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Review

Aetiological diagnosis of ischaemic stroke in young adults


Jos M Ferro, Ayrton R Massaro, Jean-Louis Mas

Despite improvements in diagnosis and treatment, ischaemic stroke in young adults remains a catastrophic event
from the patients perspective. Stroke can cause death, disability, and hamper quality of life. For the neurologist
treating a young adult with suspected ischaemic stroke, the diagnostic challenge is to identify its cause.
Contemporary neuroimaging of the brain and its vessels, and a comprehensive cardiac assessment, will enable
identication of the most frequent causes of stroke in this age group: cardioembolism and arterial dissection.
Specic diagnostic tests for the many other rare causes of ischaemic stroke in young adults (angiography, CSF
examination, screening for vasculitis and thrombophilia, genetic testing, and ophthalmological examination)
should be guided by suspected clinical ndings or by the high prevalence of diseases associated with stroke in
some countries.

Introduction

Incidence, prevalence, and demographics

The incidence of stroke rises exponentially with age and


is therefore low in young adults.1 Nevertheless, ischaemic
stroke in young adults is a common cause of admission
to stroke units and referral to neurology departments or
tertiary hospitals.2,3 Traditional risk factors for stroke such
as hypertension and diabetes are not very frequent in
young adults;2,3 however, some other permanent or
transient risk factors such as smoking, use of oral
contraceptives, migraine, trauma, use of illicit drugs, and
pregnancy or puerperium have a more important role in
this age group than in older adults. The main clinical
challenge in management of a young adult with acute
stroke is the identication of its cause. Although large
extracranial and intracranial atheroma, small-vessel
disease, and atrial brillation4,5 have a major role in cases
of stroke in older adults, these disorders are much less
frequent in young adults. Our ability to establish a
denite cause for stroke in young people has improved
in the past decades because of advances in the noninvasive imaging of the brain vessels, heart cavities, and
valves, and cardiac electrophysiology and genetic
diagnostic instruments.
In this Review, we focus on the aetiological diagnosis
of stroke in young adults with particular emphasis on
the best approaches to conrm or exclude the most
common causes of stroke in these patients, and we
describe the clinical features and diagnostic
considerations of several associated disorders and
diseases, with the aim of facilitating practising
neurologists, emergency physicians, and internists in
reaching an aetiological diagnosis of stroke in young
adults. We also describe the most relevant aspects and
advances in the descriptive and analytical (risk factors
and associated disorders) epidemiology of ischaemic
stroke in young adults. Young adults are variously
dened in published studies as aged less than 40, 45, 50,
or 55 years; here, to be inclusive, we use the upper age
limit of 55 years. Apart from a consensus proposal on
the aetiological investigation of cerebral infarction in
young adults from the Societ Franaise Neurovasculaire,6
no specic guidelines exist for the management of stroke
specically in this age group.

In a hospital-based study in Finland,2 the yearly incidence


of stroke increased from 24 per 100 000 for people aged
2024 years, to 45 per 100 000 for people aged 3034 years,
and to 329 per 100 000 for people aged 4549 years. Stroke
is slightly more frequent in women aged 2030 years and
in men older than 35 years. The proportion of strokes of
undetermined or rare causes is much higher for young
adults than for older patients.5 In young adults the
aetiological subgroups also vary with age: the proportion
of strokes of undetermined cause decreases with age,
whereas the proportion of strokes caused by large artery
atherosclerosis and small-vessel disease increases after
the age of 3540 years.2,7 In the Helsinki Young Stroke
Registry2 (1008 patients aged <50 years), cardioembolism
(20%) and cervicocerebral artery dissection (15%) were the
most frequent aetiological subgroups.
Causal data for stroke in young adults come mainly
from registries of reference hospitals in developed
countries and are therefore prone to ascertainment and
referral biases. The incidence of stroke in young adults in
developing countries is higher than in developed
countries because of the higher incidence of strokes
related to infections, rheumatic heart disease, and
undetected or uncontrolled vascular risk factors.811

www.thelancet.com/neurology Vol 9 November 2010

Lancet Neurol 2010; 9: 108596


Department of Neurosciences,
Hospital de Santa Maria,
Faculdade de Medicina de
Lisboa, Lisbon, Portugal
(Prof J M Ferro MD);
Department of Neurology,
University of Kentucky,
Lexington, USA
(A R Massaro MD); and Service
de Neurologie, Unit
Neuro-Vasculaire, Hpital
Sainte-Anne, Universit Paris
Descartes, INSERM UMR 894,
Paris, France (Prof J-L Mas MD)
Correspondence to:
Prof Jos M Ferro, Department
of Neurosciences, Hospital de
Santa Maria, 1649-035 Lisbon,
Portugal
jmferro@fm.ul.pt

Risk factors for ischaemic stroke in young adults


Understanding of risk factors for ischaemic stroke in
young adults is based mainly on hospital-based casecontrol studies and less often on population-based
case-control and cohort studies. However, case-control
studies are prone to bias and usually overestimate the
risk. The proportion of young adult patients with stroke
who have classic risk factors increases with age.2,3,7 In
dierent series, a variable proportion of women (7%2 and
45%3) were on oral contraceptives. Alcohol misuse is also
an independent risk factor for ischaemic stroke in young
and middle-aged adults.12

Smoking
Cigarette smoking is an important risk factor for cerebral
infarction in young adults.13 This nding has been
replicated in a population-based case-control study (odds
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ratio [OR] 26 [95% CI 1936]).14 The risk increased with


the duration13 and dose13,14 of the exposure, from an OR of
22 (1533) for one to ten cigarettes per day up to 91
(32260) for 40 or more cigarettes per day. The large
proportion of smokers among young adults with stroke in
countries with a high prevalence of smokers,15 particularly
in some developing countries, is of concern.16,17

