Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies

PURPOSE: Several studies have shown that carbamazepine (CBZ) may aggravate idiopathic generalized epilepsy (IGE). Oxcarbazepine (OXC) is a new drug chemically related to CBZ. We report six cases of juvenile IGE with a clear aggravation by OXC. METHODS: We retrospectively studied all patients with IGE first referred to our epilepsy department between January 2001 and June 2003 and treated with OXC. RESULTS: During this period, six patients were identified. All had an aggravation of their epilepsy in both clinical and EEG activities. OXC had been used because of an incorrect diagnosis of focal epilepsy or generalized tonic-clonic seizures (GTCSs) of undetermined origin (no syndromic classification of the epilepsy). Before OXC, only one patient had experienced a worsening of seizures with an inadequate drug (CBZ). Four had juvenile myoclonic epilepsy, one had juvenile absence epilepsy, and one had IGE that could not be classified into a precise syndrome. OXC (dosage range, 300-1,200 mg/day) was used in monotherapy in all of them except for one patient. Aggravation consisted of a clear aggravation of myoclonic jerks (five cases) or de novo myoclonic jerks (one case). Three patients had exacerbation of absence seizures. One patient had worsened dramatically and had absence status, and one had de novo absences after OXC treatment. The effects of OXC on GTCSs were less dramatic, with no worsening in frequency in three and a slight increase in three. CONCLUSIONS: OXC can be added to the list of antiepileptic drugs that can exacerbate myoclonic and absence seizures in IGE.     

Partial seizures during the course in patients with absence epilepsy]

We studied the incidence and clinicoelectrographic features of partial seizures in 46 patients with absence epilepsy. Ten patients (21.7%) showed obvious partial seizure symptoms during the course. Five patients had absence attacks with partial seizure symptoms, the ictal EEGs being a generalized 3 Hz spike-wave burst complex preceded by focal discharges. These absence attacks may be partial seizures with secondary bilateral synchronization, which originated from the frontal lobe. Three patients initially had partial seizures related to the frontal lobe, followed by absence attacks 8 months to 2.6 years after the start of CBZ therapy. The appearance of absence attacks may have been triggered by CBZ administration. Two patients had partial seizures at the relapse of epilepsy after the discontinuation of AED therapy for childhood absence epilepsy. This change of seizure types may be associated with the CNS maturation, or with localized cortical hyperexcitability subsequent to the foregoing generalized seizures. The prognosis of absence attacks in the all patients were excellent, and comparable to that of typical absence attacks. Our results suggest that localized cortical areas, especially the frontal lobe, are commonly involved in absence epilepsy. More detailed clinical observation is necessary to understand the pathogenesis of absence epilepsy.     

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.     

Clobazam Has Equivalent Efficacy to Carbamazepine and Phenytoin as Monotherapy for Childhood Epilepsy

Summary: Purpose: To compare the effectiveness of mono-therapy clobazam (CLB) to carbamazepine (CBZ) and phenytoin (PHT) in children with epilepsy.
Methods: Children aged 2–16 years with newly diagnosed epilepsy or previous failure of one drug (for poor efficacy or side effects) were assigned to one of two study arms and then randomized–CLB versus CBZ or CLB versus PHT. Eligible children had partial epilepsies or only generalized tonic-clonic seizures. After a drug initiation protocol, monotherapy treatment mimicked the usual routines used by Canadian child neurologists. Blinding used a "double dummy" technique with blinded medication serum levels (6–point scale). Intention to treat analysis using survival curves assessed the primary end-point–length of retention on the initial medication during the year after randomization.
Results: Fifteen centers entered 235 patients: 159 randomized to CLB versus CBZ and 76 to CLB versus PHT. Altogether, in all study arms, 119 received CLB, 78 CBZ, and 38 PHT. Overall, 56% continued to receive the original medication for l year with no difference between CLB and standard therapy (CBZ and PHT). Seizure control was equivalent for all three medications, as were side effects. PHT and CBZ induced more biologic side effects, such as rash, while CLB induced slightly more behavioral effects. Tolerance developed in 7.5% of patients receiving CLB, 4.2% with CBZ and 6.7% with PHT.
Conclusions: CLB should be considered as "first line" monotherapy along with CBZ and PHT for all partial and selected generalized childhood epilepsies.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Carbamazepine-exacerbated epilepsy in children and adolescents

