan Evers, University of Münster,
Br Med JGermany
2005; in migraineurs and the common vascular risk factors, at least 95% CI young adult95%
in the CI
popula-
330:63–5Allan
Canada
Purdy, Dalhousie University, tion. Migraineurs also run an increased risk of hemorrhagic stroke, while the association
between migraine and cardiovascular disease remains poorly defined. Another aspect is
Vittorio Di Piero, Sapienza University
the relationship between migraine and the presence of silent brain lesions. It has been
Schurks of*Correspondence:
MRome, Italy
et.al 2 Ischaemic
demonstrated that there is an RR 1.73 (95%
increased frequencyCI)of ischemic
RR 2.16 RR mat-
lesions in the white 1.23
BMJ (2009)
Eugenia Rota, Neurology Unit, ter of migraineurs, especially silent infarcts in the posterior95% CI territory in95%
circulation CI
patients
Guglielmo da Saliceto Hospital, Via with at least 10 attacks per month. Although there is a higher prevalence of patent foramen
339:b3914.
Taverna 49, Piacenza 29121, Italy
ovale (PFO) in migraineurs, the relationship between migraine and PFO remains controver-
e-mail: eugenia.rota.md@gmail.com
SpectorJT et al 21 sial and PFO closure is not a recommended
Ischemic OR 2.04(95% procedure
CI) to prevent
OR migraine.
2.25, As an increased
OR 1.24,
frequency of cervical artery dissections has been observed in migrainous patients, it has
Am J Med (2010) 95%
been hypothesized that migraine may represent a predisposing factor CI for cervical95% CI
artery
123:612–24 dissection. There still remains the question as to whether migraine should be considered
a true “vascular disease” or if the comorbidity between migraine and cerebrovascular dis-
ease may have underlying shared risk factors or pathophysiological mechanisms. Although
Sacco S et al 8 haemorrhagis
further studies are required toOR 1.48
clarify this(9%
issue,CI) OR 1.62
current evidence OR 1.39
supports a clinical man-
Stroke (2013) 44 (95% CI)vascular risk
agement where MA patients should be screened for other concomitant (95% CI)
factors
and treated accordingly.
(11):3032–8.
Keywords: migraine, stroke, ischemic stroke, hemorrhagic stroke, cerebrovascular disease, vascular risk factors

INTRODUCTION cerebrovascular disease, mainly IS, focusing on the most intriguing

Migraine and ischemic stroke (IS) are two highly prevalent dis-
eases. A relevant proportion of the population (up to 21% of
women, 6% of men) suffer from migraine attacks and 2/1,000 over
65 year-olds will have an IS (1–3). It has been common knowledge
for a long time in clinical practice that some migraine with aura
(MA) attacks may mimic cerebrovascular accident symptomatol-
ogy and that migraine aura may, although rarely, act as an acute
precipitant of an IS, the so-called “migrainous infarction.”
The case–control study by the Collaborative Group for the
Study of Stroke in Young Women (4) in 1975 was the first to
report a twofold risk for stroke in women affected by migraine
compared to community controls. Since then, a growing body
of evidence has demonstrated the association between migraine,
mostly MA, and IS. Moreover, MRI-based studies have demon-
strated that migraineurs have an increased frequency of subclin-
ical brain infarcts in the posterior circulation territory and that
female migraineurs have an increased risk for white matter lesions
questions arising from this issue in the perspective of the clinical
practice.
MIGRAINE AS A RISK FACTOR FOR ISCHEMIC STROKE: THE
EVIDENCE
Three meta-analyses have consistently demonstrated a relation-
ship between these two highly prevalent and disabling conditions,
i.e., migraine and IS, where MA emerges as risk factor for stroke
2
(Table 1).
The meta-analysis carried out by Etminan et al. (7) postu-
lated that there was an increased risk of IS in individuals with
migraine: relative risk (RR) 2.16 (95% CI 1.89–2.48), with a higher
risk for migraineurs with MA, RR 2.27 (95% CI 1.61–3.19), than
those without, RR 1.83 (CI 95% 1.06–3.15), which was even more
evident in females taking oral contraceptives, RR 8.72 (95% CI
5.05–15.05).
Another meta-analysis, carried out by Schurks et al. (8),
 Nov/2/17
 

The association between stroke and migraine

Study Stroke type Migraine MA MO

Kurth T. meta-analysis ischaemic RR 2.16, (95% CI) RR, 2.27; RR 1.83;
Cephalalgia, of 11 case- 95% CI 95% CI
2007, 27, control and 3
967–975 cohort

Kuo C-Y, et al. population- Hemorrhagic adjusted HR 2.13

2013. PLoS based cohort stroke (95% CI)
ONE 8(1): Age-sex p 0.0001
e55253 match (NHI
Taiwan)

Mawet J,et al Meta analysis Ischemic OR 2.04(95% CI) OR 2.51, OR 1.29,

Cephalalgia 13 case- 95% CI 95% CI
2015, Vol. 35 control and 8 P 0.0001 p>0.0001
(2) 165–181 cohort
Ischemic Woman
OR 2.89, 95% CI
younger than 45 5
OR 2.65 95% CI

Increased Risk of Hemorrhagic Stroke in Patients with

Migraine: A Population-Based Cohort Study
Cheng-Ya Kuo1, Ming-Fang Yen2, Li-Sheng Chen2, Ching-Yuan Fann3, Yueh-Hsia Chiu4, Hsiu-Hsi Chen5,6,
Shin-Liang Pan1*
1 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, 2 School of
The data used
Oral Hygiene, Collegein this
of Oral study
Medicine, Taipei were obtained
Medical University, from
Taipei, Taiwan, the complete
3 Department National
of Nutrition and Health Sciences, KainanHealth Insurance
University, Taoyuan, Taiwan,
(NHI)4 Department
claim database inofTaiwan
and Graduate Institute for theChang
Health Care Management, period 2000
Gung University, to 2003.
Tao-Yuan, Taiwan, 5 Centre of Biostatistics Consultation, College of Public
Health, National Taiwan University, Taipei, Taiwan, 6 Division of Biostatistics, Graduate Institute of Epidemiology, College of Public Health, National Taiwan University,

•  The migraine group (compare with non migraine) had a higher

Taipei, Taiwan

prevalence
Abstract of
•  Objective:
hypertension
Previous studies on the(P,0.0001),
association between migraine and the risk of developing hemorrhagic stroke (HS) have
generated inconsistent results. The aim of the present population-based, age- and sex- matched follow-up study was to
•  hyperlipidemia (P,0.0001),
investigate whether migraine is associated with an increased risk of HS.

Method: A total of 20925 persons with at least two ambulatory visits in 2001 with the principal diagnosis of migraine were
•  enrolled
coronary heart
in the migraine group. disease
The non-migraine group (P,0.0001),
consisted of 104625, age- and sex- matched, randomly sampled
subjects without migraine. The two-year HS-free survival rates for these 2 groups were estimated using the Kaplan-Meier
•  method.
chronic rheumatic
Cox proportional hazards regressionheart
was used todisease (P
estimate the effect = 0.0001),
of migraine and
on the occurrence of HS.

•  developed
other HS. Theheart
crude hazarddisease (P,0.0001)
ratio (HR) for developing than
HS in the migraine group wasthe non-migraine
Results: During the 2 year follow-up, 113 subjects in the migraine group (0.54%) and 255 in the non-migraine group (0.24%)
2.22 compared to the non-migraine
group.
group (95% confidence interval [CI]: 1.78–2.77, p,0.0001) and the adjusted HR was 2.13 (95% CI: 1.71–2.67, p,0.0001) after
controlling for demographic characteristics and comorbid medical disorders.
Kuo C-Y, Yen M-F, Chen L-S, Fann C-Y, 6
Conclusions: This population-based age- Chiu
and sex-Y-H, et al.
matched (2013).
cohort PLoS
study shows thatONE 8(1):
migraine wase55253.
linked to an increased
risk of HS.

