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Ischaemic stroke in young adults: risk factors


and long-term consequences
Noortje A. M. M. Maaijwee, Loes C. A. Rutten-Jacobs, Pauline Schaapsmeerders, Ewoud J. van Dijk
and Frank-Erik de Leeuw
Abstract | Contrary to trends in most other diseases, the average age of ischaemic stroke onset is decreasing,
owing to a rise in the incidence of stroke among ‘young’ individuals (under 50 years of age). This Review
provides a critical overview of the risk factors and aetiology of young ischaemic stroke and addresses its long-
term prognosis, including cardiovascular risk, functional outcome and psychosocial consequences. We highlight
the diminishing role of ‘rare’ risk factors in the pathophysiology of young stroke in light of the rising prevalence
of ‘traditional’ vascular risk factors in younger age groups. Long-term prognosis is of particular interest to
young patients, because of their long life expectancy and major responsibilities during a demanding phase of
life. The prognosis of young stroke is not as favourable as previously thought, with respect either to mortality or
cardiovascular disease or to psychosocial consequences. Therefore, secondary stroke prevention is probably a
life-long endeavour in most young stroke survivors. Due to under-representation of young patients in past trials,
new randomized trials focusing on this age group are needed to confirm the benefits of long-term secondary
preventive medication. The high prevalence of poor functional outcome and psychosocial problems warrants
further study to optimize treatment and rehabilitation for these young patients.
Maaijwee, N. A. M. M. et al. Nat. Rev. Neurol. 10, 315–325 (2014); published online 29 April 2014; corrected online 7 October 2014;
doi:10.1038/nrneurol.2014.72

Introduction
Stroke is a devastating disease that affects 15 million vascular risk factors and aetiology seen in older stroke
patients worldwide each year, resulting in death in about patients. However, the increase in stroke incidence in
one-third of patients and severe disability in two-thirds young adults has been found to be associ­ated with a rising
of the survivors.1,2 Approximately 80% of all strokes are prevalence of some important traditional vascular risk
ischaemic strokes, of which roughly 10% occur in individ- factors, including hypertension, hypercholesterolaemia,
uals under the age of 50 years—so-called ‘young stroke’.3 In diabetes mellitus and obesity, in this age group.10,12 We will
this article, we review the literature on ischae­mic stroke in discuss the role of these risk factors from the perspective
these young patients. Age limits defining young stroke of the increased incidence of young stroke.
differ across studies,3–6 but we chose to define young In addition to the identification of risk factors and
stroke as an ischaemic stroke in adults aged 18–49 years, aetiology, long-term prognosis after stroke is of particu-
as this was the age range generally used in large studies.5,7,8 lar interest from the perspective of young patients, as
For the sake of inclusivity, however, we will also report on they usually have a life expectancy of several decades.
results from some studies that used upper age limits of 45, Following a stroke, these individuals are suddenly
50 or 55 years.4,9 Risk factors and management strategies confronted with uncertainties about their future in a
for young stroke differ across the world, depending on period of life during which they might be preparing for
Department of factors such as genetic differences, environmental influ- decisive career moves or planning a family. Therefore,
Neurology, Radboud ences, and the development and accessibility of health information on long-term prognosis should include not
University Nijmegen
Medical Centre,
services. In this Review, we will focus on the situation in only the risk of vascular and other diseases, but also the
Donders Institute for Western s­ ocieties, unless otherwise specified. expected psychosocial consequences related to life after
Brain, Cognition and In recent years, we have witnessed a remarkable, stroke—a topic reported to be among the top 10 research
Behaviour, Centre for
Neuroscience, unprecedented decrease in the average age of onset ­priorities for patients.13
PO Box 9101, of ischaemic stroke in the overall population, which is In the first part of this Review, we provide a critical
6500 HB, Nijmegen,
Netherlands
mainly attributable to an increased incidence of stroke in overview of the existing literature on risk factors for
(N.A.M.M.M., young adults.10,11 Ischaemic stroke in young adults is often and aetiology of young ischaemic stroke. This section
L.C.A.R.‑J., P.S., thought to be related to ‘rare’ risk factors and aetiologi- will include a methodological discussion on the rare
E.J.v.D., F.‑E.d.L.).
cal features that are very different from the ‘traditional’ risk factors and aetiology that have conventionally been
Correspondence to: regarded as specific for young stroke, followed by a dis-
F.‑E.d.L.
frankerik.deleeuw@ Competing interests cussion of the growing prevalence of traditional vas-
radboudumc.nl The authors declare no competing interests. cular risk factors among younger individuals. We will

