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Lancet Neurol2010; 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); andService

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

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 eventfrom the patients perspective. Stroke can cause death, disability, and hamper quality of life. For the neurologisttreating 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 enableidentification of the most frequent causes of stroke in this age group: cardioembolism and arterial dissection.Specific diagnostic tests for the many other rare causes of ischaemic stroke in young adults (angiography, CSFexamination, screening for vasculitis and thrombophilia, genetic testing, and ophthalmological examination)should be guided by suspected clinical findings or by the high prevalence of diseases associated with stroke insome countries.

Introduction

The incidence of stroke rises exponentially with age andis therefore low in young adults.1Nevertheless, ischaemicstroke in young adults is a common cause of admissionto stroke units and referral to neurology departments ortertiary hospitals.2,3Traditional risk factors for stroke suchas hypertension and diabetes are not very frequent inyoung adults;2,3 however, some other permanent ortransient risk factors such as smoking, use of oralcontraceptives, migraine, trauma, use of illicit drugs, andpregnancy or puerperium have a more important role inthis age group than in older adults. The main clinicalchallenge in management of a young adult with acutestroke is the identification of its cause. Although large

extracranial and intracranial atheroma, small-vesseldisease, and atrial fibrillation4,5have a major role in casesof stroke in older adults, these disorders are much lessfrequent in young adults. Our ability to establish adefinite cause for stroke in young people has improvedin the past decades because of advances in the non-invasive imaging of the brain vessels, heart cavities, andvalves, and cardiac electrophysiology and geneticdiagnostic instruments.

In this Review, we focus on the aetiological diagnosisof stroke in young adults with particular emphasis onthe best approaches to confirm or exclude the mostcommon causes of stroke in these patients, and wedescribe the clinical features and diagnostic

considerations of several associated disorders anddiseases, with the aim of facilitating practisingneurologists, emergency physicians, and internists inreaching an aetiological diagnosis of stroke in youngadults. We also describe the most relevant aspects andadvances in the descriptive and analytical (risk factorsand associated disorders) epidemiology of ischaemicstroke in young adults. Young adults are variouslydefined in published studies as aged less than 40, 45, 50,or 55 years; here, to be inclusive, we use the upper agelimit of 55 years. Apart from a consensus proposal onthe aetiological investigation of cerebral infarction inyoung adults from the Societ Franaise Neurovasculaire,6no specific guidelines exist for the management of strokespecifically in this age group.

Incidence, prevalence, and demographics

In a hospital-based study in Finland,2the yearly incidenceof stroke increased from 24 per 100 000 for people aged2024 years, to 45 per 100 000 for people aged 3034 years,and to 329 per 100 000 for people aged 4549 years. Strokeis slightly more frequent in women aged 2030 years andin men older than 35 years. The proportion of strokes ofundetermined or rare causes is much higher for youngadults than for older patients.5 In young adults theaetiological subgroups also vary with age: the proportionof strokes of undetermined cause decreases with age,whereas the proportion of strokes caused by large arteryatherosclerosis and small-vessel disease increases afterthe age of 3540 years.2,7 In the Helsinki Young Stroke

Registry

2

(1008 patients aged

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ratio [OR] 26 [95% CI 1936]).14The risk increased with

the duration

13

and dose

13,14

of the exposure, from an OR of22 (1533) for one to ten cigarettes per day up to 91(32260) for 40 or more cigarettes per day. The largeproportion of smokers among young adults with stroke incountries with a high prevalence of smokers,15particularlyin some developing countries, is of concern.16,17

MigraineFindings from a meta-analysis18 showed that the risk ofischaemic stroke in people who had migraine with aurawas doubled compared with people without migraine. Anage of less than 45 years, smoking, and oral contraceptiveuse further raised the risk. However, migraine withoutaura did not seem to affect the risk. The mechanism by

which migraine with aura increases the risk of ischaemicstroke is unknown. Migrainous infarcts caused by severehypoperfusion during an attack are rare and probablyoverdiagnosed. They mostly affect the posterior cerebralartery territory, but single and multiple infarcts of anysize and location have been reported. The incidence ofmigrainous stroke is too low to explain the increased riskof stroke in people with migraine. Other potentialmechanisms include association of migraine with knownor unknown causes or risk factors for stroke (eg, patentforamen ovale, dissection). Infarcts induced by drugs (eg,ergotamine) might also be a contributing factor. Severaldisorders such as mitochondrial encephalopathy withlactic acidosis and stroke-like episodes (MELAS), cerebralautosomal dominant arteriopathy with subcorticalischaemic strokes and leucoencephalopathy (CADASIL),or essential thrombocythaemia can cause stroke and arealso associated with migraine. Finally, focal cerebral

ischaemia can induce attacks of migraine with aura.19

Cerebral infarcts in patients with migraine should beinvestigated in the same way as any cerebral infarcts inyoung people.

