Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). METHODS: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. RESULTS: In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). SIGNIFICANCE: Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. PLAIN LANGUAGE SUMMARY: Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen. METHODS: This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation. RESULTS: Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups. CONCLUSION: BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.

Interictal EEG and ECG for SUDEP Risk Assessment: A Retrospective Multicenter Cohort Study.

Objective: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict individual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. Methods: This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. Results: The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females; mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%); mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73-0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Conclusions: Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict individualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.

Patient-Reported Outcome Measures in Adult Patients Diagnosed with Epilepsy Being Treated with Perampanel.

BACKGROUND: Epilepsy is a complex disorder that can affect patients' medical, psychological, and social well-being. The purpose of this study was to evaluate the patient-reported outcome (PRO) measures of health-related quality of life (HRQoL), satisfaction, and adherence in adult patients diagnosed with epilepsy treated with perampanel in the United States (US). METHODS: A US-based, multicenter, observational cross-sectional survey was completed by 61 patients taking perampanel with or without other antiseizure medications (ASMs). Respondents were ≥18 years old, had a physician-confirmed diagnosis of epilepsy, used perampanel for ≥4 months, and provided informed consent. Patients responded to questions concerning their demographic characteristics, treatment history, experiences before perampanel, experiences while taking perampanel, HRQoL, treatment satisfaction, and medication adherence. RESULTS: Patients (N=61) were 42.8 years old on average; majority were female (63.9%) and white (75.4%). Mean time on perampanel was 2.5 years, with sodium channel blockers often (55.7%) used concomitantly with perampanel. Patients reported, on average, 5.5 (standard deviation [SD]=13.2) seizures/month after initiating perampanel, whereas these same patients reported experiencing 20.4 (SD=60.0) seizures/month prior to perampanel. When comparing their experience on perampanel with their experience with previous ASMs, more patients "strongly agreed" that perampanel allowed them to live a more normal life (36.1% vs 27.5%) and worked as intended if they missed taking a dose (16.4% vs 7.8%). Average satisfaction scores were high, with ratings of 71.8 for effectiveness, 84.0 for convenience, and 71.9 for global satisfaction (0-100 scores). Perampanel use was associated with improvements in HRQoL and fewer symptoms of depression and anxiety. The majority of patients were adherent (62.3%) to perampanel. DISCUSSION: Perampanel use was associated with reductions in number of seizures, better HRQoL, and high adherence rates. These results provide initial evidence that perampanel can be an effective, tolerable, and valid option for patients with epilepsy in the real world.

Long-term efficacy and tolerability of adjunctive brivaracetam in adults with focal to bilateral tonic-clonic (secondary generalized) seizures: Post hoc pooled analysis.

This post hoc analysis was conducted to evaluate the efficacy, tolerability, and health-related quality of life during long-term adjunctive brivaracetam (BRV) treatment in adult patients with focal to bilateral tonic-clonic seizures (FBTCS). Patients (≥ 16 years) were included in this post hoc analysis if they were randomized to BRV or placebo in double-blind, placebo-controlled (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]; core) trials, and received adjunctive BRV in the corresponding long-term follow-up (N01125 [NCT00175916], N01199 [NCT00150800], N01379 [NCT01339559]) trials, and reported FBTCS during the 8-week prospective baseline (core trial). Efficacy (concomitant levetiracetam excluded) and tolerability (concomitant levetiracetam included) were assessed from the first day of BRV in patients who initiated BRV at 50-200 mg/day. Two hundred and eighty-four patients reported FBTCS during baseline (core trials) and were included in the Efficacy Set. Patients (mean age of 37.0 years; 51.8% male; mean epilepsy duration of 22.4 years; median baseline frequency of 2.8 FBTCS per 28 days) received BRV for a median treatment duration of 2.5 years (range< 0.1-11.3) at a median modal dose of 150 mg/day. BRV was discontinued by 175 (61.6%) patients, most commonly (≥ 10% of patients) due to adverse event (18.3%), lack of efficacy (18.3%), and consent withdrawn (11.6%); the median time to discontinuation of BRV due to any reason was 358.5 days. The Kaplan-Meier (KM)-estimated retention on BRV at 1, 3, and 5 years, were 69.3%, 48.2%, and 37.3%, respectively. The KM-estimated proportion of patients not discontinuing BRV due to lack of efficacy or adverse event were 80.0%, 63.9%, and 57.2% at 1, 3, and 5 years, respectively. Overall, the median percentage reduction in FBTCS frequency from baseline was 76.2%, and the 50% and 75% responder rates for FBTCS were 68.7% and 50.7%, respectively, which were sustained over time across completer cohorts. Sustained 50%, 75%, and 100% response in FBTCS from day 1 of adjunctive BRV treatment during the entire first year was estimated for 32.5%, 21.1%, and 15.0% of patients, respectively (KM analysis), and showed maintenance or improvement in the response to BRV over time. For patients with ≥ 1 year of BRV exposure, 51.3% were free from FBTCS for ≥ 1 year during any time of the treatment period, and 22.8% of patients did not report FBTCS during the first year from the first day of treatment. Clinically meaningful improvements in total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score were reported by 43.6% and 46.4% of patients after 1 and 2 years of treatment, respectively. The largest improvements in the QOLIE-31-P score, with > 50% of patients reporting a clinically meaningful improvement, were observed in the seizure worry and daily activities/social functioning subscales after 1 and 2 years of BRV treatment. Overall, 278/313 (88.8%; Safety Set) patients reported at least one treatment-emergent adverse event (TEAE), 170 (54.3%) had a drug-related TEAE, 88 (28.1%) had a serious TEAE, and 55 (17.6%) discontinued BRV due to a TEAE. Overall, long-term adjunctive BRV was generally well tolerated and reduced the frequency of FBTCS in adults, with 22.8% of patients (who completed ≥ 1 year of treatment) not reporting any FBTCS during the first year from the first day of BRV treatment.

