Young stroke patients are often misdiagnosed at initial presentation (1); however, stroke in young adults results in devastating implications for the quality of life and ability to work, and creates a huge socio-economic burden (2-4). A previous study found that the highest incidence of stroke in China was in the north of the country (5). Knowledge of the etiology, stroke subgroups, and risk factors of stroke in young individuals could be beneficial for planning preventive strategies and improving quality of life. Previous studies have reported that the etiology and risk factors for young stroke patients vary by age, race, and region (6-8). However, these studies were small or methodologically heterogeneous (9) and limited prior research has specifically addressed stroke etiology in young patients in developing countries (10).
Due to the high expense, invasiveness, and radiation hazard of traditional vascular examination methods, few studies have focused on imaging features and cerebrovascular stenosis in young ischemic stroke (IS) patients (7,11-14). In recent years, the development of non-invasive examination methods, such as magnetic resonance angiography (MRA), transcranial Doppler (TCD), and carotid ultrasound, has helped better assessment of intracranial and extracranial vascular status. The present study analyzed the risk factors, etiologies, and the distribution of vascular stenosis in young IS patients. The prevalence of risk factors and differences in etiology between first-ever stroke and recurrent-stroke patients were also investigated.
We retrospectively analyzed the demographics and clinical data of young IS patients obtained from the stroke database of The First Hospital of Jilin University between January 1, 2013, and December 31, 2017. Patients meeting the following inclusion criteria were included in the present study: (I) aged 15–49 at stroke onset; (II) discharge diagnosis of IS; (III) underwent at least magnetic resonance imaging (MRI) or computed tomography (CT). Additional imaging studies, namely carotid artery ultrasonography, TCD or MRA, computed tomography angiography (CTA), and digital subtraction angiography (DSA), were also reviewed if conducted on those patients.
Patients were excluded from the present study if they had been diagnosed with transient ischemic attack (TIA), cerebral venous thrombosis, stroke attributable to direct head trauma or strangulation, ischemic lesion attributable to immediate complications originating from subarachnoidal hemorrhage, and any iatrogenic stroke as a consequence of angiographic imaging or major surgery (7). IS was defined as a focal neurological deficit of sudden onset that persisted beyond 24 hours or with evidence of acute brain ischemia on neuroimaging when symptoms lasted less than 24 hours. TIA was defined similarly but with symptoms lasting less than 24 hours and without corresponding imaging evidence of ischemic lesion (7). The study protocol was approved by the ethics committee of The First Hospital of Jilin University. The ethics committee provided a waiver for informed consent as patients were not contacted directly and the results of the study did not impact their care.
All patients underwent routine blood testing, chest radiography, and an electrocardiogram (ECG) at admission. Demographic data, medical history, and family history of stroke were extracted from the patient records. Risk factor variables included hypertension, dyslipidemia, diabetes, coronary artery disease, hyperhomocysteinemia, current cigarette smoking, and alcohol consumption (regular alcohol consumption in the 3 months preceding the stroke). Hypertension was defined as a medical history of hypertension or the use of antihypertensive drugs 2 weeks prior to enrolment in the study, a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg (15). Diabetes mellitus was defined as a medical history of diabetes or the use of oral hypoglycemic medication or patients with a fasting glucose ≥7.0 mmol/L (126 mg/dL) or a two-hour postprandial serum glucose ≥11.1 mmol/L (200 mg/dL) (13). Dyslipidemia was defined as a history of hyperlipidemia, taking oral antidyslipidemic drugs, or the fulfillment of one of the following criteria: a total cholesterol level (TC) of ≥5.18 mmol/L, a low-density lipoprotein cholesterol (LDL-C) level of ≥3.37 mmol/L, a high-density lipoprotein cholesterol (HDL-C) level of <1.04 mmol/L, and triglyceride (TG) level of ≥1.70 mmol/L (16,17). Hyperhomocysteinemia was defined as total homocysteine level ≥10 µmol/L, as recommended by the American Heart Association and the American Stroke Association Council on stroke (18). Individuals were considered overweight or obese if they had a body mass index (BMI) of ≥26 kg/m2 (15). Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria (19) as large-artery atherosclerosis (LAA), small-vessel disease (SVD), cardioembolism (CE), other determined etiology (ODE) and undetermined etiology (UDE). The study patients were first divided into different groups according to sex (male versus female) and age (15–44 versus 45–49 years). They were then grouped into first-ever stroke and recurrent stroke groups. If patients or their family members self-reported a previous history of stroke, which was supplemented by previous hospital records and brain imaging, they were categorized into the recurrent stroke group.
