Review

Aetiological diagnosis of ischaemic stroke in young adults

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

Despite improvements in diagnosis and treatment, ischaemic stroke in young adults remains a catastrophic event Lancet Neurol 2010; 9: 1085–96
from the patients’ perspective. Stroke can cause death, disability, and hamper quality of life. For the neurologist Department of Neurosciences,
treating a young adult with suspected ischaemic stroke, the diagnostic challenge is to identify its cause. Hospital de Santa Maria,
Faculdade de Medicina de
Contemporary neuroimaging of the brain and its vessels, and a comprehensive cardiac assessment, will enable
Lisboa, Lisbon, Portugal
identification of the most frequent causes of stroke in this age group: cardioembolism and arterial dissection. (Prof J M Ferro MD);
Specific diagnostic tests for the many other rare causes of ischaemic stroke in young adults (angiography, CSF Department of Neurology,
examination, screening for vasculitis and thrombophilia, genetic testing, and ophthalmological examination) University of Kentucky,
Lexington, USA
should be guided by suspected clinical findings or by the high prevalence of diseases associated with stroke in
(A R Massaro MD); and Service
some countries. de Neurologie, Unité
Neuro-Vasculaire, Hôpital
Introduction Incidence, prevalence, and demographics Sainte-Anne, Université Paris
Descartes, INSERM UMR 894,
The incidence of stroke rises exponentially with age and In a hospital-based study in Finland,2 the yearly incidence Paris, France (Prof J-L Mas MD)
is therefore low in young adults.1 Nevertheless, ischaemic of stroke increased from 2·4 per 100 000 for people aged
Correspondence to:
stroke in young adults is a common cause of admission 20–24 years, to 4·5 per 100 000 for people aged 30–34 years, Prof José M Ferro, Department
to stroke units and referral to neurology departments or and to 32·9 per 100 000 for people aged 45–49 years. Stroke of Neurosciences, Hospital de
tertiary hospitals.2,3 Traditional risk factors for stroke such is slightly more frequent in women aged 20–30 years and Santa Maria, 1649-035 Lisbon,
Portugal
as hypertension and diabetes are not very frequent in in men older than 35 years. The proportion of strokes of
jmferro@fm.ul.pt
young adults;2,3 however, some other permanent or undetermined or rare causes is much higher for young
transient risk factors such as smoking, use of oral adults than for older patients.5 In young adults the
contraceptives, migraine, trauma, use of illicit drugs, and aetiological subgroups also vary with age: the proportion
pregnancy or puerperium have a more important role in of strokes of undetermined cause decreases with age,
this age group than in older adults. The main clinical whereas the proportion of strokes caused by large artery
challenge in management of a young adult with acute atherosclerosis and small-vessel disease increases after
stroke is the identification of its cause. Although large the age of 35–40 years.2,7 In the Helsinki Young Stroke
extracranial and intracranial atheroma, small-vessel Registry2 (1008 patients aged <50 years), cardioembolism
disease, and atrial fibrillation4,5 have a major role in cases (20%) and cervicocerebral artery dissection (15%) were the
of stroke in older adults, these disorders are much less most frequent aetiological subgroups.
frequent in young adults. Our ability to establish a Causal data for stroke in young adults come mainly
definite cause for stroke in young people has improved from registries of reference hospitals in developed
in the past decades because of advances in the non- countries and are therefore prone to ascertainment and
invasive imaging of the brain vessels, heart cavities, and referral biases. The incidence of stroke in young adults in
valves, and cardiac electrophysiology and genetic developing countries is higher than in developed
diagnostic instruments. countries because of the higher incidence of strokes
In this Review, we focus on the aetiological diagnosis related to infections, rheumatic heart disease, and
of stroke in young adults with particular emphasis on undetected or uncontrolled vascular risk factors.8–11
the best approaches to confirm or exclude the most
common causes of stroke in these patients, and we Risk factors for ischaemic stroke in young adults
describe the clinical features and diagnostic Understanding of risk factors for ischaemic stroke in
considerations of several associated disorders and young adults is based mainly on hospital-based case-
diseases, with the aim of facilitating practising control studies and less often on population-based
neurologists, emergency physicians, and internists in case-control and cohort studies. However, case-control
reaching an aetiological diagnosis of stroke in young studies are prone to bias and usually overestimate the
adults. We also describe the most relevant aspects and risk. The proportion of young adult patients with stroke
advances in the descriptive and analytical (risk factors who have classic risk factors increases with age.2,3,7 In
and associated disorders) epidemiology of ischaemic different series, a variable proportion of women (7%2 and
stroke in young adults. Young adults are variously 45%3) were on oral contraceptives. Alcohol misuse is also
defined in published studies as aged less than 40, 45, 50, an independent risk factor for ischaemic stroke in young
or 55 years; here, to be inclusive, we use the upper age and middle-aged adults.12
limit of 55 years. Apart from a consensus proposal on
the aetiological investigation of cerebral infarction in Smoking
young adults from the Societé Française Neurovasculaire,6 Cigarette smoking is an important risk factor for cerebral
no specific guidelines exist for the management of stroke infarction in young adults.13 This finding has been
specifically in this age group. replicated in a population-based case-control study (odds