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Key points purposes of this Review, we will categorize the aetiol-


ogy according to the Trial of Org 10172 Acute Stroke
■■ Traditional vascular risk factors are more common in young patients with
Treatment (TOAST) classification, with ‘large-artery
stroke—especially those over 35 years of age—than was previously thought;
thus, ‘young’ stroke increasingly resembles ‘old’ stroke atherosclerosis’, ‘small-vessel disease’, ‘cardio­­embolic’,
■■ Long-term secondary prevention after stroke seems as important in young ‘other determined’, and ‘cryptogenic’ as important
adults as in older individuals, although trials are needed to establish which aetiological subgroups.16
patients will benefit from different treatment strategies
■■ Poor functional outcome and psychosocial problems are common among young ‘Rare’ risk factors and aetiologies
patients (under 50 years of age) with stroke In Tables 1 and 2, we summarize data on five rare risk
■■ The long-term prevalence of psychosocial consequences, and their influence on
factors and five rare aetiologies that have been linked
daily life, must be further investigated, so as to optimize specific rehabilitation
programmes for young patients with stroke
chiefly to stroke in young patients. The choice was based
on the relatively high prevalence of these factors and
aetiologies in large, Western young stroke cohorts.5,8
then review the lifelong consequences of stroke in young In other populations, the distribution of conditions in
adults, not only in terms of cardiovascular disease recur- the TOAST category ‘other determined aetiologies’
rence, but also with respect to less frequently studied but differs. For example, in Japan, moyamoya disease will be
equally relevant consequences, including cognitive and diagnosed more frequently in young patients with stroke,
social impairments, mood disorders and fatigue. because the incidence and prevalence of this disease is
much higher there than in other parts of the world, such
Risk factors and aetiology as Europe.17
The view that ischaemic stroke in young adults is dif- Aetiological subgroups, as described in Table 2, vary
ferent from ‘old stroke’ with respect to risk factors and across sex and age categories. Extracranial arterial dissec-
aetiology originated predominantly from the many pub- tions are the most common ‘rare’ aetiological subgroup.
lications—mainly based on case series from tertiary hos- Dissections are found throughout all age categories and
pitals—that reported on the high prevalence of unusual, account for approximately 20% of strokes in patients
rare conditions and risk factors among young patients under 45 years of age, but only for 2% of all ischaemic
with stroke.14 These rare risk factors and aetiologies are strokes. The highest incidence of dissections lies in the
extensively summarized in previous reviews and text- fifth decade; men and women are about equally affected,
books,14,15 and will not be outlined in detail here. The although women are, on average, 5 years younger when
term ‘risk factor’ is used to indicate that a certain factor the dissection manifests.18,19
was found to be associated with stroke in young adults. Inflammatory arteriopathies, such as vasculitis, are
However, the mere identification of a risk factor does not a heterogeneous group, mostly consisting of multi­
imply that the aetiology is fully understood. Sometimes systemic inflammatory disorders affecting arteries of all
the risk factor is somewhere in the ‘causal pathway’ sizes, depending on the disease.20 Some of these condi-
of the disease, and may give rise to a certain aetiology tions virtually never occur in young adults; for example,
that in turn is associated with the disease; for example, giant cell arteritis almost exclusively affects individuals
hypertension is a risk factor, but atherosclerosis might over 50 years of age. However, other conditions, such
be the underlying causal aetiology of the stroke. For the as Takayasu disease, predominate in young females.20

Table 1 | Top five most prevalent ‘rare’ risk factors for stroke in young* Western populations
Risk factor TOAST Prevalence in Strength of association Highest level of
classification‡ young patients evidence||
with stroke§
Migraine99–103¶ Unknown cause 20–24% Pooled effect estimate ~2.0104 A1, association proven for
migraine with aura only
Illicit drug use105–109 Other (rare) 9–20% OR 2.0 for cocaine;105 OR 2.3 for A2 for cocaine; B for
causes cannabis;108# no significant amphetamines, cannabis
association for amphetamines105 and heroin
Patent foramen Possible cardiac 24%, up to 50% in HR ~1.5 (nonsignificant)111 A2, contrasting with
ovale110–113 embolism; stroke, classified evidence from B‑level
low-risk source as cryptogenic studies
Oral Other (rare) 10–40% Summary OR 2.1115 B
contraceptives102,114–119 cause/unknown
Pregnancy/ Other (rare) 7.5% in women Relative risk 8.7 during puerperium, A2, conflicting results
puerperium120–124 cause/unknown not during pregnancy122
*Under 50 years of age. ‡TOAST classification, according to Ay et al. (2005).16 §Sum of all prevalences exceeds 100%, because data were extracted from
different study populations. In addition, conditions are not mutually exclusive in an individual patient. ||Levels of evidence: A1, systematic review, based on at
least two independent A2-level studies; A2, prospective cohort study of sufficient sample size and duration of follow-up, adequately adjusted for confounding
and selective follow-up sufficiently excluded; B, prospective cohort study, not meeting the criteria of A2, or retrospective cohort study, or case–control study;
C, noncomparative study; D, expert opinion. ¶Note that migrainous stroke is very rare;43 however, reports on the role of migraine as a risk factor for stroke are
abundant. #Not significant after correction for tobacco use.

