CHAPTER
Pathophysiology of Cerebral Infarction* ARTHUR G. WALTZ, M.D.
Doctors Didisheim and Roberts have described for you many of the events that can occur in the major blood vessels and in the blood itself and that can be associated with cerebral infarction. They also have discussed certain aspects of the prevention of cerebral infarcts in patients who mayor may not have had premonitory symptoms or a specific earlier event. However, it is quite likely that there always will be a number of persons, productive and effective, who will have acute ischemic strokes, regardless of the results of preventive measures. Therapeutic measures must be developed and used to minimize neurological disability and maximize functional capacity in such patients. It is probable that surgical procedures will be among the most effective measures for treating cerebral infarcts; thus, I plan to discuss three aspects of cerebral infarction that have a direct bearing on the therapeutic effectiveness of surgical procedures: the responses of neurons to ischemia; reperfusion of ischemic regions; and brain swelling from ischemic cerebral edema. The discussion will include results and conclusions of studies carried out in the Cerebrovascular· Clinical Research Center of the Department of Neurology, University of Minnesota, from 1971 through 1974, and earlier in the Cerebrovascular Clinical Research Center of the Department of Neurology, Mayo Clinic. RESPONSES OF NEURONS TO ISCHEMIA
Functional Activity of Individual Neurons The key to the minimization of neurological disability resulting from acute focal cerebral ischemia is the preservation or restoration of function of individual neurons. The functional behavior of individual neurons can be inferred from observations of neurological deficits, measurements of electroencephalographic and electrocorticographic activity, or detection of cortical potentials evoked by such peripheral * Partial support for the studies reported here was provided by United States Public Health Service Research Grants NS 3364, NS 6663, and RR 5566. 147
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stimuli as repetitive flashes of light, sounds, and tactile pressure. Studies of the relationships between cerebral blood flow (CBF) and electroencephalographic activity in humans undergoing carotid endarterectomy and between CBF and evoked cortical potentials in baboons undergoing occlusion of one middle cerebral artery (MCA) have shown a remarkable consistency: changes or disappearance of the electrical activity occur with decreases of regional CBF to approximately 17 to 20 ml/100 gm./ min., with recovery of the electrical activity if CBF increases after a relatively short time (4, 32, 35). Moreover, the structural integrity of brain tissue appears to be affected only if CBF is less than about 20 for an extended period (34). Direct measurement of the function of individual neurons requires detection of depolarization with intracellular or extracellular microelectrodes. Doctors W-D Heiss, T. Hayakawa, and I have recorded the action potentials of 162 individual cortical neurons in seven cats, using extracellular glass electrodes, before and up to 7 hours after occlusion of the left MCA by a device implanted transorbitally 4 to 8 days earlier (13). CBF was measured at the same times and in the same locations by recording polarographically the rate of clearance of inhaled hydrogen gas with platinized platinum-iridium electrodes 125 microns in diameter (15, 29). Immediately after MeA occlusion, abnormal patterns of neuronal activity included bursts; prolonged, high frequency repetitive discharges, or seizures; increases of frequency; decreases of frequency; and cessation of activity. Subsequently, neuronal activity was related to the corresponding CBF. No activity was detected in regions with calculated CBF values of less than 18 ml./100 gm./min.; activity was present in regions with greater CBF values, although frequently the patterns of activity were abnormal. Initial marked decreases of CBF to values less than 18 ml./100 gm./min. could be followed by spontaneous increases of CBF to higher values; a spontaneous increase after an initial decrease could be accompanied by resumption of the activity of individual neurons even though the region studied was still ischemic, with CBF less than before MCA occlusion (16). Thus, the evidence available at present indicates that in normal brain there is a considerable reserve of CBF, in that neuronal function does not cease until a relatively low value for CBF is reached, although activity may be abnormal at higher values of CBF. Moreover, neurons that cease functioning at CBF less than about 20 may resume functioning when CBF is greater than 20, although still less than normal (16). However, the patterns of neuronal activity after resumption of function may be abnormal, and it is possible that neurological deficits would not be appreciably lessened or modified. It is of particular interest that the critical
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Neurological Deficits: Prevention and Recovery
