Experimental Regional Cerebral Ischemia in the Middle Cerebral Artery Territory in Primates

Size: px

Start display at page:

Download "Experimental Regional Cerebral Ischemia in the Middle Cerebral Artery Territory in Primates"

Patrick Craig
5 years ago
Views:

CAROTID AND VERTEBRAL RESPONSE TO BETAHISTINE/Tomita el al. 387 vasodilating drugs and some related agents. Laryngoscope 79: 1956-1979, 1969 8.

1 CAROTID AND VERTEBRAL RESPONSE TO BETAHISTINE/Tomita el al. 387 vasodilating drugs and some related agents. Laryngoscope 79: , Martinez DM: The effect of betahistine hydrochloride on the circulation of the inner ear (spinal ligament and stria vascularis) of living anesthetized guinea pigs and chinchillas and associated venous and arterial pressure changes. (Report in the files of Unimed, Inc, Morristown, NJ, pp 1-7 (cited from 9)?. Meyer JS, Mathew NT, Hartmann A, Riviera VM: Orally administered betahistine and regional cerebral blood flow in cerebral vascular disease. J Clin Pharmacol 14: , Tomita M, Gotoh F, Sato T, Amano T, Tanahashi N, Tanaka K, Yamamoto M: A photoelectric method for estimating hemodynamic changes in regional cerebral tissue. Am J Physiol (in press, 1978) 11. Woods JR Jr, Brinkman CR, Dandavino A, Murayama K, Assai NS: Action of histamine and H, and H 2 blockers on the cardiopulmonary circulation. Am J Physiol 232: H73-H78, Tomita M, Gotoh F, Satoh T, Amano T, Tanahashi N, Tanaka K, Yamamoto M: Variations in resistance of larger and smaller parts of cerebral arteries with CO 2 inhalation, exsanguination, and vasodilator administration. Acta Neurol Scand 56: Suppl 64, , Pickering GW: Observation on mechanism of headache produced by histamine. Clin Sci 1: , Stead EA, Warren JV: The effect of injection of histamine into the brachial artery on the permeability of capillaries in the forearm and hand. J Clin Invest 23: , 1944 Experimental Regional Cerebral Ischemia in the Middle Cerebral Artery Territory in Primates Part 3: Effects on Brain Water and Electrolytes in the Late Phase of Acute MCA Stroke ALFONSO M. BREMER, M.D., KAZUO YAMADA, M.D., AND CHARLES R. WEST, M.D. SUMMARY Experimental regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in primates (M. mulatto) by macrosphere embolization. Determinations of percentage tissue dry weight and tissue sodium and potassium concentrations were obtained in samples from the ischemic and non-ischemic hemispheres at various times from to hours after the onset of cerebral ischemia. Samples from the cortex normally supplied by the occluded MCA showed maximal accumulation of edemafluidwith fluxes in sodium and potassium in reciprocal directions at hours and similar edematous changes in putamen at hours after embolization. By hours after MCA occlusion and despite the presence of infarction, partial reversal was observed in the redistribution of water and electrolytes in these gray matter structures. In contrast to cerebral cortex and putamen, the adjacent subcortical white matter showed progressive increases in water content from to hours and definite increases in tissue sodium with decreases in potassium were not observed until hours after MCA occlusion. This late severe white matter edema associated with cerebral infarction appears to be a major factor responsible for the hemispheric swelling observed at this stage. CLINICAL and experimental studies have shown that cerebral edema following an acute stroke is at maximum within a few days and eventually subsides in ibout 3 weeks if the patient or the experimental animal survives the acute phase. 1 " 4 Results obtained by Little et al. 5 ' 6 from morphological studies in brains of squirrel monkeys following surgical clipping of the middle cerebral irtery (MCA) have demonstrated a primary and a secondary phase in the evolution of ischemic cerebral ;dema. The initial phase begins shortly after arterial jcclusion, is characterized by mild swelling of the gray ind white matter, increases gradually in severity and asts from 3 to 6 hours. Thereafter, a secondary phase From the Department of Neurosurgery, Roswell Park Memorial institute, 666 Elm St., Buffalo, NY This work was supported in part by Grant No. R from the Jnited Cerebral Palsy Association, Inc. and in part by Research jrant Aid from the Heart Association of Western New York, Inc., i chapter of the American Heart Association. Parts 1 and 2 were published in STROKE 8: pp , Reprint requests to Dr. Bremer. begins and is characterized by massive swelling, especially of the white matter. Rapid increases in severity of this edema reached its peak at hours or longer. 6 In a previous communication we demonstrated that hemispheric swelling became apparent in the experimental side as early as 4 to 5 hours after onset of regional cerebral ischemia in the MCA territory in primates. 7 Obvious changes in gray matter water content and in tissue sodium and potassium concentrations were detected at this time. However, minimal increases in subcortical white matter water content was found without changes in electrolytes. 7 The present study was designed to extend our observations of ischemic brain tissue water content and in tissue sodium and potassium concentrations after much longer periods of MCA occlusion in macaques. Methods The left MCA of 10 adult primates (M. mulatto) (3 to 4 kg body weight) was occluded by a method of

