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Data from recently published randomized controlled trials and their meta-analyses have unequivocally shown
that in carefully selected patients with cryptogenic stroke, percutaneous PFO device closure is superior to medical
therapy alone in reducing the risk of recurrent stroke (Chapter 7) [28e35]. However, none of these newer trials
enrolled patients with paradoxical peripheral artery embolism. The PC trial was the only study that included pa-
tients with peripheral embolism as the index event in addition to those with cryptogenic stroke or TIA [14]. The trial
demonstrated no significant reduction in risk of the primary endpoint (composite of death, nonfatal stroke, TIA, or
peripheral embolism) with PFO closure versus medical therapy alone. However, the number of patients with
peripheral embolism enrolled was small (n ¼ 11 [2.7%]), and this trial had several other important limitations
including lack of statistical power, inclu sion of death and TIA in the primary composite endpoint instead of
stroke/peripheral embolism alone, attrition bias due to a lower than expected patient retention, and ascertainment
bias due to selective reporting of potential events by the clinical events committ ee (Chapter 6) [14]. Thus, there is a
paucity of evidence to support PFO closure in patients with paradoxical peripheral embolism.
Nonetheless, data from observational studies and randomized trials suggest that the rates of recurrent peripheral
embolic events, in patients who underwent PFO closure for secondary prevention of paradoxical embolic events, are
low. In a single-center study of 80 patients who underwent PFO closure, the annual risk of recurrent thromboembolic
event was 2.5% for TIA, 0% for stroke, and 0.9% for peripheral emboli at a mean follow-up of 1.61.4 years [15].
Similarly, in another single-center study of 1930 patients who underwent PFO closure, there were 63 recurrent
thromboembolic events (25 strokes, 36 TIAs, and 2 peripheral emboli) during a mean follow-up of 39 months,
most of which were attributed to atherosclerosis [36]. Nine (2 strokes, 5 TIAs, and 2 peripheral emboli) out of 63
(14%) events were considered likely or possible paradoxical embolism due to a residual shunt. The annual rate of
any recurrent paradoxical embolic event was 0.14% and of paradoxical peripheral embolism was 0.03% [36].In
the PC trial and the PFO Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence
(CLOSE) trial, there were zero peripheral embolic events in the PFO closure and medical therapy groups over a
mean follow-up of 4.1 and 4.0 years, and 5.4 and 5.2 years, respectively [14,28].
SUMMARY
The prevalence of PFO in patients presenting with peripheral embolism is similar to its prevalence in the general
population [7,8]. Among patients who have a PFO related ischemic event, w1%e7.5% present with peripheral em-
bolism as the index event [11e15]. Paradoxical peripheral embolism frequently involves the femoropopliteal arteries
resulting in acute limb ischemia; however, involvement of the aortoiliac, subclavian, brachial, ophthalmic, renal,
splenic, and mesenteric arteries have also been described [12,16e22]. The diagnosis involves exclusion of other
more common causes of per ipheral embolism (e.g., cardiac/left heart, peripheral artery diseas e) and hypercoagula-
ble disorders, as well as identifying the presence of PFO with right-to-left shunt, with or without concomitant evi-
dence of DVT and/or pulmonary embolis m. However, the presence of any of these competitive causes does not
automatically rule out a PFO-mediated event. There is a paucity of data on PFO closure for secondary prevention
of recurrent peripheral embolism [14]. The decision to pursue device closure in patients with peripheral embolism
should involve a thorough workup to exclude cardioembolic and arterial embolic sources, a multidisciplinary team
discussion, and shared-decision making between the physician and patien t to weigh the risks and potential benefits
of the procedure, which includes protection against cerebral embolism, among others.
References
[1] Johnson BI. Paradoxical embolism. J Clin Pathol 1951;4:316e32.
[2] Mojadidi MK, Zaman MO, Elgendy IY, et al. Cryptogenic stroke and patent foramen ovale. J Am Coll Cardiol 2018;71:1035e43.
[3] Mojadidi MK, Ruiz JC, Chertoff J, et al. Patent foramen ovale and hypoxemia. Cardiol Rev 2019;27:34e40.
[4] Shi YJ, Lv J, Han XT, Luo GG. Migraine and percutaneous patent foramen ovale closure: a systematic review and meta-analysis. BMC
Cardiovasc Disord 2017;17:203.
