Meningeal Contribution to Migraine Pain

A Magnetic Resonance Angiography Study

Sabrina Khan; Faisal Mohammad Amin; Casper Emil Christensen; Hashmat Ghanizada; Samaira Younis; Anne Christine Rye Olinger; Patrick J. H. de Koning; Henrik B. W. Larsson; Messoud Ashina


Brain. 2019;142(1):93-102. 

In This Article

Materials and Methods

Study Design and Participants

Patients were eligible for inclusion if they were female aged 18–50 years and had a verified diagnosis of migraine without aura as defined by the International Headache Society classification (Headache Classification Committee of the International Headache Society (IHS), 2013). Patients were eligible for inclusion if they reported their spontaneous migraine to be unilateral in ≥70% of attacks. All patients were prescreened with cilostazol, and only patients who developed a migraine-like attack after the first cilostazol induction were included in the study. Exclusion criteria included any other type of headache (apart from episodic tension-type headache ≤5 days per month), any previous serious somatic or psychiatric condition, pregnant or nursing females, drug misuse, daily intake of medication (apart from oral contraceptives), or contraindications for MRI (i.e. any type of metal implantation in the body or claustrophobia). The present study is part of a larger parent protocol (protocol H-15005669, identifier NCT02549898), where several other parameters were recorded with MRI to be published elsewhere. Exclusion criteria specific for the parent MRI protocol also included history of atopic or drug allergy, evidence of iron overload assessed by biochemical detection of ferritin, transferrin, iron and haemoglobin, and genetic screening for haemochromatosis with the HFE gene. All patients underwent a full medical examination and pregnancy testing.

All patients provided written informed consent to participate in the study. The Ethical Committee for Capital Region of Denmark approved the study, which was conducted in accordance with the Helsinki Declaration of 1964 with later revisions.

Data Acquisition and Imaging Protocols

All patients reported to the clinic migraine-free for at least 5 days, and headache-free for at least 3 days. Coffee, tea, cocoa, alcohol, other methylxanthine-containing beverages, and tobacco were not allowed for at least 12 h before study start. Patients first underwent a baseline MRA (baseline scan). Upon completion of this first scan, all patients ingested 200 mg cilostazol (Pletal®, Otsuka Pharmaceutical Europe Ltd.) orally. MRA was performed again (early attack scan) after 4 h. Headache intensity and characteristics were recorded every hour from cilostazol ingestion on a verbal rating scale from 0–10 (0, no headache; 1; very mild headache; 10, worst imaginable headache). After the early attack scan, 12 of 30 patients were allocated to treat their migraine attack with 6 mg subcutaneous injection of sumatriptan (Imigran®, GlaxoSmithKline). These patients underwent an additional MRA 1 h after sumatriptan treatment (sumatriptan scan). Those patients who did not treat their attack with sumatriptan were permitted to treat their headache with only promethazine and metoclopramide, in order to exclude any direct drug effect on the cerebral vasculature. As part of the parent study design, participating patients received an iron oxide contrast agent after their early attack respective sumatriptan scan, and reported back to the clinic the next day and underwent a late MRA (late attack scan, Figure 1).

Figure 1.

Study procedures for patients who underwent MRA with or without receiving sumatriptan treatment.

MRA was performed on a 3 T Philips Achieva Scanner (Philips Medical Systems) using a 32-channel phased-array head coil. A scout MRA was performed to plan the subsequent high resolution MRA, using field of view 200 × 200 × 74 mm3, acquired matrix size 800 × 408, acquired voxel resolution 0.25 × 0.49 × 1.00 mm3, reconstructed voxel resolution 0.20 × 0.20 × 0.50 mm3, repetition time 25 ms, echo time 3.5 ms, flip angle 20°, SENSE p reduction 2, four chunks, total scan duration 9 min 4 s.

