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The neuropathology of stroke
THE NEUROPATHOLOGY OF S T R O K E * Julio H. Garcia, M.D.?
Abstract Vascular-circulatory d e r a n g e m e n t s affecting the function o f the central nervous system may result in p a r e n c h y m a l lesions that are hemorrlmgic, ischenaic, or mixed. Most n o n t r a u m a t i c i n t r a p a r e n c h y m a l brain h e m o r r h a g e s are foutad in association with cerebral arteriolar sclerosis and o t h e r stigmata of hypertensive disease, such as hypertrophy o f tile left cardiac ventricle and granular kidneys. Global t e m p o r a r y ischemia, the type that exists d u r i n g severe and transient hypotension, resuhs in a wide variety o f p a r e n c h y m a l lesions that lnay be bilateral, unilateral, supra~.exltorial, or infi'atentorial. T h e cerebral and cerebellar cortices, white matter, basal ganglia, brain stem, and spinal cord may be involved simultaneously o r t h e r e may be isolated, tocal lesions that are confined occasionally to any one o f these areas. Regional ischemia, tile type induced t h r o u g h tile occlusion o f a major intracranial artery, evolves t h r o u g h a stage o f acute encephalomalacia, d u r i n g which the morl)hologic c h a n g e consists o f alternating cellular swelling and slMnkage. This is followed by leukocytic inflamnlation at three to f o u r days and tile beginning of resolution a t a b o u t the tenth day after arterial occlusion. In tim evolution o f this form o f abnormal circulation, after a few minutes, some n e u r o n s in the most distal arterial territories show tile first recognizable changes. In these ilealrons the mitochOndria swell massively. Astrocytes and lmurites in tile sante loci are selectively swollen, whereas oligodendrocytes and capillaries remain strtacturally u n c h a n g e d d u r i n g the initial stages o f ischemic injury.
A clinical diagnosis o f stroke, cerebrovascular accident, or a p o p l e x y implies a s u d d e n neurologic deficit attributable to either intracraniai bleeding or ischemic injury to the brain. T h u s , two major anatomic types o f stroke may be diffelentiilted. BLFFDING. Extralmrenchymal bleeding includes all h e m o r r h a g e s located ill the extradural, subdural, and subarachnoid spaces. Intral)arenchynml bleeding in-
cludes all h e n l o r r h a g e s located in tile cerebral hemispheres, pons, and c e r e b e l h n n . ISCIIEMIC DISTURBANCES. In a separate category are the circulatory disturbances that lead to softening of" the brain. T h e s e ischemic disturbances may or may not l)e occlusive ill origin. AIllOllg tile nonocclusive types o f ischemic encephalomalacia are p a r e n c h y m a l changes that result from severe hypotexlsion, strangulation,
*This work was SUplmrted in part by USI'tiS grants liE 11791 and NS (}6779 from the National Insfitmes of llcahh. "H'rofessor of Pathology, University of Maryland School of Medicine. I tead, Division of Nem'opathology, University of Maryland" tlospitai. Consuhant in Pathology, Veterans Administration Hospital and Union Memorial l lospital, r}ahimore, Maryland.
583
HUMAN PATHOLOGY--VOLUME 6, NUMBER 5 September 1975 T A B L E 1.
PARENCIIYMAI. LESIONS RESULTING FROM OCCLUSION o r MAJOR VESSELS
Patterns of Encephalomalacia Laminar necrosis
Hypotensive conditions
Hippocampal sclerosis
Cardiorespiratory dysflmction
Granular atrophy
Arterial occlusion (proximal)
Lacunae (cribriform state)
Arteriolar sclerosis
Subcortical encephalopathy
Arteriolar sclerosis
Contusion
Blunt trauma to the head
Infarction
Arterial (distal) or venous occlusion
and trauma. A second type of circulatory change inchtdes all parenchymal lesions that result from the occhtsion of a major vessel, whether arterial or venous (Table 1). The anatomy and etiology of hemorrhagic stroke are discussed here but summarily, but ischemic stroke is analyzed in more detail. The prevalence of situations that are diagnosed clinically as stroke is approxixnately as follows: cerebral infarction, 80 per cent; cerebral hemorrhage, 10 per cent; subarachnoid hemorrhage, 7 per cent; and miscellaneous, 3 per cent? HEMORRHAGIC
584
Etiologic Conditions
STROKE
Hemorrhage in the extradural (epidural) and subdural spaces of tile head and spine is most often related to nlechanical injuries to tile head or spine or to trauma distant from such areas. ~ Subarachnoid hemorrhage that is not traumatic in origin develops secondarily to rupture of anomalous arteries such as aneur)'sms or arteriovenous ntalformations, extension from an intraparenchynlal hemorrhage, or coagulopathies?" 4 Bleeding into the substance of the brain is designated herein as intraparenchymal brain hemorrhage, since such bleeding occurs not only in the cerebral hemispheres but also in the cerebellum and pons. Muhiple small petechiae in the cerebral parenchyma are encompassed under the heading of brain purpura, a condition associated with causative pllenomena that inchtde fat embolism, viral
encephalitides, allergic encep|lalomyelitis, and blood dyscrasias.3"5 Large, usually single, areas of intraparenchymal brain hemorrhage call be the result of either bhmt or penetrating trauma to the head. In young adults it is not uncoinlnon to encounter large collections of blood in tile brain parencbyma unaccompanied by noticeable hemorrhage in tile overlying scalp, skull;or meninges.oThe majority of spontaneous episodes of intraparenchymal brain hemorrhage occur in patients with anatomic evidence of hypertensive disease, snch as hypertrophy of the left ventricle, granular kidneys, and arteriolar sclerosis3 -s Ahhottgh the site of origin of parenchymal hemorrhages in hypertensive patients may be the cerebral hemispheres (85 per cent), cerebellum (10 per cent), or pons (5 per cent), in most publications they are collectively designated intracerebral or cerebral hemorrhages. ~, ,0 In addition to hypertensive arteriolar sclerosis, major nontraumatic episodes of intraparenchynlal brain hemorrhage may be associated with intracerebral saccular aneurysms or other vascular nlalformations, coagulopathies (especially in leukemic patients), and rarely with intraparenchymal primary or metastatic neoplasms) H3 A special lbrm ofintraventricular and imraparenchynlal hemorrhage is seen in newborns: most of these hemorrhages presumably are associated with inamaturity and systemic disturbances such as hypoxemia and electrolyte imbalance. H Intraparenchymal brain hemorrhage ~on-
T I l E N E U R O P A T H O I . O G Y O F S T R O K E - GARCIA T A B L E 2. CONDITIONS ASSOCIATED WITH LARGE IN'rRAPARENCI.IYMALBRAIN HEMORRIIAGE Arteriolar sclerosis usually of hypertensive origin Trauma to the head Aneurysms, arteriovenous malformations Coagulopathies (leukenfia in particular) Intracerebral neoplasms Perinatal conditions: immaturit)', metabolic disturbances Venotls occlusioII
volves both the carotid arteries in the neck and the coronary arteries) s Occasionally a brain harbors h e m o r r h a g e s (secondary to hypertensive arteriolar sclerosis), ischenaic lesions (secondary to atherosclerotic disease of the cervical carotid vessels) complicated by global ischemia (secondary to myocardial infarction or cardiac dysrhytlanfias), as well as emboli originating in the left cardiac atritun. As is discussed, in examining a btunan brain the morphologist Inust also contend with the effects of autol)'sis (as deterlnined by the death-fixation interval) and the undesirable alterations induced by i m p r o p e r methods of removal or histological processing of the brain.
fitted to the upper brainstem is most often the result of uncinate herniation (Table
MECHANISMS OF CEREBRAL ISCHEMIA
2). t5
In some hypertensive patients cerebral arteriolar sclerosis may nmnifest itself not otdy in the form of naassive intraparenchymal bleeding or stroke, but also as a slowly progressive encepltalopathy in which brain tissue changes of an ischemic type are confined primarily to the centrum ovale.tG, ,r T h e interpretation o f cerebral lesions having a circulatory origin can be difficult in a given specimen if hemorrhagic and ischemic lesions of different ages are present simultaneousl)'. It is well established that patients with Iwpertension and arteriolar sclerosis are susceptible to an accelerated course of atheromatous disease that in-
T A B L E 3.
