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(Stroke. 1997;28:866-872.)
© 1997 American Heart Association, Inc.

Articles

Characterizing the Target of Acute Stroke Therapy

Marc Fisher, MD

From the Departments of Neurology, Memorial Health Care and University of Massachusetts Medical School, Worcester.

	Abstract

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Background The development of effective therapies for acute ischemic stroke presumes the existence of potentially salvageable ischemic tissue when therapy is initiated because it is widely assumed that the effectiveness of most acute stroke therapies under development is related to reducing ultimate infarct size to promote functional improvement. Such salvageable ischemic tissue was previously labeled the ischemic penumbra and must be distinguished from irreversible injury.

Summary of Review Pathological identification of irreversibility (infarction) appears to lag behind the actual development of this condition, and reversible injury after focal ischemia should be differentiated from infarction. Imaging and biochemical markers apparently can provide clues for distinguishing potentially salvageable from irreversibly injured ischemic tissue in experimental and clinical stroke. Recent positron emission tomography and MRI studies suggest that these clinically available imaging technologies will be useful for determining the presence of ischemic penumbra in individual stroke patients. The progression from potentially reversible to irreversible injury after focal brain ischemia has many potential mechanisms that may be synergistic and vary among individuals.

Conclusions Delineating and prioritizing these mechanisms provides the opportunity to develop multiple potential acute stroke therapies that ultimately will be used in combination, perhaps directed by imaging technology.

Key Words: stroke, acute • treatment outcome

	Introduction

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Acute ischemic stroke is a common and frequently devastating disorder that remains the third leading cause of death in western countries and a major cause of disability in the elderly. Effective therapy to improve outcome has been elusive, although the results of the recently reported NIH rTPA trial are encouraging.¹ Currently, clinicians and researchers involved in the field of focal ischemic brain injury and its treatment are encouraged by many developments regarding an enhanced understanding of the basic mechanisms of focal ischemic brain injury, advances in the imaging of early focal ischemia, rational pharmacological interventions, and improved clinical trial design. These developments should enhance our efforts to produce meaningful therapies for acute ischemic stroke that will maximize functional and neurological outcome for individual patients. The development of effective stroke therapies is based primarily on the concept of salvaging ischemic tissue that is not irreversibly injured. This review will focus on how to potentially define, identify, and treat salvageable ischemic tissue, as well as mechanisms that contribute to its evolution toward irreversibility.

	Distinguishing Irreversible Focal Ischemic Injury From Infarction and Necrosis

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The target of therapeutic interventions for focal ischemia logically should be ischemic tissue that can respond to treatment and is not irreversibly injured. Such tissue will be defined as potentially salvageable ischemic tissue that has the capability of responding to appropriate and timely therapies. Such salvageable ischemic tissue must be distinguished from nonsalvageable ischemic tissue that has evolved to a status in which functional recovery is no longer possible. The nonrecoverable state of tissue subjected to focal ischemic injury has in the past been loosely called infarction, defined by the development of cellular necrosis and typically identified microscopically by the appearance of pyknotic, eosinophilic neurons (Fig 1).² The pathological identification of cellular necrosis has a time lag, as Garcia and colleagues³ demonstrated in a rat experimental stroke model with varying times to death and pathological examination. During the initial 45 to 90 minutes after the initiation of permanent MCAO, swelling of astrocytes and endothelial cells was detectable on electron microscopy, and microvascular plugging by erythrocytes and PMN was detectable in that portion of the ischemic territory with the lowest range of residual CBF (supraoptic area). Changes to the neuronal perikarya were minimal. After 1 to 3 hours, the region of astrocytic changes spread to the cortex. Swollen, pale neurons appeared in the striatum. Eosinophilic neurons, the classic marker of necrosis, did not appear in the core of the ischemic lesion (striatum) until more than 12 hours after the onset of permanent occlusion and at 24 to 48 hours in the cortical portions of the ischemic territory. Many intervention studies in rat and cat stroke models have suggested that it may not be possible to reverse focal ischemic injury in these species by reperfusion or neuroprotective therapy much beyond 3 hours after onset.^{4 5} The discrepancy between the pathological observations as to when neuronal necrosis occurs and the time window for successful intervention strongly implies that irreversible ischemic injury precedes neuronal necrosis by a wide time margin in large portions of the ischemic territory. Therefore, using infarction or necrosis as a working definition of irreversible ischemic injury appears to be inappropriate, since irreversibility to potentially appropriate interventions develops substantially in advance of these pathological changes. In primates and humans, the time period required to develop irreversible tissue injury after permanent focal ischemia is longer than in rats but likely still precedes the pathological identification of infarction.⁶ It is proposed that the term irreversible ischemic injury be used and not infarction or necrosis when delineating focal ischemic tissue that is no longer capable of recovery. How might we be able to distinguish such irreversibly injured tissue in focal ischemia, if the classic histopathologic approach is not timely?

