Stroke refers to acute vascular events involving the brain, brainstem, or spinal cord. Subtypes of stroke in the pediatric population include arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) with or without venous infarction, and hemorrhagic stroke (HS). By age, stroke subtypes can be further subdivided into perinatal (occurring from 20 weeks of gestation to 1 month of age by the broadest definition) and childhood stroke (occurring from 1 month to 18 years).¹ AIS is defined as an acute neurological deficit of any duration consistent with focal brain ischemia conforming to an arterial distribution (Figure 121-1) and evidence of infarction on neuroimaging. A transient ischemic attack (TIA) is defined as focal deficit(s) in a vascular territory lasting less than 24 hours; we include the absence of infarction on neuroimaging (restriction of water diffusion) in this definition. CSVT involves thrombosis of the superficial or deep dural venous sinuses. If thrombosis sufficiently impedes venous drainage, both ischemic and hemorrhagic infarction can occur. Hemorrhagic stroke is comprised of nontraumatic intracerebral hemorrhage (ICH) which can be intraparenchymal (IPH) and/or intraventricular (IVH) and subarachnoid hemorrhage (SAH).

Stroke incidence in the pediatric population is estimated at about 2.3 per 100,000 per year in developed countries, and unlike in adults, for whom about 85% are arterial ischemic, in children about half of all strokes are hemorrhagic.² Boys are affected more commonly than girls, and in the United States, African Americans have a higher incidence than children of other races, findings not entirely explained by sickle cell anemia or trauma.² The perinatal period is a time of particularly high risk with an incidence of 1 in 4000 live births.³ Stroke is among the top ten causes of death among US children.¹ Case fatality rates are estimated at 2% to 5% for AIS, 5% to 10% for CSVT, and 5% to 25% for ICH/SAH. Some deaths, however, may be due to comorbid disease rather than the stroke and its secondary consequences. Among survivors, two-thirds or more may have permanent neurological deficits.

ARTERIAL ISCHEMIC STROKE

Arterial ischemic stroke results when blood flow is obstructed or diminished by occlusion of an artery (Figure 121-2) (Table 121-1). This may be due to a thromboembolic mechanism that begins at a local (artery-to-artery embolus) or distal (cardioembolic or paradoxical) source, inflammatory or non-inflammatory steno-occlusive disease intrinsic to the arterial wall (arteriopathy or vasculopathy), or an extrinsic process that results in vessel wall compression (mass lesion, trauma, or cerebral edema). Ischemia deprives neurons of their two primary substrates, oxygen and glucose, thereby triggering a cascade of molecular and cellular events that culminate in cell death by apoptosis and coagulation necrosis. This is a fairly rapid process, occurring within minutes, as the brain is incapable of anaerobic metabolism. The catch-phrase “time is brain” underscores the need for rapid identification and treatment of those affected. Researchers have estimated that up to 2 million neurons may be lost each minute that a stroke goes unrecognized and therefore untreated. The extent of ischemic injury is influenced by several factors including the rate and nature of vessel occlusion, the degree of collateral circulation, the basal metabolic rate of affected cerebral tissue, and hematological factors that produce a hypercoagulable state. After an ischemic insult, there is a core of infarcted cerebral tissue encompassed by a concentric penumbra with decreased perfusion that is “at risk” for infarction if adequate blood flow is not restored. It is this penumbra that is targeted in neuroprotective and thrombolyic strategies that will be outlined in later sections.

In adults, atherosclerosis is the most common pathophysiologic mechanism underlying thromboembolic stroke. While atherosclerotic disease may begin in childhood and adolescence, it does not appear to be a significant contributor to stroke in children. Instead, pediatric stroke more commonly results from a heterogeneous group of disorders including arteriopathies (or vasculopathies) such as focal cerebral arteriopathy of childhood (Figure 121-3), post-varicella arteriopathy (Figure 121-4), moyamoya (Figure 121-5), and craniocervical dissection (Figure 121-6), cardiac disease (congenital or acquired), infection, and hematological abnormalities such as thrombophilias and hemoglobinopathies.⁴ However, up to one-third remain cryptogenic even after a thorough diagnostic evaluation. Importantly, unlike in adults, the risk of stroke recurrence in children with cryptogenic stroke is low.⁵