Within a well known range of blood pressure changes, the cerebral blood flow is maintained constant tln'ough a mechanism of autoregulation, t9 At 37 ~ C. parencbymal changes may occur in the brain whenever the systolic blood pressure falls below 60 to 70 nnn. o f mercury. These figures apply to normotensive sugiects; loss of autoregulation in a chronic hypertensive patient may occur at much higher readings. ~176 T h e effects o f abnormal circulation on the brain parencbyma vary, depending upon whether the prevailing conditions are those o f ischemia (oligemia), hyperetnia (congestion), or hentorrhage.
MECtlANIS.XISOV CEREBRAL ISCtlEMIA
I. Occlusive t h r o m b u s - axlgiol)athy, coagulopath)' iiltrinsic embolus-endocardial, angiopathy, misc. Arterial extrinsic-compression by adjacent structures thronlbolfl~lebitis (in bacterial infections) ~relIOl.lS
phlel)othrombosis (angiopathies, coagulol)athies) Simultaneous arterial and venous-strangulatio,1, hanging I I. Nonocclusive I I)'potension. shock, temporar)' cardiac arrest Blunt trauma (contusion) to the head
585
HUMAN PATHOI.OGY-VOLUME 6, NUMBER 5 September 1975
586
Iscbemia may be defined broadly as a condition in which either the arterial supply or the venous drainage is seriously impaired. 0"1 Depending upon the duration and the mechanism of prodt,ction, several patterns of parenchymal damage may develop. Some of the mechanisms through which cerebral ischemia may be induced are listed in Table 3. Arterial occlusions ma)" be intrinsic, as in the case o f thrombi at the site of intimal abnormalities or intravascular coagulopathies. Emboli also occlude arteries intrinsically. Most cerebral emboli originate in the heart: in the left atrium, the aortic and mitral valves, and the endocardium of the left ventricle, a common source of emboli being mural thrombi at the site of a healing myocardial infarction. Another source of emboli to intracrauial arteries is atberomatous plaques in the cervical arteries and the aortic arch. Intraparenchymal arteries may be embolized by fat, air, and nmterials used in open heart surgical procedures. ~ Extrinsic occlusion o f arterial walls may resuh from swellingofthesurrounding brain or other tissues. -~5 It may also resuh fi'om the displacement of an artery against a rigid immobile structure. Such is tltought t~ be the case in uncinate herniation: the ipsilateral posterior cerebral artery is driven against the sharp edge of the tentorial notch, inducing hemorrltagic encephalomalacia in the gray nmtter of the corresponding arterial territory. Most venous intracranial occlusions are associated with bacterial infection, either systemic or localized. Noninllammatory occlusion of intracranial veins or sinuses is usually associated with coagulopathies or abnormalities in the structure o f the veins, z6 In our experience, severe slowing of the cerebral blood liow is fi'equently rellected in spontaneous and preagonal thrombosis of tlte superior sagittal sinus. Simuhaneous occlusion o f arteries and veins o f the head has been induced by placing a blood pressure cuff arotmd the neck of a rabbit, z7 A similar sequence of cerebral circulatory abnormalities probably exists in human cases of strangt!lation and banging, altlmugh the species differences in die anatomy of the craniocerebral x'asculature may make dillicuh the extrapolation o f data obtained fi'om animals. T h e cerebral circulation is seriously
impaired without either arterial or venous occlusion in severe hypotensive situations, such as those d e v e l o p i n g d u r i n g o p e n heart surgery, anesthetic accidents (including cardiac arrest), extensive myocardial infarction, massive gastrointestinal bleeding, septicemic shock, and post-traunmticshock. This form of nonocclusive ischemic injury to the brain and spinal cord is designated global central nervous system ischemia be: cause it affects simultaneously multiple areas or zones of the central nervous system, including t h e spinal . cord. 2s-3~ Blunt trauma to the head or spine presents another situation without demonstrable occlusion of arteries, or _veins in which parenchynml lesions of an ischemic type are found. T hese lesions may be purely iscbemic, purely ;iaenaolxhagic, or more commonly a combination of both.-" PATTERNS OF PARENCHYMAL DAMAGE AFTER GLOBAL ISCHEMIA
Numerot~s factors influence tile type of tissue damage that may resuli, fi'om global central nervous system ischemia: I. Body temperature. Patients in h)'pothernlic states tolerate much longer periods of ischemia owing to the reduced metabolic consumption. 2. Speed o f the ischemic event. Slowly progressive bleeding restdts in much less damage than abrupt hypotension, as in cardiac arrest or myocardial infarction. 3. Duration o f the ischemic episode. This is most diflicuh to estimate because of the indirect m a n n e r of evahmting the intracranial arterial pressure. Once abnornml circulatory situations develop, blood pressure recordings in the arms or legs probably are not a true reflection of the intracranial arterial pressure. ,t. Anatomic conditions of the craniocerebral vascular tree. A normal (that is, symmetrical) circle of Willis exists in only about 20 per cent of the population. ~ In addition to the inborn variations in the anatomy of the vessels at the base of the brain, there are several sites where there are collateral or arterial-arterial connections. These modify significantly the uhinmte effect of an ischemic episode. T h e following patterns of craniocerebral collateral chan,aels nmy be seen:
T H E N E U R O P A T I IOI+OGY OF STROKE--GARClA
a. Across nficlline connections are possible throngh the anterior communicating artery, and vertebral-carotid exchanges may occur via the posterior conmmnicating arteries. b. Blood from the external carotid circulation may enter the internal carotid territory through connections between the ophtlmlmic and the angular arteries. 'c. In the cerebral henfispheres collateral filling of the middle cerebral, posterior cerebral, and anterior cerebral arteries nmy occur via connections that these vessels possess through the so-called lel)tomeningeal or "pial" anastomoses? z d. In addition to all these extracerebral connections, end to end connections exist anaong long perforating arteries in both human and animal brains, z+ e. Age. The calibdr of the entire arterial tree, including the albrementioned anastomotic sites, undergoes constant modification through acquired diseases such as atherosclerosis and arteriolar sclerosis; both are highly asymmetrical processes.
