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(Stroke. 1997;28:1913-1918.)
© 1997 American Heart Association, Inc.

Articles

Risk Factors for Stroke Due to Cerebral Infarction in Young Adults

Roger X. You, PhD; John J. McNeil, PhD, FRACP; Heather M. O'Malley, SRN; Stephen M. Davis, MD, FRACP; Amanda G. Thrift, BSc(Hons), PhD; Geoffrey A. Donnan, MD, FRACP

From the Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne (R.X.Y., H.M. O'M., G.A.D.); Department of Epidemiology and Preventive Medicine, Monash University (J.J.M., A.G.T.); and Department of Neurology, Royal Melbourne Hospital, University of Melbourne (S.M.D.) (Australia). This multicenter study was coordinated by the Department of Neurology, Austin and Repatriation Medical Centre.


*    Abstract
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 *Abstract
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Background and Purpose Stroke in the young is particularly tragic because of the potential for a lifetime of disablement. More than 10% of patients with stroke due to cerebral infarction are aged 55 years or younger. While a number of studies have addressed the issue of stroke mechanism in the young, quantitation of risk factors has rarely been undertaken. Given the importance of risk factor assessment in primary prevention, we aimed to assess this using case-control methodology in a hospital-based series and community-based control subjects.

Methods A total of 201 consecutive patients with first-onset stroke due to cerebral infarction aged 15 to 55 years (mean, 45.5 years) were accrued from four teaching hospitals during 1985 to 1992 and compared with their age- and sex-matched neighborhood controls. Information concerning potential risk factor exposure status was collected by structured questionnaire at interview. Stroke risks were estimated by calculating the odds ratios with multivariate logistic regression.

Results Significantly increased risk of stroke was found among those with diabetes (odds ratio, 11.6 [95% confidence intervals, 1.2 to 115.2]), hypertension (6.8 [3.3 to 13.9]), heart disease (2.7 [1.1 to 6.4]), current cigarette smoking (2.5 [1.3, 5.0]), and long-term heavy alcohol consumption (>=60 g/d) (15.3 [1.0 to 232.0]). However, heavy alcohol ingestion (>=60 g) within 24 hours preceding stroke onset was not a risk factor (0.9 [0.3 to 3.4]).

Conclusions Diabetes, hypertension, heart disease, current smoking, and long-term heavy alcohol consumption are major risk factors for stroke in young adults. Given that the majority of these factors are either correctable or modifiable, prevention strategies may have the potential to reduce the impact of stroke in this age group.


Key Words: cerebral infarction • risk factors • young adults


*    Introduction
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Although cerebral infarction is predominantly a disease of the senescence, its occurrence in younger age groups is not rare. A recent report of the WHO MONICA Project documented that stroke incidence varied from 48 to 240 per 100 000 people aged 45 to 54 years in 10 countries involved.1 In the United States the average annual incidence rates of all strokes under the age of 55 years was 113.8 per 100 000, while that for cerebral infarction was 73.1 per 100 000.2 More than 10% of patients with cerebral infarction were 55 years or younger.3 4 5 Stroke in the young is particularly tragic because of the potential to create a long-term burden for the victims, their families, and the community.6 7 8 However, effective stroke prevention in the young cannot be attempted until the risk factors are clearly documented. Although case reports and etiologic investigations of young patients with cerebral infarction have identified a large number of possible causes,9 10 11 12 13 14 15 major risk factors for cerebral infarction in young adults, surprisingly, have rarely been studied systematically. Reasons for this probably include difficulties in making precise diagnoses in the pre-CT era, selecting appropriate controls, and having sufficient sample size.13 15 To evaluate and quantitate risk factors for cerebral infarction in young adults, we performed a prospective case-control study of risk factors for cerebral infarction in people aged 55 years or younger.


*    Subjects and Methods
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Patients
All consecutive patients with first-ever stroke due to cerebral infarction aged 55 years or less admitted to Austin (1985 to 1992), Royal Melbourne (1988 to 1992), Box Hill, Preston, and Northcote Community (1985 to 1988) hospitals were prospectively identified as part of the Melbourne Risk Factor Study.16 17 These four general hospitals serve much of the northern and eastern area of Melbourne, which has a population of approximately 3 million. A major source of the patients was the Austin Hospital Stroke Unit, where a stroke register has been in place since 1977 and CT scans have been performed on more than 98% of patients since 1985.18 Patients who had had a previously documented stroke, experienced a stroke after admission to the hospital for other conditions, or been transferred from other hospitals or nursing homes were excluded.

