Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients

SUMMARY: PURPOSE: Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has been used in the management of neuropathic pain. We reported that daily dosing increased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. This study was designed to determine how rapidly brain GABA and the GABA metabolites, homocarnosine and pyrrolidinone, increase in response to the first dose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (four women) were studied serially after the first oral dose (1,200 mg) of GBP. Five patients (three women) taking a standard daily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single high dose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by 1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did not change significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI, 0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM; 95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased median brain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the anticonvulsant effects of increased homocarnosine and pyrrolidinone with daily therapy.     

Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy

OBJECTIVE: To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy. BACKGROUND: Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects. RESULTS: Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.     

Acute Effects of Vigabatrin on Brain GABA and Homocarnosine in Patients with Complex Partial Seizures

PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and maintenance of VGB as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week.     

Clinical science

Ognen A. C. Petroff , Fahmeed Hyder , Douglas L. Rothman , and Richard H. Mattson
Yale researchers in pioneering work have been able to study the effects of antiepileptic drugs (AEDs) on the brain chemistry of people with epilepsy in a safe and painless manner by using the principles of magnetic resonance imaging (MRI). Neurons in the human brain make homocarnosine from γ-aminobutyric acid (GABA; the brain's main inhibitory neurotransmitter) and histidine in larger amounts than the neurons of almost all other animals. Three of the newer AEDs, gabapentin (GBP; Neurontin), topiramate (TPM; Topamax), and vigabatrin (Sabril), increase human homocarnosine levels. We measured homocarnosine and GABA levels of 20 patients with complex partial seizures taking GBP and 17 patients taking TPM. Homocarnosine levels were higher in patients with better seizure control than in those whose seizure control was below the middle value (median) for the two groups. No differences were found in the GABA levels between the patients, who showed a better response to GBP or TPM, compared with those who did not. Higher homocarnosine levels (above the median) were associated with better seizure control in the patients taking GBP or TPM; higher brain GABA levels appeared to offer no additional protection. The current results are similar to our previously published findings, which showed higher brain homocarnosine levels in patients with juvenile myoclonic epilepsy with excellent seizure control, taking valproate (Depakote) or lamotrigine (Lamictal), than the levels of patients with more frequent seizures. The data support the hypothesis that increased homocarnosine and GABA levels contribute to the anticonvulsant properties of GBP and TPM, perhaps by limiting the spread of seizures from the areas where seizures start.     

Brain homocarnosine and seizure control of patients taking gabapentin or topiramate

PURPOSE: To assess the relation between seizure control and brain homocarnosine and gamma-aminobutyric acid (GABA) levels of patients with complex partial seizures taking gabapentin (GBP) or topiramate (TPM) as adjunctive therapy. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using (1)H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Poor seizure control was defined as more recent seizures than the median for the two groups of patients studied. RESULTS: Homocarnosine levels were higher in patients with better seizure control than in those with poor control. No differences were found in the intracellular GABA levels between the patients who responded to GBP or TPM compared with those who did not. CONCLUSIONS: In the visual neocortex, which is remote from the presumed seizure-onset zone, higher homocarnosine levels were associated with better seizure control in the patients taking GBP or TPM as adjunctive therapy; elevated intracellular GABA levels appeared to offer no additional protection.     

Homocarnosine and seizure control in juvenile myoclonic epilepsy and complex partial seizures

OBJECTIVE: To assess the relationship between seizure control and gamma-aminobutyric acid (GABA), homocarnosine, and pyrrolidinone levels in the visual cortex of patients with epilepsy taking valproate or lamotrigine. Previous studies suggested that poor seizure control was associated with low GABA and homocarnosine levels. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made in a 14-cm(3) volume of the occipital cortex using (1)H spectroscopy with a 2.1-Tesla MR spectrometer and an 8-cm surface coil. Twenty-six adults (eight men) taking valproate or lamotrigine were recruited; 12 had complex partial seizures (CPS) and 14 had juvenile myoclonic epilepsy (JME). RESULTS: Median homocarnosine levels were normal for patients with JME and below normal for patients with CPS. Better seizure control was associated with higher homocarnosine levels for both groups. Median GABA was below normal for patients with JME, lower than for patients with CPS. Brain GABA was lowest in patients with JME even when seizure control was excellent. Pyrrolidinone levels were above normal in almost all patients with JME. CONCLUSIONS: Low GABA levels are associated with poor seizure control in patients with CPS, but not in JME. Higher homocarnosine levels are associated with better seizure control in both types of epilepsy.     