Despite the honaogeneity of the injttr)', several studies of human and animal brains show that after global ischemia the pattern of lmren~:hymal damage is variable-multifocal, supratentorial, infi'atentorial, or spina139. 30. 34 The lleterogeneity of the parenchymal lesions probably retlectsthe variables introduced by the factors ah'eady listed. Ahhough a uniform pattern of cerebral damage resuhing from global ischemia cannot be tormttlated, it is probably accurate to state tlmt in most instances the territories at the arterial border zones are most apt to be affected.=s' as Some patterns of parenclwmal damage in both globaland regional ischemia are listed in Table. 1. The microscopic features of cells affectcd by i n vivo ischcnfia may bc overshadowed by the effects of the i)ermanent ischemia that characterizes death. Significant tfltrastrttctural changes can be detected after five minutes of absolute cerebral ischenfia at 37 ~ C. These clmnges catf be demonstrated by light microscopy following 60 to 90 minutes of delayed fixation or aotolvsis,et Moreover, the histologic appearance of cerebral tissues nlay I)C modified by the maneuvers employed in removal of the brain aGand by the use of inappropri-
ate methods for processing tissues in the histology laboratory? ~ REGIONAL
CEREBRAL
ISCHEMIA
Even when ischemia is due to arterial occlusion, the resuhing parenchymal lesion varies considerably, depending upon whether the blood flow is interrupted near the aortic arch, proximal to several collateral anastomotic sites, or beyond the major junctions for collateral circulation. Most young human adults tolerate unilateral occlusion of cervical arteries without suffering neurologic deficits.and presumably with minimal or" no parenchymal changes? 8 Slowly advancing arterial occlusion (as induced by atheronm) at the origin of the internal carotid is sometimes accompanied by cerebral changes tlmt are limited to the ipsilateral ilemispheric arterial border zone, a pattern of tissue damage that is
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587
IIUMAN PATHOLOGY--VOLUME 6, NUMBER 5 September 1975
Figure 2. Cerebellum from a chimpanzee injected with brain extracts from a patient with kuru. ~s (Fixation by perfusion, l lematoxylin and eosin stain. x 25. The material in Figures I and 2 was obtained through the courtesy o f Doctors D. C. Gajdusek, C.J. Gibbs, anti P. W. Lampert.)
designated granttlar atrophy, a9 In contrast, arterial occlusion of the distal type is accompanied by tissue changes in all or most of the territory of the respective vessel. This lesion is designated arterial infarction, since it nmy also develop after occlusion of major cerebral veins or intracranial sinnses.26, 40
588
Cerebral itffat'ction is the terminal event in a progressive dynamic injury that begins with the occlusion of a vessel. Studies in an aninml model in which a distal (middie cerebral) artery was surgically clipped throttgh an. enlarged cranial orifice suggested that the resttlting ischemic lesion evolves through four somewlmt overlap!ring states,at In the first stage ischemic injury affects a few cells within the corresponding territory. This is followed by !nicrocircttlatory alterations and changes m vascular permeability, inchtding the
escape of inflammatory cells, such as polymorphonttclear leukocytes. Healing begins with seetning capillary regeneration, reabsorption of edema fluid, and beginning of cavity formation: ~ A descriptive term for such a composite of morphologic alterations is ischemic encephalonlalacia. Prior to the arrival of mononnclear cells this is designated acute (recent) encephalomalacia. When phagocytes are the predominatlt ceils we talk of snbacute encephalomalacia, and when the lesion is mostly a cavity containing few macroptmges surrounded by reactive hyl~ertrophic astrocytes we desigbate this as chronic (old) encephalotnalacia. Since parenchymal lesions of diverse etiologies share morphologic features, the term encephalonmlacia avoids cotntnitment to a single specific etiology. Using the term infarction to describe all destructive parenchymal lesions in the central nervous system would imply a vascular occlusive etiology for all of then1, which is incorrect. 4z During the first few hours after middle cerebral artery occhtsion, only a portion of the neurons show structural evidence of irreversible injury. This is comparable to what has been described after experitnental coronary artery occlusion and in several other models of regional ischemia in the kidney, intestine, and liver: 3-4s Forty-five minutes after occlusion of a coronary artery about ,10 per cent of the myocardial fibers become irreversibly damaged, whereas after 60 tnintttes no viable myofibers remain: 6 A similar mtfltitbcal type of nerve cell involvement has been noted after occlusion of tile middle cerebral artery: ~ This phellotnenon tnay be explained on the basis of incompleteness of the ischemia (due to the plethora of collateral circulation, as demonstrated by cerebral blood flow studies): r the heterogeneous enzymatic neuronal population that confers variable sttsceptibility to many of these cells, or unknown tactors. Since the initial event in ischenaic encephalomalacia involves fluid exchanges that lead to an increase in tile volume of some cells or portions of them, the light microscopic change in this form of injury tnay be characterized as one ofvacuolation. A superficially sitnilar appearance exists in "spongiform encel~halopathies," conditions generally attributed to virttses or other transmissible agents: s Also in m eta-
T H E NEUROPATHOLOGY OF STROKE-GARctA t
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changes were limited to the n e u r o n a l perikaryon and consisted o f striking inner matrix swelling, a finding that has .been r e p o r t e d after o t h e r forms o f incomplete ischemia and following the adininistration o f ptn'omycin. 5~-53 Sucll mitochondrial changes contrast sharply with those seen in cerebral global ischemia. In the latter, flocculent densities o f inner matrix were prominent and c o m p a r a b l e to tltose r e p o r t e d in o t h e r cellular models o f global iscltemia. 5a T h e lollowing ultrastructural observations were m a d e in a model o f regional cerebral ischemia in which squirrel monkeys ( S a i m i r i s c i u r e u s ) were subjected to middle cerebral a r t e r y occhlsion via the transorbital a p p r o a c h 12 to 18 hours prior to deatlt. Controls for these studies were derived f r o m s l m m - o p e r a t e d animals.
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bolic disorders o f diverse etiology, originally n a m e d "spongy d e g e n e r a t i o n " tire light microscopic features are tliose o f vacuolation (Figs. 1, 2). 49 Figure 3 shows a sample f r o m a recently described case o f cerebral sponginess in a patient in w h o m a defect o f ganglioside anabolism was d e m o n s t r a t e d 3 ~
ULTRASTRUCTURE ISCHEMIC
IN
ENCEPIIALOMALACIA
Sl~ecimens fl'om cases o f ischenfic encephalomalacia, both global and regional, were analyzed by electron microscopy at time intervals ranging between five minutes and two Itours after the injury. 2t Significant differences between these two types o f circulatory e m b a r r a s s m e n t included the h e t e r o g e n e o u s n e u r o n a l involvement and tim earl)" selective swelling o f neuronal mitochondria that cltaracterize regional ischemia .(Fig. 4). T h e s e mitochondrial
Figure 4. Cerebral cortex from squirrel monkey with middle cerebral artery clipped 60 minutes before death induced by cardiovascular l)erfusiun with aldehydes. Note diffuse vacuolation of ncuropil and nmnerous "vesicles" in the c)'toplasm of most of the neurons shown in this figure. These represent markedly swollen mitochondria and dilated endoplasmic reticuh,m,zl (Toluidine blue stain. X 25.)
