Ischaemic cerebrovascular diseases in an autopsy series

490

JOURNAL OF THE NEUROLOGICAL SCIENCES

Ischaemic Cerebrovascular Diseases in an Autopsy Series Part 1. Prevalence, Location and Predisposing Factors in Verified Thrombo-embolic Occlusions, and their Significance in the Pathogenesis of Cerebral Infarction L. Jt3RGENSEN AND A. TORVIK Department of Pathology, Ullevdl Hospital, Oslo (Norway)

(Received 8 April, 1965)

INTRODUCTION The present study represents an analysis of the thrombo-embolic cerebrovascular occlusions in 994 consecutive autopsies performed at the Department o f Pathology, UllevcllHospital, Oslo. Accounts of the carotid occlusions in this material have already been published (ToRVIK AND J6RGENSEN 1964, 1966). Further details as to the brain infarcts will be published later (J6RGENSEN AND TORVIK 1966). In this article, 4 aspects of the ischaemic cerebrovascular diseases will be considered in some detail: (1) the frequency of thrombo-embolic occlusions, and their r61e in cerebral infarction; (2) the location of verified occlusions; (3) the frequency of thrombotic versus embolic occlusions, and their distribution according to age and sex; and (4) predisposing factors for the precipitation of thrombo-embolic occlusions. SURVEYOF THE LITERATURE In most autopsy series, an occlusion o f relevant arteries has been found in one-half of the cerebral infarcts, or a little less (Foix et al. 1927; ARING 1945; POPPER 1949; HICKS AND WARREN 1951). The underlying disorder in the large number of infarcts without vascular occlusion has often been ascribed to vasospasm, or in later years to 'cerebrovascular insufficiency'caused by a reductionin blood pressure or diminished cardiac output. In the opinion of ADAMSand co-workers, however, such mechanisms play a decisive r61e in only a small proportion of the cerebral infarcts. These authors stated that thrombotic or embolic occlusions are to be found in 90-959/0 of all large, recent infarcts, and in 80-85 ~o of all recent infarcts (ADAMS AND VANDER EECKEN 1953; ADAMSAND FISHER 1961; TORVIKet al. 1965). Similarly, ALAJOUANINE et al. (1959) maintained that vascular occlusions are demonstrable in more than twothirds of all cases with cerebral infarcts. Most angiographic studies have demonstrated vascular occlusions in about onehalf of the cases with suspected ischaemic cerebrovascular attacks (I~dlSrtEDE 1957; J. neurol. Sci. (1966) 3:490-509

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REISNER 1958; TATELMAN1958; McDOWELL et al. 1959; BULL et al. 1960; OLIVARIUS 1961; LIKEN 1963; HANS 1963). By means o f post mortem angiography, STEIN et al. (1962) found significant stenotic or occlusive disease in every case, as well as in 22% of a large number of asymptomatic cases. Many authors have considered the combination of multiple intra- and extracranial stenoses or occlusions to be important in the pathogenesis of infarction (Y'ATESAND HUTCHINSON 1961 ; STEINet al. 1962). Many of the occlusions and stenoses described in angiographic series undoubtedly represent atherosclerotic lesions. The significance of such lesions is difficult to evaluate, since they are often found in asymptomatic cases also (MARTINe t al. 1960; SCHWARTZ AND MITCHELL 1961 ; STEIN et al. 1962; SVAREet aL 1964). Only few investigators have taken into account that many infarcts which cause symptoms are so small that if they are caused by occlusion of minor arteries, the relevant vascular occlusion can easily be overlooked both by angiography and gross post mortem examination. However, by dint of careful histological examination, WINTER AND GYORI (1960) found occlusion of small arterial branches in 18 of 21 small infarcts. These findings might indicate that infarcts are caused by vascular occlusions more often than is generally believed. The most important practical point concerning the location of cerebrovascular occlusions may be the frequency of symptomatic extracranial occlusions. This has been studied in several large angiographic series. According to these reports, extracranial occlusions or stenoses are present in from 20 to 60% of all cases with cerebrovascular disease (CRAWFORDet al. 1960; RIISHEDEet al. 1960; GURDJIAN et al. 1960, 1961; HASS 1963; PRIBRAM 1963). YATES AND HUTCHINSON (1961) alone have made extensive post m o r t e m studies on the entire cerebrovascular tree in cerebral infarction. Their study comprised 74 non-embolic infarcts in 35 cases. All except 3 of these cases showed significant stenosis or occlusion of the extracranial vessels, while 45°/0 of the cases showed no significant lesions of the intracranial vessels. Thirty of the occlusions were thrombotic. Sixteen thrombi were extracranial, of which 6 were in the vertebral arteries. In the opinion of YATES AND HUTCHINSON 'cerebral infarction has rarely a single cause and is usually the result of a combination of systemic disease and stenoses of extracranial and intracranial cerebral arteries, or both (the extracranial arteries being more often associated with infarction than the intracranial)'. Since many of the reported extracranial lesions are atherosclerotic stenoses, which are known also to be common in asymptomatic cases, their pathogenic significance must be interpreted with care (GURDJIAN et al. 1961 ; STEINet al. 1962; LOWE 1962). The frequency of cerebral embolism varies from one report to another. In most clinical and p o s t m o r t e m studies, between 5 and 20% of infarcts have been considered embolic (MERRITT AND ARING 1938; MERRITT 1955; GLYNN 1956; DALSGAARDNIELSEN 1955; DELACHAUX 1959; CARTER 1960; GORMSEN et al. 1961; SCHEID 1961). These figures contrast sharply with those of ADAMS and his co-workers who have found almost one-half of the infarcts to be embolic (ADAMS AND COHEN 1947; ADAMS AND VANDER EECKEN 1953; TORVIK et aL 1965). These divergencies are probably due mainly to different criteria used in the classification of the lesions. There is general agreement that cerebral atherosclerosis is the main predisposing f a c t o r in cases of non-embolic cerebral infarction. Infarcts may be precipitated by J. neurol. Sci. (1966) 3:490-509