Forty-nine children and adolescents whose seizures reportedly worsened while receiving carbamazepine (CBZ) were studied retrospectively. Twenty-six patients met criteria for excellent documentation of carbamazepine-exacerbated seizures. Four epileptic syndromes were particularly affected: childhood absence epilepsy; focal symptomatic, frontal lobe epilepsy; Lennox-Gastaut syndrome; and severe myoclonic epilepsy of infancy. Eight of the 26 patients developed new-onset absence seizures and three patients with established absence epilepsy experienced absence status. Other seizure types, including atonic, tonic-clonic, and myoclonic, developed in eight patients treated with CBZ, and new generalized spike-and-wave discharges were observed in electroencephalograms of nine patients. CBZ is a widely used, effective antiepileptic drug, particularly for partial or partial complex seizures; however, if uncontrolled, generalized seizures occur after CBZ is prescribed for children or adolescents with absence or mixed seizures, a trial of CBZ discontinuation is warranted. The data reported here do not permit calculation of the incidence of this phenomenon.     

Nocturnal Sleep and Daytime Somnolence in Untreated Patients with Temporal Lobe Epilepsy: Changes After Treatment with Controlled-Release Carbamazepine

Summary: Purpose: To define sleep disturbances in patients with temporal lobe epilepsy (TLE) and explore the association between carbamazepine (CBZ) therapy, sleep, and daytime somnolence.
Methods: We recorded nocturnal polysomnography and measured subjective and objective daytime somnolence in a group of newly diagnosed TLE patients, who had no evidence of anatomic brain lesion on neuroimaging and had never been treated before. Recordings were performed at baseline, after the initial administration of 400 mg CBZ-controlled release (CR) and after 1 month of treatment (400 mg twice daily b.i.d.). The findings were compared with those of a group of young healthy volunteers, both at baseline and after the first administration of CBZ. The chronic effect of CBZ-CR treatment was evaluated only in TLE patients.
Results: At baseline, nocturnal sleep patterns of TLE patients did not show marked alterations when the influence of seizures, cerebral lesions, and drugs had been ruled out. In both the TLE and the control groups, initiation of CBZ therapy provoked a reduction and a fragmentation of rapid eye movement (REM) sleep and an increase in the number of sleep stage shifts. In the TLE group, these effects were almost completely reversed after 1 month of treatment, and no significant difference was noted between baseline condition and long-term follow-up. With regard to daytime sleepiness, initial administration of the drug caused an increase in objective sleepiness only in the control group. Subjective sleepiness was higher in the control group than in the TLE group but was not modified by the drug.
Conclusions: We conclude that CBZ-CR has negative effects on REM sleep during initial administration but chronic treatment does not significantly modify nocturnal sleep or daytime somnolence.     

A Pharmacoepidemiologic Study of Factors Influencing the Outcome of Treatment with Lamotrigine in Chronic Epilepsy

PURPOSE: To identify prognostic factors for freedom from seizures and long-term retention of treatment in patients receiving lamotrigine (LTG). METHODS: A multicenter, retrospective, case record study of 1,050 patients with chronic epilepsy was carried out. Logistic regression and Cox regression analyses were used to identify clinical features associated with freedom from seizures and retention of treatment, respectively. Long-term retention rates of LTG therapy were estimated using Kaplan-Meier survival analysis. RESULTS: The 1,050 patients with chronic epilepsy were included in the study. Patients with generalized epilepsy (p = 0.01), who were not receiving carbamazepine (CBZ; p = 0.02) were more likely to become seizure-free. Sixty percent of patients continued on LTG therapy >1 year and estimated retention at 8 years was 38%. Patients with generalized epilepsy (p = 0.002), patients receiving concurrent sodium valproate (VPA; p < 0.0001), those not previously exposed to gabapentin and vigabatrin (p < 0.0001), and those in whom the starting dose was lower (p < 0.0012), were more likely to remain on long-term treatment with LTG. The relationships with exposure to other antiepileptic drugs remained significant in patients with focal and with generalized epilepsy when considered separately. CONCLUSIONS: The best results from LTG treatment in terms of freedom from seizures and long-term retention of treatment were obtained in patients with generalized epilepsy. Retention of treatment was enhanced by VPA not only in generalized but also in focal epilepsy. The importance of a low starting dose of LTG was again confirmed. The apparent negative effect of CBZ in patients taking LTG merits further investigation.     