( 7"ext co, tin ued o~ page 596.) 5 8 9
![UMAN PATHOLOGY-VOI,UME
6, N U M B E R 5
September 1975
"Figure 5. Cerebral cortex fiom sham-operaled squirrel monkey; fixation by perfusion widl aldehydes. Identification of this cell as a neuron is made on tile basis of numerous synaplic contacts on I.he cell surface. (x 18,900.)
590
THE NEUROPATHOLOGY
OF STROKE--GARclA
Figure 6. Cerel)ral cortex from same animal as in Figure 5; a normal astroc)le conirl~,SlSsharply wilh tile features of the aslroc)te in Figure 8. (X __,000.)
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592
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F i g u r e 8. Cortical astrocyte f r o m same animal and arca as in Figure 7. Note tile m a r k e d v o l u m e t r i c increase and electron ]ucency o f I)otl) nucleus and c)toplasm. (• ! 8,900.)
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HUMAN PATIIOLOGY--VOLUME 6, NUMBER 5 September 1975
596
Fixation o f the brain with aldelwdes was c o n d u c t e d in vivo ttnder barbiturate anesthesia. Figures 5 and 6 ilhtstrate representative samples from the control tissue. T h e vacuolated a p p e a r a n c e o f acute ischemic encephalomalacia may be explained on the basis o f dendritic swelling, especially the postsynaptic c o m p o n e n t (Fig. 10), as rep o r t e d previously, 5s and the increased electron lucency o f a s t r o c y t e s (Fig. 8). Such changes seemingly are the result o f iota and water uptake by the c o r r e s p o n d i n g cell, wlfich occurs i n d e p e n d e n t l y o f strttctural abnornmlities in the capillary endothelium. s6 Such changes also p r e c e d e by several hours the onset o f functional capillary abnormalities d e m o n s t r a b l e t h r o u g h the use or protein t r a c e r s U Interestingly, similar synaptic and astrocytic clmnges were rep o r t e d after intracerebral ouabain injection, 5s thus pointing to the possibility that the initial effects o f regional cerebral ischemia alter directly the nettronal and glial m e m b r a n e s r a t h e r titan the capillary walls, as has been traditionally held. Althougll oligodendrocytes lmve been thouglat to be easily injured by regional ischemia, their ultrastructural features r e m a i n u n c h a n g e d long after the arterial occhtsion (Fig. 7). Mechanical obstruction o f capillary htmens by swollen astrocytes and e n d o t h e lial "blebs" was described in a model o f short term (about five minutes) strangulation; the i m p a i r m e n t o f the blood flow persisted in the strangled rabbits after release o f , t h e cervical cuff? ~ Sttch a p h e n o m e n o n was not evident in o u r model o f cerebral infarction until relatively late in the course (48 to 72 hours; Fig. 9)? 9 Moreover, the permeability o f the capillary bed in the territory o f the occhtded middle cerebral artery was tested by Kam!jyo and Garcia, G~ who injected carbon black in vivo into the cit'culation o f aninmls whose middle cerebral artery had been clipped for one to three hours. Filling o f the middle cerebral artery distal to the arterial clip o c c u r r e d in a r e t r o g r a d e faslfion tln'ough the snbaraclnmid arterial-arterial anastomosis between the a n t e r i o r and the ntiddie cerebral arteries. T h e effects o f t e m p o r a r y middle cerebral artery occlusion o n the pattern o f resulting ischemic enceplmlomalacia were studied by Kamijyo et al. 6~ T h e artery was clipped for periods o f one h o u r to t h r e e
days. Reperfusion (i.e., the tithe since clip removal) lasted f r o m o n e h o u r to eight days. In the majority o f animals in which the occhtsion was o f short d u r a t i o n and r e p e r f u s i o n lasted several days, the resulting infarctions either were smaller than in animals with p e r m a n e n t occlusion, were hemorrimgic, o r were confined to the subcortical white matter. T h e cooperative efforts o f several investigators analyzing a c o m p a r a b l e and r e p r o d u c i b l e model o f regional ischemia indt, ced tllrough the surgical occlusion o f a nfiddle cerebral artery, via the transorbital approacil, begin to reveal additional facts about cerebral blood flow changes, 4r water content, 62 leakage o f tracers, 5r ultrastructtaral featttres, 63and o t h e r features. 64,6s Better u n d e r s t a n d i n g o f the early abnormalities in the evolvement o f cerebral regiotml ischemia should lead to improved m e t h o d s o f t r e a t m e n t and a m o r e logical nosologic classification o f this c o m m o n f o r m o f injury to the central nervot,s system. ACKNOSVLEDGMENTS
Tiffs p a p e r is dedicated to Stanley *I. Aronson, f o r m e r m e n t o r , esteemed colleague, and d e a r friend. T h e a u t h o r is deeply indebted to Mrs. Debra Haines for invaluable secretarial collaboration.
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597
HUMAN PATHOLOGY-VOLUME
6, N U M B E R 5 September 1975
Special Report Series No. 300. London, t i e r Majesty's Stationary Office, 1961. -t0. Garcia, J. 1t., and Kam!jyo, Y.: Cerebral infarction. Evolution of histol,athol,,gical changes after occlusion of a middle cerebral artery in i).rimates. J. Net,ropatlL Exp. Neurol. 53:408, 197.1. 41. i ludgins, W. R.. and Garcia, J. ! I.: Tr,msorbital approach to the middle ccrcbral artery of the squirrel monkey: a technique for experimental cerebral infarction apl)licable to ultrastructural studies. Stroke, I:107, 19711. 42. Cole, F. M., and Yates, I'. O.: Intracerebral microallCttrystllS and small cerebrovascttl,lr lesions. Brain, 90:759, 1:}67. 43. Vogt, M. T., and Farber, E.: On the molecular pathology of ischerrtic renal cell death. Am. J. l'ath., 53:1, 1968. 9t-t. Robinson,J. W. I.., and Atltoniolo, J.-A.: T h e illtestinal respotlse to ischaemia, mallnyllSclmficdcbcrgs Arch. l'harm., 255:178, 1966. 9t5. (;lalla, I.., Saldana, M., l)onnellan, W. 1.., and Swenson, O.: hnmcdiate and long-term effects of act,to hepatic ischemia. II. Vascular lesions in experimental livcq" ischemia. Arch. Surg., 97:511(I, 1968. 46. Jenlfings, R. B., Baum,J. H., and tterdson, 1'. 1',.: Fine structural changes in myocardial ischemic injury. Arch. Path., 79:135, 1965. -t7. Yamaguchi, T., Waltz, A. G., and Okazaki, !I.: Hyperelnia :rod ischelnia in exl~erimental Celebral infarction: correlation of histopathology and regional blood flow. Neurology, 21:565, 1971. 9t8. I.ampert, 1'. W., Gajdusek, D. C., and Gibbs, C.J.: Sttbacute spongiform virus encephak)l):lthies. Scrapie, kuru and Creutzfeldt-lakol, disease: a review. Am. J. Path., 68:626-6t6, 1972. 9t9. Adachi. M., Schneck, L., Cara,J., and Volk, B. W.: Slmugy degel~eration o f ' t h e central llervous system (van Bogaert and Bertrand type; C,mavan's disease), tlunl:m I'ath., 4:331, 1973. 50. Tanaka, J., (;arcia,J. !1., Max, S. R., viloria,J. E., ' 9 l;,am!jyo, Y., .\lclaicn, N. K., Cornblath, M., and Brady, R. O.: Ccrcbral spongincss and (;Ms g,mgliosidosis: ultrastrt,cture and probable l,athogcnesis. J. Neurol)ath. Exp. Neurol., 34: 2-t9-262, 1975. 51. Brown, A. W., and Brierly, ,1- B.: T h e earliest ahei'atioHs in rat ilel.lrOtlS and astrocstes after anoxia-ischcmia. Acta Neurolmth., 2,~:9, 1972L 52. Shay,]., and (;o,mtas, N. K.: Electron microscopy of cat spinal cold sul,jected to circulatory a, rest and deep local hYl)othcrlni,I (15 C). Am. J. Path., 72:369, 1973.
