Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.     

Clinical heterogeneity of juvenile myoclonic epilepsy: Follow-up after an interval of more than 20 years

PurposeThe view that juvenile myoclonic epilepsy (JME) is a uniform and life-long disorder is currently being challenged. The aim of this study was to assess the seizure and psychosocial outcome of JME at least 20 years after onset.MethodsIn 1992, 42 patients with JME were identified. In 2012, 37 agreed to a semi-structured interview. In the remaining five, only medical records were available.ResultsOf 40 patients with known seizure outcome, 21 were in remission for >5 years. Seven were off antiepileptic drugs (AEDs), four being seizure free for >10 years. Myoclonic seizures (MC) evolving to generalized tonic–clonic seizures (GTC) were associated with seizure persistence (p = 0.013), whereas >1 year between MC and GTC onset was associated with a trend to GTC remission (p = 0.069). Of 19 patients with uncontrolled seizures, eight experienced remission with second generation AEDs.Favorable psychosocial outcome by interview was found in a third, whereas another third had psychiatric comorbidity, seven with substance or alcohol abuse. Psychosocial and seizure outcome did not correlate.ConclusionThis study corroborates the heterogeneity of JME in terms of seizure and psychosocial outcome, but without a clear association between the two. It confirms that seizure control may persist after AED withdrawal in some and supports MC evolving to GTC as a predictor of seizure persistence. Moreover, it suggests that newer broad spectrum AEDs may improve the prognosis of JME; their impact should be focus of prospective studies.     

Postnatal caffeine treatment affects differently two pentylenetetrazol seizure models in rats

Effects of repeated postnatal administration of caffeine (10 and 20 mg/kg s.c. daily from P7 to P11) were studied in two models of epileptic seizures characterized by spike-and-wave EEG rhythm in 18- and 25-day-old rats. Rhythmic metrazol activity (RMA, model of human absences) was induced by low dose of pentylenetetrazol (PTZ, 20 mg/kg or 40 mg/kg, i.p.) and minimal clonic seizures (model of human myoclonic seizures) by two successive doses of PTZ (20 and 40 mg/kg i.p.). Early postnatal caffeine treatment resulted in significant changes of RMA only in 18-day-old rats. Anticonvulsant effects were observed in RMA episodes elicited by the 20-mg/kg dose of PTZ in both caffeine groups whereas latency of RMA episodes induced by the 40-mg/kg dose was shortened and their duration was prolonged. No changes were found in 25-day-old animals. Incidence, EEG and motor pattern of minimal clonic seizures were not changed. Some animals in both control age groups exhibited transition to generalized tonic–clonic seizures. This type of seizures never appeared in caffeine-treated 25-day-old animals. Mixed effects of postnatal caffeine exposure were demonstrated; these predominantly anticonvulsant effects are age- and model-specific.     

Pharmacological and neuroethological studies of three antiepileptic drugs in the Genetic Audiogenic Seizure Hamster (GASH:Sal)

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic–clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5–20 mg/kg) and VPA (100–300 mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30–100 mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10 mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.     

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.     

New-onset status epilepticus and cluster seizures in the elderly

We evaluated the frequency, therapeutic response and predictors of status epilepticus (SE) and cluster seizures among elderly people. Patients over 60 years old with epilepsy (n = 201; age, 68.0 ± 7.5 years) were prospectively recruited. Among them, 64 patients (32%) who presented with new-onset cluster attacks and/or SE formed the study group. All underwent evaluation with electroencephalography (EEG) and CT scans. The mean duration of SE and cluster seizures at admission was 14.9 ± 53.7 hours. Cluster seizures were observed in 53 (26.4%) and SE in 34 (17%) elderly patients with seizures (n = 201). The types of SE were: generalized convulsive (23 patients), epilepsia partialis continua (eight patients), non-convulsive (two patients) and myoclonic (one patient). The types of epilepsy syndrome included were: acute symptomatic (37 patients; 57.8%), cryptogenic (15 patients; 23.4%) and remote symptomatic (12 patients; 18.8%). Interictal EEG was abnormal in 79.7% of patients with critical presentation compared to 53.3% of patients without critical presentation. Epileptiform activity was observed in 46.9% of patients with SE and/or cluster seizures compared to 27.0% without SE and/or cluster seizures (p = 0.001). The neuroimaging differences between the two groups were the absence of white-matter changes on CT scan in those with, compared to those without, SE and/or cluster seizures (28.1% compared to 41.6%, p = 0.06). The risk factors for SE and/or cluster seizures were: acute symptomatic seizures, simple partial seizures, a higher number of seizures, lower Glasgow coma scale (GCS) score and an absence of white-matter changes on CT scan. After multivariate analysis, lower GCS score (p = 0.01; odds ratio [OR] = 0.82) and a higher number of seizures (p = 0.03; OR = 1.03) significantly predicted the occurrence of SE and/or cluster seizures. Seizures were controlled with two antiepileptic drugs in 70.6%. To conclude, SE and/or cluster seizures are common (32%) among elderly patients with epilepsy. Early and aggressive treatment is effective in the majority.     

