doi: 10.1161/01.STR.0000021409.16314.16
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(Stroke. 2002;33:1950.)
© 2002 American Heart Association, Inc.
Original Contributions |
Etiologic Study of Young Ischemic Stroke in Taiwan
From the Departments of Neurology (T.-H.L., W.-C.H., S.-T.C.) and Radiology (C.-J.C.), Chang Gung Memorial Hospital, LinKou Medical Center, Kuei-Shan, Tao-Yuan, Taiwan.
Reprint requests to Tsong-Hai Lee, MD, PhD, Department of Neurology, Chang Gung Memorial Hospital, LinKou Medical Center, 5 Fu-Hsing ST., Kuei-Shan, Tao-Yuan, 33333 Taiwan. E-mail thlee{at}adm.cgmh.org.tw
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Abstract |
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Background and Purpose— The etiologic mechanisms of young ischemic stroke in Chinese are largely unknown. This work thus studied the etiologies of young ischemic stroke in Taiwan Chinese and made a comparison with previous reports.
Methods— From January 1997 to October 2001, a total of 264 consecutive young ischemic stroke patients (18 to 45 years old) were admitted to the Department of Neurology in our hospital. The risk factors for stroke and the distribution of stroke subtype were studied. The vascular ultrasound and angiographic findings of these patients were also studied.
Results— The sample contained 188 men and 76 women. Cerebral infarction was diagnosed in 241 patients and transient ischemic attack in 23 (8.7%). Regarding stroke subtype, stroke of small-vessel occlusion was diagnosed in 20.5% of cases, large-artery atherosclerosis in 7.2%, cardioembolism in 17.8%, other determined etiology in 22.3%, and undetermined etiology in 23.5%. The 4 most common risk factors were hyperlipidemia (53.1%), smoking (49.8%), hypertension (45.8%), and family history of stroke (29.3%). Twenty-three patients (9.6%) had significant stenosis (
50%) of the carotid (7.5%) and vertebral arteries (2.1%), the most common cause of which was dissection (60.9%). Forty-five patients (26.5%) had significant intracranial stenosis with 18.8% in the carotid and 10.6% in the vertebrobasilar system, and 5 (2.9%) had stenosis in both systems. Premature atherosclerosis (33.3%) was the most common cause of intracranial stenosis.
Conclusions— Our study found that strokes of other determined etiology and undetermined etiology were most common among the sample group, and a battery of extensive examinations is indicated to elucidate the etiology for further stroke prevention. Intracranial stenosis is more common than extracranial stenosis in both the carotid and vertebrobasilar systems.
Key Words: angiography • risk factors • stroke subtype • young adult
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Introduction |
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Young ischemic strokes occurring in patients younger than 45 years old have been considered a relatively rare event, being less than 5% of all cerebral infarctions,1 although more than 10% has also been reported.2,3 A previous epidemiological study on strokes in Taiwan demonstrated that the average annual incidence of first-ever stroke in the age group from 36 to 44 years old was 26 per 100 000.4 Another community hospital-based study in Taiwan showed that for cerebral infarction, the annual incidence of first-ever stroke in patients younger than 45 years old was 2 per 100 000.5 A recent stroke registry study in our hospital revealed that the incidence of young stroke was 6.8% of all strokes, and the proportion of young stroke patients with unknown risk factors (13.6%) was significantly higher than for elderly stroke patients (2.4%) (P<0.0001).6 However, until now, no study has examined the etiology of young ischemic stroke in Taiwan.
Regarding stroke subtypes, previous studies in western countries have found that strokes of other determined etiology and undetermined etiology occupied 50% to 72% of young ischemic stroke1,3,7–12 and that large-artery atherosclerosis was more common than small-vessel occlusion.1,7,8,11 However, among blacks, small-vessel occlusion was reported to be more common than large-artery atherosclerosis.9 Our previous work did not study stroke subtype in young ischemic stroke.6 This investigation studies the etiology and stroke subtype of young ischemic stroke in Taiwan Chinese and compares our results with those of previous reports.