Migraine
Findings from a meta-analysis18 showed that the risk of
ischaemic stroke in people who had migraine with aura
was doubled compared with people without migraine. An
age of less than 45 years, smoking, and oral contraceptive
use further raised the risk. However, migraine without
aura did not seem to aect the risk. The mechanism by
which migraine with aura increases the risk of ischaemic
stroke is unknown. Migrainous infarcts caused by severe
hypoperfusion during an attack are rare and probably
overdiagnosed. They mostly aect the posterior cerebral
artery territory, but single and multiple infarcts of any
size and location have been reported. The incidence of
migrainous stroke is too low to explain the increased risk
of stroke in people with migraine. Other potential
mechanisms include association of migraine with known
or unknown causes or risk factors for stroke (eg, patent
foramen ovale, dissection). Infarcts induced by drugs (eg,
ergotamine) might also be a contributing factor. Several
disorders such as mitochondrial encephalopathy with
lactic acidosis and stroke-like episodes (MELAS), cerebral
autosomal dominant arteriopathy with subcortical
ischaemic strokes and leucoencephalopathy (CADASIL),
or essential thrombocythaemia can cause stroke and are
also associated with migraine. Finally, focal cerebral

ischaemia can induce attacks of migraine with aura.19


Cerebral infarcts in patients with migraine should be
investigated in the same way as any cerebral infarcts in
young people.

Pregnancy and puerperium


Although the risk of ischaemic stroke for pregnant women
rises in the days before the birth and the 6 weeks post
partum, pregnancy-related stroke is rare.20,21 Nevertheless,
most causes of ischaemic stroke in young adults have
been reported during pregnancy and the puerperium.2022
Although some disorders can be triggered by pregnancy
(eg, peripartum cardiomyopathy), whether pregnancy is
coincidental or plays a part in the occurrence of stroke is
unknown. In many patients, the cause of the stroke cannot
be identied. Whether a hypercoagulable state and
changes in vessel walls associated with pregnancy have a
role in the occurrence of these otherwise unexplained
ischaemic strokes remains unknown.21,22 Eclampsia is the
main pregnancy-specic disorder that might be associated
with reversible cerebral vasoconstriction syndrome and
with non-haemorrhagic stroke-like episodes. Whereas
some of these episodes are ischaemic strokes, other focal
decits, which are usually reversible in a few days, are not
associated with restricted diusion on MRI with diusionweighted imaging (DWI) and are probably due to vasogenic
oedema rather than cytotoxic oedema. The diagnostic
approaches to stroke during pregnancy should proceed as
in the non-pregnant state, while taking into account the
welfare of the fetus.2123 Finally, a history of pregnancyrelated stroke should not be a contraindication for
subsequent pregnancy.24

Oral contraceptives
Stroke
young adult

DWI-MRI
CT

Ischaemic stroke

Echo-doppler+transcranial
doppler
or
MRA
or
CT angiography

Cervical MRI

ECG
TEE
TTE

Haemorrhagic stroke

Laboratory

MRI
CT angiography
MRA

Holter monitoring

Intra-arterial angiography

Intra-arterial angiography

Figure 1: Flow chart for the diagnosis of ischaemic stroke to identify arterial and cardiac causes
Antecubital vein injection of agitated saline can be used during TCD to detect a right-to-left shunt and grade its
intensity. DWI=diusion-weighted imaging. ECG=electrocardiogram. MRA=magnetic resonance angiography.
TCD=transcranial doppler. TEE=transoesophageal echocardiogram. TTE=transthoracic echocardiogram.

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The role of oral contraceptives as a risk factor for


ischaemic stroke remains controversial. According to the
results of a meta-analysis,25 the risk of stroke is increased
by about four times for women who take pills with a high
content of oestrogen, and is doubled for those who take
pills with low oestrogen content. Pills composed of
progestagen alone do not seem to increase the risk of
stroke.25 In one cohort study,26 the use of oestrogen oral
contraceptives did not increase the risk of stroke. Overall,
the excess risk due to oral contraceptives is low (four
incident strokes per 100 000 women per year of oral
contraceptive use).27 However, in women with migraine,
oral contraceptives are associated with a raised risk of
ischaemic stroke.28,29 Women who have prothrombotic
genetic variants are also at increased risk.30

Illicit drugs
Stroke is one of the complications of recreational drug
use.31 The frequency of illicit drug use in young adults
with stroke can be as high as 12%.32 Therefore, toxicology
screening for illicit drugs should be done in young
patients with stroke with no obvious cause, or if suggested
by history or examination. The intravenous use of drugs
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Review

Generally, the clinical diagnosis of stroke is made in a


patient with vascular risk factors and with acute onset of
symptoms and signs that match an arterial vascular
territory. However, many young adults with stroke do not
have vascular risk factors. Conversely, CNS diseases that
might mimic stroke are more frequent in young adults
than in older patients. The range of dierential diagnoses
includes multiple sclerosis, somatoform disorders,
migraine with prolonged aura, post-ictal focal decits,
neoplasms, and less often encephalitis. Many of these
disorders can only be conrmed or ruled out by MRI. A
prospective, blind comparison of non-contrast CT and
MRI with DWI and susceptibility-weighted imaging in
consecutive patients referred for assessment of suspected
acute stroke showed that MRI is better than CT for
identication of acute ischaemia, and can be used to detect
acute and chronic haemorrhage.33 Therefore, in this age
group, MRI with DWI and T2* sequences are the best
techniques to conrm the diagnosis of ischaemic stroke
in an emergency and to rule out other diagnoses, including
parenchymal haemorrhage.33 If MRI is not available, CT
should be used to rule out intracranial haemorrhage or a
neoplasm, and to identify the extent of early infarct signs
in candidates for intravenous thrombolysis (gure 1).34,35
Most series of ischaemic stroke in young adults25,7,3638
have used the aetiological Trial of Org 10172 in Acute
Stroke Treatment (TOAST) classication of stroke, which
consists of the following subtypes:39 large-vessel disease,
small-vessel disease, cardioembolic, other identiable
cause, and undetermined cause (see cryptogenic stroke
below; gure 2 and gure 3). This classication does not
include vascular risk factors in the diagnostic criteria. In
some series, migrainous strokes, strokes after use of
illicit drugs, and those occurring during pregnancy or
puerperium are included in the section of other
identiable cause36 whereas in other series, some of these
strokes are considered to be of undetermined cause.
Variations in the proportion of patients in the dierent
aetiological subgroups are mainly related to the
operational criteria for these subgroups used in each
study and to the completeness of the ancillary
investigations. Figures 2 and 3 show examples of these
discrepancies between studies.

