Children with epileptic encephalopathies experience recurrent seizures, and the effects of recurrent seizures on the developing brain differ from the effects of a prolonged seizure. Although the brain's response to neonatal seizures may differ from the response to seizures in the mature brain, it is increasingly clear that seizures alter the developing brain.

Types of changes

Kindling occurs at all ages.57,58 In this process, recurrent electrical stimulations initially result in only brief electrical discharges and mild behavioral changes but progressively result in more prolonged and intense electrical and behavioral seizures, Adult rats that underwent kindling during the first weeks of life had a reduced seizure threshold when studied as adults.59 This enduring alteration in seizure susceptibility occurs in young rats even with no discernible cell loss.

Despite the lack of cell loss with recurrent seizures, synaptic reorganization does occur in this setting. Using two models of neonatal seizures, pentylenetetrazol and flurothyl, we recently demonstrated seizure-induced changes in the mossy fiber distribution in the hippocampus in mature rats that had experienced neonatal seizures.60-62 Both models demonstrated that recurrent seizures during the neonatal period result in subsequent increases in mossy fiber growth in both the supragranular region and the CA-3 hippocampal subfield (Figure 2). The terminal sprouting in CA-3 appears to represent new growth of axons and synapses, rather than a failure of normal regression of synapses. Counting principal neurons in the hippocampus detected no cell loss after the recurrent neonatal seizures.

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Causes fig 2b

A. Example of Timm staining in the hippocampus from a control animal. Normally, little staining is seen in the pyramidal cell layer. 
B. Example of Timm staining in an animal with a history of neonatal seizures. Note the increase in staining in the pyramidal cell layer (arrow).

In addition to altering mossy fiber plasticity, recurrent seizures result in alterations of neuronal pathways activated during seizures.62 Immature rats were subjected to 50 flurothyl-induced seizures between ages P11 (postnatal day 11) and P23. Immunostaining for c-fos immunoactivity was performed to characterize the pattern of neuronal activity after the recurrent seizures. Recurrent seizures progressively activated more brain structures, as revealed by a dramatic increase in both the extent and intensity of c-fos immunostaining after the recurrent seizures; mild c-fos immunostaining was observed after the 25th recurrent seizure, whereas extensive c-fos immunostaining was observed after the 50th seizure. These findings demonstrate that recurrent seizures have a progressive effect on the extent of neuronal activation. Taken together, recent studies clearly demonstrate that immature animals undergo changes in neuronal organization after recurrent seizures, with mossy fiber sprouting in both the CA-3 subfield and supragranular region despite the lack of demonstrable hippocampal cell loss.

These in vivo studies suggest that the excessive excitability associated with recurrent seizures can alter the plasticity of mossy fiber synapses. In a novel approach to the same problem, Ikegaya63 used organotypic slice cultures and picrotoxin, a GABAA channel blocker, to study the effects of prolonged excitability on mossy fiber innervation. He found that prolonged hyperexcitability caused ectopic innervation of the mossy fibers to the stratum oriens and the dentate molecular layer. Furthermore, brief, repetitive stimulation elicited epileptiform discharges in the CA-3 region that were inhibited by an NMDA receptor antagonist. Significantly, picrotoxin did not affect synaptic responses of the Schaffer collaterals, which were fully developed at the time of hippocampal slice preparation.

Effects of changes

The aberrant network set up by recurrent seizures may make the brain vulnerable to future injury. Schmid et al.64 subjected rats to 25 seizures during the first 4 days of life. As adolescents, rats were subjected to status epilepticus, using either KA or perforant pathway stimulation. The authors found no cell death in animals that had experienced only neonatal seizures. However, animals in which neonatal seizures had occurred had significantly more severe brain injury after both KA and perforant pathway stimulation than did animals without a history of neonatal seizures. Although the mechanism by which this enhanced susceptibility to injury is not yet known, the study provides further evidence that neonatal seizures alter the brain in a maladaptive manner.

Recurrent neonatal seizures are associated with impairment in cognition and behavior. Immature rats exposed to a series of 25 flurothyl-induced seizures and tested as adults demonstrated significant abnormalities in the water maze, a test of spatial memory, and the open-field test, a test of activity level.60 As compared to control animals, the rats with neonatal seizures had increased CA-3 and supragranular mossy fiber sprouting.

Whether the morphologic changes seen with recurrent seizures are directly responsible for the reduced seizure threshold and cognitive dysfunction is not known. However, the degree of CA-3 mossy fiber projections correlates with learning. Lipp et al.65 compared the number of trials required for rats to learn to avoid a 10-second electrical shock by moving from one compartment to another after a conditioning stimuli (two-way avoidance learning) and the magnitude of the stratum pyramidale projections of mossy fibers. Learning proved to be directly related to the extent of mossy fiber projections to the pyramidal layers of CA-3. The animals having more CA-3 mossy fiber terminals performed less well than animals with fewer terminals. These authors also found an inverse relationship between the extent of infrapyramidal mossy fiber projections and two-way avoidance learning in rats treated with L-thyroxine.65

The relationship between the size of the hippocampal mossy fiber projections and learning and memory may be task-dependent.66 For example, recurrent seizures during the first weeks of life result in impairment in rats' ability to succeed in the water maze and in auditory location but not in a quality discrimination task.67

Adapted from: Holmes GL. Childhood-specific epilepsies accompanied by developmental disabilities: Causes and effects. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;23-32. 
With permission from Elsevier (www.elsevier.com). 

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Reviewed By: 
Steven C. Schachter, MD
on: 
Saturday, May 1, 2004