Cerebral Apoplexy (Stroke): Pathogenesis, Pathophysiology ...stroke.ahajournals.org/content/strokeaha/2/4/327.full.pdf · Cerebral Apoplexy (Stroke): Pathogenesis, Pathophysiology

Cerebral Apoplexy (Stroke):Pathogenesis, Pathophysiology andTherapy as Illustrated by RegionalBlood Flow Measurements in the BrainBY OLAF B. PAULSON, M.D.

Abstract:CerebralApoplexy(Stroke):Pathogenesis,Patho-physiologyand Therapyas Illustratedby RegionalBlood FlowMeasurementsin the Brain

• Pathophysiological and pathogenetic concepts, particularly in occlusivecerebrovascular disease, are reviewed and discussed with emphasis on the resultsof current research. Therapy is discussed in the context of these concepts.

When focal ischemia, with or without cerebral infarction, is not associatedwith definable arterial occlusion, studies of regional cerebral blood flow stronglysupport the thromboembolic theory; the arterial defect is relatively transientand is caused by an embolus or thrombus which rapidly disappears (fragmentsor is lysed). The treatment of transient ischemic attacks by the administrationof anticoagulant or surgical reconstruction of the appropriate artery is discussed.

When cerebral infarction is caused by arterial occlusion there is vasomotorparalysis (loss of autoregulation and of reactivity to carbon dioxide). In someinstances hypercapnia apparently causes only the vessels in nonaffected brainto dilate so that an increased amount of blood streams to these parts whileblood pressure falls in collaterals leading to the focus and blood flow to theinfarct is decreased (steal syndrome). If blood flow is decreased to nonaffectedbrain, by vasoconstriction caused by hyperventilation, increased amounts ofblood may be shunted into the infarct (reverse steal) where autoregulation islost. Vasoconstriction, as a treatment, might be beneficial. However, in patientswith severe cerebral infarction no convincing favorable affect has been noted.The potential therapeutic action of hyperventilation in patients with mildcerebral infarction has not been studied.

Extensive (global) changes in the cerebral blood flow in cerebral infarc-tion, certain aspects of intracerebral hemorrhage, and the role of hypertensionin cerebrovascular disease are also dealt with.

ADDITIONAL KEY WORDScerebral infarctionthromboembolic events

hypertensiontransient ischemic attacks

hypercapniahypocapnia

Tentative Division of Stroke• By cerebral apoplexy (stroke) is understoodthe acute occurrence of neurological symptomscaused by a vascular lesion in the brain, thebrain stem or the cerebellum. Not included aresubarachnoid bleedings and bleedings in tu-

From the Department of Neurology and theDepartment of Clinical Physiology, Bispebjerg Hos-pital, Bispebjerg Bakke 23, DK 2400, CopenhagenNV, Denmark.

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mors, nor the subdural or epidural hematomasthat most often are conditioned by traumas.Hemiparesis will be the most frequent neuro-logical symptom in cerebral apoplexy, butother symptoms are also seen, for instance,aphasia, hemianopia and sensibility distur-bances.

When employing this definition, cerebro-vascular diseases consist of two main groups:intracerebral hematoma and cerebral ischemiclesions.1 As it will appear later in this article,

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these two groups apparently present enoughpathogenic differences for them to be consid-ered two different diseases. It is especially thelatter group that shall be dealt with here. Froma clinical point of view, the two groups ofstroke have many symptoms in common, and itis sometimes not possible to make a clinicaldistinction between them.2'3

Various divisions of cerebral apoplexyhave been attempted. Millikan, Siekert andWhisnant4 have made a clinical temporaldivision of stroke into "completed stroke,""advancing stroke," "incipient or impendingstroke," and "completed stroke with evidenceof further activity of the cerebral ischemicprocess." The latter group is actually only acombination of the first and the third group. Asubsequent, modified division, therefore, con-tains only three groups as follows: "completedstroke," "stroke in evolution," and "transientischemic attacks."s' 6 A completed stroke refersto a relatively stable neurological deficit;that is, little or no change in the deficitis occurring. Severe cases with massive acutesymptoms followed by some progression andpossibly death are, however, also included forpractical reasons. A stroke in evolution refersto a patient whose neurological deficit isactively worsening during the period ofobservation. This aggravation of the conditionmay take place by steps over a period ofseveral hours, or there may be smooth,continuous, progressive worsening of thecondition. By transient ischemic attacks areunderstood attacks with focal neurologicalsymptoms followed by complete remissionwithin 24 hours.

This temporal classification is purelydescriptive and does not consider the patho-genesis of the attacks.

One reason for making strokes in evolu-tion an independent group was the possibilitythat they were caused by progressive thrombo-sis of an extracranial or intracranial artery, andthat the progression of the condition might bestopped by anticoagulation treatment. Thepathogenesis of stroke in evolution is, however,uncertain. A possible cause is progressiveartery stenosis. Other possibilities are arecurrent embolism7 or an increasing intrace-rebral edema in or around an infarct with aresultant distortion of the surrounding tissue,8

or a progressing intracerebral hematoma.The dissociation into an independent

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group of attacks with complete remission of thesymptoms within 24 hours—the transientischemic attacks—is rather artificial, as thevarious degrees of cerebral infarction mergegradually into each other, from the mildattacks with remission within a few minutes orhours, to attacks with remission within days, toattacks with moderate or severe sequelae, andto fatal attacks. Nor are there any grounds forassuming that the pathogenesis of transientischemic attacks should differ from that ofcerebral infarction proper.

However, it is practical to continue todenote these cases of apoplexy (transientischemic attacks) because, from a clinicalpoint of view, they differ essentially from thesevere cases with permanent symptoms. Thetreatment of transient ischemic attacks willalso differ in that it obviously will be solelyprophylactic.

A traditional, more etiological division ofapoplexy has been attempted with the aim of adifferentiation between intracerebral hemato-mas, thromboses, and embolism. Large hema-tomas often are recognizable clinically; how-ever, it is far more difficult to distinguishbetween minor hematomas and the varioustypes of thromboembolism, especially so ifangiography has not been done. The differenti-ation between thromboses and embolism isuncertain, and the practice most often has beenthat cases of stroke with auricular fibrillation,mitral stenosis, or the like have been classifiedas embolism, and the other cases as thrombo-ses. It is obvious that a great many thrombosesthus defined may easily be embolisms and thatsome cases of embolism conversely may bethromboses.

From an angiographical and pathoana-tomical point of view, most strokes can bedivided into intracerebral hematomas andcerebral ischemic lesions (cerebral infarction).The latter group can be subdivided into onegroup in which an arterial occlusion isdemonstrable and another in which no arterialocclusion is demonstrable. In some ischemiclesions, the cerebral artery occluded may be sosmall that the occlusion is not demonstrable,whereby the stroke will be classified asnonocclusive in spite of the arterial occlusion.However, such cases will probably make uponly a minor part of the nonocclusive cases(see below).

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CEREBRAL APOPLEXY (STROKE)

If the ischemia is sufficient, infarctionresults. Infarcts are divided into white (is-chemic) and red (hemorrhagic) types by pathol-ogists. The red areas are often found in onlypart of the infarct. It must be assumed that thehemorrhagic infarcts occur in regions wherethe blood supply has been re-established (shiftor disappearance of an occlusion). In manycases the hemorrhagic infarcts result in aslightly hemorrhagic cerebrospinal fluid.

Pathogenesis of CerebralInfarctionISCHEMIC LESIONS WITH ARTERIAL OCCLUSION

In patients in whom an arterial occlusion hasbeen demonstrated, the cause of the ischemiclesion may be either an embolus or a thrombus.The two causes cannot be distinguished insome individual cases. The embolic cases arepresumably rather frequent, as they most oftenmust be supposed to originate from theextracranial neck vessels and not from theheart. This will be further discussed under thethromboembolic theory. The most reasonabledesignation thus would be thromboembolicocclusions.

ISCHEMIC LESIONS WITHOUT ARTERIAL OCCLUSION

It is characteristic of this group of strokes that,at the time of examination, it is not possible todemonstrate any direct cause of the often verypronounced neurological symptoms. From aclinical temporal point of view, the groupcomprises all the varieties of cerebrovascularattacks from slight transient ischemic attackswith rapid remission to the most severe casesof cerebral infarction. Several theories havebeen advanced about the cause of the lesion instroke without arterial occlusion: (1) thevasospasm theory, (2) the hemodynamictheory (systemic hypotension), and (3) thethromboembolic theory. These three theoriesas well as other rare causes will be discussedbelow.

The Vajo»posm Theory

According to this theory, the stroke is causedby a spasm in a cerebral or extracranial arteryresulting in cerebral ischemia.9"14 The theory,which was predominant for a long time, waslater severely criticized by Pickering15 andDenny-Brown,10 and is now almost abandoned.While vasospasm may occur after strongmechanical irritation, or with subarachnoidhemorrhage, there are no experimental findings

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nor any other grounds for assuming thatvasospasms frequently cause cerebral infarc-tion. Moreover, angiographical examinationshave not disclosed any cases with vasospasms,which are often seen in the case of subarach-noid hemorrhage.3'17'18 So, vasospasms cannotbe considered a pathogenic mechanism ofapoplexy without arterial occlusion.

Vasospasm is often mentioned as apathogenic factor in hypertensive encephalopa-thy. However, even in this disorder thepathogenic significance of vasospasms can bequestioned.

In arterial hypertension, a change incaliber occurs in the arteries of the retina, andtreatment of the hypertension makes thischange regress. In chronic renal hyperten-sion, a reversible change in caliber ("spasms")of the pial arteries and arterioles has beendemonstrated experimentally in rats16 and inmonkeys and cats.20 At a subsequent investiga-tion of chronic, medicamentary hypertension inmice, however, no change was found in the cali-ber of the pial arteries and arterioles.21 In con-trast to what was found in the first-mentionedinvestigations, neurological symptoms did notdevelop in the mice, although cerebral edemadid develop. In another study on acute hyper-tension in cats and monkeys, no change in cali-ber was found in the pial vessels.22 On the otherhand, an investigation of the mesenteric arteriesof the rat showed a change in caliber during theacute phase of the hypertension.28-24

However, whether this change in caliber istantamount to spasms has not been proved. Aspasm must be characterized by a pronouncedcontraction so that the blood flow distal to thespasm is reduced below normal, resulting in amore or less pronounced tissue hypoxia. Thechange in caliber in the arteries may be dueonly to a combination of the normal autoregu-lation and degenerative changes in some arterysegments. Deposits of plasma proteins in thevascular wall have been demonstrated inexperimental examinations of arterial hyper-tension,23"20 and these degenerative changeswere found to be localized to the dilatedarterial segments.23-24 The contracted seg-ments, then, may be only less degeneratedvascular segments, contracted in order torestrain the blood circulation to normal values.Also, an inhomogeneous distribution in thevessels of the contractile elements might

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explain, to some extent, the segmental contrac-tion.27 Two theories have been advancedabout hypertensive encephalopathy: (1) it iscaused by vasospasms with a resultantischemia,19'27-28 and (2) it is caused bycerebral edema and perivascular hemorrhageowing to failing autoregulation under the highblood pressure.29-31 Based upon the above, itis reasonable to consider the second theory themore probable one.

The Hemodynomle Theory (Transient Sytremk Hyporemlon)

This theory was originally advanced by Denny-Brown as an alternative to the vasospasmtheory.10 According to the theory, there existsin the brain a focal region with marginal bloodsupply resulting from a stenosis in an artery. Afall in the arterial blood pressure will result ina decrease in the blood flow through the focalregion, thereby causing a focal cerebralischemic lesion.8.1(I'1T- 32-Sfl Denny-Brown32 as-sumed that hemodynamic crises (transientsystemic hypotension) were the cause ofapproximately 80% of the transient ischemicattacks. Ziilch87 and Romanul and Abramo-wicz38 believed that the infarcts occurred inmost peripheral parts of the region supplied bythe arteries, as the diffuse arteriosclerosis hereaffected the blood flow most. The infarcts,therefore, should occur where the supplyregions of two major arteries bordered, by whatZiilch called "Die letzte Wiese," and Romanuland Abramowicz called "watershed infarction."

Thompson and Smith40 and Denny-Brownand Meyer41 observed that if the arterial bloodpressure was reduced in monkeys, infarctsoccurred on ligation of the middle cerebralartery. In these experiments infarcts did notdevelop if the blood pressure was kept normal.In patients who had had several transientischemic attacks, a lowering of the bloodpressure by not more than 20% to 30%produced distinct EEG changes.42 In a laterinvestigation with a slower blood pressuredecrease, EEG changes were observed in onlythree of 39 patients, and the changes were notparticularly pronounced.43

In indirect support of the hemodynamictheory (transient systemic hypotension), it hasbeen held that an increased occurrence ofstenoses due to atherosclerosis has been found

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in the carotid and vertebral arteries at autopsyin patients with stroke.44-48 Similar findingswere made in the intracerebral vessels.49- ^However, patients with such vascular changeswere often symptom-free, and in one of thereports this was true in more than 50% of thepatients.40 Radiological examinations have alsoshown that the stenosing processes were oftenmultiple and located in several of the ves-sels.51"64 However, in another study there werealmost as many angiographical arterioscleroticchanges in a control group as in patients withcerebrovascular diseases.65 As an origin ofdistal emboli, these lesions may just as well besaid to support the thromboembolic theory(see below). Drake and Drake64 noted that inpatients with transient ischemic attacks, thedegree of stenosis in the neck vessels was oftenless than 40% of lumen, which means that thestenosis was insignificant from a hemodynamicpoint of view. Only in a few exceptional caseshas it been possible to produce transientischemic attacks by lowering the blood pres-sure. Kendell and Marshall60 examined 37patients with transient ischemic attacks andarterial hypertension. While the patients werelying on a tilt table, the arterial blood pressurewas lowered until there were signs of focalcerebral ischemia (transient ischemic attack)or global cerebral ischemia (incipient syn-cope). The signs of focal ischemia precededthose of global ischemia in only one of the 37patients.

From a clinical point of view, there is nostrong evidence either that suggests thatcerebral infarction commonly occurs in con-nection with a fall in blood pressure. Cerebralinfarction occurring during sleep has beenexplained by a decrease in blood pressure.18' 32~84, so, an A subsequent large clinical study,however, demonstrated no connection betweena fall in blood pressure and the occurrence ofcerebral infarction.04 Furthermore, in a fewpatients with transient ischemic attacks, it hasbeen possible to measure the blood pressure atthe beginning of the attack, and it was found tobe increased.r>7~5"

Regional cerebral blood flow examina-tions have further weakened the theory thathemodynamic changes are a frequent cause ofapoplexy without arterial occlusion. Only two

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patients in a series of 44* were found to havechanges in the regional cerebral blood flowthat might indicate chronic affection of thecerebral vasomotor function possibly lead-ing to a fall of the regional cerebral bloodflow during a decrease in systemic bloodpressure. In one of them there was a regionwhere the cerebral vessels could not be furtherdilated, but where contraction was possible;90

in another patient, the autoregulation waschronically slightly affected.61" Regional cere-bral blood flow determinations during the acutephase of the cerebral infarction (within the firstfew days) often disclose hyperemic foci inpatients without arterial occlusion.60 Thisfinding also makes the hemodynamic theoryunlikely, as hyperemia in these regions suggeststhat the cerebral vessels cannot have beenmaximally dilated in the resting condition, andthat only a very great fall in blood pressure,therefore, could have produced the ischemiclesion. The hemodynamic theory also seems tobe strongly disfavored in a recently completedstudy of regional cerebral blood flow measure-ments during 21 operations for carotid stenosisin patients with previous cerebrovascularsymptoms.61b The blood pressure gradient overthe carotid stenosis was only small in thesepatients. During clamping of the carotid artery,the blood pressure in the distal part of theartery fell in all the cases, but in most of themthe cerebral blood flow was either unchangedor showed only a moderate fall. A marked fallin the cerebral blood flow was seen only in afew cases and occurred especially if the fall inblood pressure in the distal part of the carotidartery was very marked. More distal in thehemisphere there was apparently not anyessential hemodynamic hindrance present eith-er, as no regions with selective loss ofautoregulation were observed.

As a result of the observations mentioned,the hemodynamic theory (transient systemic

•The results from these patients were presented in twostudies: in one of them, the material consisted of 31patients without arterial occlusion who had chronicsymptoms or in whom total remission of the symptomsoccurred later than 24 hours after the acute attack60;the other study comprised 21 patients without arterialocclusion (and three patients with arterial occlusion)in whom remission was complete or the remainingsymptoms were moderate.61" Owing to the definitionof the groups, eight of the 44 patients are included inboth studies.

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hypotension) has been abandoned as the mostcommon cause of transient ischemic attacksand cerebral infarction without demonstratedarterial occlusion.

The Thromboembollc TheoryAccording to this theory, cerebral infarction iscaused by an acute arterial occlusion or asevere stenosis resulting from a local thrombusor from an embolus coming from the intracra-nial and extracranial arteries, aorta or theheart. By a subsequent thrombolysis, the lumenis restored. If the occlusion persists at the timeof examination, the case will be classified as anischemic lesion with arterial occlusion. Thetheory is particularly attractive, as it canexplain cases of cerebral infarction with andwithout demonstrable arterial occlusion. Thedegree of severity, then, will depend on the sizeof the occluded artery, on the duration of thearterial occlusion, and on the collateral supplyto the ischemic region.

The thromboembolic theory is classic andgoes back to the last century.82 In moderntimes it was again advanced as an alternativeto the spasm theory.1" The thromboembolictheory was not generally accepted, however,until it had been demonstrated that anticoagu-lation may reduce the frequency of transientischemic attacks.63'64 The observation ofretinal microemboli in patients with attacks oftransient blindness has also strongly supportedthe theory.58-65-70 Symptom-free retinal em-boli have also been observed.71 At autopsyexaminations, microemboli have been foundconsisting of agglutinated thrombocytes,72 ofcholesterol,78 and of neutral fat.74 The originsof these emboli have recently been discussed byRoss Russell,60 who considered the extracra-nial neck vessels as well as the heart to be themost common origins of emboli. This agreeswith a high frequency of arterioscleroticchanges in these vessels44-*8' M- M and of heartdiseases in apoplectics (see below). The aorta,too, may be the origin of distal emboli.76

Furthermore, indirect support of thethromboembolic theory has been given by themany observations and investigations that tellagainst the spasm theory and the hemodynamictheory.

