Incidence

It is difficult to ascertain the general incidence of ischemic stroke in children as there is limited information regarding pediatric stroke epidemiology. A population study from Rochester, Minnesota, of children under 15 years of age detected an incidence of cerebrovascular disease (including both ischemic and hemorrhagic stroke) of 2.5 per 100,000 population. In general, retrospective studies have reported stroke incidence of approximately 2.5 to 3.1 cases per 100,000 children per year.^5,6 In Japan, a series looking at ischemic cerebrovascular disease in children under 16 years of age (excluding moyamoya syndrome) identified a rate of 0.2 cases per 100,000 children. This reported rate may be low not only because of the exclusion of strokes caused by moyamoya disease (a leading cause of stroke in Japan) but also because of low rates of congenital heart disease.⁶ The higher rate of approximately 13 cases of stroke per 100,000 children per year, in a prospective European study, probably reflects the increased availability of better imaging modalities, such as computed tomography (CT).⁷ Hemorrhagic strokes account for approximately half of all strokes in the pediatric population. In a hospital autopsy series, 8.7% of patients died of complications related to cerebrovascular disease, but the most common cause of death was hemorrhage from an AVM, not ischemic stroke. The rate of recurrence is estimated to be 20% in these children.⁸

Causes

Strokes in adults are often caused by atherosclerosis; in contrast, the etiology of stroke in children can be diverse and determining the cause can be challenging. Although many different causes and potential risk factors for childhood stroke have been described, ischemic stroke in children frequently results from cardiac embolism, prothrombotic states, or vasculopathies, including the syndrome of moyamoya.⁴

Neonatal Stroke

The presentation of children with fixed neurological deficits during the perinatal period has been a topic of debate. Often grouped under the rubric of cerebral palsy, it appears that there may be multiple etiological factors in different children that account for the resultant neurological deficits. Perinatal hypoxia may result from birth-related trauma or asphyxia, and in utero arterial occlusions may occur secondary to embolic phenomena. Perinatal systemic disease may also contribute to ischemic brain injury, including disseminated intravascular coagulation (DIC), systemic infection, and congenital heart disease.

It may be difficult to dissect out cause versus effect of strokes in children who are hypotonic or have labile systemic vital signs (hypotension, apnea, bradycardia) at birth. Use of magnetic resonance imaging (MRI), ultrasound, and CT may be helpful in evaluation of parenchymal abnormalities in association with abnormal clinical presentation. Recent appreciation of the delayed risk of radiation use in children—especially the very young—has resulted in many institutions making efforts to minimize childhood exposure to CT when possible. In general, MRI can identify ischemic stroke earlier than CT or ultrasound, and offers better anatomical definition of the affected tissue. Although infarcted tissue cannot be repaired, knowledge of extent of infarct can be useful for prognostic purposes, including immediate risks from swelling, possibility of seizure with cortical injury, and overall prognosis with substantial stroke burden.

Genetic Disorders

Several heritable conditions have been implicated in pediatric ischemic stroke. These genetic conditions may be known from family history or may be newly diagnosed in a given patient.⁹ Congenital metabolic derangements can contribute to premature arteriosclerosis and resultant ischemic stroke.

Dyslipoproteinemias, inborn errors in the metabolism of lipids and cholesterol, have been associated with increased stroke in children. Deficiencies of proteins C and S, antithrombin III deficiency, prothrombin G20210A mutant genotype, sickle cell disease, and activated protein C resistance are examples of inherited hematological abnormalities associated with ischemic stroke.^4,10,11 Homocystinuria is a genetic disorder in which endothelial cell injury occurs, with ensuing thrombotic and embolic infarcts. Other inherited metabolic disorders such as the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, Menkes disease, and Tangier disease may also be associated with strokes. Although direct correction of the underlying genetic defects of the aforementioned diseases is not yet available, treatment currently focuses on normalizing the metabolic abnormalities. Early knowledge of the predisposing condition can result in heightened vigilance in monitoring for neurological sequelae, and in some cases, stroke burden can be minimized through preventive measures.

