Initiation of Treatment and Selection of Antiepileptic Drugs in Childhood Epilepsy

Summary:  Purpose: A retrospective study was carried out on 53 cases with childhood epilepsy to evaluate the validity of the initial selection of antiepileptic drug (AED).
Methods: We investigated the AEDs selected at the beginning of the treatment from the medical records of 53 untreated cases. A follow-up study was undertaken to evaluate the effects of the AEDs. In the second study, we investigated the AEDs of 10 cases with atypical benign partial epilepsy (ABPE), to clarify whether the initial AEDs selected for rolandic epilepsy were related to the appearance of ABPE.
Results: The AEDs used at the initial stage consisted of carbamazepine (CBZ), valproic acid (VPA), phenobarbital (PB), and vitamin B₆. The main AEDs were CBZ and VPA for localization-related epilepsy, and VPA for generalized epilepsy. The initial selection of AEDs in 41 (85.4%) of 48 cases treated with AEDs were considered to be correct from the results of follow-up. We could not specify any AEDs that related to the appearance of ABPE.
Conclusions: The selection of AED in this series was considered to be most appropriate. We proposed a criterion to determine whether to begin the AED treatment immediately at the initial seizure.     

A Comparison Between One and Three Years of Treatment in Uncomplicated Childhood Epilepsy: A Prospective Study. II. The EEG as Predictor of Outcome After Withdrawal of Treatment

Summary: Purpose : We wished to evaluate the prognostic usefulness of various EEG parameters with respect to remission rates after discontinuation of antiepileptic drug (AED) therapy in children treated for epileptic seizures.
Methods : Two hundred forty-four children with uncomplicated epileptic seizures were randomized to either 1 or 3 years of treatment with AEDs. The treatment was then discontinued in patients who had been seizure-free during the last 6 months of their allotted time of treatment (n = 154). After treatment discontinuation, the children were followed for at least 2 years. EEG recordings were performed before treatment was initiated and at regular intervals during treatment.
Results : The overall relapse rate was 37%. In many children, the amount of epileptiform activity varied considerably between subsequent recordings made during the treatment. The remission rate was slightly higher for children whose last recordings before AED discontinuation were free of epileptiform activity as compared with children in whom such activity was present. However, children who had irregular generalized spike–wave (SW) activity in the recordings made before discontinuation of treatment had a clearly higher relapse rate (67%) both as compared with children without epileptiform activity (33%) and as compared with children with other types of epileptiform activity (33%) in their last EEG recordings before discontinuation. All children treated for only 1 year whose final EEGs displayed generalized irregular SW activity relapsed.
Conclusions : We conglude that the presence of epileptiform activity does not in itself necessarily influence prognosis after discontinuation of treatment but that certain types of such activity signal a high risk of relapse.     

Antiepileptic drugs management and long-term seizure outcome in post surgical mesial temporal lobe epilepsy with hippocampal sclerosis

Surgery is the treatment of choice for refractory temporal lobe epilepsies, but unexpected seizure recurrences occur and the AEDs management strategy may be an implicated factor. We evaluated the AEDs management's role in the outcome of post surgical epilepsy patients with hippocampal sclerosis (HS). Epileptic patients submitted to amigdalohippocampectomy due to HS in Engel class IA 12 months after surgery were selected. The following variables were studied: age, gender, time of post-surgical follow-up, present Engel class, number of antiepileptic AEDs before surgery and at the time of the interview, AED changes after surgery (stopped, increased, decreased, maintained), timing for AED changes after surgery and seizure recurrences. Sixty-seven consecutive patients were studied (mean time of follow-up of 4.9 ± 2.8 years). Among these, 46.3% were tapering AEDs, 38.8% had not changed and 14.9% had increased AEDs. The global recurrence rate was 32.8%. Recurrence rates for patients tapering and not tapering AEDs were similar (34.2% and 31%, respectively). Fifteen patients tapered AEDs before 2 years and 20 at or 2 years after surgery, with similar recurrence rates (33% and 30%, respectively). All patients who recurred due to AED tapering and 66.7% of the patients who recurred with no AED reduction resumed the Engel class I. This study suggests that in HS patients submitted to AHE who are seizure free during the first postsurgical year, AEDs tapering is achieved in a substantial percentage of patients. Tapering AEDs, independently of its timing, will induce seizure recurrence in about a third of patients. However, patients relapsing after tapering AEDs regain control after resuming therapy.     

