The National Institute of Neurological Disorders and Stroke and the Office of Rare Disorders sponsored a workshop on perinatal and childhood stroke in Bethesda, Maryland, on September 18 and 19, 2000. This was an international workshop to bring together experts in the field of perinatal and childhood stroke. Topics covered included epidemiology, animal models, risk factors, outcome and prognosis, and areas of future research for perinatal and childhood stroke. Stroke in infants and children is an important cause of morbidity and mortality and an emerging area for clinical and translational research. Currently, there is no consensus on the classification, evaluation, outcome measurement, or treatment of perinatal and childhood stroke. Pediatric stroke registries are needed to generate data regarding risk factors, recurrence, and outcome. The impact of maternal and perinatal factors on risk and outcome of neonatal stroke needs to be studied. This information is essential to identifying significant areas for future treatment and prevention.
The National Institute of Neurological Disorders and Stroke and the Office of Rare Disorders, National Institutes of Health, sponsored a workshop on perinatal and childhood stroke in Bethesda, Maryland, on September 18 and 19, 2000. This was an international workshop to bring together experts in the field of perinatal and childhood stroke. Topics covered included epidemiology, animal models, risk factors, outcome and prognosis, and areas of future research for perinatal and childhood stroke. Perinatal stroke was discussed separately from childhood stroke because of underlying differences in incidence, cause, and outcome.
Cerebrovascular disorders are among the top 10 causes of death in children, with rates highest in the first year of life. The US mortality rate in 1998 attributable to stroke was 7.8/100 000 in children 0 to 1 year of age, and is higher in males than females and in blacks compared with whites.1 Stroke mortality in children <1 year of age has remained the same over the last 40 years.2
The reported incidence and prevalence of stroke in children has increased over time because of improvements in imaging techniques. The first population-based study of stroke in children from the 1970s found an incidence rate of 2.52 per 100 000 children for all stroke types.3 Since then, additional population-based studies have identified rates of ischemic stroke as high as 3.3/100 000 children, and actual rates are likely to be higher. The causes of stroke have also changed over time. In the past, infections like Haemophilus influenzae meningitis were a common cause of stroke in children. Today, congenital heart disease, sickle cell anemia, coagulation disorders, extracranial carotid dissection, and varicella infection are common causes; however, in more than a third of cases, no cause is found.4–6
The treatment of stroke in children is not well-studied. There is only 1 published randomized trial of stroke in children.7 The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a prospective, randomized, clinical trial comparing regular blood transfusions with standard care for primary stroke prevention in high-risk individuals with sickle cell disease (SCD). The STOP trial was terminated in 1997 because of a 92% reduction in stroke in the treatment arm compared with standard therapy. Other treatments for childhood stroke are based on adult studies or nonrandomized trials.
The outcome reported for stroke in children varies because of differences in functional outcome measures and the population studied. More than half of survivors develop some neurologic or cognitive problem, one-third have a recurrence, and 5% to 10% of affected children die.
Perinatal stroke is defined as cerebrovascular events that occur between 28 weeks of gestation and 28 days of postnatal age. Perinatal stroke is underrecognized clinically. Variations in the definition, clinical presentation, and diagnosis of perinatal stroke complicate estimation of the incidence of the disorder. For example, some infants are neurologically asymptomatic in the newborn period, and motor impairment is recognized only after voluntary hand use develops at about 4 to 5 months of age. The few population-based studies of childhood stroke in the United States have typically excluded neonates or children <1 year of age.3,8,9 In the Canadian Pediatric Stroke Registry, one of the largest childhood stroke cohorts, a quarter of the children were term neonates.10 In one study of infants greater than 31 weeks’ gestation with neonatal seizures, 12% had underlying cerebral infarction.11 These results suggest a prevalence of neonatal stroke of 24.7/100 000 per year in infants greater than 31 weeks’ gestation and are similar to a published report of 28.6/100 000 by Perlman.12 In the National Hospital Discharge Survey (NHDS) from 1980 through 1998, the rate of stroke for infants (mostly term) <30 days of age was 26.4/100 000, the rate of hemorrhagic stroke was 6.7/100 000, and the rate of ischemic stroke was 17.8/100 000 live births per year. Based on these results, neonatal stroke is recognized in approximately 1/4000 live births per year.
