Interictal epileptiform discharges reflect a stereotyped cellular pattern of depolarization shift.71 Transition from interictal to ictal discharge is characterized by loss of hyperpolarization and by synchronization of neurons in the focus. Amplification of excitatory postsynaptic potentials that underlie the patterns of depolarization shift may be produced by mechanisms that include:72

  • withdrawal of inhibition
  • frequency potentiation of excitatory postsynaptic potentials
  • change in the space constant of the dendrites of the postsynaptic neuron
  • activation of the N-methyl-D-aspartate (NMDA) receptor
  • potentiation by neuromodulators

Biochemical injury to neurons may cause a sequence of changes, ranging from cellular loss with replacement gliosis to subtle alterations in neuronal plasma membrane. Membrane changes initiated by biochemical effects of injury may alter densities and distribution of ion channels on neuronal membrane. Alteration of membrane ionotophores could affect Na+ and Ca2+ currents, alter thresholds, and lead to progressive depolarization. Intrinsic cellular bursting may also develop with an increase in extracellular K+ or reduction of extracellular Ca2+. Development or recruitment of a critical mass of neurons sufficient to cause clinical manifestations requires synchronization of a critical mass of cells.71,72


The mechanism or critical physiologic changes causing post-traumatic epileptogenesis remains unknown. However, several processes may provide useful areas for investigation:

  • Mechanical shearing of fiber tracts, with loss of inhibitory interneurons after anterograde transynaptic neuronal degeneration73
  • Trauma-induced release of aspartate or glutamate, with attendant activation of N-methyl-D-aspartate (NMDA) receptors74
  • Elaboration of nerve growth factor75
  • Enhancement of reactive gliosis76

Assessment of hippocampal tissue obtained during surgical resection for temporal lobe seizures and stained for identification of acetylcholine esterase shows enhancement of staining in the outer portion of the molecular layer of the dentate gyrus.77 Histochemical staining of rodent kindled hippocampus shows abundant mossy fiber synaptic terminals in the supragranular region and the inner molecular layer of the dentate gyrus.78 Although speculative, synaptic reorganization may increase recurrent excitation in granule cells, favoring epileptogenesis.

Experimental foci have losses in the number of axosomatic g-aminobutyric acid (GABA)–ergic terminals, as represented by asymmetric synapses. The GABA-ergic pericellular basket plexus that provides tonic inhibition was thought to be sensitive to hypoxia, given the implied dependence on aerobic metabolism evidenced by the presence of increased numbers of mitochondria within the altered synapses.79

Adapted from: Willmore LJ. Head trauma and the development of post-traumatic epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;229–238.
With permission from Elsevier ( 

Reviewed By: 
Steven C. Schachter, MD
Thursday, April 1, 2004