Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies.

OBJECTIVE: Cognitive and psychiatric adverse events in patients with epilepsy are important determinants of therapeutic outcomes and patient quality of life. We assessed the relationship between adjunctive cenobamate treatment and selected cognitive and psychiatric treatment-emergent adverse events (TEAEs) in adults with uncontrolled focal epilepsy. METHODS: This was a retrospective analysis of pooled populations of patients with focal epilepsy from two phase 2, randomized, double-blind clinical trials; two open-label extensions (OLEs) of those trials; and a long-term, open-label, phase 3 safety study. Occurrence of cognitive and psychiatric TEAEs in patients treated with adjunctive cenobamate or placebo during double-blind treatment were evaluated. Exposure-adjusted incidence rates of the cognitive and psychiatric TEAEs, defined as the number of TEAEs per patient-year of treatment, during up to 7 years of long-term adjunctive cenobamate treatment, were determined in the pooled OLE and phase 3 patient populations. RESULTS: The pooled randomized trials resulted in a population of 442 patients treated with cenobamate (100 mg/day: n = 108; 200 mg/day: n = 223; 400 mg/day: n = 111) and 216 placebo-treated patients. The combined open-label studies resulted in pooled populations of cenobamate-treated patients ranging from n = 1690 during Year 1 to n = 103 during Year 7. Among cenobamate-treated (all doses) and placebo-treated patients during double-blind treatment, cognitive TEAEs were reported by ≤ 1.9 % (range, 0 %-1.9 %) and ≤ 0.5 % (range, 0 %-0.5 %), respectively, and psychiatric TEAEs by ≤ 3.6 % (range, 0 %-3.6 %) and ≤ 3.2 % (range, 0 %-3.2 %), respectively. During up to 7 years of open-label adjunctive cenobamate treatment, exposure-adjusted incidence rates of cognitive and psychiatric TEAEs were < 0.018 and < 0.038 events per patient-year, respectively. Discontinuation of adjunctive cenobamate due to cognitive or psychiatric TEAEs assessed in this study during double-blind or open-label treatment occurred in ≤ 0.3 % and ≤ 1.7 % of patients, respectively. CONCLUSIONS: Cognitive and psychiatric TEAEs were reported by similar numbers of cenobamate- and placebo-treated patients during double-blind adjunctive cenobamate treatment (< 4 % of patients), and exposure-adjusted incidence rates of these TEAEs remained low during open-label cenobamate treatment for up to 7 years. Treatment discontinuations due to these TEAEs were rare. The results of this post-hoc analysis indicate that adjunctive cenobamate treatment exhibits a low incidence of cognitive or psychiatric TEAEs in patients with uncontrolled focal seizures.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

OBJECTIVE: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures.

OBJECTIVE: The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. METHODS: Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status. RESULTS: Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. SIGNIFICANCE: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.

OBJECTIVE: To evaluate the efficacy and safety of USL255, Qudexy(™) XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. METHODS: In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥ 50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. RESULTS: Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. SIGNIFICANCE: The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.

Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance.

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy.

Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

A review of the effects of vitamins and other dietary supplements on seizure activity.

The role of pharmacological and surgical management of epilepsy continues to expand, but these treatments are often associated with significant side effects and morbidity. As a result, many patients with epilepsy and their physicians alike have gained interest in the role of vitamins and other dietary supplements for seizure management. In this review, we examine the potential anticonvulsant and proconvulsant effects of commonly used dietary supplements, as well as their potential effects on cognition or behavior. Our review was conducted through a literature search focusing on clinical trials involving patients with epilepsy and their seizure response to dietary supplementation. We summarize findings from previous clinical studies and comment on practical considerations regarding dietary supplementation for patients with epilepsy.

Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs. METHODS: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment. RESULTS: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%). CONCLUSION: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated. CLINICALTRIALSGOV IDENTIFIER: NCT01397968. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.

