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Migraine
Research paper
Interictal cerebral and systemic endothelial dysfunction in patients with migraine: a case–control study
  1. Roopa Rajan,
  2. Dheeraj Khurana,
  3. Vivek Lal
  1. Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
  1. Correspondence to Dr Vivek Lal, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India; vivekl44{at}yahoo.com

Abstract

Background Although systemic endothelial function is unimpaired in migraine, it is unknown whether cerebral endothelial function impairment exists in migraineurs.

Materials and methods We conducted a prospective study to assess endothelial function in migraineurs (n=45) and healthy volunteers (n=44). Cerebral endothelial function was assessed by Breath Holding Index (BHI) on transcranial Doppler in bilateral middle cerebral artery (MCA at 30–60 mm), posterior cerebral artery (PCA at 60–80 mm) and basilar artery (BA at 80–120 mm) using bilateral monitoring probes fixed on headband. Brachial artery flow-mediated dilation (FMD) was used as measure of systemic endothelial function.

Results There was no difference in baseline mean velocities of MCA, PCA, BA among migraineurs and controls. Mean BHI was significantly lower in PCA (p<0.001) and BA (p<0.001) in patients with migraine with no difference in MCA (p=0.909, 0.450). Cerebral endothelial dysfunction (BHI<1.15) was present in 62.2% of migraineurs in the right PCA (p<0.001), 57.8% in left PCA (p<0.001) and 77.8% in BA (BHI <0.83, p<0.001). There was no difference in BHI among migraineurs without and with aura (n=15). Cerebral and systemic endothelial function had no correlation in migraineurs. Increasing BMI was identified as a predictor of impaired BHI in the BA in migraineurs (p=0.020). Age, sex, presence of aura, lateralisation of headache, headache frequency, time to last attack and impaired FMD were not associated with impaired PCA and BA BHI in migraineurs.

Conclusions Migraineurs may have isolated cerebral endothelial dysfunction restricted to the posterior circulation in the absence of systemic endothelial dysfunction.

  • MIGRAINE
  • ULTRASOUND
  • CEREBROVASCULAR
  • CEREBRAL BLOOD FLOW
  • STROKE

https://doi.org/10.1136/jnnp-2014-309571

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    Introduction

    Migraine is a common neurological disorder that causes significant morbidity in terms of the quality of life. A number of observational studies and systematic reviews established that migraine increases the risk for cerebral ischaemic events, especially posterior circulation strokes.1–4 This association is particularly strong in young women experiencing migraine with aura, who otherwise have few risk factors for ischaemic events.4 Recent population-based studies that compared the burden of atherosclerosis between migraineurs and non-migraineurs provide convincing evidence against the view that migraine predisposes to atherosclerosis.5 Although migraineurs have a higher prevalence of patent foramen ovale, no evidence exists to suggest a causal relationship between patent foramen ovale and ischaemic stroke in this population.6 Cerebral vasospasm leading to migrainous infarction was documented only in a few case reports.7 Hypercoagulable states are not more common in patients with migraine.8 In the absence of traditional risk factors, endothelial dysfunction assumes importance as a potential mechanism to explain higher risk of ischaemic events in migraineurs.

    Recent studies on biomarkers and non-invasive markers of systemic endothelial function in migraineurs revealed conflicting results.9 ,10 A synopsis of such studies concluded that migraine is less likely to be a systemic vasculopathy and that isolated cerebral endothelial dysfunction may contribute to the vascular morbidity.11 No study has prospectively assessed cerebral and systemic endothelial function in patients with migraine. The present study aimed to assess endothelial function in systemic and cerebral circulations of migraineurs as compared to controls. While non-invasive assessment of systemic endothelial function is relatively well-established using brachial flow-mediated dilation (FMD), validated markers of cerebral endothelial function are not available. Carbon dioxide-mediated vasomotor reactivity (VMR) is a surrogate marker of cerebral endothelial function.12

    Materials and methods

    We conducted a prospective, hospital-based, case–control study on migraineurs attending the neurology clinic of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh from January 2012 to May 2013. The study design was approved by the Institutional Ethics Committee, PGIMER, Chandigarh. Based on previously published data that showed a difference in mean Breath Holding Index (BHI) of 0.56 between controls and migraineurs in the basilar artery (BA), assuming a power of 80%, probability of type I error of 5% and a clinically meaningful difference of 0.1, we calculated that a sample size of 34 will be required in each arm to demonstrate a significant difference in mean BHI in a single arterial territory.13