Treatment of benign focal epilepsies in children: when and how should be treated?

Benign focal epilepsies represent almost one-fourth of all childhood epilepsies and are a frequent occurrence in clinical practice. They include benign infantile seizures (BIS), Panayiotopoulos syndrome (PS), and benign childhood epilepsy with centrotemporal spikes (BCECTS) in this order of the onset age. Because the prognosis is always excellent in patients with benign focal epilepsies, we must consider the risks and benefits of chronic antiepileptic drug (AED) administration. AED treatment is usually not recommended for the patients with a first attack, but should be considered for those with a second or third attack. A choice of AED has been based on the expert opinion. Carbamazepine (CBZ) is recommended for both acute and chronic treatment of seizure clusters in patients with BIS. Valproic acid (VPA), CBZ or clobazam (CLB) appears to be a first option of AED for patients with PS. A common first choice for BCECTS is CBZ in the USA and Japan, and VPA in the EU. The treatment period should be as short as possible without waiting for EEG normalization, possibly within 2 years after the initiation of AED. We must remember that some patients with BCECTS may have an “atypical evolution”. In conclusion, when and how to treat this benign condition should be determined in an individual manner based on the length and frequency of seizures, circadian rhythm of the attacks, interictal EEG findings, cognitive and behavioral functions in daily life and the attitude of the parents toward seizure recurrences and AED side effects.     

Profile of Antiepileptic Pharmacotherapy in a Tertiary Referral Center in South India: A Pharmacoepidemiologic and Pharmacoeconomic Study

Summary: Purpose: To study the current pharmacotherapy practices of epilepsy and its economics in a developing country by correlating the epidemiology and economics of antiepileptic drug (AED) treatment in general epilepsy care and comprehensive epilepsy care.
Methods: We compared the AED-use profiles, efficacy, and tolerability at entry and at last follow-up for 972 patients seen at a comprehensive epilepsy care program in South India from 1993 to 1995. The relative cost was expressed as the average percentage of the per capita gross national product (GNP/capita) each individual spent for AED treatment.
Results: At entry, 562 (57.8%) subjects were receiving poly-therapy; at last follow-up, 743 (76.4%) patients were receiving monotherapy, an increase of 34.3% in the use of monotherapy. One or more adverse drug reactions were reported by 28.6% of patients at entry and by 19.8% at last follow-up. The proportion of patients who were seizure free increased from 29.0 to 44.8%. Carbamazepine (CBZ) was the most frequently used AED, followed by diphenylhydantoin (DPH), valproate (VPA), and phenobarbitone (PB). The relative cost (% GNP/capita) for standard AEDs were as follows: PB, 4.4%; DPH, 7.1%; CBZ, 16.8%; and VPA, 29.5%. The average annual cost of AED treatment per patient in U.S. dollars was $64.32 at entry and $47.73 at last follow-up. Reduction in polytherapy resulted in the net annual saving of $16,128 ($16.59 per patient, or 5.4% GNP/capita).
Conclusions: The more frequent use of relatively expensive drugs like CBZ and VPA and the use of polytherapy—still quite prevalent in developing countries—has escalated the cost of AED therapy. Although in recent years AEDs have become more available in developing regions, primary and secondary care physicians have not been adequately educated about the current trends in the pharmacotherapy of epilepsy.     

Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes

PURPOSE: Compulsory generic substitution of antiepileptic drugs (AEDs) may lead to adverse effects in epilepsy patients because of seizure recurrence or increased toxicity. The study objectives were (a) to quantify and compare the switchback rates from generic to brand-name AEDs versus non-AEDs, and (b) to assess clinical implications of switching from branded Lamictal to generic lamotrigine (LTG) and whether signals exist suggesting outcome worsening. METHODS: By using a public-payer pharmacy-claims database from Ontario, Canada, switchback rates from generic to branded AEDs [Lamictal, Frisium (clobazam; CLB), and Depakene (VPA; divalproex)] were calculated and compared with non-AED long-term therapies, antihyperlipidemics and antidepressants, in January 2002 through March 2006. We then assessed pharmacy utilization and AED dosage among LTG patients switching back to branded Lamictal compared with those staying on generic formulation. RESULTS: The 1,354 patients (403 monotherapy, 951 polytherapy) were prescribed generic LTG, of whom 12.9% switched back to Lamictal (11.7% monotherapy, 13.4% polytherapy). Switchback rates of other AEDs were approximately 20% for CLB and VPA. The switchback rates for AEDs were substantially higher than for non-AEDs (1.5-2.9%). Significant increases in LTG doses were observed after generic substitution for those who did not switch back (6.2%; p<0.0001). The average number of codispensed AEDs and non-AED drugs significantly increased (p<0.0001) after LTG generic entry, especially in the generic group. CONCLUSIONS: These results reflect poor acceptance of switching AEDs to generic compounds. They may also indicate increased toxicity and/or loss of seizure control associated with generic AED use.     

Antiepileptic drugs abolish ictal but not interictal epileptiform discharges in vitro

Purpose: We established the effects of the antiepileptic drugs (AEDs) carbamazepine (CBZ), topiramate (TPM), and valproic acid (VPA) on the epileptiform activity induced by 4‐aminopyridine (4AP) in the rat entorhinal cortex (EC) in an in vitro brain slice preparation. Methods: Brain slices were obtained from Sprague‐Dawley rats (200–250 g). Field and intracellular recordings were made from the EC during bath application of 4AP (50 μm ). AEDs, and in some experiments, picrotoxin were bath applied concomitantly. Results: Prolonged (>3 s), ictal‐like epileptiform events were abolished by CBZ (50 μm ), TPM (50 μm ), and VPA (1 mm ), whereas shorter (<3 s) interictal‐like discharges continued to occur, even at concentrations up to 4‐fold as high. γ‐Aminobutyric acid (GABA)_A–receptor antagonism changed the 4AP‐induced activity into recurrent interictal‐like events that were not affected by CBZ or TPM, even at the highest concentrations. To establish whether these findings reflected the temporal features of the epileptiform discharges, we tested CBZ and TPM on 4AP‐induced epileptiform activity driven by stimuli delivered at 100‐, 10‐, and 5‐s intervals; these AEDs reduced ictal‐like responses to stimuli at 100‐s intervals at nearly therapeutic concentrations, but did not influence shorter interictal‐like events elicited by stimuli delivered every 10 or 5 s. Conclusions: We conclude that the AED ability to control epileptiform synchronization in vitro depends mainly on activity‐dependent characteristics such as discharge duration. Our data are in keeping with clinical evidence indicating that interictal activity is unaffected by AED levels that are effective to stop seizures.     

Lacosamide in the treatment of acute recurrent seizures and periodic epileptiform patterns in critically ill patients

We investigated the safety, tolerability, and effectiveness of lacosamide (LCM) in patients with acute recurrent seizures or with periodic epileptiform activity captured during continuous EEG monitoring. A total of 17 patients received LCM; 12 patients received LCM as a second or third antiepileptic drug (AED), one patient as a fourth AED, and one patient as a fifth AED. No additional AEDs were introduced after LCM in 15 patients. Twelve patients responded to LCM with improvement in the seizures or periodic epileptiform activity. Two patients required further AED management or burst suppression. No adverse effects, including symptomatic bradycardia and allergic reactions, were seen for intravenous infusion dosages up to 300 mg. Eleven patients were eventually discharged on LCM. LCM is an important new AED in the add-on treatment of acute recurrent seizures and periodic epileptiform activity in critically ill patients.     