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Table 2 | Top five most prevalent ‘rare’ aetiologies for stroke in young* Western populations
Aetiology TOAST Prevalence in young patients Strength of Highest level of evidence||
classification‡ with stroke§ association
Noninflammatory arteriopathies
Arterial dissection (cervical Other (rare) 10–25% Not reported A2
or intracranial)18,19,125–127 causes
Reversible cerebral Other (rare) 1–5% Not reported B
vasoconstriction causes
syndrome8,32,128,129
Inflammatory arteriopathies
Inflammatory arteritis20¶ Other (rare) 3–5% (all autoimmune Not reported B or C, depending on the
causes vasculitides combined) underlying autoimmune disorder
Cardioembolic
Cardiomyopathy5,8,130 Cardioembolism, 2–3% Not reported A2
high-risk source
Prothrombotic state
Coagulation factors131–137 Other (rare) Antiphospholipid syndrome: 10%# OR 2.2138 A2 for antiphospholipid
cause/unknown Factor V Leiden: 3.0–7.5% OR 1.0131 syndrome, conflicting results;
Antithrombin III deficiency: 5–8% Not reported B for other factors, conflicting
Protein C deficiency: 4–11% Not reported results
Protein S deficiency: 6% (up to Not reported
23% in occasional studies)
Prothrombin mutation: 2–6% Not reported
*Under 50 years of age. TOAST classification, according to Ay et al. (2005). Conditions are not mutually exclusive in an individual patient. ||Levels of
‡ 16 §

evidence: A1, systematic review, based on at least two independent A2-level studies; A2, prospective cohort study of sufficient sample size and duration
of follow-up, adequately adjusted for confounding and selective follow-up sufficiently excluded; B, prospective cohort study, not meeting the criteria of A2, or
retrospective cohort study, or case–control study; C, noncomparative study; D, expert opinion. ¶Including primary vasculitis and vasculitis secondary to collagen
vascular diseases, and other systemic conditions (excluding those secondary to infections). 20 #Up to 46% in selected populations.

Of note, infectious diseases underlie a considerable traditional cardiovascular risk factors and a proven aeti-
proportion of cases of secondary vasculitis. In the devel- ology, such as large-artery atherosclerosis, small-vessel
oped world, hepatitis B and C remain the most common disease or cardioembolic stroke, is much higher.
underlying infections, whereas HIV is a large problem in For most of the risk factors in Table 1, only weak
the developing world.21 associ­ations with respect to young stroke have been
Within the subgroup of cardioembolic stroke, cardio­ reported. Moreover, the extent to which a risk factor
myopathy is one of the most prevalent conditions in is judged to be causal in the origin of a disease might
young patients with ischaemic stroke. 5,8 One would depend on the quality of the study. To increase the likeli­
expect cardiomyopathy to be associated with strokes hood of caus­ality, studies would have to show that the
earlier in life, because this condition often has an early effects of risk factors are, among other criteria, dose-
age of onset. However, one study that stratified young dependent and time-dependent.24 Double-blind ran­
patients with stroke by age category found no significant domized trials or large, prospective cohort studies would
difference in prevalence between patients under 42 years be needed to meet these requirements.
of age and those aged 42 years or older. In this study, Associations for most of the reported risk factors
cardio­myopathy was more than twice as prevalent in were derived from case–control studies or case series,
men than in women (15.5% versus 6.1%).8 which are prone to various forms of bias because they
Antiphospholipid syndrome is an important example are hospital-­b ased and often limited with respect to
of a prothrombotic state that is related to stroke in young sample size. First, information bias—in particular,
adults. This condition has predominantly been studied recall bias—needs to be considered. Remarkable events
in women. An increased risk of ischaemic stroke was in the recent past, such as infections, might be more
found in association with this condition in women under readily remembered by a patient in the aftermath of
50 years of age (OR 43.1, 95% CI 12.2–152.0).22 Although a stroke than by a person who has not experienced a
some studies showed a clearer relationship in younger stroke. Acute respir­atory tract infections have been
women than in older populations, another study showed implicated as trigger factors for stroke, as have chronic
no age differences in a young stroke population.23 infections, such as chronic bronchitis. 25 The poten-
Of note, some of the risk factors mentioned in Table 1, tial role of these infections as trigger factors was sup-
such as illicit drug abuse or the presence of a patent ported by the fact that their association with stroke was
foramen ovale (PFO), are seen as being quite specific time-dependent and dose-dependent. However, the
to young adults, but they can actually occur throughout evidence derives mostly from case–control studies with
the human life span. In older adults, however, the rela- methodological limitations.
tive presence of these risk factors is much lower than in Second, referral bias could be an issue. Young stroke
young adults, as the absolute numbers of patients with cases described in the literature are often selected from