Pregnancy and puerperiumAlthough the risk of ischaemic stroke for pregnant womenrises in the days before the birth and the 6 weeks postpartum, pregnancy-related stroke is rare.20,21 Nevertheless,most causes of ischaemic stroke in young adults havebeen reported during pregnancy and the puerperium.2022Although some disorders can be triggered by pregnancy(eg, peripartum cardiomyopathy), whether pregnancy iscoincidental or plays a part in the occurrence of stroke isunknown. In many patients, the cause of the stroke cannot

be identified. Whether a hypercoagulable state andchanges in vessel walls associated with pregnancy have arole in the occurrence of these otherwise unexplainedischaemic strokes remains unknown.21,22Eclampsia is themain pregnancy-specific disorder that might be associatedwith reversible cerebral vasoconstriction syndrome andwith non-haemorrhagic stroke-like episodes. Whereassome of these episodes are ischaemic strokes, other focaldeficits, which are usually reversible in a few days, are notassociated with restricted diffusion on MRI with diffusion-weighted imaging (DWI) and are probably due to vasogenicoedema rather than cytotoxic oedema. The diagnosticapproaches to stroke during pregnancy should proceed asin the non-pregnant state, while taking into account thewelfare of the fetus.2123 Finally, a history of pregnancy-related stroke should not be a contraindication forsubsequent pregnancy.24

Oral contraceptivesThe role of oral contraceptives as a risk factor forischaemic stroke remains controversial. According to theresults of a meta-analysis,25the risk of stroke is increasedby about four times for women who take pills with a highcontent of oestrogen, and is doubled for those who takepills with low oestrogen content. Pills composed ofprogestagen alone do not seem to increase the risk ofstroke.25In one cohort study,26the use of oestrogen oral

contraceptives did not increase the risk of stroke. Overall,the excess risk due to oral contraceptives is low (fourincident strokes per 100 000 women per year of oralcontraceptive use).27However, in women with migraine,oral contraceptives are associated with a raised risk ofischaemic stroke.28,29 Women who have prothromboticgenetic variants are also at increased risk.30

Illicit drugsStroke is one of the complications of recreational druguse.31 The frequency of illicit drug use in young adultswith stroke can be as high as 12%.32Therefore, toxicologyscreening for illicit drugs should be done in youngpatients with stroke with no obvious cause, or if suggestedby history or examination. The intravenous use of drugs

Figure :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.

Strokeyoung adult

Haemorrhagic strokeIschaemic stroke

ECGTEETTE

Echo-doppler+transcranialdopplerorMRAor

CT angiography

Cervical MRI

DWI-MRICT

Holter monitoring

Intra-arterial angiography

Laboratory MRICT angiographyMRA

Intra-arterial angiography

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can produce embolisation of foreign material or

endocarditis. Drugs with a sympathicomimetic effect(amphetamine, cocaine, crack) can cause ischaemicstroke through several mechanisms such as acutehypertension, enhanced platelet aggregation, and rarelyvasculitis (mainly related to amphetamine intake) of theperiarteritis nodosa or giant cell-granulomatous types.