Seizure Occurrence During Long-Term Monitoring

Summary: Purpose : Intensive long-term monitoring (LTM) for patients with refractory seizures is common and expensive. Methods to decrease the length of stay would improve patient experience and reduce cost. Therefore, we prospectively analyzed seizure occurrence in 36 patients who had LTM.
Methods : Antiepileptic drug (AED) levels and reduction were monitored and seizures were related to these changes. Patients were divided into temporal and extratemporal groups.
Results : Twenty patients had partial seizures of temporal lobe origin. The temporal lobe partial seizures occurred between LTM days 1 and 16. All but 4 of the patients required reduction or discontinuation of a least one AED and had subtherapeutic levels of the tapered medications. In 16 patients with extratemporal partial seizures, seizures occurred between LTM days 1 and 8. Six of these patients required reduction of at least one AED, and 5 of the 6 had subtherapeutic levels of that medication. These differences between length of monitoring monitoring and AED reduction in temporal and extratemporal patients were statistically significant. The groups did not differ significantly with respect to number or identity of tapered or nontapered medications or levels of nontapered medications. Reported seizure frequency at home was significantly related to number of seizures recorded in the temporal group only. The only significant predictor of secondarily generalized seizure activity during monitoring was a history of such activity occurring at home.
Conclusions : We conclude that patients with extratemporal partial seizures need little reduction of AED for seizures to be captured in a minimal time period. Patients with temporal lobe seizures, however, required drastic reduction of AEDs to allow capture of seizures in a long time period.     

Effects of valproic acid on sleep in children with epilepsy

Purpose:   Parents frequently report increased sleep duration in their children during treatment with valproic acid (VPA). We assessed sleep duration and sleep behavior before and after tapering VPA in children treated for more than 6 months.
Methods:   Sleep variables were assessed by questionnaire, diary, and actigraphy (for 7 consecutive days and nights) before and 8–12 weeks after termination of VPA.
Results:   Forty-six children (age range 1.7–17.4 years) completed the study. The questionnaire data showed no significant difference in bed and wake time, duration of sleep, and time to fall asleep before and after ending VPA treatment, although some qualitative measures on daytime sleepiness improved after tapering VPA. The actigraphy data revealed that the average sleep amount without VPA was reduced in 33 children (9 of them >30 min) and longer in 13 children (1 of them >30 min). The mean Assumed Sleep Time per Day decreased by 15.2 min or 9.5 min when the physiologic decrease of sleep duration within 0.3 years was considered. Also mean Actual Sleep Time per Day was significantly reduced after VPA termination (−15.2min; after correction −10.7 min). The reduction was only significant in children older than age 6 years.
Discussion:   Termination of VPA after long-term treatment leads to a significant reduction of sleep duration in children older than 6 years of age. The change was small in the majority, but considerable in a subgroup of children.     

Antiepileptic drug withdrawal after successful surgery for intractable temporal lobe epilepsy

