Incidence of Drug-Induced Aggravation in Benign Epilepsy with Centrotemporal Spikes

PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is characterized by an excellent prognosis. Drug therapy is necessary in only a minority of patients. Carbamazepine (CBZ) and phenobarbital (PB) have been reported to cause electroclinical aggravation in some cases. The incidence of drug-induced aggravation in BECTS has never been established. METHODS: We retrospectively studied 98 consecutive cases of BECTS, examined at the Centre Saint Paul between 1984 and 1999; 82 patients had received one or more treatments, often successively and in association. RESULTS: We found only one case of electroclinical aggravation with CBZ among 40 patients exposed to CBZ (35 in monotherapy, five in polytherapy). An additional case showed a marked EEG aggravation on CBZ + PB among 14 patients taking PB (nine with monotherapy and five with polytherapy), and PB was apparently responsible. No patient treated with valproate or benzodiazepines showed aggravation. CONCLUSIONS: Aggravation of BECTS caused by antiepileptic drugs happens only rarely. There is a minor risk of aggravation with CBZ and also probably with PB. Drug-induced aggravation may occur only during certain periods coinciding with spontaneous worsening of BECTS.     

Computerized analysis of EEG background activity in mono-therapeutic patients with epilepsy--relationships between antiepileptic drugs and types of seizures

EEG background activity influenced by antiepileptic drugs (AED) was studied in 109 monotherapy and drug-free epileptic patients using t-Statistical Significance Probability Mappings (t-SPMs). Patients taking phenobarbital (PB) had an increase in alpha 1 and a decrease in alpha 2 activity in comparison with drug-free epileptics. Patients taking PB for generalized seizures with tonic-clonic convulsion only (GTC) also had a significant increase in alpha 1 and a decrease in alpha 2, whereas those with partial seizures (PS) had an increase in theta and beta 1 and a decrease in alpha 2 activity. Patients taking valproic acid (VPA) had a decrease in only beta 1 activity. Patients taking VPA for GTC showed an increase in delta activity, but those with PS did not show any changes. Patients taking carbamazepine (CBZ) for PS exhibited marked slowing with an increase in theta and alpha 1 and a decrease in alpha 2 activity. These results mean that changes in EEG due to AEDs differ depending on the type of seizures. More interestingly, discrepancy between EEG background activity and effects of AEDs was found: In PS type of seizures, the most effective CBZ exhibited striking slowing, PB was next, and VPA was last. In GTC, VPA resulted in greater slowing than PB.     

Spike-and-wave complexes and seizure exacerbation caused by carbamazepine

The purpose of this research is to analyse patients in whom carbamazepine (CBZ) therapy adversely affected electroencephalogram (EEG) recordings leading to seizure exacerbation and to identify risk factors for these events. From a total number of 2191 patients (p.) included in the Municipal Epilepsy Center (MEC) database, 77 patients with spike-and-wave (SW) discharges while on CBZ treatment have been selected. Patient population was divided in two groups: (i) patients who were already receiving CBZ at the time of their first visit to the MEC; and (ii) patients to whom CBZ was prescribed during follow-up at the MEC. CBZ was discontinued in all patients with confirmed evidence of an increase in seizure frequency, or with no improvement of epilepsy. During follow-up, EEG findings as well as all clinical changes were duly recorded. Group 1: Carbamazepine was discontinued in 17 patients (p.) as a result of paradoxical reactions. This condition occurs when an antiepileptic drug (AED) appears to exacerbate a type of seizure against which it is usually effective, or when it leads to the onset of new types of seizures. Three p. were withdrawn because of inappropriate drug selection. Group 2: CBZ was discontinued in six patients (p.) as a result of paradoxical reactions. The paradoxical reaction was more frequent in patients with frontal epilepsy and generalized SW discharges on the EEG (P=0.09) and patients with benign rolandic epilepsy (BRE) with diffuse interictal sharp and slow-wave discharges. In both groups, clinical and electrical changes returned to their initial status upon CBZ withdrawal. On the basis of this study, it may be concluded that EEGs might eventually help to screen high-risk patients. If EEG recordings become substantially worse, with more frequent and longer generalized SW bursts after initiation of CBZ therapy, patients should be carefully monitored in order to detect any sign of clinical impairment.     