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a Men b Women with stroke, dyslipidaemia in 17–60%, diabetes in 2–10%,


70
smoking in 42–57%, and obesity in 10–20%. 3,5,9,26–29
60 Figure 1 illustrates the increase in prevalence of the trad­
50 itional vascular risk factors with age, indicating a sharp
Prevalence (%)

40
rise in the prevalence of hypertension—and, to a lesser
extent, hypercholesterolaemia—over the age of 35 years.
30
Figure 2 shows that the number of traditional vascular
20 risk factors per patient increases with age: in patients
10 over 35 years of age, only a small fraction of patients have
no vascular risk factors.
0
18–24 25–34 35–44 45–55 18–24 25–34 35–44 45–55
Despite the high prevalence of traditional vascular
Age category (years) Age category (years) risk factors in young adults with stroke, a proven causal
aetiology, such as large-artery atherosclerosis, remains to
Smoking Hypercholesterolaemia Hypertension Diabetes
be identified in a large proportion of cases.32 However,
Figure 1 | Prevalence of traditional vascular risk factors in young patients with improved diagnostics, including high-resolution plaque
stroke according to age and sex. Graphs show the prevalence of various traditional and vessel wall imaging, might increase the likelihood of
vascular risk factors by age category, for a | men and b | women. Data were pooled
diagnosing a causal aetiology, especially among patients
from the 15 Cities study,27 FUTURE study,28 and SIFAP1 study.9
with vascular risk factors, by enabling detection of earlier
stages of atherosclerosis.33
a Men b Women Given the abundance of traditional vascular risk fac­tors,
80
the proven presence of large-artery atherosclerosis might
70 obviate the need for further diagnostic work-up, although
60 the safety of this strategy requires confirmation in diag-
Prevalence (%)

50 nostic studies. In patients without any proven aetiology,


40 ancillary investigations are indicated to further unravel
30 potentially treatable rare risk factors and aetiologies.
20
Cardiovascular prognosis
10
Mortality
0 Prognosis in terms of mortality was usually considered
18–24 25–34 35–44 45–55 18–24 25–34 35–44 45–55
to be favourable in young patients with stroke, given the
Age category (years) Age category (years)
lower short-term mortality rates compared with older
No risk factors One risk factor Two or more risk factors
patients. 34 However, long-term follow-up studies in
Figure 2 | Age-specific proportions of patients with traditional vascular risk factors, young patients found 5 year cumulative mortality ranging
stratified by sex. Graphs shows the prevalence of no, one, or two or more traditional from 9–11%, while the 10 year cumulative risk of death
vascular risk factors in different age categories, for a | men and b | women. ranged from 12–17%.6,29,35–38 In 30 day survivors of a
Traditional vascular risk factors that were considered were diabetes, hypertension, young ischae­mic stroke, 20 year cumulative mortality was
smoking and hypercholesterolaemia. Data are extracted from the SIFAP1 study.9
reported to be 27%, which is four times higher than that
of individuals in the general population matched for age
a population that was referred for a second opinion to a and sex.37 As Figure 3 shows, excess mortality is present
tertiary academic centre. These cases usually rep­resent across all age groups of young patients with stroke, but
a selection of patients in whom no aetiology could be especially in those over 35 years of age, in whom vascular
established on the initial investigations. Subsequent risk factors are also highly prevalent.
additional investigations may have revealed incidental In young adults who died during a 5 year36 or a 20 year 37
or presumed abnormal findings (for example, a PFO) follow-up period after stroke, vascular disease was the
that were not necessarily causal factors. main cause of death. More than half of the deaths resulting
Last, confounding can contribute to bias; for example, from vascular disease were attributable to a vascular cause
in many small studies, traditional risk factors were not other than stroke. These findings suggest that the under-
appropriately adjusted for in the analysis. lying (vascular) disease that caused stroke at a relatively
young age continues to put these patients at an increased
Traditional vascular risk factors long-term risk of vascular disease.
Whereas the role of rare risk factors in the pathophysi-
ology of young stroke seems overestimated, the role of Recurrent vascular events
traditional vascular risk factors may have been under­ In the first few years following a young stroke, patients
estimated.3,5,9,10,26–31 The rising incidence of stroke in are at a substantial risk of stroke recurrence (annual risk
young adults coincides with an increasing prevalence of 1–3%)3,6,28,39–41 and, to a lesser extent, other cardiovascular
traditional vascular risk factors in this age group,5,9,27,32 vascular events (annual risk 0.5–1.0%).28,40,41 In the decades
which is at least supportive of a relationship between that follow, the risk of recurrent events continues to be
the two, although causality remains to be proven. elevated, leading to a cumulative risk of 20% for recurrent
Hypertension is reported in 19–39% of all young patients stroke and 17% for other cardiovascular events.28,29,40

