Intimal Change following Subarachnoid Hemorrhage Resulting in Prolonged Arterial Luminal Narrowing KuniyukiSOMEDA, KazuhikoMORITA, YasuoKAWAMURA andHiroshiMATSUMURA Department ofNeurosurgery, KansaiMedicalUniversity Osaka,Japan Abstract The luminal surface of the cerebral arteries was examined by scanning electron micro scopy. Preliminary findings of the cases which succumbed to the aneurysmal rupture are reported with those obtained by light microscopic examinations of old autopsy specimens of the ruptured aneurysm. On SEM, the endothelial cells were lost on the luminal surface of the cerebral arteries and some were covered with fibrin meshwork confining red blood cells and other corpuscles. These findings were interpreted as endothelial injury with denudation of elastica and resulting mural thrombus formation. Light microscopic examination revealed that cerebral arteries which had had narrowing after SAH showed concentrically thickened intimal layer and the presence of rich vascularization partly in the subintimal layer. These histological pictures were interpreted as organized mural thrombus. Possible role which mural thrombosis plays in the pathogenesis of prolonged narrowing after SAH from the rupture of an aneurysm and its clinical significance, especially in connection with antifibrinolytic treatment, is discussed. Key words: Vasospasm,mural thrombosis, aneurysmal rupture, subarachnoid hemorrhage

Introduction The chronological course of gradually progress ing neurological deteriorations in the ruptured intracranial aneurysm coincides considerably well with the occurrence of prolonged severe arterial spasm,2 5)which has been well known to occur 3 days to 2 weeks after subarachnoid hemorrhage (SAH). It has been noted that scat tered infarcted areas are present and they are thought to be due to local ischemia resulting from severe vasospasm,7,18) and are correlated with neurological deficits.' 22,24)In such severe cases, it has been reported that organic changes occurring in the arterial wall may be responsible for narrowing of the vascular lumen, rather than spastic contraction of smooth muscles in the arterial wall.6,12)

We examined the vascular luminal surface of the narrowed arteries in human autopsy cases of SAH due to the ruptured aneurysm by scanning electron microscopy and found that luminal surfaces of the spastic arteries were not covered with endothelial cells and moreover, some were covered with crisscrossing fibrin nets. This made us to review the autopsy specimens of the rup tured aneurysm with SAH. This report concerns some evidences which showed that mural thrombus and its organization may be respon sible for neurological deteriorations in some cases of prolonged arterial narrowing. Material and Method For scanning electron microscopic examination (SEM), major arteries at the base of the brain were removed at autopsy and their lumina were

irrigated with physiological saline solution. Small pieces of arteries were dissected and fixed with 2% paraformaldehyde-2.5% glutaral dehyde in phosphate buffer at pH 7.4. They were post-fixed for one hour with 1% phosphate buffered OsO4 and dehydrated and dried at the critical point. The luminal surfaces were coated with carbon and gold and examined on the Hitachi SSM-2 scanning electron microscope. Small portions next to those taken for SEM were cut into small pieces and fixed with 2% paraformaldehyde-2.5% glutaraldehyde in phosphate buffer. They were post-fixed with 1% OsO4 and dehydrated and embedded in Epon 812 for ordinary thin sections (TEM). Reviewed autopsy specimens were of those who had been admitted after aneurysmal rup ture to Kansai Medical University Hospital from 1968 to 1975 and died at various intervals from the time of SAH. Of those, 9 cases were selected in which one or more angiographic confirmations of the presence or absence of arterial spasm had been made and those seg ments of arteries could be identified on the formalin-fixed brain. The intradural internal carotid, middle cere bral and proximal anterior cerebral arteries , all on both sides when possible, were dissected and embedded in paraffin. 5 y sections were cut and stained with H. E., PAS-PTAH, Van Gieson and Weigert's elastic stain. Results Case No. 50099: 44-year-old male. He de veloped severe headache and vomiting on the morning of June 26, 1975. Right carotid angio graphy was performed on that day, showing berry aneurysm at the trifurcation of the right middle cerebral artery. There was no spasm . On the 9th day, he became somnolent and carotid angiogram revealed vasospasm of the middle and anterior cerebral arteries on the right side (Fig. 1). His consciousness fluctuated, but on the whole he ran the downhill course and was comatous on the 18th day in spite of various treatments and expired 22 days after SAH. The luminal surface of the proximal middle cerebral artery was, as shown in Fig. 2A, covered with a net of crisscrossing fibrin fibers and some red blood cells and other corpuscles were seen confined between them. On thin sections, there