[5] AbuRahma AF, Downham L. The role of paradoxical arterial emboli of the extremities. Am J Surg 1996;172:214e7.
[6] Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale:
the PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002;33:706e11.
[7] Ali Kausar RY, Hina H, Patel B, Cross FW. The incidence of peripheral arterial embolism in association with a patent foramen ovale (right-to-
left shunt). JRSM Short Rep 2011;2:35.
[8] 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;59:17e20.
IV. NON-CEREBRAL PARADOXICAL EMBOLISM AND PFO
9. PERIPHERAL EMBOLISM AND PFO112
https://t.me/med1917
[9] De’Ath HD, Sabharwal NK, Ormerod O, Vaidya A. Patent foramen ovale and gut ischemia in potential intestinal transplant recipients.
Transplantation 2014;98:e60e1.
[10] Crump R, Shandling AH, Van NB, Ellestad M. Prevalence of patent foramen ovale in patients with acute myocardial infarction and angio-
graphically normal coronary arteries. Am J Cardiol 2000;85:1368e70.
[11] Inglessis I, Elmariah S, Rengifo-Moreno PA, et al. Long-term experience and outcomes with transcatheter closure of patent foramen ovale.
JACC Cardiovasc Interv 2013;6:1176e83.
[12] Dao CN, Tobis JM. PFO and paradoxical embolism producing events other than stroke. Cathet Cardiovasc Interv 2011;77:903e9.
[13] Rigatelli G, Giordan M, Braggion G, et al. Incidence of extracerebral paradoxical embolisms in patients with intracardiac shunts. Cardiovasc
Revasc Med 2007;8:248e50.
[14] Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083e91.
[15] Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk
of recurrent thromboembolic events. Circulation 2000;101:893e8.
[16] Hugl B, Klein-Weigel P, Posch L, Greiner A, Fraedrich G. Peripheral ischemia caused by paradoxical embolization: an underestimated
problem? Mt Sinai J Med 2005;72:200e6.
[17] Dobrin A, Thevenot T, Alby B, Di M V, Sailley N, Meneveau N. A case of isolated splenic infarction associated with a foramen ovale and an
interatrial septal aneurysm. Gastroenterol Clin Biol 2008;32:351e3.
[18] Edoga JK, Widmann WD, McLean ER. Paradoxical embolism to the superior mesenteric artery. Clin Cardiol 1987;10:54e6.
[19] Goueffic Y, Piffeteau T, Patra P. Acute leriche syndrome due to paradoxical embolism. Eur J Vasc Endovasc Surg 2007;33:220e2.
[20] Jeong H, Woo LH, Young JJ, et al. Renal infarction caused by paradoxical embolism through a patent foramen ovale. Kidney Res Clin Pract
2012;31:196e9.
[21] Paes EH, Greven T, Heredia D. Paradoxical embolism and aortic occlusion: a case report. Int Angiol 1997;16:72e5.
[22] Ronco F, Rigatelli G, Dell’avvocata F, Giordan M, Ronco C, Cardaioli P. Embolic renal infarct, patent foramen ovale and coronary artery
dissection: a strange case of cardio-renal connection. Cardiovasc Revasc Med 2011;12:67.
[23] Loscalzo J. Paradoxical embolism: clinical presentation, diagnostic strategies, and therapeutic options. Am Heart J 1986;112:141e5.
[24] Stollberger C, Slany J, Schuster I, Leitner H, Winkler WB, Karnik R. The prevalence of deep venous thrombosis in patients with suspected
paradoxical embolism. Ann Intern Med 1993;119:461e5.
[25] Goldhaber SZ. Venous thrombosis: prevention, treatment, and relationship to paradoxical embolization. Cardiol Clin 1994;12:505e16.
[26] Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.
Neurology 2013;81:619e25.
[27] Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral
artery disease: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines. Circu-
lation 2017;135:e726e79.
[28] Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke. N Engl J Med 2017;377:
1011e21.
[29] Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017;
377:1033e42.
[30] Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;
377:1022e32.
[31] Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol 2018;71:
2335e42.
[32] Ahmad Y, Howard JP, Arnold A, et al. Patent foramen ovale closure vs. medical therapy for cryptogenic stroke: a meta-analysis of random-
ized controlled trials. Eur Heart J 2018;39:1638e49.
