Journal of the Neurological Sciences, 1978, 36:341-348 © Elsevier/North-Holland Biomedical Press
341
P A T H O G E N E T I C P R O F I L E OF T I A B E F O R E 55 A Three-Year Investigation
K. L. METTINGER and C. E. SODERSTROM Department of Neurology, Karolinska Hospital, Stockhohn (Sweden)
(Received 29 September, 1977) (Accepted 2 February, 1978)
SUMMARY Fifty-seven cases admitted to the Karolinska Hospital 1973-1976 with the diagnosis transient cerebral ischemia were reviewed. Seventeen cases were excluded as not fulfilling the strict T I A definition. An analysis of the records and the supplementary questionnaire of the remaining cases showed considerable sex differences in the stroke-prone profile. In the male group arteriosclerosis in the extracranial cerebral arteries was demonstrated in 90~o of these examined by angiography. In the female group factors recognized as interfering with the coagulation system were obvious in more than 7 0 ~ and two women had fibromuscular dysplasia. These differences may have therapeutic and prognostic implications. In the total material only 35 ~ had hypertension. Diabetes was not present in any of the patients. Of the men 46.6 ~ had abnormal blood lipids against 15.4 ~o of the women. Seventy-five of the patients with verified arteriosclerosis were regular smokers. At a mean followup time of 18.7 months only one patient, in the untreated group, developed completed stroke.
INTRODUCTION Prevention and treatment of cerebral ischemia, the dominating cause of strokes, is a challenging task for modern neurological research. The results could be of the utmost value for a very great number of patients. Cerebrovascular disease is one of the three leading causes of death in most industrial countries (World Health Stat. Rept. 1970) and ranks a m o n g the main causes of physical disability, demanding more This investigation was in part supported by a grant from tbe Loo and Hans Osterman Foundation for Medical Research.
342 hospital care than other somatic diseases, e.g. according to recent statistics of the Swedish Health Department (Socialstyrelsen 1975). Knowledge of the basic pathogenetic factors is a prerequisite for early prevention. So far most large prospective population studies have the drawback of diagnostic uncertainty. With the new possibility of exact diagnosis in almost all cases of cerebrovascutar disease by the combination of computerized tomography and quantitative CSF spectrophotometry developed in the Karolinska Hospital (Kjellin and S6derstr6m 1974; Kjellin and Steiner 1974; S6derstr6m, Kjellin and Cronqvist 1975; Cronqvist, Brismar, Kjeliin and S6derstr6m 1975; Kjellin, S6derstr6m and Cronqvist 1975; S6derstr6m 1977) we can now obtain more valid information about the natural history of cerebral infarction and hemorrhage and the outcome of specific therapy. These two modern diagnostic methods may also be tools for evaluation of the appropriate risk factors. In the new stroke unit in our department prospective studies are planned in cooperation with other centres. As a basis for future studies a retrospective analysis of young patients with stroke was performed. Our hypothesis is that characteristics of the stroke-prone profile can be detected more easily in patients with onset ot symptoms before the age when more advanced arteriosclerotic changes or complicating metabolic disturbances can be expected. This first report presents all cases of transient cerebral ischemia before the age of 55 admitted for hospital care in our department during a 3-year period. MATERIAL AND METHODS
Between 1973 and 1976 about 1200 patients with stroke were admitted to the Department of Neurology, Karolinska Hospital, Stockholm. Approximately 2 5 ~ of all patients were under 55 years of age. In a retrospective study of this young group we found 57 cases with the diagnosis of transient cerebral ischemia (Fig. 1), At critical analysis of the case histories, symFtoms were in 14 cases too prolonged (24 hours-7 days) to fulfil the criteria for TIA as specified e.g. by the Joint Committee for Stroke MATERIAL
r CAROTIE VERTEBRO -I NON-CLASSI-I ARTERY BASILAR [ FICABLE 29
ART4ERY
7
Fig. 1. Material. Classification and territorial distribution.
343
TIA BEFORE 55 F-1. ( ~
Nr of cases
20-24 25-2930-34 35-39 40-44 45-49 50-54
Age Fig. 2. Age and sex distribution in the material.
