Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine

OBJECTIVE: To evaluate plasma homocysteine (Hcy) concentrations in children receiving sodium valproate (VPA) and carbamazepine (CBZ), monotherapy, in comparison with healthy control subjects and to determine the possible relationship between Hcy levels and dosage and plasma concentrations of the antiepileptic drugs. METHODS: We measured levels of fasting and post-methionine Hcy, plasma pyridoxal 5'-phosphate (PLP, active vitamin B6), serum folate, erythrocyte folate and serum vitamin B12 in 60 epileptic patients (29 females, 31 males), aged from 14.2 to 17.9 years, subdivided into two groups according to their therapy. Sixty-three healthy sex- and age-matched children served as controls. These measurements have been performed before the beginning of therapy and after 1 year of therapy with VPA or CBZ. RESULTS: Before the beginning of therapy, there were no significant differences in fasting and post-methionine Hcy, plasma PLP, serum folate, erythrocyte folate and serum vitamin B12 values between the control group and the two groups of epileptic children. After 1 year of therapy, patients treated with VPA and CBZ showed a significant increase of the plasma concentrations of Hcy when compared to baseline data and controls values. Moreover, was observed a significant decrease of serum folate and plasma PLP. On the contrary, serum vitamin B12 and erythrocyte folate levels remained in the normal range. CONCLUSIONS: Our study demonstrates that prolonged treatment with VPA and CBZ increases plasma concentrations of Hcy.     

Withdrawal symptoms from phenytoin, carbamazepine and sodium valproate.

A prospective, double-blind, placebo-controlled investigation of possible withdrawal symptoms from phenytoin, carbamazepine and sodium valproate is reported in patients with active epilepsy, on combination therapy. There was an increase in seizures on reduction and withdrawal of carbamazepine, but there was no convincing evidence of withdrawal symptoms from any of these drugs.     

Effects of dextroamphetamine,lithium chloride,sodium valproate and carbamazepine on intraplatelet Ca2+ levels

OBJECTIVE: To explore the possible involvement of second-messenger pathways in the pathophysiology of bipolar disorder and the mechanism of action of mood stabilizers, we investigated the effects of dextroamphetamine (a model for mania) and the most widely used mood stabilizers, lithium chloride, sodium valproate and carbamazepine, on intraplatelet levels of calcium ion ([Ca2+). DESIGN: In the first part of the study, dextroamphetamine was administered in vivo in a double-blind, placebo-controlled, crossover design. In the second part of the study, platelets from untreated subjects were incubated in vitro with dextroamphetamine, lithium chloride, sodium valproate or carbamazepine. PARTICIPANTS: Fifteen healthy men between 18 and 45 years of age. OUTCOME MEASURES: Basal, thrombin-induced and serotonin- (5-HT) induced intraplatelet [Ca2+] determined by means of fura-2 fluorescent intensity. RESULTS: In vivo administration of dextroamphetamine had no effect on basal or agonist-induced intraplatelet [Ca2+]. However, in vitro basal platelet [Ca2+] was significantly higher in samples incubated with dextroamphetamine (86.8 nmol/L [standard error of the mean, SEM, 3.9], p < 0.001), lithium chloride (76.4 nmol/L [SEM 3.1], p < 0.002), sodium valproate (82.7 nmol/L [SEM 3.7], p < 0.001) and carbamazepine (84.8 nmol/L [SEM 3.3], p < 0.001) than in the controls (58.2 nmol/L [SEM 2.3]). Thrombin-induced and 5-HT-induced peak cytosolic [Ca2+] were significantly greater than control levels in samples incubated with carbamazepine (277.1 nmol/L [SEM 19.9] v. 195.8 nmol/L [SEM 12.2], p < 0.002; and 153.0 nmol/L [SEM 8.2] v. 115.4 nmol/L [SEM 5.7], p < 0.003, respectively). CONCLUSIONS: This study does not support the involvement of intraplatelet [Ca2+] in the dextroamphetamine model of mania; however, the modulation of intraplatelet [Ca2+] by the mood stabilizers lithium chloride, sodium valproate and carbamazepine implicates intracellular [Ca2+] in the therapeutic mechanisms of these drugs and the pathophysiological basis of mania.     

The effects of carbamazepine and sodium valproate on SEPs and BAEPs

SEPs and BAEPs were studied in 36 previously untreated epileptics receiving either carbamazepine (CBZ) or sodium valproate (VPA) monotherapy. CBZ prolonged central conduction times in SEPs and BAEPs. SEP latency prolongation correlated with serum CBZ levels. VPA had minimal effects on evoked potentials. The present study gives evidence of similar effects of carbamazepine and phenytoin on central neural conduction.     

Complex partial seizures: EEG foci and response to carbamazepine and sodium valproate.