Fig. 1

L-CAG

of Case

50099

with

cross-filling,

performed 9 days after SAH. Vasospasm of the right anterior, middle cerebral and internal carotid arteries (arrow). Vague opacification of the aneu rysm is noted (arrow head).

were loosening and layer (Fig. 2B), and found on the luminal were present with elements.

thickening of the intimal no endothelial lining was end, on which fibrin fibers some blood corpuscular

Case No. 50065: 46-year-old male. He had sudden headache one afternoon and became unconscious. On admission to the hospital he was in a semicomatous state and showed de cerebrate posture on noxious stimulation. His CSF was bloody and about 2 hours after his attack right carotid angiography was carried out, showing the anterior communicating aneu rysm with slight narrowing of the proximal anterior cerebral artery. He continued to be comatous and died 16 days after the rupture. The luminal surface of the right anterior cerebral artery appeared relatively smooth and no endothelial cells were noted. Some fibrous structures, which were considered to be fibrin strands, were present on the surface (Fig. 3A). On thin section, the elastic lamina was un covered and on the luminal surface a small amount of fibrin was seen. In other areas, the luminal surfaces were flat tened by the presence of fibrous tissues on the waving internal elastic lamina and the thickness

Fig. 2 A: SEM of the luminal surface of the right proximal middle cerebral artery. A net of fibrin strands covers the surface. x 1,300 B: Fine structure of the middle cerebral artery adjacent to that examined by SEM. The intima is thickened and multilayered and on the surface no endothelial cells are present; fibrin strands (Fib) are present on the luminal sruface with occasional red blood cell(E). x 2,100

of fibrous components increased partially, cov ered with a fibrin network (Fig. 3B). Case No. 52054: 29-year-old male. On the morning of March 3, 1977, he suddenly became unconscious and was admitted to a hospital, where he was in drowsy state, complaining of severe headache with frequent vomiting. Right carotid angiography was performed 5 hours after the SAH and when the second injection was done for the lateral view, he had a series of general convulsions and the lateral films showed extravasation from the r-ICPC aneurysm. He was immediately referred to our hospital and bifrontal decompression was performed. After transient improvement, he became deeply semi comatous thereafter and expired 21 days after SAH. The luminal surface of the right middle cerebral artery was found to be covered with a sheet of coarse fibrin, on which scattered cell-like structures were seen. These were thought to be regenerating endothelial cells (Fig. 4). In order to exclude possible artifacts occurring after death and during preparative procedures, autopsy materials were obtained as controls from patients who died by accident or from causes other than intracranial pathology (Table

1). The middle cerebral arteries were dissected and the luminal surfaces were examined on SEM. Fig. 5 shows those of a 35-year-old male who died of aplastic anemia. The endothelial cells are clearly noted on the surface, and in some areas they are detatched so that the subendothelial structure is exposed. The exposed areas appear rather smooth and lack structures (Fig. 5A). On thin sections, fine structures of the arterial intima are relatively well preserved in spite of fixation of the materials more than 3 hours after death (Fig. 5B). Various features seen in the control series are shown in Fig. 6. In these 18 cases, fibrin nets were never encountered on the luminal surfaces. Some had fibrous structures, but the different nature of these structures from fibrin fibers are apparently obvious (Fig. 6). From these findings we assume that during the course of severe vasospasm the endothelial cells may be injured and disappear, and a mural thrombus, composed mainly of fibrin net, may be formed, partly progressively organized, partly dissolved by fibrinolysis, followed by reen dothelialization. These organic changes may be responsible for markedly prolonged narrowing shown on the angiograms, and might also be responsible for ischemic symptoms by occluding

Fig. 3 Case 50065 A: SEM of the right anterior cerebral artery. No endothelial cells are confirmed and a small amount of fibrin strands (f) is present. x 2,000 B: The other area of the anterior cerebral artery shows thickening of the intimal layer by the fibrous tissue, which increases in thickness in part, and on the luminal side fine and darkly stained fibrin fibers attach to the fibrous intima (arrows). Embedded in Epon, 1 µ section, stained with toluidine blue. L: lumen , Int: intima, M: media.

