Stroke in young adults

Numbers

Only 3% of ischemic strokes occur in patients < 40 yrs of age.

Over 10% of ischemic strokes occur in patients ≤ 55 yrs.

Incidence:

10 per 100,000 persons age 35–44 yrs,
73 per 100,000 for age < 55 yrs.

Etiologies

Trauma

Most common cause of strokes (22%) in patients under 45 yrs.

Atherosclerosis:

20%: less common than in older population

Embolism with recognized source:

Cardiac origin is the most common (above), most have previously known cardiac disease:

Rheumatic heart disease
Prosthetic valve
Endocarditis
Mitral valve prolapse (MVP):

Present in 5–10% of young adults, in 20–40% of young adults with stroke

A-fib
Left-atrial myxoma

Fat embolism syndrome:

Neurologic manifestation is usually global neurologic dysfunction; see Fat embolism syndrome (p.870)

Paradoxical embolism:

ASD,
Pulmonary AVM including Osler-Weber-Rendu syndrome,
Patent foramen ovale

Amniotic fluid embolism: may occur typically in the post-partum period

Vasculopathy:

Inflammatory

Takayasu’s
Infective: TB, syphilis, ophthalmic zoster
Amphetamine abuse
Herpes zoster ophthalmicus (HZO):

Usually presents with delayed contralateral hemiplegia with a mean of ≈ 8 weeks following HZO

Mucormycosis:

A nasal and orbital fungal infection
Primarily in diabetics and immunocompromised patients
Causes an arteritis --> thrombose the orbital veins and ICA or ACA.
Produces proptosis, ocular palsy, and hemiplegia

Associated with systemic disease such as:

SLE
Arteritis (especially periarteritis nodosa)

When confined to CNS is usually multifocal and progressive, but may mimic stroke early

Multiple sclerosis (MS)
Cancer
Rheumatoid arthritis

Non-inflammatory

Fibromuscular dysplasia
Carotid or vertebral artery dissections (including posttraumatic)
Moyamoya disease
Homocystinuria

A genetic defect in methionine metabolism --> intimal thickening and fibrosis in almost all vessels + associated thromboembolic events (arterial and venous, including dural venous sinuses)
Risk of stroke is 10–16%.
Clinical features

Patients have a Marfan syndrome-like physical appearance,
Malar blotches
Mental retardation
Elevated levels of urinary homocysteine
Pseudoxanthoma elasticum

Coagulopathy: 10%

SLE:

Lupus anticoagulant → prolonged PTT incompletely corrects with 50/50 mix.
Collagen vascular disease only rarely presents initially with stroke

Polycythemia or thrombocytosis
Sickle cell disease
TTP (thrombotic thrombocytopenic purpura)
Antithrombin III deficiency

Controversial—not seen in large series of young adults with stroke

Protein C or protein S deficiency (familial):

Protein C attenuates hemostatic reactions
Homozygous deficiency is fatal in the neonatal period.
Heterozygous deficiency is associated with thrombotic strokes.
A rare complication during initial therapy with warfarin is a drop in protein C before other coagulation factors resulting in a hypercoagulable state

Antiphospholipid-antibody syndrome (APLAS):

Causes venous and/or arterial thrombosis.
The two best known antiphospholipid-antibodies are

Anticardiolipin antibodies (ACLA),
Lupus anticoagulant (LAC).

Treatment

Once they become symptomatic, treatment is high-intensity warfarin therapy to an INR≥ 3.27
There is a dramatic increase in thrombotic events after discontinuing warfarin.
Aspirin is useless

Following use of the street drugs

3,4-methylenedioxymethamphetamine (MDMA, commonly known as ecstasy),

Hypercoagulable state that occurs with hyperthermia when insufficient fluids are consumed in conjunction with use of the drug

Peripartum:

5% (usually within 2 wks of parturition)

Miscellaneous causes: 35%

Uncertain etiology
Oral contraceptives (BCP):

Associated with 9x increased risk for stroke, many with prior migraine history

Cerebral venous thrombosis (CVT)

Including dural sinus thrombosis:
Incidence may be increased with use of BCP

Migraine:

Widely accepted, but difficult to assess objectively

Incidence of stroke in these patients may be same as general population.

