1. XIX Symposium Neuroradiologicum
Bologna, Italy, 5. – 9. October 2010
“Time is Brain” Still a valid concept for the treatment of acute stroke patients?
Rüdiger von Kummer
Department of Neuroradiology
Dresden University Stroke Center (DUSC)
Universitätsklinikum Carl-Gustav-Carus der TU Dresden

2. Disclosures Chair, Steering Committee, DIAS-3/4
Steering Committee, ECASS-2, ECASS-3
Safety Committee, DIAS, DEDAS, DIAS-2, FAST
CT/MRI Reading Panel: ECASS, DIAS, FAST, IST3
Outcome Adjudiction: SPORTIF, MATCH, OPAL, ONYX
Fees for services, travel grants from:
AB Medica, Altana, Astellas, Bayer Schering, Boehringer Ingelheim, Lundbeck, NovoNordisk, Novartis, Paion, Penumbra, Pfizer, Sanofi, Siemens
Disclosures

3. Time is brain. Is time really brain? Be quick, but use brain, not clock!

4. Response to IV tPA (NINDS, Marler et al.,Neurology 2000. 55:1649)

5. No Treatment Beyond 3 Hours?

6. Treatment of Acute Ischemic Stroke
Challenging the Concept of a Rigid and Universal Time Window
J.C. Baron, MD; R. von Kummer, MD G.J. del Zoppo, MD Stroke 1995; 26:

7. The Time-is-Brain-Concept for Acute Ischemic Stroke
acknowledges the high vulnerability of brain tissue for even short periods of ischemia,
has fostered special and effective service for acute stroke patients (e.g. stroke units),
but widely ignores the pathophysiology of individual patients
and thus excludes many patients from treatment.
The Time-is-Brain-Concept for Acute Ischemic Stroke

8. Minimal Diagnostics in Stroke
Advantages
Time not required
Specialist not required
Special institution not required
Cheap and available
Disadvantage
Efficiency

9. Guideline “Time is Brain”: Therapeutic time window and minimal diagnostics
Within 3h of stroke
Exclusion ICH
Vessel pathology?
Brain pathology??
IV thrombolysis (rt-PA)

10. Prejustice
Early treatment with IV thrombolytics means high benefit for the patient.
The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain).
The main reason for the failure of IV thrombolytics is the disappearance of penumbra.
The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

11. Prejustice
Early treatment with IV thrombolytics means high benefit for the patient.
The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain).
The main reason for the failure of IV thrombolytics is the disappearance of penumbra.
The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

12.
245 : 3908 = 6%

13. Effectivness of IV tPA
The concept „time-is-brain“ excludes the majority of patients from treatment without a diagnosis of the individual disease.
The effectiveness of IV tPA was tested in a minority of acute ischemic stroke patients.
The beneficial effect of IV tPA in this minority was significant in 2 RCTs only, but minor as well.

14. Absolute Reduction of Disability/Mortality by IV tPA in RCTs
*NINDS1: retrospective

15. Benefit from IV Thrombolytics (Alteplase) in Randomised Controlled Studies (RCTs)
Only NINDS-2 and ECASS-3 showed a significant effect
Maximal effect:
Absolute reduction M/M: 7%
Relative reduction M/M: 9,5% (NINDS-2), 12,7% (ECASS-3)
Time-window NINDS-2: 3 hours
Time-window ECASS-3: 3 to 4.5 hours

16. Prejustice Is time really brain?
Early treatment with IV thrombolytics means high benefit for the patient.
The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain).
The main reason for the failure of IV thrombolytics is the disappearance of penumbra.
The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).
Is time really brain?

