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(Chest. 2006;130:896-901.)
© 2006 American College of Chest Physicians

The Relationship Between Migraine and Right-to-Left Shunt*

Fact or Fiction?

Martijn C. Post, MD, PhD and Werner Budts, MD, PhD

* From the Department of Cardiology (Dr. Post), St Antonius Hospital, Nieuwegein, the Netherlands; and Department of Cardiology (Dr. Budts), Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium.

Correspondence to: Martijn C. Post, MD, PhD, Department of Cardiology, St Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands; e-mail: m.post{at}antonius.net

Abstract

The prevalence of a right-to-left shunt, both cardiac and pulmonary, is high in patients with migraines, especially migraine with aura. Percutaneous closure of a right-to-left shunt seems to be associated with a pronounced decrease in the number of migraine attacks or its prevalence. In this review, the relationship between migraine and right-to-left shunting is described by highlighting the different pathophysiologic hypotheses.

Key Words: arteriovenous malformation • atrial septal defect • migraine • patent foramen ovale • shunt

Migraine is a very common type of headache, affects the quality of life importantly, and has been ranked among the most disabling medical illnesses in the world.1 Migraine seems to be a complex disorder in which genetic, environmental, behavioral, and other as-yet unidentified factors interact to trigger the typical migraine attacks.2 A causal relationship between migraine and a right-to-left shunt has been proposed, particularly in patients with migraine with aura.34 However, the underlying pathophysiologic mechanism of this relationship is not well understood and remains hypothetical. In this review, we describe the relationship between both cardiac and pulmonary right-to-left shunts and the occurrence of migraine, and highlight observations that might support some pathophysiologic hypotheses of migraine.

Migraine

Migraine is a common, chronic, incapacitating, neurovascular disorder that is characterized by severe headache and autonomic nervous system changes. The diagnosis is based on headache characteristics and associated symptoms specified by the International Headache Society.5 The typical headache is unilateral, throbbing, and may be severe. If untreated, the migraine attacks typically last 4 to 72 h. The attacks are usually associated with nausea, vomiting, or sensitivity to sound, light, or movement. In addition to this, migraine with aura is characterized by transient focal neurologic symptoms, which are usually visual, and that precede, accompany, or follow the headache attack.15 The aura is thought to be produced by cortical-spreading depression,6 which causes a release of a variety of neurochemicals.7 Coupled with these chemicals are cerebral blood flow changes that manifest as initial hyperemia followed by spreading oligemia.8 The initial cortical-spreading depressions may be triggered by microemboli.

Migraine occurs in 10 to 12% of the general population, with 6% in men and 15 to 18% in women.910 The prevalence of migraine increases with age until a peak prevalence of approximately 27% in women and 8% in men is reached in the fourth decade of life. Thereafter, it decreases with increasing age.9

Right-to-Left Shunt

Patent Foramen Ovale
The most common origin of a right-to-left shunt is the patent foramen ovale (PFO). The PFO is an important feature of fetal circulation. The interatrial septum primum on the left side and the interatrial septum secundum on the right side maintain a central communication before birth, so that blood bypasses the pulmonary circulation. After birth, the pressure in the right atrium drops below the left atrial pressure, and this results into a functional closure. The latter may lead to fusion of the septum primum and secundum (anatomic closure). However, in 25% of the overall population, this fusion does not take place and the communication remains what is called probe patent, as it can open as a (one-way) valve when the right atrial pressure exceeds the left atrial pressure.11 This right-to-left shunt may be associated with paradoxical embolization of thrombi and has been postulated as a mechanism for cryptogenic stroke in young adults.12

Pulmonary Arteriovenous Malformation
A less frequent cause of a right-to-left shunt includes pulmonary arteriovenous malformations (PAVMs). Approximately 70% of patients with PAVMs have hereditary hemorrhagic teleangiectasia (HHT), and from 15 to 33% of the patients with HHT have detectable PAVM.13 HHT is a systemic, autosomal, dominant familial disorder of angiogenesis resulting in multiple mucocutaneous teleangiectases and arteriovenous malformations in the brain, liver, and lungs.14 The prevalence rate of HHT exceeds 1 in 10,000 in specific regions in Denmark and France, and is 1 in 1,300 in the Netherlands Antilles.1516 PAVM may cause hypoxemia and dyspnea due to right-to-left shunting. In addition, severe complications may occur, such as massive hemoptysis or hemothorax, and especially neurologic complications including transient ischemic attack, cerebral stroke, and cerebral abscess. All this is explained by the shunt that facilitates the passage of (septic) emboli into the systemic and the cerebral circulation.17

Atrial Septal Defect
An atrial septal defect (ASD) accounts for approximately one third of all congenital heart defects found in adults.18 The ASD is mainly characterized by a left-to-right shunt and volume overload of the right heart.19 However, a small right-to-left shunt may occur during a Valsalva maneuver or exercise. A large defect in adult patients results in symptoms and complications such as arrhythmias, right heart failure, pulmonary arterial hypertension, and paradoxical embolism, the latter due to a right-to-left shunt.1820

Occurrence of Right-to-Left Shunt and Migraine

In patients with migraine, the prevalence of a right-to-left shunt seems to be higher when compared to the general population. Two investigational groups321 used transcranial Doppler ultrasound to determine right-to-left shunts in patients with migraine. A right-to-left shunt was found in 23% of the patients with migraine without aura.21 Forty-one to 48% of the patients with migraine with aura had a detectable right-to-left shunt. However, in only 16 to 20% of the control group could a detectable shunt be found.321 Similar findings were reported by Schwerzmann et al22 using transoesophageal echocardiography, who found that only PFOs with large shunts were found more often in patients with migraine with aura compared to control subjects.22 These observations suggest that migraine, particularly migraine with aura, may be associated with right-to-left shunting, especially in larger shunts.