Renal tubular function in patients receiving anticonvulsant therapy: a long-term study

PURPOSE: The goal of the study was to evaluate the tubular renal function in children and adolescents who are undergoing monotherapy with sodium valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB). METHODS: The urinary excretion of N-acetyl-beta-glucosaminidase (NAG), beta-galactosidase (beta-Gal), alanine-amino-peptidase (AAP), and alpha1-microglobulin (alpha1M) was measured in 58 epileptic patients (29 girls and 29 boys), aged 12.6 +/- 3.9 years, who were subdivided into three groups according to their therapy. Fifty healthy sex-and age-matched children served as controls. The measurements were taken before the beginning of therapy and after 6 months, 1 year, and 2 years of therapy. RESULTS: Before the beginning of therapy, there were no significant differences in NAG, beta-Gal, AAP, and alpha1M values between the control group and the three groups of epileptic children. After 6 months of therapy, patients treated with VPA and CBZ showed a significant increase in the urinary excretion of NAG and beta-Gal compared with baseline data and control values. After 1 and 2 years, these patients showed a persistence of the changes found after 6 months of therapy. In patients treated with PB, we did not find any significant variation in NAG, beta-Gal, AAP, and alpha1M urinary excretion. CONCLUSIONS: Our study demonstrates that in patients treated with VPA and CBZ, an impairment of tubular function can be present, whereas PB does not cause any significant change.     

Laser evoked potentials and carbamazepine in epileptic patients.

AIMS OF THE STUDY: Nerve conduction studies have demonstrated that carbamazepine (CBZ), as well as other antiepileptic drugs (AEDs), can affect peripheral nerve conduction; reports on conventional somatosensory evoked potentials and CBZ are controversial. In a previous study, assessing laser-evoked potentials (LEPs) in CBZ-treated patients with idiopathic trigeminal neuralgia, we found that LEPs were dampened even after stimulation of the non-painful side, with a strong correlation between LEP latency and daily CBZ dose. No other study investigated the influence of AEDs on LEPs. In order to clarify the effect of CBZ on LEPs we sought possible LEP changes in epileptic patients taking CBZ. MATERIALS AND METHODS: We studied LEPs after trigeminal and hand CO(2)-laser stimulation in 20 patients with epilepsy taking CBZ and 20 age-matched controls. RESULTS: Although the trigeminal LEP mean latency was slightly longer in epileptic patients (P=0.11), we did not find significant differences between epileptic patients and controls for any LEP data. LEP data did not correlate with the daily CBZ dose, CBZ blood concentration, or duration of therapy (P>0.3). CONCLUSION: The lack of a CBZ-induced dampening of LEPs suggests that small-fibre pathways, compared to large-fibre, might be less susceptible to AED's toxic effect. Although the TN patients in our previous study were older than the epileptic patients in the present study, a possible combined effect induced by drug and age in patients with TN is unlikely because LEP latency is reportedly unaffected by age. The CBZ-induced effect in patients with trigeminal neuralgia is possibly related to pathophysiological changes specific to this disease.     

Effect of carbamazepine treatment on EEG changes induced by different cortical activation patterns in newly referred epileptic patients.

Sixteen epileptic patients suffering from focal epilepsy who underwent antiepileptic drug treatment with carbamazepine (CBZ) for the first time were studied. The EEG was recorded at rest with eyes closed, during blocking reaction (BR), fixation (FIX) and mental arithmetic tasks. The computerized EEG study, performed before and after CBZ therapy, utilized spectral analysis. Data underwent statistical evaluation through Anova and correlation analysis. The parameters evaluated were the mean frequency and the mean absolute and relative power. The results have shown that after CBZ treatment there is a decrease in the alpha reactivity during BR and FIX, while a significant increase in beta activity was observed during all tasks. The effect of CBZ therapy on EEG activity during cortical activation patterns are discussed.     

