Cardiac arrhythmia and epilepsy genetic variants in sudden unexpected death in epilepsy.

Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is the leading epilepsy-related cause of death, affecting approximately 1 per 1,000 individuals with epilepsy per year. Genetic variants that affect autonomic function, such as genes associated with cardiac arrhythmias, may predispose people with epilepsy to greater risk of both sudden cardiac death and SUDEP. Advances in next generation sequencing allow for the exploration of gene variants as potential biomarkers. Methods: Genetic testing for the presence of cardiac arrhythmia and epilepsy gene variants was performed via genetic panels in 39 cases of SUDEP identified via autopsy by the Ontario Forensic Pathology Service. Variants were summarized by in-silico evidence for pathogenicity from 4 algorithms (SIFT, PolyPhen-2, PROVEAN, Mutation Taster) and allele frequencies in the general population (GnomAD). A maximum credible population allele frequency of 0.00004 was calculated based on epilepsy prevalence and SUDEP incidence to assess whether a variant was compatible with a pathogenic interpretation. Results: Median age at the time of death was 33.3 years (range: 2, 60). Fifty-nine percent (n=23) were male. Gene panels detected 62 unique variants in 45 genes: 19 on the arrhythmia panel and 26 on the epilepsy panel. At least one variant was identified in 28 (72%) of decedents. Missense mutations comprised 57 (92%) of the observed variants. At least three in silico models predicted 12 (46%) cardiac arrhythmia panel missense variants and 20 (65%) epilepsy panel missense variants were pathogenic. Population allele frequencies were <0.00004 for 11 (42%) of the cardiac variants and 10 (32%) of the epilepsy variants. Together, these metrics identified 13 SUDEP variants of interest. Discussion: Nearly three-quarters of decedents in this SUDEP cohort carried variants in comprehensive epilepsy or cardiac arrhythmia gene panels, with more than a third having variants in both panels. The proportion of decedents with cardiac variants aligns with recent studies of the disproportionate cardiac burden the epilepsy community faces compared to the general population and suggests a possible cardiac contribution to epilepsy mortality. These results identified 13 priority targets for future functional studies of these genes potential role in sudden death and demonstrates the necessity for further exploration of potential genetic contributions to SUDEP.

Alcohol-specific inhibition training in patients with alcohol use disorder: a multi-centre, double-blind randomized clinical trial examining drinking outcome and working mechanisms.

AIMS: For the first time, to our knowledge, in a clinical sample with alcohol use disorder (AUD), this study compared the effects of two versions of alcohol-specific inhibition training (Alc-IT) on drinking outcomes and on experimental parameters assessing two possible working mechanisms: stimulus devaluation and inhibitory enhancement. DESIGN: Multi-centre, double-blind, three-arm clinical RCT with 3-, 6- and 12-month follow-up comparing standard Alc-IT, improved Alc-IT and an active control condition. SETTING: Three specialized AUD treatment centres in Switzerland. PARTICIPANTS: A total of 242 detoxified, recently abstinent patients with severe AUD (18-60 years; 29.8% female). INTERVENTION AND COMPARATOR: Both interventions [standard Alc-IT (n = 84) and improved Alc-IT (n = 79)] and the comparator [unspecific inhibition training (n = 79)] consisted of six sessions of a modified inhibitory task (Go/NoGo task) with alcohol-related and neutral stimuli. Both versions of Alc-IT required response inhibition in alcohol-related trials but differed in Go/NoGo ratios (standard: 50/50; improved: 75/25), with improved Alc-IT posing higher inhibitory demands. The control condition, an unspecific inhibition training, featured alcohol-related pictures in Go as well as NoGo trials. MEASUREMENTS: The primary outcome, percentage of days abstinent, was assessed at 3-month follow-up with a time-line follow-back interview. FINDINGS: The group receiving improved Alc-IT showed a significantly higher percentage of days abstinent at 3-month follow-up compared with the control group [γcontrol = 74.30; γimproved = 85.78; ß = 11.48, 95% confidence interval (CI) = 2.57, 20.40, P = 0.012, adjusted r2 = 0.062], while for standard Alc-IT no effect significantly different from zero was detected (γstandard = 70.95; ß = -3.35, 95% CI = -12.20, 5.50, P = 0.457, adjusted r2 = -0.04). CONCLUSIONS: Alcohol-specific inhibition training with high inhibitory demands increased days abstinent at 3-month follow-up in patients with severe alcohol use disorder. Such an improved, inhibitory-demanding, alcohol-specific inhibition training outperformed the standard version of alcohol-specific inhibition training, suggesting an inhibitory working mechanism.