View larger version (136K): [in this window] [in a new window]   Figure 1. A, Complete infarction in the right cerebral hemisphere of a Wistar rat that had permanent MCAO 6 days before death (hematoxylin-eosin, original magnification x2.5) (courtesy of Dr J.H. Garcia). B, Detail of the cerebral cortex from same specimen as panel A. Irreversibly injured cortical neurons (arrowheads) are seen in a background of spongy neuropil (toluidine blue, original magnification x160) (courtesy of Dr J.H. Garcia). C, Incomplete infarction in the right cerebral hemisphere (Wistar rat). The middle cerebral artery was occluded for 30 minutes, 21 days before death. Arrowheads outline the area of the striatum where selective neuronal injury is widespread (hematoxylin-eosin, original magnification x2.5) (courtesy of Dr J.H. Garcia). D, Detail of the striatum from the same specimen shown in panel C. Irreversibly injured neurons surrounded by microglia (small arrows) are seen in the same field when intact neurons (large arrows) are also visible (toluidine blue, original magnification x160) (courtesy of Drs K.-F. Liu and J.H. Garcia).

	Potential Imaging and Biochemical Markers of Potentially Salvageable and Irreversibly Injured Ischemic Tissue

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Biochemical and imaging modalities are available that could be useful for distinguishing between potentially reversible and irreversibly injured tissue associated with focal ischemia. Many studies of experimental focal ischemia investigated the nature and time course of metabolic changes associated with focal ischemia in a variety of species. In gerbils, Paschen and colleagues⁷ observed that 90 minutes after permanent tandem right common and left external carotid occlusion, right hemispheric regions with profound reductions of CBF (<10 to 20 mL/100 g per minute) had marked reductions in ATP and glucose levels, and there was a clear relationship between CBF levels of reduction and disordered energy metabolism. Similarly, in rats ATP levels were reduced by 46% in the striatum and by only 18% in the cortex 2 hours after MCAO and did not change further at 24 hours after stroke onset in this model.⁸ Folbergrova and colleagues⁹ demonstrated more profound reductions of ATP levels (20% to 40% of control values in the ischemic core) using the suture MCAO model, as early as 30 minutes after the onset of focal ischemia. Much more modest ATP reductions occurred in ischemic regions with less severe CBF reductions. Similar changes in phosphocreatine were also observed. Lactate levels were fairly uniformly increased in ischemic regions with both severe and more moderate CBF declines. These observations imply that metabolic changes rapidly develop in ischemic regions with severe CBF declines but do not necessarily distinguish between reversible and irreversible injury. Recently, Hossmann and colleagues^{10 11} have attempted to relate these metabolic changes after focal cerebral ischemia to ischemic lesions demonstrated in vivo by DWI and autoradiographic measurements of CBF. In rats subjected to permanent MCAO by the suture occlusion method, at 7 hours after the onset of ischemia, the ischemic region depicted by DWI was almost identical to the region of severe ATP decline and tissue acidosis was identified immediately after the rats were killed.¹⁰ This combination of imaging abnormality and metabolic changes suggests that most if not all of the ischemic lesion is irreversibly injured at a time when few necrotic neurons are likely to be pathologically identified. Examining earlier time points after the onset of focal ischemia, the same group demonstrated rapid development of DWI changes that maximized in extent by 105 minutes after onset, agreeing with prior observations.^{11 12} However, the ischemic region with severe ATP depletion at this time was noticeably smaller than the region demonstrable by DWI, implying that some of the ischemic territory imaged on DWI at this time point was not severely injured and potentially salvageable. Interestingly, the DWI ischemic lesion area and that with severe acidosis were closely correlated. When severe ATP declines at 2 hours after onset of ischemia were correlated with CBF declines, it was observed that the CBF level was below 18 mL/100 g per minute in the severely reduced ATP regions. In humans, MR spectroscopic imaging can be used to measure high-energy phosphates,¹³ although the acquisition time is fairly lengthy and the voxel sizes large, leading to partial volume effects. However, as MR spectroscopy advances, it could be used along with DWI and perfusion imaging to potentially identify tissue characteristics suggestive of irreversibility and reversibility.