There are some additional clinical condi-tions to be pointed out in the discussion. Theoccurrence of heart disorders is increasedin patients with cerebral apoplexy.54-78'77 The

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thromboembolic theory is thereby substantiat-ed, as these patients are more inclined to getemboli coming from the heart, because theyhave either cardiac rhythm disturbances orendocardial defects, for instance in cases ofcoronary thrombosis. This is strongly support-ed by examinations in patients with rheumaticheart diseases.78 It was found that in a series of323 patients, 60 had suffered from classicapoplexy with rather pronounced symptoms,and 38 had had transient ischemic attacks.

Patients with cerebrovascular diseasesoften have arteriosclerotic changes in theextracranial neck vessels which may cause thedistal emboli.64 This is supported by the factthat in cases with murmur over the carotidartery, the murmur has been observed tochange its character in connection withtransient ischemic attacks.76 The fact that notall patients with lesions in the neck vessels getcerebral symptoms is probably due to the factthat in some cases the surface of the lesion issmooth and covered by endothelium, while inother cases it is ulcerated and affected byrecent thrombosis, which may cause distalemboli to develop. Gunning and co-workers58

endarterectomized the carotid artery and foundrecent thrombi on the surface of arteriosclerot-ic changes in the internal carotid artery in sixpatients who had had moderate apoplecticattacks within the last seven weeks beforeoperation. On the other hand, such thrombiwere not found in six patients in whom noattacks had occurred within the last sevenweeks before operation. It must be assumedthat the surface structure of such arteriallesions vary from time to time, which agreeswith the clinical finding that transient ischemicattacks may cease spontaneously.80

In the majority of patients with cerebralinfarction, there are symptoms from the middlecerebral artery region.81* This also supports thethromboembolic theory. Since the middlecerebral artery is the largest terminal branchfrom the internal carotid artery, a distalembolus will have the greatest possibility ofarriving in this artery. It is also well knownthat occlusions of the anterior or posteriorcerebral arteries are rare compared withocclusions of the middle cerebral artery.17-18

Transient ischemic attacks are relatively ste-reotyped in that patients with attacks oftenhave the same symptoms at each attack.4-81b-Slc

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This fact has also been adduced in support ofthe hemodynamic theory, but it is consistentwith the thromboembolic theory too, sinceretinal emboli have been demonstrated inpatients with numerous recurrent attacks ofmonocular blindness.88- ^

An angiogram made soon after cerebralinfarction may show an arterial occlusion,whereas a later one may show that theocclusion has moved to a more distal part ofthe artery or that the lumen is now normal.82"89

In such cases, the thromboembolic mechanismis well proved. It was found in one of theinvestigations86 that the occlusion was mostoften located in the main stem of the middlecerebral artery when the angiogram wasperformed early, whereas occlusion of thebranches of the middle cerebral artery wasmore frequent on later angiograms.

Finally, patients with transient ischemicattacks and a stenosis of an extracranial neckartery became symptom-free after thomboend-arterectomy that failed and resulted in totalocclusion of the artery.53-u0 These findingsobviously indicate that in these patients thecause of the attacks was thromboembolicrather than hemodynamic.

It must be concluded that the vastmajority of cerebral infarction is due to athromboembolic occlusion, irrespective ofwhether the occlusion is demonstrable or not atthe time of examination. This is also thecommon opinion of several other investiga-tors.0- M-91- °2

Ran Causes of Apoplexy With Ischemic LesionBut Without Arterial Occlusion

A brief mention shall be made of variouspathogenic conditions that in rare cases maycause apoplexy with moderate or severesymptoms.

Polycythemia is predisposing to transientischemic attacks as demonstrated by Millikan,Siekert and Whisnant.57 These authors as-sumed that an increased tendency to thrombo-sis in polycythemia patients caused the tran-sient ischemic attacks. Hemodynamic change(transient systemic hypotension) resultingfrom the increased viscosity of the blood is anunconvincing explanation, particularly sincethe blood pressure in a patient did not fallduring an attack. Thus, it must be assumedthat the transient ischemic attacks in poly-cythemia are connected with the thrombocyto-sis and thereby form a subgroup of the

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thromboembolic cases. Transient ischemic at-tacks have been observed in primary thrombo-cytosis too, and in these cases the mechanismmust be supposed to be similar to that inpolycythemia.98' 9*

Transient ischemic attacks induced bycoughing have been described in a few cases.56

It is most likely that these cases are due to ahemodynamic mechanism (transient systemichypotension), which is strongly supported bythe fact that the only patient in whom Kendelland Marshall56 could induce transient ischemicattacks during hypotension had his attackswhen coughing hard.

In very rare cases, anemic patients mayget transient ischemic attacks that end if theanemia is corrected.95 In even more rare cases,transient ischemic attacks96 or severe neurolog-ical symptoms97 have been observed inconnection with hypoglycemia. The pathogene-sis of these attacks is not quite clear, but ahemodynamic mechanism (transient systemichypotension) must be assumed to be ofimportance.

Some rare cases of transient ischemicattacks are caused by compression of a carotidartery owing to coiling or kinking, or of avertebral artery owing to rotation of thehead.9*-106 The mechanism involved in thesecases is obvious.

A certain kind of transient attack is foundin the case of the "subclavian-steal syn-drome."loe-112 In these cases there exists astenosis or an occlusion of the subclavianartery, and the brachial artery is supplied withblood via the vertebral artery, in which thedirection of the blood stream thus is reversed.When the arm is used, the blood supply to thearm is increased, which results in more bloodstreaming from the vertebral to the brachialartery; the blood pressure in the basilar arteryconsequently falls, and neurological symptomsmay occur.

INTRACEREBRAL HEM ATOM AS

Intracerebral hematoma is closely connectedwith arterial hypertension. The majority of thepatients with intracerebral hematomas havehypertension,80' US-1M and intracerebral hema-tomas are a frequent cause of death in patientswith malignant hypertension.118"120 Some hem-orrhages are due to vascular malformations orbleeding tumors,118'11B but these cases shallnot be dealt with here.

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Hemorrhagic infarcts, that is, infarcts inwhich the blood by diapedesis has extravasatedinto the tissue without formation of ahematoma, shall be considered in this work—as in most others—an infarct and not ahematoma.

Two main theories have been advancedabout the cause of an intracerebral hemato-ma.115 According to one theory, the cerebraltissue is damaged by a minor ischemic lesion(arterial occlusion) resulting in a smallnecrosis which includes the artery; the subse-quent re-establishment of the blood supply—and thereby of the local blood pressure—causeshemorrhage. According to the other theory,the hemorrhage is caused by a primaryrupture of an artery that is weak due to chronicdegenerative changes. The latter is probablycorrect.

In experimental hypertension, deposits ofplasma protein in the wall of minor arteriesmight result in degeneration and necrosis.23"26

At postmortem examinations of patients witharterial hypertension, multiple microaneurysmsrepeatedly have been found in the smallarteries and arterioles in the brain.121"125 Suchmicroaneurysms also occurred in normal, olderpeople, but were significantly less pronouncedthan in patients with arterial hypertension.Furthermore, it was found at postmortemexaminations of patients who had died fromdifferent causes that there were often smallhemorrhages in the brains of hypertensivepatients.125 Such hemorrhages were only foundin those hypertensive patients who had micro-aneurysms (approximately 50%) and theywere located in the same cerebral region aswere the microaneurysms. In a few cases ofintracerebral hematomas it has been possible todemonstrate that they originated from burstmicroaneurysms.128' m

Though it is rare, it is probable thatintracerebral hematomas also may occur if anoccluded vessel has the lumen opened. This issuggested by the fact that following acutesurgical recanalization of an occluded carotidartery, not only a hemorrhagic infarct but alsoa large, coherent hematoma have been de-scribed several times.126"128

The conclusion of these considerations isthat most, though not all, hemorrhages pre-sumably are caused by a primary vascularrupture in vessels with hypertensive, degenera-tive changes including microaneurysms.

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Pathophysiological Conditionsin Cerebral Infarction IllustratedBy Regional CerebralBlood Flow DeterminationsNORMAL CIRCULATORY CONTROL IN THE BRAIN

In young healthy persons, the cerebralblood flow is approximately 50 ml/100gm/min.12fi-131 Normally, the blood flow in thebrain is effectively controlled by homeostaticmechanisms.

The term "autoregulation" refers to thestability of cerebral blood flow in spite ofchanges in blood pressure. Thus, the cerebralblood flow is independent of the blood pressurewhen this is not abnormally low (meanblood pressure above approximately 70 mmHg) 132-ise -phis regulation agrees with theobservations made by Fog137"189 and by Forbesand co-workers140 that the pial arteries contractwhen the blood pressure is increased and dilatewhen it is reduced.

Also important in autoregulation is theintracranial pressure, as the intracranial venouspressure on the whole is equal to theintracranial pressure. The arteriovenous pres-sure difference thus corresponds to the arterialpressure minus the intracranial pressure. Whenthe intracranial pressure is altered (though notto extremely high values), the arterial bloodflow will be autoregulated and kept fairlyconstant, as is the case when the bloodpressure is altered.141 This corresponds to adilatation of the pial vessels at increasedintracranial pressure.142'14!i A primary changein the extracranial venous pressure will notalter the cerebral blood flow either.132' 144

Another important factor in the circula-tory regulation is PCo.,, especially the arterialPco2- Hypercapnia thus induces a strongcerebral vasodilatation and hypocapnia inducesa strong vasoconstriction.182'14B"149 The P 0 0 2

regulation is closely related to the localvascular segment and is not directed by anycenter in the brain stem. This has beendemonstrated by altering locally the arterialPco2 in the carotid and the vertebral region,respectively.160 Moreover, it has been shownthat the Pro., regulation mechanism is closelyconnected with the arterial PCo.,, but not withthe cerebral venous Pco.,-151 The regulationmechanism, therefore, must be local andclosely related to the arterial part of thecirculation.

Carbon dioxide in itself is not assumed tochange the contraction of the vessels, but to actby changing the pH of the tissue; actually, thepH in the arteriolar wall is assumed to be theregulating factor. 1I52~1SS The fact is that carbondioxide can diffuse freely across the blood-brain-barrier which, on the other hand, isimpermeable to bicarbonate. The blood-brain-barrier is presumably located in the endotheli-um of the vessels.156 This means that thevascular wall in the arterioles acts as a"Severinghaus electrode,"157 as pH in thevascular wall is determined by the bicarbonateconcentration in the tissue and by the POo2 °fthe arteriolar blood. This explains why thecerebral blood flow regulation is closely con-nected to the arterial PCOo- The tissue PCo2,however, can also influence the pH in the ar-teriolar wall by changing the gradients acrossthe arteriolar wall.

The arterial P0 o also influences thecerebral blood flow. A slight fall in the cerebralblood flow is seen at increased arterial Po2 and,conversely, a small rise is observed atmoderately decreased arterial P0 2. A pro-nounced increase in the cerebral blood flowoccurs, however, if the arterial POa is criticallylow.182' 184 Also changes in the cerebralmetabolism influence the cerebral blood flow,as the latter rises with a higher metabolicrate.132'1B8 According to the pH regulationtheory, these regulatory mechanisms of CBFmight be explained by a change in the tissuePco., and/or lactic acid concentration.15"

Whether the autoregulation induced bychanges in the blood pressure also can beexplained by this pH mechanism is not known.Perhaps an independent myogenous regulationmechanism also forms part of the autoregula-tion response.160

Several investigations have been carriedout to examine whether a neurogenic sympa-thetic control of the cerebral blood flow exists.The results, which to some extent have beenconflicting, seem to indicate that such a controlis only minimal and probably insignificant froma physiological point of view and thatsympathetic tonus does not seem to bepresent.182-1C1-1(t2

Most drugs will not influence the cerebralcirculation.161-ies-164 Here it shall only bementioned that papaverine causes cerebralvasodilation and aminophylline vasoconstric-tion.165-167

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DISTURBANCES IN THE CEREBRAL CIRCULATORYCONTROL IN ACUTE CEREBRAL DISEASES

The homeostatic regulation of the cerebralcirculation is disturbed in a number ofconditions, such as cerebral infarction, intra-cranial tumors, head traumas, hypoxia, com-pression of the brain, and highly increasedintracranial pressure.152 Under such conditions,vasomotor paralysis occurs in the affectedtissue with the result that the autoregulationand the responses to Paco., changes toaminophylline and to papaverine are impaired(the latter two responses have only beenexamined in a few of the said conditions).

Apparently, vasomotor paralysis is arather nonspecific phenomenon. However,some degree of tissue hypoxia must be assumedin all the conditions mentioned. The vasomotorparalysis, therefore, is probably due to a lacticacid acidosis and in some of the conditions alsoto a carbon dioxide acidosis.168 Acidosis haspreviously been demonstrated in experimentswhere occlusion of the middle cerebral arteryresulted in a low pH in the ischemic region.169

It has been demonstrated during experimentalhypoxia that the bicarbonate concentration andthe pH in the cerebrospinal fluid are reduced,170

that the lactate content in the cerebral tissue isincreased,171'172 and that the bicarbonateconcentration is reduced compared to thetissue PCo2

172 Direct demonstration of acidosisin the form of a low content of bicarbonate hasrecently been reported in brain biopsies frozenin situ in patients operated on for intracranialtumors or for intracerebral hematomas.173

The cerebral blood flow in regions withvasomotor paralysis depends on the local bloodpressure gradient and on the local cerebrovas-cular resistance. Both of these factors may beabnormal. The local arterial blood pressurethus may differ from the systemic one and beabnormally low owing to a severe arterialstenosis or occlusion, or the arteriovenousblood pressure difference may be abnormallylow owing to a much increased intracranialpressure. The local cerebrovascular resistanceeither may be abnormally low if the paralytic(dilated) vessels are not more than normallycompressed by the surrounding tissue, or itmay be abnormally high owing to a local orgeneral cerebral edema or to occlusive changesin the arterioles and capillaries.

Hyperemia as well as ischemia thus may befound in regions with focal vasomotor paraly-

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sis. A special condition arises in focalhyperemia, or rather where focal blood flowsurpasses the metabolic demands of the tissue.This condition, denoted "luxury perfusion,"168

is characterized by a high oxygen content in thevenous blood, and in the extremes by redvenous blood. Red venous blood has beenobserved at surgery on patients with cerebraltumors174 and also at experimental occlusion ofthe middle cerebral artery.175-177"'177b

THE CEREBRAL RESPONSE TO HYPOXIAAT DIFFERENT LEVELS OF THEARTERIAL CARBON DIOXIDE TENSION

Several experiments have shown that thecerebral tissue is more vulnerable to hypoxia athigher than at lower levels of the arterial PCo2-In animal experiments, analysis of cerebraltissue metabolites thus demonstrated thattissue hypoxia occurred in hypercapnic animalswhen the arterial blood pressure was reducedin order to obtain the same cerebral blood flowas during the normocapnic control condi-tion.178 Other experiments have shown thatincrease in the cerebral or spinal cord bloodflow in response to hypoxia occurred at ahigher oxygen tension during hypercapnia thanduring normocapnia or hypocapnia.179' 18On'1801'

CEREBRAL CIRCULATORY DISTURBANCES IN APOPLEXY

The focal symptoms in apoplexy withouthematomas are presumably always caused bya primary tissue ischemia, regardless of thepathogenic mechanism mentioned previously.As mentioned above, the cerebral circulation instroke is characterized by focal vasomotorparalysis.

Cerebral Infarction with Arterial Occlusion

In experimental occlusion of the middlecerebral artery with infarction, the blood flowis reduced in the infarct.181 The blood flow islikewise reduced through the region of infarc-tion in patients with occlusion of the middlecerebral artery.88 In animals with experimentalarterial occlusions, it has been found, further-more, that the blood pressure is reduced in thepial arteries of the infarction.182-184 Theoxygen tension also is much reduced in theinfarction.18r>

In the outer zone of the infarction, on theother hand, the oxygen tension is increased andthe metabolic activity continued.185 This wasdemonstrated by the fact that the oxygentension increased further following administra-tion of cyanide. At autoradiographical exami-nations, a hyperemic region in the outer zone

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of the infarction has been demonstratedsignifying a perifocal hyperemia correspondingto the regions with increased oxygen ten-sion.186' m In experimental middle cerebralartery occlusion, red veins have been observedin regions of infarction,175"17711 • 177b and it mustbe assumed that these red veins drain the peri-focal hyperemic zone. In patients with occlusionof the middle cerebral artery, perifocal hyper-emia has been demonstrated by determining theregional cerebral blood flow (Xenon-133method).88 In patients, as distinct from experi-mental animals, it is uncertain, however,whether the perifocal hyperemia observed isdue to the narrow hyperemic zone surroundingthe infarct or whether it is due to a small shiftof the occlusion with the result that previouslyoccluded arterial branches have been opened.Thus, in the above investigation, there weresigns of the occlusion having shifted in one ofthe patients with especially pronounced peri-focal hyperemia.

