Epilepsy Affects Neural Circuits

Renato M.E. Sabbatini, PhD

What happens with a neuron in an epileptic crisis? Is it destroyed, even when it maintains contact with healthy neurons? Are neuronal circuits affected because of epileptic discharges?

Epilepsy is a disorder in which the balance between cerebral excitation and inhibition is disrupted, leading to uncontrolled excitability of groups of neurons. Both clinical and experimental observations have shown that recurrent epilepsy leads to important structural and functional alterations in the nervous system, inducing a large number of molecular, cellular and functional alterations in the brain.

For example, in animals as well as in humans, seizures produce damage in two important subcortical brain structures of the limbic system, responsible for memory, emotion and many other functions: the hippocampus and the amygdala. Hippocampal injuries become more severe with age.

The alterations induced by epileptic seizures are short-term and long-term. Some of  the long-term alterations include temporary or permanent
alterations in synapses and brain circuits. For example, in temporal lobe epilepsy, seizures cause long-lasting changes in synaptic efficacy, called long-term potentiation. Even brief seizures produce changes in synaptic efficacy, which are followed several weeks later by aberrant formation of new synapses. The disruption of normal neuronal activity by seizures can affect multiple developmental processes, resulting in these long-lasting changes.

The metabolic changes in neurons that are responsible for these pathologies are not well known. Brain damage caused by persistent and highly repetitive seizures (several times a day), a condition which is named status epilepticus, is associated with excitotoxic mechanisms in several brain regions. Excitotoxins are neuron-lesioning chemical mediators produced by excessive (pathologic) stimulation, such as those ocurring in epileptic seizures. Cell receptors called NMDA (n-methyl D-aspartate) play a dominant role. The resulting alterations in hippocampal circuits may result from several causes, such as the the death of inhibitory neurons, or from misdirected regeneration of excitatory neurons. It may lead to chronic epilepsy, as it has been eloquently expressed by a scientist named Gower, in the phrase "Epilepsy begets more epilepsy".  This could be the consequence of permanent loss of normal inhibitory neuron populations, or of the increase of  excitatory connections.

Regarding the damage produced in the brain by epileptic seizures, neurologists know that there are differences between mature and immature
brains. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. On the other hand, the immature brain is less vulnerable than the mature brain to seizure-induced cell death. Seizures in the developing brain can result in irreversible alterations in neuronal connectivity. For example, status epilepticus in infants may lead to significant deficits in memory, learning and behavior as adults.

References

Ben-Ari Y. Cell death and synaptic reorganizations produced by seizures.
Epilepsia. 2001;42 Suppl 3:5-7.

Holmes GL, Ben-Ari Y. The neurobiology and consequences of epilepsy in the
developing brain. Pediatr Res. 2001 Mar;49(3):320-5.

Holmes GL. The long-term effects of seizures on the developing brain:
clinical and laboratory issues. Brain Dev. 1991 Nov;13(6):393-409.

Holmes GL. Do seizures cause brain damage? Epilepsia. 1991;32 Suppl
5:S14-28.

Lado FA, Laureta EC, Moshe SL. Seizure-induced hippocampal damage in the
mature and immature brain. Epileptic Disord. 2002 Apr;4(2):83-97.

Lynch MW, Rutecki PA, Sutula TP. The effects of seizures on the brain. Curr
Opin Neurol. 1996 Apr;9(2):97-102.

Moshe SL. Brain injury with prolonged seizures in children and adults. J
Child Neurol. 1998 Oct;13 Suppl 1:S3-6;

Salmenpera T, Kalviainen R, Partanen K, Pitkanen A. Hippocampal and
amygdaloid damage in partial epilepsy: a cross-sectional MRI study of 241
patients. Epilepsy Res. 2001 Jul;46(1):69-82.

Swann JW, Smith KL, Lee CL. Neuronal activity and the establishment of
normal and epileptic circuits during brain development. Int Rev Neurobiol.
2001;45:89-118.

Wasterlain CG, Shirasaka Y. Seizures, brain damage and brain development.
Brain Dev. 1994 Jul-Aug;16(4):279-95.