PET is another technique used to evaluate ischemic tissue that potentially can distinguish between reversible and irreversible injury. PET can be used to measure cerebral blood volume, CBF, CMRO₂, and the OEF. In normal brain, the first three parameters have a linearly proportional relationship, and OEF is uniform throughout the brain.¹⁴ With hemodynamic failure, four patterns of PET abnormality are observed: (1) increase of cerebral blood volume to maintain CBF (autoregulation); (2) reduced CBF with increased OEF to maintain CMRO₂ (oligemia); (3) reduced CBF and CMRO₂ with increased OEF (ischemia); and (4) very low levels of CBF and CMRO₂, presumed to represent irreversible injury. The term "misery perfusion" is used to describe the situation of reduced CBF and increased OEF.¹⁵ In animal stroke studies with PET, evolving patterns are detectable. Heiss et al¹⁶ observed in cats subjected to serial PET studies that at 1 hour after the onset of ischemia, pattern 3 was widely detectable. By 4 hours after permanent MCAO, pattern 4 was prevalent in the presumed central ischemic zone and pattern 3 was prevalent in the periphery. At 24 hours, pattern 4 nearly completely encompassed the ischemic territory, and there was good correlation of the territory with this PET pattern and infarct size at postmortem. A similar although less complete pattern of evolution was observed with a preliminary PET study in primates obtained 1 and 4 hours after stroke onset.¹⁷ In a more recent primate PET stroke study, Touzani et al¹⁸ serially evaluated PET parameters at 1, 4, 7, and 24 hours and 14 and 29 days after stroke onset. They used a CMRO₂ below 1.5 mL/100 g per minute to define severely hypometabolic tissue. The volume of tissue in the ischemic hemisphere below this did not change significantly over the initial 7 hours, but at 24 hours the volume of tissue with values below 1.5 mL/100 g per minute significantly increased and was larger still at 14 days. There was a significant correlation of ischemic tissue volume at 24 hours, defined as a decrease of 45% to 50% of CMRO₂, compared with contralateral values, with postmortem infarct volume. OEF was elevated at 1 hour after stroke onset, but the OEF declined markedly by 24 hours. This important study suggests that in primates the evolution of focal ischemic injury may continue over a much longer time period than was previously appreciated. The same group evaluated eight stroke patients within 7 to 17 hours of stroke onset with PET.¹⁹ They then performed a delayed PET study (13 to 41 days later) and standard CT to evaluate ultimate infarct size. CMRO₂ levels below 1.4 mL/100 g per minute were validated to represent irreversibly injured ischemic tissue. There was a highly significant increase in the percentage of the ischemic region that had this CMRO₂ threshold between the initial and late PET studies. OEF was elevated in portions of the ischemic region in all but one patient on the initial PET study. In a more recent study, the French PET group related PET parameters within 18 hours of stroke onset to CT-defined infarction at approximately day 50 after stroke (Fig 2).²⁰ The penumbra was defined as ischemic tissue with an OEF greater than 2 standard deviations from contralateral values with a CBF between 7 and 17 mL/100 g per minute. Ischemic tissue with these characteristics occurred in 10 of 11 patients, and variable portions of the penumbra ultimately were infarcted on delayed CT scanning. The volume of reversible penumbra was significantly correlated with clinical improvement in these untreated stroke patients. These human studies suggest that within 24 hours after stroke onset, many stroke patients have ischemic tissue that is potentially salvageable and that a potentially reversible ischemic penumbra can be identified. The evolution to complete irreversibility appears to occur over a more prolonged period of time than many would have imagined. These animal and human studies imply that PET could be used in individual stroke patients to assess the presence of potentially salvageable ischemic tissue, but unfortunately PET machines are expensive to purchase and maintain. It is likely that they will only be available for research studies and not become a widely available clinical imaging tool.

View larger version (80K): [in this window] [in a new window]   Figure 2. Multiple CT scan cuts show the final region of infarction (outlined by the white lines) with superimposition of initial regions (hyperintensity) where a PET study obtained within 17 hours of stroke onset demonstrated CMRO2 values above 1.40 mL/100 mL per minute (courtesy of Dr J.C. Baron).

