Andrew A. Mallick

Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study

BACKGROUND Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. METHODS Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. FINDINGS We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100 000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. INTERPRETATION Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. FUNDING The Stroke Association, UK.

The epidemiology of childhood stroke

This paper reviews the epidemiology of childhood stroke. Stroke is an important condition in children. It is one of the top ten causes of childhood death and there is a high risk of serious morbidity for the survivors. Epidemiological data are an integral part of disease understanding and high quality studies are required to ensure that this data is robust. Incidence rates from population-based studies vary from 1.3 per 100,000 to 13.0 per 100,000. Factors found to influence incidence rates include age, gender, and ethnicity but there are also many inherent differences between studies. Temporal analysis of mortality rates from childhood stroke shows falling rates but there has been little long-term study of changes in incidence rates. Improved epidemiological data should be a goal of the national and international collaborative networks that are studying childhood stroke.

Diagnostic delays in paediatric stroke

Background Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. Methods A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. Results Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3 h in AIS and 2.9 h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44 h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3 h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. Conclusions The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.

Clinical features of childhood‐onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations

To define better the phenotype and genotype of familial and sporadic cases of paroxysmal kinesigenic dyskinesia (PKD) caused by mutations in the PRRT2 gene presenting in the paediatric age group.

Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial

BACKGROUND Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone. METHODS In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27. FINDINGS Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1-24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment. INTERPRETATION Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up. FUNDING The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Childrens Hospital Zurich.

Mortality from childhood stroke in England and Wales, 1921–2000

Objective: Stroke is an important but under-recognised cause of childhood mortality. The authors aimed to describe the trends in mortality from childhood stroke in England and Wales between 1921 and 2000. Design: The study searched the Office for National Statistics mortality database for the years 1921–2000 using appropriate, previously validated International Classification of Diseases codes. Mortality rates were analysed by period of death, gender, age at death, birth cohort and stroke subtype. Results: 6029 deaths from childhood stroke were found between 1921 and 2000. Analysis by period of death demonstrated an initial decline in mortality followed by a steep rise in the 1940s. Subsequently, rates declined from the late 1960s onwards. At all time points males had a higher mortality rate than females. Infants had a relatively high mortality rate (24.5 per million person years) but rates fell steeply in early childhood (2.5 per million person years at age 5–9 years) before rising again in late adolescence (7.5 per million person years at age 15–19 years). An increased rate was found for males at all ages (RR = 1.24, p<0.0001) but was greatest in infancy (RR = 1.45, p<0.0001). Haemorrhagic stroke accounted for 71% of stroke deaths. Birth cohort analysis showed a trend of declining mortality with each successive generation since the 1950s. Conclusions: This study describes characteristics and temporal changes in childhood stroke mortality in the 20th century. In particular, the higher mortality rates in males and infants, the importance of deaths from haemorrhagic stroke and the finding of a decline in birth cohort mortality since the 1950s provide aetiological insights.

Cerebral venous sinus thrombosis: a case series including thrombolysis

Background: Cerebral venous sinus thrombosis (CVST) in children is associated with a high incidence of serious morbidity and mortality. The presenting features are variable. It can be diagnostically challenging and the optimal treatment is uncertain. Aim: To describe the features of a series of children with CVST treated in a single paediatric neurology centre and to discuss the role of local thrombolysis. Methods: Electronic databases were searched using diagnostic labels and International Classification of Diseases (ICD) codes to identify children aged 1 month to under 17 years with CVST. Their records were reviewed. Results: 21 children were identified over a period of 8.25 years with a median age of 7.1 years. The presenting symptoms included headache (15 children), vomiting (14 children) and visual disturbance (eight children). Signs found included papilloedema (16 children), fever (six children) and sixth nerve palsy (six children). The most common underlying condition was middle ear infection (13 children). All cases received unfractionated heparin and four severe cases received local pharmacological thrombolysis. 48% of cases had an adverse outcome (death, chronic intracranial hypertension, residual hemiparesis or sixth nerve palsy). Discussion: CVST has non-specific presenting features and a high risk of significant morbidity. CVST is typically found in association with a predisposing condition. Although heparin is the mainstay of treatment, thrombolysis may reverse deterioration as seen in three cases in this series. However, there is insufficient evidence to recommend the routine use of thrombolysis at present.

Research governance delays for a multicentre non-interventional study

Summary Objectives To evaluate the delay in research governance approval for a non-interventional, multicentre study in the United Kingdom. Design The times taken from application to the granting of research governance approval for an observational study of childhood stroke with ethical approval were prospectively recorded. Setting Ninety-two acute NHS Trusts in the United Kingdom. Main outcome measures Median delay (in working days) between application and research governance approval. Results The median delay between application and research governance approval was 43 working days (interquartile range 27–62, range 0–147). The reason for delay beyond 43 working days was inexplicable in 30 (70%) of 44 trusts. Conclusions There is considerable variation in the processes undertaken by research and development departments that can lead to significant delays in commencing an ethically approved study. Any improvements to the systems for gaining approval are welcome.

Outcome and recurrence one year after paediatric arterial ischaemic stroke in a population-based cohort

Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population‐based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population‐based cohort.

Risk factors and treatment outcomes of childhood stroke.

Stroke is an important cause of childhood mortality and morbidity. The risk factors and pathophysiological processes of stroke in children are very different than those in adults. The range of risk factors is very wide, with over 100 presumptive risk factors described. There are a number of clinical guidelines, but despite recent increases in research, the evidence base underpinning these guidelines is sparse. Therefore, treatment is largely based upon expert consensus and extrapolation from adult data. Mortality from childhood stroke is relatively high and at least two-thirds of survivors have neurological impairments. Stroke can affect a wide range of neurocognitive domains and a high proportion of children require additional educational support and have a reduced quality of life.