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

The Na⁺/Ca²⁺ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic–clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, and 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic–clonic components in 12–62% and 25–62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, and 30 mg/kg; p.o.), clonic and tonic–clonic PTZ-induced generalized seizures were reduced in 25–50% and 38–63% of treated animals, respectively. SN-6 (0.3, 1, and 3 mg/kg; p.o.) also significantly reduced PTZ-induced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3 and 30 mg/kg; p.o.) or SN-6 (3 and 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic–clonic PTZ-induced seizures. These findings suggested that Ca²⁺ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic–clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.     

Cerebrospinal fluid tau proteins in status epilepticus

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56 years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aβ_1–42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR = 32.5, p = 0.004) and chronic epilepsy (OR = 12; p = 0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting.This article is part of a Special Issue entitled “Status Epilepticus”.     

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.     

Age-related “Sleep/nocturnal” tonic and tonic clonic seizure clusters are underdiagnosed in patients with Dravet Syndrome

ObjectivesTo describe the semiology and EEG characteristics of the age-related pattern of sleep/nocturnal (S/N) seizures in patients with Dravet Syndrome (DS).MethodsWe retrospectively analysed the clinical and EEG data of DS patients followed at our reference centre for Rare Epilepsies. We included patients aged two years and older who fulfilled clinical and EEG criteria of DS (ILAE 1989). Genetic testing for SCN1A was done in all, followed by PCDH19 if this was negative. Patients showing a genetic abnormality in PCDH19 were excluded.Of 73 DS patients followed at our centre, 26 (15 males and 11 females), called the S/N group, experienced a switch in the circadian rhythm of seizures, from mainly awake/diurnal to mainly S/N seizures. We retrospectively analysed their clinical, EEG and genetic data.We have compared them to a second group of 7 patients (4 males and 3 females), aged more than 11 years, the non-S/N group, who did not develop S/N seizures.ResultsWe observed a pattern of S/N seizures concomitant with a decrease of awake seizures between 4 and 11 years (median 6 years 6 months). S/N seizures were brief but often occurred in clusters of 2–15 per night.Seizures were mostly focal (26) with frontal-central onset (25) and tonic or tonic-vibratory in semiology. S/N seizure clusters were difficult to control despite many AEDs trials. Benzodiazepines reduced seizure recurrence within a cluster in some patients.While no significant differences were found between groups regarding clinical features, the presence of frontal and central anomalies on wake and sleep EEG was significantly associated with the presence of the S/N pattern.ConclusionsPatients with DS often develop a characteristic clinical and EEG pattern with S/N tonic and tonic clonic seizures that is often underdiagnosed. Seizure semiology and EEG pattern differ from LGS but may worsen the quality of sleep of such patients and their families. The possible role of this pattern in SUDEP occurring mainly during sleep and at the same age should be further explored. Current AEDs have limited efficacy and specific drug trials should be proposed.     

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.     

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.     