PURPOSE: To investigate the prognosis related to antiepileptic drug (AED) discontinuation after successful surgery for intractable temporal lobe epilepsy. METHODS: The clinical courses after temporal lobectomies (TLs) were retrospectively analyzed in 88 consecutive patients. All the patients had TLs as the only surgical procedure, and they had been followed up for longer than 3 years. AED discontinuation was attempted if the patient had been seizure free without aura for >or=1 year during the follow-up period. RESULTS: Sixty-six (75%) patients achieved complete seizure freedom for >or=1 year; 28 patients were seizure free immediately after surgery (immediate success); and 38 patients became seizure free after some period of recurrent seizures (delayed success). AED discontinuation was attempted in 60 (91%) of 66 patients with a successful outcome. In 13 (22%) patients, seizure relapse developed during AED reduction (n=60), and in seven (12%) patients after discontinuation of AEDs (n=38). The seizure recurrence rate was not different between the immediate-and delayed-success groups. Among 20 patients with seizure relapse related to AED tapering, nine (45%) of them regained seizure freedom after reinstitution of AED treatment, and AEDs were eventually discontinued in six of them. Seizures that recurred after complete AED discontinuation had a better prognosis than did the seizures that recurred during AED reduction (seizure freedom in 86% vs. 23%). At the final assessment, 54 (61%) patients had been seizure free >or=1 year; 37 without AEDs and 17 with AEDs. The successful discontinuation of AEDs was more frequent for patients with a younger age at the time of surgery and for those patients with shorter disease duration. CONCLUSIONS: Our results suggest that seizure freedom without aura at >or=1 year is a reasonable indication for the attempt at AED discontinuation. The subsequent control of recurrent seizures was excellent, especially if seizures relapsed after the complete discontinuation of AEDs. Younger age at the time of surgery and a shorter disease duration seem to affect successful AED discontinuation for a long-term period.     

A study on epileptic negative myoclonus in atypical benign partial epilepsy of childhood

Objective. To investigate the clinical and neurophysiological characteristics, particularly therapeutic considerations, of epileptic negative myoclonus (ENM) in atypical benign partial epilepsy (ABPE) of childhood. Methods. From 1998 to 2006, 14/242 patients with benign children epilepsy with centrotemporal spikes (BECTS) were diagnosed as having ABPE with ENM. In all 14 patients, we performed video-EEG monitoring along with tests with the patient’s arms outstretched; 6/14 patients were also simultaneously underwent surface electromyogram (EMG). ENM manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. Results. In all cases, ENM developed after the onset of epilepsy and during antiepileptic drug therapy, and the appearance of ENM were corresponding to EEG findings of high-amplitude spikes followed by a slow wave in the contralateral motor areas with secondary generalization. This was further confirmed by time-locked silent EMG. During ENM occurrence or recurrence, habitual seizures and interictal discharges were exaggerated. In some patients, the changes in antiepileptic drug regimens in relation to ENM appearance included add-on therapy with carbamazepine, oxcarbazepine, and phenobarbital or withdrawal of valproate. ENM was controlled in most cases by administration of various combinations of valproate, clonazepam, and corticosteroids. Conclusion. The incidence of ENM or ABPE in our center was approximately 5.79%. A combination of video-EEG monitoring with the patient’s arms outstretched and EMG is essential to identify ENM. The aggravation of habitual seizures and interictal discharges indicate ENM. Some antiepileptic drugs, such as carbamazepine, oxcarbazepine, and phenobarbital, may be related to ENM occurrence during spontaneous aggravation of ABPE. Various combinations of valproate, benzodiazepines, and corticosteroids are relatively effective for treating ENM that occurs in ABPE.     

Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia

Seizure activity associated with cortical dysplasia (CD) is often resistant to standard pharmacologic treatments. Although several animal models exhibit CD, virtually nothing is known about antiepileptic drug (AED) responses in these animals. Here we have used rats exposed to methylazoxymethanol acetate (MAM) in utero, an animal model featuring nodular heterotopia, to investigate the effects of AEDs in the dysplastic brain. 4-aminopyridine (100 μM), a K⁺ channel blocker, was used to induce interictal epileptiform bursting in acute hippocampal slices from MAM-exposed and age-matched vehicle-injected control animals. Extracellular field recordings were used to monitor seizure activity in vitro. Five commonly used AEDs were tested: phenobarbital, 25–400 μM; carbamazepine, 25–200 μM; valproate (VPA), 0.19–4 mM; ethosuximide (ESM), 0.5–8 mM; and lamotrigine (LTG), 49–390 μM. 4-AP-induced bursting occurred with shorter latencies in slices from MAM-exposed rats in comparison with slices from controls, confirming the intrinsic hyperexcitability of dysplastic tissue. Each AED tested demonstrated significant burst suppression in control slices, but interictal epileptiform bursting in MAM-exposed slices was resistant to these treatments. Even at the highest concentrations, VPA, ESM and LTG had no effect on burst amplitude in slices from MAM-exposed rats. Pharmaco-resistance was further tested by measuring seizure latencies in awake, freely-moving rats after kainate administration (15 mg/kg, i.p.) with and without pre-treatment with VPA (400 mg/kg i.p.). Pre-treatment with VPA prolonged seizure latency in control rats, but had no effect in MAM-exposed animals. These results suggest MAM-exposed rats exhibit a dramatically reduced sensitivity to commonly prescribed AEDs.     

