Stroke in younger adults is less frequent than in older people; however, its health and economic impact on younger individuals, their family, and society is major (1). The incidence rates of ischemic stroke in younger adults vary from 6.6 to 11.4 in 100,000 people per year (1). Incidence rates of ischemic stroke have increased in adults aged 55 years and under in the United States (2) and in Europe (3, 4). This trend could reflect changes in the burden of classical vascular risk factors in younger individuals, such as increases in prevalences of diabetes, obesity, and hypercholesterolemia or result from the interplay of other risk factors (3).

Associations between risk factors for acute ischemic stroke and clinical outcomes have been analyzed predominantly in older rather than younger patients (5–10). However, the knowledge gleaned from research of older adults cannot always be applied to younger adults (11, 12). Previous studies showed that both younger and older age stroke patients shared the same modifiable risk factors (11). However, the prevalence of these risk factors was different in these two age groups (1, 11). Risk factors for atherosclerosis such as dyslipidemia, hypertension, and diabetes were less frequent among young stroke patients aged 40 and under, whereas other risk factors such as family history, coagulation disorders, patent foramen ovale and non-atherosclerotic vasculopathies were more frequent (1, 13).

A previous study from the National Acute Stroke ISraeli (NASIS) registry found major differences between the clinical characteristics and outcomes of the very elderly (aged ≥85 years) patients with first-ever ischemic stroke (14); therefore, the comparison group used in this study was defined as patients aged 51–84. The purpose of our study was to examine risk factors, clinical characteristics, and in-hospital outcomes of younger adults (aged ≤50 years) compared to patients 51–84 years old, with first-ever ischemic stroke in the NASIS registry.

In this nationwide study, nearly half of younger adults with first-ever ischemic stroke reported current smoking. This is considerably higher than the reported prevalence of smoking among the general Israeli population aged 21–50 (21.2%) (19). The relatively high rate of smoking among younger stroke patients highlights its significance as an important modifiable risk factor for stroke in this age group and emphasizes the need for better smoking prevention strategies that address younger adults. Similar to previous studies (20, 21), ischemic stroke among younger patients was more common among males.

The majority of stroke cases in younger adults were related to the existence of traditional stroke risk factors, though the prevalence of these factors was lower than in older patients; concurring with other studies (7). Two or more vascular risk factors in young adults were found in 55% of our patients, which was similar to the 52% reported in the registries of Zurich and Bern (9). This highlights the importance of these modifiable risk factors for the occurrence of stroke in all ages. Therefore, targeting these risk factors is essential for primary prevention of stroke. However, 17% of the young adults in our study had none of the classical risk factors. In these cases, other potential risk factors such as genetic coagulation disorders should be considered. Indeed, younger adults were more likely to have a family history of stroke than were older patients. This calls for increased awareness toward appropriate review of family history in younger adults.

Notably, among younger compared to older patients, first ischemic strokes were more likely to be caused by such etiologies as cervical artery dissection and hematologic disorders, and less likely by cardioembolic source. In line with previous studies, we found that in most cases of ischemic stroke in younger adults, the underlying etiology remained unclear (1). Similarly, in patients aged 15–49 years with first-ever ischemic stroke from 15 European stroke centers, the etiology remained undetermined in 40% (7). A reason for our particularly high proportion of undetermined stroke is that subtyping of stroke etiology was based only on information available at hospital discharge. In practice, the work-up of stroke etiology is often done following discharge by diagnostic tests performed in the community.

Younger adults had a high proportion of lacunar strokes, whereas stroke of the anterior circulation was more common among older patients. This partially explains the higher proportion of mild stroke (NIHSS ≤ 5) among younger adults in this study as lacunar strokes are known to be less severe (6, 9, 22).