Facilities (Study group on TIA criteria and detection 1974), i.e. focal cerebral dysfunction not exceeding 24 h. Three cases were excluded for other reasons, e.g. psychogenic pathogenesis was considered more probable. The remaining material consists of 23 men and 17 women. The symptoms corresponded in 29 cases to the carotid artery territory and in 4 cases to that of the vertebral artery. Seven cases could not with certainty be classified in one of these two groups. The age and sex distribution of the material is shown in Fig. 2. Sixty-three per cent of the men and 41 ~ of the women were in the age group 50-55 years. In the group under 30 years there were 5 females, but no males. The youngest woman was 20 years old. In 20 of the 23 men aortic arch angiograms were performed. Only 6 women were examined by angiography. Six cases were examined by computerised tomography which showed normal attenuation. All the 28 cases investigated by CSF spectrophotometry showed a non-hemorrhagic pattern. Results of blood pressure readings and laboratory tests were compiled from the records. Hypertension was diagnosed if the value of the blood pressure was 160/95 or higher in patients under 40, 170/105 or higher in the group of 40 years of age or older. Information about smoking habits, oral contraceptives and medical treatment obtained from the records were supplemented by a detailed questionnaire sent to all the patients. Smoking was considered significant in cases with a daily use of more than 10 cigarettes or equivalent and a duration of smoking exceeding 5 years. There was a mean observation time of 18.7 months. RESULTS
A ngiographicfindings Eighteen of the 20 men (90 700) examined by angiography had atherosclerotic changes in the relevant carotid or vertebral artery, in most cases only slight or moderate changes without visible ulceration. In 2 women angiograms revealed atherosclerosis and in a further 2 fibromuscular dysplasia (FMD) of the extracranial cerebral arteries. One of the F M D patients was a 54-year-old woman with a history of dizziness for more than 20 years, hyper-
344
Fig. 3. Fibromuscular dysplasia. Typical "corrugated" changes of the carotid-vertebral arteries in a 54-year-old woman with TIA. tension and bruits over both carotid arteries. The F M D changes were moderate and of hyperplastic type located within 5-6 cm long segments of both carotid arteries with similar lesser changes in both vertebral arteries (Fig. 3). The other case was a 50-year-old woman with hypertension and similar F M D changes in the proximal part of both vertebrals and the external carotid arteries.
Arteriosclerotic risk profile Table 1 shows the occurrence of diabetes, hypertension, blood lipid abnormalities and smoking. Hypertension was found in only 35~o of the cases. Abnormal blood lipids, which were more common among men, included 8 cases of elevated triglyceride levels and 4 of elevated cholesterol levels. None of the patients had diabetes. Heavy smoking was frequently reported among the men. This figure was remarkably high (about 75 ~ ) if the risk factor was related to identified arteriosclerotic plaques in the carotid-vertebral arteries. Interaction with the coagulation system In a high percentage of the women factors with potential involvement of the coagulation system were found (Table 2). Five patients were talcdng oral contra-
345 'TABLE 1 RISK FACTORS Number within parenthesis = percentage.
Diabetes Hypertension Lipid abnormalities Smoking
Males (n = 23)
Females (n = 17)
Cases with plaque (n = 20)
0/23 8/23 (34.7) 10/21 (47.6) 16/23 (69.6)
0/17 6/17 (35.3) 2/13 (15.4) 7/14 (50.0)
0/20 6/20 (30.0) 10/20 (50.0) 15/20 (75.0)
TABLE 2 INTERACTION WITH THE COAGULATION SYSTEM IN FEMALES n = 17 Contraceptives Estrogen treatment Pregnancy Gestagen treatment Fibrinolysis-inhibiting treatment
5 3 2 1 1 12 = 70.6%
ceptives. In 3 cases treatment against menopausal dysfunction with naturally conjugated estrogen (Promarit) was identified. One patient with menorrhagia was being treated with a fibrinolysis inhibitor.
