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Abstract

About one-fourth of ischemic strokes occur in working-aged individuals in the high-income countries, with worldwide increasing incidence in this age group from 1980s to present. Recent evidence suggests that traditional vascular risk factors are more prevalent than previously suggested in young adult stroke patients and they accumulate with age particularly in men. Accordingly, relatively high rates of atherosclerotic changes have been detected in these patients. The strength of association of vascular risk factors has gone poorly studied, however. Many young patients with ischemic stroke have, in turn, no traditional risk factors, while they may harbor other conditions with weak or uncertain association with the stroke alone. These individual conditions often represent a risk factor that may be strictly young-age specific, more prevalent in younger than older stroke patients (e.g. patent foramen ovale), or more prevalent among the young in the population. Despite high rates of vascular risk factors and atherosclerotic changes, these findings do not translate to higher frequencies of identified classical stroke mechanisms. In fact, cryptogenic causes are markedly common and even more frequent among the very young patients. Limited randomized trial evidence exists to support secondary prevention decision-making in patients, yet they face an increased risk of death and future vascular events for years to come—dependent on risk factor profile and cause of the stroke. This review provides an overview of recent data on epidemiology, risk factors, and their strength of association in ischemic stroke in the young. Furthermore, the relationship between with the risk factors and cardiovascular outcomes and key features on the evidence related to secondary prevention will be discussed.

Keywords

Stroke in young adults incidence risk factors pathogenesis patent foramen ovale prognosis

Introduction

Ischemic stroke is no longer a disease affecting just elderly people, since one-fourth of ischemic strokes occur in working-aged individuals in the high-income countries, new stroke striking an estimated 3.6 million young people each year. The burden of young stroke may be increasing further, since multiple recent studies have reported increasing incidence of ischemic strokes particularly at younger ages since 1980s, while incidence at older ages has been declining during the same period.^1–5 Globally almost half of the entire stroke burden now affects young individuals given that they have a greater likelihood to survive their strokes with long life spans ahead and because strokes occur at younger ages in low- and middle-income countries.⁶ Moreover, the overall population burden of cerebrovascular disease in the young may be underestimated, since clinically silent infarcts and white-matter changes have been shown to be prevalent even in young stroke patients.^7,8

Approximately 10% of ischemic strokes occur in people aged less than 50 years, which is the age cut off most often used to define “early onset” or “young-onset stroke” or “stroke in young adults.”^9,10 The age cut off is biologically arbitrary but is based on the differing clinical characteristics between younger and older stroke patients, in particular risk factors and etiology.¹¹

Recent evidence suggests that traditional vascular risk factors are highly prevalent in young adult stroke populations with distinct demographic characteristics,^12,13 yet the strength of association of these risk factors has received scarce attention. On the contrary, there are also young patients without traditional risk factors, while these individuals may harbor other conditions with only weak or uncertain association with the stroke alone. These conditions often represent a risk factor that may be strictly young-age specific, more prevalent in younger than older patients, or more prevalent among young people in the population.

Although vascular risk factors among young stroke patients may be more common than previously suggested and relatively high rates of atherosclerotic changes have been detected, these findings do not translate to higher frequencies of identified classical stroke mechanisms.^14,15 In fact, undetermined (or cryptogenic or hidden) causes are exceedingly common and even more frequent the younger the patients, the proportion exceeding 50% in patients younger than 30 years.^16,17

This review first provides an overview of recent epidemiological findings on ischemic stroke in the young. Second, the current knowledge on the prevalence of modifiable traditional vascular as well as unconventional risk factors and their strength of association with early onset stroke will be discussed. The last part of the review will cover the relationship between with the risk factors and cardiovascular outcomes as well as key aspects on the evidence of secondary prevention in this patient population.

Literature search

References for this review were identified through searches of PubMed with the MeSH search terms “Stroke” and (“Young Adult” or “Adult,” or “Middle Aged”). Further search restrictions were done based on the review topics, including terms “Incidence,” “Risk Factors,” (“Etiology” or “Pathogenesis”), “Patent Foramen Ovale,” (PFO) and “Prognosis.” Relevant papers were also identified through searches of author’s files and by review of reference lists of the relevant articles. Congress abstracts were excluded and only full-text articles published in English were considered.

Incidence of ischemic stroke at younger ages

Relatively few studies have assessed the incidence of ischemic stroke in the young, it is important to bear in the mind the varying upper age cut off and population when comparing the rates. From the last three decades the reported rates for individuals aged 15–45 vary from 3.4 to 21.7 per 100,000,^18–23 the highest rate observed for Blacks in the Baltimore–Washington area.²⁰ For those aged 15–49, incidence ranges from 10.8 to 11.4 per 100,000 in people of Northern European origin.^9,24

Incidence remains low among the youngest individuals, ranging from 1.2 to 4.5 per 100,000 in those aged <35 years, but then steeply increases with age, reaching 32.9 per 100,000 among those aged 45–49 years (Figure 1).⁹ Generally in the young incidence for men is higher except for a few studies reporting higher incidence for women.^23,25 There are notable gender differences in the occurrence of early onset stroke, as women outnumber men among those aged <35 years, whereas men outnumber women among those aged above 35 but less than 50 years (Figure 2).¹³ The reasons for these sex discrepancies probably include gender-specific risk factors in reproductively active young women and clustering of traditional risk factors in middle-aged men, as discussed below.

Figure 1.

Occurrence rates of ischemic stroke according to age and sex among individuals aged 15–49 years. Data are from the Helsinki Young Stroke Registry including 1008 consecutive patients with first-ever ischemic stroke.⁹

Figure 2.

Prevalence of traditional vascular risk factors in young adults with ischemic stroke according to sex and age group. Adapted from von Sarnowski et al.¹²

A number of recent epidemiological studies remarkably show that incidence of ischemic stroke at younger ages has been increasing since 1980s to present.^1–5 Some of the studies showed more pronounced incidence increase in women,^1,4 which challenges the current epidemiologic view of male preponderance in ischemic stroke.²⁶

Possible explanations for the increasing incidence include (1) artificial, i.e. improved awareness in the population or improved diagnostic accuracy; (2) growing prevalence of known stroke risk factors, e.g. increasing prevalence physical inactivity, obesity, type 2 diabetes mellitus, increasing use of alcohol and illicit drugs; (3) increasing prevalence of factors related to modern life style with limited scientific evidence and uncertain causality, e.g. 24/7 society syndrome including long work hours, shift work, long-haul flights, information overload, chronic stress, sleep deprivation; or (4) external reasons, such as increasing exposure to particulate matters in the air.