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Materials and Methods |
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This study retrospectively reviewed the records of all 15- to 45-year-old patients who were admitted to the Department of Neurology in our hospital from January 1997 to October 2001. For those who had more than 1 admission because of stroke/transient ischemic attack, medical complication, or further examination such as angiographic study during the study period, only the last admission due to a stroke episode was included in the present study. This study excluded patients with venous infarction and those with ischemic strokes caused by complications arising from trauma, cardiac surgery, and vasospasm after subarachnoid hemorrhage. A total of 264 consecutive young ischemic stroke patients (18 to 45 years old, 6.8% of a total of 3865 ischemic stroke patients) were studied. The retrospective nature of this study was a limitation, because not all patients received complete examinations and some information might have been lost. This study was approved by the Human Studies Institutional Review Board.
All patients received a chest x-ray, ECG, complete blood count (hemoglobin, hematocrit, platelet, leukocyte), and blood glucose, electrolytes, triglyceride, and total cholesterol tests. Brain CT and/or MRI was also performed on all patients to define the infarction territory and exclude cerebral hemorrhage. Cerebral infarction was classified into 5 categories according to the TOAST criteria:13 (1) small-vessel occlusion, (2) large-artery atherosclerosis, (3) cardioembolism, (4) stroke of other determined etiology, and (5) stroke of undetermined etiology.
The medical history and stroke risk factor information of each patient was obtained. Hypertension (HT) was defined as being present when (1) the patient was previously diagnosed with HT by a clinician or (2) systolic blood pressure was 140 mm Hg and/or diastolic blood pressure was 90 mm Hg on 2 different occasions measured at least 2 weeks after the acute stage depending on the severity of the stroke. Diabetes mellitus was diagnosed according to the National Institutes of Health (revised criteria, 1980).14 Current cigarette smoking was defined as a risk factor when a subject smoked 10 cigarettes per day for more than 6 months before the stroke. Alcohol consumption was regarded as a risk factor when a subject regularly drank alcohol at a level of 30 g per day or 210 g per week for more than 6 months before the stroke. Hyperlipidemia was defined as a risk factor when the fasting blood cholesterol level was 200 mg/dL and/or triglyceride level was 150 mg/dL, and hyperuricemia was defined as a risk factor when the fasting blood uric acid level was 8.0 mg/dL at admission.
Blood examination was conducted for protein C (normal range: 75% to 107%) in 162 patients, protein S (normal range: 90% to 130%) in 161, antithrombin III (normal range: 75% to 125%) in 155, lupus anticoagulant in 133, anticardiolipin antibody (positive IgG: >18 GPL units/mL; positive IgM: >10 MPL units/mL) in 185, antinuclear antibody (positive antinuclear antibody: 1:320) in 181, and VDRL/TPHA for syphilis (positive VDRL: >1:1 and TPHA: >1:80) in 154. Protein C, protein S and antithrombin III were examined mostly within 2 weeks after the onset of stroke. Patients with low levels of protein C, protein S, and antithrombin III were reexamined at least 3 months later for further confirmation. The inherited deficiency of coagulation inhibitors was diagnosed according to the criteria of Martinez et al.15 Antiphospholipid syndrome16 was suggested as causative if other possible etiologies of stroke were excluded. Migraine-related stroke was determined to be present when there was a focal and persistent neurological deficit that followed typical migraine attacks without other causes of stroke.
