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

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.     

A controlled study of oral vigabatrin (gamma-vinyl GABA) in patients with cerebellar ataxia

Vigabatrin (gamma-vinyl GABA; GVG), an irreversible inhibitor of GABA-transaminase, at a daily dose of 2-4 g, and a placebo were each administered orally for 4 months to 14 patients with cerebellar ataxia (9 with Friedreich's ataxia, 5 with olivopontocerebellar atrophy), in a double-blind, placebo-controlled crossover study. For the group as a whole, there was no significant difference between the GVG and placebo periods in any of the parameters of cerebellar symptomatology measured. Individually, one patient showed some improvement after 3 months of treatment with 2 g/day GVG. Tolerance to 4 g/day GVG was poor, whereas 2 g/day was well tolerated. The results suggest that agents which increase central GABA concentrations are not likely to be of benefit to patients with Friedreich's ataxia or olivopontocerebellar atrophy.     

Inhibitory and excitatory amino acids in cerebrospinal fluid of chronic epileptic patients

Summary We studied the levels of excitatory and inhibitory amino acids in the cerebrospinal fluid (CSF) of 28 epileptic patients (24 with partial type seizures, 4 with primary generalized seizures) and 12 controls. The levels of aspartate were 63% (p<0.01), glutamine 129% (p<0.001), and homocarnosine 127% (p< 0.005) that of controls. The concentrations of glutamate, asparagine, total GABA, free GABA, taurine, and glycine did not differ between epileptic patients and controls. Patients with partial epilepsy had a pattern of amino acids in CSF similar to that in patients with primary generalized seizures. In the present study we did not observe increased excitation or decreased inhibition in the seizure-active brains of epileptics, as far as the CSF levels of amino acids reflect their levels in the brain.     

Effect of gamma-vinyl GABA treatment on cholinergic and aminergic neurotransmission and on cyclic nucleotides in human complex partial epilepsy--a CSF study

1. Gamma-vinyl GABA (GVG) is a new anticonvulsant drug that enhances levels of GABA in the brain by irreversibly inhibiting GABA transaminase. 2. To further evaluate the effects and mechanism of action of GVG in the human brain, we measured acetylcholinesterase (AChE) activity and levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), cyclic nucleotides (cAMP, cGMP), total GABA (TGABA), and GVG in CSF of 78 patients with complex partial epilepsy. The CSF samples were taken at baseline and after 3 months of GVG administration (3 g GVG per day). Thereafter, the responders (= 50% decrease in number of seizures) were divided (double-blind) into two groups that received either 1.5 g or 3 g of GVG per day for the next 3 months. The third CSF sample was taken after this double-blind period. 3. TGABA levels were increased during the GVG treatment (p less than 0.001). In the whole group of patients AChE, HVA, 5-HIAA, and cAMP did not differ from baseline values, cGMP levels were slightly elevated after 3 months of GVG administration (p = 0.019), but were no longer elevated after 6 months. Responders had slightly lower AChE activity than nonresponders (p = 0.041). After 6 months of drug treatment the cGMP levels of patients receiving 1.5 g of GVG did not differ from those receiving 3 g. 4. In conclusion, GVG administration elevates levels of TGABA in the CSF without any clear of constant change to cholinergic and aminergic transmission or effect on cyclic nucleotides. Our study further emphasizes the specific mechanism of action of GVG via GABAergic transmission.     

The effect of vigabatrin (gamma-vinyl GABA) on cerebral blood flow and metabolism.

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.     

Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures

Electrical stimulation of the vagus nerve (VNS) is a new method for the treatment of patients with medically intractable epilepsy. Sixteen patients, ten of whom participated in a larger multicenter double-blind trial on the efficacy of VNS in epilepsy, and six who participated in pilot studies, consented to participate in the present study. Ten patients received HIGH stimulation and six patients LOW stimulation for the 3-month trial. Cerebrospinal fluid (CSF) samples (16 ml) were collected both before and after 3 months of VNS. Amino acid and neurotransmitter metabolites were analyzed. Four patients responded to VS with more than a 25% seizure reduction after 3 months. Mean and median concentrations of phosphoethanolamine (PEA) increased in responders and decreased in nonresponders. Free GABA increased in both groups but more so in the nonresponders. After 9 months of VS (6–9 months on HIGH stimulation) 4 of 15 patients had more than 40% seizure reduction. There were significant correlations between seizure reduction and increases in asparagine, phenylalanine, PEA, alanine and tryptophan concentrations. Comparison between patients with HIGH or LOW stimulation showed a significant increase in ethanolamine (EA) in the HIGH group and a decrease in glutamine in the LOW group. All patients regardless of response or stimulation intensity showed significantly increased total and free GABA levels. A decrease in CSF aspartate was marginally significant. Other trends were decreases in glutamate and increases in 5-hydroxyindoleacetic acid. Chronic VNS appears to have an effect on various amino acids pools in the brain. Most interesting are the decreases in aspartate, an excitatory amino acid, increases in GABA, an inhibitory amino acid, and increases in EA, a membrane lipid precursor.     

