Correlation or Causation: Untangling the Relationship Between Patent Foramen Ovale and Migraine

Eric Adler, MD, Barry Love, MD, Steve Giovannone, BS, Frank Volpicelli, BA, and Martin E. Goldman, MD

Corresponding author

Martin E. Goldman, MD

The Mount Sinai School of Medicine, 1 Gustave L. Levy Place,

Box 1030, New York, NY 10029, USA.

E-mail: Martin.Goldman@msnyuhealth.org

Current Cardiology Reports 2007, 9:7–12Current Medicine Group LLC ISSN 1523-3782

Copyright © 2007 by Current Medicine Group LLC

Observational evidence from the literature has shown

an association between migraine headaches and pat-

ent foramen ovale (PFO). This observation has led to

hypotheses that could explain the etiology of migraines

in those with a PFO, including right-to-left shunting

of venous agents such as serotonin that are normally

broken down in the pulmonary circulation. Further

evidence suggests that closure of a PFO may improve

migraine symptoms and serve as an effective treatment

modality for migraines. Several randomized controlled

double-blinded studies are underway that will more

definitively establish the role of specific devices in PFO

closure in those suffering from migraines.

IntroductionPhysicians have known of the patent foramen ovale (PFO) and its association with stroke for hundreds of years. Recently, physicians closing PFOs in patients who suffered cryptogenic strokes noticed an interesting trend. Patients who had their PFO closed volunteered that they had signifi-cant improvement in the incidence and severity of migraine headaches. This anecdotal evidence led to the generation of a novel hypothesis: that a PFO may contribute to the patho-genesis of migraine headaches. Given the prevalence of PFO and migraine, as well as the relative ease with which PFOs can be closed, the association has received a lot of attention from patients, physicians, and industry.

In this article, we summarize the anatomy and physiol-ogy of the PFO and discuss techniques for PFO diagnosis. We review the epidemiology of migraine and the asso-ciation between migraine and PFO. We conclude with a

review of the most recent literature evaluating the effec-tiveness of PFO closure, including ongoing clinical trials.

Atrial EmbryologyThe septum secundum is essentially a flap of tissue that grows on the right side of the heart, covering the ostium secundum. In the majority of people this flap will eventu-ally seal shortly after birth, resulting in separation of the left and right atria. In a minority of people this flap fails to seal completely, resulting in a PFO. The length of the PFO flap varies from 1 mm to 10 mm on autopsy stud-ies, with an average length of 5 mm. Their surface area is generally from 2 to 15 mm, with an average of roughly 4.5 mm. Right atrial openings of the PFO usually occur at the junction of the limbus of fossa ovalis and left atrium openings anteriorly, underneath the membranous fold [1].

In patients with PFOs, the valvula foraminis ovalis is on the left side, and most commonly extends past the foramen ovale. As a consequence of this, a functional one-way valve exists, allowing shunting from right to left but generally not left to right. Shunting only occurs when right-sided atrial pressures exceed left sided atrial pressures. This occurs normally during early ventricular systole and inspiration as well as transiently during a Valsalva maneuver [2]. In one series of 148 patients with a PFO evaluated by transesopha-geal echocardiography (TEE), 84 (57%) had right-to-left shunting at rest, and 136 (92%) had right-to-left shunting with straining or coughing [3].

Epidemiology of PFOEstimations of the incidence of PFO vary from 15% to 40% [4–8]. A French autopsy study evaluated 500 consecutive patients who died of cardiovascular disease for the pres-ence of PFO; 14.6% of patients were found to have PFO [1]. Another recent autopsy study of 965 normal hearts found that the incidence of PFO declined with age: 34% of people between the ages of 0 and 30 years had PFO, versus 25% of people 30 to 80 years of age, and 20% of patients

8 Stroke

between 80 and 90 years [9]. Investigators participating in the SPARC study used TEE to assess the prevalence of PFO in a randomly selected cohort of patients in Olmstead County, Minnesota; 581 patients had TEE performed, of whom 25.6% were found to have PFO [3].

Diagnosis of PFOPhysical examination findings are absent in the great majority of patients with PFO. The rare exception occurs in the patient with a completely incompetent large PFO that allows left-to-right shunting. In this situation physi-cal examination findings will be essentially the same as those of an atrial septal defect (ASD), including a fixed splitting of the second heart sound, and a systolic ejection murmur over the pulmonic area.