    Subjects

    Cases included individuals between the age 15–45 years diagnosed with migraine as per the International Headache Society the International Classification of Headache Disorders: Second Edition (ICHD-2) criteria.14 We excluded patients with BMI >30 kg/m2, hypertension (blood pressure >140/90 mmHg or taking antihypertensives), self-reported history of diabetes mellitus, dyslipidaemia, atherosclerotic coronary artery/ cerebrovascular disease (as these risk factors are known to impair VMR), pregnancy, smokers, individuals using nitrates, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers and oral contraceptive pills.15–17 Data was collected regarding duration, frequency, lateralisation of headache and presence of aura. Age and gender-matched healthy volunteers who conformed to the above criteria were recruited as controls.

    Methods

    Patients who satisfied the inclusion, exclusion criteria and gave their informed consent underwent transcranial Doppler (TCD) and Brachial artery FMD assessments. All patients on migraine prophylaxis medications were required to stop them for 48 h prior to the study. Non-triptan analgesics were allowed for abortive therapy of headaches.

    TCD assessment was carried out on SONORA TCD machine (VIASYS Healthcare Solutions, Wisconsin, USA). A single non-blinded examiner (RR) performed all TCD studies. Bilateral middle cerebral, bilateral posterior cerebral and basilar arteries were assessed in each patient. Two 2 MHz transducers mounted on a head frame were placed on the temporal bone window for simultaneous bilateral measurement of MCA and PCA. Doppler signals from MCA were obtained by adjusting the position for a maximal reflected signal at a depth of 30–60 mm.18 PCA signals were obtained posteriorly and slightly caudally from the MCA at a depth of 60–80 mm. Single 2 MHz transducer was placed in the suboccipital region to assess the BA at a depth of 80–120 mm. Mean Cerebral Blood Flow Velocity (MCBFV) was recorded at the baseline (BAS) in each of the arteries. Patients were then asked to voluntarily hold their breath for 30 s (duration of breath hold, DBH) after a normal inspiration. The MCBFV at the end of breath holding (BH) was recorded. The BHI was calculated using the following equation: TCD-BHI=([MCBFVBH−MCBFVBAS]/MCBFVBAS)×(100/DBH).19 Up to three trials of BH were performed in patients with inconsistent readings and average BHI of three readings was accepted as the final BHI for each artery. Values below 0.69 in the anterior circulation are considered predictive of ischaemic cerebrovascular events.20 As normative data for posterior circulation BHI is not available, representative values derived from the control population were used as cut-off for further analysis.

    Systemic endothelial function assessment was conducted by high-resolution B-mode ultrasound images using a non-invasive methodology described by Celermajer et al.21 A 7–12 MHz broad band linear array transducer probe attached to an HDI 3500 Ultrasound machine.

    HDI 3500 Ultrasound machine (Philips, Amsterdam, the Netherlands) was used for all measurements. The brachial artery was imaged in longitudinal plane 5–10 cm above antecubital fossa in the left arm. At baseline, diameter (dbasal) and blood flow velocity were determined in triplicate by time-averaging the pulsed Doppler velocity signal obtained from a mid-artery sample volume. Following this, arterial occlusion was created by inflating the blood pressure cuff to 50 mm Hg above systolic pressure for 4 min. Ninety seconds after ischaemia, three measurements of brachial artery diameter were taken during the diastolic period. The mean of these values (dmaximal) was used in subsequent analyses. The FMD was calculated by the following formula: FMD={(dmaximal−dbasal)/dbasal}×100%. A change of less than 10% in diameter of vessel wall was taken as endothelial dysfunction. Both FMD and TCD-BHI tests were carried out in the Neurosonology laboratory, Department of Neurology, PGIMER on the same day, in the same sitting.

    Outcomes

    The primary parameter evaluated was proportion of patients with cerebral and/or systemic endothelial dysfunction. Secondary parameters assessed were the association between systemic and cerebral endothelial dysfunction, endothelial dysfunction in subgroups of migraine with and without aura and baseline factors (age, gender, BMI, presence of aura, lateralisation of headache, headache frequency, time to last attack and impaired FMD) associated with cerebral endothelial dysfunction.

