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Objective: To investigate the effect of vigabatrin (VGB; gamma-vinyl gamma-aminobutyric acid [GABA]), a selective irreversible GABA-transaminase inhibitor, on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF) measured with 18F-fluorodeoxyglucose (FDG) PET and 15O water PET., Background: Antiepileptic drugs (AEDs) reduce CMRGlc to varying degrees. Phenobarbital causes a mean decrease of 30 to 40%. Phenytoin, carbamazepine (CBZ), and valproate (VPA) cause milder reductions in CMRGlc. The combination of VPA with CBZ results in a greater decrease than either drug alone. The effect of novel AEDs on both CBF and CMRGlc has not been studied extensively., Methods: Fourteen patients with refractory complex partial seizures on CBZ monotherapy for 4 weeks were included in the study. All patients had baseline 18F-FDG and 15O water PET studies followed by double-blind randomization to placebo (PLC) or VGB while on continuous CBZ treatment. PET scans were repeated after an interval of 2 months on target dose of VGB (50 mg/kg) or PLC. Quantitative PET data analysis was performed using a region of interest template. Significance was tested with the Wilcoxon rank sum test., Results: No statistically significant difference in age, duration of epilepsy, or CBZ levels was observed in the two patient groups. VGB reduced global CMRGlc by 8.1+/-6.5% and global CBF by 13.1+/-10.4%. The change in CMRGlc was different in patients taking VGB compared with those on PLC (p < 0.04). VGB patients showed regional decreases in both CMRGlc and CBF, particularly in temporal lobes. CSF total GABA increased in the VGB patient group (1.48+/-1.06 versus 4.03+/-4.19 nm/mL). The increase differed from the PLC group (p < 0.03). We found a strong relation between decreased total CSF GABA and increased CMRGlc in the VGB patient group (R2 = 0.82, p < 0.01)., Conclusions: Vigabatrin (VGB) causes mild reductions in both cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMRGlc) in contrast to other drugs such as barbiturates, which are direct agonists at the gamma-aminobutyric acid-benzodiazepine receptor complex. Conventional AEDs depress CBF and CMRGlc to a greater degree than does VGB. The relatively mild reduction could be due to pre- as well as postsynaptic effects or a use-dependent mechanism.

In this study, we investigated whether pretreatment cerebrospinal fluid (CSF) neurotransmitter concentrations of gamma-aminobutyric acid (GABA) and glutamate (GLU) were correlated with response to phenobarbital treatment in dogs with primary epilepsy. Eleven untreated dogs, 6 males and 5 females, with a median age of onset of seizures of 3 years (range: 0.5-5 years) were selected for therapy based on progressive or serious seizure patterns. The median interval between the first observed seizure and start of phenobarbital therapy was 485 days (range: 101-1,765 days). All dogs were purebred, with the exception of I male dog. Oral phenobarbital was started at 2.5 mg/kg every 12 hours. Trough serum phenobarbital concentrations were measured at 15, 45, 90, 180, 360, 540, and 720 days after the start of treatment. There was no difference in the mean trough serum concentration or in the mean number of seizures recorded between each time period of phenobarbital measurement over the 2-year evaluation. No correlation was found between CSF GLU, GABA, or GLU: GABA ratio and the total number of seizures recorded before or after initiation of phenobarbital therapy. Lower CSF GABA concentration, however, was correlated with a lower seizure frequency difference (the total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy for an identical time period of evaluation) and lower percentage reduction in seizures: ([total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy] divided by the total number of seizures before phenobarbital therapy) x 100. There was no correlation between CSF GLU and the seizure frequency difference and percentage reduction in seizures. A negative correlation between the CSF GLU:GABA ratio and seizure frequency difference was found. Thus, dogs with an initial lower CSF GABA concentration before phenobarbital therapy did not respond as well as did dogs with a higher CSF GABA concentration.

The effect of add-on administration of lamotrigine (1-12 mg/kg per day, 2-12 months) on the levels of neurotransmission related amino acids including gamma-aminobutyric acid (GABA), glutamate, aspartate, glycine and antiepileptic drugs (AEDs) in lumbar cerebrospinal fluid (CSF) was studied in 22 children and young adults with generalised therapy resistant epilepsy. Two lumbar punctures were performed, one prior to, and one following a mean of 5 months (2-12 months) of lamotrigine treatment. Lamotrigine decreased seizure incidence and severity in 12 of the 22 patients without influencing CSF GABA, glutamate, aspartate or glycine levels. Lamotrigine did not alter the concentrations of AEDs in CSF or plasma. However, CSF GABA levels were 86% higher in those patients also treated with gamma-vinyl-GABA (vigabatrin, GVG) compared with patients treated with other combinations and this was not altered by co-medication with lamotrigine. The proposed mechanism of action of lamotrigine, namely that it may inhibit glutamate release in the CNS, is not reflected by changes in CSF glutamate levels. The present findings indicate that CSF GABA, glutamate, aspartate and glycine levels may not be useful as in vivo neurochemical markers in young patients responding to the therapeutic dose of lamotrigine used in this study.

The anticonvulsant effects of gamma vinyl GABA (GVG) were investigated against pentylenetetrazol (PTZ) seizures, while sodium valproate (VP) was used as positive control. At 1000 and 1500 mg kg-1 GVG was found to decrease seizure intensity either in 4 or 24 h, as effectively as VP. At 2000 mg kg-1 GVG was found to be almost ineffective. At both doses and both time spans of drug action, seizure latency was prolonged, compared to controls and VP group.

