Transient ischemic attacks and cerebral infarcts

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1 1053 Platelet Emboli in Rat Brain Cross When the Contralateral Carotid Artery Is Occluded Gretchen E. Tietjen, MD; Nancy Futrell, MD; Julio H. Garcia, MD; and Clark Millikan, MD The pathogenesis of embolic events ipsilateral to an occluded carotid artery is uncertain. To examine this question we combined occlusion of the left common carotid artery with embolism from the right common carotid artery in rats. Following ligation of the left carotid artery in 20 experimental rats, we irradiated the right carotid artery with a laser (632 nm, 200 mw/cm 2, minutes) following the intravenous injection of 12.5 mg/kg of the photosensitizing agent Photofrin II. Controls had left carotid artery occlusion with (n=13) or without (n=6) Photofrin II. Fifteen of the 20 experimental rats survived to be perfused at 24 hours; cerebral infarcts were identified in 12 rats, with bilateral infarcts in 10. There were 112 infarcts (101 small [<2.5 mm] and 11 large [>2.5 mm] on the right and 103 (93 small and 10 large) on the left Emboli were seen in association with some infarcts and were evenly distributed in the two hemispheres (37 emboli on the right and 40 on the left, with the midline azygous artery occluded in four animals). Left carotid artery occulsion did not produce infarcts or emboli in the controls. We conclude that cerebral infarcts in the distribution of an occluded common carotid artery may be caused by emboli from the contralateral carotid artery in rats. (Stroke 1991^2: ) Transient ischemic attacks and cerebral infarcts in the distribution of an occluded carotid artery are well-recognized events. 1-7 Proposed mechanisms of embolic cerebral infarction associated with established carotid artery occlusion include embolization of material from the distal end of the internal carotid artery (ICA) thrombus and embolization from the nonobliterated proximal ICA remnant, the "stump," via the external carotid artery and its anastomotic channels The crossing of emboli from the contralateral carotid artery to the territory distal to the ICA occlusion has been considered an unlikely mechanism of cerebral ischemia and infarction. 8 Atherosclerosis, a generalized disease process, plus thrombosis account for the majority of carotid artery occlusions. 2 In most cases there are pathological changes in other intracranial and extracranial cerebral vessels, including the contralateral carotid artery, 6-11 as well. We hypothesize that emboli may be carried wherever blood flows and that, in the case of carotid artery occlusion, an infarct in the homolateral cerebral hemisphere may be caused by an embolus from the contralateral carotid From the Departments of Neurology (G.E.T., N.F., CM.) and Pathology (J.H.G), Henry Ford Hospital, Detroit, Mich. Supported by the National Stroke Association and the American Heart Association of Michigan. Address for correspondence: Gretchen E. Tietjen, MD, Room F118A, Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 4S202. Received February 20, 1991; accepted April 26, artery. We tested our hypothesis by producing platelet emboli in the right common carotid artery (CCA) after occluding the left CCA in Wistar rats, which have a complete circle of Willis. 12 Materials and Methods We used 39 male Wistar rats (20 experimental, 19 controls) weighing g. All animals were anesthetized with 12 ml/kg i.p. chloral hydrate 4.5%. In each rat the left CCA was exposed through a midline incision and separated from the vagus nerve. Two sutures were tied tightly around the vessel, and it was severed between the sutures. In the 20 experimental rats 12.5 mg/kg Photofrin II, a photosensitizing agent, was injected into the tail vein over 1 minute. The technique for carotid irradiation has been described in detail. 12 Briefly, the right CCA was surgically exposed, and 30 minutes after the injection of Photofrin II a 5-mm segment of the vessel was irradiated with red light at 632 nm for minutes with a laser power of 200 mw/cm 2. The rectal temperature was maintained between 35.5 and 37.5 C throughout the procedure. Five experimental rats were eliminated from the study because of respiratory distress requiring early sacrifice (two) or death before 24 hours (three). The 15 surviving experimental rats were all killed under chloral hydrate anesthesia between 20 and 28 hours after irradiation by transcardiac perfusion with 250

1054 Stroke Vol 22, No 8 August 1991 ml normal saline followed by 500 ml of 10% neutral buffered formalin at a pressure of 100 mm Hg. One set of controls (13 rats) received 12.