PURPOSE: To assess anger/hostility during treatment with lamotrigine adjunctive therapy versus levetiracetam adjunctive therapy in patients with partial seizures. METHODS: This randomized, double-blind, parallel-group study in adults with partial seizures included an 8-week escalation phase, during which adjunctive lamotrigine (n = 132) or adjunctive levetiracetam (n = 136) was titrated to a target dose, and a 12-week, double-blind maintenance phase, during which dosages of study medication and concomitant antiepileptic drugs were maintained. The primary endpoint was change from baseline to the end of the maintenance phase (week 20) in the Anger-Hostility subscale score of the Profile of Mood States (POMS). RESULTS: Improvement with lamotrigine relative to levetiracetam was observed for mean +/- SD (standard deviation) change from baseline to the end of the maintenance phase (week 20) on the Anger-Hostility subscale (lamotrigine -2.0 +/- 8.2, levetiracetam -0.3 +/- 8.4; p = 0.024) (the primary endpoint); the Anger-Hostility subscale on weeks 5, 6, 7, 8, 9, 11, 12, 14, 16, 18, and 19; and the Total Mood Disturbance score on weeks 6, 7, 8, 9, 11, 12, 17, 19, and 20. Improvement (p < 0.05) with lamotrigine relative to levetiracetam was also observed on the POMS subscales Depression-Dejection, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. No difference in seizure frequency was observed between groups. The most common adverse events with both medications were headache and dizziness. DISCUSSION: Adjunctive lamotrigine significantly improved Anger-Hostility subscale scores relative to adjunctive levetiracetam in patients with partial seizures at the end of 20 weeks. This difference was consistently observed throughout the treatment period. Similar improvement with lamotrigine versus levetiracetam was observed for other mood symptoms.

Evaluation of a novel EEG preamplifier.

SUMMARY: The authors performed initial clinical testing of a novel EEG transduction module (ETM), designed to record EEG signals from electrodes with high and unbalanced contact impedances. Twenty patients underwent two consecutive EEG studies. In the first, "experimental" study, electrodes were applied to an unprepared scalp, and the ETM performed initial signal transduction and pre-amplification. The second, "routine" EEG was acquired in the standard manner, with electrode contact impedances of 5 k Omega or less. Power spectral analysis was performed on all electrode signals from three experimental studies, and all studies were interpreted by three board-certified electro-encephalographers. Individual electrode impedances in the experimental studies ranged from 10 to 560 k Omega (mean 129 k Omega). Power spectra on 54 of 57 electrode signals analyzed were free of 60-Hz noise. The majority of experimental studies were technically adequate, and technical limitations were unrelated to the ETM. Interrater reliability of preparation-free and standard EEG interpretation was high. The ETM device is an effective "preparation-free" technology in the setting of a clinical EEG laboratory. It provided easily interpretable EEG signals free of 60-Hz noise, recorded from electrodes with high and unbalanced impedances placed on completely unprepared scalp with minimal electrode paste.

A review of the efficacy and safety of extended-release topiramate in the adjunctive treatment for refractory partial-onset seizures.

Topiramate has been widely utilized worldwide as an effective medication against partial- and generalized-onset seizures. Extended-release topiramate was developed to provide patients with the convenience of once-daily dosing and potentially improved tolerability by reducing serum concentration fluctuation. USL255 is a once-daily, extended-release formulation of topiramate, which was recently approved in the USA. Compared with immediate-release topiramate taken twice daily, once-daily USL255 provides equivalent topiramate exposure with a 26% reduction in plasma fluctuations. A multinational, phase III, randomized, double-blind, placebo-controlled clinical trial in patients with refractory partial-onset seizures demonstrated that USL255 (200 mg/day) significantly improved seizure control and was well tolerated with low overall neuropsychiatric and neurocognitive adverse events.

Task-related EEG and ERP changes without performance impairment following a single dose of phenytoin.

OBJECTIVES: The acute effects of a single, low dose of phenytoin on behavioral and neurophysiological measures of cognitive function were examined in healthy adults. METHODS: Electroencephalograms (EEGs) were recorded from 7 healthy volunteers while they performed spatial working memory tasks and while they rested quietly. Behavioral measures, EEG power spectra, and event-related potentials (ERPs) were compared between separate sessions in which subjects ingested either 10mg/kg of phenytoin or placebo. RESULTS: Peak serum levels of phenytoin were in the low therapeutic range. Although participants reported subjective effects of the drug, task accuracy and response time were not affected. In the resting EEG, phenytoin decreased power in the alpha band. In the task-related EEG, the frontal midline theta signal was enhanced in response to increased task difficulty following placebo but not following phenytoin. An attention-related augmentation of the N160 ERP to matching stimuli was also reduced by phenytoin. CONCLUSIONS: Neurophysiological measures displayed sensitivity to subtle alterations in attentional processing even in response to a dose of phenytoin too low to produce behavioral impairment. Such results indicate that EEG and ERP measures can provide information about the neurocognitive side effects of medications that cannot be inferred from cognitive task performance measures alone.

