Use Of Antiepileptic Drugs In Children Research Articles

50 Years Ago in TheJournalofPediatrics: Rickets and Antiepileptic Drugs: What Have We Learned?

Borgstedt AD, Bryson MF, Young LW, Forbes GB. Long-term administration of antiepileptic drugs and the development of rickets. J Pediatr 1972;81:9-15. In 1972, Borgstedt et al reported 2 neurologically impaired children who developed rickets after years of antiepileptic drug therapy. The diagnosis was based on physical findings, radiographs, and serum calcium, phosphate, and alkaline phosphatase levels. Rickets resolved with daily doses of calcium and large amounts of vitamin D, despite continuance of the antiepileptic drugs. Missing were measures of vitamin D metabolites, presumably owing to a lack of available clinical assays at that time. Our knowledge of vitamin D metabolism has progressed far beyond the already established metabolic pathways of hepatic 25-hydroxylation and renal 1-hydroxylation of that era. As the authors suspected, antiepileptic drugs, and other drugs, cause rickets by increased hepatic vitamin D catabolism. Induction of catabolic enzymes leaves less vitamin D for eventual renal conversion to the active metabolite 1,25 dihydroxyvitamin D (1,25-D). With inadequate 1,25-D, calcium absorption is impaired, contributing to inadequate bone mineralization. As extracellular calcium decreases, parathyroid hormone responds, but this response causes phosphaturia, further under mineralizing bone. In vitamin D disorders, bone chondrocyte function is also altered, leading to metaphyseal abnormalities explaining many hallmark features of vitamin D rickets, such as widened wrists and rachitic rosary. Other bone health issues in children with epileptic disorders, not related to vitamin D deficiency, include seizure-associated trauma, nonambulatory status, and nutritional deficiencies. The measurement of the main circulating metabolite, 25-hydroxyvitamin D (25-D), is widely available. Problems remain, including assay variability and an inconsistent relationship of level to clinical impact; for example, a 25-D level of 12 ng/mL may cause rickets in 1 individual and no notable signs in another. The 25-D levels are, at best, a surrogate for potential 1,25-D production. Another issue is that 25-D is measured in nanograms per milliliter, with acceptable levels in children generally considered to be more than 20 ng/mL. However, 1,25-D is measured in picograms per milliliter, or a 1000-fold less concentration. Why is a 25-D level of 10 000 pg/mL (=10 ng/mL) not enough substrate to provide adequate 1,25-D production to the 20-80 pg/mL reference range? From their inference of vitamin D deficiency, Borgstedt et al helped to identify an important preventable complication of antiepileptic drug use in children. Incorporating these findings into clinical guidelines remains to be completed.

Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy

ObjectiveWe describe the trends in antiepileptic drug (AED) use in children and adolescents with epilepsy in the United States. MethodsWe undertook a cross-sectional study based on Medicaid Analytic eXtract data set from 26 US states. Children and adolescents aged three to 18 years with at least one year continuous Medicaid fee-for-service coverage after the second outpatient or the first inpatient diagnosis of epilepsy in each calendar year during 1999 to 2009 were included in the study; therefore, 11 cohorts were established. A patient was defined as being exposed to a specific AED if he or she had at least one-day supply of the AED during the 1-year follow-up period. The annual prevalence of AEDs was reported, stratified by gender and age. The trends in AED use were evaluated through linear regression. ResultsThe sample sizes of the 11 cohorts ranged between 17,304 and 22,672. The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009, and the prevalence of carbamazepine use declined from 37.1% to 10.2%. Meanwhile, the prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009, and the prevalence of oxcarbazepine use increased from 1.3% to 19.1%. Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most commonly used AED in children and adolescents with epilepsy. The prevalence of diazepam use increased from 11.6% to 28.1%. SignificanceCompared with first- and second-generation antiepileptic drugs, third-generation AEDs have fewer adverse side effects, resulting in increased patient treatment adherence. Equally important is the economic impact of these newer AEDs. This first-of-its-kind study underscores the need for large database studies that objectively assess the cost-effectiveness of third-generation AEDs versus first- and second-generation AEDs in the treatment of childhood epilepsy.

Multiple anti-epileptic drug use in children with epilepsy in Mulago hospital, Uganda: a cross sectional study.

BackgroundSeizures in up to one third of children with epilepsy may not be controlled by the first anti-epileptic drug (AED). In this study, we describe multiple AED usage in children attending a referral clinic in Uganda, the factors associated with multiple AED use and seizure control in affected patients.MethodsOne hundred thirty nine patients attending Mulago hospital paediatric neurology clinic with epilepsy and who had been on AEDs for ≥6 months were consecutively enrolled from July to December 2013 to reach the calculated sample size. With consent, the history and physical examination were repeated and the neurophysiologic and imaging features obtained from records. Venous blood was also drawn to determine AED drug levels. We determined the proportion of children on multiple AEDs and performed regression analyses to determine factors independently associated with multiple AED use.ResultsForty five out of 139 (32.4 %) children; 46.7 % female, median age 6 (IQR = 3–9) years were on multiple AEDs. The most common combination was sodium valproate and carbamazepine. We found that 59.7 % of children had sub-therapeutic drug levels including 42.2 % of those on multi-therapy. Sub-optimal seizure control (adjusted odds ratio [ORa] 3.93, 95 % CI 1.66–9.31, p = 0.002) and presence of focal neurological deficits (ORa 3.86, 95 % CI 1.31–11.48, p = 0.014) were independently associated with multiple AED use but not age of seizure onset, duration of epilepsy symptoms, seizure type or history of status epilepticus.ConclusionOne third of children with epilepsy in Mulago receive multiple AEDs. Multiple AED use is most frequent in symptomatic focal epilepsies but doses are frequently sub-optimal. There is urgent need to improve clinical monitoring in our patients.

P157 Mortality following antiepileptic drug use in children and adolescents

P157 Mortality following antiepileptic drug use in children and adolescents

New antiepileptic drugs.

For many years, the medical treatment of epilepsy was based on the use of the same few drugs, which were chosen according to the seizure type in a fairly standardized manner. In the recent past, there have been several changes, and more are expected in the near future. Since 1993, three new antiepileptic drugs have been released in the United States, and two more are expected to be released before the end of 1997. Because the full spectrum of efficacy and side effects of these drugs has not yet been established, the present management of epilepsy requires a larger degree of flexibility, and it is necessary to become acquainted with the new drugs and to follow closely new reports on the experience with new drugs. This is particularly true for the management of epilepsy in children, because controlled studies in children tend to be completed later than those in adults and antiepileptic drug use in children is often "off label." The present review of newer antiepileptic drug consists of a brief summary of background information on each drug, followed by a closer analysis of recently published papers. Information on pediatric use is reviewed, when available. The new antiepileptic drugs selected for discussion are gabapentin, lamotrigine, felbamate, vigabatrin, and topiramate.