Current Neurology and Neuroscience Reports (2019) 19:91

https://doi.org/10.1007/s11910-019-1004-1

STROKE (H.C. DIENER, SECTION EDITOR)

Stroke in the Young: a Global Update

Mausaminben Y. Hathidara 1 & Vasu Saini 1 & Amer M. Malik 1

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Purpose of Review We aim to evaluate the epidemiology, racial and gender disparity, etiology, and treatment of stroke in the
younger population.
Recent Findings The younger age group without vascular risk factors exhibits an increased prevalence of cardio-embolism in
context of patent foramen ovale/atrial septal aneurysm strokes, from other determined etiology of non-atherosclerotic vasculop-
athy including dissection, inherited or acquired thrombophilia, and other unusual causes of stroke. Ethnic disparities also exist in
certain populations.
Summary The prevalence of stroke in the young is increasing due to several factors. Since stroke is often disabling, this trend
poses an enormous threat to socioeconomic stability especially in developing countries. In young patients with an absence of
conventional vascular risk factors and negative preliminary stroke work-up, clinicians must consider less common causes of
stroke in this population. There is prime opportunity for future investigations as there is currently a lack of evidence-based
management guidelines for these uncommon etiologies based on research completed to date.

Keywords Stroke in young . Ischemic stroke . Hemorrhagic stroke . Cryptogenic stroke . Stroke disparity . Global stroke

Introduction conventional risk factors, such as hypertension and diabetes,

is occurring as well [5]. These additive changes intensify the
Stroke is the second leading cause of death and third leading burden on the global health care systems, affecting economies
cause of disability worldwide [1]. While the age-standardized in both developed and developing nations. We aim to evaluate
mortality has decreased in recent decades, the absolute number the epidemiology, racial and gender disparity, etiology, and
of people suffering stroke-related deaths and disability has in- treatment of young stroke patients.
creased, with the highest burden in low- or middle-income
countries [2]. The trend may be due to a higher global incidence
of strokes occurring in a younger patient population. This spe-
Methods
cific population is responsible for a major impact on economy
due to the loss of productive years due to disability [3].
In our review, data was identified searching Pubmed.gov and
Contributing factors to the increased incidence may include a
from pertinent references of relevant articles published after
shift in modifiable risk factors such as a trend towards sedentary
1980. The search terms “stroke,” “ischemic,” “hemorrhagic,”
lifestyle with reduced physical activity, worse eating habits with
“epidemiology,” “global,” “young,” “incidence,” “diagnosis,”
increased sugar intake, increased salt and processed food intake,
and “treatment” were used. The authors reviewed the literature
and toxic substance use inclusive of but not limited to tobacco,
queried and reviewed papers reporting incidence, etiology,
alcohol, or illegal drugs [4]. An increasing incidence of
management, prognosis, or long-term follow-up of patients with
This article is part of the Topical Collection on Stroke ischemic or hemorrhagic stroke in patients < 50 years old (yo).