Studies of electrical activity related to neuronal function have not as yet provided information about the maximum duration of a period of ischemia from which a neuron can recover. In the studies mentioned earlier, increases of CBF occurred within minutes of the impairment of electrical activity. However, other studies in which neuronal function has been inferred from observations of neurological deficits have indicated that recovery of function may be possible many hours after the onset of acute ischemia. In an experimental model, acute focal cerebral ischemia can be induced inside an intact cranium containing cerebrospinal fluid (CSF) under normal pressure in a conscious, comfortable, and normally functioning animal (13). When the model is used in cats, regional CBF (measured by the hydrogen method) may decrease to very low values within seconds, at times becoming too low to calculate (15). Neurological deficits likewise begin within seconds to minutes and include forced deviations and circling movements as well as weakness of limbs. In certain situations, however, the exact characteristics of which are unknown, spontaneous lessening of the neurological deficits may begin within several hours of MCA occlusion and continue to the point that no neurological deficit is detectable several days after the onset of ischemia (13). Moreover, in anesthetized rhesus monkeys an occluding device can be removed from one MCA many hours after occlusion with no resultant neurological deficit (8). In some monkeys, ischemia persisting as long as 24 hours has not produced a deficit. These experimental models are not precisely comparable to an acute stroke in humans; the influences of differing collateral circulation, effects of anesthesia, and other experimental maneuvers are not known with certainty. Nonetheless, even in humans there is indirect evidence that nonfunctioning regions of brain can remain viable for up to several hours (17). Thus, functional impairment of neuronal activity due to ischemia may be reversible, and neurons may resume functioning after restoration of the flow of blood. It is obvious that focal cerebral ischemia from the occlusion of a major or minor vessel supplying the brain is not the same as total cerebral ischemia (as from cardiac arrest or clamping all major thoracic vessels) or anoxia (as from respiratory arrest) in which recovery of cerebral function may not occur after as short a time as 5 minutes of ischemia. In focal ischemia, although the flow of blood in a central zone may be undetectable, at least some flow is maintained in surrounding
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value for both neuronal function and structural integrity has been found to be roughly the same in three species: humans, baboons, and cats.
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There is, then, accumulating evidence that neurons can remain in a state of "functional paralysis" for a period of time after the onset of ischemia, during which restoration of the flow of blood may lead to recovery of function. However, there is still some concern about whether or not it is possible to restore normal perfusion in an ischemic region. With total cerebral ischemia, as from clamping the major thoracic arteries, there may be no reflow of blood into the brain after as short a time as 5 minutes to 1 hour, perhaps because of intravascular aggregation of blood elements or swelling of endothelial and perivascular tissue (1, 7, 37). However, just as with neuronal function, the situation is not the same for focal cerebral ischemia in which some flow of blood is preserved through collateral channels. There is abundant evidence from studies of experimental models that relatively normal perfusion can be restored to ischemic regions of the brain up to 24 hours after the onset of ischemia (8, 10, 12, 21, 22, 31, 33, 36). Thus, there appears to be a period of time after an acute ischemic stroke during which blood flow can be restored to the ischemic regions and impaired neuronal function can be reversed. The implication of these findings is that appropriate neurovascular surgical procedures could prevent or minimize a developing neurological disability. In practice, however, immediate surgical procedures for ischemic strokes have not met with unqualified success. Consideration must also be given to ischemic cerebral edema. BRAIN SWELLING FROM ISCHEMIC CEREBRAL EDEMA
Edema occurring in response to ischemia may be a major factor in the processes involved in the development of cerebral infarcts and neurological deficits. Although there is some information available about the characteristics of ischemic cerebral edema, conclusions about modification by therapeutic measures are largely speculative. In experimental models of acute cerebral ischemia in animals, increases of the water content of perivascular glial cells begin to develop within minutes of the onset of ischemia (2, 19). Within hours, as the water content of cerebral tissue increases and focal swelling of the brain occurs, edema can be demonstrated both intracellularly and extracellularly and in both gray matter and white matter (23, 28). Edema is maximal 1 to 3 days after the onset of ischemia (28). At this time, swelling of the brain can produce intracranial pressure gradients which may cause shifts
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zones through collateral channels, and the anatomic, enzymatic, and chemical integrity of neurons may be preserved during periods of impaired function (4, 11, 15, 25, 34, 37).