2 1054 Stroke Vol 22, No 8 August 1991 ml normal saline followed by 500 ml of 10% neutral buffered formalin at a pressure of 100 mm Hg. One set of controls (13 rats) received 12.5 mg/kg Photofrin II via tail vein injection after left CCA ligation and transection, but the right CCA was not isolated or irradiated. A second set of control animals (six rats) underwent left CCA ligation and right CCA isolation without Photofrin II injection. The right CCA was exposed to room light and air for minutes, the approximate time needed to isolate and irradiate the artery during the experimental protocol. All controls were killed 24 hours later by transcardiac perfusion as described above. Immediately after perfusion the rat's head was removed and placed in 10% neutral buffered formalin. At least 8 hours after perfusion the brain was removed from the cranium and placed in formalin for an additional 24 hours before sectioning into 3-mm-thick coronal blocks. Tissues were processed and embedded in paraffin, and 7-^m-thick sections were cut every 56 ysn and stained with hematoxylin and eosin. The diagnosis of cerebral infarction was based on shrinkage and condensation of neuronal perikarya, nuclear pyknosis, cytoplasmic eosinophilia, development of a "perineuronal halo," and vacuolation of the neuropil in a circumscribed area. Infarct size and embolus diameter were measured using a reticle. Embolus length was estimated if the same occluded vessel was visible on consecutive sections. The longest dimension of each infarct was measured, and the lesions were classified by size, territory, and laterality. Large infarcts were arbitrarily designated as those with a longest dimension of >2J5 mm, and small infarcts, as those with a longest dimension of <25 mm. Results The experimental protocol, including 24 hours' survival, was completed in 15 of the 20 experimental animals; 12 had cerebral infarcts. Infarcts were present only on the right in one, only on the left in one, and bilaterally in 10 experimental rats killed 1 day after irradiation. There were 112 infarcts on the right and 103 on the left. Of the 215 infarcts, 90% (194) were small and well circumscribed (Figure 1, top). Vessels occluded by material having the granular appearance of platelets were observed close to large and small infarcts in both hemispheres (Figure 1, bottom). Thirty-one emboli in the right hemisphere and 34 in the left hemisphere were associated with small infarcts. Six emboli in each hemisphere were near large infarcts. In several large infarcts multiple emboli were seen. Many of the occlusions were in pial arteries and arterioles <50 /im in diameter. Occlusions of large pial arteries were seen in only one rat (a 270-^.m-diameter artery was occluded on the right, and a 300-p.m-diameter artery was occluded on the left). Occlusion of the midline azygous artery was found in four experimental animals (Figure 2, top). The length of these presumed emboli varied from 500 to 1,100 ^m, and in one rat the embolus was associated with paired infarcts of the caudoputamen and septal nuclei (Figure 2, bottom). One hundred eighty-five cortical infarcts were observed in the territory of the anterior, middle, and posterior cerebral arteries, which in rats may all originate from the ICA. 13 The hippocampus was involved unilaterally in three animals and bilaterally in one rat with massive bilateral infarcts. Two infarcts were found in the right brain stem and one in the right thalamus. The cerebellum was not examined. Ten large ( mm) cortical infarcts were seen, on the right in three, on the left in three, and bilaterally in two rats. While three of the large cortical infarcts appeared to be the coalescence of many smaller lesions, the others had a laminar pattern (Figure 3). The laminar pattern of neuronal necrosis was unilateral in three rats (in two on the left and in one on the right) and bilateral in two animals. None of the 19 control animals had infarcts, and no vascular occlusions were identified. Discussion We have demonstrated that emboli from the right CCA can go to both cerebral hemispheres in a rat if the left CCA is occluded. Occasionally, emboli from the carotid artery or embolic infarcts have been found in the opposite hemisphere, the brain stem, or the cerebellum in other models of embolic cerebral infarction in rats, 14 dogs, and rabbits. 18 In this model, where occlusion of one CCA results in a larger portion of the blood supply coming from the contralateral circulation via the circle of Willis, infarcts and emboli are relatively evenly distributed between the hemispheres, and we presume that emboli cross more frequently. Occlusion of the midline azygous artery in one third of our experimental animals supports our hypothesis that emboli in the vessels of the left hemisphere have crossed the midline from the right; in these cases crossing occurs via the anterior portion of the circle of Willis. Another explanation for the infarcts in the left hemisphere would be that they were caused by embolization of stagnated blood from the ligated ends of the artery, by mechanical manipulation of either CCA, or by absorption of the photosensitizing dye. Ligation of the left CCA, with and without Photofrin II injection, did not cause cerebral infarction in our control animals. Other investigators have reported that unilateral carotid artery ligation does not produce stroke in rats. 19 Ninety percent of the brain lesions in our experimental rats were small and well-circumscribed, often associated with occluded vessels, consistent with the presumed mechanism of embolism. 12 Evidence that cerebral infarcts are caused by emboli following photochemical damage to the carotid artery has been previously reviewed Emboli were found in association with infarcts in both cerebral hemispheres, although the number of infarcts greatly exceeded the number of emboli detected. This study was not designed to locate al l of

Tietjen et al Platelet Emboli Cross FIGURE 1. 1055 Photomicrographs of sections of rat brain. Top: Bilateral small, well-circumscribed cortical infarcts. Scale marker 1 mm.

