PI: Christine K. Fox

STATUS: Data Analysis
FUNDING: Pediatric Epilepsy Research Foundation

Previously considered rare, stroke in childhood has been increasingly recognized as an important cause of childhood morbidity, lifelong disability and epilepsy. Estimates of the annual incidence of childhood stroke range from 2 –13 per 100,000 children. In neonates, the prevalence of arterial ischemic stroke is close to 1 in 5000 live births. Neurologic deficits are common after childhood stroke, affecting up to 60% of children. These deficits exert their impact over many decades of the affected child compared with stroke in adults. Despite a growing understanding of the significance of childhood stroke, we have limited data on acute management, and on factors influencing long-term outcomes after childhood stroke, including epilepsy.

Children with stroke have different clinical presentations and outcomes compared to adults. In adults, the risk of epilepsy after arterial ischemic stroke is relatively low, estimated at 2-4%. In contrast, estimates of epilepsy frequency after ischemic stroke in children vary from 5% to 67%. The variability in the literature may be due to the length of follow-up, sample size, and age at stroke. Seizures are mostly assessed in these studies during the acute stroke period (<14 days), although a 15% rate of epilepsy has been reported after stroke, including 38-60% of patients with early seizures.

Despite the high prevalence of seizures in children with stroke, published pediatric stroke guidelines remain largely silent on the matter, similar to the adult versions. The American College of Chest Physicians (CHEST) guidelines acknowledges seizure frequency at presentation and the possibility of chronic seizures yet make no recommendations on care or prevention. The American Heart Association (AHA) guidelines recommend treating acute clinical seizures with antiepileptic drugs (AEDs) and potentially using EEG monitoring, however specific details on timing, drug, dose, and length of treatment were not provided. The level of evidence assigned to all seizure-related recommendations is of the lowest grade possible, reflecting the absence of clinical evidence.

Currently, early seizures are dealt with on an ad hoc basis, as limited evidence exists to predict in which patients they will develop, making prophylactic AED use difficult. The need for early EEG monitoring to detect and treat subclinical seizures is also lacking. This is especially concerning in light of new data on neonatal stroke, in which 15/18 seizures recorded on EEG were sub-clinical and associated with poor long-term outcome (mean 58 months).

Information about how early seizures modify outcomes after childhood stroke is also limited. It has been well-established in animal models of stroke that seizures increase infarct severity, including in the immature mouse brain. Such studies demonstrate the influence of age at stroke on seizure incidence and a positive correlation of infarct size and presence of seizures. Given that early seizures tend to predict late seizures and worse outcomes, intervention at this stage could play an important role in reducing long-term morbidity. However, identifying patients prior to overt seizures and exploring the effect of AED treatment in general, let alone specific dosing, requires additional research.

The occurrence and severity of post stroke epilepsy is also poorly understood. Studies have found that cortical lesions and persistence of seizures beyond two weeks of the acute insult have previously been identified as risk factors for epilepsy, which appears to be an important determinant of cognitive outcome and treatment itself may also adversely affect behavior and recovery. The role of age at stroke and stroke subtype on the development of epilepsy is not understood. After perinatal ischemic stroke, one study found that 30% of children required a daily AED. Studies of children with perinatal or presumed perinatal stroke have begun to stratify epilepsy outcome using a scale of epilepsy severity, and suggests severe epilepsy in 11 to 24% of individuals.  However, information on severity of seizures in other groups of children after stroke is unknown.

In general, children with stroke are at risk for cognitive deficits, behavioral and psychiatric problems. Recent studies suggest that epilepsy after childhood stroke may worsen neurocognitive outcome. How stroke and epilepsy interact as predictors for neurocognitive outcomes in this setting is unknown, but the limited data available are concerning. Among 35 children with later childhood ischemic stroke in the Netherlands, 9 children developed epilepsy on average by seven years follow-up, and this group had significantly greater cognitive dysfunction. Ballantyne et al. examined 29 children with perinatal stroke and showed stable cognitive functioning over time in children without seizures. However, children with seizures after the neonatal period had lower scores on language and intelligence measures and a lower developmental trajectory. They speculated that either epilepsy or associated medication use limited brain plasticity during development. A study of 16 children with childhood ischemic stroke also suggested more neuropsychological problems in children with epilepsy. This trend was also seen after neonatal stroke. It is not known whether epilepsy is a marker of more extensive brain injury or whether seizures or medications are contributing factors to cognitive dysfunction. Although all of these studies are limited by the small number of patients studied, they suggest a possible association of post-stroke epilepsy with worse outcomes.

Improving understanding of the risk factors and sequelae of early seizures and epilepsy after childhood stroke is of paramount importance in reducing the life-long burden of the disease in survivors. Knowledge of the natural history of these seizures will inform further research aimed at improving prevention and management of the seizures and thereby improving outcomes.

In this study, we propose to determine the importance of seizures in children with ischemic stroke in a multi-center, multi-national study utilizing the existing International Pediatric Stroke Study (IPSS) infrastructure and Vascular Effects of Infection in Pediatric Stroke (VIPS) infrastructure.

Specific Aims: To measure in neonates and children with ischemic stroke:

1. The frequency, characteristics and predictors of early (<14 days) seizures.
2. The frequency, characteristics and predictors (including presence of early seizures) of epilepsy/late seizures (i.e. chronic seizures occurring 14 days or longer after stroke).
3. The impact of early seizures or the development of epilepsy on adverse outcomes, including death and neurological disability at 3 months and 1 year