Animal Models for Neonatal Stroke
The neonatal brain is selectively vulnerable to focal ischemia.13 Specific differences in the blood-brain barrier, inflammatory response, biochemistry, and vascular perfusion and reperfusion of the neonatal brain present challenges for the use of adult animals models to study neonatal stroke. There are a limited number of animal models for focal ischemic stroke in neonates.
The Rice-Vanucci model, an ischemic-hypoxia model, is the most widely used animal model to study neonatal stroke.14 The Rice-Vanucci model consists of unilateral common carotid artery ligation in a 7-day postnatal rat. This model creates ipsilateral hemisphere, caudate, putamen, hippocampal, and cortical damage, but can also lead to contralateral hemispheric changes and apoptotic cell death.
Three other rat models have been developed to study neonatal stroke and include a transient middle cerebral artery (MCA) occlusion in the 7-day postnatal Spraque Dawley rat,15 transient MCA occlusion in the 14- to 18-day postnatal rat,16 and a permanent internal carotid artery (ICA) occlusion in the 7-day postnatal Wistar rat.17 The P7 Spraque Dawley rat model results in 80% infarction rate with 100% survival and has the advantage of being able to evaluate reperfusion injury. The P14 18-day rat model creates infarct volumes of 38% to 54% within the MCA distribution, including the hippocampus, caudate, putamen, and ipsilateral cortex and serves as a good model for juvenile stroke. The P7 Wistar rat model has been shown to produce lower mean infarct volumes restricted to the cortex and is highly reproducible. The inflammatory response of the neonatal brain is robust, and differs in its response to free-radical scavengers when compared with the adult brain.
Risk Factors for Neonatal Stroke
The reported causes of neonatal stroke have included cardiac disorders, infection, blood abnormalities, and/or perinatal events, yet in a large number of cases the cause remains undetermined. In data from the NHDS (1980–1998), the most common discharge diagnoses reported in conjunction with neonatal stroke included infection, cardiac disorders, and blood disorders, with <5% associated with “birth asphyxia.” Coagulation disorders, including the factor V Leiden (fVL) and prothrombin mutation, and protein C, protein S, and antithrombin III deficiencies have been identified in up to half of infants and children with cerebral thromboembolism.18–20 Recent evidence suggests that coagulation disorders, including autoimmune syndromes and the fVL mutation, may be responsible for a greater proportion of strokes in neonates. Adverse antenatal and perinatal factors are common in children with neonatal stroke, although their role in the causation and influence on long-term prognosis is not well-understood. Maternal factors may also be responsible for stroke in the neonate. Factors suggesting that autoimmunity or hypercoagulability may be playing a role include a history of previous pregnancy loss or placental infarction.
Phospholipids are important in the activation of protein C and the coagulation pathway. Antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin, are directed against anticoagulant proteins, interfere with normal coagulation, and may be a risk factor for neonatal stroke. A recent study by Nelson et al21 found elevated titers (>1:100) of antiphospholipid antibodies in children with cerebral palsy (4 out of 31) versus controls (0 out of 65).
The fVL mutation is the most common inherited cause of thrombosis and has been observed in association with adverse maternal and neonatal outcomes. The fVL mutation is attributable to a missense mutation of the factor V (F5) gene, which substitutes guanine for adenine at nucleotide 1691(1691G-A) and predicts the replacement of arginine for glutamine at position 506 (R506Q). This amino acid substitution alters the function of the F5 molecule and makes it resistant to normal cleavage by activated protein C (APC). Protein C is activated by the thrombin-thrombomodulin complex and degrades factor Va and VIIIa. The resistance of the fVL mutation to APC results in increased thrombin generation and a shift toward increased coagulability.
Pregnancy is a time of relative hypercoagulability, during which protein S and APC ratios are decreased, whereas thrombin generation, protein C, and fibrinogen levels are increased.22 The fVL mutation has been associated with pregnancy-related thrombosis and other pregnancy disorders, including preeclampsia, intrauterine growth retardation, placental abruption, preterm delivery, placental infarction, spontaneous miscarriage, and fetal death.