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40 present (Figure 4). Cardioembolic strokes were also


Patients with stroke 18–34 years
Patients with stroke 35–50 years
associated with higher risks of mortality and recurrent
General population 18–34 years vascular events.28,37
General population 35–50 years Racial disparities in cardiovascular prognosis after
30 young stroke have also been observed. In a short-
term follow-up study of young stroke patients aged
Cumulative risk (%)

18–45 years, black individuals had the highest 30 day risk


14 extra deaths
per 1,000 of mortality: 10%, about four times the risk in Asians.45
20
person-years White individuals had an approximately 3.5-fold
increased risk of 30 day mortality compared with Asians.
These differences were independent of the p ­ resence of
10
traditional vascular risk factors.
6 extra deaths These findings indicate that prognosis in terms of
per 1,000 long-term risk of cardiovascular disease after a young
person-years
stroke is not as favourable as previously thought.6,35,44,46
0 Young patients with stroke, especially those who resem-
0 5 10 15 20 ble older stroke patients with respect to the presence of
Follow-up duration (years) traditional vascular risk factors and aetiology, also seem
Figure 3 | Long-term cumulative mortality in young patients with stroke and the to show similarity to older patients in terms of long-term
general population with similar age, sex and calendar-year characteristics. Figure cardiovascular mortality and disease.
shows the excess mortality of young patients with stroke, compared with the Of note, the prognosis for stroke patients in the ‘other
general population, stratified by age <35 years or ≥35 years. Based on data from determined’ category, which includes arterial dissection,
the FUTURE study.37 seemed relatively favourable compared with the other
categories.19,28,42 However, one must keep in mind that
this category includes a mixture of conditions, each with
a Mortality b Recurrent vascular events
80 a different disease course and treatment options and,
70
More than two risk factors thus, variable prognoses.
Two risk factors
60 One risk factor
Secondary prevention
Cumulative risk (%)

No risk factors
50 Young patients with stroke are often under-represented
40 in large secondary prevention trials on antiplatelet
30
drugs, statins and blood pressure lowering agents.43
Nonetheless, it is common practice to treat young stroke
20
patients in accordance with guidelines based on extrapo-
10 lated data from elderly patients with stroke.47 This might
0 be a sensible approach, given that a considerable propor-
0 5 10 15 20 0 5 10 15 20 tion of these young patients have the risk factors that are
Follow-up duration (years) Follow-up duration (years) targeted in these trials, and some of the trials showed
Figure 4 | Risk of death or recurrent vascular events stratified by number of greater benefits in younger individuals (under 65 years)
traditional vascular risk factors. a | Risk of mortality and b | recurrent vascular than in the older ones (65 years or over).48 These conclu-
events, stratified by the number of risk factors present. Risks are adjusted for age sions are, however, mainly based on post hoc analyses, as
and sex. Traditional vascular risk factors that were considered were diabetes,
no studies were specifically designed to investigate sec-
hypertension, smoking and hypercholesterolaemia. Based on data from the
FUTURE study.28,37
ondary prevention strategies in young adults with stroke.
Although no evidence exists that long-term secondary
prevention is particularly harmful in young patients,
Identification of high-risk groups the question of whether these long-term prevention
High-risk groups in terms of recurrent mortality and strategies are truly beneficial in all young adults with
cardiovascular events were identified on the basis of the stroke—for example, in those patients in whom no risk
TOAST classification.16 The atherothrombotic stroke factor or presumed aetiology could be found—remains
category was found to have the highest risk of mor- to be answered. In addition, treatment strategies without
tality and recurrent stroke, compared with the other proven benefit are not particularly cost-effective.
TOAST categories.28,37,42,43 Secondary prevention strategies in some subgroups
Risk factors that were associated with the highest with a specific risk factor or aetiology have been investi­
5 year risk of recurrent stroke predominantly included gated in young adults, for example, those with PFO or
the traditional vascular risk factors, including age over antiphospholipid syndrome. For a PFO, current evi-
40 years, history of transient ischaemic attack, type 1 dia- dence does not show superiority of closure, compared
betes, and the use of antihypertensive medication.41 The with medical treatment, in preventing recurrent strokes
available studies found that the risk of mortality 36,38,44 and in adults under 60 years of age. 49 Two randomized
recurrent vascular events41,28 increased in parallel with controlled trials included post hoc subgroup analyses
the number of traditional cardiovascular risk factors in patients aged 45 years or younger (approximately