Rectal carbamazepine as effective long-acting treatment after cluster seizures and status epilepticus

Carbamazepine (CBZ) is the gold standard antiepileptic drug (AED) for focal onset seizures. Despite CBZ being the benchmark AED, with readily available therapeutic drug monitoring, patients presenting with recurrent secondarily generalized tonic–clonic (or cluster) seizures or generalized tonic–clonic status epilepticus (SE) are primarily treated with other long-acting agents. The aim of the study was to examine the potential use of rectal (PR) CBZ as alternative long-acting treatment to parenteral AEDs following the termination of cluster seizures or SE with acute intravenous therapies. Oral CBZ syrup was given PR using 400-mg equivalent aliquots. Serum CBZ levels were requested after administration to confirm achievement of minimum therapeutic levels (total CBZ > 20 μmol·L^− 1). Where levels were subtherapeutic, the procedure was repeated using 400-mg CBZ bolus aliquots until therapeutic levels were achieved. Seven patients received PR CBZ to manage cluster seizures or SE following the initial termination of acute seizures with IV therapies including benzodiazepines. Six patients had no prior history of seizures, and 1 patient with a prior history was not taking AED therapy at the time of presentation. All patients subsequently remained seizure-free, and therapeutic CBZ levels were achieved in 6 of the 7 subjects within 5–10 h of initial CBZ dosing. In conclusion, the present study reports 7 patients who were safely and effectively treated with PR CBZ, which proved to be a viable and safe alternative to parenteral AEDs for maintenance of seizure freedom.     

抗癫痫药对男性癫痫患者性激素的影响

用放免法测定２０例服用苯妥英钠（ＤＰＨ），２０例服用卡马西平（ＣＢＺ）的男性癫痫患者的血清性激素水平，包括总睾酮（ＴＴ）、游离睾酮（ＦＴ）和雌二醇（Ｅ２），并与１０例性功能正常男性和２３例未服药的癫痫男性患者对比。结果发现：ＤＰＨ引起ＴＴ和Ｅ２升高，ＣＢＺ则引起下降。说明两种抗癫痫药对性激素的影响机理不同，因而处理也不完全相同。     

Oxcarbazepine in Focal Epilepsy and Hepatic Porphyria: A Case Report

PURPOSE: Despite the development of new antiepileptic agents (AEDs), the therapy of epilepsies along with hepatic porphyrias remains difficult. Most AEDs such as carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) may precipitate clinically latent porphyria by inducing hepatic metabolism and increasing hepatic heme synthesis. Actually, only gabapentin (GBP), an AED without any hepatic metabolism, is known as a potential therapy for partial seizures in patients having hepatic forms of porphyria. METHODS: We present the case of a 28-year-old man with porphyria cutanea tarda (PCT) who has had pharmacoresistant epilepsy with complex partial and secondarily generalized seizures since early childhood. Despite having undergone several AED therapies over the years, no seizure-free interval had been observed. Only CBZ could cause a seizure reduction, but this treatment had to be discontinued as an elevation of the transaminases as well as pruritus and erythema were noted. The patient was then started on oxcarbazepine (OCBZ), a ketoanalogue of CBZ similar in its pharmacologic mechanism as well as its clinical use, but which, in contrast to CBZ, has only a low hepatic induction of microsomal enzymes. A final maintenance dose four times higher than that of CBZ was prescribed. RESULTS: In the follow-up, the patient stopped having seizures, and his liver functions became normal. CONCLUSIONS: It can be concluded that OCBZ can successfully be administered to patients with hepatic porphyria and focal epilepsy who did not respond to treatment with GBP.     

Lamotrigine versus vigabatrin as an add-on therapy in refractory epilepsy: prospective study

Lamotrigine (LTG) and Vigabatrin (VGB) has been licensed widely as adjunctive therapy for partial and secondary generalized seizures. We compared the efficiency of Lamotrigine and Vigabatrin as adjuvant therapy for 33 patients (16 male and 17 female) with drug-resistant partial epileptic seizures (simple and complex) with secondary generalization receiving combination therapy (carbamazepine--CBZ and valproic acid--VPA). Patients were enrolled if they had experienced two partial seizures (simple or complex) and one secondary generalization/month, despite combination therapy. Neurologic evaluation including CT, MRI and EEG was performed every 3 months during observation. Blood specimens for CBZ and VPA plasma concentration were obtained prior to the first LTG or VGB dose and twice a year during the treatment. The assessment of LTG and VGB effectiveness was performed in 2-month intervals during 2-3 years for vigabatrin (mean daily dose 2.0 g) and 1-2 years for Lamotrigine (mean daily dose 0.3 g). The treatment (CBZ, VPA or both) with Vigabatrin or Lamotrigine as adjunctive therapy was effective in about a half of patients with refractory epilepsy. Findings suggest that the reduction in partial seizures (simple or complex) frequency with Vigabatrin is greater than that with Lamotrigine. On the other hand, Lamotrigine seems to be more effective in patients with partial epileptic seizures with secondary generalization.     

