Correspondence
Migraine and Hemorrhagic Stroke: Association or Causation?
LETTER:
Hemorrhagic stroke can be a devastating disease. Although some
risk factors have been dened such as hypertension, much re-
mains to be learned about triggers for this disease and their
prevention. Hemodynamic factors, genetics, and systemic dis-
eases will likely form some of the elements of an individualized
predictive model. Although building such a multivariate model
remains a distant goal because of the daunting task of identifying
and quantifying the relative risks of numerous variables, analyzing
some of these variables separately might enhance the way we
currently look at hemorrhagic stroke prediction and prevention.
Migraine has been suspected as a risk factor for hemorrhagic
stroke, but a denitive relation has not been clearly established
and contradictory results have been published over the past several
decades (2-4). To further rene knowledge in this area, Sacco et al.
conducted a meta-analysis with the aim to quantify the relation-
ship between migraine and hemorrhagic stroke. This meta-anal-
ysis was published in the October 2013 issue of Stroke (1).
The authors reviewed all papers indexed in MEDLINE, EMBASE,
Science citation Index and the Cochrane Library before March 2013.
They used a wide range of keywords and MeSH terms that cover the
spectrum of headaches and cerebrovascular diseases. Only papers
published in English language and studies conducted on human
subjects were included. The authors then manually selected studies
Figure 1. Adjusted effect estimates of hemorrhagic stroke in subjects with no migrain and subjects with migraine.
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meeting the inclusion criteria. These were a case-control or cohort
study with a clear denition of the diagnostic criteria for migraine,
the study of correlation between migraine and intracranial and
subarachnoid hemorrhage, the control for confounders, and the
availability of effect estimates with 95% condence interval (CI). For
overlapping data sets, the authors selected only those with the
longest follow up. To enhance the quality of their data, the authors
excluded studies referring to transient stroke like syndromes,
migranous stroke, mixed ischemic and hemorrhagic stroke as well
as rare genetic syndromes characterized by both migraine and
stroke and studies conducted on pregnant women. The odds ratios
and the hazard ratios were used to determine the effect size. The
authors then determined the adjusted effect measure with the aim of
limiting the effect of confounding variables. An overall analysis of
the association between migraine and intracranial or subarachnoid
hemorrhage was performed and subgroup analysis for migraine
with aura and migraine without aura as well as for all females
and females younger than 45 years were performed. The clinical
methodological and statistical heterogeneity of the selected papers
were evaluated based on the Cochrane Collaboration Guidelines for
systematic reviews. The authors also attempted to quantify the effect
of each study on the overall result and to correct for potential pub-
lication biases.
The authors reviewed the full text of 42 studies. Of those, only
8 met the inclusion criteria. These covered a total of 1600 hem-
orrhagic strokes. The overall pooled data showed that the adjusted
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effect estimate of hemorrhagic stroke in subjects with any
migraine versus control subjects was 1.48 (95% CI 1.116e1.88;
P 0.002), which corresponds to a 50% increase in the risk of
hemorrhagic stroke in migraineurs as compared to the general
population. The subgroup analysis for migraine with aura versus
control showed an adjusted effect estimate of 1.662 (95% CI
0.87e3.03; P 0.129). In patients who suffered migraine without
aura, this effect was 1.39 (95% CI 0.74e2.62; P 0.303). The
overall pooled adjusted effect of hemorrhagic stroke in female
migraine patients versus control was 1.55 (95% CI 1.16e2.07;
P 0.003). However, when considering female patients aged less
than 45 the effect estimate was signicantly higher as compared
to the general population and was 1.57 (95% CI 1.10e2.24;
P 0.012) (Figure 1).
Limitations of the meta-analysis at hand were largely determined
by the available data. Conclusions related to the type of the
hemorrhage (intracranial vs. subarachnoid) or the type of migraine
could not be drawn and age and sex stratication was not
possible. Further, data related to the duration of the migraine and
the issue of active migraine versus a history of migraine and its
implications was not clear. Another limitation comes from the
impact of recall bias on retrospective studies such as the ones that
were included in the meta-analysis.
The authors are to be congratulated for their work bringing to
light the correlation between migraine and hemorrhagic stroke.
However, this work raises many research problems as well as
many questions. In particular, the question of causation versus
association remains unanswered. In the context of causality, the
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question becomes whether migraine may cause hemorrhagic
stroke and whether treatment of migraine would have any effect
on preventing hemorrhagic stroke? In the context of association,
the question is whether migraine and hemorrhagic stroke share
common factors in their pathophysiology. From a clinical stand-
point, this study raises the question of whether patients with
migraine should be screened for cerebrovascular pathology and
monitored more carefully for hemorrhagic stroke risk factors such
as hypertension.
Najib E. El Tecle1, Tarek Y. El Ahmadieh1, Samer G. Zammar1,
Youssef J. Hamade1, James A. Stadler III,1 Bernard R. Bendok1,2
From the Departments of 1Neurological Surgery and 2Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Illinois, USA
To whom correspondence should be addressed: Bernard R. Bendok, M.D.
[E-mail: bbendok@nmff.org]
Published online 30 January, 2014; http://dx.doi.org/10.1016/j.wneu.2014.01.016.
REFERENCES
1. Sacco S, Ornello R, Ripa P, Pistoia F, Carolei A: Migraine and hemorrhagic stroke:
a meta-analysis. Stroke 44:3032-3038, 2013.
2. Schrks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T: Migraine and
cardiovascular disease: systematic review and meta-analysis. BMJ 339:b3914, 2009.
3. Schrks M, Rist PM, Shapiro RE, Kurth T: Migraine and mortality: a systematic
review and meta-analysis. Cephalalgia 31:1301-1314, 2011.
4. Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S: Migraine
headache and ischemic stroke risk: an updated meta-analysis. Am J Med 123:
612-624, 2010.
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