A total of 187 patients (70.8%) received transthoracic cardiac echo study. Among these 187 patients, 13 also received contrast echo study and 36 also received transesophageal echocardiography (TEE) plus contrast echo study. The echocardiographic diagnosis of mitral valve prolapse included 2-mm posterior displacement of 1 or both leaflets or holosystolic posterior "hammocking" >3 mm on M-mode, and systolic displacement of 1 or both mitral leaflets in the parasternal long-axis 2D view, particularly when they coapted on the atrial side of the annular plane. The diagnosis of mitral valve prolapse was even more certain when leaflet thickness was >5 mm and when mitral regurgitation was detected as a high-velocity eccentric jet in the late systole. The echocardiographic criteria for mitral valve prolapse also included structural changes, such as leaflet thickening, redundancy, annular dilatation, and chordal elongation. Patients with borderline degrees of displacement not associated with increased leaflet thickness, mitral regurgitation, left atrial enlargement, valve-related complications, or progression over a period of 10 years were excluded from the definition of prolapse.17,18
A total of 239 patients received vascular examinations, including ultrasound (extracranial 4-vessel and transcranial) in 211 patients and angiography (digital subtraction or MR) in 170. Among these 239 patients, 167 (69.9%) had vascular examination within 2 weeks after the onset of stroke. Of the 25 patients without vascular examination, 8 died in the acute stage of their strokes, 5 suffered cardioembolic stroke, 3 had stroke of other determined etiology, 3 were severely dependent in their daily activity, and 6 had unknown reasons. Patients with existing high-risk sources of cardioembolism13 or obvious disorders that were related to their strokes were not recommended for angiographic study.
Digital subtraction angiographic study included intracranial and extracranial portions of bilateral carotid and vertebrobasilar systems. The MR angiography was performed in patients with suspected artery dissection or intracranial stenosis on ultrasound study. Each angiogram was reviewed by 1 neuroradiologist and 1 neurologist, and diameter stenosis of the extracranial vessels (common, internal, and external carotid and extracranial vertebral artery) and intracranial vessels (main stems of the middle, anterior, and posterior cerebral artery, and the intracranial vertebrobasilar artery) was calculated according to the North American Symptomatic Carotid Endarterectomy Trial criteria.19 Significant stenosis was defined as 50% diameter stenosis.20 A total of 170 patients (64.4% of the total sample of young ischemic stroke patients) received digital subtraction (164 patients) and/or MR16 angiographic study.
SPSS 8.0 software was used for statistical analysis. The ANOVA or 
2 test was used to examine the relations between stroke subtypes and age, gender, and risk factors. Logistic regression analysis was used to evaluate possible confounding effects such as age, gender, and risk factors on stroke subtypes. P<0.05 was considered statistically significant.
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Results |
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There were 188 men (71.2%) and 76 women. Cerebral infarction was diagnosed in 241 patients and transient ischemic attack in 23. Stroke of undetermined etiology (23.5%) was the most common subtype, whereas large-artery atherosclerosis (7.2%) was the least common. Age was significantly lower in stroke of other determined etiology (mean±SD: 35.3±7.8 years old; P=0.0002, 95% CI: 0.8682 to 0.9564) and significantly higher in stroke of small-vessel occlusion (40.9±4.9; P=0.0401, 95% CI: 1.0033 to 1.1511). Cardioembolic stroke was more common in women (P=0.0283, 95% CI: 0.1430-0.8966) (Table 1).
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In the survey of risk factors (Table 1), the 4 most common risk factors were hyperlipidemia (53.1%), smoking (49.8%), HT (45.8%), and family history of stroke (29.3%). Hyperlipidemia (69.8%, P=0.006 by 2 test) and HT (66.7%, P=0.001 by 2 test) were more common in small-vessel occlusion, and logistic regression showed that HT was significantly more common in small-vessel occlusion than in other stroke subtypes (P=0.0083, 95% CI: 1.2853 to 5.4608). Logistic regression also showed that hyperuricemia was significantly more common in large-artery atherosclerosis (P=0.0333, 95% CI: 1.1066 to 11.7723), and hyperlipidemia was significantly less common in cardioembolic stroke (P=0.0056, 95% CI: 0.1566 to 0.7283). Cigarette smoking (men/women=125/5, P<0.0001, 95% CI: 11.017 to 103.352) and hyperuricemia (40/6, P=0.035, 95% CI: 1.0842 to 9.2131) were more common in men.