The fVL mutation is also associated with neonatal stroke and cerebral palsy in children. Children with stroke associated with the fVL mutation typically develop symptoms within the first months of life and in the presence of additional endogenous or exogenous risk factors for thrombosis. Since 1995, at least 25 neonates have been reported with a cerebrovascular disorder associated with the fVL mutation. A recent study by Dizon-Townson and colleagues23 found the fVL mutation in 6/28 (21%) children with cerebral palsy versus 14/407 (3%) normal controls (P < .001).
Inherited coagulation abnormalities may lead to adverse maternal and fetal events via thrombosis at the maternal-placental interface. Thrombosis on the maternal side may lead to preeclampsia, intrauterine growth restriction, miscarriage, or fetal death. Thrombosis on the fetal side produces a possible source of emboli that in the fetus can bypass the hepatic and pulmonary circulation to reach the fetal brain. Thrombosis and embolisation within the fetus or neonate with fVL are also possible.
Outcome and Prognosis of Perinatal/Neonatal Stroke
The outcome of children with neonatal stroke varies among studies because of differences in stroke type, duration of follow-up, specific outcomes, and population studied. Electroencephalography and neuroimaging studies provide measures of long-term cognitive and motor outcome. Children with an abnormal electroencephalogram during the first week after stroke typically develop hemiplegia. Mercuri and colleagues24 found that infarction involving the internal capsule predicts the development of hemiplegia, whereas involvement of other regions is less reliable. These results are similar to a previous study of preterm children with hemorrhagic infarction. In reference to language function, Trauner and colleagues25 have found that children with early unilateral brain damage exhibit prosodoic deficits when compared with controls, and the side of the lesion seems to be related to affective comprehension. In contrast to the relationship between infarct location and language deficits or hemiplegia, the location of the lesion does not adequately predict visual abnormalities. There is not a consistent association between occipital involvement and visual field defects or between parietal lesions and fixation shift abnormalities.
The recurrence rate of neonatal stroke is much less than childhood stroke. In the Canadian Pediatric Ischemic Stroke Registry (CPISR), the largest cohort of stroke in children, the recurrence rate of children with neonatal stroke was 3% to 5% and in survivors, outcome was normal in 33%.26
Childhood stroke is defined as a cerebrovascular event that occurs between 30 days and 18 years of age. The incidence of childhood stroke from population-based studies is estimated between 2–3/100 000 children in the United States and as high as 13/100 000 in France.8,27 The CPISR reported ischemic stroke in 2.7/100 000 children <18 years of age per year. Forty percent of stroke cases from the CPISR were under 1 year of age, with a male to female (1.5:1) predominance. In the NHDS, from 1980 through 1998, for children 0 to 18 years, the rate of stroke was 13.5/100 000; hemorrhagic stroke (International Classification of Diseases, Ninth Revision code 430–431) was reported in 2.9/100 000, and ischemic stroke (International Classification of Diseases, Ninth Revision code 433–437, excluding 435) was reported in 7.8/100 000 children per year.
The US mortality rate attributable stroke in children (1–15 years of age) is 0.6/100 000 children.28 The mortality rate in children attributable to stroke is higher in males than females and blacks compared with whites. The case mortality rate for childhood stroke is reported to range from 7% to 28%.3,29–31
Mechanism: Ischemic Stroke
There are no widely accepted classification systems for the cause of ischemic stroke in children. Etiologic classification systems for ischemic stroke are available for adults but are not appropriate for children. The determination of the mechanism of stroke may require extensive investigation, and etiologic evaluations of childhood stroke in the past were often limited. Recent studies using more extensive diagnostic strategies have provided important information on the cause and outcome of stroke in children.
The mechanisms by which ischemic stroke occurs in children include the following: thromboembolism from an intracranial or extracranial vessel, or the heart; acute, transient, or progressive arteriopathy; and other rare causes, but in a large percentage of cases the cause is undetermined.6
The diagnosis of stroke attributable to cardiac or transcardiac embolism has varied among cohort studies. Children with stroke attributable to cardiogenic embolism typically have some evidence of an underlying heart disorder, with or without a recognized thrombus. However, a recent study of childhood stroke categorized children with cardiac or transcardiac embolism even without a history of cardiac disease.32
Children with stroke attributable to angiopathy typically have some evidence based on angiographic, noninvasive, or other studies of arterial dissection, vasculitis, Moyamoya, transient cerebral angiopathy, or other vasculopathy.
