Proof of Premise: Proof of Paradoxical Embolism

Paradoxical embolism, due to right-to-left shunt defects, is commonly considered as presumptive, cryptogenic cause of stroke. However, demonstration of clot in-transit through defects demonstrated by direct visualization by autopsy, surgery, echocardiography, or CT/MRI imaging provides uniquely definitive proof not evident for any other cause of stroke.

Connheim J. Thrombose Und Embolie Vorlesung Uber. Pathologie Bd1, Hirschwald 1877.

Thompson T, Evans W. Paradoxical embolism. Quart J Med 1930; 23: 135-149.

Johnson BI. Paradoxical embolism. J Clin Path 1951; 4: 316-332.

Meister SG, Grossman W, Dexter L, et al. Paradoxical embolism – diagnosis during life. AM J Med 1972; 53: 292-98.

Brogno DJ. Embolus Interuptus. NEJM 1994; 33:330.

Ward R, Jones D, Haponik EF. Paradoxical embolism, an under-diagnosed problem. Chest 1995; 108: 549-558.

Carroll JD. Double standards in the world of ASD and PFO management: Closure for paradoxical embolism. Catheter and Cardiovascular Intervention 2009; 74: 1070-1071.

Meyers PO et al, Impending paradoxical embolism: Systemic review of prognostic factors and therapy. Chest 2010; 137:164-70

Risk Stratification

Risk stratification is the basis of all medical therapy used in selecting relative risk of treatment versus risk of the disorder. For example, over ten different risk stratification models have been published for left main stenting procedures. Stroke is particularly important as the outcome is often permanent and irreversible.

The American Academy of Neurology Practice Parameter for PFO (Messe S et al. Neurology 2004; 62: 1042-1050) has served as the original core of the risk stratification approach for our program for managing patients with right-to-left shunt. Our evidence-based risk stratification approach has been developed over the past decade through independent yearly reviews by the IHC Institutional Review Board (HDE period 2001-2006), University of Utah Independent Research Review (Potkin Review 2004), LDS Cardiology Division Review (2007), IMC Cardiology Division review (2010), national meeting presentations (ACC, TCT, AHA, Heart Brain Symposium), peer reviewed manuscript publications (J Interventional Cardiology 2010, 2011, 2012) and the recent textbook, Patent Foramen Ovale (AminZ, ed. 2015)

Risk stratification for PFO/ASD closure is best summarized by the Lausanne Study conclusions which are part of the American Academy of Neurology recommendations.

“In summary our study shows that the first brain event in patients with PFO may often be devastating as one-half of the patients suffered a severe initial stroke with disability. The demonstration of factors associated with increased risk of recurrence in our study and other studies suggest that high risk patients with PFO exist.” (Bogousslavsky J. Neurology 1996; 46: 1301-05)

Clinical Brain Event

Defining the presence and significance of any neurological event is pivotal to any serious treatment options, including device implantation. Since 30% of all strokes are recurrent strokes (NINDS Database) the presence of any neurologic injury, however small, carries with it a serious prediction for recurrent event. Therefore, a clear understanding and agreement as to permanent brain injury, transient brain injury, and chance of disability becomes critical to decisions regarding implementation of treatment.

1. Sacco RL, Adams R, Alberts MJ, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attacks: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke affirms the value of this guideline. Stroke 2006; Feb, 37 (2): 577-617.

2. Messe SR, Silverman IE, Kizer JR, et al, Practice parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: American Academy of Neurology; 2004; 62:1042

3. Heart and Stroke Statistics 2009: a report from the American Heart Association Statistics Committee and the Stroke Statistics Subcommittee. Circulation 2009; 119: e21-e181.

4. European Stroke Organization: guidelines for management of ischemic stroke and transient ischemic attack 2008. Cerebrovasc Dis 2008; 25: 457-507.

5. Warns CA et al. AHA/ACC 2008 Guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology / American Heart Association task force on practice guidelines. Circulation 2008; 118: e714-e833.

6. Furie KL, Kasner SE, Adams RJ et al, Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association. 2011; 42:227-276

7. Kernan WN et al, Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association. 2014;45:2160-236

8. Saver JL et al, Call to revise guidelines. Letter regarding: Guidelines for the prevention of stroke in patients with stroke or transient ischemic attacks (2014). Stroke 2015; 46-85-86

9. Messe SR, KizerJR, Homma S et al, Practice Advisory: Recurrent stroke with patent foramen ovale: Report of the guidelines committee for the American Academy of Neurology. Neurology 2016’ 87:815-21

10. Easton JD, Saver JL, Alberts MJ, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association / American Stroke Association Stroke Council. Stroke 2009; 40: 2276-2293.

11. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med 2007; 167(22): 2417-22.

12. Howard BJ, McClure LA, Meschia JF, James F, et al. High prevalence of stroke symptoms among persons without a diagnosis of stroke or transient ischemic attack in the general population. Arch Intern Med 2006, 166: 1952-1938.

13. Howard G, Safford MM, Meschia JF, Moy CS, Howard VJ, Pulley L, Gomez CR, Crowther M. Stroke symptoms in individuals reporting no prior stroke or transient ischemic attack are associated with a decrease in indices of mental and physical functioning. Stroke 2007; Sep, 38 (9): 2446-52. Epub 2007 Aug 2.

14. Wadley VG, McClure LA, Howard VJ, Unverzagt FW, Go RC, Moy CS, Crowther MR, Gomez CR, Howard G. Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Stroke 2007; Apr, 38 (4): 1143-7. Epub 2007 Feb 22.