53. Gaml~etti, !'., (;onatas, N. K., and Flexnerl I.. B.: T h e fine structure of pttrolnycin-induced changes i,l tllouse entorhinal corte.x.J. Cell Biol., 36:379, 1:)68. 54. T r u m p , B. F., I.aiho, K. U., Mergner, W.J., and Arstila, A. U.: Studies on the subeelhdar pathophysiok,gy of acute lethal cell injury. Beitr. l'ath. Anat., 152:243, 1974. 55. Garcia, J. II.: P,eversibility of'regional cerebral ischenfia. In McI)owell, F., :rod l~,rennan, R. W. (Editors): Eighth Conference, Cerebral Vascular Diseases. New "fork, (;rtme & Stratton, Inc., 197",, p. 133. 56. Garcia, J. tt., Cox, J. v., and ttudgins, W. R.: Uhr,tstructure o1" the inici'ov:tsculi~tttre in exl~erimental cercbr:d infarction. Acta Neuropath., 18:273, 1971. : 57. Olsson, Y., Crowell, R. M., and Klatzo, I.: T h e blood brain barrier to protein tracers in fi)cal cerebral ischenfia and i,lfarction caused by OCclusioll Of MCA. Acta Netnopath., 18:89, 197 I. 58. Cornog,.]. L., (,onatas, N. K:, and I:eienn,m,J. R.: Effects of imracerebral injection of otmbain on tile fine structure of rat cereb,al cortex. Am.J. Path., 51:573, 1967. 59. Crowell, R. M., and Olsson, Y.: Impaired microvascular filling after fi)cal cerebral ischemia in the monkey. Modification by treatment. Neurolog3", .99-5(10, ... 1972. 60. Kamijyo, Y., and Garcia, J. f t . : C a r o t i d arterial supply of the feline brain: applications to the study of regional cerebral ischemia. Stroke, July-August 1975. 61. Kamijyo, Y., Garcia, J. I!., and Cooper, J.: Temporary middle-cerebral-artery occlusion: a model of hemorrha,gic (and subcortical) cerebr:d infarction. Unpublished study. 62. O'Brien, M. D., Waltz, A.'G., and.Jordan, M. M.: Ischenlic cerebral edema, l)istribution of water in brains of cats after occlusioxl of the middle cerebral artery. Arch. Neurol., 30:456, 1974. ' 63. l.ittle, J. R., Kerr, F. W. I.., and Stmdt, T. 31.: Significance of neuronal :,hcr:,ti,ms in develolfing cortical ilffarction. Mayo Clin. l'roc.,-t9:827, 1974. 131. l)iChiro, G., Timills, E. l..,,]OtleS,'a. E.,JOllllStOtl, (;. S., and Ilammock, M. K.: Radionttdide
scatltling alld illicroatlgiography of'cw)lving and complcted brain infarction. Neurology,24: 9118, 197.t. 65. (;arcia, .]. I1.: Regional cerebral ischelnia. Its effects on neurons ,rod glial cells. In T r u m p , B. F., :ltld Arstila, A. U. (Editors): l'athology of Cell Membranes. New York, Academic l'rcss, Inc., 1975. l)cpartment of l'athology University of Maryland School of Medicine '2'2 S. Greene Street Bahinlore, Maryland 21201
598
Abstract Vascular-circulatory d e r a n g e m e n t s affecting the function o f the central nervous system may result in p a r e n c h y m a l lesions that are hemorrlmgic, ischenaic, or mixed. Most n o n t r a u m a t i c i n t r a p a r e n c h y m a l brain h e m o r r h a g e s are foutad in association with cerebral arteriolar sclerosis and o t h e r stigmata of hypertensive disease, such as hypertrophy o f tile left cardiac ventricle and granular kidneys. Global t e m p o r a r y ischemia, the type that exists d u r i n g severe and transient hypotension, resuhs in a wide variety o f p a r e n c h y m a l lesions that lnay be bilateral, unilateral, supra~.exltorial, or infi'atentorial. T h e cerebral and cerebellar cortices, white matter, basal ganglia, brain stem, and spinal cord may be involved simultaneously o r t h e r e may be isolated, tocal lesions that are confined occasionally to any one o f these areas. Regional ischemia, tile type induced t h r o u g h tile occlusion o f a major intracranial artery, evolves t h r o u g h a stage o f acute encephalomalacia, d u r i n g which the morl)hologic c h a n g e consists o f alternating cellular swelling and slMnkage. This is followed by leukocytic inflamnlation at three to f o u r days and tile beginning of resolution a t a b o u t the tenth day after arterial occlusion. In tim evolution o f this form o f abnormal circulation, after a few minutes, some n e u r o n s in the most distal arterial territories show tile first recognizable changes. In these ilealrons the mitochOndria swell massively. Astrocytes and lmurites in tile sante loci are selectively swollen, whereas oligodendrocytes and capillaries remain strtacturally u n c h a n g e d d u r i n g the initial stages o f ischemic injury.
A clinical diagnosis o f stroke, cerebrovascular accident, or a p o p l e x y implies a s u d d e n neurologic deficit attributable to either intracraniai bleeding or ischemic injury to the brain. T h u s , two major anatomic types o f stroke may be diffelentiilted. BLFFDING. Extralmrenchymal bleeding includes all h e m o r r h a g e s located ill the extradural, subdural, and subarachnoid spaces. Intral)arenchynml bleeding in-
cludes all h e n l o r r h a g e s located in tile cerebral hemispheres, pons, and c e r e b e l h n n . ISCIIEMIC DISTURBANCES. In a separate category are the circulatory disturbances that lead to softening of" the brain. T h e s e ischemic disturbances may or may not l)e occlusive ill origin. AIllOllg tile nonocclusive types o f ischemic encephalomalacia are p a r e n c h y m a l changes that result from severe hypotexlsion, strangulation,
*This work was SUplmrted in part by USI'tiS grants liE 11791 and NS (}6779 from the National Insfitmes of llcahh. "H'rofessor of Pathology, University of Maryland School of Medicine. I tead, Division of Nem'opathology, University of Maryland" tlospitai. Consuhant in Pathology, Veterans Administration Hospital and Union Memorial l lospital, r}ahimore, Maryland.
583
HUMAN PATHOLOGY--VOLUME 6, NUMBER 5 September 1975 T A B L E 1.