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L. Jt)RGENSEN, A. TORV1K

the atherosclerotic stenoses alone, or by superimposed thrombi. Most authors have also found a high incidence of hypertension in cases with brain infarction (see S~LVERSTEINAND DONIGER 1963). Although it may be uncertain whether the incidence of hypertension is higher than in the corresponding age groups of the general population, it is generally accepted that hypertension augments the atherosclerotic process (RoBERTSet al. 1959; YOUNG et al. 1960; STAMLER1962). Similar mechanisms may be partly responsible for the high incidence of diabetes in ischaemic cerebrovascular disease (BAUER et al. 1962; ALEX et al. 1962). Several authors have stressed the close correlation between cardiac disease, particularly myocardial infarction, and brain infarction (RuPP et al. 1948; HICKS AND BLACK 1949; WILSON et al. t951; MURRAY 1957; YATES AND HUTCHINSON 1961; BAUER et al. 1962; SCHWARTZ 1960; GORMSENet al. 1961 ; SILVERSTEINAND DONIGER t963). This finding has usually been taken to indicate that cardiac disease precipitates 'cerebrovascular insufficiency'. Alternative explanations might be that the brain and heart lesions are independent, both being due to local thrombosis in atherosclerotic vessels, and also that the heart lesions are predisposing to embolic brain infarction to a greater extent than is generally held. CASE-MATERIAL AND METHODS

This study is based on 994 consecutive autopsies performed in the Department o f Pathology, Ullevdl Hospital, between 1 January and 30 June 1959. All the cases were from the municipal hospitals of Oslo. With a total of 3900 beds, these hospitals serve virtually the whole population of the city with its 465,700 inhabitants. Every medical specialty and all types of institution for medical care were proportionately represented, including nursing homes for the aged, and the chronic sick. As the cost of hospital care is met by compulsory health insurance, social and economic factors played a minimal r61e in the selection of the cases. The total number of cases examined represented 76.5% of all deaths in the municipal hospitals of Oslo, and 40.4% of all deaths in Oslo during the same period. There was a clearcut preponderance of males in the autopsy material, and patients over 75 years of age were somewhat under-represented (Table 1). Cerebrovascular accidents were considered to be the cause of death in 17.0°(, of the autopsy material and in 16.6% of all deaths in Oslo during the same period*. Although the latter figure was based mainly on clinical diagnosis, the findings probably indicate that the frequency of manifest cerebrovascular disease in the autopsy material, is about the same as among all fatal cases in the general population of Oslo. In every one of the 994 cases, the brain and the cerebral arteries were examined by the authors. The carotid arteries were examined throughout their entire extent in every case (see TORVIKAND JORGENSEN 1964). Routine examination of the extracranial part of the vertebral arteries was not possible. Every brain with suspected vascular lesions was fixed in 10% formaldehyde for 2-3 weeks before further study. The other brains were sectioned immediately. Histological sections were taken from the brain lesions in most of the cases. * Based on statistical returns from the Municipal Board of Health of Oslo. J. neurol. Sei. (1966) 3:490-509

ISCHAEMIC

CEREBROVASCULAR

DISEASES IN AN AUTOPSY

SERIES, PART

1

493

TABLE 1 AGE AND SEX OF ALL PERSONS W H O DIED IN OSLO FROM 1 JANUARY TO 3 0 JUNE 1959", AND OF ALL PATIENTS EXAMINED POST MORTEM AT ULLEV/kL HOSPITAL D U R I N G THE SAME PERIOD

Age

Number of

(years)

deaths

Number of autopsies performed

Incidenceof autopsies(%)

67 9 15 10 75 155 446 639 1045 2461

37 5 4 4 41 70 202 275 356 994

55.2 55.6 26.7 40.0 54.7 45.2 45.3 43.0 34.1 40.4

1232 1229

540 454

43.8 36.9

0-~4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 > 75 Total

Men Women

* Based on statistical returns from the Municipal Board of Health of Oslo.

The cerebral infarcts and vascular occlusions were plotted on charts of the brain and cerebral vessels. All of the lesions were classified as either recent or old, with an arbitrary limit set at one month and a half. This age determination was based both on morphological findings and on the duration of the clinical symptoms. The recent occlusions were grouped into thrombotic, embolic, and unclassified lesions. The diagnosis of thrombosis was based on the demonstration of a red, laminated, intravascular plug, which was firmly and extensively attached to the vessel-wall. Sharply delimited plugs which were only loosely attached to the arterial wall were rated as embolic. Histological sections of the occluded arteries were prepared whenever gross examination left some doubt as to the age and type of the lesion. In recent occlusions, more than a few days old, invasion of the plug by fibroblasts and capillaries over a wide segment of the arterial wall was considered to be diagnostic of a thrombus (FONTAINE et al. 1953). Organization from only a small segment of the vessel wall in occlusions which were more than a few days old, was regarded as an indication of embolism. Recent infarcts without verified occlusions, and also old infarcts, were also grouped into embolic, non-embolic and unclassified lesions. The diagnosis of embolism was in such cases based on conventional criteria; auricular fibrillation, endocardial thrombi, absence of cerebral atherosclerosis, and multiple infarcts in other organs were considered as evidence in favour of embolism. At least two of these criteria were present in cases which were classified as embolic. The extent of atherosclerosis and the degree of atherosclerotic stenosis were graded independently from 0 to 3. As to the extent, grade 1 represented only a few small discrete plaques; grade 2, several larger and partly confluent plaques; and grade 3, widespread involvement of the arteries, with more than 50% of the intimal area covered by plaques. In estimating the degree of stenosis, the narrowing in the different J. neurol. Sci. (1966) 3:490-509