Aetiological diagnosisGenerally, the clinical diagnosis of stroke is made in apatient with vascular risk factors and with acute onset ofsymptoms and signs that match an arterial vascularterritory. However, many young adults with stroke do nothave vascular risk factors. Conversely, CNS diseases thatmight mimic stroke are more frequent in young adults

than in older patients. The range of differential diagnosesincludes multiple sclerosis, somatoform disorders,migraine with prolonged aura, post-ictal focal deficits,neoplasms, and less often encephalitis. Many of thesedisorders can only be confirmed or ruled out by MRI. Aprospective, blind comparison of non-contrast CT andMRI with DWI and susceptibility-weighted imaging inconsecutive patients referred for assessment of suspectedacute stroke showed that MRI is better than CT foridentification of acute ischaemia, and can be used to detectacute and chronic haemorrhage.33 Therefore, in this agegroup, MRI with DWI and T2* sequences are the besttechniques to confirm the diagnosis of ischaemic strokein an emergency and to rule out other diagnoses, includingparenchymal haemorrhage.33If MRI is not available, CTshould be used to rule out intracranial haemorrhage or aneoplasm, and to identify the extent of early infarct signsin candidates for intravenous thrombolysis (figure 1).34,35

Most series of ischaemic stroke in young adults 25,7,3638have used the aetiological Trial of Org 10172 in AcuteStroke Treatment (TOAST) classification of stroke, whichconsists of the following subtypes:39large-vessel disease,small-vessel disease, cardioembolic, other identifiablecause, and undetermined cause (see cryptogenic strokebelow; figure 2 and figure 3). This classification does notinclude vascular risk factors in the diagnostic criteria. Insome series, migrainous strokes, strokes after use of

illicit drugs, and those occurring during pregnancy orpuerperium are included in the section of otheridentifiable cause36whereas in other series, some of thesestrokes are considered to be of undetermined cause.Variations in the proportion of patients in the differentaetiological subgroups are mainly related to theoperational criteria for these subgroups used in eachstudy and to the completeness of the ancillaryinvestigations. Figures 2 and 3 show examples of thesediscrepancies between studies.

Extracranial or intracranial large-vessel arterial diseaseDepending on local availability and experience, magneticresonance angiography (MRA), CT angiography, or carotidand vertebral ultrasound combined with transcranial

doppler can be used to confirm or rule out extracranial orintracranial arterial disease or an occlusion (figure 1).

Systematic reviews and a meta-analysis of individualpatient data show that contrast-enhanced MRA is the mostsensitive and specific non-invasive method foridentification of carotid stenosis, closely followed bycarotid ultrasound and CT angiography, with MRA withoutcontrast being the least reliable.4143Furthermore, contrast-enhanced MRA and CT angiography offer better imagingof the vertebral and basilar arteries,44 and ultrasoundcombined with MRA is as good as intra-arterialangiography.45 If extracranial arterial dissection issuspected, cervical MRI with fat suppression is the bestmethod 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 ifvasculitis or other rare vasculopathies are suspected.

Figure :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 colleagues38is 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.

Large-vessel disease

FrequencyofTOASTsubtypes(%)

Cardioembolicdisease

Leys, 200238

Musolino, 200336

Cerrato, 20047

Varona, 200437

Putaala, 200940

70

60

50

40

30

20

10

0

Small-vessel disease Other cause Undetermi ned

Figure :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,36a 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.

Dissection0

2

4

6

8

10

Patients(%)

12

14

16

18

Vasculitis CADASIL Coagulopathy Other

Leys, 200238

Musolino, 200336

Cerrato, 20047

Varona, 200437

Putaala, 200940

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CardioembolismReview of previous electrocardiograms (ECGs), admission

ECGs, serial ECG assessments,46 and 2448 h ECGmonitoring47is crucial to detect atrial fibrillation or otherECG evidence of cardiac disease. Holter ECG isrecommended to detect paroxysmal atrial fibrillation, butits yield is low (5%).48 Extended electroencephalogram(EEG) monitoring can be used to detect additional cases(6%) of paroxysmal atrial fibrillation.49Transoesophagealechocardiography is more sensitive than the transthoracicmethod to detect potential cardiac sources of embolism,particularly for mitral valve vegetations and for sourceslocated in the left appendage, the atrial septum, and theaorta.5052 Transoesophageal echocardiography isrecommended to be part of the aetiological work up ofischaemic stroke in young patients, unless another causeof stroke is already present (eg, dissection). However, the

additional diagnostic yield of transoesophageal

echocardiography (compared with transthoracicechocardiography) with regard to high-risk cardiac sourcesof embolism is low. In young adults, high-risk sources ofembolism detected by echocardiography includemechanical prosthetic valves, mitral stenosis, endocarditis(infective and non-infective),53,54dilated cardiomyopathies,intracardiac thrombus, and cardiac tumours such asmyxoma and fibroelastoma.55The most common uncertainsources of embolism are patent foramen ovale and atrialseptal aneurysm, akinetic or dyskinetic segments of theventricular wall, and redundant mitral valve prolapse.

