Stroke in Young

Review Article

Stroke in young

Pushpendra Nath Renjen*

Sr. Consultant Neurologist & Academic Coordinator, Institute of Neurosciences, Indraprastha Apollo Hospitals,

New Delhi 110076, India

a r t i c l e i n f o

Article history:

Received 8 August 2013

Accepted 17 October 2013

Available online 20 November 2013

Keywords:

Cerebral ischemia

Prognosis

Young adult

Stroke

a b s t r a c t

Stroke in people under 45 years of age is less frequent than in older populations but has a

major impact on the individual and society. In this article we provide an overview of the

epidemiology and etiology of young stroke.

Cerebral ischemia in young adults occurs at an annual incidence rate of about 6/100,000.

Although it represents only about 1% of all strokes, it has a relevant impact on years of

potential life lost and on socioeconomic costs, considering the long life expectancy at these

ages. There is general agreement on the role of atherosclerosis in men over age 35 and of

cardiac diseases, migraine, and oral contraceptive use in women under age 35 as patho-

genic determinants for cerebral ischemia. Whether the early onset of stroke in young

adults might reflect severity of underlying pathology is still an open question. The short-

term prognosis of stroke in young adults is considered favorable, despite its relationship

with the presence and severity of complications at the time of the first event. Long-term

prognosis of young patients with transient ischemic attack is reported to be even more

favorable, although the risk of new ischemic events depends on the presence of vascular

risk factors. The available prospective studies report annual incidence rates of death and

recurrent stroke ranging from 1% to 2.6%, with higher long-term mortality in patients who

had large-vessel stroke. The prognosis has been reported to be severe in patients with

carotid stenosis and mild in patients with coexisting stroke and migraine.

Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.

1. Introduction

Stroke in people under 45 years of age is less frequent than in

older populations but has a major impact on the individual

and society. In this article we provide an overview of the

epidemiology and etiology of young stroke.

Cerebral ischemia in young adults occurs at an annual

incidence rate of about 6/100,000. Although it represents only

about 1% of all strokes, it has a relevant impact on years of

potential life lost and on socioeconomic costs, considering the

long life expectancy at these ages.1 There is general

agreement on the role of atherosclerosis in men over age 35

and of cardiac diseases, migraine, and oral contraceptive use

in women under age 35 as pathogenic determinants for ce-

rebral ischemia.2,3 Whether the early onset of stroke in young

adults might reflect severity of underlying pathology is still an

open question.3

The short-term prognosis of stroke in young adults is

considered favorable, despite its relationship with the pres-

ence and severity of complications at the time of the first

event.4,5 Long-termprognosis of young patientswith transient

ischemic attack (TIA) is reported to be even more favorable,

* Tel.: þ91 11 29871016, þ91 9810059614 (mobile).E-mail address: pnrenjen@hotmail.com.

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.elsevier .com/locate/apme

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5e2 6 9

0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2013.10.008

although the risk of new ischemic events depends on the

presence of vascular risk factors.6,7 The available prospective

studies report annual incidence rates of death and recurrent

stroke ranging from 1% to 2.6%, with higher long-term mor-

tality in patients who had a large-vessel stroke.5,8,9 The

prognosis has been reported to be severe in patients with ca-

rotid stenosis and mild in patients with coexisting stroke and

migraine.10

2. Etiologies

The range of potential etiologies for stroke in young adults is

broader than that for older adults (Table 1). Like in older

adults, stroke in younger adults is typically categorized as

primarily ischemic or hemorrhagic. Ischemic etiologies

include cardioembolic, atherosclerotic disease, and non-

atherosclerotic cerebral vasculopathies. Hemorrhagic strokes

include subarachnoid and intraparenchymal types. Of

particular note in young adults are stroke causes such as he-

matologic disorders, substance abuse, trauma, dissections,

oral contraceptive use, pregnancy and postpartum states, and

migraine.

3. Clinical manifestations

The clinical presentations for stroke in young adults are not

unique to this age group. Sudden or subacute onset of

neurologic symptoms referable to the brain should suggest

stroke as a potential explanation. The presence of a given

stroke risk factor does not assure that it is causative. Many

young patients havemultiple risk factors. Detailed history and

examination, oriented toward common and uncommon eti-

ologies, are especially important. Stroke mimics in the young

adult population include multiple sclerosis and malignancy.