[Treatment expectations of multimodal pain therapy inpatients]. / Behandlungserwartungen bei Patienten einer stationären multimodalen Schmerztherapie.

BACKGROUND: Apart from rehabilitation research, there have been no studies regarding the expectations of patients with chronic back pain in terms of inpatient multimodal pain therapy. The aim of this naturalistic longitudinal study is to explore treatment expectations, their fulfilment, and influence on the treatment success of inpatient multimodal pain therapy. METHODS: This study included 118 patients with chronic back pain who were physically examined and assessed for their psychological comorbidity. They were interviewed pre and post pain therapy. Treatment expectations were recorded via the questionnaire for assessing rehabilitational expectations and motivations (FREM-17), and further variables via the Pain Disability Index (PDI, german version) and the german Hospital Anxiety and Depression Scale (HADS-D). RESULTS: The results show that treatment expectations have an impact on therapy success or failure. In particular, patients' expectations of coping with illness and recovery could be met by inpatient multimodal pain therapy, whereas health and pension-related expectations remained unfulfilled. In addition to the treatment expectations, the therapy result was primarily determined by the patient's ability to perform before the therapy. CONCLUSIONS: From the clinical side, treatment expectations should be explored and checked for feasibility to avoid patient disappointment.

An inclusive, real-world investigation of persuasion in language and verbal behavior.

Linguistic features of a message necessarily shape its persuasive appeal. However, studies have largely examined the effect of linguistic features on persuasion in isolation and do not incorporate properties of language that are often involved in real-world persuasion. As such, little is known about the key verbal dimensions of persuasion or the relative impact of linguistic features on a message's persuasive appeal in real-world social interactions. We collected large-scale data of online social interactions from a social media website in which users engage in debates in an attempt to change each other's views on any topic. Messages that successfully changed a user's views are explicitly marked by the user themselves. We simultaneously examined linguistic features that have been previously linked with message persuasiveness between persuasive and non-persuasive messages. Linguistic features that drive persuasion fell along three central dimensions: structural complexity, negative emotionality, and positive emotionality. Word count, lexical diversity, reading difficulty, analytical language, and self-references emerged as most essential to a message's persuasive appeal: messages that were longer, more analytic, less anecdotal, more difficult to read, and less lexically varied had significantly greater odds of being persuasive. These results provide a more parsimonious understanding of the social psychological pathways to persuasion as it operates in the real world through verbal behavior. Our results inform theories that address the role of language in persuasion, and provide insight into effective persuasion in digital environments.

Ketonuria and Seizure Control in the Medium Chain Triglyceride and Classic Ketogenic Diets.

We hypothesized that children receiving medium-chain triglyceride ketogenic diet (MCTKD) experience similar seizure reduction despite lower ketosis compared with classic ketogenic diet (CKD). Children initiating CKD or MCTKD were enrolled in a prospective observational study. Forty-five children completed 6 months of KD (n = 17 MCTKD, n = 28 CKD). The proportion achieving ≥50% seizure reduction was 71% CKD group and 59% MCTKD group; ≥90% reduction was 32% and 36% in CKD and MCTKD groups, respectively. CKD had higher urine ketones (≥8 mmol/L: 79% vs. 36%, p = 0.005). Children receiving MCTKD experience similar seizure control to CKD despite lower urine ketone measures.