The new MRI technologies of diffusion and perfusion imaging are clearly useful for rapidly depicting ischemic regions in both experimental and human stroke.²¹ DWI evaluates the movement of protons in water molecules and can identify focal cerebral ischemia within minutes after the onset of experimental stroke and within 2 hours in stroke patients. In animals, ischemic lesions identified by DWI evolve over a few hours to a size that is highly correlated with postmortem confirmed infarction.¹² In stroke patients, the evolution is slower and may take 24 hours or longer in some cases before the ischemic lesion volume on DWI is well correlated with the ultimate infarct volume as characterized by a T2-weighted MRI many weeks later (Fig 3).²² Perfusion MRI is currently most commonly done by the so-called bolus contrast method that employs the rapid injection of a contrast agent such as gadolinium diethylenetriaminepentaacetic acid followed by the repetitive acquisition of T2*-weighted images every 0.5 or 1 second for 16 to 20 seconds to generate a washout curve related to a decline of the T2*-weighted signal intensity.²³ From the signal intensity curve, cerebral blood volume is represented by the area under the curve, and the mean transit time is represented by the time to the peak of the signal intensity decline. These two parameters can be used to calculate a relative index of CBF. In some stroke patients, the ischemic region demonstrated by perfusion imaging is larger than the region of DWI abnormality during the initial hours after onset. Warach et al²⁴ suggested that this mismatch of ischemic territories between DWI and perfusion MRI at early time points might represent salvageable ischemic tissue, while regions of concordance on the two MRI studies are likely irreversibly injured. The actual situation may be more complicated. In animal DWI studies, absolute measurements of the ADC, the physical parameter underlying the generation of DWI images, reveal heterogeneous ADC values in the ischemic zone early after stroke onset that worsen and become more homogeneous over time.¹² The lower the ADC value, the lower is the residual CBF and the more metabolically compromised is the ischemic tissue. In animal studies, there appears to be a range of ADC values that, when reached, identifies ischemic tissue that is no longer responsive to therapeutic interventions, ie, is irreversibly injured.²⁵ These animal studies are difficult to extrapolate to human stroke because in stroke models the precise time of onset is known and the ischemic lesions are stereotyped. In stroke patients, a combination of DWI studies that generate ADC maps and perfusion imaging will likely be necessary to attempt to segregate potentially salvageable ischemic tissue from tissue that is already likely to be irreversibly damaged. The characterization by these new MRI technologies of such a distinction remains to be established, but the future appears to be promising on the basis of animal studies. If diffusion/perfusion MRI can fulfill this promise of reliably distinguishing potentially reversible and irreversibly injured ischemic tissue in stroke patients, clinicians will have a powerful new tool to make decisions about patient management. These MRI technologies will become widely available as current MRI units are upgraded or replaced. In addition to providing potentially useful information about the status of ischemic tissue, these MRI technologies can also be used to guide therapy by identifying the presence or absence of a perfusion deficit in an arterial territory and by the early characterization of an ischemic event as a likely large- or small-artery ischemic stroke. This type of classification could be used in the future to direct therapy to such modalities as thrombolysis, NMDA antagonists, antiadhesion molecules, growth factors such as basic fibroblast growth factor, or antioxidants if these interventions are ultimately approved for the treatment of acute ischemic stroke.

View larger version (86K): [in this window] [in a new window]   Figure 3. DWI and T2-weighted (T2WI) MRI study obtained 5 hours after the onset of left homonymous hemianopsia (LHH) and left-sided (L) ataxia. The DWI demonstrates regions of hyperintensity in the left occipital lobe, while the T2-weighted study is normal (courtesy of Dr S. Warach).

	The Concept of the Ischemic Penumbra

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The characterization of potentially reversible versus irreversibly ischemic tissue is based on the ischemic penumbra hypothesis originally proposed by Astrup, Siesjö, and Symon.²⁶ It is now widely presumed that the time course of tissue injury in focal cerebral ischemia can be envisioned as falling into two distinct patterns. In ischemic regions with very low residual CBF (<10 to 15 mL/100 g per minute)—the ischemic core—the evolution to irreversible injury is relatively rapid, perhaps 1 hour or less.²⁷ In surrounding ischemic regions with more modest CBF reductions (15 to 35 mL/100 g per minute), the evolution to irreversibility is slower and, as discussed previously, may take many hours or even a day. This modestly ischemic zone or the penumbra was originally defined as tissue sufficiently ischemic to lose electric activity but able to maintain membrane potentials and transmembrane ionic potentials.²⁶ A broader definition of the ischemic penumbra has emerged. For example, Hossmann²⁸ recently defined the ischemic penumbra as "a region of constrained blood supply in which energy metabolism is preserved." In an accompanying editorial, Ginsberg and Pulsinelli²⁹ modified this definition by suggesting that energy metabolism could be intermittently compromised in the ischemic penumbra. A broader definition of the ischemic penumbra, but one that is most relevant in relationship to the development of therapeutic intervention, is that suggested by Hakim³⁰ of ischemic tissue that is "fundamentally reversible." Using a definition of potential reversibility focuses the concept of the ischemic penumbra into one that is clinically relevant and helps to identify a target of opportunity. However, this target is not stationary, because this ischemic region of potential reversibility evolves over time. It appears that CBF declines that characterize potential reversibility early after onset likely define irreversibility at later time points.²⁸ Important factors that affect the evolution of the ischemic penumbra for individual patients include time from onset, the adequacy of collateral blood flow, temperature, and systemic metabolic disturbances (eg, glucose, acidosis). Thus, each patient's ischemic penumbra has unique characteristics. If it is this penumbral tissue that is the therapeutic target, then it is easy to conceptualize that individual patients have their own time window for potentially effective intervention.³¹

