The incidence of ischemic stroke in young adults has increased by 40% in recent decades (1, 2), causing over two million young patients with stroke yearly (1, 3). Epidemiological studies have revealed an increasing proportion of ischemic stroke in young adults, which accounts for 10–20% of total ischemic stroke events (4). In contrast with the elderly, young patients with stroke have a longer life expectancy, leading to high health care costs, severe labor productivity loss, and heavy economic burdens on individuals, families, and society (3). Therefore, more efforts should be made for the identification of risk factors (RFs) and the pathogenesis of stroke in young adults to improve the management and prevention (5).

Compared with stroke in the older adults, ischemic stroke in young adults has its own features. First, the causes and risk factors are various and relatively rare, such as artery dissections, autoimmune diseases, and illicit drug use, suggesting the need for specific investigation strategies (6). Second, there are age and sex differences in risk factor distribution. For example, pregnancy and the use of contraceptive drugs are only related to ischemic stroke in young women (7, 8), and among patients aged over 35 years, the prevalence of vascular risk factors rises remarkably than in the younger population (4). Therefore, the sex-specific and age-related variations in risk factor distribution require an individualized diagnostic workup.

However, the current classifications of ischemic stroke, such asthe Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria, are developed mainly for stroke in older people. According to some large-scale studies of the etiology of ischemic stroke in young adults, a large proportion of patients were classified as other determined etiology or undetermined etiology (9–13), which is not conducive to rapid etiological identification and poses a challenge on the treatment and prevention of ischemic stroke in young adults. In addition, when TOAST classification is used for etiological diagnosis, strategy for secondary prevention is usually carried out mainly to prevent the recurrent thrombus formation without considering treating other potential mechanisms. However, a part of young patients with ischemic stroke may have other potential risk factors or pathogenic mechanisms. Based on these points, TOAST classification is not applicable to all young patients with stroke.

Therefore, increasing studies are exploring the new classifications of risk factors and the mechanism of stroke in young adults. Risk factor profiles for pediatric ischemic stroke have been proved to be distinct from those in older adults, and in 2011, researchers used a new classification which divided the presumptive risk factors of childhood ischemic stroke into ten categories in the International Pediatric Stroke Study (IPSS) (14). Since the risk factor spectrum of pediatric ischemic stroke partly overlaps with ischemic stroke among young adults, in 2018, the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study first tried to categorize the risk factors of ischemic stroke in young adults by IPSS criteria and found that at least one IPSS category could be identified in 94% of all participants and in 88% of patients classified into the stroke of unknown etiology according to TOAST criteria. Therefore, they concluded the modified risk factor inventory based on pediatric findings, providing a valuable starting point for the development of a young stroke specific classification system (15). However, to confirm its feasibility, more investigations conducted in more ethnic groups and geographical regions are required.

In this study, we aimed to identify the risk factor distribution of ischemic stroke in young adults according to the IPSS classification in a large-scale Chinese cohort. The second aim was to explore the variations in risk factor distribution between different genders and age groups, which might lead to the better identification of potential mechanism, clinical management, and the prevention of ischemic stroke in young adults.

This study is a large-scale cohort study in which we applied a risk factor categorization first used in the IPSS into the Chinese young patients with ischemic stroke. We identified at least one IPSS category in 93.3% of all patients, and 74.6% of patients classified as the stroke of undetermined etiology according to the TOAST criteria. Distinct gender and age differences in IPSS risk factor distribution were observed. Our findings suggest that the IPSS classification might be a potential supplement to better identify the risk factors of ischemic stroke in young adults and provide a basis for further understanding of stroke mechanism.

The IPSS categorization could be an effective supplement to the traditional pathogenesis classifications for ischemic stroke which, such as the TOAST criteria, are mainly designed for the older adults. It has been reported by several studies that a large proportion of young patients with ischemic stroke, approximately 15–50% (11–13), would be divided into the stroke of undetermined etiology if classified by the TOAST criteria, varying with the geographical regions and local medical resources. This suggests that current categorizations for ischemic stroke are not appropriate for young patients with stroke and might pose a challenge on the pathogenesis study and etiologic diagnosis. Moreover, present stroke classifications cannot guide the clinical management of stroke in young adults precisely, which are mainly extrapolated from the older adults (5) and often lead to a “one-size-fits-all” strategy of antithrombotic treatment rather than individualized treatment (15). Therefore, it is necessary to explore the potential risk factors and mechanisms of young adults with ischemic stroke and establish its specific classification approach to lead to rapid etiological identification and prevention strategies. In our study, at least one IPSS category was found in 93.3% of all patients and 74.6% of patients classified as the stroke of undetermined etiology, indicating the underlying feasibility of this novel risk factors categorization.

It is worth noting that although rare causes and undetermined etiology account for a large proportion of stroke in young adults, atherosclerosis and modifiable vascular risk factors are becoming increasingly prevalent among young patients with stroke (17–19). In our study, large-artery atherosclerosis was the second commonly reported TOAST subtype, and atherosclerosis-related RFs were observed in over 60% of all patients, especially in men and patients ≥35 years of age. This emphasizes the necessity of the strict management of traditional cerebrovascular risk factors in young patients with ischemic stroke, even though in those who have other causes.

