Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.     

Zonisamide-Induced Behavior Disorder in Two Children

Summary: Zonisamide (ZNS)-induced behavior disorders are reported in a 1-year-old girl and a 3-year-old boy. Both patients, who had no previous developmental or mental problems, displayed secondarily generalized motor seizures. Serum concentrations of ZNS were not high, 8.8 and 12.3 μg/ml(effective range 10–30 μg/ml) respectively. Although many cases of ZNS-related psychotic reactions and/or behavior disorders have been reported, all affected patients had complex partial seizures (CPS) and had received combination therapy with phenytoin (PHT). Thus, whether the disorders were induced only by ZNS, by an interaction between ZNS and PHT, or by CPS could not be determined. In the children reported, however, ZNS clearly induced behavior disorders at plasma ZNS levels within or even below the therapeutic range.     

A North American Registry for Epilepsy and Pregnancy, a Unique Public/Private Partnership of Health Surveillance

Summary: Purpose: A North American Registry of Epilepsy and Pregnancy (NAREP) has been established as a surveillance mechanism to identify adverse pregnancy outcomes that may be associated with fetal exposure to antiepileptic drugs (AEDs). As public attitudes become more receptive, and medical management more effective, women with epilepsy (WWE), are choosing to become pregnant in increasingly larger numbers. In the United States alone, 800,000 to 11 million WWE are of childbearing age. The offspring of these women have rates of congenital malformations of 1.25–11.5%. Although several factors could contribute to this risk, including AEDs, seizures during gestation, and maternal epilepsy, AEDs are an important variable over which we have some control. Unfortunately, no data currently exist that permit physicians to determine the relative safety of specific AEDs. With the introduction of several new AEDs, there is even further uncertainty about the potential safety of AEDs for treatment of pregnant women.
Methods: We have organized a prospective registry for pregnant WWE which will systematically monitor pregnancy outcomes. The registry can serve as an early warning system for adverse outcomes associated with specific AEDs, administered alone or in combination. The registry has required a cooperative effort between the scientific and pharmaceutical communities. The genesis of this effort is described.     

抗癫药物对妊娠癫癎患者子代的致畸风险

目的:旨在评估抗癫癎药物(AEDs)对妊娠癫癎患者子代出现先天畸形的风险。方法:对妊娠癫癎患者采用登记和随访研究,分析其孕期AEDs用药情况、癫癎发作、妊娠结局及子代出现畸形的风险。结果:入选105例妊娠癫癎患者。服用AEDs患者79/105例(75.2%),未服用AEDs患者26/105例(24.8%)。单药治疗60/79例(75.9%),其中1/60例(1.7%)流产;患者子代中2/60例(3.3%)先天性畸形(1例服用卡马西平,出现先天性心脏动脉导管未闭;1例服用拉莫三嗪,出现无胚心)。联合用药19/79例(24.1%),子代无先天畸形出现。未服用AEDs患者中有2/26例(7.7%)流产,其余患者子代未出现先天畸形。结论:妊娠癫癎孕妇多数于孕期仍服用AEDs,且以单药治疗居多;使用AEDs(分别为卡马西平和拉莫三嗪)患者子代出现2例先天性畸形;丙戊酸钠易致畸但仍在妊娠癫癎中经常使用,本研究中服用丙戊酸钠孕妇未出现子代先天性畸形。     

Pregnancies of Women with Epilepsy: A Population-Based Study in Iceland

Summary: Purpose : Women with epilepsy who become pregnant are commonly considered to be at high risk for complications during pregnancy or delivery. The offspring are also considered o have increased risk of perinatal mortality, congenital malformations, and maturational delay. Because few of these studies are population based, potential bias exists because of selection.
Methods: We performed a historical population-based cohort study in Iceland to determine the prevalence of epilepsy among pregnant women, to identify pregnancy and delivery complications in women with epilepsy, and to determine the outcome of their pregnancies as compared with that in the general population of Iceland. We identified all women with active epilepsy who gave birth during a 19-year period in Iceland.
Results: In this population, 3.3 in 1,000 pregnancies involve mothers with active epilepsy. The frequency of adverse events (AE) during pregnancy in the women with epilepsy is similar to that observed among all live births in the population, but cesarean section was performed twice as frequently as in the general population. Perinatal mortality rate and mean birth weight are not significantly different in the offspring of women with epilepsy as compared with rest of the population. The risk of major congenital malformations (MGM) is increased 2.7- fold over that expected when a mother is treated with antiepileptic drugs (AEDs) during a pregnancy.
Conclusions: Our study indicates that the rate of complications of pregnancy in mothers with active epilepsy is low and similar to that of the general population with epilepsy. Use of AEDs by the mother during pregnancy significantly increases the risk of MGM in the offspring.     