The perifocal hyperemia must be a resultof the metabolic changes in the ischemic focus.The ischemic focus is acidotic, and the acidosisis most probably due to an accumulation oflactic acid and carbon dioxide.188 It is assumedthat the acidosis induces the perifocal hypere-mia by spreading to the surrounding regionswhere the perfusion pressure is normal.168

The infarction region is affected byvasomotor paralysis (loss of autoregulation, ofreactivity to CO2, and of reactivity topapaverine and aminophylline). This has beenobserved in animal experiments183'188-191 aswell as in examinations of patients with arterialOCduSiOn.88' 1S8' 166-187, 186, 192-194 J n e a r l j e r e x _perimental investigations it has been observed,furthermore, that the oxygen tension falls inthe infarction when the blood pressure islowered185 and that the normal increase inoxygen tension during hypercapnia, and thedecrease during hypocapnia, respectively, arelost.195

By occluding the middle cerebral artery inexperimental animals infarction will developmore easily and be more pronounced duringhypotension than during normotension.40'41-m

In the focal ischemic region the normalreactions to Pac0., changes, to aminophyllineand to papaverine do not operate as men-tioned, and paradoxical reactions may even beseen in the form of a focal flow reduction atvasodilation (hypercapnia or papaverine injec-

336

tion) concomitant with a normal flow increasein the nonaffected regions—"the steal syn-drome"—or in the form of a focal flowincrease at vasoconstriction (hypocapnia oraminophylline injection) concomitant with anormal flow decrease in the nonaffectedregions—"the inverse steal syndrome."88'166'187'188,186,190,192,193 S u c h a f o c a l paradoxicalreactivity to Paco2 changes has also beenobserved in cerebral oxygen tension inexperimental animals with occlusion ofthe middle cerebral artery.195 In patientswith occlusion of the middle cerebral arteryexamined with the Xenon-133 clearance meth-od, the steal syndrome and the inverse stealsyndrome were not a predominant feature.88

This may be explained to some extent by thefact that the blood pressure rises duringhypercapnia and, owing to the lost autoregula-tion, the blood flow through the focal regionincreases and thereby conceals the stealphenomenon. Furthermore, detectors over themiddle of the infarction also count over someof the nonaffected tissue, which is comparative-ly better supplied with the isotope than are theischemic regions, and this tends to erase thefocal abnormalities on the clearance curves.Thus, it is probable that steal and inverse stealsyndromes actually occur far more frequentlyand markedly than it was observed.

The explanation of the steal syndromemust be that the hypercapnia causes only thevessels in the nonaffected parts of the brain tobe dilated, so that an increased amount ofblood is streaming to these parts, whereby theblood pressure falls in the vessels (thecollaterals) leading to the focus. The bloodpressure in the pial arteries in the region ofinfarction has been measured and shows a fallduring hypercapnia.182"184 The intercranialpressure rises during hypercapnia owing to theincreased blood flow through the nonaffectedparts of the brain. This may contribute to thesteal syndrome, as autoregulation in the focalregion is lost. In the animal experimentsmentioned, the cranium was open.

Focal blood flow increase in the inversesteal syndrome which is associated withvasoconstriction in nonaffected regions isexplained by the blood being shunted into thearea of ischemia where autoregulation is lost.In animal experiments with occlusion of themiddle cerebral artery, the infarcts are smaller

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in hyperventilated animals than in nonhyper-ventilated controls.107'108 This observation isconsistent with the theory of the inverse stealsyndrome.

Vasomotor paralysis has also been observedin the perifocal hyperemic region as well as inthe focal region. Thus, perifocal vasomotorparalysis was clearly demonstrated in a patientin whom the arterial occlusion presumably hadshifted distally.192 The oxygen tension in theperifocal hyperemic region also has been foundto vary with the blood pressure.186

It has to be added that in a few studies, focalvasomotor paralysis has not been observed. Thus,in a nine-year-old girl with occlusion of the middlecerebral artery no focal flow abnormalities wereobserved in the resting state, but during hypocap-nia the blood flow fell more in the focus thanoutside.199 The patient later recovered completely.Such a flow pattern has not been observed inother patients. The explanation of this strangefinding might be that the ischemic lesion had notbeen severe enough to produce significant acidosisand total vasoparalysis, but only a condition withso-called "dissociated vasoparalysis" with loss ofautoregulation but preserved reaction to Pa^.,changes (autoregulation was not tested in this pa-tient). In cases of dissociated vasoparalysis the re-gional cerebral blood flow may be abnormally highcompared to the metabolic rate during normocap-nia, and normal conditions with preservedautoregulation may be restored by hypocapnia.200

In some experimental studies with occlusion ofdistal branches of the middle cerebral artery indogs only partial paralysis (dissociated) or novasoparalysis was observed.201' 202 However, it iswell known that cerebral infarction only seldomoccurs in distal occlusion of the middle cerebralartery in contrast to what is the case in proximalocclusion.m' 208 Therefore, it seems reasonable toassume that cerebral infarction had not occurredin these studies and that ischemia only was soslight that minimal or no acidosis occurred.

At experimental occlusions of the middlecerebral artery, the microcirculation in theregion of infarction shows paleness of cortex,dark venous blood, reduced perfusion rate inthe pial vessels, and agglutination of theplatelets with some adhesion to the vascularwall in the veins. In severe ischemia, change incaliber of the arterioles has also been found aswell as thrombosis of the veins, venous stasis,vascular collapse, perivascular hemorrhages,and edema in the infarction region.41'175'204

Waltz and Sundt178 observed red venous blood

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as well. Cerebral edema has also been found inexperimental studies with arterial occlusion17715'205 and in patients who had died from cerebralinfarction with arterial occlusion.8

The blood-brain-barrier is destroyed inthe region of infarction. Following experimen-tal air embolism, extravasation of Iodine-131-labeled albumin and of trypan blue from thevessels shows that the capillary permeability isincreased.206 An increased uptake of Iodine-131-labeled serum protein or trypan blue andan increased water content have been observedin the ischemic hemisphere in rats in whichhypoxia was induced following occlusion ofone of the carotid arteries.207"200 Protein andother substances thus escape into the tissue anddevelop an edema that primarily must beextracellular. The development of edemas willbe furthered if the arterial occlusion disappearsand normal blood pressure is re-established inthe distal arterial branches. Under suchconditions there may be an increased occur-rence of small perivascular hemorrhages orhemorrhagic infarcts. It is possible that thetissue acidosis in itself can produce edema. Theacidosis will in fact depress the normalmetabolic processes, among those the Na+ andK+ exchange across the plasma membranes.210

This may cause intracellular edema. Finally,the metabolic breakdown products in thedestroyed tissue, including lactate, may furtherthe development of intracellular as well asextracellular edemas by increasing the numberof osmotically active particles.

Cerebral Infarction with Ischtmic Letionbut Without Arterial Occluiion

While cerebral infarction with arterial occlu-sion is characterized by vasomotor paralysisand by a region with reduced blood pressure inthe distal arterial branches, the latter phenom-enon does not occur in cerebral infarctionwithout arterial occlusion. As mentionedpreviously, the absence of arterial occlusion incerebral infarction is presumably due to aprimary thromboembolic occlusion which hasbeen dissolved. The blood pressure in thearterial branches to the infarction, therefore,will have been re-established.

In these cases it is to be expected,therefore, that there is a pronounced hypere-mia in a vasomotor paralytic region. There is ahigh frequency of hyperemic foci during the first

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days after the acute attack.60'180'192' 211-212* Inmany of these patients a simultaneous angio-graphical examination showed early filling ofregional veins and also a capillary blush. Arapid passage of the contrast media and shortvenous filling time have also been ob-served in cerebral infarction in otherinvestigations.83-218-216 Short regional venousfilling time was seen, however, in patientswithout as well as in patients with arterialocclusion. In the latter cases, the explanation isthat the occlusion has shifted distally, so thatsome of the arterial branches have been re-opened; but in some cases the perifocalhyperemia may—as mentioned above—be thecause of the early filling of the veins.

In principle, the changes in the regionalcerebral circulation in cerebral infarctionwithout persistent arterial occlusion are thesame as those found in arterial occlusion (focalhyperemia, focal ischemia, and focal vasomo-tor paralysis); however, the frequency of thevarious circulatory disturbances differs.60-61a'167, i8n Hyperemic foci thus were more frequentin the nonocclusive cases, while ischemic foci,sometimes with hyperemic perifocal regions,were predominant in arterial occlusion. Fur-thermore, in some patients with cerebral infarc-tion without arterial occlusion, the response tohypertension may be paradoxical with un-changed or even reduced blood flow throughfocus simultaneously with a rise in the bloodflow through the other parts of the hemi-sphere.00 It is, however, most probable that thisresponse will also be observed in cerebralinfarction with arterial occlusion if larger seriesare examined. The paradoxical response tohypertension will be treated in detail laterunder "extensive (global) changes in thecerebral blood flow in cerebral infarction."

After the re-opening of an experimentallyoccluded middle cerebral artery, the blood flowhas been found to rise to supranormalvalues.217 An increase to supranormal valuesmay likewise be seen in the oxygen availabilityof the tissue,185 and direct observations of thepial vessels show that they are dilated, have afast blood flow, and have red blood in theefferent veins.176 '177a '17n This experimental hy-peremia corresponds to the above-mentioned

*In Cronquist's investigation,212 a great number of thepatients had occlusion of the small, more peripheralarteries.

observations in patients with cerebral infarc-tion without arterial occlusion.

Examination of patients with cerebralinfarction without arterial occlusion some daysafter an acute attack reveals focal vasomotorparalysis but no longer combined with ahyperemic focus; on the contrary, there waseither no focal change or the vasomotorparalysis was combined with an ischemic focusduring rest (normocapnia).60 In this situationother factors must be taken into account. Thenormal vasomotor function may be re-estab-lished gradually so that there is a phase withpartial vasomotor paralysis. Focal edema mayhave developed in the same way as mentionedabove under cerebral infarction with arterialocclusion. Focal edema would account for lowblood flow and a low tissue pH with vasomotorparalysis corresponding to the conditions inexperimental examinations of anoxia.218 Lateron the focal flow abnormalities disappear, aswill be discussed below.

Hemorrhagic infarcts are probably due tothe disappearance or shifting of an arterialocclusion. Hemorrhagic infarcts are character-ized by numerous small perivascular hemor-rhages in the gray matter of the brain. Thehemorrhages may possibly become confluent,but there is no major bleeding or hematoma.There is often simultaneous ischemic infarctionin the white matter and possibly in other partsof the gray matter.219 Hemorrhagic infarcts,which are caused by tiny diffuse bleedings inthe ischemic region, are essentially differentfrom intracerebral hematomas, which normallyare caused by a primary rupture of a vessel(see above).

Hemorrhagic infarcts most often occur intissues that primarily have been severelyischemic and where the blood supply has beenwholly or partially re-established. Thus, Fisherand Adams220 found that of 66 patients withhemorrhagic infarcts, the greater part showedsigns of an embolic occlusion which had beendissolved or had shifted to more distal arterialbranches. On the other hand, in the case ofanemic infarcts, the authors as a rule coulddemonstrate an arterial occlusion. In the lastten patients with hemorrhagic infarcts exam-ined, Fisher and Adams succeeded in demon-strating embolic occlusions in more distalarterial branches of the infarction and that thecorresponding parts of the infarcts wereischemic. Similar observations of re-established

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blood flow to areas of hemorrhagic infarctionhave been made by other investigators.221 Ithas been reported, furthermore, that hemor-rhagic infarcts may occur in cerebral infarctionwhere an acutely occluded carotid artery hasbeen surgically reconstructed.126'128

Similar observations have been made inanimal experiments. Thus, it has been possibleto induce hemorrhagic infarcts by air embolismfollowed by acute arterial hypertension.222 Inexperimental occlusion of the middle cerebralartery in cats hemorrhagic infarcts have beendifficult to induce but, when it was possible, itwas always following re-opening of the occlud-ed artery.217 In the latter investigation noobservation was made of an abnormally highperfusion. However, such a phase may haveexisted prior to the blood flow determination,which was performed after the animals werekilled. An autoradiographical technique wasemployed.

Hemorrhagic infarcts have also beenassociated with arterial occlusions,30 though itis possible that the occlusion shifted to moredistal arterial branches. Fisher and Adams220

reported an arterial occlusion in a fewinstances. In animal experiments, hemorrhagicinfarcts have also been found associated witharterial occlusion. Thus, experimental occlu-sion of the middle cerebral artery combinedwith hypertension produced hemorrhagic areasin the peripheral parts of the infarct.41'204

Earlier experiments had also shown that hemor-rhagic infarcts might occur with arterialocclusion i223 however, the blood pressure wasnot recorded. In some cases of experimentalocclusion of the middle cerebral artery, Waltzand Sundt17B found perivascular hemorrhagesand in all these cases there was a slight rise inblood pressure.

Probably the pathogenesis of hemorrhagicinfarcts combined with arterial occlusion is thesame as those not combined with arterialocclusion. In both instances the hemorrhagicreaction occurs in regions with severe ischemicdamage where the blood supply and the bloodpressure in the distal vessels have been whollyor partially re-established.

Venous stasis is also of some importancein the development of hemorrhagic infarcts.Hemorrhagic infarcts occur in sinus thrombo-sis. In the investigations of air embolism, thehemorrhagic infarcts were more severe if the

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animal experiment included venous stasis.222 Asudden, marked increase in the cerebral venouspressure has produced hemorrhagic infarctsexperimentally.224 In severe ischemic lesionsproduced by occlusion of the middle cerebralartery, agglutination of thrombocytes andvenous stasis occur.41'175'2M These changesmay be of some importance to the pathogenesisof the hemorrhagic infarcts following re-establishment of the blood supply to the regionof infarction.

Extonsivo (Global) Changes In the Cerebral Blood Flowin C«rabral Infarction

In some patients with cerebral infarction, theblood flow is low not only in an ischemic focusbut also in the whole hemisphere.60'8Si 1U2'lft3--12' 225' —6 A reduced blood flow has also beenfound in the contralateral hemisphere,227 andthis phenomenon has been named transneuraldepression. The transneural depression ispresumably due to the great general reductionin mental activity in these patients with a lowmetabolic rate (postapoplectic dementia, co-matous or semicomatous state). Reduced flowand metabolic rate are also found in othertypes (not vascular) of dementia182'228 and inother forms of coma.182

An extensive loss of autoregulation mayoccur all over the affected hemisphere60' M andit has been demonstrated recently that theautoregulation also may be affected in thecontralateral hemisphere;200 this phenomenonhas been named global loss of autoregulation.It is most often combined with more severefocal blood flow disturbances.

In the patients with global loss ofautoregulation, the nonfocal responses tochanges in the arterial Paro., were normal.This implies that there is only a partialvasomotor paralysis—a so-called "dissociatedvasoparalysis," and, consequently, the autoreg-ulation seems to be the most sensitivemechanism in the regulation of blood flow. Thepathophysiological mechanism of the dissociat-ed vasoparalysis seems not clarified.200 Thedissociation between the autoregulation andthe COL. response does not necessarily meanthat these two regulation mechanisms aredifferent. Thus, dissociated vasoparalysis willnormally be present at hypercapnia.134

The global loss of autoregulation may berestored during hypocapnia,200 and a normalvasomotor function will thus be present in thenonfocal regions under this condition.

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A focal paradoxical response to hyperten-sion with a fall in the focal blood flow has beenfound in some cases with global loss ofautoregulation.00 The focal responses tochanges in Paco2 and to aminophylline wereabolished. It must be assumed that a rise in theintracranial pressure is of importance here, andthe syndrome resembles to some extent the"steal syndrome" seen in hypercapnia, as theless-affected regions steal from the affectedones. Such a focal paradoxical response tochanges in blood pressure is frequently foundin patients with intracranial tumors.229 It ispossible that in cases of cerebral infarction asimilar paradoxical blood pressure responseoccurs owing to the mass of the infarct.

Duration of Circulatory Change* In Apoplexy (Strokes)Due to Focal Ischemia

To the practical clinician, the duration ofsignificant focal cerebral ischemia is in ageneral way related to the severity andduration of the focal neurological deficit. Thus,a patient with a transient ischemic attackconsisting of left hemiplegja coming on in afew seconds, persisting 15 minutes, anddisappearing completely has had transient focalischemia for only a few minutes; and since thepatient is normal it is presumed that infarctionhas not occurred or had only occurred in"silent" areas of the brain. Focal acidosis withaccumulation of lactic acid developing duringthe period of ischemia may persist some time(hours?), however, after normal neurologicalfunction has been regained. In a study ofpatients with transient ischemic attacks, defi-nite disturbances of the regional cerebral bloodflow and its regulation thus were observed onlywithin the first hours after the attack.81

However, in another recent study wherecalculation was made of the regional cerebralblood flow in gray and white matter separatelyand of the weight distribution between whiteand gray matter, focal disturbances were oftenobserved in these flow parameters severalweeks after the patient's latest transient is-chemic attack.280 The cerebral vascular re-activity to hypocapnia was only focally ab-normal in a few cases. In most cases the flowabnormalities were observed only in one singleregion (with one of 16 scintillation de-tectors used). Presence of reduced flow orof reduced weight of the gray or whitematter was attributed to small infarction

340

(clinically silent). However, increased flowvalues were recorded even as frequently, afinding which is difficult to explain; theseinteresting results therefore need confirmation.

Disturbances of the regional cerebralblood flow and its regulation have beenobserved during the first two weeks after theattack in patients with apoplexy withoutarterial occlusion.60 In patients with occlusionof the middle cerebral artery such flowabnormalities may persist for months.8*

Other investigations of the regional cere-bral blood flow have also shown that theautoregulation is seldom affected longer thantwo weeks after the acute attack.130 On theother hand, in quite a number of patients anabnormal response to hypercapnia was ob-served more than two weeks after the attack.198

The cause of the different results is notapparent.

Regional Cerebral Blood Flow in Apoplexy (Strokes)with Intracerebral Hematoma

Determinations of the regional cerebral bloodflow have shown that the intracerebral hema-tomas may be surrounded by hyperemicregions.226'M1'282 Vasomotor paralysis hasbeen found located not only in the regionssurrounding a hematoma but also in the entirehemisphere.180 Biopsies from patients withintracerebral hematomas have demonstratedacidosis in the tissues around the hemato-mas.173

Knowledge of cerebral blood flow inpatients with intracerebral hematoma is limit-ed; however, examinations of intracranialtumors provide rather reliable information.The predominant effect of intracerebral hema-tomas, like that of intracranial tumors, is inexerting a pressure on and causing a distortionof the surrounding cerebral tissue, often with aresultant rise in the intracranial pressure. Thedisturbances found in regional cerebral bloodflow in patients with intracranial tumors are ofthe same nature as those found in patients withstroke, but are often more pronounced.220

Especially in increased intracranial pressure,the regional cerebral circulation and itsregulation will often be globally disturbed.

