Epidemiology of Ischemic Cerebrovascular Disease in Children

Incidence and Prevalence

Pediatric Ischemic Stroke: Overall

• 0.58 to 7.91 cases per 100,000 children per year: Estimates of incidence rates of pediatric ischemic stroke (regardless of etiology) range from 0.58 to 7.91 cases per 100,000 children per year (10,94,95,96,97).
• Perinatal and neonatal stroke: Findings from the Canadian Pediatric Ischemic Stroke Registry estimate that neonatal stroke occurs in 10.2 per 100,000 live births (10). The National Institute of Child Health and Human Development and NINDS estimate that perinatal stroke occurs in 1 in 2300 to 5000 births (98).

CT and MRI of a 4-week-old female presenting with seizures: (A) Non-contrast CT of the head shows a hypodense region (yellow arrow) in the right hemisphere. (B) DWI demonstrates hyperintensities in this region (yellow arrow). (C) Corresponding ADC hypointensities indicate this lesion is a cortical infarct (yellow arrow). (Images courtesy of Dr. Fabricio Goncalves and Caroline Davies of the University of Alabama at Birmingham Heersink School of Medicine.)

Coagulopathies

• Thrombophilia leads to high risk: Several mutations, including those in factor V Leiden, prothrombin G20210A, protein C, and protein S, have been implicated in the promotion of hypercoagulability. The presence of at least one prothrombotic mutation has been found in approximately 20% to 50% of children who present with arterial ischemic stroke (14,95). In their 2010 review comparing the effect of multiple prothrombotic mutations on the development of arterial ischemic stroke, Kenet et al. showed that the highest odds ratios were found for protein C deficiency, combined thrombophilic mutations, and the presence of antiphospholipid antibodies (99).

Sickle Cell Hemoglobinopathy

• Common cause of pediatric stroke: The rate of pediatric ischemic stroke is at least 200 times higher in children with sickle cell hemoglobinopathy than in those without the condition (62). Among these patients, ischemic stroke is most common in those with the HbSS and hemoglobin S-beta0 (HbS-B0) thalassemia genotypes.
• Importance of early intervention: Without intervention, approximately 11% of patients with HbSS have a clinically apparent stroke by age 20. Intervention with chronic blood transfusions in this population has been shown to decrease the rate of stroke up to 10-fold (69).

Congenital Heart Disease

• Elevated ischemic stroke risk in young patients with CHD: Ten to 12 per 1000 liveborn infants have CHD (100,101). For children with CHD, the incidence of ischemic stroke is 3% to 4%; this can be more than 10 times higher than in the general population (102). However, this incidence of ischemic stroke can vary significantly depending on the specific type of heart defect involved and the patient’s age. Additionally, 31% of pediatric ischemic stroke patients have a cardiac disorder (103).

Metabolic Disorders

• Relatively rare on a population level: Metabolic disorders associated with an increased risk of pediatric ischemic stroke are relatively rare on a population level; these include homocystinuria (approximately 1 in 200,000 to 335,000 live births) (104), Fabry disease (estimates range between 1 in 8,454 to 1 in 117,000 males) (105), and MELAS (18.4 in 100,000 children) (106).

Infections

• Common etiology of pediatric ischemic stroke: While datasets may vary, at least 10% of pediatric strokes are thought to have an infectious etiology (107).

Craniocervical Arterial Dissection

• Significant contributor to pediatric ischemic stroke: Incidence rate estimates for craniocervical arterial dissection range from 2.5 to 8 per 100,000 children per year (108). This etiology may account for 7.5% to 20% of all pediatric arterial ischemic stroke cases (108).

Noninfectious Vasculitides

• May account for 4% of pediatric ischemic strokes: Vasculitides may account for 4% of ischemic strokes in children (45).

Cerebral Venous Sinus Thrombosis

• 0.67 cases per 100,000 children per year: An estimated incidence of 0.67 cases of CVST per 100,000 children per year was derived from the Canadian Pediatric Ischemic Stroke Registry; over 40% of those affected are neonates (109).

Age Distribution

Pediatric Ischemic Stroke: Overall

• Reverse J-shaped age distribution: Pediatric ischemic stroke incidence rates by age have a reverse J-shaped distribution: highest in neonates, then steeply decreasing with increased age (lowest in children aged 5-9 years), and increasing slightly in adolescence (110).

