Effect of vigabatrin (gamma-vinyl GABA) on amino acid levels in CSF of epileptic patients.

Abstract

SUMMARY Vigabatrin (y-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity ofGABA transaminase. The effect ofvigabatrin on neurotransmission-related amino acids in CSF of 28 epileptic patients was studied and the relationship between the amino acid pattern and clinical response during 7 months of administration ofvigabatrin. Of this study population, 46% had more than 50% decrease in seizure frequency (responders). In 54% the seizures decreased less than 50% (nonresponders). In the whole study group, the levels of total GABA during vigabatrin treatment were 283%, free GABA 197%, homocarnosine 310% and glycine 128% that ofthe levels at baseline in the same patients. Glutamate, glutamine, aspartate, asparagine, and taurine concentrations did not change. The amino acid pattern in CSF during administration of vigabatrin did not differ significantly in responders and nonresponders. The study suggests that both GABAergic and glycinergic neurotransmission are affected by vigabatrin. The changes in CSF levels of neurotransmitter amino acids are, however, not necessarily related to the clinical response.Vigabatrin (y-vinyl GABA, 5-amino-4-hex-enoic acid), is an anticonvulsive drug that inhibits GABA transaminase (GABA-T, EC 2.6.1.19) activity by an irreversible mechanism.' Levels of GABA and homocarnosine (HC) in the brain and cerebrospinal fluid (CSF) of animals as well as CSF levels of GABA and HC in humans are elevated up to 2-4 fold during vigabatrin administration at doses that have anticonvulsive efficacy.'2 Previous data about the unchanged levels of markers of cholinergic, dopaminergic, serotonergic and peptidergic systems3 4 and the relatively few side effects observed in patients during vigabatrin administration suggest that the mechanism of action is quite specifip. However, the elevation of GABA levels alone seems not to explain all the effects ofvigabatrin. First, studies of the rat brain suggest that other amino acids, such as fi-alanine and hypotaurine, are also affected by vigabatrin.5 Second, the maximal elevations of GABA levels in the brain and CSF are not always correlated with maximal anticonvulsive efficacy.6 Third, elevation of CSF levels of GABA seems to be a constant finding in patients receiving vigabatrin, but the anticonvulsive effect is found only in 40-60% of these Address for reprint requests: Asla Pitkinen, MD,

γ‐Vinyl GABA (Vigabatrin) in Epilepsy: Clinical, Neurochemical, and Neurophysiologic Monitoring in Epileptic Patients

“…Levels of acetylcholinesterase (AChE), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (SHIAA), somatostatin, prolactin, and P-endorphin remained constant during GVG therapy of 3, 6, and 7 months' duration. More detailed data on the levels of the various neurotransmitter-related parameters in the CSF of these patients were reported previously (Halonen et al, 1988;Pitkanen et al, 1988;Riekkinen et al, 1989a,b).…”

Effects of Vigabatrin (γ‐vinyl GAB A) on Neuro transmission‐Related Amino Acids and on GAB A nd Benzodiazepine Receptor Binding in Rats

“…In this study, the glycine concentration in rat brain, spinal cord, CSF, and serum remained unchanged. However, glycine levels in lumbar CSF have been shown to increase during administration of GVG in humans Pitkanen et al, 1988). Species differences and the different collection site of CSF samples may explain this discrepancy.…”

Pitfalls in the diagnosis of glycine encephalopathy (non‐ketotic hyperglycinemia)

“…69 VPA competitively inhibited GCS activity not only in rat liver but also in the brain, although the inhibitory effect was greater in the liver (50%) than in the brain (35%). 75 Therapy with vigabatrin (γ-vinyl GABA) has also been shown to increase CSF glycine concentration by between 16 to 37%, [85][86][87] but not to levels significantly above the normal range. Contamination of CSF with blood as a result of a traumatic spinal tap is a major source of difficulty in interpreting CSF amino acid values.…”