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(Stroke. 2003;34:2533.)
© 2003 American Heart Association, Inc.

Controversies in Stroke

Measurement of the Ischemic Penumbra With MRI: It’s About Time

Steven Warach, MD, PhD

From the National Institute of Neurological Disorders and Stroke, Bethesda, Md.

Correspondence to Steven Warach, MD, PhD, National Institute of Neurological Disorders and Stroke, 10 Center Dr, MSC 1063, Bldg 10, Rm B1D733, Bethesda, MD 20892-1063. E-mail warachs{at}ninds.nih.gov

Key Words: cerebral blood flow • magnetic resonance imaging • penumbra • randomized controlled trials

The idea that there exist 2 ischemic thresholds in the pathogenesis of cerebral infarction came from seminal microelectrode studies of the baboon cortex the late 1970s^1,2 that measured the effects of progressive reductions in cerebral blood flow (CBF). These studies described a level of CBF reduction that led to cessation of cortical evoked responses in the absence of terminal increases in extracellular potassium or reductions in pH and a yet lower level of CBF reduction, at which occurred large increases in extracellular potassium and reductions in pH indicative of failure of membrane ion homeostasis and cell death.

Derived from animals too few and results too variable to specify a precise threshold, the insight nonetheless emerged that there were 2 levels of ischemia, one for tissue dysfunction without destruction and a lower one for irreversible cell injury. The metaphor of the ischemic penumbra was coined to describe this intermediate zone of ischemia between functionally normal and dead brain tissue. Restoration of normal CBF to the penumbral zone may reverse the functional disturbance.

Over the past 25 years, many investigators and clinicians have taken poetic liberties with the ischemic penumbra to suit their technologies and purposes. To some it is any variable that is intermediate in value between normal and that measured within the infarct. To others it is simply any noninfarcted brain with reduced CBF. To still others it is that region that is the optimal target of stroke therapy, destined for infarction if untreated but potentially salvageable if effectively treated. This last interpretation is of greatest relevance for the stroke patient and for the development of stroke therapies, and thus defines the modern ischemic penumbra.

To the originators of the concept, the penumbra was defined by the tip of a microelectrode. Neither multitracer PET nor diffusion-perfusion MRI nor any noninvasive neuroimaging technique can accurately measure the penumbra by the original definition. None have determined reliable, validated absolute thresholds for the upper and lower CBF boundaries of the penumbral zone, and none will. As we have argued elsewhere,³ the very notion of a specifiable absolute CBF threshold of tissue viability is meaningless if it is not integrated with temporal, therapeutic, and tissue factors. Definitions of penumbra that do not account for the time course of the physiological perturbation and the effects of physiological or pharmacological manipulations will be of limited value. The quantitative precision and range of metabolic variables measurable by PET should, in principle, make it the method of choice for imaging the human penumbra. However, limited numbers of PET centers exist and even fewer that can routinely study patients within the critical first few hours after a stroke. This fact and other practical limitations related to availability, radiation exposure, and arterial catheterization constrain the use of PET as a tool for managing acute stroke patients and assessing investigational therapies.

By contrast, diffusion and perfusion MRI of the less-than-6-hour stroke patient are routinely performed in hundreds of centers and have been a key element in several multicenter acute stroke trials.⁴ The goal in measuring the penumbra is to identify the patient with salvageable tissue-at-risk that is amenable to therapy. This requires a methodology that can be used emergently and used in large-scale randomized controlled trials to select patients and evaluate interventions. From the initial observations of whole brain diffusion and perfusion MRI in hyperacute stroke patients, it was evident that a larger region of hemodynamic compromise on PWI was present than the region of reduced apparent diffusion coefficient (ADC) induced by critically low CBF.⁵ The ADC on DWI reflects the CBF history of the tissue and evolves into infarction without reperfusion or neuroprotection. Hemodynamic abnormalities on PWI predict the possible futures of lesion evolution, futures affected by reperfusion and other potentially therapeutic interventions. This mismatch region is the tissue-at-risk and related to worse clinical outcome and infarct growth if early reperfusion does not occur.^6,7 The importance of this mismatch in predicting lesion expansion and growth has been described in many series from many different centers, and prospectively confirmed in a multicenter clinical trial.⁸ Quantitative models of multiparametric MRI markers of the penumbra have been developed and may lead to improvements in MRI patient selection beyond qualitative diffusion-perfusion mismatch assessments. Considerable data have emerged suggesting that the selection of patients by the diffusion-perfusion mismatch may identify the appropriate patient for effective intravenous thrombolytic therapy beyond 3 hours from onset,^9–11 and several randomized, placebo-controlled, multicenter trials are in progress to test that hypothesis.

The superior quantification by PET is indisputable but, paradoxically, not relevant to this discussion. What is the better measure of the ischemic penumbra in human stroke? The better technique is the one that will lead to effective stroke therapies. MRI is more likely than PET to achieve that goal.

Footnotes

Section Editors: Geoffry A. Donnan, MD, FRACP and Stephen M. Davis, MD, FRACP

The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.

References

1. Branston NM, Strong AJ, Symon L. Extracellular potassium activity, evoked potential and tissue blood flow: relationships during progressive ischaemia in baboon cerebral cortex. J Neurol Sci. 1977; 32: 305–321.[CrossRef][Medline] [Order article via Infotrieve]
2. Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke. 1977; 8: 51–57.[Abstract/Free Full Text]
3. Warach S. Tissue viability thresholds in acute stroke: the 4-factor model. Stroke. 2001; 32: 2460–2461.[Free Full Text]
4. Warach S. Use of diffusion and perfusion magnetic resonance imaging as a tool in acute stroke clinical trials. Curr Control Trials Cardiovasc Med. 2001; 2: 38–44.[CrossRef][Medline] [Order article via Infotrieve]
5. Warach S, Wielopolski P, Edelman RR. Identification and characterization of the ischemic penumbra of acute human stroke using echo planar diffusion and perfusion imaging. Proceedings of the Twelfth Annual Scientific Meeting of the Society of Magnetic Resonance in Medicine. 1993;12:263.
6. Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab. 1996; 16: 53–59.[CrossRef][Medline] [Order article via Infotrieve]
7. Baird AE, Benfield A, Schlaug G, Siewert B, Lovblad KO, Edelman RR, Warach S. Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann Neurol. 1997; 41: 581–589.[CrossRef][Medline] [Order article via Infotrieve]
8. Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R. Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging: Citicoline 010 Investigators. Ann Neurol. 2000; 48: 713–722.[CrossRef][Medline] [Order article via Infotrieve]
9. Parsons MW, Barber PA, Chalk J, Darby DG, Rose S, Desmond PM, Gerraty RP, Tress BM, Wright PM, Donnan GA, Davis SM. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol. 2002; 51: 28–37.[CrossRef][Medline] [Order article via Infotrieve]
10. Rother J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, et al. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke <6 hours. Stroke. 2002; 33: 2438–2445.[Abstract/Free Full Text]
11. Warach S. Thrombolysis in stroke beyond three hours: targeting patients with diffusion and perfusion MRI. Ann Neurol. 2002; 51: 11–13.[CrossRef][Medline] [Order article via Infotrieve]

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