The cranial CT scans of all patients were examined to exclude cerebral hemorrhage. Infarct sites were determined using cranial MRI (T1-, T2-, and diffusion-weighted sequences). Carotid doppler ultrasonography, TCD, MRA, CTA, or DSA were used to define stenosis as narrowing of intra- or extracranial arteries by ≥50% (20).
All analyses were performed using SPSS 23.0 (IBM Corp., Armonk, NY, USA). Pearson’s Chi-squared test and Fisher’s exact test were used to compare categorical variables across groups and Student’s t-test was used to compare means. Numerical values with non-normal distribution are shown as the median (interquartile range, IQR) and a non-parametric test was used to compare differences between the two groups. Two-sided probability values (P) <0.05 were considered statistically significant.
In total, 956 young IS patients from our database were enrolled in this study. There were 754 males (78.9% of total; male: female ratio 3.73:1). They were aged 15–49 years, with a median age (IQR) of 45 [40–47] years.
Overall, males had a significantly higher frequency of dyslipidemia and hyperhomocysteinemia than females (P=0.001 and P<0.001, respectively) (Table 1). Moreover, males were significantly more likely to be smokers and consume alcohol than females (P<0.001 for both). Conversely, females had a significantly higher frequency of valvular heart disease (P=0.013), history of migraine (P=0.003) and previous stroke or TIA (P=0.010) compared to males.
Patients were also divided into two groups according to their age; one group consisted of 442 patients aged 15–44 years (46.2%) and the second group consisted of 514 patients aged 45–49 years (53.8%) (Table 1). Comparisons of the two groups showed that hypertension and diabetes mellitus were more common in the 45–49 years age-group (P<0.001 for both) (Table 1, Figure 1).
Using the TOAST classification to identify stroke subtypes, the most common etiology of IS was LAA (43.7%), followed by SVD (39.0%). CE was uncommon (5.1%) (Table 1). Significant differences in etiology were observed between males and females (P=0.010) and the two age groups (P<0.001). The ODE stroke subtype was significantly higher in females than in males (P=0.005) whereas the UDE and CE stroke subtypes were significantly higher among the 15–44-year-old patients (P=0.006 and P=0.008, respectively) and the LAA subtype was significantly higher in the 45–49 years age-group (P=0.036).
The proportion of males in the first-ever stroke group was significantly higher than that of the recurrent stroke group (P=0.008). The age of recurrent stroke patients was slightly higher than that of first-ever stroke patients (46 versus 45, P=0.073). Hypertension, diabetes, and coronary heart disease (CHD) were significantly higher in recurrent stroke patients than those in first-ever stroke patients (P=0.002, P=0.005, and P=0.011, respectively). However, recurrent stroke patients were significantly less likely to smoke (P=0.005) and consume alcohol (P=0.001) than first-ever stroke patients (Table 2). Recurrent stroke was more frequently caused by LAA (P=0.026) and less often by SVD (P=0.008) compared to etiologies observed in first-ever stroke patients.
Carotid doppler ultrasound was performed on all patients, TCD examination in 778 (81.4%) patients, MRA examination in 406 (42.5%) patients, CTA examination in 61 (6.4%) patients, and DSA examination in 92 (9.6%) patients. Carotid doppler ultrasound reports showed that 603 patients (63.1%) had plaque, with significantly higher frequency in males (P=0.028) and 45–49-year-old patients (P<0.001).
There was no significant difference in distribution of stenosis between the different groups according to sex and age groups. Multiple artery stenosis was observed in 148 patients (15.5%) and middle cerebral artery (MCA) was the artery that was the most affected by stenosis in young patients with IS (19.6%), followed by the vertebral artery (8.2%), and internal carotid artery (ICA) (6.0%) (Table 3).