Besides atherosclerosis-related RFs, the dominant IPSS subtypes in our cohort were prothrombotic states, chronic systemic conditions, arteriopathy, and cardiac disorders, which accounted for over 10%, respectively. Prothrombotic states are much more prevalent in our cohort compared with the FUTURE study due to a relatively high percentage of hyperhomocysteinemia (21.6%) in our cohort, which is consistent with a previous Chinese epidemiological study (20). Hyperhomocysteinemia is widely acknowledged as a risk factor for both stroke and cardiac diseases (21). Its potential mechanism includes stimulating the platelet generation of thromboxane A2 (22), producing reactive oxygen species (ROS), deactivating epithelial nitric oxide (NO), inducing proliferation of intimal smooth muscle cells (23), and ultimately leading to a pro-thrombotic state. Hyperhomocysteinemia could be either an inherited or acquired disease. In previous studies, the prevalence of hyperhomocysteinemia in young patients with stroke varies with ethnic groups, from 7 to 16% in Caucasians to over 20% in Chinese (9–11). Though there are current knowledge gaps in the epidemiology of pathogenic genetic mutations among different races, the specific eating habits of some Chinese people, which leads to a deficiency of vitamin B (especially folate, B₆, and B₁₂), might be one of the causes of the relatively high prevalence.

There were obvious differences in the IPSS category distribution between male and female patients. Chronic systemic conditions and AHNDs were more prevalent among young women. By contrast, prothrombotic states and atherosclerosis-related RFs were found to be more among men. Moyamoya disease, antiphospholipid syndrome, autoimmune disease, hematological disorder, and oncologic disease were more common among women, while the prevalence of hyperhomocysteinemia in men was significantly higher. Some of those disparities, such as the variations in atherosclerosis-related RFs and autoimmune disease, are consistent with previous studies (24, 25). The underlying mechanism may include the cytoprotective properties of estrogen (26, 27) and sex differences in immune response (25). These differences shown by the IPSS profile suggest underlying etiological clues and re-emphasize the significance of sex-specific diagnostic strategies for young adults with ischemic stroke.

Moreover, the IPSS distribution significantly varied with age. In patients <35 years of age, non-atherosclerotic arteriopathy, cardiac disorder, and chronic systemic conditions were much more identified while atherosclerosis-related RFs were less frequently observed in contrast with relatively older patients. The age-related variations in the IPSS spectrum reveal the importance of different diagnostic work-up and the prevention projects of ischemic stroke in young adults according to age.

The strengths of our study are as follows. First, it was carried out in a tertiary Chinese hospital and the etiology and the risk factors of young patients with stroke were various, such as rare kinds of diseases. What' s more, the large-scale cohort provided a comprehensive risk factor profile of the Asian young patients with stroke. Finally, exploring the difference in the IPSS risk factor distribution between different age and sex groups lays a foundation for further pathogenesis research of ischemic stroke in young adults.

There are some limitations in our study. First, as the study was conducted in a top-level tertiary medical center in China, the selection bias should be taken into consideration. The prevalence of rare diseases might be overestimated and other subtypes of TOAST classification, such as small-vessel occlusion and cardiac embolism might be underestimated. Furthermore, information missing is an inevitable disadvantage of retrospective study. It might lead to a relatively low prevalence of some specific risk factors, such as migraine, which were likely to be neglected and not usually specifically documented in medical records. Additionally, some recruited patients might not perform complete investigations because of either economic or hospital stay constraints. Finally, it should be noted that the IPSS categorization is considered as a kind of presumptive risk factor categorization rather than an etiologic classification, as some of the IPSS categories might be just comorbidities or the complications of stroke. Therefore, careful differential diagnosis is required in clinical application, and the verification of causality is supposed to be focused in further research. The improvement and modification of IPSS categorization, for example, exploring a weighting points-scoring version or adopting more advanced workup into the diagnostic process, are expected in the future to make it more instructive in the clinical practice.

Overall, our study described the comprehensive risk factor profile of ischemic stroke among young Chinese adults according to a modified categorization initially designed for pediatric stroke, and explored the age and sex differences in risk factor distribution. At least one IPSS category was reported in 93.3% of all patients, and 74.6% of patients classified as the stroke of undetermined etiology according to the TOAST criteria, revealing more potential risk factors associated with other stroke mechanisms in the young than in the elderly. Meanwhile, the age-related variations and sex-specific disparities in risk factor distribution provide clues for future etiologic study of adult early-onset ischemic stroke. Our findings suggest the potential feasibility of IPSS categorization in clinical practice. We hope our study could lay a foundation for future studies conducted across different regional sites and ethnic races, and ultimately develop a specialized etiological classification for young patients with stroke, leading to better pathogenetic understanding and more individualized treatment strategies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committees of Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study.

BP, YZ, LZ, and JN: study concept and design. MT, MY, and GH: data collection and analysis. MT: manuscript drafting. LZ and JN: critical revision of the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.

This research was supported by the Central Public-interest Scientific Institution Basal Research Fund of Chinese Academy of Medical Sciences (#2021-RW320-003).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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