Cryptogenic Strokes: Evaluation and Management 77 yo man with - PDF document

Ischemic Stroke Case Cryptogenic Strokes: Evaluation and Management • 77 yo man with hypertension and hyperlipidemia developed onset of left J. Claude Hemphill III, MD, MAS hemiparesis and right gaze preference, last seen normal Kenneth Rainin Chair in Neurocritical Care at 10:00 AM Professor of Neurology and Neurological Surgery • Brought to ZSFG by University of California, San Francisco ambulance Chief of Neurology, San Francisco General Hospital • Non-contrast head CT negative Past-President, Neurocritical Care Society • Given IV t-PA with “door-to- UC SF needle” time 16 minutes Disclosures NEUROCRITICAL • Stroke CT then completed Research Support: NIH/NINDS; Cerebrotech Medical CARE PROGRAM Stock (options): Ornim Ischemic Stroke Case Ischemic Stroke Case Right middle cerebral artery occlusion endovascular embolectomy - TICI 3 flow at 2 hours 15 minutes after last known well time Page 1

Ischemic Stroke Case Cryptogenic Stroke • Over next 4 days, recovered well and remained • Symptomatic cerebral infarct for which with only left lower visual field deficit and mild no probable cause is identified after gait instability adequate diagnostic evaluation • Workup – 3 days of telemetry – no arrhythmias • ~40% of strokes in 1970s – Transthoracic echo – mild diastolic dysfunction, borderline enlarged atrium • ~15% of strokes in advanced stroke – Glucose normal centers currently – LDL 117 – Carotid imaging with CTA and angio without stenosis • Diagnosis – cryptogenic stroke Saver NEJM 2016 Ischemic Stroke Case Frequency of Stroke by Etiologic Subtype • Discharged to rehabilitation on – ASA 84% Ischemic – High-dose statin – ACE inhibitor Thrombotic 53% • Also sent with Zio patch Embolic 31% • Zio patch showed 3 self-limited runs of paroxysmal atrial fibrillation 16% Hemorrhagic • Diagnosis – cardioembolic stroke 10% Intracerebral 6% Subarachnoid Page 2

Imaging of Ischemic Stroke Ischemic Stroke Subtypes - Localization • Large Vessel – MCA http://www.uiowa.edu/~c064s01/nradcerebrovascular.html – ACA – PCA – Basilar • Small Vessel - Qureshi NEJM 2001 Lacunar Ischemic Stroke Causes • Large Vessel – Embolic » Cardiac (e.g. atrial fibrillation) » Artery-to-Artery (e.g. carotid stenosis) » Aortic Arch – Thrombotic » Atherosclerotic stenosis » Hypercoaguable state • Small vessel – Microthrombosis in chronically damaged penetrating artery – Hypertension or diabetes in most cases • Distinction between ischemic stroke risk factors and causes Hart Lancet Neurology 2014 Page 3

What’s a Good Stroke Workup? • Reason - acute treatment or stroke cause? • Large vessel versus small vessel? • Age of patient? • Vascular risk factors? • Usual start – BP, ECG, CBC, Chem7 – Lipid panel, glucose, Hgb A1C, tox screen – Carotid imaging for anterior circulation stroke (CTA, ultrasound, MRA) – Transthoracic echo if not lacunar Hart Lancet Neurology 2014 Cryptogenic Stroke • So let’s treat it • WARSS randomized trial – Warfarin-aspirin recurrent stroke study – 2206 patients with ischemic stroke – No high-grade carotid stenosis (with planned surgery) or inferred cardioembolic source (mostly atrial fibrillation) – Randomized to » ASA 325 mg daily or » Warfarin for INR 1.4-2.8 – 26% of patients classified as cryptogenic – 56% small vessel disease Mohr NEJM 2001 Mohr NEJM 2001 Page 4

Cryptogenic Stroke Intracranial stenosis WASID randomized trial • So when is it a cryptogenic stroke? • 50-99% stenosis • Doesn’t this just mean we have not • No difference in ASA and looked hard enough or smart enough? warfarin • What are stroke causes that we used to • ~22% event rate in 1.8 call cryptogenic? years – And what can we do about them? SAMMPRIS randomized • Many are known stroke causes that we trial just not had the technology to • 70-99% stenosis sufficiently evaluate (or not have • Intracranial stenting sufficiently appreciated) worse than medical therapy Chimowitz NEJM 2005 and 2011 Patent Foramen Ovale(?) Vasculitis - Angiography • Found in ~50% of cryptogenic stroke patients and ~25% of healthy people • PICSS study (substudy of WASID) – No difference in time to event between warfarin and ASA • Three randomized trials of PFO closure negative for ischemic stroke reduction • But if you find a DVT, a right-to-left shunt, and a PFO you may have a cause • Classic finding is “sausaging” of small-medium arteries • Angiography may be normal • Is abnormal angiogram diagnostic? Homma Circulation 2002 Saver NEJM 2016 Page 5

Moya-Moya Other Causes LICA RICA • Obliterative arteropathy • Hypercoaguable States with b/l distal intracranial ICA occlusions or high- – Cancer grade stenoses – Antiphospholipid antibody syndrome • Usually diagnosed angiographically (“vague or hazy puff of smoke”) • Genetic Conditions • Not restricted to Asians – CADASIL – Fabry’s disease • MRI/MRA by be strongly suggestive • Migraine-associated stroke LICA lenticulostriate • Non-inflammatory with “puff of smoke” intimal thickening and smooth muscle proliferation Undiagnosed Atrial Fibrillation CRYSTAL AF Study • As little as a single 1-hour episode of • Randomized study (n=441) of patients with atrial fibrillation during 2 years of cryptogenic stroke or TIA monitoring doubles stroke risk • ~15% of acute stroke patients have atrial • Insertable cardiac monitor (ICM) versus fibrillation at stroke onset conventional follow-up – Additional ~13% are diagnosed based on inpatient telemetry or 24 hour holter • At 6 months • Numerous studies have shown detection of paroxysmal atrial fibrillation – ICM group – afib 8.9% with prolonged monitoring – Conventional F/U – afib 1.4% • How long to monitor? • Mean time in afib was 4.3 minutes in a day – 2-4 weeks? – 2-4 years? Saver NEJM 2016 Sanna NEJM 2014 Page 6

Sanna NEJM 2014 Sanna NEJM 2014 How About a New “Cause” of Stroke • ESUS (embolic stroke of undetermined source) • Definition - a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic source with a clear indication for anticoagulation • Proposed as term to replace (most) cryptogenic stroke • “a therapeutically relevant entity” (??) Hart Lancet Neurology 2014 Hart Lancet Neurology 2014 Page 7

Hart Lancet Neurology 2014 Hart Lancet Neurology 2014 Proposed Workup Algorithm for Ischemic Stroke Saver NEJM 2016 Page 8

Cryptogenic Stroke • Despite an extensive workup, a significant % of patients will not have an identified cause of ischemic stroke – Workup is not just inpatient anymore – If your rate is >15% you aren’t looking hard enough • Recurrent annual stroke rate in “true” cryptogenic stroke is ~3-6% • Aggressive treatment of vascular risk factors is always part of the intervention – Antiplatelet agents as first-line antithrombotic • ESUS (embolic stroke of undetermined source) may become an actual diagnosis with a defined treatment – Clinical trials ongoing Page 9