Subclinical epileptiform activity in children with electrical status epilepticus during sleep: effects on cognition and behavior before and after treatment with levetiracetam.

We performed a double-blind placebo-controlled crossover study of the effects of spike activity during sleep and when awake on learning, long-term memory, vigilance and behavior before and after treatment with levetiracetam in children with electrical status epilepticus during sleep. At baseline, verbal learning declined with increasing spike activity, but there were no relations between spike activity and memory, vigilance or behavior. Levetiracetam was effective in reducing sleep-related spike activity, but on a group level, this had no clear effects on behavior, vigilance or learning and memory. Our results do not allow firm conclusions whether to treat nocturnal epileptiform activity or not; larger samples and longer follow-up may be needed.

Pharmacokinetic variability of four newer antiepileptic drugs, lamotrigine, levetiracetam, oxcarbazepine, and topiramate: a comparison of the impact of age and comedication.

BACKGROUND: Newer antiepileptic drugs (AEDs) are widely used in patients with epilepsy. There is still insufficient documentation regarding pharmacokinetic variability of these AEDs in different patient groups. PURPOSE: The purpose of this study was to compare age and comedication as factors contributing to pharmacokinetic variability between 4 newer AEDs (lamotrigine, levetiracetam, oxcarbazepine, and topiramate) among patients with refractory epilepsy. METHODS: Data regarding age, gender, use of AEDs, daily doses, and serum concentration measurements were retrieved from a therapeutic drug monitoring database, from patients admitted to the National Center for Epilepsy, Norway, 2007-2008. RESULTS: In total, 1050 patients were included, 111 younger children (2-9 years), 137 older children (10-17 years), 720 adults (18-64 years), 82 elderly (65-93 years). Fifty percent of the patients were prescribed polytherapy, in 88 different combinations. The interindividual pharmacokinetic variability was extensive, as illustrated by a 10-fold variability in serum concentration compared with dose. Age affected the apparent clearance of levetiracetam to the largest extent, as shown by a 60% increase in younger children and a 40% reduction in the elderly, respectively, compared with adults. Comedication altered the clearance of lamotrigine to the greatest extent ±70% because it is affected by both enzyme inducers and inhibitors. Hepatic enzyme inducers increased the clearance of levetiracetam and topiramate by 25% and oxcarbazepine by 75%. Valproic acid reduced the clearance of topiramate by 25%. CONCLUSION: Age and comedication are important contributors to pharmacokinetic variability. Age had the greatest impact on levetiracetam, and comedication affected the clearance of each of the 4 AEDs investigated in this study. Pharmacokinetic drug interactions must be carefully considered when multidrug therapies are prescribed. Therapeutic drug monitoring is a valuable tool for individualizing AED therapy.

The effect of levetiracetam on focal nocturnal epileptiform activity during sleep--a placebo-controlled double-blind cross-over study.

Electric Status Epilepticus during Sleep (ESES) occurs in children with and without epilepsy. It may be related to disturbances as autism spectrum disorder, attention-deficit hyperactivity disorder and acquired aphasia (Landau-Kleffner syndrome). Antiepileptic drug (AED) treatment has been reported in small studies without placebo control. This study was designed to assess AED effect in a placebo-controlled double-blind cross-over study. Levetiracetam (LEV) was chosen based on clinical evidence. Eighteen patients fulfilled the inclusion criteria. The mean spike index at baseline was 56, falling to a mean of 37 at the end of the LEV treatment period. Assessed with a 2-way ANOVA, there is a significant treatment effect (p<0.0002). To the best of our knowledge, this is the first placebo-controlled double-blind cross-over study for any AED in patients with ESES. The effect of LEV is comparable with its effect in treatment of epileptic seizures.

Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population.

BACKGROUND: Many new antiepileptic drugs (AEDs) have become available in recent years. Investigations of prescription patterns and exposure of AEDs to different patient groups are important regarding drug safety aspects. The aim of this study was to investigate the use of AEDs in epilepsy, with focus on exposure of AEDs, gender and age differences and changes in prescription patterns over time. METHOD: The data consisted of all prescriptions of AEDs from Norwegian pharmacies from the Norwegian Prescription Database (NorPD) (2004-2009), which included 44,000-47,000 patients with epilepsy each year. Variables included age, sex, diagnosis-related reimbursement codes and the use of AEDs (defined daily doses (DDDs)). RESULTS: Twenty two AEDs were in use. There were pronounced age- and gender differences regarding the use of AEDs in epilepsy. The most commonly used drugs were valproate and lamotrigine in children, carbamazepine and lamotrigine in adults, and carbamazepine and phenobarbital in the elderly. Lamotrigine and topiramate were predominantly used in female, and valproate and carbamazepine were predominantly used in male patients, respectively. Eighteen percent used polytherapy with AEDs. Of patients using lamotrigine, 14% received different generic preparations, in spite of the policy of restricted generic substitution. The use of AEDs in 2009 was 6.6 DDDs/1000 inhabitants/day, 49% of the use covered newer AEDs. CONCLUSION: The use of AEDs in epilepsy (2004-2009) was investigated in detail. All AEDs showed pronounced age and gender differences. Newer AEDs covered 49% of the total use in 2009. The study contributes to pharmacovigilance, as it offers a basis of knowledge for national decision-making authorities in the field of drug utilization.