This similarity between intracerebral he-matomas and intracranial tumors—and, more-over, to some extent also severe braintraumas—means that in the case of generalanesthesia in connection with arteriography or

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surgery, care should be taken to avoidaccumulation of carbon dioxide and employ-ment of vasodilating anesthetics. Fall in theblood flow through critically perfused regionsshould be prevented as should further rise in apossibly increased intracranial pressure. Theseproblems have been discussed in detail in arecent survey by Alexander and Lassen.238

Discussion of Therapeutic MeasuresIn Cerebral Infarction Based onPathophysiological Conditionsand Clinical ObservationsTREATMENT DURING THE ACUTE PHASEOF CEREBRAL INFARCTIONluhcmlc Leitoni with Artarial OcclusionIn these cases there is an ischemic region distalto an occlusion or a severe stenosis. It can beforeseen that an effective therapy must either(1) increase the blood flow through theischemic region, increase the blood pressure orinduce vasoconstriction in the nonaffectedvascular regions (hyperventilation or amino-phylline), (2) decrease the arterial stenosis,thrombolytic agents or vascular surgery, (3)increase the oxygen supply to the ischemicregion, hyperbaric oxygenation, (4) reduce theoxygen consumption, barbiturates or hypother-mia, (5) diminish the focal edema, hyperosmo-lar solutions, or (6) prevent a progression of athrombosis, anticoagulants. Besides having astimulating effect on the blood flow in theischemic region, hyperventilation will alsoreduce the tissue acidosis here.

The most important factor is the speedwith which ischemia is relieved—it is likelythat any of these potential treatments are ofsignificant value after a few minutes of cerebralanoxia. There will always be a lapse of timebetween the occurrence of the symptoms ofapoplexy and the initiation of the treatment. Itis uncertain how long the cerebral tissue can beischemic without being permanently injured,and the amount of functioning cerebral tissueon which treatment will be effective is thereforealso questionable. The ischemia distal to anarterial occlusion will practically never betotal, as there will always be some collateralsupply to the affected region. This supply maydiffer much between individuals, and thisvariation is exemplified by the variety of thespontaneous courses found in occlusions of theinternal carotid and the middle cerebralar ter ies . ' 2 M The amount of cerebral tissue


which can be saved will therefore vary betweenpatients even if they have the same type ofarterial occlusion. Owing to this variation inthe spontaneous course, it is difficult toevaluate the results of a therapy, and it istherefore necessary to compare the resultsbetween treated and untreated patients incontrolled studies where the two groups havebeen selected according to the same criteria.Increasing blood pressure. If an artery supply-ing the brain is occluded, there will exist an is-chemic region with vasomotor paralysis andconsequently without autoregulation. The bloodsupply to the ischemic region can be increasedby increasing the blood pressure. In experimen-tal occlusion of the middle cerebral artery it hasthus been observed that infarctions were morepronounced and sometimes developed only if theanimals were exposed to hypotension.*0'41-lfl0

Favorable results have been reported fromincreasing the blood pressure in the small seriesof patients with cerebral infarction.235'288 Insome patients the severity of the symptomsvaried with the blood pressure.236 The treat-ment has never been adequately evaluated. Inneither of the above clinical studies were theresults compared with those from a controlgroup.

When patients with acute apoplexy aretreated with hypertension, it should be borne inmind that in certain patients with acutecerebral infarction there is global loss ofautoregulation. A paradoxical focal reductionof the blood flow may occur during hyperten-sion in some of these patients. In such rareinstances, treatment with hypertension mightaggravate the condition. An increase in theblood pressure may provoke a hemorrhagicinfarction or a hemorrhage. Therefore, theblood pressure probably should not be changedin most stroke patients with arterial occlusion.However, if patients with severe hypertension,a slight reduction of the blood pressure mightbe induced carefully, and in patients with anextremely low blood pressure, it might beincreased. Further controlled investigationswould be highly interesting.Hyperventilation. Therapeutic use of hypo-capnia, which normally reduces the cere-blood flow, might be beneficial for severalreasons. As discussed above under patho-physiological considerations in cerebral in-farctions, hypocapnia may induce on "in-verse steal syndrome" and thereby increase

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the blood supply to the ischemic region.The use of a low Pa<oo will render thecerebral tissue less vulnerable to hypoxia. Theinduction of a respiratory alkalosis will reducea focal cerebral acidosis and might therebytend to normalize the metabolic processes andcounteract the formation of a focal edema. Ifglobal loss of autoregulation is present,hyperventilation restores the autoregulationand thereby counteracts the formation ofglobal cerebral edema. In addition to the effectof hypocapnia already mentioned, the produc-tion rate of the cerebrospinal fluid will bereduced.237 This, in connection with thevasoconstrictor effect in the nonfocally dis-eased brain tissue, will tend to reduce theintracranial pressure.

In patients with apoplexy, the focalneurological symptoms might not necessarilybe influenced by hypocapnia since the focaldamage may be irreversible at the onset oftreatment. This has been suggested by observa-tions in experimental brain infarction withocclusion of the middle cerebral artery. Whenhyperventilation was started before the arterialocclusion, the infarction was reduced to lessthan a tenth compared to the normocapniccontrols.307 In another study where hyperventi-lation was started half an hour after the arterialocclusion, the infarction was reduced to abouta third in the hypocapnic animals whichwere normotensive, but not in hypertensiveanimals.1"8 In a study where hyperventilationwas started one hour after the arterialocclusion and in another where it was notstarted until four to six hours after theocclusion, no reduction of the size of theinfarction was observed in hypocapnic ani-mals.238'2!!l) T n e skull was open in all thesestudies, so an effect induced via the intracranialpressure was eliminated or partly eliminated.In a recent controlled study of patients withsevere apoplexy, prolonged artificial hyperven-tilation did not seem to influence the clinicalneurological deficit, but the mortality appearedto be somewhat, though not significantly,reduced in the hypocapnic group.'-*40 In patientswith less severe apoplexy and cerebral lesiontherapeutic hyperventilation might give betterresults; however, this has not been studied atthe present time.

Based upon the same considerations,the use of slight hypocapnic anesthesiafor surgery on the neck vessels must be

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expected to be favorable from the point ofview of reducing a disabling effect of any kindof cerebral ischemia during the operation. Thisconcept has been strongly supported recentlyby studies of the regional cerebral bloodflow241'24- and of the distal pressure in theinternal carotid artery241'24S'244 during preop-erative clamping of the internal carotidartery.Aminophylline. As aminophylline acts as avasoconstrictor in the normal brain, it is able toincrease the blood supply to an ischemic regionby inducing an "inverse steal syndrome" in thesame way as hypocapnia does. Aminophylline,moreover, produces a slight hyperventilation.167

Clinical claims have been made that incertain cases intravenously injected aminophyl-line has instantaneously a pronouncedly im-proving effect on cerebral infarction; a severehemiparesis thus may disappear almost com-pletely, but the effect lasts as a rule only a fewhours or less.30' 245-247 None of these investiga-tions were controlled. In a clinical study whichincluded a control group, although it was notquite comparable to the treated group, no sureeffect of aminophylline could be observed.248

At present, the value of treatment withaminophylline is quite uncertain.Thrombolytic agents. The purpose of thistreatment is a dissolution of the thrombus.However, there is a considerable risk in-volved in employing this therapy, as hem-orrhagic infarcts and possibly hemorrhagesmay develop, and as arterial puncture inconnection with angiography may cause largehematomas to occur. In a controlled investiga-tion, where streptokinase was administered, theprognosis was poorer in the treated patientsthan in the nontreated ones, irrespective ofdosage.249 There is consequently no practicalfibrinolytic treatment using the existing meth-ods. However, investigation of new agentscontinues.Vascular surgery. When vascular surgery is per-formed, the purpose is to reconstruct a narrowedor occluded artery, to increase the blood supply tothe ischemic focus, or, in the case of a"progressive stroke," to stop a progressingarterial occlusion.

There are numerous publications onreconstructive surgery of the extracranial neckvessels (thromboendarterectomy).90' 215°-2B6 Thetime at which thromboendarterectomy wasperformed varied from a few hours or days

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after the acute attack to several weeks after theattack. Few of these investigations included aconservatively treated control group.

An operation performed within the firsthours or days after the occurrence of thesymptoms will involve an essential risk of theinfarct becoming hemorrhagic and edematous,and also of the development of hematomas inthe infarct.129"128 The mortality in theseoperations is higher during the acute phasethan during the chronic phase.90'2B0'251'25U

Neither have the results from a controlledexamination of acute carotid surgery (37operated and 39 nonoperated patients) shownany positive effect, and the higher mortalitywas even found in the group of operatedpatients.90 Arterial surgery thus seems contra-indicated in patients with acute cerebralinfarction.

If the operation is performed severalweeks after the attack, it is hardly possible thatthere still remains any functional capacity inthe damaged cerebral tissue, so a positive resultof the operation cannot be expected in this caseeither. This is also compatible with the resultsfrom a controlled investigation (27 operatedand 34 nonoperated patients), where thehigher mortality was found in the operatedpatients.90

Hyperbaric oxygenation. In a series comprisinga small number of patients, this therapy hasbeen found to improve the condition of thepatients.257-269 However, the patients cannotstand hyperbaric oxygenation for more than alimited time owing to pulmonary complications,especially, and on return to respiration of nor-mal atmospheric air the symptoms most oftenrecurred.

It is unlikely that hyperbaric oxygenationwill be of great importance in the treatment ofacute cerebral infarction.Barbiturates and hypothermia. A barbiturateanesthesia and intoxication will reduce thecerebral oxygen consumption and bloodflow.182'I61 Animal experiments have provedthat barbiturates may increase the resis-tance to anoxia.200"262 The neurological signswere fewer in the animals treated withbarbiturates.262 Neurological symptoms andsigns seldom occur in survivors of severebarbiturate intoxication with respiratory in-sufficiency.263 Consequently, it is possible thatbarbiturate anesthesia might improve thecourse of cerebral infarction by reducing the

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oxygen demand in the ischemic region. How-ever, this has not been examined.

Hypothermia is another way of reducingthe oxygen demand in the ischemic region. Ithas been shown in animal experiments thatfollowing occlusion of the middle cerebralartery, the infarcts were smaller in thehypothermic animals than in the normothermiccontrols (the arterial blood pressure and Paooowere not stated, however).264 Whether treat-ment with hypothermia has any clinical value inpatients with acute cerebral infarction isunknown as yet.Low molecular dextran (Rheomacrodex®).Besides expanding the blood volume, Rheoma-crodex also has proved capable of reducing theintravascular aggregation that occurs in experi-mental occlusion of the middle cerebralartery.265'26a The opposite effect, where theaggregation is increased, is found after hemo-concentration and after infusion of highmolecular dextran (Macrodex®).267

Rheomacrodex may increase the cerebralblood flow.268'269 This increase corresponds toa reduction in the oxygen-binding capacity andseems not to be a result of a change in theviscosity.208 This is in accordance with the factthat no increase is found in the cisternaloxygen tension following administration ofRheomacrodex, unless the patient is simulta-neously treated for shock.270

In an experimental study with occlusion ofthe middle cerebral artery, treatment withRheomacrodex resulted in essentially smallerinfarcts in the treated than in the nontreatedanimals.271 It is a great defect of theseexaminations, however, that neither the arterialblood pressure nor the arterial P 0 0 o isreported, as both factors highly influence thesize of the infarcts. It is possible that theadministration of Rheomacrodex increased theblood pressure. This might wholly or in partexplain the observed effect. In a recent study oftemporary or permanent experimental occlu-sion of the middle cerebral artery in which theblood pressure was controlled, no beneficialeffect was observed in the animals treated withRheomacrodex and /or albumin as comparedto those not receiving such treatment.177" Inanother investigation no beneficial effect ofRheomacrodex was observed either, as noessential reduction of the size of the infarctsoccurred. But simultaneous treatment withalbumin, Rheomacrodex, and urea reduced the

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size of the infarcts, whereas the size wasincreased by administration of isotonicsaline.272 However, these authors do not statethe arterial POo2

an<i blood pressure. A recentcontrolled clinical trial has shown somebeneficial effect of treatment with Rheomacro-dex in patients with apoplexy.278

The knowledge of the effect of lowmolecular dextran (Rheomacrodex) on cere-bral infarction thus seems still too limited forany therapeutic conclusion to be drawn.Hyperosmolar solutions (urea, mannitol, sorbi-tol, etc.). A reduction in the intracranial pres-sure and in the volume of the brain will takeplace following administratoin of hyperosmolarsolutions of substances that do not pass theblood-brain-barrier or that pass it only slowly.274

The cerebral blood flow is normally not changedby the administration of such agents.276 It ispossible, though unestablished, that treatmentwith hyperosmolar solutions might increase theblood flow through an ischemic infarct byreducing the intracranial pressure and therebyincreasing the arteriovenous blood pressuredifference.

The focal edema that develops in acutestroke may be diminished by administration ofosmotically active agents. In rats exposed toanoxia following ligation of one of the carotidarteries, the edema in the ischemic hemispherewas less in those animals that had been givenan intravenous injection of urea.207 Whereexperimental infarcts were induced by smallplastic emboli, the edema was likewise less inanimals treated with urea than in thecontrols.276 These studies do not state thearterial PCo2 or the arterial blood pressure.

As the blood-brain-barrier in the focalregion is destroyed, treatment with hyperosmo-lar solutions cannot directly be expected tohave any effect on the focal edema. However,the blood-brain-barrier may only be partiallydestroyed, or there may be a concentrationgradient across the capillary wall, which issuggested in the study by Spector.207 He foundthe protein content in the extracellular fluid incerebral edema to be only one-twentieth of thatin the blood. It is possible that destruction ofthe blood-brain-barrier proceeds gradually, sothat part of the function remains during theinitial phase and that treatment with osmotical-ly active agents then might be effective; later,when the destruction is complete, such agentswould have no effect. It is impossible to decide

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whether this theory holds good, but there areseveral findings in support hereof. Thus, inexperimental animals, a reduction in the size ofthe infarcts was noted when a combinedtreatment with albumin, Rheomacrodex, andurea was given before the middle cerebralartery was occluded, whereas in one case,where treatment was not given until 12 hoursafter the arterial occlusion, an aggravation ofthe infarct with increased edema wasobserved.272 Additional support of the theorythat the blood-brain-barrier is gradually de-stroyed is the finding that a brain scanning isnegative during the first days after an apoplec-tic attack and not positive until later—if ataJJ 88, 277, 278

The value of treatment of cerebralinfarction with hyperosmolar solutions isuncertain. Owing to the above considerations,no conclusions can be drawn from experimen-tal observations in animals either.The influence of glucocorticoids on the cerebraledema in cerebral infarction. It is well knownthat glucocorticoids have an improving effecton cerebral edema in patients with intracranialtumors.270 At experimental examinations ofbrain injuries, a reduction of a cerebral edemaoften has been demonstrable following gluco-corticoid treatment.274'280

At controlled examinations of ischemia inconnection with anoxia, no positive effect oftreatment with glucocorticoids has beenshown.281 At these examinations, the highermortality was found in the animals treated withglucocorticoids; the edema did not differbetween the treated and the nontreated groups.Glucocorticoid treatment also has been exam-ined in a controlled series of patients withcerebral apoplexy and was found not to haveany effect.282

Anticoagulation. Only treatment of the acuteattack will be discussed here; prophylactic treat-ment will be dealt with later. A differential diag-nosis between intracerebral hematomas andischemic lesions is of great importance, whentreatment with anticoagulants is applied to acuteattacks, because, in the case of intracerebralhematomas, this treatment involves the risk ofaggravating the bleeding. It is well known thatthis differential diagnosis is not always easilyarrived at. By investigating 378 apoplexypatients on whom autopsy had been performed,Dalsgaard-Nielsen2 found that 31% of theclinically diagnosed thromboses turned out to

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be hematomas, and 26% of the clinicallydiagnosed intracerebral hematomas werethromboses. It should be mentioned also thathypertension is considered a contraindicationto long-term anticoagulant treatment owing tothe increased frequency of intracerebral bleed-ings in these patients.

With regard to anticoagulation, a divisionof the apoplexies into "strokes in evolution"and "completed strokes" will be an advantage,as anticoagulant treatment could be expectedto be effective only in cases with "stroke inevolution" with a progressing arterial thrombo-sis. Thus, Fisher283 found that "strokes inevolution" often stopped progressing whentreated with anticoagulants. Controlled exami-nations later have proved that some effect isobtainable by treating these patients withanticoagulants.284'28B In this connection itshould be borne in mind that from a clinicalpoint of view the course of a "stroke inevolution" is seen not only in the case ofprogressing arterial thrombosis and perhaps ofrecurrent cerebral embolisms, but also in thecase of an increasing intracerebral hematoma,or of increasing focal or global edema withpossible hemorrhagic infarction, or of asubdural hematoma, or of an intracranialtumor. A critical evaluation of the individualcase, therefore, is always necessary.

In a "completed stroke," the damage hasalready reached its maximum at the time ofexamination, so no effect can be expected fromtreatment with anticoagulants. This is inaccordance with the results from severalcontrolled investigations.285"287 The mortalitywas even higher in the treated group as morecases of cerebral hemorrhage were found. Onthe other hand, other investigations showed apositive effect of anticoagulation.288-200 Inthese reports, however, the effect is mostly dueto a reduced frequency of thrombophlebitiswith complications in the treated patients.

A positive effect of anticoagulant treat-ment was found in a study on patients with"completed stroke" and cardiac diseases whichrendered probable that the apoplexy wascaused by an embolus originating from theheart.291 The treated group showed a lowermortality and a better remission than thecontrol group. First a nontreated group wasexamined during a two-year period, and then atreated group during another two-year period.The cause of death was not stated in the

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individual case. The positive effect of anticoag-ulation observed might be due to poorcomparability between the control and thetreated group, as well as to a lower frequencyof venous thromboembolic diseases and of newemboli from the heart in the treated group.