Extracranial or intracranial large-vessel arterial disease


Depending on local availability and experience, magnetic
resonance angiography (MRA), CT angiography, or carotid
and vertebral ultrasound combined with transcranial
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60
Frequency of TOAST subtypes (%)

Aetiological diagnosis

70

50

Leys, 200238
Musolino, 200336
Cerrato, 20047
Varona, 200437
Putaala, 200940

40
30
20
10
0
Large-vessel disease

Cardioembolic
disease

Small-vessel disease

Other cause

Undetermined

Figure 2: Frequency of TOAST causal subtypes in studies of young adults with stroke
The low percentage of cardioembolic stroke and the high percentage of undertermined subtype in the study by
Leys and colleagues38 is related to the non-inclusion of patent foramen ovale and intra-atrial septal aneurym as a
cardioembolic source unless an intracardiac thrombus or a paradoxical embolism was proven.

Leys, 200238
Musolino, 200336
Cerrato, 20047
Varona, 200437
Putaala, 200940

18
16
14
Patients (%)

can produce embolisation of foreign material or


endocarditis. Drugs with a sympathicomimetic eect
(amphetamine, cocaine, crack) can cause ischaemic
stroke through several mechanisms such as acute
hypertension, enhanced platelet aggregation, and rarely
vasculitis (mainly related to amphetamine intake) of the
periarteritis nodosa or giant cell-granulomatous types.

12
10
8
6
4
2
0
Dissection

Vasculitis

CADASIL

Coagulopathy

Other

Figure 3: Frequency of some specic diseases in the stroke subtype other identiable causes in studies of
young adults with stroke.
In the study by Musolino and colleagues,36 a complete thrombophilia study was done. In the same study, migraine,
pregnancy, and oral contraceptives were included in the group classied as other. The absence of dissections could
be attributable to the use of doppler sonography to investigate the extracranial arteries and to the selective use of
angiography (when doppler detected more than 70% stenosis or when dissection or vasculitis was suspected).
CADASIL=cerebral autosomal dominant arteriopathy with subcortical ischaemic strokes and leucoencephalopathy.

doppler can be used to conrm or rule out extracranial or


intracranial arterial disease or an occlusion (gure 1).
Systematic reviews and a meta-analysis of individual
patient data show that contrast-enhanced MRA is the most
sensitive and specic non-invasive method for
identication of carotid stenosis, closely followed by
carotid ultrasound and CT angiography, with MRA without
contrast being the least reliable.4143 Furthermore, contrastenhanced MRA and CT angiography oer better imaging
of the vertebral and basilar arteries,44 and ultrasound
combined with MRA is as good as intra-arterial
angiography.45 If extracranial arterial dissection is
suspected, cervical MRI with fat suppression is the best
method to show the presence of an intramural haematoma.
Catheter angiography is only done if the results of noninvasive methods are unclear or contradictory, or if
vasculitis or other rare vasculopathies are suspected.
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Test or procedure
Antiphospholipid syndrome

Lupus anticoagulant, anticardiolipin, and anti--2


glycoprotein antibodies*

Systemic lupus erythematosus, other connective


tissue diseases, Wegeners granulomatosis,
Churg-Strauss syndrome

ANA, anti-ds-DNA, ENAs, complement, ANCA

Specic infections

Serum titres for syphilis, borrelia, zoster virus, hepatitis B


and C virus, and HIV infection

Hepatitis C virus, other cryoglobulinemias

Cryoglobulins

Illicit drugs

Serum and urine toxicological screening

Primary CNS and other vasculitis, CNS and


systemic infections

CSF examination

Hyperhomocysteinaemia

Homocysteine concentrations

Specic deciencies

Antithrombin III, protein S or C concentrations

Specic mutations

Factor V Leiden, prothrombin G20210A mutations

Sickle-cell disease

Haemoglobin electrophoresis

Several inammatory, infectious and genetic


diseases, retinocerebral arteriopathies

Ophthalmological examination

Primary CNS and other medium and large-vessel


vasculitis, non-atherosclerotic arteriopathies

Intra-arterial cerebral angiography

Periarteritis nodosa

Abdominal and renal angiography

Takayasus disease

Aortic PET

Primary CNS vasculitis

Cerebromeningeal biopsy

Fabrys disease

GLA activity

CADASIL

Skin biopsy

MELAS

Muscle biopsy

Specic genetic diseases (Fabrys, CADASIL,


HANAC syndrome, MELAS, etc)

Genetic tests

*A positive lupus anticoagulant or high anticardiolipin titres should be repeated 12 weeks later to meet the diagnostic
criteria for the antiphospholipid syndrome. Prevalent infections and work up might vary accordingly to region.
Antithrombin III and protein S and C assessments should be done after the acute phase and are lowered by oral
anticoagulants. Antithrombin III concentrations are also lowered by non-fractionated heparin. Abnormally low
concentrations in the acute phase or in anticoagulated patients should be conrmed 6 weeks later or when oral
anticoagulants are stopped. In patients of African origin or descent. Intra-arterial angiography might also be useful
in patients with doubtful or contradictory ndings in other vascular imaging techniques (ultrasound, CT, or MR
angiography). ENA=extractable nuclear antigens. ANCA=antineutrophil cytoplasmic antibodies. CSF=cerebrospinal
uid. GLA=-galactosidase. CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy. MELAS=mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.
HANAC=hereditary angiopathy, nephropathy, aneurysm, and muscle cramps.

