Permanent foramen ovale: when to close? Pierre Amarenco INSERM U-698 and Denis Diderot University - Paris VII Department of Neurology and Stroke Center Bichat hospital, Paris, France
PFO - Pathology TEE
PFO - Anatomy & Pathology FOP Thrombus TEE
PFO - Cryptogenic strokes - Patients <55 yrs OverellJR et al. Neurology 2000;55:1172-9
PFO + ASA OverellJR et al. Neurology 2000;55:1172-9
FOP-ASA: Recurrent stroke Mas et al N Engl J Med 2001;345:1740-6 1 yr (IC 95%) 2 yrs (IC 95%) 3 yrs (IC 95%) 4 yrs (IC 95%) Mean annual risk No PFO no ASA 2.0 (0.4-3.6) 3.7 (1.6-5.8) 4.2 (1.8-6.6) 4.2 (1.8-6.6) 1.1 PFO only 1.8 (0.05-3.6) 1.8 (0.05-3.6) 2.3 (0.3-4.3) 2.3 (0.3-4.3) 0.6 ASA only 0 0 0 0 0 PFO + ASA 2.0 (0-5.8) 4.0 (0-9.4) 6.3 (0-13.2) 15.2 (1.8-28.5) 4.0 <55 y-o, all on Aspirin 300 mg/d
PFO an Recurrent Stroke Meta-analysis Almekhlafi MA et al. Neurology 2009;73:89-97
Case -1 65 y-o man no risk factor sudden acute left pure motor hemiparesis DWI paramedian pontine infarct normal work-up: TCD, Duplex, MRA, ECG TEE : PFO
High-Resolution MRI of the basilar artery Paramedian Pontine Infarcts (branch disease) Klein, Lavallée, Amarenco. Neurology 2005;64:551-552
Case - 2 70 y-o man sudden pure motor right-sided hemiparesis with dysarthria Total recovery within 8 days 1 year before: dysarthria and clumsy hand, totally regressive MRI: old small infarct in the corona radiata and new capsular infarct ECG: sinus rhythm TCD and Carotid duplex normal MRA extra/intracranial: normal TEE: PFO and ASA
Small Deep Atherothrombotic Brain Infarct
Lacune Arterioles <150-300 µm Lipid deposits Lipohyalinosis Hyalinosclerosis
Case - 3 PFO in the young A 25 y-o woman had a long flight from Sydney to Paris. The day after she woke up with a fronto-orbital headache. Self treatment with a triptan with weak success In the evening: massive, dense left-sided hemiplegia with total resolution within 2 hours Work-up negative: TCD, Carotid duplex, MRI, MRA, ECG, no hypercoagulation TEE : PFO and ASA
Case - 3 Fat-saturated MRI
Case - 4 41 y-o man woke up at 4:00 am with severe occipital headache Unsteadiness of walk Day after: ER: left sided dysmetria and cerebellar ataxia BP 136/88 Ultrasound ex: carotid normal, low flow in V3, normal basilar artery, hypoplastic right VA MRI: acute SCA infarct MRA and XRA normal except right VA hypoplastic TEE : FOP + ASA
Case - 4 Follow-up HR-MRI on day 18
Wrong PFO Closure
What is a «cryptogenic stroke» or «stroke of indetermined cause»?
CAUSES of STROKE Stroke 80% 20% Ischemic Hemorrhagic Large Artery Atherosclerosis Cardiac Sources Small Artery Disease Dissection and other causes Unknown cause 20% 15% 25% 2 à 3% 30-40%
Usual classification systems Consider only the most likely cause Neglect other possible, or potential cause Neglect non causally related underlying disease - e.g., MRI evidences of small vessel changes such as severe leukoaraiosis - e.g., documented atherosclerotic disease in arteries not supplying teh ischemic field) When two causes co exist, they are classified into one mixed group of «unknown cause», including: Cases with co existing actual causes Cases with insufficient work-up Cases with thorough work-up but with no cause detected
Usual classification systems Based on these classification systems, publications looking at new potential cause or biomarker, or genetic association studies analyze 5 «rigid» groups : LAA, SVD, CE, Other and Unknown causes
A-S-C-0 http://www.asco-classification.org Findings in each patient are described by an ASCO «code» A: atherothrombosis S: small vessel disease C: cardiac embolism O: other cause Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. A new approach to stroke subtyping : the A-S-C-O (phenotypic) classification of stroke. Cerebrovasc Dis. 2009 ;27 :502-508
A-S-C-0 http://www.asco-classification.org Each of the 4 A-S-C-O is graded: 1: Definitely a potential cause of the index stroke 2: Causality uncertain 3: Unlikely a direct cause of the index stroke (but disease is present) 0: no evidence of disease 9: insufficient work-up to grade
AMISTAD cohort (preliminary on the first 103 patients among 650) Distribution using TOAST 18% co-existing causes
ASCO vs. TOAST Among 52 pts classified «Undetermined cause» by TOAST Athero Small vessel Cardiac 52 52 52 52
TOAST vs ASCO Analysis: out of 103 cases TOAST: proportion of SVD n=10 [but UND n=7 (LAA+CE+SVD n=3, CE+SVD n=4)] ASCO: proportion of SVD n=48 [S1 (n=14), S2 (N=6), S3 (28)] S0 n=49 S9 n=6 Analysis: out of 103 cases TOAST: proportion of LAA n=15 [but UND n=15 (LAA+CE n=12, LAA+CE+SVD n=3)] ASCO: proportion of LAA n=86 [A1 (n=25), A2 (N=22), A3 (39)] A0 n=16 A9 n=1
ECG monitoring in SUC Elijovich L, Josephson SA, Fung GL, Wmith WS. J Stroke Cerebrovasc Dis. 2009;18(3):185-9 218 Ischemic Stroke 36 SUC 20 SUC evaluated with 30 days cardiac event monitor 4 (20%) Atrial fibrillation When it is not atrial fibrillation, it can be. atrial fibrillation
Detection of AF Telemetry: 4 to 8% 24hr Holter ECG 1% to 5% Pts with >7 premature atrial beats/24 hr on initial holter had a 26% occurrence of AF if monitoring is extended to 7 days 30 days event recorder (new generation): automatic detection of brady or tachy-arrhythmias 149 pts: 5.7% (mean monitoring duration 159 hrs) 60 pts: 6.7% (70.1±30.9 hrs) 56 pts: 23% (21 days) Implantable loop recorder (14 months monitoring) No available evidences
Conclusions PFO associated with thrombus is likely a source of cerebral embolism PFO is more frequent in patients with TIA/Stroke of unknown cause PFO may increase the risk of recurrent stroke, but this will only be proven by randomised trials conducted in patients with stroke of unknown cause However, the diagnosis of stroke of unknown cause is very difficult Undetected atrial fibrillation is likely underestimated The role of atherosclerotic disease is underestimated Small vessel disease is highly prevalent Carotid or vertebral artery dissection in the young must be thoroughly search for in patients younger than 60 years
Take home message cryptogenic stroke is the most difficult diagnosis to make Consider PFO + ASA as a potential cause only if you are confident with your negative workup Efficacy of PFO closure in this context remains to be proven
Conclusions Pending a RCT comparing aspirin, anticoagulant and PFO closure PFO alone : annual risk 0.6% -->aspirin PFO alone and Recurrent (true) cryptogenic --> PFO closure vs. OA PFO + DVT or PE: PFO closure vs. OA