Table

Fig. 4

Case

middle fibrous

The

luminal

surface

of the right

cerebral artery is covered with coarse sheet, which has strong similarity on SEM

to fibrin lower

mesh

corner.

scattered cells

52054.

could

cells. Insertion: x 1,000

shown On

in the

this

cells of about probably

insertion

fibrous 7-12

at the left

tissue,

x 20-28

be regenerating

there

are

µ and these endothelial

x 850 SEM

of

the

human

fibrin

plate.

small perforating We scrutinized had been stored

1

Control

Series

branches or by embolization. the autopsy specimens which in formalin solution to obtain

possible histological basis for this assumption. We do not intend to present and discuss the details of the reviewed old materials, but summarize them in Table 2. Three cases among those will be briefly presented and histological findings are correlated with angiographic evi dence of arterial spasm.

Fig. 5 A patient who died from aplastic anemia, which served as a control for autopsy material for fine structural examinations. A: SEM shows the marked longitudinal folds on the luminal surface and the endothelial cells (End) cover the surface as a sheet, though partly detached showing the smooth surface of the elastic lamella. B: TEM. Fine structures of the endothelial cells (End) are fairly well preserved. The denuded elastica has nothing on its luminal surface and is assumed artifactual (Insertion). Lum: lumen, EL: internal elastic lamella, N: nucleus x 6,500

Fig. 6

Various

control A:

of the luminal

surface

of the middle

cerebral

artery

of the

on SEM.

Well preserved

marginal B:

appearances

series

area,

folds covers

Endothelial

cells

in which

the luminal are

continuous

sheet

of endothelial

cells with

distinct

surface.

detached

and

partly

peeled

off, exposing

the

subintimal

tissue. C: Occasionally apparently D:

Areas,

different which

fibrous from

structures

are noted

the fibrin

fibers.

had lost endothelial

covering.

on the luminal

surface,

but

they are

Table

*Interval ACA: ICA:

after anterior internal

2

Summary

initial

subarachnoid

cerebralartery cerebral

of Autopsy

artery

Cases

hemorrhage ACCA: MCA:

Case 3: 30-year-old male. On one morning he had severe headache, followed by generalized convulsion. After admission to a hospital, he had another convulsive seizure and became com atous. The right angiogram revealed the anterior communicating aneurysm with vasospasm of bilateral anterior cerebral arteries. He was referred to our clinic and his consciousness gradually improved over the following 2 days. Right herniparesis became manifest and on the 5th day following SAH his consciousness de teriorated again and the right carotid angiogram demonstrated diffuse severe vasospasm. After the angiography he deteriorated rapidly and became semicomatous. On the 7th day neck clipping of the aneurysm and decompressive surgery were performed, but he died on the 13th day after SAH. Microscopically loose fibrous layer of various thickness was present on the luminal surfaces of the right and left anterior cerebral arteries and

anterior middle

communicating cerebral

artery

artery

the right middle cerebral artery near the carotid siphon (Fig. 7). These loose fibrous components

Fig. 7

The

carotid layer

left

internal

bifurcation of various

surface.

thickness

No endothelial

toxylin-eosin

stain.

carotid

of Case

artery

3. The

is present

loose

near

the

fibrous

on the luminal

cells are identified.

