Etiology and Pathogenesis

Estimates of the incidence of stroke in children range from two to 13 per 100,000 children per year. As opposed to adults in which ICH accounts for about 15% of stroke, ICH accounts for about half of pediatric stroke. The incidence of perinatal stroke is approximately one per 4000 live births, with 80% of these secondary to AIS. One-quarter of all strokes in children take place during the perinatal period. The incidence of cerebral venous sinus thrombosis is approximately 0.3 to 0.7 per 100,000 per year, with almost half of these occurring in the perinatal period. Strokes are more common in boys than in girls, with 55% to 60% of all childhood strokes occurring in boys. In the United States, strokes are more common among African American children, even when controlling for the presence of sickle cell disease (SCD).

Unlike adults, in whom hypertension, diabetes, and atherosclerosis predominate as risk factors for ischemic stroke, children presenting with AIS have much more varied etiologies. Approximately 50% of children presenting with stroke have an obvious underlying cause at the time of presentation, with arteriopathy, congenital heart disease, and sickle cell anemia representing some of the most common causes. In an additional 20% to 40%, an underlying cause can be found with further investigation. Somewhere between 10% and 30% are cryptogenic. Factors associated with pediatric AIS include inherited or acquired prothrombotic states, cardiac disease, arteriopathies or vasculopathies, trauma, and infections (Box 79-1). In older teenagers, traditional risk factors for adults, such as hypertension, diabetes, high cholesterol, and smoking, may also play a role. Cocaine or sympathomimetic medications are additional risk factors. Watershed strokes can be seen after cardiac arrest or other causes of shock, near drowning, and cardiac surgery.

ICH in children is also etiologically distinct from ICH in adults. Unlike adults, in whom hypertension and amyloid angiopathy are the most common causes, childhood ICH is most commonly caused by ruptured vascular malformations (e.g., arteriovenous malformations, cavernomas, and aneurysms), hematologic abnormalities, and brain tumors (Box 79-2 and Figure 79-2).

Figure 79-2 Intracerebral hemorrhage: clinical manifestations related to site.

The major risk factors for CSVT include dehydration, head and neck infections, hypercoagulable states, malignancies, congenital heart disease, inflammatory bowel disease, oral contraceptives, and the use of certain chemotherapeutics.

AIS occurs when occlusion of an artery with a thrombus or embolus prevents blood flow to the region supplied by that artery. In watershed infarctions, global or near-global hypoperfusion preferentially damages areas on the border of two different vascular territories. The end result is a complex chain of events in cerebral neurons and support cells in which lack of oxygen and glucose leads to mitochondrial dysfunction, ion pump failure, calcium influx, and glutamate-induced neurotoxicity, eventually producing cell necrosis or apoptosis. The extent of ischemic damage to the region is determined by oxygen demand, collateral blood flow, and time to reperfusion. After an acute ischemic insult, there is a core area of infarction in which cells have sustained irreversible injury. This core is surrounded by an area with reversible ischemia known as the ischemic penumbra. If no further improvement of blood flow takes place or if additional insults occur, the tissue within the penumbra will eventually infarct over a period of hours to days, potentially causing additional neurologic impairment. In TIAs perfusion is restored before infarction can take place, and neuronal dysfunction induced by ischemia is reversed.

In ICH, blood extravasates into the brain parenchyma (intraparenchymal hemorrhage) into the ventricles (intraventricular hemorrhage), or into the subarachnoid space (subarachnoid hemorrhage). Intraparenchymal hemorrhage causes neuronal damage through a combination of mechanical damage and chemical irritation. Secondary ischemic stroke can occur as well because of mechanical deformation of cerebral vasculature by mass effect, vasospasm, and altered pressure dynamics leading to decreased cerebral perfusion pressure. Intraventricular hemorrhage can lead to hydrocephalus.