The spectrum of epilepsy in children with 15q13.3 microdeletion syndrome.

PURPOSE: To further define the epilepsy phenotype in a cohort of children with 15q13.3 microdeletion syndrome. METHODS: We retrospectively reviewed the phenotypic spectrum of all children aged < 18 years with epilepsy and 15q13.3 microdeletion syndrome. RESULTS: Thirteen children were included, 69% were female. The median age of children in the cohort was 12 years (age range: 3 years-15 years). Median age at seizure onset was 4 years. Eleven children (85%) had intellectual disability. Nine of 13 children (69%) had a history of typical absence seizures with median age of onset at 5 years (2 had absence status epilepticus). Thirty-one percent (4/13) had focal with impaired awareness non-motor onset seizures. ILAE recognized absence epilepsy syndromes were diagnosed in 6/13 (46%). The remainder were classified as having genetic generalized epilepsies with overlap clinical features, combined or focal epilepsies. Electroencephalogram in the cohort showed generalized (85%) and focal epileptiform discharges (62%) and posterior dominant rhythm slowing (33%). One child had electrical status epilepticus of sleep. Neuroimaging was performed in 5 children (38%) and revealed abnormal findings in 3. Seizures were drug resistant in a third of the cohort. Valproate resulted in seizure freedom in 5 (42%). Oxcarbazepine caused clinical worsening in one child with combined seizure types. Two children tried cannabidiol and one tried the ketogenic diet; neither was effective. CONCLUSIONS: The epilepsy phenotype in children with 15q13.3 microdeletion syndrome is defined by childhood onset absence seizures, and may have atypical features such as, early onset absences, persistence into adolescence, status epilepticus, intellectual disability and treatment resistance. Focal seizures and focal EEG findings may be observed and should be treated cautiously, given the possibility of combined seizure types. Valproate appeared effective, although other treatments must be explored further.

Neurophysiological correlates of alcohol-specific inhibition in alcohol use disorder and its association with craving and relapse.

OBJECTIVE: This study investigates neurophysiological correlates of general and alcohol-specific inhibitory control in patients with Alcohol Use Disorder (AUD), focusing on its association with individual craving levels and with relapse at three-month follow-up. METHODS: 59 abstinent AUD patients and 20 healthy controls performed a Go/NoGo task incorporating alcohol-related and neutral stimuli during 64-channel electroencephalography (EEG) recording, yielding four event-related potentials (ERP) per participant (NoGo-Alcohol, Go-Alcohol, NoGo-Neutral, Go-Neutral). Whole-scalp randomization-based statistics assessed effects of the factors group (patients/controls or relapsers/abstainers), craving level, response type (NoGo/Go) and picture type (alcohol/neutral) on topography and signal strength of the ERP components N2 and P3. RESULTS: No differences on group level were observed between patients and controls. However, analyses incorporating individual craving indicated that the topographic difference between alcohol-related and neutral NoGo-N2 components increased with craving. Moreover, topographic differences in the alcohol-related and neutral NoGo-P3 component allowed for differentiation between relapsers and abstainers. CONCLUSIONS: In alcohol-related contexts, the response inhibition conflict reflected in the NoGo-N2 seems enhanced in patients with high craving. The inhibition-sensitive NoGo-P3 varies in relapsers but not in abstainers between neutral and alcohol-related contexts. SIGNIFICANCE: In AUD patients, neurophysiological correlates of inhibition vary with alcohol-related contexts and craving, and might be indicative of relapse risk.

Why child neurologists talk about SUDEP: Results from two cross-sectional surveys.