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 Review
ratio [OR] 2·6 [95% CI 1·9–3·6]).14 The risk increased with
the duration13 and dose13,14 of the exposure, from an OR of
2·2 (1·5–3·3) for one to ten cigarettes per day up to 9·1
(3·2–26·0) 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 affect 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 affect 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
Stroke
young adult
DWI-MRI
CT
Ischaemic stroke Haemorrhagic stroke
Echo-doppler+transcranial ECG Laboratory MRI
doppler TEE CT angiography
or TTE MRA
MRA
or
CT angiography Holter monitoring
Cervical MRI 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=diffusion-weighted imaging. ECG=electrocardiogram. MRA=magnetic resonance angiography.
TCD=transcranial doppler. TEE=transoesophageal echocardiogram. TTE=transthoracic echocardiogram.
1086
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.20–22
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 identified. 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-specific 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
deficits, which are usually reversible in a few days, are not
associated with restricted diffusion on MRI with diffusion-
weighted 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.21–23 Finally, a history of pregnancy-
related stroke should not be a contraindication for
subsequent pregnancy.24
Oral contraceptives
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

can produce embolisation of foreign material or

70 Leys, 200238
endocarditis. Drugs with a sympathicomimetic effect Musolino, 200336
(amphetamine, cocaine, crack) can cause ischaemic 60 Cerrato, 20047
Varona, 200437
stroke through several mechanisms such as acute

Frequency of TOAST subtypes (%)

Putaala, 200940
hypertension, enhanced platelet aggregation, and rarely 50

vasculitis (mainly related to amphetamine intake) of the

40
periarteritis nodosa or giant cell-granulomatous types.
30
Aetiological diagnosis
Generally, the clinical diagnosis of stroke is made in a 20
patient with vascular risk factors and with acute onset of
10
symptoms and signs that match an arterial vascular
territory. However, many young adults with stroke do not 0
have vascular risk factors. Conversely, CNS diseases that Large-vessel disease Cardioembolic Small-vessel disease Other cause Undetermined
might mimic stroke are more frequent in young adults disease

than in older patients. The range of differential diagnoses Figure 2: Frequency of TOAST causal subtypes in studies of young adults with stroke
includes multiple sclerosis, somatoform disorders, The low percentage of cardioembolic stroke and the high percentage of undertermined subtype in the study by
migraine with prolonged aura, post-ictal focal deficits, 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.
neoplasms, and less often encephalitis. Many of these
disorders can only be confirmed or ruled out by MRI. A
prospective, blind comparison of non-contrast CT and 18 Leys, 200238
Musolino, 200336
MRI with DWI and susceptibility-weighted imaging in 16 Cerrato, 20047
consecutive patients referred for assessment of suspected 14 Varona, 200437
acute stroke showed that MRI is better than CT for Putaala, 200940
12
identification of acute ischaemia, and can be used to detect
Patients (%)