[33] Mojadidi MK, Elgendy AY, Elgendy IY, et al. Transcatheter patent foramen ovale closure after cryptogenic stroke: an updated meta-analysis of
randomized trials. JACC Cardiovasc Interv 2017;10:2228e30.
[34] Shah R, Nayyar M, Jovin IS, et al. Device closure versus medical therapy alone for patent foramen ovale in patients with cryptogenic stroke: a
systematic review and meta-analysis. Ann Intern Med 2018;168:335e42.
[35] De RS, Sievert H, Sabatino J, Polimeni A, Sorrentino S, Indolfi C. Percutaneous closure versus medical treatment in stroke patients with patent
foramen ovale: a systematic review and meta-analysis. Ann Intern Med 2018;168:343e50.
[36] Wallenborn J, Bertog SC, Franke J, et al. Recurrent events after percutaneous closure of patent foramen ovale. Cathet Cardiovasc Interv 2013;
82:541
e6.
IV. NON-CEREBRAL PARADOXICAL EMBOLISM AND PFO
REFERENCES 113
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CHAPTER
10
Migraine Headache: Clinical Association With
PFO and Observational Studies
Heinrich P. Mattle
1
, Krassen Nedeltchev
2
, Christoph Schankin
1
, Simon Jung
1
1
University Hospital Bern, Bern, Switzerland;
2
Cantonal Hospital Aarau, Aarau, Switzerland
OUTLINE
Introduction 117
Primary Headaches 117
Secondary Headaches 118
Pathophysiology of Migraine and Migraine Aura
in Patients With Right-To-Left Shunts 119
Case-Control Studies of Prevalence of Migraine
in Individuals With PFO and Prevalence of PFO
in Individuals With Migraine 120
Prevalence of Migraine in Individuals With PFO and
Vice Versa 120
Shunt Size in Individuals With PFO and Migraine
121
Effect of PFO Closure on
Migraine Severity
121
The Link Between Migraine, PFO, and Stroke
122
Stroke in Patients with Migraine
122
Effect of Antithrombotic Therapy in Migraine
124
Discussion
124
References
126
INTRODUCTION
The association between patent foramen ovale (PFO) and cryptogenic stroke was initially discovered by case
reports and case-control studies. It had been vividly debated whether PFO and stroke were causally as sociated until
randomized controlled trials proved that PFO occlusion prevents recurrent strokes with better efficacy than standard
of care medic al therapy. Studies have also shown that PFO and migraine are associated. However, the proof of a
causal relationship has not been provided unequivocally by randomized trials, although many studies support it,
at least for migraine with aura.
PRIMARY HEADACHES
Headaches can be primary, i.e., occurring without an evident cause, or secondary as a result of organic disease or
trauma. Headache syndromes have been classified by the International Headache Society (IHS) [1]. The IHS classi-
fication has won general acceptance for research and is also highly practical for routine clinical use. Among the
primary headaches, migraine and tension-type headache are most common and sometimes difficult to distinguish
clinically. There are 2 main types of migraines: migraine without aura (MWoA) and migraine with aura (MWA). Pa-
tients who have had only migraine attacks without aura are classified as MWoA and patients who have had at least 2
117
PFO Closure for Stroke, Myocardial Infarction, Peripheral Embolism, Migraine, and Hypoxemia
Copyright © 2020 Elsevier Inc. All rights reserved.https://doi.org/10.1016/B978-0-12-816966-7.00010-5
https://t.me/med1917
migraine attacks with aura, regardless of how many attacks they have had without aura, are classified as MWA.
However, a patient who has frequent attacks with aura and also some attacks without aura should be coded accord-
ing to the IHS classification as having both MWA and MWoA. MWA occurs in about a third of people with migraine,
and up to 33% of those with MWA have both types of attacks [2]. Primary headaches can be episodic, or chronic
when they occur on 15 days per month.
Tension-type headache is characterized by attacks that can last from 30 minutes to 7 days; are usually bilateral,
pressing, squeezing, of mild to moderate intensity; and are not exacerbated by physical activity such as walking or
climbing stairs. There is no nausea or vomiting, usually no photophobia or phonophobia, and never both
photophobia and phonophobia.
Migraine without aura, also called common migraine, is a disorder with recurrent headache attacks lasting 4e72
hours. Typical characteristics of the headache are mostly a unilateral location, pulsating or throbbing quality,
moderate or severe intensity, aggravation by everyday physical activity, and association with nausea and/or photo-
phobia and phonophobia.