However, because physical examination findings will be absent in the great majority of patients with PFO, imaging modalities are required for diagnosis. Echocar-diography is currently the most commonly used method for detection of PFO. Three different approaches are used: transthoracic, transesophageal, and intracardiac. Trans-thoracic echocardiography (TTE) has several advantages over other imaging modalities: it is noninvasive, widely available, relatively inexpensive, and can provide both anatomic and physiologic information simultaneously. Shunt detection with TTE is commonly performed by injection of agitated saline peripherally. A shunt is likely to be present if bubbles are detected within three cardiac cycles of visualization of opacification of the right atrium [10]. Sensitivity varies greatly in different studies, and is estimated to be anywhere from 40% to 80%. Shunts can also be detected using color Doppler imaging, though the sensitivity is generally felt to be lower. TEE, first employed in the 1970s, is currently felt by many to be the gold stan-dard for detection of intracardiac shunt (Fig. 1) [11–13].

Shunt detection is performed in the same fashion as it is performed transthoracically. Resolution is improved due to the closer proximity of the probe to the heart as well as the use of higher-frequency imaging probes. TEE is also commonly used to assist with the accurate placement of occluder devices during transcatheter PFO and ASD closure. The most common complications of TEE occur because of anesthesia or airway management. Intracardiac echocardiography (ICE) is performed by using a trans-catheter approach to place an echocardiography probe in the right atrium. It is principally used to assist with placement of occluder devices during PFO closure. Unlike TEE, ICE does not require conscious sedation and is not associated with airway management complications. ICE is currently limited by the high cost of single-use ultrasound catheters [14,15].

In addition to echocardiography, transcranial Dop-pler (TCD) can detect PFO by visualization of shunting from the venous circulation into the cerebral arterial cir-culation. While a probe is placed against the skull over the middle cerebral artery, contrast (either with agitated saline or specific contrast agents) is given and imaging is performed both at baseline and with valsalva. Shunt frac-tion can be estimated by quantification of high-intensity transient signals [16]. Studies suggest similar sensitivity and specificity of TCD and TEE [17–19].

PFO ClosureThe surgical approach to PFO closure has been performed for many years and, until recently, has been the gold standard. Methods include either direct closure with a suture or placement of a Dacron (DuPont, Wilmington, DE) graft. Success rates (defined as complete or near com-plete obliteration of shunt) are high and mortality is low [20–23]. In a single-center retrospective study, no deaths

Figure 1. Transesophageal echocardiography image of a PFO. A, Arrow points to PFO. B, Arrows points to saline microbubbles passing

from RA into LA through PFO. C, Color flow Doppler also demonstrates communication through PFO between atria. LA—left atrium;

PFO—patent foramen ovale; RA—right atrium.

The Relationship Between Patent Foramen Ovale and Migraine Adler et al. 9

occurred in 91 consecutive cases of PFO closure. Com-plications from surgery were generally low and included transient atrial tachycardias, pericardial effusions, hem-orrhage, and superficial wound infection [21].

A transcatheter approach to PFO closure has several theoretic benefits over the surgical approach, includ-ing avoidance of coronary bypass, lower complication rates, and shorter recovery time. Device success rates are generally quite high in most published studies [24–31]. Definition of success varied in the studies, but was gener-ally defined as elimination of shunt as detected by TEE.

Multiple meta-analyses of percutaneous therapy esti-mate a risk of major complication (death, hemorrhage requiring transfusion, tamponade, need for surgical intervention, and pulmonary emboli) to be 1.5%. Minor complications, including bleeding not requiring transfu-sion, atrial arrhythmias, device embolization, device thrombosis, or air embolism occurred in 7.9% of patients [32,33]. Other less frequent complications include infec-tious endocarditis, device collapse, erosion of the free atrial wall, Eustachian valve entanglement, as well as aortic perforation and vascular access complications. A recent case report describes multiple recurrent strokes in a patient after transcatheter PFO closure for presumed paradoxical embolic stroke [34].