The EEG and clinical records were reviewed of 85 subjects who had been treated for complex partial seizures with carbamazepine alone or with a combination of carbamazepine and sodium valproate. There was a correlation between the site of the EEG abnormality and the therapeutic response to anticonvulsant therapy. Subjects who had a left sided temporal lobe EEG abnormality responded better to carbamazepine alone, while those who had an abnormality on the right responded to a combination of carbamazepine and sodium valproate.     

Neurological sequelae after intoxication with sodium valproate

A case of valproic acid poisoning with coma and neurological sequelae is presented. The course of the intoxication was severe with affection of the brain, heart and liver. The patient remained in coma for thirteen days. After this he recovered slowly although reduction in vision still persisted after two months. The toxicity of valproate is discussed.     

Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis

PURPOSE: To determine the modulation of sodium currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA), before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion. Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation but selectively shifted the voltage dependence of steady-state inactivation to more hyperpolarized potentials. One day after the last kindled generalized seizure, the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls. Five weeks after kindling, these values had recovered to a level not different from control. VPA induces at a relatively high concentration a similar but smaller shift in voltage dependence of inactivation than does CBZ. After kindling, the shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls (3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4 mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage dependence of sodium current steady-state inactivation and as a consequence reduce cellular excitability. The effect of CBZ was reduced immediately after kindling epileptogenesis, apparently by a reduced affinity of its receptor. In contrast, the shift induced by VPA was not different at any stage after kindling epileptogenesis. The change in CBZ sensitivity after kindling is related to epileptic activity rather than to the epileptic state, because it almost completely recovers in a period without seizures.     

Electroencephalographic alterations during intoxication with sodium valproate: a case report

A case of severe valproic acid poisoning with coma and insufficient respiration is reported. The clinical condition and EEG changes are presented. The patient recovered completely, and the toxicity of sodium valproate to the brain and the liver in severe intoxication is discussed.     

Early effect of sodium valproate and carbamazepine monotherapy on homocysteine metabolism in children with epilepsy

Plasma total homocysteine (p-tHcy), serum folate (s-F), serum vitamin B-12 (s-B12) and plasma pyridoxal-5'-phosphate (p-PLP) were measured in epileptic children before and after a 20-week period of sodium valproate (group A, n=32) and carbamazepine (group B, n=20) monotherapy. P-tHcy significantly increased in both groups, s-F and s-B12 significantly increased in group A, while s-F and p-PLP significantly decreased in group B. Our study showed an early effect of antiepileptic drug treatment on homocysteine metabolism.     

Effects of chronic use of carbamazepine and valproate on cognitive processes

We investigated effects on cognitive processes of chronic use of carbamazepine (CBZ) and valproate (VPA) in a group of young patients with epilepsy. Scores on various neuropsychological tests were obtained from patients treated with two monotherapy regimens, one involving CBZ and one involving VPA. In general, the cognitive profile of the two antiepileptic drugs (AEDs) was the same, except for some attention and memory aspects on which the VPA subjects scored better and for some motor tests which the CBZ group performed faster. The latter finding is in accord with results of studies reporting an increase in motor speed induced by CBZ. Furthermore, the observed impairments caused by both CBZ and VPA were relatively mild as compared with those caused by traditional AEDs such as phenytoin (PHT) and phenobarbital (PB).     

Acute intoxication with sodium valproate.

Two epileptic patients developed an acute toxic encephalopathy consisting of altered behavior, deteriorating seizure control, and confusion while taking sodium valproate alone. Serum valproate levels were greater than 100 microgram/ml in both. Toxic symptoms resolved when the dose of valproate was reduced, with a consequent fall in serum concentration of the drug.     

Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients.

Twenty-four epileptic patients (16 females, 8 males; aged 13-62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300-1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10,11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P less than 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25-69 mg/l), as CBZ-E concentrations correlated significantly with total (r = 0.5, P less than 0.05, 95% CI 0 to +0.08) and free (r = 0.7, P less than 0.001, 95% CI +0.09 to +0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.     

Color vision in epileptic adolescents treated with valproate and carbamazepine.

