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The natural history of intracranial aneurysms
American
Heart
Journal
June, 1967, Volwne 73, Number 6
Editorial The natural
history
George H. du Boulay, London, Englcl nd
B
of intracranial
M.K.C~.P.,
rolin and I-Ins&r,” in 19.58, dre\v attention to the frequency of ver\small, presumably early, aneury&s easili. overlooked at autopsy unless special steps are taken, and Hasslerlg has pursued and extended these studies. Stehbenss” has also found very small dilatations at points where the elastic tissue is degenerate. In his recent paper, SahsY illustrates and discusses such microscopic bulges and uses the word “sacculation,” xvhich I will adopt, to convey the change into frank “berry” aneurysm form. These studies are of the greatest importance in the context of etiology, but minute aneurysms cannot be demonstrated by angiogrnphy during life; thus, from the radiologic and clinical points of view it is the life story of the “saccule” jvhich is at present of greatest moment. From the pathologist’s viewpoint, Crompton’“~” has written very interesting papers al)out these larger aneurysms. Statistics and generalizations about frecluemy, prognosis, and treatn~ent”~-Z7 have I)een of great value in opening up the subject for investigation, but without minute analysis they can obscure the variety of the aneurysms natural histories, and it Frum
aneurysms
F.F.R.*
may be more graphic here to begin by describing a single case. From this, by comparisons, some few facts about the life story of the disease may emerge. Perhaps when more data have been accumulated, the closest attention to each individual aneurysm may throw light on the prognosis and help in the management of the case. In 1957, T.B., a 62-year-old woman, suffered two subarachnoid hemorrhages, with an interval between them of 3 weeks. Angiography was performed 9 days before her second hemorrhage, and as a result of the findings, operation upon an anterior communicating aneurysm \vas carried out 2 day-s after her second episode of bleeding. At operation, in the angle between the anterior cerebral branches, a bright blue sac was seen; it measured about 4 by 4 mm. (perhaps slightly larger than at angiography) and had a w-all that was tissuepaper thin. That it was going to burst was obvious as soon as it was touched, and, in fact, during dissection it did burst and came straight off the attachment to the artery. The aneurysm had no neck at all, and at its point of departure there was
the ZJational Hospitals for Servuus Diseases, St. Harthulomew’s Hospital. and the Suffield parative Medicine, London. ISngland. Received for publication Sept. IY, 1966. *.\ddrcss: Diagnostic Radiology Department, St. Bartholomew’s Ilospital. London, IC.C.1, England.
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just a small opening in the arterial wall. Hemorrhage was controlled b?. an arterial clip. The first consideration-perhaps the most important of all-is the actual appearance of the aneurysm at operation. It is clear that the sacculation of this aneurysm was an acute process, and that it could not have existed for more than a short time in the state in which it QXS found. Yet the patient was elderly. Thus, a number of central questions about the aneurysmal disease are posed, answers to which would influence the management of the patient even though the actual etiolog) of the aneurysm remained unknown. 1. What is the time relationship between bleeding and the sacculation of an aneurysm? 2. How prevalent are aneurysms among the general symptomless population? 3. What is the probable future of a symptomless aneurysm found by chance at angiography in a patient with some other condition, or of a symptomless aneurysm in a patient with multiple aneurysms? In answering the first question about the time relationship between formation of the aneurysm and bleeding, one must know whether the patient already described was typical, for in her case, at least, there can be little doubt that the macroscopic aneurysm was of very recent origin. Out of a series of patients at the fi,Iaida Vale Hospital, there were 83 in whom the aneurysm responsible for hemorrhage was seen and carefully examined at operation or autopsy. Detailed notes of the operative appearance were made for the most part by Rfr. Valentine Logue, and in 33 cases we have from the operation (or occasionall> the autopsy) an exact description of the wall of the aneurysm. In 11 of these 33 cases the whole wall of the aneurysm was tissue-paper thin. lJIost were unilocular. Five of them \\:ere surrounded by granulation tissue or adhesions whose firmness and organization seemed to be a good reflection of the interval since hemorrhage. From all of them, hemorrhage had been recent. In the other 22, however, some part---usually the neck and often also a proximal loculus of the aneurysm-was thicker than the point, blister, or loculus which repre-
Am. Heart J. Juw, 1967
sented the rupture. Not all of them had bled more than once. RIany had bled only recently. Thus, one is faced with a concept which may be usefulPmmthat in relation to the first sacculation of an aneurysm, hemorrhage may be immediate, within at the most a few weeks, sometimes, no doubt, days or hours; or it may be delayed until months or more later. The first sacculation of the aneurysm in such delayed cases may be silent, and the eventual hemorrhage when it comes may be the result of fresh weakening of some part of the now-thickened original wall of the aneurysm. In spite of the fact that, in two thirds of the cases hemorrhage appears to have been delayed, it does not necessarily follow that no aneurysm is ever safe from the risk of bleeding. In the first place, the vast majority of hemorrhages from a single aneurysm occur within a few weeks of one another, and if the patient survives this phase of acute instability, recurrent hemorrhage from the same aneurysm months or years later is uncommon. Secondly, it may be demonstrated by angiographylz as well as at autopsy, 7,21,22v33that macroscopic aneurysms are far more prevalent in the general population than is frank subarachnoid hemorrhage at the age of greatest risk (perhaps even as much as twenty times as prevalent), and with such a low chance of bleeding, the prognosis of a symptomless aneurysm may surely be considered to be a hopeful one. Thus, to the concept of immedicltr and delayed hemorrhage, one may add the third larger group of clnezlrysms that never bleed at all. .This aspect of the problem should be borne in mind whenever there is a proposal that all aneurysms, in so far as possible, should be treated by active measures (including surgical intervention whenever the aneurysm is accessible.) Patient T. R., the case cited, was seen at a moment of time when she had already had more than one hemorrhage. Although, as has been shown, the thin wall of the aneurysm was characteristic of that in one group of patients, from two other points of view her aneurysm was not altogether typical. Firstly, it was relatively free of surrounding adhesions, in spite of