PARENCIIYMAI. LESIONS RESULTING FROM OCCLUSION o r MAJOR VESSELS
Patterns of Encephalomalacia Laminar necrosis
Hypotensive conditions
Hippocampal sclerosis
Cardiorespiratory dysflmction
Granular atrophy
Arterial occlusion (proximal)
Lacunae (cribriform state)
Arteriolar sclerosis
Subcortical encephalopathy
Arteriolar sclerosis
Contusion
Blunt trauma to the head
Infarction
Arterial (distal) or venous occlusion
and trauma. A second type of circulatory change inchtdes all parenchymal lesions that result from the occhtsion of a major vessel, whether arterial or venous (Table 1). The anatomy and etiology of hemorrhagic stroke are discussed here but summarily, but ischemic stroke is analyzed in more detail. The prevalence of situations that are diagnosed clinically as stroke is approxixnately as follows: cerebral infarction, 80 per cent; cerebral hemorrhage, 10 per cent; subarachnoid hemorrhage, 7 per cent; and miscellaneous, 3 per cent? HEMORRHAGIC
584
Etiologic Conditions
STROKE
Hemorrhage in the extradural (epidural) and subdural spaces of tile head and spine is most often related to nlechanical injuries to tile head or spine or to trauma distant from such areas. ~ Subarachnoid hemorrhage that is not traumatic in origin develops secondarily to rupture of anomalous arteries such as aneur)'sms or arteriovenous ntalformations, extension from an intraparenchynlal hemorrhage, or coagulopathies?" 4 Bleeding into the substance of the brain is designated herein as intraparenchymal brain hemorrhage, since such bleeding occurs not only in the cerebral hemispheres but also in the cerebellum and pons. Muhiple small petechiae in the cerebral parenchyma are encompassed under the heading of brain purpura, a condition associated with causative pllenomena that inchtde fat embolism, viral
encephalitides, allergic encep|lalomyelitis, and blood dyscrasias.3"5 Large, usually single, areas of intraparenchymal brain hemorrhage call be the result of either bhmt or penetrating trauma to the head. In young adults it is not uncoinlnon to encounter large collections of blood in tile brain parencbyma unaccompanied by noticeable hemorrhage in tile overlying scalp, skull;or meninges.oThe majority of spontaneous episodes of intraparenchymal brain hemorrhage occur in patients with anatomic evidence of hypertensive disease, snch as hypertrophy of the left ventricle, granular kidneys, and arteriolar sclerosis3 -s Ahhottgh the site of origin of parenchymal hemorrhages in hypertensive patients may be the cerebral hemispheres (85 per cent), cerebellum (10 per cent), or pons (5 per cent), in most publications they are collectively designated intracerebral or cerebral hemorrhages. ~, ,0 In addition to hypertensive arteriolar sclerosis, major nontraumatic episodes of intraparenchynlal brain hemorrhage may be associated with intracerebral saccular aneurysms or other vascular nlalformations, coagulopathies (especially in leukemic patients), and rarely with intraparenchymal primary or metastatic neoplasms) H3 A special lbrm ofintraventricular and imraparenchynlal hemorrhage is seen in newborns: most of these hemorrhages presumably are associated with inamaturity and systemic disturbances such as hypoxemia and electrolyte imbalance. H Intraparenchymal brain hemorrhage ~on-
T I l E N E U R O P A T H O I . O G Y O F S T R O K E - GARCIA T A B L E 2. CONDITIONS ASSOCIATED WITH LARGE IN'rRAPARENCI.IYMALBRAIN HEMORRIIAGE Arteriolar sclerosis usually of hypertensive origin Trauma to the head Aneurysms, arteriovenous malformations Coagulopathies (leukenfia in particular) Intracerebral neoplasms Perinatal conditions: immaturit)', metabolic disturbances Venotls occlusioII
volves both the carotid arteries in the neck and the coronary arteries) s Occasionally a brain harbors h e m o r r h a g e s (secondary to hypertensive arteriolar sclerosis), ischenaic lesions (secondary to atherosclerotic disease of the cervical carotid vessels) complicated by global ischemia (secondary to myocardial infarction or cardiac dysrhytlanfias), as well as emboli originating in the left cardiac atritun. As is discussed, in examining a btunan brain the morphologist Inust also contend with the effects of autol)'sis (as deterlnined by the death-fixation interval) and the undesirable alterations induced by i m p r o p e r methods of removal or histological processing of the brain.
fitted to the upper brainstem is most often the result of uncinate herniation (Table
MECHANISMS OF CEREBRAL ISCHEMIA
2). t5
In some hypertensive patients cerebral arteriolar sclerosis may nmnifest itself not otdy in the form of naassive intraparenchymal bleeding or stroke, but also as a slowly progressive encepltalopathy in which brain tissue changes of an ischemic type are confined primarily to the centrum ovale.tG, ,r T h e interpretation o f cerebral lesions having a circulatory origin can be difficult in a given specimen if hemorrhagic and ischemic lesions of different ages are present simultaneousl)'. It is well established that patients with Iwpertension and arteriolar sclerosis are susceptible to an accelerated course of atheromatous disease that in-
T A B L E 3.
Within a well known range of blood pressure changes, the cerebral blood flow is maintained constant tln'ough a mechanism of autoregulation, t9 At 37 ~ C. parencbymal changes may occur in the brain whenever the systolic blood pressure falls below 60 to 70 nnn. o f mercury. These figures apply to normotensive sugiects; loss of autoregulation in a chronic hypertensive patient may occur at much higher readings. ~176 T h e effects o f abnormal circulation on the brain parencbyma vary, depending upon whether the prevailing conditions are those o f ischemia (oligemia), hyperetnia (congestion), or hentorrhage.