Transcranial doppler monitoring of both middlecerebral arteries after injection of agitated saline in theantecubital vein can also be used to detect a right-to-left

shunt and to grade its intensity.56If paradoxical embolismis suspected, the legs should be assessed for deep venousthrombosis, which can be done by ultrasound or magneticresonance venous imaging.

Small-vessel diseaseSmall-vessel single perforator disease can produce small(

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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 patientswith no evident cause for their stroke (table 1); (2) a stagedwork up is done;6or (3) a more selective approach is taken,in which only the disorders suspected on clinical groundsare investigated (table 2). The assessment strategy willaffect the proportion of patients who are attributed aspecific cause for their stroke, particularly within thesubgroup of stroke of other determined cause (figure 3).

Specific diseases and disorders associated withischaemic stroke in young adultsFor most causes of stroke in young adults, aetiologicalevidence is based on case reports and case series,

sometimes on case-control studies, and much less oftenon cohort studies. However, causality criteria for anaetiological diagnosis are not met for many of thedisorders and syndromes discussed here. We will brieflydescribe the main clinical and diagnostic aspects ofseveral of the disorders that have been associated withstroke in young adults.

Arterial dissection

Spontaneous arterial dissection

59

is one of the mostcommon causes of stroke in young adults(figure 4). Thisdisorder often affects the extracranial internal carotidartery, with dissection starting a few centimetres after thecommon carotid bifurcation, or the vertebral artery as itenters the intervertebral channel or as it leaves it beforepiercing the dura. Extracranial dissection is multiple inabout a quarter of the cases. Dissection is usuallysubintimal and the resulting haematoma causes a long,irregular stenosis or even an occlusion. Sometimes, thedissection is subadventitial, forming a pseudoaneurysm.Intracranial dissection (eg, of the intracranial vertebralartery) might rupture into the subarachnoid space. Theaetiopathogenesis of dissection is still unclear. Often

dissection is preceded hours to weeks by minor trauma tothe head or neck, but only a few of the many young peoplewho sustain minor neck injuries have an arterial dissection.The roles of other vascular risk factors, genetic factors, andminor connective tissue abnormalities sometimes detectedin skin biopsy samples of patients with arterial dissectionare unknown.6062The occurrence of multiple concomitant

Clinical signs Confirmatory 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 bruit

Carotid/vertebral ultrasound,

angiography

Small-vessel disease Hypertension, diabetes, lacunar syndrome, capsular warning syndrome MRI*

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 different arterial territories

ECG, cardiac monitoring, TTE, TEE,

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

involvement

Clinical criteria, ANA, anti-DNA and Sm

Antiphospholipid syndrome Miscarriages, venous thrombosis, prolonged aPTT Lupus anticoagulant, anticardiolipin and

-2, glycoprotein antibodies

Sne ddons syn drome Genera lised live do reticu laris, ischaemic and haemorrhag ic stroke S kin biopsy, d igital artery biops y

Takayasus 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

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

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 deficiencies, factor V Leiden, prothrombin G20210A mutation.

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

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dissections63 and the finding of many clustered earlyrecurrences64 contrast with the rarity of late recurrencesand indicate a transient vasculopathy, which might betriggered by infections.59Clinical features that are suggest-ive of dissection include a history of head or neck trauma(even minor), headache or neck pain, and local signs (suchas Horners syndrome or cranial nerve palsies), with orwithout symptoms of cerebral ischaemia.

The diagnosis of arterial dissection can be made withultrasound, MRI, CT, or catheter angiography. Ultrasoundhas a high sensitivity, and is somewhat better for carotiddissection (8096%) than for vertebral dissection(7086%).65However, it has a low sensitivity in cases withonly local signs.66 CT angiography has an excellentsensitivity (92100%) and can be used to visualise morefeatures of dissection, particularly in the vertebral arteries,than can MRA.67MRI and MRA have a high sensitivity forcarotid dissection (87100%). Cervical MRI can be used toidentify the intramural haematoma with T1-weighted fat-suppressed sequences (figure 4) and is now considered theprocedure of choice for the diagnosis of cervical arterydissection, although the dissecting haematoma hypersignalmight take some days to develop. Intra-arterial angiography

is used in doubtful cases in which the results of non-invasive diagnostic instruments are contradictory orinconclusive, or when endovascular treatment is planned.The risk of early recurrence is low (

