Clinical Characteristics of Ischemic Stroke in Japanese Young Adults Open Access

Ischemic stroke in young adults is an important topic in both developing and developed countries, given the rising incidence of stroke in this age group [1, 2]. Compared to older populations, stroke in young adults presents with a broader range of stroke etiologies based on both conventional and unconventional risk factors. Furthermore, along with functional outcomes, psychological issues and return to work (RTW) challenges after stroke are also significant concerns in young adults [1, 2]. Given these considerations, the clinical characteristics and outcome of ischemic stroke in young adults have been clarified through large registry data in Western countries over the past decade. However, there are limited registry data on the characteristics of stroke in young adults in East Asia including Japan [3‒5]. The East Asian populations have a high prevalence of hypertension, resulting to small vessel disease, and have a higher incidence of intracranial artery disease such as moyamoya disease, arterial dissection, and atherosclerosis, presumably due to genetic backgrounds. Therefore, it is reasonable to assume that ischemic stroke in young adults in Japan exhibits distinct characteristics compared to those observed in Western countries.

The purpose of our study was to clarify the clinical characteristics of ischemic stroke in young adults in Japan. In the present study, we focused on the incidence of conventional risk stroke factors and potential unconventional stroke risk factors, stroke etiologies, recurrent stroke rate, and functional and psychosocial outcome at 3 months after onset.

The SKYSTER (Shiga Kyoto Young Stroke Evaluation Registry) study is a prospective multicenter study enrolling consecutive acute ischemic stroke patients from aged 18–50 years old who were admitted within 14 days after stroke onset to 5 high-volume stroke centers (University Hospital of Kyoto Prefectural University of Medicine, Kyoto First Red Cross Hospital, Kyoto Second Red Cross Hospital, Kyoto Okamoto Memorial Hospital, and Saiseikai Shigaken Hospital) in the Kyoto-Shiga region between February 2018 and January 2023. Acute ischemic stroke was defined as having focal neurological symptoms due to brain ischemia and acute ischemic lesions confirmed by diffusion-weighted imaging.

We established a workup protocol including blood tests and imaging to determine stroke etiology accurately and comprehensively evaluate unconventional stroke risk factors in all study subjects, as shown in Table 1. Imaging workups included head magnetic resonance imaging (MRI) and intracranial magnetic resonance angiography (MRA) at baseline (admission day) and 7 days after admission (+30 days for subjects with arterial dissection), carotid ultrasound, extracranial vascular imaging (digital subtraction angiography, computed tomography angiography, or MRA), transthoracic echocardiography, and electrocardiogram monitoring for 24 h or more. The choice of modality in extracranial vascular imaging was determined by the attending physician based on clinical judgment and the availability of imaging techniques at each institution. Transesophageal echocardiography including bubble study and lower extremity venous ultrasound were performed as much as possible in the subjects without diagnosis of arterial dissection. We collected the following clinical information: age, sex, body mass index, marital status, employment status, conventional stroke risk factors such as hypertension, diabetes mellitus, dyslipidemia, and smoking, potential unconventional risk factors such as migraine, hyperhomocysteinemia, antiphospholipid syndrome, and medications such as steroids and female hormonal agents, concomitant active cancer, family history of stroke, National Institutes of Health Stroke Scale (NIHSS) score at admission, neurological symptoms, time from onset to door, treatment including reperfusion therapy and antithrombotic drugs for secondary prevention, and recurrent stroke within 3 months after the index stroke. Functional outcomes at 3 months were evaluated using modified Rankin scale (mRS). Excellent functional outcome was defined as mRS 0–1. For full-time workers before stroke, RTW rate and mental status by PHQ-9 test, which evaluates depression, were also evaluated at 3 months after stroke. Imaging data, serum, and DNA samples were stored for subsequent analysis in a core laboratory in Kyoto Prefectural University of Medicine.

Stroke etiology was categorized according to the TOAST criteria based on protocol-based workup results [6]. In addition, the proposed diagnostic criteria were used for the diagnosis of arterial dissection [7, 8]. APS and hyperhomocysteinemia were analyzed as risk factors, not as determined causes of stroke, since they were often identified in subjects with conventional stroke etiologies. APS was diagnosed when antiphospholipid antibodies were detected on two or more consecutive occasions, at least 12 weeks apart. Hyperhomocysteinemia was defined as a total homocysteine level of 15 µmol/L or higher. Genotype of ring finger protein 213 (RNF213) p.R4810K, a strong genetic susceptibility factor for moyamoya disease in East Asian populations, was determined by restriction fragment length analysis and Sanger sequencing as described previously [9].

The study was conducted in accordance with the standards of the Declaration of Helsinki. This study was approved by the Ethical Committee of Kyoto Prefectural University of Medicine and 4 other hospitals. All participants provided written informed consent prior to enrollment.