17. Beneficial Outcome after IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695) 60
120
180
240
300
360

18. Potential Causes for Progressive Failure of IV tPA in RCTs
Selection bias: Patients with poor prognosis were treated early
Spontanous recovery: no arterial occlusion, spontaneous recanalization and tissue reperfusion
Recanalisation and reperfusion not achieved
Thrombolytics cannot reach the thrombus (tandem stenosis)
Thrombus too big (too long)
Thrombus constitution (calcified, no fibrine)
Arterial obstruction not caused by thrombus, but by atheroscleosis, dissection
Recanalisation without sufficient tissue reperfusion
Re-Occlusion, thrombus migration
Adverse events, e.g. symptomatic hemorrhage
Reperfusion too late, brain already damaged to an extend that does not allow recovery

19. Good Clinical Outcome after Ischemic Stroke and Treatment with Placebo

20. Good Clinical Outcome in Trials on the Treatment with IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695)

21. Clinical deterioration (CD) In 44/374 patients (12%)
Stroke 2007;38:69

22. 51 y, m, Stroke 4 Days After Car Accident
R Hemiparesis: 15:00
CT: 17:00
US: L ICA Occlusion
IV rt-PA

23. 51 y, m, Stroke 4 Days After Car Accident 1 d later after clinical deterioration

24. 51 y, m, Stroke 4 Days After Car Accident 2 d later after clinical deterioration

25. Infarctpatterns after MCA Occlusion Zülch KJ
Infarctpatterns after MCA Occlusion Zülch KJ. Über die Entstehung und Lokalisation der Hirninfarkte. Zbl Neurochir 1961;21:

26. ECASS II (N=792): Prevalence of Ischemic Edema after Stroke Onset

27. ECASS II (N=792): Large Ischemic Edema at Baseline% 3 11 15 14 8 1
hours after symptom onset

28. Infarct Core and Penumbra (CBF) in Patients with acute MCA Occlusion (Jovin et al. Stroke 2003;34: )

29. Volumes of DW image (DWI) lesions (teal bars) and absolute mismatch volumes (red bars) for every patient in study
Copen, W. A. et al. Radiology 2009;250:
Copyright ©Radiological Society of North America, 2009

30. Infarctvolume and Time
Minutes
Hours
Days
Time

31. The ascending lenticulo-striatal arteries originate from the MCA-trunk and supply the basal ganglia. There is no collateral supply for this region.

32. In case of thrombo-embolic occlusion of the MCA-trunk, the basal ganglia become severely ischemic, whereas the cortical MCA territory

33. Prejustice
Early treatment with IV thrombolytics means high benefit for the patient.
The efficiency of IV thrombolytics disappear over time due to the steady growth of infarction. (Time is brain).
The main reason for the failure of IV thrombolytics is the disappearance of penumbra.
The treatment with IV thrombolytics bears a high risk of symptomatic brain hemorrhage if initiated after 3 hours (4.5 hours).

34. Major Brain Hemorrhage after IV tPA Pooled Analysis of all RCTs, N=3760 (Lees, Bluhmki, von Kummer et al. Lancet 2010;375:1695)

35. 74 y, m, Wake-up Stroke, R Hemiparesis
, 11:15

36. 74 y, m, Wake-up Stroke, R Hemiparesis
L ICA, , 12:00

37. 74 y, m, Wake-up Stroke, R Hemiparesis
Carotis-Wallstent: 7 mm x 50 mm, , 12:25

38. 74 y, m, Wake-up Stroke, R Hemiparesis
14:15

39. 74 y, m, Recovered from Wake-up Stroke

40. The earth is not flat and the treatment of stroke can be beneficial after 3 hours

41. New Concept
Identification of patients who should not be treated with IV tPA
No arterial obstruction/perfusion deficit
No thrombotic obstruction
Big thrombi in ICA, M1-segment, basilar artery
Extended brain damage within the affected arterial territory
No time limits
Appropriate choice of treatment
Assessment of recanalization/reperfusion

42. Diagnostic Keys of Ischemic Stroke Treatment
Arterial Obstruction Identification of Infarction
3 h after stroke onset

43. Use your Brain, but not your Clock Be quick, however