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of midline structures, transtentorial herniation, worsening of neurological deficits, or death (6, 14, 27). Lesser degrees of swelling from focal cerebral edema may be adequate to produce focal increases of vascular resistance causing decreases of blood flow in regions with impaired vascular reactivity and contributing to neurological deficits (2, 6, 14). Edema is greatest in areas of cell death and necrosis, but it also develops in regions of brain that are ischemic but not infarcted (18, 28). In studies in animals, if ischemia is severe and infarcted regions are large, edema may develop in remote, nonischemic parts of the brain, even in the opposite hemisphere (19, 28). The mechanisms involved in the development of remote edema are unknown. If an animal survives acute induced focal cerebral ischemia, edema resolves within 3 to 5 days, regardless of the resulting neurological deficit. The time course of ischemic cerebral edema-quick development to a maximum at 1 to 3 days and resolution within a few more days-is different from the time course of the transendothelial distribution of other molecules, such as sodium pertechnetate containing technetium-99m, labeled albumin, dyes, and other protein tracers (26). Thus the mechanisms that underlie ischemic cerebral edema are different from those involved in the development of necrosis and the production of a positive brain scan. The transendothelial distribution of water may take place across cellular membranes by diffusion or mass transport; the transendothelial distribution of other substances may occur through intercellular clefts, or pores, which are not normally present in the cerebral endothelium but which may be caused to "open" by ischemic or other changes in endothelial cells (5, 24, 30). Ischemic cerebral edema cannot be characterized as "cytotoxic" or "vasogenic;" ischemic cerebral edema has many, but not all, of the characteristics of both these types of edema (23, 28). Ischemic cerebral edema may be worsened by anything that worsens the ischemia, such as systemic hypotension or hypoxia (28, 36, 37). However, induced hypertension or spontaneous reactive hyperemia also may worsen ischemic cerebral edema and cause extension of a cerebral infarct if the hyperemia develops within several hours of the onset of ischemia (15). Presumably, the hypertension or hyperemia causes increased transudation of water through damaged endothelial cells in response to an increase of intracapillary and intravascular pressure. In an experimental model of acute focal cerebral ischemia in cats, spontaneous hyperemia occurring within 4 to 6 hours of MCA occlusion may cause severe brain swelling with tentorial herniation and death within 12 hours, accompanied by a characteristic Cushing response of hypertension and bradycardia associated with a massive increase of intracranial pressure (14). However, hyperemia occurring later, 2 to 3 days after occlusion,
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SUMMARY
Evidence available at present from animal studies indicates that the flow of blood can be restored to ischemic zones in the brain as long as 24 hours after the onset of ischemia, and that such reperfusion could result in the restoration of function of neurons that have not been functioning during the period of ischemia. However, reperfusion also can cause worsening of ischemic cerebral edema resulting in increased neurological disability or death. Adequate measures for control of cerebral edema will be necessary if surgical intervention is to become an effective therapy for acute ischemic cerebral infarcts. REFERENCES 1. Ames, A., III, Wright, R. L., Kowada, M., Thurston, J. M., and Majno, G. Cerebral ischemia. II. The no-reflow phenomenon. Am. J. Pathol., 52: 437-453, 1968. 2. Bartko, D., Reulen, H. J., Koch, H., and Schiirmann, K. Effect of dexamethasone on
the early edema following occlusion of the middle cerebral artery in cats. In Steroids and Brain Edema, edited by H. J. Reulen, and K. Schtlrmann, pp. 127-137. SpringerVerlag, New York, 1972.
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does not produce a catastrophic reaction of massive edema and brain swelling (15). Restoration of the flow of blood to an ischemic zone of the brain, perhaps by an appropriate neurovascular surgical procedure, may be followed by the restoration or preservation of function of neurons and the minimization of neurological disability. Alternatively, it may lead to worsening of ischemic cerebral edema with a resultant increase of neurological disability. For neurovascular surgical procedures to be effective, it appears that they must be undertaken relatively shortly after the onset of ischemia, and that worsening of edema must be prevented. Unfortunately, corticosteroids and osmotic agents are not as useful for the treatment of ischemic cerebral edema as for edema associated with cerebral tumors and head injuries (2, 3, 9, 18, 20). The resolution of this paradox awaits further study of the treatment of ischemic cerebral edema. I have not mentioned as yet the possibility of converting an ischemic infarct to a hemorrhagic infarct by increasing perfusion pressure in an ischemic zone because in experimental models in animals this has not been a problem (8, 31, 33). In humans, early surgical experience with acute cerebral infarcts included the development of hemorrhagic infarcts and left many surgeons abandoning early intervention. I understand from my surgical colleagues, however, that recent experience with vascular procedures has been different; I will leave a discussion of this aspect of surgical therapy to those with appropriate experience.
