Identifying and utilizing the ischemic penumbra

The penumbral concept is defined as different areas within the ischemic region evolve into irreversible brain injury over time and that this evolution is most critically linked to the severity of the decline in cerebral blood flow (CBF). The ischemic penumbra was initially defined as a region of reduced CBF with absent spontaneous or induced electrical potentials that still maintained ionic homeostasis and transmembrane electrical potentials. The reduction of CBF levels to between 10 and 15 mL/100 g/min and approximately 25 mL/100 g/min are likely to identify penumbral tissue, and the ischemic core of irreversible ischemic tissue has a CBF value below the lower threshold. The role of identifying this critically deprived brain tissue from CBF in triaging patients for endovascular ischemic therapy is evolving. In this review we focus on the basic science of the penumbral concept and identification using various imaging modalities (PET, MRI, and CT) in animal models and human studies. Another article in this supplement addresses the clinical implication and the current understanding and application of this concept into clinical practice of endovascular ischemic stroke therapy.

[1]  M. Fisher.  The Ischemic Penumbra: A New Opportunity for Neuroprotection , 2006, Cerebrovascular Diseases.

[2]  C. Sotak,et al.  Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats , 1999, Annals of neurology.

[3]  Marc Fisher,et al.  New approaches to neuroprotective drug development. , 2011, Stroke.

[4]  T. Neumann-Haefelin,et al.  MRI-Based and CT-Based Thrombolytic Therapy in Acute Stroke Within and Beyond Established Time Windows: An Analysis of 1210 Patients , 2007, Stroke.

[5]  A. Thiel,et al.  Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. , 2001, Brain : a journal of neurology.

[6]  F. Sharp,et al.  Multiple Molecular Penumbras after Focal Cerebral Ischemia , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  M. Fisher,et al.  Normobaric Hyperoxia and Delayed tPA Treatment in a Rat Embolic Stroke Model , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  V Hachinski,et al.  Identification of Penumbra and Infarct in Acute Ischemic Stroke Using Computed Tomography Perfusion–Derived Blood Flow and Blood Volume Measurements , 2006, Stroke.

[9]  Keith Muir,et al.  Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial , 2008, The Lancet Neurology.

[10]  K. Schmidt,et al.  Comparison of Ischemic Lesion Evolution in Embolic Versus Mechanical Middle Cerebral Artery Occlusion in Sprague Dawley Rats Using Diffusion and Perfusion Imaging , 2006, Stroke.

[11]  G. Albers,et al.  Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection. , 1999, Stroke.

[12]  E. Lo.  Experimental models, neurovascular mechanisms and translational issues in stroke research , 2008, British journal of pharmacology.

[13]  S. Lim,et al.  Phenotyping of an in vitro model of ischemic penumbra by iTRAQ-based shotgun quantitative proteomics. , 2010, Journal of proteome research.

[14]  Geoffrey A. Donnan,et al.  RAPID Automated Patient Selection for Reperfusion Therapy: A Pooled Analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study , 2011, Stroke.

[15]  Scott Hamilton,et al.  Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study , 2006, Annals of neurology.

[16]  M. Fisher,et al.  Granulocyte-Colony Stimulating Factor Delays PWI/DWI Mismatch Evolution and Reduces Final Infarct Volume in Permanent-Suture and Embolic Focal Cerebral Ischemia Models in the Rat , 2009, Stroke.

[17]  Gary Duckwiler,et al.  Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging , 2000, Annals of neurology.

[18]  H J Tochon-Danguy,et al.  The fate of hypoxic tissue on 18F‐fluoromisonidazole positron emission tomography after ischemic stroke , 2000, Annals of neurology.

[19]  M. Wintermark,et al.  Imaging of acute ischemic brain injury: the return of computed tomography , 2003, Current opinion in neurology.

[20]  W D Heiss,et al.  Ischemic Penumbra: Evidence From Functional Imaging in Man , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  S. Warach,et al.  The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase , 2005, Stroke.

[22]  G. Donnan,et al.  Proof-of-Principle Phase II MRI Studies in Stroke: Sample Size Estimates From Dichotomous and Continuous Data , 2006, Stroke.

[23]  Jean-Claude Baron,et al.  Mapping the Ischaemic Penumbra with PET: Implications for Acute Stroke Treatment , 1999, Cerebrovascular Diseases.

[24]  W. Heiss,et al.  Dynamic Penumbra Demonstrated by Sequential Multitracer PET after Middle Cerebral Artery Occlusion in Cats , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  PeterSandercock,et al.  Comparison of 10 Different Magnetic Resonance Perfusion Imaging Processing Methods in Acute Ischemic Stroke , 2007 .

[26]  Reto Meuli,et al.  Perfusion-CT Assessment of Infarct Core and Penumbra: Receiver Operating Characteristic Curve Analysis in 130 Patients Suspected of Acute Hemispheric Stroke , 2006, Stroke.

[27]  M. Ginsberg,et al.  The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke , 1994, Annals of neurology.

[28]  P. Sandercock,et al.  Comparison of 10 Different Magnetic Resonance Perfusion Imaging Processing Methods in Acute Ischemic Stroke: Effect on Lesion Size, Proportion of Patients With Diffusion/Perfusion Mismatch, Clinical Scores, and Radiologic Outcomes , 2007, Stroke.

[29]  R. Willemze,et al.  Problems and possible solutions in finding an unrelated bone marrow donor. Results of consecutive searches for 240 Dutch patients , 1997, Bone Marrow Transplantation.

[30]  M Wintermark,et al.  Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute treatment , 2007, Neurology.

[31]  J. Baron,et al.  Local Interrelationships of Cerebral Oxygen Consumption and Glucose Utilization in Normal Subjects and in Ischemic Stroke Patients: A Positron Tomography Study , 1984, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  E. Lo,et al.  A new penumbra: transitioning from injury into repair after stroke , 2008, Nature Medicine.

[33]  David L. Thomas,et al.  Measuring Cerebral Blood Flow Using Magnetic Resonance Imaging Techniques , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  V Beaudouin,et al.  Sequential studies of severely hypometabolic tissue volumes after permanent middle cerebral artery occlusion. A positron emission tomographic investigation in anesthetized baboons. , 1995, Stroke.

[35]  S. Warach,et al.  Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study , 2009, The Lancet Neurology.

[36]  À. Rovira,et al.  Safety and Efficacy of Intravenous Tissue Plasminogen Activator Stroke Treatment in the 3- to 6-Hour Window Using Multimodal Transcranial Doppler/MRI Selection Protocol , 2005, Stroke.

[37]  B. Siesjö,et al.  Thresholds in cerebral ischemia - the ischemic penumbra. , 1981, Stroke.

[38]  K. Hossmann.  Viability thresholds and the penumbra of focal ischemia , 1994, Annals of neurology.

[39]  G. Schlaug,et al.  The ischemic penumbra: operationally defined by diffusion and perfusion MRI. , 1999, Neurology.

[40]  A. Hakim.  The Cerebral Ischemic Penumbra , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[41]  Steven Warach,et al.  Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of Safety and Efficacy 3 to 9 Hours After Stroke Onset , 2006, Stroke.