The Migraine-Stroke-Endothelium Controversy

The link between migraine, vascular diseases, and endothelial function remains a subject of controversy. It is known that having migraine with aura increases the risk of ischemic stroke, and some researchers view endothelial dysfunction as a phenomenon responsible for that. If that is so, can we identify young migraineurs at risk of having a stroke by assessing their endothelial function? In a recent systematic review, Jawad Butt and colleagues explore the association of endothelial dysfunction and migraine with aura and try to answer this and other pressing questions.¹

Authors analyzed 27 studies of endothelial function in patients with migraine. They cautiously concluded that migraine with aura is not associated with endothelial dysfunction, but also pointed out that existing literature is insufficient to winnow out a clear association or the lack thereof. The absence of clarity in the association of migraine and endothelial function may stem from great heterogeneity in methods of endothelial function measurement, exclusion criteria, and study results. Addressing these methodological discrepancies will not only help clarify the connection of migraine and cardiovascular disease, but could also help identify subpopulations of migraineurs at the greatest risk.

To date, a great variety of methods has been employed to measure endothelial function, but a consensus on the most appropriate technique is lacking. Measurement of plasma level of nitric oxide (NO), an endothelium-derived vasodilator, is a common approach. Other methods measure the number of circulating endothelial progenitor cells, flow-mediated dilation, or arterial stiffness, to name a few. Some studies assess inflammation, coagulation, and oxidative stress markers of endothelial state. These markers are important because they may reflect early changes in endothelial state, which precede changes in endothelial function. The use of similar techniques to assess micro- and macrovascular endothelial function will help reduce the discrepancy in study results in the future.

Exclusion criteria also vary broadly across studies. Some of the analyzed studies did not apply exclusion criteria at all, while others excluded persons with concomitant cardiovascular disease. If endothelial dysfunction is a universal phenomenon implicated in multiple conditions, excluding persons with other cardiovascular comorbidities may create bias.

Smoking and use of oral contraceptives in study participants deserve special consideration. Endothelium responds to cigarette smoke with changes in levels of NO and reactive oxygen species, which reflect in its functional state. The use of oral contraceptives affects endothelial function and increases the risk of stroke.² Hence, the risk of stroke and endothelial function in females with migraine who use oral contraceptives warrants investigation. Even stress stemming from adverse early life experience has been associated with migraine and endothelial biomarkers of inflammation.³ Although it is virtually impossible to precisely control such a multitude of influences, it is important to assess the risk of stroke in these various groups of migraineurs and link it to endothelial function.

Understanding endothelial function and its role in the risk of stroke will help develop screening strategies and preventative therapies for at-risk individuals. A valid and widely accessible method of cerebral endothelial function assessment is not yet available. Authors mention peripheral plethysmography by EndoPAT, a new method of endothelial function assessment, as a technology that might fill this gap.

In conclusion, the authors emphasized that large-scale multicenter studies applying uniform exclusion criteria and using similar techniques will help “fully clarify whether screening for endothelial dysfunction may help identify migraine subjects at risk of an early stroke.”

References:

1. Butt JH, et al. Endothelial function in migraine with aura - a systematic review. Headache. 2015;55:35-54.

2. MacGregor EA. Contraception and headache. Headache. 2013;53(2):247-276.

3. Tietjen GE, et al. Adverse childhood experiences are associated with migraine and vascular biomarkers. Headache. 2012;52(6):920-929.