STROKE VOL 9, No 4, JULY-AUGUST 1978 TABLE 1 Animals, Number and Location of Emboli, Level of Consciousness and Postmortem Gross and Microscopical Ischemic Changes of the Experimental Hemispheres

2 STROKE VOL 9, No 4, JULY-AUGUST 1978 TABLE 1 Animals, Number and Location of Emboli, Level of Consciousness and Postmortem Gross and Microscopical Ischemic Changes of the Experimental Hemispheres Animals No. of emboli I II III IV V VI VII VIII XI 3 Location of emboli Duration of exp. (hra) Level of consciousness MCA-P and terminal ICA occluding AChA Alert wakefulness Obtundation Obtundation Coma - Died = internal carotid artery bifurcation; ICA AChA = anterior choroidal artery. = Normal. + = Slight change. + + = Moderate change = Marked change = Severe change. 1 Gross and microscopical ischemic changes Cortex Putamen White matter internal carotid artery; MCA-P = middle cerebral artery - proximal segment; selective embolization described in detail in previous reports.8-9 One minor modification of the animal preparation was that the extracranial surgical procedure was performed under mild sedation (single i.m. dose of phencyclidine 0.25 mg per kg) and sterile conditions. Thereafter, plain skull radiographs were taken and the monkeys were returned to their cage for periodical clinical examination. At the end of, and hours after embolization, samples of the brain tissue were obtained for determination of percentage dry weight, tissue sodium and potassium concentrations, and histopathology was determined from the affected and non-affected (opposite) hemispheres with similar technique previously described.7-9~18 The edema in cerebral cortex, in putamen and in subcortical white matter samples was calculated in each animal by the formula originally described by Elliot and Jasper.17 Determinations of vital signs and vital functions at the end of each experiment were obtained with similar instrumentation as in earlier reports.7'9 Results After the embolization procedure anatomical location of the radiopaque silicone spheres (Heyer-Schulte Corp., Santa Barbara, CA) was demonstrated by plain skull radiographs and confirmed at postmortem examination (table 1). All 10 animals tolerated the embolization procedure without apparent difficulties or significant change in vital signs and vital functions (table 2). However, 3 developed Homer's pupil on the side of the carotid surgery. TABLE 2 Vital Signs, Arterial Blood Gases, Plasma Electrolytes, Plasma Osmolarity and Hematocrit at the End of the Experiments Vital signs MABP (mm Hg) Pulse rate (per minute) liespiratioas (per minute) 138 ± ± 36 ± Arterial blood gases ph PO- (mm Hg) PCO2 (mm Hg) ± ± ± 2.9 Plasma electrolytes Sodium (meq/l) Potassium (meq/l) Chloride (meq/l) ± ± ± 6.0 Plasma Osmolarity ± 4.5 Hematocrit (%) 39 ± 1.4 The values correspond to 9 monkeys. (Monkey X is not included). FIGURE 1. Posterior view of a coronalsection of a monkey brain hours after MCA occlusion. Note on the left side of thefigurethe swollen hemisphere with midline shift from left to right. There is ischemic pallor and widening of the Sylvian and insular cortexes. The affected putamen is also pale with increased surface area.