Table 1: Ancillary tests and procedures for comprehensive diagnosis of rare causes of stroke in young adults

Cardioembolism
Review of previous electrocardiograms (ECGs), admission
ECGs, serial ECG assessments,46 and 2448 h ECG
monitoring47 is crucial to detect atrial brillation or other
ECG evidence of cardiac disease. Holter ECG is
recommended to detect paroxysmal atrial brillation, but
its yield is low (5%).48 Extended electroencephalogram
(EEG) monitoring can be used to detect additional cases
(6%) of paroxysmal atrial brillation.49 Transoesophageal
echocardiography is more sensitive than the transthoracic
method to detect potential cardiac sources of embolism,
particularly for mitral valve vegetations and for sources
located in the left appendage, the atrial septum, and the
aorta.5052
Transoesophageal
echocardiography
is
recommended to be part of the aetiological work up of
ischaemic stroke in young patients, unless another cause
of stroke is already present (eg, dissection). However, the
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additional diagnostic yield of transoesophageal


echocardiography
(compared
with
transthoracic
echocardiography) with regard to high-risk cardiac sources
of embolism is low. In young adults, high-risk sources of
embolism detected by echocardiography include
mechanical prosthetic valves, mitral stenosis, endocarditis
(infective and non-infective),53,54 dilated cardiomyopathies,
intracardiac thrombus, and cardiac tumours such as
myxoma and broelastoma.55 The most common uncertain
sources of embolism are patent foramen ovale and atrial
septal aneurysm, akinetic or dyskinetic segments of the
ventricular wall, and redundant mitral valve prolapse.
Transcranial doppler monitoring of both middle
cerebral arteries after injection of agitated saline in the
antecubital vein can also be used to detect a right-to-left
shunt and to grade its intensity.56 If paradoxical embolism
is suspected, the legs should be assessed for deep venous
thrombosis, which can be done by ultrasound or magnetic
resonance venous imaging.

Small-vessel disease
Small-vessel single perforator disease can produce small
(<15 mm diameter) deep hemispherical or brainstem
lacunar infarcts in young adults, usually in patients with
hypertension and diabetes and in those older than
35 years.2 Infections, vasculitis, Fabrys disease, and
CADASIL can also cause lacunar infarcts. Patients often
have additional imaging evidence of small-vessel disease
such as old silent lacunar infarcts, leukoaraiosis on CT,
deep or periventricular white matter lesions on
T2-weighted and uid-attenuated inversion-recovery MRI,
or microbleeds on T2* MRI sequences.40 When classifying
a patient in the subgroup of small-vessel disease, two
potential pitfalls should be avoided: (1) proximal arterial or
cardiac embolic source that can cause a small deep infarct
should not be missed and (2) atheroma of the wall of a
large vessel (eg, basilar artery) impinging on the ostium of
the perforator as the cause of the lacunar infarct should be
excluded. Detection of multiple acute small infarcts,
suggesting embolism, can be achieved by doing acute
MRI with DWI. High-resolution MRI and MRA can be
used to distinguish between atheroma plaques of a largevessel and penetrating vessel disease.57

Other identiable causes


First-line tests (complete blood and platelet count;
erythrocyte sedimentation rate; C-reactive protein; serum,
electrolytes, glycaemia, lipid prole, renal, and hepatic
functions; activated partial thromboplastin time; and
prothrombin time)58 can detect biological risk factors and
can provide insight into rare causes of ischaemic stroke
such as coagulation disorders (eg, thrombocythaemia) or
systemic diseases (eg, lupus).
With the exception of infections in some regions, all
other causes of stroke in young adults are rare
(eg, antiphospholipid syndrome, vasculitis) or very rare
(eg, prothrombotic disorders and other systemic and
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genetic diseases). Three options for aetiological diagnosis


are possible, depending on resources and local practice:
(1) a comprehensive assessment is done in all patients
with no evident cause for their stroke (table 1); (2) a staged
work up is done;6 or (3) a more selective approach is taken,
in which only the disorders suspected on clinical grounds
are investigated (table 2). The assessment strategy will
aect the proportion of patients who are attributed a
specic cause for their stroke, particularly within the
subgroup of stroke of other determined cause (gure 3).

Specic diseases and disorders associated with


ischaemic stroke in young adults
For most causes of stroke in young adults, aetiological
evidence is based on case reports and case series,
sometimes on case-control studies, and much less often
on cohort studies. However, causality criteria for an
aetiological diagnosis are not met for many of the
disorders and syndromes discussed here. We will briey
describe the main clinical and diagnostic aspects of
several of the disorders that have been associated with
stroke in young adults.

Arterial dissection
Spontaneous arterial dissection59 is one of the most
common causes of stroke in young adults (gure 4). This
disorder often aects the extracranial internal carotid
artery, with dissection starting a few centimetres after the
common carotid bifurcation, or the vertebral artery as it
enters the intervertebral channel or as it leaves it before
piercing the dura. Extracranial dissection is multiple in
about a quarter of the cases. Dissection is usually
subintimal and the resulting haematoma causes a long,
irregular stenosis or even an occlusion. Sometimes, the
dissection is subadventitial, forming a pseudoaneurysm.
Intracranial dissection (eg, of the intracranial vertebral
artery) might rupture into the subarachnoid space. The
aetiopathogenesis of dissection is still unclear. Often
dissection is preceded hours to weeks by minor trauma to
the head or neck, but only a few of the many young people
who sustain minor neck injuries have an arterial dissection.
The roles of other vascular risk factors, genetic factors, and
minor connective tissue abnormalities sometimes detected
in skin biopsy samples of patients with arterial dissection
are unknown.6062 The occurrence of multiple concomitant

Clinical signs

Conrmatory tests

Cervical arterial dissection

Minor head or cervical trauma, headache, facial or neck pain, Horners


syndrome, XII palsy

Cervical MT MRI with fat suppression,


angiography

Atherosclerotic large-vessel disease

Multiple vascular risk factors, stroke preceded by transient ischaemic attacks, Carotid/vertebral ultrasound,
carotid bruit
angiography

Small-vessel disease

Hypertension, diabetes, lacunar syndrome, capsular warning syndrome

Patent foramen ovale

Stroke during Valsalvas manoeuvre, stroke after prolonged immobilisation

TEE, TCD with microbubbles

Other cardioembolic diseases

Clinical history and examination, cortical stroke*, haemorrhagic


transformation, multiple infarcts in dierent arterial territories

ECG, cardiac monitoring, TTE, TEE,


Holter

Pulmonary stulae

Right-to-left shunt, no patent foramen ovale, Rendu-Osler disease

Chest CT

Systemic lupus erythomatosus

Anaemia, low platelet count, arthralgias, fever, high ESR, skin or kidney
involvement