Treatment and prognosis Fifteen patients were treated with anticoagulants for one year or longer. Platelet-inhibiting drugs - - in most cases aspirin combined with dipyridamol - were used when anticoagulants were contraindicated or as a long-term prophylaxis after withdrawal of anticoagulants. Carotid endarterectomy was performed in two cases. So far only one patient, belonging to the untreated group, has developed cerebral infarction. Only 6 patients in the total material have had further cerebral ischemic attacks. The cases with fibromuscular dysplasia were treated with platelet inhibiting therapy and no further attacks have occurred. DISCUSSION During the last decade great interest has been focused upon transient ischemic attacks as a warning of brain infarction. Various figures have been given for the incidence of cerebral infarction following TIA and about 30 ~ might represent a mean value. (Hutchinson and Acheson 1975). When even slight clinical symptoms or minimal neurological deficit remains after 24 hr the diagnosis of T I A should not
346 be made according to the present definition. In 1969 Bauer, Meyer, Fields, Remington, Macdonald and Callen suggested calling such episodes TIA with incomplete recovery (TIA-IR). Others have referred to them as prolonged TIA, minor strokes or reversible ischemic neurologic deficit (RIND). Modern neuroradiological diagnostic methods indicate that the separation of TIA from cerebral infarction must be considered as debatable. From the pathophysiological point of view death of brain cells or microinfarcts are likely to occur after only a few minutes of focal cerebral ischemia, even if an increased collateral circulation or increased fibrinolytic activity (Fletcher and Alkjaersig et al 1976) might prevent the further development to a detectable infarct. Rees, Du Boulay, Bull, Marshall, Russell and Symon (1970) found by rCBF measurements that focal disturbance at the site of the lesion may be detected as long as 90 days after the last clinical event. In our study one case had changes consistent with a vascular lesion on the isotope scan, while all the cases examined by computerised tomography showed no abnormality. However, in an earlier study with computerised tomography on 25 patients one case showed a definite infarction in spite of complete recovery within the 24-hr limit. On the other hand, cases with supratentorial infarction with slight clinical symptoms frequently show no detectable abnormality on computerised tomography and isotope encephalography (S6derstr6m 1977). The possibility of microhemorrhage as cause of a single transient focal dysfunction has been discussed by some authors (Marshall 1976; Yates 1976). Therefore most cases were examined by spectrophotometry of CSF, a method extremely sensitive to even trace amounts of hemorrhagic components. In this study no spectrophotometrical signs of bleeding were detected. The results correspond with previous investigations in TIA cases (Kjellin and S6derstr6m 1974; S6derstr6m 1977). Julian, Dye, Jarid and Hunter in 1963 described ulcerative lesions at the carotid artery bifurcation and these were later suggested as a cause of TIA and thromboembolic strokes (Soloway and Aronsson 1964; Moore and Hall 1968). This concept is today widely accepted especially since it has been proved that hemodynamic influence on the cerebral circulation is likely to occur only if atherosclerotic stenosis reduces the lumen by 80-90 ~ (Brice, Dowsett and Lowe 1964). In our study 9 0 ~ of the men examined by angiography had atherosclerotic changes in the extracranial cerebral arteries. Most patients had only slight or moderate changes which gives considerable support to the thrombo-embolic theory. Lipid abnormalities, in most cases elevated triglyceride levels, were significantly more common among the men and were found in 5 0 ~ of the cases with demonstrated atheroma. This result is in agreement with the studies of Fogelholm and Aho (1973) and Ryttman (1975) except for the sex difference. Diabetes, which has been found in 25 ~ of young patients with cerebral infarction (Louis and McDowell 1967), was not found in any patient in this study. Hypertension, which in several studies has been recognized as the most important risk factor for ischemic strokes (Hutchinson and Acheson 1975; Wolf 1975) was present in only 3 5 ~ of the cases. The frequency of cigarette smoking was remarkably high (about 75 ~) if this risk factor was related to identified atherosclerotic plaques in the carotid-vertebral arteries. To relate risk