In CSVT, obstruction of venous blood by clot formation alters blood flow dynamics and overall venous drainage is decreased. Increased cerebral venous pressure causes resistance to cerebral perfusion and can cause venous infarction or hemorrhage. All contribute to increasing intracranial pressure (ICP).

Clinical Presentation

The clinical presentation of a child with stroke depends on the location, type, and size of the stroke and the age and developmental stage of the child. The diagnosis is often missed or delayed in children because of a low index of suspicion on the part of care providers. In addition, children are much more likely than adults to present with headaches, seizures, or altered mental status as the first sign of stroke. Any child with acute onset of a focal neurologic deficit should be investigated for possible stroke, but other situations that should be investigated for possible stroke include seizures in the newborn, seizures in a child of any age occurring after cardiac surgery, and changes in mental status associated with headache.

Approximately 75% percent of AIS in children occurs in the anterior circulation coming from the internal carotid arteries. Older children with ischemic strokes most commonly present with acute hemiparesis, hemisensory loss, or aphasia but may also present with isolated seizures or hemichorea. Children with posterior circulation strokes affecting the vertebrobasilar distributions may present with ataxia, vertigo, visual field cut, or brainstem signs. Children with watershed strokes can present with proximal greater than distal weakness.

Intraparenchymal hemorrhage classically presents with focal neurologic signs or seizures accompanied by severe headache, emesis, and loss of consciousness but may be impossible to distinguish from AIS based on clinical features alone because presentations vary (see Figure 79-2). Children with CSVT may present acutely with headaches, emesis, seizures, altered mental status, or focal neurologic signs but can also present more insidiously with symptoms of increased ICP such as chronic headache, blurry vision, or diplopia secondary to sixth cranial nerve palsies.

Differential Diagnosis

The most common mimics of stroke in children are complicated migraine and postictal Todd’s paralysis. Other considerations are hypoglycemia and other metabolic derangements, syncope, cerebral mass lesions such as brain tumor or abscess, demyelinating diseases, and functional disorders. Clues to the diagnosis of complicated migraine include a strong personal or family history of migraine, headache appearing after the onset of neurologic symptoms, and the presence of positive visual phenomena such as scintillating scotoma. Clues to the diagnosis of Todd’s paralysis include a history of convulsions, characteristic aura occurring before the onset of symptoms, and nonvascular distribution of weakness. It is crucial to recognize that diagnoses such as complicated migraine are diagnoses of exclusion.

Evaluation

The initial evaluation of a child with suspected stroke should focus on confirming the diagnosis and ruling out common stroke mimics. The initial history and physical examination should assess the child’s ability to maintain a natural airway and adequate perfusion. Initial testing should include a complete blood count, electrolytes, blood glucose, prothrombin time, international normalized ratio, partial thromboplastin time, toxicology screen, and electrocardiography (ECG). Brain imaging should be obtained as soon as is possible. In most cases, unless MRI can be performed immediately, head computed tomography (HCT) should be performed first. HCT is fast and widely available and allows for the quick assessment of hemorrhage or mass lesions. In AIS, HCT results may be normal early in symptom evolution, but subtle findings of AIS, such as hyperdense middle cerebral artery (MCA) sign or blurring of the gray-white matter border can sometimes be seen. However, MRI is usually required to confirm the diagnosis of AIS. The most sensitive MRI sequence for detecting acute ischemic stroke is diffusion-weighted imaging with apparent diffusion coefficient; abnormalities on these sequences usually last 7 to 10 days from the acute stroke (Figure 79-3).

Figure 79-3 Diagnostic tests for infarction.

Additional testing should attempt to identify the etiology of the stroke (Box 79-3). Imaging of the vessels of the head and neck with MR angiography (MRA) or computed tomography angiography (CTA) should be performed to look for arterial dissection (Figure 79-4) or other arteriopathy. In certain cases, conventional catheter angiography may be necessary.

Figure 79-4 Arterial dissection.