Migraine with aura has been previously named classic migraine, migraine accompagne
´
e, or complicated
migraine. Depending on the neurological deficit, other terms were ophthalmic, hemiparesthetic, hemiplegic, or
aphasic migraine. Migraine aura is defined by the IHS as a disorder with recurrent attacks, lasting at least
several minutes, of unilateral, fully reversible, visual, sensory, or other central nervous system symptoms that
usually develop gradually. Migraine aura is usually, but not always, followed by headache of migrainous
phenotype.
The aura, a complex of mostly positive neurological symptoms, usually occurs before the headache, but
may occasionally begin within the headache or continue into the headache phase. Visual aura is most
common, occurring at least in some attacks in over 90% of MWA patients. The typical kind of visual aura
is a scintillating scotoma, a flashing figure bordered by a bright zigzag line (also called fortification figure).
Typically, it arises in the center of 1 visual hemifield and then travels outward to the periphery for 5e15
minutes, leaving behind a transient impairment of vision. Rarely, the visual disturbance affects 1 eye only (retinal
migraine). Less common than visual symptoms are sensory disturbances, in the form of pins and needles moving
slowly from the point of origin and affecting a greater or smaller part of 1 side of the body, face, and/or tongue.
Numbness may occur in its wake, but numbness may also be the only symptom. Less frequently, speech distur-
bances, that are usually aphasic, or brainstem or vestibular symptoms occur as aura. However, different auras
probably do not indicate different disorders, and therefore the IHS classifies all aura types in the category of MWA.
SECONDARY HEADACHES
When 1 or more clinical symptoms or signs do not fit into the IHS classification of primary headache disorders,
secondary headaches are to be considered. Secondary headaches are manifestations of underlying organic disorders
or result from trauma.
Migraine is especially interesting in this context. In most patients, migraine is a primary headache
disorder; however, migraine attacks can be the first manifestation of cerebral ischemi a or may occur
repeatedly as a symptom of several neurological disorders. Olesen et al. described a series of 15 patients
with symptomatic migraine attacks induced by ischemia [3]. Three patients had a 1 month flurry of daily attacks
of migraine auras with or without headache. A severe internal carotid stenosis/occlusion and reduced regional
cerebral blood flow was demonstrated. Borderline ischemia may thus have primed the brain for developing
migrainous aura with or without headache. Four patients had a combination of permanent deficits after the
very first migraine attack, severe atherosclerosis, risk factors for stroke, advanced age, and no family history of
migraine. In these cases, the evidence indicates that thromboembolic ischemia triggered an attack of migraine
with aura.
In addition to the seminal publication of Olesen et al., Kurth et al. have compiled a list of disorders that might
manifest with migraine aura-like symptoms or increase the risk of migrainous headaches with aura and stroke (Ta-
ble 10.1) [4]. These are disorders where the aura and migraine headache are secondary to the underlying disease and
not a primary syndrome. Furthermore, case-control studies have demonstrated that the risk of stroke is doubled in
patients with MWA, but not in MWoA [5e7].
10. MIGRAINE HEADACHE: CLINICAL ASSOCIATION WITH PFO AND OBSERVATIONAL STUDIES118
V. MIGRAINE AND PFO
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PATHOPHYSIOLOGY OF MIGRAINE AND MIGRAINE AURA IN
PATIENTS WITH RIGHT-TO-LEFT SHUNTS
Current evidence indicates that migraine is not a disease per se, but rather a pathophysiologic reaction of the brain
in health and disease.
A typical migraine attack can be divided into:
- the premonitory phase where mood change, yawning, concentration difficulties, or polyuria can occur,
- the aura phase preceding or accompanying the headache,
- the headache phase
- the postdrome phase after resolution of headache.
Electrophysiologic, positron emission tomography (PET), and magnetic resonance imaging (MRI) studies have
shown hypothalamic activity changes already in the hours preceding the headache and later alterations in the tha-
lamocortical circuits and cortical activity, as well as brainstem activation. The release of neuropeptides, such as calci-
tonin geneerelated peptide (CGRP), appears as an important link to the generation of pain [8]. In animal
experiments, cortical spreading depolarization, previously described as cortical spreading depression, has been
shown to be the neurophysiological substrate of aura [9]. Functional MRI and magnetoencephalography have
corroborated the correlation of cortical spreading depolarization and migraine aura in humans [10,11]. It has also
been shown that cortical spreading depolarization can activate the trigeminovascular system, i.e., pain signaling
via both peripheral trigeminal and central descending pathways, that may then trigger migraine headache [12,13].