It can be concluded that anticoagulanttreatment of acute cerebral infarction isindicated in those cases where the course is a"stroke in evolution," and where the latter isdue to a gradually occluding arterial thrombo-sis.Stellate ganglion block and sympathectomy.As the sympathicus has but a very small anduncertain physiological influence on the cere-bral blood flow,182'161 no effect can beexpected from stellate ganglion block orsympathectomy in the treatment of cerebralinfarction. At experimental examinations inmonkeys with occlusion of the middle cerebralartery, it was demonstrated that the region witha low oxygen tension remained unchangedafter cervical sympathectomy.18* Yet, sympa-thetic block has been rather widely usedclinically as a possible way of dilating thecollaterals to the ischemic region.292"296 How-ever, as it might have been expected, controlledexaminations showed that sympathetic blockdid not have any effect on the course ofapoplexy.291'296'286 Millikan and co-workersfound the poorer prognosis in the treatedpatients (in this examination, the selection oftreated and nontreated patients was not quite arandom one).Vasodilators. Such agents may be contraindi-cated, as they may reduce the blood flow in theischemic region by inducing a "steal syn-drome."165' 166 Vasodilators probably will notincrease the blood circulation in the ischemicregion. The clinical effect of the vasodilatingagents has been the object of only very limited,poorly controlled investigation. A controlled in-vestigation showed that the course of cerebralinfarction in patients treated with papaverineand in nontreated patients did not differsignificantly—though there was some indica-tion of a better course in the treatedpatients.297

Ischemic Leilons Without Arterial Occluiian

The vast majority of this type of cerebralinfarction is caused by a thromboembolicocclusion that has disappeared by the time ofexamination. Therefore, the blood supply to

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much of the ischemic region has been re-established. However, there may be hyperemia,altered metabolic processes, or focal edemawith a resultant secondary ischemia. Thesechanges are associated with a lactate acidosisin the injured tissue; but other factors,including disruption of the blood-brain-barrier,may be important.

The general purpose of the treatmentsdealt with under ischemic lesions with arterialocclusion was to increase the blood supplyand/or the oxygen supply to the ischemicregion distal to the occlusion. This therapeuticprinciple cannot be expected to be directlyeffective in ischemic lesions without arterialocclusion.

The theoretical purposes of a treatmentfor cerebral infarction without arterial occlu-sion are to decrease the focal acidosis (byreducing the arterial PCo2) and therebyrestore normal focal metabolic processes; or todiminish the focal edema (by reducing thearterial PCo2 by administration of hyperosmo-lar solutions); or to reduce the oxygenconsumption in this region (with barbiturateanesthesia, hypothermia); or, in the case of asecondary ischemia due to a focal edema, toincrease the blood supply to the focal region(by increasing the blood pressure, by inducingvasoconstriction in the nonaffected tissues ofthe brain). In the last instance, it should benoted that an increase in the blood supply mayeasily aggravate the focal edema. The thera-peutic principles outlined above do not differfundamentally from the principles of treatmentof cerebral infarction with arterial occlusion.In cerebral infarction without arterial occlu-sion, our knowledge of the most effectivetreatment is even less than in the case ofcerebral infarction with arterial occlusion.

PROPHYLAXIS AGAINST NEWCEREBROVASCULAR EVENTS

Natural History After Previous CerebrovascularEvents. In cerebrovascular diseases, the naturalhistory of each category is important whenevaluating a prophylactic therapy. In patientswith previous transient ischemic attacks there isa mortality of about 5 % each year of follow-up,cardiovascular diseases being the most com-mon cause of death. A similar number ofpatients have cerebral infarction with moresevere symptoms.80' ^s-soo The frequency ofnew transient ischemic attacks was essentiallyhigher, and about 50% of the patients had

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fresh attacks within the first year. Patients whopreviously have had a more severe cerebralinfarction (non transient) have an annualmortality rate of approximately 10%, and aslightly smaller number of patients get newcerebral infarcts with severe symptoms; thefigures vary from study to study.801-309 Alsofor these patients, the most common cause ofdeath is cardiac disease.

Statements about the natural history ofeach category show considerable variabilityfrom patient to patient, and as the prophylactictherapies applicable have a marginal oruncertain effect, a comparison between atreated group and a control group, selectedaccording to the same criteria, is of the utmostimportance.Vascular surgery. Vascular surgery is performedprophylactically, especially on patients withtransient ischemic attacks, in order to reducethe frequency of transient ischemic attacks andto diminish the risk of cerebral infarction withchronic focal symptoms or of death. A problemof special interest is whether the risk of asubsequent severe cerebral infarction or ofdeath can be diminished, as the frequency oftransient ischemic attacks can be reduced withanticoagulant treatment.

Cerebral infarcts associated with stenosisof the carotid artery most often are caused byemboli coming from the diseased artery. Evenmild stenoses may produce emboli and possiblyindicate surgery.

No evaluation of prophylactic vascularsurgery based on a controlled series has beenmade until recently. In a large cooperativestudy the selection of operated and nonoperat-ed patients was made according to exactly thesame criteria, namely by lot.258'810 A reportfrom this study deals with the cumulativesurvival rates in 1,225 patients who werefollowed during 42 months.253 The mortalitywas significantly reduced following surgery onpatients with previous transient ischemic at-tacks or minor cerebral infarction where theonly vascular lesion was a unilateral stenosis ofone internal carotid artery. Patients of thesame clinical category with one carotid arteryoccluded and the other stenosed had a slight,but not significant, reduction in mortality. Onthe other hand, no beneficial effect of surgerywas seen if there was a unilateral occlusion ora bilateral stenosis of the internal carotidartery. Mortality was significantly increased in




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the operated patients with permanent symp-toms after cerebral infarction. Higher mortalityfollowing surgery was noted in such patientswho had unilateral stenosis of the carotidartery or where one carotid artery wasoccluded and the other stenosed. Anotherreport dealt with the prognosis of newcerebrovascular attacks and death in 316patients with previous transient ischemic at-tacks.810 The recurrence of transient ischemicattacks was not reduced among operatedpatients with bilateral carotid artery stenosisand with stenosis of one and occlusion of theother carotid artery, but was reduced in thosewith unilateral carotid stenosis. The follow-upalso showed that the occurrence of nonfataland fatal strokes was reduced in the operatedgroups. However, the operative mortality wasnot included and if one adds this figure, nodifference between operated and nonoperatedpatients was demonstrable.

As the disease picture is mild in thepatients whose prognosis can be improved byprophylactic vascular surgery and as thepatients have a normal neurological examina-tion at the time of operation it is veryimportant that the risk of operation be kept ata minimum.252'2BIi It must be taken intoaccount that angiography of the extracranialneck vessels is necessary to select those whocan be treated by surgery and that thisprocedure may involve some risk.58'311-812

Finally, it is possible that improvedsurgical technique may better the results. If so,vascular surgery may become an applicabletherapy in other subdivisions of cerebrovascu-lar disease.Anticoagulation. The purpose of prophylacticanticoagulant treatment is to reduce the fre-quency of transient ischemic attacks and todiminish the risk of serious cerebral infarction.Hypertension is a contraindication to long-termanticoagulant treatment because of the risk ofcerebral hemorrhages. Dementia and old age tosome degree must also be considered acontraindication of long-term anticoagulanttreatment.

In patients with transient ischemic at-tacks, Millikan, Siekert and Shick68-M observedthat the attacks decreased or could be stoppedby anticoagulant treatment. This finding subse-quently has been confirmed by several investi-gations, most of which include a comparablecontrol group.283' 288' B13-31f' In two investiga-

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tions, the same frequency of transient ischemicattacks was found in treated and in nontreatedpatients with a previous history of apoplexy806

and transient ischemic attacks,817 respectively.Some investigations showed that antico-

agulation may reduce the risk of cerebralinfarction in patients with transient ischemicattacks.283'318'314 Subsequently, critically con-trolled investigation did not confirm such areduction of cerebral infarction in patientstreated with anticoagulation.815'317 However,in other controlled studies, a significant reduc-tion of the occurrence of cerebral infarctionwas found in the patients treated with anti-coagulation; there were also some instances ofcerebral hemorrhage in these patients.285'81B

Patients who previously had cerebralinfarction associated with rheumatic heartdisease (mitral stenosis, auricular fibrillation)have the frequency of recurrence 50% reducedby long-term treatment with anticoagulant818

Patients who have completed cerebralinfarction do not benefit from long-termanticoagulant treatment.285'808'819 The risk ofcerebral hemorrhage increased somewhat inthe treated patients. In another study, however,the risk of recurrent cerebral infarction wasfound to be smaller in patients treated withanticoagulants, even if the occurrence ofhemorrhages here also was somewhat in-creased in the treated patients.820 When theseinvestigations are considered collectively, itappears that anticoagulant treatment does notseem effective in reducing the frequency ofrecurrence in patients with a history of cerebralinfarction, unless it can be assumed that thecerebral infarction was caused by rheumaticheart disease.

The conclusion that can be drawn on thebasis of these investigations is that anticoagu-lant treatment improves the prognosis inpatients with transient ischemic attacks andreduces the frequency of attacks. In patientswith rheumatic heart disease who previouslyhave suffered from cerebral infarction causedby an embolus originating from the heart,treatment with anticoagulants may reduce thefrequency of recurrence.Antiplatelet agglutination. Dipyridamole (Per-santin®) has been demonstrated in vitro tohinder platelet aggregation821 and in vivoto hinder the development of thrombiin the injured vessels of the rabbit.322

Dipyridamole recently has been employed in a

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controlled study of thromboembolic complica-tions in patients who had undergone surgeryfor cardiac-valve replacement: the treatedgroup, which was given dipyridamole as well asanticoagulants, showed no thromboemboliccomplications in contrast to 17% in the con-trol group which was given anticoagulantsonly.828

In patients who had previously sufferedfrom cerebral infarction, a controlled investiga-tion of treatment with dipyridamole did notshow any effect on the mortality or theoccurrence of new cerebrovascular events.824

This investigation did not include simultaneousadministration of anticoagulants which mighthave been of interest considering the abovepositive results with this combination.Antihypertensive treatment. Several investi-gations indicate that treatment of hyper-tension will diminish the risk of subsequent se-vere cerebrovascular attacks.119' s26-827 This hasrecently been confirmed in a randomizedcontrolled clinical trial of antihypertensivetreatment of patients with previous cerebro-vascular attacks.828 In this connection it hasto be mentioned that the occurrence ofcoronary infarction does not seem to beinfluenced by the antihypertensive treatment.As mentioned previously, hypertension will bepresent in most patients with intracerebralhematomas (congenital malformations beingexcluded). Thus, it has been discussed whetherantihypertensive treatment will diminish onlythe risk of intracerebral hematomas or also therisk of ischemic cerebrovascular lesions. Thecontrolled trial mentioned seems to indicatethat the occurrence of both types of cerebro-vascular lesions is reduced.828 Independentlyhereof it must be stated that treatment ofhypertension has a clearcut beneficial effect.For the use of antihypertensive treatment it isalso important to recognize that the vastmajority of cerebral ischemic lesions are due tothromboembolic arterial occlusion often withsubsequent rapid thrombolysis. Hemodynamicmechanism involving systemic arterial hypo-tension is only seldom responsible for theapoplectic attack. This has been discussed indetail above under the pathogenesis ofcerebral infarction.

SummaryThe aim of this survey has been to discusspathogenic, pathophysiological and therapeutic

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aspects of cerebral apoplexy with specialregard to recent experimental and clinicalresearch on the regional cerebral circulation.Ischemic cerebral lesions are discussed exten-sively, whereas intracerebral hematomas areonly shortly commented on. The whole surveyshall not be summarized here but some majorpoints will be mentioned.

In apoplexy with ischemic lesion anarterial occlusion may or may not be demon-strated. In those patients where no arterialocclusion is present, recent studies of the re-gional cerebral blood flow strongly support thethromboembolic theory according to which theischemic lesion is due to a thromboembolicarterial occlusion with rapid subsequent throm-bolysis. It is concluded, not only on the basisof these studies but even more on the basis ofthe large amount of studies in the literature,that these short-lasting thromboembolic occlu-sions must be responsible for the majority ofapoplexy without arterial occlusion and oftransient ischemic attacks.

The studies on the regional cerebralcirculation have provided new essential patho-physiological information; among other things,a characteristic finding is focal vasomotorparalysis with loss of the normal ability ofvasoconstriction and of vasodilation. The focalflow may even show paradoxical reactions withflow decrease during stimuli normally causingflow increase—"steal syndrome"—or withfocal flow increase during stimuli normallycausing flow decrease—"inverse steal syn-drome."

Therapeutic measures in apoplexy at thepresent time have been of rather limited value.Only prophylactic treatment of selected caseswith anticoagulation or carotid surgery, pro-phylactic antihypertensive treatment, and acutetreatment of selected cases with anticoagula-tion seem to have shown some effect. In theacute phase the outlined new pathophysiologi-cal knowledge may be of significant importancefor a rational treatment. Thus, vasodilatorsshould be avoided as they may be harm-ful, whereas vasoconstrictor treatment mightbe beneficial by inducing an inversedsteal. Animal experiments have shown abeneficial effect of hyperventilation, but thetime interval from the onset of cerebralischemia until hyperventilation was started wascritical. No convincing effect was observed inpatients with severe apoplexy where hyper-

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ventilatory treatment was started as soon aspossible but several hours after the onset ofsymptoms. Probably the infarction was com-pletely irreversible in these severe cases whenhyperventilation treatment was undertaken.Treatment with hyperventilation may be ofvalue in less severe cases; however, it has notyet been studied.

AcknowledgmentI want to thank Mrs. Ilona Munck for translation ofthis manuscript. The translation was supported bythe Rask-0rsted Foundation, Copenhagen.

References1. Report by an ad hoc committee, Advisory

Council for the National Institute of Neurolog-ical Diseases and Blindness, Public HealthService. A classification and outline of cere-brovascular disease. Neurology (Minneap) 8:395-434, 1958

2. Dalsgaard-Nielsen T: Some clinical experi-ence in the treatment of cerebral apoplexy.Acta Psychiat Neurol Scand (Suppl 108) :101-119, 1956

3. Riishede J: Cerebral apoplexy: Statistical anddiagnostic considerations. Canad Med Assoc J97: 151-160, 1967

4. Millikan CH, Siekert RG, Whisnant JP:Occlusive disease in the carotid arterialsystem. Int J Neurol (Montevideo) 1:223-241,1960

5. Millikan CH, Siekert RG, Whisnant JP (eds) :Cerebral Vascular Diseases. First PrincetonConference, New Jersey. New York & London,Grune & Strarton, 1961

6. Marshall J : The Management of Cerebrovasc-ular Disease. Second edition, London, Chur-chill, 1968

7. McDonald W l : Recurrent cholesterol embo-lism as a cause of fluctuating cerebralsymptoms. J Neurol Neurosurg Psychiat 30 :489-496, 1967

8. Adams JH, Graham D l : Twelve cases of fatalcerebral infarction due to arterial occlusion inthe absence of atheromatous stenosis orembolism. J Neurol Neurosurg Psychiat 30:479-488, 1967

9. Westphal K: Ober die Entstehung des Schla-ganfalles. I I . Klinische Untersuchungen zumProblem der Entstehung des Schlaganfalles.Drsch Arch Klin Med 151: 31-95, 1926

10. Neubiirger K: Zur Frage des Wesens und derPathogenese der weissen Hirnerweichung. Zges Neurol Psychiat 105: 193-212, 1926

11. Foix C, Ley J : Contribution a I'etude duramollissement cerebral envisage au point devue de sa frequence, de son siege et de l'£tat

anatomique des arteres du territoire necrosedJ Neurol (Brux) 27:658-684, 1927

12. Spielmeyer W: Vasomotorisch trophischeVerdnderungen bei zerebraler Arterioskle-rose. Mschr Psychiat Neurol 68: 605-620,1928

13. Arlng CD: Vascular diseases of the nervoussystem. Brain 68: 28-55, 1945

14. Hicks SP, Warren S: Infarction of the brainwithout thrombosis. An analysis of onehundred cases with autopsy. Arch Path 52:403-412, 1951

15. Pickering GW: Transient cerebral paralysis inhypertension and in cerebral embolism.JAMA 137:423-430, 1948

16. Denny-Brown D: The treatment of recurrentcerebrovascular symptoms and the questionof "vasospasm." Med Clin N Amer 35: 1457-1474, 1951

17. Riishede J: Cerebral apoplexy. An arterio-graphical and clinical study of 100 cases.Thesis. Acta Psychiat Neurol Scand (Suppl118) 1957

18. Silverstein A: Arteriography of stroke: I I .Factors relating to the normal angiogram.Arch Neurol (Chicago) 13:441-446, 1965

19. Byrom FB: The pathogenesis of hypertensiveencephalopathy and its relation to the malig-nant phase of hypertension. Lancet I I : 2 0 1 -211, 1954

20. Meyer JS, Waltz AG, Gotoh F: Pathogenesis ofcerebral vasospasm in hypertensive encepha-lopathy. I I . The nature of increased irritabilityof smooth muscle of pial arterioles in renalhypertension. Neurology (Minneap) 10: 859-867, 1960

21 . Rosenblum W l , Donnenfeld H, Aleu F:Effects of increased blood pressure oncerebral vessels in mice. Arch Neurol (Chica-go) 14:631-643, 1966

22. Meyer JS, Waltz AG, Gotoh F: Pathogenesis ofcerebral vasospasm in hypertensive encepha-lopathy. I. Effects of acute increases inintraluminal blood pressure on pial bloodflow. Neurology (Minneap) 10: 735-744,1960

23. Giese J: The Pathogenesis of HypertensiveVascular Disease. Thesis. Munksgaard, Co-penhagen, 1966

24. Giese J: The pathogenesis of hypertensivevascular disease. Dan Med Bull 14: 259-267,1967

25. Kojimahara M: Healing and exacerbation ofarterial lesions in rats with experimentalhypertension, with special reference to effectsof antihypertensive drugs on arterial lesions.Gunma J Med Sci 16: 1-42, 1967

26. Olsen F: Penetration of circulating fluores-cent proteins into walls of arterioles and

Stroke, Vol. 2, July-August J97J 349



ownloaded from


PAULSON

venoles in rats with intermittent acute angio-tensin-hypertension. Acta Path MicrobiolScand74: 325-332, 1968

27. Byrom FB: The nature of malignancy inhypertensive disease. Evidence from the reti-na of the rat. Lancet I : 516-520, 1963

28. Byrom FB: The significance of hypertensiveencephalopathy. Lect Sci Basis Med 8: 256-268, 1958-1959

29. Pickering GW: The pathogenesis of malig-nant hypertension. Circulation 6: 599-612,1952

30. Fishberg A M : Hypertension and Nephritis.Fifth edition, Lea Gr Febiger, Philadelphia,p 354, 1954

3 1 . Byrom FB: The Hypertensive Vascular Crisis.Will iam Heinemann, Medical Books Limited,London, 1969