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.     

Value of therapeutic drug level monitoring and unbound (free) levels.

Therapeutic drug monitoring (TDM) has declined with newer anti-epileptic drugs (AEDs) having no therapeutic window. Use of unbound (free) fraction has almost completely disappeared. The case reported highlights its importance and offers sound reason for its retention. A 66-year-old Caucasian man with known epilepsy was admitted with vomiting, ataxia and nystagmus presumably due to AED toxicity. Medications included valproate (VPA) 1g bd; phenytoin (PHT) 200mg tds; carbamazepine (CBZ) 400mg mane, 200mg midi, 400mg nocte; levetiracetam (LEV) 250mg bd. Initial AED-TDM revealed total serum levels of CBZ: 27mumol/L; PHT: 37mumol/L; VPA 499mumol/L, therapeutic or subtherapeutic. Free levels were subsequently measured demonstrating CBZ: 8.2mumol/L; PHT: 5mumol/L; VPA 93mumol/L. Consequently, VPA was initially omitted and dosage reduced with cessation of toxicity. AED regimen was greatly simplified and remained efficacious. This case highlights the value of TDM with polypharmacy and suggested AED toxicity. Total AED levels failed to identify the cause, which the unbound, free fraction identified. While total PHT was borderline subtherapeutic (37mumol/L; range: 40-80) the free level was therapeutic (5mumol/L; range: 4-8) and while VPA was therapeutic (VPA 499mumol/L; range: 300-750) the free level was supratherapeutic (93mumol/L; range: 30-75). Acknowledgement of discordance between total and free levels for highly protein-bound AED is highlighted.     

Seizure recurrence and risk factors after antiepilepsy drug withdrawal in children with brain tumors

Summary:  Purpose: To study seizure outcome after antiepilepsy drug (AED) withdrawal in brain tumor patients and to analyze risk factors for seizure recurrence.
Methods: Brain tumor patients with seizures and at least one attempt at AED discontinuation were identified from the hospital database and neurology clinic records. After defining study variables, patient charts were abstracted for clinical and demographic data. Statistical analyses used log-rank tests and multivariable Cox proportional hazards models.
Results: Sixty-two patients discontinued AEDs at a median time of 5.6 years from the first seizure (range, 1.2–19.6 years). Median time since AED withdrawal was 2.3 years (range, 0.4–15.1 years). Seizures recurred in 17 (27%) patients within a median time of 0.8 years (range, 0.06–7.7 years). Median seizure-free period before AED withdrawal was 1.3 years (range, 0.1–11 years). More than one tumor resection and whole-brain radiation treatment (WBRT) were associated with seizure recurrence, whereas posterior fossa tumor location was correlated with reduced seizure recurrence risk. At seizure recurrence, control was easily reestablished in 10 patients with AED reinstitution and after dose adjustment in five; two patients with poor drug compliance continue to have seizures. In 48 patients who had an EEG before AED withdrawal, spikes or slow waves did not correlate with seizure recurrence.
Conclusions: AED withdrawal can be successfully achieved in majority of carefully selected patients. WBRT and multiple tumor resections seem to be associated with an increased hazard for seizure recurrence.     