Clinical criteria, ANA, anti-DNA and Sm

Antiphospholipid syndrome

Miscarriages, venous thrombosis, prolonged aPTT

Lupus anticoagulant, anticardiolipin and


-2, glycoprotein antibodies

Sneddons syndrome

Generalised livedo reticularis, ischaemic and haemorrhagic stroke

Skin biopsy, digital artery biopsy

Takayasus disease

Absent pulses in upper limbs, blood pressure dierence between arms

CT or MRA, aortic PET

Primary CNS vasculitis

Multiple strokes, encephalopathy, headache

Lumbar puncture, angiography,


meningeal-brain biopsy

Moyamoya syndrome

Multiple strokes, haemorrhagic stroke, cognitive decline

Angiography

Retinoarteriopathy and
retinocochlearcerebral arteriopathy

Visual loss, progressive or episodic deafness, abnomal fundoscopy

ENT and ophthalmological consultation

Sickle-cell disease

African ethnic origin

Hg electrophoresis, genetic testing, TCD

Genetic thrombophilic diseases

Arterial and venous strokes, family history

Antithrombin, protein C and S


concentrations, genetic testing

CADASIL

Family history, multiple strokes, migraine, dementia, psychosis

Skin biopsy, genetic testing

HANAC syndrome, other COL4A1


disorders

Small-vessel disease, cerebral aneuryms, porencephaly, retinal arterial


tortuosity, kidney disease, muscle cramps

Genetic testing

Fabrys disease

Skin, ocular, or kidney involvement; vertebrobasilar dolicoectasia

Genetic testing, GLA activity

MELAS

Migraine, seizures, myopathy, deafness, short stature

EMG, muscle biopsy, genetic testing

MRI*

MT=magnetisation transfer. TEE=transoesophageal echocardiogram. TCD=transcranial doppler. ECG=electrocardiogram. TTE=transthoracic echocardiogram. Sm=Smith.
aPTT=activated partial thromboplastin time. MRA= MR angiography. ENT=ear, nose, and throat. Hg=haemoglobin. CADASIL=cerebral autosomal dominant arteriopathy with
subcortical infarcts and leucoencephalopathy. HANAC=hereditary angiopathy, nephropathy, aneurysm, and muscle cramps. GLA=-galactosidase. MELAS=mitochondrial
encephalopathy with lactic acidosis and stroke-like episodes. EMG=electromyography. *MRI (DWI/ADC sequences) is better than CT for detection of small new cortical and
subcortical infarcts and for detection and assessment of white matter lesions. Antithrombin, proteins S and C deciencies, factor V Leiden, prothrombin G20210A mutation.

Table 2: Diagnosis of a non-infectious cause of stroke guided by clinical signs

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Figure 4: CT and MRI scans of a 43-year-old woman with unilateral headache and transient episodes of aphasia caused by cervical internal carotid dissection
CT (A) and MR (B) disclosing small left frontal infarct. (C) Thrombus visible in the left internal carotid artery. (D) Crescent image on MRI with contrast.
(E) Flame-shaped aspect of the dissection on MRA. (F) MRA with collateral supply from the contralateral carotid artery. MRA=MR angiography.

dissections63 and the nding of many clustered early


recurrences64 contrast with the rarity of late recurrences
and indicate a transient vasculopathy, which might be
triggered by infections.59 Clinical features that are suggestive of dissection include a history of head or neck trauma
(even minor), headache or neck pain, and local signs (such
as Horners syndrome or cranial nerve palsies), with or
without symptoms of cerebral ischaemia.
The diagnosis of arterial dissection can be made with
ultrasound, MRI, CT, or catheter angiography. Ultrasound
has a high sensitivity, and is somewhat better for carotid
dissection (8096%) than for vertebral dissection
(7086%).65 However, it has a low sensitivity in cases with
only local signs.66 CT angiography has an excellent
sensitivity (92100%) and can be used to visualise more
features of dissection, particularly in the vertebral arteries,
than can MRA.67 MRI and MRA have a high sensitivity for
carotid dissection (87100%). Cervical MRI can be used to
identify the intramural haematoma with T1-weighted fatsuppressed sequences (gure 4) and is now considered the
procedure of choice for the diagnosis of cervical artery
dissection, although the dissecting haematoma hypersignal
might take some days to develop. Intra-arterial angiography
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is used in doubtful cases in which the results of noninvasive diagnostic instruments are contradictory or
inconclusive, or when endovascular treatment is planned.
The risk of early recurrence is low (<1%), although very
early multiple recurrence (usually asymptomatic) might
occur.64 The risk of recurrence is higher in patients with
stroke or transient ischaemic attack than in those with
local signs. Most recurrent strokes happen during the rst
month, and long-term risk of recurrent dissection
(0314%), stroke (0334% per year), and vascular
death are low.68
Stenotic lesions resolve in about 70% of patients,
whereas recanalisation of occluded arteries is less
frequent and occurs mainly within the rst 6 months.69
Carotid aneurysms persist in about two-thirds of cases,
whereas vertebral aneurysms frequently resolve. Because
complications of persistent aneurysms are rare, the main
issue in cervical arterial dissection is the severity of the
initial stroke rather than the risk of recurrence.