two hemorrhages, and, secondly, it consisted of a single smooth loculus. To amplify this statement it is necessary to consider what natural courses of events may afflict an aneurysm once it has formed. Leave aside the serious side effects of arterial spasm. A devastating hemorrhage (it is probably only a few milliliters of blood) is liable to cause death by disruption of the brain; but very small leaks may be instrumental in giving rise to adhesions around the aneurysm and to fibrosis with thickening of its walls and adhesions to the brain, a finding that is common enough. A second hemorrhage, if again it is a small one, may then result in a localized intracerebral collection of blood, the surface of which is defined by gliosis and fibrosis. The center of this small hematoma may clot or remain as a cavity in communication with the vessel of origin. The appearance, changes in, and obliteration of such extra loculi and accessory cavities have been observed on repeated angiography n-hen the examination became necessary for clinical reasons; and some of them have subsequently been confirmed by the operative findings. It is in such cases very difficult to see any difference between true and false sacs. Some perhaps remain small, but others develop by degrees layer upon layer of organizing fibrous tissue in their \valls and cause symptoms, not by further hemorrhage so often as by pressure and the occupation of space. Very large aneurysms formed in this way are relatively rare but comprise a distinct clinical group of spaceoccupying Iesion. Not by any means a,re all aneurysms which show loculus formation embedded in the brain, however, and there are probably other mechanisms by which they form. Be that as it may, recent bleeding and loculus formation are undoubtedly very closely connected; more than a third of all aneurysms which bleed and are shown 1)) angiography within the first few weeks reveal more than one loculus, whereas, by contrast, aneurysms not responsible for recent hemorrhage are hardly ever loculated in the same way. Some aneurysms have more than two loculi, and, of course, some aneurysms bleed two, three, or more times; but the actual relationship betlveen the number of bleeds and the number of
loculi shown angiographically is not a particularly close one. This relationship must be affected by the tendency of loculi to clot spontaneously. Uid they not do so, the number of loculated aneurysms demonstrated would probably have been greater in the RIaida Vale series on \jrhich these generalizations are Ijased. In that series, some were actually demonstrated to have gone through the cycle of loc~~lus formation (with bleedingj and loculus oblitera tion. The sudden appearance or sudden expansion of loculi is by no means uncommon. If a nerve is compressed or hemorrhage takes place, the expansion of loculus is accompanied by symptoms, but cases have also been seen in which angiography has detnonstrated the appearance or expansion of a loculus taking place silently. The obliteration of a loculus after operation, such as carotid ligation, is also a common phenomenon. So much then for the dynamic appearance and spontaneous clotting of loculi of aneurysms during their period of instability. The quiet thickening of the aneurysm \vhich turns an exceedingly thin-walled bulge into a much more stable and rigid structure is not susceptible to radiologic demonstration, but it is probable that the thin wall immediatel!~ after sacculation begins at once to grow stronger by the laying down of fresh laJ.ers of fibrous tissue. Furthermore, some aneur~~sms are probably thick walled almost. from the beginning, hcause the initial damage to the arteria1 wall is slight and leads onl\T to an oozing of IJood and to the grolvth of surrounding adhesions before any great expansion takes place. Sahs”’ illustrates two minute aneurysms capped by proliferated connective tissue. It is no doubt because of the thickness of the wall that most aneurysms of long standing are dormant and silent. Delayed hemorrhage when it occurs seems to be the result of a \l\-eakening of the mall of the aneurysm at one pointy, the fresh appearance of ;I thin-walled s;~c (this time a Ioculus of the origin:11 aneurysm), and the Ijeginning again of a cycle of events Lvhich once more rna>~ lead to devast;lting hemorrhage or to healing. The question of etiolog!is here left until
726
a14 Hodtr y
last, and the answers are not all established but the problem is becoming clearer. Since Eppinger13 and Turnbull, 3g and particularly since Forbus’ work’” describing the presence of defects in the medial muscular coat of the arteries of the circle of Willis, and critical papers by Schmidt32 Strauss ~~er~;‘~~~rt~~~~?e::1ynn,L7 Forster and < ‘ ,526 and many others, most aneurysms in the head have been ascribed to two causes: (1 j congenital weakness of the arterial wall, and (2) atherosclerosis, with hypertension as a possible factor either in their formation or in their rupture. Another theory w:ith several variations, that these aneurysms arise at points at which embryologic vessels have not been completely absorbed, was favored lq, Padget, Bremer,” and Bassett,’ but does not seem to be very probable in the light of recent histologic studies. It is generally agreed that ectasia of cerebral vessels is a manifestation of atherosclerosis; but, on the other hand, the term “berry” aneurysms still suggests to IXU~J people a lesion of congenital origin. Yevertheless, many berry aneurysms show atherosclerotic changes, and Craxvford, in 1959, on the basis of postmortem studies, has suggested a combination of the congenital and atherosclerotic causes in various proportions in every case. Radiologically, one would like to add that there is no particular magic about the “berry” shape, and all acutely formed aneurysms in the head, even traumatic ones, are liable to take on the same general configuration. The association of atherosclerosis with intracranial aneurysm is certainly veq close. All large aneurysms and many small ones show gross atherosclerotic changes. As Crawford points out, severe cerebral atheroma is much more common in patients who die of subarachnoid and cerebral hemorrhage than in those who die from noncerebral and noncardiac causes. Atherosclerosis is commonly present in the circle of Willis, even in very young patients when aneurysms have been demonstrated, and even below the age of 20 years; but aneurysm at this age is in any case rare. The distribution of atherosclerosis in the cerebral circulation is veqr silnilar to the distribution of aneurysms, I)oth in its
predilection for a larger vessel and in the tendency for both conditions to occur most severely and most commonly at arterial branchings. Macroscopic atheroma has been found in cerebral vessels in almost all cases in the series of patients dying with aneurysm at the Rlaida \,‘ale Hospital, and microscopic evidence of atheroma was seen in the remainder but not necessarily in the immediate vicinity of the aneurysm itself. The incidence of symptomless aneuqrsm in patients with transient cerebral ischemia suffering from occlusive vascular disease seems to l)e higher than that in patients with tumor and suggests a causative association with atheroma. Bull and his associates” and RatinoP have pointed out that atheroma magi I)e diagnosed in its severer fornl 1)). irregularit). of the lumen of cereljral arteries. ITsing this irregularit\: as a sign, one may demonstrate that the disease is much more common in patients who present with symptoms due to aneurysm formation than in those who have no such sy~nptoms and whose arteriograms are normal or reveal the presence of a tumor. The association of aneurysm lvith angiographic evidence of atherosclerosis increases steadily with age, and there seems to l)e some slight sex difference (30 per cent males, 38 per cent females), I)ut increasing frequenqr of atherosclerosis with advancing age in the tumor series is far less obvious than in the aneurysm series. After the age of 3.5 in the tumor series the frequency of the finding is stead!. emI)etween one fifth and one sixth of the patients show definite evidence of irregularit!, of the vessel walls and in that series the disease is found in the same proportion of men and \\;omen. Atheroma was associated with the formation of aneurysms in one of the veq. few animals in which a cerebral aneurysm has been discovered.:j7 In spite of this very close association of two diseases, and in spite of the influence of established atheroma on the later stages of large chronic aneuq-sms, changes which would I)e universally recognized as atheroma are often not found close to the origins of early ;meurysms. The piitient used as a11 e.xample a1 the Iqinning of this essa)’ had no m;lc-roscopic atheroma near the anew