In cardioembolism (Table 2), the 3 most common etiologies were mitral valve prolapse (38.3%), rheumatic heart disease (19.1%), and patent foramen ovale (17.0%). In stroke of other determined etiology (Table 3), the 3 most common etiologies were dissection (39.0%), antiphospholipid syndrome (16.9%), and moyamoya disease (15.3%).
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Echocardiography was performed on 187 patients, whereas 45 patients (24.1%) had mitral valve prolapse. In our study, 1.8% of patients (4 of 181) had positive antinuclear antibody, 7.6% (14 of 185) had positive anticardiolipin antibody, 3.9% (6 of 154) had positive VDRL and/or TPHA, and 0.8% (1 of 133) had positive lupus anticoagulant.
Inherited deficiency of protein C was noted in 2.5% of patients (4 of the 162 examined), protein S was noted in 6.8% (11 of 161), and antithrombin III was noted in 1.9% (3 of 155). Two patients had inherited deficiencies of both proteins C and S. Mortality was seen in 12 patients (3.8%). The causes of death were basilar artery occlusion in 3 patients and brain herniation due to large infarction in 7. The other 2 died after acute stroke as a result of myocardial infarction and fulminant hepatitis, respectively.
Our previous study has shown that carotid duplex ultrasound has >90% accuracy in diagnosing significant extracranial stenosis,21,22 and transcranial Doppler is unreliable in detecting intracranial stenosis.23 In a survey of stroke etiology, the diagnosis of vascular anomaly, arterial dissection, and moyamoya disease depends on angiographic study. We evaluated the ultrasound and angiographic findings of the extracranial artery in the 239 patients, and we found that 23 patients (9.6%) had significant stenosis of the carotid (18 patients, 7.5%) and vertebral (5 patients, 2.1%) arteries. Dissection (14 patients, 60.9%) was the most common cause of extracranial stenosis, with 10 cases occurring in the carotid and 4 in the vertebral system. In the intracranial artery, we studied only the angiographic findings. We found that in the 170 patients with an intracranial angiographic study, 45 (26.5%) had significant stenosis, including 32 (18.8%) in the carotid (8 at the siphon area), 18 (10.6%) in the vertebrobasilar, and 5 (2.9%) in both systems. In intracranial stenosis, 29 patients had risk factors, including moyamoya disease in 9 patients; dissection in 6; inherited low protein S in 4; inherited low antithrombin III in 3; positive anticardiolipin antibody in 3; and fibromuscular dysplasia, neurosyphilis, radiation vasculopathy, inherited low protein C, and positive antinuclear antibody, all in 1 patient each. One patient had no obvious risk factors. The remaining 15 patients (33.3%) had vascular risk factors, including hyperlipidemia in 11, HT in 7, smoking in 6, hyperuricemia in 5, alcohol and diabetes mellitus, in 2 each; and the stenosis was presumed to be caused by premature atherosclerosis. Hyperlipidemia was significantly more common in premature atherosclerosis than in patients with other etiologies (P=0.0461, 95% CI: 1.004 to 47.003).
In the 170 patients with angiographic study, dissection was seen in 24 (14.1%) patients, with carotid dissection in 13 and vertebral dissection in 11. Of the 13 patients with carotid dissection, 9 had dissection shortly above the bifurcation, 2 at the petrous portion, and 2 at the common carotid artery. Two had bilateral carotid dissections shortly above the bifurcation. Of the 11 patients with vertebral dissection, 5 had extracranial dissection, 6 had intracranial dissection, and 1 had bilateral extracranial dissection.
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Discussion |
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Compared with previous reports (Table 4), our study found that 71.4% of young ischemic stroke patients were men, similar to the studies in Korea (75.2%)24 and India (76.3%)25 but different from those in western countries (44.1% to 58.9%).1,3,7,8,10–12,26,27 Regarding stroke subtype, large-artery atherosclerosis (7.9%) was less common than small-vessel occlusion (22.4%) in our series, resembling the results of the study of US blacks (9% versus 21%).9 However, our study is different from those in western countries1,7,8,11 and Korea,24 which indicate that large-artery atherosclerosis is more common than small-vessel occlusion. The distribution of cardioembolism is similar for studies in the United States and Asia. The distribution of stroke of other determined etiology and undetermined etiology differed considerably among different reports, which may depend on the extent of examination.