Conclusion

a. Clinical stroke is defined as a focal neurologic event with duration of greater than 24 hours (AAN Criteria 2006).

b. Stroke is defined as a focal neurologic event associated with MRI brain imaging, including T2/FLAIR abnormalities (American Stroke Association Guidelines).

c. TIA is defined as a focal neurologic brain event lasting less than 24 hours (AAN criteria) or a focal neurologic brain event of less than 24 hours with negative brain imaging (ASA criteria).

d. A transient ischemic attack is no longer considered a benign event and has significant early and late stroke and disability risk. TIA should be managed with the same approach as for stroke as the cause and treatment are the same.

e. Brief neurologic events, as defined by the REGARDS studies, are associated with permanent physical impairment and cognitive impairment.

f. Societal guidelines for ASD closure are broad and well accepted

g. Societal guidelines for PFO closure are variable and contested

MRI Brain Imaging

All current recommendations favor magnetic resonance imaging of the brain over CT imaging for stroke/ TIA management. Terms such as “white spots,” “UBO” (unidentified bright objects), and “nonspecific white matter” are no longer acceptable. Brain MRI imaging prior to 2002 could not distinguish between the presence of water (spinal fluid) and brain injury, hence the terminology “white spots.” Modern imaging utilizes a FLAIR sequence (Fluid Attenuation Inversion Recovery). This means that defects which are T2/ FLAIR positive are not water and are, therefore, of significance.

15. Easton JD, Saver JL, Alberts MJ, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council. Stroke 2009; 40: 2276-2293.

16. Inatomi Y, Kimura K, Yonehara T, Fujioka S, Uchino M. DWI abnormalities and clinical characteristics in TIA patients. Neurology 2004; Feb 10, 62 (3): 376-80.

17. Oppenheim C, Lamy C, Touzé E, Calvet D, Hamon M, Mas JL, Méder JF. Do transient ischemic attacks with diffusion-weighted imaging abnormalities correspond to brain infarctions? AJNR AM J Neuroradial 2006; Sep, 27 (8): 1782-7.

18. Jauss M, Wessels T, Trittmacher S, Allendörfer J, Kaps M. Embolic lesion pattern in stroke patients with patent foramen ovale compared with patients lacking an embolic source. Stroke 2006; Aug, 37 (8): 2159-61. Epub 2006 Jul 6.

19. Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a risk factor for subclinical brain lesions. JAMA 2004; Jan 28, 291 (4): 427-34.

20. Kruit MC, Launer LJ, van Buchem MA, et al. MRI findings in migraine. Rev Neurol 2005; 161: 661-665.

21. Kruit MC, Launer LJ, Ferrari MD, et al. Brainstem and cerebellar hyper-intensity lesions in migraine. Stroke 2006; 37: 1109-1112.

22. Kruit MC, Launer LJ, Ferrari MD, et al. Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA Study. Brain 2005; 128: 2068-2077.

23. Kuller LH, Longstreth Jr WT, Arnold AM, Bernick C, Bryan RN, Beauchamp Jr NJ, Cardiovascular Health Study Collaborative Research Group. White matter hyper-intensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 2004; Aug, 35 (8):1821-5. Epub 2004 Jun 3.

24. Bonati LH, Kessel-Schaefer A, Linka Z, et al. Diffusion-weighted imaging in stroke attributed to patent foramen ovale: significance of concomitant atrial septal aneurysm. Stroke 2006; 37: 2030-2034.

25. Feurer J, Sadikovic S, Esposito L, et al. Lesion pattern in patients with cryptogenic stroke with and without right-to-left shunt. Eur J Neurol 2009; 16: 1077-82.

26. Huang YY et al, Differential lesions on T2WI and FLAIR sequences in cryptogenic stroke patients with patent foramen ovale. Neurologist 2015; 20:75-9

Conclusion

a. Brain MRI white matter lesions are clinically significant and are associated with adverse outcome of disability, stroke, and cognitive dysfunction.

b. T2/FLAIR lesions on modern brain MRI imaging have been demonstrated to be a natural evolution from diffusion-positive stroke and, therefore, represent healed, previous stroke (Oppenheim; Inatomi). Multifocal T2/FLAIR lesions are most compatible with “proximal cause” stroke, i.e. embolic or paradoxical embolic source.

c. Brain MRI imaging in migraine patients demonstrates abnormalities and posterior circulation stroke which are compatible with embolic event.

d. Multiple ischemic brain MRI lesions are three times more common in cryptogenic stroke patients with right-to-left shunt (Feurer et al.). The association remains after correction for vascular risk factors for stroke (Bonati et al.).

Resting Shunt as a Manifestation of Permanent Shunt: High Risk Feature

Multiple lines of evidence demonstrate that resting shunt has the highest risk for paradoxical embolization. This conclusion derives from the very high incidence of stroke and brain abscess in cyanotic congenital heart disease (37% in the first year of life), 40% fatal or disabling stroke in patients with pulmonary AV malformations, and a variety of PFO studies.

27. Giardini A, Donti A. Formigari R, Salomone L, Palareti G, Guidetti D, Picchio FM. Spontaneous large right-to-left shunt and migraine headache with aura are risk factors for recurrent stroke in patients with a patent foramen ovale. Int J Cardiol 2007; Sep 3, 120 (3): 357i-62. Epub 2006 Dec 12.

28. De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM, Beccia M, Colonnese C, Fedele F, Fieschi C, Pandian NG. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; Oct, 31 (10): 2407-13.

29. Caputi L, Carriero MR, Falcone C, Parati E, Piotti P, Materazzo C, Anzola GP. Transcranial Doppler and transesophageal echocardiography: comparison of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection. J Stroke Cerebrovasc Dis 2009; Sep-Oct, 18 (5): 343-8.

30. Cartoni D, De Castro S, Valente G, Costanzo C, Pelliccia A, Beni S, Di Angelantonio E, Vitali Serdoz L, Fedele F. Identification of professional scuba divers with patent foramen ovale at risk for decompression illness. Am J Cardiol 2004; Jul 15, 94 (2): 270-3.

