Is patent foramen ovale closure indicated for migraine?
Migraine is a heterogeneous primary headache disorder.1 Migraine prevalence in the general population of the United States is ≈28 million people (13%) and results in significant costs to the healthcare system.2 Aura consists of 1 or more focal neurological symptoms, such as visual, sensory, or speech disturbances,1 and is present in ≈30% of migraineurs.3 Cortical spreading depression (CSD), a neuroelectrical phenomenon first described in the rabbit cortex and implicated in the genesis of aura, is characterized by a self-propagating wave of neuronal and glial depolarization followed by hyperpolarization across the cortex.3
Response by Carroll and Carroll on p 468
Patent foramen ovale (PFO) closure resulted in partial or complete relief of migraine symptoms in several retrospective, single-center studies.4–6 In these studies, PFO closure was performed for secondary stroke prevention4 or shunt-related conditions such as decompression illness in scuba divers.6 Because no diagnostic or provocative test exists to link PFO to migraine, it is difficult to discern which patients are most likely to respond to elimination of the right-to-left circulatory shunt associated with PFO closure. Migraineurs with aura have a higher prevalence of PFO than migraineurs without aura and nonmigraineurs4 and are ≈4.5 times more likely to have >50% reduction in migraine frequency after PFO closure than migraineurs without aura.7
The goals of closing a PFO for migraine headache are to decrease headache burden4,5,8 and reduce functional disability (ie, inability to perform usual activities or go to work/school because of headache).9 Other possible clinical advantages of closure should not be overlooked and include reduction in paradoxical embolic sequelae such as ischemic stroke, myocardial infarction,10,11 and cognitive dysfunction. Although not previously reported, prevention of headache chronification by intervening with PFO closure in the more benign episodic time point of the disease may also be beneficial (Table 1). Current estimates are that 4% of the population experiences chronic migraine12 and in 75% it is a transformation from episodic migraine.13 Brain parenchymal changes have been seen with migraine, both in white and in gray matter.14,15 Eradicating the source of migraine may benefit these progressive pathological processes. This article will link together multiple aspects of migraine and PFO to make the case that PFO closure, in the absence of an appropriately targeted randomized clinical trial, is warranted in a selected population of headache sufferers, and to introduce the term “PFO headache” into the lexicon of headache management.
|Reduction in headache frequency4,5,8|
|Reduction in migraine-related functional disability9 with improved quality of life|
|Prevention of recurrent ischemic stroke/TIA10|
|Prevention of other paradoxical embolic sequelae, eg, myocardial infarction11|
|Prevention of decompression illness in divers6|
|Prevention or reduction in progression of cognitive dysfunction|
|Prevention of migraine chronification and potential medication overuse|
|Prevention of brain parenchymal changes (white and gray matter)|
PFO and Migraine: Perspectives on a Link
The prevalence of PFO in migraine with aura ranges between 41% and 89%,4 whereas it is between 7% and 34% in migraineurs without aura and between 20% and 25% in nonmigraineur controls.4 This association is bidirectional in that the odds of a person with a PFO having migraine is 5.1 times (95% CI, 4.67 to 5.59) greater than that of a person without a PFO.8 Furthermore, mean size of right-to-left shunt as measured by transcranial Doppler (TCD) increases from controls without migraine, to migraineurs without aura, and to migraineurs with aura.16 Patients with both migraine and a history of stroke have the largest shunts.