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arteries was roughly averaged. Grade 1 indicated a reduction of the lumen by less than one-quarter of the square area; grade 2, a reduction by one-quarter to one-half; in grade 3, more than one-half of the lumen was occluded. Plaques which caused severe localized stenosis were individually recorded upon charts of the cerebral vessels. Data as to the blood pressure was obtained from the clinical records. As a rule, several measurements had been made, often both before and after the onset of the cerebrovascular accidents. The highest blood pressure was chosen, irrespective of the time of its measurement. The weight of the heart was recorded in every case and compared with that of corresponding age-groups without cerebrovascular disease in the autopsy series. Instances of cardiac hypertrophy which might have been caused by factors other than hypertension, were excluded. In the statistical evaluation of the results, conventional parametric tests for normal and binomial distribution were used. In age-comparisons the non-parametric MANNWHITNEY U-test was performed as described by SIEGEL(1956). R E S U L T S A N D COMMENTS

The frequency of the various types of cerebrovascular disease in the material is shown in Table 2. A m o n g the 994 autopsies there were 320 cases, or 32.2%, which showed evidence of ischaemic cerebrovascular disease; 196 patients (19.7 %) had symptomatic ischaemic disease. In 7 of these, no relevant gross lesions could be found at autopsy although there was a definite history of a stroke with clearcut symptoms. In comparison there were 61 cases with symptomatic spontaneous brain haemorTABLE 2 ISCHAEMIC AND HAEMORRHAGIC CEREBROVASCULAR DISEASES IN

994 AUTOPSIES Patients

Type of cerebrovaseular disease

Thrombo-embolic occlusions with or without infarcts Infarcts (> 0.5 cm in diameter) without verified thromboembolie occlusion Total

Lacunar state (deep-seated infarcts < 0.5 era) Stroke without verified thromboembolic occlusions or cerebral infarcts Total number with ischaemic disease Spontaneous brain haemorrhage Ruptured saceular aneurysms Total number with cerebrovascular disease

Lesions

total

117

101

87

297 414

165 223*

109 177"

155

15

7

7

320* 65 8

196" 61 8

345*

252*

with symptoms

* The total number of patients is less than the sum of the figures because several eases had more than one type of lesion. J. neurol. Sci. (1966) 3:490-509

ISCHAEMIC CEREBROVASCULAR DISEASESIN AN AUTOPSY SERIES, PART 1

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rhage (6.1%). I s c h a e m i c c e r e b r o v a s c u l a r accidents were the p r i n c i p a l cause o f d e a t h in 121 cases (12.2%), a n d s p o n t a n e o u s b r a i n h a e m o r r h a g e in 48 cases (4.8%). F o r reasons a l r e a d y m e n t i o n e d , it is likely t h a t this m a t e r i a l is fairly representative for the p o p u l a t i o n o f Oslo.

The Frequency o f Thrombo-embolic Occlusions, and their R6le in Cerebral Infarction I n all, 117 gross t h r o m b o - e m b o l i c c e r e b r o v a s c u l a r occlusions were f o u n d in 101 p a tients (Table 2). I n one case, there a p p e a r e d to be a c o m p l e t e atherosclerotic occlusion o f the left vertebral artery. N o o t h e r c o m p l e t e atherosclerotic occlusion was seen, b u t multiple, severe atherosclerotic stenoses were c o m m o n b o t h in cases with a n d w i t h o u t evidence o f c e r e b r o v a s c u l a r disease. T h e fact t h a t t h r o m b o - e m b o l i c occlusions were f o u n d in only o n e - t h i r d o f the cases with i s c h a e m i c c e r e b r o v a s c u l a r disease s h o u l d n o t be t a k e n to indicate t h a t m o s t infarcts occur w i t h o u t vascular occlusion. M a n y o f the infarcts were so small that a p p r o p r i a t e v a s c u l a r occlusions c o u l d easily be o v e r l o o k e d on n a k e d - e y e examination. F u r t h e r m o r e , failure to d e m o n s t r a t e vascular occlusions in old infarcts m u s t be i n t e r p r e t e d with care, since t h r o m b o - e m b o l i c occlusions m a y be altered so as to resemble atherosclerotic plaques (DuGUID 1946; HAND AND CHANDLER 1962; JORGENSEN 1966). It was therefore felt a p p r o p r i a t e to examine separately the frequency o f occlusions in large, recent infarcts. All recent lesions were analysed which covered m o s t o f the t e r r i t o r y o f one o f the larger i n t r a c r a n i a l vessels, such as the anterior, m i d d l e a n d p o s t e r i o r cerebral, or the s u p e r i o r a n d inferior p o s t e r i o r cerebellar arteries. This g r o u p c o m p r i s e d 82 infarcts, all o f which were less t h a n 45 days old. T h r o m b o e m b o l i c occlusions o f the a p p r o p r i a t e arteries were f o u n d in 73 (89.0%), while gross occlusion was a b s e n t in 9 cases. T h e cause o f the infarction in the 9 cases with p a t e n t m a j o r vessels could n o t be definitely established. H o w e v e r , f r o m the case-histories a n d the c o m p l e t e post mortem e x a m i n a t i o n , there was some i n d i c a t i o n t h a t 4 o f the infarcts were embolic. T h e e x p l a n a t i o n for the l a c k o f occlusion in these 4 cases m i g h t be that the e m b o l i c plug h a d been f r a g m e n t e d or dissolved, as suggested by ADAMS (1954). In 2 cases circulatory failure m i g h t have been the m a i n cause. N o causative factors could be suggested in 3 cases. T h e findings in two cases will be briefly described as illustrations.