31. Barak MN, Katz Y. Microbubbles: pathophysiology and clinical implications. Chest 2005; 128: 2918-2932.

32. Vigna C, Marchese N, Inchingol V, et al. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions. A case control study. JACC Cardiovascular Intervention 2009; 2: 107-13.

33. Polak JS, Saluja S, et al. Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations. J Vasc Interventional Radiology 2006; 17: 35-44.

34. Mable WY, deVeber G, Roach ES, Rela AR, et al. Stroke in children: recognition, treatment, and future directions. Semin Pediatr Neurol 2000; 7: 309-17.

35. Blom NA, Ottenkamp J, Jongeneel TH, et al. Morphogenic differences of secundum atrial septal defects. Pediatr Cardiol 2005; 26: 338-43.

36. Kumar K. Neurological complications of congenital heart disease. Indian Journal of Pediatrics 2000; 67: 15-9.

Conclusion

a. Rest shunting represents permanence of shunt and is associated with increased risk of stroke and paradoxical embolism.

b. High level rest shunting is primarily associated with fossa ovalis defects rather than PFO, as PFO are defined as a unidirectional flap valve defects.

c. Rest shunting is affected by posture and may be severe when upright and negative at rest. TCD is best for defining rest shunt presence and severity.

d. Rest shunting is also associated with increased risk of decompression illness.

e. The Vigna classification incorporates rest and Valsalva shunting and is a reliable way of overall risk assessing patients.

Valsalva/Respiratory Strain Shunt: Large Defect and Latent Shunt

There is a modest amount of medical literature of low event rates in patients who have very minor shunting. This includes studies such as PICSS, SPARC, and CLOSURE 1. Conversely, there is a very large amount of literature that indicates the risk of stroke and recurrent stroke is strongly related to the size of defect or more clearly the severity of shunt. This is true for measurements as to bubble count, TCD shunting, balloon sizing, or membrane separation.

37. Sastry S, Riding G, Morris J, Taberner D, Cherry N, Heagerty A, McCollum C. Young Adult Myocardial Infarction and Ischemic Stroke: the role of paradoxical embolization and thrombophilia (The YAMIS Study). J Am Coll Cardiol 2006; Aug 15, 48 (4): 686-91. Epub 2006 July 25.

38. Homma S, Di Tullio MR, Sacco RL, Mihalatos D, Li Mandri G, Mohr JP. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study. Stroke 1994; Mar, 25 (3): 582-6.

39. Anzola GP, Zavarize P, Morandi E, Rozzini L, Parrinello G. Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale. Eur J Neurol 2003; Mar, 10 (2): 129-35.

40. Serena J, Segura T, Perez-Ayuso MJ, Bassaganyas J, Molins A, Dávalos A. The need to quantify right-to-left shunt in acute ischemic stroke: A case-control study. Stroke 1998; Jul, 29 (7): 1322-8.

41. De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM, Beccia M, Colonnese C, Fedele F, Fieschi C, Pandian NG. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; Oct, 31 (10): 2407-13.

42. Schuchlenz HW, Weihs W, Berghol D, et al. Secondary prevention after cryptogenic cerebrovascular events in patients with patent foramen ovale. Int J Cardiol 2005; 101:7782.

43. Serena J, Marti-Fabregas J, Santamarina E, et al. Recurrent stroke and massive right-to-left shunt. Results from the prospective Spanish multicenter (CODICIA Study). Stroke 2008; 39: 3131.

44. Wessler BS et al, The RoPE Score and right-to-left shunt severity by transcranial Doppler in the CODICIA study. Cerebrovasc Dis 2015; 40:52-8

Valsalva Respiratory Strain: Small Shunt and Low Risk of Stroke

45. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale; patent foramen ovale and cryptogenic stroke study. Circulation 2002; 105: 2625-2631.

46. DiTullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multi-ethnic population. J Am Coll Cardiol 2007; 49: 797-802.

47. Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: Innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006; 47: 440-5.

48. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular events. Mayo Clin Proc 2006; 81: 602-608.

49. Furlan A. CLOSURE 1: a multicenter, randomized clinical trial to evaluate the safety and efficacy of the STARflex septal closure system versus best medical therapy in patients with a stroke or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale. Circulation 2010 (Supplement); AHA 2010 oral abstract.

Conclusion

a. The risk of stroke and recurrent event is related to defect size manifest by measured size, severity of shunting by TCD, and presence of atrial septal aneurysm.

b. The risk of stroke or recurrent stroke appears to be low in patients with trivial shunt — low stroke rate for the PICSS Study where 60% to 70% of the patients had trivial shunting and YAMIS where stroke rates were low for mild shunting.

Transcranial Doppler (TCD) for Risk Stratification

Transcranial Doppler is a simple noninvasive technique which has been available for shunt diagnosis and quantification for over ten years. This technique is not anatomy specific but does provide important physiologic information which is quantitative and reproducible.

50. Jauss M, Zanett E, for consensus conference. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovascular Disease 2010; 490-491.

51. Angeli S, Delsette M, Beelke M, et al. Transcranial Doppler in the diagnosis of cardiac patent foramen ovale. Neuro Science 2001; 22: 353-356.

52. Spencer MP, Moehring MA, Jesurum J, et al. Power M-mode transcranial Doppler for diagnosis of PFO and assessing transcatheter closure. J of Neuro Imaging 2004; 14: 342-349.

53. Woods T, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiography 2006; 19: 215-222.

54. Sastry S, McNab A, Daly K, et al. Transcranial Doppler detection of venous-to-arterial circulation shunts: criteria for patent foramen ovale. J Clin Ultrasound 2009; 37: 276-280.

55. Zito C, Dattilo G, Oreto G, et al. Patent foramen ovale: Comparison among diagnostic strategies in cryptogenic stroke and migraine. Echocardiography 2009; 26: 495-503.

