1. Cardioembolic Stroke Robert A. Felberg, MD Stroke Program Director Department of Neurology Geisinger Medical Center Danville, Pennsylvania

2. Irregularly, Irregular Rhythm in a Regular elderly female 87 year old Black Female History of Hypertension, well compensated Congestive Heart Failure, Hip Fracture 2 years ago with pinning Chief Complaint: Lightheadedness Exam reveals: –Irr. Irr. rhythm –EKG: Atrial Fibrillation rate 83/min Normal Recent Thyroid Studies

3. Irr. Irr. Rhythm in a Regular elderly female How do you treat this patient? A: “Benign Neglect” B: Check Echo and Chemically Convert to NSR C: Aspirin 325mg Daily and write note about fall risk in chart D: Warfarin 5mg Daily (Goal INR 2.0-2.5)

4. Irr. Irr. Rhythm in a Regular elderly female How do you treat this patient? A: “Benign Neglect” B: Check Echo and Chemically Convert to NSR C: Aspirin 325mg Daily and write note about fall risk in chart D: Warfarin 5mg Daily (Goal INR 2.0- 2.5)

5. Overview of Trials

6. Examples of Other Stratifications

7. A Warfarin Treatment Guideline Based Largely on SPAF High risk embolism: one or more of the following- mitral stenosis, prosthetic valve, Previous TIA/Stroke, thyrotoxicosis, LV dysfctn, current systolic HTN, female >75, ECHO “smoke”, LA thrombus Intermediate embolism: none of the high risk, HX of HTN High bleeding: non compliance, active bleeding, recent ICH Intermediate bleeding: age >80, leukoareosis, HX of falls

9. Stroke in the Young 34 year old right handed white female. No significant PMHx. Sudden onset of Right Hemiparesis and Aphasia. Receives IV-TPA in the Emergency room with dramatic recovery.

10. Stroke in the Young MRI shows a small area of acute stroke in the Left MCA territory –And B/L embolic sub acute stroke in both hemispheres as well as Right Cerebellum Carotid U/S is Normal Non-Smoker, Normotensive, Normal Lipids No history of DVT or miscarriage

11. Stroke in the Young How do you manage this patient? A. Antiplatelet therapy and discharge B. Check 2-d transthoracic echo C. Check hypercoagulable Labs D. Check Tran-esophageal echo and hypercoagulable labs

12. Stroke in the Young How do you manage this patient? A. Antiplatelet therapy and discharge B. Check 2-d transthoracic echo C. Check hypercoagulable Labs D. Check Tran-esophageal echo and hypercoagulable labs

13. To Diagnose Cardioembolic Stroke- You’ll need to look at the films! The pattern of Stroke on imaging is key to finding the etiology –Especially MRI imaging

14. Embolic Stroke Wedge Shaped Peripheral Typically Cortical

15. Cardioembolic Strokes Multiple StrokesMultiple Strokes EmbolicEmbolic Separated by TimeSeparated by Time Separated by LocationSeparated by Location

16. Cardioembolic Strokes Isolated PCA or Superior Cerebellar StrokesIsolated PCA or Superior Cerebellar Strokes

17. Cardioembolic Strokes Isolated Posterior Division MCAIsolated Posterior Division MCA

18. Clinical Clues to Suggest Cardioembolism Stroke during Valsalva Maneuver –Cough –Sneeze –Sexual Intercourse Pain: consider dissection Blue Toe Syndrome Splinter Hemorrhages Renal Failure Corneal hemorrhages

19. Clinical Clues to Suggest Cardioembolism Clinical Point –AFIB is the most common cause of stroke in patients over the age of 80 Clinical Point –To evaluate for Stroke –2D echo is not valuable –TEE with Bubble study is the national standard of care

20. Diagnosis of Cardioembolic Sources For Stroke Evaluation –TEE is the Standard of Care –TTE is not sufficient, not indicated, not sensitive, not appropriate, and not likely to lead to diagnosis or change in therapy Can not bill for TTE An echo is not required for every patient –Only those with a suspected cardiac source Perform a Bubble study with the TEE –TCD can be a non-invasive screen Screen

21. TCD/PMD IMAGING FOR DIAGNOSIS OF PFO courtesy Dr. Merrill Spencer

22. What are we looking for? The micro bubbles will cross the right to left shunt Enter the cerebral circulation Be detected by TCD Courtesy of Mark Moehring Spencer Technolgy

23. Patent Foramen Ovale: Significant cause of stroke in the youngSignificant cause of stroke in the young PFO found in 40% of Idiopathic Stroke casesPFO found in 40% of Idiopathic Stroke cases

24. PFO in stroke: Pathophysiology Paradoxical Embolism Focal Thrombosis

25. Lechat, NEJM 1988 Webster, NEJM 1988 De Belder 1992 Di Tullio1992 Hausmann 1992 Cabanes 1993 54% 50% 13% 47% 50% 56% 10% 15% 3% 4% 11% 18% < 0.01 Cryptogenic Stroke Control P value Incidence of PFO in cryptogenic stroke versus normals

26. RA LA RV

27. The MAS Study A Multi-Center Prospective Observational Study to determine the rate of recurrent stroke/TIA in young idiopathic stroke patients with sub-group comparison of those with septal abnormalities to those with normal septal findings. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J; Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001 Dec 13;345(24):1740-6.