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45% of the study cohort), which showed no beneficial in many cases, their role as a caregiver for a young family.
effects of PFO closure in this subgroup.50,51 For patients The studies performed to date have not addressed these
with antiphospho­lipid syndrome, guidelines from the issues. Moreover, one must keep in mind that young
American Heart Association and American Stroke stroke survivors with a poor functional outcome have to
Associ­ation recommend treatment with oral anti­ cope with this consequence for a considerable number of
coagulants, with an international normalized ratio (INR) years, given their generally long life expectancy.
between 2.0 and 3.0.52 However, an expert panel could not
reach consensus and noted that the evidence supporting Epilepsy
higher or lower INR intensities or other ­strategies, such as Poststroke epilepsy is reported to affect 2.4–14.4%
antiplatelet therapy, was uniformly weak.53 of young patients with ischaemic stroke. 29,40,46,58–60
To discover which patients will benefit the most from The highest prevalence was found in a study that included
secondary prevention strategies, we suggest that recruit- patients aged 50 years and under;60 most other studies
ment of patients for future (multicentre) trials should be only included patients up to 45 years of age. The lowest
based on aetiological subgroups rather than age, so that prevalence was found in a study that only included
younger patients are not excluded. crypto­genic stroke.58 Factors that were associated with
epilepsy, either with or without recurrent seizures,
Physical impairments and complications included a more severe stroke and involvement of cortical
The risk factors and aetiology underlying a stroke have a structures.40,60 A study with a decade of follow-up revealed
substantial impact on cardiovascular mortality and mor- a long-term association between poststroke epilepsy and a
bidity. With respect to functional outcome and psycho­ poor functional outcome, as measured with the mRS.56
social consequences, however, the prognosis is more
likely to be determined by a combination of factors, Pain
including not only aetiology, but also stroke severity The prevalence of poststroke pain has frequently been
and subsequent cerebral damage, comorbidity, demands studied in the older stroke population, and estimates
from the patient’s environment, and the patient’s coping vary considerably, from as low as 1% to as high as almost
strategies. The sections that follow provide an overview 50%.61–64 This broad range is probably explained by the
of prognosis in terms of physical problems (functional wide variation in methods used to assess poststroke
outcome, pain and epilepsy) and psychosocial con­ pain. Moreover, poststroke pain originates from multi-
sequences (cognitive impairment, depression, anxiety, ple sources, including central pain from both thalamic
fatigue, sexual dysfunction, and return to work) after a and extrathalamic lesions, and peripheral pain from
young stroke. musculo­skeletal abnormalities, such as joint contrac-
tures.61 No studies have specifically addressed the preva-
Functional outcome lence of pain after stroke in young adults. A recent report
Neurological deficits due to a stroke are often registered suggested a link between poststroke pain and increased
during hospital admission and discharge, as a measure mortality in young patients with stroke.65
of stroke severity on the NIH Stroke Scale. However, as
no studies have described these neurological deficits in Psychosocial consequences
the years after discharge, the frequency of neurological Cognitive impairment
deficit over time is not known. Cognitive performance is an important determinant
Functional outcome is assessed in terms of disability, of social functioning in a young patient with stroke.66
most commonly with the modified Rankin Scale (mRS), 1 year after stroke, up to 60% of young stroke patients
a scale that predominantly assesses motor function. had impaired cognitive performance compared with
Using this scale, functional outcome is usually found stroke-free controls, depending on the cognitive domain
to be better in younger than in older adults after short- tested.67,68 In younger patients in particular, cognitive
term follow-up.54 For young adults, however, information recovery is likely to continue beyond 1 year after stroke.
on long-term physical disability is equally important, However, one study reported that after a mean follow-up
because of their long life expectancy. Only a few studies of 11 years, 50% of young patients with stroke still had
have reported long-term functional outcomes after to cope with impairment or below-average performance
young ischaemic stroke. Proportions of individuals with in at least one cognitive domain.69 Elderly patients with
poor functional outcome (mRS score >2) among young stroke commonly exhibit prominent frontal executive
stroke survivors range from 6–20% after a mean follow- impairment,70 whereas young patients generally show
up duration of 3–12 years,29,46,55,56 compared with 40% deficits in multiple cognitive domains, including visuo-
after short-term follow-up in older stroke survivors.57 construction, delayed verbal memory, attention, and
Independence with regard to basic activities of daily executive function. Most of these deficits are especially
living may not necessarily mean a good outcome for pronounced in patients with left-hemispheric lesions,
young patients: the ability to live independently as with the exception of visuoconstruction, which seems
a young adult also requires independence in perform- to be more impaired after right-hemispheric strokes.69
ing more-complex tasks. In addition, demands from These findings suggest that cognitive impairment in
society on these young patients might be higher than young patients with stroke displays a more global pattern
in the elderly, because of occupational obligations and, than one would expect on the basis of a focal lesion,