Patent foramen ovale


The foramen ovale is a remnant of the fetal circulation that
remains patent in about 25% of the general population.
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Review

Transoesophageal echocardiography with a contrast study


is the most sensitive diagnostic test for detection of a patent
foramen ovale (gure 5), followed by contrast-enhanced
transcranial doppler and transthoracic echocardiography.
Interobserver agreement for the diagnosis of patent
foramen ovale is not perfect: disagreement can reach 14%
for the presence of the disorder and 27% for the severity of
shunting.70 Transcranial doppler can also be used to identify
other causes of a right-to-left shuntnamely, a pulmonary
arteriovenous stula. Many case-control studies have
established a statistical association between patent foramen
ovale and cryptogenic stroke.71,72 In a meta-analysis of these
studies,72 the summary OR for patent foramen ovale in
cryptogenic stroke versus controls was 29 (95% CI 2140).
The corresponding OR was 51 (3378) for younger
patients (<55 years) and 20 (>1037) for older patients
(55 years). The association has also been reported to be
stronger in patients with large right-to-left shunts and in
those who have an atrial septal aneurysm in addition to a
patent foramen ovale.71,72 Results from a population-based
study73 suggest that selective referral of cases and underrecognition of patent foramen ovale in comparison groups
of patients referred for echocardiography might have led to
an overestimation of the role of patent foramen ovale in
cryptogenic strokes.
By contrast with case-control studies, longitudinal
studies have been unable to show an increased risk of
rst74 or recurrent75 stroke in patients with patent foramen
ovale. In a meta-analysis of 15 studies,75 the pooled
absolute rate of recurrent stroke in medically treated
patients with cryptogenic stroke and patent foramen
ovale was 16 events per 100 person-years (95% CI
1121). The four studies with a non-patent foramen
ovale comparison group did not support an increased
relative risk of recurrent ischaemic events in those with
patent foramen ovale versus those without (pooled
RR 08 [95% CI 0513]). One study showed an
increased risk of stroke recurrence in young adults with
both patent foramen ovale and atrial septal aneurysm
who were given aspirin for secondary prevention.76
The mechanism of stroke in patients with a patent
foramen ovale is not well dened. A shunt via a
patent foramen ovale might allow passage of thrombotic
material from the venous bed into the arterial circulation,
which denes paradoxical embolisation. This mechanism
is supported by rare case reports in which a thrombus was
visualised within a patent foramen ovale at autopsy or
echocardiography. However, in most patients with
cryptogenic stroke associated with patent foramen ovale,
no direct or indirect (eg, venous thrombosis, Valsalvas
manoeuvre preceding stroke onset) signs of paradoxical
embolism can be noted. Other potential stroke
mechanisms, such as direct embolisation of thrombi
formed in situ and paroxysmal arrhythmia, remain
unproven. This uncertainty suggests that other
mechanisms unrelated to patent foramen ovale might
be operant in many cases. In this respect, it should be
www.thelancet.com/neurology Vol 9 November 2010

Figure 5: Transoesophageal echocardiogram in a young patient with stroke


with patent foramen ovale and interatrial septum aneurysm
(A) Right-to-left shunt (arrow) through a patent foramen ovale. (B) Atrial septal
aneurysm as a bulging of the interatrial septum into the right atrium.

kept in mind that patent foramen ovale is a common


nding in the normal population and must coexist by
chance alone in about a third of patients with ischaemic
stroke.72 Consequently, for some patients, stroke is
erroneously attributed to a patent foramen ovale.

Infections
The epidemiological relevance of stroke related to specic
infections is closely related to the epidemiological burden
of such infections in dierent regions. Examples are HIV
infection in sub-Saharan Africa, cysticercosis, and Chagas
disease in South America, and syphilis and tuberculosis
in the Indian subcontinent (panel).
Syphilis can produce stroke both during its early and
late phases. Most strokes caused by syphilis occur in the
early (secondary) phase. In the early phase, a sudden
cerebral infarction can be the only clinically apparent
manifestation of subacute meningitis with perivascular
inammation and arteritis. Cranial nerve palsies and palm
and sole cutaneous eruption might also be present. In late
syphilis there is a transmural proliferative endarteritis.
This arteritis can aect the major (large and medium size)
basal brain vessels (Heubners arteritis), especially the
middle cerebral artery or the deep perforating vessels
(Nills-Alzheimers arteritis). Stroke can also be secondary
to late cardiac complications of syphilis. CSF examination
is recommended for diagnosis of neurosyphilis. Reports
of meningovascular syphilis have become more common
with the AIDS epidemic. HIV tests are recommended in
all patients with meningovascular syphilis, whereas a
CSF-venereal disease research laboratory (VDRL) or rapid
plasma reagin (RPR) test is needed in every patient with
HIV who develops cerebrovascular disease. The CSFVDRL or RPR sensitivity are about 99% but their specicity
is 7075%.77 Therefore, a CSF-treponemal antibody test
might be necessary in some cases to conrm diagnosis.
Borreliosis is a tick-borne, inammatory disorder
caused by the spirochete Borrelia burgdorferi and can be
associated with a meningovascular process. Data that
lend support to an association between Borrelia burgdorferi
infection and stroke are scarce.78,79 A history of tick bites
or erythema chronicum migrans in an endemic region
suggests a diagnosis of borreliosis.
1091

Review

Panel: Recommended tests for infectious causes of stroke in young patients


Serum venereal disease research laboratory and HIV testing in all cases
In high-prevalence areas, review CT/MRI to look for cysts of neurocysticercosis or
lesions suggestive of neurotuberculosis
In high-prevalence areas, test serum and CSF for borreliosis
In cases without apparent cause, do lumbar puncture and test CSF for syphilis,
borreliosis, tuberculosis, and varicella zoster virus
Consider infective endocarditis (multiple strokes) and, in high-prevalence areas, also
rheumatic valvular heart disease and Chagas disease as possible causes of
cardioembolic stroke

