The pathogenic and progressive features of chronic human hippocampal epilepsy

Mathern, Gary W.; Babb, Thomas L.; Leite, Joao P.; Pretorius, James K.; Yeoman, Kristin M.; Kuhlman, Paula A.

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Volume 26, Issue 1 , Pages 151-161, December 1996

The pathogenic and progressive features of chronic human hippocampal epilepsy

Gary W. Mathern
- Corresponding author. Tel.: +1 (310) 206-8777; fax: +1 (310) 206-8461
- Divisions of Neurosurgery and Clinical Neurophysiology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
- Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
Thomas L. Babb
- Departments of Neuroscience and Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USA
Joao P. Leite
- The Brain Research Institute, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
James K. Pretorius
- The Brain Research Institute, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
Kristin M. Yeoman
- The Brain Research Institute, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA
Paula A. Kuhlman
- Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA

Received 26 October 1995; accepted 26 February 1996.

Abstract

To design useful experimental models of epilepsy, it is necessary to clearly understand the known clinical-pathologic features of the disease process. Studies of mesial temporal lobe epilepsy (MTLE) patients have identified several distinctive clinical and pathophysiologic characteristics and many of these can be analyzed in experimental models. For example, patients with typical MTLE have medical histories that often contain an initial precipitating injury (IPI), are likely to have hippocampal sclerosis in the surgical specimen, and have better seizure outcomes than patients with atypical idiopathic temporal seizures (i.e. cryptogenic). Hippocampi from children as young as age 1 year with IPI histories also demonstrate neuron damage similar to adults with hippocampal sclerosis. Compared to IPI patients without seizures (i.e. trauma, hypoxia, etc.), IPI cases with severe seizures showed younger ages at the IPI, shorter latent periods, and longer durations of habitual MTLE. Hippocampal damage is often bilateral, however, the epileptogenic side shows hippocampal sclerosis and the opposite side usually shows only mild neuron losses. Moreover, MTLE patients show declines in hippocampal neuron densities with very long histories of habitual seizures (15 to 20 years), however, the additional neuron loss adds to the template of hippocampal sclerosis and occurs in limited subfields (granule cells, CA1 and prosubiculum). Hippocampal axon and synaptic reorganization is another pathologic feature of MTLE, and involves granule cell mossy fibers and axons immunoreactive for neuropeptide Y, somatostatin, and glutamate decarboxylase (which synthesizes GABA). Finally, MTLE patients with hippocampal sclerosis show increased granule cell mRNA levels for brain derived neurotrophic factor, nerve growth factor, and neurotrophin-3 that correlate with mossy fiber sprouting or with declines in Ammon's horn neuron densities. Taken together, our data support the following concepts: (1) The pathogenesis of MTLE is associated with IPI histories that probably injure the hippocampus at some time prior to habitual seizure onsets, (2) most of the damage seems to occur with the IPI, (3) there can be additional neuron loss associated with long seizure histories, (4) another pathologic feature of MTLE is axon reorganization of surviving fascia dentata and hippocampal neurons, and (5) reorganized axon circuits probably contribute to seizure genesis or propagation.

Keywords: Childhood seizures, Synaptic reorganization, Neurotrophic factors, Seizure models

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