3 Tietjen et al Platelet Emboli Cross FIGURE Photomicrographs of sections of rat brain. Top: Bilateral small, well-circumscribed cortical infarcts. Scale marker 1 mm. Bottom: Arteriole occluded with granular material, probably platelets, at periphery of infarct. Scale marker 50 fim. the emboli, which could be done only with serial sections. Studies of autologous clot models of cerebral embolism suggest that emboli are not detectable near all experimental embolic infarcts, presumably because emboli spontaneously fragment and move distally.16 Studies of human autopsy material suggest that some emboli produce cerebral infarction before disintegrating or migrating to a vessel distal to the infarct.20 Embolic cerebral infarcts following photochemical damage to the right CCA in rats have measured up to 1.6 mm in diameter.12 Addition of contralateral CCA ligation to the experimental protocol resulted in the unexpected production of large and even massive cerebral infarcts. It might be expected that large infarcts would occur predominantly in the hemisphere ipsilateral to the arterial occlusion, but the large cortical and caudoputaminal infarcts were relatively evenly distributed (nine on the right and seven on the left). The presence of occluded arteries and arterioles in association with six of the 16 large infarcts suggests that emboli may be part of the mechanism producing large infarcts. Mechanisms in addition to embolism are likely to have been involved

4 1056 ' r Stroke Vol 22, No 8 August 1991 ' * *..; - i : / : FIGURE 2. Photomicrographs of sections of rat brain. Top: Occluded midline azygous artery. Scale marker 100 yjn. Bottom: Paired infarcts ofcaudoputamen and septal nuclei proximal to occluded azygous artery. Scale marker 1 mm. in the generation of some of the large cerebral infarcts, possibly related to disruption of potential collateral flow patterns when most of the blood supply to both hemispheres must be provided by a single carotid artery. The laminar pattern seen in some infarcts (Figure 3, bottom) might suggest systemic hypotension, except that in three rats the laminar pattern was unilateral, and in one of these animals the laminar pattern was contralateral to the occluded CCA. Blood pressure was not monitored during the experiment, but previous work with Photofrin II is notable for the absence of hypotension after injection.12 In addition to the difference in the laterality and size of the infarcts produced in this model compared with the model of carotid irradiation alone, we noted a difference in the distribution of infarcts within the ipsilateral hemisphere. Only 3.6% (four) of the 112 right-sided infarcts involved hippocampal structures, whereas the original experiment of platelet embolism without extracranial vessel occlusion produced 27.5% (22 of 80) infarcts in the hippocampal region.12 This difference is significant (/><0.001). Redistribution of embolic infarcts in rats with an occluded left CCA may imply redistribution of blood flow following left CCA occlusion. When the left CCA is occluded and the right CCA must supply parts of both hemispheres, perfusion pressure on the right may decrease, promoting collateral blood flow to the hippocampus from the vertebrobasilar system.

$Infarcts coalesced in subsequent section to large left cortical infarct. Scale marker 50 \JJTU Bottom: Laminar pattern of neuronal necrosis is prominent in deep cortex of left hemisphere.$

5 Tietjen et al Platelet Emboli Cross FIGURE Photomicrographs of sections of rat brain. Top: Discrete infarcts associated with occluded pial arteries (arrow). Infarcts coalesced in subsequent section to large left cortical infarct. Scale marker 50 \JJTU Bottom: Laminar pattern of neuronal necrosis is prominent in deep cortex of left hemisphere. Scale marker 500 \tm. w. The results from this study may have mechanistic implications for humans with atherosclerotic cerebrovascular disease. Patients with transient ischemic attacks and cerebral infarcts in the setting of carotid artery occlusion are more likely to have significant contralateral stenosis than those with asymptomatic occlusions.6 There are also patients who improve after carotid endarterectomy contralateral to their ischemic symptoms and the site of occlusion.21 These findings have been explained by alterations in collateral blood flow, but the possibility that the stenotic carotid artery serves as an embolic source should be considered. It might also be noted that neonates undergoing CCA ligation for extracorporeal membrane oxygenation are observed to have both ipsilat- eral and contralateral cerebral infarcts.22 The etiology of infarcts in this population is multifactorial, but documentation of blood flow reversal through the circle of Willis23 allows for speculation that emboli might cross into an area of impoverished blood flow. We conclude that, in rats, cerebral infarcts in the distribution of an occluded CCA may be caused by emboli from the contralateral CCA. The possibility of a similar phenomenon in humans warrants further consideration. Acknowledgments The authors gratefully acknowledge the technical assistance of Nancy Allar and Alexandra Halvorsen and preparation of the manuscript by George Potts.