Stroke is common in patients with tuberculous


meningitis and is associated with the severity of
meningitis, hydrocephalus, and meningeal exudates.80,81
Vasculitis can be recorded in the basal cerebral arteries
and their perforating branches. Brain infarcts aect the
so-called tuberculosis zone, which consists of the
territories of the lenticulostriate and thalamoperforating
arteries. Bilateral basal ganglia infarcts are a characteristic
feature of tuberculous meningitis. Moreover, transcranial
doppler is a valuable non-invasive instrument for the
diagnosis of tuberculous arteritis.
Patients with acute bacterial meningitis can develop
cerebrovascular complications, most of which occur
within 2 weeks of the infection. Transcranial doppler
studies show the haemodynamic eects of the
vasculopathy in patients with bacterial meningitis.82
Varicella-zoster virus vasculopathy aects both
immunocompetent and immunocompromised patients,
occurs after zoster or varicella, and can be either focal or
multifocal.83 Cerebral vasculopathy arises frequently after
ophthalmic herpes zoster, is commonly located on the
side of the skin lesion, and is often distributed in the
middle and anterior cerebral arteries. Usually, the clinical
course is characterised by gradual resolution of cutaneous
herpes zoster ophthalmicus followed by the acute onset
of contralateral hemiparesis, hemisensory symptoms, or
aphasia. Optic nerve infarction can be noted in some
patients, and rash can be absent in others.84 Angiography
can show irregular segmental narrowing of both large
and small arteries.83 Infarcts often occur at the grey-white
matter junctions, as shown by MRI. The most common
CSF ndings are of high mononuclear cell counts, raised
protein, and normal concentrations of glucose. Varicellazoster virus antigens, DNA, and antibodies against the
virus can be detected in the CSF to conrm the diagnosis
of infection in the CNS. Only negative results on both
PCR and tests of IgG antibodies for varicella-zoster virus
in CSF can exclude the diagnosis of varicella-zoster virus
vasculopathy.83
Patients infected with HIV have a higher risk of both
ischaemic and haemorrhagic stroke than do those not
infected. This increased risk occurs through dierent
mechanisms such as cerebral vasculopathy, cardioembolism, and haematological factors.85 HIV-associated
vasculopathy has been described in young adults and can
1092

aect either large or medium extracranial or intracranial


arteries. A small-vessel vasculopathy has also been noted
in patients with AIDS. Moreover, risk of accelerated
atherosclerosis is potentially associated with antiretroviral
treatment.
Stroke is one of the most feared complications of
cysticercosis, which is more frequent in patients with
subarachnoid neurocysticercosis. Usually the middle and
posterior cerebral arteries are aected by the inammatory
process. Lacunar infarctions can occur as a result of
inammation of small penetrating arteries. Ischaemic
strokes are less frequent in patients with parenchymal
neurocysticercosis and usually arise in the vicinity of
cysts. Transcranial doppler is a useful method for the
diagnosis and follow-up of patients with arteritis caused
by neurocysticercosis.86
Chagas cardiomyopathy increases the risk of embolic
ischaemic stroke.87 This disease is caused by
Trypanosoma cruzi and is transmitted to man
by triatomine bugs that deposit faeces on the mucous
membranes or skin while they bite. Chagas disease
progresses in stages, and most patients are infected
during their early years. The cardiac system is aected in
many patients with this disease.

Primary and secondary vasculitis and connective tissue


disorders
Primary vasculitis and connective tissue disorder rarely
present as a stroke syndrome. Exceptions are systemic
lupus erythematosus, antiphospholipid syndrome,88 and
Takayasus disease in which stroke is common and might
even be the presenting manifestation. A few case reports
document arterial strokes due to Churg-Strauss, Wegeners
vasculitis, polyarteritis nodosa, cryoglobulinaemia, and to
other systemic inammatory disorders such as Behets
disease, inammatory bowel disease, and sarcoidosis.
The most common mechanisms of stroke in systemic
lupus erythematosus are hypertensive small-vessel disease,
cardioembolism, and the presence of a prothrombotic
state.89 Sneddons syndrome refers to a rare disorder
featuring widespread generalised livedo reticularis and
multiple strokes,90 and it can be isolated or associated with
antiphospholipid syndrome.
Stroke is a rare manifestation in patients with primary
angiitis of the CNS.91 Most patients present with
encephalopathy and headache. Lumbar puncture usually
shows lymphocytic pleiocytosis, and cerebral angiography
either shows signs that suggest vasculitis or is normal. A
meningeal brain biopsy should be done to conrm the
diagnosis before starting aggressive treatment with highdose steroids and cyclophosphamide. However, the biopsy
sample can be negative or inconclusive, although its
sensitivity is moderate (5060%).92 Cerebral vasculitis
should be distinguished from the more common reversible
cerebral vasoconstriction syndromes, in which various
segmental narrowings of the intracranial vessels disappear
on control angiograms and the CSF is usually normal.93,94
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Review

Other rare non-inammatory arteriopathies


Other arteriopathies include radiation arteriopathy,
bromuscular dysplasia, and moyamoya syndrome,95,96
which is still very rare in populations from developed
countries. The rarest causes of stroke in young adults are
the retinocerebral or retinocochlearcerebral arteriopathies,
such as Eales disease (retinopathy with neovascularisation),
Susacs syndrome (encephalopathy, hearing loss, and
retinal artery branch occlusions),97 and acute posterior
multifocal placoid pigment epitheliopathy (multiple creamcoloured lesions of the retinal pigment epithelium).

Haematological disorders
Apart from sickle-cell anaemia,98 other haematological
diseases aecting young adults can be occasionally
complicated by arterial stroke. Examples are paroxysmal
nocturnal haemoglobinuria, thrombotic thrombocytopenic purpura, erythrocytosis, leukaemias, and
intravascular lymphoma.

Monogenic diseases
There are more than 50 monogenic diseases that can
cause stroke, but they account for a very low percentage
of strokes. These disorders are very rare, apart from
drepanocytosis, which is an important cause of stroke in
children and young adults of African ethnic origin.98,99 In
young patients of African origin with stroke, sickle-cell
disease should always be looked for by use of haemoglobin
electrophoresis (haemoglobin S) or genetic testing
(Val-Glu substitution in the globin chain). Follow-up of
intracranial stenosis can be done non-invasively with
transcranial doppler.
Subcortical vascular dementia, depression and other
psychiatric disorders, migraine with aura, and recurrent
strokes are the main clinical features of CADASIL. The
diagnosis is suspected if there is a family history
(autosomal dominant) and if MRI shows the characteristic
conuent subcortical white matter changes extending to
the temporal lobes. The diagnosis is conrmed by skin
biopsy and genetic testing (Notch 3 mutations).100 The
estimated prevalence of CADASIL in young patients with
stroke is very low (05% of lacunar strokes; 2% in patients
younger than 65 years with white matter changes).101
Hypertension and smoking are associated with an
increased probability of stroke in patients with CADASIL,
suggesting that vascular risk factors might modulate the
clinical expression of this disorder.102
The availability of an eective enzyme (-galactosidase)
substitution therapy has led to a renewed interest
in Fabrys disease as a cause of stroke in young adults.
Fabrys disease is a systemic disorder aecting mainly the
kidney, skin (angiokeratoma), and eye (corneal opacities).
It causes a painful neuropathy. The diagnosis in
symptomatic men can be conrmed by a decit in serum
-galactosidase, but usually needs genetic testing,
particularly in women, who can have normal concentrations
of -galactosidase.103 Vertebrobasilar dolicoectasia and the
www.thelancet.com/neurology Vol 9 November 2010

