Stroke in young adults is surprisingly common. The differential diagnosis for
potential etiologies is broader than that for older adults. Elements of the
initial workup, including neuroimaging, bloodwork, and other ancillary studies,
are reviewed. Emphasis is placed on areas in which the diagnostic approach to
stroke in young adults differs from that for older patients. Clinical
manifestations and management are usually similar to, but prognosis is often
better than, those in an older population.
Introduction. This article will emphasize aspects of a diagnostic approach to
young adults (up to 45 years of age) with stroke as it differs from a standard
approach for older adults, with emphasis on initial work-up.
Stroke in young adults is surprisingly common. The annual stroke incidence was
estimated at 34/100000 in Swedish adults under 55 years of age, and 10/100000 in
a Mayo Clinic study of women ages 15 to 29. Ischemic stroke is much more common
than hemorrhagic, the latter comprising 12% of strokes in the Lausanne registry
for patients 30 to 45 years old.1 The ubiquity of stroke in young adults and its
potential for devastating consequences mean that healthcare providers must have
a high index of suspicion for stroke. This is especially true when a patient’s
clinical picture is not easily explained otherwise.
Etiologies. The range of potential etiologies for stroke in young adults is
broader than that for older adults. (Table) Like in older adults, stroke in
younger adults is typically categorized as primarily ischemic or hemorrhagic.
Ischemic etiologies include cardioembolic, atherosclerotic disease, and
nonatherosclerotic cerebral vasculopathies. Hemorrhagic strokes include
subarachnoid and intraparenchymal types. Of particular note in young adults are
stroke causes such as hematologic disorders, substance abuse, trauma,
dissections, oral contraceptive use, pregnancy and postpartum states, and
|Table . Differential diagnosis of stroke in young
adults (adapted from references 1, 2)
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 — systemic lupus
erythematosus, rheumatoid arthritis, Sjögren’s syndrome,
polyarteritis nodosa; Takayasu’s disease, Wegener’s
syndrome, cryoglobulinemia, sarcoidosis, inflammatory bowel
disease, isolated central nervous system angiitis)
- Moyamoya disease
- Toxic (illicit drugs — cocaine, heroin, phencyclidine;
therapeutic drugs — L-asparaginase, cytosine arabinoside)
Small vessel disease
- Vasculopathy (infectious, noninfectious, microangiopathy)
- Sickle-cell disease
- 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
- Polycythemia vera
- Thrombotic thrombocytopenic purpura
- Venous occlusion (dehydration, parameningeal infection,
meningitis, neoplasm, polycythemia, leukemia, inflammatory bowel
Subarachnoid hemorrhage (cerebral aneurysm)
- Arteriovenous malformation
- Neoplasm (primary central nervous system, metastatic,
- Hematologic (sickle-cell disease, neoplasm, thrombocytopenia)
- Drug use (warfarin, amphetamines, cocaine, phenypropanolamine)
- Iatrogenic (peri-procedural)
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 have multiple risk factors. Detailed history
and examination, oriented toward common and uncommon etiologies, are especially
important. Stroke mimics in the young adult population include multiple
sclerosis and malignancy.
The physical exam should include neurologic, cardiovascular, ophthalmologic and
dermatologic assessments. Relevant ocular findings include corneal arcus (hypercholesterolemia)
or corneal opacity (Fabry’s disease); Lisch nodules, optic atrophy (neurofibromatosis);
lens subluxation (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
(hyperlipidemia); café-au-lait spots, neurofibromas (neurofibromatosis);
purpura (coagulopathy); and capillary angiomata (cavernous malformation).3
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 endocarditis) and arrhythmias. Mitral valve
prolapse and patent foramen ovale are common but are typically not causes of
stroke when present. An atrial septal aneurysm is less likely to be associated
with stroke when found in isolation than when it occurs with other cardiac
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 extracranial internal
carotid, the vertebrobasilar system, or, less commonly, the intracranial carotid
system. They are associated with major or minimal trauma, chiropractic
manipulation, or can occur spontaneously. Other associations include
fibromuscular dysplasia, Marfan syndrome, Ehlers-Danlos syndrome type IV,
moyamoya and sympathomimetic drug abuse. Symptoms and signs may include neck
pain, transient or lasting ischemia of retina, cerebral hemispheres, or
posterior fossa, Horner’s syndrome, hemicranial pain, or subarachnoid
hemorrhage. Extracranial ultrasound or magnetic resonance angiography (MRA) may
confirm the clinical impression. Often catheter angiography is required for
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 hypersensitivity vasculitis (eg,
drug-induced) are seen much more often than primary central nervous system
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
Hypercoagulable states may be responsible for 2% to 7% of cases in young
adults.4 Inherited (primary) thrombophilic disorders include entities that are
recently described (hyperhomocysteinemia, factor
V Leiden, prothrombin G20210A), well- established (deficiencies of antithrombin,
protein S or protein C), and extremely rare (dysfibrinogenemia, thrombomodulin
deficiency, heparin cofactor II deficiency).5 Acquired (secondary) causes
include malignancy, pregnancy/postpartum states, oral contraceptive use and
sickle-cell disease. Prior thromboembolic disease in a young patient or in
family members should raise suspicion.4 Please refer to Dr. Trevarthen’s
accompanying article for further information on this topic.
Cerebral venous thrombosis can cause ischemic or hemorrhagic 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 contraceptives. Presenting symptoms include
headache, emesis, lethargy, and seizures. Papilledema may accompany focal signs.4,
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 encephalomyopathy 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
Up to 45% of strokes in young
adults are due to spontaneous intracerebral hemorrhage.4 Approximately half are
one-quarter are in basal ganglia or internal capsule.7 Vascular malformations,
aneurysms, hypertension, and illicit drug use are the
main causes.4, 7
Investigations. The initial work-up should be as expeditious as possible to
allow consideration of acute therapies, such as tissue plasminogen activator
(t-PA).8 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 normalized ratio), activated partial
thromboplastin time, glucose, chemistries, electrolytes, serology for syphilis,
and an erythrocyte sedimentation rate.
A more detailed coagulation profile (anticardiolipin antibodies, 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 advantageous 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
Most patients should have high-quality brain magnetic resonance imaging (MRI)
and often MRA.4, 9 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 which may be salvageable.10
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).11 Also, MRA’s
resolution is not yet on par with conventional angiography.
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 ultrasound can be helpful. Please see Dr. Ricci’s article in this
issue for more information on neuroimaging.
Toxicologic studies are often productive, even when drug use is not
Other blood tests may include homocysteine, fibrinogen, antinuclear antibody,
lipid panel, lipoprotein (a), serum protein 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.4
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.5
A patient with one or more risk factors, such as migraine or diabetes, should be
thoroughly investigated for other possibilities. The cause of stroke in young
patients may remain undetermined in 20% to 30% of cases, even after a detailed
Management. General management
of ischemic8, 12, 13 and
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.4, 15
and secondary17 preventive measures have recently been reviewed.
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.18 The overall
annual recurrence rate is less than 1%.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 recurrence is low (2% over 5 years)
in women whose first stroke occurred in pregnancy.19
Conclusion. Strokes in young adults make up a significant proportion of strokes
in general. A thorough investigation is recommended, looking into a broad array
of potential etiologies, common and uncommon. Management is similar overall to
that for older adults, with some aspects of treatment dictated by specific
causes found. Health care providers must stress prevention with all of their
young adult patients, especially those with identifiable risk factors. The
potential for devastation is great in any case of stroke but prognosis in this
population is better than
that for older adults.
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