* Amer M. Malik
amalik@med.miami.edu
Epidemiology
1
Vascular Neurology Division, Department of Neurology, University
of Miami Miller School of Medicine, 1120 NW 14th Street, Suite The incidence of strokes in a younger population ranges from
1366, Miami, FL 33136, USA 5 to 10% in subjects aged < 45 yo in Western countries and
 91 Page 2 of 8
from 19 to 30% in developing countries [6, 7]. Multiple stud-
ies have shown that the incidence of strokes has increased in
the younger population over the past few decades [7]. Exact
comparison between these studies is difficult due to disparity
in age thresholds when defining “stroke in the young” popu-
lations. Subject populations in various studies ranged in age
from < 45 to < 65 yo. A systematic review of the incidence of
stroke in young adults analyzed 29 studies published between
1980 and 2009, included 3589 patients < 45 yo with crude
rates of first-ever stroke ranging from 5.76 to 39.79 per
100,000 and standardized rates ranging from 6.14 to 48.51
per 100,000 [7]. In addition, the reported proportionate range
of ischemic strokes was 21 to 77.9%, intracerebral hemor-
rhage 3.7 to 38.5%, and subarachnoid hemorrhage 9.6 to
55.4%, respectively [7]. In one recent European study, ische-
mic stroke among young adults was diagnosed in 61% of
cases, intracerebral hemorrhage in 17%, and subarachnoid
hemorrhage in 22%, respectively [8]. According to data from
the Global Burden of Disease 2013, absolute number esti-
mates for the global prevalence of ischemic stroke for age
group of 20–64 yo were 7,258,216 cases (95% UI
6,996,272–7,569,403) and for hemorrhagic stroke was
3,725,085 cases, respectively (95% UI 3,548,098–
3,871,018). The study also highlighted the increase in the
absolute numbers and prevalence rates in both ischemic stroke
and hemorrhagic stroke for younger adults between 1990 and
2013 [3].
The wide range in stroke prevalence and its subtypes ob-
served globally highlights the differences based on geographic
distribution, race and ethnicity, socioeconomic status, and
prevalence of vascular risk factors. In the Global Burden of
Disease study from 1990 to 2010, the age-standardized inci-
dence of stroke significantly decreased by 12% in high-
income countries and, though not statistically significant, in-
creased by 12% in low-income and middle-income countries
[9]. Despite the overall reduced stroke incidence in developed
countries, epidemiological studies in the USA have reported
an increase in strokes among young adults with about 30,000
more stroke hospitalizations in 2013 than in 2003 [5].
Although the trend of increased incidence of stroke may also
be partly due to changes in diagnostic classification systems,
the true effect of improved diagnostic tools such as use of
magnetic resonance imaging (MRI) and better reporting
mechanisms in recent years is uncertain [10] and beyond the
scope of this review article.
There are noted ethnic and racial disparities with a higher
risk of strokes in Black and Hispanic populations compared
with White populations in the USA [11, 12]. This disparity
might be due to the increased prevalence of conventional vas-
cular risk factors such as hypertension in Black populations
and diabetes in Hispanic populations compared with White
populations [13]. It is pertinent to note that a Taiwanese study
highlighted the difference in prevalence of vascular risk
Curr Neurol Neurosci Rep (2019) 19:91
factors in Asian populations with a higher prevalence of hy-
perlipidemia and smoking followed by hypertension [14].
Males are at a higher risk of ischemic stroke compared with
females. Although socioeconomic status and lifestyle might
be confounding factors to account for such differences in
prevalence, the difference itself underscores the importance
of further investigations to determine accurate stroke etiology
to effectively treat patients for better stroke prevention.
Stroke Subtype
Hemorrhagic Stroke
While the greater proportion of subarachnoid hemorrhage as
well as intracerebral hemorrhage is seen in young patients (40
to 55%) compared with the general population (15 to 20%),
hemorrhagic stroke still remains less common than ischemic
stroke [11, 15]. Few studies have examined the cause for in-
tracerebral hemorrhage suggesting different etiologies may be
influenced by ethnicity. One study suggested hypertension is
the most common etiology and accounted for 64% of intrace-
rebral hemorrhage in people younger than 45 yo although
88% of the patients in the study were Black [16]. A
Mexican study identified arteriovenous malformation (AVM)
as the cause of intracerebral hemorrhage in 33% of patients <
40 yo admitted with intracerebral hemorrhage and cavernous
angioma in 16% of patients in the same population [17]. A
recent Chinese study evaluated 401 young patients aged <
45 yo and identified hypertension as the most common etiol-
ogy present in 226 patients (56.4%), followed by 41 (10.2%)
patients with cerebral AVM and 27 (0.25%) with other etiol-
ogies such as moyamoya disease, cerebral venous thrombosis,
drug abuse, hemorrhagic tumor, or autoimmune causes [18].
While the risk of cerebrovascular malformation–related hem-
orrhages was higher in the younger age group of 20–29 yo, the
risk of hypertensive-related hemorrhages increased with age
despite the same underlying risk factors such as smoking or
alcohol [18].
Ischemic Stroke
Ischemic strokes in the young population are 10 to 15% of
total ischemic strokes [8]. Etiology of cerebral infarction is
more heterogenous for the younger population. Multiple
retrospective and prospective studies have investigated
stroke etiology in the young, although the differences that
exist in the methodology and patient selection criteria for
each study makes it difficult to fully categorize them. We
summarize here etiology classification by Trial of Org
10172 in Acute Stroke Treatment (TOAST) criteria used
in some of the larger international stroke studies focused
on stroke in the young [19] (Table 1).
