Migraine headache is not associated with cerebral
or meningeal vasodilatationça 3T magnetic
resonance angiography study
G.G. Schoonman,1J. vander Grond,2C.Kortmann,1R. J. vander Geest,2G.M.Terwindt1and M.D.Ferrari1
1Department of Neurology and2Department of Radiology, Leiden University Medical Centre, Leiden,The Netherlands
Correspondence to: G.G. Schoonman, MD, Department of Neurology (K5-Q), Leiden University Medical Centre,
PO Box 9600, 2300 RC Leiden,The Netherlands
Migraine headache is widely believed to be associated with cerebral or meningeal vasodilatation. Human
evidence for this hypothesis is lacking. 3 T esla magnetic resonance angiography (3T MRA) allows for repetitive,
non-invasive, sensitive assessment of intracranial vasodilatation and blood flow.Nitroglycerine (NTG) can faith-
fully induce migraine attacks facilitating pathophysiological studies in migraine. Migraineurs (n=32) randomly
received NTG (IV 0.5kg/kg/min for 20min; n=27) or placebo (n=5; for blinding reasons).Using 3T MRA, we
measured: (i) blood flow in the basilar (BA) and internal carotid arteries (ICA) and (ii) diameters of the middle
meningeal, externalcarotid,ICA, middle cerebral,BA and posteriorcerebral arteries atthree timepoints: (a) at
baseline, outside an attack; (b) during infusion of NTG or placebo and (c) during a provoked attack or, if no
attack had occurred, at 6h after infusion. Migraine headache was provoked in 20/27 (74%) migraineurs who
received NTG, but in none of the five patients who received placebo. The headache occurred between 1.5h
and 5.5h after infusion and was unilateral in 18/20 (90%) responders. During NTG (but not placebo) infusion,
there was a transient 6.7^30.3% vasodilatation (P_0.01) of all blood vessels. During migraine, blood vessel
diameters were no different from baseline, nor between headache and non-headache sides. There were no
changes in BA and ICA blood flow during either NTG infusion or migraine. In contrast to widespread belief,
migraine attacks are not associated with vasodilatation of cerebral or meningeal blood vessels. Future
anti-migraine drugs may not require vasoconstrictor action.
Keywords: migraine; nitroglycerine; magnetic resonance angiography; cerebral blood flow; middle meningeal artery
Abbreviations: BA=basilar artery; CGRP=calcitonin gene related peptide; ECA=external carotid artery; ICA=internal
carotid artery; MCA=middle cerebral artery; MMA=middle meningeal artery; NTG=nitroglycerine; PCA=posterior
cerebral artery; 3T MRA=3 Tesla magnetic resonance angiography
Received February17 , 2008. Revised April 8, 2008. Accepted April 22, 2008. Advance Access publication May 23, 2008
Migraine is a neurovascular disorder typically characterized
by attacks of severe, throbbing,
associated autonomic symptoms and, in one third of
patients, focal neurological aura symptoms (Goadsby et al.,
2002). Since the seminal work by Wolff and colleagues
(Wolff, 1948), showing that stimulation of cerebral and
meningeal arteries caused headache, there is a widespread
belief that vasodilatation of intracranial blood vessels is the
underlying mechanism for migraine headache (Ferrari and
Saxena, 1993). This hypothesis was further fed by a number
of other observations. Balloon dilatation of the middle
cerebral artery (MCA) may cause migraine-like headache
(Nichols et al., 1990). Vasoactive substances such as the
nitric oxide donor nitroglycerine (NTG) (Thomsen et al.,
1994) and calcitonin gene related peptide (CGRP) (Lassen
et al., 2002) can trigger migraine in susceptible subjects.
In fact, the recent development of novel CGRP antagonists
for treating migraine attacks was at least partly based on the
hypothesis that prevention or reversal of vasodilation would
block migraine headache (Olesen et al., 2004; Doods et al.,
2007). Animal and in situ pharmacological experiments
(Goadsby et al., 2002; Tfelt-Hansen et al., 2000) and human
in vivo studies using transcranial Doppler (Iversen et al.,
1990; Friberg et al., 1991; Thomsen et al., 1995) have shown
that acute anti-migraine agents (ergots and triptans)
doi:10.1093/brain/awn094Brain (2008),131, 2192^2200
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constrict cerebral and meningeal blood vessels (Edvinsson
et al., 2005). In fact, the triptan class was specifically
designed to selectively constrict intracranial blood vessels
(Ferrari and Saxena, 1993).
