Biochemical Pathogenesis of Intractable Epilepsy Due to Mesial Temporal Sclerosis

Abstract & Commentary

Source: Eid T, et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: Possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet. 2004;363:28-37.

The concept that epilepsy arises from an imbalance between excitatory and inhibitory influences in epileptogenic tissue has become fundamental to further investigations of the pathophysiology of this disorder. The primary observation motivating the study of Eid and colleagues is that glutamate levels are elevated in patients with mesial temporal sclerosis (MTS), perhaps the most common cause of medication-resistant epilepsy. This finding emerges from in vitro and in vivo studies from rodents and humans; elevated glutamate levels are detected by microdialysis techniques in MTS patients undergoing prolonged intracranial studies in preparation for hippocampal resection.

In principle, elevated extracellular glutamate levels could result from increased glutamate synthesis, decreased glutamate catabolism (via disruption of glutamate-to-glutamine conversion by astrocytic glutamine synthetase [GlnS]), or decreased glutamate uptake by glia at the synaptic cleft. The current study serves to distinguish between the latter 2 possibilities. Eid et al studied GlnS levels in surgical and autopsy specimens from 14 epilepsy patients with MTS as compared to 15 patients with mesial temporal lobe epilepsy not due to MTS.

The main findings were as follows: (1) GlnS protein (as assessed by western blotting) was decreased by approximately 40% (P = .043) in MTS vs non-MTS controls; (2) GlnS protein was deficient in the appropriate regions of sclerosis (specifically the CA1 subfield of Ammon’s horn) by immunohistochemistry; (3) GlnS enzymatic activity was decreased by 38% (P = .006) in MTS patients compared to controls; and (4) There was no significant difference in the amount of the predominant glial glutamate transporter in MTS vs non-MTS.


Eid et al make a compelling case for the role of diminished GlnS in hippocampal sclerosis to account for increased extracellular glutamate in MTS. The GlnS detected by western blotting presumably functions normally since the total GlnS activity is decreased proportionately (40% by immunoblot, 38% by enzymatic assay). By contrast, increased glutamate is less likely to be due to defects in glial glutamate uptake.

The challenge remains to determine the cause of decreased GlnS in MTS. We are again confronted with the chicken-egg problem discussed previously by Neurology Alert. Does the GlnS deficiency have a genetic basis? Could a symptomatic insult, such as a prolonged febrile seizure, lead to loss of GlnS? Two studies suggest themselves that might provide clues to answering these questions. If feasible, northern blotting or in situ hybridization studies with a GlnS cDNA probe could tell us whether the loss of GlnS arises from decreased expression of the GlnS gene. Also, although it would be a heroic study to acquire sufficient numbers of patients to achieve a statistically significant result, a comparison of GlnS levels from sclerotic hippocampus to the contralateral (non-MTS) hippocampus from the same patient may help resolve the nature vs nurture question. One suspects, as in many disorders, a multifactorial process with both genetic and environmental influences.

Finally, as Eid et al mention, loss of GlnS suggests the possibility of novel therapeutic strategies to enhance GlnS expression and function. One strategy might involve the use of gene therapy to restore GlnS function in the already damaged hippocampus. Another option to exploit the current findings would be to design a pharmacological agent that could be used to abort acute seizures (particularly in the case of status epilepticus, in which such a drug might also be neuroprotective) or as a chronic anticonvulsant. — Andy Dean

Dr. Dean, Assistant Professor of Neurology and Neuroscience; Director of the Epilepsy Monitoring Unit, Department of Neurology, New York Presbyterian Hospital Cornell Campus, is Assistant Editor of Neurology Alert.