Febrile seizures in patients with complex partial seizures

Febrile seizures occurred in 14 of 155 (9%) out-patients with complex partial seizures. Twelve patients had prolonged or recurrent febrile seizures, convulsive status epilepticus or a transient postictal neurological deficit. Febrile seizures were associated with perinatal abnormalities, an earlier onset of epilepsy and with a poor seizure control. Recurrent febrile seizures or those with complicating features are associated with an unfavourable therapeutic outcome in adult patients with complex partial seizures.     

Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacetic acid in patients with complex partial epilepsy

Vigabatrin, as a single oral dose of 50 mg/kg, was administered to 11 patients with drug-refractory complex partial epilepsy. Serial lumbar punctures were performed prior to and 5 times within the first week following treatment. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vigabatrin were determined as well as blood vigabatrin levels. CSF GABA, homocarnosine, HVA and 5-HIAA concentrations increased by 6 h after the single dose and remained elevated for up to 5-7 days. In contrast, CSF and blood vigabatrin levels were maximal within the first 24 h and were no longer detectable thereafter. Hence, these results are consistent with vigabatrin acting as an irreversible inhibitor of GABA-transaminase and suggest that it may also increase biogenic amine turnover.     

急性脑梗死患者脑脊液兴奋性氨基酸水平的变化及其临床意义

目的 研究急性脑梗死患者脑脊液（CSF）兴奋性氨基酸含量变化及其临床意义。方法 采用高效液相层析方法测定30例急性脑梗死患者及20例偏头痛患者（对照组）CSF谷氨酸（Glu）、天门冬氨酸（Asp）的含量。结果 脑梗死组患者CSF中Glu、Asp含量显著高于对照组（均P〈0．001）。脑梗死组患者CSF中Glu和Asp含量与梗死体积呈显著正相关（r=0．75，P〈0．01；r=0.437，P〈0．05），CSF中Clu含星与神经功能缺损程度亦呈正相关（r=0．55，P〈0．01）。结论 脑梗死发生后CSF中Glu、Asp含量明显升高提示其参与了脑梗死的病理生理过程CSP中Glu、Asp含量可反映脑梗死患者的病情及梗死灶的大小。     

Therapeutic drug monitoring of lamotrigine in patients suffering from resistant partial seizures

Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment as add-on therapy for resistant partial seizures and receiving carbamazepine (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug monitoring (TDM). The aim was to evaluate the possible relation between serum levels and the clinical effect of LTG, to verify whether CNS toxicity has to be considered the result of a pharmacokinetic or a pharmacodynamic interaction with CBZ, and to investigate whether possible changes in the clinical response during long-term treatment are dependent on LTG serum level variations. Sixteen patients achieved complete control, 26 a >or=50% reduction in seizures, the remainder did not respond. Mean LTG serum concentrations were higher in responders than in nonresponders, the difference being statistically insignificant. The best results were observed in VPA-cotreated patients with the highest LTG blood levels. CNS toxicity occurred after giving LTG to subjects who subsequently developed the highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ-epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was observed even in patients showing a reduction in the response during long-term treatment.     

Levels of total gamma-aminobutyric acid (GABA), free GABA and homocarnosine in cerebrospinal fluid of epileptic patients before and during gamma-vinyl-GABA (vigabatrin) treatment

Levels of total gamma-aminobutyric acid (TGABA), free GABA (FGABA), and homocarnosine (HC) were studied in CSF taken from 12 controls and 28 patients with drug-refractory epilepsy before and during 7 months of gamma-vinyl-GABA (GVG) administration. At baseline TGABA and FGABA in CSF of epileptic patients did not differ from that of the controls. In epileptic patients HC was 127% of that in controls. During GVG treatment TGABA was 283%, FGABA 197%, and HC 310% of the levels at baseline in the same patients. The patients who had over 50% reduction in seizure frequency during GVG (responders, 46% of the study population) at baseline had higher TGABA and HC in CSF than patients with less than 50% reduction in seizures (non-responders). During GVG the responders and nonresponders had similar levels of different GABAergic markers. The present study shows that in man GVG treatment effectively suppresses seizures in nearly half of the epileptic patients who had previously been drug-refractory. The elevated levels of GABAergic markers in CSF are not, however, necessarily related to good seizure control during GVG.     

Prognosis of chronic epilepsy with complex partial seizures.