Curr Neurol Neurosci Rep (2019) 19:91
In general, younger age group < 45 yo without vascular
risk factors had a higher risk of cardio-embolism in the pres-
ence of patent foramen ovale (PFO)/atrial septal aneurysm
(ASA) strokes, from other determined etiology of non-
atherosclerotic vasculopathy including dissection, inherited
or acquired thrombophilia, and other unusual causes of stroke.
With increasing age, there is an increased prevalence of con-
ventional vascular risk factors as well as atherosclerosis as the
etiology for ischemic stroke. Some specific ethnicities such as
young Black [13], Taiwanese [14], and Chinese [23•] have a
high prevalence of adverse vascular risk factors even at a
younger age, explaining the greater distribution of atheroscle-
rosis or small vessel disease as ischemic stroke etiology.
Once conventional vascular risk factors are identified in the
young, the management of those patients for secondary stroke
prevention is the same as that of elderly population. However,
for patients with a negative initial standard stroke work-up
(transthoracic echo, ambulatory cardiac monitoring, cerebro-
vascular imaging and labs to identify hyperlipidemia or dia-
betes), a thorough history and expansion of investigations to
include some less common etiologies for young patients is
required. We review here some of those etiologies and current
management approaches based on evidence for secondary
stroke prevention.
Cervical Artery Dissection
Cervical artery dissection accounts for up to 2% of all ische-
mic strokes and is a more common cause of stroke in young
patients and accounts for 10 to 25% of strokes [25]. Internal
carotid artery dissection is slightly more common than verte-
bral artery dissection. Dissection causes a tear of the intimal
vessel wall which produces turbulent blood flow and throm-
bus formation which can embolize and cause ischemic stroke.
In addition to trauma, other genetic causes of arterial dissec-
tion include underlying connective tissue disorder such as
E h l e r- D a n l o s s y n d r o m e , M a r f a n s y n d r o m e , a n d
fibromuscular dysplasia could be predisposing factors.
Migraine, prothrombotic state from hyperhomocysteinemia
and oral contraceptive pill use, alpha-1 anti-trypsin deficiency,
and neck manipulation have also been associated with a
higher risk of dissection [26]. For management of dissection,
the CADISS trial concluded non-inferiority of anti-platelets
over anti-coagulation for secondary stroke prevention for
these patients [27••]; however, the methodology and analysis
have some shortcomings. First, it should be noted that the
majority of patients had spontaneous dissection and thereby
have an already lower risk of recurrence. Second, the recruit-
ment period was up to 7 days and because of that time frame,
early dissection recurrence might already be missed. Third,
20% of the patients did not have dissection confirmed on
central radiographic images which required peer review.
Fourth, patients with the presence of thrombus formation at
Page 3 of 8 91
the site of dissection might be at a higher risk for stroke, but
this fact was not taken into account in deciding treatment [28].
More randomized controlled trials with better power and bet-
ter patient selection criteria are needed to definitively answer
these questions.
PFO and Cryptogenic Stroke
Cryptogenic stroke patients have a higher prevalence of PFO
up to 35 to 40% as seen in multiple studies. Whether this is an
incidental finding or causative for stroke risk is a point of
controversy [29]. PFO-related ischemic stroke can be ex-
plained by three major mechanisms: (i) paradoxical embolism,
(ii) in situ thrombosis at PFO, (iii) arrhythmia related to PFO
[30]. A meta-analysis is suggestive that PFO with certain mor-
phologic features such as a large PFO with greater right-to-left
shunting or the presence of ASA in a younger patient popula-
tion is associated with cryptogenic stroke [29]. To measure
PFO as a causative etiology for ischemic stroke and guide
further management, the ROPE score can be a useful tool
[31]. Younger age, absence of conventional risk factors, and
embolic appearance of stroke on imaging point towards a
higher ROPE score which is associated with a higher recur-
rence of stroke due to PFO.
The management approach for PFO-related ischemic
stroke has been controversial for decades. Underlying
hypercoagulability-related venous thromboembolism and in
situ thrombosis formation in PFO might be the main underly-
ing mechanism for stroke while the PFO simply serves as a
conduit for paradoxical emboli. Therapeutic anti-coagulation
to prevent thromboembolism as opposed to mechanical clo-
sure of PFO for secondary stroke prevention has been debated.
Until a few years ago, trials like CLOSURE, PC Trial, and
RESPECT had shown no significant improvement in second-
ary stroke prevention with mechanical PFO closure compared
with anti-platelet treatment [32–35]. The latest AHA guide-
lines from 2014 for secondary stroke prevention for patients
with cryptogenic stroke and PFO recommend to be treated
with anti-coagulation if there is presence of deep vein throm-
bosis (DVT). In the absence of DVT, if patients are not anti-
coagulated, then, anti-platelet is recommended and PFO clo-
sure was not recommended from the available data at that time
[36]. However, in the past few years, three major trials
(CLOSE, REDUCE, and long-term outcomes from
RESPECT) concluded that patients with PFO closure experi-
enced a lower risk of recurrent stroke compared with those
with anti-platelet therapy [37••, 38••, 39••]. Better inclusion
criteria with a higher ROPE score, exclusion of patients with
conventional risk factors, and longer follow-up could be the
reason for the positive findings compared with previous trials.
Notably, the CLOSE trial had as a prerequisite inclusion cri-
terion the presence of ASA or greater right-to-left shunting.
RESPECT follow-up study and REDUCE also had a higher
 91