Case 1 A 77-year-old diabetic woman sustained a slight transitory paresis of the right leg on the 12th of December, 1958. The weakness recurred 4 days later, and on the following morning the leg became paralyzed. Later that day she had some difficulty in expressing herself. The speech disturbances increased over the following days. She was admitted to hospital on the 19th of December with a severe right-sided hemiparesis and aphasia. The blood-pressure was 170/95. The pulse was regular, 90/min. At first in hospital, her state of consciousness and pareses fluctuated. She then became increasingly drowsy with slight fever. Her blood sugar rose to 494 mg/100 ml on the 30th of December. She later became comatose, and died on the 1st of January. On post mortem examination, a pulmonary embolus was found. There was also a chronic pyelonephritis and an old myocardial infarct. The cerebral arteries were moderately atherosclerotic and showed only slight stenoses. No occlusion was found in the carotid or any other cerebral artery. A narrow elongated, and well-demarcated recent infarct was found in the left frontal and parietal lobes in the border zone between the anterior and middle cerebral arteries. On microscopical examination of the infarcted area no occlusions of the small intracerebral or leptomeningeal vessels were J. neuroL Sci. (1966) 3:490-509

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L. JORGENSEN, A. TORVIK

found, except for a small aggregate of platelets with fibrin in one single, large leptomeningeal artery,. This aggregate appeared to have been formed shortly before death. C o m m e n t . The history o f this case, with an intermittent and increasing course, and the location of the infarct within the 'water-shed' zone, were taken to indicate that the lesions had been precipitated by some type o f circulatory failure. Similar lesions without gross vascular occlusions have recently been described by ROMANUL AND ABRAMOVICZ (1964). Case 2

A 94-year-old woman was admitted to hospital on the 13th of February, 1959, because of incipient gangrene of the left leg. She had auricular fibrillation and a blood pressure of 180/105. Two or 3 days before death she became comatose with a right-sided hemiplegia. She died on the 3rd of March, 1959. On post rnortern examination, an organized thrombotic or embolic occlusion was found within the left femoral artery. There was an old myocardial infarct and the left auricle was filled with thrombi. The cerebral arteries showed only a moderate atherosclerosis, and no significant stenoses. No gross cerebrovascular occlusions could be demonstrated. In the left cerebral hemisphere there was a large, recent, haemorrhagic infarct which involved the greater part of the territories of the anterior and middle cerebral arteries. On microscopical examination no occlusions were found within the intracerebral or leptomeningeal vessels. C o m m e n t . A l t h o u g h p r o o f is lacking, the most likely explanation for this infarct was considered to be an embolus to the left carotid artery which had later been fragmented or broken up. Similar findings were made in the three other cases o f this group. Large, recent infarcts in this series were thus caused by thrombo-emboli in 90-9Y!/o o f the cases. Only 2 (2.4%) o f 82 large infarcts showed any indication that circulatory failure without gross vascular occlusion ('cerebrovascular insufficiency') was the main underlying cause. These findings do not necessarily imply that 90% o f all infarcts were caused by thrombo-emboli. It would not appear to be unlikely that, in general, infarcts caused by circulatory failure are smaller than those produced by gross thrombo-embolic occlusions. Such small infarcts would also presumably have a more favourable prognosis and frequently appear as old lesions. It is not possible to evaluate accurately the total n u m b e r o f recent and old lesions caused by such processes. However, by reviewing all cases without vascular occlusions, there came to light a small n u m b e r o f cases with characteristic pathological and clinical findings, which might represent examples of this type. These cases, to be described more fully in another paper (J(JRGENSEN AND TORVIK 1966), had lesions which could be classified either as water-shed infarcts (FISHER 1954; Z/3LCH 1961; ROMANUL AND ABRAMOWICZ 1964; TORVIK AND JORGENSEN 1966) (see Case 1 above), or else as a combination o f recent and old infarcts superimposed within the same vascular territory. Often there were also atherosclerotic stenoses o f the associated arteries. Clinically they had an intermittent, stepwise or slowly progressive course. The pathogenesis in these cases m a y well be complex. However, they are difficult to explain on the basis o f a t h r o m b o - e m b o l i c occlusion o f a single artery, too small to be found on naked-eye examination. I n all, there were 7 cases with recent and 21 cases with old lesions belonging to the above mentioned groups. Five o f the 21 patients with old lesions later developed J. neurol. S¢i. (1966) 3:490-509

I S C H A E M I C C E R E B R O V A S C U L A R DISEASES IN A N A U T O P S Y SERIES, P A R T

1

497

thrombotic occlusions at the site of atherosclerotic stenoses, and died of massive recent infarcts. The 7 cases represent 6°/0 of all recent symptomatic infarcts with or without major occlusion. Similarly, the 21 cases represent 22% of all the old symptomatic infarcts. These figures are not intended to be accurate indications of the frequency of infarcts caused by mechanisms other than thrombo-embolic occlusion of the appropriate feeding artery. However, they may indicate that such lesions are rather more frequent among small than large infarcts, as suggested above. Taken together with the findings from the large, recent lesions, the findings may further indicate that the incidence of such 'non-occlusive' ischaemic lesions lies somewhere between 5 and 20%. The Location o f Verified Thrombo-embolic Occlusions

The location of the gross thrombo-embolic occlusions in the material is shown in Table 3. Altogether, 117 occlusions were found in 101 patients. Almost one-half(47.9°/0) of the occlusions were located in the carotid arteries and between one-third and onefourth in the middle cerebral arteries (28.2%). Twenty-six of the carotid occlusions were primarily extracranial (see TORVIK AND JORGENSEN 1964). Less than one-fourth (22.2%) of the occlusions therefore, were located extracranially in the carotid arteries. TABLE 3 LOCATION OF 117 THROMBO-EMBOLIC OCCLUSIONS IN 101 PATIENTS

Carotid artery intracranial extracranial unknown primary site Middle cerebral artery Anterior cerebral artery Posterior cerebral artery Basilar artery Vertebral artery Inferior posterior cerebellar artery Subclavian artery

29 26 1 33 4 9 5 7 2 1 Total

117

When considering the frequency of extracranial occlusions, it should be borne in mind that many of the infarcts were so small that occlusion of the intracranial feeding-vessels would escape recognition on macroscopic inspection. However, some of these infarcts might also be caused by extracranial atherosclerotic stenoses, thus increasing the number of infarcts caused by extracranial vascular lesions. It should also be stressed that the extracranial portions of the vertebral arteries were not examined in our series. It may be appropriate to deal only with ischaemic lesions productive of symptoms. Altogether there were 113 cases with recent, and 95 with old lesions which gave rise to symptoms. Of the recent lesions 13.3%, and 4.2% of the old ones, were caused by extracranial thrombo-emboli in the carotid arteries. Six cases with atherosclerotic J. neurol. Sci. (1966) 3:490-509

