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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
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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Review
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
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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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
www.thelancet.com/neurology Vol 9 November 2010
Review
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 (%)
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.
Review
Test or procedure
Antiphospholipid syndrome
Specic infections
Cryoglobulins
Illicit drugs
CSF examination
Hyperhomocysteinaemia
Homocysteine concentrations
Specic deciencies
Specic mutations
Sickle-cell disease
Haemoglobin electrophoresis
Ophthalmological examination
Periarteritis nodosa
Takayasus disease
Aortic PET
Cerebromeningeal biopsy
Fabrys disease
GLA activity
CADASIL
Skin biopsy
MELAS
Muscle biopsy
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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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
Review
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
Multiple vascular risk factors, stroke preceded by transient ischaemic attacks, Carotid/vertebral ultrasound,
carotid bruit
angiography
Small-vessel disease
Pulmonary stulae
Chest CT
Anaemia, low platelet count, arthralgias, fever, high ESR, skin or kidney
involvement
Antiphospholipid syndrome
Sneddons syndrome
Takayasus disease
Moyamoya syndrome
Angiography
Retinoarteriopathy and
retinocochlearcerebral arteriopathy
Sickle-cell disease
CADASIL
Genetic testing
Fabrys disease
MELAS
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.
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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.
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.
Review
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.
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Review
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
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.
Review
1094
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