Objective: To characterize SUDEP discussion practices of child neurologists approximately 6 and 12 months after publication of the American Academy of Neurology SUDEP Clinical Practice Guideline and explore factors associated with discussion practice. Methods: Child Neurology Society members (~2450) were electronically surveyed in November 2017 and May 2018 regarding their practice of discussing SUDEP with patients with epilepsy or their caregivers. Multivariable proportional odds ordinal logistic regression evaluated factors associated with discussing SUDEP with a greater proportion of epilepsy patients/caregivers. Reasons for changing practice were described. Results: Among the 369 child neurologist respondents, 36% reported discussing SUDEP with at least half of their epilepsy patients/caregivers including 12% who discuss with all or almost all (>90%) of their epilepsy patients/families. Those who discussed SUDEP with an increased proportion of their patients were more likely to agree that they knew enough to talk about SUDEP, agree that healthcare providers have an ethical obligation to discuss SUDEP, and disagree that there is not enough time to talk about SUDEP. Those who agreed SUDEP could provoke excessive anxiety or worry were less likely to discuss SUDEP with an increased proportion of their patients. Reading the SUDEP Clinical Practice Guideline was a frequently cited reason among respondents who reported a recent change in discussion practice. Significance: Most child neurologists do not follow the current SUDEP Clinical Practice Guideline regarding SUDEP discussion. Feeling sufficiently knowledgeable and ethically obligated to discuss SUDEP were associated with increased discussion practice, suggesting an educational intervention may be effective at increasing SUDEP discussion rates.

Autopsy-reported cause of death in a population-based cohort of sudden unexpected death in epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a diagnosis of exclusion; the definition includes individuals with epilepsy who die suddenly without an identifiable toxicological or anatomical cause of death. Limited data suggest underidentification of SUDEP as the cause of death on death certificates. Here, we evaluate the autopsy-reported cause of death in a population-based cohort of SUDEP cases. METHODS: Case summaries of forensic autopsies conducted in Ontario, Canada between January 2014 and June 2016 were retrospectively screened using a language processing script for decedents with a history of epilepsy or seizures. After manual review for potential SUDEP cases, two neurologists independently examined the autopsy reports and classified deaths by Nashef criteria. Demographic characteristics and consideration by the forensic pathologist of the role of epilepsy, seizure, and SUDEP in death were summarized. RESULTS: One hundred and eight Definite, 34 Definite Plus, and 22 Possible SUDEP cases were identified. Seventy-five percent of Definite/Definite Plus SUDEP cases identified by the neurologists were attributed to SUDEP, epilepsy, or seizure disorder in the autopsy report. There was a significant association between the proportion of cases listed in the autopsy report as SUDEP, epilepsy, or seizure disorder and neurologists' SUDEP classification (86% of Definite, 38% of Definite Plus, 0% of Possible). Age was significantly associated with SUDEP classification; Definite cases were younger than Definite Plus, which were younger than Possible SUDEP cases. SIGNIFICANCE: Most SUDEP cases identified by neurologists were classified concordantly by forensic pathologists in Ontario, Canada; however, concordance decreased with increased case complexity. Although the role of epilepsy/seizures was considered in most Definite/Definite Plus cases, this study highlights the need for autopsy report review of potential SUDEP cases in research studies and assessments of the public health burden of SUDEP. The relationship between age and SUDEP classification has important public health implications; SUDEP incidence may be underappreciated in older adults.

Neutropenia in Children Treated With Ketogenic Diet Therapy.

OBJECTIVES: The objectives were to investigate the relationship between ketogenic diet therapy and neutropenia in children with epilepsy. METHODS: A retrospective chart review of children who initiated ketogenic diet at the Hospital for Sick Children between January 1, 2000, and May 1, 2018 was performed. Factors associated with the development of neutropenia during ketogenic diet therapy were evaluated and the relationship between development of a significant or suspected infection and neutrophil count was analyzed. RESULTS: One hundred two children met inclusion criteria and were followed on the diet for up to 24 months. Thirteen of 102 (13%) children were neutropenic at diet initiation. In the remaining 89 children, 27 developed neutropenia. Developing neutropenia was significantly associated with the ketogenic diet at 6 (13%), 12 (23%), and 24 (25%) months follow-up. Developing neutropenia was associated with higher urinary ketones (OR = 4.26, 95% CI: 1.27, 14.15) and longer duration of ketogenic diet therapy (OR = 3.29, 95% CI: 1.42, 7.96). There was no significant association between development of a clinically significant infection and neutropenia. CONCLUSION: Ketogenic diet therapy is associated with neutropenia in children with epilepsy, however, it does not have a significant clinical impact. Concern regarding neutropenia should not discourage the use of the ketogenic diet in children.