Hema

were thicker between wavings elastic lamina. No endothelial

of the internal lining could be

confirmed. These findings show the presence of the mural thrombus on the luminal surface of severely narrowed cerebral arteries and are considered to be an early stage of concentric fibrous thickening of the intima, which is noted in cases of long survival after SAH. Case 7: 57-year-old female. She suddenly de veloped headache, nuchal pain and frequent vomiting and became unconscious. Carotid angiograms, right on the 7th day and left on the 9th day from the attack, revealed anterior communicating aneurysm and vasospasm of the left anterior and middle cerebral arteries. There was still arterial narrowing over the proximal portion of the anterior cerebral artery on the 19th day. On the 29th day direct obliteration of the aneurysm by trapping the anterior com municating artery was performed. About 2 weeks following surgery she died from sepsis.

Microscopic examination of the proximal anterior cerebral artery revealed concentric narrowing of the lumen by the thickened intimal layer. There was a clump of small blood vessels lined by the endothelial cells partly in the subintimal tissue (Fig. 8). The presence of the blood vessels in the subintimal layer suggested that this thickened layer was the organized mural thrombus, as will be discussed later. Case 9: 61-year-old female. Rupture of an anterior communicating aneurysm. She was found unconscious and the right carotid angio gram revealed aneurysm of the anterior com municating artery on the day of the attack. She gradually became alert on the following day. On the 5th day from the attack she noted right hemiparesis and speech disturbance and on the 8th day she gradually became obtunded. The left carotid angiogram on the next day revealed vasospasm of the anterior cerebral artery. Neck clipping was performed on the 11th day, fol lowed by V-P shunt 3 days afterwards. She had been stuporous and apathetic and died from respiratory complications 4 months later. A left carotid angiogram after the operation still showed localized narrowing just proximal to the anterior communicating artery. Low power view of this narrow segment with adjacent aneurysmal dome is shown in Fig. 9. The proximal anterior cerebral artery is severely narrowed by concentri cally thickened intimal layer, the luminal surface of which was lined by the endothelial cells. Discussion

Fig. 8

The proximal

7. There

the subintimal subintimal intimal mural

anterior

are numerous

layer

layer. layer

This

artery

vascular

in part

that from

Hematoxylin-eosin

of Case

channels

vascularization

suggests

is derived

thrombus.

cerebral

small

this

in

in the thickened

the organized stain.

Our preliminary data obtained by SEM post mortem examination of the cerebral arteries of the patients who succumbed to the ruptured intracranial aneurysm suggested that prolonged narrowing of the intracranial arterial trees was due to the mural thrombus at least in some gravely ill patients. Light microscopic findings of autopsy specimens which had been stored in formalin are also compatible with this assump tion and, moreover, localized rich vasculari zation of the subintimal fibrous layer seems to suggest positively that the origin of this subin timal tissue was derived from the mural thrombus by organization and reendo thelialization. Conway and McDonald6) re ported that the lumina of the intracranial ar

Fig. 9 The left anterior cerebral artery of Case 9. Localized severe narrowing of the anterior cerebral artery just proximal to the anterior communicating artery was still present on the carotid angiogram performed 70 days after SAH. Microscopic exam ination of the narrow portion revealed that concentric fibrous layer narrowed the arterial lumen. The aneurysmal sac, the fundus of which adheres to the arterial wall, is seen on the left. A small arterial branch seen on the upper part has also severely constricted vascular lumen. Hematoxylin-eosin stain.

teries were narrowed by subendothelial granu lation tissue and they thought that initial vaso spasm causes either mechanical or anoxic damage to the intima and subsequent intimal proliferation. Although sustained vasospasm damage to the intima, damage causes mural

we agree with them that causes some kind of we suggest that intimal thrombosis and sub

sequent organization resulting in narrowing the lumen. Since anti-fibrinolytic treatment

of to

prevent rebleeding from the aneurysm has recently been enthusiastically introduced, these findings are of great significance. If its effective blood level sufficient to inhibit fibrinolysis is maintained in patients with intimal damage caused by severe vasospasm, deleterious effects, including total occlusion of spastic arteries, might

be brought

about.