Only scarce systematic data are available thus far regarding the reasons for the increasing incidence of early onset stroke. Kissela and coworkers demonstrated a growing use of MRI in stroke diagnostics from early 1990s to 2005 correlating to improving diagnostic accuracy, but similar change in MRI use was seen across all age groups and with even greater magnitude for those aged ≥65 years.³ National surveys suggest an increase in the population prevalence of obesity, hypercholesterolemia, and diabetes (www.cdc.gov/nchs/nhanes) and in young stroke patients smoking, alcohol drinking, and illicit drug use have been increasing during the same period as the observed increase of incidence.²⁷ Probably some of the increment might be explained by improved diagnostics and disease awareness, but the strong risk factors becoming more prevalent appear among the most robust potential explanations underlying the increasing incidence at younger ages.

Prevalence of traditional modifiable risk factors in young patients

The Stroke in Young Fabry Patients (SIFAP1) study was a prospective European multicenter study, which primary aim was to decipher the prevalence of Fabry disease in unselected 5024 young (age 18–55 years) stroke patients, recruited from 2007 to 2010. While definitive Fabry disease was diagnosed in 0.5% of the entire cohort,¹⁶ the database also provided—for the first time in this scale—systematic information on the prevalence of well-documented vascular risk factors in young stroke patients. The four most frequent risk factors were current smoking (56%), physical inactivity (48%), hypertension (47%), and dyslipidemia (35%). One out of 10 had diabetes mellitus.¹²

Obesity defined as body mass index (BMI) ≥ 30 emerged in 22% of the SIFAP1 study patients, yet if defined with waist circumference (≥94 cm for men, ≥80 cm for women), abdominal obesity was in fact the most prevalent risk factor in the cohort (i.e. 69%).¹² BMI ≥ 30 has been shown to be more prevalent among younger individuals in the population²⁸ and this measure of obesity has recently been associated with young-onset stroke in a case–control study.²⁹ However, the risk effect of BMI ≥ 30 may be mediated through associated conditions such as hypertension and diabetes mellitus since the association was greatly attenuated after adjusting for these factors.²⁹ Compared to BMI, anthropometric measures of abdominal fat including waist circumference, waist-to-hip ratio, and waist-to-stature ratio may, however, more accurately predict stroke risk and independent of other risk factors³⁰ and should be used in future studies addressing stroke risk.

In the SIFAP1 study, most of the modifiable risk factors, including current smoking, hypertension, dyslipidemia, diabetes, and excess alcohol drinking were more prevalent among men, while physical inactivity and high waist circumference were more prevalent in women. In addition, there was a notable clustering of these vascular risk factors with age in both sexes but significantly more pronounced in men (Figure 2).¹² Outstandingly, only 7% of men aged 45–55 and 9% of women of the same age group harbored none of the traditional risk factors in the study. Similar findings of risk factor clustering have been noted in other retrospective studies as well, with no differences in the risk factor profiles across European regions.¹³

Strength of association of early onset vascular risk factors

For stroke in the young, the strength of association of risk factors is probably most solidly proven for smoking. Several studies with participants from multiple ethnicities have shown the association for smoking and early onset ischemic stroke, with odds ratios (OR) ranging from 1.6 to 7.7.^31–37 A cumulative dose effect for smoking has been demonstrated with no significant heterogeneity between etiologic subtypes appeared.³⁷

In contrast to smoking, surprisingly scarce data are available regarding the strength of association of other well-documented risk factors in young adults. For hypertension, ORs have ranged from 1.6 to 8.9 in the few case–control studies including young adults.^31–36,38 Interestingly, in the INTERSTROKE study OR for hypertension was 3.14 for ischemic stroke, but a substantial risk augmentation was observed for those ≤45 years (OR, 8.53), yet this estimate was for all stroke including ischemic and hemorrhagic stroke.³⁹

There is also other—yet limited and indirect—evidence that the association of traditional vascular risk factors may be stronger for younger individuals. For instance, the INTERSTROKE OR for diabetes mellitus was 1.6, but in young adults the few studies have suggested ORs ranging from 3.3 to 11.6, or even as high as 22.9 for white men in the Baltimore–Washington area.^31,32,34,36 There is dearth of data regarding the diabetes subtypes in young adults with stroke, but it is reasonable to suggest that the strength of association would be stronger for type 1 juvenile diabetes mellitus than for type 2 diabetes mellitus.⁴⁰ Notably, a study that followed patients with type 2 diabetes mellitus found that the hazard of any macrovascular complication was twofold but the hazard stroke even 10-fold for those with early onset form of type 2 diabetes compared with patients with usual-onset type 2 diabetes despite similar average time to require insulin in the groups.⁴¹ At least to some extent vascular comorbidities emerging at young age may thus represent earlier and more aggressive forms of the diseases—i.e. “early onset forms of older-onset risk factors,” leading to loss of the relative protection of youth.⁴¹

Physical inactivity is among the most prevalent modifiable risk factors in young stroke patients, but its strength of association has remained nearly unstudied. A study performed on a Thai population aged 18–45 years found that history of no or irregular exercise increased stroke risk by eightfold after adjusting for confounders. This OR was of similar magnitude as for hypertension in that population.³⁸ Physical inactivity is linked to metabolic syndrome and its components and so an Indian study found the presence of three or more components of the metabolic syndrome to be associated with early onset stroke.³²

Regarding cholesterol and its components, an association between low high-density lipoprotein cholesterol and ischemic stroke at young age has been demonstrated,^32,35,38 but no clear association has been shown for total cholesterol, low-density lipoprotein cholesterol, or triglycerides. A recent meta-analysis suggests that the association of lipoprotein(a) and ischemic stroke is stronger for young adults aged <55 years than for older individuals.⁴²

A few studies found rather modest association for a composite variable of heart disease with varying definitions.^33,34,36 Association of early onset atrial fibrillation has not been assessed in young stroke patient populations, although its prevalence might be underestimated.⁴³ Regarding obstructive sleep apnea, one study suggests higher stroke risk for women aged ≤35 years compared to older age groups and relatively higher risk for women compared to men.⁴⁴

The associations of long-term³⁶ and recent heavy drinking^34,45,46 and ischemic stroke have been demonstrated in young adults. The association of heavy drinking may also be stronger for younger adults.^47,48 One study has also shown a protective effect of mild-to-moderate drinking in young women,⁴⁹ which is in accordance with the J-shape association found in nonselected populations.⁴⁸ Binge drinking pattern is more common in young individuals,⁵⁰ a risk factor for both ischemic and hemorrhagic stroke particularly in young adults.^34,51

Are there risk factors specific for young stroke?