Citation: Kuo C-Y, Yen M-F, Chen L-S, Fann C-Y, Chiu Y-H, et al. (2013) Increased Risk of Hemorrhagic Stroke in Patients with Migraine: A Population-Based Cohort
Study. PLoS ONE 8(1): e55253. doi:10.1371/journal.pone.0055253
Editor: Weili Zhang, FuWai hospital, Chinese Academy of Medical Sciences, China
Received July 6, 2012; Accepted December 24, 2012; Published January 25, 2013
Copyright: ! 2013 Kuo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by grants DOH93-TD-M-113-030, DOH94-TD-M-113-004, and DOH95-TD-M-113-002 from the Department of Health, 3  
Executive Yuan, Republic of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: panslcb@gmail.com

Introduction whether migraine is associated with increased risk of developing

HS.
Migraine is a neurological disease characterized by recurrent
episodes of headache [1]. The reported prevalence in men and
 Nov/2/17  

REVIEW ARTICLE
published: 08 October 2014
doi: 10.3389/fneur.2014.00193

Migraine and stroke: “vascular” comorbidity

Donata Guidetti , Eugenia Rota*, Nicola Morelli and Paolo Immovilli
Neurology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy

MA patients tended to have

Edited by: Several comorbidities are associated to migraine. Recent meta-analyses have consis-
•  high-blood pressure
Vincenzo Guidetti, Sapienza University
of Rome, Italy
(OR
tently demonstrated = 1.76between
a relationship 95% migraine
CI 1.04–3.0),
and stroke, which is well-defined
for ischemic stroke and migraine with aura (MA), even stronger in females on oral contra-
Reviewed by:
•  a worse cholesterol profile
ceptives or smokers.
Stefan Evers, University of Münster, (total
However, cholesterol
there seems ≥240
to be no clear-cut mg/dL:
association between stroke
Germany in migraineurs and the common vascular risk factors, at least in the young adult popula-
OR = 1.43 95% CI 0.97–2.1),
tion. Migraineurs
Allan Purdy, Dalhousie University, also run an increased risk of hemorrhagic stroke, while the association
Canada
between migraine and cardiovascular disease remains poorly defined. Another aspect is
•  an earlier onset
Vittorio Di Piero, Sapienza University
of Rome, Italy of coronary
the relationship between migraineheart disease
and the presence ofor stroke
silent (ORIt has
brain lesions. = been
demonstrated that there is an increased frequency of ischemic lesions in the white mat-
3.96;
*Correspondence:
95%
Eugenia Rota, Neurology Unit,
CI 1.1–14.3), with a twofold probability of
ter of migraineurs, especially silent infarcts in the posterior circulation territory in patients
having an
Guglielmo da Saliceto Hospital, Via
Taverna 49, Piacenza 29121, Italy
elevated
with at least 10Framingham risk,
attacks per month. Although resulting
there in a higher
is a higher prevalence of patent foramen
ovale (PFO) in migraineurs, the relationship between migraine and PFO remains controver-
cardiovascular
e-mail: eugenia.rota.md@gmail.com
sial andrisk profile
PFO closure is not a. recommended procedure to prevent migraine. As an increased
frequency of cervical artery dissections has been observed in migrainous patients, it has
been hypothesized that migraine may represent a predisposing factor for cervical artery
Guidetti B et
dissection. al. still
There frontiers
remainsinthe
Neurology
question as 2014
to whether migraine should be considered
7
a true “vascular disease” or if the comorbidity between migraine and cerebrovascular dis-
ease may have underlying shared risk factors or pathophysiological mechanisms. Although
further studies are required to clarify this issue, current evidence supports a clinical man-
agement where MA patients should be screened for other concomitant vascular risk factors
and treated accordingly.
Keywords: migraine, stroke, ischemic stroke, hemorrhagic stroke, cerebrovascular disease, vascular risk factors

INTRODUCTION cerebrovascular disease, mainly IS, focusing on the most intriguing

Migraine and ischemic stroke (IS) are two highly prevalent dis- questions arising from this issue in the perspective of the clinical
Special Issue Article
eases. A relevant proportion of the population (up to 21% of practice.
women, 6% of men) suffer from migraine attacks and 2/1,000 over Cephalalgia
65 year-olds will have an IS (1–3). It has been common knowledge MIGRAINE AS A RISK FACTOR
2015, Vol. 35(2)FOR ISCHEMIC STROKE: THE
132–139
Migraine, cardiovascular disease, and
for a long time in clinical practice that some migraine with aura EVIDENCE ! International Headache Society 2014
Reprints and permissions:
(MA) attacks may mimic cerebrovascular Special Issue accident
Article symptomatol- Three meta-analyses sagepub.co.uk/journalsPermissions.nav
have consistently demonstrated a relation-
stroke during pregnancy: Systematic
ogy and that migraine aura may, although rarely, act as an acute ship between these two DOI:highly prevalentCephalalgia
and disabling conditions,
10.1177/0333102414554113
precipitant of an IS, the so-called “migrainous infarction.” i.e., migraine and IS,cep.sagepub.com
where MA emerges as risk Headache
factorSociety
2015, Vol. 35(2) 132–139
for 2014
stroke
review of the literature Migraine, cardiovascular
The case–control study by the Collaborative Group for the (Table 1).
disease, and ! International
Reprints and permissions:

Study of Stroke in Young Women stroke (4) in 1975during was thepregnancy:

first to The Systematic
meta-analysis carried out by Etminan
sagepub.co.uk/journalsPermissions.nav
et al. (7) postu-
DOI: 10.1177/0333102414554113

report a twofold risk for Wabnitz

strokereview A and
in women ofBushnell
theby literature
affected migraine C. Cephalalgia 2015, Vol. 35(2)
lated that there was an increased risk of IS in individuals with
132–139
cep.sagepub.com

compared to community controls. Since then, a growing body migraine: relative risk (RR) 2.16 (95% CI 1.89–2.48), with a higher
there
Ashley is an
Wabnitz
of evidence increased
and Cheryl
has demonstrated risk of
Bushnell
the association (pregnant
between migraine, risk migraineurs
for migraineurs with MA, compared
RR 2.27 (95% CIto 1.61–3.19), than
nonmigraineurs).
mostly MA, and IS. Moreover, MRI-based Ashley Wabnitz studiesand haveCheryl
demon-Bushnell those without, RR 1.83 (CI 95% 1.06–3.15), which was even more
strated that migraineurs have an increased frequency of subclin- evident in females taking oral contraceptives, RR 8.72 (95% CI
Abstract
Abstract
ical brain
Objective: infarcts inofthe
The objective thisposterior
article iscirculation
to reviewterritory and that
the literature 5.05–15.05).
relating migraine, cardiovascular disease, and stroke
•  female
during gestational
migraineurs
pregnancy in order to hypertension
have an
better during pregnancy (OR
in order between
to better range
definemigraines from 1.23
and meta-analysis,
relationship vascular
between tocarried
disease.
migraines 1.68)
and and
Objective: The objective of this article is to review the literature relating migraine, cardiovascular disease, and stroke
increased
definerisk theforrelationship
white matter lesions the Another outdisease.
vascular by Schurks et al. (8),
preeclampsia
(WMLs) (5, 6).
(OR
a systematicMethods:
range
reviewWeofconducted
1.08 to 3.5)
included 25Cochrane
heterogeneous studies and demonstrated that there
Methods: We conducted a systematic
the literature usingreview of theand
Medline literature using Medline
Review and Cochrane
with the Review
following with the following
search terms: migraine AND pregnancy and vascular disease OR myocardial infarction OR heart disease OR stroke OR
The question
search terms: migraineremains exactlycerebrovascular
AND pregnancy to and
whatvascular
extent there
ORishypertension
disease
disease aOR gener- inwas
myocardial ainfarction
specific
pregnancy. We also increase
OR heart
reviewed inthe
the
diseaseIS risk
OR correlated
bibliographies stroke
of papers to eachintype
ORidentified this of
alized vasculopathy
cerebrovascular disease OR in migraine
hypertension or vascular
search in obtain
to risk
pregnancy. factors, genetic
Werelevant
additional also studies. migraine
reviewed (RR 1.73; 95%ofCI
the bibliographies 1.31–2.29),
papers withinthethis
identified highest values for
•  traits,
search toacuteor other
obtain myocardial
pathophysiological
additional relevant studies. infarction
Results:mechanisms,
Of the 219 papers includingand
obtained with heart
the the primary
MA disease
(RRsearch,
2.16; we
95%found (OR
CI171.53–3.03),
that 4.9;
were topically
while the 95%
relevant.
is an increased risk both of gestational hypertension (OR range from 1.23 to 1.68) and preeclampsia (OR range 1.08 to
Altogether,
percentages CIwere
there not

