Cross-sensitivity of patient-perceived adverse cognitive effects with antiepileptic drug use

ObjectiveThe extent to which adverse cognitive effects (ACEs) to a specific antiepileptic drug (AED) affect the chance of developing ACEs to other AEDs (i.e., cross-sensitivity) is unknown. We investigated the rates of cross-sensitivity of ACEs among AEDs and examined the association between clinical characteristics and occurrence of having ACEs to multiple AEDs in adults with epilepsy.MethodsThe rates of cross-sensitivity of intolerable ACEs (IACEs; i.e., ACEs leading to dosage reduction or discontinuation) and the non-AED predictors of IACEs were investigated in 2269 patients who had taken at least two AEDs at a single center. We accounted for AED load and looked for specific cross-sensitivities between AEDs as well as cross-sensitivity based on the AED mechanism of action.ResultsAmong the 2269 patients, the highest rates of IACEs were seen with TPM (26.3%), ZNS (9.8%), PHT (8.8%), and VPA (8.5%). Intolerable ACEs to two or more AEDs occurred in 100 patients (4.4%). History of psychiatric condition(s) and absence seizure type were independent predictors of IACEs to two or more AEDs. High rates of cross-sensitivity of IACEs were seen between phenytoin (PHT) and lamotrigine (LTG), valproate (VPA) and phenytoin, and valproate and zonisamide (ZNS). For example, of patients who had IACEs to VPA and were also prescribed ZNS, 46.2% had IACEs to ZNS (abbreviated as VPA → ZNS: 46.2%); of patients who had IACEs to ZNS and were also prescribed VPA, 37.5% had IACEs to VPA (abbreviated as ZNS → VPA: 37.5%). Other results are as follows: LTG → PHT: 28.6%, PHT → LTG: 20.0%, PHT → VPA: 42.9%, and VPA → PHT: 27.3%. No specific cross-sensitivities were found among AEDs sharing a similar mechanism of action.SignificanceThe probability of ACE intolerability to an AED can increase if a patient developed ACE intolerability to another AED. The cross-sensitivity rates for ACE intolerability between LTG and PHT, PHT and VPA, and VPA and ZNS were found to be particularly high. The cross-sensitivity rates provided here may be clinically useful for predicting ACE intolerability in patients taking certain AEDs and for AED selection in individual patients.     

Cross-reactivity of skin rashes with current antiepileptic drugs in Chinese population

ObjectiveDue to less experience with the cross-reactivity of antiepileptic drugs (AEDs) in Chinese population, we surveyed the rates of cross- reactivity of rash among commonly used AEDs in Chinese patients with epilepsy, particularly between the traditional and the new compounds.MethodsWe have retrospectively reviewed the medical records concerning all antiepileptic drug treatment in consecutive Chinese patients with epilepsy in our center. The incidence of AED-related rash was determined in 3793 outpatients, taking at least one of the AEDs-carbamazepine (CBZ), valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), clonazepam (CZP), oxcarbazepine (OXC), lamotrigine (LTG), gabapentin (GBP), topiramate (TPM), levetiracetam (LEV) and traditional Chinese medicine (TCM). We have performed telephone interviews among all patients with AEDs-related rash. We described the clinical characteristics of the 18 patients with cross-reactivity involving the AEDs, and the cross- reactivity pattern for CBZ, PHT, OXC, and LTG.ResultsA total of 3.61% (137/3793) of patients experienced a skin rash to at least one AEDs, of these patients, 73 (53.28%) were female and 64 were males (46.72%). While 18 patients had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 17), 52.9% had a rash to PHT (abbreviated as CBZ → PHT: 52.9%); of patients who had a rash to PHT and were also prescribed CBZ (n = 13), rate of rash was 69.2% (i.e., PHT → CBZ: 69.2%). Other results: CBZ → LTG: 25% (n = 16); LTG  → CBZ: 44.4% (n = 9); CBZ → OXC: 40% (n = 10); OXC → CBZ: 66.7% (n = 6); LTG → PHT: 20% (n = 5); PHT → LTG: 16.7% (n = 6); OXC → LTG: 25% (n = 4); LTG → OXC: 33.3% (n = 3); OXC → PHT: 25% (n = 4); PHT → OXC: 16.7% (n = 6). There was a highly significant mutual risk for cross- reactivity for CBZ and PHT, and OXC, and LTG (p < 0.001), mutual risk reached statistical significance for LTG and CBZ (p = 0.01).ConclusionCross-reactivity rates between certain AEDs are high, especially when involving carbamazepine and phenytoin. There were also too few patients with rash to reach definitely conclusions about possible cross-reactivity. Larger numbers of patients would be needed to assess this and the mechanism. Caution should be exercised when prescribing certain AEDs (especially CBZ and PHT, but also OXC, and LTG).     

Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register

Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N = 118), the incidences for LTG (N = 243), carbamazepine (CBZ) (N = 302) and VPA (N = 224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

Population-based study of antiepileptic drug exposure in utero—Influence on head circumference in newborns

PurposeTo study the effect of AED exposure on head circumference in the newborn.MethodsData on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index.ResultsA significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS) = 0.15, p < 0.001) and valproic acid (VPA) (SDS = 0.10, p = 0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR = 2.85, 95% CI: 1.74–4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ or VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time.ConclusionsCBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored.     

Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome

Approximately 60–80% of girls with Rett Syndrome (RTT) have epilepsy, which represents one of the most severe problems clinicians have to deal with, especially when patients are 7–12 years old.The aim of this study was to analyze the antiepileptic drugs (AEDs) prescribed in RTT, and to assess their effectiveness and tolerability in different age groups from early infancy to adulthood.We included in this study 104 girls, aged 2–42 years (mean age 13.9 years): 89 had a mutation in MECP2, 5 in CDKL5, 2 in FOXG1, and the mutational status was unknown in the remaining 8.Epilepsy was present in 82 patients (79%). Mean age at epilepsy onset was 4.1 years.We divided the girls into 5 groups according to age: < 5, 5–9, 10–14, 15–19, 20 years and older.Valproic acid (VPA) was the most prescribed single therapy in young patients (< 15 years), whereas carbamazepine (CBZ) was preferred by clinicians in older patients. The most frequently adopted AED combination in the patients younger than 10 years and older than 15 was VPA and lamotrigine (LTG).Seizures in the group aged 10–14 years were the most difficult to treat, requiring a mean of three different AEDs, often used in combination and mostly including VPA. Seizures in fifteen patients (18%) were considered drug resistant. VPA was reported as the most effective AED in younger girls (in 40% of the patients aged < 5 years, in 19% of the girls aged 5–9 years), and CBZ the most effective in the patients 15 years or older. Adverse reactions did not differ from expected: agitation, drowsiness, and weight loss were the most frequently reported. In our sample, LTG was the least tolerated AED. We did not find correlations with MECP2 mutations in terms of effectiveness or adverse reactions.Conclusion: in this study we observed different effectiveness of AEDs based on age, and suggest that clinicians consider age-dependency when prescribing appropriate AEDs in the RTT population.     

Pharmacodynamic and pharmacokinetic interactions of perampanel and other antiepileptic drugs in a rat amygdala kindling model

PurposeThis study explored the pharmacodynamic and pharmacokinetic effects of combining perampanel (PER) with commonly co-administered AEDs.MethodA strong stimulus intensity (three-fold higher than after-discharge threshold) was used to elicit drug-resistant seizures in a rat amygdala kindling model. Vehicle, low-dose PER (0.75 mg/kg), or high-dose PER (1.5 mg/kg), in combination with vehicle, levetiracetam (LEV) 50 mg/kg, lamotrigine (LAM) 20 mg/kg, carbamazepine (CBZ) 20 mg/kg, or valproic acid (VPA) 200 mg/kg, were administered intraperitoneally to groups of 6–13 rats. Seizure score, electroencephalography (EEG) seizure duration, and motor seizure duration were evaluated, with pharmacodynamic interactions determined by two-way analysis of variance (ANOVA). Motor impairment was evaluated by rotarod test and two-way ANOVA.ResultsHigh-dose PER, but not low-dose PER, LEV, LAM, CBZ, or VPA, reduced EEG seizure duration, motor seizure duration, and seizure score compared with vehicle alone. However, when low-dose PER was administered in combination with LEV, LAM, CBZ, or VPA, seizure severity parameters were reduced compared with the concomitant AEDs alone. These pharmacodynamic interactions were statistically significant in some cases, but the same AED combinations were not associated with statistically significant neurotoxic interactions. Efficacy may have been slightly affected by changes in PER plasma concentrations in the presence of other AEDs:PER plasma concentrations increased with LEV or LAM co-administration, and decreased with CBZ or VPA co-administration.ConclusionOverall, these data support published Phase III data demonstrating the efficacy of PER as adjunctive therapy for the treatment of refractory partial-onset seizures in patients aged ≥12 years.     