Teratogenicity of Antiepileptic Drugs: Analysis of Possible Risk Factors

To determine the primary factors responsible for the increased incidence of malformation in the off-spring of antiepileptic drug (AED)-treated epileptic mothers, special attention was paid to drug combinations in a prospective study of 172 deliveries. Variables used for analysis were eight antiepileptic drugs (AEDs) and total daily dosages (drug score), and seven background factors consisting of maternal age at delivery, gravida, outcome of previous pregnancy, etiology and type of epilepsy, occurrence of seizures in the first trimester of pregnancy, and seizure frequency during pregnancy. The overall rate of malformation was 14.0%. Thirty-one patients were administered a single drug, and the rate of malformation was 6.5%. The remaining 141 patients were treated with multiple AEDs, and the rate of malformation was 15.6%. The drug score of the latter group was significantly higher than the former (p = 0.01). There was no definite dose-dependent increase in the incidence of malformations associated with any individual AEDs. There was no relationship between the type of defect and individual AEDs. Wilcoxon rank-sum test revealed significant association between the drug score, valproate (VPA), and congenital malformation. Carbamazepine (CBZ) also reached an almost significant level. Furthermore, VPA polypharmacy produced the highest incidence of malformation, higher than that produced by any other AED or drug combination. There was no significant association between the presence of malformations and the other putative risk factors. These results suggest that high dose of AEDs reflecting polypharmacy, VPA polypharmacy in particular, are primary factors responsible for the increased incidence of congenital malformation in the offspring of treated epileptic mothers.     

Birth defects after prenatal exposure to antiepileptic drugs

BACKGROUND: Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs. RECENT DEVELOPMENTS: Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified. WHERE NEXT?: Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development.     

Zonisamide Monotherapy in Newly Diagnosed Infantile Spasms

Summary: Purpose: We determined the short-term efficacy of zonisamide (ZNS) monotherapy in newly diagnosed patients with infantile spasms (IS).
Methods : Eleven hospitals participated in this open, prospective trial. ZNS 3-10 mg/kg/day was administered as the second-choice drug to 11 newly diagnosed patients with IS (cryptogenic 3, symptomatic 8) who failed to respond to high-dose vitamin B6.
Results : Four infants with symptomatic IS had cessation of spasms and disappearance of the hypsarrhythmia. In these responders, the spasms ceased after a few days (1–5 days) of treatment at a dose of ZNS 4–5 mg/kg/day which produced plasma ZNS concentrations ranging from 5.2 to 16.3 kg/ml (mean 9.8 pg/ml). There were two relapses (50%) 4–6 weeks after cessation of seizures, however. Relapse was predicted by effects of ZNS on EEG; the 2 infants in whom an abnormal EEG persisted had relapses, whereas the 2 whose EEG normalized remained seizure-free (follow-up 20 and 26 months). No adverse reactions were noted.
Conclusions : ZNS may be effective in the initial treatment of selected patients with IS.     

Infant Monkey Hyperexcitability After Prenatal Exposure to Antiepileptic Compounds

Summary: Purpose : A monkey (Macaca fascicularis) model was previously used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT), stir-ipentol (STP) or PHT + STP. To explore this issue further, we studied additional monkey infants in those groups, as well as groups prenatally exposed to carba-mazepine (CBZ) in monotherapy (n = 5) or CBZ + STP poly therapy (n = 10).
Methods : The drug-exposed groups were compared with a group of control infants (n = 10) for whom procedures were matched except that there was no prenatal drug exposure. All adult female monkeys were equipped with tether systems and stomach catheters so that drug administration (or water for controls) could be initiated before they were mated and continued throughout pregnancy. During pregnancy, PHT, STP, and CBZ plasma levels were maintained between 4–12, 4–10, and 1–6 μg/ml, respectively (for both monotherapy and polytherapy). At birth, infants were separated from mothers and transferred to the University of Washington's (Seattle, WA, U.S.A.) Infant Primate Research Laboratory (IPRL) for postnatal care and follow-up testing. During tests of recognition memory administered between 2 weeks and 3 months of age, infants were rated on a hyperexcitability scale.
Results : Previously reported data indicated that infants prenatally exposed to PHT, in monotherapy or polytherapy with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not the case for infants prenatally exposed to STP monotherapy.
Conclusions : Our results confirm previous findings and also demonstrate that infants prenatally exposed to CBZ or CBZ + STP, like controls, are not hyperexcitable during testing.     