1.7-14.),
Results:patent
Of foramen
the 219 ovale obtained
papers (PFO), may
to stroke. risk both of gestational
is an increased
with
3.5) play
ischemic
the
in aprimary
role in linking
migraineurs search,
compared
stroke in pregnancy
hypertension (OR range
migraine
weto found statistically
17 that
nonmigraineurs.
(ORfromrange 1.23CItoto
7.9
were
In
30.7),
significant
topically
addition,
0.90–1.69).
there
andFemale
1.68)particularly
foranindividuals
relevant.
is
preeclampsia
association
withmigraineurs (OR seem
active migraine.
withoutthere
Altogether,
between
There
range to1.08
anaura (RR 1.23;
increased
isbealso
at
tothe
risk of95%
highest risk
an association
This narrative review toaimed between migraine
at the examinationand increased risk
of thereof acute
the is(RR myocardial
2.08; infarction and
95% CI 1.13–3.84),an heart disease (OR 4.9;
those under 45risk 95%
yearsCI 1.7, 14.2), and
3.5) in migraineurs compared nonmigraineurs. In addition, (deepan association
thrombosisbetween
OR 2.4; 95% CIincreased ofofembolus
age (RR 2.65;
•  current
ischemic thromboembolic
strokeevidence on the(OR
in pregnancy range events
thromboembolic events
relationship
3.1; 95%7.9 CIbetween
to 30.7),
1.7,
during
during pregnancy
5.6). migraine
particularly pregnancy
and with95%
venous
CI 1.41–4.97),
active migraine. (deep is venous
and females
There
1.3, 4.2 and pulmonary
alsoonanoral contraceptives (RR 7.02;
association
OR

betweenthrombosis
migraine and increased (OR of2.4;
riskbased on the 95%
acute myocardial CI 1.3
infarction
available literature. Given the - limited
and 4.2)
Conclusion: In this review, we summarized the association between migraine and risk of vascular disease during pregnancy,
heartamountdisease (OR 4.9; 95% CI 1.7, 14.2), and
of data, more research on these associations is needed to
thromboembolic events during pregnancy determine (deep venous
which womenthrombosis
with migraineOR may 2.4;
be at95% CI 1.3,
risk while 4.2 and pulmonary embolus OR
pregnant.
www.frontiersin.org October 2014 | Volume 5 | Article 193 | 1
• 
3.1; 95%
pulmonary
CI 1.7, 5.6).
embolus
Conclusion: In this review, we summarized Keywords
(OR 3.1; 95% CI 1.7 - 5.6).
the association between migraine and risk of vascular disease during pregnancy,
Migraine, migraine with aura, stroke, pregnancy, hypertensive disorders in pregnancy 8
based on the available literature. Given the limited amount of data, more research on these associations is needed to
Date received: 9 May 2014; revised: 7 August 2014; 2 September 2014; 9 September 2014; accepted: 11 September 2014
determine which women with migraine may be at risk while pregnant.

Keywords
Migraine, migraine with aura, stroke, pregnancy, hypertensive disorders in pregnancy
Introduction ischemic stroke appears to be strongest in young
Date received: 9 May 2014; revised: 7 AugustMigraine
2014; 2 September
headache 2014;
is a 9primary
September 2014; accepted:
headache disorder 11 women
September 2014
under the age of 45, as shown in two different
characterized by severe attacks of painful headaches meta-analyses (8,9).
with associated autonomic nervous system dysfunction. Women have the highest prevalence of migraines
The World Health Organization has now ranked between the ages of 20 to 39 years, i.e. childbearing 4  
migraine headaches in the top 20 among all diseases years (10). Despite most migraine sufferers reporting
worldwide causing disability, with migraine accounting improvement in their headaches during pregnancy, par-
for 1.3% of years lost because of disability (1). Several ticularly in the third trimester (11–14), research has
studies have linked migraine with other comorbidities implicated a diagnosis of migraines as an independent
Introduction that would put migraineurs in particular at higher risk
ischemic stroke
for vascular events. For instance, migraineurs may appears
be to be strongest in young
Migraine headache is a primarymore headache be obese (2,3),women
likely to disorder underadjusted
have a higher the age Wake
of 45, as shown in two different
Forest School of Medicine, Department of Neurology, NC, USA
total cholesterol and lower adjusted high-density lipo-
characterized by severe attacks ofprotein
painful
(HDL) headaches meta-analyses
(4,5), be less likely (8,9). Corresponding author:
to exercise regularly Cheryl Bushnell, Wake Forest School of Medicine, Department of
with associated autonomic nervous(5)
system more likely to smokeWomen
and bedysfunction. compared have the highest
to nonmi- prevalence
Neurology, Medical of migraines
Center Boulevard, Winston Salem, NC 27157, USA.
graineurs (5–7). The relationship between migraine and Email: cbushnel@wakehealth.edu
 Nov/2/17  

correlation between migraine with stroke and coronary heart

disease
•  Cross sectional study, 90 patients, July - September 2017
•  Migraine and stroke PR= 1.21 (95% CI 0.80-1.84)
•  Mgraine and Coronary heart Disease PR =0.83 (95% CI
0.51- 1.40)

Harizah Q.E, Sjahrir H, Nasution IK. Presented at National Annual Meeting of

Indonesian Neurological Association, Pekan Baru Indonesia Oct 2017

The association between stroke and migraine

Study Stroke type Migraine MA MO
Wabnitz A Systematic ischemic pregnancy
Cephalalgia review (OR range
2015, Vol. 35(2) 7.9-30.7)
132–139
ICH Pregnancy
OR 9.1
Gelland AA et al. Cohort No association
Cephalalgia among
2015, Vol. 35(14) children
1252–1260 KPNC

Mawet J,et al Meta analysis ischemic Smokers (OR

Cephalalgia 13 case- 9.03, 95% CI
2015, Vol. 35(2) control and 8
165–181 cohort
meta white matter OR 3.9, 95%
analysis case MRI CI
control hyperintens 10

5  
 Nov/2/17  

The association between stroke and migraine

Study Stroke type Migraine MA MO
Monteith TS et al. population- No
Neurology® based cohort association
2015;85:715–721 study in
olders
Northern ischemic Smokers
Manhattan HR 3.17 95% CI

Linxin Li, et al. a population- cryptogenic OR 1.73 95% CI

Neurology® based cohort
2015;85:1444– study Oxford Vascular
1451 study

Peng KP et al. Population ischemic aHR: 1.24, 95% CI aHR:

Cephalalgia based cohort p<0.0001 1.08, 95%
2017, Vol. 37(4) study CI:
327–335
NIH Taiwan women aged HR:
< 45 years 4.58,
HR: 3.44, 95% 95% CI:
CI;p<0.0001 11

Original Article
Cephalalgia
2017, Vol. 37(4) 327–335
Migraine and incidence of ischemic stroke: Original Article
! International Headache Society 2016
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A nationwide population-based study sagepub.co.uk/journalsPermissions.nav

DOI: 10.1177/0333102416642602
Cephalalgia
2017, Vol. 37(4) 327–335
Migraine and incidence of ischemic stroke: journals.sagepub.com/home/cep
! International Headache Society 2016
Reprints and permissions:
Peng KP etpopulation-based
A nationwide al. Cephalalgia 2017,
studyVol. 37(4) 327–335 sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0333102416642602
journals.sagepub.com/home/cep

Cohort
Kuan-Po Peng1,2,3,
study was*, conducted 3,4,
using
Yung-Tai Chen data from
*, Jong-Ling Fuh3,5the
, Taiwan National Health Insurance
Kuan-Po Peng1,2,3,*, Yung-Tai Chen3,4,*, Jong-Ling Fuh3,5,
2004-2009 6
Chao-Hsiun Tang and Shuu-Jiun Chao-Hsiun
Wang 2,3,5
Tang and Shuu-Jiun Wang2,3,5
6

Abstract
•  Abstract
This study with shortBackground: duration of 3.6
The association betweenyears
migraine andcompared
the incidence of ischemic
patients. We aimed to clarify this association using a population-based database.
tostroke10 years
varies in of
in different subgroups