    Statistical analysis

    Statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc, Chicago, Illinois, USA, V.16.0 for Windows). Data was presented as mean or percentage as applicable with SEM as dispersion measure. For normally distributed data, means were compared using parametric tests (independent t test) and one-way analysis of variance for more than two groups. The proportions were compared using χ2 or Fisher's exact test whichever was applicable. ROC curve was used to identify BHI value threshold in the posterior circulation arteries. Linear regression was applied to look for correlation between BHI and FMD. Binary logistic regression analysis was performed to identify factors influencing BHI, testing a model comprising baseline patient and headache characteristics. All statistical tests were two-sided and were performed at a significance level of α=0.05

    Observations and results

    Forty-five patients with migraine and 44 healthy controls that satisfied the inclusion and exclusion criteria were enrolled following a fully informed consent (see online supplementary figure S1). Baseline characteristics were comparable between migraineurs and controls (table 1).

    View this table:
    Table 1

    Baseline characteristics of patients with migraine and controls

    Among patients with migraine (n=45), 33.3% had migraine with aura. Twenty per cent had predominantly left-sided headache, 24.4% had right-sided predominance while 55.6% had no particular lateralisation for their headaches. The mean frequency of attacks for all migraine patients was 8.47±1.09 attacks per month. The last attack of headache occurred 4.44±0.46 days prior to enrolment. No patient received triptan therapy in the preceding 48 h. A higher proportion of females were noted in the group migraine without aura compared to migraine with aura (p=0.04). No other difference was noted in headache characteristics between the two groups (see online supplementary table S1).

    TCD-BHI (cerebral endothelial function)

    There was no significant difference in the baseline mean velocities of bilateral MCA (right: 51.4±1.21 vs 51.7±1.03 (p=0.83), left: 51.9±1.19 vs 53.3±0.88 (p=0.39)) PCA (right: 36.8±0.89 vs 36.9±0.76 (p=0.90), left: 36.0±1.06 vs 36.1±0.68 (p=0.96)) and BA (44.6±1.02 vs 45.1±0.54, p=0.44) among patients and controls. Mean BHI values in migraine patients and controls are shown in table 2.

    View this table:
    Table 2

    Mean BHI in patients with migraine and controls

    There was no significant difference in mean BHI among patients and controls in bilateral MCA. However, migraine patients had significantly lower BHI in all the three posterior circulation arteries (bilateral PCA, BA) compared to controls (figure 1). For further analysis, ROC curve determined cut-offs were used to identify abnormal BHI in PCA (<1.15, AUC=0.862±0.04 (95% CI 0.787 to 0.937), sensitivity−77.8%, specificity−79.5%) and BA (<0.83, AUC=0.848±0.05 (95% CI 0.757 to 0.939) sensitivity−77.8%, specificity−90.9%). Proportion of patients with impaired BHI as per these cut-offs is shown in table 3.

    Figure 1
    Figure 1

    Boxplot diagram showing distribution of right and left posterior cerebral artery (PCA), basilar artery Breath Holding Index (BHI) values in patients and controls.

    View this table:
    Table 3

    Cerebral endothelial dysfunction (impaired BHI) in patients with migraine and controls

    No statistically significant difference was noted in baseline velocities, mean BHI or proportion of patients with impaired BHI in bilateral MCA, PCA and BA between patients with migraine with and without aura (table 4).

    View this table:
    Table 4

    Mean BHI values in patients with migraine with and without aura

    Brachial FMD (systemic endothelial function)

    Mean brachial FMD was 15.1±0.37% in controls and 16.5±0.43% in patients with migraine. There was no significant difference between the groups (p=0.97). One patient in the control group and two patients with migraine had impaired FMD (<10%). Of the two patients with migraine with impaired FMD, one had migraine with aura and the other migraine without aura. There was no significant difference in the distribution of systemic endothelial dysfunction among controls, migraine with aura and without aura (p=0.72).

    Correlation between cerebral and systemic endothelial function

    There was poor correlation between right PCA BHI (R=0.097, p=0.526), left PCA BHI (R=0.210, p=0.17), BA BHI (R=0.104, p=0.50) and FMD in patients with migraine (figure 2). Impaired BHI was not associated with any of the baseline, headache characteristics or FMD. The independent factors assessed were age, sex, presence of aura, presence of lateralised headache, frequency of headache, duration since last attack, BMI and brachial FMD. For right PCA (p=0.524) and left PCA (p=0.405) none of these factors were found to significantly contribute to the impaired BHI. For BA, the above predictors as a set reliably accounted for normal and impaired BHI (p=0.007). However, only BMI made a significant contribution to prediction (p=0.020). For each one unit (kg/m2) rise in BMI, the odds for having impaired basilar BHI was 2.1. All the other parameters including FMD were not significant predictors of cerebral endothelial dysfunction (see online supplementary table S2).