rysm. The very small aneurysms illustrated by Hassler, by Stehbens, and blr Sahs are associated with alterations in the elastic of the arterial wall but not with the deposition of fat or with other wellrecognized atherosclerotic manifestations. It seems to be probable that work on the relationship of these alterations in the elastic lamellae to atheron~a1fi~1g~2n~28 will throw light not only on the etiology of aneurysm formation, but also on the nature of very early or pre-atheromatous arterial disease. What then is the role of medial muscle defects? There is no doubt, of course, that the openings of most large intracranial aneurysms involve those parts of the artery in lvhich the muscle of the media is deficient; this has been shown by many people since Forbus in 1930. There are, however, a variety of reasons for doubting that it is the absence of muscle which constitutes a congenital lveakness reponsible for dilatation of the vessel. Both Stehbens and Sahs have shown that very small aneurysms do not bear a constant relationship to the defects. The aneurysms occur at the distal angle of a point of branching, whereas the defects are also found at lateral angles, and in some cases the neck of the aneurysm involves part of a defect, but part also of the neighboring muscular wall. SIoreover, the defects are present in the great majority of cerebral vessels and also in other arteries of the bod>..14,17J5 The normal elastica by itself is sufficient to contain a greatly raised blood pressure. It is not correct to speak of muscular defects as congenital abnormalities; they are anatomic features presumably having a physiologic purpose. One may speculate about the function of the so-called defect. The muscle coat of an intracranial artery is arranged almost entirely in a circular (probably a helical) fashion without longitudinal fibers. Consider an artery from which a small bulge protrudes at right angles, and let us suppose that the whole junction is sheathed in muscle so that the coat of the main artery and its Ixanch are completely continuous all around the orifice. The circle in the diagram (Fig. l,(l) represents the origin of this small bulge. The force \vhich results from contraction
Cl
b
Fig. I. a, ‘l’he three small radial arrows represent the force of caltraction at the origin of a hrallch entirely sheathed in muscle. The three vertical arrows represent the force of contraction of the parent vessel at those points if that also is sheathed in muscle. The resultants are shown b>, arrmvs with double heads. b, IJeformit>of the origin of the branch which would result. A% fibroelastic pad at S (in a) would relieve the origin of the sm;~ll branch from the effect of contraction of the parent vessel.
I;ig. 2. A three-dimellsiotlal representation of the situation. On the left, half of the orifice of a branch is shown. 011 the right, the forces are drawn a~ in Fig. 1,~.
of its muscle coat may be represented by small radial arrows. The strength and direction of the forces which would be applied at the same points by the contraction of the muscle fibers of the parent artery are also shown in the diagram. If the stimulus to contract were applied simultaneousl>r to the muscle coat of both the parent artery and the branch, the resultants of these opposing forces would tend to deform the opening of the vessel, making it oval shaped (Fig. 1,b) or even occluding it. The deformity of the origin of the vessel would in any case diminish the cross-sectional area of the branch to a greater degree than if it had remained circular. The actual degree of clefornlity lx-ould vary with, among other factors, the angle at which the
728
.4m. Head J. June, 1967
du Bouluy
.,IA L
T Fig. 3. At Y junctions the muscles of the two branches oppose each other at the distal angle (A) and some elasticity at this point might be expected.
I
to
b
Fig. 4. Very small branches sometimes come off at a tangent from the side of the parent and thus have oval orifices (a.i section and a.ii elan). If there were muscle over their outside walls’, its contraction might result in the deformity shown in (b,i section and b,ii) plan.
branch left its parent. The situation is represented again in three-dimensional form in Fig. 2. The necessity for muscular defects at other points at which they are found is indicated in Figs. 3 and 4. The provision of a break in the continuity of a muscle near the arterial division-a break filled by a pad of elastic tissue-would clearly go some way to solving these hydrodynamic difficulties, hence, perhaps, the so-called medial defect. Intracranial aneurysms seem to be exceedingly rare in animals other than man, although the histologic structure of the
cerebral arteries is similar in other mammals, and all show medial defects at many points of branching.12Jgs23J4 The mechanical qualities necessary in arterial walls await more profound investigation, but it is clear from the survival of some patients with exceedingly thin aneurysms that the mere loss of a layer of muscle from the wall of the artery is likely to be of little consequence. In fact, the majority of so-called medial muscular defects in healthy mammalian arteries are well filled with very fine elastic fibers from the adventitia. Whatever the role of these defects in the formation of aneurysms, it must be a secondary one, and they should not be allowed to obscure the main objective when one looks for a preventable or treatable cause. The formation of aneurysms seems histologically to be related to a breakdown of strength and cohesion of the whole of the arterial wall, including as well its most important parts-the elastica. It may be that the process which leads to the formation of aneurysms is an acute degenerative incident which in some cases, l)ut not in all, goes on to overt atheroma. The fact that aneurysms are common in the head and rare elsewhere need not imply a primary cause found only in the head, but could be explained by different local conditions. The nature of the adventitia of the artery, the concentration of elastic chiefly into the internal elastic lamina, and the striking involvement of the media in established atheroma may determine the frequency of formation and saccrnation of aneurysms. The possible part played by the adventitia deserves special mention. Within the head the adventitia is exceedingly frail, and much of it seems to be ill-suited to be a final defense barrier against the sudden expansion or rupture of an artery whose wall has been damaged by an acute pathologic process. Elsewhere in the body the close investment of arteries by stronger tissues with an independent supply of blood may be thought to be important in preventing the formation of aneurysms. KEFEKESCES 1. Bassett, rosurg.