Behavioral adverse events with brivaracetam, levetiracetam, perampanel, and topiramate: A systematic review.

PURPOSE: To understand the currently available post-marketing real-world evidence of the incidences of and discontinuations due to the BAEs of irritability, anger, and aggression in people with epilepsy (PWE) treated with the anti-seizure medications (ASMs) brivaracetam (BRV), levetiracetam (LEV), perampanel (PER), and topiramate (TPM), as well as behavioral adverse events (BAEs) in PWE switching from LEV to BRV. METHODS: A systematic review of published literature using the Cochrane Library, PubMed/MEDLINE, and Embase was performed to identify retrospective and prospective observational studies reporting the incidence of irritability, anger, or aggression with BRV, LEV, PER, or TPM in PWE. The incidences of these BAEs and the rates of discontinuation due to each were categorized by ASM, and where possible, weighted means were calculated but not statistically assessed. Behavioral and psychiatric adverse events in PWE switching from LEV to BRV were summarized descriptively. RESULTS: A total of 1500 records were identified in the searches. Of these, 44 published articles reporting 42 studies met the study criteria and were included in the data synthesis, 7 studies were identified in the clinical trial database, and 5 studies included PWE switching from LEV to BRV. Studies included a variety of methods, study populations, and definitions of BAEs. While a wide range of results was reported across studies, weighted mean incidences were 5.6% for BRV, 9.9% for LEV, 12.3% for PER, and 3.1% for TPM for irritability; 3.3%* for BRV, 2.5% for LEV, 2.0% for PER, and 0.2%* for TPM for anger; and 2.5% for BRV, 2.6% for LEV, 4.4% for PER, and 0.5%* for TPM for aggression. Weighted mean discontinuation rates were 0.8%* for BRV, 3.4% for LEV, 3.0% for PER, and 2.2% for TPM for irritability and 0.8%* for BRV, 2.4% for LEV, 9.2% for PER, and 1.2%* for TPM for aggression. There were no discontinuations for anger. Switching from LEV to BRV led to improvement in BAEs in 33.3% to 83.0% of patients (weighted mean, 66.6%). *Denotes only 1 study. CONCLUSIONS: This systematic review characterizes the incidences of irritability, anger, and aggression with BRV, LEV, PER, and TPM, and it provides robust real-world evidence demonstrating that switching from LEV to BRV may improve BAEs. While additional data remain valuable due to differences in methodology (which make comparisons difficult), these results improve understanding of the real-world incidences of discontinuations due to these BAEs in clinical practice and can aid in discussions and treatment decision-making with PWE.

A review of the drug-drug interactions of the antiepileptic drug brivaracetam.

Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes. The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug-drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment, and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug-drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam. The strong enzyme-inducing AEDs carbamazepine, phenytoin and phenobarbital/primidone have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent CYP inducer, rifampin. Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John's wort. In summary, brivaracetam (50-200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug-drug interactions.

Randomized open-label trial of intravenous brivaracetam versus lorazepam for acute treatment of increased seizure activity.