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3. Bauer, R. B., and Tellez, H. Dexamethasone as treatment in cerebrovascular disease. 2. A controlled study in acute cerebral infarction. Stroke, 4: 547-555, 1973. 4. Branston, N. M., Symon, L., Crockard, H. A., and Pasztor, E. Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon. Exp. Neurol., 45: 195-208, 1974. 5. Brightman, M. E., Hori, M., Rapoport, S. I., Reese, T. S., and Westergaard, E. Osmotic opening of tight junctions in cerebral endothelium. J. Compo Neurol., 152: 317-326, 1973. 6. Brock, M., Beck, J., Markakis, E., and Dietz, H. Intracranial pressure gradients associated with experimental cerebral embolism. Stroke, 3: 123-130, 1972. 7. Chiang, J., Kowada, M., Ames, A., Ill, Wright, R. L., and Majno, G. Cerebral ischemia. Ill. Vascular changes. Am. J. Pathol., 52: 455-476, 1968. 8. Crowell, R. M., Olsson, Y., Klatzo, I., and Ommaya, A. Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke, 1: 439-448, 1970. 9. Donley, R. F., and Sundt, T. M., Jr. The effect of dexamethasone on the edema of focal cerebral ischemia. Stroke, 4: 148-155, 1973. 10. Garcia, J. H., Cox, J. V., and Hudgins, W. R. Ultrastructure of the microvasculature in experimental cerebral infarction. Acta Neuropathol., 18: 273-285, 1971. 11. Garcia, J. H., and Kamijyo, Y. Cerebral infarction: evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J. Neuropathol. Exp. Neurol., 33: 408-421, 1974. 12. Harrington, T., and DiChiro, G. Effect of hypocarbia and hypercarbia on experimental brain infarction: a microangiographic study in the monkey. Neurology, 23: 294-299, 1973. 13. Hayakawa, T., and Waltz, A. G. Immediate effects of cerebral ischemia: evolution and resolution of neurological deficits after experimental occlusion of one middle cerebral artery in conscious cats. Stroke, 6: 321-327, 1975. 14. Hayakawa, T., and Waltz, A. G. Intracranial pressure, blood pressure, and pulse rate after occlusion of a middle cerebral artery in cats. J. Neurosurg., 43: 399-407,1975. 15. Heiss, W-D., Hayakawa, T., and Waltz, A. G. Unpublished observations, 1974a. 16. Heiss, W-D., Hayakawa, T., and Waltz, A. G. Unpublished observations, 1974b. 17. Heyman, A., Saltzman, H. A., and Whalen, R. E. The use of hyperbaric oxygen in the treatment of cerebral ischemia and infarction. Circulation, 33 (Suppl. II): 20-27, 1966. 18. Hoppe, W. E., Waltz, A. G., Jordan, M. M., and Jacobson, R. L. Effects of dexamethasone on distributions of water and pertechnetate in brains of cats after middle cerebral artery occlusion. Stroke, 5: 617-622, 1974. 19. Kogure, K., Busto, R., Scheinberg, P., and Reinmuth, O. M. Energy metabolites and water content in rat brain during the early stage of development of cerebral infarction. Brain, 97: 103-114, 1974. 20. Lee, M. C., Mastri, A. R., Waltz, A. G., and Loewenson, R. B. Ineffectiveness of dexamethasone for treatment of experimental cerebral infarction. Stroke, 5: 216-218, 1974. 21. Levy, D. E., Brierly, J. B., Silverman, D. G., and Plum, F. Brief hypoxia-ischemia initially damages cerebral neurons. Arch. Neurol., 32: 450-456,1975. 22. Little, J. R., Kerr, F. W. L., and Sundt, T. M., Jr. Microcirculatory obstruction in focal cerebral ischemia: relationship to neuronal alterations. Mayo Clin. Proc., 50: 264-270, 1975. 23. Little, J. R., Sundt, T. M., Jr., and Kerr, F. W. L. Neuronal alterations in developing
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cortical infarction: an experimental study in monkeys. J. Neurosurg., 40: 186-198, 1974. Lorenzo, A. V., Shirahige, I., Liang, M., and Barlow, C. F. Temporary alteration of cerebrovascular permeability to plasma protein during drug-induced seizures. Am. J. Physiol., 223: 268-277, 1972. MacDonald, V. D., Sundt, T. M., Jr., and Winkelmann, R. D. Histochemical studies in the zone of ischemia following middle cerebral artery occlusion in cats. J. Neurosurg., 37: 45-54, 1972. O'Brien, M. D., Jordan, M. M., and Waltz, A. G. Ischemic cerebral edema and the blood-brain barrier: distributions of pertechnetate, albumin, sodium, and antipyrine in brains of cats after occlusion of middle cerebral artery. Arch. Neurol., 30: 461-465, 1974. O'Brien, M. D., and Waltz, A. G. Intracranial pressure gradients caused by experimental cerebral ischemia and edema. Stroke, 4: 694-698, 1973. O'Brien, M. D., Waltz, A. G., and Jordan, M. M. Ischemic cerebral edema: distribution of water in brains of cats after occlusion of middle cerebral artery. Arch. Neurol., 30: 456-460, 1974. Pasztor, E., Symon, L., Dorsch, N. W. C., and Branston, N. M. The hydrogen clearance method in assessment of blood flow in cortex, white matter and deep nuclei of baboons. Stroke, 4: 556-567, 1973. Rapoport, S. I., Hori, M., and Klatzo, I. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am. J. Physiol., 223: 323-331, 1972. Sundt, T. M., Jr., Grant, W. C., and Garcia, J. H. Restoration of middle cerebral artery flow in experimental infarction. J. Neurosurg., 31: 311-322, 1969. Sundt, T. M., Jr., Sharbrough, F. W., Anderson, R. E., and Michenfelder, J. D. Cere braI blood flow measurements and electroencephalograms during carotid endarterectomy. J. Neurosurg., 41: 310-320, 1974. Sundt, T. M., Jr., and Waltz, A. G. Cerebral ischemia and reactive hyperemia: studies of cortical blood flow and microcirculation before, during, and after temporary occlusion of middle cerebral artery of squirrel monkeys. Circ. Res., 28: 426-433, 1971. Symon; L., Crockard, H. A., Dorsch, N. W. C., Branston, N. M., and Juhasz, J. Local cerebral blood flow and vascular reactivity in a chronic stable stroke in baboons. Stroke, 6: 482-492, 1975. Trojaborg, W., and Boysen, G. Relation between EEG, regional cerebral blood flow and internal carotid artery pressure during carotid endarterectomy. Electroencephalogr. Clin. Neurophysiol., 34: 61-69, 1973. Waltz, A. G. Pathophysiology of cerebral ischemia. In Cerebral Vascular Diseases: Transactions of the Eighth Conference, edited by F. H. McDowell, and R. W. Brennan, pp. 119-126. Grune & Stratton, New York, 1973. Waltz, A. G., and Sundt, T. M., Jr. The microvasculature and microcirculation of the cerebral cortex after arterial occlusion. Brain. 90: 681-696, 1967.