28. Background Despite many theories regarding therapy, there is poor natural history data regarding the absolute and relative risk of PFO and ASA in the setting of “stroke in the young” An observational study was undertaken to determine the natural history of PFO/ASA vs non-PFO/ASA in young idiopathic stroke –NOTE: Not a comparison of stroke patients vs. normal controls.

29. Clarification: “ASA”: Aspirin Atrial Septal Aneurysm

30. Trial Design Concurrent Idiopathic Stroke Patients –age 18-55 All patients had a standard stroke evaluation –Excluded those for whom cause was found Lacunar stroke Atrial fibrillation Hypercoagulable States All patients had a TEE with bubble study Patients were split into 4 groups and followed for 2 years No septal abnormality PFO only ASA only PFO+ASA in combination

31. Kaplan–Meier Analysis of Survival without Vascular Events (Brain Infarction, Myocardial Infarction, Peripheral Embolism, or Death from Vascular Causes), According to Plaque Thickness in the Aortic Arch Proximal to the Ostium of the Left Subclavian Artery. The French Study of Aortic Plaques in Stroke Group. NEJM 334:1216-1221 331 patients with stroke331 patients with stroke >60 years of age>60 years of age TEE Confirmed Aortic AtheromaTEE Confirmed Aortic Atheroma GradedGraded Aortic plaques >4 mm thick (including the thickness of the aortic wall)Aortic plaques >4 mm thick (including the thickness of the aortic wall) Recurrent brain infarctionRecurrent brain infarction relative risk, 3.8;relative risk, 3.8; P = 0.0012P = 0.0012 All vascular eventsAll vascular events relative risk, 3.5;relative risk, 3.5; P<0.001P<0.001

32. Mas, J.-L. et al. N Engl J Med 2001;345:1740-1746 Kaplan-Meier Estimates of the Risk of Recurrent Cerebrovascular Events within Four Years after the Index Stroke

33. What IS PICCS? Patent Foramen Ovale In Cryptogenic Stroke Study Substudy of WARRS –A study designed to compare ASA and warfarin for the prevention of recurrent ischemic stroke in patients with prior (<30 days) noncardioembolic ischemic stroke

34. What IS PICCS? Patients eligible if event not attributed to high-grade carotid stenosis for which surgery was planned and not associated with an inferred cardioembolic source Composite endpoint of death or recurrent ischemic stroke over two years after enrollment

35. PICSS Results Death was the endpoint in 23% of patients Composite endpoint for entire group (at 2 yrs) 13.2% in aspirin group vs 16.5% in warfarin group (p=NS) Composite endpoint in group with cryptogenic stroke and PFO (n=98): 17.9% in ASA group vs 9.5% in warfarin group (p=NS) This group of 98 (4.4% of the original 2206) patients represents the only group of cryptogenic stroke/PFO patients enrolled in a randomized trial (not placebo-controlled) of medical therapy.

37. NMT Medical, Inc. The STARFlex Occluder: Double umbrella design with auto centering microsprings Framework is MP35n Tissue matrix is polyester fabric (Dacron)

38. The Amplatzer Occluder

39. PFO in Embolic Stroke Annual recurrence rate (Stroke, TIA,) after PFO closure Hung et. al. Circulation 20003.2 % Meier; Circulation Feb 20002.5 % Sievert et al, Abstract AHA Nov 2001, 3.1 % Palacios, Circulation, Aug 20020.9% Lock; Circulation Jan 20033.0% March 2003

40. Very little information to make an informed treatment decision

41. Especially if you wish to rely on evidence and not anecdote

42. Remember: Some evidence is more reliable than others

43. PFO in Embolic Stroke What do we really know about recurrent event rates for each form of therapy? Only that a definitive, randomized, controlled study is needed! March 2003

44. Investigating the PFO Stroke connection NMT Medical, Inc. RESPECT TRIAL AGA Medical

45. Other Cardioembolic Sources of Stroke Artificial Valves –New devices –New Anticoagulants Arrythmias –Atrial Fibrillation –Frequent PAC’s Cardiomyopathy –WARCEF trial

46. Aortic Arch Atheroma Atherosclerotic disease of the aortic arch is found in 60 percent of patients 60 years of age or older who have had brain infarctionAtherosclerotic disease of the aortic arch is found in 60 percent of patients 60 years of age or older who have had brain infarction Usually divided into three groups according to the thickness of the wall of the aortic archUsually divided into three groups according to the thickness of the wall of the aortic arch <1 mm <1 mm 1 to 3.9 mm 1 to 3.9 mm >4 mm>4 mm <1 mm >4 mm