OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal stroke? What are the typical findings for this disease?

Newborns with acute symptomatic stroke typically present with seizure in the neonatal period, usually within the first week after birth. Neonatal seizures signify dysfunction in the central nervous system, and therefore underlying causes are myriad. The most common causes of seizures in the neonatal period include hypoxia-ischemia, intracranial hemorrhage, infection, and ischemic stroke.

Other causes of neonatal seizures are less common, but potentially catastrophic if not recognized early, including metabolic disturbances or inborn errors of metabolism. Therefore, immediate attention must be paid to address potentially treatable causes of neonatal seizures, and work-up should begin with a comprehensive metabolic panel (including ammonia) and lumbar puncture when appropriate.

Although neonatal seizures can have broad clinical manifestations that differ from older infants and children – including isolated apneic events or bicycling limb movements – seizures associated with neonatal stroke are typically distinct. Focal seizure (usually involving an arm) is the hallmark presentation of acute symptomatic neonatal stroke (~70%); a newborn with a focal seizure is thought to have a stroke until proven otherwise.

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Although some newborns may present with encephalopathy (~40%) or abnormalities of muscle tone (~40%), the neurological examination is usually normal and without focal signs. Again, in the setting of encephalopathy or abnormalities of muscle tone (i.e. an “ill appearing” newborn) initial work-up should address potentially life-threatening etiologies such as infection or metabolic disturbances/inborn errors of metabolism, all the while recognizing that stroke may also be a cause of these clinical findings.

What other disease/condition shares some of these symptoms?

  • Hypoxic-ischemic encephalopathy

  • Intracranial hemorrhage

  • Cortical brain malformations

  • Neonatal seizures from non-structural lesions (i.e., inborn errors of metabolism, metabolic defects)

What caused this disease to develop at this time?

Labor and delivery is a high risk period for stroke. Fetal cerebral vasculature is particularly vulnerable. The mechanism of neonatal stroke is currently unknown and is most likely multifactorial. The complex relationship between the maternal, placental, and fetal environments is suspected to contribute. Risk factors such as maternal infection (such as chorioamnionitis), prolonged rupture of membranes, and maternal antiphospholipid antibody syndrome have been associated with newborn stroke. Placental abnormalities such as vasculitis and thromboses may be associated, but data are limited.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A hypercoagulability panel should be ordered only AFTER the diagnosis of arterial ischemic stroke is made by magnetic resonance imaging (MRI). Since this often requires a large volume of blood for a newborn, a staged approach is recommended:

1st Stage



Factor V Leiden

Prothrombin 20210A

Antithrombin III

Protein C

Protein S

2nd Stage

Homocysteine (elevated in methyl-tetrohydrofolate reductase deficiency)


Antiphospholipid antibodies

Maternal antiphospholipid antibodies should be tested for as soon after delivery as possible.

An EEG can help with both localization of seizures and evaluation of subclinical seizures.

Would imaging studies be helpful? If so, which ones?

An MRI/MRA of the head and neck is the gold standard for diagnosis. A head computed tomography (CT) or cranial ultrasound (CUS) is not ideal, but may be utilized if an MRI not readily available. CT scans are difficult to interpret in newborns due to high brain water content and decreased myelination. A CUS can miss areas of ischemia.

A transthoracic echocardiogram should be performed to evaluate for the possibility of intracardiac thromboses or conditions that might predispose to thrombosis. The presence of a patent foramen ovale provides a route for a clot from the right atrium or venous circulation to reach the left heart. However, many newborns have clinically insignificant patent foramen ovales (PFOs) that will close on their own.

If you are able to confirm that the patient has a neonatal stroke, what treatment should be initiated?

  • Acute treatment

    Anti-epileptic medication for seizure control

    Lorazepam 0.5mg IV prn seizure > 5 minutes

    Phenobarbital 20mg/kg IV for persistent seizures/status epilepticus; maintenance dose 5mg/kg/d (infants metabolize this quickly and may require higher doses)

    Leviteracetam 20-30mg/kg IV for persistent seizures/status epilepticus; maintenance starting dose 15mg/kg IV or PO BID

    If the infant is not receiving enteral feedings, maintenance fluid with NS (avoid large amounts of dextrose-containing fluid because of the risk of cerebral edema)

    If the cardiac echocardiogrram and hypercoagulability panel are normal, therapies such as aspirin or heparin are not indicated given the low risk of recurrence

    If congenital heart disease or genetic thrombophilia present, aspirin may be considered on case-by-case basis.

  • Long-term therapies may include:

    Physical therapy

    Occupational therapy

    Speech therapy

    Behavioral or cognitive therapy

    Special education

    Assistive devices (i.e., AFO, wrist splint)

What are the adverse effects associated with each treatment option?

Anti-epileptic medication: allergic reaction (rare in those used in newborns), sleepiness, feeding difficulties.

Aspirin, heparin, etc: bleeding including hemorrhagic transformation of cerebral infarct, abdominal bleeding.

What are the possible outcomes of neonatal stroke?

If no cardiac defect or genetic thrombophilia, the risk of recurrence is <5%. If a genetic thrombophilia is present but absent in the family, recurrence in subsequent pregnancies is rare.

One-third have a normal outcome a neonatal stroke. Two-thirds have sequelae ranging from mild learning disabilities to severe motor and cognitive delay. Strokes involving the posterior limb of the internal capsule have worse motor outcomes. Strokes involving the basal ganglia have worse cognitive outcome.

Cognitive and/or behavioral disability is usually not manifest until children are older (school-age). The incidence of later epilepsy is unknown. We are hopeful that the newborn brain has a greater capacity for recovery and reorganization than adults.

Early recognition and intervention is the key to maximizing potential and better outcomes.

What causes this disease and how frequent is it?


Prevalence: approx 1 in 2000 live births

5-year recurrence risk: < 5%

Seasonal variation: no

Age distribution: 28 weeks gestational age to 28 days after birth

Predisposing exposures: unknown.

How do these pathogens/genes/exposures cause the disease?

To date, the pathophysiology of neonatal stroke is unknown. Given the low rate of recurrence, it is thought that the maternal-placental-fetal triad is an inherent risk factor. Ongoing research suggests that pregnancy-related inflammation and coagulation disorders may contribute.

What complications might you expect from treatment of the disease?

Complications would be those associated with antiepileptic drugs.

Are additional laboratory studies available; even some that are not widely available?

How can neonatal stroke be prevented?

To date, there is no primary prevention of neonatal stroke.

What is the evidence?

Lee, J, Croen, LA, Backstrand, KH, Yoshida, CK, Henning, LH, Lindan, C. “Maternal and infant characteristics associated with perinatal arterial stroke in the infant”. JAMA. vol. 293. 2005. pp. 723-9. (To date, this is the largest nested case-control study on neonatal stroke which defines prevalence as well as maternal and infant predictors. The overall population is within the Northern California Kaiser Permanente Medical Care Program. The population prevalence of neonatal stroke was found to be 20 per 100,000 live births. Risk factors that were independent predictors of neonatal stroke were maternal history of infertility, preeclampsia, prolonged rupture of membranes, and chorioamnionitis. The authors also found that the risk of neonatal stroke increased when multiple risk factors were present. Placenta information, as well as infant outcome data are limited in this study.)

Ongoing controversies regarding etiology, diagnosis, treatment

Little is known about causation, but symptomatic treatment of consequences of neonatal stroke is not controversial.