The Migraine Intervention with Starflex Technology (MIST) trial17 detected a right-to-left shunt in 260 patients (60%) with migraine using transthoracic echocardiography of which 163 (38%) were interpreted as being due to a moderate or large PFO. In the remaining 97 patients with right-to-left shunt, 72 (16.7%) were small atrial or pulmonary shunts, 22 (5.1%) were large pulmonary shunts, and 3 (0.7%) were atrial septal defects.17 Several studies investigated the importance of PFO and atrial anatomy in migraine patients. One study demonstrated similar PFO diameter by balloon sizing and tunnel length in migraineurs and nonmigraineurs, but migraineurs conducted larger volumes of agitated saline to the cerebral circulation than nonmigraineurs at rest and following the Valsalva maneuver as measured by TCD.18 It is unclear why this would occur, but further investigation is warrranted. In another study, a prominent Eustachian valve and Chiari network were more frequently found in migraine with aura (100% of migraineurs with aura versus 55% of nonmigraineurs),19 which could explain increased right-to-left shunting. Another study focused on septal anatomy associated with migraine and found 13% of subjects with migraine had evidence of atrial septal aneurysm versus 1.9% of controls without migraine (P=0.05).20 The increased frequency of atrial septal aneurysm was predominantly driven by the patients with migraine with aura (28%) versus migraine without aura (3.6%).20
The association between PFO and migraine headache has been established by studies reporting not only the elimination or reduction of migraine after closure of a PFO but also the triggering of headache in patients receiving devices for closure of atrial septal defects.21 Why the latter would occur is unknown but supports the provocative notion of a link between the heart and migraine and more specifically the atrial septum. Theories include platelet activation or thrombosis caused by the implant. One could speculate that the mechanism for headache in the nonimplant patient could be platelet activation within the tunnel, the overlap between the septum primum and secundum, of a PFO. This potentially turbulent segment between the 2 tissues could activate platelets, especially in the presence of an atrial septal aneurysm. Furthermore, our group22 recently studied a small sample of migraine patients and found that 24% (95% CI, 12% to 36%) were resistant to aspirin therapy, suggesting platelet hyper-reactivity. Clopidogrel and aspirin are more effective then aspirin alone in reducing headache exacerbated after PFO closure in the early follow-up period,23 indicating that platelet microaggregates may be responsible for postclosure migraine and may play a central role in the genesis of the headache.
A PFO with right-to-left shunt would require a susceptible neurological substrate and a vulnerability to a substance that bypasses the pulmonary circulation and induces headache. The endothelium of the pulmonary circulation has significant metabolic activity. The lung metabolizes, activates, or inactivates many compounds including vasoactive amines and other humoral substances.24 Prostaglandins E1, E2, and F2α are almost completely removed from the blood; serotonin is 85% to 95% removed; 70% of angiotensin I is converted to angiotensin II; and ≈80% of bradykinin is inactivated.25 Whether these unaltered substances increase the susceptibility of the brain to environmental or intrinsic migraine triggers is unknown at present.
Genetics of Migraine and PFO
Rare forms of migraine are inherited in a Mendelian pattern, and in these instances are caused by defects in ion channels or ion transport molecules.26 Unfortunately, the molecular pathogenesis of the more common episodic migraine remains unknown.
Atrial shunts may be inherited in an autosomal dominant fashion,27 which partially explains migraine inheritance in some families.28 Siblings of patients with stroke with PFO were more likely to have PFO than siblings of patients with stroke without PFO (odds ratio [OR], 3.64; 95% CI, 1.3 to 10.5; P=0.015), driven by the increased prevalence of PFO among female sibling pairs (OR, 9.8; 95% CI, 2 to 47.9; P<0.01).29 Persons with “shunt-associated migraine” are more likely to have a family history of migraine than those who had migraine without shunt,30 suggesting a genetic link. Atrial septal aneurysms are associated with migraine,20 indicating that these two conditions may be genetically linked in some individuals.
Methylenetetrahydrofolate reductase (MTHFR) polymorphism, specifically the common single nucleotide cytosine replacement by thymidine at base position 677, has been reported to increase the risk of migraine with aura in some case-control and cohort studies.31 The polymorphism is one of the most extensively investigated in cerebral ischemia and has been linked to stroke. In this regard, migraine could be considered an intermediate factor in the complex pathway from MTHFRC677T to ischemic stroke.31 Patients with migraine and aura who underwent PFO closure had a higher incidence of thrombophilia (P=0.007) and had significantly higher prevalence of hyperhomocysteinemia and MTHFRC677T mutation than nonmigraineurs who also underwent PFO closure (31% versus 13%; P=0.038).32 Whether PFO connects the MTHFR polymorphism to clinical manifestations of migraine and stroke is provocative and warrants further investigation.
