Characteristics and Outcomes of Young Patients with First-Ever Ischemic Stroke Compared to Older Patients: The National Acute Stroke ISraeli Registry

Background Nationwide data on the clinical profile and outcomes of ischemic stroke in younger adults are still scarce. Our aim was to analyze clinical characteristics and outcomes of young patients with first-ever ischemic stroke compared to older patients. Methods The National Acute Stroke ISraeli registry is a nationwide prospective hospital-based study performed triennially. Younger adults, aged 50 years and younger, were compared with patients, aged 51–84 years regarding risk factors, clinical presentation, stroke severity, stroke etiology, and outcomes. A logistic model for stroke outcome was fitted for each age group. Results 336 first-ever ischemic strokes were identified among patients aged 50 years and younger and 3,243 among patients 51–84 years. Younger adults had lower rates of traditional vascular risk factors, but 82.7% had at least one of these risk factors. Younger adults were more likely to be male (62.8%), current smokers (47.3%), and to have a family history of stroke (7.4%). They tended to have less common stroke presentation such as sensory disturbances or headache and were more likely to arrive at the hospital independently by car. The majority of young adults (70%) had a favorable outcome (modified Ranking Scale; mRS ≤ 1) at discharge, but 11.7% had poor outcome (mRS > 3) and 18.2% had an in-hospital complication. According to a multivariable regression model, in young adults, only baseline stroke severity (National Institute of Health Stroke Scale > 5) was associated with poor outcome at discharge (p < 0.001), whereas in older adults, stroke severity (p < 0.001), female gender (OR = 1.35, CI 95% 1.03–1.76), older age (OR = 1.08, CI 95% 1.01–1.16), atrial fibrillation (OR = 1.62, CI 95% 1.16–2.26), and anterior circulation territory (OR = 2.10, CI 95% 1.50–2.94) were all significantly associated with poor outcome. Conclusion Our findings, in this nationwide registry, demonstrate the relatively high rate of smoking and family history of stroke, and the lower rate of hospital arrival by ambulance among young adults. This calls for increasing awareness to the possibility of stroke among young adults and for better prevention, especially smoking cessation.

inTrODUcTiOn Stroke in younger adults is less frequent than in older people; however, its health and economic impact on younger individu als, 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 indi viduals, 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)(6)(7)(8)(9)(10). However, the know ledge 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 firstever ischemic stroke (14); therefore, the com parison 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 inhospital outcomes of younger adults (aged ≤50 years) compared to patients 51-84 years old, with firstever ischemic stroke in the NASIS registry.

MaTerials anD MeThODs study Design and Population
National Acute Stroke ISraeli is a prospective hospitalbased nationwide registry performed triennially (15). Data were collected prospectively by coordinating physicians for all conse cutive cases of acute cerebrovascular diseases hospitalized during 2month periods in 2004,2007,2010, and 2013 at all general hospitals in Israel. The NASIS registry was approved by the ethical committees of all participating hospitals.

Data collection
The registry was previously described in detail (15). In brief, for the NASIS registry, a specially designed structured form was used to collect data, including demographics, risk factors, comorbidities, stroke characteristics, inhospital management, and inhospital outcome. Stroke severity was determined using the National Institute of Health Stroke Scale (NIHSS) score (16). The modified Ranking Scale (mRS) (17) was used for assessing disability before stroke and at discharge. The TOAST classifica tion was used to define the etiology of stroke based on inhospital investigation (18). Prior atherosclerosis was defined as prior TIA, carotid stenosis, peripheral artery disease, or ischemic heart disease. Modifiable vascular risk factors included diabetes, dyslipidemia, smoking, hypertension, and obesity. Participants were classified into four groups: no risk factors, one, two, and three or more modifiable risk factors.

Outcome Variables
Two outcomes were studied. Poor outcome-defined as severe disability or death (mRS > 3) at discharge; and complications during hospitalization, categorized to neurological, cardiac, infectious, and other.

statistical analysis
Younger adults, aged 50 years and younger, were compared with patients, aged 51-84 years regarding their baseline character istics, stroke severity at admission, stroke etiology, and stroke outcomes.
Chisquare test was used to determine the differences between groups in the categorical variables. Continuous vari ables were compared using the Ttest or the Mann-Whitney test. Univariate and multivariable logistic regression models were fit ted separately for each age group (aged 50 years and younger and 51-84 years) to identify covariates associated with poor outcome. The registry period, age, and gender were entered in all multi variable models. Other predictors that had a level of significance of less than 0.1 in the univariate analysis were included in the final multivariable logistic regression models. Additionally, we tested for potential interactions between the predictors and no significant interactions were found. We excluded from the logis tic regression models patients with prior disability (mRS ≥ 2) and patients with length of hospitalization of more than 1 month (approximately 1.6% among younger adults and 3.1% among patients 51-84 years old). The analyses were performed using SPSS 23 software (SPSS Inc., Chicago, IL, USA).