While the risk factors discussed in the previous section represent conditions with solid scientific evidence,³⁹ there is a range of unconventional risk factors, of which many may be considered specific to young adults (Table 1). Young-age-specific risk factor may only exist at young age, can exist at all ages but the association appears stronger at younger ages, or the factor can be related to hazardous behavior that is more common at younger ages.

Table 1.

Risk factors for ischemic stroke that may be considered specific to young adults.

Risk factor	Estimated prevalence in patients^c	Strength of association^a	Comment
Pregnancy/puerperium⁵²	7.5% in women	RR 8.7 during puerperium	No significant association found for pregnancy; mixed results
Combined oral contraceptives⁵³	10–40% in women	OR 2.1 for pills with ≥50 µg of estrogen versus nonuse	Mixed results; no significant association for any dose of estrogen or lower than 50 µg dose of estrogen
Migraine^54–56	20–27%	OR 2.3	Stronger association found for women, migraine with aura, smokers, oral contraceptive users, active migraine, and cryptogenic stroke
Patent foramen ovale⁵⁷	24–50%	OR 5.1 for age <55 years	No association found in population-based studies⁵⁸
Antiphospholipid antibodies^b,59,60–65	18–46%	Lupus anticoagulant: OR 2.2–43.1 (women)	Mixed results; studied mostly in women; stronger association for smokers and oral contraceptive users
		Anticardiolipin antibodies: nonsignificant to 1.78, depending on isotype
		Anti-β₂-glycoprotein-I antibodies (cut off 90th percentile of control subjects): OR 2.3 (women)
Genetic thrombophilia^66–70	Prothrombin G20210A mutation: 2–6%	OR 1.5 for prothrombin G20210A mutation in cases aged ≤55 years; stronger association for cases ≤42 years	Often studied in selected populations; heterogeneous and conflicting results between individual studies
	Factor V Leiden G1691A mutation: 3.0–7.5%	Factor V Leiden G1691A mutation: OR 1.4–2.7 depending on patient selection
	Protein C deficiency: 4–21%	Methylenetetrahydrofolate reductase C677T: OR 1.2
	Protein S deficiency: 6–23%	OR not reported for protein C, protein S, and antithrombin III deficiency
	Antithrombin III deficiency: 0.3–8%
Activated intrinsic coagulation proteins⁷¹	≈50% in women	OR for all studied coagulation proteins ≈2.5	Studied in young women (mean age 39 years); increasing risk with oral contraceptive use
Periodontitis⁷²	Unknown	OR 6.1 for >6 mm attachment loss	Significant association only for patients <60 years; stronger association for cryptogenic stroke
Long work hours⁷³	≈9%	RR 1·33 for working ≥55 h/week	RR is for all stroke; dose–response association found
Shift work⁷⁴	Unknown	RR 1.05
Psychological stress⁷⁵	≈29%	OR 3.5	Mean age of the study population was 56 years
Air pollution⁷⁶	NA	OR 1.11 for particulate matter <10 µm	Case-crossover analysis; significant association found for individuals aged <55 years but not for those ≥55 years
Heavy drinking^34,36	12–59%	OR 15.3 for long-term alcohol consumption of ≥60 g/d	The association might be stronger for younger adults^47,48
Illicit drug use^77–79	9–20%	OR 2.3 for cannabis	No independent association for cannabis if adjusted for smoking; no significant association for amphetamine use
		OR 2.0 for cocaine

OR: odds ratio; RR: relative risk.

Pooled estimate of the risk if meta-analysis level of data available.

In the absence of antiphospholipid antibody syndrome or systemic lupus erythematosus.

Variability in the prevalence is primarily due to selection of cohorts and usually higher for cryptogenic cases.

Generally, the evidence base underlying the association of the risk factors presented in Table 1 is much weaker than for the well-documented vascular risk factors; the results have often been inconsistent between studies. Most of the original studies are small case–control studies prone to different sources of bias. Meta-analysis level of evidence is limited and virtually restricted to most extensively studied conditions such as migraine.^54–56 Only very few of these risk factors have shown dose dependency and time dependency, which would be needed to increase the probability of causal link between the risk factor and studied endpoint. It remains largely speculative, how much of young stroke would be attributable to these risk factors.

A notable common feature for the less well-documented risk factors is that most of them are frequent in the background population. Therefore, it is plausible to hypothesize that several concomitant factors may be needed to cause the effect, endpoint stroke. Examples of such situations include antiphospholipid antibodies needing an external trigger or concomitant factor such as infection⁸⁰ or estrogen use.⁵⁹ Also for migraine with aura, additional factors may be needed including smoking and estrogen to aggravate the low independent risk.⁸¹ PFO constitutes another similar condition with uncertain risk alone, as discussed below.

The high burden of risk factors does not translate into large proportion of definitive stroke mechanisms in young adults

The single most frequent cause of young-onset ischemic stroke in high-income countries is arterial dissection.⁸² Dissection together with other generally rare causes considered the typical causes for young-onset stroke explains only about one-fourth or one-fifth of all causes. These rare causes include, e.g. Fabry disease, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke), Moyamoya disease, reversible cerebral vasoconstriction syndrome, systemic or primary central nervous system vasculitis, cardiomyopathies, HANAC syndrome (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps), Sneddon’s syndrome, sickle-cell disease, and specific coagulopathies.⁸³ Full account of the rare conditions is beyond the scope of this review.