Rectal carbamazepine as effective long-acting treatment after cluster seizures and status epilepticus

Carbamazepine (CBZ) is the gold standard antiepileptic drug (AED) for focal onset seizures. Despite CBZ being the benchmark AED, with readily available therapeutic drug monitoring, patients presenting with recurrent secondarily generalized tonic–clonic (or cluster) seizures or generalized tonic–clonic status epilepticus (SE) are primarily treated with other long-acting agents. The aim of the study was to examine the potential use of rectal (PR) CBZ as alternative long-acting treatment to parenteral AEDs following the termination of cluster seizures or SE with acute intravenous therapies. Oral CBZ syrup was given PR using 400-mg equivalent aliquots. Serum CBZ levels were requested after administration to confirm achievement of minimum therapeutic levels (total CBZ > 20 μmol·L^− 1). Where levels were subtherapeutic, the procedure was repeated using 400-mg CBZ bolus aliquots until therapeutic levels were achieved. Seven patients received PR CBZ to manage cluster seizures or SE following the initial termination of acute seizures with IV therapies including benzodiazepines. Six patients had no prior history of seizures, and 1 patient with a prior history was not taking AED therapy at the time of presentation. All patients subsequently remained seizure-free, and therapeutic CBZ levels were achieved in 6 of the 7 subjects within 5–10 h of initial CBZ dosing. In conclusion, the present study reports 7 patients who were safely and effectively treated with PR CBZ, which proved to be a viable and safe alternative to parenteral AEDs for maintenance of seizure freedom.     

Antiepileptic drug prescribing patterns in Iraq and Afghanistan war veterans with epilepsy

ObjectiveWe examined patterns of antiepileptic drug (AED) use in a cohort of Iraq/Afghanistan war veterans (IAVs) who were previously identified as having epilepsy. We hypothesized that clinicians would be more likely to prescribe newer AEDs and would select specific AEDs to treat seizures based on patient characteristics including gender and comorbidities.MethodsFrom the cohort of IAVs previously identified with epilepsy between fiscal years 2009 and 2010, we selected those who received AEDs from the Veterans Health Administration in FY2010. Regimens were classified as monotherapy or polytherapy, and specific AED use was examine overall and by gender. Multivariable logistic regression examined associations of age; gender; race/ethnicity; medical, psychiatric, and neurological comorbidities; and receipt of neurology specialty care associated with the six most commonly used AEDs.ResultsAmong 256,284 IAVs, 2123 met inclusion criteria (mean age: 33 years; 89% men). Seventy-two percent (n = 1526) received monotherapy, most commonly valproate (N = 425) and levetiracetam (n = 347). Sixty-one percent of those on monotherapy received a newer AED (levetiracetam, topiramate, lamotrigine, zonisamide, oxcarbazepine). Although fewer women than men received valproate, nearly 90% (N = 45) were of reproductive age (≤ 45 years). Antiepileptic drug prescribing patterns were associated with posttraumatic stress disorder, bipolar disorder, cerebrovascular disease, dementia/cognitive impairment, headache, and receipt of neurological specialty care (all p < 0.01).SignificanceIn this cohort of veterans with epilepsy, most received AED monotherapy and newer AEDs. Prescribing patterns were different for men and women. The patterns observed between AEDs and neurological/psychiatric comorbidities suggest that clinicians are practicing rational prescribing.     