3 ISCHEMIA IN MCA TERRITORY: Part 1/Bremer et al. 389 Clinical and Morphological Observations Contralateral motor weakness and ipsilateral conjugate eye deviation, developing shortly after macrosphere embolization, persisted in 9 of 10 monkeys throughout the entire, and hour observation periods. These animals also manifested alterations in the level of consciousness of variable degree (table 1). Grossly, these brains showed flattening of gyri with increased distances between sulci of the affected Sylvian cortex. Hemispheric swelling with marked midline shift was unmistakable on coronal sections (fig. 1). Variable degrees of advanced ischemic necrosis were recognized in histological sections of both gray and white matter within the territory of the occluded MCA (table 1). Hemorrhagic infarct was found in only one animal (Monkey VI) of the entire series. Water and Electrolyte Content Results presented in figures 2 and 3 show that hours after MCA occlusion, swollen Sylvian cortex and putamen (9.3% to 37.7% tissue swelling) also exhibited increases in tissue sodium (up to 96% of control value) and decreases in potassium (down to 61% of control value). In the hour experiments, changes in percentage of dry weight and electrolytes of ischemic Sylvian cortex were variable, but putamen edema was massive (38.7% to 58.9% tissue swelling) with large increases in tissue sodium (up to 133% of control value) while potassium was markedly decreased (down to 77% of control value). By hours after MCA occlusion and despite evidence for the presence of infarction, partial reversal in the redistribution of water and electrolytes in both Sylvian cortex and putamen was observed. In contrast to cerebral cortex and putamen, the percentage of tissue swelling in adjacent subcortical white matter showed a rapid upward trend hours after MCA occlusion. Definite increases in tissue sodium (up to 45% of control value) with decreases in potassium (down to 32% of control value) were only seen by the end of hours after MCA occlusion (figures 2 and 3). Discussion We have previously demonstrated that cerebral ischemia in primates following acute MCA occlusion o 34 r 30 > 25 CE Q O if 20 o cr UJ 15 - I3 L SYLVIAN CORTEX A- CONTROL A- ISCHEMIC MCA OCCLUSION PUTAMEN CONTROL ISCHEMIC WHITE MATTER O CONTROL ISCHEMIC vt J -*---._ TIME (HOURS) FIGURE 2. The time course of edema in gray and white matter as reflected by the percent dry weight (average, S.D.). This is progressive in white matter but begins to recede in gray matter after - hours. CO co 80 -,- 80 co 2 E UJ 80 0 u SYLVIAN CORTEX PUTAMEN WHITE MATTER -tf SODIUM =. POTASSIUM =o- L _L -iff- J CONTROL VALUES TIME AFTER MCA OCCLUSION (HOURS) FIGURE 3. Control values for sodium and potassium concentrations (average, S.D.) correspond to non-ischemic hemispheres (14 animals). Increases in sodium and decreases in potassium concentrations in ischemic gray matter structures show maximal changes when edema in these structures is at its peak. The late development of electrolyte changes in white matter begins between and hours.

3MJ STROKE VOL 9, No 4, JULY-AUGUST 1978 FIGURE 4. The 2 coronal sections on the left side of thefigurecorrespond to the experimental (ischemic) hemisphere on Monkey X (Bodian and H & E stains).

