Pediatric Stroke Treatment Comes of Age
Disclosure: I receive support from the North and Central Texas Clinical and Translational Science Initiative from the NIH KL2 RR024983 and from the First American Real Estate Information Services, Inc. I have no conflicts of interest to report.
Pub Date: Sept. 29, 2008
Author: Michael Morgan Dowling, MD, PhD
Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G, Ferriero D, Jones BV, Kirkham FJ, Scott RM, Smith ER., Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008; 39: 2644-2691 Published online before print July 17, 2008, doi: 10.1161/STROKEAHA.108.189696
Stroke is one of the top ten killers of children. Of the survivors, over 40% have neurologic deficits that will persist for their lifetime, which for many children will be the better part of a century. One in ten children with ischemic stroke will have a recurrence within 5 years1. Improvements in awareness and imaging as well as the increasing survival of children with conditions that place them at risk for stroke, such as sickle cell disease (SCD), congenital heart disease, and cancer, have led to an increased incidence of arterial ischemic stroke (AIS) and cerebral venous sinus thrombosis (CVST) to the range of 2.3-13 per 100,000 per year in children, with stroke in neonates occurring in 1 in 4,000 live births.2-5
Stroke is as common as childhood leukemia or brain tumors, yet unlike these disorders, until recently, there were no clinical guidelines, systematic research programs, or randomized clinical trials for stroke intervention or prevention in children. That is changing.
As recently as 2004, two sets of guidelines were published. One, the so called Chest guidelines, was written primarily by hematologists and provided specific guidelines for antithrombotic therapy for a broad array of conditions in children, including AIS and CVST.6 These guidelines focused on therapy, reviewing but not making specific recommendations for diagnostic evaluations or further therapy beyond that directed at the thrombus itself. The second set of guidelines, the UK Guidelines, were written by the Pediatric Stroke Working Group7, which included pediatric neurologists along with a hematologist, neuroradiologist, neurosurgeon, psychologist, therapists, nurses, and representatives from parent and patient associations. These guidelines focus only on AIS in children (excluding neonates) but address a broader scope--from diagnosis to investigation, clinical management, and rehabilitation.
Now an even more encompassing set of guidelines, the American Heart Association (AHA) Scientific Statement on the Management of Stroke in Infants and Children, has arrived8, offering evidence-based recommendations for stroke prevention and treatment of stroke in children. This effort encompasses AIS and CVST in neonates, infants, and children and specifically addresses subtypes that include stroke in SCD, moyamoya syndrome, cervicocephalic arterial dissection, congenital heart disease, and hypercoagulable states. Also included are recommendations for rehabilitation as well as specific recommendations and specific protocols for the use of low-molecular-weight heparin (LMWH), warfarin, aspirin, and alteplase (tPA). There are also recommendations for the evaluation and treatment of hemorrhagic stroke.
How Good Are the Guidelines?
Guidelines are only as good as the evidence. Of the 93 specific recommendations given, only two are graded "A" on the AHA Stroke Council's Levels of Evidence grading algorithm: (i) to provide periodic transfusions to children with SCD and abnormal TCD for primary stroke prevention and (ii) to provide factor replacement therapy for children with coagulation factor deficiencies to prevent stroke. Only these two guidelines derive from randomized clinical trials. Of the remainder, 17 rely on less secure "level B" evidence from single or nonrandomized trials; the rest derive from "level C" evidence based on expert opinion, case studies, or standard-of-care.
The grading algorithm also ranks the evidence by the size of the treatment effect: Class I studies show a clear benefit, Class II studies show less certainty in the risk/benefit ratio, but in Class IIa the treatment is more highly favored then in Class IIb. In these guidelines, only 31 recommendations rank as Class I. In this system, Class III can be confusing because this category is reserved for treatments where the risks outweigh the benefits. So, in terms of treatment guidelines, Class III recommendations may be as important as Class I. In the stroke guidelines, there are only 11 Class III recommendations, most based on level C evidence.
