Abstracts

Homocarnosine is an inhibitory neuromodulator synthesized from GABA and histidine in a sub-class of GABAergic neurons. A minor peptide in rodent brain, homocarnosine is present in human CSF and brain in greater amounts than in most other mammals. Autopsy-based studies show that regional homocarnosine and GABA levels vary independently. Low intracellular homocarnosine and GABA levels are associated with poor seizure control in patients with complex partial seizures treated with valproate or lamotrigine. Patients with juvenile myoclonic epilepsy with good seizure control usually have high homocarnosine levels, but below normal GABA levels. A number of the new antiepileptic drugs, i.e., topiramate, lamotrigine, levetiracetam, gabapentin, increase cellular homocarnosine. The objective of this study is to assess the relationship between seizure control and intracellular homocarnosine and GABA levels in the visual cortex of patients with complex partial seizures taking carbamazepine or phenytoin.
In vivo measurements of homocarnosine and GABA were made in a 14-cm3 volume of the occipital cortex using proton spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twenty-nine patients (11 men) with complex partial seizures taking carbamazepine or phenytoin were invited to participate in this project, which was approved by the Yale University Human Investigations Committee. Ten (5 men) drug-free, epilepsy-free volunteers served as controls.
Intracellular homocarnosine concentrations were lower in epilepsy patients (0.45 mM, standard error 0.03) than non-epileptic subjects (0.53 mM, se 0.03). Homocarnosine levels were normal (0.50 mM, se 0.05) in the six patients with good seizure control and below normal (0.43 mM, se 0.04) with poor seizure control. Intracellular GABA concentrations were lower in patients (0.77 mM, se 0.06) than non-epileptic subjects (1.05 mM, se 0.06). GABA levels were lowest (0.73 mM, se 0.07) in the 23 patients with seizures within one month of the measurements. Occipital GABA levels, remote from the presumed frontal or temporal seizure focus, were low normal (0.90 mM, se 0.08) in patients with better seizure control.
Intracellular homocarnosine and GABA concentrations were both low in the visual cortex of patients with refractory localization-related epilepsy treated with carbamazepine and phenytoin. They were both normal in patients whose seizures were under better control. The observations are similar to those made in patients with localization-related epilepsy treated with valproate or lamotrigine. Low homocarnosine and GABA appear to contribute to cortical hyperexcitability, allowing seizures to spread from the epileptogenic zone. Morbidly depressed patients without epilepsy often have low intracellular GABA with normal homocarnosine. Low neocortical homocarnosine and GABA levels appear to be biomarkers for epileptogenicity.
[Supported by: NIH-NINDS NS6208 and NS32518]