    Figure 2
    Figure 2

    Scatter plot showing correlation between right posterior cerebral artery (PCA), left PCA, basilar artery Breath Holding Index (BHI) and flow-mediated dilation (FMD) in patients with migraine.

    Discussion

    Our data shows that patients with migraine have impaired endothelial function restricted to the posterior cerebral circulation. Previous studies that assessed systemic endothelial function in migraineurs utilising brachial FMD failed to show significant impairment, similar to our findings.9 ,22 This is in concordance with the clinical scenario as well; stroke and myocardial infarction are two well-reported vascular events in migraineurs, while peripheral vascular occlusive disease which may coexist in atherosclerotic vascular disease is not linked to migraine. These studies suggest that in migraine, endothelial dysfunction may selectively affect the cerebral circulation.

    The vasodilatory response to CO2 is nitric oxide mediated via the endothelial Nitric Oxide Synthase pathway and cerebral VMR to CO2 can assess endothelial function.12 BH as a vasodilatory stimulus has been validated to be comparable to 95% carbon dioxide inhalation in clinical practice.19 We used the BHI, a widely used TCD-based parameter reflective of cerebral VMR, a marker of cerebral endothelial function.

    Previous studies that assessed cerebral VMR in migraine have yielded conflicting results. Initial studies found increased BHI in migraineurs compared to controls using carbogen inhalation and calculation of CO2 reactivity index.23 Methodological differences might account for the observed differences. Further studies showed impaired VMR in patients with migraine, especially in the posterior circulation. A study involving 30 patients with migraine found reduced mean BHI in the BA in patients with migraine with aura (0.83) compared to controls (1.39) and migraine without aura (1.42; p<0.001).13 In another study, cerebral VMR to l-arginine was significantly impaired in the PCAs of patients with migraine (without aura: 14.4, with aura: 14.3) compared to controls (21.3; p=0.002).24 These findings are quite similar to ours. Studies have also shown higher VMR on the predominant headache side compared to the other side, which was not observed in our patients.25

    Impaired cerebral endothelial function could be a contributory factor for the development of an ischaemic stroke. Corroboratory clinical evidence is available from studies that identified an over-representation of asymptomatic ischaemic lesions in the posterior circulation of patients with migraine, especially migraine with aura.26 Why impaired endothelial function is limited to the posterior circulation arteries is not clear. With the trigeminovascular system being implicated in pathogenesis of migraine, we would expect the anterior circulation arteries to be involved as well. A study on silent posterior circulation infarcts in migraine proposed a combination of hypoperfusion during migraine attack and artery to artery embolism to account for these lesions.26 In migraine with aura, cortical spreading depression is thought to alter blood–brain barrier permeability and result in local ischaemia which aggravates the post ictal hypoperfusion.24 Migraineurs do not have increased predisposition to atherosclerosis, which makes artery to artery embolism less likely.27 Our study suggests that, rather than atherosclerosis-related embolism, direct impairment of the endothelial function might be contributing to posterior circulation infarcts in patients with migraine.

    Two mechanisms could account for the endotheliopathy in migraine. Neurotransmitters like calcitonin gene-related peptide (CGRP) and neuropeptide Y are released locally during activation of the trigeminovascular system.28 These molecules have multiple downstream effects through their receptors, including effects on vascular smooth muscle and angiogenesis. Second, sterile neurogenic inflammation and protein extravasation that occur with trigeminovascular system activation may also contribute to endothelial dysfunction.29

    Age, sex, duration of migraine, frequency of attacks, presence of a predominant headache side and time since the last headache did not affect the impaired BHI in the posterior circulation. This suggests the presence of impaired endothelial function in migraineurs independent of the above factors, even in the absence of other risk factors for endothelial dysfunction. Increasing BMI as a predictor of impaired endothelial function was seen only in the BA. A posthoc analysis attempting to correlate systemic FMD and cerebral (cerebrovascular reactivity to l-arginine) endothelial function in migraineurs found no correlation between systemic and cerebral endothelial functions and concluded that these two may be independent in patients with migraine.30 We analysed the same in a prospective manner and no correlation was observed between systemic and cerebral endothelial function in the posterior circulation of patients with migraine.