56. Caputi L, Carriero MR, Parati E, et al. Postural dependency of right-to-left shunt: role of contrast-enhanced transcranial Doppler and its potential clinical implications. Stroke 2008; 39: 2380-2381.

57. Lao AY, Sharma VH, Tsivgoulis G, et al. Effect of body positioning during transcranial Doppler detection of right-to-left shunts. Eur J Neuro 2007; 14: 1035-1039.

58. Orzan F, Laboni W, Bonzano A, et al. Follow-up of residual shunt after patent foramen ovale closure. Acta Neuro Scand 2009; 10: 1600.

59. Lao AY, Sharma VJ, Tsivgoulis G, et al. Detection of right-to-left shunts: comparison between international consensus and Spencer logarithmic scale criteria. J Neuro Imaging 2008; 18: 402-406.

Conclusion

a. Transcranial Doppler is a simple reproducible technique providing functional information.

b. Transcranial Doppler compared with transesophageal echo is superior for detection of physiology related to position, rest shunting, and amount of shunting.

c. Power M-mode transcranial Doppler is superior to single gate Doppler (International criteria).

d. Transcranial Doppler measures physiology of shunt but is not anatomy specific. Utilization in conjunction with contrast bubble TTE is reasonable reserving trans- esophageal echo for specific problems and specifications.

Atrial Septal Aneurysm as a Risk for Stroke

Although there is some disagreement primarily based on the PICSS Study, most studies of interatrial septal aneurysm indicate that this abnormality is associated with an increased risk of stroke, increased risk of recurrent stroke and increased risk of stroke disability.

60. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebral vascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 24, 345: 1740-6.

61. De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM, Beccia M, Colonnese C, Fedele F, Fieschi C, Pandian NG. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; Oct, 31 (10): 2407-13.

62. Bonati LH, Kessel-Schaefer A, Linka AZ, Buser P, Wetzel SG, Radue EW, Lyrer PA, Engelter St. Diffusion-weighted imaging in stroke attributable to patent foramen ovale: Significance of concomitant atrial septal aneurysm. Stroke 2006; Aug, 37 (8): 2030-4. Epub 2006 Jun 29.

63. Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007; Nov 29, 357 (22): 2262-8.

64. Meier B. Stroke in migraine: a cardiologist’s headache. Heart 2009; 95: 595-602.

65. Lamy C, Gianesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale; the PFO-ASA (atrial septal aneurysm) Study. Stroke 2002; 33: 706-11.

66. Carroll JD et al, Closure of patent foramen ovale vs medical therapy after cryptogenic stroke. NEJM 2013; 368: 1092-100

Conclusion

a. Although some differing results exist, there is general consensus that atrial septal aneurysm is associated with an increased risk of stroke.

b. The risk of stroke is increased due to interatrial septal aneurysm regardless of age.

c. The presence of atrial septal aneurysm may occur without septal defects but when present with a defect in patients with events appears to increase the risk of recurrent event fourfold even when treated with antiplatelet therapy.

IHS Migraine Headache as a Risk for Stroke

An extensive literature spanning 40 years now demonstrates that migraine headache, particularly with aura, is associated with a substantial increased risk of stroke. This information derives from brain imaging studies, prospective follow-up studies (Women’s Health Study), and meta-analysis of 14 studies over 40 years.

67. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005; Jan 8, 330: 63.

68. Giardini A, Donti A, Formigari R, Salomone L, Palareti G, Guidetti D, Picchio FM. Spontaneous large right-to-left shunt and migraine headache with aura are risk factors for recurrent stroke in patients with a patent foramen ovale. Int J Cardiol 2007; Sep 3, 120 (3): 357-62. Epub 2006 Decrease 12.

69. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Migraine and risk of cardiovascular disease in women. JAMA 2006; Jul 19, 296 (3): 283-91.

70. Bogousslavsky J, Garazi S, Jeanrenaud X, Aebischer N, Van Melle G. Stroke recurrence in patients with patent foramen ovale: The Lausanne Study, Lausaunne Stroke with Paradoxical Embolism Study Group. Neurology 1996; May, 46 (5): 1301-5.

71. Wilmshurst P, Nightingale S, Pearson M, Morrison L, Walsh K. Relation of atrial shunts to migraine in patients with ischemic stroke and peripheral emboli. Am J Cardiol 2006; Sep 15, 98 (6): 831-3. Epub 2006 Aug 2.

72. Swartz RH, Kern R. Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis. Archives of Neurology 2004; 61: 1366-1368.

73. Bushnell CD, Jamison M, et al. Migraines during pregnancy linked to stroke and vascular disease: U. S. population-based case control study. BMJ 2009; 338: b664.

74. Anzola GP, Morandi E, Casilli F, et al. Different degrees of right-to-left shunting predict migraine and stroke. Data from 420 patients. Neuro 2006; 66: 765-767.

Conclusion

a. Migraine is strongly associated with stroke with a significant increased risk for the presence of migraine, use of oral contraceptives, smoking, and pregnancy.

b. Stroke related to migraine is most likely due to the presence of right-to-left shunting as 60% of patients have right-to-left shunting. Traditional vascular constriction views have been superseded by neurogenic views of migraine (spreading cortical depression).

c. Migraine in stroke is particularly important in patients with right-to-left shunting due to the increased risk related to contraception and pregnancy. Some (Meier et al.) have recommended closure as a primary indication for planned pregnancy.

d. Population-based studies (NOMAS and the Garg P Study Circulation) utilize population prevalence and diagnosis of PFO based upon a single bubble and are considered not to disprove the relationship.

Migraine Relief with Right-to-Left Shunt Resolution

Migraine headache is an inherited neurological disorder characterized by activation of a stereotypical brain migraine pathway by endogenous and exogenous triggers. Contemporary understanding of migraine refutes older concepts of vascular constriction and dilatation with imaging studies demonstrating meningeal activation / inflammation by the trigeminal nerve and spreading cortical depression. Migraine is often a disabling and progressive disorder which responds poorly to a large array of medications eventuating in opiate reliance.