The influence of the number of part-set cues on order retention.

Across seven experiments, the present article examined the influence of the number of part-set cues on order retention, as assessed by both reconstruction of order and serial recall tests. Historically, part-set cueing facilitation occurs when half of the items are provided as valid part-set cues on tests of order memory. Using a variety of list lengths (10 or 16), numbers of cues (0-14), and types of cues (full or partial), the present experiments showed disparate effects of the number of part-set cues on reconstruction and serial recall tasks. On reconstruction tests, a minimum number of full cues was required before part-set cueing facilitation was produced and the magnitude of facilitation increased as the number of cues increased. Generally, partial cues did not influence order retention until almost the entire list was provided as partial cues. On serial recall tests, part-set cueing facilitation was only evident with a few full cues. In contrast, part-set cueing impairment was the norm when many partial cues were provided. These results were largely consistent with predictions of the retrieval strategy disruption hypothesis, as well as with an anchoring account of part-set cueing for order.

The Neurophysiology of Implicit Alcohol Associations in Recently Abstinent Patients With Alcohol Use Disorder: An Event-Related Potential Study Considering Gender Effects.

BACKGROUND: Neuroscientific models of alcohol use disorders (AUDs) postulate an imbalance between automatic, implicit, and controlled (conscious) processes. Implicit associations towards alcohol indicate the automatically attributed appeal of alcohol-related stimuli. First, behavioral studies indicate that negative alcohol associations are less pronounced in patients compared to controls, but potential neurophysiological differences remain unexplored. This study investigates neurophysiological correlates of implicit alcohol associations in recently abstinent patients with AUD for the first time, including possible gender effects. METHODS: A total of 62 patients (40 males and 22 females) and 21 controls performed an alcohol valence Implicit Association Test, combining alcohol-related pictures with positive (incongruent condition) or negative (congruent condition) words, while brain activity was recorded using 64-channel electroencephalography. Event-related potentials (ERPs) for alcohol-negative and alcohol-positive trials were computed. Microstate analyses investigated the effects of group (patients, controls) and condition (incongruent, congruent); furthermore, possible gender effects in patients were analyzed. Significant effects were localized with standardized low-resolution brain electromagnetic topography analysis. RESULTS: Although no behavioral group differences were found, ERPs of patients and controls were characterized by distinct microstates from 320 ms onwards. ERPs between conditions differed only in patients with higher signal strength during incongruent trials. Around 600 ms, controls displayed higher signal strength than patients. A gender effect mirrored this pattern with enhanced signal strength in females as opposed to male patients. Around 690 ms, a group-by-valence interaction indicated enhanced signal strength in congruent compared to incongruent trials, which was more pronounced in controls. CONCLUSIONS: For patients with AUD, the pattern, timing, and source localization of effects suggest greater effort regarding semantic and self-relevant integration around 400 ms during incongruent trials and attenuated emotional processing during the late positive potential timeframe. Interestingly, this emotional attenuation seemed reduced in female patients, thus corroborating the importance of gender-sensitive research and potential treatment of AUD.

Temporal trends and autopsy findings of SUDEP based on medico-legal investigations in the United States.