An important group of hospitalized patients at high risk of stroke are those with congenital and acquired cardiac disease. Risk in this population is dependent on underlying cardiac diagnosis, hemodynamics, medical comorbidities, need for cardiac surgery, intravascular procedures, and/or mechanical circulatory support devices. Children with cyanotic and complex congenital heart disease, particularly those with single-ventricle physiology, appear to be at greatest risk, as are those needing extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). Those with right-to-left shunts, for example those with hypoplastic left heart syndrome, are at risk for systemic emboli that form during surgery, a prolonged hospitalization, or catheterization from entering the cerebral circulation. Stroke occurred within 72 hours of cardiac surgery or at the time of diagnostic or interventional cardiac catheterization in about 25% of children with cardiac disease in one study by the International Paediatric Stroke Study.⁶ While children with stroke and heart disease were less likely to have an arteriopathy than those without heart disease, still about 25% had an arteriopathy as well, a finding that demonstrates the need for a complete diagnostic evaluation, even when one risk factor for stroke is known.

Estimates of stroke incidence in children with congenital heart disease range widely owing to its heterogeneity but has been reported to occur with a frequency of 132 in 100,000 per year in all children with congenital heart disease,⁷ in 5.4 in 1000 undergoing cardiac surgery with bypass,⁸ and in up to 5% to 10% after each of the planned palliative staged procedures for single-ventricle physology.^9,10 There may be an age-related risk of thrombosis as time from Fontan completion increases.¹¹ While duration of ECMO support is typically shorter than duration of VAD support, it appears that the incidence of stroke per day of support is higher in patients on ECMO (1–2 per 100 days) than on VAD (0.5 per 100 days).^12,13

CEREBRAL SINOVENOUS THROMBOSIS

Blood and CSF is drained from the brain into the internal jugular veins by a system of superficial and deep venous sinuses and veins lying within the dura and subarachnoid space. Superficial drainage occurs by way of cortical veins, the superior sagittal sinus (SSS), torcula (or confluence of sinuses), paired transverse and sigmoid sinuses, and the paired internal jugular veins. Arachnoid villi project into the dural venous sinuses, especially the SSS, and these are important for CSF reabsorption. The right transverse sinus is dominant in the majority of individuals and may appear visibly larger than the left transverse sinus on venography. This may confound neuroimaging interpretation and it may be difficult to discern a congenitally narrow left transverse sinus from one that is narrowed by thrombus.

Deep drainage originates in the medullary veins which empty blood from the white matter and basal ganglia, and this passes onward to a pair of internal cerebral veins that form the vein of Galen, followed by the straight sinus, the basal vein of Rosenthal, and the torcula. Deep outflow then drains by way of the final common pathway of transverse and sigmoid sinuses to the internal jugular veins. Both internal jugular veins empty into the superior vena cava, and then the right atrium of the heart. There are additional venous outflow tracts including the extrajugular collaterals, venous vertebral plexus, and extracranial emissary veins. Their role depends upon positioning (supine vs. upright) and age.

Cerebral sinovenous thrombosis occurs when a blood clot forms in any of the venous sinuses or veins of the deep and/or superficial venous systems (Figure 121-7). Thrombosis most frequently involves the superior sagittal sinus or transverse sinuses, and both occlusive and non-occlusive clots may occur.¹⁴ If collateral venous channels are unable to sufficiently drain blood (and consequently CSF) around a thrombus, intracranial pressure will increase and ischemia and/or hemorrhagic infarction can occur when capillary hydrostatic pressure exceeds arterial pressure. Venous infarction occurs in up to one-third, and hemorrhage in up to 20% of affected older infants and children.^14,15