Brain Parenchymal Changes in Migraine
Some migraineurs have changes in the brain that can be detected by MRI. White matter abnormalities (WMA) are hyperintense signals seen on MRI characterized by gliosis, axonal loss, and ischemic demyelination resulting from microvascular damage. The pathogenesis of WMA includes acute ischemia due to disruption of blood flow in a perforating artery or chronic ischemia in the periventricular and deep white matter regions of the brain both of which are internal watershed regions with low perfusion. Confluent WMA are an important cause of cognitive decline and vascular dementia.33 WMA are seen more frequently in migraine with aura than in migraine without aura.14 Cerebral ischemia during attacks of migraine with aura might cause changes to the primary visual cortex, the area where aura arises3. The OR of WMA in migraineurs was 3.9 (95% CI, 2.3 to 6.7) versus nonmigraineur controls in 1 meta-analysis.34 In the “Cerebral Abnormalities in Migraine Epidemiological Risk Analysis” study,14 migraineurs with aura had an increased risk of cerebellar WMA than did patients with migraine without aura (OR, 13.7; 95% CI, 1.7 to 112). The load of such hyperintensities is believed to be exponential to the duration and frequency of migraine attacks, suggesting that migraine is a progressive brain disorder. A recent study35 reported that women who had migraine with aura in midlife were more likely to have cerebellar infarct-type lesions when elderly (OR, 1.9; 95% CI, 1.4 to 2.6). The increased prevalence of cerebellar lesions was not seen in men with migraine with aura in midlife (OR, 1.0; 95% CI, 0.6 to 1.8).35 Patients with migraine and WMA who underwent PFO closure experienced significant improvement in migraine frequency, with a decrease from 32�9 to 7�7 in 6 months versus controls who did not undergo PFO closure (36�13 to 30�21 in 6 months).36 Migraine resolution was seen in 34% of the closure group and 7% of the controls (P=0.007); in addition, only patients in the closure group reported a significant reduction in migraine severity.36
Gray matter changes have also been observed in migraineurs. Compared with matched nonmigraineur controls, migraineurs had areas of reduced gray matter density in the frontal and temporal lobes; however, migraineurs showed increased periacqueductal gray matter density.15 Migraine patients with aura had increased density of periacqueductal gray matter and the dorsolateral pons relative to migraine patients without aura.15 Repeated attacks of headache or aura have been shown to lead to iron accumulation in the periacqueductal gray matter, causing progressive impairment of the antinociceptive system that controls activity in the trigeminovascular system.37 The authors suggested that iron homeostasis in the gray matter was selectively, persistently, and progressively impaired in the migraine and chronic daily headache groups, possibly by repeated migraine attacks.
The potential for PFO closure to interrupt the development of gray and WMA that may contribute to cognitive dysfunction in migraineurs with aura33 should be studied as long-term end points in randomized PFO closure trials.
