Levetiracetam in the treatment of epilepsy

Epilepsy is a common chronic disorder that requires long-term antiepileptic drug therapy. Approximately one half of patients fail the initial antiepileptic drug and about 35% are refractory to medical therapy, highlighting the continued need for more effective and better tolerated drugs. Levetiracetam is an antiepileptic drug marketed since 2000. Its novel mechanism of action is modulation of synaptic neurotransmitter release through binding to the synaptic vesicle protein SV2A in the brain. Its pharmacokinetic advantages include rapid and almost complete absorption, minimal insignificant binding to plasma protein, absence of enzyme induction, absence of interactions with other drugs, and partial metabolism outside the liver. The availability of an intravenous preparation is yet another advantage. It has been demonstrated effective as adjunctive therapy for refractory partial-onset seizures, primary generalized tonic-clonic seizures, and myoclonic seizures of juvenile myoclonic epilepsy. In addition, it was found equivalent to controlled release carbamazepine as first-line therapy for partial-onset seizures, both in efficacy and tolerability. Its main adverse effects in randomized adjunctive trials in adults have been somnolence, asthenia, infection, and dizziness. In children, the behavioral adverse effects of hostility and nervousness were also noted. Levetiracetam is an important addition to the treatment of epilepsy.     

Levetiracetam monotherapy for childhood occipital epilepsy of gastaut

Objectives – The aim of this open label pilot study was to evaluate the efficacy and tolerability of levetiracetam (LEV) as ‘de novo’ monotherapy in children and adolescents with late onset childhood occipital epilepsy–Gastaut type (COE‐G). Material and methods – Twelve patients suffering from COE‐G were enrolled in this prospective study. The age of seizures onset ranged from 6.1 to 16.2 years with a peak of frequency at mean (±SD) 10.54 ± 2.77 years. Therapy with LEV was started at 10 mg/kg/day and, after titration, the final dose was generally achieved within 4 weeks and ranged from 20.7 to 45.2 mg/kg/day. Results – At the 6 month evaluation, 11 (91.6%) of the 12 patients studied were seizure free, and one (8.3%) showed four additional episodes. Electroencephalography (EEG) activity was normal in six (54.5%) patients, unchanged in two (18.1%) children, and in four (33.3%) patients sporadic occipital abnormalities persisted. At the 12‐month evaluation all patients were completely seizure free. Four patients (33.3%) continued to show some EEG abnormalities, while eight (72.8%) patients had normal EEG. At the 18‐month evaluation all patients were seizure free and 10 patients (83.3%) showed a complete normalization of EEG abnormalities. Discussion – Monotherapy with LEV was effective and well tolerated in patients with COE‐G. Nevertheless, prospective, large, long‐term double‐blind studies are needed to confirm these findings.     

Levetiracetam treatment of idiopathic generalised epilepsy

Levetiracetam (LEV) is effective for treating localisation-related epilepsy, but it is uncertain whether it is effective for treating idiopathic generalised epilepsy. We compared 12-week baseline and LEV treatment periods for patients with generalised seizure types-myoclonic, tonic-clonic and absence seizures--who had failed other anticonvulsants. The majority of 55 patients (76%) had >50% seizure reduction with LEV therapy, 40% became seizure-free; 15% discontinued LEV due to adverse events, mostly sedation. This is preliminary evidence that LEV is effective for treating idiopathic generalised epilepsy.     

Levetiracetam for benign epilepsy of childhood with centrotemporal spikes-three cases.

Benign epilepsy with centrotemporal spikes (BECTS), also known as benign rolandic epilepsy (BRE) of childhood represents 15% of all childhood epilepsies [Handbook of Epilepsy Treatment (2000)]. A majority of these patients do no require treatment; however, in those cases where treatment is justified, the most efficacious medication with a benign safety profile should be selected. We present three clinical cases of otherwise healthy children with BECTS who were treated only with levetiracetam. All three of these children remain seizure-free and are experiencing no reported side effects.     

Levetiracetam in absence epilepsy

The aim of the study was to assess the efficacy, tolerability, and safety of levetiracetam therapy in children and adolescents with absence epilepsy. Twenty-one participants (11 male, 10 female) with typical absence seizures were enrolled in this prospective study from seven centres in Italy. The mean age and age range at time of enrollment into the study were 8 years 9 months (SD 0.9) and 5 years 1 month to 13 years respectively. All patients were carefully evaluated at 6 months from baseline, and 12 patients were also re-evaluated at 12 months after the beginning of therapy with levetiracetam. At the 6-month evaluation, out of 21 patients studied, 11 were seizure free and one showed 'decreased' seizures (more than 50% reduction in seizures). A less than 50% reduction in seizures was observed in nine patients. At the 12-month evaluation, 10 patients were completely seizure free and two were seizure free with some anomalies in electroencephalograms. Two patients who had shown no improvement at 6 months had decreased seizures at the second follow-up. Our results suggest that monotherapy with levetiracetam could be effective and well tolerated in patients with childhood absence epilepsy and juvenile absence epilepsy. Prospective, large, long-term double-blind studies are needed to confirm these findings.     

