Title: Improving the Management of Stroke in Childhood
Funder: Department of Health (England)

Abstract: I. Overarching aims and research questions: Aims: (i) To clarify the aetiology of stroke in children (ii) To describe the outcome of stroke in children in the population (iii) To provide an evidence base for therapy of childhood stroke Research Questions: (i) What are the risk factors significantly associated with the occurrence of Arterial Ischaemic Stroke and Haemorrhagic Stroke in children (ii) What clinical and genetic factors are significantly associated with recurrent stroke in children (iii) What is the long-term (5 year) impact of childhood stroke on (a) motor, cognitive and behavioural function and (b) quality of life (iv) What is the optimum modality of antiplatelet therapy following Arterial Ischaemic Stroke in children? II.Background to the proposed research programme: The WHO defines stroke as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer, or leading to death, with no apparent cause other than of vascular origin.”(1) In children this definition includes the vascular stroke syndromes of arterial ischaemic stroke (AIS), haemorrhagic stroke or intracranial haemorrhage (ICH) and cerebral venous thrombosis (CVT). Stroke is estimated to affect 1.3-13 per 100,000 children per year(2, 3). It is one of the top 10 causes of child death in the western world(4). It has a significant mortality and morbidity. The case fatality rate may be as high as 28% and there is a significant chance (c.20%) of recurrence within 5 years(5, 6). The majority of survivors will have impairment in one or more functional domains(7). It is a condition with significant impact on the NHS. Currently there is little robust population-based evidence describing risk factors and outcome nor any evidence base to inform treatment strategies. Our programme will address this need by delivering evidence concerning risk factors and outcome and will provide evidence for a rational basis to treatment. III.Importance of the proposed research programme and its relevance to the priorities and needs of the NHS: Evidence-based children's medical care is a defined NHS priority (National Service Framework for Children, Young People and Maternity Services 2004-14 10 year strategy). Our programme is relevant to the standards targeted in this document, including: promoting children’s health and well-being, prevention of ill-health, early intervention for ill children; giving parents the right information to enable them to care for their children and keep them safe; and enabling decisions about medicines to be based on sound information. Evidence-based care for stroke patients is an NHS priority (2007 National Stroke Strategy). Our programme is relevant to the aims outlined in this document, including: reduction in number of strokes; better information about prevention; and giving the best therapeutic medical care. The Stroke Association (SA) in their 2010-15 Manifesto identify the need for “an urgent prioritisation of research into the causes and outcomes of child stroke and the best method of treatment”. Our programme will contribute to the achievement of these NHS-prioritised and SA-identified aims IV.The need for research in this area and rationale for the particular lines of research you ultimately plan to pursue: Childhood stroke is a significant health problem with a high cost in terms of mortality, morbidity and resources. There is a relative lack of rigorous evidence concerning risk factors, outcome, and treatment strategies. The evidence relevant to designing and justifying effective prevention and treatment strategies needs to be built on information about (a) the causes, (b) the best acute and prophylactic therapy, and (c) the longer-term outcome of child stroke. Our lines of research are planned to deliver this information. V.Past and current research that justifies the proposed research and shows that it will add distinct value to what is already known, or in progress: 1.Infection and/or inflammation of CNS blood vessels has been associated with child stroke. Bacterial (e.g. meningitis) and viral infections (e.g. chicken pox) and non-infectious inflammatory conditions (vasculitides) may all lead to inflammation of the intracranial blood vessels, causing arterial ischaemia or haemorrhage(8-10). These represent aetiologies of child stroke with potential for preventative or therapeutic intervention e.g. immunosuppression or vaccination. Currently the evidence for such associations comes from small case series or case-control studies. We intend to investigate these associations via an adequately designed and powered case-control study. 2.Haematological disorders have been associated with child stroke and current recommendations are that children with AIS should undergo thrombophilia screening(11). The evidence base for such recommendations is weak. A recent systematic review of thrombophilia and ischaemic stroke in childhood found that only two factors (protein C deficiency and the thrombophilic mutation MTHFR C677T) were significantly associated with the occurrence of a first AIS(12). Protein C deficiency and raised levels of lipoprotein (a) have been associated with increased risk of recurrence(13). There is little evidence about platelet function in childhood stroke. More robust evience is needed to justify national recommendations of expensive and invasive haematological screening. We intend to address this need via a case-control study to investigate the haematological risk factors for child stroke. 3.Cardiac disease is one of the most commonly identified risk factors in childhood ischaemic stroke. It is identified in 15-30% of cases of AIS(14, 15). At least 40% of the strokes that occur in relation to cardiac disease occur in association with cardiac surgery or catheterisation(16). The causes of stroke in the peri-cardiac surgery period are not clear. Possible contributors to the increased risk of stroke are hypoxia, hypocarbia, hypotension, embolisation, haemodilution, changes in body temperature associated with intraoperative blood loss, cardiopulmonary by-pass and deep hypothermic circulatory arrest. We intend, via a case-control study, to elucidate the risk factors for stroke during cardiac surgery. 4. There is a clear link between childhood AIS and a number of genetic conditions e.g. Down Syndrome, Sickle Cell Disease, Fabry Disease. Recently there has been the discovery of a single gene disorder (COL4A1 mutations) responsible for familial haemorrhagic strokes(17). Childhood AIS has also been linked with single nucleotide polymorphisms (SNPs) of genes involved in immune and inflammatory pathways such as tumour necrosis factor alpha promoter, cytotoxic T-Lymphocyte antigen 4 and CD28 and also genes involved in the regulation of vascular nitric oxide(18-20). We intend to collect DNA from all cases and controls in our prospectively ascertained cohorts to investigate possible single gene disorders in familial cases and also to perform association studies using SNPs. 5. Outcome: Many survivors of stroke are left with multiple long-term impairments but some children are minimally affected. The reasons for this variability are unknown. Clinicians are unable to prognosticate accurately at the time of diagnosis or target therapy and scarce rehabilitation resources to those patients most likely to need them. The literature lacks systematic population-based studies of the outcome of childhood stroke. The research team have begun to address some of these issues and the PI is currently running a population based study looking at the outcome of childhood stroke at one year (www.childstroke.org) in motor, cognitive, behavioural and quality of life domains. Our aim will be to extend follow-up of this population-based cohort five years after their initial stroke. 6. Treatment: Despite the fact that current expert consensus guidelines advocate anti-platelet regimes in childhood AIS, there are no randomised trials looking either at the efficacy of particular treatments or optimal duration of treatment(11). After consulting widely during the programme development grant stage to identify where equipoise exists, we intend to run a randomised clinical trial looking at either type or duration of anti-platelet therapy in childhood AIS. VI:Preparatory work already undertaken towards developing the proposed research programme: (a) Assembly of a multi-disciplinary team to steer the development of the programme grant proposal, covering the areas of neurology, infectious diseases, rheumatology, haematology, genetics, cardiac anaesthesia, epidemiology and medical statistics. The study team also has experiece in running Delphi processes which is a key component of the development work. (b) Ascertainment and initial follow-up of a population based cohort of childhood stroke cases that will form the basis of the outcome study in the programme grant. (c) Involvement in the International Paediatric Stroke Study that will allow access to international collaborators essential for success of the treatment trial. VII: Current Barriers to undertaking research programme: (a) In order for the case-control study to be hypothesis driven it is necessary to establish from the international research community what are the most important aetiological hypotheses to explore. This will be achieved via the Delphi Process and the research symposium. (b) Lack of knowledge as to where clinical equipoise with regard to anti-platelet therapies lies within the international clinical community. This will be addressed via the Delphi process.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: STROKE