Changes of seizures activity during rapid withdrawal of lamotrigine

Quantitatively evaluating the rapid withdrawal effects of lamotrigine (LTG) and carbamazepine (CBZ) on seizure activity during pre-surgical evaluation in patients with pharmacoresistant complex partial epilepsy. The duration and frequency of seizure activities and electrographic seizure onset of 41 patients totally withdrawing from CBZ monotherapy (n = 20), LTG monotherapy (n = 10) and CBZ + LTG combined therapy (n = 11) were intensively studied by therapeutic intensive seizure analysis (TISA) method. Study phases ran from the baseline phase to the antiepileptic drug (AED) withdrawal phase until the AED free phase, 3 days for each phase. Seizure duration and frequency obviously increased during the withdrawal process in each group (P < 0.05). The duration of secondarily generalized clonic signs markedly increased with the tapering of each drug; tonic signs, however, only in the AED free phase (P < 0.05). The frequency of secondary tonic and clonic signs only increased in the CBZ and CBZ + LTG group. Intergroup comparisons of all variables were insignificant (P > 0.05). There was no change of ictal EEG localization during all withdrawal protocols. All patients experienced more severe seizures during the withdrawal processes. An earlier aggravation of the clonic signs than the tonic signs was observed in each group. Difference between the withdrawal effects of LTG and CBZ monotherapy and LTG + CBZ polytherapy was mainly in the frequency change of ictal signs. The withdrawal process did not influence the ictal EEG localization. This study justified the withdrawal in pre-surgical localization, rationalized precautions for possible accompanying risks, and also aroused attentions in clinical anticonvulsant trials and substitutions involving withdrawal process.     

Effects of the Removal of Phenytoin, Carbamazepine, and Valproate on the Electroencephalogram

We report the EEG changes that occurred on discontinuance of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in patients with active epilepsy. Discontinuation of CBZ was associated with an increase in mean frequency of dominant rhythm and reduction in amount of slow activity. Patients who had a marked increase in seizures on discontinuation of an antiepileptic drug had a slower mean dominant rhythm at baseline than did patients who did not have an increase in seizures. Subsequent EEGs, during and at the end of drug reduction, showed an increase in bursts of interictal epileptiform activity (IEA) and in slow activity in patients who had a marked increase in seizures. The amount of slow activity and IEA did not alter in patients who did not have an increase in seizures. No patients developed photosensitivity.     

Withdrawal of phenobarbital and carbamazepine in epileptic patients: a preliminary neuropsychological report.

We systematically investigated the neuropsychological effects of controlled withdrawal of antiepileptic therapy with a battery of tests exploring intelligence, vigilance, attention, memory and sensori-motor performance. 16 patients without seizures for at least 2 years, 9 on therapy with phenobarbital (PB) and 7 with carbamazepine (CBZ), were examined 4 times over a period of 21 months. No significant correlation was found between drug levels and performance in the tests. The slight differences found between the PB and CBZ groups at full doses disappeared completely one year after withdrawal.     

Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers

PURPOSE: Antiepileptic drug (AED) therapy can be associated with neurotoxic side effects including cognitive dysfunction. Objective methods for detection of neurotoxicity in individual patients would be useful. We studied the effects of gabapentin (GBP) and carbamazepine (CBZ) on neurophysiologic and cognitive/behavioral measures in healthy volunteers. METHODS: In a 12-week, randomized, double-blind, parallel-group study of CBZ and GBP in healthy volunteers, 23 subjects completed the protocol. All achieved the target dose of 1,200 mg CBZ or 3,600 mg GBP. A structured EEG for quantitative analysis and a cognitive test battery were administered before AED therapy and again after 12 weeks of therapy. Test-retest differences were compared with those of 72 untreated control subjects. RESULTS: Both CBZ and GBP significantly decreased the peak frequency of the posterior (alpha) rhythm, with CBZ exerting a greater effect. Ten CBZ and six GBP subjects exceeded the 95% confidence interval (CI) for an individual. Cognitive tests revealed AED vs. control group effects for two of seven measures (Digit Symbol, Stroop) and all subjective measures. However, few subjects exceeded the 95% CI for any objective test. Differences between CBZ and GBP were not significant. Greater EEG slowing was associated with greater subjective neurotoxicity and poorer test-retest performance on a cognitive test summary measure. CONCLUSIONS: Prolonged CBZ and GBP therapy induced EEG slowing that correlated with cognitive complaints and often exceeded the confidence interval for individual subjects. Quantitative EEG measures may be useful in the objective determination of AED-related neurotoxicity.     