Rare.
Usually occurs in women, with a benign long-term course;
Recurs in < 3%.
Possible mechanisms include:

Vasospasm,
Platelet dysfunction and
Arteriopathy.

Strokes often occur during a migrainous attack or shortly thereafter

Cocaine or alkaloidal cocaine abuse:

Mech

Vasoconstriction, or
HTN in the presence of aneurysms or AVMs

Frank vasculitis occurs but is rare with cocaine, unlike amphetamines);

Equally divided between ischemic and hemorrhagic

Posterior reversible encephalopathy syndrome (PRES)

Risk factors

Diabetes: odds ratio =12

HTN: odds ratio = 6.8

Current cigarette smoking: odds ratio = 2.5

Long-term heavy alcohol consumption: odds ratio = 15

Heavy alcohol ingestion within 24 hrs preceding the stroke was not a risk factor

Evaluation

History & physical exam directed at uncovering systemic disease (see above) and modifiable risk factors (see above)

Cardiology work-up including EKG and echocardiogram

Bloodwork:

Routine:

U/E, CBC, platelet count and/or function, ESR (elevation may suggest SLE, arteritis, atrial myxoma… but a normal ESR does not rule out vasculitis), PT/PTT, VDRL (should be obtained in all young adults with stroke), fasting lipid profile

For unexplained stroke:

ANA, antithrombin III, protein C, protein S, homocysteine, factor V Leiden, PPD, sickle-cell screen, toxicology screen (blood and urine, to R/O drugs such as cocaine), SPEP, lupus anticoagulant, serum amino acid, tissue plasminogen-activator and -inhibitor

Miscellaneous tests:

U/A, CXR, CSF exam when indicated

Cerebral angiography:

Not always necessary for patients with obvious systemic disease or strong evidence for cardiac embolism;
May occasionally diagnose cerebral embolism if performed within 48 hrs of ictus

Thrombolysis

Tissue plasminogen activator (tPA)

An enzyme that is naturally found in vascular endothelial cells.

Catalyzes: plasminogen --> plasmin (fibrinolytic compound, the major enzyme involved in thrombolysis).

Manufactured using recombinant DNA technology (rtPA, or just tPA).

Example

Alteplase (Activase®, Actilyse®) is the primary agent used clinically. It is FDA approved for the IV treatment of acute ischemic stroke (see below).
Tenecteplase (TNKase®), an alternative tPA, has not shown superiority or inferiority to alteplase, and pending further investigation may be considered in patients with minor neurologic deficit and no major intracranial occlusion
Other agents: benefits are unproven, and their use is not recommended outside of clinical trials

Timing of tPA

Within 3 hours of stroke onset has been shown to be safe and effective in multiple randomized controlled trials and by extensive community experience in numerous countries.

Within 4.5 hours in 2009 after ECASS-3, but the study population differed (see Eligibility below).

Guidelines for the administration of IV tPA Eligibility:

Age ≥ 18 years (although use in childhood stroke is increasing)

Time since last seen normal ≤ 4.5 hrs prior to administration

(NB: the 3–4.5 hr window was not studied in patients ≥ 80 years of age, patients with severe stroke (NIHSS (p.1348) score > 25), and patients with prior stroke +DM. However, it may still be reasonable to treat these patients

tPA is reasonable in otherwise eligible patients with history of ≤10 cerebral microbleeds on MRI

Arterial Ischemic Stroke (AIS) in adults with known sickle cell disease

Contraindications:

Intracerebral haemorrhage (ICH):

On admitting CT,
History of prior ICH

Patients with history of> 10 cerebral microbleeds showed an increased risk of ICH and the benefits of tPA are uncertain but treatment may be beneficial if there is substantial potential benefit (Level II1)