How Do They Compare to Previous Guidelines?
Given the general paucity of evidence, it is reassuring that there is general consensus among the three guidelines. The areas of disagreement highlight important questions for future clinical trials. For the treatment of childhood AIS, there is general agreement between the Chest and AHA guidelines, recommending unfractionated heparin (UFH) or LMWH for approximately 1 week while seeking evidence for the etiology. The UK guidelines, on the other hand, call for aspirin first, with anticoagulation considered for those with extracranial arterial dissection or a cardiac source of emboli, etiologies that may take a few days to sort out. Gabrielle deVeber has pointed out this discrepancy between the UK and Chest guidelines and assessed the feasibility and acceptability of a randomized controlled trial; unfortunately, her sample size calculation of 1,500 children with AIS appears difficult to attain.9
For arterial dissection, there is consensus among the three calling for an extended period of anticoagulation, but the AHA guidelines allow for treatment with aspirin and add important specificity with a Class III recommendation against anticoagulation for children with an intracranial dissection. This restriction to treat only extracranial dissections is implied in the UK guidelines, but no distinction between intracranial and extracranial dissection is made in the Chest guidelines.
Concerning the treatment of moyamoya, there is another subtle difference, with the UK guidelines apparently recommending against aspirin, while in a Class I recommendation, the AHA guidelines indicate that aspirin may be considered. The UK guidelines recommend referral for evaluation for surgical revascularization, while the AHA guidelines recommend and discuss revascularization procedures in three different Class I recommendations. No specific recommendations for moyamoya are given in the Chest guidelines.
CVST appears to be the diagnosis with the least consensus among the three guidelines. For neonates with CVST, the Chest guidelines suggest initial treatment with either UFH or LMWH followed by LMWH for 3 months, except for those with large ischemic infarction or intracranial hemorrhage (ICH), in whom radiographic monitoring and commencement of anticoagulation are recommended if extension occurs. The AHA guidelines state that until additional information is available, a recommendation on the use of anticoagulation in neonates with CVST is not possible but does indicate that anticoagulation with LMWH or UFH may be considered in selected neonates with severe thrombophilic disorders, multiple cerebral or systemic emboli, or clinical or radiological evidence of propagating CVST despite supportive therapy. Neonatal CVST is not addressed in the UK guidelines.
A similar disparity occurs in recommendations for children with CVST, with the disagreement concerning anticoagulation in the presence of ICH. All three guidelines recommend anticoagulation in CVST, but the Chest and AHA guidelines differ from the UK in recommending anticoagulation even in the presence of secondary hemorrhage. These two areas of nonconsensus and uncertainty, the treatment of CVST in neonates and the treatment of CVST in children in the presence of ICH, should be addressed in clinical trials.
These questions of nonconsensus may not be a matter of scientific equipoise, but rather, one of ignorance. The problem is one of too limited data. The majority of the studies in pediatric stroke are still small and descriptive. These new AHA guidelines offer a broad assessment of the scope of the field and the current clinical consensus of experts, providing a framework along which further epidemiologic studies and clinical trials can progress.
Research Directions for Pediatric Stroke
So what are the necessary directions for research in pediatric stroke to provide "level A" evidence for the next set of guidelines for stroke in children? Clearly, better and more complete epidemiologic information, with recurrence rates and outcomes, on children who suffer stroke is needed. Single-center studies are yielding to statewide or national networks. The major international network, the International Pediatric Stroke Study (IPSS) founded in 2003, has now grown to include over 30 centers on five continents.10 The IPSS is poised to report on its initial findings on the first 1,200 children enrolled with AIS or CVST. This network will serve as the foundation for the next generation of clinical trials in pediatric stroke.