Interictal Autonomic Nervous System Function in Patients with Epilepsy

Summary: We studied 24 patients with partial seizures receiving carbamazepine (CBZ) monotherapy and 40 normal controls, 17 of whom were tested with and without CBZ therapy. Autonomic nervous system assessment included baseline heart rate (HR) and blood pressure (BP); BP and HR changes during orthostasis and cold pressor test (CPT); and HR changes during sinus arrhythmia, Valsalva maneuver, and cold face test with apnea (CFTA). Our study demonstrated normal interictal autonomic function in patients with epilepsy, but, variations in BP and HR during orthostasis and CPT were significantly (p CBZ. Epilepsy patients had higher initial increases in BP and greater subsequent decreases in BP than did nonmedicated controls during CPT. Controls with CBZ had higher HR during orthostasis and CFTA than did those without CBZ. CBZ levels correlated with baseline and orthostatic BP and HR during deep breathing (sinus arrhythmia). Our results showed that patients with epilepsy have greater BP and HR variability and reactivity than controls, attributable in part to CBZ levels.     

Practical Management Issues for Idiopathic Generalized Epilepsies

Summary:  The idiopathic generalized epilepsies (IGE) are a group of epilepsies that are genetically determined, have no structural or anatomic cause, and usually begin early in life. Neurologic examination, intelligence, and imaging studies are normal, and EEG shows only epileptiform abnormalities (i.e., no abnormal slow activity or evidence for diffuse encephalopathy). In some IGE, the genetic substrate has been identified, whereas in most, it remains unknown. Depending on the age at onset and predominant seizure type, individual subtypes of IGE (syndromes) are defined. However, overall, there are more similarities than there are differences among the various subtypes, and the IGE are best viewed as a spectrum or continuum of conditions. In general, IGE respond to treatment, with 80–90% becoming fully controlled. However, not all antiepileptic drugs (AED) are equally effective in IGE. Some AED are ill advised because they either do not work or exacerbate seizure types other than generalized tonic–clonic (GTC) seizures, that is, absence and myoclonic seizures. These include carbamazepine, oxcarbazepine, phenytoin, gabapentin, and tiagabine. Their use is the main cause of "pseudo-intractability," and at least in the United States where PHT and CBZ are the most commonly used AEDs, patients with IGE are often on inadequate medications. For patients with clear IGE, the drug of choice is generally valproic acid because it effectively controls absence myoclonic seizures and GTC seizures. Second-line drugs (when first-line drugs fail or are not tolerated) may include benzodiazepines, but the use of second-line drugs is evolving rapidly. Some of the newer AEDs are considered broad spectrum, meaning that they work in IGE and focal epilepsies, although the evidence is largely preliminary at this point. These newer AEDs include lamotrigine, topiramate, levetiracetam, and zonisamide.     

Practical Aspects of Oxcarbazepine Treatment

Summary: In patients with refractory seizures, substitution of oxcarbazepine (OCBZ) for carbamazepine (CBZ) may be associated with reduced seizure frequency and an improved mental state. The recommended dosage of OCBZ as monotherapy for adults with epilepsy is 600-1,200 mg orally per day but may be higher in patients with refractory seizures and in patients requiring combination therapy. When OCBZ is substituted for ongoing CBZ therapy, it is possible to change the dosage immediately so that the patient finishes treatment with CBZ on one day and starts with a full dosage of OCBZ on the next day, even when the full dosage is 50% greater in milligrams than the corresponding CBZ dosage. Allergic skin reactions are rare, and crossreactivity is seen in about 25% of patients hypersensitive to CBZ. Hyponatremia after the use of OCBZ is usually benign, as long as the acute water intoxication is effectively treated. Because of its pharmacokinetic advantages' and efficacy, we believe OCBZ is better than CBZ. We therefore consider OCBZ as the drug of first choice for conditions in which CBZ is currently indicated.     