Control Subjects
Community-based control subjects individually matched with case subjects by the same sex and age (within 5 years) were identified by using "neighborhood" selection techniques, as described before.16 17 Here a standardized method of identifying a matched control subject was used by starting in the house on the immediate right of that of the subject in the same street. Sequential houses to the right were then visited until a matched control subject was found. To eliminate bias due to omitting people at work or absent for other reasons, all people in each house were identified and, if the house was empty, at least three return visits were made outside working hours. People with a history of documented stroke were excluded.

Information Ascertainment
Information about potential risk factor exposure status of eligible case and control subjects was collected by a constructed questionnaire at interview, as previously described.16 17

Definitions
Definitions were as follows: Stroke due to cerebral infarction: acute onset of a focal neurological deficit lasting longer than 24 hours, in which CT scan excludes causes other than cerebral infarction. Those with deficits lasting less than 24 hours but CT or MRI evidence of infarction were not included. Lacunar syndrome: acute onset of one of the five recognized lacunar syndromes (pure motor hemiplegia, ataxic hemiparesis, dysarthria–clumsy hand syndrome, sensorimotor stroke, and pure sensory stroke) in which CT had excluded underlying cerebral hemorrhage. In many cases the site of infarction was identified on CT scan, but this was not an absolute requirement for classification as a lacunar syndrome. Thromboembolic infarction: acute onset of focal neurological deficit with documentation of the site of infarction on CT scan in either cerebral hemisphere or hind brain, in which the mechanism of infarction was attributed to large-vessel extracranial or intracranial vascular disease. Cardiac embolic cerebral infarction: acute onset of a focal neurological deficit in which the site of infarction had been documented on CT scan in the presence of atrial fibrillation, myocardial infarction within the preceding 3 weeks, or cardiomyopathy. In some cases cerebral angiography or noninvasive studies of the extracranial circulation were done to help exclude carotid occlusive disease as a casual mechanism, but this was not an absolute requirement. Cerebral infarct site or mechanism uncertain: acute onset of a focal neurological deficit in which the site of infarction or the mechanism of its genesis was unclear, but nonvascular causes were excluded by the CT scan. Current smoker: a person who smoked at least one cigarette per day for the preceding 3 months or more. Ex-smoker: a person who smoked at least one cigarette per day for 3 months or more at some period during his/her life but has not smoked for the preceding 3 months or more. Never smoker: a person who does not meet the criteria for a current smoker or ex-smoker. Ever-drinker/never drinker: a subject who has ever/never drunk alcohol in his/her lifetime. Hypertension, Heart disease, Diabetes mellitus, and High cholesterol: history of such advised by a medical practitioner. Use of oral contraceptives: past and/or current use of birth control pills either for contraception or other indications. Physical exercise: current engagement in active physical exercise that caused perspiration and breathlessness, such as brisk walking, running, swimming, cycling, squash, and vigorous team sports. According to the exercise frequency, this variable was reduced to three subcategories of "never/rarely" (reference category), "1 to 2 times per week," and ">=3 times per week." Mechanisms of stroke were as defined previously.16

Statistical Analysis
A conditional logistic regression model (EGRET19 statistical package) was used to analyze the case-control pair-matched data set. Odds ratios of stroke for risk factors under study were estimated with adjustments for potentially confounding variables by multivariate analysis of the regression model. The significance level was set at P<.05. The two-sample t test was used to compare mean ages between the two groups.


*    Results
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A total of 201 case subjects with cerebral infarction aged 15 to 55 years and the same number of neighborhood control subjects matched by sex and age were identified. Table 1Down demonstrates the age and sex frequency distribution in the case and control subjects. All case and control subjects were white. The mean ages of the case (45.2) and control (45.5) subjects were not significantly different (t=0.32, P=.75, df=396). Men (60.2%) were more commonly seen than women (39.8%).


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  		Table 1. Sex and Age Frequency Distribution Among 201 Young Case Subjects With Stroke Due To Cerebral Infarction and Their Neighborhood Controls Matched by Age and Sex

The frequency distribution of presumed stroke mechanisms is shown in Table 2Down. While the majority (52%) of the cases were presumably thromboembolic, the mechanism and site of cerebral infarction in 14% of cases remained uncertain.


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  		Table 2. Frequency Distribution of Presumed Stroke Mechanism and Location Among 201 Young Case Subjects With Stroke Due to Cerebral Infarction

Comparison of the prevalence rates of and odds ratios for the main risk factors in case subjects recruited during 1985 to 1988 and 1988 to 1992 did not show statistically significant differences (current smoking, 63%, 54%; hypertension, 45%, 50%; heart disease, 20%, 23%, respectively; all P>.2 for ratio of their two odds ratios). This provides evidence to suggest that the case subjects recruited in the two periods in the same region were more likely to be homogeneous in terms of risk factor exposure and can therefore be considered as a single group for analysis.