Several different devices are available for percutane-ous PFO closure. The most commonly used devices are the Amplatz PFO Occluder (AGA Medical, Golden Valley, MN) and the STARFlex septal occlusion system (NMT Medical, Boston, MA).

Migraine EpidemiologyMigraine headache is a significant cause of morbidity throughout the world. Estimates of its prevalence range between 12% to 17% of the adult population, and is roughly three times more likely in women than in men [35,36]. Migraines are most prevalent in those between 25 and 55 years of age and on average those who suffer from migraines miss 5 work days annually as a direct result [35,37,38]; therefore, the economic impact of migraines on society far outweighs the direct treatment costs.

The Relationship Between Migraine and PFOThe possible connection between migraine and PFO was initially based on anecdotal evidence [39,40]. Patients with PFO closure for recurrent stroke reported to their physicians a significant decrease in migraine frequency. Some larger studies have supported this association. In the PFO/ASA study [41], 538 patients with cryptogenic stroke were assessed with TEE. Those with a PFO were nearly twice as likely to suffer migraines in comparison with those without PFO (27% vs 14%) [41].

Other studies suggest that PFO is more prevalent in those with migraine with aura than in those with migraine

without aura [42]. In a group of patients presenting to the emergency department with migraine with aura, 22 of 25 had a PFO according to transcranial Doppler [43]. In another study group, PFO was detected in 161 of 260 patients who experienced migraine with aura (61.9%), and in only 12 of 74 of migraineurs without aura (16.2%). The authors concluded that PFO was not likely to play an etiologic role in the pathogenesis of migraine without aura, given the negative association in their study [44]. In general, studies have shown an increased prevalence of PFO in migraine with aura but not in those without aura, as compared with the general population.

Two principal hypotheses have been developed to explain the association of migraine headache and PFO. The first hypothesis is that vasoactive substances normally broken down by the lung, such as serotonin, travel through the shunt to the brain where they cause vasodilatation and headache. The second hypothesis is that patients with migraines have frequent microemboli traveling through the shunt, and that these microemboli trigger migraine [45,46].

The first hypothesis is supported by the fact that other conditions that lead to increased serotonin circulating to the brain have also been associated with migraines. One exam-ple of this correlation is found in hereditary hemorrhagic telangiectasia, in which the incidence of migraine with aura is 50% [47]. In this condition, serotonin may bypass the lung through large pulmonary atrioventricular fistulae. Another example exists with increased migraine prevalence in left heart pathology such as left atrial myxoma and mitral valve prolapse, conditions leading to platelet activation and serotonin release beyond the lung filter [48,49].

It is also plausible that paradoxical emboli traveling through a right-to-left shunt is a contributing mechanism leading to migraines. Support for this second hypothesis can be found in observational studies that show several types of thrombophilia to be an independent risk factor for patients with a PFO and migraine with aura [50]. Additional evidence is demonstrated by the fact that anti-coagulation therapy improves the severity of migraine attacks, an observation that cannot be explained by the first hypothesis [51].

Shunt size also apparently plays a role in the patho-genesis of migraines. When 93 migraineurs with aura were compared with 93 healthy control subjects, small shunts as measured by TEE were detected equally in both groups (nine of 93 in each). However, a moderate shunt was detected in 10 of 93 and a large shunt in 25 of 93 in the migraine group, compared with four of 93 and three of 93 in the control group, respectively [52]. As the embolic potential of vasoactive substances and microem-boli increases with shunt size, so does the prevalence of migraines. This observation further implies PFO and its resulting shunt has a causative role in migraines.

Preliminary results from the MIST trial [53••], a ran-domized trial evaluating PFO treatment in migraine studies

10 Stroke

first presented in May of 2005, suggest that prevalence of PFO among a randomly selected group of migraine sufferers may be as high as 50%. Severity and frequency of migraine correlated with size of PFO. Of interest, an additional 10% of the patients without PFO had intrapulmonary shunting, further supporting the hypothesis that shunting plays a role in migraine pathogenesis (Table 1) [53••].

Effectiveness of PFO Closure in Treating MigrainesMultiple retrospective nonrandomized studies have shown benefit in the treatment of migraine with PFO closure [54]. In a 2005 retrospective study of patients with PFO and cryptogenic stroke, 35% of patients with PFO had migraines. At 1 year, 80% had a reduction in migraine frequency and roughly half of these patients had complete resolution of migraine symptoms [55••]. Another small retrospective questionnaire-based study found a signifi-cant decrease in migraine severity and frequency in those with percutaneous ASD closure [56].