Cortical spreading depolarization seems to trigger migraine attacks without a premonitory phase, and it can be
elicited by many acute triggers. In animals, electrical or mechanical stimulation, hypoxia, ischemia, emboli without
ischemia, local changes in ion concentration, and various substances including air bubbles, cholesterol crystals, or
TABLE 10.1 Disorders Associated With Stroke and Secondary Migraine With Aura.
Disorders with brain vessel wall abnormalities
CADASIL (NOTCH3 mutations)
Brain arteriovenous malformations
Leptomeningeal angiomatosis (SturgeeWeber syndrome)
Moyamoya syndrome
Hereditary hemorrhagic telangiectasia
Sneddon syndrome
Mitochondrial disorders (MELAS)
Disorders related to COL4A1 mutations
Disorders related to TREX1 mutations
Cardiac disorders
PFO with or without atrial septal aneurysm
Cardiac myxoma
Blood disorders
Antiphospholipid antibody syndrome
Systemic lupus erythematosus
Essential thrombocythemia
Polycythemia
CADASIL ¼ cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
COL4A1 ¼ collagen type IV alpha 1 chain; MELAS ¼ mitochondrial encephalopathy, lactic acidosis, and
stroke-like episodes; TREX1 ¼ three prime repair exonuclease 1.
Reproduced from Kurth T, Chabriat H, Bousser MG. Lancet Neurol 2012;11:92e1000.
V. MIGRAINE AND PFO
PATHOPHYSIOLOGY OF MIGRAINE AND MIGRAINE AURA IN PATIENTS WITH RIGHT-TO-LEFT SHUNTS 119
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endothelin were shown to trigger cortical spreading depolarization [4]. Similarly in humans, the aura can be
triggered acutely by focal ischemia, small cortical subarachnoid hemorrhages, cerebral venous thrombosis, focal
hypoperfusion without ischemia, or emboli [4]. In patients with right-to-left shunts (RLS), vasoactive substances
such as serotonin (5-hydroxytryptamine), platelet emboli, or paradoxical emboli or gaseous bubbles in divers or
simply hypoxemic blood may bypass the lung filter and trigger cortical spreading depolarization and thus elicit
migraine aura [14e17]. In rats, it has been proved that microemboli can cause cortical spreading depolarization
[18]. By analogy, microemboli that bypass the lung filter in patients with RLS could explain the pathophysiology
of migraine attacks in patients with pat ent foramen ovale (PFO), atrial septal defect, or pulmonary arteriovenous
malformations by triggering cortical spreading depol arization.
In MWoA, unlike in MWA, cortical spreading depolarization has not been demonstrated. Blood flow changes in
the brainstem may occur in attacks of MWoA, as may cortical changes of regional cerebral blood flow secondary to
pain activation. However, cerebral blood flow imaging shows no changes suggestive of cortical spreading depolar-
ization during such attacks [1].
CASE-CONTROL STUDIES OF PREVALENCE OF MIGRAINE IN INDIVIDUALS WITH
PFO AND PREVALENCE OF PFO IN INDIVIDUALS WITH MIGRAINE
Takagi and Umemoto recently published a meta-analysis of case-control studies of the association between
migraine and PFO [19]. They identified 21 eligible studies, 17 with cases of migraine and controls of no migraine,
and 4 studies with cases of PFO and controls of no PFO. In total, their meta-analysis included data on 5572 partic-
ipants. Despite noted heterogeneity in the definition of cases and controls among the studies, they included all of
these studies in the quantitative meta-analysis.
Prevalence of Migraine in Individuals With PFO and Vice Versa
Pooled analyses of 17 unadjusted and only 4 adjusted relative risk estimates demonstrated a 3.36-fold (unadjusted
OR, 3.36; 95% CI, 2.04e5.55; P < .00001) and 3.17-fold (adjusted OR, 3.17; 95% CI, 1.75e5.75; P ¼ .0001) MWA
prevalence in PFO patients relative to no-PFO subjects, respectively. A pooled analysis of 14 unadjusted relative
risk estimates demonstrated a nonsignificant 1.30-fold frequency of migraine-without-aura prevalence (unadjusted
OR, 1.30; 95% CI, 0.85e1.99; P ¼ .22) among patients who had a PFO compared to those with no PFO.