Surgical treatment for refractory epilepsy: review of patient evaluation and surgical options.

Treatment of epilepsy often imposes an exposure to various antiepileptic drugs and requires long-term commitment and compliance from the patient. Although many new medications are now available for the treatment of epilepsy, approximately 30% of epilepsy patients still experience recurrent seizures and many experience undesirable side effects. Treatment of epilepsy requires a multidisciplinary approach. For those patients with medically refractory seizures, surgical treatment has increased in prevalence as techniques and devices improve. With increased utilization, proper patient selection has become crucial in evaluating appropriateness of surgical intervention. Epilepsy syndromes in which surgery has shown to be effective include mesial temporal sclerosis, cortical dysplasia, many pediatric epilepsy syndromes, and vascular malformations. Monitoring in an epilepsy monitoring unit with continuous scalp or intracranial EEG is an important step in localization of seizure focus. MRI is the standard imaging technique for evaluation of anatomy. However, other imaging studies including SPECT and PET have become more widespread, often offering increased diagnostic value in select situations. In addition, as an alternative or adjunct to surgical resection, implantable devices such as vagus nerve stimulators, deep brain stimulators, and direct brain stimulators could be useful in seizure treatment.

New and emerging treatments for epilepsy: review of clinical studies of lacosamide, eslicarbazepine acetate, ezogabine, rufinamide, perampanel, and electrical stimulation therapy.

Although many different medical and surgical treatment options for epilepsy exist, approximately 30% of epilepsy patients remain poorly controlled. For those patients who are refractory to medical treatment, epilepsy surgery often provides meaningful improvement. However, when surgical resection of epileptic foci cannot be offered or failed, combined administration of AEDs or the application of novel AEDs is the most appropriate therapeutic options. The most recent AEDs tend to offer new mechanisms of action and more favorable safety profiles than the first generation of AEDs. More recently, alternative options of thalamic or cortical stimulation emerged as potentiall effective treatment for epilepsy. The purpose of this article is to compare and review clinical information for the new and emerging medications such as lacosamide, eslicarbazepine acetate, ezogabine (retigabine), rufinamide, perampanel, as well as deep brain stimulation and responsive neurostimulation devices.

New treatment option for partial-onset seizures: efficacy and safety of lacosamide.

More than 30% of epilepsy patients remain refractory despite the advent of new antiepileptic drugs (AEDs) over two decades. Although a small percentage of these refractory patients may become seizure free when a new AED is added, combined administration of AEDs or the application of novel AEDs is the most common therapeutic option when surgical treatment cannot be offered. The most recently approved AED in Europe and the USA is lacosamide (LCM), which offers new mechanisms of action and favorable safety profiles. This article reviews LCM's molecular mechanisms of action, pharmacokinetic profiles as well as efficacy and safety from phase II and III clinical trials. In addition, comparison between LCM and other existing AEDs is discussed.

Lacosamide: new adjunctive treatment option for partial-onset seizures.

IMPORTANCE OF THE FIELD: Epilepsy is one of the most common neurological disorders, affecting up to 2% of the population worldwide. Studies show that patients with refractory seizures have higher morbidity and mortality rates, as well as a poorer quality of life, than those with controlled seizures. Therefore, treatment that reduces the frequency of seizures may improve patients' quality of life. Lacosamide (LCM) is a recently approved anticonvulsant in Europe and the USA which offers new mechanisms of action and favorable safety profiles. Efficacy data have shown fast onset of anticonvulsant effects and significant reduction of partial-onset seizures as adjunctive therapy at LCM 200 and 400 mg/day, even in a severely refractory population. AREAS COVERED IN THIS REVIEW: This article reviews three pivotal clinical trials of LCM, including its efficacy and tolerability over 7 years. In addition, LCM's key pharmacodynamics and pharmacokinetics from a search of the literature are reviewed in detail. This article also includes recent publications on the safety and use of intravenous LCM solution for patients with epilepsy. WHAT THE READER WILL GAIN: This article provides comprehensive review of efficacy and safety information of LCM along with comprehensive pharmacokinetic information, which includes absolute bioavailability, low protein binding, lack of hepatic enzyme induction or inhibition, and low potential for drug-drug interactions. TAKE HOME MESSAGE: Considering the fact that more than 30% of epilepsy patients remain refractory despite various antiepileptic drugs, LCM may provide added benefit to patients with refractory seizures.