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Transoesophageal echocardiography with a contrast study

is the most sensitive diagnostic test for detection of a patentforamen ovale (figure 5), followed by contrast-enhancedtranscranial doppler and transthoracic echocardiography.Interobserver agreement for the diagnosis of patentforamen ovale is not perfect: disagreement can reach 14%for the presence of the disorder and 27% for the severity ofshunting.70Transcranial doppler can also be used to identifyother causes of a right-to-left shuntnamely, a pulmonaryarteriovenous fistula. Many case-control studies haveestablished a statistical association between patent foramenovale and cryptogenic stroke.71,72In a meta-analysis of thesestudies,72 the summary OR for patent foramen ovale incryptogenic stroke versus controls was 29 (95% CI 2140).The corresponding OR was 51 (3378) for younger

patients (1037) for older patients(55 years). The association has also been reported to bestronger in patients with large right-to-left shunts and inthose who have an atrial septal aneurysm in addition to apatent foramen ovale.71,72Results from a population-basedstudy73 suggest that selective referral of cases and under-recognition of patent foramen ovale in comparison groupsof patients referred for echocardiography might have led toan overestimation of the role of patent foramen ovale incryptogenic strokes.

By contrast with case-control studies, longitudinalstudies have been unable to show an increased risk offirst74or recurrent75stroke in patients with patent foramenovale. In a meta-analysis of 15 studies,75 the pooledabsolute rate of recurrent stroke in medically treatedpatients with cryptogenic stroke and patent foramenovale was 16 events per 100 person-years (95% CI1121). The four studies with a non-patent foramenovale comparison group did not support an increasedrelative risk of recurrent ischaemic events in those withpatent foramen ovale versus those without (pooledRR 08 [95% CI 0513]). One study showed anincreased risk of stroke recurrence in young adults withboth patent foramen ovale and atrial septal aneurysmwho were given aspirin for secondary prevention.76

The mechanism of stroke in patients with a patentforamen ovale is not well defined. A shunt via a

patent foramen ovale might allow passage of thromboticmaterial from the venous bed into the arterial circulation,which defines paradoxical embolisation. This mechanismis supported by rare case reports in which a thrombus wasvisualised within a patent foramen ovale at autopsy orechocardiography. However, in most patients withcryptogenic stroke associated with patent foramen ovale,no direct or indirect (eg, venous thrombosis, Valsalvasmanoeuvre preceding stroke onset) signs of paradoxicalembolism can be noted. Other potential strokemechanisms, such as direct embolisation of thrombiformed in situ and paroxysmal arrhythmia, remainunproven. This uncertainty suggests that othermechanisms unrelated to patent foramen ovale mightbe operant in many cases. In this respect, it should be

kept in mind that patent foramen ovale is a common

finding in the normal population and must coexist bychance alone in about a third of patients with ischaemicstroke.72 Consequently, for some patients, stroke iserroneously attributed to a patent foramen ovale.

InfectionsThe epidemiological relevance of stroke related to specificinfections is closely related to the epidemiological burdenof such infections in different regions. Examples are HIVinfection in sub-Saharan Africa, cysticercosis, and Chagasdisease in South America, and syphilis and tuberculosisin the Indian subcontinent (panel).

Syphilis can produce stroke both during its early andlate phases. Most strokes caused by syphilis occur in theearly (secondary) phase. In the early phase, a suddencerebral infarction can be the only clinically apparentmanifestation of subacute meningitis with perivascularinflammation and arteritis. Cranial nerve palsies and palmand sole cutaneous eruption might also be present. In latesyphilis there is a transmural proliferative endarteritis.This arteritis can affect the major (large and medium size)basal brain vessels (Heubners arteritis), especially themiddle cerebral artery or the deep perforating vessels(Nills-Alzheimers arteritis). Stroke can also be secondaryto late cardiac complications of syphilis. CSF examinationis recommended for diagnosis of neurosyphilis. Reportsof meningovascular syphilis have become more common

with the AIDS epidemic. HIV tests are recommended inall patients with meningovascular syphilis, whereas aCSF-venereal disease research laboratory (VDRL) or rapidplasma reagin (RPR) test is needed in every patient withHIV who develops cerebrovascular disease. The CSF-VDRL or RPR sensitivity are about 99% but their specificityis 7075%.77 Therefore, a CSF-treponemal antibody testmight be necessary in some cases to confirm diagnosis.