In children with ICH, MRA, CTA, or conventional angiography should be performed to evaluate for vascular malformations. If such a lesion is suspected but is not found in the acute setting, arterial imaging may need to be repeated at intervals because overlying hemorrhage may obscure the detection of vascular malformations. In children with suspected or confirmed CSVT, MR venography is the modality of choice to evaluate the dural sinuses for clot and residual blood flow.

In children with either AIS or CSVT, an evaluation for prothrombotic states should be performed. Hematology should be consulted regarding the most up-to-date recommendations, but currently testing includes protein C and S activity, factor V Leiden mutation, antithrombin III level, antiphospholipid antibodies (anticardiolipin antibodies, β2 glycoprotein, diluted Russell’s viper venom time), prothrombin gene mutation, lipoprotein (a), and homocysteine. In the appropriate clinical setting, testing for infectious causes of vasculopathy, including varicella, HIV, and syphilis, is appropriate. Evaluation of the heart for cardiac sources of thrombi should be performed in all children with AIS. Transthoracic echocardiography is usually the initial cardiac imaging modality, but if there is a strong suspicion for a cardiac source, transesophageal echocardiography should be considered, even when the transthoracic test results are normal. A “bubble study” (agitated saline contrast) during the ECG is used to detect any abnormal arterial–venous connections. More extensive testing may be appropriate if the initial evaluation does not demonstrate a clear cause or if an underlying metabolic, infectious, or inflammatory disease is suspected.

Management

The phrase “time is brain” has been used in adult stroke to emphasize that a stroke is a “brain attack” that should be recognized and treated emergently. Unfortunately, treatment of childhood stroke is often delayed by more than 24 hours because parents and physicians often do not recognize childhood stroke immediately. The goal of therapy in acute ischemic stroke is to save as much of the penumbra as possible by restoring perfusion, minimizing demand, and avoiding additional insults such as hyperglycemia. Thrombolytics have not been studied in children younger than 18 years of age, so therapy is primarily supportive.

An overview of initial therapy is summarized in Figure 79-5. In the acute setting, the child should lie supine with the head of the bed flat and isotonic intravenous fluids given to maximize perfusion. Hypertension is an adaptive response to ischemia, and thus outside of extreme hypertension, blood pressure should not be aggressively reduced. In most cases, aspirin should be given after hemorrhage has been excluded with neuroimaging; however, in many centers, anticoagulation with a heparinoid is started after hemorrhage is excluded. In certain cases of AIS such as arterial dissection, cardioembolism, or a known prothrombotic disorder, anticoagulation should strongly be considered (see Figure 79-5). Fever and seizures should be treated to minimize additional metabolic demands, and normoglycemia should be maintained. After the neonatal period, dextrose-free fluids are preferred to minimize the risk of hyperglycemia.

Figure 79-5 Acute management of a child with suspected acute stroke.

After the child has been stabilized, attention should be directed at identifying the cause of the stroke and minimizing risk factors for recurrence. Speech, physical, and occupational therapy and other rehabilitation services should be involved early in the child’s hospitalization course so a recovery plan can be initiated in a timely manner.

In the acute management of patients with ICH and CSVT, the head of the bed should be elevated to at least 30 degrees to promote venous drainage and thereby lower ICP. The management of ICH is sometimes surgical, and prompt consultation with a neurosurgeon is advised. The need for acute lowering of ICP should be continuously reassessed. In CSVT, anticoagulation should be strongly considered, even in the presence of associated hemorrhage. In neonatal CSVT, the data for anticoagulation is less clear, and the approach should be highly individualized.

Conclusions and Future Directions

Stroke is a common cause of morbidity and mortality in children. Childhood stroke includes AIS, ICH, and CSVT. The outcome of stroke in children varies from severe deficits to complete recovery and may depend in part on timely recognition and treatment. The future of this field rests on collaborative trials to evaluate acute therapies such as thrombolytics in AIS and therapies to enhance recovery of function such as transcranial magnetic stimulation. In addition, efforts to improve the classification of childhood AIS and to identify predictors of outcome in childhood ICH are underway.