the WHS,
Background: still between
The association identified
migraine andan
Method: A association
thenationwide
incidence of ischemic
cohort between
stroke
study was variesusing
conducted in differentmigraine
data fromsubgroups and
the TaiwanofNational Health Insurance Research
Database. Two cohorts were extracted: a neurologist-diagnosed migraine cohort, and a non-headache, propensity score-
patients. We aimed to clarify this association matched
using a comparison
population-based
cohort. database.
ischemic stroke (aHR
Method: A nationwide cohort study was conducted
1.24
through theusing
end of
95%
data from
2010,
CI)
All participants were enrolled in this study between 2005 and 2009, and were followed
theorTaiwan
death, Nationalof ischemic
the occurrence Health Insurance Research
stroke. Adjusted hazard ratios (aHRs) and 95% confidence
intervals (CIs) were calculated with a Cox proportional hazards model to compare the between-group risks.
Database. Two cohorts were extracted: a neurologist-diagnosed
Results: Both cohorts migraine cohort,
(n ¼ 119,017 andwere
each) a non-headache, propensity
followed for a mean periodscore-
of 3.6 " 1.3 years. A total of 744 migraine
patients (429,741 person-years) and 617 matched comparison individuals (436,141 person-years) developed ischemic
•  found an increased risk of ischemic stroke in men withwithmigraine
matched comparison cohort. All participants were
stroke
enrolled
during the
in this
research
study
period.
between
Compared
2005
to the
and 2009,
comparison
and were
cohort,
followed
patients migraine were at an increased risk
through the end of 2010, death, or the occurrence of ischemic
of ischemic stroke.1.24,
stroke (aHR: Adjusted
95% CI: hazard
1.12–1.38,ratios (aHRs)Subgroup
p < 0.001). and 95%analysis
confidence
by age and sex revealed the highest risk in
(aHR:
intervals 1.20,
(CIs) were calculated95%
with a CoxCI: 1.01–1.42,
women
proportional aged # 45
4.58, 95% CI: hazards
years (aHR:
model
2.45 – 8.56,
pto compare
=0.036).
3.44,
p < 0.001).
95% CI: 2.20–5.39,
A trendthe
p < 0.001),
between-group
for increased
especially
risks.
stroke risk
among those with migraine with aura (aHR:
was observed in men aged # 45 years (aHR: 1.54,
Results: Both cohorts (n ¼ 119,017 each) were followed for a mean period of 3.6 " 1.3 years. A total of 744 migraine
•  patients
Subgroup analyses Conclusion:
(429,741 person-years) and 617 matched
by ageMigraine
95% CI: 0.96–2.48,
and
p ¼ 0.075).
migraine
is associated with an increasedsub- risk of type revealed
ischemic stroke, a trend
especially in younger (age # 45 years)
womencomparison
with migraineindividuals (436,141
with aura. The person-years)
trend toward ischemic developed ischemic
stroke in younger men merits further exploration.
toward
stroke the period.
during the research development
Compared to the comparison of ischemiccohort, patients with strokemigraine were in atyounger
an increased risk (age <45
years)
of ischemic stroke male
(aHR: 1.24, patients (aHR:
Keywords
95% CI: 1.12–1.38, p <migraine,
Stroke, 1.54,
0.001). Subgroup
aura, Asian 95% CI: 0.96–2.48,
analysis by age and sex revealed the highest risk in p =0.075).
12
women aged # 45 years (aHR: 3.44, 95% CI: 2.20–5.39, p < 0.001), especially among those with migraine with aura (aHR:
Date received: 13 September 2015; revised: 17 November 2015; accepted: 7 December 2015
4.58, 95% CI: 2.45 – 8.56, p < 0.001). A trend for increased stroke risk was observed in men aged # 45 years (aHR: 1.54,
95% CI: 0.96–2.48, p ¼ 0.075).
increased risk of ischemic stroke, especially in younger (age # 45 years)
Conclusion: Migraine is associated with an Introduction
women with migraine with aura. The trend toward Migraine ischemic strokeand
is a common in younger
disabling men merits
disorder, withfurther exploration.
an migraine patients, namely female patients with MA
overall one-year prevalence of 8%–15% (4.5%–6% in (7,10). Male patients with migraine, in contrast, were
men, 14%–18% in women). The incidence of migraine
peaks at 25–55 years of age (1–3). Migraine is con-
Keywords
6  
1
sidered to be a neurovascular disease, in which the tri- Department of Internal Medicine, Taipei Veterans General Hospital,
Taoyuan Branch, Taiwan
Stroke, migraine, aura, Asian geminovascular system plays a major role (4). In 2
Institute of Brain Science, National Yang-Ming University, Taiwan
addition, migraine is associated with other vascular dis- 3
National Yang-Ming University School of Medicine, Taiwan
orders, including ischemic and hemorrhagic stroke 4
Department of Nephrology, Institute of Internal Medicine, Taipei City
Date received: 13 September 2015; revised: 17 November 2015;coronary
(5–7), accepted:artery
7 December 2015
disease (8) and peripheral arter- Hospital Heping Fuyou Branch, Taiwan
5
ial disorders (9). Department of Neurology, Neurological Institute, Taipei Veterans
General Hospital, Taiwan
Migraine is classified into migraine with aura (MA) 6
School of Health Care Administration, Taipei Medical University, Taiwan
and migraine without aura (MO). Early migraine stu-
dies reported an increased risk of ischemic stroke *K.-P.P. and Y.-T.C. contributed equally to this study.
among migraine patients (5), and subsequent cohort
Corresponding author:
studies confirmed this association (10,11). However,
Introduction those studies showed that the increased risk of ischemic
Shuu-Jiun Wang, Department of Neurology, Neurological Institute, Taipei
Veterans General Hospital, Taipei 11217, Taiwan.
stroke existed exclusively in a specific subgroup of Email: sjwang@vghtpe.gov.tw
 Nov/2/17  

Review Article
Migraine and stroke: In search of shared
Cephalalgia
2015, Vol. 35(2) 165–181
Review Article
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DOI: 10.1177/0333102414550106 Cephalalgia
2015, Vol. 35(2) 165–181

literature review of experimental and stroke:

Migraine and clinical evidence
In search of shared cep.sagepub.com ! International Headache Society 2014
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DOI: 10.1177/0333102414550106
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Jerome Mawet1,2,3, Tobias Kurth4,5,6 and Cenk Ayata1,7
•  Cerebral Abnormalities in Migraine and Epidemiological Risk Analysis1,2,3 4,5,6 1,7
Jerome Mawet , Tobias Kurth and Cenk Ayata
Abstract(CAMERA) population-based MRI lesion prevalence study
Abstract
Background: Migraine, particularly with Background:
aura, increases the particularly
risk for ischemic stroke, at leastrisk
in aforsubset of stroke,
patients.at least in a subset of patients.
•  Results: increased
The underlying mechanisms are poorly The understood
risk
Migraine,
underlyingand
ofmultifactorial.
probablyare
mechanisms
subclinical
with aura, increases the posterior ischemic circulation
poorly understood and probably multifactorial.
infarct-like
lesions,
Methods: We carried mostly
out an extended literature located
Methods: We carried
review in the
out an extended
of experimental cerebellum,
andliterature
clinical review in
of experimental
evidence supporting migraineurs
and association
the compared
clinical evidence supporting the association
between migraine and ischemic stroke to identify potential mechanisms that can explain the association.
between migraine and ischemic stroke to identify potential mechanisms that canevidence
explainsupport
the association.
to controls (OR Results:
Results: Observational, imaging and genetic
7.1,
evidence
clinical
95%
Observational,
support data,
and experimental
CIpropose
). mechanistic
imaging and genetic
a linkwebetween migraine and
a link between migraine and ischemic stroke. Based on
ischemictostroke.
hypotheses explain Based
the link,on
such as microembolic triggers of
migraine and enhanced sensitivity to ischemic injury in migraineurs.
•  The risk wasDiscussion:
clinical and experimental data, we propose
migraine and enhanced sensitivity to ischemic
substantially
mechanistic hypotheses
We discuss
injury
screening
the possible
in migraineurs.
and management,
higher
to explain
practicalthe in MAmicroembolic(OR
link, suchofasclinical
implications 13.7, 95% CI),
triggersdata,
and experimental of such as aggressive risk factor
stroke prophylaxis and specific acute stroke management in migraineurs. However, evidence
Discussion:• We especially withimplications
frequent of clinicalmigraine
and experimentalattacks (>1 attack/
risk factor month) (OR
from prospective clinical trials is required before modifying the practice in this patient population.
discuss the possible practical data, such as aggressive
screening and management, stroke prophylaxis and specific acute stroke management in migraineurs. However, evidence
15.8, 95% CI 1.8–140),
Keywords
from prospective clinical trials is required beforeischemic
Migraine, modifying (Kruit
the cerebrovascular
stroke,
MT
practice in thisdisease, 2015)
patientspreading
population.
depression, migrainous infarct
Date received: 21 May 2014; revised: 26 June 2014; 23 July 2014; accepted: 3 August 2014