Embolic Stroke: Congenital Heart Disease

Strokes may occur in children with either congenital or acquired heart disease. Congenital heart disease is reported to occur in approximately 5 to 10 per 1000 live births and has been implicated in up to one third of all ischemic strokes via embolic phenomena.^12,13 Emboli can result from a right-to-left shunt, valvular disease (including mitral valve prolapse), endocardial disease, thrombus/tumor in the left side of the heart, pulmonary arteriovenous fistula, or after cardiac surgery when bypass has been employed. Children with emboli from bacterial endocarditis are also at risk for mycotic aneurysms. The risk for stroke in patients with endocarditis is higher if the disease involves the left side of the heart.

Special note is made of the Fontan operation: essentially an anastomosis of the right atrium to the pulmonary artery. It is one of the most common cardiac operations for children over 1 year of age with congenital heart disease and the surgery is associated with a 2.6% risk of stroke. The risk period for stroke extends from the first postoperative day to 32 months following the Fontan procedure.¹⁴

Thrombotic Stroke: Sickle Cell Disease and Hypercoagulable Conditions

Thrombotic stroke is a phenomenon described in children, often in association with polycythemia, dehydration, and infection. One of the most common entities associated with thrombotic stroke in children is sickle cell disease.⁴

Sickle cell disease affects nearly 1 in 400 African Americans, with a nearly 10% lifetime risk of stroke.¹⁵ Many strokes occur in children, with most strokes occurring before 10 years of age.¹⁶ Cerebral infarction is often caused by progressive occlusion of the distal internal carotid artery, usually involving the anterior cerebral and middle cerebral artery distributions. Treatment includes hydration, transfusion, and in some cases bone marrow transplant to correct the underlying genetic disorder. Of particular note, recent literature—from our group and others—has highlighted the finding that a substantial number of children with sickle cell disease will fail medical therapy and develop moyamoya syndrome.^17,18 Importantly, there is evidence supporting the premise that this subset of children respond well to surgical treatment of their moyamoya disease and should thus be considered for referral to a neurosurgical center experienced in the management of this condition.^4,17,18

Other conditions are also associated with prothrombotic disorders. In children who present with ischemic strokes, between 10% and 50% have been reported to have some type of prothrombotic state.^19–21 These prothrombotic processes can be genetic, such as factor V Leiden mutation, antiphospholipid antibodies, hyperhomocysteinemia, and elevated lipoprotein(a), or acquired, such as deficiencies in clotting pathways resulting from infection, medications, hepatic disease, or renal disease. Protein C, protein S, and antithrombin III deficiency may be either inherited or acquired. In all children who present with ischemic stroke, laboratory investigation of these hypercoagulable states should be undertaken.

Extracranial Arterial Dissection

Dissection of the carotid or vertebral arteries can occur in children spontaneously or may be secondary to trauma. Stroke can result from emboli from the site of dissection or from reduced blood flow from the narrowed vessel caliber. Of all patients (adult and pediatric) with dissections of these vessels, 6.8% were under the age of 18.²² Presenting symptoms are usually pain (either headache or neck pain) and neurological signs referable to the site of injury. With carotid dissections, Horner syndrome may be present due to injury of the sympathetic plexus surrounding the artery, in addition to neurological deficits referable to the regions of the brain supplied by the carotid. In the posterior circulation, Horner syndrome can also be caused as a result of lateral medullary infarction.

The history may be notable for no injury or seemingly insignificant trauma and there may be an interval of several days between the presumed causative event and the presenting symptoms. Although the gold standard remains conventional six-vessel angiography, the diagnosis of craniocervical dissection is increasingly being made with noninvasive imaging modalities, such as computed tomographic angiography (CTA) and magnetic resonance angiography (MRA).²³ Because of technique constraints, MRA and CTA may miss some dissections, particularly those involving the posterior circulation. Particular attention should be paid to the C1-C2 region, as that is the most common site of vertebral artery dissection.²⁴

Treatment is predicated on minimizing embolic events and allowing the injured vessel wall to heal. The risk for recurrent dissection is 12% and seems to be particularly high in the first several months immediately following presentation.²² Optimal treatment remains controversial. At Children’s Hospital Boston, we favor the use of anticoagulation, using heparin initially, followed by conversion to warfarin (Coumadin) for 6 months. Follow-up angiography often discloses healing of the dissection, after which anticoagulation is discontinued. If recurrent symptoms or radiographic progression occurs, endovascular therapy is considered.