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L. JORGENSEN, A. TORVIK

carotid stenoses, 4 of which were extracranial, were associated with clinical symptoms, possibly caused by 'cerebrovascular insufficiency'. Two of the cases with extracranial stenoses had recent, and 2 had old lesions. Thus, there is some indication that the symptoms were caused by extracranial occlusions or stenoses of the carotid arteries in 15.0°~ of the cases with recent lesions, and in 6.3% of those with old lesions. In addition to these figures, there exists an unknown number of extracranial vertebral occlusions. The entire extracranial part of the vertebral arteries has recently been examined in 358 consecutive cases in this laboratory (SOLBERG 1965). Only 3 cases with recent or old thrombo-embolic occlusions were found in this series. Extracranial thrombo-emboli in the vertebral arteries thus appear to be rare, and it does not seem likely that examination of these arteries would have added many cases to our series with symptoms due to extracranial vascular occlusions. Our estimates of the frequency of cerebrovascular accidents caused by extracranial vascular lesions are somewhat lower than those contained in most earlier reports. Several factors may be responsible for these discrepancies. The most important factor may be that atherosclerotic stenoses have been held responsible for a far larger number of the infarcts than appears likely from our material. Many of the stenoses which have been classified as 'significant' may well have been too slight to cause any definite reduction in blood-flow (LowE 1962; TINDALL et al. 1962; B~lCE et al. 1964). Many of the stenoses are known to have been asymptomatic. In fact, since atherosclerosis is usually a pre-requisite for arterial thrombosis, the association between both intra- and extracranial atherosclerotic stenoses and brain infarction may not necessarily imply a causal relationship. We therefore question the importance of many of the non-extreme extracranial stenoses in the genesis of cerebral infarction. Another reason for the preponderance of symptomatic extracranial occlusions in the clinical reports may lie in the composition of the material. It is probably correct to assume that most of the angiographic series have been more or less selected. Cases with a progressive, intermittent or stepwise course may be favoured because of the possible therapeutic consequences, while cases with an acute and stormy course are less likely to have had an angiogram performed. Extracranial vascular occlusions will predominate in the former group (ToRvIK AND JORGENSEN 1966). T h r o m b o t i c versus E m b o l i c Occlusions

Since it might be expected that there is a difference in prognosis between thrombotic and embolic cases (JORGENSEN AND TORVIK 1966), it was felt that the most reliable index of the relative frequency between embolic and non-embolic occlusions was obtained if an attempt were made tO classify both recent and old lesions. The material was therefore divided into 3 groups, namely: (i) cases with verified recent thromboembolic occlusions (less than 45 days old); (ii) cases with recent (and mostly small) infarcts without verified vascular occlusions; and (iii) cases with old infarcts with or without verified occlusions (more than 45 days old). The criteria used in the classification of embolic and non-embolic lesions are given on p. 493. In group (i) the classification was mainly based upon the gross and microscopic appearance of the thrombo-embolic occlusions. Groups (ii) and (iii) were classiJ. neurol. Sci. (1966) 3:490-509

ISCHAEMICCEREBROVASCULARDISEASESIN AN AUTOPSYSERIES, PART 1

499

fled according to conventional criteria. At least two of the criteria mentioned were present in cases which were considered to be embolic. Infarcts below 0.5 cm were excluded from the classification. In all groups there were many cases which we were unable to classify (Tables 4 and 5). It was felt that the most reliable distinction between thrombi and emboli was obtained in group (i). For obvious reasons the classification of the old lesions (iii) was somewhat uncertain. Table 4 shows the classification of verified recent occlusions. A m o n g 79 occlusions which could be relegated to this group there were approximately as many thrombi as emboli. This applies also to the number of c a s e s which could be classified. Moreover, the number of symptomatic cases was the same in the two groups. The classification of the two other groups is shown in Table 5. Although classified according to different criteria, the recent lesions again showed more or less as many embolic as non-embolic infarcts. However, only 19% of the old infarcts (and cases) with old lesions were classified as embolic. Thus, the patients with non-embolic TABLE 4 CLASSIFICATION OF

91 RECENT THROMBO-EMBOLIC OCCLUSIONS IN

8 0 PATIENTS

Number

Number o f cases

Thrombotic Embolic

42 ( 53 %) 37 ( 47 %)

37 ( 53 %) 33 ( 47 %)

Total Unclassified

79 (100%) 12

70 (100%) 10

Total

91

80

Type

TABLE 5 CLASSIFICATION OF RECENT INFARCTS WITHOUT OCCLUSION AND OF OLD INFARCTS WITH OR WITHOUT OCCLUSION

Number o f recent lesions infarcts

cases

Number o f oM lesions infarcts

cases

Non-embolic Embolic

29 (54%) 25 ( 46 %)

29 ( 59 %) 20 (41%)

191 (81%) 45 ( 19 %)

104 (81%) 25 ( 19 %)

Total Unclassified

54 (100%) 9

49 (100%) 6

236 (100%) 37

129 (100%) 14

Total

63

55

273

143

lesions have a greater chance of survival than the embolic ones. This is not only due to a poorer prognosis of the embolic cerebral lesions, but also to the more serious underlying disorders in these cases. Since many old infarcts were small and asymptomatic, it may be appropriate to consider separately old symptomatic lesions which could be classified. In this group of 86 cases there were 20 (23%) embolic and 66 (77%) which were considered as nonembolic, a distribution which is not very different from that of the whole group. J. neurol. Sci. (1966) 3:490-509

500

L. JORGENSEN, A. TORVIK

It is not possible from these figures to calculate the true clinical incidence of cerebral emboli. However, it is probably safe to conclude that between 20 and 50°/~, of the cerebral infarcts are embolic. In all probability, the exact incidence lies somewhat closer to the upper than the lower limit. The location of verified thrombo-embolic occlusions is shown in Table 6. It is worthy of notice that 29 of the 42 thrombi were within the carotid arteries, and that the middle cerebral arteries contained 22 emboli and only 3 thrombi. Almost twothirds of all emboli were located within the middle cerebral arteries. A similar tendency for the embolic occlusions to be located in the middle cerebral arteries was also found by POPPER (1949), HALL et al. (1952) and TAKABATAKEet al. (1960). TABLE 6 LOCATION OF