Shunt-associated migraine has been recognized for over a decade since observations by Wilmshurst suggested improvement with migraine after resolution of shunt and a 60% prevalence of venous-to-arterial shunting (pulmonary AVM, ASD, and PFO) in migraine patients. Listed below are 28 observational studies and one meta-analysis which demonstrate improvement of migraine with shunt resolution of three structural causes of venous-to-arterial shunting (p-AVM, ASD, PFO) treated by multiple techniques (surgery, coil embolization, vascular plugs, and septal closure devices). A single randomized trial, MIST, has been considered negative but is mired in controversy over data suppression, slander litigation, presumed severe residual shunting (which would negate a negative finding), and poor device design and materials.

75. Butera G, Biondi-Zoccai GG, Carminati M, et al. Systematic review in meta-analysis of currently available clinical evidence on migraine in patent foramen ovale percutaneous closure: catheter. Cardiovasc Interv 2010; 75: 494-504.

76. Lip DZ et al, Patent foramen ovale and migraine attacks: a systematic review. Am J Med 2014; 127:411

77. Mojaddi MK, The association of patent foramen ovale and migraine. In Amin Z ed. Patent Foramen Ovale, 1st edition, Springer Verlag 2015

78. Anzola GP, Frisoni GB, Morandi E, Casilli F, Onorato E. Shunt-associated migraine responds favorably to atrial septal repair: a case-controlled study. Stroke 2006; Feb, 37 (2): 430-4. Epub 2005 Dec 22.

79. Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R. Association of interatrial shunts and migraine headaches: Impact of transcatheter closure. J Am Coll Cardiol 2005; Feb 15, 45 (4): 489-92.

80. Chessa M, Colombo C, Butera G, Negura D, Piazza L, Varotto L, Bussadori C, Fesslova V, Meola G, Carminati M. Is it too early to recommend patent foramen ovale closure for all patients who suffer from migraine? A single-centre study. J Cardiovasc Med (Hagerstown) 2009; May, 10 (5): 401-5.

81. Dubiel M, Bruch L, Schmehl I, Liebner M, Winkelmann A, Stretz A, Grad MO, Kleber FX. Migraine headache relief after percutaneous transcatheter closure of interatrial communications. J Interv Cardiol 2008; Feb, 21 (1): 32-7. Epub 2007 Dec 18.

82. Giardini A, Donti A, Formigari R, Salomone L, Prandstraller D, Bonvicini M, Palareti G, Guidetti D, Gaddi O, Picchio FM. Transcatheter patent foramen ovale closure mitigates aura migraine headaches abolishing spontaneous right-to-left shunting. Am Heart J 2006; Apr, 15 (4): 922, e1-5.

83. Giardini A, Donti A, Formigari R, Salomone L, Palareti G, Guidetti D, Picchio FM. Long-term efficacy of transcatheter patent foramen ovale closure on migraine headache with aura and recurrent stroke. Catheter Cardiovasc Interv 2006; Apr, 67 (4): 625-9.

84. Jesurum JT, Fuller CJ, Kim CJ, Krabill KA, Spencer MP, Olsen JV, Likosky WH, Reisman M. Frequency of migraine headache relief following patent foramen ovale “closure” despite residual right-to-left shunt. Am J Cardiol 2008; Oct 1, 102 (7): 916-20. Epub 2008 Jul 18.

85. Kimmelstiel C, Gange C, Thaler D. Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study. Catheter Cardiovasc Interv 2007; Apr 1, 69 (5): 740-6.

86. Luermans JG, Post MC, Temmerman F, Thijs V, Schonewille WJ, Plokker HW, Suttorp MJ, Budts WI. Closure of patent foramen ovale is associated with a decrease in prevalence of migraine: a prospective observational study. Acta Cardiol 2008; Oct, 63 (5): 571-7.

87. Morandi E, Anzola GP, Angeli S, Melzi G, Onorato E. Transcatheter closure of patent foramen ovale: a new migraine treatment? J Interv Cardiol 2003 Feb; 16 (1): 39-42.

88. Mortelmans K, Post M, Thijs V, Herroelen L, Budts W. The influence of percutaneous atrial septal defect closure on the occurrence of migraine. Eur Heart J 2005; Aug, 26 (15):1533-7. Epub 2005 Mar 3.

89. Na SJ, Cho HM, Park JS. A case of successful surgical treatment of migraines in a patient with sporadic pulmonary arteriovenous malformations. J Korean Med Sci 2009; Apr, 24 (2): 330-2. Epub 2009 Apr 20.

90. Papa M, Gaspardone A, Fracasso G, Ajello S, Gioffrè G, Iamele M, Iani C, Margonato A. Usefulness of transcatheter patent foramen ovale closure in migraineurs with moderate to large right-to-left shut and instrumental evidence of cerebrovascular damage. Am J Cardiol 2009; Aug 1, 104 (3): 434-9. Epub 2009 Jun 6.

91. Post MC, Thijs V, Schonewille WJ, Budts W, Snijder RJ, Plokker HW, Westermann CJ. Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine. Neurology 2006; Jan 24, 66 (2): 202-5.

92. Post MC, van Gent MW, Snijder RJ, Mager JJ, Schonewille WJ, Plokker HW, Westermann CJ. Pulmonary arteriovenous malformations and migraine: a new vision. Respiration 2008; 76 (2): 228-33. Epub 2008 May 20.

93. Post Mc, Thijs V, Herroelen L, Budts WI. Closure of patent foramen ovale is associated with a decrease in prevalence of migraine. Neurology 2004; Apr 27, 62 (8): 1439-40.