The vascular reactions to intimal damage of various sorts have been intensively investigated mainly in connection with atherosclerosis.' °) It is known that focal intimal damage brings about progressive intimal thickening with rapid reen dothelialization.3.5) However, when a superficial injury over a large area is concerned, the lesion is characterized by delayed reendothelia lization.4) Complete stripping of the intima

of an artery gives rise to mural thrombosis in all cases,29) but the amount of mural throm bus formed at the site of injury is not gross and rarely leads to massive thrombosis of blood flow is maintained.14) The thrombus formed in flowing blood is composed mainly of a fine meshwork of fibrin in which red cells are trap ped.14.29)SEM findings of the luminal surface of the right middle cerebral artery, as shown in Fig. 2, seem to indicate just the same process in progress on the luminal surface of the arteries in severe vasospasm as is described in experimental models of mural thrombosis in flowing blood. The fates of these mural deposits are three fold: 1) to be dislodged, giving rise to em bolization; 2) to be removed by fibrinolysis; and 3) to be organized and endothelialized, bringing about intimal thickening. When fragments of mural thrombi are dis lodged and occlude arterial branches, the pa tient may show sudden neurological deteriora tion. The occurrence of embolization, however, would be rare because mural thrombus is mainly composed of fibrin meshwork, and frequent fragmentation seems improbable. In fact, sud den clinical deterioration other than apparent rebleeding can occur only rarely. Resolution 'of thrombi is achieved mainly by fibrinolysis. The fibrinolytic activity is known to increase several days on after SAH .26,211) As the time course of an increase in the fibrinolytic activity may be correlated with an increasing risk of rebleeding from aneurysms, dissolution of the thrombus which has been formed at the site of aneurysmal rupture progresses with an increase in fibrinolytic activity and the diminished clot gives way to rebleed. It also seems valid for a mural thrombus and its thickness may reduce and the vascular lumen may be restored partially or fully. Thus the luminal narrowing by the mural thrombus is not necessarily progressive, and although the ultimate state is the similar thickened intimal layer, this mechanism is in contrast to intimal thickening by subintimal granulation tissue discussed by Conway and McDonald.6) Some of mural thrombi, remained unresolved in situ, are gradually organized and reendo thelialized. It was reported that reendothelia lization after desquamation by mechanical trauma was slow in the aorta of a rabbit,' 7) but Bjorkerud and Bondjers demonstrated

that the reendothelialization of the denuded elastica in the rabbit aorta was rather rapid and complete within 4 weeks.4) Bjorkerud argued that the rapid reendothelialization may be explained by the small size of the defects. Organization and reendothelialization of a diffuse mural thrombus have been intensively investigated using arterial grafts.14) Light microscopic findings of the concentri cally thickened intimal layer with intact en dothelial lining remind us of a histology of arterial grafts. A fibrous layer of various thickness are present interior to the waving internal elastic lamina with a continuous en dothelial lining at the luminal surface. The subintimal layer of the arterial grafts are certainly derived from the organized mural thrombus. In the experimental study of mural thrombi in the pig aorta, Woolf et al 29)reported the rapid vascularization in the mural thrombus and the new vascular channels appear to be derived entirely from clefts occurring in the substance of thrombi. The presence of a clump of small blood vessels in the thickened subintimal layer in our Case 7 strongly suggests that the latter is the organized thrombus. It is known that there are scattered areas of cerebral infarcts after SAH from the rupture of the aneurysm. 2,7.18.19.22)They are distributed largely in the territories of the narrowed cerebral arteries. However, their distribution cannot always be correlated with the distribution of prolonged vasospasm, nor with severity of vasospasm.2,19) If the vascular lumen was physi cally constricted solely by contraction of smooth muscles in the vessel wall, the distribution of these ischemic lesions would be within the territories of spastic arteries and their occurrence would inevitably require severe narrowing of the spastic arteries .21) The presence of mural thrombi may itself interfere blood stream if the vascular lumen is narrowed sufficiently. But on the other hand, the mural thrombi may occlude the orifices of small perforating branches of the cerebral arteries, regardless of the severity of constriction of the vascular lumen. The latter mechanism may well explain wide distribution of the ischemic cerebral lesions following SAH. It can also be easily understood that permanent neurological deficits may occasionally be en countered in some cases in which neither severe vasospasm with decreased perfusion nor oc

