Pediatric Stroke: Evaluation, Treatment, and Follow-up

A stroke is a devastating event, perhaps even more so in the pediatric population, since affected youngsters may require medical assistance for the rest of their lives. Adding insult to injury is the fact that many victims of pediatric stroke already suffer from a chronic disease. Since most parents are unaware that stroke can occur in children, several hours may elapse before medical attention is sought.

Once medical attention is obtained, it is not unusual for even more time to elapse before a proper diagnosis is made. One study⁴ puts the time from clinical onset of stroke in a child to first medical contact at an average of 28.5 hours and the time to definitive diagnosis at an average of 35.7 hours. Since delay in diagnosis is commonplace, children are rarely candidates for certain treatments (such as thrombolytic therapy) that may improve outcome if administered within a few hours of the event. In the hope of heightening professional awareness about the importance of a timely diagnosis, we present a review of pediatric stroke, with emphasis on the evaluation of children with acute onset of a neurologic deficit.

Case report

A 4-year-old white boy presented to an acute care facility complaining of a painful burning sensation in his right eye. His mother described him as quieter than usual, speaking with a "funny-sounding speech," and displaying a "funny smile." He had appeared well earlier that morning, with no other preceding symptoms. His past medical history was significant only for allergic rhinitis.

His physical examination revealed a well-appearing boy with normal vital signs. Findings were unremarkable, except for his cardiac and neurologic examinations, which revealed a grade 2/6 systolic heart murmur. His neurologic examination showed left facial weakness, with a left facial droop and prominence of the right labial fold. Other abnormalities included left ankle clonus and left upper extremity weakness, with generalized slower coordination of the left side of his body. Because of the significance of this child's presentation, he was transferred to tertiary care for pediatric and neurologic consultation.

After assurance of the ABCs of emergency care, a CT scan of the brain revealed an abnormal area of low attenuation in the right basal ganglia. An MRI scan of the brain showed an acute infarction in the putamen and caudate nucleus and adjacent internal capsule.

The results of intracranial magnetic resonance angiography (MRA) and extracranial (neck) MRA suggested intimal dissection of the right middle cerebral artery, with no abnormalities of the extracranial vasculature. Subsequent cerebral angiography found no dissection but did show a nonocclusive, adherent filling defect involving the right middle cerebral artery, which was determined to be a subocclusive, adherent thrombus.

An echocardiogram was significant for a patent foramen ovale (PFO) without intracardiac thrombi or vegetations. Results of an extensive laboratory investigation were normal except for an elevated cardiolipin antibody IgM level of greater than 150 IgM phospholipid (MPL) U/mL (greater than 80 MPL U/mL considered positive) and a cardiolipin antibody IgG level of 24 IgG phospholipid (GPL) U/mL (20 to 79 GPL U/mL considered moderately positive). A diagnosis of antiphospholipid syndrome was considered, but the criteria were not fulfilled. The exact cause of the stroke ultimately remained undetermined.

This case highlights 2 important points: the underlying cause of a significant proportion of pediatric strokes will remain unknown despite exhaustive evaluation, and the discovery of elevated anti- phospholipid antibody levels is of limited value. These antibody levels may be acutely elevated because of infection, and titers that remain elevated for 8 weeks are of greater significance.

The exact role of increased IgG titers in predicting recurrent stroke is controversial. A recent study by Lanthier and colleagues⁵ found that increased anticardiolipin antibody IgG titers do not predict future thromboembolism in children.

Pediatric Risks Differ

Atherosclerosis, a common underlying cause of adult stroke, is rare in children. Several other conditions (Table 1) put a child at risk for stroke. Congenital heart disease (particularly cyanotic lesions plus polycythemia) and sickle cell disease are at the top of the list. A review in the October 2005 issue of Applied Neurology⁶ describes the association of a PFO with cryptogenic stroke in patients younger than 55 years. Acquired heart diseases, collagen vascular diseases, CNS infections, hematologic and coagulation defects (hemophilias, thrombophilias), CNS vascular anomalies, inborn errors of metabolism (such as mitochondrial encephalopathies and homocystinuria), trauma (leading to vascular dissection), and other illnesses and their treatments (such as cancer and chemotherapy) are general classifications of the conditions that can increase a child's risk of stroke.

Several genetic disorders are associated with stroke⁷ or conditions that can lead to stroke, such as the association of trisomy 21 syndrome with moyamoya disease.⁸ A cerebrovascular accident may be the initial presentation of HIV infection in children.⁹ Varicella also has been described as a predisposing factor for pediatric stroke.

Arteriovenous malformations are the most common cause of hemorrhagic stroke in children.¹ Along with vascular malformations, malignancy, trauma, hemophilia, thrombocytopenia, liver failure, and warfarin administration also are associated with the development of hemorrhagic stroke.