Keywords
The ischemic
Migraine, population-based Epidemiology
stroke, cerebrovascular disease, of Vascular
spreading depression, migrainous infarct Aging study (780
participants, mean age
Date received: 21 May 2014; revised: 26 June 2014;
of 69) also found
23 July 2014; accepted: 3 August 2014
Introduction
an increased risk of cerebral
infarcts in migraineurs Migrainewith aura
is the most common only (Kurth
neurological disorderT ofBMJ 2011)
worldwide (14). The prevalence of both ischemic (85%
all strokes) and hemorrhagic stroke in the US is13
and a major cause of disability in the western world, 2.9% in individuals 18 years or older (13), much
with a prevalence of approximately 13% (9% among lower than the prevalence of migraine. And lastly,
men, 18% among women in the United States (US)) stroke is predominantly a disease of the elderly, while
(1). An aura is present in up to 30% of migraineurs, migraine prevalence peaks around age 40. As per
usually during the hour preceding the headache (2,3). International Headache Society (IHS) criteria, migraine
Introduction Spreading depression (SD), an intense neuronal and
worldwide (14). propagates
The prevalence of both ischemic (85%
glial depolarization wave that slowly in
1
brain tissue at a rate of
of around 3 mm/min, is widely Neurovascular Research Laboratory, Department of Radiology,
Migraine is the most common neurological disorder all strokes) and hemorrhagic stroke in the Hospital,
US isHarvard Medical School, MA, USA
accepted as the electrophysiological substrate of Massachusetts 2
General
and a major cause of disability in the western
migraine aura (4,5). 2.9% in individuals 18 years Hopitaux
world, or older
Emergency (13),Center,
Headache
de Paris, France
much
Lariboisiere Hospital, Assistance Publique-

with a prevalence of approximately 13% (9% among

Migraine lower been
has traditionally thanviewed
the prevalence
as a benign, of 3DHU migraine. And
NeuroVasc, Francelastly,
chronic episodic condition. However, accumulating evi- 4
Inserm Research Center for Epidemiology and Biostatistics (U897),
men, 18% among women in the United denceStates (US))
suggests stroke isparticularly
that migraine, predominantly a disease
with aura, Teamof the elderly, while
Neuroepidemiology, France
5
associated withmigraine
(1). An aura is present in up to 30%canofbemigraineurs, increased prevalence
risk for strokepeaksand around
6 age 40. As per
University of Bordeaux, College of Health Sciences, France
Division of Preventive Medicine, Department of Medicine, Brigham and
white matter lesions (6–12). The association is even Women’s Hospital, Harvard Medical School, MA, USA
usually during the hour preceding themore
headache (2,3). International Headache Society (IHS) criteria, migraine
striking considering the clinical contrasts between 7Stroke Service and Neuroscience Intensive Care Unit, Department of
Spreading depression (SD), an intense neuronal
migraine and Unlike migraine, stroke is an Neurology, Massachusetts General Hospital, Harvard Medical School,
and stroke.
glial depolarization wave that slowlyacute and often catastrophic
propagates in cerebrovascular event. In MA, USA
contrast to the perceived1 benign nature of migraine
brain tissue at a rate of around 3 mm/min, is widely Neurovascular Research Laboratory, Department of Radiology,
Corresponding author:
(i.e. no imminent risk of injury), stroke is the leading Cenk Ayata, Neurovascular Research Lab, MGH Neuroscience Center,
Massachusetts
disabilityGeneral Hospital,
in theHarvard Medical School, MA, USA
accepted as the electrophysiological causesubstrate
of acquiredof physical
2
in adults US 149 13th St., Room 6408, Charlestown, MA 02129, USA.
Emergency Headache Center, Lariboisiere Hospital,
(13), and the second leading cause of mortality Email: cayata@partners.org Assistance Publique-
migraine aura (4,5). Hopitaux de Paris, France
Migraine has traditionally been viewed as a benign, 3
DHU NeuroVasc, France
chronic episodic condition. However, accumulating evi- 4
Inserm Research Center for Epidemiology and Biostatistics (U897),
dence suggests that migraine, particularly with aura, Team Neuroepidemiology, France
5
University of Bordeaux, College of Health Sciences, France
can be associated with increased risk for stroke and 6
Division of Preventive Medicine, Department of Medicine, Brigham and
white matter lesions (6–12). The association is even Women’s Hospital, Harvard Medical School, MA, USA
more striking considering the clinical contrasts between 7
Stroke Service and Neuroscience Intensive Care Unit, Department of
migraine and stroke. Unlike migraine, stroke is an Neurology, Massachusetts General Hospital, Harvard Medical School,
acute and often catastrophic cerebrovascular event. In MA, USA
contrast to the perceived benign nature of migraine
Corresponding author:
(i.e. no imminent risk of injury), stroke is the leading Cenk Ayata, Neurovascular Research Lab, MGH Neuroscience Center,
cause of acquired physical disability in adults in the US 149 13th St., Room 6408, Charlestown, MA 02129, USA.
(13), and the second leading cause of mortality Email: cayata@partners.org

14

7  
 Nov/2/17  

Migraine with aura may be a direct cause of migrainous infarction (the

classification made by the International Headache Society (IHS) in
2013)
(Guidetti B et al. frontiers in Neurology 2014)

•  Migrainous infarction is defined as a stroke that occurs during an

attack of migraine with aura in which aura symptoms persist for > 60
minutes.
•  Migrainous infarction accounts for 0.2% to 0.5% of all ischemic
strokes in cross-sectional studies using large stroke registries.

(Lee MJ et al. Journal of Stroke 2016;18(2):

146-156)
15

MIGRAINE WITH AURA

aura visual

16

8  
 Nov/2/17  

•  The concept of “cortical spreading depression (CSD)” has been

accepted as the main pathogenetic mechanism of migraine aura.
•  CSD, can cause severe vasoconstriction which is a unique
pathophysiologic mechanism of migraine aura, may precipitate an
ischemic stroke
(Lee MJ et al. Journal of Stroke 2016;18(2):146-156)

Potential mechanisms of migrainous infarction include vasospasm,

hypercoagulability, and vascular changes related to cortical
spreading depression.
(Tietjen GE. Cephalalgia, 2007, 27, 981–987)

17

•  endothelin- 1-induced vasospasm and microembolism may be a link

between CSDs and MA,
•  a continuum of CSDs, hypoxic-ischaemic episodes can induce MA
attacks and hypoperfusion was established
•  the intense reduction of CBF enabled turbulence and the subsequent
stagnation of blood flow, severe enough for a thrombosis to develop

18

9  
 Nov/2/17  

Special Issue Article

Cephalalgia
2015, Vol. 35(2) 132–139
Migraine, cardiovascular disease, and Special Issue Article
! International Headache Society 2014
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DOI: 10.1177/0333102414554113 Cephalalgia
2015, Vol. 35(2) 132–139
cep.sagepub.com
review of the literature
Migraine, cardiovascular disease, and
Wabnitz A and Bushnell C. Cephalalgia 2015, Vol. 35(2) 132–139
! International Headache Society 2014
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DOI: 10.1177/0333102414554113
cep.sagepub.com
review of the literature
•  migraine can also contribute to a
hypercoagulable
Ashley state
Wabnitz and Cheryl of Wabnitz and Cheryl Bushnell
Bushnell
Ashley
pregnancy Abstract
Abstract Objective: The objective of this article is to review the literature relating migraine, cardiovascular disease, and stroke
•  Estrogen is responsible
Objective: The objective of this article is to review
during
for the literature
pregnancy in order torelating migraine,
better define
Active
cardiovascular
the relationship
migraine
disease,
between migraines and
and stroke
vascular
places
disease.
during pregnancy in order to better define Methods: We conducted a systematic review of the literature using Medline and Cochrane Review with the following
the relationship between migraines and vascular disease.
increased procoagulants
Methods: We conducted a systematic review during
of the literature
cerebrovascular disease OR using Medline inand
hypertension Cochrane
pregnancy. women
We also Review
reviewed at
with significantly
search terms: migraine AND pregnancy and vascular disease OR myocardial infarction OR heart disease OR stroke OR
the following
the bibliographies of papers identified in this

pregnancy
search terms: migraine ANDthrough
pregnancy stimulation
andsearch
vascular disease of
to obtain additional relevant studies.
Results: Of the 219 papers
ORobtained
myocardial infarction OR
with the primary search,higherwe found 17risk
heart disease OR for
that were
stroke ischemic
OR
topically relevant. Altogether, there
cerebrovascular disease OR hypertension inis pregnancy. Weboth alsoof reviewed the bibliographies
(OR rangeoffrompapers
1.23 toidentified in this (OR range 1.08 to
hepatic synthesis of clotting
search to obtain additional relevant studies.3.5)
an increased risk gestational hypertension
in migraineurs compared to nonmigraineurs. In addition, stroke there isduring
1.68) and preeclampsia
an association between an increased risk of

factors.
Results: primarymigraine
search, andwe foundrisk
increased 17 ofthat
acutewere pregnancy.
ischemic stroke in pregnancy (OR range 7.9 to 30.7), particularly with active migraine. There is also an association
Of the 219 papers obtained with thebetween topically
myocardial relevant.
infarction Altogether,
and heart disease (ORthere4.9; 95% CI 1.7, 14.2), and
thromboembolic events during pregnancy (deep venous thrombosis OR 2.4; 95% CI 1.3, 4.2 and pulmonary embolus OR
is an increased risk both of gestational hypertension
3.1; 95% CI(OR range from 1.23 to 1.68) and preeclampsia (OR range 1.08 to
1.7, 5.6).

• 3.5) in migraineurs compared to nonmigraineurs.