K. C.: Intracranial 6:216, 1919.
aneurysms,
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Bremer, J. L.: Congenital aneurysms of the cerebra1 arteries: An embryological study, Arch. Path. 35:819, 1943. Brolin, S. E., and Hassler, 0.: Minute aneurysms detected by microdissection of basal cerebral arteries. Actn Path. Microbial. Scandinav. 44:59, 1958. Bull, J. W’. D., Couch, R. S. C., Joyce, D., Marshall, J., Potts, D. G., and Shaw, D. A.: Observer variation in cerebral angiography: An assessment of the value of minor angiographic - - . changes in the radiological diagnosis of cerebrovascular disease. Brit. I. Radio]. 35:16.5. 1960. Carmichael, R.: Gross defects in the muscular and elastic coats of the larger cerebral arteries, J. Path. Bact. 57:345, 1945. Carmichael, R.: The pathogenesis of noninflammatory cerebral aneurysms, J. Path. Bact. 62:1, 1950. Chason, J. I.., and Hindman, W. M.: Berry aneurysms of the circle of Willis: Results of a planned autopsy study, Neurology; 8:41, 19.58. Crawford, T.: (i) The pathogenesrs of atherosclerosis: The trends of recent work, Proc. Roy. Sot. Med. 52:537, 1959. Crawford, T.: (ii) Some observations on the pathogenesis and natural history of intracranial aneurysms, J. Neurol. Neurosurg. & Psychiat. 22:259, 1959. Crompton, M. R.: The pathology of ruptured middle-cerebral aneurysms, with special reference to the differences between the sexes, Lancet 2:421, 1962. Crompton, M. R.: Intracerebral haematomn complicating ruptured cerebral berry aneurysms, J. Neurol. Neurosurg. & Psychiat. 25:378, 1962. Du Boulay, G. H.: Some observations on the natural history of intracranial aneurysms, Brit. J. Radio]. 38:721, 1965. Eppinger, H. : Pathogenesis (Histogenesis und Aetiologie) der Aneurysmen einschliesslich des Aneurysma equi verminosum, Arch. klin. Chir., Suppl. 35, 1887. Forbus, W. D.: On the origin of miliary aneurysms of the superficial cerebral arteries, Bull. Johns Hopkins Hosp. 47:237, 1930. Forster, F. M., and Alpers, B. J.: Anatomical defects and pathological changes in congenital cerebral aneurysms, J. Neuropath. & Exper. Neural. 4:146, 1945. Friedman, M. : Pathogenesis of the spontaneous atherosclerotic plaque: A study on -the cholesterol-fed rabbit, Arch. Path. 76:318. 1963. Glynn, L. F.: Medial defects in the circle of ii’illis and their relation to aneurysm formation, I. Path. Bact. 51:213. 1940. Hassler, 0.: (i) Histochemical study of the arterial elastic lamella at the edge of the intracranial berry aneurysms, Acta Sot. Med. Uppsalien 66:263, 1961. Hassler, 0.: (ii) Morphological studies on the large cerebra1 arteries, with reference to the aetiology of subarachnoid haemorrhage, Acta
Psychiat. Neural. Scandinav., Suppl. 154, 1961. Hassler, 0. : (iii) On the etiology of intracranial aneurysms, in Fields, W. S., and Sahs, A. C., editors: Intracranial aneurysms and subarachnoid haemorrhage, Springlield, Ill., 1965, Charles C Thomas. DD. 25-37. 21. Helpern, M., and Rabson, S. M.: Sudden and unexpected natural death. III. Spontaneous subarachnoid haemorrhage, Am. J. hf. Sc. 220~262, 1950. E. M., and Pool, J. C.: A systematic 22. Housepin, analysis of intracranial aneurysms from autopsy file of the Presbvterian Hosoital. 1914-1956. J. Neuropath. & Exper. Nemo]. 1’7:409, 19.58: M. A., Florey, H. WT., Stephens, \V. 23. Jennings, C., and French, J. C.: lntimal changes in the arteries of a pig, J. Path. Bact. 81:49, 1961. LV., Paine, K., and MTalsh, E.: 24. McKissock, i\n analysis of the results of treatment of ruptured intracranial aneurysms, J. Neurosurg. 17 :762, 1960. 25. McKissock, W., Richardson, A. E., and LValsh, E.: Middle-cerebral aneurysms. Further results in the controlled trial of conservative and surgical treatment of ruptured intracranial aneurysms, Lancet 2:1203, 1960. W., and \%-alsh, E.: Subarachnoid 26. McKissock, haemorrhage due to intracranial aneurysms. Results of treatment of 249 verified cases, Brit. M. J. 2:X9, 1956. IV., Richardson, A., W.alsh, I*., 27. McKissock, and Owen, E.: Multiple intracranial aneurysms, Lancet 1:623, 1964. H. D.: Coronary arteries in fetuses, in28. >Ioon, fants and juveniles, Circulation 16:263, 1957. 29. Padget, I). H.: The circle of \Villis, in Dandy, I$:. E., editor: Intracranial arterial aneurysms, Ithaca, New York, 1944, Comstock Publishing Co., pp. 67-90. 30. Iiatinov, G.: Extradural intracranial portion of carotid artery: A clinicopathological study, Arch. Neurol. 10:66, 1961. 31. Sahs, A. L.: Observations on the pathology of saccular aneurysms, J. Neurosurg. 24:792, 1966. 32. Schmidt, ill.: Intracranial aneurysms, Brain 53 :489, 1930. 33. Stehbens, 1%‘. E.: Intracranial arterial aneurysms, Australasian Ann. Med. 3:214, 1954. W. E.: IMedial defects of the cerebral 34. Stephens, arteries of some mammals, Nature 179:327, 1957. W. E.: Medial defects of the cerebra1 3.5. Stehbens, arteries of man, J. Path. Bact. 78:179, 1959. W. E. : (i) Histopathology of cerebral 36. Stehbens, aneurysms, Arch. Neurol. 8:272, 1963. W. E. : (ii) Cerebral aneurysms of ani37. Stehbens, mals other than man, J. Path. Bact. 86:161, 1963. 38. Strauss, I., Globus, J. I-I., and Ginsburg, S. I\‘.: Spontaneous subarachnoid hemorrhage: its reiation to aneurysms of cerebral blood vessels, Arch. Neurol. & Psychiat. 27:1080, 1932. 39. Turnbull, H. M.: Intracranial aneurysms, Brain 41:50, 1918. 20.
