Older Antiepileptic Drugs Research Articles

O-31 Antiepileptic drug (aed) exposure in pregnancy and pregnancy outcome from national drug usage data

Background Antiepileptic drugs (AEDs) taken during pregnancy are known to increase the risk of fetal malfor-mations and potentially affect the neurodevelopment in children exposed. This study aimed to investigate the use of AEDs by pregnant women and women during their childbearing years in New Zealand and the association between AED use and rates of pregnancy termination, spontaneous abortion and stillbirth. Methods Retrospective population based cohort study using administrative databases in New Zealand between 2008 and 2014. Women who had been pregnant were identified by the National Minimum Dataset and were linked to the Pharmaceutical Collection to obtain infor-mation on use of AEDs. Women aged between 15 and 45 years dispensed AEDs were identified in the Pharmaceu-tical Collection. Results There was a significant increase in the number of women of child-bearing potential prescribed AEDs, from 9 women per 1000 women in 2008 to 11.4 wom-en per 1000 women in 2014. Use of the older generation AEDs declined over the time period while use of the newer generation AEDs increased. General practitioners provided 60% of the prescriptions of AEDs to women of child-bearing potential. Women who had been dis-pensed an AED had an increased rate of spontaneous abortion and pregnancy termination compared to those not dispensed an AED, 13.16 spontaneous abortions per 100 pregnancies, compared with, 8.00 per 100 pregnancies (risk ratio 1.64, 95% CI 1.50 to 1.80), and 21.29 terminations per 100 pregnancies compared with 19.50 per 100 pregnancies (risk ratio 1.09, 95% CI 1.02–1.17). Conclusion Use of newer AEDs is increasing in women of child-bearing potential in New Zealand leading to an overall increase in AED use in this group despite a fall in the use of older AEDs. AED use is this study was associat-ed with an increased risk of spontaneous abortion and increased rate of pregnancy termination.

Pharmacoresistance with newer anti-epileptic drugs in mesial temporal lobe epilepsy with hippocampal sclerosis

This study aims to evaluate the overall prognosis, prognostic factors, and efficacy of treatment in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who have access to third generation anti-epileptic drugs but not to epilepsy surgery. Eighty-five MTLE-HS patients were retrospectively placed into a seizure-free (seizure-free for >1year) or drug-resistant group, and the two groups were compared on the basis of age, sex, age at onset of seizures, duration of epilepsy, side of lesion, handedness, EEG findings, history of CNS infection, history of febrile convulsions, history of head trauma, history of cognitive impairment, family history of seizures, number of current anti-epileptic drugs (AEDs), total number of AED trials, and presence of individual AEDs. Only 24.7% of MTLE-HS patients had achieved seizure freedom for >1 year. Poor prognosis and drug-resistance were associated with younger age at onset of seizures (p=0.002), longer duration of epilepsy (p=0.018), greater number of current AEDs (p<0.001), and greater total number of AED trials (p<0.001). In addition, regimens with newer AEDs had no greater efficacy than regimens with older AEDs. Most medically managed MTLE-HS patients do not achieve seizure freedom despite multiple AED trials, and treatment with third generation AEDs should not preclude evaluation for epilepsy surgery.

Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures.

Eslicarbazepine acetate is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug–drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy.

Is Depression Related to Low Folate Levels in People with Epilepsy? An Observational Study and Meta-analysis.