Clinical features associated with a successful or unsuccessful response to high dose antiepileptic drug therapy were evaluated prospectively in 82 patients with chronic complex partial seizures. Complete seizure control was observed during high dose drug therapy in 18 patients at plasma concentrations of either 9-35 micrograms/ml phenytoin, 32 and 40 micrograms/ml phenobarbitone, 8 micrograms/ml carbamazepine, or a combination of 25 micrograms/ml phenobarbitone and 4 micrograms/ml carbamazepine. Patients who became free of seizures had a markedly lower number of three seizures (range: 1-29) in the year before the high dose treatment as compared to 40 seizures (range: 3-328) in patients with an increased or unchanged seizure frequency (p less than 0.0001). Complex partial seizures without automatism were found only in patients with complete seizure control (22%). Patients whose seizures remained uncontrolled more frequently gave a history of severe depression or psychotic episodes, clusters of complex partial seizures, two or more seizures per day, and an aura preceding the attack. The results suggest that taking a careful history will uncover clinical features associated with a successful or unsuccessful response to high dose antiepileptic drug therapy in an epileptic out-patient with chronic complex partial seizures.     

Dream experience during REM and NREM sleep of patients with complex partial seizures

This study examined the effectiveness of the cognitive processes underlying dreaming in patients with complex partial seizures (CPS), by assessing the frequency of recall and the structural organization of dreams reported after awakenings provoked alternately during REM and stage 2 NREM sleep on 12 cognitively unimpaired CPS-patients (six with epileptic focus in the right hemisphere and six in the left one). Each patient was recorded for three consecutive nights, respectively, for adaptation to the sleep laboratory context, for polysomnography and for dream collection. The frequency of dream recall was lower after stage 2 NREM sleep than REM sleep, regardless of the side of epileptic focus, while the length and structural organization of dreams did not significantly differ in REM and NREM sleep. However, the length of story-like dreams was influenced by global cognitive functioning during REM sleep. These findings indicate that in CPSs-patients the elaboration of dream experience is maintained in both REM and NREM sleep, while the access to information for conversion into dream contents and the consolidation of dream contents is much less effective during NREM rather than during REM sleep. Further studies may distinguish between these two possibilities and enlighten us as to whether the impaired memory functioning during NREM sleep is a side effect of anticonvulsant treatment.     

Development of myoclonus in patients with partial epilepsy during treatment with vigabatrin: an electroencephalographic study

In the context of a study of the effects of γ-vinyl-GABA (GVG) on seizure occurrence and on EEG abnormalities we present three cases with focal epilepsy in which new clinical and EEG paroxysmal manifestations were observed during GVG therapy. At that time, whereas an amelioration or no change in patients' habitual seizures were observed, myoclonic jerks appeared with related changes in the EEG paroxysmal abnormalities, represented by generalized polyspike and wave complexes. An electroclinical correlation was recorded in one case. These data indicate that, although occurring rarely, it is possible to have epileptic myoclonus during GVG treatment. Mechanisms underlying these manifestations are difficult to explain. Probably a shift in the anti/proconvulsant GABAergic balance towards the latter may compromise the therapeutic effect of GVG.     

Electrophysiologic pathologic correlations in patients with complex partial seizures

We studied interictal activity and site of ictal onset in 26 patients with complex partial seizures of temporal lobe origin. All patients had prolonged electrocorticographic recordings from subdural electrode arrays placed both over the convexity and beneath the temporal lobe. We found a significant correlation between the epileptogenic focus and the type of pathologic lesion found at time of surgery. Macroscopic lesions strongly tended to have an epileptogenic focus on the lateral surface of the temporal lobe; patients with only microscopic abnormalities tended to have an epileptogenic focus in the mesial/basal region of the temporal lobe.     

Microwave oven injuries in patients with complex partial seizures

Microwave ovens are often recommended as a safe cooking alternative for persons with epilepsy. We report four patients who suffered serious burns to their hands while handling microwave-heated liquids during a complex partial seizure (CPS). Injuries were due to the contact of the skin with a very hot container. The fact that all patients held on to the hot containers despite being burned and that they did not remember experiencing any pain at the time of the accident indicates that neither high temperatures nor pain will prevent patients who are having a CPS from suffering this type of injury. Unfortunately, there is no foolproof way to prevent the individual from opening the oven and removing its contents during a CPS. The only solution for this problem is "prevention"-individuals with poorly controlled CPS should be cautioned about these risks. The use of microwave settings that permit the heating but not boiling of liquids and the use of gloves while heating food and liquids to scalding temperatures may minimize the risk of this type of injury.     