A 32 year old patient with refractory complex partial seizures was treated with vigabatrin for 3.5 years. Before starting treatment and at 42 months, lumbar punctures were done and the CSF analyzed for amino acids including GABA. Although the patient experienced a 50% seizure reduction, he underwent a left sided temporal lobectomy, and the tissue sample was also analyzed for amino acid content. It was found that vigabatrin caused a three-fold increase in total and free GABA in both the tissue sample and CSF. There were no other significant changes in the other amino acids analyzed. Seizure reduction seen initially was maintained over the long-term observation period. The finding of a specific increase of GABA in brain tissue and CSF of this patient treated with vigabatrin provides additional support to the concept that the primary effect of vigabatrin is as a selective enzyme activated irreversible inhibitor of GABA transaminase.

We report long-term clinical, neurochemical, and electrophysiologic data of gamma-vinyl GABA (GVG, vigabatrin) in three groups of patients. GVG was started as add-on therapy for 75 patients with refractory complex partial seizures (group A) and for 36 mentally handicapped patients with severe epilepsy (group B). The third group (C) consisted of 20 patients with carbamazepine (CBZ) monotherapy, in half of whom GVG monotherapy was substituted. After 3 months, 55% of patients in group A and 42% in group B were responders (reduction in seizure frequency greater than 50%). After 6 (group A) and 3 years (group B) of follow-up, 27 and 33% of the patients, respectively, still had good response to GVG. Neurochemical measurements showed a twofold increase in CSF GABA concentrations and minimal or no changes in other neurotransmitter-related parameters. In group C, substitution of GVG as medication tended to normalize the lengthened latencies in somatosensory evoked potentials (SEPs) observed during CBZ treatment.

Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment. The influence of vigabatrin on the cerebrospinal fluid concentrations of free and total GABA, homocarnosine, homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol, as well as of the drug itself, was assessed. All patients demonstrated a clinical response to vigabatrin, and the drug was well tolerated over the entire observation period. Mean (+/- SD) reduction of seizure frequency was 65% +/- 23% (range, 26% to 100%) when comparing the end of the treatment period to the previgabatrin baseline. The cerebrospinal fluid concentrations of both free and total GABA and of the dipeptide homocarnosine showed approximately 2- to 5-fold increases over baseline values, with free GABA and homocarnosine being the more sensitive variables. Cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were not altered in a significant manner over the observation period. These findings support the concept that the effects of vigabatrin are restricted to an effect on GABA catabolism and do not extend to the neurotransmitters dopamine and norepinephrine. Clinical efficacy and elevation of GABA and homocarnosine concentration were sustained over the period of observation.

In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.

1. Vigabatrin, 50 mg kg-1, was administered orally as add-on therapy to 11 patients with drug-resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA-histidine dipeptide), homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre-treatment levels with subsequent dosing schedules. In contrast, 5-HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre-treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.

Vigabatrin (gamma-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity of GABA transaminase. The effect of vigabatrin 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 of vigabatrin. 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 of the 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.

The mean gamma-aminobutyric acid (GABA) level in lumbar CSF of 31 children with epilepsy was not significantly different from that of 41 age-matched controls. However, when the epileptic children were subdivided into untreated patients and patients treated with antiepileptic drugs, the medication-free subgroup had a significantly lower mean CSF GABA level than nonepileptic children. Patients controlled by anticonvulsant therapy had significantly higher CSF GABA levels than untreated epileptic patients. A more detailed analysis of the children taking antiepileptic medication indicated that the only drug that significantly increased GABA in CSF was valproic acid. Analysis of CSF data with respect to the seizure type of the patients showed that, compared with controls, significantly reduced average GABA levels were present in children with infantile spasms (mostly untreated) and unmedicated generalized tonic-clonic seizures, whereas treated children with generalized tonic-clonic seizures and patients with partial epilepsy (mostly treated) did not significantly differ from controls. The data provide further evidence that impairment of the central GABA system may be involved in human epilepsy.

Lumbar free CSF GABA and amino acid concentrations were measured in 43 patients with newly diagnosed untreated epilepsy and 26 patients with chronic drug-resistant epilepsy. The results were compared with those from 51 control patients. No differences in free CSF GABA concentration could be detected between patients with epilepsy, either treated or untreated, and controls. Untreated patients with primary generalised epilepsy and partial seizures had similar free CSF GABA concentrations. These results would not support the hypothesis that patients with epilepsy have a global disturbance of GABA function. CSF taurine, asparagine, aspartate, glycine and alanine were significantly reduced in patients with epilepsy compared to the control population.

1. To evaluate the relationship between the clinical response and enhancement of GABAergic neurotransmission, for 6 months we administered vigabatrin (gamma-vinyl-GABA, GVG) to 75 patients with complex partial epilepsy. Total GABA (TGABA), free GABA (FGABA), homocarnosine (HC), and GVG concentrations were measured in CSF of these patients before and during GVG treatment. 2. Over 50% reduction in seizures was found in 55% of the patients. Dose-reduction resulted in a relapse, i.e. the return of seizures. 3. At baseline TGABA, FGABA, and HC did not differ in responders and nonresponders. After GVG treatment, the TGABA and HC levels were lower in nonresponders (P less than 0.001), but the GVG and FGABA levels did not differ. The GVG dose reduction resulted in a concomitant decrease in TGABA, FGABA, HC and GVG (P less than 0.001). 4. According to our results GVG is an effective anticonvulsant drug in complex partial seizures. In nonresponders the poor anticonvulsant response may be related to the lower elevation of the CSF markers of GABAergic neuronal activity in this group compared with the responders.