Coagulopathies

• No clear trend: While the presence of one or more thrombophilic risk factors has been found to increase the overall risk of arterial ischemic stroke in the pediatric population, no significant correlation has been found between the age group of the affected patients (perinatal/neonatal versus children) and stroke risk when looking at coagulopathies overall; however, differences in the prevalence of specific prothrombotic mutations may contribute to varying age distributions of arterial ischemic stroke risk by mutation (99,111).

Sickle Cell Hemoglobinopathy

• Protective factors in early life: The presence of fetal hemoglobin is thought to decrease stroke risk early in life, contributing to minimal stroke risk for patients with HbSS who are younger than 2 years (112).
• Increased risk thereafter: Stroke risk for patients with HbSS is highest between ages 2 and 5 years (about 1% per year); without intervention, approximately 11% of patients with HbSS have clinically apparent strokes by age 20 (112).
• An opposite relationship: While rates of both ischemic and hemorrhagic stroke are high for patients with HbSS who are younger than 20 years, the rate of ischemic stroke decreases from ages 20 to 29 years before rising again in patients over age 30 (112). Conversely, the rate of hemorrhagic stroke increases in HbSS patients in their 20s and decreases thereafter (112,113).

Congenital Heart Disease

• Perinatal and childhood stroke: Children with CHD often present with ischemic stroke in the first year of life, although the risk of ischemic stroke in this patient population is elevated during childhood and young adulthood (102,114).

Metabolic Disorders

• Homocystinuria: Untreated patients may present with thromboembolic stroke before age 20 (115).
• Fabry disease: In a cohort of 138 patients with Fabry disease who experienced strokes, 30 patients (21.7%) had strokes when younger than age 30 (36).
• MELAS: The onset of stroke-like episodes in MELAS usually occurs between ages 2 and 15 years (116).

Infections

• Younger children may be at higher risk: In one study of pediatric ischemic stroke with infection in the prior week, the median age was 4.0 years (117).

Craniocervical Arterial Dissection

• Average age is 8.6 years: A review of 182 patients with craniocervical arterial dissection found an average age of 8.6 years (108). It is plausible that older children and adolescents may be at elevated risk given the higher rate of trauma and involvement in contact sports in these age groups.

Noninfectious Vasculitides

• Poorly defined age distribution: Any age predilection that exists likely resembles the age predilection for any vasculitis associated with pediatric stroke.

Cerebral Venous Sinus Thrombosis

• Neonates most commonly affected: Within the pediatric population, neonates are far more likely to develop CVST than infants, children, and adolescents. Findings from the Canadian Pediatric Ischemic Stroke Registry revealed that 43% of children affected by CVST were neonates, and 54% of children were younger than 1 year (109).

Sex Predilection

Pediatric Ischemic Stroke: Overall

• Male predominance: Pediatric ischemic stroke has a male predilection regardless of age (neonates versus later childhood), stroke subtype (arterial ischemic stroke versus CVST), or history of trauma (118).

Coagulopathies

• For most conditions, no sex predilection: Most coagulopathies in children appear to occur at an approximately 1:1 ratio, with no significant associations between sex and stroke risk. The prevalence of certain conditions and their associated stroke risk, however, can change throughout life and predispose one sex to increased risk of arterial ischemic stroke. For instance, antiphospholipid syndrome has a male to female ratio of 1:1.2 in children, whereas in adults, the ratio is 1:5 and correlates with an increased risk of stroke in adult females (99,119,120).

Sickle Cell Hemoglobinopathy

• No known sex predilection: An autosomal recessive disorder, HbSS affects males and females at similar rates. No significant difference has been shown between rates of ischemic stroke in either sex (121).

Congenital Heart Disease

• No known sex predilection: Current data do not suggest a significant difference in incidence rates between male and female patients with CHD.

Metabolic Disorders

• Homocystinuria: There is no known sex predilection.
• Fabry disease: Fabry disease is inherited in an X-linked manner; hemizygous males are severely affected, whereas heterozygous females may be relatively asymptomatic or, in some cases, as severely affected as males (122,1233).
• MELAS: There is no known sex predilection.

Infections

• No known sex predilection: There is no evidence of a sex predilection for pediatric ischemic stroke with an infectious etiology.