Risk Factors: Ischemic Stroke
A risk factor is an attribute, inherited or acquired, that increases the probability of a specific disease or outcome. The most frequently reported risk factors for stroke in children include cardiac disorders, coagulation disorders, SCD, infection, moyamoya, arterial dissection, and other rare genetic disorders.33
Cardiac disease, as previously stated, is a common cause of stroke in children, accounting for up to 50% of strokes in case series.34 In the CPISR, cardiac disease was identified in 25% of children with ischemic stroke. Several cardiac disorders are associated with stroke in children, including congenital heart disease, intracardiac defects, cardiac procedures, and acquired heart disease.
Several acquired and genetic coagulation factor abnormalities have been associated with ischemic stroke in children. Five coagulation abnormalities are associated with thrombosis in children, including deficiencies in protein C, protein S, and antithrombin III, and the fVL and prothrombin 20 210 A mutations. A study of cerebral thromboembolism that included 92 children from the Hospital for Sick Children in Toronto found coagulation abnormalities in 38% of children studied.19
Antiphospholipid antibodies are associated with a variety of systemic disorders, including endocarditis, chorea, recurrent fetal loss, and childhood stroke. Antiphospholipid antibodies have been reported in a quarter of patients with a first stroke.35 In a study by Angelini et al,36 75% of children with cerebral ischemia were positive for antiphospholipid antibodies.
SCD is the most common risk factor for stroke in black children. Sickle cell-related stroke is associated with large vessel stenosis of the proximal middle cerebral or distal internal carotid artery. The mechanism by which stenosis develops is unclear. Children with sickle cell have a risk of stroke 200 to 400 times that of children without SCD. Most strokes are seen in individuals with homozygous sickle cell anemia. One tenth of children with SCD will go on to develop symptomatic stroke by 20 years of age, and 20% will develop clinically silent strokes over the same time period.37 The recurrence risk is extremely high, as much as 50% by 3 years.38
Infectious disorders are also associated with stroke in children. A recent study by Sebire and colleagues39 of children with transient cerebral angiopathy found an increase in varicella zoster viral infection in cases versus controls and suggests a temporal link between chicken pox and the development of stroke in children. In children aged 6 months to 10 years with stroke, up to 30% have postvaricella angiopathy.40
Children with postvaricella angiopathy have characteristic findings of intracranial arterial stenosis within the distal internal carotid and proximal cerebral arteries with associated subcortical infarction. Serial angiograms in children with transient cerebral angiopathy reveal a complete resolution of stenosis over time.41
Moyamoya is a chronic, noninflammatory occlusive intracranial vasculopathy of unknown cause and accounts for 10% to 20% of arterial infarcts in children. Moyamoya is seen primarily in the Japanese but has been reported in all ethnic groups. Ten percent of cases are familial and a concordance rate of 80% has been reported in monozygotic twins. The disease is seen in both children and adults. Moyamoya causes symptoms of transient ischemic attack (TIA), seizures, involuntary movements, and in teenagers and adults, intracranial and subarachnoid hemorrhage. The diagnosis is based on an angiographic finding of bilateral stenosis of the internal carotid and the development of an extensive collateral network with the appearance of a “puff of smoke.”
Extracranial arterial dissection is a common cause of stroke in young adults and children. Intracranial arterial dissection occurs almost as frequently as extracranial dissection in children. Arterial dissection has been associated with a variety of conditions but most cases are because of trauma. The diagnosis is based on magnetic resonance angiography (MRA) or conventional angiography abnormalities. There may be a long segment of narrowing, a double-barrel lumen, an intimal flap, a tapering occlusion, dissecting aneurysm, and/or distal embolisation.
Risk Factors: Sinus Venous Thrombosis (SVT)
Data from the CPISR reveal that the incidence of SVT in children is 0.6/100 000 children per year and is highest in the first year of life.42 The clinical presentation of SVT in children is often subtle and approximately 50% present with focal abnormalities or seizures. The majority of thromboses are located within the superior sagittal sinus with or without associated lateral sinus thrombosis.