acute and chronic haemorrhage.33 Therefore, in this age
group, MRI with DWI and T2* sequences are the best
techniques to confirm 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 (figure 1).34,35
Most series of ischaemic stroke in young adults2–5,7,36–38
have used the aetiological Trial of Org 10172 in Acute
Stroke Treatment (TOAST) classification of stroke, which
consists of the following subtypes:39 large-vessel disease,
small-vessel disease, cardioembolic, other identifiable
cause, and undetermined cause (see cryptogenic stroke
below; figure 2 and figure 3). This classification 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
identifiable cause36 whereas in other series, some of these
strokes are considered to be of undetermined cause.
Variations in the proportion of patients in the different
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
10
8
6
4
2
0
Dissection Vasculitis CADASIL Coagulopathy Other
Figure 3: Frequency of some specific diseases in the stroke subtype other identifiable 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 classified 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 confirm or rule out extracranial or
intracranial arterial disease or an occlusion (figure 1).
Systematic reviews and a meta-analysis of individual
patient data show that contrast-enhanced MRA is the most
sensitive and specific non-invasive method for
identification of carotid stenosis, closely followed by
carotid ultrasound and CT angiography, with MRA without
contrast being the least reliable.41–43 Furthermore, contrast-
enhanced MRA and CT angiography offer 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 non-
invasive methods are unclear or contradictory, or if
vasculitis or other rare vasculopathies are suspected.