Table 1 Recent studies investigating ischemic stroke in the young, summarized by TOAST criteria

Study Cohort characteristics Cardio-embolism Large vessel Small vessel Other determined etiology Unknown etiology Multiple
disease disease etiologies
Page 4 of 8

atherosclerosis

Baltimore-Washington Young N = 428 15% 2% 10% 5.6% non-atherosclerotic 31% 19%

Stroke Group, 1997 15–44 yo vasculopathy (vasculitis,
(USA; prospective) [20] 51.4% female dissection)
60% Black 9% hematologic
36% White 5% illicit drug use
Population studied 1988–1991 3% oral contraception

NOMAS, 2002 N = 74 6% 15% (intra + extracranial) 18% 6% 55% n/a

(USA; prospective) [11] 20–45 yo
47% female 80% Hispanic
Population studied 1993–1997

Cardoso et al. 2003 N = 581 11.4% 28.6% 14.3% 11.4% (dissection and 25.7% (8.6% due to early death) n/a
(Portugal; retrospective) [21] 18–45 yo fibromuscular dysplasia)
48.6% female
Population studied 1998–1999

Helsinki Young Stroke, 2009 N = 1008 20% 8% 14% 15% 33% n/a
(Finland; retrospective) [22] 15–49 yo (dissection)
37.7% female
Population studied 1994–2007

Swiss Young Stroke Study, 2016 N = 284 16% 7% 7% 20% 15% (negative evaluation) 19%
(Switzerland; prospective) [4] 16–45yo 16% (insufficient evaluation)
40% female (total out of 624)
Population studied 1988–1991

Swiss Young Stroke Study, 2016 N = 340 13% 20% 20% 10% 13% (negative evaluation) 11%
(Switzerland; prospective) [4] 46–55 yo 13% (insufficient evaluation)
40% female (total out of 624)
Population studied 1988–1991

Li et al. 2017 (Northern China; N = 1395 6.5% 42.7% 16.1% 6% 14.6% 11% (multiple
Curr Neurol Neurosci Rep

retrospective) [23] 18–45 yo causes)

20.9% female 2.9% (missing)
Population studied 2008–2014

Montanaro et al. 2017 N = 134 15.7% 4.5% (supra-aortic) 0.7% 29.9% 49.3% n/a
(Brazil; retrospective) [24] 18–45 yo
56% female
(2019) 19:91

