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Pediatric Stroke


Stroke is a leading cause of disability and death in children. Three distinct time periods can be used to categorize stroke in the pediatric population: fetal (14 weeks of gestation until the onset of labor), perinatal/neonatal (between late third trimester and the first month of life), and childhood (beyond the first month of life until adulthood). The true incidence of fetal stroke is unknown, particularly because the causes of fetal demise are often uncertain, and neurologic deficits in a surviving fetus are largely undetectable until birth. The incidence of stroke observed in the perinatal/neonatal period is between 1 per 1,600 and 1 per 5,000 live births. Therefore neonates constitute the second most common age group, after adults, in which stroke occurs. In children, ages 30 days to 19 years, the overall incidence is approximately 2 per 100,000. Among children who survive the neurologic insult, more than 50% will develop permanent neurologic or cognitive sequelae, frequently resulting in a large economic burden to the family and society.

Detection rates of stroke across fetal, neonatal, and childhood populations are rising due to improved imaging techniques, as well as higher awareness of pediatric stroke among medical professionals. However, despite improved diagnostic modalities, the cause of the stroke often cannot be determined with certainty; delays in diagnosis along with multiple, overlapping risk factors frequently complicate the clinical picture. The causes of stroke in the pediatric population are shown in Box 37.1 . These etiologies can be categorized by both patient age and the vessel of origin: arterial versus venous. In the United States, the epidemiology of pediatric stroke has shifted from infectious etiologies, still common in the developing world, to congenital and genetic disorders, such as congenital heart disease, sickle cell anemia, extracranial carotid dissection, and thrombophilia.

Box 37.1
Causes of Pediatric Stroke

Arterial Ischemic Stroke

Cardiac

  • Congenital heart disease

  • Valvular heart disease

  • Neoplasm, myxomas

  • Cardiac surgery

  • Myocarditis, cardiomyopathy

Cerebral Vasculopathy

  • Infection (e.g., meningitis)

  • Collagen vascular disease (e.g., systemic lupus erythematosus, giant cell arteritis, Takayasu arteritis, Kawasaki arteritis)

  • Primary angiitis of the central nervous system

  • Viral infection (e.g., varicella)

  • Trauma, dissection

Disorders of Coagulation

  • Protein C or S deficiency

  • Antithrombin III deficiency

  • Anticardiolipin antibodies

  • Lupus anticoagulant

  • Dysfibrinogenemia

  • Polycythemia and hyperviscosity

Moyamoya

  • Idiopathic/familial (Japanese)

  • Secondary (e.g., sickle cell disease)

  • Neurofibromatosis 1

  • Radiation vasculopathy

Inborn Errors of Metabolism

  • Fabry disease

  • Hyperhomocysteinemia

  • Ehlers-Danlos syndrome (type IV)

Sinovenous Thrombosis

  • Infection of the head and neck

  • Dehydration

  • Hypercoagulable states

  • Chemotherapeutic agents

  • Iatrogenic

Delayed recognition of pediatric stroke is common and leads to important delays in treatment. Clinical presentation of pediatric stroke differs by age and etiology, which frequently confounds early diagnosis. In a study of perinatal stroke, clinical presentations included seizures (72%), diffuse neurologic signs (63%), abnormal tone (38%), or encephalopathy (39%). In children presenting to emergency rooms, several symptoms independently associated with stroke include: being well the week before presentation, face weakness, arm weakness, and inability to walk. In children presenting with venous thrombosis, 58% of the children had seizures, 76% had diffuse neurologic signs, and 42% had focal neurologic signs. Because the presentation, causes, diagnosis, treatment, and outcomes of pediatric stroke differ significantly from adults, approaches to adult stroke are not necessarily applicable to the pediatric population. While treatment guidelines have been established for adults, the hyperacute management of pediatric stroke continues to emerge. Tissue plasminogen activator is now being administered in several pediatric stroke centers to children over the age of 2 years with stroke of less than 4.5 hours duration, and the use of endovascular thrombectomy, while nascent, is emerging in children over the age of 2 years with a somewhat longer timeframe.

Fetal Stroke

Fetal stroke is defined as occurring between 14 weeks of gestation until the onset of labor. Although diagnosis may be made by prenatal ultrasound, it has a low sensitivity for identifying fetal infarcts, and strokes identified by antenatal ultrasound screening are typically large. Detection of fetal stroke is often delayed until the neonatal period or even later in life, when deficits become clinically perceptible and the child is diagnosed with presumed perinatal stroke. These poor detection rates limit the assessment of fetal stroke incidence rates.

Risk Factors

Fetal stroke has different risk factors, clinical presentation, and outcomes compared with perinatal or childhood strokes. In more than 50% of cases of fetal stroke, no obvious cause is determined. Maternal conditions associated with fetal stroke include: diabetic ketoacidosis, immune thrombocytopenic purpura, warfarin use, trauma, maternal fever with gastroenteritis, and antiepileptic medications. Pregnancy-related factors include: fetal alloimmune thrombocytopenia, placental hemorrhage/thrombosis, abruptio placenta, multiple gestations, and twin-twin transfusion syndrome. Fetal conditions include: pyruvate decarboxylase deficiency, cytomegalovirus infection, non-A/non-B hepatitis, von Willebrand disease, and protein C deficiency.