Rufinamide for refractory focal seizures: An open-label,multicenter European study

PurposeThe present study aimed to assess the efficacy and tolerability of rufinamide as adjunctive drug for the treatment of a large series of children, adolescents and adults with refractory cryptogenic or symptomatic focal epilepsy.MethodsPatients were recruited in a prospective, add-on, open-label treatment study from six Italian and one German centers for pediatric and adolescent epilepsy care. Inclusion criteria were: (1) age 3 years or more; (2) diagnosis of cryptogenic or symptomatic focal epilepsy refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (3) more than one seizure per month in the last 6 months; (4) use of at least one other AED, but no more than three, at baseline; (5) informed consent from parents and/or caregivers.ResultsSixty-eight patients (40 males, 28 females), aged between 3 and 63 years (mean 19.9 years, median 16.0) ± SD 12.58, with cryptogenic (28 pts, 41.2%) or symptomatic focal epilepsy (40 pts, 58.8%), were recruited in the study. After a mean follow-up period of 10.4 ± 10.29 months, twenty-two patients (32.3%) had a 50–99% seizure reduction, and none became seizure-free. Twelve patients (17.6%) had a 25–49% seizure decrease, while in 30 (44.1%) seizure frequency was unchanged. A seizure worsening was reported in 5 patients (7.3%). A better response to rufinamide occurred in frontal lobe seizures (51.6%) and secondary generalized tonic–clonic seizures (50%).ConclusionRufinamide was effective against focal-onset seizures, particularly in the treatment of secondary generalized frontal lobe seizures.     

Lacosamide intoxication in attempted suicide

The anticonvulsant drug lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and has been shown to be an effective add-on treatment for partial-onset seizures. Common adverse events (frequency ?10%) of lacosamide doses up to 600 mg/day include nonspecific central nervous system effects (e.g., dizziness, ataxia, diplopia, and somnolence). There are no human data regarding the safety of very high dosages of lacosamide. We report the clinical course of a patient with bitemporal epilepsy who ingested 12 g of lacosamide, 56 g of gabapentin, 2 g of topiramate, and 2.8 g of zonisamide during a suicide attempt. The patient was found comatose and experienced repeated generalized tonic–clonic seizures, aspiration with subsequent pneumonia, hypotension, and an increase in PR interval. Complete physical recovery occurred after several days of supportive treatment. We conclude that intoxication with lacosamide, in combination with overdoses of multiple AEDs, can be survived without sequelae, even after ingestion of 12 g lacosamide.     

Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤ 24 h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose > 200 mg versus ≤ 200 mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended.     

Duration of focal complex,secondarily generalized tonic–clonic,and primarily generalized tonic–clonic seizures — A video-EEG analysis

IntroductionIdentifying seizures with prolonged duration during video-electroencephalographic (EEG) monitoring is of importance to inform clinicians when to start emergency treatment of seizures to prevent status epilepticus. The aims of this study were to assess the clinical and EEG seizure duration (SD) in consecutive patients with epilepsy who underwent prolonged video-EEG monitoring and to identify a seizure type-dependent time point to start emergency treatment based on the likelihood that seizures will not stop spontaneously. Furthermore, we sought to determine predictors of SD and explored the relationship between antiepileptic drug (AED) serum levels and SD.Material and methodsWe retrospectively analyzed 1796 seizures in 200 patients undergoing video-EEG monitoring between January 2006 and March 2008.ResultsFocal simple seizures lasted significantly shorter (clinical SD: 28 s, EEG SD: 42 s) compared with focal complex seizures (clinical SD: 64 s, EEG SD: 62 s), and both seizure types lasted significantly shorter compared with secondarily generalized tonic–clonic seizures (GTCSs; clinical SD: 90 s, EEG SD: 96 s). There was no difference between the duration of the convulsive phase of primary GTCSs (defined as nonfocal) and that of secondarily GTCSs (each 65 s). Cumulative clinical SD (99%) was 7 min in focal complex seizures and 11 min in focal simple seizures. Mixed linear regression model demonstrated that history of status epilepticus (P = 0.034), temporal lobe seizure onset (P = 0.040), and MRI lesions (P = 0.013) were significantly associated with logarithmic EEG SD in focal epilepsies recorded with scalp electrodes. We found significant negative correlations between the AED serum level and the EEG SD in patients treated with monotherapy: carbamazepine (P < 0.001), levetiracetam (P = 0.001), oxcarbazepine (P = 0.001), and valproic acid (P = 0.038) but not with lamotrigine monotherapy and EEG SD.DiscussionBased on the results of this study, we propose 2 min of convulsive seizure activity (irrespective of focal or generalized onset) as a prolonged seizure, which could serve as a time point to consider treatment to prevent status epilepticus. In focal complex seizures, we suggest an upper limit of 7 min, and in focal simple seizures 11 min, as definition of prolonged seizures. History of status epilepticus, temporal seizure onset, and lesional MRI findings are factors associated with significantly longer SD. Negative correlations of carbamazepine, levetiracetam, oxcarbazepine, and valproic acid serum levels and SD suggest a prolonging effect on seizures during withdrawal of these AEDs during video-EEG monitoring sessions.This article is part of a Special Issue entitled “Status Epilepticus”.     