clusion of arterial branches is demonstrated on angiograms.8,11) It is demonstrated that prolonged spasms cause ultrastructural changes mainly in the medial layer, refered to as myonecrosis.9) Fein et al.9) also noted that 2-7 days after SAH there is prominent loss of tight junctions between the endothelial cells and numerous platelets are adherent to the denuded elastica. Though their experimental model o f SAH failed to show that these changes continued to be present beyond one week after SAH, presence of the intimal changes with adherent platelets to the denuded elastica would progress to further deposition of fibrin network, forming the mural thrombus in certain conditions. Severity of vasospasm and its duration which is sufficient to evoke and ag gravate these intimal changes still remain uncertain. Antifibrinolytic treatments have been cur rently used to prevent possible rebleeding from the ruptured aneurysm and successful results with few untoward complications have been reported .20,27) However, definitely thrombotic complications were also reported. 13,15,23) Antifibrinolytic drugs per se, such as epsilon amino-caproic acid, have no effect to induce thrombus formation, but it was demonstrated by Patterson16) that the weight of induced thrombus is greater with use of antifibrinolytic drug than control. We assume that the thrombotic com plications in connection with antifibrinolytic agents after the rupture of the aneurysm might be due to the growth of mural thrombus which otherwise would be scavenged and/or prevented to grow further by fibrinolytic activity. Indeed, antifibrinolytic treatment may be effective to prevent rebleeding in low grade patients with little vasospasm but there could be a potential danger to aggravate ischemic complications in the cerebrum in those who are severely ill due to the presence of prolonged vasospasm. We believe from our present study that indiscriminate use of antifibrinolytic medication should be avoided and that in cases with severe prolonged vascular narrowing its use is contraindicated. Acknowledgment This work was supported in part by the grant No. 148246 from the Ministry of Education, Science and Culture. A part of this paper was presented

at the 34th annual meeting of the Japan Neurosurgical Society, Nagoya, On October 23, 1975, and at the 6th International Congress of Neurological Surgery, Sao Paulo, Brazil, on June 23, 1977. References 1) Allcock, J. M., Drake, C. G.: Ruptured in tracranial aneurysms-The role of arterial spasm. J Neurosurg 22: 21-29, 1965. 2) Birse, S. H., Tom, M. I.: Incidence of cerebral infarction associated with ruptured intracranial aneurysms. A study of 8 unoperated cases of anterior cerebral aneurysm. Neurology 10: 101-106, 1960. 3) Bjorkerud, S.: Reaction of the aortic wall of the rabbit after superficial, longitudinal, mechanical trauma. Virchows Arch [Pathol Anat] 347: 197-210, 1969. 4) Bjorkerud, S., Bondjers G.: Arterial repair and atherosclerosis after mechanical injury. Part 1. Permeability and light microscopic characteris tics of endothelium in non-atherosclerotic and atherosclerotic lesions. Atherosclerosis 13: 355-363, 1971. 5) Bjorkerud, S., Bondjers, G.: Arterial repair and atherosclerosis after mechanical injury. Part 2. Tissue response after induction of a total local necrosis (Deep longitudinal injury). Athero sclerosis 14: 259-276, 1971. 6) Conway, L. W., McDonald, L. W.: Structural changes of the intradural arteries following subarachnoid hemorrhage. J Neurosurg 37: 715-723, 1972. 7) Crompton, M. R.: Cerebral infarction following the rupture of cerebral berry aneurysms. Brain 87: 263-280, 1964. 8) Fein, J. M., Boulos R.: Local cerebral blood flow in experimental middle cerebral artery vasospasm. J Neurosurg 39: 337-347, 1973. 9) Fein, J. M., Flor, W. J., Cohan, S. L., Park hurst, J.: Sequential changes of vascular ultra structure in experimental cerebral vasospasm. J Neurosurg 41: 49-58, 1974. 10) French, J. E.: Atherosclerosis in relation to the structure and function of the arterial intima, with special reference to the endothelium. Int Rev Exp Pathol 5: 253-353, 1961. 11) Heilbrun, M. P., Olesen, J., Lassen, N. A.: Regional cerebral blood flow studies in sub arachnoid hemorrhage. J Neurosurg 37: 36-44, 1972. 12) Kin, H., Mizukami, M., Araki, G., Yoshida, Y.: The pathological study of so-called vasospasm. Neurol Med Chir 16: 115-125, 1976. (Jap with