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 Review

additional diagnostic yield of transoesophageal

Test or procedure
echocardiography (compared with transthoracic
Antiphospholipid syndrome Lupus anticoagulant, anticardiolipin, and anti-β-2 echocardiography) with regard to high-risk cardiac sources
glycoprotein antibodies*
of embolism is low. In young adults, high-risk sources of
Systemic lupus erythematosus, other connective ANA, anti-ds-DNA, ENAs, complement, ANCA
tissue diseases, Wegener’s granulomatosis, embolism detected by echocardiography include
Churg-Strauss syndrome mechanical prosthetic valves, mitral stenosis, endocarditis
Specific infections Serum titres for syphilis, borrelia, zoster virus, hepatitis B (infective and non-infective),53,54 dilated cardiomyopathies,
and C virus, and HIV infection† intracardiac thrombus, and cardiac tumours such as
Hepatitis C virus, other cryoglobulinemias Cryoglobulins myxoma and fibroelastoma.55 The most common uncertain
Illicit drugs Serum and urine toxicological screening sources of embolism are patent foramen ovale and atrial
Primary CNS and other vasculitis, CNS and CSF examination septal aneurysm, akinetic or dyskinetic segments of the
systemic infections ventricular wall, and redundant mitral valve prolapse.
Hyperhomocysteinaemia Homocysteine concentrations Transcranial doppler monitoring of both middle
Specific deficiencies Antithrombin III, protein S or C concentrations‡ cerebral arteries after injection of agitated saline in the
Specific mutations Factor V Leiden, prothrombin G20210A mutations antecubital vein can also be used to detect a right-to-left
Sickle-cell disease Haemoglobin electrophoresis§ shunt and to grade its intensity.56 If paradoxical embolism
Several inflammatory, infectious and genetic Ophthalmological examination is suspected, the legs should be assessed for deep venous
diseases, retinocerebral arteriopathies
thrombosis, which can be done by ultrasound or magnetic
Primary CNS and other medium and large-vessel Intra-arterial cerebral angiography¶
vasculitis, non-atherosclerotic arteriopathies
resonance venous imaging.
Periarteritis nodosa Abdominal and renal angiography
Small-vessel disease
Takayasu’s disease Aortic PET
Small-vessel single perforator disease can produce small
Primary CNS vasculitis Cerebromeningeal biopsy
(<15 mm diameter) deep hemispherical or brainstem
Fabry’s disease GLA activity
lacunar infarcts in young adults, usually in patients with
CADASIL Skin biopsy
hypertension and diabetes and in those older than
MELAS Muscle biopsy
35 years.2 Infections, vasculitis, Fabry’s disease, and
Specific genetic diseases (Fabry’s, CADASIL, Genetic tests
HANAC syndrome, MELAS, etc)
CADASIL can also cause lacunar infarcts. Patients often
have additional imaging evidence of small-vessel disease
*A positive lupus anticoagulant or high anticardiolipin titres should be repeated 12 weeks later to meet the diagnostic such as old silent lacunar infarcts, leukoaraiosis on CT,
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
deep or periventricular white matter lesions on
anticoagulants. Antithrombin III concentrations are also lowered by non-fractionated heparin. Abnormally low T2-weighted and fluid-attenuated inversion-recovery MRI,
concentrations in the acute phase or in anticoagulated patients should be confirmed 6 weeks later or when oral or microbleeds on T2* MRI sequences.40 When classifying
anticoagulants are stopped. §In patients of African origin or descent. ¶Intra-arterial angiography might also be useful a patient in the subgroup of small-vessel disease, two
in patients with doubtful or contradictory findings in other vascular imaging techniques (ultrasound, CT, or MR
angiography). ENA=extractable nuclear antigens. ANCA=antineutrophil cytoplasmic antibodies. CSF=cerebrospinal potential pitfalls should be avoided: (1) proximal arterial or
fluid. GLA=α-galactosidase. CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and cardiac embolic source that can cause a small deep infarct
leucoencephalopathy. MELAS=mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. should not be missed and (2) atheroma of the wall of a
HANAC=hereditary angiopathy, nephropathy, aneurysm, and muscle cramps.
large vessel (eg, basilar artery) impinging on the ostium of
Table 1: Ancillary tests and procedures for comprehensive diagnosis of rare causes of stroke in young adults 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
Cardioembolism MRI with DWI. High-resolution MRI and MRA can be
Review of previous electrocardiograms (ECGs), admission used to distinguish between atheroma plaques of a large-
ECGs, serial ECG assessments,46 and 24–48 h ECG vessel and penetrating vessel disease.57
monitoring47 is crucial to detect atrial fibrillation or other
ECG evidence of cardiac disease. Holter ECG is Other identifiable causes
recommended to detect paroxysmal atrial fibrillation, but First-line tests (complete blood and platelet count;
its yield is low (5%).48 Extended electroencephalogram erythrocyte sedimentation rate; C-reactive protein; serum,
(EEG) monitoring can be used to detect additional cases electrolytes, glycaemia, lipid profile, renal, and hepatic
(6%) of paroxysmal atrial fibrillation.49 Transoesophageal functions; activated partial thromboplastin time; and
echocardiography is more sensitive than the transthoracic prothrombin time)58 can detect biological risk factors and
method to detect potential cardiac sources of embolism, can provide insight into rare causes of ischaemic stroke
particularly for mitral valve vegetations and for sources such as coagulation disorders (eg, thrombocythaemia) or
located in the left appendage, the atrial septum, and the systemic diseases (eg, lupus).
aorta.50–52 Transoesophageal echocardiography is With the exception of infections in some regions, all
recommended to be part of the aetiological work up of other causes of stroke in young adults are rare
ischaemic stroke in young patients, unless another cause (eg, antiphospholipid syndrome, vasculitis) or very rare
of stroke is already present (eg, dissection). However, the (eg, prothrombotic disorders and other systemic and

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 Review

genetic diseases). Three options for aetiological diagnosis Arterial dissection

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
affect the proportion of patients who are attributed a
specific cause for their stroke, particularly within the
subgroup of stroke of other determined cause (figure 3).
Specific 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 briefly
describe the main clinical and diagnostic aspects of
several of the disorders that have been associated with
stroke in young adults.
Spontaneous arterial dissection59 is one of the most
common causes of stroke in young adults (figure 4). This
disorder often affects 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.60–62 The occurrence of multiple concomitant