The physical exam should include neurologic, cardiovas-

cular, ophthalmologic and dermatologic assessments. Rele-

vant ocular findings include corneal arcus

(hypercholesterolemia) or corneal opacity (Fabry’s disease);

Lisch nodules, optic atrophy (neurofibromatosis); lens sub-

luxation (Marfan’s syndrome, homocystinuria); and retinal

perivasculitis (sickle-cell disease, syphilis, connective tissue

diseases, inflammatory bowel disease), occlusions (emboli),

angioma (cavernous malformation), or hamartoma (tuberous

sclerosis). Among dermatologic associations are splinter

hemorrhages or needle tracks (endocarditis); xanthoma

Table 1 e Differential diagnosis of stroke in young adults.

Ischemic

Cardiac disease (including congenital, rheumatic valve disease, mitral valve prolapse, patent foramen ovale, endocarditis, atrial myxoma,

arrhythmias, cardiac surgery)

Large vessel disease

� Premature atherosclerosis.

� Dissection (spontaneous or traumatic).

� Inherited metabolic diseases (homocystinuria, Fabry’s, pseudoxanthoma elasticum, MELAS syndrome).

� Fibromuscular dysplasia.

� Infection (bacterial, fungal, tuberculosis, syphilis, Lyme).

� Vasculitis (collagen vascular diseases e systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, polyarteritis nodosa;

Takayasu’s disease, Wegener’s syndrome, cryoglobulinemia, sarcoidosis, inflammatory bowel disease, isolated central nervous system

angiitis).

� Moyamoya disease.

� Radiation.

� Toxic (illicit drugs e cocaine, heroin, phencyclidine; therapeutic drugs e l-asparaginase, cytosine arabinoside).

Small vessel disease

� Vasculopathy (infectious, noninfectious, microangiopathy).

Hematologic disease

� Sickle-cell disease.

� Leukemia.

� Hypercoagulable states (antiphospholipid antibody syndromes, deficiency of antithrombin III or protein S or C, resistance to activated

protein C, increased factor VIII).

� Disseminated intravascular coagulation.

� Thrombocytosis.

� Polycythemia vera.

� Thrombotic thrombocytopenic purpura.

� Venous occlusion (dehydration, parameningeal infection, meningitis, neoplasm, polycythemia, leukemia, inflammatory bowel disease).

Migraine

Hemorrhagic

Subarachnoid hemorrhage (cerebral aneurysm)

Intraparenchymal hemorrhage

� Arteriovenous malformation.

� Neoplasm (primary central nervous system, metastatic, leukemia).

� Hematologic (sickle-cell disease, neoplasm, thrombocytopenia), moyamoya disease.

� Drug use (warfarin, amphetamines, cocaine, phenylpropanolamine).

� Iatrogenic (peri-procedural).

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5e2 6 9266

(hyperlipidemia); cafe-au-lait spots, neurofibromas (neurofi-

bromatosis); purpura (coagulopathy); and capillary angioma

(cavernous malformation).11

One-fifth to one-third of strokes in the young may be

caused by cardioembolic phenomena. Transesophageal

echocardiography (TEE) is usually indicated. Causes include

congenital heart disease, valvular disease (including endo-

carditis) and arrhythmias. Mitral valve prolapse and patent

foramen ovale are common but are typically not causes of

strokewhen present. An atrial septal aneurysm is less likely to

be associated with stroke when found in isolation than when

it occurs with other cardiac abnormalities.

Premature atherosclerotic cerebrovascular disease can be

symptomatic in young adults, just as atherosclerosis can

begin in childhood. The symptoms and signs are similar to

those for older adults.

Cervicocephalic arterial dissections can involve the extra-

cranial internal carotid, the vertebrobasilar system, or, less

commonly, the intracranial carotid system. They are associ-

atedwithmajororminimal trauma, chiropracticmanipulation,

or can occur spontaneously. Other associations include fibro-

muscular dysplasia, Marfan syndrome, EhlerseDanlos syn-

drome type IV, moyamoya and sympathomimetic drug abuse.