MECtlANIS.XISOV CEREBRAL ISCtlEMIA
I. Occlusive t h r o m b u s - axlgiol)athy, coagulopath)' iiltrinsic embolus-endocardial, angiopathy, misc. Arterial extrinsic-compression by adjacent structures thronlbolfl~lebitis (in bacterial infections) ~relIOl.lS
phlel)othrombosis (angiopathies, coagulol)athies) Simultaneous arterial and venous-strangulatio,1, hanging I I. Nonocclusive I I)'potension. shock, temporar)' cardiac arrest Blunt trauma (contusion) to the head
585
HUMAN PATHOI.OGY-VOLUME 6, NUMBER 5 September 1975
586
Iscbemia may be defined broadly as a condition in which either the arterial supply or the venous drainage is seriously impaired. 0"1 Depending upon the duration and the mechanism of prodt,ction, several patterns of parenchymal damage may develop. Some of the mechanisms through which cerebral ischemia may be induced are listed in Table 3. Arterial occlusions ma)" be intrinsic, as in the case o f thrombi at the site of intimal abnormalities or intravascular coagulopathies. Emboli also occlude arteries intrinsically. Most cerebral emboli originate in the heart: in the left atrium, the aortic and mitral valves, and the endocardium of the left ventricle, a common source of emboli being mural thrombi at the site of a healing myocardial infarction. Another source of emboli to intracrauial arteries is atberomatous plaques in the cervical arteries and the aortic arch. Intraparenchymal arteries may be embolized by fat, air, and nmterials used in open heart surgical procedures. ~ Extrinsic occlusion o f arterial walls may resuh from swellingofthesurrounding brain or other tissues. -~5 It may also resuh fi'om the displacement of an artery against a rigid immobile structure. Such is tltought t~ be the case in uncinate herniation: the ipsilateral posterior cerebral artery is driven against the sharp edge of the tentorial notch, inducing hemorrltagic encephalomalacia in the gray nmtter of the corresponding arterial territory. Most venous intracranial occlusions are associated with bacterial infection, either systemic or localized. Noninllammatory occlusion of intracranial veins or sinuses is usually associated with coagulopathies or abnormalities in the structure o f the veins, z6 In our experience, severe slowing of the cerebral blood liow is fi'equently rellected in spontaneous and preagonal thrombosis of tlte superior sagittal sinus. Simuhaneous occlusion o f arteries and veins o f the head has been induced by placing a blood pressure cuff arotmd the neck of a rabbit, z7 A similar sequence of cerebral circulatory abnormalities probably exists in human cases of strangt!lation and banging, altlmugh the species differences in die anatomy of the craniocerebral x'asculature may make dillicuh the extrapolation o f data obtained fi'om animals. T h e cerebral circulation is seriously
impaired without either arterial or venous occlusion in severe hypotensive situations, such as those d e v e l o p i n g d u r i n g o p e n heart surgery, anesthetic accidents (including cardiac arrest), extensive myocardial infarction, massive gastrointestinal bleeding, septicemic shock, and post-traunmticshock. This form of nonocclusive ischemic injury to the brain and spinal cord is designated global central nervous system ischemia be: cause it affects simultaneously multiple areas or zones of the central nervous system, including t h e spinal . cord. 2s-3~ Blunt trauma to the head or spine presents another situation without demonstrable occlusion of arteries, or _veins in which parenchynml lesions of an ischemic type are found. T hese lesions may be purely iscbemic, purely ;iaenaolxhagic, or more commonly a combination of both.-" PATTERNS OF PARENCHYMAL DAMAGE AFTER GLOBAL ISCHEMIA
Numerot~s factors influence tile type of tissue damage that may resuli, fi'om global central nervous system ischemia: I. Body temperature. Patients in h)'pothernlic states tolerate much longer periods of ischemia owing to the reduced metabolic consumption. 2. Speed o f the ischemic event. Slowly progressive bleeding restdts in much less damage than abrupt hypotension, as in cardiac arrest or myocardial infarction. 3. Duration o f the ischemic episode. This is most diflicuh to estimate because of the indirect m a n n e r of evahmting the intracranial arterial pressure. Once abnornml circulatory situations develop, blood pressure recordings in the arms or legs probably are not a true reflection of the intracranial arterial pressure. ,t. Anatomic conditions of the craniocerebral vascular tree. A normal (that is, symmetrical) circle of Willis exists in only about 20 per cent of the population. ~ In addition to the inborn variations in the anatomy of the vessels at the base of the brain, there are several sites where there are collateral or arterial-arterial connections. These modify significantly the uhinmte effect of an ischemic episode. T h e following patterns of craniocerebral collateral chan,aels nmy be seen:
T H E N E U R O P A T I IOI+OGY OF STROKE--GARClA
a. Across nficlline connections are possible throngh the anterior communicating artery, and vertebral-carotid exchanges may occur via the posterior conmmnicating arteries. b. Blood from the external carotid circulation may enter the internal carotid territory through connections between the ophtlmlmic and the angular arteries. 'c. In the cerebral henfispheres collateral filling of the middle cerebral, posterior cerebral, and anterior cerebral arteries nmy occur via connections that these vessels possess through the so-called lel)tomeningeal or "pial" anastomoses? z d. In addition to all these extracerebral connections, end to end connections exist anaong long perforating arteries in both human and animal brains, z+ e. Age. The calibdr of the entire arterial tree, including the albrementioned anastomotic sites, undergoes constant modification through acquired diseases such as atherosclerosis and arteriolar sclerosis; both are highly asymmetrical processes.
Despite the honaogeneity of the injttr)', several studies of human and animal brains show that after global ischemia the pattern of lmren~:hymal damage is variable-multifocal, supratentorial, infi'atentorial, or spina139. 30. 34 The lleterogeneity of the parenchymal lesions probably retlectsthe variables introduced by the factors ah'eady listed. Ahhough a uniform pattern of cerebral damage resuhing from global ischemia cannot be tormttlated, it is probably accurate to state tlmt in most instances the territories at the arterial border zones are most apt to be affected.=s' as Some patterns of parenclwmal damage in both globaland regional ischemia are listed in Table. 1. The microscopic features of cells affectcd by i n vivo ischcnfia may bc overshadowed by the effects of the i)ermanent ischemia that characterizes death. Significant tfltrastrttctural changes can be detected after five minutes of absolute cerebral ischenfia at 37 ~ C. These clmnges catf be demonstrated by light microscopy following 60 to 90 minutes of delayed fixation or aotolvsis,et Moreover, the histologic appearance of cerebral tissues nlay I)C modified by the maneuvers employed in removal of the brain aGand by the use of inappropri-
ate methods for processing tissues in the histology laboratory? ~ REGIONAL
CEREBRAL
ISCHEMIA
Even when ischemia is due to arterial occlusion, the resuhing parenchymal lesion varies considerably, depending upon whether the blood flow is interrupted near the aortic arch, proximal to several collateral anastomotic sites, or beyond the major junctions for collateral circulation. Most young human adults tolerate unilateral occlusion of cervical arteries without suffering neurologic deficits.and presumably with minimal or" no parenchymal changes? 8 Slowly advancing arterial occlusion (as induced by atheronm) at the origin of the internal carotid is sometimes accompanied by cerebral changes tlmt are limited to the ipsilateral ilemispheric arterial border zone, a pattern of tissue damage that is
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587
IIUMAN PATHOLOGY--VOLUME 6, NUMBER 5 September 1975
Figure 2. Cerebellum from a chimpanzee injected with brain extracts from a patient with kuru. ~s (Fixation by perfusion, l lematoxylin and eosin stain. x 25. The material in Figures I and 2 was obtained through the courtesy o f Doctors D. C. Gajdusek, C.J. Gibbs, anti P. W. Lampert.)