32. Denny-Brown D: Recurrent cerebrovascularepisodes. Arch Neurol (Chicago) 2: 194-210,1960

33. Corday E, Rothenberg SF, Putnam TJ :Cerebral vascular insufficiency. An explana-tion of some types of localized cerebralencephalopathy. Arch Neurol Psychiat (Chi-cago) 69: 551-570, 1953

34. Corday E, Rothenberg SF: The clinicalaspects of cerebral vascular insufficiency. AnnInt Med 47: 626-639, 1957

35. Frantzen E, Harvald B, Haugsted H: Thearteriographic and electroencephalographicfindings in cerebral apoplexy. Dan Med Bull6: 12-19, 1959

36. Meyer JS: Occlusive cerebrovascular disease.Pathogenesis and treatment. Amer J Med 30:577-588, 1961

37. Ziilch KJ : Ober die Entstehung und Lokalisa-tion der Hirninfarkte. Zbl Neurochir 2 1 : 158-178, 1961

38. Romanul FCA, Abramowicz A: Changes inbrain and pial vessels in arterial border zones.Arch Neurol (Chicago) 11:40-65, 1964

39. Olivarius B de Fine: Apoplexia cerebri. Enklinisk og patologisk undersOgelse medspecielt henblik p<5 patogenesen. Thesis.Munksgaard, Copenhagen, 1964

40. Thompson RK, Smith GW: Experimentalocclusion of the middle cerebral artery duringarterial hypotension. Trans Amer NeurolAssoc (seventy-sixth annual meeting) p 203-207, 1951

4 1 . Denny-Brown D, Meyer JS: The cerebralcollateral circulation. 2. Production of cere-bral infarction by ischemic anoxia and itsreversibility in early stages. Neurology (Min-neap) 7: 567-579, 1957

42. Meyer JS, Leiderman H, Denny-Brown D:Electroencephalographic study of insufficien-

cy of the basilar and carotid arteries in man.Neurology (Minneap) 6 :455-477, 1956

43. Haimsen P, Skinh0j E: EEG changes duringcontrolled hypotension in patients with cere-brovascular diseases. Under preparation

44. Fisher M : Occlusion of the carotid artery:Further experiences. Arch Neurol Psychiat(Chicago) 72: 187-204, 1954

45. Hutchinson EC, Yates PO: Carotico-vertebralstenosis. Lancet I : 2-8, 1957

46. Martin MJ, Whisnant JP, Sayre GP: Occlusivevascular disease in the extracranial cerebralcirculation. Arch Neurol (Chicago) 3: 530-538, 1960

47. Yates PO, Hutchinson EC: Cerebral infarc-tion: The role of stenosis of the extracranialcerebral arteries. Spec . Rep Ser Med ResCoun, no. 300, 1961

48. Torvik A, Jorgensen L: Thrombotic andembolic occlusions of the carotid arteries inan autopsy series. Part 1 . Prevalence, locationand associated diseases. J Neurol Sci 1 : 24-39,1964

49. Baker AB, Dahl E, Sandier B: Cerebrovascu-lar disease. Neurology (Minneap) 13: 445-454, 1963

50. Jorgensen L, Torvik A: Ischaemic cerebrovas-cular disease in an autopsy series. Part 1.Prevalence, location and predisposing factorsin verified thrombo-embolic occlusions andtheir significance in the pathogenesis ofcerebral infarction. J Neurol Sci 3: 490-509,1966

51 . Burrows EH, Marshall J : Angiographic inves-tigation of patients with transient ischaemicattacks. J Neurol Neurosurg Psychiat 28: 533-539, 1965

52. Sutton D, Davies ER: Arch aortography andcerebrovascular insufficiency. Clin Radiol 17:330-345, 1966

53. Gurdjian ES, Thomas LM: Evaluation andIndications for surgery in extracranial cere-brovascular disease. J Neurosurg 26: 235-243, 1967

54. Drake WE, Drake MAL: Clinic and angio-graphic correlates of cerebrovascular insuffi-ciency. Amer J Med 45: 253-270, 1968

55. Faris AA, Poser CM, Wilmore DW, et a l :Radiologic visualization of neck vessels inhealthy men. Neurology (Minneap) 13: 386-396, 1963

56. Kendell RE, Marshall J : Role of hypotensionin the genesis of transient focal cerebralischaemic attacks. Brit Med J 10: 344-348,1963

57. Millikan CH, Siekert RG, Whisnant JP:Intermittent carotid and vertebral-basilar in-

350 Stroka, Vol. 2, July-Augutt 1971



ownloaded from



sufficiency associated with polycythemia. Neu-rology (Minneap) 10: 188-196, 1960

58. Gunning AJ, Pickering GW, Robb-SmithAHT, et o l : Mural thrombosis of the internalcarotid artery and subsequent embolism.Quart J Med 33: 1 55-195, 1964

59. Marshall J : The differential diagnosis of"l i t t le strokes." Postgrad Med J 44: 543-548,1968

60. Paulson OB, Lassen NA, SkinhjSj E: Regionalcerebral blood flow in apoplexy withoutarterial occlusion. Neurology (Minneap) 20:125-138, 1970

61a. SkinhjJj E, H0edt-Rasmussen K, Paulson OB,et a l : Regional cerebral blood flow and itsautoregulotion in patients with transient focalcerebral ischaemic attacks. Neurology (Min-neap)) 20: 485-493, 1970

61b. Boysen G, Ladegaard-Pedersen HJ, HenriksenH, et a l : Effects of POQQ^ on regional cerebralblood flow and internal carotid artery pressureduring carotid clamping. Anesthesiology, inpress

62. Jackson JH: On a case of temporary lefthemiplegia. Brain 3 : 433-451, 1880

63. Millikan CH, Siekert RG, Shick RM: Studiesin cerebrovascular disease. I I I . The use ofanticoagulant drugs in the treatment ofinsufficiency of thrombosis within the basilararterial system. Proc Mayo Clin 30: 116-126,1955

64. Millikan CH, Siekert RG, Shick RM: Studiesin cerebrovascular disease. V. The use ofanticoagulant drugs in the treatment ofintermittent insufficiency of the internalcarotid arterial system. Proc Mayo Clin 30:578-586, 1955

65. Fisher CM: Observations of the fundus oculiin transient monocular blindness. Neurology(Minneap) 9: 333-347, 1959

66. Hollenhorst RW: Significance of brightplaques in the retinal arterioles. Trans AmerOphth Soc 59: 252-273, 1961

67. Russell RW Ross: Observations on the retinalblood-vessels in monocular blindness. LancetI I : 1422-1428, 1961

68. Russell RW Ross: Atheromatous retinal em-bolism. Lancet I I : 1354-1356, 1963

69. Russell RW Ross: The source of retinalemboli. Lancet l i : 789-792, 1968

70. Ashby M, Oakley N, Lorentz I, et a l :Recurrent transient monocular blindness. BritMed J 2 : 894-897, 1963

7 1 . Skovborg F, Lauritzen E: Symptomless reti-nal embolism. Lancet I I : 361-362, 1965

72. McBrien DJ, Bradley RD, Ashton N: Thenature of retinal emboli in stenosis of theinternal carotid artery. Lancet I: 697-699,1963

73. David NJ, Klintworth GK, Friedberg SJ, et a l :Fatal atheromatous cerebral embolism associ-ated with bright plaques in the retinalarterioles. Neurology (Minneap) 13: 708-713, 1963

74. Cogan DC, Kunabara T, Moser H: Fat emboliin the retina following angiography. ArchOphthal (Chicago) 71:308-313, 1964

75. Sturgill BC, Netsky MG: Cerebral infarctionby atheromatous emboli. Arch Path 76: 189-196, 1963

76. Stiirup H: Coronary thrombosis and otherforms of circulatory insufficiency coincidingwith cerebral apoplexy. Acta Med Scand 144:189-195, 1952

77. Gormsen J, Dyrbye M, Eiken M, et a l : Acutecerebral infarct. Extracerebral genesis withparticular reference to cardiovascular status.Acta Med Scand 169: 455-466, 1961

78. Hutchinson EC, Stock JPP: Paroxysmalcerebral ischemia in rheumatic heart-disease.Lancet I I : 653-656, 1963

79. Siekert RG, Millikan CH: Changing carotidbruit in transient cerebral ischemic attacks.Arch Neurol (Chicago) 14:302-304, 1966

80. Acheson J, Hutchinson EC: Observations onthe natural history of transient cerebralischemia. Lancet I I : 871-874, 1964

81a. Balow J, Alter M, Resch JA: Cerebralthromboembolism. A clinical appraisal of 100cases. Neurology (Minneap) 16: 559-564,1966

81b. Millikan CH, Siekert RG: Studies in cerebro-vascular disease. I. The syndrome of inter-mittent insufficiency of the basilar arterialsystem. Proc Mayo Clin 30: 61-68, 1955

81c. Millikan CH, Siekert RG: Studies in cerebro-vascular disease. IV. The syndrome of inter-mittent insufficiency of the carotid arterialsystem. Proc Mayo Clin 30: 186-191, 1955

82. Jacobsen H-H, Skinh0j E: Occlusion of themiddle cerebral artery. An analysis of thirty-six arteriographed cases. Dan Med Bull 6: 9-12, 1959

83. Zatz LM, lannone AM, Eckman PB, et a l :Observations concerning intracerebral vascu-lar occlusions. Neurology (Minneap) 15:389-401, 1965

84. Dalai PM, Shah PM, Aiyar RR: Arteriograph-ic study of cerebral embolism. Lancet I I : 358-361, 1965

85. Dalai PM, Shah PM, Sheth SC, et a l : Cerebralembolism. Angiographic observations onspontaneous clot lysis. Lancet 1 : 61-64,1965

86. Bladin PF: A'radiologic and pathologic studyof embolism of the internal carotid-middlecerebral arterial axis. Radiology 82: 615-625,1964

Strok; Vol. 2, July-Augutf 1971 351



ownloaded from


PAULSON

87. Fieschi C, Bozzao L: Transient embollcocclusion of the middle cerebral and internalcarotid arteries in cerebral apoplexy. J NeurolNeurosurg Psychiat 32: 236-240, 1969

88. Paulson OB: Regional cerebral blood flow inapoplexy due to occlusion of the middlecerebral artery. Neurology (Minneap) 20 :63-77, 1970

89. Sidermann F, Dichgans J, Bergleiter R:Occlusion of the middle cerebral artery andits branches: Angiographic ond clinical corre-lates. Brain 92: 607-620, 1969

90. Bauer RB, Meyer JS, Gorham JE, et a l : Acontrolled study of surgical treatment ofcerebrovascular disease—42 months' experi-ence with 183 cases. In Millikan CH, SiekertRG, Whisnant JP (eds) : Cerebral VascularDiseases. Fifth Conference. Grune & Stratton,New York, 1966

9 1 . Fisher CM: Concerning recurrent transientcerebral ischemic attacks. Canad Med Assoc J86: 1091-1099, 1962

92. Millikan CH: The pathogenesis of transientfocal cerebral ischemia. Circulation 32: 438-450, 1965

93. Olivarius B de Fine: Cerebral manifestationsin thrombocythemia. Acta Psychiat NeurolScand 32: 77-82, 1957

94. Levine J, Swanson PD: Idiopathic thrombocy-tosis. A treatable cause of transient ischemicattacks. Neurology (Minneap) 18: 711-713,1968

95. Siekert RG, Whisnant JP, Millikan CH:Anemia and intermittent focal cerebral arteri-al insufficiency. Arch Neurol (Chicago) 3:386-390, 1960

96. Meyer JS, Portnoy HD: Localized cerebralhypoglycemia simulating stroke. Neurology(Minneap) 8 :601-614,1958

97. Richardson JS, Chambers RA, Heywood PM:Encephalopathies of anoxia and hypoglyce-mia. Arch Neurol (Chicago) 1 : 178-190,1959

98. Boldrey E, Maass L, Miller E: The role ofatlantoid compression in the etiology ofinternal carotid thrombosis. J Neurosurg 13:127-139, 1956

99. Sheehan S, Bauer RB, Meyer JS: Vertebralartery compression in cervical spondylosis.Arteriographic demonstration during life ofvertebral artery insufficiency due to rotationand extension of the neck. Neurology (Min-neap) 10: 968-986, 1960

100. Toole JF, Tucker SH: Influence of headposition upon cerebral circulation. ArchNeurol (Chicago) 2 :616-623, 1960

101. Bauer RB, Sheehan S, Meyer JS: Arterio-graphic study of cerebrovascular disease. I I .Cerebral symptoms due to kinking, tortuosity,

and compression of carotid and vertebralarteries in the neck. Arch Neurol (Chicago)4 : 119-131, 1961

102. Metz H, Murray-Leslie RM, Bannister RG, eta l : Kinking of the internal carotid artery inrelation to cerebrovascular disease. Lancet I :424-426, 1961

103. Derrick JR, Smith T: Carotid kinking as acause of cerebral insufficiency. Circulation25:849-853, 1962

104. Henly WS, Cooley DA, Gordon WB, et al :Tortuosity of the internal carotid artery.Postgrad Med 3 1 : 133-144, 1962

105. Weibel J, Fields WS: Tortuosity, coiling, andkinking of the internal carotid artery. Neurol-ogy (Minneap) 15:462-468, 1965

106. Contorni L: II circolo collaterale vertebro-vertebrale nella obliterazione dell'arteria suc-clavia alia sue origine. Minerva Chir 15: 268-271, 1960

107. Reivich M, Holling H, Roberts B, et a l :Reversal of blood flow through the vertebralartery and its effect on cerebral circulation.New Eng J Med 265: 878-885, 1961

108. Editorial article: A new vascular syndrome—"The subclavian steal." New Eng J Med 265:912-913, 1961

109. North RR, Fields WS, DeBakey ME, et al :Brachial-basilar insufficiency syndrome. Neu-rology (Minneap) 12: 810-820, 1962

1 10. Toole JF: Reversed vertebral-artery flow.Subclavian-steal syndrome. Lancet I : 872-873,1964

111. Killen DA, Foster JH, Gobbel WG, et a l : Thesubclavian steal syndrome. J Thorac Cardio-vascSurg 5 1 : 539-560, 1966

112. Larsen PS, Nielsen JA: Subclavian stealsyndrome. Ugeskr Laeg 131 : 835-838,1969

113. Russell DS: Spontaneous intracranial haemor-rhage. Proc Roy Soc Med 47: 689-693, 1954

1 14. Cohen M M : Cerebrovascular accidents (Astudy of two hundred one cases). Arch Path60:296-307, 1955

1 15. Mutlu N, Berry RG, Alpert BJ: Massivecerebral hemorrhage. Arch Neurol (Chicago)8 :644-661, 1963

116. Cole FM, Yates PO: Comparative incidence ofcerebrovascular lesions in normotensive andhypertensive patients. Neurology (Minneap)18:255-259, 1968

117. Kannel WB: An epidemiologic study ofcerebrovascular disease. In Millikan CH,Siekert RG, Whisnant JP (eds) : CerebralVascular Diseases. Fifth Conference. Grune &Stratton, New York, 1 966

118. Hudson AJ, Hyland HH: Hypertensive cere-brovascular disease: A clinical and pathologic

352 Strokm, Vol. 2, July-August 7971



ownloaded from



review of 100 cases. Ann Int Med 49: 1049-1072, 1958

119. Leishman A W D : Merits of reducing highblood pressure. Lancet I: 1284-1288, 1963

120. Hood B, Bjork S, Sannerstedt R, et a l :Analysis of mortality and survival in activelytreated hypertensive disease. Acta Med Scand174: 393-406, 1963

121. Charcot J -M, Bouchard C: Nouvelles re-cherches sur la pathogenie de I'hemorrhagiecerebrale. Arch de Physiol Norm et Pathol 1 :110-127, 643-665, 725-734, 1868

122. Russell RW Ross: Observations of intracere-bral aneurysms. Brain 86: 425-442, 1963

123. Dinsdale HB: Spontaneous hemorrhage in theposterior fossa. Arch Neurol (Chicago) 10:200-217, 1964

124. Cole FM, Yates PO: The occurrence andsignificance of intracerebral microaneurysms.J Path Bact 93 : 393-41 1, 1967

125. Cole FM, Yates PO: Intracerebral micro-aneurysm and small cerebrovascular lesions.Brain 90: 759-768, 1967

126. Bruetman ME, Fields WS, Crawford ES, et a l :Cerebral hemorrhage in carotid artery sur-gery. Arch Neurol (Chicago) 9: 458-467,1963

127. Wylie EJ, Hein MF, Adams JE: Intracranialhemorrhage following surgical revasculariza-tion for treatment of acute strokes. J Neuro-surg 2 1 : 212-215, 1964

128. Gonzalez LL, Lewis CM: Cerebral hemorrhagefollowing successful endarterectomy of theinternal carotid artery. Surg Gynec Obstet122: 773-777, 1966

129. Kety SS, Schmidt CF: The nitrous oxidemethod for the quantitative determination ofcerebral blood flow in man: Theory, proce-dure and normal values. J Clin Invest 27 :476-483, 1948

130. Ingvar DH, Cronqvist S, Ekberg R, et a l :Normal values of regional cerebral blood flowin man, including flow and weight estimatesof grey and white matter. Acta Neurol Scand(Suppl 14) : 72-78, 1965

131. H0edt-Rasmussen K: Regionol cerebral bloodflow. The intra-arterial injection method.Thesis, Munksgaard, Copenhagen, 1967

132. Lassen NA: Cerebral blood flow and oxygenconsumption in man. Physiol Rev 39: 183-238, 1959

133. Lassen NA: Autoregulation of cerebral bloodflow. Circulation Research 15 (Suppl 1) : 2 0 1 -204, 1964

134. Hdggendal E, Johansson B: Effects of arterialcarbon dioxide tension and oxygen saturationon cerebral blood flow autoregulation in dogs.Acta Physiol Scand (Suppl 258) : 27-53,1965

135. Harper A M : Autoregulation of cerebral bloodflow: Influence of the arterial blood pressureon the blood flow through the cerebral cortex.J Neurol Neurosurg Psychiat 29: 398-403,1966

