Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 52, Num. 1, 2004, pp. 82-86

Neurology India, Vol. 52, No. 1, January-March, 2004, pp. 82-86

Original Article

Clinico-pathological study of cerebral aneurysms

Rajesh BJ, Sandhyamani S, Bhattacharya RN

Departments of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum
Correspondence Address:Departments of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum bjraj1@sctimst.ker.nic.in

Code Number: ni04020

Abstract

Introduction

During the last 25 years, besides mycotic aneurysms,[1],[2],[3] a large number of cerebral aneurysm cases with no definite cause, were encountered at Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST). Although clinical aspects of cases operated upon were reported earlier,[4] a detailed histopathological study was not carried out on them. Preliminary studies indicated the occurrence of mucoid degenerative changes in the aneurysm wall, similar to mucoid vasculopathy, identified by Sandhyamani as a distinct diet induced vascular connective tissue entity in Kerala, resulting from nutritional imbalance with low-protein high-starch diets.[5],[6],[7] A clinico-pathological study was conducted to ascertain the histopathological nature and associated risk factors in cases of cerebral aneurysm admitted to SCTIMST, Trivandrum, during a 2-year period. The observations are presented in this paper.

Material and Methods

During the 2-year period from Jan 1999 to Dec 2000 a total of 255 cases of cerebral aneurysms were operated on. The present study was conducted on 57 of these cases where the aneurysm sac could be excised and subjected to histopathological study. The study did not include mycotic aneurysm. Aneurysm sacs were fixed in 10% buffered formalin, processed through graded alcohol and embedded in paraffin wax. 5m thick sections were examined, using hematoxylin and eosin, Verhoeff van Gieson′s and toluidine blue staining techniques. Histopathological observations were analyzed and correlated with clinical features.

Results

Clinical data
There were 57 patients whose aneurysm sacs were excised during the period Jan 1999-Dec 2000 and were available for analysis. The age of the patients ranged from 17-65 years and there were 33 males and 24 females [Table - 1]. Twenty-six patients were chronic smokers, 19 patients had hypertension and 3 patients had diabetes mellitus. Of the 23 patients in whom lipid profiles were estimated, 5 had raised total serum cholesterol and 14 had low serum HDL-cholesterol levels. As per the gradation system used by our hospital, 19 cases belonged to the high-income category and 38 cases belonged to the lower income category. Fifty-two patients presented with subarachnoid hemorrhage and 5 patients had no demonstrated subarachnoid bleed. All the patients underwent surgery with clipping of the aneurysms and excision of the sac. Aneurysms involved both anterior (52 cases) and posterior (5 cases) circulation. In selected cases of fusiform aneurysms, the adjoining segment of the affected vessel was also excised. Preoperative angiography had revealed vasospasm in 7 patients. Fifty-four aneurysms were saccular and 3 were fusiform (2 were vertebral artery dissecting aneurysms and 1 was M2 segment aneurysm). Thirty-nine patients were asymptomatic on follow-up, 7 patients had significant residual neurological deficits, 5 patients expired and 6 patients were lost to follow-up.

Histopathology
Histologically, the biopsy samples were classified as: true and false aneurysms [Table - 2]. The histomorphological features are shown in [Figure - 1] and [Figure - 2 a, b, c-d, e]. In 7 false aneurysm cases, the specimen consisted of extravasated blood clot only, surrounded at places by a thin rim of adventitial fibrous connective tissue. Amongst 50 cases with an identifiable aneurysm sac, there were 16 true aneurysms and 34 false aneurysms. True aneurysms were identified by the presence of intima, internal elastic lamina and medial elements in the wall, often with an abrupt or gradual transition to false aneurysm structure, suggestive of focal rupture of the aneurysm sac. The internal elastic lamina of true aneurysms and of the proximal artery stump where available, showed varying degenerative changes. It appeared thick and beaded or thin attenuated and reduplicated, with focal fragmentation. In false aneurysms, organizing blood was contained by a fibrous wall, lacking internal elastic lamina and media, and lined by a layer of thin or thick exuberant granulation tissue. In 13 true aneurysms and 22 false aneurysms [Table - 2], the wall had a varying thickness with large pools of acid mucopolysaccharide material. The mucoid material was seen between hyperplastic spindle-shaped and stellate myofibroblasts and in true aneurysms, in the intima and between medial smooth muscle cells also. In some of the cases, this appeared as mucoid intimal plaques or nodules of myxomatous tissue bulging into the lumen of the aneurysm. The proximal artery stump and vasa vasora in some of these cases showed mucoid degenerative changes in the intima and media. Focal spotty calcification and hemosiderin deposits were noticed in the aneurysm wall in some cases. There was no evidence of inflammation and atherosclerosis in any of the sections of the proximal artery, nor any lipid deposits (atheromatosis) in the aneurysm sacs.