94. Reisman M, Christofferson RD, Jesurum J, Olsen JV, Spencer MP, Krabill KA, Diehl L, Aurora S, Gray WA. Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol 2005; Feb 15, 45 (4): 493-5.

95. Rigatelli G, Cardaioli P, Giordan M, Dell’Avvocata F, Braggion G, Chianaglia M, Roncon L. Transcatheter interatrial shunt closure as a cure for migraine: Can it be justified by paradoxical embolism-risk-driven criteria? Am J Med Sci 2009; Mar, 337 (3): 179-81.

96. Rigatelli G, Cardaioli P, Braggion G, Giordan M, Fabio D, Aggio S, Roncon L, Chinaglia M. Resolution of migraine by transcatheter patent foramen ovale closure with Premere Occlusion System in a preliminary series of patients with previous cerebral ischemia. Catheter Cardio- vasc Interv 2007; Sep, 70 (3): 429-33.

97. Rigatelli G, Cardaioli P, Dell’Avvocata F, et al. Transcatheter patent foramen ovale closure is effective in reducing migraine independently from specific atrial septum anatomy and closure devices design. Cardiovasc Revasc Med 2010; 11: 29-33.

98. Rigatelli G, Cardaioli P, Dell’Avvocata F, et al. May migraine post-patent foramen ovale clo-sure sustain the microembolic genesis of cortical spread depression. Cardiovasc Revasc Med 2010; 10, Epub.

99. Schwerzmann M, Wiher S, Nedeltchev K, Mattle HP, Wahl A, Seiler C, Meier B, Windecker S. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 2004; Apr 27, 62 (8): 1399-401.

100. Suresh CG, Neal D, Coupe MO. Warfarin treatment and migraine. Postgrad Med J 1994; Jan, 70 (819): 37-8.

101. Trabattoni D, Fabbiocchi F, Montorsi P, et al. Sustained long-term benefit of patent foramen ovale closure on migraine. Catheter Cardiovasc Interv 2011; Jan 4, Epub.

102. Vigna C, Marchese N, Inchingolo V, Giannatempo GM, Pacilli MA, Di Viesti P, Impagliatelli M, Natali R, Russo A, Fanelli R, Loperfido F. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions: a case-control study. JACC Cardiovasc Interv 2009; Feb, 2 (2): 107-13.

103. Wahl A, Praz F, Findling O, Nedeltchev K, Schwerzmann M, Tai T, Windecker S, Mattle HP, Meier B. Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical treatment. Catheter Cardiovasc Interv 2009; Jul 1, 74 (1): 124-9.

104. Wahl A, Praz F, Tai T, et al. Improvement of migraine headaches after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism. Heart 2010; 96: 967-73.

105. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000; Nov 11, 356 (9242): 1648-51.

Randomized Migraine Trials

106. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention with STARFlex technology Trial (MIST). A prospective, multicenter, double blind, sham controlled trial to evaluated the effectiveness of PFO closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008; 117: 1397-1404.

107. Carrol JD. Migraine intervention with STARflex Technology Trial: a controversial trial of migraine and patent foramen ovale closure. Circulation 2008; 117 (11): 1397-1404.

108. MIST II: Cancelled/not completed

109. ESCAPE: Cancelled/not completed

110. PRIMA. Mattie HP et al, Percutaneous closure of patent foramen ovale in migraine with aura, A randomized clinical trial. Eur Heart J 2016; 37:2029-36
(stopped early due to slow enrollment)

111. PREMIUM. Tobis J, Charles A, Silberstein S, Sorensen SG et al. Results of the PREMIUM TRIAL. Patent foramen ovale closure with the Amplatzer PFO occlude for the prevention of migraine; presented TCT 2015; JACC Supplement

Conclusion

a. Observational studies and a meta-analysis of correction of right-to-left shunting in three different disorders (p-AVM, ASD, PFO) using multiple treatment modalities have consistently demonstrated statistically significant, sustained improvement of migraine headache.

b. The MIST RCT, a very controversial trial, may be considered as demonstrating a failure of a specific device rather than disproof of premise. Three PFO migraine relief randomized trials in the United States have been terminated due to poor recruitment/ restrictive criteria.

c. PREMIUM and PRIMA missed primary end points. However both demonstrated migraine improvement in patents with aura and even complete cessation of headache in 10% of patients

Stroke Prevention: PFO Closure vs Medical Management

Meta-Analyses: 10,000 Total Patients

112. Khairy P et al. Systematic overview of medical treatment versus percutaneous PFO closure in patients with cryptogenic stroke. Ann Int Med 2003; 139: 753-60.

113. Wohrle J. Closure of Patent foramen ovale after cryptogenic stroke. Lancet 2006; 368: 350-2.

114. Homma S, Sacco RL. PFO and stroke. Circulation 2005; 112: 1063-10.

115. Lanzberg MJ, Khairy P. Indications for the closure of PFO. Heart 2004; 90: 219-224.

Prospective Studies / Randomized Trials / RCT Meta-Analyses

116. Schuchlenzh W, Weihs W, Berghold A, et al. Secondary prevention after cryptogenic cerebrovascular events in patients with PFO. Int J Cardiol 2005; 101: 77-82.

117. Windecker S, Wahl A, Nedeltchev K, et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll CardIol 2004; 44: 750-8.