The estimates of stroke risk for the examined risk factors are show in Table 3Down. A significantly increased risk of stroke was associated with diabetes mellitus (odds ratio, 11.6 [95% confidence interval, 1.2 to 115.2]); hypertension (6.8 [3.3 to 13.9]); heart disease (2.7 [1.1 to 6.4]); current smoking (2.5 [1.3 to 5.0]); and long-term heavy drinking (>=60 g alcohol per day) (15.3 [1.0 to 232.0]). However, recent heavy drinking (>=60 g alcohol within the preceding 24 hours) was not a significant risk factor (0.9 [0.3 to 3.4]). The remaining factors also did not reach significance. These odds ratios and confidence intervals largely varied by no more than 10% when heart disease was excluded from the multivariate analysis. The exceptions to this were current smoking, diabetes, and ever use of the oral contraceptive pill, in which cases the multivariate odds ratios and 95% confidence intervals without adjustment for heart disease were 2.9 (1.4 to 5.6), 13.6 (1.4 to 128.2), and 0.7 (0.2 to 2.0), respectively. No effects of interactions between the examined risk factors on the risk of stroke were found.


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  		Table 3. Crude and Adjusted Odds Ratios for Stroke Risk Due to Cerebral Infarction Estimated by Multiple Conditional Logistic Regression


*    Discussion
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 *Discussion
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The present study of a large number of young subjects with stroke due to cerebral infarction and community-based control subjects has provided insight into the associations of cerebral infarction with a set of common vascular risk factors.

Hypertension is widely considered as a major contributor to stroke in the general population. However, hypertension-related risk of stroke in the young has been infrequently assessed with adjustment for confounding variables,20 although the prevalence of hypertension in stroke patients at younger ages has been occasionally reported.4 14 21 22 23 24 25 Although the age-specific prevalence rates of hypertension (22%, 26%, and 33% in the age groups of 15 to 25, 15 to 35, and 15 to 45 years, respectively) in the case subjects of the present study were close to or slightly higher than those in other hospital-based case-control studies,4 14 23 24 25 26 27 28 29 the overall prevalence rates of hypertension were 49% in the case subjects and 16% in the control subjects, indicating a 6.8-fold increased risk of stroke for young hypertensives (Table 4Down). In the interpretation of this finding, the possibility of bias, confounding effects, and chance in producing the result must be considered. First, we designed this study to try to minimize potential biases in each stage of subject selection, data collection, and analysis, although the possibility that the hospital-based nature of the study may have selectively attracted hypertensive subjects cannot be excluded. Second, the potentially confounding effects of sex, age, and socioeconomic and regional factors have been controlled for by selecting sex- and age-matched neighbors as control subjects. Other confounding variables including smoking, diabetes, and heart disease have been adjusted for by multivariate regression. Finally, since the Australian community prevalence rate of hypertension is approximately 14% among people aged 20 to 59 years according to a national survey performed in 1989 by Australian Heart Foundation (AHF),30 the rate of 19% among the control subjects aged 15 to 60 years was unlikely to be unusually low to result in an overestimate of hypertension-related risk of stroke in this case-control study. Therefore, it appears that the observed high risk of cerebral infarction associated with hypertension in the young group most likely reflects a true association between hypertension and stroke due to cerebral infarction in young adults, at least in this study population. Clearly, this association needs to be examined further.


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  		Table 4. Comparison of Age-Specific Prevalence Rates of Hypertension Among Patients With Ischemic Stroke Aged <55 Years in the Present and Other Recent Studies

Similarly, the role of diabetes mellitus in the development of stroke has been well documented in general populations, in particular the elderly,31 32 33 34 35 36 37 38 39 but not yet in young adults. Most studies have only described a prevalence rate of diabetes mellitus as a possible cause or risk factor without estimating the relative risk for diabetes per se.4 14 23 24 25 While some authors reported that the prevalence of diabetes in patients with ischemic stroke under 50 years was not significantly different from that of patients with infectious diseases at similar age,40 others estimated the relative risk of stroke for diabetes.31 41 42 In the present study 15 case subjects (7%) and only one (0.5%) control subject had a history of diabetes, presenting a more than 10-fold increased risk of stroke related to diabetes. However, the interpretation of this high risk estimate with a wide 95% confidence interval is difficult because the frequency of diabetes among control subjects was relatively low, probably by chance, compared with those community prevalence rates observed in the AHF survey (1.2% in the group aged 20 to 59 years),30 a Swedish study (1.5% for those aged 50 years),43 and the Honolulu Heart Program (9.2% among those aged 45 to 59 years).34

The estimate of a 2.7-fold increased risk of stroke due to cerebral infarction associated with heart disease in this study was in agreement with those found in general populations of previous studies.37 38 44 45 Twenty-one percent of cases in the current study were considered to have a mechanism of embolism from the heart, a finding similar to that of Adams et al,14 who found a cardiac source of embolism in 23% of cases. Since the risk of stroke may vary with different types of heart diseases,20 45 a more refined definition is critically important in further study of cardiac risk factors.