A number of risk factors are linked to the development of SVT, including head and neck infections, dehydration, perinatal complications, and coagulation disorders. In one study, prothrombotic abnormalities were present in half of children with SVT and many of these children had multiple risk factors.19
Risk Factors: Hemorrhagic Stroke
Hemorrhagic stroke is less common than ischemic stroke in children. Several risk factors for hemorrhagic stroke have been identified in children, including vascular malformations, malignancy, and trauma. Hemorrhagic stroke in children is also associated with primary and secondary coagulation disorders including hemophilia, thrombocytopenia, liver failure, leukemia, and warfarin therapy.
Arteriovenous malformations (AVM) are the most common cause of hemorrhagic stroke in children. The development of an AVM results from failure in the formation of the capillary bed between primitive arteries and veins in the brain during the first trimester of fetal life. The incidence of AVM in children is 1/100 000 and approximately 10% to 20% of all AVMs will become symptomatic during childhood.43 The average probability of a first hemorrhage is 2% to 4% per year, with a recurrence risk as high as 25% by 5 years.44 Magnetic resonance (MR) imaging and MRA confirm the diagnosis of AVM.
Approximately 1% to 2% of aneurysms become symptomatic during childhood. Aneurysms in children are typically associated with other vascular lesions or chronic disorders. Cavernous malformations can also lead to hemorrhagic stroke in children. One third of cavernous malformations are familial. Cavernous malformations have recently been linked to abnormalities in the long arm of chromosome 7.45
Evaluation of Stroke in Children
There are no published consensus guidelines on the evaluation of stroke in children, but a few systematic approaches have been recommended.46,47 The evaluation should rule out other nonvascular causes and identify the cause of the stroke. The evaluation of stroke in children should also include hematologic, metabolic, and angiographic studies, as recent evidence suggests that the identification of multiple risk factors predicts worse long-term outcome.48
The evaluation should include questions about any history of head or neck trauma, unexplained fever or recent infection, drug ingestion, developmental delay, family history of bleeding problems, and associated headache. A careful family and birth history should also be taken, with special attention to premature vascular disease, hematologic disease, and mental retardation.
Cranial ultrasound is useful for interventricular and germinal matrix hemorrhage, but is inadequate for identifying ischemic stroke, particularly cortically based or posterior infarcts. Transcranial doppler can be performed at the bedside and is useful in sickle cell-related stroke. Children with SCD that have a peak mean velocity of greater than 200 cm within the terminal ICA or proximal MCA are at an increased risk for stroke.49 Computed tomography scanning is readily available and useful for identifying acute hemorrhage. Several new MR techniques have been used for the evaluation of ischemic stroke in children, including diffusion, perfusion, gradient echo, and FLAIR imaging.50,51 MRA is also useful in the evaluation of arteriopathies and computed tomography and MR venography for SVT.52 MR imaging should be considered in the evaluation of children with suspected extracranial arterial dissection. Ultrasonography may also be useful, as ultrasound can detect abnormal flow patterns in greater than 90% of patients with extracranial arterial dissection. Functional MR evaluates changes in blood flow with motor or language function, and is useful in monitoring changes in the localization of function over time related to recovery. Recent work with MR spectroscopy demonstrates lactate changes in children with hypoxic ischemia at birth that may be related to prognosis.53 Conventional angiography is recommended when MR scanning has failed to identify a cause.
Treatment for Childhood Stroke
There have been no randomized, clinical trials for the acute treatment of ischemic stroke in children. Treatment recommendations are based on small, nonrandomized trials or adult stroke studies. Historically, children have been excluded from adult stroke studies. Tissue plasminogen activator (TPA) is the only approved treatment for acute ischemic stroke, and has not been tested in children. There are several reports in the literature of children receiving thrombolytic agents for acute ischemic stroke,54–58 and at the conference, 4 other cases were reported. The Hospital for Sick Children in Toronto evaluated the use of TPA for the treatment of systemic blood clots and found that 25% of treated children required a blood transfusion because of excessive bleeding.
There are no established guidelines for the treatment of SVT in children. Anticoagulation is recommended for SVT in adults and may be indicated in children.59 Data from the CPISR revealed that two thirds of newborns and one third of older children did not receive any form of anticoagulant therapy for SVT.