Prenatal and family risks of children born to mothers with epilepsy: effects on cognitive development

The offspring of mothers with epilepsy are considered to be at developmental risk during pregnancy from: (1) generalized maternal seizures (hypoxia); (2) teratogenicity of antiepileptic drugs (AEDs); and (3) adverse socio-familial conditions associated with having a chronically sick mother. Sixty-seven children of mothers with epilepsy and 49 children from non-affected mothers, matched for control variables, were followed from birth to adolescence (53 males, 63 females; mean age 14y 2mo, range 10-20y). Prediction of intellectual performance of these children during adolescence was calculated from the following variables: maternal generalized seizures, prenatal exposure to AEDs, and quality of family stimulation (HOME Inventory) assessed in children at 2 years of age. Children who were prenatally exposed to AEDs achieved lower IQs than control children at adolescence. This effect was moderately significant for children who had been exposed to monotherapy (6 IQ points lower), but was considerable in those exposed to polytherapy (12 IQ points lower). Generalized seizures during pregnancy, observed in half the mothers, did not exacerbate this effect. Relative to prenatal risk status, the quality of the family environment had varied effects on intellectual development. Children with prenatal risks appeared to be more vulnerable to environmental disadvantage than control children, but they also showed longer-lasting effects of environmental support.     

Language Disturbances as Side Effects of Topiramate and Zonisamide Therapy

Reversible side effects of two sulfa-containing antiepileptic drugs (AEDs), topiramate (TPM) and zonisamide (ZNS), are reported. These effects differ from those of other AEDs in that language impairment was the predominant cognitive complaint. Information was available for 42 patients exposed to TPM. Twenty-two (52%) complained of adverse effects; 12, specifically of deficits in language-related functions. Brief neuropsychological testing in four patients on TPM confirmed verbal deficits. These deficits could appear shortly after initiating TPM and disappear variably after drug withdrawal. Similar complaints were seen in a pilot study of ZNS monotherapy, administered in supratherapeutic doses, confirmed by neuropsychological testing. TPM and ZNS both contain a sulfa moiety, suggesting that verbal processing is especially sensitive to these sulfa-containing AEDs.     

Maternal Use of Antiepileptic Drugs and the Risk of Major Congenital Malformations: A Joint European Prospective Study of Human Teratogenesis Associated with Maternal Epilepsy

Summary: Purpose: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and poly-therapy. Methods: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. Results: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2–4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6–15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3–18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4–67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1–57.6). Offspring of mothers using > 1,000 mg VPNday were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed ≥600 mg VPNday (RR 6.8; 95% CI: 1.4–32.7). No difference in risk of MCA was found between the offspring exposed to 601–1,000 mg/day and ≥600 mg/day. Conclusions: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.     

Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE)

SUMMARY: PURPOSE: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. METHODS: Information on all malformed infants (1990-1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries. RESULTS: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid. CONCLUSIONS: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports.     

The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months.