136. Agnoli A, Fieschi C, Bozzao L, et a l :Autoregulation of cerebral blood flow. Stud-ies during drug-induced hypertension innormal subjects and in patients with cerebralvascular diseases. Circulation 38: 800-812,1968

137. Fog M : Om piaarteriernes vasomotoriskereaktioner. Thesis, Munksgaard, Copenhagen,1934

138. Fog M : Cerebral circulation. I. The reactionof the pial arteries to a fall in blood pressure.Arch Neurol Psychiat (Chicago) 37 : 351-364,1937

139. Fog M : Cerebral circulation. I I . Reaction ofpial arteries to increase in blood pressure.Arch Neurol Psychiat (Chicago) 41 : 260-268,1939

140. Forbes HS, Nason Gl, Wortman RC: Cerebralcirculation. XLIV. Vasodilation in the piafollowing stimulation of the vagus, aortic andcarotid sinus nerves. Arch Neurol Psychiat(Chicago) 37: 334-350, 1937

141. Hdggendal E, Lofgren J, Nilsson NJ, et a l :Effects of varied cerebrospinal fluid pressureon cerebral blood flow in dogs. Acta PhysiolScand 79: 262-271, 1970

142. Wolff HG, Forbes HS: The cerebral circula-tion. Arch Neurol Psychiat (Chicago) 20 :1035-1047, 1928

143. Fog M : Influence of intracranial hypertensionupon the cerebral circulation. Acta PsychiatNeurol Scand 8: 191-198, 1933

144. Jacobson I, Harper AM, McDowall DG:Relationship between venous pressure andcortical blood flow. Nature (London) 200:173-175, 1963

145. Kety SS, Schmidt CF: The effects of activeand passive hyperventi lotion on cerebralblood flow, cerebral oxygen consumption,cardiac output and blood pressure of normalyoung men. J Clin Invest 25: 107-1 19,1946

146. Kety SS, Schmidt CF: The effects of alteredarterial tensions of carbon dioxide andoxygen on cerebral blood flow and cerebraloxygen consumption of normal young men. JClin Invest 27 : 484-492, 1948

147. Alexander SC, Wollman H, Cohen PJ, et a l :Cerebrovascular response to Pa r 0 o duringhalothane anesthesia in man. J Appl Physiol19 :561-565, 1964

148. Reivich M : Arterial Pco->a n c ' cerebral

hemodynamics. Amer J Physiol 206: 25-35,1964

Stroke, Vol. 2, July-August 1971 353



ownloaded from


PAULSON

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

Harper AM, Glass H I : Effect of alterations inthe arterial carbon dioxide tension on theblood flow through the cerebral cortex atnormal and low arterial blood pressures. JNeurol Neurosurg Psychiat 28: 449-452,1965Skinh0j E, Paulson OB: Carbon dioxide andcerebral circulatory control. Arch Neurol(Chicago) 20 :249-252, 1969Severinghaus JW, Lassen N: Step hypocapniato separate arterial from tissue Pc 0 in theregulation of cerebral blood flow. CirculationResearch 20: 272-278, 1967Ingvar DH, Lassen NA, Siesjo BK, et al (eds) :I I I . International symposium on cerebralblood flow and cerebrospinal fluid, Lund-Copenhagen. Scand J Clin Lab Invest (Suppl102) 1968

Gotoh F, Tazaki Y, Meyer JS: Transport ofgases through brain and their extravascularvasomotor action. Exp Neurol 4 : 48-58,1961Bentz E, Kozak R: Der Einfluss der Was-serstoffionenkonzentration der Gehimrindeauf die Regulation der corticalen Durchblu-tung. Pflijgers Arch ges Physiol 293: 56-67,1967Wahl M, Destjen P, Thurau K, et a l :Micropuncrure evaluation of the importanceof perivascular pH for the arreriolar diameteron the brain surface. Pfliigers Arch gesPhysiol 316: 152-163, 1970Crone C, Lassen NA (eds) : Capillary Perme-ability. Munksgaard, Copenhagen, 1970Severinghaus JW, Bradley AF: Electrodes forblood POij and Ppj-,,, determinations. J ApplPhysiol 13: 515-520" 1958Ingvar DH, Risberg J : Increase of regionalcerebral blood flow during mental effort innormals and in patients with focal braindisorders. Exp Brain Res 3: 195-21 1, 1967Skinh0j E: Regulation of cerebral blood flowas a single function of the interstitial pH inthe brain. A hypothesis. Acta Neurol Scand42: 604-607, 1966Siesio BK, Zwetnow N N : The effect ofhypovolemic hypotension on extra- and intra-cellular acid-base parameters and energymetabolites in the rat brain. Acta PhysiolScand 79: 114-124, 1970Sokoloff L: The action of drugs on thecerebral circulation. Pharmacol Rev 1 1 : 1 -85,1959Waltz AG, Yamaguchi T, Regli F: Cerebralvascular reactivity after sympathetic denerva-tion. In Russell RW Ross (ed) : Brain andBlood Flow. London, Pitmans, 1971Gortstein U: Einzeldarstellungen aus dertheoretischen und klinischen medizin. Band

15: Der Himkreislauf unter dem Einflussvasoaktiver Substanzen. Dr. Alfred HuthigVerlag, Heidelberg, 1962

164. Gottstein U: The effect of drugs on cerebralblood flow especially in patients of older age.Pharmakopsych Neuro-Psychopharmako 2 :100-109, 1969

165. McHenry LC, Jaffe ME, Kawamura J, et a l :Effect of papaverine on regional blood flow infocal vascular disease of the brain. New Eng JMed 282: 1 167-1 170, 1970

166. Olesen J, Paulson OB: The effect of intra-arterial popoverine on the regional cerebralblood flow in patients with apoplexy orintracranial tumor. Stroke 2 : 148-159,1971

167. Skinh0j E, Paulson OB: The mechanism ofaction of aminophylline upon cerebral vascu-lar disorders. Acta Neurol Scand 46: 129-140,1970

168. Lassen NA: The luxury-perfusion syndromeand its possible relation to acute metabolicacidosis localized within the brain. Lancet I I :1113-1115, 1966

169. Meyer JS, Denny-Brown D: The cerebralcollateral circulation. 1. Factors influencingcollateral blood flow. Neurology (Minneap)7: 447-458, 1957

170. Cotev S, Cullen D, Severinghaus J: CerebralECF acidosis induced by hypoxia at normaland low P,COo Scand J Clin Lab Invest(Suppl 102) : E, 1968

171. Schmahl FW, Betz E, Dettinger E, et a l : En-ergistoffwechsel der Grosshirnrinde und Elektro-encephalogramm bei Sauerstoffmangel. PfliigersArch ges Physiol 292: 46-59, 1966

172. Kaasik AE, Nilsson L, Siesjo BK: The effectof asphyxia upon lactate, pyruvate andbicarbonate concentrations of brain tissue andcisternal CSF, and upon the tissue concentra-tion of phosphocreotine and adenine nucleo-tides in anesthetized rats. Acta Physiol Scand78:433-447, 1970

173. Olesen J: Total CO2, lactate and pyruvate inbrain biopsies taken after freezing the tissuein situ. Acta Neurol Scand 46: 141-148,1970

174. Feindel W, Perot P: Red cerebral veins. Areport on arteriovenous shunts in tumors andcerebral scars. J Neurosurg 22: 315-325,1965

175. Waltz AG, Sundt TM Jr: The microvascula-ture and microcirculation of the cerebralcortex after arterial occlusion. Brain 90: 681 -696, 1967

176. Waltz AG: Red venous blood: Occurrence andsignificance in ischemic and nonischemiccerebral cortex. J Neurosurg 3 1 : 141-148,1969

354 Stroke, Vol. 2, July-August 1971



ownloaded from



177a. Sundt TM, Grant WC, Garcia JH: Restorationof middle cerebral artery flow in experimen-tal infarction. J Neurosurg 3 1 : 311-322,1969

177b. Sundt TM, Waltz AG: Cerebral ischemia andreactive hyperemia: Studies of cortical bloodflow and microcirculation before, during andafter temporary occlusion of middle cerebralartery of squirrel monkey. Circulation Research28: 426-433, 1971

178. Siesjo B, Nielsson L, Rokeach M, et a l : Energymetabolism of the brain at reduced cerebralperfusion pressures and in arterial hypoxe-mia. In Brierley JB (eds) : Brain Hypoxia, inpress

179. Grote J, Kreuscher H, Russ HJ, et a l : Theinfluence of Pa0 and Pv0 on the cerebralblood flow regulation under various acid-baseconditions. Pflugers Arch ges Physiol 319: R65-R 66, 1970

1 80a. Flohr H, Poll W, Brock M : Regulation of spinalcord blood flow. In Russell RW Ross (ed) :Brain and Blood Flow. London, Pitmans, 1971

1 80b. Winso I: Cerebral blood flow at hyperventila-tion. Thesis. Goteborg, Sweden, 1971

181. Waltz AG, Sundt TM Jr, Owen CA: Effect ofmiddle cerebral artery occlusion on corticalblood flow in animals. Neurology (Minneap)16: 1185-1190, 1966

182. Symon L: Effects of vascular occlusion onmiddle cerebral arterial pressure in dogs andmacacus rhesus. J Physiol 165: 62-63 P,1963

183. Brawley BW, Strandness DE, Kelly WA: Thephysiologic response to therapy in experimen-tal cerebral ischemia. Arch Neurol (Chicago)17: 180-187, 1967

184. Shalit M N : Some hemodynamic aspects ofregional brain ischemia. In Betz E, Wiillen-weber R (eds) : Pharmakologie der lokalenGehirndurchblutung. Messmethoden undErgebnisse. "Arztliche Forschung" Sonder-band. Werk-Verlag, Dr. Edmund Banaschew-ski, Munchen-Grafelfing, 1969

185. Meyer JS, Fang HC, Denny-Brown D: Polaro-graphic study of cerebral collateral circula-tion. Arch Neurol Psychiat (Chicago) 72:296-312, 1954

186. Fieschi C, Agnoli A, Battistini N, et a l :Derangement of regional cerebral blood flowand of its regulatory mechanisms in acutecerebrovascular lesions. Neurology (Min-neap) 18: 1166-1179, 1968

187. Blair G, Waltz AG: Regional cerebral bloodflow during acute ischemia: Correlation ofautoradiographic measurements with observa-tions of cortical microcirculation. Neurology(Minneap) 20 :802-808, 1970

188. Kindt GW, Youmans JR, Albrand O: Factors

influencing the autoregulation of the cerebralblood flow during hypotension and hyperten-sion. J Neurosurg 26: 299-305, 1967

189. Waltz AG: Effect of blood pressure on bloodflow in ischemic and in nonischemic cerebralcortex. The phenomena of autoregulation andluxury perfusion. Neurology (Minneap) 18:613-621, 1968

190. Waltz AG: Effect of PaCOo on blood flow andmicrovasculature of ischemic and nonische-mic cerebral cortex. Stroke 1 : 27-37, 1970

191. Regli F, Yamaguchi T, Waltz AG: Effects ofinhalation of oxygen on blood flow andmicrovasculature of ischemic and non-ischemic cerebral cortex. Stroke 1 : 314-319,1970

192. H0edt-Rasmussen K, Skinh0j E, Paulson O, eta l : Regional cerebral blood flow In acuteapoplexy. The "luxury perfusion syndrome"of brain tissue. Arch Neurol (Chicago) 17:271-281, 1967

193. Fieschi C, Agnoli A, Prencipe M, et a l :Impairment of the regional vasomotor re-sponse of cerebral vessels to hypercarbia invascular diseases. Europ Neurol 2 : 13-30,1969

194. Huber P: Functional tests in angiography ofcerebrovascular disease. Neuroradiology 1 :122-131, 1970

195. Halsey JH, Clark LC: Some regional circula-tory abnormalities following experimentalcerebral infarction. Neurology (Minneap)20:238-246, 1970

196. Ralston B, Rasmussen T, Kennedy T: Occlu-sion of the middle cerebral artery. Undernormotension, and anemically induced andchemically induced hypotension. J Neurosurg12:26-33, 1955

197. Soloway M, Nadel W, Albin MS, et a l : Theeffect of hyperventi lotion on subsequentcerebral infarction. Anesthesiology 29: 975-980, 1968

198. Battistini N, Casacchia M, Fieschi C, et a l :Treatment of experimental cerebral infarc-tion with passive hyperventilation. In. RussellRW Ross (ed) : Brain and Blood Flow. London,Pitmans, 1971

199. Brock M, Hadjidimos AA, Schiirmann K:Possible adverse effects of hyperventilationon rCBF during the acute phase of totalproximal occlusion of a main cerebral artery.In Brock M, Fieschi C, Ingvar DH, et al(eds) : Cerebral Blood Flow. Springer-Verlag,Berlin, Heidelberg, New York, 1969

200. Paulson OB, Olesen J, Christensen MS:Restoration of autoregulation of cerebralblood flow by hypocapnia. Neurology (Minne-ap), in press

Strok; Vol. 2, July-August 7977 355



ownloaded from


PAULSON

201. Kpgure K, Fujishima M, Scheinberg P, et a l :Effects of changes in carbon dioxide pressureand arterial pressure on blood flow inischemic regions of the brain in dogs.Circulation Research 24: 557-565, 1969

202. Yamamoto YL, Hodge CP, Phillips KM, et a l :Microflow patterns after experimental occlu-sion of middle cerebral artery demonstratedby fluorescein angiography and 133-Xenonclearance. In Brock M, Fieschi C, Ingvor DH,et al (eds) : Cerebral Blood Flow. Springer-Verlag, Berlin, Heidelberg, New York,1969

203. Sundt TM, Waltz AG: Experimental cerebralinfarction: Retro-orbital, extradural approachfor occluding the middle cerebral artery. MayoClin Proc 41 : 159-168, 1966

204. Meyer JS: Importance of ischemic damage tosmall vessels in experimental cerebral infarc-tion. J Neuropath Exp Neural 17: 571-585,1958

205. Zaren MA, Weinstein JD, Langfirt TW:Experimental ischemic brain swelling. J Neu-rosurg 32 :227-235, 1970

206. Lee JC, Olszewski J : Effect of air embolismon permeability of cerebral blood vessels.Neurology (Minneap) 9 :619-625, 1959

207. Spector RG: Water content of the brain inanoxic-ischemic encephalopathy in adult rats.Brit J Exp Path 42 : 623-630, 1961

208. Hills CP, Spector RG: Anoxia and cerebralwater content in the adult rat. Nature(London) 199: 393, 1963

209. Plum F, Posner JB, Ellsworth CA: Edema andnecrosis in experimental cerebral infarction.Arch Neurol (Chicago) 9: 563-570, 1963

210. Wyke B: Brain Function and MetabolicDisorders. Butterworths, London, 1 963

211. Cronqvist S, Laroche F: Transitory "hy-peremia" in focal cerebral vascular lesionsstudied by angiography and regional cerebralblood flow measurements. Brit J Radiol 40:270-274, 1967

212. Cronqvist S: Regional cerebral blood flowand angiography in apoplexy. Acta RadiolDiagnosis 7: 521-534, 1968

213. Woringer E, Baumgartner J, Braun JP: Lesigne de I'opacification veineuse locor£gionaleprecoce au cours de la se>ioangiographierapide carotidienne. Acta Radiol (Stockholm)50: 125-131, 1958

214. Lanner LO, Rosengren K: Angiographicdiagnosis of intracerebral vascular occlusions.Acta Radiol Diagnosis 2: 129-137, 1964

215. Taveras JM, Wood EH: Diagnostic Neurora-diology. Williams and Wilkins, Baltimore,1964

216. Ferris EJ, Shopiro JH, Simeone FA: Arterio-venous shunting in cerebrovascular occlusive

disease. Amer J Roentgen 98: 631-636,1966

217. Fieschi C, Battistini N, Nardini M: Experi-mental cerebral infarction: Focal or perifocalreactive hyperemia and its relationship withthe red softening. In Meyer JS, Reivich M,Lechner H, et al (eds) : Research on the cere-bral circulation. Fourth International SolzburgConference, CC Thomas, Springfield, Illinois,1970

218. Betz E, Heuser D: Cerebral cortical bloodflow during changes of acid-base equilibriumof the brain. J Appl Physiol 23: 726-733,1967

219. Fazio C: Red softening of the brain. JNeuropath Exp Neurol 8: 43-60, 1949

220. Fisher M, Adams RD: Observations on brainembolism with special reference to themechanism of hemorrhagic infarction. JNeuropath Exp Neurol 10: 92-93, 1951

221. Jorgensen L, Torvik A: Ischaemic cerebrovas-cular diseases in an autopsy series. Part 2.Prevalence, location, pathogenesis, and clini-cal course of cerebral infarction. J Neurol Sci9:285-320, 1969

222. Fazio C, Sacchi U: Experimentally producedred softening of the brain. J Neuropath ExpNeurol 13 :476-481 , 1954

223. Hain RF, Westhaysen PV, Swank RL: Hemor-rhagic cerebral infarction by arterial occlu-sion. J Neuropath Exp Neurol 1 1 : 34-43,1952

224. Denny-Brown D, Horenstein S, Fang HCH:Cerebral infarction produced by venous dis-tension. J Neuropath Exp Neurol 15: 146-180, 1956

225. Fieschi C, Agnoli A, Battistini N, et a l :Regional cerebral blood flow in patients withbrain infarcts. Arch Neurol (Chicago) 15:653-663, 1966

226. Jaffe ME, McHenry LC, Goldberg H I : Region-al cerebral blood flow measurements withsmall probes. Neurology (Minneap) 20 : 225-237, 1970

227. H0edt-Rasmussen K, Skinh0j E: Transneuraldepression of the cerebral hemispheric me-tabolism in man. Acta Neurol Scand 40 : 4 1 -46, 1964

228. Simard D, Olesen J, Paulson OB, et a l :Regional cerebral blood flow and its regula-tion in dementia. Brain, in press

229. Palvolgyi R: Regional cerebral blood flow inpatients with intracranial tumors. J Neurosurg3 1 : 149-163, 1969

230. Rees JE, du Boulay GH, Bull JWD, et a l :Regional cerebral blood-flow in transientischaemic attacks. Lancet I I : 1210-1213,1970

356 Stroke, Vol. 2, July-Augutf 1971



ownloaded from



231. Paulson OB, Cronqvist S, Risberg J, et o l :Regional cerebral blood flow: A comparisonof 8-detector and 16-detector instrumentation.J Nucl Med 10: 164-173, 1969 244.