Takagi and Umemoto demonstrated in their subsequent pooled analyses of 17 unadjusted and 6 adjusted relative
risk estimates a statistically significant 2.46-fold (unadjusted OR, 2.46; 95% CI, 1.55e3.91; P ¼ .0001) and 1.94-fold
migraine-with/without-aura prevalence (adjusted OR, 1.94; 95% CI, 1.24e3.05; P ¼ .004) in PFO patients relative
to no-PFO subjects, respectively [19]. Migraine with/without-aura denotes either MWA or MWoA.
To assess the impact of qualitative heterogeneity in stu dy design and participant selection on the pooled effect
estimate, Takagi and Umemoto performed several sensitivity analyses. Exclusion of any single study from the
unadjusted analysis did not substantively alter the overall result of their analysis for MWA, MWoA, and migraine
with/without-aura, respectively. To assess publication bias, they generated a funnel plot of the logarithm of odds
ratio versus the reciprocal of standard error for each study for MWA, MWoA, and migraine with/without-aura,
respectively. There was no evidence of significant publication bias (2-tailed P ¼ .19 for migraine with aura, .97 for
MWoA, and .43 for migraine with/without aura by the linear regression test).
Two large studies were published from China and Japan. The Chinese multicenter case-control study investi gated
the prevalence and grade of RLS in 931 patients (240 had MWA and 691 had MWoA) using contrast-enhanced trans-
cranial Doppler sonography; 282 healthy adults served as controls [20]. The prevalence of RLS was 63.8% and 39.9%
in the MWA group and MWoA group, respectively, significantly higher than that of the healthy group (29.4%,
P < .001 for both). The positive rate of large RLS in the MWA group and MWoA group was 32.1% and 16.5%, respec-
tively, significantly higher than in the healthy group (6.4%, P < .001 for both). This large multicenter case-control
study confirmed previous findings that there is an association between RLS and migraine with and without aura,
especially when the shunt size is large. The Japanese study had a smaller cohort [21]. Iwasaki et al. examined 112
patients with MWA and MWoA using contrast transcranial Doppler sonography. The prevalence of RLS in the
MWA group was significantly higher than in the MWoA group (RLS, 62.9% vs. 44.0%, P ¼ .046; PFO, 54.8% vs.
30.0%, P ¼ .008).
V. MIGRAINE AND PFO
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According to a small retrospective Italian study, MWA patients with a positive family history for migraine were
shown to have a higher prevalence of PFO [22].
Shunt Size in Individuals With PFO and Migraine
Wilmshurst examined 200 individuals referred for investigation of decompression illness to determine the
association between right-to-left shunts and migraine aura after diving, and migraine in daily life unconnected
with diving [15]. Migraine with aura in daily life unconnected with diving occurred significantly more frequently
in individuals who had a large shunt which was present at rest (38 of 80; 47.5%) compared with those who had a
shunt which was smaller or only seen after a Valsalva maneuver (4 of 40; 10%) or those with no shunt (11 of 80;
13.8%) (P < .001). Post-dive migraine aura was significantly more frequent in individuals who had a large resting
shunt (21 of 80; 26.3%) compared with those who had a shunt that was smaller or only seen after a Valsalva maneu-
ver (5 of 40; 12.5%) or no shunt (1 of 80; 1.3%) (P < .001). Thus, individuals with a large RLS have an increased
prevalence of migraine with aura in daily life, and they also have an increased incidence of migraine aura after dives.
Schwerzmann et al. performed a case-control study with transesophageal contrast echocardiography in 93
consecutive patients who had migraine with aura and 93 healthy controls [23]. A PFO was present in 44 (47%
[95% CI 37%e58%]) MWA patients and 16 (17% [95% CI 10%e26%]) control subjects (OR 4.56 [95% CI
1.97e10.57]; P < .001). A small shunt was equally prevalent in migraineurs (10% [95% CI 5%e18%]) and controls
(10% [95% CI 5%e18%]), but a moderate-sized or large shunt was found more often in the migraine group (38%
[95% CI 28%e48%] vs. 8% [95% CI 2%e13%] in controls; P < .001). The presence of more than a small shunt
increased the odds of having migraine with aura by 7.78-fold (95% CI 2.53e29.30; P < .001).
