Abstracts

RATIONALE: The expression of developmentally regulated cytoskeletal proteins, such as the neural epithelial stem cell protein, nestin, downregulates during normal corticogenesis. However, in children with early onset seizures, intracellular proteins accumulate, do not decrease with age, and may either contribute to or interfere with synaptic functions. We studied anomalous nestin densities to determine whether these protein accumulations were related to epileptic hyperexcitability.
METHODS: Specimens were analyzed from four patients aged 2, 7, 8, and 13 years at time of surgery, with seizure onset ages 3 months, 20 months, 7 years, and 2 days, respectively. Subdural EEG grid monitoring defined regions of onset, spiking rates, and relatively normal activity. The anatomic pathology was related to the EEG activity after the margins of the resection were defined.
Nestin immunoreactivity was identified in four different cell types: pyramidal cells, [dsquote]giant cells[dsquote], and round cells with and without neuritic processes. Serial sections were stained with Cresyl Violet. Protein amounts were measured using Western blots, and relative cell densities for each cell type were noted and analyzed in relation to age of onset, EEG activity, and clinical history.
RESULTS: Two patients with clinical history of Tuberous Sclerosis Complex (age of seizure onset: 3 months) and Parry-Romberg Syndrome/Rasmussen[ssquote]s Encephalitis (age of seizure onset: 7 years) showed highest density of nestin immunoreactive cells of all four types, with almost equal distribution in EEG active, or [dsquote]spiking[dsquote], and EEG inactive, or [dsquote]normal[dsquote] cortex. In the other two patients, nestin postive cells were highest in the spiking and onset cortex, compared to the relatively normal cortex. Round type cells without processes were found almost exclusively in regions of seizure onset and frequent spiking in three of the patients. However, in the TSC patient, in which the surgery was designed to remove the tuberous cortex, nestin immunoreactivity was highest compared to the other patients, and round type cells were abundant in all regions, while pyramidal cells were sparse. Giant cells were also found in both white and gray matter of the TSC patient.
CONCLUSIONS: 1. The presence of nestin immunoreactive cells in epileptic cortex represents another example of arrested cortical development characteristic of other protein changes found in receptors of brains with migration disorders.
2. Nestin cell densities are highest in the regions of pathology and may contribute to focal neuronal loss, such as decreased pyramidal cells.
3. Nestin positive round cells were most abundant in regions of severe pathology and high EEG spiking may indicate a failure to differentiate from a brain stem cell progenitor to a neuron or glial phenotype. If these immature cells remain throughout childhood, receptor protein configurations and synaptic activity may result in intractable epilepsy.
[Supported by: National Institutes of Health Grant: NS38150]