Borreliosis is a tick-borne, inflammatory disordercaused by the spirochete Borrelia burgdorferiand can beassociated with a meningovascular process. Data thatlend support to an association between Borrelia burgdorferiinfection and stroke are scarce.78,79A history of tick bitesor erythema chronicum migrans in an endemic regionsuggests a diagnosis of borreliosis.

Figure :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.

A B

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Stroke is common in patients with tuberculousmeningitis and is associated with the severity ofmeningitis, hydrocephalus, and meningeal exudates.80,81

Vasculitis can be recorded in the basal cerebral arteriesand their perforating branches. Brain infarcts affect theso-called tuberculosis zone, which consists of theterritories of the lenticulostriate and thalamoperforatingarteries. Bilateral basal ganglia infarcts are a characteristicfeature of tuberculous meningitis. Moreover, transcranialdoppler is a valuable non-invasive instrument for thediagnosis of tuberculous arteritis.

Patients with acute bacterial meningitis can developcerebrovascular complications, most of which occurwithin 2 weeks of the infection. Transcranial dopplerstudies show the haemodynamic effects of thevasculopathy in patients with bacterial meningitis.82

Varicella-zoster virus vasculopathy affects bothimmunocompetent and immunocompromised patients,occurs after zoster or varicella, and can be either focal ormultifocal.83Cerebral vasculopathy arises frequently afterophthalmic herpes zoster, is commonly located on theside of the skin lesion, and is often distributed in themiddle and anterior cerebral arteries. Usually, the clinicalcourse is characterised by gradual resolution of cutaneousherpes zoster ophthalmicus followed by the acute onsetof contralateral hemiparesis, hemisensory symptoms, oraphasia. Optic nerve infarction can be noted in somepatients, and rash can be absent in others.84Angiographycan show irregular segmental narrowing of both largeand small arteries.83Infarcts often occur at the grey-white

matter junctions, as shown by MRI. The most commonCSF findings are of high mononuclear cell counts, raisedprotein, and normal concentrations of glucose. Varicella-zoster virus antigens, DNA, and antibodies against thevirus can be detected in the CSF to confirm the diagnosisof infection in the CNS. Only negative results on bothPCR and tests of IgG antibodies for varicella-zoster virusin CSF can exclude the diagnosis of varicella-zoster virusvasculopathy.83

Patients infected with HIV have a higher risk of bothischaemic and haemorrhagic stroke than do those notinfected. This increased risk occurs through differentmechanisms such as cerebral vasculopathy, cardio-embolism, and haematological factors.85HIV-associatedvasculopathy has been described in young adults and can

affect either large or medium extracranial or intracranial

arteries. A small-vessel vasculopathy has also been notedin patients with AIDS. Moreover, risk of acceleratedatherosclerosis is potentially associated with antiretroviraltreatment.

Stroke is one of the most feared complications ofcysticercosis, which is more frequent in patients withsubarachnoid neurocysticercosis. Usually the middle andposterior cerebral arteries are affected by the inflammatoryprocess. Lacunar infarctions can occur as a result ofinflammation of small penetrating arteries. Ischaemicstrokes are less frequent in patients with parenchymalneurocysticercosis and usually arise in the vicinity ofcysts. Transcranial doppler is a useful method for thediagnosis and follow-up of patients with arteritis caused

by neurocysticercosis.86Chagas cardiomyopathy increases the risk of embolic

ischaemic stroke.87 This disease is caused byTrypanosoma cruzi and is transmitted to manby triatomine bugs that deposit faeces on the mucousmembranes or skin while they bite. Chagas diseaseprogresses in stages, and most patients are infectedduring their early years. The cardiac system is affected inmany patients with this disease.