What potential processes affect the ischemic penumbra to foster its evolution from a potentially reversible state toward irreversibility? A number of possible mechanisms emerged as knowledge about the pathogenesis of ischemic injury expanded, and it will become increasingly important to prioritize the contribution of individual mechanisms in individual patients. We should not presume that each mechanism has the same relevance toward the evolution of the ischemic penumbra in every patient. The contribution of calcium influx into ischemic cells to ultimately promote irreversible injury was hypothesized by Meldrum³² and Choi.^{33 34} The activation of receptor-mediated calcium conducting channels by excitatory neurotransmitters such as glutamate is well documented in experimental ischemia, and elevation of glutamate was recently confirmed in the cerebrospinal fluid of stroke patients.³⁵ The activation of glutamate-mediated channels such as the NMDA and to a lesser extent the AMPA channels promotes intracellular accumulation of calcium and the activation of voltage-mediated calcium channels, release of intracellular calcium stores, and the activation of deleterious intracellular enzymes that cause irreversible cellular injury.³⁴ Intracellular calcium accumulation can also promote oxygen free radical expression, and these molecules can also induce cellular injury by a variety of mechanisms. The glycine and polyamine receptor sites of the NMDA complex are also important because activation of these modulatory sites affects calcium conductance by this channel and implies that these modulatory sites can be additional targets for therapeutic intervention. Glutamate is present for many hours after the onset of focal ischemia and may promote further injury in relatively mildly ischemic regions by diffusing out from the ischemic core and by initiating the formation of other intercellular messengers such as nitric oxide and arachidonic acid.³⁶

Another mechanism that may contribute to the evolution of injury in the ischemic penumbra is microvascular compromise and the accumulation of PMN. The phenomenon of "postischemic hypoperfusion" is likely related to several potential mechanisms.³⁷ Poor circulation in the microvasculature can be caused by the accumulation of red blood cells and PMN since both types of blood cells are observed within partially perfused ischemic tissue within a few hours after onset.³⁸ The microvasculature could also be compromised by endothelial cell and astroglial swelling, as well as the formation of microthrombi and vasospasm. In addition to mechanically occluding the microcirculation, PMN may also contribute to maturation of the ischemic penumbra by the release of oxygen free radicals and cytokines.² In experimental stroke models, antiadhesion molecules consistently reduce ischemic lesion volume when temporary but not permanent ischemia is induced.^{39 40} These experimental observations suggest that PMN do contribute to the evolution of focal ischemic injury and that antiadhesion molecules might be combined with thrombolytic therapy in future stroke therapy trials.

Peri-infarct spreading waves of depolarization, similar to the phenomenon of spreading depression, occur in various animal species subjected to experimental focal ischemia.⁴¹ The number of these peri-infarct depolarizations significantly correlates with the ultimate size of the infarction.⁴² It was hypothesized that these depolarizations could contribute to the evolution of the ischemic penumbra toward irreversible injury because they are an energy-consuming process.²⁸ In normal brain, the increased energy demand can be compensated for by increasing CBF, but in focal ischemia this is not possible. Therefore, the increased energy demand produced by peri-infarct depolarizations places additional metabolic stress on already compromised ischemic tissue, leading to enhancement of the ischemic injury. These peri-infarct depolarizations can now be imaged with DWI, appearing as a spreading wave of ADC decline outside of the ischemic core concurrently with an appropriate change on DC potential monitoring.⁴³ With the use of DWI monitoring of peri-infarct depolarizations, it was observed that this phenomenon directly contributes to the evolution of focal ischemia and that it has a greater effect when CBF is more compromised.^{44 45} In experimental stroke models, neuroprotective agents that antagonize the NMDA or AMPA channels reduce the occurrence of these peri-infarct depolarizations, and this reduction correlates well with their neuroprotective effect.^{41 46} Hossmann²⁸ hypothesized that impeding peri-infarct depolarizations could be an important mechanism for inducing neuroprotection by drugs that antagonize receptor-mediated calcium channels. Reducing peri-infarct depolarizations could be a novel approach for producing neuroprotection by serotonin and -aminobutyric acid agonists because these neurotransmitters appear to hyperpolarize neurons and impede depolarization. It remains uncertain whether peri-infarct depolarizations occur in human stroke and whether they contribute to the evolution of focal ischemia, but the animal observations are intriguing. The availability of DWI in patients will now allow investigators to study this phenomenon in humans and to define its potential contribution to the evolution of focal ischemia.

Other mechanisms may also contribute to the evolution of ischemic tissue toward irreversibility. Recently, it was suggested that programmed cell death (apoptosis) can promote the development of infarction in addition to the well-characterized contribution of necrosis.⁴⁷ With apoptosis, protein synthesis is required, and this ceases at CBF levels below 30 to 35 mL/100 g per minute.²⁸ Therefore, apoptotic contributions to ultimate ischemic lesion size are only likely to occur in regions of modest ischemia or after reperfusion. This possibility is supported by a recent animal study showing that apoptosis only appeared to contribute to delayed ischemic lesion development in animals subjected to 30 minutes of temporary ischemia but not 90 minutes.⁴⁸ The protein synthesis inhibitor cycloheximide inhibited the potential apoptotic contribution to ischemic injury.