Heart
Journal
June, 1967, Volwne 73, Number 6
Editorial The natural
history
George H. du Boulay, London, Englcl nd
B
of intracranial
M.K.C~.P.,
rolin and I-Ins&r,” in 19.58, dre\v attention to the frequency of ver\small, presumably early, aneury&s easili. overlooked at autopsy unless special steps are taken, and Hasslerlg has pursued and extended these studies. Stehbenss” has also found very small dilatations at points where the elastic tissue is degenerate. In his recent paper, SahsY illustrates and discusses such microscopic bulges and uses the word “sacculation,” xvhich I will adopt, to convey the change into frank “berry” aneurysm form. These studies are of the greatest importance in the context of etiology, but minute aneurysms cannot be demonstrated by angiogrnphy during life; thus, from the radiologic and clinical points of view it is the life story of the “saccule” jvhich is at present of greatest moment. From the pathologist’s viewpoint, Crompton’“~” has written very interesting papers al)out these larger aneurysms. Statistics and generalizations about frecluemy, prognosis, and treatn~ent”~-Z7 have I)een of great value in opening up the subject for investigation, but without minute analysis they can obscure the variety of the aneurysms natural histories, and it Frum
aneurysms
F.F.R.*
may be more graphic here to begin by describing a single case. From this, by comparisons, some few facts about the life story of the disease may emerge. Perhaps when more data have been accumulated, the closest attention to each individual aneurysm may throw light on the prognosis and help in the management of the case. In 1957, T.B., a 62-year-old woman, suffered two subarachnoid hemorrhages, with an interval between them of 3 weeks. Angiography was performed 9 days before her second hemorrhage, and as a result of the findings, operation upon an anterior communicating aneurysm \vas carried out 2 day-s after her second episode of bleeding. At operation, in the angle between the anterior cerebral branches, a bright blue sac was seen; it measured about 4 by 4 mm. (perhaps slightly larger than at angiography) and had a w-all that was tissuepaper thin. That it was going to burst was obvious as soon as it was touched, and, in fact, during dissection it did burst and came straight off the attachment to the artery. The aneurysm had no neck at all, and at its point of departure there was
the ZJational Hospitals for Servuus Diseases, St. Harthulomew’s Hospital. and the Suffield parative Medicine, London. ISngland. Received for publication Sept. IY, 1966. *.\ddrcss: Diagnostic Radiology Department, St. Bartholomew’s Ilospital. London, IC.C.1, England.
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just a small opening in the arterial wall. Hemorrhage was controlled b?. an arterial clip. The first consideration-perhaps the most important of all-is the actual appearance of the aneurysm at operation. It is clear that the sacculation of this aneurysm was an acute process, and that it could not have existed for more than a short time in the state in which it QXS found. Yet the patient was elderly. Thus, a number of central questions about the aneurysmal disease are posed, answers to which would influence the management of the patient even though the actual etiolog) of the aneurysm remained unknown. 1. What is the time relationship between bleeding and the sacculation of an aneurysm? 2. How prevalent are aneurysms among the general symptomless population? 3. What is the probable future of a symptomless aneurysm found by chance at angiography in a patient with some other condition, or of a symptomless aneurysm in a patient with multiple aneurysms? In answering the first question about the time relationship between formation of the aneurysm and bleeding, one must know whether the patient already described was typical, for in her case, at least, there can be little doubt that the macroscopic aneurysm was of very recent origin. Out of a series of patients at the fi,Iaida Vale Hospital, there were 83 in whom the aneurysm responsible for hemorrhage was seen and carefully examined at operation or autopsy. Detailed notes of the operative appearance were made for the most part by Rfr. Valentine Logue, and in 33 cases we have from the operation (or occasionall> the autopsy) an exact description of the wall of the aneurysm. In 11 of these 33 cases the whole wall of the aneurysm was tissue-paper thin. lJIost were unilocular. Five of them \\:ere surrounded by granulation tissue or adhesions whose firmness and organization seemed to be a good reflection of the interval since hemorrhage. From all of them, hemorrhage had been recent. In the other 22, however, some part---usually the neck and often also a proximal loculus of the aneurysm-was thicker than the point, blister, or loculus which repre-
Am. Heart J. Juw, 1967
sented the rupture. Not all of them had bled more than once. RIany had bled only recently. Thus, one is faced with a concept which may be usefulPmmthat in relation to the first sacculation of an aneurysm, hemorrhage may be immediate, within at the most a few weeks, sometimes, no doubt, days or hours; or it may be delayed until months or more later. The first sacculation of the aneurysm in such delayed cases may be silent, and the eventual hemorrhage when it comes may be the result of fresh weakening of some part of the now-thickened original wall of the aneurysm. In spite of the fact that, in two thirds of the cases hemorrhage appears to have been delayed, it does not necessarily follow that no aneurysm is ever safe from the risk of bleeding. In the first place, the vast majority of hemorrhages from a single aneurysm occur within a few weeks of one another, and if the patient survives this phase of acute instability, recurrent hemorrhage from the same aneurysm months or years later is uncommon. Secondly, it may be demonstrated by angiographylz as well as at autopsy, 7,21,22v33that macroscopic aneurysms are far more prevalent in the general population than is frank subarachnoid hemorrhage at the age of greatest risk (perhaps even as much as twenty times as prevalent), and with such a low chance of bleeding, the prognosis of a symptomless aneurysm may surely be considered to be a hopeful one. Thus, to the concept of immedicltr and delayed hemorrhage, one may add the third larger group of clnezlrysms that never bleed at all. .This aspect of the problem should be borne in mind whenever there is a proposal that all aneurysms, in so far as possible, should be treated by active measures (including surgical intervention whenever the aneurysm is accessible.) Patient T. R., the case cited, was seen at a moment of time when she had already had more than one hemorrhage. Although, as has been shown, the thin wall of the aneurysm was characteristic of that in one group of patients, from two other points of view her aneurysm was not altogether typical. Firstly, it was relatively free of surrounding adhesions, in spite of
