CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine actionin seizure control

Several lines of evidence suggest that the binding affinity of glutamate de carboxylase (GAD) to the active form of pyridoxine is low in cases of pyrid oxine-dependent seizures (PDS) and that a quantitative imbalance between ex citatory (i.e. glutamate) and inhibitory (i.e. gamma -aminobutyric acid, GA BA) neurotransmitters could cause refractory seizures. However, inconsisten t findings with GAD insufficiency have been reported in PDS. We report a ca se of PDS that is not accompanied by an elevated cerebrospinal fluid (CSF) glutamate concentration. Intravenous pyridoxine phosphate terminated genera lized seizures which were otherwise refractory to conventional anti-epilept ic medicines. No seizure occurred once oral pyridoxine (13.5 mg/kg per day) was started in combination with phenobarbital sodium (PB, 3.7 mg/kg per da y). The electroencephalogram (EEG) normalized approximately 8 months after pyridoxine was started. The patient is gradually acquiring developmental mi lestones during the 15 months follow-up period. The CSF glutamate and GABA concentrations were determined on three separate occasions: (1) during stat us epilepticus; (2) during a seizure-free period with administration of pyr idoxine and PB; and (3) 6 days after suspension of pyridoxine and PB and im mediately before a convulsion. The CSF glutamate level was below the sensit ivity of detection (<1.0 <mu>M) on each of the three occasions; the CSF GAB A level was within the normal range or moderately elevated. The CSF and ser um concentrations of vitamin B-6-related substances, before pyridoxine supp lementation, were within the normal range. We suggest that (1) PDS is not a discrete disease of single etiology in that insufficient activation of GAD may not account for seizure susceptibility in all cases and (2) mechanism( s) of anti-convulsive effect of pyridoxine, at least in some cases, may be independent of GAD activation. (C) 2001 Elsevier Science B.V. All rights re served.