Effect of Seizures on the Developing Brain and Cognition

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Epilepsy is a complex disorder, which involves much more than seizures, encompassing a range of associated comorbid health conditions that can have significant health and quality-of-life implications. Of these comorbidities, cognitive impairment is one of the most common and distressing aspects of epilepsy. Clinical studies have demonstrated that refractory seizures, resistant to antiepileptic drugs, and occurring early in life have significant adverse effects on cognitive function. Much of what has been learned about the neurobiological underpinnings of cognitive impairment following early-life seizures has come from animal models. Although early-life seizures in rodents do not result in cell loss, seizures cause in changes in neurogenesis and synaptogenesis and alteration of excitatory or inhibitory balance, network connectivity and temporal coding. These morphological and physiological changes are accompanied by parallel impairment in cognitive skills. This increased understanding of the pathophysiological basis of seizure-induced cognitive deficits should allow investigators to develop novel targets for therapeutic interventions.

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

References (80)

  • J.M. Barry et al.

    T2 relaxation time post febrile status epilepticus predicts cognitive outcome

    Exp Neurol

    (2015)
  • H.B. Karnam et al.

    Effect of age on cognitive sequelae following early life seizures in rats

    Epilepsy Res

    (2009)
  • J.K. Kleen et al.

    Early-life seizures produce lasting alterations in the structure and function of the prefrontal cortex

    Epilepsy Behav

    (2011)
  • H.B. Karnam et al.

    Early life seizures cause long-standing impairment of the hippocampal map

    Exp Neurol

    (2009)
  • A.F. Hoffmann et al.

    Cognitive impairment following status epilepticus and recurrent seizures during early development: Support for the “two-hit hypothesis”

    Epilepsy Behav

    (2004)
  • I. de Rogalski Landrot et al.

    Recurrent neonatal seizures: Relationship of pathology to the electroencephalogram and cognition

    Brain Res Dev Brain Res

    (2001)
  • L. Huang et al.

    Long-term effects of neonatal seizures: A behavioral, electrophysiological, and histological study

    Brain Res Dev Brain Res

    (1999)
  • J.N. Lugo et al.

    Early-life seizures result in deficits in social behavior and learning

    Exp Neurol

    (2014)
  • J.C. Neill et al.

    Recurrent seizures in immature rats: Effect on auditory and visual discrimination

    Brain Res Dev Brain Res

    (1996)
  • G.L. Holmes et al.

    Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide

    Neurobiol Dis

    (2015)
  • E. Isaeva et al.

    Long-term suppression of GABAergic activity by neonatal seizures in rat somatosensory cortex

    Epilepsy Res

    (2009)
  • A.E. Hernan et al.

    Altered short-term plasticity in the prefrontal cortex after early life seizures

    Neurobiol Dis

    (2013)
  • E. Isaeva et al.

    Alteration of synaptic plasticity by neonatal seizures in rat somatosensory cortex

    Epilepsy Res

    (2013)
  • J. O’Keefe et al.

    The hippocampus as a spatial map: Preliminary evidence from unit activity in the freely-moving rat

    Brain Res

    (1971)
  • H.D. Baumbach et al.

    Visuocortical epileptiform discharges in rabbits: Differential effects on neuronal development in the lateral geniculate nucleus and superior colliculus

    Brain Res

    (1981)
  • L.H. Ostrach et al.

    Effects of bicuculline-induced epileptiform activity on development of receptive field properties in striate cortex and lateral geniculate nucleus of the rabbit

    Brain Res

    (1984)
  • A.E. Hernan et al.

    Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits

    Neurobiol Dis

    (2014)
  • O.I. Khan et al.

    Interictal spikes in developing rats cause long-standing cognitive deficits

    Neurobiol Dis

    (2010)
  • Committee on the Public Health Dimensions of the Epilepsies, Board on Health Sciences Policy, and Institute of...
  • G.L. Holmes

    Cognitive impairment in epilepsy: The role of network abnormalities

    Epileptic Disord

    (2015)
  • G.L. Holmes

    What is more harmful, seizures or epileptic EEG abnormalities? Is there any clinical data?

    Epileptic Disord

    (2014)
  • J.R. Farwell et al.

    Neuropsychological abilities of children with epilepsy

    Epilepsia

    (1985)
  • M. Sillanpaa et al.

    Long-term prognosis of seizures with onset in childhood

    N Engl J Med

    (1998)
  • J.M. Buelow et al.

    Adaptive functioning in children with epilepsy and learning problems

    J Child Neurol

    (2012)
  • L.L. Bailet et al.

    The impact of childhood epilepsy on neurocognitive and behavioral performance: A prospective longitudinal study

    Epilepsia

    (2000)
  • B.F.D. Bourgeois et al.

    Intelligence in epilepsy: A prospective study in children

    Ann Neurol

    (1983)
  • A.T. Berg et al.

    Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: A prospective cohort study

    Neurology

    (2012)
  • R. Nabbout et al.

    Epileptic encephalopathies: A brief overview

    J Clin Neurophysiol

    (2003)
  • W.D. Shields

    Catastrophic epilepsy in childhood

    Epilepsia

    (2000)
  • A.T. Berg et al.

    Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009

    Epilepsia

    (2010)
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    Supported by National Institute of Health, United States Grants NS074450, NS074450, and NS073083 and the Michael J. Pietroniro Research Fund.

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