	The Relationship of Reversible/Irreversible Ischemic Injury to Developing Acute Stroke Therapies

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The goal of acute therapeutic interventions for acute stroke patients is to improve functional outcome weeks, months, and years after the event. In experimental stroke models potential therapies are traditionally assessed on the basis of their ability to reduce ischemic lesion volume. This approach presumes that reducing ischemic lesion size will translate into a better functional outcome, although it can be difficult in animal models to relate changes in lesion volume to improved function. Thus far in stroke patients, only the recently published NIH rTPA study demonstrated improved functional outcome 3 months after onset, but there was no documentation that this improvement related to reduction of ischemic lesion volumes in the treated group.¹ Many types of neuroprotective drugs are currently at various stages of development. Some neuroprotective interventions such as competitive and noncompetitive NMDA antagonists, glycine antagonists, presynaptic modulators of excitatory amino acid release, polypeptide growth factors (specifically, basic fibroblast growth factor), and serotonin agonists reduce infarct size in both permanent and temporary occlusion animal stroke models.⁴⁹ These interventions might be considered in stroke patients irrespective of documented reperfusion and could be viewed as potentially primary therapies that could be given independent of or prior to thrombolytic therapy. Many drugs in these categories are currently being evaluated in clinical trials, although proof of efficacy remains lacking. Other neuroprotective strategies such as antiadhesion molecules and antioxidants appear to only be effective in temporary ischemia stroke models, and therefore drugs in these categories will likely be more appropriate as adjunctive interventions after successful thrombolysis restores flow.

Based on the likely mechanisms of action of most thrombolytic and neuroprotective drugs, the presumed therapeutic target is to salvage potentially reversible ischemic tissue to reduce infarct size and improve functional outcome. This basic logic to the design of acute stroke therapy assumes that individual stroke patients have reversible ischemic tissue (an ischemic penumbra) at the time when a potentially useful intervention is given. Clinically it is not possible to reliably detect whether a given patient has potentially salvageable ischemic tissue, nor is it possible to decide which of the multitude of mechanisms that can promote its evolution to irreversibility are operative in an individual patient at a given time point after stroke onset. It is unlikely that any one therapy for acute ischemic stroke will markedly improve the ultimate functional outcome in most patients given the apparent complexity of the ischemic injury process. Presumably, combinations of thrombolytic and neuroprotective therapies will prove to be more effective than monotherapies in appropriately selected stroke patients.

The availability of potentially reversible ischemic tissue or lack thereof directly relates to the therapeutic time window issue. Traditionally in acute stroke trials an outer limit for initiating therapy is delineated. In the NIH rTPA trial this time window for starting treatment was 3 hours. In other thrombolytic and neuroprotective trials the time limit is typically 6 hours.^{49 50} These time windows are arbitrary and are chosen so that a sufficient number of patients will be included who likely still have ischemic tissue that has not crossed the threshold into an irreversibly injured condition. The recent PET and MRI data suggest that in some patients the time window for the existence of potentially reversible ischemic tissue may be substantially longer. Conversely, in the European rTPA trial there were patients treated within 2 to 3 hours of stroke onset who had subtle signs of infarction on CT.⁴⁹ These patients typically did not respond to treatment and were at substantially increased risk for fatal hemorrhagic side effects. These observations support the concept that individual stroke patients have their own therapeutic time windows based on factors such as residual collateral CBF, temperature, blood pressure, and the systemic metabolic milieu. If we accept the hypothesis that the target of most acute stroke therapies is that portion of the ischemic penumbra that has not yet evolved to irreversibility (not defined as infarcted or necrotic by traditional pathological assessment), then it is hoped that in the near future imaging technology will afford clinicians the opportunity to determine the presence of such potentially reversible ischemic tissue to individualize therapeutic decisions. The future capability to identify potentially reversible ischemic tissue or its lack, as well as the availability of multiple thrombolytic and neuroprotective therapies, should provide the means to have a great impact on the outcome of individual stroke patients. To safely and effectively maximize improvement after acute ischemic stroke should be the therapeutic target as care for these patients moves into the next millennium.

	Selected Abbreviations and Acronyms

 

ADC = apparent diffusion coefficient of water AMPA = -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid CMRO2 = cerebral metabolic rate of oxygen DWI = diffusion-weighted MRI MCAO = middle cerebral artery occlusion NIH = National Institutes of Health NMDA = N-methyl-D-aspartate OEF = oxygen extraction fraction PET = positron emission tomography PMN = polymorphonuclear leukocytes rTPA = recombinant tissue plasminogen activator

	Footnotes

 
Reprint requests to Marc Fisher, MD, Memorial Health Care, 119 Belmont St, Worcester, MA 01605-2982.

Received November 26, 1996; revision received January 10, 1997; accepted January 28, 1997.