Despite the recent studies showing a high prevalence of traditional risk factors in young adults with ischemic stroke, this fact does not translate into high frequency of patients classified as having typical older-onset causes for their stroke.^9,16,17 The SIFAP1 study is the largest cohort to date of young stroke patients aged 18–55 with standardized diagnostic approach and brain MRI in all patients, and 3396 patients with ischemic stroke and 1071 with transient ischemic attack (TIA) enrolled.¹⁶ According to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification,⁸⁴ the frequency of large-artery atherosclerosis in the SIFAP1 cohort was 18.6% and that of small-vessel disease 13.5%, with higher frequencies in men. Most patients with these diagnoses fell in the oldest age group of 45–55 years, while 33.4% of the entire cohort had undetermined cause. Notably, the proportion of cryptogenic strokes was larger among younger age groups. Another study that pooled data from 15 hospital-based registries of ischemic stroke at age of 15–49 (n = 3331) also showed increasing frequency of large-artery atherosclerosis and small-vessel disease with age and higher prevalence of these causes in men.¹⁷ In accordance with SIFAP1 study, the frequency of cryptogenic strokes in that study was substantial and larger among the youngest age groups, being up to 57% among those aged < 30 years if PFOs were included in the count (Figure 3).¹⁷

Figure 3.

Distribution of etiologic subgroups in young adults with ischemic stroke according to TOAST classification in pooled data from 15 hospital-based registries. Data adapted from Yesilot Barlas et al.¹⁷

Regardless of the large proportion of unknown causes, recent findings, however, challenge the traditional view about low prevalence of atherosclerosis in young stroke patients. Another analysis based on the SIFAP1 cohort showed overall prevalence of extracranial stenoses of 8.9% and of intracranial stenoses of 11.8%. Together with nonstenotic plaques, one-fifth of the cohort had symptomatic or asymptomatic atherosclerotic findings.¹⁴

How do the etiologic classification schemes perform in young stroke?

An important issue that may artificially increase the proportion of both young and old cryptogenic strokes is the nature of classification systems. The most widely applied classification, TOAST, was developed for more than two decades age for the purposes of a clinical trial and may be simply too robust and unspecific for young patients. Furthermore, it has an overall rather modest reliability between raters. A recent study on young ischemic stroke patients⁸⁵ utilized a new online classification system developed based on the old TOAST, the Causative Classification for Stroke, which uses certain sophisticated rules to guide the rater and has greater inter- and intra-rater reliability.⁸⁶ Utilizing careful and extensive diagnostic workup, that study⁸⁵ suggested that causal etiology could not be determined in only 11% of patients. However, a large proportion of cardioembolic strokes had only isolated PFO, with no proof of its causality.

The new ASCO (A for atherosclerosis, S for small-vessel disease, C for cardiac source, O for other cause) classification characterizes patient phenotype in a more comprehensive manner, considering relevant underlying diseases and grades of evidence of the causative pathology as follows: grade 1, definitive cause; grade 2, causality uncertain; grade 3, unlikely a direct cause but the disease is present. Nevertheless, attempts to classify young patients with ASCO may lead to even larger proportions of undetermined causes, as exemplified by a study by Larrue and colleagues where 52.7% of their subcohort aged 16–44 years and 39.0% of those aged 45–54 years had no definite cause (grade 1 pathology).⁸⁷ Reclassification of the SIFAP1 patient population led to an even larger proportion of those without definitive grade 1 cause, 70.7%. Absence of grade 1 or 2 pathology was detected in 45.9%, but about 50% of patients in that study had more than one finding with uncertain causality and high prevalence of findings compatible with concomitant atherosclerosis in the large arteries or findings supportive of small-vessel disease.¹⁵

PFO—An example of a simple structure with a complex role in the chain of causality

Much of the uncertainty in classifying the potential cause considers PFO, constituting a significant proportion of undetermined young-onset strokes. PFO can serve as a conduit for paradoxical embolism originating in deep vein thrombosis, but as simple as it appears in case reports, PFO in fact exemplifies the entire complexity of determining the potential pathogenetic mechanism for stroke in the absence of a definite cause. As many other risk factor with uncertain causality, PFO is common (≈25%) in the general population,⁸⁸ which leads to high probability that PFO is just an innocent bystander.⁸⁹ Although case–control studies demonstrate an association for PFO and stroke,⁵⁷ no association appears in strictly population-based studies.⁵⁸ Proving the definite causality in clinical practice remains a challenge as it requires that the venous thrombosis be diagnosed prior to stroke, which is rarely the case. It is therefore reasonable to argue there must be other concomitant factors—persistent or transient, recent or remote—predisposing to paradoxical embolism in individuals with suggested PFO-related stroke. These include transesophageal echocardiography features—such as PFO length and size, presence of atrial septal aneurysm, and right-to-left shunt at rest⁹⁰—as well as precipitants elevating the risk for venous thrombosis (e.g. bed rest, long travel, immobilization, trauma, lower extremity caster), infections, prothrombotic conditions,⁹¹ and recent physical activity, particularly those inducing Valsalva maneuver.

Most studies have applied no criteria for adjudicating PFO as causal or incidental, so the decision has merely relied on the individual physician or investigator. A recently developed Risk of Paradoxical Embolism (RoPE) score may help to identify those PFOs that would be causally relevant. The score, ranging from 0 to 10, is composed of age (0–5 points: 5 points if age 18–29 years, 0 point if age ≥70 years), presence of cortical infarct, and lack of traditional risk factors (one point for each of the following: no hypertension, no diabetes, no history of stroke or TIA, nonsmoker).⁹² It was further evaluated whether the transesophageal echocardiography characteristics were associated with the clinical features assessed with the RoPE score suggesting that PFO would be pathogenic—but no evidence of such association was found.⁹³ Therefore, additional measures for determining the pathogenetic role of PFO are needed and alternative causes to paradoxical embolism, such as vulnerability to atrial arrhythmia⁹⁴ and thrombosis generation in PFO itself should be explored. In addition, venous thrombosis in the pelvic veins or pulmonary embolism might be underestimated sources for embolism as suggested by a few rather small prospective⁹⁵ and retrospective^96,97 studies, albeit some of the results are conflicting,⁹⁸ warranting larger prospective investigations.