A recent nonrandomized study performed at the Uni-versity of California, Los Angeles evaluated migraine frequency in patients with either PFO or ASD before and after closure. Prior to closure, 45% of the patients studied admitted having migraines. Of these patients, 40% had complete resolution of migraine symptoms and 76% had some level of improvement in symp-toms, based on a standardized migraine questionnaire [57]. In a study published in April 2006, the effect of transcatheter PFO closure on migraines was measured retrospectively. Of a group of patients who underwent closure because of cryptogenic stroke, 35 suffered from migraine headaches with aura. After a mean follow-up of approximately 2 years, migraine symptoms disap-peared completely in 29 of 35 patients as measure by the Migraine Disability Assessment questionnaire, and in three of the remaining six patients, there was an improvement of at least two grades in the incidence and severity of symptoms [50].

A prospective case-control study published in February of 2006 showed that in a group of migraine sufferers with PFO, atrial septal repair resulted in decreased migraine severity at 1-year follow-up compared with controls whose PFOs were treated medically. Furthermore, out of 27 people who suffered from aura, only seven reported aura 1 year after PFO closure, whereas 21 out of 21 con-trols continued to experience aura [58].

All of the aforementioned studies suggest a significant benefit to PFO closure. However, none these studies were randomized or blinded and most suffer from questionnaire bias. Fortunately, several randomized blinded clinical tri-als are beginning enrollment that should provide some insight into the true effectiveness of this novel treatment modality. The MIST trial [53] is a prospective randomized blinded trial evaluating the efficacy of the STARFlex sep-tal repair implant in patients with migraine; 147 patients were included in the trial and in order to be included, needed to have at least a 1-year migraine history, be refractory to at least two classes of migraine medication, and have PFOs larger than the general population. After randomization, patients in the treatment arm underwent PFO closure and those in the control arm underwent general anesthesia with a groin incision. Endpoints being measured are complete headache cessation, 50% reduc-tion in headache days, and reduced headache burden.

Preliminary results from the MIST trial [53] show no difference between PFO closure and sham surgery in achieving complete headache cessation, as only three patients in each group have achieved this endpoint. How-ever, a significant improvement in patients in the treatment arm is seen in reduced number of headache days by 50% (42% vs 23%, P = 0.038), and in reduced headache bur-den (37% vs 17%, P = 0.033). It should be noted as well that the results of the study may change with longer fol-low-up, as migraine may improve over longer periods of time following repair. Nevertheless, it is likely that some of the observational studies suggesting a near-complete resolution of migraines in the majority of patients follow-ing closure may have been misleading, and that complete cure of migraine may be very difficult to achieve. It will be important to analyze whether certain subpopulations are more likely to benefit from the procedure; for example, if age, sex, shunt size, or aura type are predictive factors for improvement. These factors are difficult to assess with a small sample size, but may prove to be significant in larger studies. The MIST II trial, also sponsored by NMT Medical, has initiated enrollment in the United States, expecting to recruit 600 people by the end of 2006.

The PREMIUM trial is an industry-sponsored trial by AGA Medical of a new closure device. Patients with migraines will be screened for PFO using transcranial Dop-pler. Those with confirmed PFO by ICE will be randomized to occluder device or no treatment. Both the patient and neu-rologist following the patient will be blinded to whether the patient receives an occluder. By performing intracardiac cath-

Table 1. Prevalence of migraine in patients with PFO

Study Patients, nPFO with

migraine, %With

aura, %

Azarbal et al. [57] 66 45 66

Reisman et al. [55••] 162 35 68

Post et al. [59] 66 39.4 46

Sztajzel et al. [60] 44 36

Wilmshurst [53••] 37 57 76

Lamy et al. [41] 267 27.3 n/a

Mortelmans et al. [56]

75 29 38

PFO—patent foramen ovale.