Risk factors for sinus venous thrombosis include head and neck infections (such as orbital cellulitis and sinusitis), dehydration, cancer treatment (particularly with asparaginase), head trauma, surgery, and thrombophilias. Although several predisposing factors for pediatric stroke have been identified, a large proportion of cases will be classified as idiopathic.

Prothrombotic abnormalities deserve special mention because they are significant risk factors for ischemic stroke in children,¹⁰ even though their exact role is not fully understood. In one study¹¹ of 59 children with arterial ischemic stroke or porencephaly, two thirds had at least 1 prothrombotic risk factor--and many had several risk factors. Examples of prothrombotic conditions include protein C deficiency; protein S deficiency; antithrombin III deficiency; and the presence of factor V Leiden mutation, factor II G20219A variant, methylenetetrahydrofolate reductase variant, and antiphospholipid antibodies (specifically, lupus anticoagulant, anticardiolipin, anti- b2-glycoprotein).^10,12

Determining the mechanism of stroke is crucial because it will guide treatment and predict risk of recurrence. Recurrences are most likely in children with embolic stroke or an underlying systemic disease (such as sickle cell disease) and in children with a progressive arteriopathy (such as moyamoya disease).¹³ In the study that looked at the prevalence of prothrombotic risk factors,¹¹ stroke recurred in one fifth of the patients who had a prothrombotic abnormality.

Clinical Presentation

The clinical presentation of stroke may be subtle in a young child, but in the first month of life, seizures, apnea, and persistent hypotonia are the predominant manifestations.¹⁴ Beyond the neonatal period, hemiplegia is the most common initial symptom. Other symptoms include headache, mental status changes, sudden collapse with loss of consciousness, speech disturbances, sensory complaints (numbness or tingling), and cranial nerve or cerebellar deficits.² The acute neurologic changes that can occur may be confused with those that accompany other CNS disturbances such as hemorrhage, abscess, encephalitis, meningitis, drug ingestion, malignancy, sei- zures, and migraine. Along with these entities, stroke must be included in the differential diagnosis for any child in whom an acute neurologic change occurs.

History and physical examination A detailed history of illness is necessary to support a diagnosis of stroke. What are the exact symptoms, and when did they begin? Inquiries into family history of predisposing factors such as sickle cell disease, prothrombotic conditions, and collagen vascular disease should be made. A thorough physical examination, focusing on the cardiac and nervous systems, will reveal any signs of underlying heart disease (such as a murmur or cyanosis) or neurologic deficits.

A more in-depth evaluation may include neurologic imaging and vascular, laboratory, and cardiac studies. Not all the studies listed may be necessary to diagnose stroke properly and treat each child. Physicians should choose their tests judiciously based on the patient's history and clinical presentation.

Neuroimaging studies Noncontrast CT is typically the initial diagnostic study because of its wide accessibility and its ability to detect nearly any lesion capable of producing an acute neurologic abnormality.¹⁵ Acute hemorrhage usually is detected by CT. Early ischemia is commonly not detected, but CT perfusion imaging may allow earlier identification of subtle indicators of infarction and clarify the amount of viable tissue.^16,17

Although an MRI scan of the brain is more sensitive than CT for detecting brain infarction, it is usually much more difficult to obtain quickly. Obtaining an MRI scan for a pediatric patient requires careful scheduling and finesse, because younger children will need more sedation than adults or may even require general anesthesia.

Vascular studies Vascular studies used to evaluate children include CT angiography (CTA), MRA, and conventional angiography. CTA is helpful for identifying patients with occlusion of the major circle of Willis or extracranial cerebral arteries. Thanks to recent improvements in technique, CTA is superior to MRA in some instances.¹⁵ CTA is less prone to some of the artifacts that can limit MRA, and it can be used in patients with metallic implants.¹⁵

MRA is an important study performed at many centers as part of a fast MRI protocol for acute ischemic stroke. Vascular stenosis or occlusion can be identified with this modality, as can aneurysms, arteriovenous malformations, arterial dissections, and arteriopathies. Conventional angiography, which is helpful in detecting vasculitis, is performed when the screening tests do not fully define the lesion and more characterization of the anatomy is warranted. CT or magnetic resonance venography is useful in the evaluation of sinus venous thrombosis.

Laboratory studies Potential laboratory studies are numerous and mostly geared toward trying to identify patients with a hypercoagulable state. Table 2 lists studies that can identify a child at risk for stroke. A pediatric hematologist should be involved in the management of a child with suspected or proven prothrombotic factors. Obtaining these studies is most important when the child has no evidence of cyanotic heart disease as a predisposing factor. If the child is of African descent, a screen for sickle cell disease is needed if the hemoglobin status of the child is unknown. A urine toxicology screen for illicit drugs may be necessary in certain situations, such as when an otherwise healthy adolescent experiences a stroke. In patients who have had a hemorrhagic stroke, evaluation for hemophilia and bleeding diathesis is essential.

