1. RADOSLAV RAYCHEV, MD DEPARTMENTS OF NEUROLOGICAL SURGERY AND NEUROLOGY UNIVERSITY OF CALIFORNIA IRVINE SCHOOL OF MEDICINE

2. Acute Stroke Facts Leading cause of disability worldwide 2 nd leading cause of death worldwide >5 million stroke survivors $40 to $50 billion per year in the US 90% of those who survive will have deficits 80 % of strokes can be prevented

3. In a typical acute ischemic stroke, every minute the brain loses 1.9 million neurons 14 billion synapses 7.5 miles myelinated fibers -- Saver, Stroke 2006

4. Patient Knowledge Calling 911 EMS ED Staff Stroke Team Stroke Unit

5. Stroke recognition and patient awareness

6. Patient Awareness: IV TPA Under 3 Hours Changes in Outcome Due to Treatment Outcome NNTB Nl/Near Normal 8.3 Improved 3.1 For every 100 patients treated with tPA under 3 h, 32 benefit, 3 harmed --Saver, Arch Neurol 2004; 61:1066-1070; Stroke 2007; 38:2279-2283 --AAN/ACEP/AHA Patient Educational Tool 2008

7. Designed and validated by UCLA physicians Now part of paramedic training worldwide for recognizing stroke in the field UCLA Stroke Center Stroke Diagnosis by EMS

8. Currently Available Recanalization Therapies in Acute Cerebral Ischemia Intravenous  IV TPA under 3 hours  FDA approved, guideline endorsed, RCT supported  IV TPA 3-.4.5 hours  RCT supported, guideline endorsed, under FDA review Catheter  Mechanical embolectomy ≤ 8 h (Stentrievers)  FDA approved for clot clearance, no RCTs  Mechanical aspiration ≤ 8 h (Penumbra device)  FDA approved for clot clearance, no RCTs  Mechanical angioplasty/stenting  FDA approved for failed medical therapy  IA fibrinolytics ≤ 6 h  Off label, 1.5 positive RCTs, weakly guideline endorsed

9. Good outcome for patients with NIHSS > 20 in IMS III Trial:  23.8% with Endovascular treatment  16.8% with IV TPA Catheter Intervention - For Large Vessel Occlusion

10. Ticking Clock Tissue Clock > 3 hours

11. Bioenergetic Compromise Hemodynamic Compromise Occlusions or Stenoses DWIPWIMRA Tissue StatusPerfusion Status Vessel Status CBV CTPCT CTA Multimodal CT Multimodal MRI

12. Stroke Systems: Two Tier US Model EMS --Trained dispatchers, high priority triage --Paramedics trained in stroke recognition (e.g. LAPSS) --Deliver patients to nearest stroke capable hospital --Pre-arrival notification Primary Stroke Centers - Spokes --Able to provide initial, acute care --Able to use rt-PA and other acute therapies in a safe and efficient manner --Can admit patients if they have a Stroke Unit Comprehensive Stroke Centers - Hubs -- Able to care for complex patients --Advanced treatments (i.e. coils, stents, etc) --Trained specialists in key areas (Vascular neurology, Neurointerventional procedures, Neurocritical Care, Vascular Neurosurgery)

13. Brain Attack Coalition American Academy of Neurology American Association of Neurological Surgeons American Association of Neurosciences Nurses American College of Emergency Physicians American Heart Association American Society of Neuroradiology National Institute of Neurologic Disorders and Stroke National Stroke Association Neurocritical Care Society Stroke Belt Consortium Society of NeuroInterventional Surgery Veterans Administration

14. Supportive Data – Efficacy of Stroke Systems Stroke units (↓ LOS, ↓ complications) Stroke teams (more rapid responses) Neurological expertise (↓ mortality) Use of rt-PA Utility of QI/QA programs Care-Maps

15. Circulation (2009) 790 US hospitals, 2003-2007 322,847 consecutive ischemic stroke and TIA patients

16. EMS Stroke Center Diversion to primary stroke center: New York Experience Pre 6 wks Door to stroke team (mins) 3517 Door to CT16186 Door to TPA11478 IV TPA rate in TPA eligible29%50%

17. Impact of Acute Ischemic Stroke Treatments NNT Benefit per 100 pts TPA1-3h 3 32 Thrombectomy (lCA/M1) 5 20 TPA 3-4.5h 6 16 IA Lytics 7 14 Stroke Unit10 10 Aspirin77 1

