Comparative Pharmacokinetic Study of Chewable and Conventional Carbamazepine in Children

Summary: Fifteen children (7 boys and 8 girls) with generalized tonic-clonic seizures (GTCS) and partial seizures with elementary or complex symptomatology, treated with carbamazepine (CBZ) alone (n = 7) or in combination with either phenobarbital (PB, n = 6) or clobazam (CLB, n = 2) given for at least 3 months at stable individualized doses and regimens, entered an open, withinpatient, change-over study of consecutive periods, each lasting 2 weeks. During period 1, conventional CBZ was given; during period 2, a chewable CBZ formulation was substituted for conventional CBZ and given at the same total daily dosage with the same schedule as in period 1. Blood samples for measuring plasma concentration of both total CBZ and CBZ-10, 11 epoxide (CBZ-E) were taken on the last day of each period. No significant difference between the two periods was noted in the mean ±SD of C_max, Css mean, and area under the curve (AUC) of total CBZ and CBZ-E. The two different CBZ formulations, administered at the same total daily dosage, can be considered bioequivalent.     

Follow-Up of 146 Children with Epilepsy after Withdrawal of Antiepileptic Therapy

The relapse rate after discontinuation of antiepileptic drug treatment was investigated in 146 children with epilepsy, in whom medication was withdrawn according to a predesigned protocol, after a seizure-free period of at least 2 years and normalization of the EEG. The cumulative probability of remaining seizure-free in this series was 74.5%. Three-quarters of the relapses occurred during the withdrawal period and in the 2 years thereafter. From multivariate analysis, the factors indicating a significantly higher relapse risk were seizures with a known cause and female sex. In primary generalized epilepsy, no factor significantly increased the likelihood of a recurrence. In partial epilepsy, significant factors predictive of recurrence were the presence of a neurological deficit (focal neurological signs and/or mental retardation), female sex, a positive family history for epilepsy, and the number of drugs necessary for control of the seizures. The present results are compared with the available literature data. It is argued that using multivariate analysis after elimination of EEG variables uncovers significant clinical predictive factors that in other studies may have remained hidden. Finally, it is argued that statistical analysis may be used to enable the clinician to predict the likelihood of recurrence in individual children with a given set of relevant predictive factors.     

Carbamazepine (CBZ) Controlled Release Compared with Conventional CBZ: A Controlled Study of Attention and Vigilance in Children with Epilepsy

To compare the effects on attention and vigilance of conventional carbamazepine (CBZ) and CBZ controlled release (CBZ-CR), 15 schoolchildren with epilepsy and normal intelligence receiving CBZ were switched to CBZ-CR. Psychological examination was performed on the day before (day A) and 1 month after substitution (day B). Measurements of attention and vigilance were repeated throughout the day at 2-h intervals. Both on days A and B, CBZ plasma levels were monitored during a 12-h period. Fifteen matched healthy controls were submitted to identical test programs, allowing comparisons within subjects as well as between patients and control children. Variability of performance over sessions was neither increased nor decreased with CBZ-CR. Consistent differences over sessions did not exist between patients and controls with either drug. No relation was noted between reaction time and CBZ plasma level. The pharmacologic data confirm results of earlier studies in children. We noted a reduction in intradose fluctuations of CBZ level with CBZ-CR as compared with conventional CBZ. The neuropsychological results do not show a difference between the drugs. Neither were differences noted with respect to antiepileptic efficacy and side effects. At the end of the study, all but one of the children (and their parents) opted to receive CBZ-CR for ease of dosage administration and overall satisfaction.     

Carbamazepine Versus Phenobarbital for Partial Onset Seizures in Children

Thirty-nine children were treated with either phenobarbital (PB) or carbamazepine (CBZ) for newly diagnosed partial onset seizures. Drug selection was randomized in 33 subjects. Parents and the psychologist evaluating the child were blind to drug identity. Psychometric and behavioral evaluations were done at intake and at 6- and 12-month follow-ups. There were no significant differences between drugs in effect on behavior or cognitive function. CBZ caused more systemic problems. There was a trend toward better seizure control with CBZ, but this was not statistically significant. Although individual children in each group had changes in behavior or cognitive status, neither group changed significantly, in either acute or chronic follow-up.     