The rising blood pressures
ischemic stroke in pregnancy (OR range 7.9
Conclusion: In this
addition,
in review, we
based on the available
to 30.7),
there is an the
summarized association between
association between an increased
migraine risk ofdisease during pregnancy,
and risk of vascular
literature. Given the limited amount of data, more research on these associations is needed to
whichparticularly with active
may bemigraine. There is also an association
migraineurs duringrisk of preeclampsia
determine women with migraine at risk while pregnant.
between migraine and increased acute myocardial infarction and heart disease (OR 4.9; 95% CI 1.7, 14.2), and
have aevents
thromboembolic linkduring
with stroke
pregnancy (deep venous thrombosis OR 2.4; 95% CI 1.3, 4.2 and pulmonary embolus OR
Keywords
Migraine, migraine with aura, stroke, pregnancy, hypertensive disorders in pregnancy
3.1; 95% CI 1.7, 5.6). 19
Date received: 9 May 2014; revised: 7 August 2014; 2 September 2014; 9 September 2014; accepted: 11 September 2014
Conclusion: In this review, we summarized the association between migraine and risk of vascular disease during pregnancy,
based on the available literature. Given the limited amount of data, more research on these associations is needed to
determine which women with migraine may be at risk while pregnant.
Introduction ischemic stroke appears to be strongest in young
Keywords Migraine headache is a primary headache disorder women under the age of 45, as shown in two different
characterized by severe attacks of painful headaches meta-analyses (8,9).
Migraine, migraine with aura, stroke, pregnancy, hypertensive
with associated disorders
autonomic nervousin pregnancy
system dysfunction. Women have the highest prevalence of migraines
The World Health Organization has now ranked between the ages of 20 to 39 years, i.e. childbearing
Date received: 9 May 2014; revised: 7 August 2014; 2migraine
Septemberheadaches
2014; 9 September
in the top2014; accepted:
20 among all 11 September
diseases 2014(10). Despite most migraine sufferers reporting
years
worldwide causing disability, with migraine accounting improvement in their headaches during pregnancy, par-
for 1.3% of years lost because of disability (1). Several ticularly in the third trimester (11–14), research has
studies have linked migraine with other comorbidities implicated a diagnosis of migraines as an independent
that would put migraineurs in particular at higher risk
for vascular events. For instance, migraineurs may be

MIGRAINE
more likely to be obese (2,3), have a higher adjusted Wake Forest School of Medicine, Department of Neurology, NC, USA
total cholesterol and lower adjusted high-density lipo-
Corresponding author:
protein (HDL) (4,5), be less likely to exercise regularly Cheryl Bushnell, Wake Forest School of Medicine, Department of
Introduction (5) and be more likely to smoke compared to nonmi- Neurology, Medical Center Boulevard, Winston Salem, NC 27157, USA.
ischemic between
stroke migraine
appears
graineurs (5–7). The relationship and toEmail:
be cbushnel@wakehealth.edu
strongest in young
Migraine headache is a primary headache disorder women under the age of 45, as shown in two different
SSRIs
characterized by severe attacks of painful Reduced
headaches platelet
meta-analysesaggr (8,9). HS
with associated autonomic nervous system dysfunction. Women have the highest prevalence of migraines
The World Health Organization has now ranked between the ages of 20 to 39 years, SAH i.e. childbearing
RCVS BRAIN EDEMA
Vasculopathy
migraine headaches in the top 20 among all diseases years (10). Despite most migraine sufferers reporting
worldwide causing disability, with migraine accounting improvement in their headaches during pregnancy, par-
for 1.3% of years lost because of disability (1). Several ticularly in the third trimester (11–14), research has
studies have linked migraine with other comorbidities implicated a diagnosis of migraines as an independent
that would put migraineurs in particular at higher risk
•  reversible cerebral
for vascular events. vasoconstriction
For instance, migraineurs may be syndrome (RCVS), a clinical and
more likely to be obese (2,3), have a higher adjusted Wake Forest School of Medicine, Department of Neurology, NC, USA
radiological
total cholesterol and lower adjusted characterized
syndrome high-density lipo- by severe unusual headache and
transient
protein (HDL)multifocal cerebral
(4,5), be less likely to exercise vasoconstriction
Corresponding author:
regularly Cheryl Bushnell, Wake Forest School of Medicine, Department of
(5) and be more likely to smoke compared to nonmi- Neurology, Medical Center Boulevard, Winston Salem, NC 27157, USA.
•  the link(5–7).
graineurs between RCVS
The relationship and
between migraine
migraine and Email:may also contribute to the higher risk
cbushnel@wakehealth.edu
of HS in migraineurs.

Kuo C-Y, et al et al. (2013). PLoS ONE 8(1): e55253.

Mawet J, Kurth T and Ayata C. Cephalalgia 2015, Vol. 35(2) 165–181 20

10  
 Nov/2/17  

Oral contraceptive/hormonal and stroke

•  Oral contraceptives, even at low doses, significantly increase the risk

of cerebral venous thrombosis
•  migraine is a contraindication for OC use. ( a progestogen-only OC
might be recommended)
•  there are no data on the relationship between hormone replacement
therapy, migraine and stroke.
•  However, there are reasons to be concerned that HRT may contribute
to stroke risk

BousserM-G & Kittner SJ. Oral contraceptives and stroke.Cephalalgia 2000;20:183±189.

Kittner SJ & Bousser M-G. Post-menopausal hormone replacement therapy and stroke risk. Cephalalgia
2000; 20:208±213 21

J Headache Pain (2012) 13:177–189

DOI 10.1007/s10194-012-0424-y

REVIEW ARTICLE J Headache Pain (2012) 13:177–189

Migraine in women: the role of hormones and their impact

igraine status and COCs use
on vascular diseases
ve Risk of ischemicSimona
stroke
Sacco OR; 95%
Silvia Ricci •
CIDegan Risk of ischemic stroke OR; 95% CI
Diana • •