Substantia nigra is an anticonvulsant site of action of topiramate in the focal pilocarpine model of limbic seizures

PURPOSE: The substantia nigra pars reticulata (SNR) is known to play a role in gating and control of seizures. Prompted by the observation that intrahippocampal topiramate (TPM) administration does not suppress limbic seizures in the focal pilocarpine model, we investigated the role of the SNR in the anticonvulsant mechanism of action of TPM. METHODS: Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. Changes in hippocampal extracellular (EC) glutamate and GABA concentrations were monitored. Effects of intraperitoneal (10-200 mg/kg), intrahippocampal (1-5 mM), and bilateral intranigral (100-300 nmol) TPM administration on pilocarpine-induced seizures and neurochemical changes were evaluated. Effects of TPM administration alone on hippocampal and nigral EC amino acid concentrations were also studied. RESULTS: Systemic and intranigral, but not intrahippocampal TPM administration suppressed pilocarpine-induced seizures and neurochemical changes. Nigral GABA(A) receptor blockade by picrotoxin abolished the anticonvulsant effect of TPM in SNR. Systemic TPM administration increased hippocampal glutamate and decreased GABA. Intranigral TPM administration increased hippocampal glutamate, but not GABA. Intrahippocampal TPM increased hippocampal glutamate and GABA, but only at high concentrations. CONCLUSIONS: In the focal pilocarpine model, TPM does not exert its anticonvulsant effect at the site of seizure initiation. We identified the SNR as a site of action of TPM, and showed that the nigral GABA-ergic system is central to TPM's anticonvulsant effect in SNR. Anticonvulsant effects and neurochemical changes in hippocampus following intranigral TPM administration suggest the existence of a nigro-hippocampal circuit, which may be involved in the control of limbic 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.     

Inhibitory and excitatory amino acids in CSF of patients suffering from complex partial seizures during chronic treatment with gamma-vinyl GABA (vigabatrin)

The effect of chronic administration of gamma-vinyl GABA (GVG; vigabatrin) on levels of neurotransmission-related amino compounds was studied in lumbar cerebrospinal fluid of 65 patients with complex partial epilepsy. The first sample of cerebrospinal fluid was taken before a 3-month period of treatment with 3 g gamma-vinyl GABA/day, and the second was taken afterwards. From patients who showed a greater than 50% reduction in seizures (responders) or marked improvement in global performance, a third sample was taken at the end of the next 3-month phase, during which 3 g or 1.5 g gamma-vinyl GABA had been administered daily. During treatment with 3 g gamma-vinyl GABA/day, 55% of the patients showed more than 50% reduction in complex partial seizures; and at the same time free GABA, total GABA, homocarnosine, and glycine concentrations in the cerebrospinal fluid increased by 104%, 151%, 194% and 16%, respectively. After reduction of the daily dose to 1.5 g, the levels of free GABA, total GABA and homocarnosine were still increased by 65%, 115% and 102%, respectively. gamma-Vinyl GABA correlated with the levels of free GABA (P less than 0.002) and glycine (P less than 0.001). Concentrations of homocarnosine at baseline and homocarnosine and total GABA during gamma-vinyl GABA treatment were lower (P less than 0.005) in the group of non-responders than in the responder group. Glutamic acid, glutamine, aspartic acid, asparagine, and taurine levels did not change during gamma-vinyl GABA treatment. In conclusion, administration of gamma-vinyl GABA reduces epileptic seizures and produces dosage-dependent increases in levels of free GABA, GABA-containing peptides and of glycine in cerebrospinal fluid, without concomitant change in levels of excitatory amino acids.     

Pharmacokinetic Effects of Vigabatrin on Cerebrospinal Fluid Amino Acids in Humans

Summary: A study was conducted to assess the impact of single dosing and different dosing intervals of vigabatrin [gamma vinyl GABA (GVG)] in 11 patients with drug-resistant complex partial seizures. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), GVG, and 5- hydroxyindolacetic acid were measured up to seven days after a single dose. GVG levels were maximal within 24 h, suggesting that GVG acts to inhibit GABA-transami-nase, and may also increase biogenic amines.     

Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy

Summary:  Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol.
Methods: Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague–Dawley rat experienced convulsive status epilepticus for >3 h. Six 1-month trials (n = 6–10 rats) assessed the effects of 0.3–100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures.
Results: A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3–100 mg/kg) were dose dependent.
Conclusions: These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose–effect and time-course-of-recovery studies.     

Concentration-Effect Studies with Topiramate on Selected Enzymes and Intermediates of the GABA Shunt

Summary: Purpose: Topiramate (TPM) is a new antiepileptic agent with a multifactorial mechanism of action. The drug potentiates responses to γ-aminobutyric acid (GABA) at the GABA_A receptor and has inhibitory effects on neuronal sodium channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase. Recent evidence has, however, suggested that the drug also increases brain GABA concentrations in humans. These studies were designed to investigate the neurochemical basis of this observation.
Methods: Adult male mice were randomised into two groups and administered TPM (0–1,000 mg/kg) intraperitoneally either as a single dose or daily for 8 days. At 4 h after the final dose, brain tissues were analysed for concentrations of GABA, glutamate, and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. TPM levels in brain also were determined.
Results: Single-dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the brain at doses of ≥10 mg/kg.
Conclusions: These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug.     

Low brain GABA level is associated with poor seizure control

Low gamma-aminobutyric acid (GABA) concentrations in the cerebrospinal fluid are seen in a variety of epileptic syndromes. Low GABA levels outside of the epileptic focus may facilitate spread of discharges beyond the focus. In vivo measurements of GABA were made by ¹H spectroscopy using a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 14-cm³ volume in the occipital lobe. Patients with complex partial seizures had lower GABA levels (1.03 mmol/kg of brain; 95% confidence interval [CI], 0.95?1.12; n = 28; p < 0.02) than did subjects without epilepsy (1.18; 95% CI, 1.13?1.24; n = 19). There was a significant association between low GABA levels and recent seizures (correlation coefficient of 0.548, p < 0.01, df of 32). Conversely, patients with well-controlled seizures had higher brain GABA levels than did patients with recent seizures. Patients with seizures within a day of the measurement had lower GABA levels (0.92 mmol/kg; 95% CI, 0.78?1.06; n = 7) than did patients who were seizure free for 5 years or longer (1.28; 95% CI, 1.09?1.47; n = 4). Poor seizure control is associated with low brain GABA levels.     

Vigabatrin increases human brain homocarnosine and improves seizure control

Homocarnosine, a dipeptide of γ-aminobutyric acid (GABA) and histidine, is thought to be an inhibitory neuromodulator synthesized in subclasses of GABAergic neurons. Homocarnosine is present in human brain in greater amounts (0.4–1.0 μmol/g) than in other animals. The antiepileptic drug vigabatrin increases human cerebrospinal fluid homocarnosine linearly with daily dose. By using ¹H nuclear magnetic resonance spectroscopy, serial occipital lobe GABA and homocarnosine concentrations were measured in 11 patients started on vigabatrin. Daily low-dose (2 g) vigabatrin increased both homocarnosine and GABA. Larger doses of vigabatrin (4 g) further increased homocarnosine but changed GABA levels minimally. Seizure control improved with increasing homocarnosine and GABA concentrations. Patients whose seizure control improved with the addition of vigabatrin had higher mean homocarnosine, but the same mean GABA concentrations, than those whose seizure control did not improve. Increased homocarnosine may contribute to improved seizure control.     

Topiramate as add-on drug in children,adolescents and young adults with Lennox-Gastaut syndrome: an Italian multicentric study

The purpose of the study was to evaluate the efficacy and safety of topiramate (TPM) as adjunctive therapy in children, adolescents and young adults with Lennox-Gastaut syndrome (LGS). We performed a prospective open label add-on study in 45 patients (age 4-34 years, mean 15.9 years) with LGS and refractory seizures. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. TPM was initiated at the daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h, up to a maximum daily dose of 12 mg/kg. After a mean period of 15.8 months of treatment (range 3-98 months), at a mean dose of 4.1 mg/kg/24 h (range 1.4-12 mg/kg), 18 patients (40%) had a seizure reduction more than 50%. TPM appeared to be effective mainly in major seizures (drop attacks, tonic and tonic-clonic seizures). Mild to moderate adverse events were present in 24 patients (53.3%), mostly represented by drowsiness, nervousness, hyporexia with or without weight loss and cognitive dulling. In conclusion, TPM adjunctive therapy reduced the number of drop attacks and major motor seizures in 40% of patients with LGS and produced only mild or moderate adverse events.     