232. Agnoli A, Fieschi C, Prencipe M, et a l :Relationships between regional hemodynam-ics in acute cerebrovascular lesions andclinico-pathological aspects. In Meyer JS,Reivich M, Lechner H, et al : Research on the 245.Cerebral Circulation. Fourth InternationalSalzburg Conference, 1968, CC Thomas,Springfield, Illinois, 1970 246.

233. Alexander SC, Lassen NA: Cerebral circula-tory response to acute brain disease. Anesthe-siology 32: 60-68, 1 970 247.

234. Jacobsen H-H, Skinh0j E: Thrombosis of theinternal carotid artery verified by arteriogra-phy. Dan Med Bull 4 : 240-248, 1957 248.

235. Shanbrom E, Levy L: The role of systemicblood pressure in cerebral circulation incarotid and basilar artery thromboses. Clini-cal observations and therapeutic implicationof vasopressor agents. Amer J Med 23: 197- 249.204, 1957

236. Farhat SM, Schneider RC: Observations onthe effect of systemic blood pressure onintracranial circulation in patients with cere-brovascular insufficiency. J Neurosurg 27 :441-445, 1967

237. Oppelt WW, Maren TH, Owens ES, et a l : 250.Effects of acid-base alterations on cerebrospi-nal fluid production. Proc Soc Exp Biol Med114: 86-89, 1963 251 .

238. Soloway M, Moriarty G, Fraser JG, et a l : Theeffect of delayed hyperventilation on experi-mental middle cerebral occlusion. In Russel RWRoss (ed) : Brain and Blood Flow. London, 252.Pitmans, 1971

239. Yamaguchi T, Regli F, Waltz AG: Effect ofPaCOo on hyperemia and ischemia in experi-mental cerebral infarction. Stroke 2: 139- 253.147, 1971

240. Christensen MS: Stroke treated with pro-longed hyperventilation. In Russell RW Ross(ed) : Brain and Blood Flow. London, Pitmans,1971 254.

241. Boysen G, Ladegaard-Pedersen HJ, HenriksenH, et a l : Effect of Pa00 on regional cerebralblood flow and internal carotid artery pres-sure during carotid clamping. Anesthesiolog/,in press 255.

242. Pistolese GR, Citone G, Faraglla V, et a l :Effects of hypercapnia on cerebral blood flowduring the clamping of the carotid arteries in 256.surgical management of cerebrovascular in-sufficiency. Neurology (Minneap) 2 1 : 95-100, 1971

243. Ehrenfeld WK, Hamilton FN, Larson CP, et 257.a l : Effect of CO2 and systemic hypertension

Sfroka, Vol. 2, July-August 1977

on downstream cerebral arterial pressureduring carotid enda rterectomy. Surgery 67:87-96, 1970Fourcade HE, Larson CP, Ehrenfeld WK, eta l : The effects of C02 and systemic hyperten-sion on cerebral perfusion during carotidendarterectomy. Anesthesiology 33: 383-390,1970Mainzer F: Fruhbehandlung des Schlaganfallsmit Aminophylline. Schweiz Med Wschr 79:108-110, 1949Mainzer F: Treatment of incipient apoplexywith intravenous aminophylline. Acta MedScand 146: 362-374, 1953Olivarius B de Fine: Behandling af friskecerebrale infarkter med theofyllamin. UgeskrLaeg 123: 376-382, 1961Hadorn W: Berichterstattung iiber dieEuphyllin-Behandlung des Hirnschlags aufGrund der statistischen Verarbeitung von 705Fallen. Schweiz med Wschr 46: 1301-1302,1960Meyer JS, Gilroy J, Barnhart ME, et a l :Therapeutic thrombolysis in cerebral throm-boembolism: Randomized evaluation of intra-venous streptokinase. In Millikan CH, SiekertRG, Whisnant JP (eds) : Cerebral VascularDiseases. New York, Grune Gr Stratton,1965Riishede J, Ottosen P, Sjlndergaard T:Cerebral apoplexy. Dan Med Bull 7: 185-192,1960Gurdjian ES, Hardy WG, Lindner DW, et a l :Results of endarterectomy in the treatment ofcerebrovascular disease. Angiology 15: 88-102, 1964Thompson JE, Kartchner MM, Austin DJ, eta l : Carotid endarterectomy for cerebrovascu-lar insufficiency (stroke) : Follow-up of 359cases. Ann Surg 163:751-763, 1966Bauer RB, Meyer JS, Fields WS, et a l : Jointstudy of extracranial arterial occlusion. 111.Progress report of controlled study of long-term survival in patients with and withoutoperation. JAMA 208: 509-518, 1969Heyman A, Young WG Jr, Brown IW, et a l :Long-term results of endarterectomy of theinternal carotid artery for cerebral ischemiaand infarction. Circulation 36: 212-221,1967

Boysen G, Engell HC, Lauridsen P: Operationaf stenosis arteriae carotis internae hos 21patienter. Nord Med 79: 582-588, 1968Blaisdell WF, Clauss RH, Galbriath JG, et a l :Joint study of extracranial arterial occlusion.IV. A review of surgical considerations. JAMA209: 1889-1895, 1969Ingvar DH, Lassen NA: Treatment of focalcerebral ischemia with hyperbaric oxygen.

357



ownloaded from


PAULSON

Report of 4 cases. Acta Neurol Scand 41 : 92-95, 1965

258. Smith G: Experimental and clinical results inthe treatment of cerebral hypoxia by hyper-baric oxygenation. In Millikan CH, SiekertRG, Whisnant JP (eds) : Cerebral VascularDiseases. Fourth Conference, Grune £r Strat-ton, New York, London, 1 965

259. Heyman A, Saltzman HA, Whalen RE: Theuse of hyperbaric oxygenation in the treat-ment of cerebral ischemia and infarction.Circulation 33 (Suppl II) : 20-27, 1966

260. Arnfred I, Secher O: Anoxia and barbiturates.Tolerance to anoxia in mice influenced bybarbiturates. Arch Int Pharmacodyn 139: 67-74, 1962

261. Wilhjelm BJ, Arnfred I: Protective action ofsome anaesthetics against anoxia. Acta Phar-macol 22 : 93-98, 1965

262. Goldstein A Jr, Wells BA, Keats AS: Increasedtolerance to cerebral anoxia by pentobarbital.Arch Int Pharmacodyn 161: 138-143, 1966

263. Myschetzky A : Suicidal and accidental intoxi-cations. Dan Med Bull 5: 131-137, 1958

264. Rosomoff HL: Hypothermia and cerebralvascular lesions. 1. Experimental interruptionof the middle cerebral artery during hypo-thermia. J Neurosurg 13: 332-343, 1956

265. Boschenstein FK, Reilly JA, Yahr MD, et a l :Effect of low molecular weight dextran oncortical blood flow. Arch Neurol (Chicago)14:288-293, 1966

266. Sundt T M Jr, Waltz AG: Hemodilution andanticoagulation. Effects on the microvascula-ture and microcirculation of the cerebralcortex after arterial occlusion. Neurology(Minneap) 17:230-238,1967

267. Waltz AG, Meyer JS: Effects of changes incomposition of plasma on pial blood flow. I I .High molecular weight substances, bloodconstituents and tonicity. Neurology (Minneap)9: 815-825, 1959

268. Haggendal E, Norbdck B: Effect of viscosityon cerebral blood flow. Acta Chir Scand(Suppl 364) : 13-22, 1966

269. Gottsten U, Held K: Effekt der Hamodilutionnach intravenoser Infusion von niedermoleku-laren Dextranen auf die Hirnzirkulation desMenschen. Dtsch Med Wschr 1 1 : 522-526,1969

270. Jarnum S, Lorenzen I, SkinhpSj E: Cisternalfluid oxygen tension in man. Neurology(Minneap) 14:703-707, 1964

271. Cyrus AE Jr, Close AS, Foster LL, et a l : Effectof low molecular weight dextran on infarctionafter experimental occlusion of the middlecerebral artery. Surgery 52: 25-30, 1962

272. Sundt TM Jr, Waltz AG, Soyre GP: Experi-mental cerebral infarction: Modification by

treatment with hemodiluting hemoconcentrat-ing and dehydrating agents. J Neurosurg 26:46-56, 1 967

273. Gilroy J, Barnhart M l , Meyer JS: Treatmentof acute stroke with dextran 40. JAMA 210:293-298, 1969

274. Bakay L, Lee JC: Cerebral Edema. Charles CThomas, Springfield, Illinois, 1965

275. Harper AM, Bell RA: The failure of intrave-nous urea to alter the blood flow through thecerebral cortex. J Neurol Neurosurg Psychiat26 :69-70, 1963

276. Tzonos T: Experimentelle Untersuchungenzur Beeinflussung des Hirnodems im Model-Iversuch. Dtsch Z Nervenheilk 188: 12-24,1966

277. Molinari GF, Pircher F, Heyman A : Serialbrain scanning using technetium 99m inpatients with cerebral infarction. Neurology(Minneap) 17:627-636, 1967

278. Paulson OB, Bjerrum JK, Fahrenkrug A:Hjernescanning med «idioaktive isotoper.Ugeskr Laeg 131: 1043-1050, 1969

279. Galicich JH, French LA, Melby JC: The use ofdexamethasone in the treatment of cerebraledema with brain tumors. J Lancet 81 : 46-53,1961

280. Rovit RL, Hagan R: Steroids and cerebraledema: The effects of glucocorticoids onabnormal capillary permeability followingcerebral injury in cats. J Neuropath Exp Neurol27:277-299, 1968

281. Plum F, Alvord EC Jr, Posner JB: Effect ofsteroids on experimental cerebral infarction.Arch Neurol (Chicago) 9 :571-573, 1963

282. Dyken M, White PT: Evaluation of cortisonein the treatment of cerebral infarction. JAMA162: 1531-1534, 1956

283. Fisher CM: The use of anticoagulants incerebral thrombosis. Neurology (Minneap)8: 311-332, 1958

284. Carter AB: Anticoagulant treatment in pro-gressing stroke. Brit Med J 2 : 70-73, 1961

285. Baker RN, Broward JA, Fang HC, et a l :Anticoagulant therapy in cerebral infarction.Neurology (Minneap) 12:823-835, 1962

286. Carter AB: The immediate treatment ofnonembolic hemiplegic cerebral infarction.Quart J Med 28: 125-140, 1 959

287. Marshall J, Shaw DA: Anticoagulant therapyin acute cerebrovoscular accidents. A con-trolled trial. Lancet I : 995-998, 1960. .

288. Dalsgaard-Nielsen T, Skinh0j E: Antikoagu-lationbehandlung von Patienten mit Throm-bosis Cerebri. Confin Neurol (Basel) 17: 315-327, 1957

289. Groch SN, McDevitt E, Wright IS: A long-term study of cerebral vascular disease. AnnInt Med 55: 358-367, 1961

358 Sirok; Vol. 2, July-Augutt 1971



ownloaded from



290. Hansen OE, Lund M: Antikoagulansbehan- 306.dling af det akutte, cerebrale infarkt. UgeskrLaeg 124: 1719-1723, 1962

291. Carter AB: The immediate treatment ofcerebral embolism. Quart J Med 26: 335-338, 307.1957

292. Mackey WA, Scott LDW: Treatment ofapoplexy by infiltration of the stellate gang- 308.lion with Novocaine. Brit Med J 2 : 1-4,1938

293. Naffziger HC, Adams JE: Role of stellateblock in various intracranial pathologic states. 309.Arch Surg 61 : 286-293, 1950

294. Walsh RC: Stellate ganglion block in thetreatment of cerebrovascular disease. ProcRoy Soc Med 49: 161-164, 1955 310.

295. Millikan CH, Lundy JS, Smith LA: Evaluationof stellate ganglion block for acute focalcerebral infarcts. JAMA 151: 438-440,1953

296. Carter AB: Cerebral Infarction. London,Pergamon Press, 1964

297. Gilroy J, Meyer JS: Controlled evaluation of 311.cerebral vasodilator drugs in the progressivestroke. In Millikan CH, Siekert RG, WhisnantJP (eds) : Cerebral Vascular Diseases. Fifth 312.Conference, New York, Grune £r Stratton,1966

298. Marshall J : The natural history of transientischaemic cerebrovascular attacks. Quart J 313.Med 33: 309-324, 1964

299. Baker RN, Ramseyer JC, Schwartz WS:Prognosis in patients with transient cerebralischemic attacks. Neurology (Minneap) 18: 314.1157-1 165, 1968

300. Friedman GD, Wilson WS, Moiser JM, et a l :Transient ischemic attacks in a community.JAMA 210: 1428-1434, 1969 315.

301. Pincock JG: The natural history of cerebralthrombosis. Ann Int Med 46: 925-930,1957

302. Marshall J, Shaw DA: The natural history ofcerebrovascular disease. Brit Med J 1 : 1614-1617, 1959 316.

303. Robinson RW, Cohen WD, Higano N, et a l :Life-table analysis of survival after cerebralthrombosis; ten-year experience. JAMA 161:1149-1155, 1959 317.

304. Marshall J, Kaeser AC: Survival after non-haemorrhagic cerebrovascular accidents. Aprospective study. Brit Med J 2 : 73-77, 318.1961

305. Thygesen P, Christensen E, Dyrbye M, et a l :Cerebral apoplexy. A clinical, radiological, 319.electroencephalographic and pathologicalstudy with special reference to the prognosisof cerebral infarction and the result of long- 320.term anticoagulation therapy. Dan Med Bull11:233-257, 1964

Katz S, Ford AB, Chinn AB, et a l : Prognosisafter strokes. I I . Long-term course of 159patients. Medicine (Baltimore) 45: 236-246,1966Ford AB, Katz S: Prognosis after strokes. I. Acritical review. Medicine (Baltimore) 45:223-236, 1966Baker RN, Schwartz WS, Ramseyer JC:Prognosis among survivors of ischemicstroke. Neurology (Minneap) 18: 933-941,1968Marquardsen J : The natural history of acutecerebrovascular disease. A retrospective studyof 769 patients. Thesis. Munksgaard, Copen-hagen, 1969Fields WS, Maslenikov V, Meyer JS, et a l :Joint study of extracranial arterial occlusion.V. Progress report of prognosis followingsurgery or nonsurgical treatment for transientcerebral ischemic attacks and cervical carotidartery lesions. JAMA 211: 1993-2003,1970Silverstein A: Arteriography of stroke: I I I .Complications. Arch Neurol (Chicago) 15:206-210, 1966Hass WK, Fields WS, North RR, et a l : Jointstudy of extracranial arterial occlusion. I I .Arteriography techniques, sites, and complica-tions. JAMA 203 : 961-968, 1968Siekert RG, Millikan CH, Whisnant JP:Anticoagulant therapy in intermittent cere-brovascular insufficiency. Follow-up data.JAMA 176: 19-22, 1961Siekert RG, Whisnant JP, Millikan CH:Surgical and anticoagulant therapy of occlu-sive cerebrovascular disease. Ann Int Med 58:637-641, 1963Report of the Veterans Administration Co-operative Study of Atherosclerosis, NeurologySection. An evaluation of anticoagulant thera-py in the treatment of cerebrovascular dis-ease. Neurology (Minneap) 11 (#4, part 2) :132-138, 1961

Baker RN, Schwartz WS, Rose AS: Transientischemic strokes. A report of a study ofanticoagulant therapy. Neurology (Minneap)16:841-847, 1966Pearce MJS, Gubbay SS, Walton JN: Long-term anticoagulant therapy in transient cere-bral ischemic attacks. Lancet 1: 6-9, 1965McDevitt E, Carter SA, Gotje BW, et a l : Use ofanticoagulants in treatment of cerebral vascu-lar disease. JAMA 166: 592-597, 1958Hill AB, Marshall J, Shaw DA: Cerebrovascu-lar disease: A trial of long-term anticoagulanttherapy. Brit Med J 2 : 1003-1006, 1962McDoewll F, McDevitt E, Wright IS: Antico-agulant therapy. Arch Neurol (Chicago) 8:209-214, 1963

Stroke, Vol. 2, July-Augutt 7971 359



ownloaded from


PAULSON

321 . Emmons PR, Harrison MJ, Honour AJ, et a l :Effect of dipyridamole on human plateletbehavior. Lancet I I : 603-606, 1965

322. Emmons PR, Harrison MJ, Honour AJ, et a l :Effect of pyrimidopyrimidine derivation onthrombus formation in rabbit. Nature (Lon-don) 208:255-257, 1965

323. Sullivan JM, Harken DE, Gorlin R: Pharma-cologic control of thromboembolic complica-tions of cardiac-valve replacement. New Eng JMed279 : 576-580, 1968

324. Acheson J, Danta G, Hutchinson EC: Con-trolled trial of dipyridamole in cerebralvascular disease. Brit Med J 1 : 614-615,1969

325. Farmer RG, Gifford RW Jr, Hines EA Jr:

Effect of medical treatment of severe hyper-tension. A follow-up study of 161 patientswith group 3 and group 4 hypertension. ArchIntMed 112: 118-128, 1963

326. Hood B, Aurell M, Falkheden T, et a l : Activeantihypertensive treatment and cerebrovascu-lar lesions. In Millikan CH, Siekert RG,Whisnant JP (eds) : Cerebral Vascular Dis-eases. Fifth Conference. New York, Grune &Stratton, 1966

327. Hodge JV, Smirk FH: The effect of drugtreatment of hypertension on the distributionof deaths from various cases. Amer Heart J73: 441-452, 1967

328. Carter AB: Hypotensive therapy in strokesurvivors. Lancet I: 485-489, 1969

360 Stroke, Vol. 2, July-Augusi 1977



ownloaded from


OLAF B. PAULSONRegional Blood Flow Measurements in the Brain

Cerebral Apoplexy (Stroke): Pathogenesis, Pathophysiology and Therapy as Illustrated by

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