Clinical signs Confirmatory tests

Cervical arterial dissection Minor head or cervical trauma, headache, facial or neck pain, Horner’s Cervical MT MRI with fat suppression,
syndrome, XII palsy 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 MRI*
Patent foramen ovale Stroke during Valsalva’s manoeuvre, stroke after prolonged immobilisation TEE, TCD with microbubbles
Other cardioembolic diseases Clinical history and examination, cortical stroke*, haemorrhagic ECG, cardiac monitoring, TTE, TEE,
transformation, multiple infarcts in different arterial territories Holter
Pulmonary fistulae 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 Clinical criteria, ANA, anti-DNA and Sm
involvement
Antiphospholipid syndrome Miscarriages, venous thrombosis, prolonged aPTT Lupus anticoagulant, anticardiolipin and
β-2, glycoprotein antibodies
Sneddon’s syndrome Generalised livedo reticularis, ischaemic and haemorrhagic stroke Skin biopsy, digital artery biopsy
Takayasu’s disease Absent pulses in upper limbs, blood pressure difference 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 Visual loss, progressive or episodic deafness, abnomal fundoscopy ENT and ophthalmological consultation
retinocochlearcerebral arteriopathy
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 Small-vessel disease, cerebral aneuryms, porencephaly, retinal arterial Genetic testing
disorders tortuosity, kidney disease, muscle cramps
Fabry’s disease Skin, ocular, or kidney involvement; vertebrobasilar dolicoectasia Genetic testing, GLA activity
MELAS Migraine, seizures, myopathy, deafness, short stature EMG, muscle biopsy, genetic testing

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=α-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 deficiencies, factor V Leiden, prothrombin G20210A mutation.