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24.
CLINICAL NEUROSURGERY
Pathophysiology of Cerebral Infarction* ARTHUR G. WALTZ, M.D.
Doctors Didisheim and Roberts have described for you many of the events that can occur in the major blood vessels and in the blood itself and that can be associated with cerebral infarction. They also have discussed certain aspects of the prevention of cerebral infarcts in patients who mayor may not have had premonitory symptoms or a specific earlier event. However, it is quite likely that there always will be a number of persons, productive and effective, who will have acute ischemic strokes, regardless of the results of preventive measures. Therapeutic measures must be developed and used to minimize neurological disability and maximize functional capacity in such patients. It is probable that surgical procedures will be among the most effective measures for treating cerebral infarcts; thus, I plan to discuss three aspects of cerebral infarction that have a direct bearing on the therapeutic effectiveness of surgical procedures: the responses of neurons to ischemia; reperfusion of ischemic regions; and brain swelling from ischemic cerebral edema. The discussion will include results and conclusions of studies carried out in the Cerebrovascular· Clinical Research Center of the Department of Neurology, University of Minnesota, from 1971 through 1974, and earlier in the Cerebrovascular Clinical Research Center of the Department of Neurology, Mayo Clinic. RESPONSES OF NEURONS TO ISCHEMIA
Functional Activity of Individual Neurons The key to the minimization of neurological disability resulting from acute focal cerebral ischemia is the preservation or restoration of function of individual neurons. The functional behavior of individual neurons can be inferred from observations of neurological deficits, measurements of electroencephalographic and electrocorticographic activity, or detection of cortical potentials evoked by such peripheral * Partial support for the studies reported here was provided by United States Public Health Service Research Grants NS 3364, NS 6663, and RR 5566. 147
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stimuli as repetitive flashes of light, sounds, and tactile pressure. Studies of the relationships between cerebral blood flow (CBF) and electroencephalographic activity in humans undergoing carotid endarterectomy and between CBF and evoked cortical potentials in baboons undergoing occlusion of one middle cerebral artery (MCA) have shown a remarkable consistency: changes or disappearance of the electrical activity occur with decreases of regional CBF to approximately 17 to 20 ml/100 gm./ min., with recovery of the electrical activity if CBF increases after a relatively short time (4, 32, 35). Moreover, the structural integrity of brain tissue appears to be affected only if CBF is less than about 20 for an extended period (34). Direct measurement of the function of individual neurons requires detection of depolarization with intracellular or extracellular microelectrodes. Doctors W-D Heiss, T. Hayakawa, and I have recorded the action potentials of 162 individual cortical neurons in seven cats, using extracellular glass electrodes, before and up to 7 hours after occlusion of the left MCA by a device implanted transorbitally 4 to 8 days earlier (13). CBF was measured at the same times and in the same locations by recording polarographically the rate of clearance of inhaled hydrogen gas with platinized platinum-iridium electrodes 125 microns in diameter (15, 29). Immediately after MeA occlusion, abnormal patterns of neuronal activity included bursts; prolonged, high frequency repetitive discharges, or seizures; increases of frequency; decreases of frequency; and cessation of activity. Subsequently, neuronal activity was related to the corresponding CBF. No activity was detected in regions with calculated CBF values of less than 18 ml./100 gm./min.; activity was present in regions with greater CBF values, although frequently the patterns of activity were abnormal. Initial marked decreases of CBF to values less than 18 ml./100 gm./min. could be followed by spontaneous increases of CBF to higher values; a spontaneous increase after an initial decrease could be accompanied by resumption of the activity of individual neurons even though the region studied was still ischemic, with CBF less than before MCA occlusion (16). Thus, the evidence available at present indicates that in normal brain there is a considerable reserve of CBF, in that neuronal function does not cease until a relatively low value for CBF is reached, although activity may be abnormal at higher values of CBF. Moreover, neurons that cease functioning at CBF less than about 20 may resume functioning when CBF is greater than 20, although still less than normal (16). However, the patterns of neuronal activity after resumption of function may be abnormal, and it is possible that neurological deficits would not be appreciably lessened or modified. It is of particular interest that the critical
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Neurological Deficits: Prevention and Recovery
