Causes and effects, accompanied by developmental disabilities

Although they can occur at any age, seizures are far more common in children than adults. Among children, the highest incidence occurs during the first few years of life.1,2 Animal studies have suggested that the increased excitability in the developing brain is secondary to a developmental imbalance between maturation of excitatory and inhibitory circuits.3–8 The main inotropic receptors display a sequential developmental pattern of participation in neuronal excitation in the neonatal hippocampus.6 These receptors are:

  • gamma-aminobutyric acid type A (GABAA)
  • N-methyl-D-aspartate (NMDA)
  • alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)

GABA, the main inhibitory transmitter in the adult, provides the main excitatory drive to hippocampal neurons at early stages of postnatal development, owing to a chloride gradient that leads to depolarization of young neurons (as opposed to the hyperpolarization observed in adults).7

The other major postsynaptic inhibitory system (postsynaptic GABAB, adenosine, and 5-hydroxytryptamine–G protein–coupled potassium channels) also experiences delayed maturation, suggesting that the neonatal circuit operates without transmitter-gated inhibition.

In contrast, presynaptic inhibition, mediated by adenosine, GABAB, or other metabotropic receptors, is fully operational at birth, providing evidence that the major form of inhibition in the neonatal circuit is the control of transmitter release.3

Seizures in children with developmental disabilities Children with developmental disabilities are at even higher risk for seizures than is the general population.9–11 In most children, the pathologic process responsible for the disability is responsible also for the epilepsy. The risk of epilepsy in children with developmental disabilities varies considerably. In general, the more severe and extensive the cerebral pathology, the higher is the likelihood of epilepsy. For example, among children with cerebral palsy, those with quadriplegia (also termed double hemiplegia) have the highest incidence of epilepsy, whereas children with diplegia have the lowest incidence.11–13

As discussed under "Effects" below, in other situations, the epilepsy itself may be responsible for the disability.

Effects

Substantial evidence now supports the view that, in some situations, frequent seizures or epileptiform discharges result in substantial cognitive decline in children. The term epileptic encephalopathy frequently is used to describe these conditions.14They include such disorders as:

Animal studies have convincingly demonstrated that seizures during early development, such as infantile spasms, can lead to damage. All the clinical and animal data support the caution that clinicians should make every attempt to diagnose quickly and aggressively treat infantile spasms. Delays in the recognition of infantile spasms or the use of inappropriate therapies may be very detrimental to the child.

Whether the changes noted in animal models are applicable to humans is not yet clear. However, one could speculate that infantile spasms, through activity-dependent mechanisms, result in the establishment of aberrant neuronal connections. This may explain the observation that children with intractable infantile spasms may continue to have tonic seizures that display the clinical and EEG features of infantile spasms. Teenagers and adults without a history of infantile spasms never develop such spasms, but intractable infantile spasms may lead to changes in connectivity that permit this seizure type to continue.

The following pages present infantile spasms as an example of a syndrome in which the epileptic condition is responsible for all or part of the disability. The biological effects of seizures on the developing brain are reviewed, using infantile spasms as a backdrop.

Acknowledgments

The research reported in these pages was supported by the National Institutes of Health (NS27984).

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