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

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 Review
A B
D E
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 finding 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 suggest-
ive of dissection include a history of head or neck trauma
(even minor), headache or neck pain, and local signs (such
as Horner’s 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 (80–96%) than for vertebral dissection
(70–86%).65 However, it has a low sensitivity in cases with
only local signs.66 CT angiography has an excellent
sensitivity (92–100%) 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 (87–100%). Cervical MRI can be used to
identify the intramural haematoma with T1-weighted fat-
suppressed sequences (figure 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
1090
C
F
is used in doubtful cases in which the results of non-
invasive 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 first
month, and long-term risk of recurrent dissection
(0·3–1·4%), stroke (0·3–3·4% 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 first 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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Transoesophageal echocardiography with a contrast study
is the most sensitive diagnostic test for detection of a patent
foramen ovale (figure 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 shunt—namely, a pulmonary
arteriovenous fistula. 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 2·9 (95% CI 2·1–4·0).
The corresponding OR was 5·1 (3·3–7·8) for younger
patients (<55 years) and 2·0 (>1·0–3·7) 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 under-
recognition 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
first74 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 1·6 events per 100 person-years (95% CI
1·1–2·1). 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 0·8 [95% CI 0·5–1·3]). 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 defined. A shunt via a
patent foramen ovale might allow passage of thrombotic
material from the venous bed into the arterial circulation,
which defines 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, Valsalva’s
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
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Review
A B
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
finding 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 specific
infections is closely related to the epidemiological burden
of such infections in different 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
inflammation 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 affect the major (large and medium size)
basal brain vessels (Heubner’s arteritis), especially the
middle cerebral artery or the deep perforating vessels
(Nills-Alzheimer’s 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 CSF-
VDRL or RPR sensitivity are about 99% but their specificity
is 70–75%.77 Therefore, a CSF-treponemal antibody test
might be necessary in some cases to confirm diagnosis.
Borreliosis is a tick-borne, inflammatory 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.
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 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 affect 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 effects of the
vasculopathy in patients with bacterial meningitis.82
Varicella-zoster virus vasculopathy affects 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 findings are of high mononuclear cell counts, raised
protein, and normal concentrations of glucose. Varicella-
zoster virus antigens, DNA, and antibodies against the
virus can be detected in the CSF to confirm 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 different
mechanisms such as cerebral vasculopathy, cardio-
embolism, and haematological factors.85 HIV-associated
vasculopathy has been described in young adults and can
1092
affect 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 affected by the inflammatory
process. Lacunar infarctions can occur as a result of
inflammation 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 affected 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
Takayasu’s disease in which stroke is common and might
even be the presenting manifestation. A few case reports
document arterial strokes due to Churg-Strauss, Wegener’s
vasculitis, polyarteritis nodosa, cryoglobulinaemia, and to
other systemic inflammatory disorders such as Behçet’s
disease, inflammatory 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 Sneddon’s 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 confirm the
diagnosis before starting aggressive treatment with high-
dose steroids and cyclophosphamide. However, the biopsy
sample can be negative or inconclusive, although its
sensitivity is moderate (50–60%).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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Other rare non-inflammatory arteriopathies
Other arteriopathies include radiation arteriopathy,
fibromuscular 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),
Susac’s syndrome (encephalopathy, hearing loss, and
retinal artery branch occlusions),97 and acute posterior
multifocal placoid pigment epitheliopathy (multiple cream-
coloured lesions of the retinal pigment epithelium).
Haematological disorders
Apart from sickle-cell anaemia,98 other haematological
diseases affecting young adults can be occasionally
complicated by arterial stroke. Examples are paroxysmal
nocturnal haemoglobinuria, thrombotic thrombo-
cytopenic 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 β 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
confluent subcortical white matter changes extending to
the temporal lobes. The diagnosis is confirmed by skin
biopsy and genetic testing (Notch 3 mutations).100 The
estimated prevalence of CADASIL in young patients with
stroke is very low (0·5% 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 effective enzyme (α-galactosidase)
substitution therapy has led to a renewed interest
in Fabry´s disease as a cause of stroke in young adults.
Fabry´s disease is a systemic disorder affecting mainly the
kidney, skin (angiokeratoma), and eye (corneal opacities).
It causes a painful neuropathy. The diagnosis in
symptomatic men can be confirmed by a deficit in serum
α-galactosidase, but usually needs genetic testing,
particularly in women, who can have normal concentrations
of α-galactosidase.103 Vertebrobasilar dolicoectasia and the
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Review
coexistence of large-vessel and small-vessel disease are
suggestive of Fabry’s disease. Fabry’s disease is more
frequent in young patients with cryptogenic ischaemic
stroke.104 In two large multicentre studies of young patients
with stroke, α-galactosidase pathogenic mutations were
recorded in 2·4%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
α-galactosidase pathogenic mutations were more frequent
in patients with evidence of small-vessel disease (lacunes
or leukoaraiosis; 4·5%), more so if they were not
hypertensive (7%), and in normotensive patients with
posterior circulation strokes (12·5%). Of importance is the
fact that stroke frequently arises before diagnosis of Fabry’s
disease and in the absence of other clinical findings.106
In COL4A1 mutations—namely, in hereditary
angiopathy, nephropathy, aneurysm, and muscle cramps
(HANAC) syndrome—the 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
identified 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 small-
vessel 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 fluctuate, 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 vaso-
constriction 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 identification 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 files. 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, community-
based 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
Fabry’s disease.3,104–106 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, definition 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 different 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 differ from those in developed
countries. The aetiological diagnosis of stroke in young
adults needs a different and more complex diagnostic
work up than does stroke in older adults. Studies
comparing the cost-effectiveness of different strategies
(eg, comprehensive vs staged vs clinically oriented) are also
needed to search for the causes of stroke in this age group.
Finally, guidelines specifically 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 first draft, apart from
the sections written by ARM and JLM, and prepared tables 1 and 2 and
figures 1–4 and 6. ARM wrote the first draft of the sections on infections
and prepared the panel. JLM wrote the first draft of the sections on
migraine, pregnancy, and patent foramen ovale and prepared figure 5.
All authors contributed equally to the review of the subsequent drafts
and final version, which they read and approved.
Conflicts of interest
We declare that we have no conflicts of interest.
1094
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