Migraine Headache Is Not Associated With Cerebral Or Meningeal Vasodilatation - A 3T Magnetic Resonance Angiography Study

G. G. Schoonman; J. van der Grond; C. Kortmann; R. J. van der Geest; G. M. Terwindt; M. D. Ferrari


Brain. 2008;131(8):2192-2200. 

In This Article

Summary and Introduction


Migraine headache is widely believed to be associated with cerebral or meningeal vasodilatation. Human evidence for this hypothesis is lacking. 3 Tesla magnetic resonance angiography (3T MRA) allows for repetitive, non-invasive, sensitive assessment of intracranial vasodilatation and blood flow. Nitroglycerine (NTG) can faithfully induce migraine attacks facilitating pathophysiological studies in migraine. Migraineurs (n = 32) randomly received NTG (IV 0.5 µg/kg/min for 20 min; 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, external carotid, ICA, middle cerebral, BA and posterior cerebral arteries at three 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 6 h 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 1.5 h and 5.5 h 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.


Migraine is a neurovascular disorder typically characterized by attacks of severe, throbbing, unilateral headache, 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) 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 vasodilation of meningeal or cerebral blood vessels as a primary trigger for migraine headaches, and consider vasoconstriction 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. Vasodilation would primarily be involved in sustaining and worsening 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 extrapolations of observations in experimental animal models, with very little evidence from human studies. This is primarily due to lack, until recently, of sensitive non-invasive imaging techniques to directly and reliably assess intracranial 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 indirectly 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, 4-5 h later, in 60-80% of migraine, but not in non-migraine study subjects (Thomsen et al., 1994; Sances et al., 2004). The symptomatology 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 provocation 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, posterior cerebral arteries (PCA) and MMA between three conditions: (a) at baseline, outside an attack; (b) during infusion of NTG or placebo (to assess the immediate vascular effects of NTG) and (c) during NTG-provoked migraine attacks or, if no attack had occurred, at 6 h 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.


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