What do epileptologists recommend about discontinuing antiepileptic drugs for a second time in children?

ObjectiveThere is a broad consensus that antiepileptic drugs (AEDs) may be withdrawn after two years of seizure freedom for most children with epilepsy. If seizures recur and are, again, completely controlled with AEDs, little is known about discontinuing a second time. We surveyed American and Canadian pediatric epileptologists to understand their current practice.MethodsIn 2014, a survey was sent via e-mail to 193 pediatric epileptologists to learn about AED discontinuation practices in children. The survey asked direct questions about practice and posed five “real-life” cases where the decision to discontinue might be difficult. Participants were identified through membership lists of several US and Canadian epilepsy organizations.ResultsThere were 94 (49%) completed surveys. Sixty-three participants had ≥ 10 years in practice (“more experienced”: mean 23 ± 9 years), and 31 had < 10 years (“less experienced”: mean 6 ± 2). Overall, 62% recommended AED discontinuation for the first time after 2–3 years of seizure freedom, and 61% recommended discontinuation for the second time after 2–3 years. Fifty-six percent of “more experienced” clinicians required a longer seizure-free period prior to a second discontinuation (p < 0.001) compared with 26% of “less experienced” clinicians (p = ns). Overall, most participants suggested an AED taper duration of 2–6 months for the first and second attempts, 52% and 68%, respectively. Both groups wean AEDs more slowly during the second attempt (p < 0.001). There was only 40–60% agreement among participants to discontinue AEDs in four of the cases.ConclusionNearly half (46%) of pediatric epileptologists require a longer seizure-free period the second time they attempt to discontinue AEDs compared with the first attempt and wean down AEDs somewhat more slowly. Although a variety of factors influence decision-making, there was a high level of disagreement to discontinue AEDs a second time in “real-life” cases.     

Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs)

PurposeLevetiracetam (LEV) therapeutic range (20–40 mg/L) and potential drug interactions were assessed in people with epilepsy (PWE).MethodFifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20–40 mg/L – LEV; 25–50 μmol/L – total CBZ; 6–13 μmol/L – free CBZ; 300–750 μmol/L – total VPA; 30–75 μmol/L – free VPA; and 40–60 μmol/L – LTG. Seizure-freedom was assessed and patients followed for almost two years.Results23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had ‘therapeutic’ LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had ‘therapeutic’ LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy.ConclusionLEV range (20–40 mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy.     

Differential effects of lacosamide,phenytoin and topiramate on peripheral nerve excitability: An ex vivo electrophysiological study

BackgroundAntiepileptic drugs (AEDs) are mainly used to control cortical hyperexcitability. Some of them (e.g. phenytoin (PHT) and topiramate (TPM)) have also effects on the peripheral nervous system (PNS). Lacosamide (LCM) is a novel AED that stabilizes hyperexcitable neuronal membranes by selectively enhancing the slow inactivation of voltage-gated sodium channels (VGSCs). Although the mechanism of action of LCM is fairly well understood, there are no in vitro data available regarding any possible PNS effects of LCM.ObjectiveTo investigate, in vitro, the effects of LCM on peripheral nerve excitability in comparison with PHT and TPM, two AEDs that act, in part, by stabilizing the fast inactivation state of VGSCs.MethodsExperiments were conducted on the isolated sciatic nerve of the adult rat using standard electrophysiological methods. The effects of LCM on the amplitude and latency of the evoked compound action potential (CAP) during a 48 h period of drug exposure were recorded and compared with the effects of PHT and TPM.ResultsLCM produced inhibitory effects on CAP at concentrations significantly higher than the therapeutic levels (>25 μg/ml). At these concentrations (62.57–125.15 μg/ml), an acute and immediate increment of the latency and decrement of the amplitude of the CAP were observed. In contrast to LCM, PHT caused an acute decrement in the amplitude as well as an increment in the latency of the CAP even at subtherapeutic levels (5 μg/ml). With regard to TPM, the amplitude of the CAP was not affected at the supratherapeutic concentrations but at the therapeutic concentration of 33.94 μg/ml a reduced decrement of the CAP amplitude compared to the controls was observed.ConclusionsLCM, PHT and TPM exert differential effects on peripheral nerve excitability. PHT inhibited the sciatic nerve CAP even at subtherapeutic levels whereas LCM was safe within the therapeutic concentration range. TPM did not affect the CAP amplitude even at high supratherapeutic concentrations whereas in the therapeutic range a neuroprotective effect was observed. Possible underlying mechanisms and the clinical implications of these findings are discussed.     

