Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs.

PURPOSE: Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. METHODS: Patients 18-50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B(12), and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. RESULTS: Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 microm; physiologic range 5-13 microm] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm; normal > 6.8 nm) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) microm, respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) microm]. DISCUSSION: Oxcarbazepine and topiramate might cause hyper-tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper-tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy.

Hyperhomocysteinemia in patients with epilepsy: does it play a role in the pathogenesis of brain atrophy? A preliminary report.

PURPOSE: Brain atrophy (BA) is observed in 20-50% of patients with epilepsy. Hyper-total-homocysteinemia (hyper-tHcy), which occurs in 10-40% of patients, is considered to be a risk factor for cardiovascular diseases and BA. The present study was aimed at investigating the possible association of hyper-tHcy with BA in a population of patients with epilepsy. METHODS: Fifty-eight patients (33 M/25 F, 43.5 +/- 13.1 years of age) chronically treated with antiepileptic drugs (AEDs) and 60 controls matched for age and sex were enrolled. All participants underwent determination of plasma tHcy, folate, vitamin B(12), and C677T methylene-tetrahydrofolate-reductase (MTHFR) polymorphism genotyping, and brain magnetic resonance imaging (MRI). RESULTS: Patients exhibited significantly higher tHcy and lower folate levels than controls; hyper-tHcy was significantly associated with the variables group (patients vs. controls), MTHFR genotype, and their interaction terms. BA was observed in 30.1% of patients and was significantly associated with hyper-tHcy (beta = 0.45, p = 0.003) and polytherapy (beta = 0.31, p < 0.001). DISCUSSION: Our investigation suggests that hyper-tHcy plays a role in the development of BA in patients with epilepsy. Although the real origin of this phenomenon is not yet fully elucidated, experimental data support the hypothesis of a link of the neuronal Hcy-mediated damage with oxidative stress and excitotoxicity.

Antiepileptic drugs and MTHFR polymorphisms influence hyper-homocysteinemia recurrence in epileptic patients.

The influence of antiepileptic drugs (AEDs) and/or common polymorphisms (677C --> T, 1298A --> C) of the methylene-tetrahydrofolate-reductase (MTHFR) gene on the recurrence time of hyper-total-homocysteinemia (tHcy > 13 micromol/L) was investigated in 59 hyper-homocysteinemic patients (34M/25F, 20-49 years). Plasma tHcy and folate were assayed before and after 1-month folate supplementation (5 mg/day), and after 2, 4, and 6 months. Four MTHFR polymorphism groups were identified with the following tHcy (micromol/L) and folate (nmol/L) levels (mean +/- SD): (a) MTHFR677TT/1298AA, 24 patients, 36.0 +/- 4.8, 4.1 +/- 0.7; (b) MTHFR677CT/1298AC 27.1 +/- 2.7, 5.3 +/- 1.0 (n = 15); (c) MTHFR677CT/1298AA 16.6 +/- 3.6, 6.8 +/- 1.0 (n = 11), all taking enzyme-inducing AEDs; and (d) MTHFR677TT/1298AA 24.5 +/- 3.2, 5.6 +/- 1.1 (n = 9), treated with new AEDs. After folate therapy, plasma t-Hcy and folate were normal in all patients. At 6 months, 43 patients (72.9%) exhibited hyper-tHcy, the greater proportion belonging to the EI-AED-MTHFR677TT/1298AA (39%). Knowledge of the hyper-tHcy recurrence time after folate therapy discontinuation may help in optimizing folate supplementation pulses.

Tiagabine and vigabatrin reduce the severity of NMDA-induced excitotoxicity in chick retina.

The possible neuroprotective effects of two GABAergic drugs, tiagabine (TGB) and vigabatrin (VGB), against N-methyl-D-aspartate (NMDA)-induced excitotoxicity have been investigated in the isolated chick embryo retina model. Retina segments were incubated either with NMDA alone (100 microM) or with NMDA and TGB or VGB (10-1,000 microM, added 5 min before NMDA). Retina damage was assessed after 24 h by measuring lactate dehydrogenase (LDH) activity present in the medium and by histological analysis. Both drugs reduced LDH release in a dose-dependent manner with comparable mean maximal values of 56.6-63.7% achieved at concentration of 1 mM. Histological analysis of retina slices was in line with the biochemical assays and showed partial preservation of drug exposed retina structure with reduced edema especially in the inner plexiform layer. The present data provide pharmacological evidence that both TGB and VGB reduce the severity of NMDA-induced excitotoxic damage. Although an increase in GABAergic transmission might play a role, this in itself is insufficient to explain the neuroprotective effect of the two drugs and the exact mechanism remains to be elucidated.

Effects of psychotropic drugs on seizure threshold.

Psychotropic drugs, especially antidepressants and antipsychotics, may give rise to some concern in clinical practice because of their known ability to reduce seizure threshold and to provoke epileptic seizures. Although the phenomenon has been described with almost all the available compounds, neither its real magnitude nor the seizurogenic potential of individual drugs have been clearly established so far. In large investigations, seizure incidence rates have been reported to range from approximately 0.1 to approximately 1.5% in patients treated with therapeutic doses of most commonly used antidepressants and antipsychotics (incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%). In patients who have taken an overdose, the seizure risk rises markedly, achieving values of approximately 4 to approximately 30%. This large variability, probably due to methodological differences among studies, makes data confusing and difficult to interpret. Agreement, however, converges on the following: seizures triggered by psychotropic drugs are a dose-dependent adverse effect; maprotiline and clomipramine among antidepressants and chlorpromazine and clozapine among antipsychotics that have a relatively high seizurogenic potential; phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine and trazodone among antidepressants and fluphenazine, haloperidol, pimozide and risperidone among antipsychotics that exhibit a relatively low risk. Apart from drug-related factors, seizure precipitation during psychotropic drug medication is greatly influenced by the individual's inherited seizure threshold and, particularly, by the presence of seizurogenic conditions (such as history of epilepsy, brain damage, etc.). Pending identification of compounds with less or no effect on seizure threshold and formulation of definite therapeutic guidelines especially for patients at risk for seizures, the problem may be minimised through careful evaluation of the possible presence of seizurogenic conditions and simplification of the therapeutic scheme (low starting doses/slow dose escalation, maintenance of the minimal effective dose, avoidance of complex drug combinations, etc.). Although there is sufficient evidence that psychotropic drugs may lower seizure threshold, published literature data have also suggested that an appropriate psychotropic therapy may not only improve the mental state in patients with epilepsy, but also exert antiepileptic effects through a specific action. Further scientific research is warranted to clarify all aspects characterising the complex link between seizure threshold and psychotropic drugs.