347 factors to the major pathogenetic correlate itself seems highly relevant to future studies aiming at prevention. Arteriosclerosis is unusual in women before the menopause and in this group other factors influencing the coagulation system were obvious in more than 70~o. Angiography was therefore rarely performed. In the 5 women on oral contraceptives the type of preparation was identified and the estrogen component was in all cases only 50 #g indicating that low dosage preparations might also cause cerebral ischemia (Nyman, Mettinger and S6derstr6m 1977). The potential danger of estrogen treatment in the menopause has so far not been much considered. Our series includes 3 women all having used the same preparation (Promarit). Diffuse capillary thrombosis has been noticed (Charytan and Purtilo 1969) in a patient with EACA. Fibrinolysis inhibitor causing TIA seems not to have been reported earlier. Fibromuscular dysplasia in the extracranial arteries was found in 2 of the 6 angiographies performed in women in this study. This is a remarkably high percentage, especially as only about 10 cases with involvement of both the carotid and vertebral arteries have been reported (Boudin, Guillard and Romion 1974). In about 10~ of reported cases (Houser, Baker, Sandok and Holley 1971) as well as in our own series of 23 cases (Mettinger and Ericsson 1977) the clinical presentation has been with TIA. This condition is probably a more common cause of cerebral ischemia in middle aged women than has hitherto been recognized. The exact mechanism behind the cerebral ischemia in the condition has not been proved but turbulence causing platelet aggregation seems to be the possible explanation. Even if the mean observation time in this study is only 18.7 months some remarks could be made about the short-term prognosis. Although only slightly more than half of the patients had prophylactic treatment, only one patient in the total material has developed cerebral infarction during the tollow up. CONCLUSION
This study shows considerable differences in pathogenetic profile between young male and female patients with TIA. Among men arteriosclerosis in the extracranial arteries seems to be the dominating pathogenetic mechanism. Among young women other causes must also be considered, e.g. disturbance of the coagulation system and fibromuscular dysplasia. These differences should be considered when deciding the therapy and prognosis in a young patient with TIA.
REFERENCES Bauer, R. B., J. S. Meyer, W. S. Fields, R. Remington, M. C. Macdonald and P. Callen (1969) Joint study of extracranial arterial occlusion, Part 3 (Progress report of controlled study of long-term survival in patients with and without operation), Boudin, G., A. Guillard and A. Romion (1974) Dysplasies fibro-musculaires des art~res carotides et vert~brales - - A p r o p o s de quinze cas, Ann. reed. int. (Paris), 125: 863-875.
348 Brice, J. G., D. J. Dowsett and R. D. Lowe (1964) The effect of constriction on carotid blood-ttow and pressure gradient, Lancet, 1 : 84-85. Charytan, C. and D. Purtilo (1969) Glomerular capillary thrombosis and acute renal failure after }+aminocapronic acid therapy, New Engl. J. Med., 280:1102. Cronqvist, S., J. Brismar, K. G. Kjellin and C. E. S6derstr6m (1975) Computer assisted axial tomography in cerebrovascular lesions, Acta radiol, diagn., 16:135-145. Fletcher, A. P., N. Alkjaersig et al. (1976) Blood coagulation and plasma fibrinolytic enzyme system Pathophysiology in stroke, Stroke, 7: 337-348. Fogelholm, R. and K. Aho (1973) lschaemic cerebrovascular disease in young adults, Part 2 (Serum cholesterol and triglyceride values), ,4cta neurol, scand., 49: 428433. Houser, O. W., H. L. Baker, B. A. Sandok and K. E. Holley (1971) Cephalic arterial fibromuscular dysplasia, Radiology, 101 : 605-611. Hutchinsson, E. C. and E. J. Acheson (1975) Strokes - - Natural History, Pathology and Surgical Treatment, Saunders, London. Julian, O. C., W. S. Dye, H. Javid and J. A. Hunter (1963) Ulcerative lesions of the carotid artery bifurcation, Arch. Surg., 86: 803-809. Kjellin, K. G. and C. E. S6derstrom (1974) Diagnostic significance of CSF spectrophotometry in cerebrovascular diseases, J. neurol. Sci., 23 : 359-369. Kjellin, K. G. and L. Steiner (1974) Spectrophotometry of cerebrospinal fluid in subacute and chronic subdural haematomas, J. Neurol. Neurosurg. Psychiat. , 37:1121-1127. Kjellin, K. G., C. E. S6derstrom and S. Cronqvist (1975) Cerebrospinal fluid spectrophotometry and computerized transverse axial tomography (EMI scanning) in cerebrovascular diseases, Europ. Neurol., 13 : 315-331. Louis, S. and F. McDowell (1967) Stroke in young adults, ,4nn. int. Med., 66: 932-938. Marshall, J. (1976) The Management of Cerebrovascular Disease, 3rd edition, Blackwell, Oxford. Mettinger, K. L. and K. Ericsson (1977) Fibromuscular dysplasia in the cervical arteries, To be published. Millikan, C. H., R. G. Siekert and R. M. Schick (1955) Studies in cerebrovascular disease, Part 5 (Use of anticoagulant drugs in the treatment of intermittent insufficiency of the internal carotid arterial system), Proc. Mayo Clin., 30: 578-586. Moore, W. S. and A. D. Hall (1968) Ulcerated atheroma of the carotid artery - - A major cause of transient cerebral ischemia, ,4mer. J. Surg., 116: 237-242. Nyman, D., K. L. Mettinger and C. E. S6derstr6m (1977) Oral contraception and cerebral ischemia, To be published. Poller, L. (1969) Relation between oral contraceptive hormones and blood clotting, J. elin. Path., Suppl. 3, 23: 67. Rees, J. E., G. H. Du Bulay, J. W. D. Bull, J. Marshall, R. W. Ross Russell and L. Symon (1970) Regional cerebral blood-flow in transient ischaemic attacks, Lancet, 2:1210-1213. Ryttman, A. (1975) ,4therosclerosis and Ectasia Estimated by Cerebral ,4ngiography and related to Plasma Lipid Concentration and Cerebral Blood Flow, Thesis, Stockholm. Socialstyrelsen (1975) Patientstatistik: 18, Gtiteborgs Offset-tryckeri AB, Stockholm. Soloway, H. B. and S. M. Aronsson (1964) Atheromatous embolism to central nervous system, Arch. Neurol. (Chic.), 11:657. S6derstr6m, C. E. (1977) Diagnostic significance of spectrophotometry of CSF and computer tomography in cerebrovascular disease, Stroke, 8: 606-612. S6derstr6m, C. E., K. G. Kjellin and S. Cronqvist (1975) Computer tomography compared with spectrophotometry of cerebrospinal fluid in cerebrovascular diseases, ,4eta RadioL, Suppl. 346, pp. 130-142. Study Group on TIA Criteria and Detection, XI (1974) Transient focal cerebral ischemia - - Epidemiological and clinical aspects, Stroke, 5 : 277-287. Thomson, J. M. (1970) .4 Practical Guide to Blood Coagulation and Haemostasis, Churchill, London, p. 145. Wolf, P. A. (1975) Hypertension as a risk factor for stroke. In : J. P. Whisnant and B. A. Sandok (Eds.), Cerebral Vascular Diseases (Transactions of the 9th Princeton Conference), Grune and Stratton, New York, N.Y., pp. 105-112. World Health Statistics Report (1970) The Ten Leading Causes of Death for Selected Countries in North America, Europe and Oceania, 1964-1966, World Health Organization, Geneva. Yates, P. O. (1976) The pathogenesis of transient ischemic attacks. In : F. J. Gillingham, C. Mawdsley and A. E. Williams (Eds.), Stroke (Proceedings of the 9th Pfizer International Symposium), Churchill Livingstone, Edinburgh, pp. 178-187.
341
P A T H O G E N E T I C P R O F I L E OF T I A B E F O R E 55 A Three-Year Investigation
K. L. METTINGER and C. E. SODERSTROM Department of Neurology, Karolinska Hospital, Stockhohn (Sweden)
(Received 29 September, 1977) (Accepted 2 February, 1978)
SUMMARY Fifty-seven cases admitted to the Karolinska Hospital 1973-1976 with the diagnosis transient cerebral ischemia were reviewed. Seventeen cases were excluded as not fulfilling the strict T I A definition. An analysis of the records and the supplementary questionnaire of the remaining cases showed considerable sex differences in the stroke-prone profile. In the male group arteriosclerosis in the extracranial cerebral arteries was demonstrated in 90~o of these examined by angiography. In the female group factors recognized as interfering with the coagulation system were obvious in more than 7 0 ~ and two women had fibromuscular dysplasia. These differences may have therapeutic and prognostic implications. In the total material only 35 ~ had hypertension. Diabetes was not present in any of the patients. Of the men 46.6 ~ had abnormal blood lipids against 15.4 ~o of the women. Seventy-five of the patients with verified arteriosclerosis were regular smokers. At a mean followup time of 18.7 months only one patient, in the untreated group, developed completed stroke.