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perhaps as a result of diffuse network dysfunction remote Anxiety


from the site of the lesion.69,71 Anxiety is present in 19% of patients with young ischae­
Aphasia has not been specifically tested in long-term mic stroke after 12 years of follow-up,7 but no studies
follow-up studies.69 One study that assessed language dis- exist on its influence on daily life.
turbances in the subacute phase after stroke found that
young patients (under 51 years) were prone to nonfluent Fatigue
aphasia, whereas older patients were more likely to exhibit Poststroke fatigue is present in about 50% of young
fluent aphasia, probably owing to a higher proportion of patients with stroke,80 and seems to be associated with
posterior infarcts in the older age group.72 poor functional outcome80 and inability to regain pre-
Cognitive impairment can have life-changing con­ stroke activities.81,82 However, most of the studies that
sequences for young adults. For example, return to work assessed this complaint were limited with respect to
may be impaired due to memory problems.7 A short- sample size82 or follow-up duration.81,82
term follow-up study found that the number of cognitive Some short-term follow-up studies in older stroke
deficits predicted later inability to return to work.73 This patients found fatigue to be associated with certain
is not a surprising finding, as disturbances in multiple lesion locations. 83,84 In young patients with stroke,
domains might interact, thereby diminishing the ability however, fatigue could be the result of an imbalance
to compensate for impairments. For example, visual field between demands from society and reduced cognitive
defects can lead to reading disorders, and alexia could or physical capacity after stroke. Moreover, factors that
exaggerate this effect.74 underlie fatigue in the short term after stroke may differ
from those in the long term, but these factors remain to
Depression be clarified.
Depressive symptoms are present in 28–46% of young
patients with stroke 6,7,75 after follow-up durations of Sexual dysfunction
6–12 years. Depressive symptoms can have a large One short-term follow-up study on sexual dysfunction,
impact on recovery and daily life after stroke. These focusing on young patients with stroke (aged 18–45 years),
symptoms have been associated with poor functional found diminished sexual function in 22.5% of patients.59
outcomes in an unadjusted analysis, but this association In the general stroke population, sexual dysfunction is
might have been confounded, for example, by recurrent caused by multiple factors, varying from neuro­logical
vascular events.7 deficits (for example, hemisensory neglect85 or aphasia) to
Patients with stroke were also found to have an psychological problems such as depression.86 The relative
increased risk of suicide (up to 7%), or suicidal i­ deation contributions and long-term effects of the various factors
(6–15%) in both the acute and the chronic phase, especi­ in a young stroke population are unknown.
ally when patients had current or past mood ­disorders.76,77 Hypersexuality may also be an issue after a young
Young adults seemed to be at particular risk.77 stroke. One study found this problem in just one of 71
In one study conducted in the general population, young stroke patients, which may have been an under­
younger individuals tended to be classified as having estimation, as the opinion of the patients’ partners was
a ‘non-vascular depression’ profile, which was charac- not investigated.59 Hypersexuality is thought to result from
terized by a higher risk of suicide and more psychotic disinhibition due to lesions in the frontostriatal circuits,
features, whereas older individuals more often displayed and also in the temporal lobe, after ischaemic stroke.87
a ‘vascular depression’ profile, with a higher prevalence
of functional disability and anhedonia. 78 The small Return to work
study sample resulted in large confidence intervals, and Return to work after young stroke is an important
the findings need further confirmation in large stroke determinant of life satisfaction,88,89 and might even be a
cohorts. One might expect that the proportions of vascu- necessity for many people to provide for themselves. In
lar and non-vascular depression profiles would not differ addition to the personal implications for patients, inabil-
markedly between young and older patients in a stroke ity to return to work after stroke imposes an economic
cohort, since both age groups have vascular lesions. burden on society as a whole, owing to loss of productive
However, elderly individuals might still exhibit a greater years of employment.90 However, only a few studies have
propensity towards a vascular depression profile owing addressed this important subject.
to accumulation of vascular damage with age. Reports to date indicate that 50–80% of stroke
Depressive symptoms should not be confused with patients returned to work after a maximum follow up of
emotionalism (that is, emotional expressions outside a 4 years.82,91–94 However, most young patients with stroke
patient’s normal control), which was reported in 22.5% will be of vocational age for more than a decade of their
of the general stroke population the first month post- remaining life, which stresses the need for further studies
stroke.79 Although the two conditions co-occurred in on the very long-term prognosis with respect to return
one patient, and depressed mood was more likely to be to work. In one study with follow-up of almost 12 years,7
present in patients with emotionalism, most patients only 40% of patients had returned to full-time employ-
with emotionalism were found not to be depressed. No ment by the end of the study period. However, these
studies on emotionalism versus depression have been data must be regarded with caution, as the study was
conducted specifically in young patients with stroke. ­retrospective with a relatively low response rate.