Background:Both depression and low serum levels of folate are common in people with epilepsy (PWE), the latter especially in patients on hepatic enzyme-inducing antiepileptic drugs (AEDs). We did a cross-sectional study and a meta-analysis to assess if lower folate levels have any relation with depression in PWE.Materials and Methods:Two hundred and one PWE were recruited and assessed for depression using the Inventory of Depressive Symptomatology-Self-Rated (IDS-SR) and Inventory of Depressive Symptomatology-Clinician Rated; serum folate levels were measured in them at the same time. Literature search was carried out and studies with data on depression as well as folate levels in PWE were included. Statistical analysis to determine frequency of depression, low folate levels, and relation between them among our cases and the pooled data from the included studies was done.Results:Depression was observed in 65.68% and low serum folate (<4 ng/ml) in 48.75% of PWE (over 80% on older AEDs); there was no statistically significant correlation between them. However, on analyzing the pooled data of six studies including the present, the Fisher's z-transformed correlation coefficient was −0.1690 (95% confidence interval [−0.3175, −0.0124], P = 0.0464).Conclusions:Depression and low folate levels are common in PWE. Low folate levels have a mild but significant negative correlation with depression in this population, and folate supplementation would be advisable for those on the older AEDs.

Erratum to: Changes in utilisation of antiepileptic drugs in epilepsy and non-epilepsy disorders-A pharmacoepidemiological study and clinical implications.

The purpose of this study was to investigate changes in utilisation of antiepileptic drugs (AEDs) in epilepsy and non-epilepsy disorders in Norway and furthermore to study the retention rates of the most commonly used AEDs in these indications in long-term use. The data consisted of all prescriptions of AEDs from Norwegian pharmacies in the Norwegian Prescription Database (NorPD) (2004–2012). Variables included anonymous data regarding age, gender, diagnosis specific reimbursement codes and utilisation of AEDs. In recent years (2008–2012), the utilisation of AEDs in non-epilepsy disorders accounted for 45–53 % of the total use. In epilepsy, the most commonly used AED was lamotrigine, followed by levetiracetam, carbamazepine and valproate. Lamotrigine was also the predominant AED used in psychiatry, while pregabalin and gabapentin were mostly used in neuropathic pain. In migraine, topiramate predominated but accounted for <1 % of the total utilisation of AEDs. The majority of prescriptions were by general practitioners and only 20 % by specialists. Regardless of indication, newer AEDs had higher retention rates (34–48 %) and were used for a longer period before discontinuation. The use of AEDs in non-epilepsy disorders is increasing and accounted for 53 % in 2012. Newer AEDs were predominantly used and demonstrated higher retention rates than older AEDs in all indications. This nationwide study demonstrates an increased exposure to AEDs in new patient groups, and details in prescription patterns and clinical and safety considerations should be closely monitored. This contributes to long-term post-marketing data of AED and accordingly improved pharmacovigilance.

Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy.

Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974-August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46μg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In general, routine CPM of levetiracetam cannot be recommended for pediatric patients with epilepsy. However, CPM may be beneficial in select cases, such as patients in whom noncompliance is suspected, those who have severe overdoses, those switching between product brands, or patients for whom an 'individual therapeutic concentration' is documented. Nonetheless, in the majority of pediatric patients with epilepsy, measurement of levetiracetam concentrations is not expected to yield a therapeutic benefit. Thus, clinical assessment and judgment, without measuring drug concentrations, remain the monitoring strategy of choice for levetiracetam therapy.

Correlation between prescribed daily dose, seizure freedom and defined daily dose in antiepileptic drug treatment.

Background Although defined daily doses (DDD) for antiepileptic drugs (AED) have been assigned only in combination therapy, based on the literature, most patients take them in monotherapy. Furthermore, discrepancies between DDD and prescribed daily dose (PDD) were observed. Objective First, to determine PDDs of AEDs and to reveal PDD/DDD ratio among seizure free versus not seizure free patients in everyday clinical practice. Second, to test the applicability of 75% cut-off of DDD to achieve seizure freedom. Furthermore, to find out what factors might influence PDD. Setting Outpatient data files at a Hungarian university hospital were studied. Methods A retrospective, 20-year cross-sectional database was compiled from 1282 epileptic outpatients' files. Main outcome measure Seizure freedom and PDD were used as outcome measures. Results The mean DDD% of all prescribed AEDs increased steadily from monotherapy, through bitherapy towards polytherapy (p<0.0001). Most seizure free patients took AEDs in doses in the range of ≤75% of DDDs in monotherapy and bitherapy. Older AEDs (carbamazepine and valproate) were given in a significantly higher mean dose in bitherapy in the seizure free group. Among the newer types, only levetiracetam and lamotrigine had a significantly higher DDD% in mono-, bi-, and polytherapy. Confirmed by logistic regression analysis, gender, age, type of epilepsy, and number of AEDs had a significant impact on the value of 75% DDD. Conclusion No significant unfavourable impact of the lower ratio of PDD/DDD on the outcome of achieving seizure freedom has been confirmed. As a measure of seizure freedom, 75% of DDD may be used, although individual therapy must be emphasised. Precisely quantified DDD would provide a more accurate calculation of other derived values.