Studies of electrical activity related to neuronal function have not as yet provided information about the maximum duration of a period of ischemia from which a neuron can recover. In the studies mentioned earlier, increases of CBF occurred within minutes of the impairment of electrical activity. However, other studies in which neuronal function has been inferred from observations of neurological deficits have indicated that recovery of function may be possible many hours after the onset of acute ischemia. In an experimental model, acute focal cerebral ischemia can be induced inside an intact cranium containing cerebrospinal fluid (CSF) under normal pressure in a conscious, comfortable, and normally functioning animal (13). When the model is used in cats, regional CBF (measured by the hydrogen method) may decrease to very low values within seconds, at times becoming too low to calculate (15). Neurological deficits likewise begin within seconds to minutes and include forced deviations and circling movements as well as weakness of limbs. In certain situations, however, the exact characteristics of which are unknown, spontaneous lessening of the neurological deficits may begin within several hours of MCA occlusion and continue to the point that no neurological deficit is detectable several days after the onset of ischemia (13). Moreover, in anesthetized rhesus monkeys an occluding device can be removed from one MCA many hours after occlusion with no resultant neurological deficit (8). In some monkeys, ischemia persisting as long as 24 hours has not produced a deficit. These experimental models are not precisely comparable to an acute stroke in humans; the influences of differing collateral circulation, effects of anesthesia, and other experimental maneuvers are not known with certainty. Nonetheless, even in humans there is indirect evidence that nonfunctioning regions of brain can remain viable for up to several hours (17). Thus, functional impairment of neuronal activity due to ischemia may be reversible, and neurons may resume functioning after restoration of the flow of blood. It is obvious that focal cerebral ischemia from the occlusion of a major or minor vessel supplying the brain is not the same as total cerebral ischemia (as from cardiac arrest or clamping all major thoracic vessels) or anoxia (as from respiratory arrest) in which recovery of cerebral function may not occur after as short a time as 5 minutes of ischemia. In focal ischemia, although the flow of blood in a central zone may be undetectable, at least some flow is maintained in surrounding
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/23/CN_suppl_1/147/4100452 by guest on 25 October 2019
value for both neuronal function and structural integrity has been found to be roughly the same in three species: humans, baboons, and cats.
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REPERFUSION OF ISCHEMIC REGIONS
There is, then, accumulating evidence that neurons can remain in a state of "functional paralysis" for a period of time after the onset of ischemia, during which restoration of the flow of blood may lead to recovery of function. However, there is still some concern about whether or not it is possible to restore normal perfusion in an ischemic region. With total cerebral ischemia, as from clamping the major thoracic arteries, there may be no reflow of blood into the brain after as short a time as 5 minutes to 1 hour, perhaps because of intravascular aggregation of blood elements or swelling of endothelial and perivascular tissue (1, 7, 37). However, just as with neuronal function, the situation is not the same for focal cerebral ischemia in which some flow of blood is preserved through collateral channels. There is abundant evidence from studies of experimental models that relatively normal perfusion can be restored to ischemic regions of the brain up to 24 hours after the onset of ischemia (8, 10, 12, 21, 22, 31, 33, 36). Thus, there appears to be a period of time after an acute ischemic stroke during which blood flow can be restored to the ischemic regions and impaired neuronal function can be reversed. The implication of these findings is that appropriate neurovascular surgical procedures could prevent or minimize a developing neurological disability. In practice, however, immediate surgical procedures for ischemic strokes have not met with unqualified success. Consideration must also be given to ischemic cerebral edema. BRAIN SWELLING FROM ISCHEMIC CEREBRAL EDEMA
Edema occurring in response to ischemia may be a major factor in the processes involved in the development of cerebral infarcts and neurological deficits. Although there is some information available about the characteristics of ischemic cerebral edema, conclusions about modification by therapeutic measures are largely speculative. In experimental models of acute cerebral ischemia in animals, increases of the water content of perivascular glial cells begin to develop within minutes of the onset of ischemia (2, 19). Within hours, as the water content of cerebral tissue increases and focal swelling of the brain occurs, edema can be demonstrated both intracellularly and extracellularly and in both gray matter and white matter (23, 28). Edema is maximal 1 to 3 days after the onset of ischemia (28). At this time, swelling of the brain can produce intracranial pressure gradients which may cause shifts
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/23/CN_suppl_1/147/4100452 by guest on 25 October 2019
zones through collateral channels, and the anatomic, enzymatic, and chemical integrity of neurons may be preserved during periods of impaired function (4, 11, 15, 25, 34, 37).