OBJECTIVE: The objective of the present trial was to assess efficacy and safety of intravenous (IV) brivaracetam (BRV) vs. lorazepam (LZP) in patients with epilepsy undergoing evaluation in an epilepsy monitoring unit (EMU) who experienced seizures requiring acute treatment. METHODS: This was a phase 2, open-label, randomized, active-control, proof-of-concept trial (EP0087; NCT03021018). Patients (18-70 years) admitted to EMU were randomized 1:1:1 to single-dose bolus IV LZP (dose per investigator's practice), IV BRV 100 mg, or IV BRV 200 mg. Trial medication had to be administered within 30 min of qualifying seizure. Primary efficacy outcome was time to next seizure (clinical observation with electroencephalogram [EEG] confirmation) or to rescue medication use within 12 h of trial medication administration. Secondary outcomes included seizure freedom and rescue medication use within 12 h of trial medication administration. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Overall, 46 patients were randomized, and 45 received trial medication for a qualifying seizure. Patients in the LZP arm had doses from 1 to 4 mg (median: 1 mg). Eleven of 45 patients had a seizure within 12 h of trial medication administration (LZP 5/15 [median time to next seizure: 5.55 h], BRV 100 mg 3/15 [5.97 h], BRV 200 mg 3/15 [3.60 h]). No patients received additional rescue medication to control their qualifying seizure. Most patients were seizure-free over 12 h (LZP 9/15 [60.0%], BRV 100 mg 12/15 [80.0%], BRV 200 mg 12/15 [80.0%]). Rescue medication use within 12 h was numerically higher for LZP (6/15 [40.0%]) vs. BRV 100 mg (1/15 [6.7%]) and vs. BRV 200 mg (2/15 [13.3%]). Treatment-emergent adverse events were reported by 5/16 (31.3%), 6/15 (40.0%), and 3/15 (20.0%) of LZP, BRV 100 mg, and BRV 200 mg patients; one LZP patient had a serious TEAE (seizure cluster). Most common TEAEs (≥10% of patients) were sedation and somnolence with LZP, and dizziness, headache, and nausea with BRV. SIGNIFICANCE: Intravenous LZP, IV BRV 100 mg, and IV BRV 200 mg showed similar efficacy in controlling acute seizure activity in the EMU. Treatment-emergent adverse events were as expected for each medication. Although this trial should be interpreted with caution because of small patient numbers, it suggests a possible role of BRV in the acute treatment of increased seizure activity.

Pharmacokinetic interaction of brivaracetam on other antiepileptic drugs in adults with focal seizures: Pooled analysis of data from randomized clinical trials.

OBJECTIVE: To assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). METHODS: Data were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1-2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4-8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50-200 mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80-1.25 limits. RESULTS: Within the population for analysis (n = 1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. CONCLUSION: In adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.

SUDEP in the North American SUDEP Registry: The full spectrum of epilepsies.

OBJECTIVE: To obtain medical records, family interviews, and death-related reports of sudden unexpected death in epilepsy (SUDEP) cases to better understand SUDEP. METHODS: All cases referred to the North American SUDEP Registry (NASR) between October 2011 and June 2018 were reviewed; cause of death was determined by consensus review. Available medical records, death scene investigation reports, autopsy reports, and next-of-kin interviews were reviewed for all cases of SUDEP. Seizure type, EEG, MRI, and SUDEP classification were adjudicated by 2 epileptologists. RESULTS: There were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1-70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%. CONCLUSIONS: NASR participants commonly have clinical features that have been previously been associated with SUDEP risk such as young adult age, ASM nonadherence, and frequent GTCS. However, a sizeable minority of SUDEP occurred in patients thought to be treatment responsive or to have benign epilepsies. These results emphasize the importance of SUDEP education across the spectrum of epilepsy severities. We aim to make NASR data and biospecimens available for researchers to advance SUDEP understanding and prevention.

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury.

OBJECTIVES: After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate-to-severe traumatic brain injury and to correlate continuous electroencephalography features with functional outcome. DESIGN: Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study (ClinicalTrials.gov: NCT00805818). Continuous electroencephalography was initiated upon admission to the ICU. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. SETTING: Twenty U.S. level I trauma centers. PATIENTS: Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4-12 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 152 patients with continuous electroencephalography (age 34 ± 14 yr; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in four (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; p = 0.01) and Injury Severity Score (r = 0.49; p = 0.01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% CI, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. CONCLUSIONS: Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate-to-severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention.

Sudden unexpected death in epilepsy (SUDEP) is one of the most important direct epilepsy-related causes of death, with an incidence in adults of 1.2 per 1000 person-years. Generalized tonic-clonic seizures have consistently emerged as the leading risk factor for SUDEP, particularly when such seizures are uncontrolled. High seizure burden, lack of antiepileptic drug (AED) treatment, polytherapy, intellectual disability, and prone position at the time of death are other key risk factors. Unfortunately, despite advances in treatment, overall mortality rates in epilepsy are rising. It is imperative that we learn more about SUDEP so that effective prevention strategies can be implemented. To help identify persons at greater risk of SUDEP and in need of closer monitoring, biomarkers are needed. Candidate biomarkers include electrocardiographic, electroencephalographic, and imaging abnormalities observed more frequently in those who have died suddenly and unexpectedly. As our knowledge of the pathophysiologic mechanisms behind SUDEP has increased, various preventative measures have been proposed. These include lattice pillows, postictal oxygen therapy, selective serotonin reuptake inhibitors, and inhibitors of opiate and adenosine receptors. Unfortunately, no randomized clinical trials are available to definitively conclude these measures are effective. Rather, gaining the best control of seizures possible (with AEDs, devices, and resective surgery) still remains the intervention with the best evidence to reduce the risk of SUDEP. In this evidence-based review, we explore the incidence of SUDEP and review the risk factors, biomarkers, and latest prevention strategies.