In an observational study using transesophageal contrast echocardiography, PFO with an atrial septal aneurysm
was strongly associated with MWA (OR 2.71, 95% CI 1.23e5.95, P ¼ .01) and shunts in such patients were larger than
in those with lone PFO [24]. In a small transcranial Doppler study, RLS size was larger in patients with MWA than in
those with stroke related to PFO [25].
In patients with PFO, MWA attacks occurred earlier in life compared to patients without PFO as demonstrated in
a retrospective analysis (mean age onset: patients with PFO 17.6 years SD 8.2; patients without PFO 29.8 years SD
10.4; ManneWhitney test, P < .0001) [22]. Furthermore, increasing size of RLS as assessed with transcranial Doppler
was associated with occurrence of MWA at younger age (Spearman Rhod481, P < .0001) [22].
EFFECT OF PFO CLOSURE ON MIGRAINE SEVERITY
Two recent systematic reviews have summarized the effect of migraine closure on migraine headache severity
[26,27]. Lip and Lip analyzed 18 case series and categorized the headaches into “resolved,” “improvement,” “no
change,” and “worsened.” For 9 of these studies, they presented the results for MWA and MWoA patients separately.
Migraine with aura resolution varied from 28.6% to 92.3% and MWoA resolution from 13.6% to 82.9%. Migraine with
aura improvement ranged from 4.17% to 64.3% and from 0% to 68.2% in MWoA. “No change” and “worse” were
noted in up to 28.6% and 4.48% of MWA and 33.3% and 0% of MWoA patients, respectively.
Tariq et al. identified 20 observational studies examining the effect of PFO closure on migraine. Six of them
included a control group [27]. Antiplatelet therapy after PFO closure was standard intervention in all studies except
in 1 case series. Eight of these studies reported outcomes defined as reduction in migraine intensity and frequency in
a qualitative manner (improved, worsened, decrease in disabling attacks) in contrast to the standard outcome mea-
sures in migraine studies defined by reduction in number of migraine days or other quantitative outcomes. A total of
1194 migraine patients underwent PFO closure (mean age 35e54 years). The mean follow-up time after PFO closure
ranged from 3 to 50 months. The subset of patients who had MWA ranged in different studies from 13% to 100%.
Resolution of migraine was reported in 10%e83% of patients, improvement in 14%e83%, no change in 1%e54%,
and worsening in 4%e8%.
The range of patients lost to follow-up was reported between 0% and 17%. Only 2 of the 6 case-control studies
reported OR estimates. One study reported OR 0.008 (95% CI, 0.0008e0.0801) and the second study reported OR
at 25.2, 95% CI, 7.6e83.6, sugge sting significant heterogeneity [28,29]. This reflects the ratio of the odds of overall
migraine improvement in PFO closure patients (cases) to the group of patients who did not undergo the procedure
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(controls). Tariq et al. determined the grade of evidence to be low to moderate and concluded that PFO closure does
not significantly reduce the intensity and severity of migraine.
Twelve studies in Tariq’s analysis failed to address procedural complications. In the studies that did report
procedural adverse events, the complications ranged from 0% to 12%. The most common complications were atrial
fibrillation and inguinal hematoma, the latter either due to catheterization or an effect of antiplatelet medication,
or both. Rare complications included transient ischemic attacks, ischemic stroke, and infective endocarditis.
THE LINK BETWEEN MIGRAINE, PFO, AND STROKE
In a prospective population-based study, the Oxford Vascular Study, both migraine with and without aura
increased the odds of cryptogenic events, both transient ischemic attacks and stroke, with an odds ratio of 1.73
(95% CI, 1.38e2.16) relative to those without migraine [30]. According to the above-mentioned case-control studies,
however, the risk of stroke is increased only in patients with MWA and this is independent of vascular risk factors
[5e7].
Several neuroimaging studies using MRI have shown an increased prevalence of clinically silent white matter
hyperintensities in people with migraine that seemed to increase with the frequency of migraine attacks [31e35].
While 2 studies reported lesion locations predominantly in the cerebellum and brainstem , another study found le-
sions mainly outside the cerebellum and brainstem.