The health effect of cigarette smoking in young people is an important public issue because of the increasing prevalence of smoking in this age group.46 47 48 The AHF national survey found current smokers in one of four Australians (24.5%) aged 20 to 59 years.30 Compared with the community prevalence, a slightly higher rate in the control subjects (33%) and a much higher rate in the case subjects (56%) were observed in this study and indicated a 2.6-fold increased risk of cerebral infarction for the young current smokers. If this estimate is correct, the attributable risk would be considerable because of the high prevalence of young smokers in the community. At least from the perspective of stroke risk, education concerning the adverse effects of cigarette smoking is appropriate for the young and is particularly important because of the reported increase in smoking prevalence in the young in some societies.49

Alcohol consumption as a risk factor for stroke in young adults has been observed in some studies.50 51 52 53 54 55 56 57 58 59 We found that alcohol consumption was a risk factor when long-term heavy ingestion of 60 g or more alcohol per day was considered. However, recent intake of large amounts (>=60 g alcohol within 24 hours preceding stroke onset, which also included no habitual drinkers) was not a risk factor. This pattern is somewhat different from that found by Hillbom et al,57 who showed that ingestion of alcohol more than 40 g within 24 hours preceding disease onset was an independent risk factor in their population. When we considered alcohol drinking as a dichotomous variable, no increase in stroke risk was found.

Our study has many of the limitations associated with retrospective case-control methodology. As mentioned earlier, many of the potential biases of case selection and influence of confounding variables have been minimized by study design, particularly by using the neighborhood control technique. Here past access to medical care of case subjects compared with control subjects is likely to be similar, so that definitions concerning past illnesses are more likely to be standardized. Even so, the measurement of past risk factor exposure is always particularly difficult and undoubtedly results in an underestimation of the prevalence in both case and control subjects. The use of oral contraceptive use is a case in point in which past use was probably underestimated and current usage was low. Here, the combined "ever used" grouping was used, which is less clinically useful. In view of recent findings that low-dose oral contraceptives probably do not increase stroke risk,28 29 it would be of interest to develop an expanded sample size to test this hypothesis in our population.

There are four directly comparable case-control studies of stroke in the young. Hillbom et al52 studied 75 consecutive subjects aged 16 to 40 years with first-ever ischemic brain infarction and compared these with 133 hospital-based control subjects. They found that recent alcohol ingestion, arterial hypertension, cardiac disease, diabetes, and migraine were significant risk factors, whereas smoking was not. The lack of association with smoking in their study may be in part due to use of hospital-based control subjects, in which a bias toward smoking in the control group may exist.60 Haapaniemi et al59 focused on weekend and holiday timing of stroke onset as a risk factor for ischemic stroke in young women. Among all cases (male and female) 141 subjects were studied, but a control group was not used. In our group, the timing of onset of stroke was not analyzed. Marini et al26 studied 333 subjects with stroke aged 15 to 44 years and used both hospital- and community-based (railway workers) controls. Like us, they found the vascular risk factors of hypertension, diabetes, and smoking to be associated with stroke, as did Rohr et al,27 who found these risk factors to be particularly important among blacks.

In summary, in the population studied here, the risk factors for ischemic stroke in those younger than 55 years were hypertension, diabetes, heart disease, and current smoking, all factors that are likely to promote premature atherosclerosis. Screening for atherosclerosis in this high-risk group may therefore be reasonable. Although this group of young patients with stroke represents only approximately 10% of the total, long-term disability in this group is of greater consequence than in older subjects. Quantitation of risk factors is therefore particularly important, and those identified are either modifiable or preventable. These findings need to be further validated in community-based studies.


*    Acknowledgments
 
This study was supported by grants from the Victorian Health Promotion Foundation and National Stroke Foundation. Dr You was supported by a Postgraduate Research Scholarship of the Australian National Health and Medical Research Council.


*    Footnotes
 
Reprint requests to Professor Geoffrey A. Donnan, Department of Neurology, Austin and Repatriation Medical Centre, Heidelberg, Vic 3084, Australia.

Received January 22, 1997; revision received July 15, 1997; accepted July 15, 1997.


*    References
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 up arrowSubjects and Methods
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 *References
 

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