What does the U.S. Medicare administrative claims database tell us about initial antiepileptic drug treatment for older adults with new-onset epilepsy?

Disparities in epilepsy treatment are not uncommon; therefore, we examined population-based estimates of initial antiepileptic drugs (AEDs) in new-onset epilepsy among racial/ethnic minority groups of older US Medicare beneficiaries. We conducted retrospective analyses of 2008-2010 Medicare administrative claims for a 5% random sample of beneficiaries augmented for minority representation. New-onset epilepsy cases in 2009 had ≥1 International Classification of Diseases, Ninth Revision (ICD-9) 345.x or ≥2 ICD-9 780.3x, and ≥1 AED, AND no seizure/epilepsy claim codes or AEDs in preceding 365 days. We examined AED use and concordance with Quality Indicators of Epilepsy Treatment (QUIET) 6 (monotherapy as initial treatment = ≥30 day first prescription with no other concomitant AEDs), and prompt AED treatment (first AED within 30 days of diagnosis). Logistic regression examined likelihood of prompt treatment by demographic (race/ethnicity, gender, age), clinical (number of comorbid conditions, neurology care, index event occurring in the emergency room (ER)), and economic (Part D coverage phase, eligibility for Part D Low Income Subsidy [LIS], and ZIP code level poverty) factors. Over 1 year of follow-up, 79.6% of 3,706 new epilepsy cases had one AED only (77.89% of whites vs. 89% of American Indian/Alaska Native [AI/AN]). Levetiracetam was the most commonly prescribed AED (45.5%: from 24.6% AI/AN to 55.0% whites). The second most common was phenytoin (30.6%: from 18.8% Asians to 43.1% AI/AN). QUIET 6 concordance was 94.7% (93.9% for whites to 97.3% of AI/AN). Only 50% received prompt AED therapy (49.6% whites to 53.9% AI/AN). Race/ethnicity was not significantly associated with AED patterns, monotherapy use, or prompt treatment. Monotherapy is common across all racial/ethnic groups of older adults with new-onset epilepsy, older AEDs are commonly prescribed, and treatment is frequently delayed. Further studies on reasons for treatment delays are warranted. Interventions should be developed and tested to develop paradigms that lead to better care.

Drug therapy of epileptic seizures among adult epileptic outpatients of University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia.

ObjectiveThe aim of this study was to assess the practice of pharmacotherapy of epilepsy and its treatment outcomes in adult epileptic outpatients at the University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia.MethodsAn institution based, retrospective cross-sectional study was conducted from the medical charts of 336 adult epileptic patients at the outpatient epileptic clinic of Neurology Department of University of Gondar Teaching Hospital from May 2014 to April 2015. Reviewing follow-up information from the medical charts was used to evaluate antiepileptic drug (AED) prescribing patterns and treatment outcome. Data were collected by using data collection format and analyzed using SPSS software version 16.ResultsThe most common type of seizure diagnosed was generalized tonic–clonic seizure (n=245, 72.91%). Monotherapy with an AED accounted for 80.35% of the cases, whereas dual therapy and polytherapy with three AED combinations accounted for 16.37% and 3.28%, respectively. The most frequently prescribed AED was phenobarbitone (62.47%) followed by carbamazepine (17.91%). From the total epileptic cases, 277 (82.4%) had well-controlled seizure status in the last three consecutive months.ConclusionMost of the patients were maintained by monotherapy, and largely this was by the older antiepileptic drug, phenobarbitone. Considering the development of pharmacotherapy of epilepsy and other patient related factors, the standard treatment guideline for Ethiopia needs to be revised periodically.