Primary and secondary vasculitis and connective tissuedisordersPrimary vasculitis and connective tissue disorder rarelypresent as a stroke syndrome. Exceptions are systemiclupus erythematosus, antiphospholipid syndrome,88 andTakayasus disease in which stroke is common and mighteven be the presenting manifestation. A few case reportsdocument arterial strokes due to Churg-Strauss, Wegenersvasculitis, polyarteritis nodosa, cryoglobulinaemia, and toother systemic inflammatory disorders such as Behetsdisease, inflammatory bowel disease, and sarcoidosis.

The most common mechanisms of stroke in systemiclupus erythematosus are hypertensive small-vessel disease,cardioembolism, and the presence of a prothromboticstate.89 Sneddons syndrome refers to a rare disorderfeaturing widespread generalised livedo reticularis andmultiple strokes,90and 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 withencephalopathy and headache. Lumbar puncture usuallyshows lymphocytic pleiocytosis, and cerebral angiographyeither shows signs that suggest vasculitis or is normal. Ameningeal brain biopsy should be done to confirm thediagnosis before starting aggressive treatment with high-dose steroids and cyclophosphamide. However, the biopsysample can be negative or inconclusive, although itssensitivity is moderate (5060%).92 Cerebral vasculitisshould be distinguished from the more common reversiblecerebral vasoconstriction syndromes, in which varioussegmental narrowings of the intracranial vessels disappearon control angiograms and the CSF is usually normal.93,94

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

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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 developedcountries. The rarest causes of stroke in young adults arethe retinocerebral or retinocochlearcerebral arteriopathies,such as Eales disease (retinopathy with neovascularisation),Susacs syndrome (encephalopathy, hearing loss, andretinal artery branch occlusions),97 and acute posteriormultifocal placoid pigment epitheliopathy (multiple cream-coloured lesions of the retinal pigment epithelium).

Haematological disordersApart from sickle-cell anaemia,98 other haematologicaldiseases affecting young adults can be occasionally

complicated by arterial stroke. Examples are paroxysmalnocturnal haemoglobinuria, thrombotic thrombo-cytopenic purpura, erythrocytosis, leukaemias, andintravascular lymphoma.

Monogenic diseasesThere are more than 50 monogenic diseases that cancause stroke, but they account for a very low percentageof strokes. These disorders are very rare, apart fromdrepanocytosis, which is an important cause of stroke inchildren and young adults of African ethnic origin. 98,99Inyoung patients of African origin with stroke, sickle-celldisease should always be looked for by use of haemoglobinelectrophoresis (haemoglobin S) or genetic testing(Val-Glu substitution in the globin chain). Follow-up ofintracranial stenosis can be done non-invasively withtranscranial doppler.

Subcortical vascular dementia, depression and otherpsychiatric disorders, migraine with aura, and recurrentstrokes are the main clinical features of CADASIL. Thediagnosis is suspected if there is a family history(autosomal dominant) and if MRI shows the characteristicconfluent subcortical white matter changes extending tothe temporal lobes. The diagnosis is confirmed by skinbiopsy and genetic testing (Notch 3 mutations).100 Theestimated prevalence of CADASIL in young patients withstroke is very low (05% of lacunar strokes; 2% in patients

younger than 65 years with white matter changes).101Hypertension and smoking are associated with anincreased probability of stroke in patients with CADASIL,suggesting that vascular risk factors might modulate theclinical expression of this disorder.102

The availability of an effective enzyme (-galactosidase)substitution therapy has led to a renewed interestin Fabrys disease as a cause of stroke in young adults.Fabrys disease is a systemic disorder affecting mainly thekidney, skin (angiokeratoma), and eye (corneal opacities).It causes a painful neuropathy. The diagnosis insymptomatic men can be confirmed by a deficit in serum-galactosidase, but usually needs genetic testing,particularly in women, who can have normal concentrationsof -galactosidase.103Vertebrobasilar dolicoectasia and the

coexistence of large-vessel and small-vessel disease are

suggestive of Fabrys disease. Fabrys disease is morefrequent in young patients with cryptogenic ischaemicstroke.104In two large multicentre studies of young patientswith stroke, -galactosidase pathogenic mutations wererecorded in 24%3 of 493 and 1%105 of 1000 patients withstrokes, more often in those with ischaemic stroke (bothcryptogenic and non-cryptogenic). In one of these studies,3-galactosidase pathogenic mutations were more frequentin patients with evidence of small-vessel disease (lacunesor leukoaraiosis; 45%), more so if they were nothypertensive (7%), and in normotensive patients withposterior circulation strokes (125%). Of importance is thefact that stroke frequently arises before diagnosis of Fabrysdisease and in the absence of other clinical findings.106