Clinical Monitoring During Carbamazepine Slow-Release, Once-Daily Monotherapy

Forty-eight patients with complex partial and/or tonic-clonic seizures were treated with an 8 p.m. single dose of carbamazepine slow release (CBZ-SR) monotherapy. The steady-state serum level profiles of carbamazepine (CBZ) and its metabolites CBZ-10,11-epoxide (CBZE) and 10,11-dihydro-CBZ-10,11-diole (CBZD) during 24 h in 21 of 48 patients treated with daily single doses of 8.4 (+/- 2.4) mg/kg body weight CBZ-SR were determined by a high-performance liquid chromatography procedure. The 8 a.m. CBZ levels correlated very well with the mean CBZ levels of the 24-h profile. Unlike CBZD, the individual 24-h mean CBZE levels also correlated well with the respective CBZ levels (CBZE = 14.2% +/- 2.9 of CBZ). Increasing CBZ-SR doses does not result in a proportional increase of CBZ levels. Clinical efficacy of changing from CBZ standard tablets under mono- or combination therapy or from therapy with other antiepileptic drugs to once-daily evening CBZ-SR monotherapy or commencement CBZ-SR therapy in previously untreated patients was monitored in 35 of 48 patients for a period of 8 months to 2 years. Complete seizure control was observed in 51% of patients and more than 75% reduction of seizure frequency in 14%. Eight of 11 previously untreated patients became seizure free. With change from CBZ monotherapy to CBZ-SR single-dose therapy, five of six patients became seizure free. Changing from other therapeutic regimens to CBZ-SR once-daily evening monotherapy was less successful.     

Progabide-Induced Changes in Carbamazepine Metabolism

Carbamazepine (CBZ) and carbamazepine 10,11 epoxide (CBZ-E) concentrations were measured during a safety and efficacy trial of progabide. The average CBZ and CBZ-E serum concentrations were calculated from serial measurements during placebo and active treatment periods. Significant decreases in CBZ and significant increases in CBZ-E were observed after the first dose of progabide, and these changes persisted during 3 months of active treatment. Ninety-five percent of the patients had increases in the epoxide/CBZ ratio at the end of 3 months of treatment. These changes are consistent with displacement of CBZ from protein binding sites and inhibition of CBZ-E metabolism induced by progabide and are analagous to the interaction between valproate and CBZ.     

Hepatotoxic Reactions Associated with Carbamazepine Therapy

Hepatotoxic reactions in patients receiving carbamazepine (CBZ) therapy have been reported, and some have been considered fatal. We present two patients with hepatic dysfunction secondary to CBZ therapy. Liver biopsies were compatible with hepatotoxic damage, and the symptoms were reversible with medication withdrawal. Our patients are representative of those in the literature, most of whom have granulomatous hepatitis and sometimes have associated cholangitis. The patients with fatal reactions differed clinically and pathologically from the others, and may represent a different entity. The clinical syndrome resembles a viral hepatitis. Elderly patients seem to be particularly susceptible and their hepatic function should be monitored closely when CBZ therapy is initiated.     

Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study of the Effects of Monotherapy on the Long-Term Course of Epilepsy

Summary: A cohort of 280 previously untreated epilepsy subjects (159 men and 121 women aged 2–81 years) recruited in 14 Italian centers were treated with antiepileptic drug (AED) monotherapy and followed for a median period of 48 months to investigate the rates of seizure remission (i.e., complete control), in general and with reference to various prognostic factors. The cumulative probability of achieving 1-year remission was 62% by 1 year after onset of treatment, 81% by 2 years, 92% by 3 years, and 98% by 5 years. The corresponding figures for 2- and 3-year remission at 5 years were 92 and 78%, respectively. Sixty-two patients (22.1%) had no remission period with monotherapy. Remission rates were significantly lower among patients with two or more seizure types and were inversely correlated to the number of seizures before treatment. The rate of seizure relapses during the first year of follow-up appear to correlate to the risk of developing refractory epilepsy (i.e., with no remission).     

Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study

A multicenter prospective study was initiated at the time of first antiepileptic treatment for afebrile seizures with 283 unselected patients in Italy. Each patient started with monotherapy at standard daily doses. Data were collected at admission, at scheduled 6-month exams, and at unscheduled exams and included age, sex, general profile of the disease, and treatment. Prognosis of epilepsy was evaluated by actuarial methods using first seizure relapse after onset of treatment to indicate unfavorable prognosis. In addition, a maximum interval of complete seizure control was calculated and related to length of follow-up in order to grade the severity of the disease (defined as mild, moderate, or severe). The average length of follow-up was 21.6 months (range 2-40). Seizure relapse occurred in 52% of cases during follow-up (36% by 3 months, 43% by 6 months, and 49% by 12 months). A larger number of seizures before therapy and the presence of combined seizure patterns were the variables most commonly associated with relapse. In general, epilepsy was mild in 65% of the cases, moderate in 28%, and severe in 7%. The earlier the first relapse the higher the risk of developing more severe disease. A larger number of seizures before treatment, combined seizure types, earlier age at onset, and prolonged disease duration (1 month to 1 year) seemed to be more frequently associated with the development of moderate-to-severe epilepsy.     

Intractable Diarrhea from Carbamazepine

Diarrhea has been reported as an early, mild, and uncommon complication of carbamazepine (CBZ) therapy. We report three cases of intractable diarrhea induced by CBZ necessitating discontinuation of the drug.     

Adenosine Antagonist Properties of Carbamazepine

The binding of adenosine agonists and antagonists to the adenosine receptor is differentially affected by both temperature and guanine nucleotides. Agonist binding is facilitated at higher temperatures; the reverse is true for adenosine antagonists. In the present study, we demonstrate the feasibility of utilizing the temperature dependency of agonist/antagonist binding to the adenosine receptor in binding inhibition studies. We show that the anticonvulsant drug carbamazepine (CBZ) and several of its structural analogs behave in a manner identical to that of a series of adenosine antagonists; i.e., they are more potent inhibitors of [3H]cyclohexyladenosine (CHA) binding at 8 degrees C as compared to 37 degrees C and are equipotent as inhibitors of [3H]diethylphenylxanthine (DPX) binding at 0 and 30 degrees. We also show that the potency of CBZ and derivatives as inhibitors of [3H]CHA binding is markedly increased in the presence of 10 microM GppNHp, whereas their potency as inhibitors of [3H]DPX binding is unaffected by this guanine nucleotide. These data in conjunction with past studies support the hypothesis that CBZ and its derivatives act as adenosine antagonists at the level of binding interactions at the adenosine receptor.     

Treatment of Intractable Childhood Epilepsy with High-Dose Valproate

Forty-six children with refractory epilepsy (12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 20 with undetermined epilepsy) were treated by high-dose (serum level above 100 micrograms/ml) valproate (VPA) therapy. Monotherapy was used with 34 patients and two drugs with 12. Serum VPA concentrations ranged from 105.1 to 198.4 micrograms/ml. Assessment of initial response to treatment, after the serum level had reached the appropriate level, showed seizures to be completely controlled in 15 (32.6%) of 46 patients and improved in 12 (26.1%) (50% or more). Follow-up of more than 6 months after the time of initial response showed control of seizures in 14 (30.4%) and improvement in 11 (23.9%). The initial effect on EEG was the disappearance of epileptic discharges in 3 (6.5%) of 46 patients and marked improvement in 15 (32.6%). Follow-up revealed the disappearance of epileptic discharges in 7 (15.2%) and marked improvement in 9 patients (19.6%). High-dose VPA therapy was especially effective for West syndrome and for epilepsy with continuous spike-waves during slow-wave sleep. Control of atypical absences and myoclonic seizures was relatively good. Hypofibrinogenemia and thrombocytopenia were sometimes encountered but these side effects were reversible with reduction of dosage.     

Antiepileptic Drug Treatment After Temporal Lobe Epilepsy Surgery: A Randomized Study Comparing Carbamazepine and Polytherapy

Temporal lobectomy is an effective treatment in selected patients with medically intractable temporal lobe epilepsy (TLE). Postoperative antiepileptic drug (AED) treatment guidelines have not been established, and patients are often treated with polytherapy postoperatively. We prospectively randomized 40 patients undergoing temporal lobectomy to monotherapy with carbamazepine (CBZ, 20) or to continuation of their presurgical polytherapy (20) to assess the efficacy and safety of each regimen during the first year after operation. No significant differences between groups were noted with respect to seizure recurrence rate and type or time of recurrence. Patients in the polytherapy group had a 30% incidence of drug-related side effects as compared with only 10% in the CBZ group. These results suggest that after temporal lobectomy for intractable epilepsy, patients can be safely treated with CBZ monotherapy and that treatment with multiple AEDs is not necessary.     