118. CLOSURE 1. Furlan AJ et al, Closure or medical therapy for cryptogenic stroke with patent foramen ovale. NEJM 2012; 366:991-9

119. Thaler DE. Wahl A. Critique of “Closure or medical therapy for cryptogenic stroke with patent foramen ovale. Stroke 2012; 43:3147-49

120. Taaffe M et al, Comparison of three patent foramen ovale closure devices in a randomized trial (Amplatzer vs CardioSEAL/STARflex vs HELEX occluder). Am J Cardiol 2008; 101:1353-8

121. Hurnung M et al, Long-term results of a randomized trial comparing three different devices for percutaneous closure of patent foramen ovale. Eur Heart J 2013;34:3362-9
x
122. RESPECT. Carroll JD et al, Closure of PFO versus medical therapy after cryptogenic stroke. NEJM 2013; 368:1092-100

123. PC TRIAL. Meier B et al, A randomized clinical trial comparing the efficacy of percutaneous closure of patent foramen ovale with medical treatment in patients with cryptogenic stroke. NEJM 2013; 368:1083-91

124. Khan AR et al, Device closure of patent foramen ovale versus medical therapy and cryptogenic stroke: a systematic review and meta-analysis. JACC Cardiovasc Interv 2013; 6:1316-23

125. Stortecky S et al, Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis. Eur Heart J 2015; 36:120-8

126. Kent DM et al, Device closure of patent foramen ovale after stroke: Pooled analysis of completed randomized clinical trials. JACC2016; 67:907-17

Failure of Coumadin Therapy

Although Coumadin therapy was originally recommended (2001) as a treatment under the HDE, there is no data to support Coumadin therapy. Recent studies have indicated failure of Coumadin therapy in non-atrial fibrillation stroke. Indeed, Coumadin has been excluded from the recent randomized trial (FDA- approved REDUCE). Aspirin therapy is the currently recommended medical therapy for stroke, despite no evidence of its efficacy for PFO. “Best medical therapy” for PFO remains unknown. Anticoagulation treatment or anticoagulation therapy failure are not indicated for stroke prevention for ASD II or pulmonary AVM.

127. Mohr JP, Thompson JL, Lazar MR, et al. A comparison of Warfarin and aspirin for prevention of recurrent ischemic stroke (WARSS). NEJM 2001; 345: 1444-51.

128. Sacco RL, Prabhakarin S, Thompson JL, et al. Comparison of Warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin Aspirin Recurrent Stroke Study. Cerebrovasc Dis 2006; 22: 4-12.

129. Hankey GJ. Warfarin Aspirin Recurrent Stroke Study (WARSS) Trial. Is Warfarin really a reasonable therapeutic alternative to aspirin for preventing recurrent non-cardioembolic ischemic stroke? Stroke 2002; 33: 1723-6.

130. SPIRIT Study Group: A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial. Ann Neurol 1997; 42: 857-65.

131. Kasner SE, Lynn MJ, Chimowitz MI, Frankel MR, et al. Warfarin versus aspirin for symptomatic intracranial stenosis: subgroup analysis from WASID. Neurol 2006; 67: 1275.

132. Howard G, McClure LA, Krakauer JW, et al. Stroke and the statistics of the Aspirin/ Clopidogrel Secondary Prevention Trials. Curr Opin Neurol 2007; 220: 71-7.

Conclusion

a. Coumadin is no longer recommended for prevention of stroke in patients with septal defects based upon the absence of benefit of Coumadin by three randomized trials (SPIRIT, WASID, and WARSS). Of note, the most recent FDA-sponsored multi- center international PFO stroke trial REDUCE excludes Coumadin as a treatment option. Indeed, both SPIRIT and WASID were stopped by respective DSMB.

b. Available evidence indicates that aspirin therapy is essentially without benefit and has the poorest result for stroke prevention for PFO. The recommendation for patients to fail aspirin therapy is, therefore, odd in that it represents an ineffective therapy.

c. Based on current information as defined above, the risk of recurrent stroke, TIA, or combined neurologic events is lowest with device management.(RESPECT 10 and 13 year late lock)

d. CLOSURE 1 should be excluded from analysis: underpowered, minor shunt, and inferior device compared to Amplatzer and HELEX)

Comorbidities

A variety of circumstances and disorders increase the risk of paradoxical embolic stroke and paradoxical embolic problems related to septal defects:

a. Medical conditions which increase right heart pressures: sleep apnea, tricuspid regurgitation, and pulmonary hypertension

b. Hypercoagulable states both inherited and acquired

c. Hormonal-related risk: oral contraceptives, hormone replacement therapy, and pregnancy

d. Medical procedures carry substantial risk of stroke in association with septal defects including:

i. Upright neurosurgical procedures

ii. Major orthopedic procedures, particularly back, hip, knee replacement, and intramedullary procedures

iii. Chronic indwelling vascular access devices (CVAD) particularly Port-A-Caths due to a 5% to 10% incidence of catheter thrombus as well as reservoir thrombus

iv. Pacing leads, including leads from AICDs, have a 30% incidence of thrombus and a three-fold increased risk of stroke in patients with septal defects.

e. Activities related to barometric change which include:

i. Increased incidence of HAPE (high altitude pulmonary edema) in climbers with septal defects

ii. Increased risk of moderate to severe (DCI II) decompression illness in scuba divers

iii. Increased risk in tunnel workers, astronauts, and high altitude aviation

f. DVT and pulmonary embolism are associated with a four to eight-fold increased risk of stroke, death, and systemic embolization in patients with septal communications.

g. Travel is associated with a significant risk of DVT and, therefore, paradoxical embolism:

i. 18% relative increased risk of DVT per two hours of car travel

ii. 26% relative increased risk of DVT per two hours of air travel

iii. Economy class syndrome

h. Pre-existing brain injury — Patients with other neurologic conditions which result in brain injury are at a higher risk for disability due to paradoxical embolic stroke: multiple sclerosis, traumatic brain injury, birth injury, and surgical brain injury.

i. Dementia and cognitive dysfunction — Cognitive dysfunction is associated with micro-embolization of the brain due to any cause (carotid endarterectomy, coronary bypass surgery, aortic arch plaque, and paradoxical embolism). Recent studies indicate that the presence of cognitive dysfunction from any cause is dramatically worsened by the presence of persistent and recurrent micro-embolic events.

j. Silent sub-clinical micro-embolization — Recent cardiac MRI studies using LGE have demonstrated evidence of subclinical myocardial infarction in 10% PFO cryptogenic stroke patients without coronary artery disease.