Resolving ambiguities in SUDEP classification.

OBJECTIVE: To examine the consistency of applying the Nashef et al (2012) criteria to classify sudden unexpected death in epilepsy (SUDEP). METHODS: We reviewed cases from the North American SUDEP Registry (n = 250) and Medical Examiner Offices (n = 1301: 698 Maryland, 457 New York City, 146 San Diego). Two epileptologists with expertise in SUDEP and epilepsy-related mortality independently reviewed medical records, scene investigation, autopsy, and toxicology and assigned a SUDEP class. RESULTS: Major areas of disagreement arose between adjudicators concerned differentiating (1) Definite SUDEP Plus Comorbidity from Possible SUDEP and (2) Resuscitated (Near) SUDEP from SUDEP. In many cases, distinguishing between contributing and competing causes of death when trying to classify Definite SUDEP Plus Comorbidity versus Possible SUDEP is ambiguous and relies on judgement. Similarly, determining if an intervention was lifesaving or not (Resuscitated SUDEP or Not SUDEP), or if resuscitation merely delayed SUDEP (Resuscitated SUDEP or SUDEP) is often a judgement call and can differ between experienced adjudicators. Given these persisting ambiguities, we propose more explicit criteria for distinguishing these categories. SIGNIFICANCE: Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy-related mortalities.

Automated Detection of Postictal Generalized EEG Suppression.

Although there is no strict consensus, some studies have reported that Postictal generalized EEG suppression (PGES) is a potential electroencephalographic (EEG) biomarker for risk of sudden unexpected death in epilepsy (SUDEP). PGES is an epoch of EEG inactivity after a seizure, and the detection of PGES in clinical data is extremely difficult due to artifacts from breathing, movement and muscle activity that can adversely affect the quality of the recorded EEG data. Even clinical experts visually interpreting the EEG will have diverse opinions on the start and end of PGES for a given patient. The development of an automated EEG suppression detection tool can assist clinical personnel in the review and annotation of seizure files, and can also provide a standard for quantifying PGES in large patient cohorts, possibly leading to further clarification of the role of PGES as a biomarker of SUDEP risk. In this paper, we develop an automated system that can detect the start and end of PGES using frequency domain features in combination with boosting classification algorithms. The average power for different frequency ranges of EEG signals are extracted from the prefiltered recorded signal using the fast fourier transform and are used as the feature set for the classification algorithm. The underlying classifiers for the boosting algorithm are linear classifiers using a logistic regression model. The tool is developed using 12 seizures annotated by an expert then tested and evaluated on another 20 seizures that were annotated by 11 experts.

Ranking the Leading Risk Factors for Sudden Unexpected Death in Epilepsy.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is rare in well-controlled epilepsy. However, SUDEP is a common cause of death in drug-resistant epilepsy. Over the last 30 years, multiple cohort and population studies have identified clinical risk factors associated with an increased risk for SUDEP. OBJECTIVE: To identify and rank the leading SUDEP risk factors from major cohort and population-based studies. The incidence of SUDEP is also evaluated in special clinical situations, including antiepileptic drug treatment, epilepsy surgery, devices, and assignment to placebo in clinical trials. METHODS: A PubMed search for English language human cohort studies for the terms Sudden, Death, and Epilepsy was performed for the years 1987-2017. Risk factors for SUDEP were identified and ranked by the weighted log adjusted odds ratio (OR)/relative risk ratio (RR). FINDINGS: The top 10 leading risk factors ranked from highest to lowest log adjusted OR/RR are the following: ≥3 GTC seizures per year; ≥13 seizures in the last year; No Antiepileptic Drug (AED) treatment; ≥3 AEDs; ≥3 GTCs in the past year; 11-20 GTC seizures in the last 3 months; age of onset 0-15 years old; IQ < 70; 3-5 AED changes in the last year; ≥3 AEDs. Two risk factors from separate sources (≥3 GTC seizures and ≥3 AEDs) occur twice in the top 10 risk factors. CONCLUSION: The top 10 risk factors for SUDEP are identified and ranked. A ranking of the top risk factors could help clinicians identify patients at highest risk for SUDEP.