Antiepileptic drug use in Italian children over a decade.

The aim of the study was to evaluate prescription profiles of antiepileptic drugs (AEDs) and to assess hospitalizations and specialist visits in pediatric patients with epilepsy. The data sources were administrative health databases of Italy's Lombardy Region, which collect prescriptions for drugs, diagnostic tests, specialist visits, and hospital discharge forms. All patients aged 0-16years with at least seven AED (group N03A of the International Anatomical Therapeutic Chemical Classification) prescriptions over two consecutive years between 2003 and 2010 were identified and classified as prevalent or incident cases (no prescriptions in two previous years). The first prescription to incident cases was analyzed. For each incident case, drug prescriptions, specialist visits, diagnostic tests, and hospitalizations in the 24months following the first (index) prescription were monitored. A total of 6527 incident cases (5.4/10,000 person-years, 95% CI 5.4-5.5) were identified. Valproic acid and carbamazepine were the most prescribed drugs (65.9 and 15.0%, respectively). The use of newer AEDs increased over time. In the 24-month observation period, 74% of incident cases continued the treatment with the index AED. The percentage of cases who changed therapy was higher in preschoolers (34%) and decreased with age. In all, 21% of incident cases were hospitalized for epilepsy and 86% had a specialist visit in the 24months after the first AED prescription. In conclusion, older AEDs, particularly valproic acid, remained the first therapeutic approach to pediatric epilepsy in Italy. For three quarters of cases, the initial AED treatment was likely effective and well tolerated.

Estudio comparativo del uso de fármacos antiepilépticos durante el embarazo en un periodo de 12 años. Eficacia de los nuevos fármacos lamotrigina, levetiracetam y oxacarbamacepina

IntroductionThe prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. Material and methodsAfter signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) ResultsWe compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. ConclusionsThe prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV provides similar seizure control to that of the older AEDs, and it is more effective and better than LTG.

Changes in utilisation of antiepileptic drugs in epilepsy and non-epilepsy disorders-a pharmacoepidemiological study and clinical implications.

The purpose of this study was to investigate changes in utilisation of antiepileptic drugs (AEDs) in epilepsy and non-epilepsy disorders in Norway and furthermore to study the retention rates of the most commonly used AEDs in these indications in long-term use. The data consisted of all prescriptions of AEDs from Norwegian pharmacies in the Norwegian Prescription Database (NorPD) (2004-2012). Variables included anonymous data regarding age, gender, diagnosis specific reimbursement codes and utilisation of AEDs. In recent years (2008-2012), the utilisation of AEDs in non-epilepsy disorders accounted for 45-53% of the total use. In epilepsy, the most commonly used AED was lamotrigine, followed by levetiracetam, carbamazepine and valproate. Lamotrigine was also the predominant AED used in psychiatry, while pregabalin and gabapentin were mostly used in neuropathic pain. In migraine, topiramate predominated but accounted for <1% of the total utilisation of AEDs. The majority of prescriptions were by general practitioners and only 20% by specialists. Regardless of indication, newer AEDs had higher retention rates (34-48%) and were used for a longer period before discontinuation. The use of AEDs in non-epilepsy disorders is increasing and accounted for 53% in 2012. Newer AEDs were predominantly used and demonstrated higher retention rates than older AEDs in all indications. This nationwide study demonstrates an increased exposure to AEDs in new patient groups, and details in prescription patterns and clinical and safety considerations should be closely monitored. This contributes to long-term post-marketing data of AED and accordingly improved pharmacovigilance.