Population studied 2008–2012

Curr Neurol Neurosci Rep (2019) 19:91
prevalence of ASA patients. Despite having an anti-
coagulation arm in the CLOSE trial, no comparison was made
between PFO closure and anti-coagulation; therefore, the orig-
inal question of whether therapeutic anti-coagulation is supe-
rior to mechanical closure could not be answered with these
studies since they only compared anti-platelet to PFO closure.
Inherited and Acquired Thrombophilia
Inherited and acquired thrombophilia might explain a propor-
tion of cryptogenic strokes in the young patient population. A
list of the more common conditions includes the following:
anti-thrombin III deficiency, prothrombin gene mutation, fac-
tor V Leiden mutation, protein C and S deficiency, anti-
phospholipid antibody syndrome, methylenetetrahydrofolate
reductase (MTHFR) mutation, hyperhomocysteinemia. It is
controversial whether certain thrombophilia conditions such
as MTHFR heterozygous mutation, isolated hyperhomocys-
teinemia, and factor V Leiden heterozygous mutation are be-
nign variant or indeed pathogenic.
There are multiple small retrospective studies that analyzed
the prevalence of an individual risk factor, such as prothrom-
bin gene G20210A, factor V Leiden mutation, protein C de-
ficiency, and its positive association with stroke [40–42].
Conversely, there are other studies which did not show asso-
ciation between stroke and thrombophilia. A recently com-
pleted retrospective trial from the Cornell Acute Stroke
Registry identified that 40% of the patients with cryptogenic
stroke had at least one thrombophilia condition that was pos-
itive on the hypercoagulable screening panel which included
the aforementioned listed conditions; however, only approxi-
mately 8% of patients had a resulting change in clinical man-
agement and that was mostly in the scenario of positive anti-
phospholipid antibody testing [43]. However, there are many
limitations such as the low power of the study and the single-
center experience, as results cannot be generalized and the
choice of treatment anti-coagulation versus PFO closure ver-
sus anti-platelet therapy was at physician discretion.
Moreover, these patients were not followed in the long term
to better provide insight into recurrent stroke risk for positive
thrombophilia conditions.
Therefore, larger multicenter studies are needed to over-
come these deficiencies and draw definitive conclusion for
appropriate screening work-up and appropriate treatment.
However, there is a suggestion that it is reasonable to screen
for thrombophilia in younger patients with a positive family
history of stroke at a young age or with a history of deep
venous thrombosis, spontaneous miscarriages, or autoimmune
conditions. Since hypercoagulability is a “two hits” phenom-
enon and known to be provoked by dehydration and inflam-
mation [44, 45], at a minimum caution against prolonged im-
mobility should be advised.
Page 5 of 8 91
Genetic Causes
Some of the rare conditions associated with stroke include
CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarct and leukoencephalopathy), CARASIL (ce-
rebral autosomal recessive arteriopathy with subcortical in-
farct and leukoencephalopathy), Fabry’s disease, Marfan syn-
drome, MELAS (mitochondrial encephalopathy, lactic acido-
sis, and stroke-like episodes), sickle cell disease, and vascular
Ehlers-Danlos syndrome. Although these conditions are rare,
key clinical and radiographic features help recognize them as
a potential stroke etiology. Due to a dearth of epidemiological
data, the true incidence is unknown; however, a high index of
suspicion and good clinical history is very important to recog-
nize some of these rare conditions. Continued research ad-
vancements might reward us with distinct treatment ap-
proaches and better diagnostic tools.
Inflammatory and Non-inflammatory Vasculopathy
Infectious vasculitis associated with human immunodeficien-
cy virus (HIV), varicella zoster virus (VZV), syphilis, and
inflammatory vasculopathy such as Cogan syndrome, Susac
syndrome, Sneddon syndrome, or Eales disease are included
in this category. Isolated primary central nervous system
(CNS) vasculitis and other vasculopathies such as moyamoya
syndrome or disease and reversible cerebral vasoconstriction
syndrome (RCVS) also are included in this disease category.
Infections have been well described in the pathogenesis of
stroke from local inflammation of cerebral parenchyma and
meninges or through systemic inflammation by promoting