Health-care costs and utilization related to long- or short-acting antiepileptic monotherapy use

PurposeThis study aimed to compare health-care utilization and costs in patients treated with long-acting (LA) vs. short-acting (SA) antiepileptic drug (AED) monotherapy.MethodsWe conducted a cross-sectional study of claims from the OptumInsight™ database. Our analysis was restricted to adults diagnosed with epilepsy and who used AED monotherapy. Patients were excluded if they used > 1 type of AED, had < 9 months of treatment, or had a treatment gap of > 60 days. Antiepileptic drugs were classified as LA or SA based on published data and expert opinion. Medical and pharmacy claims were used to estimate health-care utilization and costs, and baseline group differences were adjusted using multivariate analyses.ResultsThere were 4058 (49.6%) LA AED users and 4122 (50.4%) SA AED users. Medication possession ratios (MPRs) were not significantly different between LA AED users and SA AED users (P = 0.125). Long-acting AED users had lower mean overall health-care costs ($9757 vs. $12,689), lower epilepsy-related costs ($3539 vs. $5279), and lower rate of overall (8.8% vs. 10.9%) and epilepsy-related hospitalizations (5.7% vs. 7.6%) compared with SA AED users (all P < 0.01). After adjusting for demographics and clinical characteristics, mean overall costs were lower by $686 and the mean epilepsy-related costs were lower by $894 in LA AED users.ConclusionAlthough MPRs were similar in LA AED and SA AED groups, patients treated with LA monotherapy had a lower economic burden compared with those treated with SA monotherapy, indicating that using AEDs with extended duration of action is associated with decreased health-care use and lower health-care costs.     

Comparison of the effectiveness of four antiepileptic drugs in the treatment of status epilepticus according to four different efficacy criteria

The preliminary data presented here shall give an impression on how different criteria for the identification of an antiepileptic drug (AED) with a possible or certain treatment effect can have an influence on the results of retrospective case series. We present a data subset from a large retrospective study which, when completed, will cover all treatment episodes of status epilepticus (SE) at the neurological department of the Universitätsmedizin Rostock from January 2010 to June 2013. We compare and contrast the results of four different efficacy criteria for the effectiveness of phenytoin (PHT), valproate (VPA), levetiracetam (LEV), and lacosamide (LCM): criterion 1 = the last AED administered before SE termination; criterion 2 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination and without changes in the comedication; criterion 3 = the last drug introduced into the antiepileptic therapy or increased in dose within 24 h before SE termination without changes in the comedication; and criterion 4 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination, even allowing changes in the comedication. Thirty-seven treatment episodes in 32 patients (13 male and 19 female, mean age at first episode: 68 years, SD: 17) could be analyzed. In 31 episodes, at least one AED was given intravenously. Efficacy rates in the whole case series according to all four criteria were not significantly different between the four AEDs, but there was a considerable difference in the efficacy rates of each AED when evaluating them with the different efficacy criteria. Our data show that statistically significant results concerning the efficacy of different AEDs in different subtypes of SE may depend on the outcome criteria. Therefore, efficacy criteria for the effectiveness of AEDs in the treatment of SE should be standardized.This article is part of a Special Issue entitled Status Epilepticus.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.     

Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort

IntroductionPhenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) and is being replaced by newer AED, increasing the costs and causing major budget problems, particularly for developing countries.ObjectiveThe objective of this study was to determine ADR frequency, explore, and establish related risk factors.MethodsProspective data were collected from a cohort of inpatients using PHT for the first time. Pharmacovigilance was performed during hospitalization and after one month from the discharge. Clinical variables, plasma levels, and concomitant medications were collected and their association with the occurrence of different ADRs was explored.ResultsOne hundred patients were included: 59 were women, and mean age was 59 ± 21 years. Thirty-three patients presented ADR, all moderate and idiosyncratic. The most frequent were rash (17%), fever (10%), and elevated transaminases (10%). Female gender (85% vs 52%, p = 0.029), younger age (mean age: 49 vs 62 years, p = 0.032), and higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9 μg/mL, p = 0.040) were found to be associated with rash. A higher number of concomitant medications were also found to be associated with the risk for developing any ADR. The multivariate analysis revealed an association between rash and younger age (cut-off: 35 years old; relative risk (RR) = 11.7; p = 0.026), and higher PHT plasmatic levels (cut-off: 16 μg/mL; RR = 12.5; p = 0.021); and increased risk of elevated transaminases with use of PHT inductors (RR = 18; p = 0.006). A longer hospital stay was found in patients who developed fever (mean: 43 days, p < 0.0001) and elevated transaminases (mean: 26 days, p = 0.041) compared with patients without ADR (mean: 17 days).ConclusionsPhenytoin is a widely used AED associated with easily detectable ADR through structured pharmacovigilance. The development of ADR is associated with longer hospital stays. Recognition of local risk factors may lead to ADR prevention in a near future. Larger studies are needed to better define PHT-related ADR risk profile and to individualize treatment regimens.     

Seizure outcome after AED failure in pediatric focal epilepsy: Impact of underlying etiology

ObjectiveThis study aimed to identify long-term seizure outcome in pediatric nonsyndromic focal epilepsy after failure of serial antiepileptic drugs (AEDs) due to lack of efficacy.MethodsChildren (1 month–17 years) with new-onset focal epilepsy not meeting the criteria for a defined electroclinical syndrome diagnosed between 1980 and 2009 while residing in Olmsted County, MN, were retrospectively identified. Medical records of those followed for ≥ 2 years were reviewed to assess etiology, the number of AEDs that failed due to lack of efficacy, and seizure outcome at final follow-up. Etiology was classified into structural/metabolic, genetic, or unknown. Favorable outcome was defined as seizure freedom ≥ 1 year, on or off AEDs, without prior epilepsy surgery. Poor outcome was defined as ongoing seizures in the preceding year or having undergone prior epilepsy surgery.ResultsNonsyndromic focal epilepsy accounted for 275/468 (59%) of all patients with newly diagnosed epilepsy — of these, 256 (93%) were followed for a minimum of two years and were included in the study. Median duration of follow-up was 10.0 years. At least one AED had failed due to lack of efficacy in 100 (39.1%) children. Favorable outcomes occurred in 149/156 (95.5%) children with no AED failure, 16/30 (53.3%) with one AED failure, 8/25 (32%) with two AED failures, and only 2/45 (4.4%) with three AED failures. After two AED failures, the seizures of nearly one-quarter of children who had epilepsy with an unknown cause responded favorably to the third AED compared with only 7.8% of the cohort that had epilepsy with a structural/metabolic cause. Children with a remote brain insult had a significantly higher likelihood of favorable outcome with serial AEDs than those with other structural abnormalities.SignificanceEtiology is an important determinant of pharmacoresistance in nonsyndromic focal epilepsy. Surgical evaluation should be considered after failure of 1–2 AEDs in those who have epilepsy with structural causes, excluding remote brain insults. Conversely, as surgical success is lower with normal MRI or more diffuse brain insults, it appears reasonable to hold off surgical evaluation until 2–3 AEDs have failed in such children.     

Specific adverse effects of antiepileptic drugs — A true-to-life monotherapy study

BackgroundIn patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy.MethodsAll patients ≥ 16 years of age with epilepsy for ≥ 12 months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database.ResultsOut of 841 patients, 438 (61% female, mean age: 44.7 ± 17.1 years) on monotherapy were included in this study. Levetiracetam (n = 151), lamotrigine (n = 167), valproic acid (n = 73), or controlled-release carbamazepine (n = 47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score ≥ 45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands.ConclusionIndividual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence.     

Differential effects of antiepileptic drugs on neonatal outcomes

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.