Craniocervical Arterial Dissection

• More common in males: A review of 182 cases found a male predominance of 68%, likely attributable to the higher rate of trauma in males (108).

Noninfectious Vasculitides

• Male predominance in some: Childhood primary angiitis of the central nervous system, Henoch-Schönlein purpura, and Kawasaki disease have a male predilection (124,125,126).

Cerebral Venous Sinus Thrombosis

• Possible male predilection in neonates: Overall, the pediatric CVST cohort from the Canadian Pediatric Ischemic Stroke Registry had a roughly even sex distribution (54% male and 46% female) (109). However, in neonates, a 75% to 78.1% male predominance has been reported (127,128).

Geographic distribution

• Overall geographic variance unclear: It is unclear whether any geographic variance in the incidence of pediatric ischemic stroke exists given the lack of registry data from most countries. In the United States, pediatric stroke mortality rates are higher in the “Stroke Belt” (Southeastern United States) (129).

Coagulopathies

• Factor V Leiden: The factor V Leiden mutation is most prevalent in Europeans, particularly among those of Greek ancestry (281).
• Prothrombin G20210A: The prothrombin G20210A mutation is most prevalent in southern and northern Europe, and it is rare in individuals of Asian and African descent (282).

Sickle Cell Hemoglobinopathy

• Malaria hypothesis: The heterozygous carrier state known as sickle cell trait is hypothesized to confer resistance against malaria (283). Accordingly, sickle cell hemoglobinopathy is most prevalent in regions where malaria is endemic, including sub-Saharan Africa and the Mediterranean, Middle East, and Indian subcontinent regions (283,284). It is also common in Latin America and the Caribbean (285). Within the United States, the estimated prevalence of sickle cell hemoglobinopathy is highest in the Southern and Eastern United States (286). Stroke associated with sickle cell hemoglobinopathy is highly prevalent in Africa, which may be due to limited resources for screening and prevention (287).

Congenital Heart Disease

• Geographic variance unlikely: There appears to be no geographic variance in the incidence of CHD. There is, however, variability in its recognition that may be related to the availability of advanced diagnostic methods (288).

Metabolic Disorders

• Homocystinuria: This metabolic disorder is known to be more prevalent in Ireland and Qatar due to consanguinity (130,131).
• Fabry disease: There is no known geographic predilection.
• MELAS: There is no known geographic predilection.

Infections

• Geographic variance is unclear but plausible: Although not well-established in the literature, pediatric ischemic stroke due to infectious etiologies may be more common in regions where vaccination rates for certain pathogens are lower or where the ability to treat certain infections is limited.

Craniocervical Arterial Dissection

• No known variance: There are no data supporting any variance in incidence as a function of geographic location.

Noninfectious Vasculitides

• Some geographic variance exists: Kawasaki disease is particularly common in the Japanese population, and Behçet’s disease is more common in Turkey than in other geographic regions (132). This is likely attributable to geographic variance in genetic factors.

Cerebral Venous Sinus Thrombosis

• No known variance: There are no data supporting any variance in incidence as a function of geographic location.

Risk Factors

Coagulopathies

• Multiple factors, genetic and otherwise, contribute to risk: Several mutations have been associated with increased risk of arterial ischemic stroke. Protein C deficiency, antiphospholipid syndrome and lupus anticoagulant, elevated lipoprotein, or a combination of two or more genetic thrombophilias have been implicated in statistically significant increased ischemic stroke risk. Other factors that contribute to hypercoagulability — for example, neoplasms, disseminated intravascular coagulation, oral contraceptive use, vitamin K deficiency, and liver dysfunction — may also increase the risk of arterial ischemic stroke in pediatric populations. Additionally, leukocytosis, thrombocytosis, and iron-deficiency anemia are associated with increased AIS risk (21,95,99).

Sickle Cell Hemoglobinopathy

• Genotype: Of all sickle cell genotypes, HbSS and HbS B0 thalassemia are associated with the highest risk of stroke in hemoglobinopathy patients (62).
• Genetic factors may modify risk: Certain genetic polymorphisms, such as concomitant alpha thalassemia, have been found to lower the risk of stroke in patients with HbSS; however, the presence and significance of genetic risk modifiers are not yet well understood and warrant further study (133).

Metabolic Disorders

• Family history: Although sporadic mutations may be responsible for metabolic disorders, the mutations responsible for these disorders are generally inherited from a parent; thus, a family history of metabolic disorders is a risk factor.