BACKGROUND: Most women with epilepsy need to take antiepileptic drugs (AEDs) in pregnancy to prevent the potentially harmful effects of seizures. Retrospective studies have demonstrated an increased chance of having a child with a birth defect (BD) in women with epilepsy taking AEDs. It is uncertain how much of this risk is directly caused by the AEDs and whether certain drugs or combinations are associated with a greater risk. AIMS: To establish a register to evaluate prospectively the incidence of adverse pregnancy outcomes in women exposed to specific AEDs; to determine whether certain AEDs or combinations were associated with a greater risk; and to determine whether other factors influenced the risk. METHODS: An Australia-wide, prospective, voluntary, telephone-interview based, observational register. Three groups of pregnant women were enrolled: those with epilepsy taking AEDs, those with epilepsy not taking AEDs, and those taking AEDs for a non-epileptic indication. The pregnancy outcomes were evaluated by follow-up interviews and by reference to hospital and treating doctors' records. RESULTS: Over the first 30 months of the study (till December 2001) 334 eligible women were enrolled, with all states and territories being represented. Two hundred and ninety two pregnancies had been completed, of which 256 (88%) resulted in a healthy live birth, 19 (6.5%) a live birth with a birth defect, four an induced abortion because of a detected malformation on ultrasound, one premature labour with a stillbirth and 12 (4%) spontaneous abortions. Of the completed pregnancies, 269 were exposed to at least one AED during the first trimester. The incidence of birth defects in relation to specific AEDs was: valproate (16.7%), phenytoin (10.5%), lamotrigine (7.7%) and carbamazepine (3.3%), none of which was significantly different from that in women with epilepsy not taking an AED (4.3%, n.s.). The dose of valproate taken was higher in pregnancies with BD compared to those without (mean 2081 mg vs. 1149 mg, p<0.0001). The incidence of folate supplementation being taken prior to conception did not differ for pregnancy outcomes with or without BD (70% vs. 66%, n.s.). CONCLUSIONS: The model for the Australian Pregnancy Register appears to be successful, with strong enrolment from all regions over the first 30 months. The study is prospective and includes reference to all new AEDs approved in Australia over the past decade. Analysis of the pregnancy outcomes to date may reveal early trends, but numbers are still to small for any definitive conclusions to be made regarding the relative risk in pregnancy of individual AEDs.     

A pilot open‐label trial of zonisamide in Unverricht‐Lundborg disease

Action myoclonus frequently remains the primary cause of disability in Unverricht‐Lundborg disease (EPM1) patients. Pharmacological treatment of myoclonus in these patients continues to be challenging; indeed conventional AEDs may be poorly effective in monotherapy or even in combination. We carried out a pilot, open‐label trial of add‐on zonisamide (ZNS) in patients with EPM1. Twelve EPM1 patients with epilepsy and action myoclonus were included in the study. Oral ZNS was gradually titrated until the target dose of 6 mg/Kg/day. Unified Myoclonus Rating Scale was obtained in each subject before and after ZNS add‐on. A significant reduction of myoclonus severity was reached after ZNS introduction. ZNS was generally well tolerated and only two patients withdrew due to mild adverse effects. Our trial suggests that ZNS may be a valuable therapeutic option in EPM1 patients. © 2010 Movement Disorder Society     

IgA and IgG2 Deficiency Associated with Zonisamide Therapy: A Case Report

Summary: Purpose : To report a previously undescribed adverse effect, IgA/IgG subclass deficiency associated with zonisamide (ZNS) therapy.
Methods : Serum IgA and IgG subclass levels were determined by the turbidimetric immunoassay and enzyme-linked immunosorbent assay, respectively, in a 2–year-old boy with postmeningitis sequelae who was treated by ZNS.
Results : Four months after initiation of ZNS, combined deficiency of IgA and IgG2 was noted. After cessation of ZNS, serum IgA level was promptly increased. IgG2 level was gradually increased, but remained subnormal after 7 months.
Conclusions : This case documents, for the first time, the action of ZNS on IgG immune system as well as IgA system. If patients with ZNS therapy showed IgA deficiency and recurrent infections, it is preferable to check serum IgG subclass concentrations as well.     

Reproductive Activity and Offspring Health of Young Adults with Childhood-Onset Epilepsy: A Controlled Study

Summary: Purpose : To study reproductive activity and offspring health in a prospective follow-up setting.
Methods : After a 35-year follow-up of a population-based patient cohort with childhood-onset "epilepsy only", 100 (56.8%) of 176 surviving patients were shown to have "epilepsy only", i.e., recurrent unprovoked seizures with no associated neuroimpairment. Their reproductivity and offspring health were compared with those of matched controls.
Results : The marriage rate and fertility of patients with "epilepsy only" were significantly reduced as compared with those of matched controls. Continuation of antiepileptic drug (AED) treatment was significantly associated with reduced reproduction, whereas occurrence of seizures during the previous 5 years was not. The incidence of epilepsy was nine times greater among the children of patients than among those of controls. No higher risks were observed in pregnancy or delivery in patients, nor were increased rates of birth defects in their offspring than in those of contols. Exposure to AEDs during pregnancy did not increase these risks.
Conclusions : Patients with "epilepsy only" since childhood have fewer marriages and fewer children than expected. However, when they marry, their pregnancies and deliveries are unremarkable and their children do not have increased congenital health problems. Obviously, etiologies causative of both epilepsy and associated neurological impairments are more harmful to the course of pregnancy and delivery and offspring health than are those resulting in "epilepsy only".     