Successful Treatment of Massive Carbamazepine Overdose

Overdose of carbamazepine (CBZ) can be fatal. We report the case of a patient with near-lethal toxicity due to delayed absorption of drug. A 36-year-old woman was admitted with coma, hypotension, and unusual movements. Carbamazepine (CBZ) level several hours later was 36 mg/L. Gastric lavage revealed no pill fragments, and activated charcoal was administered. CBZ level initially fell, reaching 28 mg/L 36 h after admission. Blood level then rose sharply, reaching 54 mg/L 64 h after admission. The pattern of rise suggested renewed absorption of drug. Vigorous cathartics were given, and further doses of charcoal were administered. Three hours after onset of diarrhea, roving eye movements occurred. Two hours later she grimaced to pain. Eight hours after the onset of diarrhea, she was awake. In CBZ overdose, activated charcoal therapy coupled with aggressive intestinal purging helps prevent continued absorption of drug, late exacerbation of symptoms, and potentially fatal outcome.     

Carbamazepine Does Not Affect Short-Latency Somatosensory Evoked Potentials: A Longitudinal Study in Newly Diagnosed Epilepsy

Somatosensory evoked potentials from median nerve stimulation were recorded in 12 patients with newly diagnosed epilepsy, before and after 1 year of treatment with carbamazepine. The plasma concentrations of the drug were consistently within therapeutic range. We assessed the latencies of the early components at the level of the cervical spine (N9 and N13) and on the parietal scalp (P14, N20, P25) and the interpeak latencies (N9-N13, N13-N20, P14-N20). None of the patients presented anomalies in any of the parameters, and there was no significant difference between the patient and control means or between the patient means before and after 1 year of treatment.     

Prognosis of Benign Childhood Epilepsy with Centrotemporal Spikes: A Foliow-Up Study of 168 Patients

A spontaneous and complete recovery of benign childhood epilepsy with centrotemporal or rolandic spikes (BECT) is taken for granted. However, some authors have reported the occurrence of generalized tonic-clonic seizures in a few adult patients and in some children who have seizures after a long period without problems. The aims of this study were (a) to search for early predictors of outcome and (b) to ascertain the long-term prognosis of BECT in a large group of patients. An attempt to relocate 268 patients born between 1941 and 1967 and consecutively seen as outpatients was undertaken. The outcome after age 20 is known for only 168. Being adults and cured, the others are no longer in touch with their clinics or have moved. Only one indicator of short-term prognosis was found: The earlier the onset of BECT, the longer the period with seizures. Of the 168 patients, 165 are seizure-free with follow-up ranging from 7 to 30 years. Three patients experienced generalized tonic-clonic seizures at age 18, 22-24, and 35. Two apparently had an isolated seizure. The occurrence of such seizures after recovery from BECT is a rare event (approximately 2% of cases) and a relapse with partial seizures is quite uncommon. These patients do not differ from patients remaining seizure-free.     

Steady-State Pharmacokinetics of Topiramate and Carbamazepine in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ). Methods: We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300–800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at -2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy. Results: Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC_(0–12)), C_min(0), and C_avg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC_(0–12)) C_max, C_min(0), and C_avg values were -40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered. Conclusions: When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.     

Prognosis of Childhood Seizure Disorders: Present and Future

Summary: The prognoses for seizure disorders have been examined since the beginnings of epileptology, and only recently has the realization emerged that, ultimately, prognosis depends on causation, which, in turn, determines whether a condition is self-limited or progressive. This factor is more important than either mode or alacrity of therapeutic intervention. The epilepsies are a series of conditions that have the final common path of either increasing cerebral irritability or synchronizing normally occurring electrical activity in such a manner that seizures result. In turn, some seizure disorders are characterized by secondary changes in neuronal synaptogenesis, leading to the development of circuits of predilection, which then render the process autonomous. Epilepto-genesis has then become epilepsy, which is the norm in acquired rather than genetic epileptogenesis. An understanding of the basic differences between the primary (idiopathic) epilepsies and the secondary (acquired or symptomatic) epilepsies is basic to a discussion concerning prognosis and to the development of a definitive individualized treatment plan. An elucidation of the genetic factors in idiopathic epilepsy and their neurochemical consequences represents a major frontier in epileptology.