OBJECTIVE: To determine time trends and distinguishing autopsy findings of sudden unexpected death in epilepsy (SUDEP) in the United States. METHODS: We identified decedents where epilepsy/seizure was listed as cause/contributor to death or comorbid condition on the death certificate among all decedents who underwent medico-legal investigation at 3 medical examiner (ME) offices across the country: New York City (2009-2016), San Diego County (2008-2016), and Maryland (2000-2016). After reviewing all available reports, deaths classified as definite/probable/near SUDEP or SUDEP plus were included for analysis. Mann-Kendall trend test was used to analyze temporal trends in SUDEP rate for 2009-2016. Definite SUDEPs were compared to sex- and age ±2 years-matched non-SUDEP deaths with a history of epilepsy regarding autopsy findings, circumstances, and comorbidities. RESULTS: A total of 1,086 SUDEP cases were identified. There was a decreasing trend in ME-investigated SUDEP incidence between 2009 and 2016 (z = -2.2, S = -42, p = 0.028) among 3 regions. There was a 28% reduction in ME-investigated SUDEP incidence from 2009 to 2012 to 2013-2016 (confidence interval, 17%-38%, p < 0.0001). We found no correlation between SUDEP rates and the month of year or day of week. There was no difference between SUDEP and non-SUDEP deaths regarding neurodevelopmental abnormalities, pulmonary congestion/edema, and myocardial fibrosis. CONCLUSIONS: There was a decreasing monotonic trend in ME-investigated SUDEP incidence over 8 years, with a 28% reduction in incidence from 2009-2012 to 2013-2016. Unlike SIDS and sudden cardiac death, we found no correlation between SUDEP and the season of year or day of week. No autopsy findings distinguished SUDEP from non-SUDEP deaths.

Magnetoencephalographic (MEG) brain activity during a mental flexibility task suggests some shared neurobiology in children with neurodevelopmental disorders.

BACKGROUND: Children with neurodevelopmental disorders (NDDs) exhibit a shared phenotype that involves executive dysfunctions including impairments in mental flexibility (MF). It is of interest to understand if this phenotype stems from some shared neurobiology. METHODS: To investigate this possibility, we used magnetoencephalography (MEG) neuroimaging to compare brain activity in children (n = 88; 8-15 years) with autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as they completed a set-shifting/mental flexibility task. RESULTS: Neuroimaging results revealed a similar parietal activation profile across the NDD, groups suggesting a link to their shared phenotype. Differences in frontal activity differentiated the three clinical groups. Brain-behaviour analyses showed a link with repetitive behaviours suggesting shared dysfunction in the associative loop of the corticostriatal system. CONCLUSION: Our study supports the notion that NDDs may exist along a complex phenotypic/biological continuum. All NDD groups showed a sustained parietal activity profile suggesting that they share a strong reliance on the posterior parietal cortices to complete the mental flexibility task; future studies could elucidate whether this is due to delayed brain development or compensatory functioning. The differences in frontal activity may play a role in differentiating the NDDs. The OCD group showed sustained prefrontal activity that may be reflective of hyperfrontality. The ASD group showed reduced frontal activation suggestive of frontal dysfunction and the ADHD group showed an extensive hypoactivity that included frontal and parietal regions. Brain-behaviour analyses showed a significant correlation with repetitive behaviours which may reflect dysfunction in the associative loop of the corticostriatal system, linked to inflexible behaviours.

Addressing the Language Binding Problem With Dynamic Functional Connectivity During Meaningful Spoken Language Comprehension.

During speech, how does the brain integrate information processed on different timescales and in separate brain areas so we can understand what is said? This is the language binding problem. Dynamic functional connectivity (brief periods of synchronization in the phase of EEG oscillations) may provide some answers. Here we investigate time and frequency characteristics of oscillatory power and phase synchrony (dynamic functional connectivity) during speech comprehension. Twenty adults listened to meaningful English sentences and non-sensical "Jabberwocky" sentences in which pseudo-words replaced all content words, while EEG was recorded. Results showed greater oscillatory power and global connectivity strength (mean phase lag index) in the gamma frequency range (30-80 Hz) for English compared to Jabberwocky. Increased power and connectivity relative to baseline was also seen in the theta frequency range (4-7 Hz), but was similar for English and Jabberwocky. High-frequency gamma oscillations may reflect a mechanism by which the brain transfers and integrates linguistic information so we can extract meaning and understand what is said. Slower frequency theta oscillations may support domain-general processing of the rhythmic features of speech. Our findings suggest that constructing a meaningful representation of speech involves dynamic interactions among distributed brain regions that communicate through frequency-specific functional networks.