Data Analysis

Baseline, early attack and sumatriptan scans. After acquisition, MRA scans were transferred to a separate workstation in DICOM format, and analysed with the LKEB-MRA vessel wall analysis software program, which has previously been applied in similar studies (Asghar et al., 2011; Amin et al., 2014) and has demonstrated inter- and intra-observer variation below 5% (Amin et al., 2014). The program provides automated contour detection and quantification of the luminal boundaries every 0.2 mm perpendicular to the centre line in the chosen vessel segment. The investigators (S.K., C.E.C. and F.M.A.) reviewed the chosen segment and for each vessel a segment with no branches was selected to ensure the most reliable measurement. The same segment was chosen within each subject between scans and days. If the vessel segment displayed too many side branches or too curved a pattern to provide reliable circumference estimation, the measurement was excluded from the analysis.

We performed measurements on intracranial and extracranial vessels. The intracranial arteries were further classified as cerebral or extracerebral. The cerebral vessels included the middle cerebral artery (MCA), the cerebral part of internal carotid artery (ICAcerebral), and basilar artery. The cavernous part of the internal carotid artery (ICAcavernous) served as an extracerebral artery. The extracerebral vessels included the MMA, the superficial temporal artery (STA), and the external carotid artery (ECA). We identified MCA by marking the branch from the main trunk of the ICA. We identified ICAcerebral by setting the starting point in MCA and measuring caudally from where ICA branches into MCA and the anterior cerebral artery. The basilar artery segment was identified by using the point at which the two vertebral arteries conjoin as a reference. We identified the start of ICAcavernous by the point where ICA enters the intracranial cavity (prior to entering the cavernous sinus). The MMA was identified by marking the branch from the main trunk of the maxillary artery (or in some cases directly from the ECA), and STA and ECA were identified as either side of where the maxillary artery branches off from ECA.

Investigators who performed MRA analyses (S.K., F.M.A., and C.E.C.) were masked to patients' headache laterality.

Explorative late attack scan analyses. As part of the parent study design, participating patients received an intravenous iron oxide contrast agent after their early attack respective sumatriptan scan (Figure 1), and underwent a late attack scan on the next day. Iron oxides exhibit a relatively long intravascular phase, for which reason the late attack MRA demonstrated both intra- and extravascular enhancement, in some cases segmentally contorting the lumen boundaries detected by the LKEB-MRA vessel wall analysis software program. Because of this technical caveat of the late attack MRA, we analysed data for this specific scan exploratively. If extravascular tissue or small side branches were included due to effects of contrast enhancement, we manually corrected the measurement if possible. If not possible, the measurement was excluded from the dataset. For the late attack scan, we included three vessels; the MCA, ICAcavernous, and MMA.

Statistical analysis. Sample size was calculated for the parent study. We calculated our sample size based on detection of at least 20% change in arterial wall thickness between the pain side and non-pain side during attack, at 5% significance (two-tailed) and with 80% power. The estimated standard deviation of arterial wall thickness changes was assumed to be 16%. Based on these assumptions, we calculated that 10 patients should be included, but increased our sample size to 30 for increased confidence in our findings.

All absolute values are presented as mean ± standard deviation (SD). Per cent changes are reported as mean and 95% confidence intervals (CI). Headache score is presented as median with interquartile range (IQR).

The primary endpoints of the study were (i) difference in circumference change of cranial arterial segments between the pain side and the non-pain side during unilateral migraine attacks; and (ii) difference in circumference change of cranial arterial segments between the pain side and the non-pain side during unilateral migraine attacks after sumatriptan treatment.

We tested for absolute differences in arterial circumference between baseline, attack, and treatment conditions and for possible side-to-side differences between the pain side and the non-pain side using the paired t-test. We made no adjustment for multiple analyses.

Data from the late attack scan were studied exploratively and mean circumference change of the vessels is presented on line graphs. We used SPSS (version 23.0) for all statistical analyses. All P-values were two-sided and considered significant if <0.05.

Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.