Migraine is a primary headache disorder that causes significant suffering in approximately 13 percent of the population of the United States. It accounts for an estimated $23 billion in annual cost to the economy through health-care expenses and lost productivity.
Two major features of migraine are migraine aura (MA) and headache. MA occurs in nearly one-third of migraine patients and consists of one or more focal neurological symptoms that develop gradually over 5-20 minutes and persist for less than 60 minutes. MA typically precedes development of migraine headache.
Several years ago single-center retrospective analyses first reported an apparent association between partial or complete relief of migraine symptoms and transcatheter closure of patent foramen ovale (PFO) for secondary stroke prevention (Reisman M, et al., 2005). The foramen ovale normally serves as a one-way valve in the interatrial septum for physiologic right-to-left shunt in utero. Complete fusion of interatrial septae normally occurs by two years of age. When septae fail to fuse, however, the PFO is a potential tunnel that can be opened by reversal of the interatrial pressure gradient. PFO is the most common form of right-to-left circulatory shunt (RLS).
Studies have shown that as many as 50 percent of individuals with MA will have a PFO, whereas PFO is present in about 25 percent of the general population and in migraineurs without aura (MO). In analyses performed by Swedish researchers, MA patients had a larger RLS than patients with MO, despite similar interatrial anatomy (Jesurum JT, et al., 2007), and were about 4.5 times more likely to have greater than 50 percent reduction in migraine frequency following PFO closure (Jesurum JT, et al., 2008). These observations indicated a potential pathophysiological relationship between migraine and PFO.
The mechanism for this potential relationship is not understood, but investigators have focused on possible interatrial transit of vasoactive chemicals that bypass the pulmonary capillary bed, or on microemboli from the venous circulation which might trigger cortical spreading depression and transient regional hypoperfusion. Migraineurs may have higher platelet reactivity (Jesurum JT et al., 2010) or pro-coagulant state (e.g., protein C or S deficiency) than non-migraineurs, possibly resulting in greater load of microemboli in the arterial circulation. The brains of migraineurs may be more sensitive to circulatory changes than are the brains of those without migraine. The combination of potential triggers and susceptible neuronal substrate may result in an enhanced risk of MA among patients with PFO.
The Migraine Intervention with STARFlex Technology (MIST) trial was a randomized trial of PFO closure in migraine (Dowson A et al.). The failure of the trial to meet its primary endpoint (cessation of headache) and secondary endpoint (>50-percent reduction in headache frequency and days) was surprising. Eligibility criteria for the trial may have excluded those patients who were most likely to benefit from PFO closure. For instance, patients were excluded from MIST if they had a history of stroke or hypercoagulability, and subjects had to fit within a narrow range of headache frequency. If patients with a greater migraine burden or hypercoagulability were more likely to achieve meaningful reductions in headache frequency and severity, these exclusion criteria could have altered the study outcome.
Other trials are in progress or in the pipeline that may better elucidate the effect of PFO closure on migraine. The migraine-PFO association offers opportunities for collaboration between scientists and clinicians in both neurology and cardiology. The long-term goals of collaborative trials are improved quality of life and reduced cerebrovascular sequelae for individuals who suffer from migraine.