Timothy Bernard is developing a comprehensive and validated stroke classification system to serve as a pediatric version of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, expanding earlier efforts.11-13 Given the diverse etiologies for stroke in children, such a unified classification system is vital for research studies. The complexity of this task and its importance are already apparent in the guidelines, in which the recommendations for one stroke subtype are not recommended for another. The clearest example of this is the recommendation for moyamoya syndrome in SCD, where surgical revascularization procedures are to be considered as a last resort, while for children with moyamoya without SCD, consideration of revascularization is a Class I recommendation. Likewise, whether to give aspirin to children with SCD is a perennial question that is now receiving attention in an National Institutes of Health (NIH)-funded clinical trial headed by Norma Lerner.14
Also underway is the first NIH-funded, multicenter, clinical trial in pediatric stroke outside of SCD, designed to validate the NIH Stroke Scale in children.15, 16 Before any treatment trial, a validated measure of stroke severity at onset must be in place. Outcome measures are also more difficult to define in children than adults, given the underlying developmental progression and normal maturation of the brain. Functional outcomes in adults, such as returning to work or home duties, or even simple motor measures, such as walking, simply do not apply in developing children. Several outcome measures for childhood stroke are ready and validated, including the Pediatric Stoke Activity Limitation Measure and the Pediatric Stroke Outcome Measure.17, 18
Opportunities for primary prevention of stroke in children outside of those with SCD or congenital heart disease are limited due to their rarity, but, with a recurrence risk of up to 25%, there is a need to understand the risk factors for and approaches to prevention of recurrence.19 Such efforts, focusing on the children with increased risk of recurrence due to cerebral vasculopathy, are growing out of the IPSS.
Treatment trials must emphasize that children are not just little adults and that, while lessons learned in adults can be illuminating, the radically different and diverse mechanisms of stroke in children may require a different approach. In addition, treatments will differ from those for adults due to age-dependent variations in the coagulation systems, in the metabolism of antithrombotic drugs, and even in the brain's response to hypoxia-ischemia.
The AHA guidelines on thrombolytic therapy point out that there is an urgent need for a safety study of tPA in children. In a Class III recommendation, the guidelines state that tPA is not generally recommended for children with AIS outside of a clinical trial, until there are additional published safety and efficacy data. The authors hedge by indicating that there was no consensus about the use of tPA in older adolescents who otherwise meet standard adult tPA eligibility criteria. As centers gain experience with tPA and stroke is recognized more rapidly in children, more children will be treated off protocol. A safety study in children is a priority, and a dose-finding safety study for intravenous (IV) and intra-arterial (IA) tPA in children is being developed through the IPSS by Catherine Amlie-Lefond.
The issues regarding treatment of CVST in neonates and in children with ICH, which are areas of nonconsensus between the existing guidelines, as discussed earlier, are also opportunities for research. Given the required sample sizes in the range of 700-750 children9, networks like the IPSS have the capability of addressing these questions in realistic time scales.
Reversal of "Trickle-Down" Research
In clinical research, the direction of information flow is usually downward: Lessons learned in adults are then applied to children. For stroke, however, this may not be the best approach. Again, children are not just little adults--their brains are different and they have an enhanced capacity for recovery, repair, and regeneration. These factors have the potential to make research in pediatric stroke illuminating for adult stroke treatment. Children's increased capacity for neurogenesis, superior neural plasticity, and better stroke recovery suggest that we direct more laboratory and clinical research efforts toward children, with the aim of improving care for adult stroke. As a "model system," children provide the potential for increased "signal" for interventions and an increased "effect size" for target interventions in acute therapies, neuroprotection, and rehabilitation.
An outstanding example of this "pediatric potential" is the recent observation of what has been called "pre-Wallerian degeneration," detected by the presence of restricted diffusion along the descending corticospinal tract (DCST) outside the area of ischemia following stroke in children.20, 21 This abnormal signal, presumably a marker of early axonal loss in the DCST, is apparent in children within the subacute period and appears to correlate better with motor outcomes than other predictors. Whether this phenomenon is restricted to children, or has not been fully appreciated in adults, remains to be determined, but the availability of a strong outcome predictor within the first weeks after stroke will greatly improve patient classification in research studies and could vastly increase the power of clinical trials.