In COL4A1 mutationsnamely, in hereditaryangiopathy, nephropathy, aneurysm, and muscle cramps(HANAC) syndromethe cerebral vascular phenotypeinvolves an association between a subcortical small-vesseldisease and aneurysms of the carotid siphon.107

Hereditary endotheliopathy with retinopathy,nephropathy, and stroke (HERNS) is associated withmutations of the TREX1gene and its phenotype includespsychiatric symptoms, dementia, subcortical strokes, andleucoencephalopathy.

Cryptogenic strokeIn about 30% of patients, the cause of stroke cannot beidentified despite the detailed and comprehensiveaetiological work up described in this Review. Some ofthese patients might have classic vascular risk factors, butthey do not show evidence of large atherosclerotic or small-vessel arterial disease. Minor atherosclerotic lesions mightbe missed by current diagnostic and imaging techniques.A frequent mistake is the diagnosis of cryptogenic strokein patients with incomplete or delayed aetiologicalinvestigation.108 This misdiagnosis is of particularimportance in dissection, which can resolve quickly, and inintracardiac thrombus, which can either resolve orfragment and embolise. Results of some biologicaldiagnostic tests (eg, antiphospholipid antibodies forantiphospholipid syndrome or platelet count for

thrombocythaemia) can fluctuate, and therefore repeatedassessment is needed. Repeated or extended Holtermonitoring might be necessary if paroxysmal arrhythmiasare suspected. Repeated angiography might also benecessary to distinguish between reversible cerebral vaso-constriction syndrome, in which the various segmentalarterial narrowings are reversible, and vasculitis,atherosclerosis, or other vasculopathies of intracranialarteries, in which the narrowings persist or even progress.

Conclusions and future directionsProgress in the identification of the causes andmechanisms of stroke in young adults has been slow butconstant, mainly because of technological advances inimaging and genetic diagnosis. Despite this progress,

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several methodological issues and many unansweredclinical questions still need to be addressed.

Most of the case series of stroke in young adults wereassembled in tertiary hospitals. Therefore, incompletecase ascertainment and selection bias towards more severe

cases or rare causes is inevitable. However, community-based studies are not very helpful to widen our knowledgeabout the causes and prognosis of stroke in young adultsbecause only a few cases of stroke will be detected in thisgroup, in view of the low incidence of stroke before theage of 50 years. Therefore, in the past decade, we havewitnessed an increased collaboration between individualcentres in the study of some causes of stroke in youngadults, such as patent foramen ovale,76dissection,109,110andFabrys disease.3,104106These collaborations should also bepursued in the setting of multicentre registries andrandomised clinical trials, thus gathering the requiredsample sizes that are needed for answering relevantclinical questions and for preplanned subgroup analyses.Moreover, definition of subtypes of stroke and associateddisorders should be uniform and explicit. Studies withlonger follow-up are needed to investigate the outcomesas young patients age. More observational data are neededon the safety of pregnancy after stroke in young women.Centres in developing countries in different continentsshould actively participate in such studies, because moststrokes in young adults take place in these settings.Furthermore, the causes of stroke are diverse and resourceallocation strategies differ from those in developedcountries. The aetiological diagnosis of stroke in youngadults needs a different and more complex diagnosticwork up than does stroke in older adults. Studies

comparing the cost-effectiveness of different strategies(eg, comprehensive vsstaged vsclinically oriented) are alsoneeded to search for the causes of stroke in this age group.Finally, guidelines specifically dedicated to stroke in youngadults, such as those already available for stroke inchildren,111would be welcome.

Contributors

JMF generated the outline of the Review, wrote the first draft, apart fromthe sections written by ARM and JLM, and prepared tables 1 and 2 andfigures 14 and 6. ARM wrote the first draft of the sections on infectionsand prepared the panel. JLM wrote the first draft of the sections onmigraine, pregnancy, and patent foramen ovale and prepared figure 5.All authors contributed equally to the review of the subsequent draftsand final version, which they read and approved.

Conflicts of interest

We declare that we have no conflicts of interest.

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