coexistence of large-vessel and small-vessel disease are


suggestive of Fabrys disease. Fabrys disease is more
frequent in young patients with cryptogenic ischaemic
stroke.104 In two large multicentre studies of young patients
with stroke, -galactosidase pathogenic mutations were
recorded in 24%3 of 493 and 1%105 of 1000 patients with
strokes, more often in those with ischaemic stroke (both
cryptogenic and non-cryptogenic). In one of these studies,3
-galactosidase pathogenic mutations were more frequent
in patients with evidence of small-vessel disease (lacunes
or leukoaraiosis; 45%), more so if they were not
hypertensive (7%), and in normotensive patients with
posterior circulation strokes (125%). Of importance is the
fact that stroke frequently arises before diagnosis of Fabrys
disease and in the absence of other clinical ndings.106
In COL4A1 mutationsnamely, in hereditary
angiopathy, nephropathy, aneurysm, and muscle cramps
(HANAC) syndromethe cerebral vascular phenotype
involves an association between a subcortical small-vessel
disease and aneurysms of the carotid siphon.107
Hereditary
endotheliopathy
with
retinopathy,
nephropathy, and stroke (HERNS) is associated with
mutations of the TREX1 gene and its phenotype includes
psychiatric symptoms, dementia, subcortical strokes, and
leucoencephalopathy.

Cryptogenic stroke
In about 30% of patients, the cause of stroke cannot be
identied despite the detailed and comprehensive
aetiological work up described in this Review. Some of
these patients might have classic vascular risk factors, but
they do not show evidence of large atherosclerotic or smallvessel arterial disease. Minor atherosclerotic lesions might
be missed by current diagnostic and imaging techniques.
A frequent mistake is the diagnosis of cryptogenic stroke
in patients with incomplete or delayed aetiological
investigation.108 This misdiagnosis is of particular
importance in dissection, which can resolve quickly, and in
intracardiac thrombus, which can either resolve or
fragment and embolise. Results of some biological
diagnostic tests (eg, antiphospholipid antibodies for
antiphospholipid syndrome or platelet count for
thrombocythaemia) can uctuate, and therefore repeated
assessment is needed. Repeated or extended Holter
monitoring might be necessary if paroxysmal arrhythmias
are suspected. Repeated angiography might also be
necessary to distinguish between reversible cerebral vasoconstriction syndrome, in which the various segmental
arterial narrowings are reversible, and vasculitis,
atherosclerosis, or other vasculopathies of intracranial
arteries, in which the narrowings persist or even progress.

Conclusions and future directions


Progress in the identication of the causes and
mechanisms of stroke in young adults has been slow but
constant, mainly because of technological advances in
imaging and genetic diagnosis. Despite this progress,
1093

Review

Search strategy and selection criteria


We searched PubMed for articles published between 2000 and
July, 2010, with the terms stroke(s) young adults, ischaemic
stroke young adults, and infarction young adults. We
included articles published in English, French, Portuguese, and
Spanish and those from our own les. An inclusive upper age
limit of 55 years was considered for the literature review.

several methodological issues and many unanswered


clinical questions still need to be addressed.
Most of the case series of stroke in young adults were
assembled in tertiary hospitals. Therefore, incomplete
case ascertainment and selection bias towards more severe
cases or rare causes is inevitable. However, communitybased studies are not very helpful to widen our knowledge
about the causes and prognosis of stroke in young adults
because only a few cases of stroke will be detected in this
group, in view of the low incidence of stroke before the
age of 50 years. Therefore, in the past decade, we have
witnessed an increased collaboration between individual
centres in the study of some causes of stroke in young
adults, such as patent foramen ovale,76 dissection,109,110 and
Fabrys disease.3,104106 These collaborations should also be
pursued in the setting of multicentre registries and
randomised clinical trials, thus gathering the required
sample sizes that are needed for answering relevant
clinical questions and for preplanned subgroup analyses.
Moreover, denition of subtypes of stroke and associated
disorders should be uniform and explicit. Studies with
longer follow-up are needed to investigate the outcomes
as young patients age. More observational data are needed
on the safety of pregnancy after stroke in young women.
Centres in developing countries in dierent continents
should actively participate in such studies, because most
strokes in young adults take place in these settings.
Furthermore, the causes of stroke are diverse and resource
allocation strategies dier from those in developed
countries. The aetiological diagnosis of stroke in young
adults needs a dierent and more complex diagnostic
work up than does stroke in older adults. Studies
comparing the cost-eectiveness of dierent strategies
(eg, comprehensive vs staged vs clinically oriented) are also
needed to search for the causes of stroke in this age group.
Finally, guidelines specically dedicated to stroke in young
adults, such as those already available for stroke in
children,111 would be welcome.
Contributors
JMF generated the outline of the Review, wrote the rst draft, apart from
the sections written by ARM and JLM, and prepared tables 1 and 2 and
gures 14 and 6. ARM wrote the rst draft of the sections on infections
and prepared the panel. JLM wrote the rst draft of the sections on
migraine, pregnancy, and patent foramen ovale and prepared gure 5.
All authors contributed equally to the review of the subsequent drafts
and nal version, which they read and approved.
Conicts of interest
We declare that we have no conicts of interest.

1094

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