Cerebral Vasculitis

Cerebral vasculitis is an uncommon cause of stroke in children. The vasculitis may be infectious or noninfectious. Infectious cases include sepsis of any type (particularly meningitis), varicella, human immunodeficiency virus (HIV), and mycoplasma.^25–30 Noninfectious causes include a wide variety of autoimmune disorders, including Behçet disease, sarcoidosis, Sjögren syndrome, ulcerative colitis, Kawasaki disease, and Schönlein-Henoch purpura (SHP), among others.^4,31,32

Cerebral vasculitis is often a difficult diagnosis to make. It should be considered when the stroke is associated with systemic manifestations such as fever, anorexia, myalgias, arthralgias, renal disease, and skin lesions. Presentation may be nonspecific, including both global (encephalopathy) and focal (often multiple) neurological deficits. Further complicating the diagnosis, stroke and other neurological symptoms might be the result of vasculitis or the result of a nonspecific disease process.

Previous work has demonstrated that only 4% of strokes in children were attributable to vasculitis.³³ Further study did not find any cause of vasculitis in children younger than 14 years of age with cerebrovascular disease.⁵ Taken together, these findings suggest that the incidence of vasculitis, even in at-risk populations, is very low. These data are important, as the neurosurgeon will often be consulted for consideration of brain biopsy in an attempt to make the diagnosis of cerebral vasculitis.

Miscellaneous Causes

One increasingly common cause for stroke in children is the use of illicit drugs. Strokes have been reported in association with the use of amphetamines, cocaine, and phencyclidine (PCP) among others. Suggested mechanisms include transient cerebral vasoconstriction, unmasking of a preexisting cardiovascular disease, toxic vasculitis, and prothrombotic tendencies.³⁴

Migraines are usually benign in children; however, there are reports of infarcts, usually in the vertebrobasilar distribution, associated with this disorder. Presumably these permanent deficits are the result of decreased vessel caliber during the migraine, leading to ischemia and infarction.⁴

Atherosclerotic cerebrovascular disease in children, although rare, has been implicated in stroke. Disorders of lipids may contribute to this process, as well as uncontrolled hypertension and diabetes.

Fibromuscular dysplasia has been associated with childhood stroke. Management of this disease is controversial, but many favor medical treatment with antiplatelet agents. Rarely, surgery or endovascular therapy may be utilized to bypass or dilate affected vessel segments.

Radiation-induced vasculopathy is a cause of stroke in patients involving either large or small vessels. Most commonly seen in patients treated for tumors, it may present in a delayed fashion. A recent study found that approximately 6% of children with central nervous system tumors treated with radiation had radiographic evidence of stroke.³⁵ One of the most important stroke syndromes associated with radiotherapy is moyamoya syndrome (see following section).^36,37

Epidemiology

First described in Japan, moyamoya syndrome has now been observed throughout the world and affects individuals of many ethnic backgrounds, with increasing detection of this disease in American and European populations.^42,43 In Japan, it is the most common pediatric cerebrovascular disease; affecting females almost twice as much as males with a prevalence of approximately 3 per 100,000.^39,44 In Europe, a recent study cited an incidence of 0.3 patients per center per year, which is approximately one tenth of the incidence in Japan.⁴⁵ A 2005 U.S. study suggests an incidence that was 0.086 per 100,000 persons. The ethnicity-specific incidence rate ratios compared to whites were 4.6 (95% confidence interval [CI]: 3.4 to 6.3) for Asian Americans, 2.2 (95% CI: 1.3 to 2.4) for African Americans, and 0.5 (95% CI: 0.3 to 0.8) for Hispanics.⁴⁶

In the United States and Korea, reports corroborated historical claims of a bimodal age distribution of moyamoya syndrome, one group in the pediatric age range (around the first decade of life) and a second group of adults in the 30- to 40-year-old range. Adults—who still predominantly present with stroke—have a sevenfold increased likelihood of presenting with hemorrhage as compared to children.^38,47,48 In contrast, children usually present with TIAs or strokes, which may prove more difficult to diagnose because of the patient’s age, leading to delayed recognition of the underlying moyamoya.^38,49

Associated Conditions

A number of clinical conditions or predisposing factors have been associated with moyamoya syndrome.^18,50–52 Table 11.2 summarizes the clinical associations noted in a recently published series.⁵¹

TABLE 11.2 Comorbid Conditions, Risk Factors, and Syndromes Associated with Moyamoya Syndrome