This study showed that males were the most affected in young stroke patients of northeast China and that the proportion of conventional stroke risk factors in young patients was very high and were not well managed. The proportion of intracranial vascular stenosis observed was higher than that of previous studies. The most common etiology was LAA, followed by SVD; CE was less common.
The median age of patients in our study was 45 years, which was higher than that reported in young stroke studies in other countries (6,7,21); however, the high proportion of male patients in our study is consistent with what has previously been reported (7,22-26).
The current study provides a meaningful overview of the risk factors for young IS. Patients in our study had a high rate of conventional stroke risk factors, which is consistent with other studies (27,28). The most common risk factor in our study was hypertension. Hypertension in China is associated with high salt intake, obesity, smoking, alcohol consumption, and low education (29,30). In our study, dyslipidemia, hyperhomocysteinemia, smoking, and alcohol consumption were highly common in male patients. In fact, smoking and alcohol consumption surpassed hypertension as the most common risk factors for IS in young male patients, which has also been reported elsewhere (7,13,31-33). Estrogen has a protective effect on ischemia, which may explain the lower prevalence of IS in females (34). Females, however, showed a higher incidence of migraines and valvular heart disease, which was similar to previous studies (13,32,35).
A few studies have been done in young patients with recurrent stroke. In our study, recurrent stroke was associated with hypertension, diabetes, and CHD, which is similar to other studies (32,36). We also found that behavioral risk factors, that is smoking and alcohol consumption, were significantly lower in the recurrent stroke group; however, the proportions were still high (44.3% and 38.3%, respectively). These results suggest that secondary prevention has not been sufficiently conducted in patients who already experienced stroke once, as has been previously shown (32,36).
In terms of stroke etiology, the proportion of patients with LAA was higher than that with SVD, which is similar to findings of studies conducted in Korea (37) and the USA (26). In contrast, studies in Taiwan (24) and Finland (7) have shown that SVD was more common than LAA. However, the proportion of LAA and SVD in these studies was low, which was different from what we observed in our study. Furthermore, some studies in Europe found that most young strokes were caused by cardiac embolisms (7,38,39), which was uncommon in our study. These differences in stroke etiology might potentially be caused by a different distribution of risk factors or ethnic groups. In fact, in a recent study of ischemic stroke in young people of northern China showing results similar to ours, the authors indicated that the stroke etiology could be related to the higher prevalence of atherosclerosis in northern China (40).
Recent studies have shown that intracranial stenosis is common in young stroke, in particular at the MCA, which is highly vulnerable to stenosis (13). This is in line with our observations, where MCA stenosis was the most common subtype of symptomatic intracranial arterial stenosis in young adults. In previous studies, the incidence of intracranial stenosis or occlusion in young Asian stroke patients was 22–26%, and in a European study, it was 11.8%, which was lower than our study (12,41-43). Furthermore, anterior circulation stenosis of cerebral vessels was observed in a significant proportion of patients in our study, which is consistent with what was previously known (13).
For young stroke patients of northeast China, there are fewer studies on a larger sample and fewer studies on vascular conditions due to some technical limitations. Our study solves these problems. The vascular examination and imaging examination of the patients in our study were comprehensive, and the number of patients was relatively large. In addition, grouping patients into first-ever and recurrent stroke groups at admission also guided secondary prevention of stroke through a better understanding of its behavioral risk factors.
Our study had certain limitations. There were some missing data as this was a retrospective study and we, therefore, had to rely on patient reports previously stored in the computer database. Moreover, although our study sample size was relatively large, our patients originated from several provinces and cities of northeast China; therefore, a multi-center study is still needed to analyze regional characteristics.
LAA is the most common etiology in Chinese young stroke patients, especially in those with recurrent stroke. Our data highlight the need of screening of LAA and prevention and management of conventional stroke risk factors in young people of China. Secondary prevention and post-stroke education need to be more widely available.
Funding: This work was supported by the National Natural Science Foundation of China (grant number 81971620).
Conﬂicts of Interest: The authors have no conﬂicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work and in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study protocol was approved by the ethics committee of The First Hospital of Jilin University and all methods were performed in accordance with the relevant guidelines and regulations. The ethics committee provided a waiver for informed consent as patients were not contacted directly and the results of the study did not impact their care.
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