Differential diagnosis of epilepsy.

Epilepsy is a relatively common neurologic disorder that has important implications for patients, health care providers, and society. Making the correct diagnosis for transient neurologic events as with many neurologic conditions starts with an accurate and complete history and consequently leads to a directed diagnostic workup. In this chapter, we present transient neurologic events that are commonly included in the differential diagnosis for epilepsy and how to evaluate and distinguish among the possibilities. Making the correct diagnosis of epilepsy or one of its mimickers allows the practitioner to prescribe appropriate therapy for what are often divergent conditions.

Cognitive effects of lamotrigine versus topiramate as adjunctive therapy in older adults with epilepsy.

Older individuals may be more susceptible to cognitive side effects of antiepileptic drugs than are younger adults. This randomized, double-blind study compared the cognitive effects of lamotrigine (median maintenance dosage, 500.0 mg/d) and topiramate (median maintenance dosage, 300.0 mg/d) as adjunctive therapy for 16 weeks in patients ≥50 years of age. Fifty-one patients (lamotrigine, n=25; topiramate, n=26) were enrolled, and 28 patients (lamotrigine, n=15; topiramate, n=13) completed the study. In a combined analysis of all cognitive tests performed, no significant differences between treatment groups were noted. However, analyses of individual cognitive test results revealed that lamotrigine-treated patients had significantly better results on the Controlled Oral Word Association Test and the Symbol-Digit Modalities Test, whereas topiramate-treated patients had significantly more favorable results on the Digit Cancellation Test and the Rey Auditory-Verbal Learning Test. Larger studies are needed to further clarify the differences in the cognitive effects of lamotrigine and topiramate in older patients.

Differences in self-reported depressive symptoms between patients with epileptic and psychogenic nonepileptic seizures.

Depression is a multidimensional condition encompassing affective, physiological, and cognitive symptoms. Although depression's high comorbidity with both epileptic and psychogenic nonepileptic seizures (ES and PNES) has been established, few studies have addressed whether the types of depressive symptoms experienced differ by seizure type (ES and PNES). This study compared the self-reported depressive symptomatology of patients (n=60 ES and 59 PNES) who underwent video-EEG monitoring and completed self-reported objective measures of psychopathology (PAI and BDI-II). Differences in depressive symptoms were also compared by gender and among several subgroups with ES. Results revealed the PNES group, particularly PNES females, endorsed a significantly higher level of physiological symptoms of depression as measured by the PAI DEP-P subscale than the ES group; the BDI-II did not differ between groups. These findings have potential clinical implications for the identification and management of depressive symptoms among these patient groups.

Interobserver agreement in the interpretation of EEG patterns in critically ill adults.

The significance of rhythmic and periodic EEG patterns in critically ill patients is unclear. A universal terminology is needed to facilitate study of these patterns, and consistent observer agreement should be demonstrated in its use. The authors evaluated inter- and intraobserver agreement using the standardized terminology (Hirsch et al., J Clin Neurophysiol 2005;22:128-135) recently proposed by the American Clinical Neurophysiology Society. Trained electroencephalographers viewed a series of 10-second EEG samples from critically ill adults (phase I), a set of >/=20-minute EEGs from the same patient cohort (phase II), and then reevaluated the first sample set (phase III). The readers used the proposed terminology to "score" each EEG. For each possible term, interobserver agreement (phases I and II) and intraobserver agreement (phase III) were calculated using pairwise kappa (kappa) values. Moderate agreement beyond chance was seen for the presence/absence of rhythmic or periodic patterns and for localization of these patterns. Agreement for other terms was slight to fair. Inter- and intraobserver agreement were consistently lower for optional terms than mandatory terms. Even when standardized terminology is used, the description of rhythmic and periodic EEG patterns varies significantly. Further refinement of the proposed terminology is required to improve inter- and intraobserver agreement.