Mechanism-based therapy of stroke

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• Professor Jean-Claude Baron, Department of Clinical Neurosciences, Cambridge
• Wednesday 30 September 2009, 11:15-11:45
• West Road Concert Hall.

If you have a question about this talk, please contact Hannah Critchlow.

This talk is part of the Cambridge Clinical Neuroscience and Mental Health Symposium, 29th – 30th September 2009 at West Road Concert Hall. This event is free to attend for cambridge neuroscientists although registration is required. To register, and for further information, please visit: http://www.neuroscience.cam.ac.uk/cnmhs/

Abstract: Preventing death and limiting handicap from stroke are major goals that can be achieved only if the pathophysiology of early infarct expansion is properly understood. Seminal primate studies showed that following occlusion of the middle cerebral artery (MCA) – the most frequent stroke subtype -, local tissue fate depends on the severity of hypoperfusion and duration of occlusion, with the MCA territory being initially in a functionally impaired but viable, i.e., “penumbral”, state which inexorably progresses to infarction unless reperfused early enough..

Physiological imaging has translated this knowledge in man and confirmed the presence of extensive penumbra early after stroke. These observations underpinned key trials of thrombolysis, now approved in clinical routine up to 3hrs after stroke onset – hopefully soon to be extended to 4.5hrs. However, only patients who are likely to benefit should ideally be exposed to its risks. Imaging has shown considerable pathophysiological heterogeneity from patient to patient, largely unpredictable from elapsed time or clinical presentation. Accordingly, imaging-based diagnosis is rapidly becoming an essential component of stroke assessment, replacing the clock by individually customized management. For instance, diffusion- and perfusion-MR and CT-based perfusion imaging are increasingly being used, and have undergone formal validation against established but clinically non-accessible quantitative techniques. Their clinical utility is currently being tested in controlled trials. As penumbra can be present up to 16hrs after onset in some patients, appropriate patients who may still benefit from treatment may be identified by imaging beyond currently accepted time limits.

Secondary physiological disturbances such as hypotension, hyperglycaemia and hypoxia may also cause infarct expansion, and clinical benefits from preventing them is currently emerging, underpinning the established benefit from early admission to acute stroke units. Early brain swelling may expose to “malignant” MCA infarction, which causes death in over 80% of the cases and severe disability in the survivors. By raising intracranial pressure, vasogenic edema is a major cause of secondary drops in cerebral perfusion pressure and hence perfusion in situation of persistent occlusion. Based on this, early surgical brain decompression has been shown in RCTs to markedly reduce mortality, but also disability in the survivors. Finally, there is currently no place for neuroprotection in the clinical setting as all RCTs have so far failed, which may in part reflect the inclusion of heterogeneous samples instead of targeting subsets matching the drug’s presumed mode of action.

Suggested reading: 1. Muir KW, Buchan AM, von Kummer R, Rother J, Baron JC. Imaging of Acute Stroke. Lancet Neurol., 2006; 5: 755-768. 2. Moustafa RR, Baron JC. Pathophysiology of Ischaemic Stroke: Insights from Imaging and Implications for Therapy and Drug Discovery. Brit. J. Pharmacol. 2008; 153(S1):S44-S54. 3. Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection for trials of acute stroke therapy. Lancet Neurol., 2009; 8: 261–69.

Biosketch: Jean-Claude Baron received his medical education and trained in Medical Physics and Neurology at the University of Paris. He was research fellow at Harvard University in 1976-77, Head of Neurosciences research at CEA Orsay in 1978-1988, and Head of the INSERM Neuroscience Unit and Scientific Director of the PET laboratory at the University of Caen, France in 1988-2000. In 2000 he was appointed Chair of Stroke Medicine, Dept of Clinical Neurosciences, University of Cambridge, and Neurology Consultant at Addenbrooke’s Hospital, Cambridge, UK. He is member of the Executive Committee and Chair of the PET Users Group of the Wolfson Brain Imaging Centre, University of Cambridge. His main area of research is the pathophysiology of stroke and the mechanisms of functional recovery, assessed mainly with imaging methods. His work is mainly supported by MRC , the Stroke Association and the EU.

This talk is part of the Clinical Neuroscience and Mental Health Symposium series.

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