Psychiatric comorbidity in patients with epilepsy: a population-based study.

PURPOSE: Patients with epilepsy often suffer from concomitant psychiatric disorders. Treatment patterns and the extent of comorbidity are insufficiently investigated and appropriate methods are scarce. The purpose of the study was to estimate the prevalence of psychiatric comorbidity in patients with epilepsy and to investigate prescription patterns of drugs prescribed for psychiatric disorders in epilepsy. METHODS: Prescription data from the Norwegian Prescription Database (NorPD) regarding the use of CNS-active drugs included anonymous data from almost 190,000 patients and 1.1-1.3 million prescriptions per year (2004-2007). Searches were based upon use of specific drugs, defined daily doses, number of patients, prescriptions, gender, and age. Reimbursement codes related to psychiatric diagnosis were used as indicators for clinical use. RESULTS: The prevalence of psychiatric comorbidity in patients with epilepsy was estimated to be 32%. There were 56% women and 44% men participating in the study. Among patients using antidepressants two thirds were women, but no gender differences were seen with antipsychotic medication. Antidepressants and antipsychotics were used 3.4 (20.9%) and 5.8 (13.4%) times more frequently than in the general population, accounting for 7.88 and 1.99 defined daily doses (DDDs)/1,000 inhabitants/day/year respectively. Lamotrigine was the most commonly used antiepileptic drug (AED) in epilepsy, accounting for 33% of the use of AEDs (in total 5.65 DDDs/1,000 inhabitants/day/year). The use of benzodiazepines was 9.55 DDDs/1,000 inhabitants/day/year. The patients had complex pharmacotherapy with two to eight concomitant drugs. CONCLUSION: The present study gives an estimate of psychiatric comorbidity of 32% in patients with epilepsy in a nation-wide population. The pharmacotherapy in this patient population is complex. The results provide valuable data on prescription patterns that contribute to pharmacovigilance on a national scale.

[Benzodiazepines in the treatment of epilepsy]. / Benzodiazepiner i epilepsibehandling.

In epilepsy benzodiazepines are mainly used to stop ongoing attacks. In hospitals intravenous diazepam is the drug of choice for status epilepticus. Outside of hospitals buccal midazolam is in the process of replacing rectal diazepam. Clonazepam, clobazam and nitrazepam (to children) are partially used as additional medication to prevent seizures.

Antiepileptic drugs in epilepsy and other disorders--a population-based study of prescriptions.

PURPOSE: The aim of the study was to quantify the use of antiepileptic drugs (AEDs) in epilepsy and other indications in a nation-wide population using a prescription database. MATERIALS AND METHODS: Prescription data of AEDs were collected from the Norwegian Prescription Database for the period 2004-2007, including 5.1 million prescriptions from 144,653 patients, all having at least one prescribed and dispensed AED. Diagnosis-related reimbursement codes were used as indicators for clinical use. RESULTS: Of the AEDs used, 71% was in epilepsy, 15% in psychiatry, 13% in neuropathic pain, and <1% in migraine, trigeminus neuralgia and cancer adjuvance. The use in epilepsy increased steadily from 7.0 to 7.5 DDDs/1000 inhabitants/day (7%) from 2004 to 2007. The use of AEDs in other indications increased considerably more from 2004 to 2007: Neuropathic pain to 1.40 DDDs/1000 inhabitants/day (360%), psychiatry to 1.59 (200%), and migraine to 0.005 (642%). The prevalence of AED users increased and in 2007 it was 0.97% in epilepsy, 0.8% in neuropathic pain, 0.33% in psychiatry and 0.001% in migraine. In 2007, 49% of the AEDs used in epilepsy were a new drug, carbamazepine, lamotrigine and valproate being most frequently used. New AEDs were used in 96% in migraine prophylaxis, 94% in neuropathic pain, and 64% in psychiatry. CONCLUSIONS: Based on a nation-wide prescription database, this study quantifies the wide and increasing use of AEDs, in particular the newer drugs.