Imaging Findings

Prenatal ultrasound is the most common screening tool for fetal brain abnormalities but is limited for the evaluation of stroke. Ultrasound detection rates are low for small and acute infarcts, and imaging findings are often not specific to stroke. Injury location and suggestion of a vascular distribution may raise concern for infarction; however, ultrasound cannot provide a definitive diagnosis.

Detection of a brain abnormality on prenatal ultrasound is often further evaluated with fetal magnetic resonance imaging (MRI). Fetal MRI has improved detection for ischemia and is the imaging modality of choice for confirming and assessing the extent of fetal ischemic brain injury ( e-Fig. 37.1 ). Single-shot turbo (fast) spin echo T2-weighted sequences are most frequently utilized to minimize motion artifacts. It is also possible to obtain T1-weighted images, T2*-weighted images, T2/T1-weighted images, diffusion-weighted imaging (DWI), and spectroscopic data. Importantly, unlike in older children and adults, fetal diffusion-weighted MRI sequences may not be reliable in predicting the approximate onset of an ischemic event.

e-Figure 37.1, Fetal infarct.

The most common findings associated with fetal stroke are intraparenchymal hemorrhage (91%), ventriculomegaly (59%), porencephaly (13%), and hydrocephalus. The pattern of parenchymal injury can suggest a venous or arterial origin of the stroke. Arterial ischemic strokes (AIS) in the prenatal period usually involve the major arterial territories, most commonly the middle cerebral artery (MCA). Venous strokes frequently result in hemorrhage, and hemorrhagic infarct should raise concern for venous thrombosis.

The age of the fetus at the time of infarct can contribute to the subsequent pathology and pattern of injury. As early as 12 weeks' gestation, supratentorial hydranencephaly can be seen as the result of bilateral internal carotid artery infarcts. If an ischemic event occurs during neuronal migration, particularly between 22 to 24 weeks' gestational age, the injury may result in cortical disorganization and polymicrogyria. Before approximately 27 weeks' gestational age, the fetal brain lacks a glial response to injury; after 27 weeks, the fetal brain can demonstrate a glial response, which is typically seen as T2 hyperintense signal at the periphery of the infarct. Schizencephaly occurs at less than 24 weeks of gestation and is thought to be due to destruction and defective development of a segment of the immature prosencephalic cortical mantle, potentially a consequence of ischemic etiologies. Porencephaly resulting from cystic degeneration, without gliosis, can be seen before 27 weeks' gestation. The transmantle variant of porencephaly that follows prenatal AIS results from insults greater than 24 weeks' gestation.

Outcomes

There is minimal data available regarding outcomes in fetal stroke. In one study, 78% (35/45) of in utero strokes resulted in either death or adverse neurodevelopmental outcome at ages 3 months to 6 years. Survivors may have developmental delay, cerebral palsy, and seizures. In another small study, those with resulting cystic encephalomalacia plus atrophy had worse cognitive outcomes than children with atrophy or gliosis alone. However, generalization of these data to individual fetuses is difficult due to the small numbers of cases as well as variability in infarct location and size.

Perinatal/Neonatal Stroke

Perinatal stroke occurs between late third trimester and the first month of life, usually defined between 28 weeks' gestational age to 28 days old. The incidence of AIS in newborns is reported as 1 in 2,300 to 5,000 deliveries, and the yearly incidence of cerebral sinovenous thrombosis (SVT) in term newborns is reported as 1.4 to 12 per 100,000. In this age group, the differentiation of ischemic stroke from hypoxic-ischemic injury may be challenging, particularly due to significant overlap in imaging findings, as well as coexisting pathophysiology. However, accurate interpretation is important given the differences in management and prognosis.

Risk Factors

Risk factors differ by arterial and venous etiologies, as well as by hemorrhagic infarct. Risk factors for perinatal stroke in term infants can be categorized by maternal, fetal and placental factors. However, the cause of perinatal stroke is not identified in over half of patients.

In AIS, maternal factors include: thrombophilia, infertility, prolonged rupture of membranes, preeclampsia/hypertension, gestational diabetes, abnormal maternal gestational bleeding, smoking, illegal drug use, intrauterine growth retardation, infection, and maternal fever. Fetal conditions include: thrombophilia, congenital heart disease, arteriopathy, hypoglycemia, perinatal asphyxia, infection, need of resuscitation, and Apgar score of less than 7 at 5 minutes. Placental factors include: chorioamnionitis, placental infarcts, and placenta weighing less than tenth percentile.

In SVT, maternal risk factors include: preeclampsia/HELLP syndrome, diabetes, maternal shock, maternal surgery, and history of clotting disorder. Perinatal risk factors include: complicated delivery, perinatal asphyxia, and fetomaternal transfusion. Neonatal risk factors include: sepsis or meningitis, dehydration, congenital heart defect, and extracorporeal membrane oxygenation (ECMO). Prothrombotic risk factors include: antithrombin level, protein C and S levels, factor V Leiden, prothrombin factor II, and other abnormalities. Independent risk factors for idiopathic hemorrhagic stroke are lower maternal age, primiparity, prior spontaneous abortion, difficult fetal transition (bradycardia and low Apgar scores), and being small for gestational age.

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