91

RECENT THROMBO-EMBOLIC OCCLUSIONS IN 8 0 PATIENTS

Thrombi

Emboli

Undetermined

14 } 15 29 3 1 4 4 1

17} 8 22 4 0 3 0

8

Carotid artery extracranial intracranial Middle cerebral artery Basilar artery Vertebral artery Other intracranial arteries Subclavian artery

42

Total

2 0 0 2 0

37

12

TABLE 7 AGE AT DEATH AND SEX OF

37

CASES W I T H THROMBI AND

Age (years)

CASES W I T H EMBOLI

Thrombi

35--44 45-54 55-64 65-74 75-84 85Total

Median age Median age in and women

33

Emboli

men

women

men

women

1 1 3 7 10 2

0 0 2 8 3 0

0 0 4 5 6 0

0 0 2 5 10 1

24

13

15

18

74.8

70.4

72.9

76.0

men

72.7

75.0

The frequency ofemboli in the main stem and major branches of the middle cerebral arteries was in contrast to the paucity of thrombi in these arteries. A similar distribution of thrombo-emboli was found in an autopsy series from Boston (ToRv~K e t at. 1965). Thrombosis of the middle cerebral artery was also rare in the material of BLACKWOOD et al. (1961) and not listed in Fismm's series (1954). J. neural. Sei. (1966) 3:490-509

ISCHAEMICCEREBROVASCULARDISEASESIN AN AUTOPSYSERIES,PART 1

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The age and sex-distribution in cases with thrombotic and embolic occlusion is shown in Table 7. The median age was 72.7 years in cases with thrombi, and 75.0 years in the embolic group (P = 0.50). In cases with recent infarcts without vascular occlusion, the median age was 76.1 years in the non-embolic and 72.0 years in the embolic group (P = 0.13). The corresponding figures for the old infarcts with or without occlusion were 76.7 and 72.5 years (P = 0.04). In none of the groups was any significant age-difference between males and females. The advanced age of the embolic patients was somewhat unexpected, and contrasted with most reports. This may be due to a shift in the underlying diseases of the embolic cases. At an earlier period, most emboli were caused by rheumatic valvular heart disease and bacterial endocarditis, while the predominating disorders in this material were myocardial infarction and other forms of atherosclerotic and hypertensive heart disease. This shift in age and underlying disorders of the embolic cases may not have been fully appreciated in all recent series and it calls for a revision of the clinical criteria for the diagnosis of cerebral embolism.

TABLE 8 RATIO BETWEEN MEN AND WOMEN IN EMBOLIC AND NON-EMBOLIC LESIONS*

Men

Women

Ratio men~women

Cases with verified occlusions thrombotic embolic

24 15

13 18

1 : 0.64 1 : 1.43

Cases with recent infarcts without verified occlusions non-embolic embolic

14 7

15 13

1 • 1.27 1 : 2.21

Cases with old infarcts non-embolic embolic

56 13

48 12

1 : 1.02 1 : 1.10

* Corrected for the preponderance of men in the autopsy material.

Twenty-four of the patients with verified thrombi occurred in males and 13 in females (1:0.64) (Table 8). The preponderance of males was not statistically significant (P = 0.19). However, it was considered of interest also to analyse the sex-ratio in non-embolic groups. In the groups with recent and old non-embolic infarcts the ratio of males to females was 1 : 1.27, and 1 : 1.02 respectively. None of these groups showed any significant difference between the sexes. Nor could any sex difference be found when the different age-groups were analysed separately. This finding was in contrast to some of the published reports, where a considerable preponderance of males has been found (MERRITT 1955; ZIMMERMAN 1955; SCHURMANN AND DIETZ 1961; BOYLE AND SCALZITTI 1963). There may also be a difference between cerebral and myocardial infarcts in this respect. A m o n g the 994 cases in the present autopsy series there were 125 patients with recent myocardial infarcts: 82 of these were men and 43 were women (1 : 0.62; P = 0.007). This difJ. neurol. Sci. (1966) 3:490-509

502

L. JORGENSEN,A. TORVIK

ference in sex-ratio may indicate a difference in pathogenesis between myocardial and cerebral infarction. In the group with verified embolic occlusions there were 15 men and 18 women (1 : 1.43) (Table 8). The ratio of males to females in the embolic groups without vascular occlusion were (: 2.21 among recent and 1 : 1.10 among old lesions. None of these differences is statistically significant. Both thrombi and emboli were equally represented on the right and left sides in all groups of infarcts. An equal lateral representation in embolism was also found in the studies by HALL et al. (1952), ADAMS AND VANDER EECKEN (1953), KEEN AND LEVEAUX(1958) and TAKABATAKEet al. (1960). The length of the thrombo-embolic occlusions was examined in order to see if anteroor retrograde propagation of the occlusions could have produced an increase in the size of the infarcts by successive blocking of arterial branches. Thirteen of 29 recent thrombi in the carotid arteries were greater than 3 cm in length and 10 were more than 5 cm. Two cases with thrombi in the vertebral and basilar arteries measured more than 5 cm in length. In all other arteries the thrombi were less than 3 cm. Propagation by recent coagulation thrombi are included in these figures. Similarly, 4 of 8 embolic carotid occlusions were more than 3 cm. All other embolic occlusions were shorter. Antero- and retrograde propagation of thrombo-embolic occlusions, therefore, seems to occur to some extent only in the carotid and vertebralbasilar arteries. Predisposing Factors in the case o f Thrombo-embolic Occlusions