The Relationship Between Patent Foramen Ovale and Migraine Adler et al. 11

eterization on all patients the trial will be less prone to bias from the placebo effect than the MIST trial, in which only a groin incision was performed on the control group. Another industry-spondored trial by St. Jude Medical (St. Paul, MN), the ESCAPE migraine trial, anticipates enrollment of 500 patients with migraine and PFO to determine the effective-ness of the Premere (St. Jude) device. The primary endpoint being measured in this trial is a 50% reduction of migraine periods compared with baseline. Like the PREMIUM trial, all patients will undergo right heart catheterization but only one group will undergo PFO repair.

ConclusionsGiven the prevalence and morbidity associated with migraine and the generally encouraging results of the aforementioned studies, there is tremendous excitement both among those who suffer from migraines and health care professionals. No doubt some of this is based on the economic boom that would result for device manufacturers and interventional cardiologists if endovascular closure became a standard treatment modality for those with migraine and PFO. There are several ongoing trials whose results are eagerly being awaited. The ultimate hope is that these studies will provide clinicians with definitive evidence that may one day improve the quality of life in those suffering from migraines.

Clinical Trials AcronymsESCAPE—Effect of Septal Closure of Atrial PFO on Events of Migraine With Premere; MIST—Migraine Intervention with STARFlex Technology; PFO/ASA—Patent Foramen Ovale/Atrial Septal Aneurism; PREMIUM—Prospective Randomized Investigation to Evaluate Incidence of Head-ache Reduction in Subjects with Migraine and PFO Using the AMPLATZER PFO Occluder Compared to Medical Management; SPARC—Stroke Prevention Assessment of Risk in a Community.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

1. Penther P: [Patent foramen ovale: an anatomical study. Apropos of 500 consecutive autopsies]. Arch Mal Coeur Vaiss 1994, 87:15–21.

2. Langholz D, Louie EK, Konstadt SN, et al.: Trans-esophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension.J Am Coll Cardiol 1991, 18:1112–1117.

3. Meissner I, Whisnant JP, Khandheria BK, et al.: Prevalence of potential risk factors for stroke assessed by transesopha-geal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999, 74:862–869.

4. Augoustides JG, Weiss SJ, Weiner J, et al.: Diagnosis of patent foramen ovale with multiplane transesophageal echocardiography in adult cardiac surgical patients. J Cardiothorac Vasc Anesth 2004, 18:725–730.

5. Yahia AM, Shaukat A, Kirmani JF, Qureshi AI: Age is not a predictor of patent foramen ovale with right-to-left shunt in patients with cerebral ischemic events. Echocardiography 2004, 21:517–522.

6. Beelke M, Angeli S, Del Sette M, et al.: Prevalence of patent foramen ovale in subjects with obstructive sleep apnea: a transcranial Doppler ultrasound study. Sleep Med 2003, 4:219–223.

7. Serafini O, Misuraca G, Greco F, et al.: [Prevalence of structural abnormalities of the atrial septum and their asso-ciation with recent ischemic stroke or transient ischemic attack: echocardiographic evaluation in 18631 patients]. Ital Heart J Suppl 2003, 4:39–45.

8. Natanzon A, Goldman ME: Patent foramen ovale: anatomy versus pathophysiology--which determines stroke risk? J Am Soc Echocardiogr 2003, 16:71–76.

9. Hagen PT, Scholz DG, Edwards WD: Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984, 59:17–20.

10. Homma S, Sacco RL: Patent foramen ovale and stroke. Circulation 2005, 112:1063–1072.

11. Woods TD: Transesophageal echocardiography and stroke. Curr Atheroscler Rep 2005, 7:255–262.

12. Cerrato P, Imperiale D, Priano L, et al.: Transoesophageal echocardiography in patients without arterial and major cardiac sources of embolism: difference between stroke subtypes. Cerebrovasc Dis 2002, 13:174–183.

13. Heckmann JG, Niedermeier W, Brandt-Pohlmann M, et al.: [Detection of patent foramen ovale. Transesophageal echocardiography and transcranial Doppler sonography with ultrasound contrast media are “supplementary, not competing, diagnostic methods”]. Med Klin (Munich) 1999, 94:367–370.

14. Brochet E, Habib G: [Intracardiac echocardiography during percutaneous closure of atrial septal defect and patent foramen ovale]. Arch Mal Coeur Vaiss 2005, 98:25–28.