Moreover, in patients with a right-to-left shunt, the prevalence of migraine seems to be higher when compared to those without a shunt. This finding is first reported by Wilmshurst and Nightengale,23 who found that in patients with decompression illness and a large right-to-left shunt, the prevalence of migraine with aura was 48%, compared to 14% in those without a shunt. Later, similar findings were reported by Sztajzel et al,4 who observed a prevalence of migraine with aura of 36% in patients with a PFO, compared to 13% in those without. In addition, we and others242526 have reported a prevalence of migraine without aura between 11% and 21% and a prevalence of migraine with aura between 17% and 24% in patients with a PFO.

Two small retrospective studies2728 found a high prevalence of migraine of 43 to 59% in patients with large PAVMs. These observations were confirmed by a recent study29 that focused on HHT patients; the prevalence of migraine was significantly higher in those patients with a PAVM compared to those without a pulmonary right-to-left shunt: 21% vs 13%, respectively.

Finally, the prevalence of migraine with and without aura seems to be increased in patients with a significant ASD when compared to the overall prevalence. In patients with a symptomatic ASD, the prevalence of migraine varies from 13 to 19% for migraine without aura, and 11 to 17% for migraine with aura.3031

We have to realize, however, that all these percentages are probably influenced by a selection bias due to the patient selection criteria. The selection bias is more pronounced in retrospective trials compared to prospective studies. Nevertheless, almost all available reports in the literature suggest a significant higher prevalence of PFO in migraine.

Shunt Closure and Migraine

PFO
We and others242526313233 have described the changes in prevalence of migraine after percutaneous PFO closure. These data are summarized in Table 1 . All studies, except for the study by Schwerzmann et al,25 showed a significant reduction in the prevalence of migraine and migraine with aura after percutaneous PFO closure. The relative reduction in prevalence of migraine varied from 29 to 59%. For migraine with aura, the relative reduction in prevalence was even more pronounced and varied from 33 to 74%.


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  		Table 1.. The Prevalence of Migraine and Migraine With Aura Before and After Percutaneous PFO Closure*

 
Although Schwerzmann et al25 could not identify a significant decrease in prevalence of migraine, they found a reduction in the frequency of migraine attacks by 62% in patients with migraine without aura and 54% in those with migraine with aura. The major criticism of these studies was their retrospective and nonrandomized design. However, recently, Anzola et al34 reported a case-control study that showed a significant overall improvement of migraine after percutaneous PFO closure in comparison to medical treatment during a 1-year follow-up. This seems to be independent of migraine subtype and of previous cerebrovascular disease.34

PAVM
A recent study35 determined the effect of percutaneous closure by embolization of PAVM in patients with HHT on the occurrence of migraine. During a median follow-up time of 48 months, the overall prevalence of migraine decreased from 45% before to 35% after embolization. For migraine with aura, the prevalence decreased from 33% before to 19% after embolization of PAVM.

ASD
We and others have described the effect of percutaneous ASD closure on the prevalence of migraine. These data are summarized in Table 2 . We were the first to determine the effect of shunt closure in a larger cohort of patients with secundum-type ASD. All ASDs were closed by an Amplatzer ASD occluder (AGA Medical Corporation; Golden Valley, MN). We found no difference in the overall prevalence of migraine and migraine with aura before and after percutaneous ASD closure. However, the frequency of migraine attacks in patients with preexisting migraine decreased significantly.30 These findings were supported by Azarbal et al,31 who found a significant reduction in the frequency of migraine attacks in a cohort of patients after percutaneous closure of their ASD or PFO. In contrast, Yankovsky and Kuritzky36 reported aggravation of migraine with aura into a daily pattern after closure of an ASD in a single patient. The latter was also suggested by Mortelmans et al,30 who found an aggravation of migraine with aura after percutaneous ASD closure with relatively larger Amplatzer ASD devices. However, the reason for this observation remains unexplained. It is hypothesized that an increased nickel release from the closing device might induce cortical-spreading depressions.37 These depressions have been suggested to be associated with migraine with aura.38 However, Mortelmans et al30 suggested that microthrombi formed on the left-sided disk during the endothelization process could embolize and provoke migraine attacks. Indeed, even macrothrombi seem not to be so uncommon after device closure.39


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  		Table 2.. The Prevalence of Migraine and Migraine With Aura Before and After Percutaneous ASD Closure*

 
Migraine Criteria
In almost all reports that describe the relationship between shunt closure and migraine, the diagnosis of migraine and migraine with aura was based on the International Headache Criteria,5 except for the report by Azarbal et al.31 In their study,31 the presence or absence of migraine was self-reported by patients on the basis of a diagnosis made by either their primary care physician or their neurologist. However, in this study31 the validated Migraine Disability Assessment Questionnaire was used to assess migraine severity.

