Effect of Seizures on the Developing Brain and Cognition
Introduction
Although seizures are the most striking clinical manifestation of childhood epilepsy, children with epilepsy are at risk not only for seizures, but also for a myriad of comorbid health problems that occur at a higher rate than would be expected by chance.1 Among the comorbidities associated with epilepsy in children, cognitive abnormalities are among the most common and troublesome.2, 3 The distribution of intelligence quotient (IQ) scores of children with epilepsy is skewed toward lower values4, 5 and the number of children with epilepsy experiencing difficulties in school because of learning disabilities is greater than children without epilepsy.6, 7, 8, 9, 10, 11
Although most children with epilepsy maintain stable IQ scores, there is now strong evidence that some of them slow, or even regress, in their mental development.5, 12, 13 In a community-based cohort study, Berg et al14 assessed and prospectively followed 198 children (aged < 8 years) with new-onset epilepsy for 8-9 years. In this cohort refractoriness to antiepileptic drugs (AEDs) was associated with an 11.4 point lower full scale IQ. There was substantial age-resistance to treatment interactions for IQ, indicating a lessening impact of recurrent seizures with increasing age. The authors appropriately concluded that uncontrolled seizures impair cognitive function with effects being most severe in infancy. Cognition is of particular concern in children with an epileptic encephalopathy,15, 16, 17 a condition characterized by the slowing or regression of development due to seizures, abnormal interictal cortical and subcortical EEG activity, or both, rather than to the underlying etiology of the epilepsy.15
Much of the cognitive impairment that occurs in people with epilepsy is related to its underlying etiology. Both acquired disorders such as trauma, hypoxic-ischemic insults, and mesial temporal sclerosis secondary to prolonged febrile seizures and genetic disorders, including tuberous sclerosis, fragile X, Rett, and Dravet syndromes, can lead to significant cognitive impairment in addition to causing epilepsy. Although etiology of the epilepsy clearly plays a major role in cognitive development, there are indications that early-life seizures (ELS) independent of etiology can lead to cognitive impairment.18, 19 For example, in a study of neuropsychological function in children with focal cortical dysplasia by Korman et al.19 It was found that age of onset of epilepsy and extent of the dysplasia each contributed independently to cognitive dysfunction indicating that early onset of epilepsy disrupted critical periods of development leading to poor cognitive outcomes.
To prevent, limit, and reverse cognitive comorbidities, it is essential to understand the neurobiological basis of cognitive dysfunction of seizures in children. While studies have indicated that children with ELS, particularly when frequent and resistant to therapy, are at highest risk for cognitive deficits, it is difficult to ascertain the neurobiological disturbances that lead to cognitive impairment. In the clinic it is difficult to differentiate the effects of the number, duration and seizure type, EEG abnormalities and AED therapy from the etiology of the epilepsy (Fig. 1). For this reason, many of the advances in our understanding of the long-term effects of ELS come from rodent studies in which the investigator has control over the etiology and treatment of the seizures.
Section snippets
Genetic Models
Animal models of ELS include genetic and acquired models. The discovery of multiple genetic mutations associated with human epileptic encephalopathies and advances in genetic techniques have resulted in the generation of multiple models in animals carrying the human equivalent of these genes. Mutations in the gene coding for the type-1 alpha subunit of the Nav 1.1 sodium channel in neurons, SCN1A, has been linked to the epileptic encephalopathies, especially Dravet syndrome and generalized
Acquired Models
Acquired models of ELS have been more extensively studied than the genetic models. With acquired models the investigator has control of age of seizure onset and seizure frequency in normal developing rats and thus can distinguish the effects of seizures from etiology of the seizures. Far more work on the cognitive effects of seizures on the developing brain has been done in the acquired models rather than the genetic models. For that reason, this article deals primarily with the 2 models of
Effects of Seizures on the Developing Brain
Using the flurothyl model of recurrent ELS in rat pups to human mimic neonatal seizures, we have shown cognitive impairment when the animals are tested during adolescence or adulthood.39, 42, 43, 44, 45, 46, 47 Cognitive deficits seen following ELS include deficits of spatial cognition in the water maze,43, 48 nonmatch to sample task,40 impaired auditory discrimination,49 and reduced behavioral flexibility.42 Although ELS do not result in cell death,46, 50 there is evidence for synaptic
Effects of Interictal Spikes on the Developing Brain
In addition to seizures, interictal spikes (IIS) can result in cognitive impairment in both rats and humans. Following intrahippocampal pilocarpine infusion, rats develop IIS that result in transient impairment in the delayed-match-to-sample test, a hippocampal-dependent operant behavior task.72 Hippocampal IIS that occur during memory retrieval strongly impairs performance. However, IIS that happen during memory encoding or memory maintenance do not affect performance. In a similar study of
Conclusions
In summary, while etiology of the seizures is the primary factor in cognitive outcome, rodent models of childhood epilepsy have shown that both seizures and IIS can be detrimental to brain development. With further refinement of our knowledge of the pathophysiological underpinnings of seizure-related cognitive deficits it is hoped that future therapies would target cognition as much as seizures. Although not covered in this article, AEDs can also contribute to cognitive impairment in both
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