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



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) >10 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 8 a.m. and 10 a.m. on the day of the study. No medication, coffee, tea or alcohol was allowed in the 12 h prior to the start of the experiment. From 1 hour before the experiments until the very end of the experiments, 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 the experiment.

Migraine patients (n = 32) were scanned: (i) at baseline, outside an attack; (ii) during randomly allocated and double-blind infusion of NTG (0.5 µg/kg/min over 20 min; n = 27) or placebo (n = 5) and (iii) during an ensuing migraine attack or, if no migraine had occurred, at 6 h after infusion. The duration of the scan sessions was ∼25 min. The study subjects remained in the scanner between the baseline and the NTG or placebo infusion scanning sessions, which began 10 min after onset of the infusion. Heart rate and blood pressure were monitored during the experiments. Two days after the experiment, subjects were contacted by telephone to check whether a migraine attack had occurred beyond the 6-hour time window (Ferrari and Saxena, 1993).

Placebo administration was included in the protocol to minimize patient and observer's bias for diagnosing whether or not NTG infusion had provoked a migraine headache [as this diagnosis is based on subjective assessment of symptoms (Headache Classification Committee of the International Headache Society, 2004)]. We choose for an unequal and incomplete allocation to receiving NTG or placebo mainly for two reasons. First, NTG administration was only used as a well-established tool to provoke migraine attacks. Our study objective was primarily to assess intra-individual changes from baseline, rather than comparing the effect of NTG with that of placebo. Secondly, we wanted to minimize the number of patients who would contribute only very little to the study results (placebo was only given for masking reasons) to reduce unnecessary burden to patients, investigators and MRI scanning time (the study protocol was very time consuming).


The MR investigations were performed on a 3.0-Tesla whole-body system (Philips Medical Systems, The Netherlands). The MRA protocol consisted of two parts, one to assess blood vessel diameter changes and one to assess blood flow changes.

The 'blood vessel diameter protocol' consisted of a thick 2D phase contrast sagittal localizer survey through the circle of Willis, followed by a 3D time-of-flight MRA sequence to visualize the BA and ECA, ICA, PCA and MCA on both sides. This scan had the following imaging parameters: repetition time/echo time: 22 ms/3.5 ms; flip angle 15°; field of view: 220 x 220 mm; number of excitations: 1; slice orientation: transverse; slice thickness: 0.65 mm; number of slices: 200; scan percentage 100%, matrix reconstruction size: 512 x 512 resulting in a nominal voxel size (x, y, z) of 0.43 x 0.43 x 0.65 mm; total acquisition time: 4 min 30 s. Based on the reconstruction of this 3D-time-of-flight, a second 3D-time-of-flight with a higher spatial resolution was performed to visualize the extra- and intra-cranial parts of the MMA on both sides. This scan had the following imaging parameters: repetition time/echo time: 15 ms/2.1 ms; flip angle 15°; field of view: 200 x 200 mm; number of excitations: 1; slice orientation: transverse; slice thickness: 0.25 mm; number of slices: 130; scan percentage 100%, matrix reconstruction size: 512 x 512 resulting in a nominal voxel size (x, y, z) of 0.39 x 0.39 x 0.25 mm; total acquisition time: 8 min 31 s.

For the 'blood flow protocol', a 2D phase contrast section was positioned on the basis of two thick slab localizer MRA scans in the coronal and sagittal plane at the level of the skull base, perpendicular on the ICA and BA, to measure the flow volume. The MRA flow volume measurements in the present study are derived from previously developed and optimized protocols (Spilt et al., 2002a, b; Bakker et al., 1995, 1996). Acquisition parameters: repetition time/echo time: 16 ms/8.5 ms; flip angle 10°; field of view: 150 x 150 mm; number of excitations: 20; slice orientation: transverse; slice thickness: 5.0 mm; number of slices: 1; scan percentage 100%; phase contrast velocity encoding: 140 cm/s; matrix reconstruction size: 256 x 256 resulting in a nominal voxel size (x, y, z) of 0.59 x 0.59 x 50 mm; total acquisition time: 56 s. Figure 1 illustrates the positioning of the 2D phase contrast section through the ICA and BA. On an independent workstation, quantitative flow values were calculated in each vessel by integrating across manually drawn regions of interest that enclosed the vessel lumen closely.

Figure 1.

MRA, coronal maximum intensity projection. Horizontal line indicates the positioning of the 2D phase contrast section through the ICA and the BA.

Image Post-processing: Diameter Calculations

All MRA images were transferred to a remote workstation for quantitative analysis using the Quantitative-MRA (QMRA) software package developed at our institution. A full description of the contour detection methods used and the validation have been described previously (de Koning et al., 2003). The software provides automated contour detection and quantification of the luminal boundaries in selected vessel segments in 3D MRA datasets. The only user interaction required is the definition of the vessel segment of interest by placing a proximal and distal point in the 3D dataset. Subsequently, the software detects a 3D path line following the centre of the vessel lumen and cross-sectional multiplanar recontructions are generated perpendicular to the centreline at 0.5 mm intervals. In each of these multiplanar recontructions, a contour around the vessel lumen is detected automatically. From these contours, based on the assumption of circular vessel cross-sections, the average diameter of the selected vessel segment is derived. Blood vessel segments were selected as follows: (i) the MMA was measured in an extra-cranial segment (from the origin at the maxillary artery to the end, 5-6 mm distally; Figure 2); (ii) the ECA from the origin at the superficial temporal artery to the end, 10 mm proximally; (iii) the ICA from just proximally of the syphon to the end, 15 mm distally; (iv) the MCA, onset after A1 segment and end 8 mm distally; (v) the BA, from the origin at the PCA to the end 12 mm proximally; (vi) the PCA, beginning at the origin at BA and end 8 mm distally. Location of measured vessel segments were kept constant within subjects.

Figure 2.

MRA of the MMA region and position of the measured segment: (A) maxillary artery, (B) MMA.

Statistical Analysis

We first tested the left-to-right differences in diameters for bilateral blood vessels (MMA, ICA, ECA, MCA and PCA) using paired t-tests. Since the differences were not statistically significant, we only present the mean diameters for the right and left blood vessels throughout the manuscript. The effect of NTG and migraine attack on blood vessel diameters and blood flow were tested using a linear mixed model. Patients with a migraine attack (n = 20) were compared with patients without an attack after NTG (n = 7). Data from patients receiving placebo were not used for statistical testing. P < 0.05 was considered statistically significant.


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