Levetiracetam in refractory pediatric epilepsy

Levetiracetam, one of the newer-generation antiepilepsy drugs, is not currently approved for use in children. Given its favorable efficacy, pharmacokinetic, and, particularly, safety profile in adults, we felt that it may be a useful antiepilepsy drug for children with refractory epilepsy. We treated 39 patients (mean age 8.6 years) with open-label levetiracetam for up to 9 months. Seizure frequency, drug dosages, adverse events, and neurologic examinations were documented at baseline and routine follow-up visits. Levetiracetam, as add-on therapy, was effective in reducing seizure frequency in a variety of seizure types but was most effective for partial-onset seizures. Fourteen patients were discontinued for lack of efficacy or adverse events. Ten patients reported improvements in cognition or behavior. Levetiracetam was generally effective and well tolerated in this open-label study. Its apparent positive effects on cognition in some patients are encouraging. Large, well-controlled studies are needed to fully define levetiracetam's potential in children with refractory epilepsy.     

Oxcarbazepine in the treatment of childhood epilepsy

In this study, oxcarbazepine was began as monotherapy to evaluate the efficacy and safety of the drug. Forty-two patients (19 females, 23 males) with partial or generalized epilepsy more than 4 years of age were included (mean age, 11.9 +/- 3.4 years). The mean age at epilepsy onset 8.9 +/- 4 years. Complete blood count, liver function tests, electrolytes, lipid levels, electrocardiography, electroencephalography, and magnetic resonance imaging were performed in all patients. Oxcarbazepine dose was begun at 10 mg/kg/day twice daily and increased to 30 mg/kg/day at the end of the second week. Patients with inadequate seizure control even with the dose of 45 mg/kg/day or intolerable side effects were excluded. Intolerable headache and leukopenia led to discontinuation of the drug in two patients. At the sixth month, 35 of the patients (87.5%) were seizure free (91.7% of the generalized epilepsy patients and 81.2% of the partial epilepsy patients). The most frequent tolerable side effect was drowsiness in 12 patients. As a result, we found oxcarbazepine safe and effective in children with either generalized or partial epilepsy.     

Levetiracetam monotherapy in children with epilepsy

Although levetiracetam has shown efficacy in children with epilepsy, when used as adjunctive therapy, limited data are available regarding its use as monotherapy. The objective of this study is to evaluate the efficacy and tolerability of levetiracetam monotherapy in a cohort of pediatric patients with epilepsy. A retrospective analysis of pediatric epilepsy patients receiving levetiracetam at a single institution was performed over a 3-year period. Eighty-one patients were identified, 18 of whom received levetiracetam as monotherapy (mean age, 9.6 years). Epilepsy types were partial in 14 and generalized in 4. Conversion to levetiracetam monotherapy occurred in 16 patients due to lack of efficacy or adverse events, and 2 patients were initially started on monotherapy. Dose range of levetiracetam was 14-60 mg/kg, and duration of therapy ranged from 2-24 months. Eleven patients became seizure free on levetiracetam, one had at least 50% reduction in seizures, and six others had no change in seizure frequency. Adverse events included worsening of behavior, irritability, and possible cognitive changes, seen in 4 patients. Levetiracetam was discontinued in seven patients overall. Levetiracetam monotherapy appeared to be effective and well tolerated in this group of children with epilepsy and warrants further investigation in a well-controlled, prospective study.     

Levetiracetam psychosis in children with epilepsy

PURPOSE: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children. METHODS: In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures. RESULTS: A 5-year-old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13-year-old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16-year-old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17-year-old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits. CONCLUSIONS: Reversible treatment-emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established.     

Rational treatment of refractory epilepsy in childhood

A multifaceted study on childhood refractory epilepsy disclosed an insufficient classification of epilepsies and epileptic seizures, and inappropriate polypharmacy as the most important factors preventing appropriate therapy. By means of an adjustment of AEDs based on the accurate classification of epilepsies and epileptic seizures, the number of AEDs could be reduced in 37.5% and monotherapy was successful in 13.8% of refractory cases. Most of the latter were those of partial epilepsy and generalized epilepsy with the monoseizure type. The exacerbation of seizures due to AEDs was also mentioned as one of the important side effects of AEDs.     

Levetiracetam monotherapy in juvenile myoclonic epilepsy.