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Our study found cigarette smoking to be more prevalent in men. This result is consistent with a previous community study in Taiwan, which showed a higher prevalence of tobacco use in men (men versus women=61.9% versus 4.5%).28 Our result is similar to the young stroke study in Korea (67.0% versus 2.7%)24 but is different from that in northern Sweden (33.8% versus 38.6%).1 Our study also found hyperuricemia to be more prevalent in men (men versus women=22.3% versus 8.6%). This result is similar to a previous community study in Taiwan, which found a higher prevalence of hyperuricemia in men (25.8% versus 15.0%).29
Among the 62 patients with stroke of undetermined etiology, 6 died without detailed study and 31 had nonlacunar infarct on brain image with no significant vascular stenosis and negative blood tests. Of these 31 patients, 30 had no TEE or contrast echo study. It is reported that atrial septal abnormalities, ie, patent foramen ovale or atrial septal aneurysm, are frequent findings in young patients with brain infarction of unknown causes and are independently associated with ischemic stroke in case-control studies.30 Previous studies have shown patent foramen ovale to have a prevalence of around 24% to 50% in stroke patients younger than 45 years.31–33 Kristensen et al1 found that with additional diagnostic information derived from advanced cardiac imaging, the proportion of undetermined etiology could be reduced from 37% to 21%. The detection of atrial septal abnormalities depends on the skill of the echocardiographer and can be improved if TEE and contrast echo are used.33 It is possible that some of our patients of undetermined etiology might be classified as cardioembolic stroke by TOAST criteria if TEE and contrast echo were studied.
Inherited deficiency of coagulation inhibitors was seen in 16 patients. Among them, low protein C was noted in 4 patients (2.5% of the patients examined), low protein S in 11 (6.8%), and low antithrombin III in 3 (1.9%). Two patients had inherited deficiency of both proteins C and S. The incidence of inherited deficiency of coagulation inhibitor in our study is similar to that in the previous reports by Adams et al34 in 1986, Hart and Kanter35 in 1990, and Barinagarrementeria et al36 in 1994, all of whom reported an incidence of about 4% in young ischemic strokes. However, our study is different from the study of Iowa registration of young stroke by Adams et al8 in 1995, which reported only 3 in 329 patients and is also different from the more recent studies in Korea24 and in northern Sweden,1 which found no or rare case of inherited deficiency of coagulation inhibitors. In our 16 patients with inherited deficiency of coagulation inhibitors, none had venous thrombosis, whereas 4 had a family history of stroke, 3 had recurrent strokes, and 12 had abnormal angiographic findings, with carotid involvement in 10 and vertebrobasilar in 8. Our results are different from the previous report by Barinagarrementeria et al37 who summarized a series of 25 patients and found that only 2 had involvement in the vertebrobasilar system. The intracranial involvement is present in 83.3% in our patients, higher than the previous report of 64% by Barinagarrementeria et al.37 Also, among these 16 patients, positive antinuclear antibody, moyamoya disease, and neurosyphilis were noted in 1 patient each, whereas 2 patients had carotid dissection, and 5 had mitral valve prolapse or atrial septal aneurysm. A previous report found that 4 in 10 children with moyamoya syndrome may have a prothrombotic disorder, with inherited deficiency of protein S in 1 and positive lupus anticoagulant and anticardiolipin antibody in 3.38 These findings suggest that patients with deficiency of coagulation inhibitors may be associated with other abnormalities, and a thorough evaluation is indicated.