Does the choice of antiepileptic drug affect survival in glioblastoma patients?

Patients with glioblastoma (GBM) often suffer from symptomatic epilepsy. Older antiepileptic drugs (AEDs) which affect the enzyme system cytochrome P450 have been in extensive use, but there is an increasing focus on interactions with other drugs. This study investigated whether newer AEDs with little or no enzyme effect are increasingly preferred. Previous research has indicated that valproate improves survival in GBM. We investigated the impact of AEDs on overall survival in GBM patients. All GBM patients diagnosed in Norway 2004-2010 were included through a linkage of national registries, and follow-up data on the malignancy and drug usage were analyzed. In a multivariate cox proportional-hazards regression, AEDs were adjusted for each other and for relevant factors. Immortal time bias was eliminated with time-dependent variables. The study population was 1263 patients with histologically confirmed GBM. Carbamazepine was the most frequently prescribed AED to patients diagnosed with GBM during 2004-2006, while levetiracetam was increasingly prescribed to patients diagnosed later. Taking AEDs on a reimbursement code of epilepsy was not beneficial for survival. None of the six AEDs valproate, levetiracetam, carbamazepine, oxcarbazepine, lamotrigine or phenytoin significantly altered overall survival. There has been a shift in the prescriptions of AEDs to GBM patients from older to newer AEDs over time. We found no significant survival benefit in GBM patients neither from treatment with AEDs for epilepsy in general, nor from the usage of six separate AEDs.

Patterns of antiepileptic drugs use in epileptic pediatric patients in Jordan

Objectives:To determine prescribing patterns of antiepileptic drugs (AEDs) in pediatric patients with confirmed diagnosis of epilepsy, and to provide knowledge of general practice of physicians.Methods:The study was a multi-center cross-sectional observational study, in specialized clinics for management of epilepsy in north, central and south Jordan. This study was conducted from January 2014 to July 2014. These were 3 from university tertiary care hospitals and 4 from governmental tertiary care hospitals.Results:A total of 694 pediatric patients were included. Monotherapy AED use had the highest frequency 465 (67.0%), followed by dual therapy 162 (23.3%). The frequency of monotherapy in university hospitals was lower than governmental hospitals (p<0.05); however, Polytherapy was more frequent in younger children. Two old AEDs were most frequently prescribed as a monotherapy; Valproic acid 235 (50.5%) and carbamazepine 155 (33.3%). The most common combination in dual therapy was valproic acid with carbamazepine 28 (17.3%). The second most common combinations were carbamazepine with levetiracetam 21 (13.0%) or valproic acid with levetiracetam 20 (12.3%).Conclusion:Older AED remain first line drugs for use in both monotherapy and combination therapy for epileptic disorders. Polytherapy is associated with younger kids and being treated in a university hospital.

Utilization of antiepileptic drugs in Israel

The aim of the study was to identify trends in utilization of antiepileptic drugs (AEDs) over time in a nation-wide population in Israel. Data on AED utilization (for all indications) for the period 2010-2014 were obtained from pharmaceutical companies that distribute AEDs in Israel. Prevalence of AED utilization was reported as defined daily doses (DDD)/1000 inhabitants/day. The utilization of most AEDs included in our analysis remained stable over the study period. The greatest increases in utilization of drugs established in Israel were observed for lamotrigine (33%), oxcarbazepine (31%), and primidone (18%). Decreases in use were recorded for carbamazepine (18%) and phenobarbital (15%). Use of older AEDs appeared to be relatively high, compared with the use of newer AEDs. During the study period of 2010-2014, conventional AEDs remained a main treatment choice in Israel, in certain cases in contrast to current recommendations and guidelines, for reasons yet to be revealed in further research.

Clobazam and Its Use in Epilepsy.