4 3MJ STROKE VOL 9, No 4, JULY-AUGUST 1978 FIGURE 4. The 2 coronal sections on the left side of thefigurecorrespond to the experimental (ischemic) hemisphere on Monkey X (Bodian and H & E stains). This monkey sustained hours of simultaneous embolic occlusion of the anterior choroidal artery and MCA on the experimental side. Note the extensive infarction of the basal ganglia, internal capsule, adjacent subcortical white matter, the entire Sylvian cortex and temporal lobe. In contrast, the 2 coronal sections on the right correspond to the experimental hemisphere of a monkey 4 weeks after embolic occlusion of the MCA without participation of the anterior choroidal artery (Bodian and H & E stains). Note that by this time the infarcted area becomes well demarcated and the tissue is replaced by loose, spongy-like glial network with some cavitation. Obvious sparing of the temporal lobe and part of the Sylvian cortex is a frequent finding in this type of occlusion. produced by macrosphere embolization is sufficient to induce brain edema within the territory of the occluded MCA.7 We also emphasized the importance of the gray matter edema as a major contributory factor for the development of hemispheric swelling during the early phase of MCA stroke.7 This study provides evidence that cerebral cortical edema with large increases in sodium and decreases in potassium concentrations is maximal at hours and similar edematous changes in putamen are at their peak hours after MCA occlusion. These extensive chemical changes have been considered as indicative of cell death by several investigators.19'20 Indeed, advanced ischemic necrosis was found on histological sections of both Sylvian cortex and putamen from the experimental hemispheres of these monkeys. Despite the presence of large infarction in all the monkey brains hours after MCA occlusion, partial clearing of gray matter edema, in both deep subcortical structures and cortex, is clearly demonstrated by the end of this period. It is not clear what mechanism is involved in the resolution of ischemic edema, but it is possible that improvement in residual blood flow through collateral channels may contribute to some clearing of cortical edema fluid. However, it is more difficult to explain on this basis the reversible edematous changes in the putamen in which the collateral vascular supply is less extensive.9'20 It is worthy of mention that our percentage dry weight values of cortical samples from non-ischemic hemispheres (opposite side) of one hour and of all the hour monkeys after MCA occlusion were significantly lower (/* < 0.05) when compared against the percentage dry weight control value (19.73 ± 0.65) obtained from cortical samples of non-ischemic hemispheres of 14 monkeys that sustained from 2 to 5 hours of regional cerebral ischemia previously reported.7 We failed to recognize definite significant histological or morphological change in these cortical samples with abnormal increases in water content, however, contralateral structural abnormalities have been recognized in another morphological study on squirrel monkey brains sacrificed hours or longer after MCA clipping.21 In contrast to findings on cerebral cortex and putamen, the delayed extensive chemical changes in subcortical white matter are similar to those seen in vasogenic edema This severe white matter edema associated with tissue necrosis of adjacent gray matter structures appears to be the main factor responsible for the hemispheric swelling recognized in all the monkeys surviving hours after MCA occlusion. The question remains as to whether ischemic cerebral edema, more pronounced than that induced by macrosphere embolic occlusion of the MCA alone in the primate, can be a major cause of death in the acute phase. In this respect, we call attention to Monkey X which died at hours after embolization. In this animal, simultaneous occlusion of the anterior choroidal artery and MCA with resultant massive cerebral infarction extending beyond the territory of the MCA and ipsilateral uncal herniation was found on post mortem examination (table 1 and fig. 4). According to Symon et al., when severe brain swelling was desired in their primate MCA clipping model, simultaneous occlusion of the anterior choroidal artery and MCA or terminal ICA and MCA was necessary. Therefore, it seems that we cannot overemphasize the importance of the involvement of the anterior choroidal artery in our primate MCA stroke model. In fact, occlusion of both of these arteries resulted in massive brain swelling associated

ISCHEMIA IN MCA TERRITORY: Part 1/Bremer et al. 391 with extensive cerebral infarction and was also a relatively early lethal combination. Further studies are proceeding on this point.