Antonio Carolei
Women with Collaborative
Women with Group Women with Women without
migraine using migraine not using migraine using migraine using
COCs vs. women COCs vs. women COCs vs. women COCs vs. women
without migraine
Received: 26without migraine
January 2012 / Accepted: withonline:migraine
8 February 2012 / Published 26 February 2012 without migraine
! The Author(s) 2012. This article is published with open access at Springerlink.com
not using COCs not using COCs not using COCs not using COCs
Abstract Migraine is a predominantly female disorder. Introduction
Menarche, menstruation, pregnancy, and menopause, and
5.9; 2.9–12.2 4.9; 2.9–8.3
also the use of hormonal contraceptives and hormone Migraine is a predominantly female disorder. Women,
replacement treatment may influence migraine occurrence. compared with men, have a 1-year migraine prevalence
13.9; 5.5–35.1 3.7; 1.5–9.1
Migraine usuallySacco
startsSafter
et almenarche,
J Headache
occursPain
more(2012)
fre- 13:177–189
3.5; 1.5–8.3
nearly threefold higher (17 vs. 6%) and lifetime incidence
22
quently in the days just before or during menstruation, and more than twofold higher (43 vs. 18%) [1, 2]. Moreover,
COCs ameliorates during pregnancy and menopause. Those menarche, menstruation, pregnancy, and menopause as use
variations are mediated by fluctuation of estrogen levels of oral contraceptives and of hormone replacement treat-
2.08; 1.19–3.65 0.88; 0.44–1.76
through their influence on cellular excitability or cerebral ment (HRT) may influence migraine occurrence. Until
vasculature. Moreover, administration of exogenous hor- puberty, migraine affects both sexes equally [3]. After the
COCs 16.9; 2.72–106 2.27; 0.69–7.47 2.76; 1.01–7.55
mones may cause worsening of migraine as may expose menarche there is an increasing prevalence of migraine in
migrainous women to an increased risk of vascular disease. women [4, 5]. The mechanism for the gender difference in
bined oral contraceptives In fact, migraine with aura represents a risk factor for migraine is not clear even if endogenous sex steroids are 11  
stroke, cardiac disease, and vascular mortality. Studies considered to play a relevant role.
have shown that administration of combined oral contra-
ceptives to migraineurs may further increase the risk for
ischemic stroke. Consequently, in women suffering from Migraine during women’s life
migraine with aura caution should be deserved when pre-
scribing combined oral contraceptives. The woman’s reproductive cycle is regulated by the hypo-
thalamic-hypophyseal-ovarian axis through the release of
 documented cases are rare (21,24,25). One can hypothesize that migraineurs, or serve as a marker of endothelial perturbati
ictal release of vasoconstrictive substances into the systemic cir- Oral contraceptive pills increase both the likelihood of migra
culation could also cause coronary artery spasm, accounting for (45), and also the risk of ischaemic stroke in migraine
the association of Rose angina and migraine (26). (10,11,15). Oral contraceptive pill use has been associated w
Nov/2/17  
increased levels of fibrinogen (46), the protein that binds a
Hypercoagulability vated platelets, and thereby may lead to a synergy of risk
When challenged by hypoxia, and calcitonin gene-related pep- migraineurs on OCP.
tide (released by activated trigeminal endings during migraine),
cerebral endothelial cells, platelets and mast cells have been MIGRAINE AS A RISK FACTOR FOR ISCHAEMIA
shown to release platelet-activating factor (PAF) (27), which in Arterial dissection
turn targets neurones, glial and microglial cells, endothelial cells, Arterial dissection, a well-recognized cause of stroke in
monocytes and macrophages. PAF has been ICTALimplicated
MIGRAINE in ner- young, has been found to be more common in migraineurs (4
vous tissue ischaemia and in apoptosis. A potent inducer of The association with dissection and intimal tears is postulated
platelet activation and aggregation, PAF also prompts the release be due to elevations of serum elastase activity, as has been d
of von Willebrand Factor (VWF), which similarly affects plate- umented in older migraineurs (48).
VASOCONSTRICTIVE SUBSTANCES SUCH
lets.ASVon Willebrand AND
ENDOTHELIN factor,SEROTONIN
a large endothelial-derived glycopro-
tein, indirectly activates the platelet IIb/IIIa receptor, crucial for Endothelial dysfunction
binding fibrinogen, and leading to primary haemostasis
INCREASED (28). OFThe
LEVELS PAFendothelium
AND OF vWF is a mechanical and biological barrier betw
Small clinical studies in migraineurs, have demonstrated ictal the blood and vacular wall. Endothelial dysfunction is charac
platelet aggregation (29–32), and increased levels of PAF (27) ized by reduction in bioavailablility of vasodilator (such as N
VASOSPASM
and of VWF (33) compared with the interictal measurements. increase in endothelial-derived contracting factors, and con
PLATELET AGGREGATION
One can hypothesize a scenario in which, during the course of quent impairment of the reactivity of the vasculature, includ
a migraine attack, thrombosis occurs within a focally constricted the microvasculature (49). It also comprises endothelial act
vessel. In an alternate scenario, hypercoagulability-related cere- tion, characterized by a procoagulatory, proinflammatory
bral ischaemia may induce CSD, MIGRAINOUS
i.e. symptomaticINFARCTION
migraine (34– proliferative state, which, in turn, predisposes to atherogene
36). Attacks of migraine with aura have, for example, been In this context, endothelial dysfunction is associated with,
•  PAF is released from cerebral endothelial cells, platelets and mast cells in response to hypoxia
associated with thrombocytosis (37) and with polycythemia vera predicts, an increased rate of cerebro- and cardiovascu
and calcitonin gene-related peptide (CGRP), and in turn, prompts the release of von Willebrand
(PCV)
Factor.(38), both conditions associated with increased ischaemic ischaemic events, in essence representing ‘the ultimate risk of
•  risk
vWF,(39,40).
a largeA endothelial-derived
causative relationship between hypercoagulability
glycoprotein, indirectly activates therisk factors’
platelet (49).
IIb/IIIa Traditional risk factors are known to hav
receptor,
crucial
and for binding
migraine fibrinogen,
is suggested by similarly
reports that migraine
affects plateletsattacks are significant impact on endothelial dysfunction. There is a
agregration
controlled by use of antiplatelet agents and agrylin in the case of increasing evidence that
Tietjen GE. Cephalalgia, 2007, 27, 981–987 23
migraine may be a non-traditional
thrombocytosis (41), and by periodic phlebotomy in the case of factor for endothelial dysfunction, which links it to ischae
PCV (42,43). Underlying genetic reasons for hypercoagulability stroke and heart disease (Figure 1).
in migraineurs have not been identified (43). The acquired Evidence of enothelial dysfunction in migraine is mounti
antiphospholipid antibodies, which predispose to clotting One of the most widely accepted biomarkers of endothelial d
through an unknown mechanism, are probably not associated function is VWF (50). In two previous studies, levels of VW
with migraine per se (44), but may increase clotting risk in antigen and VWF activity were significantly higher

Potential Mechanism of Ischemia in Migraine.

vWF MIGRAINE

ACE-DD
Oxidative stress
MTHFR C677TT
polymorphism
Endothelial dysfunction

Thrombosis Inflammation Vascular reactivity Fig 1.—Potential Mechanism of Ischemia in

Migraine. Migraine is associated with endothe
dysfunction, a process: 1) mediated by oxidat
stress, 2) causing thrombosis, inflammation, a
vascular reactivity, 3) and associated with vascu
STROKE ISCHAEMIC HEART DISEASE
disease.

•  © Blackwell
AC-DD:angiotensin-converting enzyme gene deletion polymorphism increased
Publishing Ltd Cephalalgia, 2007, 27, 981–987
frequency of attacks
•  MTHFR: methylenetetrahydrofolate reductase associated with susceptibility to MA
Tietjen GE. Cephalalgia, 2007, 27, 981–987 24

12  
 Nov/2/17  

Biomarkers of endothelial
dysfunction, i.e., elevated vWF
antigen, vWF activity, high-
sensitivity C-reactive protein
and reduced nitrate/nitrite
levels, •  increase in endothelial-derived
vasoconstrictors(endothelin & serotonin)
Endothelial •  endothelial progenitor cell (EPC) decrease
•  endothelial microparticles increased
dysfunction
in Migraineurs lead to a procoagulatory, proinflammatory and
proliferative state, which predisposes to
atherosclerosis

THROMBOSIS

Lee MJ et al. Journal of Stroke 2016;18(2):146-156 25

Martı́ nez-Sánchez
Martı́nez-Sánchez
Martı́nez-Sánchez al. et al.
etet al. 1613 1613 1613
Laboratory analyses in migraine and non-migraine patients
(a prospective
Table 2.Table 2. study
Laboratory
Table 2. Laboratory of patients
Laboratory analyses
analyses
analyses <and
in migraine 55non-migraine
ininmigraine years
migraine and of age with
andnon-migraine brain
patients
non-migraine
patients ischemia.)
patients

All patientsAll(N¼154)
patients (N ¼ 154)(N Brain
All patients ¼ 154) Brain<50infarctions
infarctions <50 years
years oldBrain
(N¼79) old (N ¼ 79)
infarctions <50 years old (N ¼ 79)