Younger adults with stroke were more likely to arrive to the hospital by private car than were older patients. This finding is of interest since according to our data, arrival by car was associated with longer onset-to door and door-to-CT times. Provision of timely treatment in acute stroke is critical, especially in the current era of stroke care, with the advancement of reperfusion strategies by thrombolysis and mechanical thrombectomy (21). Not only is early hospital arrival in acute stroke critical to reperfusion therapy but it also increases the probability of survival and affects other clinical outcomes in all patients with ischemic stroke, even when reperfusion therapy is not used (23). Possibly, the delay in hospital arrival of young adults is due to less common stroke presentation, as reported here. In addition, younger adults may have lower awareness to the possibility of stroke. In this study, motor weakness was the most frequent disturbance in both age groups; however, the proportions with sensory disturbances and headaches were higher among the younger patients. Indeed, in our study, patients with sensory disturbances or headaches were more likely to arrive by private car than were patients presenting with motor weakness, decreased consciousness, or speech disturbances.

Another important finding of this study is the substantial decline in poor stroke outcome (mRS > 3) among both age groups. A decline in stroke severity (NIHSS > 5) during the 9-year registry period was observed in both age group; however, only among older patients it reached statistical significance. This can be explained by improved management of known vascular risk factors such as hypertension, dyslipidemia, and diabetes mellitus (24). In addition, the growing use of reperfusion modalities may have also contributed to the improved outcomes. It should be noted that in the registry periods the use of reperfusion therapy was still limited but has been expected to grow since, especially following the publications of landmark studies that established the efficacy of mechanical revascularization (25, 26). The decline in the overall complication rate in both age groups during the 9-year registry period can be at least partially explained by improved acute stroke care (27). Of the factors investigated in this study, only the severity of stroke at admission was positively associated with poor outcome in younger adults. In the Zurich and Bern ischemic stroke registries, stroke of the anterior circulation, older age, and severity of stroke were associated with unfavorable outcome or death at 3 months (9), while in the Swiss Young Stroke Study, severity of stroke and diabetes were reported to predict unfavorable outcome at 3 months (8). This difference might be explained by the fact that previous studies focused on clinical outcomes at 3 months after the ischemic stroke (8, 9), while this study focused only on in-hospital outcomes. Yet, prior atherosclerosis, female gender, and posterior circulation territory were found to be associated with unfavorable clinical outcome among younger adults with borderline significance; this may be due to insufficient statistical power.

Our study has several methodological strengths, including its good external validity since data were obtained from a non-selective nationwide registry. In addition, our study used a validated measure of functioning, which was consistently measured at admission and at discharge. Some methodological limitations, however, should be considered. A major limitation of our study is the extremely high rate of stroke of undetermined origin, because the data collected were limited to the hospitalization period. In Israel, diagnostic tests aimed at identifying the stroke etiology (such as coagulation and genetic tests, echocardiography, Holter ECG) is often performed in the community. Yet, other studies with the exception of three studies (9, 10, 28) showed that despite a broad diagnostic approach and availability of accurate diagnostic tools, the proportion of stroke of undetermined etiology still remains high among young stroke patients (7, 11). Second, the study included only hospitalized stroke patients; and information on patients not admitted was not available. Nonetheless, there are no known barriers for hospital admission in the Israeli health-care system. Other limitation is the absence of data on recreational drug and oral contraceptive; however, recreational drugs are a rare risk factor for stroke in young Western populations (13), and the role of oral contraceptives as a risk factor for ischemic stroke remains still controversial (12). Another limitation is the absence of data on neuroimaging features such as ischemic stroke volume and previous small vessel disease, which can affect stroke outcome. It is well known that small-vessel disease can produce small deep hemispherical or brainstem lacunar infarcts in young adults, usually in patients with vascular risk factors (12).

In conclusion, our findings, in this nationwide registry, demonstrate that young adults have high prevalence of modifiable vascular risk factors and especially a high rate of smoking. In addition, our findings demonstrate a relatively high rate of family history of stroke, and lower rate of hospital arrival by ambulance among young adults. In our study, stroke in young patients was associated with poor outcome at discharge in almost 12%, and this may lead to major morbidity and long-term socioeconomic consequences. This calls for increasing awareness to the possibility of stroke among young adults and for better prevention, especially smoking cessation.

The NASIS registry was approved by the ethical committees of all participating hospitals.

ML, IZ, TS, and DT contributed to the design, data interpretation, and critical review. DT contributed to the data collection. ML and IZ contributed to draft the manuscript and data analysis. All authors contributed to revising the manuscript for publication and approved the final version for publication.

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.