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Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study

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Summary

Background

Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial and intracranial arteries during attacks of migraine without aura.

Methods

In this cross-sectional study, we recruited patients aged 18–60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical) arteries. The intracranial arterial segments were the cavernous (ICAcavernous) and cerebral (ICAcerebral) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered at Clinicaltrials.gov, number NCT01471314.

Findings

Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% [95% CI −5·7 to 8·2] p=0·985, STA 3·6% [–3·7 to 11·0] p=0·532, MMA 1·7% [–1·7 to 5·2] p=0·341, and ICAcervical 2·3% [–0·3 to 4·9] p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% [6·4 to 19·6] p=0·001, ICAcerebral 11·5% [5·6 to 17·3] p=0·0004, and ICAcavernous 11·4% [5·3 to 17·5] p=0·001), except for the BA (1·6% [–2·7 to 5·9] p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% [0·7–20·3] p=0·044, ICAcerebral (14·4% [4·6–24·1] p=0·013), and ICAcavernous (9·1% [3·9–14·4] p=0·003) but not of the extracranial arteries (ECA, 2·1% [–3·8 to 9·2] p=0·238, STA, 3·6% [–3·7 to 10·8] p=0·525, MMA, 2·7% [–1·3 to 5·6] p=0·531, and ICAcervical, 5·0% [–0·5 to 10·4] p=0·119).

Interpretation

Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation.

Funding

University of Copenhagen, the Lundbeck Foundation, the Research Foundation of the Capital Region of Denmark, Danish Council for Independent Research-Medical Sciences, and the Novo Nordisk Foundation.

Introduction

Migraine is the most prevalent neurological disorder, affecting more than 100 million people in Europe1 and the USA.2 It ranks in the top 20 of the most disabling medical illnesses globally, and has substantial effects on the quality of life of patients and their families and on health costs.3 However, the pathophysiological mechanisms of migraine are not fully understood.4 For decades, the throbbing pain during migraine headache was thought to originate from dilated cranial arteries. Tunis and Wolff5 reported increased pulsation of the superficial temporal artery (STA) during attacks. Unilateral stimulation of extracranial and intracranial arteries was associated with ipsilateral head pain.6

During the past two decades, however, the focus on this vascular hypothesis has diminished, and neuronal mechanisms have been suggested to generate migraine headache without abnormal activation of perivascular sensory fibres.7 Findings from studies using novel brain imaging methods during migraine attacks lent support to this view.8, 9 The vascular hypothesis was further challenged by the advent of non-vasoconstrictor anti-migraine treatments, such as ditans10 and calcitonin-gene-related peptide (CGRP)-receptor antagonists,11 which questioned the role of vasoconstriction in the antimigraine action of triptans. Findings from studies using high-resolution magnetic resonance angiography (MRA) suggested that vasodilatation might be involved, but also provided conflicting results.12, 13 These MRA studies can be criticised because they used pharmacological triggers—glyceryl trinitrate12 and CGRP13—to provoke migraine attacks.

Large-scale studies of spontaneous migraine attacks with MRA are challenging for logistical reasons and have not been done. During attacks, patients are nauseated and afraid of vomiting, and their pain is aggravated by physical activity. For these reasons, they do not want to travel and are therefore not easily recruited. Furthermore, the attacks occur unpredictably and, when the attack occurs, immediate access to an MRI scanner is necessary. Consequently, to the best of our knowledge, MRI-based direct measurement studies of cerebral or extracerebral arteries during spontaneous migraine attacks have not been done.

We set up to test the hypothesis that intracranial and extracranial arteries would be dilated on the headache side during a migraine attack. We also hypothesised that therapeutic use of the selective antimigraine drug sumatriptan, a 5-hydroxytryptamine (5-HT1B/1D) agonist, would cause vasoconstriction as well as pain relief.

Section snippets

Study design and participants

We recruited participants via an announcement on a Danish website for recruitment of volunteers to health research and from the outpatient clinic at the Danish Headache Center (Glostrup Hospital, Copenhagen, Denmark). We approached only the patients who lived within 50 km of Glostrup Hospital. Patients were eligible for inclusion if they were aged 18–60 years and had a verified diagnosis of migraine without aura in accordance with the International Headache Society criteria.14 Exclusion

Results

We recruited 78 patients, of whom 19 completed the scan during a migraine attack and were included in the final analysis (figure 2). Eight of these 19 patients were recruited through the Danish recruitment website and 11 were recruited at the Danish Headache Center. All patients recruited were women. Median age was 33 years (range 19–52), median duration of disease was 16 years (5–34), and median attack frequency was 3 per month (1–8) for the whole group. 15 (79%) of the 19 patients had

Discussion

In our study, extracranial dilatation of arteries did not occur during spontaneous migraine attacks. These findings are in contrast with the classic hypothesis suggested by Harold G Wolff and still seen in many textbooks: that dilatation of extracranial arteries might be the cause of migraine pain.12, 13 Another major finding from our study was that sumatriptan relieved migraine pain in parallel with constriction of normal calibre extracerebral arteries, but that it had no effect on dilated

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