PURPOSE: To describe our experience with levetiracetam (LEV) as initial or conversion monotherapy treatment for juvenile myoclonic epilepsy (JME). Valproate, the usual first line agent for JME, has chronic adverse effects, particularly for women of childbearing potential. Since JME requires lifetime treatment, chronic adverse effects of therapy are important consideration. METHODS: We reviewed the medical records of patients with JME treated with LEV in the first 4 years after marketing. We recorded demographic data, results of EEG and imaging studies, antiepileptic drug (AED) history, LEV initial dose and final dose, side effects related to LEV, and therapeutic response to treatment. We classified JME into definite and probable based on clinical and EEG criteria. The minimum duration of follow up was 1 year. RESULTS: LEV was the first therapy in 12 patients and the initial appropriate agent in 16. Fourteen patients had been treated with another appropriate AED. Eighty percent (24/30) of patients became seizure free with LEV monotherapy and two additional patients showed improved seizure control. Final therapeutic doses of LEV ranged from 12 to 50mg/(kgday). Complete seizure control using LEV was not predicted by previous AED use. Treatment failure with valproate also did not predict failure of LEV. Patients with definite JME responded best within the study group (11 of 11 seizure free, p<0.05). CONCLUSIONS: This study supports consideration of LEV for first line treatment of JME and suggests the need for a large prospective trial.     

Pharmacological treatment of childhood absence epilepsy

This review discusses current pharmacological treatment of childhood absence epilepsy (CAE). The key to successful treatment is the correct diagnosis of the epileptic syndrome, hence the initial part of the paper discusses the definition, diagnostic criteria and epidemiology. This is followed by a detailed analysis of pharmacological agents used in the treatment of CAE. The characteristics of old and new anticonvulsants used in the treatment of CAE are also reviewed. For each of the drugs, the mechanism of action, usual dose, common side effects and recommendations for treatment are also discussed. A separate section focuses on instances when anticonvulsants may exacerbate seizures. Particular emphasis is given to the evidence currently available, on which clinical practice needs to be based.     

Ezogabine treatment of childhood absence epilepsy

Generalised‐onset absence seizures can be resistant to treatment with currently available antiepileptic drugs. Ezogabine (retigabine), a potassium channel opener, is approved for the treatment of focal‐onset seizures. This is a case report of an adult with childhood absence epilepsy whose daily absence seizures ceased with adjunctive ezogabine. A 59‐year‐old woman, with a history of typical absence seizures since the age of 6 years, had multiple seizures daily despite trials of over 11 antiepileptic drugs. While taking lamotrigine and zonisamide, ezogabine at 50 mg daily was added. The dose was slowly increased and once a total dose of only 200 mg/day was reached, she became seizure‐free for three months. After subsequently discontinuing zonisamide, absence seizures returned. Further increasing the ezogabine to 400 mg/day, in addition to lamotrigine, did not restore seizure freedom, but adding back zonisamide at half dose again reduced their frequency. Ezogabine at low dose, added to lamotrigine and zonisamide, led to sustained absence seizure freedom. The return of seizures after zonisamide discontinuation suggests that the seizure freedom may have been the result of the different mechanisms of action of the antiepileptic drugs.     

Surgical treatment of medically refractory epilepsy in childhood

Twenty-five percent of children with epilepsy continue to seize despite the best medical management and may be defined as medically refractory. Many children with medically refractory localization-related epilepsy, i.e. seizures which originate in a particular area of the brain and secondarily spread to involve other brain regions, may benefit from a variety of surgical treatments including hemispherectomy, corpus callosotomy, focal cortical resection of the temporal lobe, focal cortical resection of extratemporal regions of the brain, and multiple subpial resections. A successful outcome from epilepsy surgery is generally defined as a seizure-free state with no imposition of neurologic deficit. In order to achieve these twin goals two criteria must be fulfilled. First, precise localization of the epileptogenic zone in the brain is necessary. The epileptogenic zone may be defined as the region of epileptogenic cerebral cortex whose removal will result in a seizure-free state. Second, one must determine the anatomic localization of eloquent cortex in the brain in order to spare these areas during any planned cortical excision of epileptogenic cortex. Several diagnostic measures may be used to achieve a successful surgical outcome. A clinical history to ascertain the earliest symptom in the clinical progression of the seizure (semiology) is imperative as is ictal and interictal scalp EEG, neuropsychological testing, magnetic resonance imaging, positron emission tomography, single photon emission computerized tomography, and interictal magnetoencephalography. In the typical child undergoing evaluation for epilepsy surgery, if the clinical, neuropsychological, EEG, and radiological data are all concordant and point to the same area of epileptogenicity in the brain, cortical excision of the suspected epileptogenic zone is undertaken. However, if the data are discordant, and/or the epileptogenic zone resides wholly or in part within eloquent cortex, invasive intracranial monitoring from depth and/or subdural electrodes during a seizure is required to map out the areas of epileptogenicity in the brain. The assessment of potential risks and benefits for this type of epilepsy surgery in children involves complex age-related issues, including the possible impact of uncontrolled seizures, medication, or surgery on learning and development.     