    The strengths of our study are its prospective study design and being adequately powered to detect a difference in cerebral endothelial dysfunction between patients with migraine and controls. The exclusion of patients with most known risk factors for atherosclerosis/endothelial dysfunction ensured that the results would be likely attributable to migraine only. However, this study was not adequately powered to detect the difference between migraine with and without aura. A single non-blinded observer performed all the studies and lack of blinding could be a limitation. The absence of neuroimaging is another limitation, as evidence of ischaemic lesions would have corroborated with impaired endothelial function in migraineurs.

    Conclusions

    This preliminary study provides evidence that patients with migraine have isolated cerebral endothelial dysfunction restricted to the posterior circulation in the absence of systemic endothelial dysfunction. Further studies with larger sample sizes are required to identify differences between patients with migraine with and without aura. Studies that follow these patients longitudinally and correlate clinical and MRI features of ischaemia with cerebral endothelial function are required to corroborate this evidence clinically.

    Acknowledgments

    The authors wish to thank Ms. Kusum Chopra for help with statistical analysis.

    References

    1. ↵
      1. Merikangas K,
      2. Fenton B,
      3. Cheng S, et al
      . Association between migraine and stroke in a largescale epidemiological study of the United States. Arch Neurol 1997;54:362–8. doi:10.1001/archneur.1997.00550160012009
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Milhaud D,
      2. Bogousslavsky J,
      3. van Melle G, et al
      . Ischemic stroke and active migraine. Neurology 2001;57:1805–11. doi:10.1212/WNL.57.10.1805
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Etminan M,
      2. Takkouche B,
      3. Isorna F, et al
      . Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330:63–6. doi:10.1136/bmj.38302.504063.8F
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Kurth T,
      2. Diener H
      . Current views of the risk of stroke for migraine with and migraine without aura. Curr Pain Headache Rep 2006;10:214–20. doi:10.1007/s11916-006-0048-5
      OpenUrlCrossRefPubMed
    5. ↵
      1. Schwaiger J,
      2. Kiechl S,
      3. Stockner H, et al
      . Burden of atherosclerosis and risk of venous thromboembolism in patients with migraine. Neurology 2008;71:937–43. doi:10.1212/01.wnl.0000325918.48056.75
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Diener H,
      2. Kurth T,
      3. Dodick D
      . Patent foramen ovale, stroke and cardiovascular disease in migraine. Curr Opin Neurol 2007;20:310–27. doi:10.1097/WCO.0b013e328136c22d
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Marshall N,
      2. Maclaurin W,
      3. Koulouris G
      . MRA captures vasospasm in fatal migrainous infarction. Headache 2007;47:280–3. doi:10.1111/j.1526-4610.2007.00695.x
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Rajan R,
      2. Ahluwalia J,
      3. Lal V
      . Prothrombotic states in migraine. Clin Appl Thromb Hemost 2014;20:851–6. doi:10.1177/1076029613486538
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Perko D,
      2. Pretnar-Oblak J,
      3. Šabovič M, et al
      . Endothelium-dependent vasodilation in migraine patients. Cephalalgia 2011;31:654–60. doi:10.1177/0333102410390396
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Vernieri F,
      2. Moro L,
      3. Altamura C, et al
      . Patients with migraine with aura have increased flow mediated dilation. BMC Neurology 2010;10:18–24. doi:10.1186/1471-2377-10-18
      OpenUrlCrossRefPubMed
    11. ↵
      1. Tietjen GE
      . Migraine as a systemic vasculopathy. Cephalalgia 2009;29:989–96. doi:10.1111/j.1468-2982.2009.01937.x.Review
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Lavi S,
      2. Gaitini D,
      3. Milloul V, et al
      . Impaired cerebral CO2 vasoreactivity: association with endothelial dysfunction. Am J Physiol Heart Circ Physiol 2006;291:H1856–81. doi:10.1152/ajpheart.00014.2006
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Silvestrini M,
      2. Baruffaldi R,
      3. Bartolini M, et al
      . Basilar and middle cerebral artery reactivity in patients with migraine. Headache 2004;44:29–34. doi:10.1111/j.1526-4610.2004.04006.x
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(Suppl 1):9–160.
      OpenUrlFREE Full Text