Clinico-pathological correlation
Mucoid changes were commonly seen in patients in the 5^th and 6^th decades. There were 20 males and 15 females having mucoid changes. Multiple aneurysms with mucoid changes were common in females (4 cases). Middle cerebral artery aneurysms were more common in males (8 cases). Amongst the 35 cases with mucoid changes, 18 patients were chronic smokers, 15 patients were hypertensive, and 2 patients were diabetic, 2 patients had a raised serum total cholesterol level and 9 had a low serum HDL-cholesterol level [Table - 2]. Ten of the 19 patients in "D" group (high income category of our hospital) had mucoid changes; 12 of the 38 in the lower income groups had mucoid changes. Thirteen of the 16 true aneurysm cases and 22 of the 34 false aneurysm cases showed mucoid degenerative changes and approximately half of the true and false aneurysm cases were associated with risk factors like hypertension and smoking [Table - 2].

Discussion

In the last decade there was a considerable increase in the number of cerebral aneurysm cases operated upon at this Institute. The number increased from 88 cases in the year 1990 to 136 in the year 2000. Cases of mycotic aneurysm, mostly iatrogenic, following lumbar puncture at peripheral hospitals, were referred to this Institute and reported previously.[1],[2],[3] Besides these, in a large number of cases, the exact nature and cause of the aneurysms were not clear. No infective organisms were demonstrated histologically, nor did the patients have any associated inherited forms of connective tissue disorders. There were no cases with tumour embolism. The present study, carried out on 57 consecutive cases over a period of 2 years, focuses our attention on distinct mucoid degenerative lesions in a number of cases and their association with known risk factors like hypertension and smoking. As reported in the literature aneurysmal rupture is more common in 6th and 7th decades of life,[8] however, in our study group the incidence was more in 5th and 6th decades. In our study the males were predominant, although some studies identify a clear female preponderance (1.6:1).[9] Hypertension has been reported in about 16% to 43.5% of patients with aneurysmal subarachnoid hemorrhage.[10],[11],[12] Hypertension was seen in 33.33% (19) of our cases. Smoking, another important risk factor for cerebral aneurysms[13] was seen in 45.6% (26) of our cases. Although reported occasionally,[14] atherosclerosis is not considered an important risk factor for cerebral aneurysms.[15]

The etiopathogenesis of cerebral aneurysms is uncertain and the cause of subsequent rupture is not evident in all cases.[16] The congenital or medial defect theory hypothesizes a weakness in the artery wall due to maldevelopment.[17] Support for a congenital origin comes from the frequency of multiple aneurysms, familial occurrence of aneurysms and association of systemic inherited diseases of vascular connective tissue, such as Marfan′s syndrome, Ehlers-Danlos syndrome and inherited forms of dyscollagenosis and polycystic kidney.[18],[19] Alternately, the degenerative theory suggests an acquired defect in the vessel wall.[20],[21],[22],[23],[24],[25],[26],[27],[28] This theory is supported by the increased frequency of aneurysms with age, hypertension, smoking and arteriosclerosis.[25] The present consensus is that atherosclerosis does not lead directly to the formation of aneurysms.[15],[25] Combinations of maldevelopment and degeneration may also exist. It is known that cerebral arteries differ from extra-cranial vessels in having a thin or absent external elastic lamina. Structural integrity is provided by the internal elastic lamina, the cellular elements dispersed in the extracellular ground substance and fibrillar proteins in the matrix of the intima and media. Any alterations or damage to these vessel wall components, especially the internal elastic lamina and media, along with local hemodynamic factors can lead to the development of aneurysms.[28],[29],[30] The effects of associated risk factors, particularly hypertension and smoking, may be mediated through damage to the internal elastic lamina.[15],[25]