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REVIEWS

Screening and treatment of age. This high prevalence coincides with a rising inci-
Cognitive impairment, mood disorders and fatigue seem dence of stroke in young adults, suggesting that tradi-
to be very common in young patients with stroke, and tional vascular risk factors might contribute more to the
functional outcome is poor in a substantial proportion aetiology of young stroke than was previously thought.
of these young adults. If not actively screened for, these The presence of these risk factors, however, is not
consequences often go unnoticed by caregivers, possibly always related to causal aetiologies such as large-artery
leading to frustration in young patients when they are ­atherosclerosis, as assessed with current diagnostic tools.
not able to return to their prestroke activities.95 The first Young patients with stroke are at increased risk of
step in treatment of these ‘invisible’ psychosocial issues, cardiovascular mortality and morbidity compared with
therefore, is their recognition. the general population, sometimes even approach-
The next step is to start treatment for these symp- ing the risks observed in the older stroke population.
toms. The current treatment strategies, which are sub- The patients whose condition is classified as athero­
optimal, consist primarily of occupational therapy 96 or thrombotic stroke, with highly prevalent traditional
medical treatment, for example, with antidepressants.97,98 risk factors, have the highest risk. In these patients, life-
long treatment with secondary prevention seems to be a
Directions for future research plausible approach. However, further trials are needed
Currently, only limited data exist on long-term psycho­ to establish which patients will benefit from different
social consequences and their impact on daily life func- forms of secondary prevention. Recruitment of patients
tioning after stroke in young adults. Future studies for these trials should be based on aetiological subgroups
should focus on the influence of these psychosocial rather than age.
factors on daily life and try to find clinical and demo- Although many ‘young’ stroke patients are ‘old’ with
graphic factors that can predict future psychosocial respect to aetiology and prognosis, they are ‘young’
effects. Large, prospective cohort studies are needed for when psychosocial consequences come into play, as most
this purpose. These predictors might, in turn, provide patients have a life expectancy of decades that includes
insight into the pathophysiological mechanisms that phases of their lives in which important life-changing
underlie these psychosocial consequences, although decisions have to be made. To fulfil these needs, treat-
imaging studies, postmortem studies or animal models ment strategies tailored to the needs of young patients
would provide us with more-fundamental insights. must be developed.
In addition, treatment strategies should be developed, Stroke in young adults is an acute disease, but its
and their effects quantified in clinical trials. Individuals life-long consequences are becoming increasingly rec-
who experience a stroke at a younger age have differ- ognized. Treatment and guidance, accompanied by a life-
ent rehabilitation goals from their older counterparts,95 long perspective, should be offered to each young stroke
and specific programmes need to be developed that are survivor in order to attain the highest possible quality of
adjusted to the specific needs of these young patients. poststroke life.

Conclusions and recommendations


In the past, stroke in individuals under 50 years of age Review criteria
(‘young stroke’) has been viewed as a disease with dif-
The articles for this Review were selected from PubMed. The
ferent risk factors and aetiology—and usually a better most important search term was “stroke” with filters for
prognosis—in comparison with stroke in older patients. the English or Dutch language, full text available, and
After a critical review of the available literature, however, publishing year after 1990. This search term was combined
this view may be challenged. with other search terms, based on the topics covered in
Traditional vascular risk factors in young adults with this Review. Subsequently, we filtered with age limits “young
stroke have been somewhat neglected in the literature, adult: 19–24”, “adult: 19–44 years”, and “middle-aged:
which seems unjustified given their high prevalence,43 45–65 years”. Reference lists of the articles were searched
for other relevant articles on the topic.
especially in young patients between 35 and 50 years

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135. Boekholdt, S. M. & Kramer, M. H. Arterial F.‑E.d.L. received funding from the Dutch Epilepsy provided substantial contributions to discussions of
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Semin. Thromb. Hemost. 33, 588–596 (2007). a Vidi innovational grant from the Dutch Organization manuscript before submission.

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CORRIGENDUM
Ischaemic stroke in young adults: risk factors and long-term
consequences
Noortje A. M. M. Maaijwee, Loes C. A. Rutten-Jacobs,
Pauline Schaapsmeerders, Ewoud J. van Dijk and Frank-Erik de Leeuw
Nat. Rev. Neurol. 10, 315–325 (2014); doi:10.1038/nrneurol.2014.72
In Figure 3 of the originally published article, the x-axis label was incorrect: it should read
‘Follow-up duration (years)’. This error has been corrected in the HTML and PDF versions of
the article.

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