Approximately 30% percent of migraineurs have headaches preceded by 1 or more focal neurologic symptoms collectively known as aura.3 Aura symptoms, predominantly localized to the cerebral cortex, can include transient visual disturbances, marching unilateral paresthesias and numbness or weakness in an extremity or the face, language disturbances, and vertigo.1 The aura will often last for <1 hour. The proposed mechanism of aura is CSD, which is associated with transient decreases in cerebral blood flow that are most often posterior in origin, based on results of perfusion studies.3 These cerebral blood flow changes show an apparent anterior migration with time, and the magnitude of the decrement in cerebral blood flow seems to be smaller than that associated with ischemic injury.38
Approximately half of migraineurs with aura have PFO.4 It is theorized that the right-to-left shunt allows microemboli and vasoactive substances to escape pulmonary filtration and be conducted to the cerebral circulation, where they can produce transient ischemia and CSD.6 Aura is initiated in the occipital lobe, supplied by the posterior circulation.3 TCD studies have detected a significant propensity for paradoxical emboli in the posterior circulation in patients with right-to-left shunt,39 which may be due to altered vasomotor reactivity in this region. The occipital lobe has been identified as a predominant area of infarct in patients with migraine and aura.40 However, microemboli from PFO or other right-to-left shunt may trigger aura by producing transient ischemia, leading to CSD. In support of this hypothesis, injection of polystyrene microspheres into the carotid artery of anesthetized mice triggered CSD without MRI evidence of cerebral infarctions.41
Not all migraineurs with aura have typical aura symptoms, and aura symptoms can occur without subsequent headache.1 Atypical aura and aura without headache may be subject to misinterpretation as transient ischemic attacks (TIA). The inconsistent relationship between aura and pain lateralization, the occurrence of aura with other primary headaches, and the observation that some treatments improve aura but not pain further confound the diagnosis. The prevalence of PFO is reportedly different between migraineurs with typical and atypical aura (46.3% and 79.2%, respectively; P=0.009).42 Typical aura without headache affects ≈4% of migraine patients,3 although it is unknown how many of these patients have a PFO. This condition is characterized by paroxysmal episodes of prolonged visual auras; atypical sensory, motor, or visual aura; confusion; dysarthria; focal neurological deficits; or gastrointestinal manifestations or other constitutional symptoms with or without a headache.1 The high degree of overlap in visual, motor, speech, and sensory symptoms between aura and TIA may become key features in the ability to identify patients who could benefit from PFO closure.
Migraine and Stroke: The PFO Bridge
The association between migraine and stroke is well recognized.43 Despite the many hypotheses linking the 2 disorders, the precise mechanism is unknown. Migraine and stroke may share common processes in the central nervous system. Both are characterized by release of inflammatory mediators and increased platelet reactivity and share the MTHFRC677T polymorphism as a risk factor.31 During aura, cerebral blood flow is reduced by 17% to 35%,3 which may result in arterial thrombosis.
Migraine with aura is associated with an increased stroke risk compared with nonmigraineurs, especially in women (OR, 1.80; 95% CI, 1.16 to 2.79).44 Forty-five percent of patients (age, 49�13 years; 66% women) presenting with a cryptogenic stroke report a history of migraine. In the Women’s Health Study,44 the association between active migraine with aura and ischemic stroke was apparent in young women with the lowest Framingham risk score (hazard ratio, 3.99; 95% CI, 1.8 to 9.08). A meta-analysis43 showed that the relative risk of ischemic stroke was increased 2.3-fold (95% CI, 1.61 to 3.19) in migraineurs with aura and 1.8-fold (95% CI, 1.06 to 3.15) in those without aura compared with nonmigraineurs. Analysis from a United Kingdom database45 showed that the relative risk of stroke in migraineurs was 2.2 (95% CI, 1.7 to 2.9). It was highest for patients with a migraine diagnosis recorded within 30 days before a stroke (OR, 11.1, 95% CI, 5.69 to 21.5). The relative risk of TIA in this study in migraineurs compared with nonmigraineurs was 2.4 (95% CI, 1.8 to 3.3).45 Subclinical microinfarctions have been located in the cerebellum of migraineurs, particularly those with aura.14,35
How can PFO be implicated as the bridge between migraine and stroke? Migraineurs have dysfunctional platelets22 and are at higher risk of deep vein thrombosis than nonmigraineurs (18.9% versus 7.6%, P=0.031),46 which could be the source of microemboli for shunt-associated strokes. In our PFO Closure database, migraineurs with PFO had a high prevalence of protein C (14%) or protein S (9%) deficiency (Jesurum, Fuller, and Reisman, unpublished data). Taken together, the PFO may be a conduit for emboli that are more likely to occur in migraineurs.
PFO Closure and Migraine
Since the initial report that prophylactic closure of a PFO in divers led to an amelioration of migraine6 and the high incidence of PFO in migraine patients,4 there have been >10 observational studies that have reported reductions in migraine frequency after PFO closure for reduction of recurrent stroke or TIA risk.4 On average, PFO closure brought about complete resolution of migraine attacks in 57% (range, 29% to 84%) and an improvement in 43% of patients (range, 8% to 83%).4–6,8 A study by our group7 demonstrated headache relief in patients who had residual shunt after PFO closure but a significant reduction in conduction of microbubble contrast as determined by TCD. Larger shunts are more likely to be associated with migraine with aura versus smaller shunts.16 These results support the hypothesis of a “neurological threshold” of the brain to noxious substances, and that partial or complete PFO closure may reduce conductance of these substances below the level that triggers migraine.