The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy

The aim of the present study was to assess the effect of long-term carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB) treatment on serum lipids and apolipoproteins in epileptic children. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TGs) were measured and the LDL-C/HDL-C and TC/HDL-C ratios were calculated in 320 children and adolescents (129 receiving CBZ, 127 receiving VPA and 64 receiving PB) suffering from various types of epilepsy. Additionally, in a subgroup of 181 children (68 CBZ; 78 VPA; 35 PB) apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), HDL2-C and HDL3-C were measured and apoA-I/apoB and HDL2-C/HDL3-C ratios were calculated. Results of the measurements were compared with those of 169 age-and sex-matched healthy controls. None of the variables considered was significantly correlated with time elapsed since start of treatment or with drug concentration in serum. TC and LDL-C serum levels were high in children receiving CBZ or PB and low in those treated with VPA. Serum LDL-C level exceeded 130 mg/dl in 27.9% of CBZ-group, 31.8% of the subjects receiving PB, but only in 7% of those receiving VPA and in 11.8% of control group subjects. CBZ-treated children also showed high HDL-C and HDL3-C values. In the group receiving VPA, HDL2-C, HDL2-C/HDL3-C ratio and apo B were significantly lower than in the control group. Mean apoA-I levels were low in all treated groups: by contrast, in neither group did TGs, VLDL-C levels and TC/HDL-C or LDL-C/HDL-C ratios differ significantly from the corresponding control group. Our results suggest that the effects of long-term AED therapy on lipid profile and, particularly, on apolipoprotein serum levels increase risk of atherosclerosis-related disease. Moreover, these results confirm our previously reported increased risk in CBZ and PB-treated patients.     

Elevated plasma concentrations of homocysteine in antiepileptic drug treatment

PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.     

Plasma levels of antiepileptic agents in the treatment of epilepsy

From a total of 560 different epileptics visited during 16 months, we have practiced 140 plasmatic dosifications of antiepileptic drugs according to EMIT technic. The antiepileptic drugs studied were: PB, DPH, PRM, VPA, CBZ and ESM. In this study only the 70 patients treated with PB in monotherapy or combined with DPH, CBZ, VPA and PRM are considered. From the 70 patients, 45 have been controlled; from them 21 (46,5%) did not reach efficient levels from anyone of the used antiepileptics. From the 70 patients 25 have been partially or bad controlled, 20 of them (80%) had PB in efficient levels, 13 (52%) had the other antiepileptic in efficient levels, 12 (47%) had both antiepileptics in efficient levels and 4 (16%) had no antiepileptic drug in efficient levels in spite of using the efficient dose in mg/Kg/day. The conclusions of this results are: we reached a good effect by using PB alone or combined under the considered efficient levels in a 46.5% of the patients; the bad controlled patients, kept on being bad controlled in spite of having 80% of them PB, the other antiepileptic or both in efficient levels.     

'Iatrogenic' Wernicke's encephalopathy in Japan

'Iatrogenic' Wernicke's encephalopathy has appeared to occur more frequently in Japan, probably induced by the change of our Japanese national health insurance policy in 1992. We report 4 nonalcoholic patients with such Wernicke's encephalopathy, which occurred during the early postoperative oral food intake period following intravenous nutrition without vitamin supplements. We analyzed the medical records of 4 patients, 3 men and 1 woman, aged between 55 and 71 years, who were admitted to our hospital between 1992 and 1995. Three patients underwent gastrointestinal surgery and 1 suffered chronic pyothorax. We diagnosed our patients as having Wernicke's encephalopathy based on typical neurological abnormalities, in addition to typical cranial magnetic resonance image findings, low serum vitamin B(1) levels, or both. Although all of the patients were treated with vitamin B(1) and showed some improvement, 1 patient developed Korsakoff syndrome, 2 made incomplete neurological recovery, and 1 died. We speculated that the body vitamin B(1) stores had been decreasing in our patients who did not receive any vitamin supplements during intravenous hyperalimentation or hydration. Subsequent administration of high calorie and high carbohydrate oral diets increased the demand for vitamin B(1), further depleting the vitamin stores, thereby causing 'iatrogenic' Wernicke's encephalopathy. The change of our national health insurance policy in 1992 discouraged the routine administration of vitamins, probably causing Wernicke's encephalopathy in our patients.     

Free drug levels monitoring as a detector of false metabolic refractory epilepsy

Unbound and total plasma levels of carbamazepine (CBZ) and phenobarbital (PB) were evaluated in a group of 12 refractory patients out of 397 subjects, with normal values of total drug concentration and unbound levels below the expected ones. We established a minimal acceptable 'subtherapeutic' free drug level, i.e. less than 9.62 micrograms/ml for PB and 1.36 micrograms/ml for CBZ. PB and CBZ dosages were increased during a 3-month period. We observed a normalization of free levels, unaccompanied by a significant decrease in seizure frequency. Free drug level monitoring may prove to be an unchallenged detector of false metabolic refractory epilepsy.     