    15. ↵
      1. Rodriguez-Flores M,
      2. Garcia-Garcia E,
      3. Cano-Nigenda CV, et al
      . Relationship of obesity and insulin resistance with the cerebrovascular reactivity: a case control study. Cardiovasc Diabetol 2014;13:2. doi:10.1186/1475-2840-13-2
      OpenUrlCrossRefPubMed
    16. ↵
      1. Settakis G,
      2. Pall D,
      3. Molnar C, et al
      . Cerebrovascular reactivity in hypertensive and healthy adolescents: TCD with vasodilatory challenge. J Neuroimaging 2003;13:106–12. doi:10.1111/j.1552-6569.2003.tb00166.x
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Vuletic V,
      2. Cengic L,
      3. Basic S, et al
      . Impaired cerebral vasoreactivity in type 2 diabetes mellitus. Coll Antropol 2011;35:27–31.
      OpenUrlPubMed
    18. ↵
      1. Ringelstein E,
      2. Kahlscheuer B,
      3. Niggemeyer E, et al
      . Transcranial Doppler sonography: anatomical landmarks and normal velocity values. Ultrasound Med Biol 1990;16:745–61. doi:10.1016/0301-5629(90)90039-F
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Markus HS,
      2. Harrison MJ
      . Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke 1992;23:668–73. doi:10.1161/01.STR.23.5.668
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Silvestrini M,
      2. Vernieri F,
      3. Pasqualetti P, et al
      . Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA 2000;283:2122–7. doi:10.1001/jama.283.16.2122
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Celermajer D,
      2. Sorenson K,
      3. Gooch V, et al
      . Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–15. doi:10.1016/0140-6736(92)93147-F
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Tietjen GE,
      2. Herial NA,
      3. White L, et al
      . Migraine and biomarkers of endothelial activation in young women. Stroke 2009;40:2977–82. doi:10.1161/STROKEAHA.109.547901
      OpenUrlAbstract/FREE Full Text
    23. ↵
      1. Kastrup A,
      2. Thomas C,
      3. Hartmann C, et al
      . Cerebral blood flow and CO2 reactivity in interictal migraineurs. Headache 1998;38:608–13. doi:10.1046/j.1526-4610.1998.3808608.x
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Perko D,
      2. Pretnar-Oblak J,
      3. Šabovič M, et al
      . Cerebrovascular reactivity to l-arginine in the anterior and posterior circulations in migraine patients. Acta Neurol Scand 2011;124:269–74. doi:10.1111/j.1600-0404.2010.01468.x
      OpenUrlCrossRefPubMedWeb of Science
    25. ↵
      1. Vernieri F,
      2. Tibuzzi F,
      3. Pasqualetti P, et al
      . Increased cerebral vasomotor reactivity in migraine with aura: an autoregulation disorder? A transcranial Doppler and Near-infrared spectroscopy study. Cephalalgia 2008;28:689–95. doi:10.1111/j.1468-2982.2008.01579.x
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Kruit M,
      2. Launer L,
      3. Ferrari M, et al
      . Infarcts in the posterior circulation territory in migraine. The population based MRI CAMERA study. Brain 2005;128(Pt 9):2068–77. doi:10.1093/brain/awh542
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Stam A,
      2. Weller C,
      3. Janssens AJ, et al
      . Migraine is not associated with enhanced atherosclerosis. Cephalalgia 2013;33:4228–35. doi:10.1177/0333102412466966
      OpenUrl
    28. ↵
      1. Goadsby PJ,
      2. Edvinsson L,
      3. Ekman R
      . Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183–7. doi:10.1002/ana.410280213
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Curter F,
      2. Limmroth V,
      3. Woeber C, et al
      . New targets for antimigraine drug development. In: Goadsby P, Silberstein S. eds. Headache: bluebooks of practical neurology. Philadelphia, PA: Butterworth-Heinemann, 1997:59–120.
    30. ↵
      1. Perko D,
      2. Pretnar-Oblak J,
      3. Šabovič M, et al
      . Associations between cerebral and systemic endothelial function in migraine patients: a post-hoc study. BMC Neurol 2011;11:146–51. doi:10.1186/1471-2377-11-146
      OpenUrlCrossRefPubMed

    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors RR was involved in concept of study, data collection, review of literature and writing of manuscript. DK was involved in concept of study, review of data and review of manuscript. VL was responsible for critical review of manuscript and study design.

    • Competing interests None.

    • Ethics approval Institutional Ethics Committee, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

    • Provenance and peer review Not commissioned; externally peer reviewed.