When discussing migraine in nonrandomized open-label studies, it is impossible to avoid implicating the placebo effect, especially when patients are improving in the presence of residual shunts.7 In an analysis of migraine prevention studies, the placebo effect is 14% to 50%.47 Interestingly, the placebo effect is stronger in the setting of double-blind studies, and the placebo response is less in patients with more significant symptoms.48 However, in early PFO closure studies, preprocedural expectation of headache relief was absent.5
To date the only large randomized trial to be completed for PFO closure in migraine was the MIST trial,17 a courageous attempt to validate in a double-blind, prospective, randomized trial results seen in retrospective single-center studies of cessation and reduction in migraine headache. The failure to meet both the primary (cessation of headache) and the secondary (>50% reduction in headache frequency and days) end points17 were a disappointment to many clinical researchers, who had observed patients with remarkable improvements in headache and function after PFO closure. So what happened? Much has been written about the overreaching primary end point, the substandard operation, and adjudication of the trial results.49 The failure of the trial may primarily be due to patient selection. Table 2 outlines differences between MIST and nonrandomized studies in eligibility criteria and methodology. Two randomized double-blind studies, ESCAPE and MIST II, investigating PFO closure for migraine were recently discontinued in the United States. Both trials were plagued by slow enrollment predominantly due to narrow inclusion criteria. At our MIST II site, many of our patients that were screened exceeded the upper limit in headache days, and thus were excluded.
Future Trial Design
The challenges of MIST, MIST II, and ESCAPE offer direction for future randomized trials to gain acceptance for PFO closure for migraine prevention. The results of the MIST trial should be carefully analyzed, so that future investigators can be better directed to trial design and patent selection. It is critical to enroll patients who have similar characteristics that have achieved benefit in the observational studies. To date, the favorable outcomes in observational PFO closure studies were seen most often in patients with neurological symptoms of aura, TIA, or stroke. In addition, the end points should focus on improvement in functional disability and not on headache frequency alone. Migraine researchers have expanded beyond “motor tract” symptoms and are now adjudicating with greater focus the effect on cognitive function. We have recently completed the Retro study (Reisman et al, unpublished data), which included patients with PFO and documented migraines who underwent PFO closure. The patients were interviewed systematically by an independent migraine expert to better distill from the patients a consistent symptom constellation that identifies those who may achieve the greatest benefit from PFO closure. The presence of prolonged aura, focal neurological deficits, and exertional headache were prominent in these patients. In a systematic analysis,9 criteria used for PFO closure in migraineurs included all of the following: shunt present during normal respiration; curtain shunt pattern on TCD; presence of atrial septal aneurysm; class 3 to 4 Migraine Disability Assessment score, indicative of moderate to severe functional disability; symptomatic significant aura; coagulation abnormalities (eg, MTHFRC677T); and migraine refractory to conventional drugs (Table 3). After a follow-up of 10�3.1 month (range, 6 to 14), patients who met these inclusion criteria had statistically and clinically significant improvements in migraine symptoms (mean change in Migraine Disability Assessment score 3.0�2.1, P<0.03).9
On the basis of these previous studies, we can begin to define the characteristics of the PFO headache (Table 3). Future randomized PFO closure trials should be designed to target migraine patients who will derive the most benefit from PFO closure, based on these inclusion criteria.