5 ISCHEMIA IN MCA TERRITORY: Part 1/Bremer et al. 391 with extensive cerebral infarction and was also a relatively early lethal combination. Further studies are proceeding on this point. Acknowledgment The authors are grateful for the professional advice of Walter A. Olszewski, M.D., to Mrs. lime Teene for preparing the histological stains, and to Yoshiaki Tsukada, M.D. for reviewing the histopathology. We also wish to thank the Roswell Park Departments of Medical Photography and X-ray, and to thank D. Bucheit and A. Kirisits for technical assistance. References 1. Shaw CM, Alvord EC, Berry RG: Swelling of the brain following ischemic infarction with arterial occlusion. Arch Neurol 1: , Oxbury JM, Greenhall RCD, Grainger KMR: Predicting the outcome of stroke: Acute stage after cerebral infarction. Br Med J 3: 5-7, Crowell RM, Olsson Y, Klatzo I, Ommaya A: Temporary occlusion of the middle cerebral artery in the monkey: Clinical and pathological observations. Stroke 1: , O'Brien MD, Waltz AG: Ischemic cerebral edema: Distribution of water in brains of cats, after occlusion of the middle cerebral artery. Arch Neurol 30: , Little JR, Kerr, FWL, Sundt TM Jr: Neuronal alterations in developing cortical infarction. J Neurosurg : , Little JR: Microvascular alterations and edema in focal cerebral ischemia. In Pappius HM, Feindel W (eds): Dynamics of Brain Edema. Heidelberg, Springer-Verlag, pp 236-3, Watanabe O, West CR, Bremer AM: Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 2: Effects on brain water and electrolytes in the early phase of MCA stroke. Stroke 8: 71-76, Bremer AM, Watanabe O, Bourke RS: Artificial embolization of the middle cerebral artery in primates. Description of an experimental model with extracranial technique. Stroke 6: , Watanabe O, Bremer AM, West CR: Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 1: Angio-anatomy and description of an experimental model with selective embolization of the internal carotid artery bifurcation. Stroke 8: 61-70, Pappius HM, McCann WP: Effects of steroids on cerebral edema in cats. Arch Neurol 20: , Norris JW, Pappius HM: Cerebral water and electrolytes: Effect of asphyxia, hypoxia and hypercapnia. Arch Neurol 23: 8-258, Yates AJ, Thelmo M, Pappius HM: Postmortem changes in the chemistry and histology of normal and edematous brains. Am J Pathol 79: , Pappius HM, Ho JH, Dossetor JB: The effects of rapid hemodialysis on brain tissues and cerebrospinal fluid on dogs. Can J Physiol Pharmacol 45: 9-147, Bourke RS, Greenberg ES, Tower DB: Variations of cerebral cortex fluid spaces in vivo as a function of species brain size. Am J Physiol 208: , Faas FH, Ommaya A: Brain tissue electrolytes and water content in experimental concussion in the monkey. J Neurosurg 28: , Bourke RS, Nelson KM: Further studies on K-dependent swelling of primate cerebral cortex in vivo: The enzymatic basis of the K-dependent transport of chloride. J Neurochem 19: , Elliot KA, Jasper H: Measurement of experimentally induced brain swelling and shrinkage. Am J Physiol 157: 2-9, Bourke RS, Tower DB: Fluid compartmentation and electrolytes of cat cerebral cortex in vitro. I. Swelling and solute distribution in mature cerebral cortex. J Neurochem 13: , Plum F, Posner JB, Alvord EC Jr: Edema and necrosis in experimental cerebral infarction. Arch Neurol 9: , Shibata S, Hodge CP, Pappius HM: Effect of experimental ischemia on cerebral water and electrolytes. J Neurosurg 41: , Garcia JH, Kamijyo Y: Evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropath Exp Neurol 33: 8-421, Klatzo I: Neuropathological aspects of brain edema. J Neuropath Exp Neurol 26: 1-14, Pappius HM: Biochemical studies on experimental brain edema. In Klatzo I, Seitelberger F (eds): Symposium on Brain Edema, Vienna 1965; New York, Springer-Verlag pp , Symon L, Dorsch NWC, Crockard HA: The production and clinical features of a chronic stroke model in experimental primates. Stroke 6: 476-1, 1975

Comparative Responses of the Carotid and Vertebral Arterial Systems of Rhesus Monkeys to. Betahistine

Comparative Responses of the Carotid and Vertebral Arterial Systems of Rhesus Monkeys to. Betahistine 382 STROKE VOL 9, No 4, JULY-AUGUST 1978 patterns in experimental traumatic paraplegia. J Neurosurg 38: 52-58, 1973 4. Osterholm JL: Pathophysiologic response to spinal cord injury. J Neurosurg 40: 5-33,