designated granttlar atrophy, a9 In contrast, arterial occlusion of the distal type is accompanied by tissue changes in all or most of the territory of the respective vessel. This lesion is designated arterial infarction, since it nmy also develop after occlusion of major cerebral veins or intracranial sinnses.26, 40
588
Cerebral itffat'ction is the terminal event in a progressive dynamic injury that begins with the occlusion of a vessel. Studies in an aninml model in which a distal (middie cerebral) artery was surgically clipped throttgh an. enlarged cranial orifice suggested that the resttlting ischemic lesion evolves through four somewlmt overlap!ring states,at In the first stage ischemic injury affects a few cells within the corresponding territory. This is followed by !nicrocircttlatory alterations and changes m vascular permeability, inchtding the
escape of inflammatory cells, such as polymorphonttclear leukocytes. Healing begins with seetning capillary regeneration, reabsorption of edema fluid, and beginning of cavity formation: ~ A descriptive term for such a composite of morphologic alterations is ischemic encephalonlalacia. Prior to the arrival of mononnclear cells this is designated acute (recent) encephalomalacia. When phagocytes are the predominatlt ceils we talk of snbacute encephalomalacia, and when the lesion is mostly a cavity containing few macroptmges surrounded by reactive hyl~ertrophic astrocytes we desigbate this as chronic (old) encephalotnalacia. Since parenchymal lesions of diverse etiologies share morphologic features, the term encephalonmlacia avoids cotntnitment to a single specific etiology. Using the term infarction to describe all destructive parenchymal lesions in the central nervous system would imply a vascular occlusive etiology for all of then1, which is incorrect. 4z During the first few hours after middle cerebral artery occhtsion, only a portion of the neurons show structural evidence of irreversible injury. This is comparable to what has been described after experitnental coronary artery occlusion and in several other models of regional ischemia in the kidney, intestine, and liver: 3-4s Forty-five minutes after occlusion of a coronary artery about ,10 per cent of the myocardial fibers become irreversibly damaged, whereas after 60 tnintttes no viable myofibers remain: 6 A similar mtfltitbcal type of nerve cell involvement has been noted after occlusion of tile middle cerebral artery: ~ This phellotnenon tnay be explained on the basis of incompleteness of the ischemia (due to the plethora of collateral circulation, as demonstrated by cerebral blood flow studies): r the heterogeneous enzymatic neuronal population that confers variable sttsceptibility to many of these cells, or unknown tactors. Since the initial event in ischenaic encephalomalacia involves fluid exchanges that lead to an increase in tile volume of some cells or portions of them, the light microscopic change in this form of injury tnay be characterized as one ofvacuolation. A superficially sitnilar appearance exists in "spongiform encel~halopathies," conditions generally attributed to virttses or other transmissible agents: s Also in m eta-
T H E NEUROPATHOLOGY OF STROKE-GARctA t
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bolic disorders o f diverse etiology, originally n a m e d "spongy d e g e n e r a t i o n " tire light microscopic features are tliose o f vacuolation (Figs. 1, 2). 49 Figure 3 shows a sample f r o m a recently described case o f cerebral sponginess in a patient in w h o m a defect o f ganglioside anabolism was d e m o n s t r a t e d 3 ~
ULTRASTRUCTURE ISCHEMIC
IN
ENCEPIIALOMALACIA
Sl~ecimens fl'om cases o f ischenfic encephalomalacia, both global and regional, were analyzed by electron microscopy at time intervals ranging between five minutes and two Itours after the injury. 2t Significant differences between these two types o f circulatory e m b a r r a s s m e n t included the h e t e r o g e n e o u s n e u r o n a l involvement and tim earl)" selective swelling o f neuronal mitochondria that cltaracterize regional ischemia .(Fig. 4). T h e s e mitochondrial
Figure 4. Cerebral cortex from squirrel monkey with middle cerebral artery clipped 60 minutes before death induced by cardiovascular l)erfusiun with aldehydes. Note diffuse vacuolation of ncuropil and nmnerous "vesicles" in the c)'toplasm of most of the neurons shown in this figure. These represent markedly swollen mitochondria and dilated endoplasmic reticuh,m,zl (Toluidine blue stain. X 25.)
( 7"ext co, tin ued o~ page 596.) 5 8 9
![UMAN PATHOLOGY-VOI,UME
6, N U M B E R 5
September 1975
"Figure 5. Cerebral cortex fiom sham-operaled squirrel monkey; fixation by perfusion widl aldehydes. Identification of this cell as a neuron is made on tile basis of numerous synaplic contacts on I.he cell surface. (x 18,900.)
590
THE NEUROPATHOLOGY
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Figure 6. Cerel)ral cortex from same animal as in Figure 5; a normal astroc)le conirl~,SlSsharply wilh tile features of the aslroc)te in Figure 8. (X __,000.)
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HUMAN PATIIOLOGY--VOLUME 6, NUMBER 5 September 1975
596
Fixation o f the brain with aldelwdes was c o n d u c t e d in vivo ttnder barbiturate anesthesia. Figures 5 and 6 ilhtstrate representative samples from the control tissue. T h e vacuolated a p p e a r a n c e o f acute ischemic encephalomalacia may be explained on the basis o f dendritic swelling, especially the postsynaptic c o m p o n e n t (Fig. 10), as rep o r t e d previously, 5s and the increased electron lucency o f a s t r o c y t e s (Fig. 8). Such changes seemingly are the result o f iota and water uptake by the c o r r e s p o n d i n g cell, wlfich occurs i n d e p e n d e n t l y o f strttctural abnornmlities in the capillary endothelium. s6 Such changes also p r e c e d e by several hours the onset o f functional capillary abnormalities d e m o n s t r a b l e t h r o u g h the use or protein t r a c e r s U Interestingly, similar synaptic and astrocytic clmnges were rep o r t e d after intracerebral ouabain injection, 5s thus pointing to the possibility that the initial effects o f regional cerebral ischemia alter directly the nettronal and glial m e m b r a n e s r a t h e r titan the capillary walls, as has been traditionally held. Althougll oligodendrocytes lmve been thouglat to be easily injured by regional ischemia, their ultrastructural features r e m a i n u n c h a n g e d long after the arterial occhtsion (Fig. 7). Mechanical obstruction o f capillary htmens by swollen astrocytes and e n d o t h e lial "blebs" was described in a model o f short term (about five minutes) strangulation; the i m p a i r m e n t o f the blood flow persisted in the strangled rabbits after release o f , t h e cervical cuff? ~ Sttch a p h e n o m e n o n was not evident in o u r model o f cerebral infarction until relatively late in the course (48 to 72 hours; Fig. 9)? 9 Moreover, the permeability o f the capillary bed in the territory o f the occhtded middle cerebral artery was tested by Kam!jyo and Garcia, G~ who injected carbon black in vivo into the cit'culation o f aninmls whose middle cerebral artery had been clipped for one to three hours. Filling o f the middle cerebral artery distal to the arterial clip o c c u r r e d in a r e t r o g r a d e faslfion tln'ough the snbaraclnmid arterial-arterial anastomosis between the a n t e r i o r and the ntiddie cerebral arteries. T h e effects o f t e m p o r a r y middle cerebral artery occlusion o n the pattern o f resulting ischemic enceplmlomalacia were studied by Kamijyo et al. 6~ T h e artery was clipped for periods o f one h o u r to t h r e e
days. Reperfusion (i.e., the tithe since clip removal) lasted f r o m o n e h o u r to eight days. In the majority o f animals in which the occhtsion was o f short d u r a t i o n and r e p e r f u s i o n lasted several days, the resulting infarctions either were smaller than in animals with p e r m a n e n t occlusion, were hemorrimgic, o r were confined to the subcortical white matter. T h e cooperative efforts o f several investigators analyzing a c o m p a r a b l e and r e p r o d u c i b l e model o f regional ischemia indt, ced tllrough the surgical occlusion o f a nfiddle cerebral artery, via the transorbital approacil, begin to reveal additional facts about cerebral blood flow changes, 4r water content, 62 leakage o f tracers, 5r ultrastructtaral featttres, 63and o t h e r features. 64,6s Better u n d e r s t a n d i n g o f the early abnormalities in the evolvement o f cerebral regiotml ischemia should lead to improved m e t h o d s o f t r e a t m e n t and a m o r e logical nosologic classification o f this c o m m o n f o r m o f injury to the central nervot,s system. ACKNOSVLEDGMENTS
Tiffs p a p e r is dedicated to Stanley *I. Aronson, f o r m e r m e n t o r , esteemed colleague, and d e a r friend. T h e a u t h o r is deeply indebted to Mrs. Debra Haines for invaluable secretarial collaboration.
REFERENCES
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