Topiramate on ictal seizure semiology: a quantitative, randomized, low and medium dose-controlled study

OBJECTIVE: Intensive and quantitative evaluation of the severity and frequency of seizures and ictal signs during topiramate (TPM) treatment. METHODS: Twenty patients with refractory partial seizures undergoing presurgical evaluation were randomized into a low dosage (100 mg daily) and a parallel medium dosage (200 mg daily) group of TPM add-on medication. Study phases included a 3-day baseline video-EEG phase, a 10-day TPM titration phase without video-EEG and a 3-day TPM dose maintenance phase with video-EEG. During the baseline and the dose maintenance phase seizures were recorded using video-EEG monitoring and the following parameters were measured: duration (lasting seconds of each seizure and ictal sign), intensity (on a 0-3 scale), N/24 h (numbers of attacks per 24 h), D/24 h (duration per 24 h) of both seizures and defined ictal signs. RESULTS: A total of 399 seizures during the baseline phase and the dose maintenance phase were intensively analyzed. Intergroup comparison suggested that duration, N/24 h and D/24 h of all seizures decreased more in the medium dosage group computing the reduction from baseline to the dose maintenance phase (P<0.05). There were statistically more significant reductions in the duration, intensity and N/24 h of ictal signs like hypermotoric movements, fumbling and vocalization in the medium dosage group (P<0.05). CONCLUSION: Topiramate has an early dose-dependent effect on ictal seizures. SHORT COMMUNICATION: The present study intensively analyzed the duration, intensity, N/24 h and D/24 h of ictal seizure manifestations. The quantitative data suggested that topiramate had an early effect on ictal phenomena like ictal hypermotoric movements, fumbling and vocalization (P<0.05); effects were more prominent in the medium dosage group (200 mg daily) than the low dosage group (100 mg daily).     

Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial

PURPOSE: This study was to evaluate the efficacy and safety of topiramate (TPM) in patients with severe myoclonic epilepsy in infancy (SMEI) and refractory seizures. METHODS: We performed a prospective multicentric open label add-on study in 18 patients (age 2-21 years, mean 9 years) with SMEI and refractory seizures of different types. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. RESULTS: TPM was initiated at a daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h up to a maximum daily dose of 12 mg/kg. After a mean period of 11.9 months (range 2-24 months), three patients (16.7%) had 100% fewer seizures and ten patients (55.5%) had a more than 50% seizure decrease. In no patient there was a seizure worsening. Mild to moderate adverse events were present in four patients (22.2%), represented by weight loss, hypermenorrhoea, renal microlithiasis, nervousness and dysarthric speech. CONCLUSION: TPM may be a useful drug in patients with SMEI, being particularly effective against generalized tonic-clonic seizures. Further studies are needed to evaluate the early use of this drug in such a severe syndrome.     

Topiramate in refractory partial-onset seizures in children, adolescents and young adults: a multicentric open trial

PURPOSE: This study was to evaluate the efficacy and safety of topiramate (TPM) in refractory partial epilepsy in children, adolescents and young adults. Methods: We performed a prospective open label add-on study in 55 patients (age 2-30 years, mean 15 years) with refractory partial seizures. Topiramate was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. RESULTS: TPM was initiated at a daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24h, up to a maximum daily dose of 12 mg/kg. After 9 months of treatment, 11 patients (20%) had 100% fewer seizures and 25 patients (45%) had a more than 50% seizure reduction. TPM appeared to be effective both in cryptogenic (76.2%) and symptomatic (58.8%) partial epilepsies. Mild to moderate adverse events were present in 25 patients (45.4%), mostly represented by drowsiness, nervousness and hyporexia with or without weight loss. CONCLUSION: TPM was an overall effective and safe add-on drug both in cryptogenic and symptomatic childhood refractory partial seizures, the adverse reactions being generally mild or moderate.     