The relationship of clustering risk factors and dismal cardiovascular prognosis after stroke in the young

Although it may seem favorable as compared to older stroke patients, recent follow-up studies have challenged the traditional view, which considered the prognosis of young adult stroke generally favorable. A Dutch study showed a fourfold higher mortality for young patients with stroke compared to age- and sex-matched background population, with excess mortality present across all age groups, but particularly for those aged 35–50 years.⁹⁹ In the most recent studies on long-term mortality in young adult stroke, cumulative mortality has ranged from 1.9 to 5.2% at one year, 9 to 11% at five years, 12 to 17% at 10 years, and 27% at 20 years, with the highest annual rate in the first year.^99–105 Importantly, more than half of the deaths in the long term seem to occur due to vascular causes, of which majority are other than strokes.^99,101 Regardless of stroke etiology and demographic factors, increasing number of vascular risk factors has been shown to be an independent marker of elevated risk of death in the long term.^106,107 Of the TOAST categories, large-artery atherosclerosis carries the highest risk for death.¹⁰⁶

Cumulative risk of recurrent stroke in young stroke survivors is nonnegligible, ranging from 9.4% at five years to 19.4% at 20 years in the largest of the recent consecutive series.^108,109 Composite of any vascular event occurred at a rate of 11.5% at five years,¹⁰⁸ 30.4% at 10 years,¹⁰⁰ and 32.8% at 20 years.¹⁰⁹ As for mortality, the risk for recurrent stroke and vascular events is highest during the first year but remains high for years after the index event. Increasing number of vascular risk factors independently predict as well recurrent vascular events in these patients.^106,109,110 Compared with undetermined causes and other determined rare causes, the highest risk for recurrent stroke and vascular events emerge for large-artery atherosclerosis, cardioembolism, and small-vessel disease, yet recurrences occur across all etiologic subgroups.^108,109

Scarcity of evidence is guiding secondary prevention

General guidelines are adopted for the treatment of early onset strokes, despite young patients typically are underrepresented in randomized trials and so the results may not be directly translated to apply all young patients. The virtually only randomized data for secondary prevention that considers specifically younger patients or causes that are common among young patients come from the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS),¹¹¹ the Cervical Artery Dissection in Stroke Study (CADISS),¹¹² and from the recently completed three trials comparing transcatheter closure of PFO with best medical treatment.¹¹³ PICSS was a subcohort to a larger study and showed no difference in the risk of stroke or death in rather young patients (mean age 59 years) between those treated with aspirin or warfarin. There was, however, a nonsignificant trend in favor of warfarin in the subgroup of cryptogenic strokes, yet of similar magnitude in patients with and without PFO.¹¹¹ CADISS study showed a very low rate of recurrent strokes in patients aged 49 years with cervical or vertebral artery dissection and so managed to show no difference between aspirin and anticoagulation.¹¹² Finally, after none of the individual trials comparing transcatheter closure of PFO with best medical treatment showed a treatment effect favoring either one of the treatments, a Cochrane meta-analysis of the three trials concluded that closure might in fact be harmful due to increased risk of atrial fibrillation. However, there might be benefit from the closure using a device with a high rate of success in carefully selected patients, yet further studies are warranted.¹¹³

Conclusions

The impact of early onset stroke is becoming more important in the population due their increasing incidence from 1980s to present, with young stroke causing now almost half of the entire stroke burden globally.

One of the main reasons for the increase in incidence may be that vascular risk factors have become more prevalent in the population. Recent findings are thus challenging the traditional view that classical risk factors would play a minor role in young stroke. As opposite, vascular risk factors are highly prevalent and in parallel with the clustering of vascular risk factors with distinct demographic patterns, mortality and risks of recurrent stroke and other vascular events are increased for years after the index stroke, exceeding the corresponding risks in the background population.

Regarding stroke subtypes, the highest risk of recurrent events appears in subtypes considered typical for older-onset stroke. There may be special features in the vascular risk factors that manifest early in life and associate with early onset stroke endpoint. As an important practical implication, the identified high-risk patient groups should be subjected to more close follow-up and aggressive management of the underlying diseases.

As more knowledge has been accumulating on the traditional risk factors, a very large proportion of young patients still remain without elusive pathophysiology for their stroke. In such situations the evidence base for secondary prevention is very thin and the patients have to live in uncertainty for years. These individuals also face increased risks of death and recurrent vascular events suggesting active underlying pathologies. A number of less well-documented risk factors with generally weak associations and poorly known role in the chain of causality often are present in young patients with ischemic stroke.

There are now strong incentives to initiate large prospective collaborative studies to explore the specific features and pathogenetic roles of both early onset forms of known vascular risk factors and the less-well documented risk factors considered specific to young adults. Furthermore, the utility of novel diagnostic modalities, e.g. for cardiac and vessel-wall imaging should be investigated,¹¹⁴ as well as collect samples particularly for studies of coagulopathies¹¹⁵ and genetics¹¹⁶ in order to establish new risk factors and causal disease mechanisms leading to early onset strokes. All this should eventually lead to developing next-generation phenotyping schemes that better fit young individuals and allow for personalized treatments and better care for young stroke patients.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work received support from the Helsinki and Uusimaa Hospital District.

Informed consent

N/A

Ethical approval

N/A

Guarantor

Contributorship

N/A

References

Rosengren

Giang

Lappas

et al.

Twenty-four-year trends in the incidence of ischemic stroke in Sweden from 1987 to 2010. Stroke 2013; 44: 2388–2393.

George

Tong

Kuklina

et al.

Trends in stroke hospitalizations and associated risk factors among children and young adults, 1995–2008. Ann Neurol 2011; 70: 713–721.

Kissela

Khoury

Alwell

et al.

Age at stroke: temporal trends in stroke incidence in a large, biracial population. Neurology 2012; 79: 1781–1787.

Vangen-Lonne

Wilsgaard

Johnsen

et al.

Time trends in incidence and case fatality of ischemic stroke: the tromso study 1977–2010. Stroke 2015; 46: 1173–1179.

Bejot

Daubail

Jacquin

et al.