two hemorrhages, and, secondly, it consisted of a single smooth loculus. To amplify this statement it is necessary to consider what natural courses of events may afflict an aneurysm once it has formed. Leave aside the serious side effects of arterial spasm. A devastating hemorrhage (it is probably only a few milliliters of blood) is liable to cause death by disruption of the brain; but very small leaks may be instrumental in giving rise to adhesions around the aneurysm and to fibrosis with thickening of its walls and adhesions to the brain, a finding that is common enough. A second hemorrhage, if again it is a small one, may then result in a localized intracerebral collection of blood, the surface of which is defined by gliosis and fibrosis. The center of this small hematoma may clot or remain as a cavity in communication with the vessel of origin. The appearance, changes in, and obliteration of such extra loculi and accessory cavities have been observed on repeated angiography n-hen the examination became necessary for clinical reasons; and some of them have subsequently been confirmed by the operative findings. It is in such cases very difficult to see any difference between true and false sacs. Some perhaps remain small, but others develop by degrees layer upon layer of organizing fibrous tissue in their \valls and cause symptoms, not by further hemorrhage so often as by pressure and the occupation of space. Very large aneurysms formed in this way are relatively rare but comprise a distinct clinical group of spaceoccupying Iesion. Not by any means a,re all aneurysms which show loculus formation embedded in the brain, however, and there are probably other mechanisms by which they form. Be that as it may, recent bleeding and loculus formation are undoubtedly very closely connected; more than a third of all aneurysms which bleed and are shown 1)) angiography within the first few weeks reveal more than one loculus, whereas, by contrast, aneurysms not responsible for recent hemorrhage are hardly ever loculated in the same way. Some aneurysms have more than two loculi, and, of course, some aneurysms bleed two, three, or more times; but the actual relationship betlveen the number of bleeds and the number of
loculi shown angiographically is not a particularly close one. This relationship must be affected by the tendency of loculi to clot spontaneously. Uid they not do so, the number of loculated aneurysms demonstrated would probably have been greater in the RIaida Vale series on \jrhich these generalizations are Ijased. In that series, some were actually demonstrated to have gone through the cycle of loc~~lus formation (with bleedingj and loculus oblitera tion. The sudden appearance or sudden expansion of loculi is by no means uncommon. If a nerve is compressed or hemorrhage takes place, the expansion of loculus is accompanied by symptoms, but cases have also been seen in which angiography has detnonstrated the appearance or expansion of a loculus taking place silently. The obliteration of a loculus after operation, such as carotid ligation, is also a common phenomenon. So much then for the dynamic appearance and spontaneous clotting of loculi of aneurysms during their period of instability. The quiet thickening of the aneurysm \vhich turns an exceedingly thin-walled bulge into a much more stable and rigid structure is not susceptible to radiologic demonstration, but it is probable that the thin wall immediatel!~ after sacculation begins at once to grow stronger by the laying down of fresh laJ.ers of fibrous tissue. Furthermore, some aneur~~sms are probably thick walled almost. from the beginning, hcause the initial damage to the arteria1 wall is slight and leads onl\T to an oozing of IJood and to the grolvth of surrounding adhesions before any great expansion takes place. Sahs”’ illustrates two minute aneurysms capped by proliferated connective tissue. It is no doubt because of the thickness of the wall that most aneurysms of long standing are dormant and silent. Delayed hemorrhage when it occurs seems to be the result of a \l\-eakening of the mall of the aneurysm at one pointy, the fresh appearance of ;I thin-walled s;~c (this time a Ioculus of the origin:11 aneurysm), and the Ijeginning again of a cycle of events Lvhich once more rna>~ lead to devast;lting hemorrhage or to healing. The question of etiolog!is here left until
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last, and the answers are not all established but the problem is becoming clearer. Since Eppinger13 and Turnbull, 3g and particularly since Forbus’ work’” describing the presence of defects in the medial muscular coat of the arteries of the circle of Willis, and critical papers by Schmidt32 Strauss ~~er~;‘~~~rt~~~~?e::1ynn,L7 Forster and < ‘ ,526 and many others, most aneurysms in the head have been ascribed to two causes: (1 j congenital weakness of the arterial wall, and (2) atherosclerosis, with hypertension as a possible factor either in their formation or in their rupture. Another theory w:ith several variations, that these aneurysms arise at points at which embryologic vessels have not been completely absorbed, was favored lq, Padget, Bremer,” and Bassett,’ but does not seem to be very probable in the light of recent histologic studies. It is generally agreed that ectasia of cerebral vessels is a manifestation of atherosclerosis; but, on the other hand, the term “berry” aneurysms still suggests to IXU~J people a lesion of congenital origin. Yevertheless, many berry aneurysms show atherosclerotic changes, and Craxvford, in 1959, on the basis of postmortem studies, has suggested a combination of the congenital and atherosclerotic causes in various proportions in every case. Radiologically, one would like to add that there is no particular magic about the “berry” shape, and all acutely formed aneurysms in the head, even traumatic ones, are liable to take on the same general configuration. The association of atherosclerosis with intracranial aneurysm is certainly veq close. All large aneurysms and many small ones show gross atherosclerotic changes. As Crawford points out, severe cerebral atheroma is much more common in patients who die of subarachnoid and cerebral hemorrhage than in those who die from noncerebral and noncardiac causes. Atherosclerosis is commonly present in the circle of Willis, even in very young patients when aneurysms have been demonstrated, and even below the age of 20 years; but aneurysm at this age is in any case rare. The distribution of atherosclerosis in the cerebral circulation is veqr silnilar to the distribution of aneurysms, I)oth in its
predilection for a larger vessel and in the tendency for both conditions to occur most severely and most commonly at arterial branchings. Macroscopic atheroma has been found in cerebral vessels in almost all cases in the series of patients dying with aneurysm at the Rlaida \,‘ale Hospital, and microscopic evidence of atheroma was seen in the remainder but not necessarily in the immediate vicinity of the aneurysm itself. The incidence of symptomless aneuqrsm in patients with transient cerebral ischemia suffering from occlusive vascular disease seems to l)e higher than that in patients with tumor and suggests a causative association with atheroma. Bull and his associates” and RatinoP have pointed out that atheroma magi I)e diagnosed in its severer fornl 1)). irregularit). of the lumen of cereljral arteries. ITsing this irregularit\: as a sign, one may demonstrate that the disease is much more common in patients who present with symptoms due to aneurysm formation than in those who have no such sy~nptoms and whose arteriograms are normal or reveal the presence of a tumor. The association of aneurysm lvith angiographic evidence of atherosclerosis increases steadily with age, and there seems to l)e some slight sex difference (30 per cent males, 38 per cent females), I)ut increasing frequenqr of atherosclerosis with advancing age in the tumor series is far less obvious than in the aneurysm series. After the age of 3.5 in the tumor series the frequency of the finding is stead!. emI)etween one fifth and one sixth of the patients show definite evidence of irregularit!, of the vessel walls and in that series the disease is found in the same proportion of men and \\;omen. Atheroma was associated with the formation of aneurysms in one of the veq. few animals in which a cerebral aneurysm has been discovered.:j7 In spite of this very close association of two diseases, and in spite of the influence of established atheroma on the later stages of large chronic aneuq-sms, changes which would I)e universally recognized as atheroma are often not found close to the origins of early ;meurysms. The piitient used as a11 e.xample a1 the Iqinning of this essa)’ had no m;lc-roscopic atheroma near the anew