	References

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1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587. [Abstract/Free Full Text]
2. Garcia JH. Mechanisms of cell death in ischemia. In: Caplan LR, ed. Brain Ischemia: Basic Concepts and Clinical Relevance. Berlin, Germany: Springer-Verlag; 1994:7-18.
3. Garcia JH, Yoshida Y, Chen H, Li Y, Zhang ZG, Lian J, Chen S, Chopp M. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol. 1993;142:623-635. [Abstract]
4. Memezawa H, Smith M-L, Siesjö BK. Penumbral tissue salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke. 1992;23:552-559. [Abstract/Free Full Text]
5. Park CK, Nehls DG, Graham D, Teasdale GM, McCulloch J. Focal cerebral ischemia in the cat: treatment with the glutamate antagonist MK-801 after the induction of ischemia. J Cereb Blood Flow Metab. 1988;8:757-762. [Medline] [Order article via Infotrieve]
6. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, Fitzgibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal ischemia in awake monkeys. J Neurosurg. 1981;54:773-782. [Medline] [Order article via Infotrieve]
7. Paschen W, Mies G, Hossmann K-A. Threshold relationship between cerebral blood flow, glucose utilization and energy metabolism during development of stroke in gerbils. Exp Neurol. 1992;117:325-333. [Medline] [Order article via Infotrieve]
8. Nowicki J-P, Assumel-Lurdin D, Duverger D, MacKenzie ET. Temporal evolution of regional energy metabolism following middle cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1988;8:462-473. [Medline] [Order article via Infotrieve]
9. Folbergrova J, Memezawa H, Smith M-L, Siesjö BK. Focal and perifocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. J Cereb Blood Flow Metab. 1992;12:25-33. [Medline] [Order article via Infotrieve]
10. Back T, Hoehn-Berlage M, Kohno K, Hossmann K-A. Diffusion nuclear magnetic resonance imaging in experimental stroke: correlation with cerebral metabolites. Stroke. 1994;25:494-500. [Abstract]
11. Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann K-A. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction of cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab. 1995;15:1002-1015. [Medline] [Order article via Infotrieve]
12. Reith W, Hasegawa Y, Latour LL, Dardzinski BJ, Sotak CH, Fisher M. Multislice diffusion mapping for 3-D evolution of cerebral ischemia in a rat stroke model. Neurology. 1995;45:172-177. [Abstract/Free Full Text]
13. Levine SR, Helpern JA, Welch KM, Van de Linde AMQ, Sawaya KL, Brown EE, Ramadan NM, Deveshwar RK, Ordidge RK. Human focal cerebral ischemia: evaluation of brain pH and energy metabolism with P-31 NMR spectroscopy. Radiology. 1992;185:537-544. [Abstract/Free Full Text]
14. Baron JC. Positron emission tomography (PET) in acute ischemic stroke. In: Caplan LR, ed. Brain Ischemia: Basic Concepts and Clinical Relevance. Berlin, Germany: Springer-Verlag; 1994:19-27.
15. Baron JC. Pathophysiology of acute cerebral ischemia: PET studies in humans. Cerebrovasc Dis. 1991(suppl 1):22-31.
16. Heiss W-D, Graf R, Wienhard K, Lottgen J, Saito R, Fujita T, Rosner G, Wagner R. Dynamic penumbra demonstrated by sequential multi-tracer PET after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab. 1994;14:892-902. [Medline] [Order article via Infotrieve]
17. Pappata S, Fiorelli M, Rommel T, Hartmann A, Dettmers C, Yamaguchi T, Chabriat H, Poline JB, Crouzel C, Di Giamberardino L, Baron JC. PET study of changes in local brain hemodynamics and oxygen metabolism after unilateral middle cerebral artery occlusion in baboons. J Cereb Blood Flow Metab. 1993;13:416-424. [Medline] [Order article via Infotrieve]
18. Touzani O, Young OR, Derlon JM, Beaudouin V, Marchal G, Rioux P, Mezenge F, Baron JC, MacKenzie ET. Sequential studies of severely hypometabolic tissue volumes after permanent middle cerebral artery occlusion: a positron emission tomographic investigation in anesthetized baboons. Stroke. 1995;26:2112-2119. [Abstract/Free Full Text]
19. Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke. Stroke. 1996;27:599-606. [Abstract/Free Full Text]
20. Furlan M, Marchal G, Viader F, Derlon JM, Baron JC. Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra. Ann Neurol. 1996;40:216-226. [Medline] [Order article via Infotrieve]
21. Fisher M, Prichard JW, Warach S. New magnetic resonance techniques for acute ischemic stroke. JAMA. 1995;274:908-911. [Abstract]
22. Warach S, Gaa J, Siewart B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol. 1995;37:231-241. [Medline] [Order article via Infotrieve]
23. Rosen BR, Belliveau JW, Chien D. Perfusion imaging by nuclear magnetic resonance. Magn Reson Q. 1989;5:263-281. [Medline] [Order article via Infotrieve]
24. Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging. J Cereb Blood Flow Metab. 1996;16:53-59. [Medline] [Order article via Infotrieve]
25. Hasegawa Y, Fisher M, Latour LL, Dardzinski BJ, Sotak CH. MRI diffusion mapping of reversible and irreversible ischemic injury in focal brain ischemia. Neurology. 1994;44:1484-1490. [Abstract/Free Full Text]
26. Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke. 1981;12:723-725. [Free Full Text]
27. Pulsinelli W. Pathophysiology of acute cerebral ischemia. Lancet. 1992;359:533-536.
28. Hossmann K-A. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36:557-565. [Medline] [Order article via Infotrieve]
29. Ginsberg MD, Pulsinelli W. The ischemic penumbra, injury thresholds and the therapeutic time window for acute stroke. Ann Neurol. 1994;36:553-554. [Medline] [Order article via Infotrieve]
30. Hakim AM. The cerebral ischemic penumbra. Can J Neurol Sci. 1987;14:557-559. [Medline] [Order article via Infotrieve]
31. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke: challenging the concept of a rigid and universal time window. Stroke. 1995;26:2219-2221. [Free Full Text]
32. Meldrum B. Protection against ischemic neuronal damage by drugs acting against excitatory neurotransmission. Cerebrovasc Brain Metab Rev. 1990;2:27-57. [Medline] [Order article via Infotrieve]
33. Choi DW. Excitotoxic cell death. J Neurobiol. 1992;23:1261-1276. [Medline] [Order article via Infotrieve]
34. Choi DW. Excitotoxicity and stroke. In: Caplan LR, ed. Brain Ischemia: Basic Concepts and Clinical Relevance. Berlin, Germany: Springer-Verlag; 1994:29-36.
35. Castillo J, Davalos A, Naveiro J, Noya M. Neuroexcitatory amino acids and their relationship to infarct size and neurological deficit in ischemic stroke. Stroke. 1996;27:1060-1065. [Abstract/Free Full Text]
36. Matsumoto K, Graf R, Rosner G, Taguchi J, Heiss W-D. Elevation of neuroactive substances in the cortex of cats during prolonged focal ischemia. J Cereb Blood Flow Metab. 1993;15:586-594.
37. Ames A, Wright LW, Kowada M, Thurston JM, Majors G. Cerebral ischemia: the no-reflow phenomenon. Am J Pathol. 1968;52:437-453. [Medline] [Order article via Infotrieve]
38. Garcia JH, Liu K-F, Yoshida Y, Chen S, Lian J. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994;144:188-199. [Abstract]
39. Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF. Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol. 1994;35:458-463. [Medline] [Order article via Infotrieve]
40. Chopp M, Zhang RL, Chen Y, Li Y, Jiang N, Rusche JR. Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke. 1994;25:869-876. [Abstract]
41. Back T, Kohno K, Hossmann K-A. Cortical negative DC deflections in rat cortex following middle cerebral artery occlusion and KCl-induced spreading depression: effect on blood flow, tissue oxygenation and electroencephalogram. J Cereb Blood Flow Metab. 1994;14:12-19. [Medline] [Order article via Infotrieve]
42. Iijima T, Mies G, Hossmann K-A. Repeated negative DC deflections in rat cortex are abolished by MK-801: effect on volume of injury. J Cereb Blood Flow Metab. 1992;12:727-733. [Medline] [Order article via Infotrieve]
43. Gyngell ML, Back T, Hoehn-Berlage M, Hossmann K. Transient cell depolarization after permanent middle cerebral artery occlusion: an observation by diffusion-weighted MRI and localized ¹H-MRS. Magn Reson Med. 1994;31:337-341. [Medline] [Order article via Infotrieve]
44. Takano K, Latour LL, Formato JE, Carano RA, Helmer KG, Hasegawa Y, Sotak CH, Fisher M. The role of spreading depression in focal ischemia evaluated by diffusion mapping. Ann Neurol. 1996;39:308-318. [Medline] [Order article via Infotrieve]
45. Rother J, deCrespigny AJ, D'Arceuil H, Iwai K, Moseley ME. Recovery of apparent diffusion coefficient after ischemia-inducing spreading depression relates to cerebral perfusion gradient. Stroke. 1996;27:980-986. [Abstract/Free Full Text]
46. Mies G, Kohno K, Hossmann K-A. Prevention of peri-infarct DC shifts with glutamate antagonist NBQX following occlusion of the middle cerebral artery in rat. J Cereb Blood Flow Metab. 1994;14:802-807. [Medline] [Order article via Infotrieve]
47. Chopp M, Chan PH, Hsu CY, Cheung ME, Jacobs TP. DNA damage and repair in central nervous system injury. Stroke. 1996;27:363-369. [Abstract/Free Full Text]
48. Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab. 1996;16:196-201.
49. Silver B, Weber J, Fisher M. Medical therapy for ischemic stroke. Clin Neuropharmacol.. 1996;19:101-128. [Medline] [Order article via Infotrieve]
50. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Blumhmki E, Hoxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke: the European Cooperative Study (ECASS). JAMA. 1995;274:1017-1025.[Abstract]

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