Right-to-left shunts and hormonal therapy influence cerebral vasomotor reactivity in patients with migraine with aura.

Federica Assenza,Nicoletta Brunelli,Angelo Cascio Rizzo,Simona Sacco,Fabrizio Vernieri,Claudia Altamura,Mauro Silvestrini,Matteo Paolucci,Gianluca Cecchi

doi:10.1371/journal.pone.0220637

Federica Assenza, Nicoletta Brunelli + Show 7 more

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https://doi.org/10.1371/journal.pone.0220637

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Abstract

Patent Foramen Ovale and impaired cerebral hemodynamics were proposed among the pathophysiological mechanisms explaining the increased risk for stroke in patients with Migraine with Aura (MA). Our study aimed at comparing the vasomotor reactivity (VMR) of the anterior and the posterior cerebral circulation in patients with Migraine with Aura, in patients with acute vascular ischemic accidents, and in controls. We hypothesized that VMR in MA patients is preserved in the anterior circulation and reduced in the posterior circulation. We prospectively assessed with Transcranial Doppler the vasomotor reactivity to breath holding of the Middle and Posterior Cerebral Arteries (MCA, PCA) in MA patients, in acute vascular patients and healthy controls. We also evaluated the possible effect of clinical characteristics of MA (attack frequency, aura length or type, disease history), vascular factors and the presence of right-to-left shunt on VMR. Diverging from our hypothesis, MA patients displayed a higher breath-holding index (BHI) than controls in the MCA (1.84±0.47%/s vs 1.53±0.47%/s, p = .001) as well as in the PCA (1.87±0.65%/s vs 1.47±0.44%/s, p < .001). In MA patients, MCA BHI was higher in those with large right-to-left shunts (2.09±0.42 vs 1.79±0.47, p = .046) and lower in those taking estrogens (1.30±0.30%/s vs 1.9±0.45%/s, p = .009). We did not observe an effect of MA characteristics on BHI. The increased BHI in MA patients with large right-to-left shunts could be explained by the vasoactive effect in the cerebral circulation of substances bypassing the deactivating pulmonary filters or by a constitutional trait of the vascular system associating persistent right-to-left shunts and hyper-reactive hemodynamics. Our results discourage the hypothesis that altered hemodynamics contribute to increasing the stroke risk in all MA patients. However, estrogens can lower VMR, curtailing the hemodynamic resources of MA patients.

Highlights

Migraine and Migraine with Aura (MA) is associated with an increased risk of ischemic stroke, [1] that increases exponentially in smokers and in patients taking oral contraceptives.[2]
We investigated whether right-to-left shunts (RLS) and other clinical factors are associated with an impairment of vasomotor reactivity (VMR) in MA patients
To define RLS of presumed cardiac origin we considered only hyperintense transient signals (HITS) observed within 30 seconds from microbubbles injections, as delayed HITS are suggestive of arterio-venous lung shunts

Summary

Introduction

Migraine and Migraine with Aura (MA) is associated with an increased risk of ischemic stroke, [1] that increases exponentially in smokers and in patients taking oral contraceptives.[2] Among other mechanisms, high prevalence of patent foramen ovale (PFO) and of genetic thrombophilic mutations and impairment of cerebral hemodynamics have been proposed to subtend this pathological link.[3]. Studies addressing cerebral hemodynamics in MA patients produced contradictory results:[5,6] some reported that VMR is preserved or even increased in the anterior circulation [7,8,9] while that is less efficient posteriorly.[10,11,12] Consistently, migraine patients may display an increased subclinical vascular burden at magnetic resonance imaging mainly in the posterior territory.[13] recent reports refuted this finding, in patients with right-to-left shunts (RLS)[14] or with migraine with aura [15]. PFO is the most frequent locus of right-to-left shunt of cardiac origin, is present in around 25–30% of the adult population and is usually clinically silent.[16]

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