rysm. The very small aneurysms illustrated by Hassler, by Stehbens, and blr Sahs are associated with alterations in the elastic of the arterial wall but not with the deposition of fat or with other wellrecognized atherosclerotic manifestations. It seems to be probable that work on the relationship of these alterations in the elastic lamellae to atheron~a1fi~1g~2n~28 will throw light not only on the etiology of aneurysm formation, but also on the nature of very early or pre-atheromatous arterial disease. What then is the role of medial muscle defects? There is no doubt, of course, that the openings of most large intracranial aneurysms involve those parts of the artery in lvhich the muscle of the media is deficient; this has been shown by many people since Forbus in 1930. There are, however, a variety of reasons for doubting that it is the absence of muscle which constitutes a congenital lveakness reponsible for dilatation of the vessel. Both Stehbens and Sahs have shown that very small aneurysms do not bear a constant relationship to the defects. The aneurysms occur at the distal angle of a point of branching, whereas the defects are also found at lateral angles, and in some cases the neck of the aneurysm involves part of a defect, but part also of the neighboring muscular wall. SIoreover, the defects are present in the great majority of cerebral vessels and also in other arteries of the bod>..14,17J5 The normal elastica by itself is sufficient to contain a greatly raised blood pressure. It is not correct to speak of muscular defects as congenital abnormalities; they are anatomic features presumably having a physiologic purpose. One may speculate about the function of the so-called defect. The muscle coat of an intracranial artery is arranged almost entirely in a circular (probably a helical) fashion without longitudinal fibers. Consider an artery from which a small bulge protrudes at right angles, and let us suppose that the whole junction is sheathed in muscle so that the coat of the main artery and its Ixanch are completely continuous all around the orifice. The circle in the diagram (Fig. l,(l) represents the origin of this small bulge. The force \vhich results from contraction
Cl
b
Fig. I. a, ‘l’he three small radial arrows represent the force of caltraction at the origin of a hrallch entirely sheathed in muscle. The three vertical arrows represent the force of contraction of the parent vessel at those points if that also is sheathed in muscle. The resultants are shown b>, arrmvs with double heads. b, IJeformit>of the origin of the branch which would result. A% fibroelastic pad at S (in a) would relieve the origin of the sm;~ll branch from the effect of contraction of the parent vessel.
I;ig. 2. A three-dimellsiotlal representation of the situation. On the left, half of the orifice of a branch is shown. 011 the right, the forces are drawn a~ in Fig. 1,~.
of its muscle coat may be represented by small radial arrows. The strength and direction of the forces which would be applied at the same points by the contraction of the muscle fibers of the parent artery are also shown in the diagram. If the stimulus to contract were applied simultaneousl>r to the muscle coat of both the parent artery and the branch, the resultants of these opposing forces would tend to deform the opening of the vessel, making it oval shaped (Fig. 1,b) or even occluding it. The deformity of the origin of the vessel would in any case diminish the cross-sectional area of the branch to a greater degree than if it had remained circular. The actual degree of clefornlity lx-ould vary with, among other factors, the angle at which the
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du Bouluy
.,IA L
T Fig. 3. At Y junctions the muscles of the two branches oppose each other at the distal angle (A) and some elasticity at this point might be expected.
I
to
b
Fig. 4. Very small branches sometimes come off at a tangent from the side of the parent and thus have oval orifices (a.i section and a.ii elan). If there were muscle over their outside walls’, its contraction might result in the deformity shown in (b,i section and b,ii) plan.
branch left its parent. The situation is represented again in three-dimensional form in Fig. 2. The necessity for muscular defects at other points at which they are found is indicated in Figs. 3 and 4. The provision of a break in the continuity of a muscle near the arterial division-a break filled by a pad of elastic tissue-would clearly go some way to solving these hydrodynamic difficulties, hence, perhaps, the so-called medial defect. Intracranial aneurysms seem to be exceedingly rare in animals other than man, although the histologic structure of the
cerebral arteries is similar in other mammals, and all show medial defects at many points of branching.12Jgs23J4 The mechanical qualities necessary in arterial walls await more profound investigation, but it is clear from the survival of some patients with exceedingly thin aneurysms that the mere loss of a layer of muscle from the wall of the artery is likely to be of little consequence. In fact, the majority of so-called medial muscular defects in healthy mammalian arteries are well filled with very fine elastic fibers from the adventitia. Whatever the role of these defects in the formation of aneurysms, it must be a secondary one, and they should not be allowed to obscure the main objective when one looks for a preventable or treatable cause. The formation of aneurysms seems histologically to be related to a breakdown of strength and cohesion of the whole of the arterial wall, including as well its most important parts-the elastica. It may be that the process which leads to the formation of aneurysms is an acute degenerative incident which in some cases, l)ut not in all, goes on to overt atheroma. The fact that aneurysms are common in the head and rare elsewhere need not imply a primary cause found only in the head, but could be explained by different local conditions. The nature of the adventitia of the artery, the concentration of elastic chiefly into the internal elastic lamina, and the striking involvement of the media in established atheroma may determine the frequency of formation and saccrnation of aneurysms. The possible part played by the adventitia deserves special mention. Within the head the adventitia is exceedingly frail, and much of it seems to be ill-suited to be a final defense barrier against the sudden expansion or rupture of an artery whose wall has been damaged by an acute pathologic process. Elsewhere in the body the close investment of arteries by stronger tissues with an independent supply of blood may be thought to be important in preventing the formation of aneurysms. KEFEKESCES 1. Bassett, rosurg.