急、慢性精神分裂症患者血浆兴奋性和抑制性氨基酸含量的研究

目的探讨精神分裂症可能的发病和衰退机理。方法利用日立８３５型快速氨基酸分析仪，测定和分析３０例住院精神分裂症患者（急性１５例，慢性１５例）的血浆谷氨酸（Ｇｌｕ）、牛磺酸（Ｔａｕ）、γ氨基丁酸（ＧＡＢＡ）、甘氨酸（Ｇｌｙ）的含量变化，并与对照组（健康志愿者１０例）比较。结果（１）血浆Ｇｌｕ和ＧＡＢＡ含量患者组（８３±２４μｍｏｌ／Ｌ，５６±１７μｍｏｌ／Ｌ）显著低于对照组（１２６±５７μｍｏｌ／Ｌ，９０±１７μｍｏｌ／Ｌ），而血浆Ｔａｕ和Ｇｌｙ含量两组间差异无显著性；（２）慢性患者的血浆Ｇｌｕ和ＧＡＢＡ含量（９３±３１μｍｏｌ／Ｌ，６６±２２μｍｏｌ／Ｌ）高于急性患者（６９±１９μｍｏｌ／Ｌ，４９±１１μｍｏｌ／Ｌ），存在随病程迁延而增高的趋势；（３）３０例患者血浆ＧＡＢＡ的含量与阴性症状（ｒ＝０．４７０，Ｐ＜０．０１）和社会功能缺陷（ｒ＝－０．５６７，Ｐ＜０．０１）的严重程度呈显著性相关。结论精神分裂症可能与Ｇｌｕ能和ＧＡＢＡ能神经系统功能低下有关。中枢神经系统Ｇｌｕ和ＧＡＢＡ严重的功能失调可能导致精神分裂症慢性衰退的结局。     

Inhibitory and excitatory amino acids in cerebrospinal fluid of neurolathyrism patients, a highly prevalent motorneurone disease

Neurolathyrism is caused by overconsumption of seeds containing 3-N-oxalyl-L-2,3-diaminopropanoic acid (β-ODAP). Amino acids levels of cerebrospinal fluid (CSF) were studied in 50 patients with neurolathyrism and 12 healthy volunteers. The levels of excitatory amino acids glutamate and aspartate were 281% and 71% respectively of control values. The concentration of inhibitory amino acids glycine and taurine were 277 % and 198% respectively of the levels in CSF from control individuals. There was a significant correlation between the level of glycine and the duration of the disease. We also found increased levels of threonine, serine and alanine. In contrast to reports on other motor neurone diseases where an increase of isoleucine was observed we found a significant decrease of isoleucine. The results suggest a disturbance of amino acid metabolism due to excitotoxic damages caused by β-ODAP, a dietary excitatory amino acid.     

Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats

Excitatory amino acids (EAAs) are involved in the development of opioid tolerance. The present study reveals that an increasing of CSF EAAs concentration might be responsible for the losing of morphine's antinociceptive effect in morphine tolerant rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters and one microdialysis probe, then continuously infused i.t. for 5 days with saline (1 microl/h; control group), morphine (15 micrograms/h), the NMDA antagonist, MK-801 (5 micrograms/h), or morphine (15 micrograms/h) plus MK-801 (5 micrograms/h). Each day, tail-flick responses were measured; in addition, CSF dialysates were collected and CSF amino acids measured by high performance liquid chromatography using a fluorescence detector. Morphine started to lose its analgesic effect on day 2 and this effect was overcome by MK-801. The AD(50) (AD: analgesic dose) was 1.33 micrograms in control animals, 83.83 micrograms in morphine-tolerant rats (a 63-fold shift), and 11.2 micrograms (a 8.4-fold shift) in rats that had received MK-801 plus morphine. No significant differences were observed in CSF amino acid release between the groups from day 1 to day 5. On day 5, after basal dialysate collection, a 10-micrograms challenge of morphine was administered i.t., and CSF samples collected over the next 3 h. After morphine challenge, morphine-tolerant rats showed a significant increase in the release of glutamate and aspartate (131+/-9.5% and 156+/-12% of basal levels, respectively), and no antinociceptive effect in the tail-flick latency test, while MK-801/morphine co-infused rats showed no increase in morphine-induced EAA release and a partial antinociceptive effect (MPE=40%). The present study provides direct evidence for a relationship between EAA release and a lack of an antinociceptive response to morphine, and shows that the NMDA antagonist, MK-801, attenuates both of these effects.     

The psychotherapy of patients with complex partial seizures.

The direct neurological effect of complex partial seizures (CPS) is described, as is the psychological and interpersonal impact of the disorder, with emphasis on the iterative nature of the process. A model for the psychotherapy of CPS patients is presented that is based on an understanding of the neurological changes and continuous interaction between these changes and the psychological demands of adaptation.