Trends in the incidence of ischaemic stroke in young adults between 1985 and 2011: the Dijon Stroke Registry. J Neurol Neurosurg Psychiatry 2014; 85: 509–513.

Krishnamurthi

Moran

Feigin

et al.

Stroke prevalence, mortality and disability-adjusted life years in adults aged 20–64 years in 1990–2013: data from the Global Burden of Disease 2013 study. Neuroepidemiology 2015; 45: 190–202.

Putaala

Kurkinen

Tarvos

et al.

Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke. Neurology 2009; 72: 1823–1829.

Fazekas

Enzinger

Schmidt

et al.

MRI in acute cerebral ischemia of the young: the Stroke in Young Fabry Patients (SIFAP1) Study. Neurology 2013; 81: 1914–1921.

Putaala

Metso

et al.

Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke 2009; 40: 1195–1203.

10.

Maaijwee

Rutten-Jacobs

Schaapsmeerders

et al.

Ischaemic stroke in young adults: risk factors and long-term consequences. Nat Rev Neurol 2014; 10: 315–325.

11.

Fromm

Waje-Andreassen

Thomassen

et al.

Comparison between Ischemic stroke patients <50 years and ≥50 years admitted to a single centre: The Bergen Stroke Study. Stroke Res Treat 2011; 2011: 183256.

12.

von Sarnowski

Putaala

Grittner

et al.

Lifestyle risk factors for ischemic stroke and transient ischemic attack in young adults in the Stroke in Young Fabry Patients study. Stroke 2013; 44: 119–125.

13.

Putaala

Yesilot

Waje-Andreassen

et al.

Demographic and geographic vascular risk factor differences in European young adults with ischemic stroke: the 15 Cities Young Stroke Study. Stroke 2012; 43: 2624–2630.

14.

von Sarnowski

Schminke

Tatlisumak

et al.

Prevalence of stenoses and occlusions of brain-supplying arteries in young stroke patients. Neurology 2013; 80: 1287–1294.

15.

Wolf

Grittner

Bottcher

et al.

Phenotypic ASCO characterisation of young patients with ischemic stroke in the prospective multicentre observational SIFAP1 study. Cerebrovasc Dis 2015; 40: 129–135.

16.

Rolfs

Fazekas

Grittner

et al.

Acute cerebrovascular disease in the young: the Stroke in Young Fabry Patients study. Stroke 2013; 44: 340–349.

17.

Yesilot Barlas

Putaala

Waje-Andreassen

et al.

Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study. Eur J Neurol 2013; 20: 1431–1439.

18.

Nencini

Inzitari

Baruffi

et al.

Incidence of stroke in young adults in Florence, Italy. Stroke 1988; 19: 977–981.

19.

Guidetti

Baratti

Zucco

et al.

Incidence of stroke in young adults in the Reggio Emilia area, northern Italy. Neuroepidemiology 1993; 12: 82–87.

20.

Kittner

McCarter

Sherwin

et al.

Black-white differences in stroke risk among young adults. Stroke 1993; 24: I13–I15.

21.

Kristensen

Malm

Carlberg

et al.

Epidemiology and etiology of ischemic stroke in young adults aged 18 to 44 years in northern Sweden. Stroke 1997; 28: 1702–1709.

22.

Marini

Totaro

De Santis

et al.

Stroke in young adults in the community-based L’Aquila registry: incidence and prognosis. Stroke 2001; 32: 52–56.

23.

Jacobs

Boden-Albala

Lin

et al.

Stroke in the young in the northern Manhattan stroke study. Stroke 2002; 33: 2789–2793.

24.

Naess

Nyland

Thomassen

et al.

Incidence and short-term outcome of cerebral infarction in young adults in western Norway. Stroke 2002; 33: 2105–2108.

25.

Rasura

Spalloni

Ferrari

et al.

A case series of young stroke in Rome. Eur J Neurol 2006; 13: 146–152.

26.

Appelros P, Stegmayr B and Terént A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009; 40: 1082--1090.

27.

de los Rios

Kleindorfer

Khoury

et al.

Trends in substance abuse preceding stroke among young adults: a population-based study. Stroke 2012; 43: 3179–3183.

28.

Andersen

Olsen

. Age- and gender-specific prevalence of cardiovascular risk factors in 40,102 patients with first-ever ischemic stroke: a Nationwide Danish Study. Stroke 2010; 41: 2768–2774.

29.

Mitchell

Cole

McArdle

et al.

Obesity increases risk of ischemic stroke in young adults. Stroke 2015; 46: 1690–1692.

30.

Winter

Rohrmann

Linseisen

et al.

Contribution of obesity and abdominal fat mass to risk of stroke and transient ischemic attacks. Stroke 2008; 39: 3145–3151.

31.

Rohr

Kittner

Feeser

et al.

Traditional risk factors and ischemic stroke in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Arch Neurol 1996; 53: 603–607.

32.

Lipska

Sylaja

Sarma

et al.

Risk factors for acute ischaemic stroke in young adults in South India. J Neurol Neurosurg Psychiatry 2007; 78: 959–963.

33.

Naess

Nyland

Thomassen

et al.

Etiology of and risk factors for cerebral infarction in young adults in western Norway: a population-based case-control study. Eur J Neurol 2004; 11: 25–30.

34.

Haapaniemi

Hillbom

Juvela

. Lifestyle-associated risk factors for acute brain infarction among persons of working age. Stroke 1997; 28: 26–30.

35.

Albucher

Ferrieres

Ruidavets

et al.

Serum lipids in young patients with ischaemic stroke: a case-control study. J Neurol Neurosurg Psychiatry 2000; 69: 29–33.

36.

You

McNeil

O’Malley

et al.

Risk factors for stroke due to cerebral infarction in young adults. Stroke 1997; 28: 1913–1918.

37.

Love

Biller

Jones

et al.

Cigarette smoking. A risk factor for cerebral infarction in young adults. Arch Neurol 1990; 47: 693–698.

38.

Bandasak

Narksawat

Tangkanakul

et al.

Association between hypertension and stroke among young Thai adults in Bangkok, Thailand. Southeast Asian J Trop Med Public Health 2011; 42: 1241–1248.

39.

O’Donnell

Xavier

Liu

et al.

Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010; 376: 112–123.

40.

Janghorbani

Willett

et al.

Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study. Diabetes Care 2007; 30: 1730–1735.

41.

Hillier

Pedula

. Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth. Diabetes Care 2003; 26: 2999–3005.

42.

Nave

Lange

Leonards

et al.

Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis. Atherosclerosis 2015; 242: 496–503.

43.

Prefasi

Martinez-Sanchez

Rodriguez-Sanz

et al.

Atrial fibrillation in young stroke patients: do we underestimate its prevalence?

Eur J Neurol 2013; 20: 1367–1374.

44.

Chang

Chuang

Lin

et al.

High incidence of stroke in young women with sleep apnea syndrome. Sleep Med 2014; 15: 410–414.

45.

Hillbom

Kaste

. Does ethanol intoxication promote brain infarction in young adults? Lancet 1978; 2: 1181–1183.

46.

Hillbom

Numminen

Juvela

. Recent heavy drinking of alcohol and embolic stroke. Stroke 1999; 30: 2307–2312.

47.

Zhang

Qin

Chen

et al.

Alcohol intake and risk of stroke: a dose-response meta-analysis of prospective studies. Int J Cardiol 2014; 174: 669–677.

48.

Reynolds

Lewis

Nolen

et al.

Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003; 289: 579–588.

49.

Malarcher

Giles

Croft

et al.

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women. Stroke 2001; 32: 77–83.

50.

Naimi

Brewer

Mokdad

et al.

Binge drinking among US adults. JAMA 2003; 289: 70–75.

51.

Taylor

Combs-Orme

. Alcohol and strokes in young adults. Am J Psychiatry 1985; 142: 116–118.

52.

Tate

Bushnell

. Pregnancy and stroke risk in women. Womens Health (Lond Engl) 2011; 7: 363–374.

53.

Roach

Helmerhorst

Lijfering

et al.

Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev 2015; 8: CD011054.

54.

Spector

Kahn

Jones

et al.

Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 2010; 123: 612–624.

55.

Etminan

Takkouche

Isorna

et al.

Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005; 330: 63.

56.

Chang

Donaghy

Poulter

. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318: 13–18.

57.

Overell

Bone

Lees

. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55: 1172–1179.

58.

Davis

Gregson

Willeit

et al.

Patent foramen ovale, ischemic stroke and migraine: systematic review and stratified meta-analysis of association studies. Neuroepidemiology 2013; 40: 56–67.

59.

Urbanus

Siegerink

Roest

et al.

Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol 2009; 8: 998–1005.

60.

Brey

Hart

Sherman

et al.

Antiphospholipid antibodies and cerebral ischemia in young people. Neurology 1990; 40: 1190–1196.

61.

Brey

Stallworth

McGlasson

et al.

Antiphospholipid antibodies and stroke in young women. Stroke 2002; 33: 2396–2400.

62.

Nencini

Baruffi

Abbate

et al.

Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischemia. Stroke 1992; 23: 189–193.

63.

Toschi

Motta

Castelli

et al.

High prevalence of antiphosphatidylinositol antibodies in young patients with cerebral ischemia of undetermined cause. Stroke 1998; 29: 1759–1764.

64.

Blohorn

Guegan-Massardier

Triquenot

et al.

Antiphospholipid antibodies in the acute phase of cerebral ischaemia in young adults: a descriptive study of 139 patients. Cerebrovasc Dis 2002; 13: 156–162.

65.

Singh

Gaiha

Shome

et al.

The association of antiphospholipid antibodies with ischaemic stroke and myocardial infarction in young and their correlation: a preliminary study. J Assoc Physicians India 2001; 49: 527–529.

66.

Jiang

Ryan

Hamedani

et al.

Prothrombin G20210A mutation is associated with young-onset stroke: the genetics of early-onset stroke study and meta-analysis. Stroke 2014; 45: 961–967.

67.

Hamedani

Cole

Cheng

et al.

Factor V leiden and ischemic stroke risk: the Genetics of Early Onset Stroke (GEOS) study. J Stroke Cerebrovasc Dis 2013; 22: 419–423.

68.

Hamedani

Cole

Mitchell

et al.

Meta-analysis of factor V Leiden and ischemic stroke in young adults: the importance of case ascertainment. Stroke 2010; 41: 1599–1603.

69.

Soare

Popa

. Deficiencies of proteins C, S and antithrombin and factor V Leiden and the risk of ischemic strokes. J Med Life 2010; 3: 235–238.

70.

Casas

Hingorani

Bautista

et al.

Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 2004; 61: 1652–1661.

71.

Siegerink

Govers-Riemslag

Rosendaal

et al.

Intrinsic coagulation activation and the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis in relation to Oral contraceptives (RATIO) case-control study. Circulation 2010; 122: 1854–1861.

72.

Grau

Becher

Ziegler

et al.

Periodontal disease as a risk factor for ischemic stroke. Stroke 2004; 35: 496–501.

73.

Kivimaki

Jokela

Nyberg

et al.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603,838 individuals. Lancet 2015; 386: 1739–1746.

74.

Vyas

Garg

Iansavichus

et al.

Shift work and vascular events: systematic review and meta-analysis. BMJ 2012; 345: e4800.

75.

Jood

Redfors

Rosengren

et al.

Self-perceived psychological stress and ischemic stroke: a case-control study. BMC Med 2009; 7. . doi: 10.1186/1741-7015-7-53.

76.

Yitshak Sade

Novack

Ifergane

et al.

Air pollution and ischemic stroke among young adults. Stroke 2015; 46: 3348–3353.

77.

Barber

Pridmore

Krishnamurthy

et al.

Cannabis, ischemic stroke, and transient ischemic attack: a case-control study. Stroke 2013; 44: 2327–2329.

78.

Sordo

Indave

Barrio

et al.

Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 2014; 142: 1–13.

79.

Westover

McBride

Haley

. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients. Arch Gen Psychiatry 2007; 64: 495–502.

80.

Mackworth-Young

. Antiphospholipid syndrome: multiple mechanisms. Clin Exp Immunol 2004; 136: 393–401.

81.

Bousser

. Estrogens, migraine, and stroke. Stroke 2004; 35: 2652–2656.

82.