18. PRIMARY STROKE CENTER MAP

19. Multidisciplinary group; AAN, ACEP, AANS, AHA, NSA AANN, NIH, ASNR, SBC – Stroke 2005

20. Comprehensive Stroke Centers: Key Components Neurologists, neurosurgeons, ED personnel, and experts in neuroendovascular procedures Full intensive care unit Neuroimaging interpreted within 20 minutes of acquisition Neurosurgical personnel within 30 minutes Door-to-needle time 60 minutes for IV tPA Door-to-groin puncture time 90 minutes for IA Availability of rehabilitation services

21. Pre Hospital Diversion to Comprehensive Stroke Centers: Endorsed by AHA/ASA

22. UCI Stroke Center

23. Pre Hospital Acute Stroke Treatment The Field Administration of Stroke Therapy – Magnesium (FAST-MAG) Phase III Trial

24. NIH FAST-MAG Trial throughout LA and Orange County Los Angeles and Orange Counties  Ethnically diverse population 13.3 million Prehospital  2298 paramedics  40 EMS Provider Agencies  315 ambulances Hospital  60 receiving hospitals  952 Physicians Sample  1700 Patients enrolled Jan 2005 – March 2013 Saver et al, International Stroke Conference 2014, San Diego, CA

25. FAST-MAG: Novel Aspects Diagnosis of Stroke in the field/ambulance  LAPSS  Physician Cellphone interview Rating Pretreatments Stroke Severity  LAMS Consent  Physician cell phone elicitation Randomization  Pre-encounter randomization Saver et al, International Stroke Conference 2014, San Diego, CA

26. FAST-MAG: Results Specific Aim - Unsuccessful  No benefit of Magnesium System Aim – Successful  Field enrollment in phase 3 clinical trial is practical and feasible Fastest Delivery of Stroke Treatment in a Clinical Trial  74.3% of stroke patients treated in the first “golden hour”  75% of stroke patients treated in the first 20 min of ambulance arrival Pre-hospital EMS assessment with physician by cell phone  LAPSS – 97% accuracy Saver et al, International Stroke Conference 2014, San Diego, CA

27. Videocart ED Videorobot Neuro ICU Video cellphone Ambulance

28. Prehospital Thrombolysis: A Manual from Berlin STEMO - A specialized ambulance equipped with:  Mobile CT scanner  Point of care laboratory  Telemedicine Mobile Stroke Units – Future of AIS treatment Ebinger et al, J Vis Exp 2013

29. Case Example 60 y/o male with acute aphasia and R hemiplegia (NIHSS 22) Witnessed onset at work 911 called EMS transported the patient to a primary stroke center within 15 min (Riverside county) UCI Stroke Center

30. Head CT – ASEPCTS score 9 UCI Stroke Center

31. Primary Stroke Center Patient was evaluated by teleneurology NIHSS 22 (global aphasia and R hemiplegia) Received IV TPA No improvement noted

32. Comprehensive Stroke Center Transferred to UCI Stroke Center via ambulance Arrived at UCI within 3.5 hours after onset Repeat exam showed persistent global aphasia and R sided hemiplegia – NIHSS 22 UCI Stroke Center

33. Multimodal Imaging UCI Stroke Center

34. INR suite  within 60 minutes of CT completion UCI Stroke Center

35. Solitaire FR UCI Stroke Center

37. Follow up Substantial improvement within 24 hours:  Patient is moving the right side against gravity, comprehends and utters simple words = NIHSS 10 UCI Stroke Center

38. Day 1 NIHSS 22 Day 5 NIHSS 5

39. Last known well @ 7:00 AM 911 call @ 10 min Primary Stroke Center arrival@ 30 min Teleneurology consult @ 1hr 05 min IV TPA @ 2hr Comprehensive Stroke Center arrival @ 3hr 30 min Multimodal Imaging@ 3hr 50 min IA Recanalization @ 5hr 10 min 60 y/o male with acute right sided weakness and inability to speak

40. Acute Ischemic Stroke Care in the 21 st Century Symptoms Primary Stroke Center EMS Call Comprehensive Stroke Center EMSIV Lytic IA Mechanical or Lytic Angiogram INR Suite Stroke Unit UCI Stroke Center Multimodal Imaging Imaging Telemedicine