coagulation and endothelial dysfunction. In some cases, direct
invasion of the pathogen into the arterial wall can cause pro-
liferation of smooth muscles and release of cytokines and
thereby cause ischemic stroke. It is very important to keep a
high index of suspicion for the various vasculopathies when
evaluating younger stroke patients. Cerebrospinal fluid (CSF)
analysis and angiographic images are usually necessary to
identify these uncommon causes of stroke [46].
Non-infectious and inflammatory vasculopathy should be
suspected when a younger patient exhibits an unusual stroke
location and/or pattern. Primary CNS vasculitis patients have
a progressive course of symptoms that typically involve
stroke, encephalopathy, and seizures. Susac syndrome in-
volves small arterioles of the cochlea, retina, and cerebrum
causing encephalopathy, hearing loss, and vision loss, respec-
tively. Infarcts involving the corpus callosum are frequent in
Susac syndrome. Sneddon syndrome causes a lacy reticular
rash, seizures, renal involvement, and cognitive impairment in
addition to ischemic stroke. Comprehensive diagnostic ap-
proach with CSF analysis, autoimmune work-up, and at times
brain biopsy might be necessary to accurately diagnose these
conditions before starting immunosuppressive treatment.
 91 Page 6 of 8
Illicit Drug Use
Approximately 4.8% of the world’s population aged 15–64 yo
uses illicit drugs annually and 25 million are classified as
chronic users and the problem is even worse in the age sub-
group of 18 yo [47]. Cocaine and methamphetamine pose the
biggest threat among illicit drugs for cerebrovascular compli-
cations. Multiple theories have been described for the patho-
genesis of cocaine-related ischemic stroke including cerebral
vasospasm, arrhythmia, increased platelet activation, and vas-
culitis. Opioids, psychotomimetic drugs, and cannabis are less
implicated but also associated with ischemic and hemorrhagic
stroke. With increasing urbanization and drug trafficking,
drug abuse may continue to contribute to the increased inci-
dence of stroke in the young.
Malignancy
There is an increasingly recognized risk of ischemic strokes in
patients with malignancy. A recently published large multi-
center cancer survival study for patients between 15 and
39 yo (N = 178,962 patients) found that there is a 40% higher
than expected incidence of ischemic stroke. Survivors of CNS
tumors, head and neck tumors, and leukemia were at highest
risk [48•]. The link between malignancy and ischemic stroke
could be due to secondary hypercoagulable state, direct inva-
sion of tumor, radiation vasculopathy, or toxic chemotherapy
effect. Despite the increased prevalence of ischemic strokes in
these populations, there are currently no well-established
guidelines for malignancy screening or choice of anti-
thrombotic agent for secondary stroke prevention.
Conclusion
The prevalence of stroke in the young is increasing due to
several factors including a trend of increasing conventional
vascular risk factors at an earlier age and an increased preva-
lence of modifiable lifestyle risk factors such as reduced ex-
ercise or polysubstance abuse. Since stroke is often disabling,
this trend poses an enormous threat to socioeconomic stability
especially in developing countries. In young patients with an
absence of conventional vascular risk factors and negative
preliminary stroke work-up, clinicians must keep a low
threshold of suspicion for some of the less common causes
of stroke in this population such as arterial dissection, inflam-
matory and non-inflammatory arteriopathy, hypercoagulable
state, high-risk PFO, and genetic causes. Despite improve-
ment in diagnostic yield, one challenge that remains is that
there is a lack of evidence-based management guidelines for
these uncommon etiologies based on research that has been
completed to date. Recent advancements in identification of
and therapeutics for genetic disorders provide hope for
Curr Neurol Neurosci Rep (2019) 19:91
improved management strategies in the near future. Despite
these advances, greater awareness of healthy lifestyle habits
and importance of primary prevention should not be
underestimated to address the increased prevalence of conven-
tional vascular risk factors in young patients.
Compliance with Ethical Standards
Conflict of Interest Mausaminben Y. Hathidara, Vasu Saini, and Amer
M. Malik each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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