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of midline structures, transtentorial herniation, worsening of neurological deficits, or death (6, 14, 27). Lesser degrees of swelling from focal cerebral edema may be adequate to produce focal increases of vascular resistance causing decreases of blood flow in regions with impaired vascular reactivity and contributing to neurological deficits (2, 6, 14). Edema is greatest in areas of cell death and necrosis, but it also develops in regions of brain that are ischemic but not infarcted (18, 28). In studies in animals, if ischemia is severe and infarcted regions are large, edema may develop in remote, nonischemic parts of the brain, even in the opposite hemisphere (19, 28). The mechanisms involved in the development of remote edema are unknown. If an animal survives acute induced focal cerebral ischemia, edema resolves within 3 to 5 days, regardless of the resulting neurological deficit. The time course of ischemic cerebral edema-quick development to a maximum at 1 to 3 days and resolution within a few more days-is different from the time course of the transendothelial distribution of other molecules, such as sodium pertechnetate containing technetium-99m, labeled albumin, dyes, and other protein tracers (26). Thus the mechanisms that underlie ischemic cerebral edema are different from those involved in the development of necrosis and the production of a positive brain scan. The transendothelial distribution of water may take place across cellular membranes by diffusion or mass transport; the transendothelial distribution of other substances may occur through intercellular clefts, or pores, which are not normally present in the cerebral endothelium but which may be caused to "open" by ischemic or other changes in endothelial cells (5, 24, 30). Ischemic cerebral edema cannot be characterized as "cytotoxic" or "vasogenic;" ischemic cerebral edema has many, but not all, of the characteristics of both these types of edema (23, 28). Ischemic cerebral edema may be worsened by anything that worsens the ischemia, such as systemic hypotension or hypoxia (28, 36, 37). However, induced hypertension or spontaneous reactive hyperemia also may worsen ischemic cerebral edema and cause extension of a cerebral infarct if the hyperemia develops within several hours of the onset of ischemia (15). Presumably, the hypertension or hyperemia causes increased transudation of water through damaged endothelial cells in response to an increase of intracapillary and intravascular pressure. In an experimental model of acute focal cerebral ischemia in cats, spontaneous hyperemia occurring within 4 to 6 hours of MCA occlusion may cause severe brain swelling with tentorial herniation and death within 12 hours, accompanied by a characteristic Cushing response of hypertension and bradycardia associated with a massive increase of intracranial pressure (14). However, hyperemia occurring later, 2 to 3 days after occlusion,
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SUMMARY
Evidence available at present from animal studies indicates that the flow of blood can be restored to ischemic zones in the brain as long as 24 hours after the onset of ischemia, and that such reperfusion could result in the restoration of function of neurons that have not been functioning during the period of ischemia. However, reperfusion also can cause worsening of ischemic cerebral edema resulting in increased neurological disability or death. Adequate measures for control of cerebral edema will be necessary if surgical intervention is to become an effective therapy for acute ischemic cerebral infarcts. REFERENCES 1. Ames, A., III, Wright, R. L., Kowada, M., Thurston, J. M., and Majno, G. Cerebral ischemia. II. The no-reflow phenomenon. Am. J. Pathol., 52: 437-453, 1968. 2. Bartko, D., Reulen, H. J., Koch, H., and Schiirmann, K. Effect of dexamethasone on
the early edema following occlusion of the middle cerebral artery in cats. In Steroids and Brain Edema, edited by H. J. Reulen, and K. Schtlrmann, pp. 127-137. SpringerVerlag, New York, 1972.