Over a study period of 5 years, 6,989 acute ischemic stroke patients were admitted to 5 stroke centers. Of these, 296 cases were young adult ischemic strokes, accounting for 4.2% of all ischemic strokes. After excluding 21 cases where informed consent could not be obtained for various reasons, 275 cases (71% male, with a median age of 46 years) were enrolled in the SKYSTER study. The examination rate in protocol-based workup was 90% or more for most imaging studies and blood tests (Table 1).

Table 2 shows the baseline characteristics of the study subjects. The major risk factors were dyslipidemia (59%), any history of smoking (53%), and hypertension (49%). The common concomitant diseases were hyperhomocysteinemia (21%), migraine (11%; without aura 7%, with aura 4%), and APS (5%). Protein S deficiency was diagnosed in 0.4%, whereas no subjects had protein C deficiency or antithrombin deficiency. Twelve subjects (4.5%) had heterozygous RNF213 p.R4810K variant, including 6 subjects with moyamoya disease and 4 with intracranial artery stenosis.

The most common stroke etiologies were small vessel occlusion (26%) and arterial dissection (25%) (Fig. 1a). In cases of arterial dissection, 81% were intracranial arterial dissection (IAD) and 19% were extracranial dissection. The most affected arteries were the intracranial vertebral artery (34%), followed by the middle cerebral artery (13%), the anterior cerebral artery (10%), the extracranial vertebral artery (10%), and the posterior inferior cerebellar artery (7%) (Fig. 1b). Subjects diagnosed with IAD underwent repeated intracranial vascular imaging in 100%, vessel wall imaging MRI in 85%, and digital subtraction angiography in 57%. The other determined causes were identified in 9% (moyamoya disease in 7 cases, vasculitis in 5, cancer-associated thrombosis in 4, carotid web in 2, reversible cerebral vasoconstriction syndrome in 1, bow hunter syndrome in 1, protein S deficiency in 1, heparin-induced thrombocytopenia in 1, and essential thrombocytosis in 1). Patent foramen ovale was identified in 32% of cryptogenic stroke. However, most patients with patent foramen ovale did not have venous thrombosis and were classified into stroke of undetermined cause.

The median NIHSS score at admission was 2 points. For acute reperfusion therapy, 6% of the subjects underwent intravenous thrombolysis and 12% underwent endovascular treatment (2% underwent both). Outcome data at 3 months were available for 97% of all enrolled subjects (267/275). The stroke recurrence rate was 5.2% (14 subjects) at 3 months. Stroke etiologies in subjects with stroke recurrence were other causes in 7 (arterial dissection in 3, cancer-associated thrombosis in 2, heparin-induced thrombocytopenia in 1, and bow hunter syndrome in 1), undetermined causes in 6, and small vessel occlusion in 1. The rate of excellent functional outcome at 3 months was 76%, and the mortality rate was 0.7% (Fig. 2a). Among 207 full-time workers, 80% showed an excellent functional outcome at 3 months, whereas only 61% were able to return to their previous full-time work at 3 months. Among 115 subjects who answered the PHQ-9 test, 31% exhibited symptoms of depression (PHQ-9 score 5–9 [mild depression] in 21% and 10 or more [moderate or severe] in 10%) (Fig. 2b). Depression was more prevalent in subjects who were unable to return to their previous work despite having an excellent functional outcome (41%) compared to those who successfully returned to work (26%).

We demonstrated the clinical characteristics and outcomes of ischemic stroke in Japanese young adults through a prospective multicenter registry study. The strength of our study was a protocol-based workup characterized by a high examination rate, leading to an accurate diagnosis of stroke etiology and comprehensive evaluation of unconventional risk factors. As a result, our registry underscored small vessel occlusions and arterial dissection as the most frequent etiologies, each accounting for a quarter of young adult strokes. Regarding outcomes, most young stroke patients exhibited favorable outcomes. However, some of them encountered problems relating to employment or mental health after experiencing a stroke [3, 5]. Previous studies in Japan have primarily focused on the clinical characteristics of young adult stroke. Expanding on these aspects, our study is the first in Japan to examine social outcomes such as RTW and poststroke mental health, highlighting the challenges young stroke survivors face despite achieving excellent functional outcomes.

The rate of small vessel occlusion in our registry (26%) is consistent with recent Japanese young adult stroke registries (28–31%) [3, 5]. Small vessel occlusion is the common stroke etiology based on a higher prevalence of hypertension in Japan [5, 10]. Also, in young adults, small vessel occlusion was reported to be more prevalent in Asian populations than in non-Asian populations [11].

Regarding arterial dissection, IAD constituted a substantial majority (81%) of arterial dissection cases and accounted for 20% of stroke etiologies for all young stroke subjects. Notably, we clarified the detailed location of IAD in young adult stroke. The intracranial vertebral artery emerged as the predominantly affected vessel, while other intracranial arteries, such as the anterior cerebral artery, middle cerebral artery, and posterior inferior cerebellar artery, were also involved. There were few studies focusing on IAD in young adult ischemic stroke. Only one Japanese young adult stroke registry demonstrated that IAD (9.6%) was more frequent than extracranial arterial dissection (6.0%) as a stroke etiology of young adult stroke [3]. On the other hand, several studies on young adult stroke in Western countries have reported the proportion of arterial dissection (without distinguishing between extracranial and intracranial dissection) or cervical artery dissection to be between 10% and 24%, but no studies have mentioned the prevalence of IAD [12‒17].