The treatment for hemorrhagic stroke in children depends on the cause and the condition of the patient. Vascular lesions in infants and children are much different from those in adults, and in particular, vein of Galen malformations can interfere with normal brain development. The proper characterization of these lesions is essential to determine the best therapy. Treatments for vascular malformations include surgery, endovascular embolization, and radiosurgery.43
In the past, cohort studies of children with SCD revealed high rates of stroke and recurrent stroke. SCD is associated with a prothrombotic and proinflammatory state. Chronic transfusion programs were developed to treat children with SCD and the rate of stroke decreased. Transcranial Doppler studies were also found to be useful in predicting which children would go on to have stroke. One early study found that the risk of stroke was 13% per year over 3 years in children with elevated mean velocities of the middle cerebral artery.38
In 1994, the first stroke study in children was initiated. The STOP study was a prospective, randomized, clinical trial comparing regular blood transfusions with standard care in children with SCD. The STOP study enrolled children greater than 2 years of age who were homozygous for SCD. Children were required to have 2 abnormal transcranial Dopplers (TCD) with mean velocities greater than 200 cm/sec, and were randomized to standard therapy or chronic transfusion to lower hemoglobin S levels from 90% to <30%. The trial was terminated in 1997 because of early positive results showing a 92% reduction in stroke in the treatment arm compared with standard therapy.
A follow-up review of the STOP data revealed several interesting findings. First, the abnormal TCD studies in a percentage of children in the normal care group regressed to the normal range and a percentage of children in the treatment group did not improve with therapy. Second, MRA did not correlate well with the severe stenosis identified by TCD. Last, the incidence of “silent infarcts” (radiologically evident but not overtly symptomatic) was decreased in the chronic transfusion group and suggests that chronic transfusion may be effective in the prevention of silent infarcts in children with SCD.7
There have been no secondary prevention trials for stroke in children. Based on adult studies and the underlying pathophysiology of the stroke, antiplatelet and antithrombotic agents are prescribed for the secondary prevention of stroke in children. However, platelets function differently in neonates, children, and adults, and bleeding time is prolonged in neonates but is shortened in children when compared with adults. These issues make it difficult to extrapolate effective dosages for children or neonates from adult studies.
Outcome and Recurrence
The outcome of children after stroke varies among studies because of differences in functional measures, stroke type, and population studied. Data from the CPISR, which includes 402 children with arterial ischemic stroke and 160 children with sinus thrombosis, revealed that 27% of children were neurologically normal, 61% were abnormal, 21.6% recurred, and 12% were dead by the outcome evaluation period. Certain neuroimaging abnormalities and seizures at presentation are associated with a poor outcome in children with stroke. Children with infarct volumes greater than 10% of intracranial volume have a worse outcome than children with less than 10% infarct volume.
The recurrence rate of stroke in children ranges from 20% to 40%.10,32,48 An English longitudinal cohort study of 250 children revealed a recurrence rate of TIA or stroke of 37%. In this group, the recurrence rate was highest among individuals with recurrent TIA, moyamoya, vasculitis, 5,10 methylenetetrahydrofolate reductase homozygosity, elevated homocysteine, elevated anticardiolipin antibodies, and lymphopenia. The recurrence rate of stroke in children from the CPISR is 21.6% after several years of follow-up.
Future Research: Perinatal Stroke
The study of risk factors of perinatal stroke, including hematologic and autoimmune disorders, offers promising possibilities for intervention and prevention. Studies of these risk factors should include data on factors affecting the maternal-fetal environment. Technical measurement standards need to be established and norms defined for coagulation factors, anticardiolipin antibodies, and glycoprotein abnormalities. Diagnostic criteria for stroke and radiographic techniques need to be standardized, because early symptoms of perinatal stroke may be quite variable. The timing of the insult should be correlated with the onset of symptoms, to determine a window of possible interventions or neuroprotective measures, such as hypothermia. Most importantly, to advance clinical research in perinatal cerebrovascular disorders, we need to encourage cooperation among multidisciplinary teams including obstetricians, neonatologists, hematologists, neurologists, and neuroradiologists.