INTRODUCTION Prevention and treatment of cerebral ischemia, the dominating cause of strokes, is a challenging task for modern neurological research. The results could be of the utmost value for a very great number of patients. Cerebrovascular disease is one of the three leading causes of death in most industrial countries (World Health Stat. Rept. 1970) and ranks a m o n g the main causes of physical disability, demanding more This investigation was in part supported by a grant from tbe Loo and Hans Osterman Foundation for Medical Research.
342 hospital care than other somatic diseases, e.g. according to recent statistics of the Swedish Health Department (Socialstyrelsen 1975). Knowledge of the basic pathogenetic factors is a prerequisite for early prevention. So far most large prospective population studies have the drawback of diagnostic uncertainty. With the new possibility of exact diagnosis in almost all cases of cerebrovascutar disease by the combination of computerized tomography and quantitative CSF spectrophotometry developed in the Karolinska Hospital (Kjellin and S6derstr6m 1974; Kjellin and Steiner 1974; S6derstr6m, Kjellin and Cronqvist 1975; Cronqvist, Brismar, Kjeliin and S6derstr6m 1975; Kjellin, S6derstr6m and Cronqvist 1975; S6derstr6m 1977) we can now obtain more valid information about the natural history of cerebral infarction and hemorrhage and the outcome of specific therapy. These two modern diagnostic methods may also be tools for evaluation of the appropriate risk factors. In the new stroke unit in our department prospective studies are planned in cooperation with other centres. As a basis for future studies a retrospective analysis of young patients with stroke was performed. Our hypothesis is that characteristics of the stroke-prone profile can be detected more easily in patients with onset ot symptoms before the age when more advanced arteriosclerotic changes or complicating metabolic disturbances can be expected. This first report presents all cases of transient cerebral ischemia before the age of 55 admitted for hospital care in our department during a 3-year period. MATERIAL AND METHODS
Between 1973 and 1976 about 1200 patients with stroke were admitted to the Department of Neurology, Karolinska Hospital, Stockholm. Approximately 2 5 ~ of all patients were under 55 years of age. In a retrospective study of this young group we found 57 cases with the diagnosis of transient cerebral ischemia (Fig. 1), At critical analysis of the case histories, symFtoms were in 14 cases too prolonged (24 hours-7 days) to fulfil the criteria for TIA as specified e.g. by the Joint Committee for Stroke MATERIAL
r CAROTIE VERTEBRO -I NON-CLASSI-I ARTERY BASILAR [ FICABLE 29
ART4ERY
7
Fig. 1. Material. Classification and territorial distribution.
343
TIA BEFORE 55 F-1. ( ~
Nr of cases
20-24 25-2930-34 35-39 40-44 45-49 50-54
Age Fig. 2. Age and sex distribution in the material.
Facilities (Study group on TIA criteria and detection 1974), i.e. focal cerebral dysfunction not exceeding 24 h. Three cases were excluded for other reasons, e.g. psychogenic pathogenesis was considered more probable. The remaining material consists of 23 men and 17 women. The symptoms corresponded in 29 cases to the carotid artery territory and in 4 cases to that of the vertebral artery. Seven cases could not with certainty be classified in one of these two groups. The age and sex distribution of the material is shown in Fig. 2. Sixty-three per cent of the men and 41 ~ of the women were in the age group 50-55 years. In the group under 30 years there were 5 females, but no males. The youngest woman was 20 years old. In 20 of the 23 men aortic arch angiograms were performed. Only 6 women were examined by angiography. Six cases were examined by computerised tomography which showed normal attenuation. All the 28 cases investigated by CSF spectrophotometry showed a non-hemorrhagic pattern. Results of blood pressure readings and laboratory tests were compiled from the records. Hypertension was diagnosed if the value of the blood pressure was 160/95 or higher in patients under 40, 170/105 or higher in the group of 40 years of age or older. Information about smoking habits, oral contraceptives and medical treatment obtained from the records were supplemented by a detailed questionnaire sent to all the patients. Smoking was considered significant in cases with a daily use of more than 10 cigarettes or equivalent and a duration of smoking exceeding 5 years. There was a mean observation time of 18.7 months. RESULTS
A ngiographicfindings Eighteen of the 20 men (90 700) examined by angiography had atherosclerotic changes in the relevant carotid or vertebral artery, in most cases only slight or moderate changes without visible ulceration. In 2 women angiograms revealed atherosclerosis and in a further 2 fibromuscular dysplasia (FMD) of the extracranial cerebral arteries. One of the F M D patients was a 54-year-old woman with a history of dizziness for more than 20 years, hyper-
344
Fig. 3. Fibromuscular dysplasia. Typical "corrugated" changes of the carotid-vertebral arteries in a 54-year-old woman with TIA. tension and bruits over both carotid arteries. The F M D changes were moderate and of hyperplastic type located within 5-6 cm long segments of both carotid arteries with similar lesser changes in both vertebral arteries (Fig. 3). The other case was a 50-year-old woman with hypertension and similar F M D changes in the proximal part of both vertebrals and the external carotid arteries.