These comprehensive AHA guidelines are an early, but significant, developmental milestone in pediatric stroke research. Further study in pediatric stroke and rehabilitation is needed, including functional magnetic resonance imaging studies to follow cortical reorganization in children and studies to follow the effects of transcranial magnetic stimulation in the more plastic brains of children. Clinical trials in pediatric stroke victims may be better able to demonstrate the effect of neuroprotective agents, given the potentially more "responsive" immature brains of children. Such efforts will come with time. Research in children with stroke could provide insight and guidance for research that will grow to benefit not only other children, but their elders as well.
- Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.
- Lynch JK, Hirtz DG, deVeber G, et al. Report of the National Institute of Neurological Disorders and Stroke Workshop on perinatal and childhood stroke. Pediatrics 2002;109:116-123.
- deVeber G and Canadian Paediatric Ischaemic Stroke Study Group. Canadian Paediatric Ischaemic Stroke Registry: analysis of children with arterial ischaemic stroke Ann Neurol 2000;48:526.
- Fullerton HJ, Wu YW, Zhao S, et al. Risk of stroke in children: ethnic and gender disparities. Neurology 2003;61:189-194.
- Giroud M, Lemesle M, Gouyon JB, et al. Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J Clin Epidemiol 1995;48:1343-1348.
- Monagle P, Chan A. Massicotte P, et al. Antithrombotic therapy in children: the Seventh ACCP Conference on antithrombotic therapy. Chest 2004;126:645S-687S.
- Paediatric Stroke Working Group. Stroke in childhood: clinical guidelines for diagnosis, management and rehabilitation, 2004. http://www.rcplondon.ac.uk/pubs/books/childstroke/ (Accessed May 20, 2008.)
- Roach ES, Golomb MR, Adams R, et al. American Heart Association scientific statement on the management of stroke in infants and children. Stroke 2008;39:2644-2691.
- deVeber G. In pursuit of evidence-based treatments for pediatric stroke: the UK and Chest guidelines. Lancet Neurol 2005;4:432-436.
- International Pediatric Stroke Study. http://app3.ccb.sickkids.ca/cstrokestudy/
- Sebire G. Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood. Curr Opin Pediatr 2004;16:617-622.
- Wraige E, Pohl KR, Ganesan V. A proposed classification for subtypes of arterial ischaemic stroke in children. Dev Med Child Neurol 2005;47(4):252-256.
- Gordon DL, Bendixen BH, Adams HP Jr, et al. Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators. Neurology 1993;43:1021-1027.
- Lerner NB, Platania BL. Aspirin prophylaxis in sickle cell disease. http://clinicaltrials.gov/ identifier NCT00178464.
- Ichord R. Validation of the NIH stroke scale in children. http://pednihss.com
- Ichord, R, Smith SE, Garcia-Espana FJ, et al. Pediatric adaptation of the NIH Stroke Scale predicts outcome after arterial ischemic stroke in children. Stroke 2005;36:480-481.
- deVeber G, MacGregor D, Curtis R, et al. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. J Child Neurol 2000;15:316-324.
- Kitchen L, Anterson PE, Friefeld S, et al. A validation study of the Pediatric Stroke Outcome Measure. Stroke 2003;24:316.
- Fullerton H, Lynch JK, deVeber G. The call for multicenter studies of pediatric stroke. Stroke 2006;37:330-331.
- Kirton A, Shroff M, Visvanathan T, et al. Quantified corticospinal tract diffusion restriction predicts neonatal stroke outcome. Stroke 2007;38(3):974-980.
- Kirton A, Domi T, Shroff M, et al. Acute descending corticospinal tract diffusion changes predict motor outcome and reorganization patterns in children with arterial ischemic stroke. Neurology 2007;68(14):S48.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association