15. Bartel T, Konorza T, Neudorf U, et al.: Intracardiac echo-cardiography: an ideal guiding tool for device closure of interatrial communications. Eur J Echocardiogr 2005, 6:92–96.

16. Sliwka U, Job FP, Wissuwa D, et al.: Occurrence of tran-scranial Doppler high-intensity transient signals in patients with potential cardiac sources of embolism. A prospective study. Stroke 1995, 26:2067–2070.

17. Droste DW, Schmidt-Rimpler C, Wichter T, et al.: Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis 2004, 17:191–196.

18. Schulte-Altedorneburg G, Nam EM, Ritter M, et al.: On the origin of microembolic signals--a clinical and postmortem study. J Neurol 2003, 250:1044–1049.

19. Droste DW, Lakemeier S, Wichter T, et al.: Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Stroke 2002, 33:2211–2216.

20. Droste DW, Jekentaite R, Stypmann J, et al.: Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts: comparison of Echovist-200 and Echovist-300, timing of the Valsalva maneuver, and general recommendations for the performance of the test. Cerebrovasc Dis 2002, 13:235–241.

21. Sloan MA, Alexandrov AV, Tegeler CH, et al.: Assess-ment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004, 62:1468–1481.

22. Mohrs OK, Petersen SE, Erkapic D, et al.: Diagnosis of pat-ent foramen ovale using contrast-enhanced dynamic MRI: a pilot study. AJR Am J Roentgenol 2005, 184:234–240.

12 Stroke

23. Buecker A, Spuentrup E, Grabitz R, et al.: Magnetic resonance-guided placement of atrial septal closure device in animal model of patent foramen ovale. Circulation 2002, 106:511–515.

24. Wahl A, Meier B, Haxel B, et al.: Prognosis after percu-taneous closure of patent foramen ovale for paradoxical embolism. Neurology 2001, 57:1330–1332.

25. Wahl A, Windecker S, Eberli FR, et al.: Percutaneous closure of patent foramen ovale in symptomatic patients. J Interv Cardiol 2001, 14:203–209.

26. Hijazi Z, Wang Z, Cao Q, et al.: Transcatheter closure of atrial septal defects and patent foramen ovale under intracardiac echocardiographic guidance: feasibility and comparison with transesophageal echocardiography. Catheter Cardiovasc Interv 2001, 52:194–199.

27. Waight DJ, Cao QL, Hijazi ZM: Closure of patent foramen ovale in patients with orthodeoxia-platypnea using the amplatzer devices. Catheter Cardiovasc Interv 2000, 50:195–198.

28. Windecker S, Wahl A, Chatterjee T, et al.: Percutaneous closure of patent foramen ovale in patients with paradoxi-cal embolism: long-term risk of recurrent thromboembolic events. Circulation 2000, 101:893–898.

29. Schwerzmann M, Windecker S, Wahl A, et al.: Percutane-ous closure of patent foramen ovale: impact of device design on safety and efficacy. Heart 2004, 90:186–190.

30. Wahl A, Krumsdorf U, Meier B, et al.: Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients. J Am Coll Cardiol 2005, 45:377–380.

31. La Rosee K, Krause D, Becker M, et al.: [Transcatheter clo-sure of atrial septal defects in adults. Practicality and safety of four different closure systems used in 102 patients]. Dtsch Med Wochenschr 2001, 126:1030–1036.

32. Nedeltchev K, Arnold M, Wahl A, et al.: Outcome of patients with cryptogenic stroke and patent foramen ovale. J Neurol Neurosurg Psychiatry 2002, 72:347–350.

33. Bruch L, Parsi A, Grad MO, et al.: Transcatheter closure of interatrial communications for secondary prevention of paradoxical embolism: single-center experience. Circula-tion 2002, 105:2845–2848.

34. Börgermanna J HK, Friedricha I, Diez C: Recurrent thromboembolic events after percutaneous device closure of patent foramen ovale. Interac Cardiovasc Thorac Surg 2003, 2:125–127.

35. Lipton RB, Bigal ME: The epidemiology of migraine. Am J Med 2005, 118(Suppl)1:3S–10S.

36. Bigal ME, Lipton RB, Stewart WF: The epidemiology and impact of migraine. Curr Neurol Neurosci Rep 2004, 4:98–104.

37. Steiner TJ, Scher AI, Stewart WF, et al.: The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia 2003, 23:519–527.