Arteriosclerotic risk profile Table 1 shows the occurrence of diabetes, hypertension, blood lipid abnormalities and smoking. Hypertension was found in only 35~o of the cases. Abnormal blood lipids, which were more common among men, included 8 cases of elevated triglyceride levels and 4 of elevated cholesterol levels. None of the patients had diabetes. Heavy smoking was frequently reported among the men. This figure was remarkably high (about 75 ~ ) if the risk factor was related to identified arteriosclerotic plaques in the carotid-vertebral arteries. Interaction with the coagulation system In a high percentage of the women factors with potential involvement of the coagulation system were found (Table 2). Five patients were talcdng oral contra-
345 'TABLE 1 RISK FACTORS Number within parenthesis = percentage.
Diabetes Hypertension Lipid abnormalities Smoking
Males (n = 23)
Females (n = 17)
Cases with plaque (n = 20)
0/23 8/23 (34.7) 10/21 (47.6) 16/23 (69.6)
0/17 6/17 (35.3) 2/13 (15.4) 7/14 (50.0)
0/20 6/20 (30.0) 10/20 (50.0) 15/20 (75.0)
TABLE 2 INTERACTION WITH THE COAGULATION SYSTEM IN FEMALES n = 17 Contraceptives Estrogen treatment Pregnancy Gestagen treatment Fibrinolysis-inhibiting treatment
5 3 2 1 1 12 = 70.6%
ceptives. In 3 cases treatment against menopausal dysfunction with naturally conjugated estrogen (Promarit) was identified. One patient with menorrhagia was being treated with a fibrinolysis inhibitor.
Treatment and prognosis Fifteen patients were treated with anticoagulants for one year or longer. Platelet-inhibiting drugs - - in most cases aspirin combined with dipyridamol - were used when anticoagulants were contraindicated or as a long-term prophylaxis after withdrawal of anticoagulants. Carotid endarterectomy was performed in two cases. So far only one patient, belonging to the untreated group, has developed cerebral infarction. Only 6 patients in the total material have had further cerebral ischemic attacks. The cases with fibromuscular dysplasia were treated with platelet inhibiting therapy and no further attacks have occurred. DISCUSSION During the last decade great interest has been focused upon transient ischemic attacks as a warning of brain infarction. Various figures have been given for the incidence of cerebral infarction following TIA and about 30 ~ might represent a mean value. (Hutchinson and Acheson 1975). When even slight clinical symptoms or minimal neurological deficit remains after 24 hr the diagnosis of T I A should not
346 be made according to the present definition. In 1969 Bauer, Meyer, Fields, Remington, Macdonald and Callen suggested calling such episodes TIA with incomplete recovery (TIA-IR). Others have referred to them as prolonged TIA, minor strokes or reversible ischemic neurologic deficit (RIND). Modern neuroradiological diagnostic methods indicate that the separation of TIA from cerebral infarction must be considered as debatable. From the pathophysiological point of view death of brain cells or microinfarcts are likely to occur after only a few minutes of focal cerebral ischemia, even if an increased collateral circulation or increased fibrinolytic activity (Fletcher and Alkjaersig et al 1976) might prevent the further development to a detectable infarct. Rees, Du Boulay, Bull, Marshall, Russell and Symon (1970) found by rCBF measurements that focal disturbance at the site of the lesion may be detected as long as 90 days after the last clinical event. In our study one case had changes consistent with a vascular lesion on the isotope scan, while all the cases examined by computerised tomography showed no abnormality. However, in an earlier study with computerised tomography on 25 patients one case showed a definite infarction in spite of complete recovery within the 24-hr limit. On the other hand, cases with supratentorial infarction with slight clinical symptoms frequently show no detectable abnormality on computerised tomography and isotope encephalography (S6derstr6m 1977). The possibility of microhemorrhage as cause of a single transient focal dysfunction has been discussed by some authors (Marshall 1976; Yates 1976). Therefore most cases were examined by spectrophotometry of CSF, a method extremely sensitive to even trace amounts of