CSVT is often multifactorial in origin and careful history-taking will reveal one of the following risk factors in the vast majority of affected children:^14,15 head and neck infection (most frequently otitis media and/or mastoiditis), dehydration, iron deficiency anemia, systemic inflammatory and chronic conditions (congenital heart disease, inflammatory bowel disease, nephrotic syndrome, Behcet disease, systemic lupus erythematosus, or malignancy), head/neck trauma or recent surgery, prothrombotic abnormalities (protein C, protein S, or antithrombin III deficiency; mutations in either Factor V Leiden or prothrombin 20210 genes; elevated homocysteine), and use of prothrombotic drugs (oral contraceptives, steroids, or L-asparaginase). Hospitalized patients most at risk for CSVT are children with acute lymphoblastic leukemia and L-asparaginase and/or steroid exposure,¹⁶ congenital heart disease (in particular those with single-ventricle physiology),⁸ meningitis, and recent head and neck surgery or head trauma.¹⁷

Prothrombotic abnormalities may be inherited or may be secondary to a comorbid medical condition or medication. For example, children with congenital heart disease or nephrotic syndrome may lose proteins like antithrombin III through pleural effusions, protein losing enteropathy, or renal loses. Use of L-asparaginase is associated with an acquired deficiency of antithrombin III, though this may not be the only mechanism of thrombosis associated with this chemotherapeutic agent. Overall, local and/or systemic infection appears to be the most common risk factor for CSVT, occurring in up to a third of all children with CSVT.¹⁴

INTRACEREBRAL HEMORRHAGE AND SUBARACHNOID HEMORRHAGE

In the pediatric population, most nontraumatic ICH is due to rupture of vascular malformations, most commonly arteriovenous malformations (AVMs; Figure 121-8) followed by cavernous angiomas and aneurysms, while a smaller proportion is attributed to hematologic abnormalities such as primary or secondary coagulopathies or platelet dysfunction, brain tumors, sickle cell anemia, and late effects of moyamoya vasculopathy. Hypertension and drug-related hemorrhage are rare in the pediatric population. Nontraumatic SAH (Figure 121-9) is most commonly caused by ruptured aneurysms. The mechanisms underlying ICH-induced brain injury include chemical irritation of neurons via red blood cell lysis, thrombin formation, iron toxicity, and edema formation. Similarly, in both ICH and SAH, intraventricular and subarachnoid blood can cause irritation to the ependymal lining of the ventricle and obstruction of arachnoid granulations (or villi), resulting in secondary obstructive or communicating hydrocephalus. Children with ICH or SAH may suffer from secondary arterial ischemic or watershed infarction due to compression of adjacent arteries, vasospasm, or decreased blood flow resulting from increased intracranial pressure with decreased cerebral perfusion pressure.

ARTERIAL ISCHEMIC STROKE

Arterial ischemic stroke usually presents as acute-onset, new-focal neurological symptoms or signs. Careful clinical and radiographic localization of AIS is important to determine the stroke etiology and to plan timely therapeutic interventions. A child’s stroke presentation is dependent upon the stroke location in the brain (Table 121-2), which may be classified by circulation (anterior vs. posterior), arterial territory involved (anterior cerebral, middle cerebral, posterior cerebral, vertebral, or basilar arteries), or by structures involved (cortex, subcortex [basal ganglia, thalamus], brainstem, or cerebellum). As outlined in Table 121-2, stroke at a specific site (i.e. cortex or subcortical white matter) can produce varying clinical manifestations. It is also important to recognize that a neurologic symptom or sign may occur due to lesions at different sites. For example, pure motor hemiparesis can occur due to a stroke involving cortex and subcortical white matter of the frontal or temporal lobes, but may also result from an isolated brainstem stroke impacting the descending cortical spinal tracts. The ability to rapidly differentiate between these may have critical importance on the acute management of the patient.