Effect of topiramate on the anticonvulsant activity of conventional antiepileptic drugs in two models of experimental epilepsy

PURPOSE: The objective of this study was to evaluate the interaction of the novel antiepileptic drug (AED), topiramate (TPM), with conventional AEDs against amygdala-kindled seizures in rats and pentylenetetrazol-induced convulsions in mice. METHODS: Experiments were performed on mice and fully kindled rats. In pentylenetetrazol test, the chemoconvulsant was used at its CD97 dose of 105 mg/kg, producing clonic seizures in 97% of mice. Adverse effects were evaluated with the chimney test and passive avoidance task. Plasma levels of AEDs were measured with immunofluorescence. RESULTS: TPM at 20 mg/kg exerted a significant anticonvulsant effect as regards seizure and afterdischarge durations in amygdala-kindled seizures in rats, being ineffective at lower doses. Coadministration of TPM (10 mg/kg) with valproate (VPA; at a subtherapeutic dose of 50 mg/kg) resulted in essential reductions of seizure and afterdischarge durations. TPM (10 mg/kg) combined with carbamazepine (CBZ; at a subtherapeutic dose of 15 mg/kg) significantly increased afterdischarge threshold, simultaneously decreasing the remaining seizure parameters (duration or severity of seizures and afterdischarge duration). TPM (10 mg/kg) given with phenobarbital (PB; 15 mg/kg) markedly shortened seizure severity and seizure and afterdischarge durations. Combinations of TPM with diphenylhydantoin (PHT) were ineffective against kindled seizures in rats. TPM combined with VPA and PB did not alter their plasma levels, but its combination with CBZ resulted in an increased free plasma CBZ concentration. TPM (10 and 20 mg/kg) alone and its combinations with conventional AEDs affected neither motor coordination nor long-term memory, evaluated in the chimney and passive avoidance tests, respectively, in rats. In pentylenetetrazol-evoked convulsions in mice, TPM (175 and 200 mg/kg) showed anticonvulsant effects per se. Moreover, TPM (at its subtherapeutic dose of 150 mg/kg), significantly potentiated the anticonvulsant action of ethosuximide (ESM), but not that of VPA, PB, or clonazepam (CZP) against pentylenetetrazol-induced seizures. Either TPM alone (150 mg/kg) or its combination with ESM did not result in significant undesired effects. CONCLUSIONS: The experimental data indicate that except for PHT, the combinations of TPM with conventional AEDs are beneficial against amygdala-kindled seizures in rats. In the pentylenetetrazol test, this novel AED potentiated only the protection offered by ESM.     

Short-Term Mortality After a First Epileptic Seizure: A Population-Based Study

PURPOSE: To determine the short-term mortality in a prospective incidence cohort of patients included after any kind of first afebrile epileptic seizure (i.e., provoked and unprovoked). METHODS: Information on death occurring within the first year of follow-up was collected in a cohort of 804 patients with a first seizure between March 1, 1984, and February 28, 1985, in southwest France. The variables analyzed were the etiology of seizure, cause of death, interval between seizure and death, and age of patients. RESULTS: By the end of the 1-year follow-up, there were 149 deaths among these patients as compared with 16 expected deaths [standardized mortality ratio (SMR), 9.3; 95% confidence interval (CI), 7.9-10.9]. There were no deaths in patients with idiopathic seizures. Patients with cryptogenic seizures had slightly increased mortality (SMR, 1.6; 95% CI, 0.4-4.1). Mortality was increased for patients with remote symptomatic seizures (SMR, 6.5; 95% CI, 3.8-10.5), provoked seizures (SMR, 10.1; 95% CI, 8.1-12.4), and seizures due to a progressive neurologic condition (SMR, 19.8; 95% CI, 14.0-27.3). Causes of death were underlying pathology (64%), unrelated condition (20%), unknown cause (9%), seizure-related death (6%), and one suicide. CONCLUSIONS: Early mortality clearly differed according to the etiology of the first seizure. The highest mortality was associated with provoked seizures and with seizures caused by progressive central nervous system disorders. Patients died far more often from underlying or unrelated conditions than from seizures.