Extensive cerebral atherosclerosis was a very common finding in every" case with cerebrovascular disease. However, total occlusion of the vessels by atherosclerosis was seen in only one artery. Atherosclerotic stenoses were almost always multiple and located both intra- and extracranially. There was no indication in our material that extracranial atherosclerotic stenoses protected against intracranial atherosclerosis (see TORVIK AND JORGENSEN 1964). Table 9 shows the various forms of associated and underlying diseases in verified recent thrombo-embolic occlusions. Since the diagnosis of embolism in these cases was based on the gross and microscopical appearence of the occlusion, this list also demonstrates the underlying disorders in embolism. In 78.4% of the cases with recent thrombi the extent of atherosclerosis was grade 2 or 3, and 5 9 . 5 ~ had grade 2 or 3 stenosis. It was somewhat unexpected that the embolic cases showed almost the same degree of atherosclerosis. In 57.6 ~ of the embolic cases the extent of the atherosclerosis was grade 2 or 3, and 69.7 ~o had grade 2 or 3 stenosis. The explanation for this finding probably lies in the underlying disorders in the embolic cases (see below). It might be objected that an arbitrary grading of atherosclerosis entails considerable error (see GIERTSEN 1960). However, it has been our experience that when the grading is done by only two closely cooperating observers, a surprisingly uniform evaluation is obtained. On the other hand, it must be realized that only major variations will be demonstrated by this method. As will be seen from Table 9, our material showed a high frequency of various J. neurol. Sci. (1966) 3:490-509

ISCHAEMIC CEREBROVASCULAR DISEASESIN AN AUTOPSY SERIES, PART 1

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TABLE 9 ASSOCIATED A N D U N D E R L Y I N G DISEASES I N RECENT T H R O M B I A N D

Disease

Grade 2 or 3 cerebral atherosclerosis (extent) Grade 2 or 3 cerebral atherosclerotic stenosis Manifest cardiac failure Myocardial infarct Cardiac valvular disease Auricular fibrillation* Other severe cardiac arrhythmias* Auricular fibrillation without myocardial infarct or valvular disease* Endocardial thrombi Non-cerebral and non-cardiac arterial thrombo-embolism Marked chronic pyelonephritis Marked nephrosclerosis Intracerebral haemorrhage recent old Diabetes mellitus Polycythaemia

33

37 CASES W I T H

CASES W I T H RECENT EMBOLI

Thrombosis cases

Embolism cases

number

%

number

%

29

78.4

19

57.6

22 5 9 8 10

59.5 13.5 24.3 21.6 32.3

23 11 14 10 23

69.7 33.3 42.4 30.3 82.1

5

16.1

2

7.1

2 0

6.4 0.0

7 15

25.0 45.5

7 4 3

18.9 10.8 8.1

12 2 0

36.4 6.1 0.0

1 2 2 2

2.7 5.4 5.4 5.4

0 0 0 0

0.0 0.0 0.0 0.0

* Information about pulse and/or ECG was available in 31 cases with thrombi and 28 cases with emboli.

f o r m s o f c a r d i a c disease. Since all cases listed also h a d verified cerebrovascular occlusions, this finding c a n n o t be t a k e n to indicate t h a t the cerebral infarcts were prec i p i t a t e d by ' c e r e b r o v a s c u l a r insufficiency', as has often been implied. I n o u r cases the c a r d i a c disease h a d either caused cerebral emboli, or the b r a i n a n d heart were indep e n d e n t l y affected, usually with generalized atherosclerosis as the m a i n u n d e r l y i n g cause. A s m i g h t be expected, the frequency o f the various forms o f c a r d i a c disease was c o n s i d e r a b l y lower in the g r o u p with t h r o m b i t h a n in the e m b o l i c g r o u p (Table 9). Thus, the frequency o f obvious c a r d i a c failure was 13.5% in the g r o u p with t h r o m b i , a n d 33.3% in the e m b o l i c group. T h e frequency o f recent a n d / o r old m y o c a r d i a l infarcts was 24.3 a n d 42.4% respectively in the two groups. T h e occurrence o f recent m y o c a r d i a l infarcts in the two g r o u p s was 10.8 a n d 18.2%. I n the whole a u t o p s y material, the frequency o f recent m y o c a r d i a l infarcts was as high as 12.6%. A l t o g e t h e r 82.10/0 o f the cases with verified e m b o l i h a d auricular fibrillation, a n d a n o t h e r 7.10/0 h a d o t h e r severe c a r d i a c a r r h y t h m i a s (Table 9). E n d o c a r d i a l t h r o m b i were f o u n d in 45.5°/0 o f the e m b o l i c group. I n 2 cases the e m b o l i were caused b y t h r o m b o t i c n o n b a c t e r i a l ( ' t e r m i n a l ' ) endocarditis. There were no cases with bacterial e n d o c a r d i t i s in this group. O f the e m b o l i e cases 67% h a d severe c o r o n a r y o r hyperJ. neurol. Sci. (1966) 3:490-509

504

L. JORGENSEN, A. T O R V I K

tensive heart disease (myocardial infarction included), and only 30Q,I' had valvular heart disease. Myocardial infarction and atherosclerotic or hypertensive heart disease are thus the most important underlying disorders in cerebral embolism. This not only explains the late age of the embolic cases, but also the extensive cerebral atherosclerosis and the hypertension in this group (see below). The blood pressure in the cases with recent thrombo-emboli is shown in Tables 10 and 11. In the cases with thrombi the average blood pressure was 181/102 mm Hg in males and 219/113 mm Hg in females. The corresponding figures in the embolic group were 183/102 in males and 206/104 in females. No statistically significant difference in blood pressure was found between the two groups. TABLE 10 SYSTOLIC BLOOD PRESSURE IN 37 CASES WITH THROMBI AND 32 CASES WITH EMBOLI*