A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures

This noninterventional, observational, postauthorization safety study (SP0942, NCT00771927) evaluated the incidence of predefined cardiovascular- (CV) and psychiatric-related treatment-emergent adverse events (TEAEs), in patients with epilepsy and uncontrolled partial-onset seizures, when initiating adjunctive therapy with lacosamide or another approved antiepileptic drug (AED) according to standard medical practice. Active recording of predefined TEAEs of interest took place at three-monthly recommended visits for up to 12 months. Of 1004 patients who received at least one dose of adjunctive AEDs, 511 initially added lacosamide therapy, 493 added another AED, 69 were ≥ 65 years of age, and 72 took concomitant antiarrhythmic drugs. Patients in the lacosamide cohort had a higher median frequency of partial-onset seizures (6.0 versus 3.5 per 28 days) despite taking more concomitant AEDs (84.9% versus 66.9% took ≥ 2) at baseline. Patients who added lacosamide took a modal dose of 200 mg/day over the treatment period (n = 501), and 50.1% (256/511) completed 12 months of treatment. Fifty-one point nine percent (256/493) of patients who added another AED completed the study, with the most commonly added AED being levetiracetam (28.4%). Four patients (0.8%) in each cohort, all < 65 years of age, reported predefined CV-related TEAEs. None were considered serious or led to discontinuation. One event each of sinus bradycardia (lacosamide), atrioventricular block first degree (lacosamide), and syncope (other AED) were judged to be treatment-related. Another patient in the other AED cohort reported bradycardia while taking concomitant antiarrhythmic drugs. Predefined psychiatric-related TEAEs were reported by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort. Depression was the most common to be treatment-related (7/11 and 12/18 of patients reporting treatment-related psychiatric TEAEs, respectively). Serious psychiatric-related TEAEs were reported by four patients who added lacosamide (two cases of depression, two of suicide attempt) and one who added another AED (depression). Seven deaths occurred, all of which were considered unrelated/unlikely related to study medication. This thorough evaluation revealed a low incidence of predefined CV- and psychiatric-related TEAEs in patients taking adjunctive AED therapy according to standard medical practice. No specific safety concerns related to adjunctive lacosamide therapy were noted.     

Distinguishing between patients with pure psychogenic nonepileptic seizures and those with comorbid epilepsy by means of clinical data

Patients with psychogenic nonepileptic seizures (PNESs) often have additional epileptic seizures (ESs). Distinguishing between those with ESs and those without ESs is difficult but mandatory. We hypothesize that these two patient groups differ in clinical data, which might be useful for establishing diagnosis. All patients with PNESs (n = 114) from the Bethel Epilepsy Centre treated between 1/11/2010 and 1/11/2011 were included. Thirty-six percent had additional epilepsy. In contrast, 84 of the 114 patients with PNESs took antiepileptic drugs (AEDs) (AED treatment: patients with PNESs = 44/73, patients with PNESs + ESs = 40/41), most of them (65.5%) as polytherapy. Significant differences between both groups were as follows: patients with PNESs were older at disease onset, had a shorter duration from onset to inpatient visit, were less frequently on AEDs, were less frequently on antiepileptic polytherapy, and had a normal EEG compared with patients with PNESs + ESs. Multivariate stepwise logistic regression revealed age at seizure onset, number of AEDs, and difference between number of AEDs and psychiatric drugs as significant predictors of patients with ESs in PNESs (Nagelkerke's r² = 0.59). Therefore, clinical data proved to be useful in the diagnostic process.