A review of the literature revealed the occurrence of cerebral aneurysms (saccular and dissecting types) with mucoid degeneration, in other parts of the world also, but these were only sporadic reports of single or a small number of cases[27],[29],[31] and therefore not directly comparable with our cases. Various authors used different terminologies such as cystic medial necrosis,[32],[33] intimal fibroelastic thickening,[34] medial mucoid degeneration,[35] segmental mediolytic arteriopathy,[36] myxoid degeneration[27] and mediolytic arteriopathy,[37] to describe the nature of the lesions in the cerebral and extracerebral cervical vasculature. In all these reports, the common finding was the deposition of mucoid material in the intima and media with fragmentation of the internal elastic lamina causing weakening of the vessel wall. Generalized involvement of the extracranial vessels in addition to cerebral vessels has been reported by some.[31],[37] Associated risk factors like hypertension and smoking resulted in further weakening of the wall leading to aneurysm formation, dissection and even rupture.[27]

Mucoid vasculopathy is a non-atherosclerotic, non-inflammatory disorder, with generalized deposition of abnormal acid mucopolysaccharides in the walls of blood vessels, accompanied by dystrophic changes in elastin and collagen.[5],[6],[7] Besides stenotic lesions, the condition was responsible for aneurysms at various sites, such as aorta, pulmonary artery and carotid artery.[38],[39],[40],[41],[42] A monkey model established the role of nutritional imbalance, with low-protein high starch diets, in its etiology.[43] Mucoid vasculopathy is similar to mucoid arteriopathy and aortopathy described from Uganda[44],[45] and to intimo-medial mucoid degeneration described from South Africa[46],[47],[48] where similar diets as consumed in Kerala, may be responsible for mucoid degenerative vascular disease.[49]

In this study, a significant number of patients showed dystrophic changes in the internal elastic lamina. It is well known that structural gaps in the internal elastic lamina are responsible for the development of cerebral aneurysms at bifurcation points.[20] Such gaps aggravated by acquired degenerative changes in elastic laminae may have predisposed arteries to aneurysmal dilatation at bifurcation and non-bifurcation sites in our cases. We postulate that mucoid degeneration and dystrophic changes in the internal elastic lamina in blood vessels are brought about by an acquired disorder of mucopolysaccharide and protein metabolism due to exposure to a low-protein and high-carbohydrate diet for many years. This mucoid and elastic tissue degeneration or mucoid arteriosclerotic vasculopathy, weakens the vessel wall and when combined with risk factors like hypertension and smoking, it may lead to the formation of aneurysms in the 5^th and the 6^th decades of life. The presence of such histopathological lesions in the parent vessel and in the walls of true and false aneurysms, appears to reflect the underlying diet-induced metabolic disorder and the tendency to lay down excessive amounts of myxomatous tissue during organization of a thrombus or extravasated blood. Estimation of serum mucopolysaccharides was done in a few of our patients and was found to be elevated. This test may be an important marker for the underlying metabolic disorder.

Acknowledgements

The authors are grateful to Dr. K. Mohandas, Director, SCTIMST, Trivandrum, for institutional help; to Dr.V. V. Radhakrishnan, for valuable comments on the histology of five cases and on the paper; to the technical staff of the Department of Pathology and project staff for assistance; and to the Department of Science and Technology, New Delhi, for partial support for carrying out the histopathological studies.

References

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