Symptoms and signs may include neck pain, transient or last-

ing ischemiaof retina, cerebralhemispheres, orposterior fossa,

Horner’s syndrome, hemicranial pain, or subarachnoid hem-

orrhage. Extracranial ultrasound or magnetic resonance angi-

ography (MRA) may confirm the clinical impression. Often

catheter angiography is required for diagnosis.

Cerebral vasculitis should be considered for cases of

ischemic or hemorrhagic stroke, recurrent strokes, stroke

with encephalopathy, and stroke with fever, multifocal

symptoms, skin abnormalities, or abnormal renal function or

sedimentation rate. Infectious vasculitis (eg, with syphilis,

tuberculosis, purulent meningitis), necrotizing vasculitis (eg,

polyarteritis nodosa), vasculitis with collagen vascular disease

(eg, lupus, rheumatoid arthritis), giant cell arteritis, and hy-

persensitivity vasculitis (eg, drug-induced) are seen much

more often than primary central nervous system vasculitis.

Moyamoya is a noninflammatory vasculopathy associated

with extensive collateral vasculature. It can present with

transient ischemic attacks, headaches, hemiparesis, seizures,

cerebral infarction, or hemorrhage. MRA screening is useful.

Angiographic findings are distinctive and resemble in part a

“puff of smoke”.12

Hypercoagulable states may be responsible for 2%e7% of

cases in young adults. Inherited (primary) thrombophilic dis-

orders include entities that are recently described (hyper-

homocysteinemia, factor V Leiden, prothrombin G20210A),

well-established (deficiencies of antithrombin, protein S or

protein C), and extremely rare (dysfibrinogenemia, thrombo-

modulin deficiency, heparin cofactor II deficiency).13 Acquired

(secondary) causes include malignancy, pregnancy/post-

partum states, oral contraceptive use and sickle-cell disease.

Prior thromboembolic disease in a young patient or in family

members should raise suspicion.12

Cerebral venous thrombosis can cause ischemic or hem-

orrhagic strokes. Septic thrombosis usually occurs at the

cavernous sinus as a complication of facial infection. Signs

include proptosis, chemosis, and gaze palsies. Aseptic

thromboses are seen disproportionately in women during

pregnancy or postpartum periods, or while taking oral con-

traceptives. Presenting symptoms include headache, emesis,

lethargy, and seizures. Papilledema may accompany focal

signs.12,14

Strokes induced by migraines are rare, considering that

perhaps 20% of US adults may suffer migraines. Symptoms

include persistent visual, motor, sensory or aphasic deficits,

which began in the course of a typical migraine attack, where

other causes are excluded. Mitochondrial encephalomyop-

athy with lactic acidosis and stroke-like episodes (MELAS)

syndrome and cerebral autosomal dominant arteriopathy

with subcortical infarcts and leukoencephalopathy (CADASIL)

are inherited causes of stroke which can include migraine as

part of the clinical presentation.11,12

Up to 45% of strokes in young adults are due to sponta-

neous intracerebral hemorrhage.12 Approximately half are

lobar; one-quarter are in basal ganglia or internal capsule.15

Vascular malformations, aneurysms, hypertension, and

illicit drug use are the main causes.12,15

4. Investigations

The initial work-up should be as expeditious as possible to

allow consideration of acute therapies, such as tissue plas-

minogen activator (t-PA).16 Brain computed tomography (CT)

is usually the initial imaging study of choice as it is readily

available and is highly sensitive for acute hemorrhage. Blood

work should include a complete blood count with differential

and platelet count, prothrombin time (international normal-

ized ratio), activated partial thromboplastin time, glucose,

chemistries, electrolytes, serology for syphilis, and an eryth-

rocyte sedimentation rate.

A more detailed coagulation profile (anticardiolipin anti-

bodies, lupus anticoagulants, protein S, protein C, activated

protein C resistance, antithrombin III) is requested in patients

without a firmly identified cause of stroke or if the patient or

family members have a history of thromboses. It is advanta-

geous to send such a profile prior to initiating anticoagulation,

as heparin can alter interpretation of some of those assays.

Therefore, consider ordering these assays at the beginning of

the work-up.