Immunoglobulin treatment for severe childhood epilepsy

We have used intravenous immunoglobulin to treat pediatric patients with various severe epileptic conditions. This retrospective, multicenter study comprised 64 consecutive patients treated with immunoglobulins for either epileptic encephalopathy or refractory epilepsy. The rate of full or partial improvement according to specific syndrome involved three of four patients with idiopathic West syndrome, six of 12 patients with electrical status epilepticus in sleep, eight of 19 patients with an undefined syndrome, one of three patients with Landau-Kleffner syndrome, and one of two patients with Rasmussen encephalitis. Intravenous immunoglobulins were ineffective in 10 patients with symptomatic West syndrome, nine with febrile infection-related status epilepticus, three with myoclonic astatic epilepsy, and two with Lennox-Gastaut syndrome. Nine patients (14%) demonstrated complete resolution, and 10 (15.6%) exhibited partial improvement. Of these 19 responders (29.7%), eight relapsed. Although intravenous immunoglobulin is not suitable for all cases of epilepsy, it may prove efficacious for specific epileptic syndromes, mainly idiopathic West syndrome and electrical status epilepticus during sleep.     

Surgical treatment of medically refractory epilepsy in childhood

Twenty five percent of children with epilepsy continue to seize despite best medical management and may be defined as medically refractory. Many children with medically refractory localization-related epilepsy, i.e. seizures which originate in a particular area of brain and secondarily spread to involve other brain regions, may benefit from a variety of surgical treatments including hemispherectomy, corpus callosotomy, focal cortical resection of the temporal lobe, focal cortical resection of extratemporal regions of brain, and multiple subpial resections. A successful outcome from epilepsy surgery is generally defined as a seizure-free state with no imposition of neurologic deficit. In order to achieve these twin goals two criteria must be fulfilled. First, precise localization of the epileptogenic zone in the brain is necessary. The epileptogenic zone may be defined as the region of epileptogenic cerebral cortex whose removal will result in a seizure-free state. Second, one must determine the anatomic localization of eloquent cortex in brain in order to spare these areas during any planned cortical excision of epileptogenic cortex. Several diagnostic measures may be used to achieve a successful surgical outcome. A clinical history to ascertain the earliest symptom in the clinical progression of the seizure (semiology) is imperative as is ictal and interictal scalp EEG, neuropsychological testing, magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computerized tomography (SPECT), interictal magnetoencephalography (MEG). In the typical child undergoing evaluation for epilepsy surgery, if the clinical, neuropsychological, EEG, and radiological data are all concordant and point to the same area of epileptogenicity in brain, cortical excision of the suspected epileptogenic zone is undertaken. However, if the data are discordant, and/or the epileptogenic zone resides wholly or in part within eloquent cortex, invasive intracranial monitoring from depth and/or subdural electrodes during a seizure is required to map out the areas of epileptogenicity in brain. The assessment of potential risks and benefits for this type of epilepsy surgery in children involve complex age-related issues, including the possible impact of uncontrolled seizures, medication, or surgery, on learning and development.     

Intractable epilepsy of childhood and its treatment

This paper discusses the concept of epilepsy intractability as the criterium qualifying for the administration of polytherapy, inclusion of new antiepileptic drugs /AEDs/ and application of neurosurgical treatment. There were also diagnostic criteria and complication discussed. To define the concept of epilepsy intractability correctly and to administer appropriate treatment, it is necessary to classify the kind of seizures and their possible reasons, to apply suitable AEDs, their doses and to treat patients with them for a suitable period of time. Intractable forms of epilepsy are diagnosed at about 20-30% of patients with suitable treatment. The disease prevalence is different at particular age groups and depends also on seizure type or epileptic syndrome. Therefore, Ohtahar syndrome, West, Lennox and Gastaut syndromes, epilepsia partialis continua belong to intractable epileptic syndromes at children. There is the biggest risk of psychic disorders appearance among patients resistant to antiepileptic treatment. Moreover, long-term application of AEDs may be associated with the induction of epileptic seizures, occurrence of side and toxic symptoms. Great interest in intractable epilepsy is connected with huge progress in treatment of this disease which has resulted in introduction of many new AEDs for the last few years. Its inclusion into treatment, first as add--on therapy, and then, due to clinical examinations, also as a monotherapy, enables the improvement in seizure control and in the quality of patients' life.