Valproate Metabolites in High-Dose Valproate Plus Phenytoin Therapy

Summary: Purpose: We wished to determine the relation between liver function, β-, and ω-, and ω-1-oxidation metabolites and 4-en-valproate (VPA).
Methods: We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/SIM).
Results: In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total β -oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total β -oxidation metabolites were increased, and the E-2-en-VPM3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (μ M ) was decreased and the concentrations of (ω+ (ω - 1)]-oxidation metabolites (μ M) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transarninase (GOT), glutarnic-pyruvic transaminase (GPT) and lactic dehy-drogenase (LDH) did not correlate significantly with the (β/ω+ (ω - 1) metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently.
Conclusions: Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharrnacological antiepileptic drug (AED) therapy.     

Computerized tremor analysis of valproate-induced tremor: a comparative study of controlled-release versus conventional valproate

PURPOSE: Valproate (VPA) induces postural tremor in 6-45% of patients. The characteristics of VPA-induced tremor have not yet been quantitatively assessed, and it is not known whether tremor prevalence or severity is affected by VPA formulation (controlled-release CR-VPA vs. conventional VPA). The aim of this study was quantitatively to assess tremor in epilepsy patients receiving VPA and to compare the effects of two VPA formulations (CR-VPA vs. VPA) on tremor severity. METHODS: In a prospective study, 18 consecutive patients with newly diagnosed focal or generalized epilepsy were assigned to receive alternately either VPA (n=10) or CR-VPA (n=8) monotherapy. Computerized tremor analysis was performed at baseline 1 day before initiating VPA treatment and repeated after a seizure-free period of >or=8 weeks, during which VPA doses had remained stable. Rest and postural tremor were recorded by accelerometry, and surface electromyograms (EMGs) were recorded from the wrist flexors and extensors. RESULTS: At baseline, the two groups had similar postural tremor amplitudes. At follow-up, the CR-VPA group had remained at the same level, whereas VPA subjects exhibited a significant increase in tremor amplitudes (p<0.05) despite comparable VPA doses and comparable plasma VPA concentrations at the time of tremor testing. CONCLUSIONS: This is the first study to assess quantitatively VPA-induced tremor by standardized tremor analysis. These results suggest that CR-VPA may cause less tremorigenic activity as compared with standard VPA. The mechanisms underlying this difference are unclear but may include greater peak-trough variation with VPA than with CR-VPA.     

Clobazam in the Treatment of Epilepsy: A Review of the Literature

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short-term and long-term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long-term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short-term add-on therapy; but it should also be tried as long-term therapy in some situations, especially as add-on therapy for patients with refractory epilepsy, as add-on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.     

Clinical and electromyographic examinations of Parkinsonian tremor

Background: The clinical presentations of postural Parkinsonian tremor are variable and different types of tremors have been described. The aim of this study was to re-evaluate the clinical and electromyographic (EMG) pattern of different tremors in Parkinsonian patients.

Methods: One hundred and ten patients with Parkinsonian tremor were included in the study. Patients were subdivided into four groups according to the presence or absence of postural tremor, in addition to a resting tremor and its EMG pattern. The first group consisted of patients without postural tremor. The second group consisted of patients with fast postural tremor (>7 Hz). The third group consisted of patients with slow postural tremor with alternating EMG activity. Patients with slow postural tremor with synchronous EMG activity were included in the fourth group. In each limb position, the tremor of the most involved body part was graded on the Webster Tremor Scale. Surface EMG recordings of the most involved limb in all positions were performed.

Results: Postural tremor in addition to the rest one was found in 84% of the patients. The postural tremor was with lower amplitude than the rest one. The frequencies and EMG patterns of the postural tremors were different and correlated with some specific clinical symptoms. Patients with alternating postural tremor had a kinetic and intention tremor in addition.

Conclusions: Four different subtypes of Parkinsonian tremor were found according to the presence and type of postural tremor. These subtypes had some differing clinical characteristics and probably different relationships to essential tremor.