One of reasons for the increased prevalence of IAD in our study is presumably due to the difference in ethnic backgrounds. In general populations, IAD is reportedly more common in Asian populations compared to European populations [7]. Several studies from East Asian countries showed IAD accounted for a significant proportion of intracranial steno-occlusive disease with ischemic stroke [18‒20]. Although genetic backgrounds may be associated with the prevalence of IAD in East Asian populations, the RNF213 p.R4810K variant, which was a significant risk allele for moyamoya disease and intracranial artery disease in East Asian populations, was not identified in the patients with IAD. Therefore, we need to explore the genetic factors associated with IAD in the future. Another possible reason for the increased prevalence of IAD in our study is the high examination rate of repeated intracranial vascular imaging and vessel wall imaging MRI. A recent study from South Korea showed two-thirds of stroke patients with IAD were misclassified as having intracranial atherosclerotic stenosis based on luminal imaging techniques such as MRA. The study advocated the utilization of high-resolution MRI techniques as vessel wall imaging MRI for accurate differential diagnosis between IAD and atherosclerotic stenosis [20]. Given these findings, we should increase awareness of IAD as a common stroke etiology in young adult stroke patients with intracranial steno-occlusive disease in East Asian populations.

Our study showed 78% of the patients achieved an excellent functional outcome at 3 months, significantly higher compared to those in stroke patients across all age groups in large Japanese stroke registry datasets [21, 22]. The high rate of excellent functional outcome at 3 months in young adult stroke was also reported in previous studies from other countries [4, 23, 24]. On the other hand, only 61% of full-time workers were able to return to their previous full-time work and 31% exhibited symptoms of depression at 3 months after stroke. Furthermore, depression was more prevalent in subjects who were unable to return to their previous work despite having an excellent functional outcome. Our findings suggest an association between depressive symptoms and difficulties in RTW. A recent systematic review demonstrated many young adult stroke patients did not return to work despite good functional outcomes [25]. RTW after young adult stroke is shaped not only by functional disability but also by complex psychological and systemic factors. Volz et al. [26] reported that successful RTW was associated with lower depressive symptoms, whereas Matos et al. [27] found that RTW, despite promoting community integration, may negatively impact mental health. These findings highlight the complexity of RTW and depression, emphasizing the need for integrated approaches that address both psychological barriers and workplace support. Future research should explore these interactions and develop targeted interventions to support vocational reintegration.

Our study has some limitations. First, we prospectively enrolled consecutive acute ischemic stroke patients admitted only to the neurology department in 5 stroke centers and did not enroll some stroke patients admitted to other departments due to severe disease. Therefore, we might miss some stroke patients associated with COVID-19 infection, infectious endocarditis, and advanced cancer. Second, our study focused exclusively on Japanese stroke patients, so our findings may not be applicable to other ethnic populations. Nevertheless, our research is of considerable importance as it provides data on young adult stroke in East Asians, contributing to a deeper understanding of stroke etiology and risk factors within this population.

The leading stroke etiologies in young adults in Japan were small vessel occlusion and IAD, which differs from those observed in Western countries. While most young stroke patients had favorable outcomes, some faced challenges related to employment or mental health after their stroke.

The authors express their gratitude to all the participants in the SKYSTER study. The authors also thank stroke physicians, health workers, and laboratory technicians at the University Hospital of Kyoto Prefectural University of Medicine, Kyoto First Red Cross Hospital, Kyoto Second Red Cross Hospital, Kyoto Okamoto Memorial Hospital, and Saiseikai Shigaken Hospital for their assistance in conducting the SKYSTER study.

The study was conducted in accordance with the standards of the Declaration of Helsinki. This study protocol was reviewed and approved by the Kyoto Prefectural University of Medicine Ethics Review Committee and the Institutional Review Boards of Kyoto First Red Cross Hospital, Kyoto Second Red Cross Hospital, Kyoto Okamoto Memorial Hospital, and Saiseikai Shigaken Hospital, with approval no. ERB-C-1024. All participants provided written informed consent prior to enrollment.

The authors have no conflicts of interest to declare.

This work was partially supported by JSPS KAKENHI Grant No. JP22K07521.

T.O.: conceptualization, methodology, formal analysis, and writing – original draft; N.M.: data curation and writing – review and editing; J.F.: conceptualization, methodology, and data curation; K.M.-K., D.F, E.T., H.T., N. T., T.Y., S.O., and M.M.: data curation; A.F.: methodology and data curation; Y.N.: methodology and writing – review and editing; K.I.: methodology; I.M.: investigation and writing – review and editing; and T.M.: writing – review and editing and supervision.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (T.O.) upon reasonable request.