|Subject Inclusion Criterion or Study Design||Observational Studies||MIST17|
|History of stroke and TIA||Included4,8||Excluded|
|Medication failures||Not applicable or not reported5||Failure of at least 2 classes of preventive medications|
|Migraine frequency||No stringent criteria4,5,8 frequently episodic migraine headaches||At least 5 migraine days per month, but at least 7 headache-free days per month|
|Aura status||Migraineurs�aura4,5,8||Aura patients only|
|White matter abnormalities||Included in one study36||Not used for eligibility|
|Atrial anatomy||Included19||Not used for eligibility|
|Timing of follow-up||Variable, but often>12 mo9||6 mo|
|Migraine with symptomatic, significant (prolonged) aura|
|Migraine with class 3 or 4 Migraine Disability Assessment score|
|Right-to-left shunt with normal respiration|
|Large right-to-left shunt following Valsalva maneuver|
|Atrial septal aneurysm or other persistent embryologic structures such as Eustachian valve, Chiari network|
|Coagulation abnormalities (Factor V Leiden, MTHFRC677T mutation, protein C or protein S deficiency, anticardiolipin or antiphospholipid antibodies, and antithrombin III)|
|Migraine with previous history of stroke or TIA|
|White matter abnormalities|
|No secondary source of right-to-left shunt (eg, pulmonary arteriovenous malformation)|
Migraine is not only a painful headache but also a functional disability that robs individuals of their ability to work and have normal family and community interactions. In a recent survey, 44% of American Headache Society members supported use of an invasive procedure (either PFO closure or neurostimulator) for treatment of intractable headache.50 This is a testimonial to the need for additional and more effective treatments for migraine. PFO closure has the potential not only to reduce the functional disability of migraine but also to reduce the risk of stroke in young, otherwise healthy individuals. In addition, it may have a disease-modifying effect on brain parenchyma to reduce cognitive dysfunction. The impressive results seen in single-center, nonrandomized studies cannot be ignored. Challenges to adoption of PFO closure as a treatment for migraine include completion of randomized trials that have appropriate inclusion criteria, realistic end points, adequate statistical power to detect differences between closure and placebo groups, and sufficient duration of follow-up. The ability to establish a unique fingerprint for the PFO headache that distinguishes it from the spectrum of migraine headache is critical in the evolution of this therapy. Whether this fingerprint is based on symptoms, atrial anatomy, degree of shunting, genetic factors, a provocative test, or a combination of criteria will become clearer with further research.
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John D. Carroll, MD; Eugenia P. Carroll, MD
Drs Reisman and Fuller have written an exciting review and outline the many tantalizing links, suggesting a causative relationship rather than a statistical association, in some patients with both patent foramen ovale (PFO) and migraine. They propose the term “PFO headache” as part of a plausible hypothesis built on their review of the literature and extensive clinical experience. Table 3 in their article is useful as a preliminary step toward identifying hints and potential “clinical pearls” that a patient may have PFO headaches. The potential tautology is that a PFO headache will disappear with closure of the PFO, whereas the persistence of migraine post-PFO closure indicates it was not a PFO headache. In the absence of definite clinical characteristics as an accurate and validated means to identify patients who would benefit from having their PFO closed, there will be the need for a novel provocative test. Drs Reisman and Fuller state “a PFO with right-to-left shunt would require, a susceptible neurological substrate and a vulnerability to a substance that remains noxious to the brain when bypassing the pulmonary circulation to induce headache.” Rarely, migraine is precipitated by the venous injection of the standard agitated saline-blood bolus to detect shunting. Perhaps, an additive is needed to mimic the natural onset of a migraine, a PFO-headache producing cocktail, so to speak, to enhance the diagnostic yield. The safety and reversibility of such a central nervous system stress test would need to be assured. We are in agreement that further research, not off-label, noninvestigative PFO closure, is needed to investigate the potential role of PFO closure in some subsegment of the large population of migraineurs. Research is needed to prove true causation of PFO and shunting in migraine pathophysiology. It is an unacceptable approach of simply implanting a permanent device in thousands of individuals suffering from migraine and then retrospectively trying to figure out why some had a therapeutic effect. The question remains how such a series of studies can be organized, designed, and funded.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part I of a 2-part article. Part II appears on page 475.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part I of a 2-part article. Part II appears on page 475.
Dr Reisman received a grant from Coherex and has served on the scientific advisory board for Coaptus Medical. Dr Fuller received a grant from Coherex.