A growing body of data suggests that there are important differences in the distribution of occlusive vascular disease between races. Atherosclerosis of the larger extracranial arteries is more prevalent in whites, whereas occlusive disease of the intracranial arteries is more often seen in patients of black or oriental origin.39–41 Liu et al20 reported that in Taiwan Chinese, 35.2% of acute stroke patients aged 44 to 85 years old had significant extracranial carotid stenosis, 38.0% had significant intracranial carotid stenosis, and 6.5% had both significant intracranial and extracranial carotid stenosis. However, the above study used MR angiography as an assessing parameter and did not include the carotid siphon and vertebrobasilar stenosis because of technical limitations. Among our young stroke patients, we found that 9.6% had extracranial stenosis, with carotid involvement in 7.5% and vertebral in 2.1%, whereas 26.5% had intracranial stenosis, with carotid involvement in 18.8%, vertebrobasilar in 10.6%, and 2.9% had stenosis in both systems.
In our 170 angiographic studies, the most common cause of extracranial vasculopathy was arterial dissection. Carotid dissection was seen in 13 patients (7.6%), lower than the previously reported 10% of stroke patients aged 
40 years old.42 Two patients were found to have bilateral internal carotid dissection, but no patient had simultaneous carotid and vertebral dissection. In vertebral dissection, De Bray et al43 reported in their series that 44% had extracranial dissection and 56% had intracranial dissection, whereas 38% had bilateral dissection. In our series, 11 patients had vertebral dissection, with 45.5% at the extracranial and 54.5% at the intracranial portion. One patient had extracranial vertebral dissection with bilateral involvement. In artery dissection, only 2 patients had history of traumatic injury. One patient had positive anticardiolipin antibody, 1 had inherited low protein S, 1 had inherited low proteins C and S, and 1 had basilar invagination diagnosed on MRI.
Conclusion
Our study showed a higher prevalence of small-vessel occlusion in Taiwan in contrast to the higher prevalence of large-artery atherosclerosis in western countries. Also, men occupied a higher percentage of young ischemic stroke patients in Asian than in western countries. Our study also demonstrated that significant intracranial stenosis is more common in young ischemic stroke patients than extracranial stenosis in both the carotid and vertebrobasilar systems. The most common cause of significant extracranial stenosis is dissection, and the most common cause of significant intracranial stenosis is presumed to be premature atherosclerosis.
Received September 21, 2001; revision received April 1, 2002; accepted April 9, 2002.
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J. Putaala, A. J. Metso, T. M. Metso, N. Konkola, Y. Kraemer, E. Haapaniemi, M. Kaste, and T. Tatlisumak Analysis of 1008 Consecutive Patients Aged 15 to 49 With First-Ever Ischemic Stroke: The Helsinki Young Stroke Registry Stroke, April 1, 2009; 40(4): 1195 - 1203. [Abstract] [Full Text] [PDF]
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 K Lipska, P N Sylaja, P S Sarma, K R Thankappan, V R Kutty, R S Vasan, and K Radhakrishnan Risk factors for acute ischaemic stroke in young adults in South India J. Neurol. Neurosurg. Psychiatry, September 1, 2007; 78(9): 959 - 963. [Abstract] [Full Text] [PDF]
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T.-H. Lee and K.-C. Chang Editorial Comment--Are We in Another Unavoidable 'Diagnose and Adios' Era? Stroke, September 1, 2005; 36(9): 1852 - 1853. [Full Text] [PDF]
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C. Jackson and C. Sudlow Are Lacunar Strokes Really Different?: A Systematic Review of Differences in Risk Factor Profiles Between Lacunar and Nonlacunar Infarcts Stroke, April 1, 2005; 36(4): 891 - 901. [Abstract] [Full Text] [PDF]
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U.G.R. Schulz, E. Flossmann, and P.M. Rothwell Heritability of Ischemic Stroke in Relation to Age, Vascular Risk Factors, and Subtypes of Incident Stroke in Population-Based Studies Stroke, April 1, 2004; 35(4): 819 - 824. [Abstract] [Full Text] [PDF]
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S.-S. Tsai, W. B. Goggins, H.-F. Chiu, and C.-Y. Yang Evidence for an Association Between Air Pollution and Daily Stroke Admissions in Kaohsiung, Taiwan Stroke, November 1, 2003; 34(11): 2612 - 2616. [Abstract] [Full Text] [PDF]
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