Antiplatelet Medication and Migraine Relief
The use of antiplatelet or anticoagulant medication after the percutaneous device closure might have a substantial effect on the decrease in prevalence of migraine. Indeed, aspirin, at dose of 1,000 mg/d, has been assessed as a possible treatment for migraine.40 However, the use of low-dose aspirin (ie, 100 mg/d) seemed not be related with a reduction in migraine attacks.41 In the PFO closure studies,242526313233 low-dose aspirin, 100 mg to 325 mg/d, was administered.

Secondly, aspirin was taken for a maximum of 6 months, and clopidogrel was taken for 3 months. Three studies263242 had had a follow-up period of 6 months and showed a persistent significant reduction in the prevalence of migraine, even after the antiplatelet medication had been stopped.

Thirdly, patients who underwent a percutaneous ASD closure also received low-dose aspirin and clopidogrel. In these patients, the prevalence of migraine did not decrease significantly after the percutaneous closure.30

Fourthly, we recently reported a significant reduction in the prevalence of migraine after embolization of PAVM. In these patients, no antiplatelet or anticoagulation medication had been used prior or after the embolization.35

These findings suggests that the decrease in prevalence of migraine could not be explained by the use of low-dose aspirin or clopidogrel. However, we have to realize that the placebo effect in migraine therapy is potent, but the decrease in the prevalence of migraine in the shunt closure studies is larger than the reported placebo effect rates of 20 to 40%.43

Pathophysiologic Hypothesis

Different pathophysiologic hypotheses have been proposed to explain these findings. Firstly, trigger substances might enter the systemic circulation through the right-to-left shunt instead of being trapped in the pulmonary capillaries. These trigger substances could induce cerebral vascular instability or increased excitability of the CNS and provoke migraine attacks. In individuals without a right-to-left shunt or after percutaneous closure, a larger amount of trigger substances is needed to induce migraine by overwhelming the filter capacity of the lungs. These trigger substances are proposed to be vasoactive chemicals such as serotonin or (micro) emboli.21 The latter might also explain the increased risk of ischemic stroke or transient ischemic attack in patients with migraine with aura.44 This increased risk might be explained by the elevated levels of platelet activation and platelet/leukocyte interaction in patients with migraine. The same interactions have been reported in the pathophysiology of ischemic stroke.45 Moreover, it has been shown that the incidence of subclinical brain infarction diagnosed with magnetic imaging is higher in patients with migraine with aura when compared to control subjects.46 As mentioned, the effect of shunt closure on the occurrence of migraine seemed to be more pronounced in patients who had migraine with aura. In support of this hypothesis, aura is accompanied by hypoperfusion of the occipital cortex, and emboli seem to have a predilection to embolize in this brain area.47 Consistent with this hypothesis is the finding that anticoagulant and high-dose antiplatelet therapy seems to decrease the incidence of migraine.4048

Secondly, a particular genetic substrate might determine both atrial septal abnormalities and migraine. Wilmshurst et al49 found that the occurrence of atrial shunts was consistent with autosomal dominant inheritance in 20 probands with 71 relatives and that this was linked to the inheritance of migraine with aura in some families.

Thirdly, some authors36 suggested that atrial natriuretic peptide (ANP) might play a role in the pathogenesis of migraine in patients with an atrial shunt by intra-atrial pressure imbalances. In support, transient changes in ANP levels after percutaneous ASD closure have been reported.50 However, no clear relationship is documented between ANP levels and migraine.

Conclusion

There is more and more evidence of a strong association between the presence of a right-to-left shunt, both cardiac and pulmonary, and the occurrence of migraine. It is hypothesized that vasoactive substances or microemboli of the venous circulation enter the systemic circulation by a right-to-left shunt and, finally, might provoke a migraine attack. This hypothesis is enforced by the fact that the presence of a right-to-left shunt, rather than the localization, seems to play a role in the pathogenesis of migraine. In addition, shunt closure is related to a decrease in prevalence of migraine, especially in migraine with aura. However, most of the available studies have several limitations. All were nonrandomized with a relatively small number of patients with migraine. Most of the reports were retrospective and none of the interventional studies were placebo controlled. Before percutaneous shunt closure will become a new treatment in patients with migraine, especially migraine with aura, large prospective randomized trials will be necessary.

Footnotes

Abbreviations: ANP = atrial natriuretic peptide; ASD = atrial septal defect; HHT = hereditary hemorrhagic teleangiectasia; PAVM = pulmonary arteriovenous malformation; PFO = patent foramen ovale

No financial or other conflicts of interest exits for both authors.

Received for publication December 11, 2005. Accepted for publication February 21, 2006.

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