MigraineMigraine
Migraine Non-migraine
Non-migraine Non-migraine
Migraine Migraine Non-migraine
Non-migraine Migraine Non-migraine
Variable
VariableVariable (n ¼44) (n ¼(n44) 110) (n ¼ 110)
¼(n¼44) p
p(n ¼ 110)
(n¼18) (n p¼ 18)
(n¼ 61) (n ¼ (n ¼p18)
61) p (n ¼ 61) p
Hypercoagulable
Hypercoagulable
Hypercoagulable states*,states*,
states*, n (%) n (%) 19 (38.6)1919
n (%) (38.6)
18(38.6) <0.01
(16.4) 18 (16.4) <0.01
18 (16.4) 8 (44.4) <0.01 8 (44.4)
11 (18) 8110.03
(18)
(44.4) 0.0311 (18) 0.03
CProtein
ProteinProtein orCSorCdeficiency
Sordeficiency
S deficiency 6 (13.6) 6 (13.6)3 (2.7) 3 (2.7)
6 (13.6) 0.013 (2.7)0.012 (11.1) 0.01 2 (11.1)
3 (4.9) 2 30.31
(4.9)
(11.1) 0.31 3 (4.9) 0.31
Prothrombin Prothrombin
Prothrombin G20210A G20210A
G20210A mutation**,
mutation**,
mutation**, n (%) nn (%)
(%)5 (11.4) 5 (11.4)3 (2.7) 3 (2.7)
5 (11.4) 0.043 (2.7)0.042 (11.1) 0.04 2 (11.1)
2 (3.3) 2 20.22
(3.3)
(11.1) 0.22 2 (3.3) 0.22
• Factor Factor
HSFactor
Vmore
Leiden**, Vfrequent
Leiden**,
V Leiden**, (%) n (%)
nn (%) in the migraine 3 (6.8)
3 (6.8)than 4 (3.6) 4 (3.6)
3 (6.8)
non-migraine 0.4 4 (3.6) 0.4
(38.6% 2 (11.1)
2 (11.1) vs.0.4 3 (4.9) p2<30.31
16.4%, (4.9)
(11.1) 0.31 3 (4.9) 0.31
Anticardiolipin
Anticardiolipin
Anticardiolipin
0.01). as antibodies,
antibodies,
antibodies,
well asprotein
activated n (%)
n n
(%)
in theCgroup (%) of brain infarction patients under 50 years old (1.6)
4
resistance. (9.1) 4 (9.1)
4 (9.1)
4 (3.6) 4 (3.6)
0.22 4 (3.6)0.22
3 (16.7) 3
0.22(16.7)
1 (1.6) 3 1
0.03
(16.7) 0.03 1 (1.6) 0.03
yy y
(44.4% Thrombocytosis,
Thrombocytosis, vs. 18%,
Thrombocytosis, n n(%)(%)n (%)
p <0.03) 1 (2.3) 1 (2.3) 2 (1.8) 2 (1.8)
1 (2.3) 1 2 (1.8)11 (5.6) 11 (5.6)
2 (3.3) 1 20.54
(3.3)
(5.6) 0.54 2 (3.3) 0.54
Lupus
Lupus anticoagulant,
Lupus anticoagulant,
anticoagulant, (%)n (%)
nn (%) 0 (0) 0 (0) 0 (0)1 (0.9) 1 (0.9) 1 1 (0.9)10 (0) 10 (0)0 (0) 0 0–(0)
(0) – 0 (0) –
• APCR,
MAAPCR,
npatients
(%)nyy(%)nyy(%)presented a higher0 (0)HS 0frequency
APCR, yy
(0)
0 (0)1 (0.9) 1 than 1 1 MO
(0.9) (0.9)10although
(0) 10 (0)this
0 (0) difference
0 0–(0)
(0) – 0 (0) –
was NS
Lipid
Lipid profile
Lipid profile
profile
26
TotalTotal
Total cholesterol cholesterol
cholesterol(mg/day), (mg/day),
(mg/day), Samean
mean
n mean(SD)
(SD)
́ chez (SD)209.4
PM 209.4
(47.7)
et al. 209.4(47.7) (44.4)194.5
194.5(47.7)
Cephalalgia 2011.(44.4)
194.5
0.27 (44.4)
31(16) 0.27(45.7) 197.40.27
197.4
1609–1617 (45.7)(43.7)197.4
196 1960.9(43.7)
(45.7) 0.9 196 (43.7) 0.9
HDLHDL
HDL (mg/dl); (mg/dl);
(mg/dl);
meanmeanmean(SD) (SD)
(SD) 48.8
48.8 (13.9) (13.9)
48.8 (11.8)44.6 (11.8)
44.6(13.9) 44.6 46.50.12(15.4) 46.50.12
0.12 (11.8) (15.4)(11.4) 46.5
42.5 42.50.29
(11.4)
(15.4) 0.2942.5 (11.4) 0.29
LDLLDL
LDL (mg/dl), (mg/dl),
(mg/dl),
mean meanmean(SD) (SD)
(SD) 134.1
134.1 (39.8)
134.1(39.8) (37.8)123.4 (37.8)
123.4(39.8) 123.4 134.20.14(37) 134.20.14
0.14 (37.8) (37)(39.1)134.2
123.4 123.40.36
(39.1)
(37) 0.36
123.4 (39.1) 0.36
Triglycerides
Triglycerides
Triglycerides
(mg/dl), (mg/dl),
(mg/dl), medianmedian
median (IQR) (IQR) 112 (113)112112
(IQR) (113)
130.5(113) 130.5 (108.75)
(108.75) 130.5 169.10.97(76.8) 169.10.97
0.97 (108.75) (76.8)(120.40)
161.1 161.10.82
169.1 (120.40)
(76.8) 0.82
161.1 (120.40) 0.82
*Three
*Three migraineurs
*Three migraineurs
migraineursandand twoandnon-migraineurs
two two non-migraineurs
non-migraineurspresentedpresented
more thanmore
presented onemorethan one hypercoagulable
hypercoagulable
than one state.
state.hypercoagulable state.
**All**All
**All heterozygous. heterozygous.
heterozygous. 13  
y
y
PlateletyPlatelet
Platelet
count countcount
>450 >450# 10 1010/L
101010#/L/L
#>450
yy yy yy
Patients
PatientsPatients
with with with
activated activated
activated protein
protein protein
C Cresistance
resistance
C resistance and
andnotnot
and not FV. FV. FV.
Factor VFactorFactor
Leiden Vindicates
Leiden
V Leiden indicates
indicates Factor
Factor Factor
V LeidenV G1691A
Leiden G1691A
V Leiden G1691A
mutation; mutation;
APC,
mutation;APC,protein
activated activated
APC, protein C resistance.
C activated
resistance. protein C resistance.

patients,
patients,
patients,
although although
although this this difference
thisdifference was notwas
difference was notnotstatistically
statistically patients (p¼0.17).
statistically (pThe¼ 0.17).
patientspatients The¼ofassociation
association
(p 0.17).
PFO and of PFO
The
ASA and ASA of PFO and ASA
association
 Nov/2/17  

pro coagulation chemistry

•  carriers of factor V Leiden or factor II

G20210A mutations (OR 1.76, 95% CI
1.02– 3.06)
A recent study in •  elevated pro- thrombin factor,
1456 women MA
(mean age 34) •  decreased resistance to activated
protein C,
•  protein S deficiency

Mawet J, Kurth T and Ayata C. Cephalalgia 2015, Vol. 35(2) 165–181

27
Lee MJ et al. Journal of Stroke 2016;18(2):146-156

A meta-analysis of case-control studies OF PFO

RISK OR 5.13
PFO MIGRAINE

RISK OR 2.54

•  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.
•  PFO closure in reducing migraine attack frequency, such as headache
resolution in up to 80% of patients

Tietjen GE. Cephalalgia, 2007, 27, 981–987

Mawet J, Kurth T and Ayata C. Cephalalgia 2015, Vol. 35(2) 165–181
Wabnitz A and Bushnell C. Cephalalgia 2015, Vol. 35(2) 132–139
28

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Cervical Arterial dissection

•  In a metaanalysis, migraine (MO) is associated with a two-fold

increased risk of cervical artery dissection (OR = 2.06, 95% CI ).
•  Arterial dissection, a well-recognized cause of stroke in the young more
common in migraineurs
•  Elevations of serum elastase activity and shared genetic alterations
such as MTHFR polymorphism are possible mechanisms.
•  A recent genome- wide association study of cervical arterial dissection
identified a significant association of the PHACTR1(Phosphatase and
actin regulator 1) locus, which is also associated with migraine

Lee MJ et al. Journal of Stroke 2016;18(2):146-156 29

There are 2 genetic mutations that show a stroke with migraine symp

•  Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and

Leukoencephalopathy (CADASIL), is Notch-3 mutation is the gene involved in
encoding a transmembrane receptor primarily expressed in systemic small cerebral
arterial smooth-muscle cells.
•  TIA and ischemic strokes are the most frequent occurring in 60%-85% of
patients CADASIL with migraine features.
•  Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS) is
a genetically heterogeneous mitochondrial disorder characterized by features of
central nervous system involvement (seizures, hemiparesis, hemianopia, cortical
blindness, sensori- neural deafness, and/or episodic vomiting).
•  Headache is a common manifestation, which is either a recurrent
migraine-like attack or a presenting symptom of stroke-like episodes

Lee MJ et al. Journal of Stroke 2016;18(2):146-156 30

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31

Independent risk factors of

ischemic stroke in migraineurs

•  Migraine with Aura (OR 2.3 95%CI)

•  Woman Age < 45 years (OR 2.6 95% CI)
•  Oral contraceptive use (OR 5.9 95% CI)
•  Smoking (HR 3.2-9.3 95% CI)

•  Migraine with aura may be a direct cause of migrainous infarction

•  Migraine particularly MA, were at increased risk of death from coronary heart disease
and stroke (Gudmundsson LS et al.BMJ 2010)"

32

16  
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Migraineurs men have a risk of ischemic stroke about HR 1.2

found an increased risk of ischemic

migraineurs men have an increased
risk of stroke compared with men
without migraine.HR 1.12
" " " " " " "(Kurth T et al.Arch Intern
Med. 2007)"
stroke in men with migraine (aHR:
1.20, 95% CI: 1.01–1.42, p =0.036).
Peng KP et al. Cephalalgia 2017, Vol. 37
(4) 327–335

The migraine group had a higher prevalence of

•  hypertension (P,0.0001),
•  hyperlipidemia (P,0.0001),
•  coronary heart disease (P,0.0001),

33

Prevention & treatment of stroke in migraineurs

1.  triptans and ergotamine are not recommended in patients with MA

2.  Smoking cessation

3.  Antithrombotics are not recommended to reduce a risk of stroke in

migraineurs.

4.  headache specialists should take care not only of relieving pain but
also of assessing and treating concurrent vascular risk factors

5.  gynecologists, should consider prescribing oral contraceptives.

Sacco S et al. Cephalalgia 2012, 32(10) 785
Mawet J, Kurth T and Ayata C. Cephalalgia 2015, Vol. 35(2) 165–181
Lee MJ et al. Journal of Stroke 2016;18(2):146-156 34

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Thank you

35

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