According to the case-control studies, where the risk of stroke is doubled in migraine with aura, it is the aura that
seems to be the link between migraine and stroke [4]. However, according to clini cal experience, patients with a his-
tory of migraine can suffer a stroke that does not present with an aura, and patients without migraine can present
with aura as an early manifestation of their stroke. The pathophysiological explanation seems to be cortical
spreading depolarization, which refers to waves of abrupt, sustaine d mass depolarization across the gray matter
of the central nervous system [36]. Cortical spreading depolarization, which spreads from neuron to neuron in
the affected tissue, is characterized by a rapid loss of the neuronal transmembrane ion gradients. It can be induced
by hypoxic conditions such as ischemia and facilitates neuronal death in energy-compromised tissue. Spreading de-
polarization in migraine aura, where depolarization is assumed to revert in well-nourished tissue, is typically
benign. However, the spreading depolarization wave can propagate from an energy-depleted tissue like the co re
of an ischemic stroke into surrounding, well-nourished tissue. In such a situation, the clinical presentation of stroke
can be with an aura. This has been shown in malignant middle cerebral artery infarction by subdural electrocorti-
cography where spreading depolarization and depression occurs in the periinfarct zone, causing secondary
neuronal damage and infarct expansion [37]. Within the ischemic penumbra, cortical spreading depolarization
seems to be a common phenomenon and human studies suggest that each cycle of cortical spreading depolarization
results in progressive loss of penumbral tissue [38].
Migraine stroke is defined as 1 or more migraine aura symptoms occurring in association with an ischemic brain
lesion in the appropriate territory demonstrated by neuroimaging, with onset during the course of a typical migraine
with aura attack.
Wolf et al. published a series of 17 patients with migrainous infarcts [39]. Eleven (65%) had a PFO. The migrainous
infarctions mostly occurred in the posterior circulation, and in younger women with a history of migraine with aura.
Waters et al. reported a series of 14 patients with ischemic stroke with evidence of acute infarction on MRI who pre-
sented with symptoms consistent with a clinical diagnosis of migraine aura, 7 due to cardioembolic, atheroembolic,
or small vessel disease [40]. Seven were diagnosed as embolic stroke of unknown source (ESUS). Of these, a PFO was
identified in 4 out of 5 of those who underwent transoesophageal echocardiography, with large right-to-left shunts
demonstrated in 3. This case series lends further support to the assumption that emboli, whatever their size, can
trigger a migraine aura. This also suggests that the stroke that occurs more frequently in MWA is due to a PFO
with R to L embolus and not the migraine process itself.
Figs. 10.1 and 10.2 show 2 examples of migraine strokes.
Stroke in Patients with Migraine
Wilmshurst et al. were the first to report a high prevalence of PFO in migraineurs who developed a stroke. In his
study of 60 patients who presented with a stroke and had a histo ry of migraine with aura, 84% had evidence of a PFO
with an RLS [41]. Similar evidence is presented in the publication of West et al. [42]. In their analysis of 68 well-
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FIGURE 10.2 A 75-year-old woman with a migraine stroke but without an earlier history of headaches had experienced a scintillating scotoma
for about 20 minutes the previous morning, followed by a holocephalic headache. Three hours later, similar visual symptoms recurred for
10 minutes and for 5 minutes on the following morning. The magnetic resonance imaging scan showed acute ischemic lesions in the left cerebellar
hemisphere (A) and the left thalamus (B) and scattered small lesions in the occipital cortex (C). All other ancillary investigations were normal
indicating a cryptogenic stroke. There was no PFO with transesophageal echocardiography.
FIGURE 10.1 A 41-year-old woman with a migraine stroke and a PFO had a history of MWA and MWoA as a teenager. Most of her attacks
were without aura and rarely with a visual aura. One morning she felt paresthesia on the right angle of her mouth, which spread quickly to the
entire right side of her body. A dull pressure around her head ensued. The following day she came to the emergency room because of right-sided
loss of sensation. The diffusion-weighted magnetic resonance imaging scan showed an acute ischemic stroke of the left thalamus (A) and
hippocampus (B). Transesophageal echocardiography showed a PFO and no other potential cause of stroke was found. In summary, this patient
suffered a PFO-associated stroke. The initial clinical manifestation was a migraine with aura attack. Of note, the sensory aura at the beginning of
the attack was different from all her previous attacks.
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