Future Research: Childhood Stroke
Currently, there is no consensus on the classification, evaluation, outcome measurement, or treatment of childhood stroke. Childhood stroke registries are needed to generate data regarding risk factors, outcome, and recurrence. This information is essential to identifying issues important for study planning and feasibility. Clinical trials in childhood stroke directed at acute therapies, primary prevention, and secondary prevention are urgently needed.
TPA has been shown to be effective for the acute treatment of ischemic stroke in adults, but is not approved for children. To study the efficacy of TPA in children, it is necessary to first address issues of safety and proper dosing of this medication, as well as techniques that can confirm the diagnosis of stroke in children in the first several hours. On average, children present to the hospital around 24 hours after the onset of stroke symptoms. Delays in recognition are likely attributable to the rarity of childhood stroke and the possibility that the focal neurologic symptoms are attributable to another cause, such as migraine.
The STOP study has provided much-needed information on the risk of stroke in children with SCD, but additional studies are needed. Additional information regarding the risk and pathogenesis of sickle cell-related stroke is necessary to develop more effective treatment and prevention strategies. For example, immunodeficiency, hypoxemia, and obstructive sleep apnea may be risk factors for sickle cell-related stroke. The prognostic value of severe MRA lesions in SCD has not been established. It is also important to measure cognitive, as well as motor, outcomes in SCD-related stroke.
The secondary prevention of stroke in children cannot be extrapolated from adult trials: accurate age-specific information on the actual risk of recurrence in children is first required. Subgroups of children with stroke, like SCD, may have a much higher risk of recurrence, whereas the risk in other subgroups may be minimal. Multicenter and multinational collaborations are needed to generate the large numbers of patients required for clinical trials. The treatment of stroke in children associated with antiphospholipid antibodies remains to be determined. Studies are needed to discover whether the risk of recurrence outweighs the risk of treatment or long-term anticoagulation.
The current outcome measures used for childhood stroke need validation. Neuroimaging techniques using diffusion weighted imaging can provide information on ischemic changes over time. Improved quality and faster imaging techniques will enable better quantification of blood flow dynamics. This may require the development of new contrast agents, which will need to be evaluated and approved in children.
Future Research: Animal Studies
Animal models need to be developed to address maturational changes of diffusion-perfusion relationships and coagulation function, particularly in the neonate. These may include transgenic mice models, such as platelet-activating factor knockouts. Studies are needed to determine age-related susceptibility to injury and how a focal ischemic injury to the immature animal brain matures over time. Studies of stroke in immature animals should also include measures of functional outcome. New behavioral paradigms must be developed and used to determine whether structural and biochemical abnormalities are related to functional recovery.
Stroke in infants and children is an important cause of morbidity and mortality and an emerging area for clinical and translational research. The clinical presentation of neonatal stroke is subtle and varied, which presents challenges in diagnosis as well as ascertainment of risk factors and outcome. Collaboration across specialty disciplines and among multiple medical centers is needed to provide adequate information on risk factors, outcome, and recurrence. Such information is critical for adapting current treatment strategies now used in adults, and identifying significant areas for future treatment in children with stroke.
Gabrielle deVeber, MD, Toronto, Canada; E. Steve Roach, MD, Dallas, Texas
Robert Adams, MD, Augusta, Georgia; Frances Cowan, MD, London, England; Gabrielle deVeber, MD, Toronto, Canada; Donna Dizon-Townson, MD, Salt Lake City, Utah; Donna Ferriero, MD, San Francisco, California; Bhuwan Garg, MD, Indianapolis, Indiana; Jill Hunter, MD, Philadelphia, Pennsylvania; Fenella Kirkham, MD, London, England; Pierre Lasjaunias, MD, Le Kremlin Bicentre, France; John Marler, MD, Bethesda, Maryland; Karin Nelson, MD, Bethesda, Maryland; Guillaume Sebire, MD, PhD, Bruxelles, Belgium; and Yehuda Shoenfeld, MD, Tel-Hashomer, Israel
Gabrielle deVeber, MD, Toronto, Canada; Deborah G. Hirtz, MD, Bethesda, Maryland; John Kylan Lynch, DO, Bethesda, Maryland; Karin Nelson, MD, Bethesda, Maryland; E. Steve Roach, MD, Dallas, Texas; Joanna Rosario, MD, MPH, Bethesda, Maryland; and Quandra Scudder, Bethesda, Maryland
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