Patient characteristics
A total of 336 (9.4%) first ever ischemic strokes were identified among patients aged 50 years and younger and 3,243 among patients 51-84 years (Figure 1).
Characteristics and healthrelated conditions of the patients, by age group, are presented in Table 1. Male gender and Arab ethnicity were significantly associated with the younger age group. Younger adults were more likely to be current smokers than were older patients (47.3 vs. 21.9%) and were more likely to have a first degree relative who had a stroke before the age of 55 years (7.4 vs. 2.0%). The younger group comprised a higher proportion of patients without vascular risk factors (17.4 vs. 5.9%) and a lower proportion with three or more vascular risk factors (26.7 vs. 41.9%). However, a total of 82.7% had at least one modifiable vascular risk factor.
Stroke characteristics by age group categories are presented in Table 2. The distribution of stroke etiology was significantly different between the two groups. Younger adults had a smaller  proportion of cardioembolic strokes (8.0 vs. 12.0%) and of occlu sive disease strokes (17.6 vs. 24.0%), while strokes due to artery dissection and/or hematological disorder were more common in this group (6.0 vs. 0.5%). The two age groups also differed in the clinical classification of strokes and its severity ( Table 2).
The presenting symptoms of stroke by age groups are depicted in Figure 2. Motor weakness was the most frequent disturbance in both age groups. Sensory disturbances and headache were more common among younger than older patients, while speech disturbances were less common.
Only onethird (32%) of younger adults arrived by ambulance compared to almost half (48%) of the older patients ( Table 1). Among younger patients with nonminor strokes (baseline NIHSS > 5) only 61.0% arrived by ambulance compared to 71.4% of older patients (data not shown). In both age groups, the median time elapsing from the onset of symptoms to hos pital arrival (onsettodoor) and the median time elapsing from hospital arrival to undergoing CT (doortoCT) were shorter in patients who arrived by ambulance compared to patients who arrived independently (2.2 h compared to 5.2 h; 1.3 and 2.3 h, respectively) (Figures 3A,B).

stroke Outcome at Discharge
Stroke outcome was more favorable among younger adults (70%), with lower rates of poor outcome (mRS > 3) at discharge (11.7%) and lower rates of in hospital complications (18.2%) compared to older patients ( Table 3). Over the four registry periods, the rates of severe disability or death (mRS > 3) declined among both groups, from 14.3% in 2004 to 5.6% in 2013 (p for trend = 0.05) among younger adults and from 35.5% in 2004 to 20.7% in 2013 (p for trend <0.001) among older patients (Figures 4A,B). No significant decline was found in stroke sever ity distribution during the 9year registry period among young adults (p for trend = 0.18), whereas among older patient, there  was a significant decline in severity NIHSS > 5 during the 9year registry period with p for trend <0.001 (data not shown). Multivariable logistic regression models for poor outcome were fitted separately for each age group ( Table 4). The vari ables adjusted for in these final models were chosen according to univariate models in Table S1 in Supplementary Material. According to multivariable regression models, stroke severity (NIHSS > 5) at admission was positively associated with poor outcome (mRS > 3) in both age groups ( Table 4). In older patients, older age (OR = 1.08, CI 95% 1.01-1.16), female gender (OR = 1.35, CI 95% 1.03-1.76), atrial fibrillation (OR = 1.62, CI 95% 1.16-2.26), and anterior circulation territory (OR = 2.10, CI 95% 1.50-2.94) were also associated with poor outcome. In younger adults, female gender (OR = 2.37, CI 95% 0.89-6.33), posterior circulation territory (OR = 4.25, CI 95% 0.93-19.42), and prior atherosclerosis (OR = 2.89, CI 95% 0.91-9.18) were associated with poor outcome; however, these associations did not reach statistical significance ( Table 4).

DiscUssiOn
In this nationwide study, nearly half of younger adults with firstever 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 firstever ischemic stroke from 15 European stroke centers, the etiology remained undetermined in 40% (7). A reason for our particularly high proportion of unde termined stroke is that subtyping of stroke etiology was based only on information available at hospital discharge. In practice,  the workup 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 propor tion 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 onsetto door and doortoCT times. Provision of timely treatment in acute stroke is critical, especially in the cur rent era of stroke care, with the advancement of reperfusion strat egies 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 present ing 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 9year 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 reper fusion 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 complica tion rate in both age groups during the 9year registry period can be at least partially explained by improved acute stroke care (27). Of the factors investigated in this study, only the sever ity 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 inhospital 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 vali dated 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 diagnos tic 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 healthcare 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 smallvessel 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 modifi able 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 longterm socioeconomic consequences. This calls for increasing awareness to the possibility of stroke among young adults and for better prevention, especially smoking cessation.

eThics sTaTeMenT
The NASIS registry was approved by the ethical committees of all participating hospitals. aUThOr cOnTriBUTiOns ML, IZ, TS, and DT contributed to the design, data interpreta tion, 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 publica tion and approved the final version for publication.

FUnDing
The NASIS Project was supported by the Israeli Center for Disease Control, Israeli Ministry of Health, and by MSD, NovoNordisk, Pfizer, SanofiAventis, Rafa Laboratories, and Teva.