Carbamazepine-exacerbated epilepsy with multifocal shifting independent epileptiform discharges on electroencephalogram: A case report

Abstract A 7 year old girl with epilepsy and spastic quadriplegia secondary to an episode of status epilepticus at 4 months of age is reported. At the age of 6 years, she began to experience increased generalized myoclonic and tonic seizures during treatment with carbamazepine (CBZ) 200 mg/day and clonazepam 1.5 mg/day. When the CBZ was increased to 400 mg/day, the seizures increased dramatically in frequency. Following discontinuation of CBZ, the seizure frequency decreased to a level less than that prior to starting CBZ. Serial electroencephalograms displayed multifocal independent epileptiform discharges (MIED) characterized by shifting localization, which could be one of the risk factors for exacerbation by CBZ. In this case MIED may indicate widespread rather than localized cerebral dysfunction.     

The Influence of Electroencephalographic Focus Laterality on Efficacy of Carbamazepine in Complex Partial and Secondarily Generalized Tonic-Clonic Seizures

Forty-five outpatients with chronic epilepsy with complex partial seizures (CPS) alone or associated with secondarily generalized tonic-clonic seizures (SGTCS) were treated with carbamazepine (CBZ) monotherapy. All patients had only a unilateral scalp electroencephalographic (EEG) focus. Left- (n = 29) and right- (n = 16) sided foci patients were comparable for age, sex, duration, and etiology of epilepsy as well as total and free CBZ serum levels. CBZ significantly improved CPS irrespective of the side of the EEG focus, whereas SGTCS were controlled for greater than 1 year in 15 of 19 patients with left focus and in three of 11 patients with right focus. When patients with poorly controlled seizures discontinued CBZ and changed to other therapies, they achieved a significant reduction in number of SGTCS, whereas the number of CPS was unchanged. The side of EEG focus seemed to be relevant to the control of SGTCS by CBZ. Interhemispheric neurotransmitter asymmetries may be involved in the EEG focus side-dependent CBZ response.     

Stimulus-induced focal motor seizure in a pediatric patient with carbamazepine overdose

IntroductionCarbamazepine (CBZ) is a common antiepileptic drug that may cause overdoses with seizures as a common neurological manifestation. In previous reports, patients with CBZ overdose exhibited stimulus-induced generalized clinical or electrical seizures. To date, no previous cases of focal motor seizures have been reported.Case reportWe report the case of an 11-year-old girl with spontaneous and stimulus-induced clustering of focal motor seizures following CBZ overdose. The patient had been treated with CBZ (150 mg daily) for focal epilepsy since the age of six years. At the age of 11, she forgot to take a morning dose, took ten CBZ pills (CBZ 1000 mg) as compensation, and presented with generalized seizures. The patient arrived at the hospital in a coma. She demonstrated clustering of focal-to-bilateral tonic-clonic seizures induced by pain stimulus or spontaneously, with focal epileptiform discharges observed on EEG. Her CBZ blood concentration measured 40.4 μg/mL and she was diagnosed with CBZ overdose. The patient showed improvement without any specific treatment, and was later discharged without neurological sequelae.ConclusionPrevious cases of CBZ overdose with stimulus-induced generalized seizures resulted in death or required intensive care. Stimulus-induced focal seizures may indicate a favorable prognosis for CBZ overdose.     

Folate, homocysteine and methionine loading in patients on carbamazepine

OBJECTIVES: Some antiepileptic drugs (AEDs) are associated with low levels of serum (S-FA) and erythrocyte folate (E-FA) and high levels of plasma total homocysteine (p-tHcy). We have explored the concentrations of S-FA, E-FA and p-tHcy in patients on carbamazepine (CBZ). The methionine loading test was applied for better assessment of mildly impaired homocysteine metabolism. MATERIAL AND METHODS: The study comprised 42 adult patients on CBZ and 42 matched healthy controls. Blood samples were drawn prior to and 6 h post methionine loading (6 h-PML) (0.1 g/kg body weight). RESULTS: The patients on CBZ had significantly lower concentrations of fasting S-FA and E-FA than the controls (P=0.0004, P=0.003, respectively). Fasting and 6 h-PML p-tHcy concentrations were significantly higher in the patients than in the controls (P=0.03 and P=0.0001, respectively). The methionine loading test identified additional patients with hyperhomocysteinemia undetected by fasting p-tHcy. CONCLUSION: CBZ therapy may be associated with low folate and high p-tHcy levels.