Antiepileptic drug treatment of children at a referral centre for epilepsy--does admission make a difference?

PURPOSE: To study the antiepileptic drug treatment of children at a referral centre for epilepsy, including a follow-up study three months after discharge. MATERIAL AND METHODS: The study includes children admitted to The National Centre for Epilepsy in Norway. Data were collected from the medical records of 261 children, and a questionnaire regarding the pharmacological treatment was sent to their parents three months after discharge. RESULTS: The most common reasons for admission to the referral centre were medical and diagnostic evaluation. New antiepileptic drugs were used more frequently than old, in 251 and 158 cases, respectively. 53 and 54% were using polytherapy at admission and discharge, respectively. Levetiracetam, valproate and lamotrigine were the most frequently used antiepileptic drugs before, during, and after the stay at the centre. Levetiracetam was the only drug being more frequently used at discharge/three months after discharge than at admission. Dosage adjustments were made in 83% of the patients following measurement of serum concentrations and clinical evaluation. According to the parents the number of adverse effects had been reduced by 20% three months after discharge. Likewise 40% stated that their children experienced better seizure control, and 47% that their family experienced a better everyday life after the stay. CONCLUSION: Close comprehensive follow-up of children admitted to the referral centre, with main focus on optimalization of the pharmacological treatment, is of importance regarding quality of life aspects both to the children and their families.

[Use of antiepileptic drugs in nursing home residents]. / Bruk av antiepileptika hos sykehjemsbeboere.

BACKGROUND: Epilepsy is prevalent in elderly above 65 years of age, and treating epileptic seizures in this age group may be challenging. The aim of this study was to establish the prevalence of epilepsy and the use of antiepileptic drugs in nursing homes in two counties close to Oslo. MATERIAL AND METHODS: The two counties Asker and Baerum have 155,000 inhabitants and 19 nursing homes. The prescription charts of 1053 nursing home residents were examined in January 2005; for those who used antiepileptic drugs the medical records were also examined. RESULTS: 116 of the 1053 residents (11%) used antiepileptic drugs; 83 of the 116 (72%) due to epilepsy. 17 residents used antiepileptic drugs against pain, and 14 as psychotropic drugs. 92 residents (79%) were using antiepileptic drugs on a regular basis; 77 used one antiepileptic drug, 14 residents used two such drugs and one resident used four antiepileptic drugs. In 77% of the prescriptions, older antiepileptic drugs were prescribed, and slow-release formulations were seldom used. 24 of the residents reported side effects caused by antiepileptic drugs; sedation and dizziness being the most common. The last year, therapeutic drug monitoring was performed in 42%. Average number of drugs used, including antiepileptic drugs, was seven (range 1-16). In the epilepsy population 69 (83%) had a symptomatic, localization-related epilepsy. Cerebrovascular disease was the cause of epilepsy in 44 patients (53%). INTERPRETATION: Antiepileptic drug treatment and care for nursing home residents with epilepsy are suboptimal and could be improved.

Clinical use of antiepileptic drugs at a referral centre for epilepsy.

PURPOSE: The National Centre for Epilepsy in Norway admits patients with refractory epilepsy from the whole country. The purpose of this study was to investigate how antiepileptic drugs (AEDs) are used at the centre and compare it with the total consumption in the country and international guidelines regarding clinical use of AEDs. MATERIAL AND METHODS: A prevalence study was carried out from patient records from 264 patients (136 adults and 128 children). The use of AEDs, gender, polytherapy, common drug combinations, serum concentration measurements, concomitant medication and comorbid conditions were investigated. RESULTS: Of the 15 AEDs in use, valproate, lamotrigine and levetiracetam were most frequently used. In the country at large, carbamazepine, valproate and lamotrigine were used the most. Valproate and lamotrigine occurred most frequently in combination. In adults, oxcarbazepine and topiramate were used more frequently in women than in men. Children used benzodiazepines three times as often as adults. Newer AEDs were mostly used for partial seizures, in accordance with international guidelines. Thirty-five percent of adults and 20% of children suffered from comorbid CNS-related conditions. The use of concomitant medication was widespread. Serum concentrations were in accordance to recommended therapeutic ranges. CONCLUSION: The results demonstrate that newer AEDs were much more frequently used at the epilepsy centre than in the country as a whole. The use of polytherapy was common, and therapeutic drug monitoring was used for optimal individualized drug treatment. AEDs were used in accordance to international guidelines and recommendations, which can serve as a reference for other prescribers.