Clinical presentation of SAH (even with negative CT)

Known intracranial aneurysm or AVM

Active internal bleeding

Known bleeding diathesis, including but not limited to the following:

Full anticoagulation with LMWH within the previous 24 hours
Platelet count<100,000/mm3 (given the low risk of unsuspected abnormal platelet counts or coagulation studies, it is reasonable that urgent tPA should not be delayed to wait for test results)

Serious head trauma, serious stroke, or intracranial surgery within past 3 months

SBP> 185mm Hg, or DBP>110mm Hg that cannot be controlled despite use of nicardipine infusion or IV labetalol

Cautions:

Seizure witnessed at the time of onset of stroke symptoms

Major surgery within the last 14 days

Arterial puncture at non-compressible site within past 7 days

Recent lumbar puncture

Rapidly improving or minor symptoms.

Note: IV tPA should not be delayed to monitor for further improvement (possible harm)

Blood glucose> 400mg/dl or <50 mg/dl

History of GI or urinary tract haemorrhage within past 21 days

Post myocardial infarction pericarditis

Additional issues relevant to giving IV tPA:

Hypoattenuation on CT is not a criteria to withhold IV tPA

Hyperdense MCA sign is not a criteria to withhold IV tPA

Routine use of MRI to exclude cerebral microbleeds before IV tPA is not recommended use of imaging criteria to select candidates for IV tPA when the time of onset of symptoms is unknown is not recommended do not delay IV tPA to obtain multimodal CT and/or MRI.

For candidates for endovascular therapy, a non-invasive vascular study is recommended during the initial evaluation, but should not delay administration of IV tPA if indicated (Level I1) do not administer abciximab concurrently with tPA (potential harm1)

Rule out hypoglycaemia and hyperglycaemia

Be prepared to treat complications of tPA including:

Bleeding complications
Angioedema (may require intubation)

Hypertension is aggressively controlled

The use of antithrombic therapy within the 1st 24 hours of IV tPA is uncertain. Use may be considered when there is substantial benefit.

Treatment protocol:

Initiate < 4.5 hrs from onset of deficit or last known well

NINDS protocol:

0.9 mg/kg (up to a maximum of 90mg total) given as follows:

IV bolus 10% of the dose over 1 min, followed immediately by the remainder as a constant infusion over 60 minutes.
If there is an indication for anticoagulation, obtain a non-contrast CT 24 hours prior to starting anticoagulation since there is a risk of subclinical intracerebral hemorrhage.

ICH following IV tPA

There is an increased risk of symptomatic intracerebral haemorrhage (ICH) with the use of tPA

Evidence

NINDS study: 6.4% vs. 0.6% with placebo;

In spite of this, the NINDS study found that mortality in the tPA group was similar to controls at 3 mos (17% vs. 21%).

ECASS II: 8.8% vs. 3.4%

The following factors were associated with an increased risk of symptomatic ICH (with only a 57% efficiency rate of predicting ICH):

Severity of NIHSS score, or
Pre-treatment CT showing brain oedema or mass effect.

In one study, ICH did not influence outcome except in the rare instance when a massive hematoma occurred.
Outcomes were still better in the treated group, and the conclusion is that these patients are still reasonable candidates for tPA.

Since then, multicentre analyses have demonstrated that size of infarction and elevated blood sugar are independent risk factors for symptomatic ICH.

Management of post-tPA ICH:

Discontinue tPA infusion of and obtain STAT head CT
Send labs:

PT
aPTT
Platelet count
Fibrinogen
Cross match

Prepare to administer

6–8 units cryoprecipitate containing Factor VIII

If emergent EVD placement or other interventional procedure is needed, consider the use of recombinant Factor VIIa (40–80mg/kg) immediately beforehand (NB: this is only a temporizing measure and cryoprecipitate still needs to be given)

6–8 units of platelets