hemorrhagic components. In this study no spectrophotometrical signs of bleeding were detected. The results correspond with previous investigations in TIA cases (Kjellin and S6derstr6m 1974; S6derstr6m 1977). Julian, Dye, Jarid and Hunter in 1963 described ulcerative lesions at the carotid artery bifurcation and these were later suggested as a cause of TIA and thromboembolic strokes (Soloway and Aronsson 1964; Moore and Hall 1968). This concept is today widely accepted especially since it has been proved that hemodynamic influence on the cerebral circulation is likely to occur only if atherosclerotic stenosis reduces the lumen by 80-90 ~ (Brice, Dowsett and Lowe 1964). In our study 9 0 ~ of the men examined by angiography had atherosclerotic changes in the extracranial cerebral arteries. Most patients had only slight or moderate changes which gives considerable support to the thrombo-embolic theory. Lipid abnormalities, in most cases elevated triglyceride levels, were significantly more common among the men and were found in 5 0 ~ of the cases with demonstrated atheroma. This result is in agreement with the studies of Fogelholm and Aho (1973) and Ryttman (1975) except for the sex difference. Diabetes, which has been found in 25 ~ of young patients with cerebral infarction (Louis and McDowell 1967), was not found in any patient in this study. Hypertension, which in several studies has been recognized as the most important risk factor for ischemic strokes (Hutchinson and Acheson 1975; Wolf 1975) was present in only 3 5 ~ of the cases. The frequency of cigarette smoking was remarkably high (about 75 ~) if this risk factor was related to identified atherosclerotic plaques in the carotid-vertebral arteries. To relate risk
347 factors to the major pathogenetic correlate itself seems highly relevant to future studies aiming at prevention. Arteriosclerosis is unusual in women before the menopause and in this group other factors influencing the coagulation system were obvious in more than 70~o. Angiography was therefore rarely performed. In the 5 women on oral contraceptives the type of preparation was identified and the estrogen component was in all cases only 50 #g indicating that low dosage preparations might also cause cerebral ischemia (Nyman, Mettinger and S6derstr6m 1977). The potential danger of estrogen treatment in the menopause has so far not been much considered. Our series includes 3 women all having used the same preparation (Promarit). Diffuse capillary thrombosis has been noticed (Charytan and Purtilo 1969) in a patient with EACA. Fibrinolysis inhibitor causing TIA seems not to have been reported earlier. Fibromuscular dysplasia in the extracranial arteries was found in 2 of the 6 angiographies performed in women in this study. This is a remarkably high percentage, especially as only about 10 cases with involvement of both the carotid and vertebral arteries have been reported (Boudin, Guillard and Romion 1974). In about 10~ of reported cases (Houser, Baker, Sandok and Holley 1971) as well as in our own series of 23 cases (Mettinger and Ericsson 1977) the clinical presentation has been with TIA. This condition is probably a more common cause of cerebral ischemia in middle aged women than has hitherto been recognized. The exact mechanism behind the cerebral ischemia in the condition has not been proved but turbulence causing platelet aggregation seems to be the possible explanation. Even if the mean observation time in this study is only 18.7 months some remarks could be made about the short-term prognosis. Although only slightly more than half of the patients had prophylactic treatment, only one patient in the total material has developed cerebral infarction during the tollow up. CONCLUSION
This study shows considerable differences in pathogenetic profile between young male and female patients with TIA. Among men arteriosclerosis in the extracranial arteries seems to be the dominating pathogenetic mechanism. Among young women other causes must also be considered, e.g. disturbance of the coagulation system and fibromuscular dysplasia. These differences should be considered when deciding the therapy and prognosis in a young patient with TIA.
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