Eng abstract) 13) Mullan, S., Dawley, J.: Antifibrinolytic therapy for intracranial aneurysms. J Neurosurg 28: 21-23, 1968. 14) Mustard, J. F., Murphy, E. A., Roswell, H. C., Downie, H. G.: Factors influencing thrombus formation in vivo. Am J Med 33: 621-647, 1962. 15) Norlen, G., Thulin, C.: The use of antifibri nolytic substances in ruptured intracranial - aneu rysms. Neurochirurgia 12: 100-102, 1969. 16) Patterson, R. H., Harpel, P: The effect of epsilon aminocaproic acid and tranexamic acid on thrombus size and strength in a simulated arterial aneurysm. J Neurosurg 34: 365-371, 1971. 17) Poole, J. C. F., Sanders, A. G., Florey, H. W.: The regeneration of aortic endothelium. J Pathol 75: 133-143, 1958. 18) Schneck, S. A., Kricheff, I. I.: Intracranial aneurysm rupture, vasospasm, and infarction. Arch Neurol 11: 668-680, 1964. 19) Schneck, S. A.: On the relationship between ruptured intracranial aneurysm and cerebral infarction. Neurology 14: 691-702, 1964. 20) Sengupta, R. P., So, S. C., Villarejo-Ortega, F. J.: Use of epsilon aminocaproic acid (EACA) in the preoperative management of ruptured in tracranial aneurysms. J Neurosurg 44: 479-484, 1976. 21) Simeone, F. A., Trepper, P. J., Brown, D . J.: Cerebral blood flow evaluation of prolonged experimental vasospasm. J Neurosurg 37: 302-311, 1972. 22) Simeone, F. A., Trepper, P.: Cerebral vaso spasm with infarction. Stroke 3: 449-455, 1972. 23) Sontag, V. K. H., Stein, B. M.: Arteriopathic complications during treatment of subarach noid hemorrhage with epsilon-amino caproic acid. J Neurosurg 40: 480-485, 1974. 24) Stornelli, S. A., French, J. D.: Subarachnoid hemorrhage. Factors in prognosis and manage ment. J Neurosurg 21: 769-780, 1964. 25) Sundt, T. M., Jr.: Management of ischemic complications after subarachnoid hemorrhage. J Neurosurg 43: 418-425, 1975. 26) Tamaki, N., Kusunoki, T., Ohi, S., Taomoto, K., Matsumoto, S.: Clinical study of cerebral aneurysms. With special references to the warn ng signs of rebleeding and antifibrinolytic i treatment during waiting time for surgery. Neurol Surg (Tokyo) 3: 647-654, 1975. (Jap with Eng abstract) 27) Tovi, D.: The use of antifibrinolytic drugs to prevent early recurrent aneurysmal sub arachnoid haemorrhage. Acta Neurol Scand 49: 163-175, 1973.

28)

29)

Tovi, D., Nilsson, I. M., Thulin, C.: Fibrinolytic activity of the cerebrospinal fluid after sub arachnoid haemorrhage. Acta Neurol Scand 49: 1-9, 1973. Woolf, N., Bradley, J. W. P., Crawford, T., Carstairs, K. C.: Experimental mural thrombi in

the pig aorta. Exp

Address partment Moriguchi,

Pathol

reprint

early

natural

49: 257-264,

The

1968.

requests

to: Kuniyuki

of Neurosurgery, Osaka Japan 570

Kansai

history.

Someda, Medical

M.D.

Br

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University,