Decompression in Divers

133. Schwerzmann M, Seiler C, Lipp E, Guzman R, Lövblad KO, Kraus M, Kucher N. Relation between directly detected patent foramen ovale and ischemic brain lesions in sports divers. Ann Intern Med 2001; Jan 2, 134 (1): 21-4.

134. Wilmshurst P, Byrne JC, Webb-Peploe MM. Relation between inter-atrial shunts and decompression sickness in divers. Lancet 1989; 2: 1302-6.

135. Balestra C, Germonpre’ P, Marroni A, et al. PFO and the diver. Best Publishing 2007;

136. KnauthM, Ries S, Pohimann S, et al. Cohort study of multiple brain lesions in sports divers: role of patent foramen ovale. BMJ 1997; 314: 701-705.

137. Torti SR, Billinger M, Schwerzmann M, et al. Risk of decompression illness among 230 divers in relation to the presence and size of patent foramen ovale. European Heart Journal 2004; 25: 1014-1020.

138. Smart D et al, Joint position statement on persistent foramen ovale (PFO) and diving: South Pacific Underwater Medicine Society(SPUMS) and the United Kingdom Sports Diving Committee (UKSSDMC). Diving Hyperbar Med 2015; 45:129-31

Pulmonary Embolism, DVT, Travel

139. Konstantinides S, Geibel A, Kasper W, Olschewski M, Blümel L, Just H. Patent foramen Ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation 1998; May 19, 97 (19):1946-51.

140. Cannegieter SC, Doggen CJ, Van Houweling HC, et al. Travel-related venous thrombosis: results from a large population-based case control study (MEGA Study). PLs Med 2006; 3: E307.

141. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: Results of the paradoxical emboli from large veins in ischemic stroke (PELVIS Study). Stroke 2004; 35: 46-50.

142. Chandra D, Parisini E, Mozaffarian D. Travel and risk for venous thromboembolism. Annals of Internal Medicine 2009; 115: 1-12.

143. Heckmann JG, Stadter M, Reulbach U, et al. Increased frequency of cardioembolism and patent foramen ovale in patients with stroke and positive travel history suggesting economy class stroke syndrome. Heart 2006; 92: 1265-8.

Indwelling Lines

144. Khairy P, Landzberg MJ, Gatzoulis MA, et al. Epicardial versus endocardial pacing and thrombolic events (EVENT). Circulation 2006; 113: 2391-2396.

Sleep Apnea

145. Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005; Dec 1, 172(11): 1447-51. Epub 2005 Sep 1.

Dementia and Cognitive Dysfunction

146. Purandare N, Oude Voshaar RC, McCollum C, et al. Paradoxical embolization and cerebral white matter lesions in dementia. British Journal of Radiology 2008; 81: 30-34.

147. Purandare N, Oude Voshaar RC, Morris J, et al. Asymptomatic spontaneous cerebral emboli predict cognitive and functional decline in dementia. Biol Psychiatry 2007; 62: 339-44.

148. Purandare N, Burns A, Daley KG, et al. Cerebral emboli as a potential cause of Alzheimer’s disease and vascular dementia: a case control study. BMJ 2006; 332: 1119-24.

149. Purandare N, Oude Voshaar RC, Burns A, et al. Paradoxical embolization: a potential cause of cerebral damage in Alzheimer’s disease. Neurol Res 2006; 28: 679-84.

Pregnancy and Contraception

150. Bushnell CD, Jamison M, et al. Migraines during pregnancy linked to stroke and vascular disease. A U.S. population-based case control study. BMJ 2009; 338: b664.

151. Harris M. Headache and stroke risk with contraception. J Contraception 2009; 80: 417.

152. Meier B. Stroke in migraine: A cardiologist’s headache. Heart 2009; 95: 595-602.

153. Kozelj M, Novakantoli CZ, Grad Anton, et al. Patent foramen ovale as a potential cause of paradoxical embolism in the postpartum period. European Journal of Obstetrics and Gynecology and Reproductive Biology 1999; 84: 55-57.

154. Schrale RG, Ormerod JM. Percutaneous device closure of a patent foramen ovale during Pregnancy. Catheter and Cardiovasc Intervention 2007; 69: 579-583.

155. Yap SC, Drenthen W, Meijboom FJ, et al. Comparison of pregnancy outcomes in women with repaired versus unrepaired atrial septal defects. BJOG 2009, 116: 1593-1601.

156. Siu SC, Coleman JM. Congenital heart disease; heart disease and pregnancy. Heart 2001; 85: 710-715.

134. Siu SC, Sermer M, Harrison DA, et al. Risk and predictors for pregnancy-related complications in women with heart disease. Circulation 1997; 96: 2789-2794.

135. Treadwell SD, Thanvi B, Robinson TJ. Stroke in pregnancy and puerperium. Post Grad Med J 2008, 84: 238-245.

134. Alkashkari A, Hijazi ZM. ASDs: clinical perspectives. Chapter 3, 27-36 in Transcatheter Closure of ASDs and PFOs, Cardiotest 2010, Hijazi ZM ed.

135. Angeli S, Delsette M, Beelke M, et al. Transcranial Doppler in the diagnosis of cardiac patent foramen ovale. Neuro Science 2001, 22: 353-356.

Myocardial Infarction

136. Wohrle J, Kochs M, Hombach V, et al. Prevalence of myocardial scar in patients with cryptogenic cerebral ischemic events and patent foramen ovale. JACC CV Imaging 2010; 833-9.

Family History

137. Seshadri S, Belser A, Pikula A, et al. Parental occurrence of stroke and risk of stroke in their children: the Framingham Study. Circulation 2010; 121: 1304-12.