Pregnancy and epilepsy

The management of women with epilepsy who are planning a pregnancy or who are currently pregnant remains one of the most perplexing and engaging clinical issues for neurologists. A refinement of surveillance methods, along with a greater understanding of teratogenesis, has provided us with better information regarding specific antiepileptic drug (AED)-associated teratogenic risk than in the past. A recent finding from multiple worldwide AED pregnancy registries is an increased teratogenic risk with valproate compared with the other AEDs, supporting previous retrospective reports. Valproate use and independently having more than five convulsive seizures during pregnancy are associated with a risk of decreased verbal intelligence quotient (IQ) in the offspring. The European pregnancy register confirms that most women who are seizure-free early in pregnancy have an excellent chance of maintaining seizure freedom throughout pregnancy. The management of AEDs during pregnancy continues to be explored, and considerations for dosing and therapeutic monitoring are discussed herein. The metabolism of both lamotrigine and oxcarbazepine is induced during pregnancy, and careful clinical monitoring and frequent level assessment are emerging as important for these AEDs.     

Comparative retention rates and long-term tolerability of new antiepileptic drugs.

OBJECTIVE: Retention rates of five new anti-epileptic medications (AEDs) were compared in order to evaluate their long-term tolerability and efficacy. METHOD: We acquired the retention data on levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM), and zonisamide (ZNS) from the electronic database. The data included patient's age, gender, seizure type, current and previous medications, dosage, main reasons for discontinuation, and duration of therapy. The retention rates of these AEDs were evaluated at 4, 12, 24, 52, and 104 weeks. RESULTS: A total of 828 new AED exposures were obtained (LEV=196, LTG=251, OXC=97, TPM=156, ZNS=128) from patients with partial or generalized epilepsy. At 2 years, retention rate was highest with LTG (74.1%), followed by ZNS (60.2%), OXC (58.8%), LEV (53.6%), and TPM (44.2%). When these AEDs were discontinued, it was mainly due to inefficacy (29.5%) and sedating side-effects (20.5%), and commonly within 6 months into therapy. Several important AED specific side-effects leading to discontinuation were identified, including behavioral or irritability from LEV, rash from LTG and OXC, nausea from OXC and ZNS, hyponatremia from OXC, and kidney stones from TPM and ZNS. CONCLUSION: Comparing retention rates of new AEDs can provide useful insight into their tolerability and efficacy. This study showed highest retention rate with LTG, which was significantly different from ZNS (p=0.0025), LEV (p<0.0001), OXC (p=0.0024), and TPM (p<0.0001). Beside ineffectiveness, other leading causes of discontinuation were adverse behavioral effects with LEV, rash with LTG and OXC, and sedation for TPM and ZNS.     

Dose-dependent memory effects and cerebral volume changes after in utero exposure to valproate in the rat

Purpose:   Recent clinical studies raised concern of a cognitive teratogenicity of the major antiepileptic drug valproate. To investigate possible cerebral correlates, we established a forced self-application schedule by diluting valproate in the drinking water of pregnant Wistar rats.
Methods:   After application of medium (MD) and high doses (HDs) with mean daily intakes of about 470 and 720 mg/kg during the entire pregnancy, we analyzed effects on offspring performance in a series of behavioral paradigms as well as brain volumetric changes by magnetic resonance imaging (MRI).
Results:   While high dosages with peak serum concentrations slightly above 100 μg/ml induced early decrements in general activity and deficits in learning and memory, medium dosages led to improved watermaze performance in 30-day-old rats. MRI analyses indicated increased hippocampal volumes in the MD condition, whereas in the HD condition significantly decreased cortical and brainstem volumes were registered. Cortical volume reduction was correlated with spatial acuity in the watermaze.
Conclusions:   The results indicate that effects of valproate in utero on offspring cognitive capabilities might depend on total drug load differentially affecting cerebral development during adolescence in the rat.