Thrombi

Systolic pressure

males

-129

Emboli

females

males

females

0

1

0

1

130-169

7

2

5

5

170-209 210-249 250-

11 4 1 24 180.8

2 6 3 t3 219.0

5 3 1 15 182.8

6 2 4 17 205.7

Total

Mean systolic pressure

* Systolicpressure not recorded in one patient. TABLE

1t

DIASTOLIC BLOOD PRESSURE IN 36 CASES WITH THROMBI* AND 32 CASES WITH EMBOLI*

Thrombi

Diastolic pressure

males - 79

80- 99 100-119 120-139 140Total

Mean diastolic pressure

Emboli

females

males

females

2

1

2

1

4 14 2 1 23 102.1

2 5 2 3 13 113.3

6 2 4 1 15 102.5

5 6 5 0 17 104.3

* Diastolic pressure not recorded in two patients. The most relevant control material for an evaluation of the blood pressure is probably that of BOE et al. (1957). These authors recorded the blood pressure in 68,000 adults in the city of Bergen in Norway (77% of the adult population). In the age groups with the highest blood pressure in their series, the mean values were 170/92 mm Hg in males and 183/95 mm Hg in females. This is considerably lower than the mean values for all age-groups in our series of thrombo-embolic cases. ~neurol. Sci. (1966) 3:490-509

ISCHAEMICCEREBROVASCULARDISEASESIN AN AUTOPSYSERIES,PART 1

505

Since the blood pressure in many of our cases was measured shortly after the onset of the apoplectic attack, it might be argued that these figures are not representative. In order to examine whether there was any general trend towards a rise or a fall of the blood pressure in connection with the ischaemic accidents, every patient was examined in whom information was available as to the blood pressure both before and after the attack had occurred. In all, 28 men and 27 women in the groups with verified thromboemboli were analysed in this respect. Despite considerable variations in the individual cases, there was no significant tendency to suggest that either a fall or a rise in the blood pressure after the attack had occurred in any of the groups. TABLE 12 HEART WEIGHT IN

29 CASES WITH

Heart weight (g)

250-349 350-449 450-549 550-649 650-749 750Total

Mean heart weight

THROMBI* AND

23 CASES WITH

Thrombi

EMBOLI**

Emboli

males

females

males

females

4 11 1 1 0 1

1 5 5 0 0 0

0 4 5 1 2 0

0 4 6 1 0 0

18 420.0

11 438.2

12 511.7

11 475.0

•• * 108} caseswith valvular heart diseasenotincluded. Additional information concerning the influence of the blood pressure was sought from analysis of the heart weight (Table 12). In cases with verified thrombi the mean heart weight was 420 g in males and 438 g in females. In the embolic group the mean heart weight was 512 g in males and 475 g in females. Cases with valvular heart disease were excluded from this analysis. The heart-weight was significantly higher in the embolic than in the thrombotic group for men (0.02 < P < 0.05). The explanation for this difference between the embolic and thrombotic groups may be that the embolic cases include a higher number of cases with more advanced cardiac disease (Table 9). As mentioned above, the blood pressure was almost identical in the embolic and thrombotic groups. The duration of hypertension (170/100 or more) was known with a fair degree of certainty in 27 cases with recent thrombi, and 17 cases with recent emboli. In both groups the mean duration was 7.0 years. The average heart-weight in cases above 35 years without cerebro-vascular disease in the autopsy series, was 416.0 g in males and 357.5 g in females. These groups naturally include many hypertensive cases. Both men and women in the embolic group showed significantly higher heart-weight than the control material (men: 0.01 > P >0.001 ; women: P < 0.001). In the thrombotic group women only showed a somewhat higher heart-weight than the control material (men: P > 0.2; women: P = 0.01). J. neurol. Sci. (1966) 3:490-509

506

L. JORGENSEN, A. TORVIK

Our observations with regard to blood-pressure and heart-weight are not conclusive. However, taken together, the findings seem to support the view that hypertension plays a r61e in the precipitation of thrombo-emboli, probably by enhancing the atherosclerotic process of the cerebral arteries and by its untoward effects on the heart.

SUMMARY

During a 6-month period, 994 consecutive cases which came to autopsy at the Department of Pathology, Ullevgd Hospital, Oslo, were examined as to the incidence of cerebrovascular disease. The brains and all of the cerebral vessels, except for the extracranial part of the vertebral arteries, were examined by the authors. Every cerebral lesion and every thrombo-embolic occlusion was recorded. Altogether 117 gross cerebrovascular occlusions were found in 101 patients. Evidence of ischaemic cerebrovascular disease was found in 320 cases. Since many of these lesions were small and old, recent, large infarcts were analysed separately for the occurrence of thrombo-embolic occlusions. Among 82 infarcts in this group, 73 (89%) were caused by gross thrombo-emboli. Although the frequency of thromboembolic occlusions may be somewhat lower in small infarcts, there is some indication that the great majority of all infarcts are caused by thrombo-emboli. The combination of single or multiple atherosclerotic stenoses and episodic circulatory failure ('cerebrovascular insufficiency') is probably responsible for less than 20~','~ of the cerebral infarcts. Twenty-six out of 117 thrombo-emboli were located within the extracranial portion of the carotid arteries. From an analysis of all the symptomatic cases with ischaemic lesions, there is an indication that 15% of all cases with recent, and 6% of all with old lesions, were caused by extracranial carotid occlusions or stenoses. Out of 79 recent thrombo-emboli which could be classified, there were 37 emboli (47 ~o) and 42 thrombi (53 ~). Similarly, 4 6 ~ of all recent infarcts without verified vascular occlusions were considered embolic. Among the old infarcts only 19 ~ were considered to be embolic. Thus, in the non-embolic cases there is a better prognosis than in the embolic ones. Males and females were about equally represented both in the embolic and nonembolic series. In the same autopsy series, recent myocardial infarcts were twice as common in males than in females. The average age was 72.7 years in cases with verified thrombosis, and 75.0 years in the corresponding embolic group. The advanced age of the embolic cases was probably due to the fact that atherosclerotic and/or hypertensive heart disease was the underlying disorder in 67% of the embolic cases. Valvular heart disease was found in only 30%. Cases with verified embolism and thrombosis did not show any significant difference in the level of blood pressure or in the degree of cerebral atherosclerosis. There is some indication that the level of blood pressure may be somewhat higher in cases with cerebral thrombo-embolism than in control subjects from the general population. J. neurol. Sci.

(1966) 3:490-509

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J. neurol. Sci. (1966) 3:490-509