1058 Stroke Vol 22, No 8 August 1991 References 1. Barnett HJM: Delayed cerebral ischemic episodes distal to occlusion of major cerebral arteries. Neurology 1978;28: 769-744 2.

6 1058 Stroke Vol 22, No 8 August 1991 References 1. Barnett HJM: Delayed cerebral ischemic episodes distal to occlusion of major cerebral arteries. Neurology 1978;28: Castaigne P, Lhennitte F, Gautier J-C, Escourolle R, Derouesnd C: Internal carotid artery occlusion: A study of 61 instances in 50 patients with post-mortem data. Brain 1970;93: Fields WS, Lcmak NA: Joint study of extracranial arterial occlusion: X. Internal carotid artery occlusion. JAMA 1976; 235: Mohr JP, Caplan LR: The Harvard Cooperative Stroke Registry. Neurology 1978;28: Fisher M: Occlusion of the internal carotid artery. Arch Neurol Psychiatry 1951;65: Pierce GE, Kerushkerian SM, Hermreck AS, Diopoulos JI, Thomas JH: The risk of stroke with occlusion of the internal carotid artery. / Vase Surg 1988;8: Cote R, Bamett HJM, Taylor DW: Internal carotid occlusion: A prospective study. Stroke 1983;14: Barnett HJM, Peerless J, Kaufmans JCE: "Stump" of internal carotid artery: A source of further cerebral embolic ischemia. Stroke 1978;9: Pessin MS, Hinton RC, Davis KR, Duncan GW, Roberson GH, Ackerman RH: Mechanisms of acute carotid stroke. Ann Neurol 1979;6: Ringelstein EB, Zeumer H, Angelou D: The pathogenesis of strokes from internal carotid artery occlusion: Diagnostic and therapeutic implications. Stroke 1983;14: Harrison MJG, Marshall J: The variable clinical and CT findings after carotid occlusion: The role of collateral blood supply. / Neurol Neurosurg Psychiatry 1988^1: Futrell N: An improved photochemical model of embolic cerebral infarction in rats. Stroke 1991;22: Ogata J, Fujishima M, Morotomi Y, Omae T: Cerebral ligation following bilateral carotid artery ligation in normotensive and spontaneously hypertensive rats: A pathological study. Stroke 1977;8: Futrell N, Millikan C, Watson BD, Dietrich WD, Ginsberg MD: Embolic stroke from a carotid arterial source in the rat: Pathology and clinical implications. Neurology 1989;39: Swank RL, Hain RF: The effect of different sized emboli on the vascular system and parenchyma of the brain. / Neuropathol Exp Neurol 1952;ll: Hill ND, Millikan CH, Wakim KG: Experimental production of cerebral infarction by intracarotid injection of homologous blood clot. Mayo Clin Proc 1955^30: Molinari GF: Experimental cerebral infarction: 1. Selective segmental occlusion of intracranial arteries in the dog. Stroke 1970;1: Steegman AT, Fuente J: Experimental cerebral embolism: II. Microembolism of the rabbit brain with seran polymer resin. / Neuropathol Exp Neurol 1959;18: Pagan H, Levine S, Strerel R: Effects of cerebral ischemia in various strains of rats. Proc Soc Exp Biol Med 1965;120: Fisher CM, Adams RD: Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951;10: Machleder HI, Barker WF: Stroke on the wrong side: Use of the Doppler Ophthalmic Test in cerebral vascular screening. Arch Surg 1972;105: Taylor GA, Short BL, Fitz CR: Imaging of cerebrovascular injury in infants treated with extracorporeal membrane oxygenation. J Pediatr 1989;114: Raju TNK, Kim SY, Meller JL, Srinivasan G, Ghai V, Reyes H: Circle of Willis blood velocity and flow direction after common carotid artery ligation for neonatal extracorporeal membrane oxygenation. Pediatrics 1989;83: KEY WORDS carotid arteries cerebral infarction embolism rats

Although plaque morphology of patients with

Although plaque morphology of patients with 1740 Short Communications Rupture of Atheromatous Plaque as a Cause of Thrombotic Occlusion of Stenotic Internal Carotid Artery Jun Ogata, MD, Junichi Masuda, MD, Chikao Yutani, MD, and Takenori Yamaguchi,