Debette

Leys

. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009; 8: 668–678.

83.

Ferro

Massaro

Mas

. Aetiological diagnosis of ischaemic stroke in young adults. Lancet Neurol 2010; 9: 1085–1096.

84.

Adams

Jr Bendixen

Kappelle

et al.

Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35–41.

85.

Schwamm

Pervez

et al.

Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA Neurol 2013; 70: 51–57.

86.

Benner

Arsava

et al.

A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38: 2979–2984.

87.

Larrue

Berhoune

Massabuau

et al.

Etiologic investigation of ischemic stroke in young adults. Neurology 2011; 76: 1983–1988.

88.

Hagen

Scholz

Edwards

. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59: 17–20.

89.

Alsheikh-Ali

Thaler

Kent

. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40: 2349–2355.

90.

Goel

Tuzcu

Shishehbor

et al.

Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients. Am J Cardiol 2009; 103: 124–129.

91.

Karttunen

Hiltunen

Rasi

et al.

Factor V Leiden and prothrombin gene mutation may predispose to paradoxical embolism in subjects with patent foramen ovale. Blood Coagul Fibrinolysis 2003; 14: 261–268.

92.

Kent

Ruthazer

Weimar

et al.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81: 619–625.

93.

Wessler

Thaler

Ruthazer

et al.

Transesophageal echocardiography in cryptogenic stroke and patent foramen ovale: analysis of putative high-risk features from the risk of paradoxical embolism database. Circ Cardiovasc Imaging 2014; 7: 125–131.

94.

Berthet

Lavergne

Cohen

et al.

Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31: 398–403.

95.

Cramer

Rordorf

Maki

et al.

Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004; 35: 46–50.

96.

Osgood

Budman

Carandang

et al.

Prevalence of pelvic vein pathology in patients with cryptogenic stroke and patent foramen ovale undergoing MRV pelvis. Cerebrovasc Dis 2015; 39: 216–223.

97.

Lapergue

Decroix

Evrard

et al.

Diagnostic yield of venous thrombosis and pulmonary embolism by combined CT venography and pulmonary angiography in patients with cryptogenic stroke and patent foramen ovale. Eur Neurol 2015; 74: 69–72.

98.

Liberman

Daruwalla

Collins

et al.

Diagnostic yield of pelvic magnetic resonance venography in patients with cryptogenic stroke and patent foramen ovale. Stroke 2014; 45: 2324–2329.

99.

Rutten-Jacobs

Arntz

Maaijwee

et al.

Long-term mortality after stroke among adults aged 18 to 50 years. JAMA 2013; 309: 1136–1144.

100.

Spengos

Vemmos

. Risk factors, etiology, and outcome of first-ever ischemic stroke in young adults aged 15 to 45—the Athens Young Stroke Registry. Eur J Neurol 2010; 17: 1358–1364.

101.

Putaala

Curtze

Hiltunen

et al.

Causes of death and predictors of 5-year mortality in young adults after first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke 2009; 40: 2698–2703.

102.

Waje-Andreassen

Naess

Thomassen

et al.

Long-term mortality among young ischemic stroke patients in western Norway. Acta Neurol Scand 2007; 116: 150–156.

103.

Yeh

Lin

et al.

Prognosis of young ischemic stroke in Taiwan: impact of prothrombotic genetic polymorphisms. Thromb Haemost 2004; 92: 583–589.

104.

Varona

Bermejo

Guerra

et al.

Long-term prognosis of ischemic stroke in young adults. Study of 272 cases. J Neurol 2004; 251: 1507–1514.

105.

Leys

Bandu

Henon

et al.

Clinical outcome in 287 consecutive young adults (15 to 45 years) with ischemic stroke. Neurology 2002; 59: 26–33.

106.

Putaala

Haapaniemi

Kaste

et al.

How does number of risk factors affect prognosis in young patients with ischemic stroke?

Stroke 2012; 43: 356–361.

107.

Gjerde

Naess

. Risk factor burden predicts long-term mortality after cerebral infarction. Acta Neurol Scand 2014; 129: 173–177.

108.

Putaala

Haapaniemi

Metso

et al.

Recurrent ischemic events in young adults after first-ever ischemic stroke. Ann Neurol 2010; 68: 661–671.

109.

Rutten-Jacobs

Maaijwee

Arntz

et al.

Long-term risk of recurrent vascular events after young stroke: The FUTURE study. Ann Neurol 2013; 74: 592–601.

110.

Pezzini

Grassi

Lodigiani

et al.

Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults. Circulation 2014; 129: 1668–1676.

111.

Homma

Sacco

Di Tullio

et al.

Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105: 2625–2631.

112.

Markus

Hayter

et al.

CADISS trial investigators. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14: 361–367.

113.

Liu

et al.

Closure versus medical therapy for preventing recurrent stroke in patients with patent foramen ovale and a history of cryptogenic stroke or transient ischemic attack. Cochrane Database Syst Rev 2015; 9: CD009938.

114.

Bang

Ovbiagele

Kim

. Evaluation of cryptogenic stroke with advanced diagnostic techniques. Stroke 2014; 45: 1186–1194.

115.

Maino

Rosendaal

Algra

et al.

Hypercoagulability is a stronger risk factor for ischaemic stroke than for myocardial infarction: a systematic review. PLoS One 2015; 10: e0133523.

116.

Cheng

Cole

Kittner

et al.

Genetics of ischemic stroke in young adults. Circ Cardiovasc Genet 2014; 7: 383–392.

Ischemic stroke in the young: Current perspectives on incidence,risk factors,and cardiovascular prognosis

Abstract

Keywords

Introduction

Literature search

Incidence of ischemic stroke at younger ages

Prevalence of traditional modifiable risk factors in young patients

Strength of association of early onset vascular risk factors

Are there risk factors specific for young stroke?

The high burden of risk factors does not translate into large proportion of definitive stroke mechanisms in young adults

How do the etiologic classification schemes perform in young stroke?

PFO—An example of a simple structure with a complex role in the chain of causality

The relationship of clustering risk factors and dismal cardiovascular prognosis after stroke in the young

Scarcity of evidence is guiding secondary prevention

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

Informed consent

Ethical approval

Guarantor

Contributorship

References