OBJECTIVE: The aims of our study were to evaluate whether deficits in color vision exist in epileptic adolescents, to study if monotherapy with valproic acid (VPA) and carbamazepine (CBZ) can affect color vision, and to determine the possible relationship between abnormal color vision tests and AEDs dosage and their serum concentrations. PATIENTS: We examined 45 epileptic patients before the beginning of therapy and after 1 year of VPA or CBZ monotherapy and 40 sex- and age-matched healthy controls. METHODS: Color vision was evaluated with Farnsworth Munsell 100 (FM100) hue test and achromatic and short-wavelength automated perimetry (SWAP). STATISTICAL ANALYSIS: To evaluate intergroup differences we used ANOVA with Scheffe's post hoc test, when appropriate. Repeated measures ANOVA was used to evaluate the intragroup modifications of total error score (TES) and perimetric threshold during the follow-up. Pearson's correlation test was performed to correlate chromatic sense and perimetric data and AEDs dosage and serum concentrations. RESULTS: Before the beginning of therapy, there were no differences in central color vision and SWAP between controls and epileptic patients. After 1 year, patients treated with VPA or CBZ showed a deficit in FM100 hue test and SWAP parameters while no significant deficit was found in achromatic perimetry. In particular, with the FM100 hue test a higher number of errors was found in both groups of patients (CBZ patients: 166.00 +/- 27.72 TES; VPA patients: 151.19 +/- 44.09, P < 0.001) in comparison with controls (controls: 109.29 +/- 24.73) and baseline values (CBZ patients: 110.65 +/- 22.9; VPA patients 107.43 +/- 21.70). With SWAP patients of both groups showed significant variation of foveal threshold (controls: 21.07 +/- 2.01 dB; CBZ patients: 19.35 +/- 1.32, P < 0.001; VPA patients: 18.88 +/- 1.89, P < 0.001), full-field mean threshold perimetric sensitivity (controls: 18.50 +/- 1.24 dB; CBZ patients: 16.60 +/- 1.47, P < 0.001; VPA patients: 16.23 +/- 1.55, P < 0.001) and mean threshold perimetric sensitivity of the three evaluated subareas of the visual field (area 1 controls: 21.01 +/- 1.15; CBZ patients: 19.45 +/- 1.74, P = 0.001; VPA patients: 18.25 +/- 1.61, P < 0.001; area 2 controls: 18.40 +/- 1.43; CBZ patients: 16.07 +/- 1.58, P +/- 0.001; VPA patients: 16.13 +/- 1.46, P = 0.001; area 3 controls: 17.20 +/- 1.49; CBZ patients: 14.28 +/- 1.51, P < 0.001; VPA patients: 14.31 +/- 2.90, P = 0.001). CONCLUSIONS: Our study demonstrates that treatment with VPA or CBZ can affect significantly both central and paracentral color vision after a short treatment period.     

Adaptation of hepatic ammonia metabolism after chronic valproate administration in epileptics treated with phenytoin

The effects of phenytoin (PHT) on the modifications of ammonia (NH+4) metabolism caused by sodium valproate (VPA) are here studied in order to identify the drug combinations susceptible of evoking stuporous states in epileptics, a rare condition attributed to a hyperammonemic encephalopathy induced by VPA. During chronic treatment with PHT or VPA-PHT, the acute injection of VPA increases the kidney's output of NH+4. During chronic PHT treatments, the acute injection of VPA modifies the liver's NH+4 metabolism and the arterial hyperammonemia is high (mean = 90 mumol/l). During chronic VPA-PHT treatments, the acute injection of VPA does not affect the hepatic NH+4 metabolism, suggesting that adaptation occurs, and the arterial hyperammonemia is moderate (mean = 60 numol/l). Disturbances of the hepatic adaptive mechanisms may explain certain complications observed during multiple-drug regimens.     

Comparative trial of valproate sodium and clonazepam in chronic epilepsy.

A crossover comparative study of valproate sodium and clonazepam in the treatment of 32 adult epileptic patients receiving multiple drug therapy is described. Serum concentrations of other anticonvulsant drugs were unchanged by the addition of clonazepam. However, patients receiving high doses of other anticonvulsant drugs had lower serum concentrations of clonazepam (p less than .01). With valproate sodium, phenobarbital concentrations increased (P less than .05) in patients receiving phenobarbital but not significantly in patients receiving primidone. Phenytoin concentrations were reduced (P less than .05) during treatment with valproate sodium. Both drugs significantly reduced the frequency of minor seizures, with valproate sodium having the greater effect. However, it is important to monitor serum concentrations of other anticonvulsant drugs during treatment with valproate sodium since changes in these may influence seizure control or cause side effects.     

The manic syndrome: factors which may predict a patient''s response to lithium, carbamazepine and valproate.

Studies suggest that 80% to 90% of all patients in the manic state respond to lithium provided that they are relatively free of dysphoria ("pure mania"). In contrast, less than 40% of individuals in the manic state who cycle rapidly or are substantially dysphoric ("dysphoric mania") respond to lithium. These patients appear to be more responsive to carbamazepine and valproate. The authors conclude that carbamazepine and valproate are the drugs of choice if one desires to treat a rapidly cycling individual or patient with dysphoric mania with just one agent. However, they emphasize that a prospective study designed to identify the predictors of response of primary mania to lithium, carbamazepine and valproate is required. Studies assessing the relative value of lithium, carbamazepine or valproate as prophylactic agents in the care of patients with specific subtypes of mania are also needed. These studies would address the most important issues confronting researchers interested in the drug treatment of mania.