Most patients should have high-quality brain magnetic

resonance imaging (MRI) and often MRA.12,17 Where available,

MRI with diffusion-weighted imaging (DWI) and perfusion

imaging (PI) is becoming standard. DWI-PI has the potential to

distinguish irreversibly injured tissue from that whichmay be

salvageable.18

Additional studies in initial screening include pregnancy

testing, a chest roentgenogram, and an electrocardiogram. An

echocardiogram (consider transesophageal), and extracranial

(carotid-vertebral) Doppler ultrasound are routinely obtained,

although often after initial antiplatelet or anticoagulation

therapy is started.

Keep in mind the limitations of studies performed. CT will

miss a minority of acute bleeds. MRI with DWI, quite sensitive

for acute stroke, has an occasional false negative result (17 out

of 782 patients in a recent study).19 Also, MRA’s resolution is

not yet on par with conventional angiography.

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5e2 6 9 267

Consider conventional angiography of cerebral and neck

vessels for patients in whom dissection is suspected or in

whom no other cause is found. Transcranial Doppler ultra-

sound can be helpful.

Toxicologic studies are often productive, even when drug

use is not acknowledged.

Other blood tests may include homocysteine, fibrinogen,

antinuclear antibody, lipid panel, lipoprotein (a), serum pro-

tein electrophoresis, hemoglobin electrophoresis, and sickle-

cell assay. Cerebrospinal fluid analysis is indicated for cases

suspicious for infectious, vasculitic, or occult hemorrhage

origins. Telemetry monitoring for arrhythmias is occasionally

revealing.12

Prothrombin mutation G20210A testing is of uncertain

utility in cerebrovascular disease, but may be appropriate for

patients with a personal history of thromboembolic disease or

family history of thrombophilia.

A patient with one ormore risk factors, such asmigraine or

diabetes, should be thoroughly investigated for other possi-

bilities. The cause of stroke in young patients may remain

undetermined in 20%e30% of cases, even after a detailed

work-up.12

5. Management

General management of ischemic and hemorrhagic strokes is

similar to that for older adults and is beyond the scope of this

article. Additional specific measures are oriented toward any

underlying etiology found.

6. Prognosis

The outcome of stroke in young adults is better than that for

older adults. In a recent study of 330 patients with first stroke

or transient ischemic attack, followed for an average of 96

months, 8% died, 3% had another stroke, and 3% had a

myocardial infarction. Approximately 16% were dependent,

but 56% had returned to work. Unfortunately, only a minority

of those who smoked at the time of their stroke subsequently

stopped using tobacco. The overall annual recurrence rate is

less than 1%. Prognosis is often closely associated with the

underlying cause. A relatively good outcome may be found

after many cases of arterial dissection. Risk of stroke recur-

rence is low (2% over 5 years) in women whose first stroke

occurred in pregnancy.

7. Conclusion

In summary, stroke in the young requires a different approach

to investigation and management than stroke in the elderly

given differences in the relative frequencies of possible un-

derlying causes. Haemorrhagic stroke is common, and

vascular imaging is recommended given a high frequency of

underlying vascular anomalies. It is also important to explore

the possibility of illicit drug use in these cases. With regard to

ischemic stroke, the increased frequency of dissection man-

dates a high index of suspicion for imaging the extracranial

and intracranial vessels. Whilst the commonest cause of

cardioembolic stroke in the elderly is atrial fibrillation, in a

young patient transesophageal echocardiography looking for

the presence of a patent foramen ovale � an atrial septal

aneurysm will have a higher yield. One must not forget,

however, that atherosclerosis still contributes to a large pro-

portion of stroke in young patients and likely explains at least

some of the ethnic differences noted in the incidence of

stroke, emphasizing the need for aggressive risk factor man-

agement. This, as well as differences in the prevalence of

other causative etiologies, such as rheumatic fever and

infection, combined with a younger background population

age distribution, may contribute to an increased incidence of

young stroke in developing countries. Finally, the incidence of

stroke appears greater in women than men under the age of

30, and women are at increased risk of hemorrhage and

infarction in the puerperium. Additional history, including

use of the oral contraceptive pill, and testing for anti-

phospholipid antibodies is important in young women. There

is a need for further research in young stroke, particularly

population-based studies utilizing standardizedmethodology.

