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Patent foramen ovale closure and migraine: science and sensibility Expert Rev. Neurother. 10(9), 1409–1422 (2010)
Vinod Kumar Gupta Migraine-Headache Institute, S-407, Greater Kailash-II, New Delhi – 110048, India Tel.: +91 991 175 6123 Fax: +91 140 537 197
[email protected]
Migraine has been associated with patent foramen ovale (PFO), and PFO closure has become the most high-profile nonpharmacologic invasive therapy recommended for the prevention of recurrent migraine attacks, as well as for preventing further attacks in cryptogenic stroke. The results of Migraine Intervention with STARFlex Technology (MIST), a controversial but important recent randomized clinical trial (RCT) of PFO closure for migraine, do not support PFO closure for preventing migraine attacks. All patients with migraine, however, do not have a PFO, and the characteristic periodicity and predictability of migraine cannot be explained on the basis of paradoxical embolism through the PFO. Closure of the PFO or atrial septal defect can aggravate migraine suddenly. PFO increases in size with age, but migraine generally subsides with the passage of years. Serendipity does play a role in some medical discoveries, but in the absence of a logically defensible theoretical basis, chance and statistics can both become misleading. With soft end points, RCTs in migraine patients can generate conflicting and irreconcilable data. RCTs cannot supplant or substitute clinical common sense or justify serendipity. Scientific progress mandates that any serendipitous research must ultimately conform to the principles of the basic sciences surrounding the chance discovery. PFO closure for preventing migraine attacks is an unfortunate, but sobering, chapter in the migraine research saga. Keywords : migraine • paradoxical embolism • patent foramen ovale
The foramen ovale is a hole between the right atrium and left atrium that is important during development of the fetus. Normally, a flap of tissue closes up the foramen ovale after birth, but in some individuals the flap does not produce complete closure. These individuals are said to have patent foramen ovale (PFO). Recently, PFO and its closure has generated tremendous interest in interventional cardio logy, as well as in neurology. For two decades, the potential role of PFO and atrial septal aneurysm (ASA) has been investigated for elucidating the genesis of ischemic stroke/cryptogenic stroke in young adults [1,2] . Currently, PFO closure is being actively investigated in randomized clinical trials (RCTs) as a seemingly logical management for cryptogenic stroke. In addition, an exciting but uncertain therapeutic and pathophysiological interface has also evolved between PFO, paradoxical embolism (PE) and migraine, with PFO closure purportedly offering an effective long-term (and possibly permanent) migraine preventive strategy – through abolition of presumed PE – superior www.expert-reviews.com
10.1586/ERN.10.125
to available preventive pharmacologic therapies. This article will rea nalyze the theoretical and logical basis for advocating PFO closure as a definitive therapeutic measure for migraine. Paradoxical embolism: a common feature or a clinical rarity?
The fundamental tenet surrounding PFO closure involves elimination of PE, whether the invasive procedure is used to prevent recurrent migraine attacks or cryptogenic stroke. PE itself is difficult, if not impossible, to document clinically. Barring a few post-mortem or echocardiographic studies showing thrombus lying in the PFO, there is little to conclude with scientific conviction that PE does occur on a frequent or regular basis in those suffering frequent migraine (as frequent as daily) attacks or recurrent cryptogenic stroke. Intriguingly, the case for PE as a clinically significant pathophysiologic mechanism has never been proved beyond reasonable doubt [2] . Nevertheless, the passage of air bubbles across PFO has evolved into an acceptable investigative surrogate for
© 2010 Vinod Kumar Gupta
ISSN 1473-7175
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trans-atrial thromboembolism that has widely been adopted as a marker for possible and common real-life occurrence of PE in an individual. Key limitations of RCTs and meta-analyses are that they do not seem to offer hope for any meaningful progress in this discipline (see later). A series of assumptions (myths) and omissions have carefully and (seemingly) justifiably laid the groundwork for the launch of the Migraine Intervention with STARFlex Technology (MIST) trial [3] , as well as other trials for PFO closure in patients with migraine (or in patients with cryptogenic stroke). The results of RCTs of PFO closure on migraine attacks have proven contrary and controversial. While the links in the migraine–PFO–PE chain are far from robust, RCTs of PFO closure have given clinical respectability to this novel, but entirely serendipitous, invasive therapeutic approach. The phenomenology of migraine has been well defined. The validity of the assumptions surrounding the PFO–PE–migraine nexus can best be examined against established clinical characteristics of migraine. PFO–PE–migraine nexus: the illusion of absolute certitude
Central to all known (such as ASA, small additional atrial septal defect[s], eustachian valve or Chiari network) or unknown static or dynamic aberrations associated with PFO that might confer a long-term risk for cerebrovascular events is occurrence of PE [2] . The single most important limitation to our understanding of PFO and its closure is that PE, in the vast majority of individuals with PFO, is a presumed and unrecorded – not a factual – event. All experimental studies of PFO closure for stroke or migraine prevention, therefore, rest on a major mechanistic assumption. How robust is the assumed link between PE and PFO [2,4] ? Cases demonstrating a thrombus actually traversing the PFO are relatively very few [2] . With 60–70 million Americans (20–25% of the general population) estimated to have a PFO [2] , and, given the intense interest of interventional cardiologists studying PFO and pursuing PFO closure in clinical trials, the striking rarity of right atrial thrombus-in-evolution or -in-passage through the PFO – with or without ASA – is inexplicable. Second, the risk of first ischemic stroke in individuals with PFO remains unknown [2,5] . Third, even the presumed higher risk of recurrent stroke in patients with both PFO and ASA is controversial, while the mechanistic basis of the flapping action of ASA directing small clots coming from the inferior vena cava into the defect is purely speculative [2,6,7] . Fourth, no consistent link between stroke and Valsalva maneuver (VM) – that might lead to a transient rightto-left shunt (RLS) or to PE – has been established; also, the PFO subgroup at high risk for PE has not been consistently identified [2,8] . Fifth, the relationship between PFO size and PE appears to be complex. Remarkably, using balloon sizing for measurement, a link between PFO diameter and recurrent cryptogenic stroke [9] , or between maximal potential PFO diameter and preclosure neurologic event [10] , could not be found. Furthermore, while PFO increases in size with age [2] , the importance of PFO in stroke, as well as in migraine pathophysiology, inexplicably declines with advancing age [4] . Sixth, clinical states associated 1410
with hypercoagulability and clinical thromboembolism have not demonstrated any particular association either with PFO or with migraine attacks. Seventh, since PFO is present at birth, why does PE-mediated (cryptogenic) ischemic stroke or migraine not manifest in infants/toddlers or the preschool pediatric population [4,9] ? While age is indeed an important risk factor for venous thrombosis with the risk of deep venous thrombosis rising every decade, states of hypercoagulability, such as dehydration, immobilization, surgery and genetic predispositions, are common in the pediatric population. Strokes attributable to atherothrombosis are indeed uncommon in children and adolescents; thromboemboli originating in the arterial circuit and resulting in strokes clearly do not involve the PFO. Eighth, while coughing, straining at stools, lifting or any other form of VM are common activities at all age groups, why does such ‘straining’ predispose only young adults (