38. Lipton RB, Liberman JN, Kolodner KB, et al.: Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 2003, 23:441–450.

39. Diener HC, Weimar C, Katsarava Z: Patent foramen ovale: paradoxical connection to migraine and stroke. Curr Opin Neurol 2005, 18:299–304.

40. Finsterer J, Sommer O, Stiskal M, et al.: Closure of a patent foramen ovale: effective therapy of migraine and occipital stroke. Int J Neurosci 2005, 115:119–127.

41. Lamy C, Giannesini C, Zuber M, et al.: Clinical and imag-ing findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA study. Atrial septal aneurysm. Stroke 2002, 33:706–711.

42. Anzola GP, Magoni M, Guindani M, et al.: Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology 1999, 52:1622–1625.

43. Ferrarini G, Malferrari G, Zucco R, et al.: High prevalence of patent foramen ovale in migraine with aura. J Headache Pain 2005, 6:71–76.

44. Dalla Volta G, Guindani M, Zavarise P, et al.: Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype. J Headache Pain 2005, 6:328–330.

45. Tietjen GE: The risk of stroke in patients with migraine and implications for migraine management. CNS Drugs 2005, 19:683–692.

46. Gupta VK: Patent foramen ovale/atrial septal defect closure and migraine: searching the rationale for the procedure. J Am Coll Cardiol 2005, 46:737–738.

47. Steele JG, Nath PV, Burn J, et al.: An association between migrainous aura and hereditary hemorrhagic telangiectasia. Headache 1993, 33:145–148.

48. Garnier P, Michael D, Antoine JC, et al.: Myxoma of the left atrium with neurological manifestations: 8 cases. Rev Neurol 1994, 150:776–784.

49. Spence JD, Wong DG, Melendez LJ, et al.: Increased preva-lence of mitral valve prolapse in patients with migraine. Can J Neurol Sci 1984, 131:1457–1460.

50. Giardini A, Donti A, Formigari R, et al.: Transcatheter patent foramen ovale closure mitigates aura migraine headaches abolishing spontaneous right-to-left shunting. Am Heart J 2006, 151:922.e1–922.e5.

51. Rahimtoola H, Egberts AC, Buurma H, et al.: Reduction in the intensity of abortive migraine drug use during coumarin therapy. Headache 2001, 41:768–773.

52. Schwerzmann M, Nedeltchev K, Lagger F, et al.: Preva-lence and size of directly detected patent foramen ovale in migraine with aura. Neurology 2005, 65:1415–1418.

53. •• Wilmshurst P: Migraine Intervention With STARFlex Technology (MIST) trial. Presented at the annual European Association of Percutaneous Cardiovascular Interventions meeting. Paris: May 24–27, 2005.

Largest randomized study to date evaluating the efficacy of closure devices.54. Diener HC, Weimar C, Katsarava Z: Patent foramen ovale:

paradoxical connection to migraine and stroke. Curr Opin Neurol 2005, 18:299–304.

55.•• Reisman M, Christofferson RD, Jesurum J, et al.: Migraine headache relief after transcatheter closure of patent fora-men ovale. J Am Coll Cardiol 2005, 45:493–495.

The authors provide some of the most compelling data for the treatment of migraine with PFO closure.56. Mortelmans K, Post M, Thijs V, et al.: The influence of

percutaneous atrial septal defect closure on the occurrence of migraine. Eur Heart J 2005, 26:1533–1537.

57. Azarbal B, Tobis J, Suh W, et al.: Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol 2005, 45:489–492.

58. Anzola GP, Frisoni GB, Morandi E, et al.: Shunt-associated migraine responds favorably to atrial septal repair: a case-control study. Stroke 2006, 37:430–434.

59. Post MC, Thijs V, Herroelen L, et al.: Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine. Neurology 2004, 62:1439–1440.

60. Sztajzel R, Genoud D, Roth S, et al.: Patent foramen ovale, a possible cause of symptomatic migraine: a study of 74 patients with acute ischemic stroke. Cerebrovasc Dis 2002, 13:102–106.