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does not produce a catastrophic reaction of massive edema and brain swelling (15). Restoration of the flow of blood to an ischemic zone of the brain, perhaps by an appropriate neurovascular surgical procedure, may be followed by the restoration or preservation of function of neurons and the minimization of neurological disability. Alternatively, it may lead to worsening of ischemic cerebral edema with a resultant increase of neurological disability. For neurovascular surgical procedures to be effective, it appears that they must be undertaken relatively shortly after the onset of ischemia, and that worsening of edema must be prevented. Unfortunately, corticosteroids and osmotic agents are not as useful for the treatment of ischemic cerebral edema as for edema associated with cerebral tumors and head injuries (2, 3, 9, 18, 20). The resolution of this paradox awaits further study of the treatment of ischemic cerebral edema. I have not mentioned as yet the possibility of converting an ischemic infarct to a hemorrhagic infarct by increasing perfusion pressure in an ischemic zone because in experimental models in animals this has not been a problem (8, 31, 33). In humans, early surgical experience with acute cerebral infarcts included the development of hemorrhagic infarcts and left many surgeons abandoning early intervention. I understand from my surgical colleagues, however, that recent experience with vascular procedures has been different; I will leave a discussion of this aspect of surgical therapy to those with appropriate experience.
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3. Bauer, R. B., and Tellez, H. Dexamethasone as treatment in cerebrovascular disease. 2. A controlled study in acute cerebral infarction. Stroke, 4: 547-555, 1973. 4. Branston, N. M., Symon, L., Crockard, H. A., and Pasztor, E. Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon. Exp. Neurol., 45: 195-208, 1974. 5. Brightman, M. E., Hori, M., Rapoport, S. I., Reese, T. S., and Westergaard, E. Osmotic opening of tight junctions in cerebral endothelium. J. Compo Neurol., 152: 317-326, 1973. 6. Brock, M., Beck, J., Markakis, E., and Dietz, H. Intracranial pressure gradients associated with experimental cerebral embolism. Stroke, 3: 123-130, 1972. 7. Chiang, J., Kowada, M., Ames, A., Ill, Wright, R. L., and Majno, G. Cerebral ischemia. Ill. Vascular changes. Am. J. Pathol., 52: 455-476, 1968. 8. Crowell, R. M., Olsson, Y., Klatzo, I., and Ommaya, A. Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke, 1: 439-448, 1970. 9. Donley, R. F., and Sundt, T. M., Jr. The effect of dexamethasone on the edema of focal cerebral ischemia. Stroke, 4: 148-155, 1973. 10. Garcia, J. H., Cox, J. V., and Hudgins, W. R. Ultrastructure of the microvasculature in experimental cerebral infarction. Acta Neuropathol., 18: 273-285, 1971. 11. Garcia, J. H., and Kamijyo, Y. Cerebral infarction: evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J. Neuropathol. Exp. Neurol., 33: 408-421, 1974. 12. Harrington, T., and DiChiro, G. Effect of hypocarbia and hypercarbia on experimental brain infarction: a microangiographic study in the monkey. Neurology, 23: 294-299, 1973. 13. Hayakawa, T., and Waltz, A. G. Immediate effects of cerebral ischemia: evolution and resolution of neurological deficits after experimental occlusion of one middle cerebral artery in conscious cats. Stroke, 6: 321-327, 1975. 14. Hayakawa, T., and Waltz, A. G. Intracranial pressure, blood pressure, and pulse rate after occlusion of a middle cerebral artery in cats. J. Neurosurg., 43: 399-407,1975. 15. Heiss, W-D., Hayakawa, T., and Waltz, A. G. Unpublished observations, 1974a. 16. Heiss, W-D., Hayakawa, T., and Waltz, A. G. Unpublished observations, 1974b. 17. Heyman, A., Saltzman, H. A., and Whalen, R. E. The use of hyperbaric oxygen in the treatment of cerebral ischemia and infarction. Circulation, 33 (Suppl. II): 20-27, 1966. 18. Hoppe, W. E., Waltz, A. G., Jordan, M. M., and Jacobson, R. L. Effects of dexamethasone on distributions of water and pertechnetate in brains of cats after middle cerebral artery occlusion. Stroke, 5: 617-622, 1974. 19. Kogure, K., Busto, R., Scheinberg, P., and Reinmuth, O. M. Energy metabolites and water content in rat brain during the early stage of development of cerebral infarction. Brain, 97: 103-114, 1974. 20. Lee, M. C., Mastri, A. R., Waltz, A. G., and Loewenson, R. B. Ineffectiveness of dexamethasone for treatment of experimental cerebral infarction. Stroke, 5: 216-218, 1974. 21. Levy, D. E., Brierly, J. B., Silverman, D. G., and Plum, F. Brief hypoxia-ischemia initially damages cerebral neurons. Arch. Neurol., 32: 450-456,1975. 22. Little, J. R., Kerr, F. W. L., and Sundt, T. M., Jr. Microcirculatory obstruction in focal cerebral ischemia: relationship to neuronal alterations. Mayo Clin. Proc., 50: 264-270, 1975. 23. Little, J. R., Sundt, T. M., Jr., and Kerr, F. W. L. Neuronal alterations in developing
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