Clinical localization of stroke is generally limited by a child’s age and premorbid developmental status, particularly their cognitive and verbal skills and capacity to report symptoms. Stroke may be difficult to discern clinically when it is small in size or when a hospitalized patient is under the influence of anesthetic agents, has prolonged post-surgical sedation, or is pharmacologically paralyzed. These latter circumstances mask symptoms and signs and necessitate a low index of suspicion as well as judicious use of neuroimaging for clarification when stroke is suspected. Rapidly progressive encephalopathy or coma is rare in pediatric stroke, but may be seen with large middle cerebral artery territory strokes with accompanying malignant cerebral edema,^18,19 large cerebellar strokes with edema and herniation,²⁰ or when there is brainstem stroke.²¹

While about 90% of neonates (birth to 28 days of life) with AIS present with seizures, up to a quarter of infants and children >1 month old with stroke have acute symptomatic seizures at presentation.²² Neonatal stroke is not a focus of this chapter, but stroke should be suspected in a neonate presenting with seizures in the first 24 to 48 hours of life. These seizures can be subtle apneas or episodic stereotyped movements. The younger the child at time of stroke, the more likely they are to present with acute symptomatic seizures. Seizures are typically focal in onset given the focal nature of cerebral infarction, but they can progress to a secondarily generalized seizure. Many children with stroke report a headache as part of their clinical syndrome. Given the high prevalence of headache and seizure in children and the frequency of headache and seizure at time of presentation, AIS is often misdiagnosed as a Todd’s paresis or migraine with aura. Delays in diagnosis of pediatric stroke frequently result. When asked retrospectively, many parents will relate that they knew that their child’s neurological symptoms and signs could be explained by stroke, but they did not know that stroke could occur in childhood. A similar failure to recognize pediatric stroke symptoms also occurs in health care settings, with pediatricians, emergency department (ED) triage nurses and physicians, and occasionally pediatric neurologists attributing a child’s symptoms to a more common stroke “mimic” such as seizure or migraine. A study published by Rafay et al evaluating delays in pediatric stroke diagnosis showed a median time of 1.7 hours from stroke symptom onset to ED presentation and a median time of 12.7 hours for neuroimaging diagnosis, but only 38% of physicians evaluating children ultimately diagnosed with stroke included stroke in their differential diagnosis.²³ Factors that lead to the delay of stroke diagnosis included younger age, absence of seizure at presentation, milder stroke symptoms, and lack of altered level of consciousness.

CEREBRAL SINUS VENOUS THROMBOSIS

The clinical presentation of CSVT can be catastrophic, with sudden-onset severe headache and rapid progression to coma, but clinical manifestations are also often nonspecific. A high index of suspicion is necessary when confronted with at-risk children to ensure accurate diagnosis and prompt institution of treatment. Symptoms secondary to increased intracranial pressure (ICP) from venous thrombosis include headache which is often calvarial (top of the head) or occipital, severe, escalating, or worse when supine or with bending over or valsalva, visual disturbance (blurry vision or diplopia from abducens nerve palsy; visual field deficits due to concentric optic nerve compression), encephalopathy, and nausea and/or vomiting. CSVT can present with isolated headache, though the history may be atypical, with new onset symptoms, unremitting pain, and progression in severity over a short period of time. Acute symptomatic seizures may occur in up to half of older infants and children, especially when there is associated venous infarction or hemorrhage.¹⁴ Focal neurological deficits such as hemiparesis or hemisensory loss may also result, particularly when there is concomitant venous ischemia or hemorrhage.

Children presenting with new-onset daily headache with or without nausea, vomiting, and visual symptoms should have venography added to neuroimaging sequences obtained to rule out CSVT. Less frequently, CSVT may be subclinical, detected only when neuroimaging is performed after neurosurgery or in evaluation of intracranial or parameningeal infections such as meningitis or mastoiditis.

INTRACEREBRAL HEMORRHAGE AND SUBARACHNOID HEMORRHAGE

The most common symptoms of ICH and SAH include headache and emesis in nearly 80% and 60%, respectively. While headache can be of variable severity, classically headache from ICH or SAH is sudden onset and severe in nature. Any complaint of the “worst headache of the life” should prompt an immediate evaluation for ICH or SAH. Altered mental status and focal neurological deficits like hemiparesis and aphasia occur in about half of patients each. Seizures are a presenting symptom in about 40%.²⁴