Faculty Bibliography

The identification and characterization of sudden unexpected deaths in epilepsy (SUDEP) may be improved, helping to optimize prevention and intervention. We set out to assess the frequency and demographic and clinical characteristics of SUDEP cases in a sudden death cohort. All out-of-hospital deaths were investigated from March 1, 2013 to February 28, 2015 in Wake County, NC, attended by the Emergency Medical Services. Cases were screened and adjudicated by three physicians to identify sudden death cases from any cause among free-living adults, aged 18-64. In total, 399 sudden death victims were identified during this two-year period. Seizure history, demographic and clinical characteristics, and healthcare utilization patterns were assessed from death records, emergency response scene reports, and medical records. Sudden death cases with a history of seizures were summarized by an experienced chart abstractor (SC) and adjudicated by an experienced neurologist (OD). We then compared demographic and clinical characteristics and healthcare utilization patterns of neurologist-identified SUDEP cases to other sudden death victims in our population-based registry of sudden death from any cause. SUDEP accounted for 5.3% of sudden deaths. However, seizures or complications of seizures were only considered the primary cause of death on death certificates in 1.5% of sudden deaths. SUDEP cases were more likely to have a history of alcohol abuse. Mental health disorders and a low level of medication compliance and healthcare utilization were common among SUDEP victims. SUDEP accounts for approximately 5.3% of sudden deaths from any cause in individuals aged between 18 and 64. Death certificates underestimate the burden of sudden death in epilepsy, attributing only 1.5% of sudden deaths to seizures or complications of seizures. Accurate documentation of epileptic disorders on death certificates is essential for the surveillance of SUDEP. Further, interventions that promote better use of medical services and patient engagement with healthy living practices may reduce sudden deaths in epilepsy.

OBJECTIVE:Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS:Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS:Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE/CONCLUSIONS:Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.

OBJECTIVE:Since cardic fibrosis was previously found more frequently in patients with sudden unexpected death in epilepsy (SUDEP) than control cases, we compared blinded and quantitative reviews of cardiac pathology in SUDEP to multiple control groups. METHODS:We adjudicated causes of death in epilepsy patients as part of consecutive out-of-hospital sudden cardiac deaths (SCDs) from the Postmortem Systematic Investigation of Sudden Cardiac Death (POSTSCD) study. Blinded cardiac gross and microscopic examinations were performed by forensic and cardiac pathologists. RESULTS:= 0.013). Compared to trauma cases, SUDEP cases had similar cardiac pathology including CF. CONCLUSION/CONCLUSIONS:Among SUDEP cases, cardiac pathology was less severe than in SAD cases but similar to trauma and epilepsy controls. Our data do not support prior studies finding elevated rates of CF among SUDEP cases compared to controls. Larger studies including molecular analyses would further our understanding of cardiac changes associated with SUDEP.

Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions.

PURPOSE/OBJECTIVE:Anxiety and depression have been associated with poor seizure control after epilepsy surgery. This study explored the effect of presurgical anxiety or depression on two- and five-year seizure control outcomes. METHODS:Adult subjects were enrolled between 1996 and 2001 in a multicenter prospective study to evaluate outcomes of resective epilepsy surgery. A Poisson regression was used to analyze the association of depression and anxiety with surgical outcome, while adjusting for gender, age, ethnicity, number of years with seizures, and presence of mesial temporal sclerosis. RESULTS:The relative risk (RR) of presurgical depression on two-year seizure-free outcome in this cohort is 1.12 (95% confidence interval (CI), 0.84-1.49) and 1.06 (CI, 0.73-1.55) on five-year seizure free outcome. The RR of presurgical anxiety on two-year seizure outcome is 0.73 (CI, 0.50-1.07) and 0.70 (CI, 0.43-1.17) on five-year seizure outcome. When including Engel classes I and II, the RRs of presurgical depression, anxiety, or both two years after surgery were 0.96 (p=0.59), 0.73 (p<0.05), and 0.97 (p=0.70), respectively, and they were 0.97 (p=0.82), 0.84 (p=0.32), and 0.89 (p=0.15), respectively, five years after surgery. Only presurgical anxiety was associated with worse epilepsy surgery outcome two year after surgery but not at five years postsurgery. Depression was not a risk factor for poor epilepsy surgical outcome in the long term. CONCLUSION/CONCLUSIONS:These findings from a prospective study that utilized a standardized protocol for psychiatric and seizure outcome assessment suggest that presurgical mood disorders have no substantial impact on postsurgical seizure outcome for up to five years after surgery.

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/CONCLUSIONS: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.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

BACKGROUND:Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS:In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS:A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS:Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).