Thesewill provide clarity by enabling comparison of incidence

rates between countries and trends overtime, and insights

into underlying etiological mechanisms.

Conflicts of interest

The author has none to declare.

r e f e r e n c e s

1. Carolei A, Marini C, Di Napoli M, et al. High stroke incidencein the prospective community-based L’Aquila registry(1994e1998): first year’s results. Stroke. 1997;28:2500e2506.

2. Tzourio C, Tehindrazanarivelo A, Iglesias S, et al. Case-control study of migraine and risk of ischaemic stroke inyoung women. BMJ. 1995;310:830e833.

3. Carolei A, Marini C, Ferranti E, Frontoni M, Prencipe M,Fieschi C, The National Research Council Study Group. Aprospective study of cerebral ischemia in the young: analysisof pathogenic determinants. Stroke. 1993;24:362e367.

4. Chancellor AM, Glasgow GL, Ockelford PA, Johns A, Smith J.Etiology, prognosis and hemostatic function after cerebralinfarction in young adults. Stroke. 1989;20:477e482.

5. Hindfelt B, Nilsson O. Long-term prognosis of ischemic strokein young adults. Acta Neurol Scand. 1992;86:440e445.

6. Johnson S, Skre H. Transient cerebral ischemic attacks in theyoung and middle aged: a population study. Stroke.1986;17:662e666.

7. Larsen BH, Sorenson PS, Marquardsen J. Transient ischaemicattacks in young patients: a thromboembolic or migrainousmanifestation? A 10 year follow-up study of 46 patients. JNeurol Neurosurg Psychiatr. 1990;53:1029e1033.

8. Bogousslavsky J, Regli F. Ischemic strokes in adults youngerthan 30 years of age: cause and prognosis. Arch Neurol.1987;44:479e482.

9. Kappelle LJ, Adams HP, Heffner ML, Torner JC, Gomez F,Biller J. Prognosis of young adults with ischemic stroke: along-term follow-up study assessing recurrent vascularevents and functional outcome in the Iowa Registry of Strokein Young Adults. Stroke. 1994;25:1360e1365.

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5e2 6 9268

10. Carolei A, Marini C, Nencini P, et al, The National ResearchCouncil Study Group. Prevalence and outcome ofsymptomatic carotid lesions in young adults. BMJ.1995;311:1363e1366.

11. Stern BJ, Wityk RJ. Stroke in the young. In: Feldmann E, ed.Current Diagnosis in Neurology. St. Louis, MO: Mosby;1994:34e40.

12. Biller J. Strokes in the young. In: Toole JF, ed. CerebrovascularDisorders. 5th ed. Philadelphia, PA: Lippincott Williams andWilkins; 1999:283e316.

13. Nguyen A. Prothrombin G20210A polymorphism andthrombophilia. Mayo Clin Proc. 2000;75:595e604.

14. Ameri A, Bousser MG. Cerebral venous thrombosis. NeurolClin. 1992;10:87e111.

15. Ruız-Sandoval JL, Cantu C, Barinagarrementeria F. Intracerebralhemorrhage in young people: analysis of risk factors, location,causes and prognosis. Stroke. 1999;30:537e541.

16. Brott T, Bogousslavsky J. Drug therapy: treatment of acuteischemic stroke. N Engl J Med. 2000;343:710e722.

17. Provenzale JM, Barboriak DP. Brain infarction in young adults:etiology and imaging findings. Am J Roentgenol.1997;169:1161e1168.

18. Fisher M, Albers GW. Applications of diffusion-perfusionmagnetic resonance imaging in acute ischemic stroke.Neurology. 1999;52:1750e1756.

19. Ay H, Buonanno FS, Rordorf G, et al. Normal diffusion-weighted MRI during stroke-like deficits. Neurology.1999;52:1784e1792.

a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 6 5e2 6 9 269

Apollo hospitals: http://www.apollohospitals.com/Twitter: https://twitter.com/HospitalsApolloYoutube: http://www.youtube.com/apollohospitalsindiaFacebook: http://www.facebook.com/TheApolloHospitalsSlideshare: http://www.slideshare.net/Apollo_HospitalsLinkedin: http://www.linkedin.com/company/apollo-hospitalsBlog:Blog: http://www.letstalkhealth.in/