Antiepileptic drug effects on somatosensory evoked potentials

Some evoked potential changes have been documented in chronic phenytoin (PHT), valproate (VPA), or benzodiazepine therapy, whereas other studies have suggested little change with carbamazepine (CBZ) or phenobarbital (PB). We recorded median and posterior tibial nerve somatosensory evoked potentials (SEPs) in complex partial seizure patients taking PHT, CBZ, or VPA in monotherapy with stable therapeutic serum levels and no toxic symptoms. Ten patients each were studied with PHT, CBZ, and VPA and were compared with age-matched controls. Median nerve responses were recorded at Erb's point, cervical spine, and contralateral cerebral sites; tibial nerve evoked potentials were recorded from popliteal fossa, lumbar, cervical spine, and midline scalp electrodes. Epileptic patients and controls did not differ in SEP latency, amplitude, or central condition time. PHT prolonged Erb's point and popliteal fossa latencies, but not central conduction time. CBZ had no effect on latencies or amplitudes. Evoked potential amplitudes were reduced by VPA, and cortical response latencies were minimally prolonged. Chronic antiepileptic therapy without toxicity had little effect on SEPs. PHT may have a slight effect on peripheral nerve conduction, and VPA may have an effect on amplitude of cerebral responses.     

Aging variabilities of level-dose relationship in antiepileptic monopharmacy--with reference to drug interaction between mono- and bipharmacy

The influences of age, dose and comedication on the dose-level relationship were investigated using the ratio of plasma level to dose per body weight (microgram/ml/mg/kg/day) as an index in patients who had received the therapeutic doses of antiepileptic drug(s) for a long term. Samples of the blood concentrations were taken from 1,922 patients ranging in age from one to 40: 1,567 measured values were obtained under medication with phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) or valproate (VPA) alone, and 2,201 under medication with any two of the above-mentioned antiepileptic drugs. With regard to PB, PHT, CBZ and VPA, when used alone, the L/D ratio was the lowest in the youngest age group, increased toward the latter half of teens, reached a peak at about age 20 and slightly decreased in the rest between the 20s and 30s. The age when the L/D ratio changes with aging is consistent with the age when the body weight of children obviously increases. As a result, during such a term, the fairly constant blood concentration can be maintained without overtly changing the daily dose. In the same age group given a single antiepileptic drug, the L/D ratio for PHT steeply increased at the dose of 4 in adults or 5 mg/kg/day in children, while the ratio rather decreased for CBZ and VPA. Clinical considerations should be paid to the fact that there was a non-linear relationship between the dose and the plasma concentration not only of PHT but of CBZ and VPA, and that the turning points were all within the range of therapeutic doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy

PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.     

Pharmacokinetic Interactions Between Lamotrigine and Other Antiepileptic Drugs in Children with Intractable Epilepsy

Summary: Purpose : We wished to determine the oral pharmacokinetics of lamotrigine LTG and to assess possible interactions with other AEDs in an unselected population of children. Concentration data in plasma and in CSF for lamotrigine as well as for the other AEDs are presented.
Methods : Thirty-one children, children and young adults aged > 2 years with intractable generalized epilepsy despite adequate duration and dose of at least three conventional AEDs were studied.
Results : There was a linear relation between the dose administered and the maximal plasma concentration, indicating that saturation of absorption or elimination mechanisms did not occur in the dose range studied. The median elimination half-life (t1/2) in patients receiving concomitant valproate (VPA) was 43.3 h; in patients receiving carbamazepine (CBZ) and/or phenobarbital (PB), it was 14.1 h; and in patients receiving both VPA and CBZI PB or other antiepileptic drugs (AEDs), it was 28.9 h. No clinically important changes in the plasma levels of CBZ, VPA, valproate, ethosuximide, or PB were observed in the follow-up period (2–12 months). No dose adjustments of concomitant AEDs were necessary. The plasma concentration of clonazepam (CZP) was reduced when LTG was introduced.
Conclusions : The complex interaction between LTG and other AEDs in children with intractable epilepsy makes therapeutic drug monitoring (TDM) desirable.