The role of vasodilatation in migraine has been vividly
debated in the past [for review see: (Humphrey and
Goadsby, 1994)] and more recently (Goadsby et al., 2002;
Parsons and Strijbos, 2003). Some researchers view vasodi-
lation of meningeal or cerebral blood vessels as a primary
trigger for migraine headaches, and consider vasoconstric-
tion necessary for acute anti-migraine efficacy (Villalon
et al., 2003). Others feel that vasodilation is a secondary
phenomenon, due to activation of the trigeminovascular
system and release of vasoactive neuropeptides. Vasodila-
tion would primarily be involved in sustaining and worsen-
ing of the headache during migraine attacks (Waeber and
Moskowitz, 2005). A third line of thinking holds that
vasodilation is irrelevant or, at best, ‘an innocent bystander’
in the pathogenesis of migraine headache. Consequently,
vasoconstriction may not be needed to treat migraine
headaches (Hoskin et al., 1996a, b; Goadsby, 2005). This
would be an enormous advantage as the currently available
most effective anti-migraine agents, triptans and ergots, all
possess (sometimes strong and sustained) vasoconstrictor
activity (Ferrari et al., 2001). They may cause myocardial
and cerebral ischaemia in patients with (risk factors for)
vascular disease (Dodick et al., 2004). Novel anti-migraine
agents, which are devoid of vasoconstrictor activity, would
be safer and could thus also be used by the many
migraineurs with vascular disease.
Remarkably, the three opposing views on the role of
vasodilation in migraine are all primarily based on extra-
polations of observations in experimental animal models,
with very little evidence from human studies. This is pri-
marily due to lack, until recently, of sensitive non-invasive
imaging techniques to directly and reliably assess intracra-
nial blood flow and blood vessel diameters in humans.
Previous studies have used invasive methods such as carotid
angiography (Masuzawa et al., 1983), or could only indi-
rectly estimate diameter changes of cerebral blood vessels
using transcranial Doppler (Friberg et al., 1991; Markus,
2000). Meningeal blood vessels proved too small to be
investigated quantitatively. With the advent of 3 Tesla
magnetic resonance imaging (3T MRA) a sensitive and
non-invasive imaging technique has become available to
reliably measure intracranial blood flow and diameter
changes of cerebral and meningeal blood vessels (Krabbe-
Hartkamp et al., 1998) as small as the middle meningeal
artery (MMA) (Schoonman et al., 2006).
Infusion of NTG can reliably and faithfully provoke
migraine headaches in migraineurs (Thomsen, 1997; Sances
et al., 2004; Afridi et al., 2005b). The response to NTG
infusion is typically biphasic: an initial, brief and mild
bilateral headache during the infusion in nearly all migraine
and non-migraine study subjects (Afridi et al., 2005b),
followed by a typical migraine, 4–5h later, in 60–80%
of migraine, but not in non-migraine study subjects
(Thomsen et al., 1994; Sances et al., 2004). The symptom-
atology of provoked attacks is no different from that of
spontaneous attacks of migraine without aura (Thomsen
et al., 1994), including premonitory symptoms (Afridi et al.,
2004), response to anti-migraine drugs (Iversen and Olesen,
1996), and increase of CGRP, a marker for activation of the
trigeminovascular system (Juhasz et al., 2003). This provo-
cation model has greatly facilitated the logistics of studying
pathophysiological changes during migraine attacks.
In the present study, we used 3T MRA to intra-
individually compare: (i) blood flow in the basilar (BA)
and internal carotid arteries (ICA) and (ii) the diameters of
the external carotid arteries (ECA), ICA, MCA, BA, poste-
rior cerebral arteries (PCA) and MMA between three con-
ditions: (a) at baseline, outside an attack; (b) during
infusion of NTG or placebo (to assess the immediate vas-
cular effects of NTG) and (c) during NTG-provoked
migraine attacks or, if no attack had occurred, at 6h
post-infusion (to assess whether migraine attacks are
associated with vasodilatation). We will demonstrate that
there is no detectable vasodilation of cerebral or meningeal
blood vessels during NTG-provoked migraine attacks,
suggesting that vasoconstriction may not be required to
treat migraine headaches.
In total 32 migraine patients (n=5 with aura; n=27 without aura)
were recruited from the neurology outpatient clinic of Leiden
University Medical Centre. Inclusion criteria were: (i) age between
18 years and 55 years; (ii) diagnosis of migraine according to the
diagnostic criteria of the International Headache Society (Headache
Classification Committee of the International Headache Society,
2004); (iii) an average attack frequency between 1 and 8 attacks/
2 months in the 6 months prior to the study and (iv) moderate or
severe headache during spontaneous migraine attacks. Exclusion
criteria included: (i)410 days of headache per month; (ii) inability
to differentiate between migraine and other forms of headache;
(iii) contra-indications for the use of triptans; (iv) current use of
vasoactive drugs and (v) MRI-specific contra-indications (such
as claustrophobia). The study was approved by the local medical
ethics committee and the subjects gave informed consent prior
to the start of the study.
Experimental procedure and NTG provocation
All subjects arrived at the hospital between 8a.m. and 10a.m. on
the day of the study. No medication, coffee, tea or alcohol was
allowed in the 12h prior to the start of the experiment. From
1hour before the experiments until the very end of the exper-
iments, study subjects were not allowed to smoke. Patients had to
be free of migraine for at least the 3 days prior to the study day
and they could not have any form of headache at the beginning of
Migraine patients (n=32) were scanned: (i) at baseline, outside
an attack; (ii) during randomly allocated and double-blind
infusion of NTG (0.5mg/kg/min over 20min; n=27) or placebo
A 3T MRA studyBrain (2008),131, 2192^22002193
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