Clobazam (CLB) is an older anti-epileptic drug, with a slightly different chemical structure from that of the classic benzodiazepines currently used in the treatment of epilepsy, which confers less sedative properties in terms of negative adverse effects. It is also thought to be better tolerated than other anti-epileptic drugs, whilst maintaining a very similar level of efficacy. It has been tested extensively in over 50 studies on more than 3000 patients with epilepsy and is now approved as an adjunctive treatment of epilepsy in >100 countries. The aim of this review is to evaluate several existing studies on the effectiveness of CLB as an adjunctive therapy in the treatment of epilepsy and whether this therapy is more useful in particular types of epilepsy or seizure prevention. This is not a systematic review but a general overview of some of the most recent studies on the effectiveness of CLB as an adjunctive therapy. Additionally, the benefits of having an oral suspension of CLB will be evaluated with regards to patient groups benefiting from this formulation. The last issue addressed is that of the importance of prescribing CLB by brand, along with the benefits and risks of not doing so.

Seizure treatment in Angelman syndrome: A case series from the Angelman Syndrome Clinic at Massachusetts General Hospital.

Epilepsy is a common feature of Angelman syndrome (~80-90%), with the most common seizure types including myoclonic, atonic, atypical absence, focal, and generalized tonic-clonic. Seizure types are similar among the various genetic subtypes, but epilepsy in those with maternal deletions is more frequent and more refractory to medication. Treatment with older antiepileptic drugs such as valproic acid and clonazepam is effective, but these medications tend to have less favorable side effect profiles in Angelman syndrome compared with those in newer medications. This study aimed to assess the use of newer antiepileptic drug therapies in individuals with Angelman syndrome followed at the Angelman Syndrome Clinic at the Massachusetts General Hospital. Many of the subjects in this study were on valproic acid therapy prior to their initial evaluation and exhibited increased tremor, decreased balance, and/or regression of motor skills, which resolved after tapering off of this medication. Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. The low glycemic index treatment also provided effective seizure control with minimal side effects. The majority of subjects remained on combination therapy with levetiracetam, lamotrigine, and clobazam being the most commonly used medications, indicating a changing trend when compared with prior studies.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Adverse cognitive and behavioural effects of antiepileptic drugs in children.

The literature was evaluated for cognitive and more general behavioural effects. We distinguished the older antiepileptic drugs (AEDs), from the newer and newest AEDs. The striking finding was the lack of information on children. From the available evidence it would appear that there may be negative cognitive effects with phenobarbital, phenytoin, topiramate and zonisamide, and adverse behavioural effects with phenobarbital, valproate, gabapentin, topiramate, levetiracetam and zonisamide. There is inconclusive data on ethosuximide, clobazam, vigabatrin, felbamate, pregabalin, stiripentol, rufinamide, lacosamide and retigabine. The following drugs appear to be neutral with regard to cognitive effects: valproate, carbamazepine, gabapentin and oxcarbazepine. Carbamazepine appears to be neutral with regard to behavioural effects. Positive cognitive effects have been reported with lamotrigine and levetiracetam. Positive behavioural effects have been reported with lamotrigine. Recommendations are provided.

Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health.

Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0%; p<0.001 in levetiracetam vs. -9.8%; p<0.001 in older AED group), FA (-1.46%; p<0.001 vs. -0.96%; p<0.001, respectively) and radial trabecular BMD (-1.46%; p=0.048 and -2.31%; p=0.013, respectively). C-terminal telopeptides of type I collagen (βCTX; bone resorption marker) decreased in both groups (-16.1%; p=0.021 vs. -15.2%; p=0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3%; p=0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1year at clinically relevant fracture sites and a reduction in bone turnover.

Antiepileptic Drugs

Treatment of epilepsy starts with antiepileptic drug (AED) monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. Older-generation AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer-generation AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, and, more recently, zonisamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer-generation AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.