Infections

• Key risk factors for infection: These include immunocompromised states, exposure to bacterial meningitis, and recent viral illness.

Craniocervical Arterial Dissection

• Risk factors are either greater exposure to trauma or lower resilience against trauma: Head and neck injury (trauma), hereditary connective tissue disorders (including Ehlers-Danlos syndrome), and male sex are known risk factors of craniocervical arterial dissection (89).

Noninfectious Vasculitides

• Genetic risk factors: Although childhood cerebral vasculitis can be idiopathic or due to sporadic mutations, heritable genetic risk factors are present and may be indicated by the family history (132).

Cerebral Venous Sinus Thrombosis

• Several risk factors: Major risk factors for CVST include infections (otitis media and mastoiditis), fever, dehydration, anemia, vascular trauma, CHD, nephrotic syndrome, malignancy, and several prothrombotic factors (134,135).

Miscellaneous Risk Factors of Pediatric Ischemic Stroke

• Drug use: Adolescents and young adults who use illicit or recreational drugs such as amphetamines, ecstasy, cocaine, phencyclidine, heroin, and crack cocaine may be at elevated risk of stroke, possibly due to transient vasoconstriction of the cerebral arteries (136,137).

MRI and MRA of an 18-year-old female presenting with cocaine vasospasm: (A) Axial T2-weighted and (B) FLAIR MRI demonstrates white matter hyperintensities in the left hemisphere (yellow arrows). (C) Coronal T2-weighted MRI shows hyperintensities in the left corona radiata (yellow arrow). White matter hyperintensities (yellow arrows) on (D) DWI and corresponding hypointensities (yellow arrows) on (E) ADC mapping indicate these lesions are white matter infarcts. (F) MRA demonstrates profound vasospasm of the left MCA and its branches (yellow arrow). (Images courtesy of Dr. Fabricio Goncalves and Caroline Davies of the University of Alabama at Birmingham Heersink School of Medicine.)

• Migraine with aura: Although supported by very limited evidence, migraine with aura in adolescents may be a risk factor for ischemic stroke (138). The reason for this association is unclear.
• Radiation therapy: Radiation therapy for pediatric brain tumors is associated with lacunar infarcts, which may be caused by radiation-induced vasculopathy (139).

Relationships to Other Disease States and Syndromes

Coagulopathies

• Association with hypercoagulable states: Hypercoagulability due to neoplasms, disseminated intravascular coagulation, and/or pregnancy may increase the risk of ischemic stroke in pediatric patients. Coagulopathies secondary to protein C and/or S deficiencies may be associated with renal and/or liver disease. Examples include nephrotic syndrome and liver dysfunction with decreased coagulation factors.

Sickle Cell Hemoglobinopathy

• Moyamoya arteriopathy: Secondary moyamoya arteriopathy is associated with HbSS and may increase the risk of seizures and recurrent strokes (83,140,141).
• Additional risk factors: Stroke risk may also be exacerbated in HbSS patients by comorbid anemia, malnutrition, or meningitis (142).

Congenital Heart Disease

• Coagulopathies: Coagulation disorders are commonly observed in patients with CHD and can increase the risk of ischemic events (143).

Metabolic Disorders

• Homocystinuria: Patients with homocystinuria have an increased risk of cardiovascular disease and venous thromboembolism (144).
• Fabry disease: Fabry disease is associated with renal failure and cardiac disease; the latter includes left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrythmias (145,146).
• MELAS: MELAS is associated with hearing loss, seizures, and diabetes (116).

Craniocervical Arterial Dissection

• Trauma and connective tissue disorders: Trauma to the head and neck may precipitate traumatic dissections. Hereditary connective tissue disorders, such as vascular Ehlers-Danlos syndrome, may predispose patients to spontaneous and/or traumatic dissections (89,147).

Noninfectious Vasculitides

• Association with autoimmune and infectious diseases: Vasculitides associated with ischemic stroke in children may be associated with autoimmune diseases and antecedent or concurrent infections (132,148).

Cerebral Venous Sinus Thrombosis

• Association with several disease states: As described previously, CVST in children may be associated with several disease states, including infections, anemia, trauma, CHD, nephrotic syndrome, malignancy, and prothrombotic factors (134,135).