Cardiac studies A transthoracic or transesophageal echocardiogram and ECG should be obtained in all pediatric patients to search for previously undiagnosed congenital heart disease, including the presence of a PFO. Although typically not needed in a young child, a bolus of agitated saline injected into the antecubital vein will help identify a PFO.

The echocardiogram is an important diagnostic tool. The ECG may identify patients with an arrhythmia as a possible source of emboli. Arrhythmia is more likely in a child with a history of heart disease or surgery.

Acute Treatment

Addressing the ABCs of life support is the initial treatment of the child after stroke. Securing the airway, monitoring cardiovascular parameters, and controlling seizures are paramount. Immediate transfer to a pediatric ICU is mandatory. Cerebral edema in the first several hours must be managed.

The exact role of thrombolytic therapy in children in the acute setting is unknown; large randomized controlled trials are not available. Some case reports and extrapolation from adult studies indicate that these medications may have a role in the care of pediatric patients.

Although not approved for use in children, recombinant tissue plasminogen activator has been reported to be successful in managing pediatric stroke.¹⁸ Barnes and colleagues¹⁹ also have documented the successful use of urokinase in children with cerebral sinus venous thrombosis, but they note that the risk of symptomatic hemorrhage argues against thrombolysis as first-line therapy.

In 2002, the FDA approved a new formulation of urokinase, but only for the treatment of pulmo- nary embolism in adults.²⁰ Since information is so limited, the routine use of antithrombolytics in a child is not recommended unless he or she is participating in a controlled clinical trial. However, the physician must use clinical judgment in each case, and weigh the risks and benefits with the family when deciding whether to administer thrombolytics in the setting of acute stroke. The delay that often accompanies the diagnosis of pediatric stroke usually precludes the use of antithrombolytic agents. More studies are needed to clarify the use of these agents in children.

A novel treatment alternative to antithrombolytic agents is the Merci Retrieval System (Concentric Medical). This device can restore vascular patency during acute ischemic stroke if used within 8 hours of symptom onset.²¹ The usefulness of this intervention in children needs to be determined, but its success in treating adults has been reported.²¹

Long-Term Treatment and Prevention

In the long term, the decision to use an anticoagulant (antiplatelet agents, warfarin) should be made on a case-by-case basis with consideration of the underlying cause and risk of recurrence. Although large-scale clinical trials of anticoagulant use in children are also not available, aspirin is thought to be safe and effective for pediatric stroke; however, there is no universal agreement about when and how it should be used. The optimal dosage still needs to be determined. The risk of Reye syndrome in association with aspirin use is a special consideration in children.

Warfarin is even more controversial and is used most frequently in children with congenital heart disease and hypercoagulable states. The use of any anticoagulant requires careful monitoring and titration so that bleeding complications may be avoided while a future CNS event is prevented.

Hemorrhagic stroke is a contraindication to anticoagulation therapy, and consultation with a pediatric hematologist and pediatric cardiologist (if heart disease is present) is recommended whenever long-term anticoagulation therapy is considered in a child after ischemic stroke. Treatment of hemorrhagic stroke depends on its cause; for instance, surgery and embolization are options for vascular malformations.

It is important for the neurologist to define the child's post-stroke disabilities and recommend ongoing adjuvant interventions such as speech, occupational, and physical therapies. Close monitoring for the development of sei- zures is necessary, along with educating the family about the risk of seizures post-stroke. The primary care provider coordinates and monitors the overall care, which may involve several subspecialists and other professionals.

Research concerning primary prevention strategies for pediatric stroke is lacking except in patients with sickle cell disease. A majority of children with sickle cell disease will have a recurrence. Regular blood transfusions to keep hemoglobin S to less than 30% have been shown to decrease the risk of recurrence²² but may cause serious complications (iron overload, transmission of infection, erythrocyte alloantibody and autoantibody production). An ongoing trial by the National Heart, Lung, and Blood Institute is focusing on the use of hydroxyurea plus phlebotomy as a preventive measure.

General preventive measures for all patients include counseling about the dangers of smoking and the use of illicit drugs and emphasizing the rewards of a good diet and an active lifestyle. Families with known thrombotic risk factors should be educated about the possibility of pediatric stroke and its presenting signs and symptoms. Raising awareness in families that stroke can occur in childhood and encouraging clinicians always to consider it as a possible cause in children with acute neurologic deficits may allow for a more timely diagnosis and treatment of this devastating event. *

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