K. C.: Intracranial 6:216, 1919.
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Bremer, J. L.: Congenital aneurysms of the cerebra1 arteries: An embryological study, Arch. Path. 35:819, 1943. Brolin, S. E., and Hassler, 0.: Minute aneurysms detected by microdissection of basal cerebral arteries. Actn Path. Microbial. Scandinav. 44:59, 1958. Bull, J. W’. D., Couch, R. S. C., Joyce, D., Marshall, J., Potts, D. G., and Shaw, D. A.: Observer variation in cerebral angiography: An assessment of the value of minor angiographic - - . changes in the radiological diagnosis of cerebrovascular disease. Brit. I. Radio]. 35:16.5. 1960. Carmichael, R.: Gross defects in the muscular and elastic coats of the larger cerebral arteries, J. Path. Bact. 57:345, 1945. Carmichael, R.: The pathogenesis of noninflammatory cerebral aneurysms, J. Path. Bact. 62:1, 1950. Chason, J. I.., and Hindman, W. M.: Berry aneurysms of the circle of Willis: Results of a planned autopsy study, Neurology; 8:41, 19.58. Crawford, T.: (i) The pathogenesrs of atherosclerosis: The trends of recent work, Proc. Roy. Sot. Med. 52:537, 1959. Crawford, T.: (ii) Some observations on the pathogenesis and natural history of intracranial aneurysms, J. Neurol. Neurosurg. & Psychiat. 22:259, 1959. Crompton, M. R.: The pathology of ruptured middle-cerebral aneurysms, with special reference to the differences between the sexes, Lancet 2:421, 1962. Crompton, M. R.: Intracerebral haematomn complicating ruptured cerebral berry aneurysms, J. Neurol. Neurosurg. & Psychiat. 25:378, 1962. Du Boulay, G. H.: Some observations on the natural history of intracranial aneurysms, Brit. J. Radio]. 38:721, 1965. Eppinger, H. : Pathogenesis (Histogenesis und Aetiologie) der Aneurysmen einschliesslich des Aneurysma equi verminosum, Arch. klin. Chir., Suppl. 35, 1887. Forbus, W. D.: On the origin of miliary aneurysms of the superficial cerebral arteries, Bull. Johns Hopkins Hosp. 47:237, 1930. Forster, F. M., and Alpers, B. J.: Anatomical defects and pathological changes in congenital cerebral aneurysms, J. Neuropath. & Exper. Neural. 4:146, 1945. Friedman, M. : Pathogenesis of the spontaneous atherosclerotic plaque: A study on -the cholesterol-fed rabbit, Arch. Path. 76:318. 1963. Glynn, L. F.: Medial defects in the circle of ii’illis and their relation to aneurysm formation, I. Path. Bact. 51:213. 1940. Hassler, 0.: (i) Histochemical study of the arterial elastic lamella at the edge of the intracranial berry aneurysms, Acta Sot. Med. Uppsalien 66:263, 1961. Hassler, 0.: (ii) Morphological studies on the large cerebra1 arteries, with reference to the aetiology of subarachnoid haemorrhage, Acta
Psychiat. Neural. Scandinav., Suppl. 154, 1961. Hassler, 0. : (iii) On the etiology of intracranial aneurysms, in Fields, W. S., and Sahs, A. C., editors: Intracranial aneurysms and subarachnoid haemorrhage, Springlield, Ill., 1965, Charles C Thomas. DD. 25-37. 21. Helpern, M., and Rabson, S. M.: Sudden and unexpected natural death. III. Spontaneous subarachnoid haemorrhage, Am. J. hf. Sc. 220~262, 1950. E. M., and Pool, J. C.: A systematic 22. Housepin, analysis of intracranial aneurysms from autopsy file of the Presbvterian Hosoital. 1914-1956. J. Neuropath. & Exper. Nemo]. 1’7:409, 19.58: M. A., Florey, H. WT., Stephens, \V. 23. Jennings, C., and French, J. C.: lntimal changes in the arteries of a pig, J. Path. Bact. 81:49, 1961. LV., Paine, K., and MTalsh, E.: 24. McKissock, i\n analysis of the results of treatment of ruptured intracranial aneurysms, J. Neurosurg. 17 :762, 1960. 25. McKissock, W., Richardson, A. E., and LValsh, E.: Middle-cerebral aneurysms. Further results in the controlled trial of conservative and surgical treatment of ruptured intracranial aneurysms, Lancet 2:1203, 1960. W., and \%-alsh, E.: Subarachnoid 26. McKissock, haemorrhage due to intracranial aneurysms. Results of treatment of 249 verified cases, Brit. M. J. 2:X9, 1956. IV., Richardson, A., W.alsh, I*., 27. McKissock, and Owen, E.: Multiple intracranial aneurysms, Lancet 1:623, 1964. H. D.: Coronary arteries in fetuses, in28. >Ioon, fants and juveniles, Circulation 16:263, 1957. 29. Padget, I). H.: The circle of \Villis, in Dandy, I$:. E., editor: Intracranial arterial aneurysms, Ithaca, New York, 1944, Comstock Publishing Co., pp. 67-90. 30. Iiatinov, G.: Extradural intracranial portion of carotid artery: A clinicopathological study, Arch. Neurol. 10:66, 1961. 31. Sahs, A. L.: Observations on the pathology of saccular aneurysms, J. Neurosurg. 24:792, 1966. 32. Schmidt, ill.: Intracranial aneurysms, Brain 53 :489, 1930. 33. Stehbens, 1%‘. E.: Intracranial arterial aneurysms, Australasian Ann. Med. 3:214, 1954. W. E.: IMedial defects of the cerebral 34. Stephens, arteries of some mammals, Nature 179:327, 1957. W. E.: Medial defects of the cerebra1 3.5. Stehbens, arteries of man, J. Path. Bact. 78:179, 1959. W. E. : (i) Histopathology of cerebral 36. Stehbens, aneurysms, Arch. Neurol. 8:272, 1963. W. E. : (ii) Cerebral aneurysms of ani37. Stehbens, mals other than man, J. Path. Bact. 86:161, 1963. 38. Strauss, I., Globus, J. I-I., and Ginsburg, S. I\‘.: Spontaneous subarachnoid hemorrhage: its reiation to aneurysms of cerebral blood vessels, Arch. Neurol. & Psychiat. 27:1080, 1932. 39. Turnbull, H. M.: Intracranial aneurysms, Brain 41:50, 1918. 20.