Effectiveness of antiepileptic drug tapering in the pediatric epilepsy monitoring unit.

OBJECTIVE: Limited evidence on the relationship between antiepileptic drug (AED) tapering and the likelihood of a seizure during an Epilepsy Monitoring Unit (EMU) admission is available, and no evidence specific to the pediatric population has been published. Our study sought to determine whether AED tapering leads to increased seizure likelihood in a pediatric EMU setting. METHODS: We performed a retrospective chart review of children admitted to the pediatric EMU at the Hospital for Sick Children in Toronto between June 1, 2014 and June 1, 2016. Data collected included demographics, reason for EMU referral, and epilepsy and medical characteristics. Among those with nondaily seizures, Kaplan-Meier curves were fit to compare probability of EMU seizure in those who were tapered fully from at least one AED to those not tapered. A Cox proportional hazards model was fit to evaluate this relationship after adjustment for subject sex, distance traveled to hospital, epilepsy duration, seizure frequency, time since last seizure, whether EMU referral was part of presurgical planning, magnetic resonance imaging (MRI) findings, and number of prescribed AEDs. An interaction between medication taper and number of prescribed AEDs was also included. Terms not significant at p < 0.3 were removed from the model, and the reduced model was recomputed. RESULTS: Of the 281 children included in the study, 159 had nondaily seizures. Kaplan-Meier curves indicated fully tapering at least one AED was associated with increased likelihood of seizure during EMU; however, after adjustment for confounding variables, this association was not preserved. Abnormal MRI findings, referral for presurgical evaluation, and shorter (≤3 months) time since last seizure were associated with increased likelihood of seizure during EMU. SIGNIFICANCE: Short-term AED tapering in pediatric patients may not be effective for increasing seizure likelihood in the EMU.

Intra-operative cortical motor mapping using subdural grid electrodes in children undergoing epilepsy surgery evaluation and comparison with the conventional extra-operative motor mapping.

OBJECTIVES: The objective of this study was to review our experience with intra-operative "train of five" stimulation using subdural grid for motor mapping in children undergoing epilepsy surgery evaluation. METHODS: Twenty consecutive children below 18-years of age with drug-refractory epilepsy who underwent invasive-EEG monitoring using subdural-grid placement and intra-operative motor mapping using direct cortical stimulation by sub-dural grid electrodes (IODCS-SDG) at our institution between January-2016 and June-2017 were reviewed. Stimulation was delivered through the subdural-grid electrodes using a train-of-five pulses and muscle responses were recorded by motor-evoked-potentials (MEPs). Intra-operative direct cortical stimulation delivered through a ball-tipped probe (IODCS-probe) and extra-operative motor-mapping (EODCS-SDG) were also performed. RESULTS: IODCS-SDG was completed in 20 patients and subsequent EODCS-SDG was done in 17/20 patients. MEP responses were more commonly obtained in the deltoid (19/20), extensor-digitorum-communis (20/20) and first-dorsal-interosseus (19/20). The median thresholds varied between 40 V and 60 V for the six muscle groups. The respective IODCS-probe thresholds tended to be similar. No stimulation-provoked seizures or anaesthesia-related complications were noted during IODCS-SDG. EODCS-SDG could not be completed in 4/17 children and mapping data obtained was frequently inadequate. Nine patients demonstrated 100% concordance between IODCS-SDG and EODCS-SDG for the common mapped body regions. Stimulation-provoked seizures during EODCS-SDG were seen in 6/17 (35.3%) and after-discharges in 7/17 (41.2%) children. CONCLUSIONS: IODCS-SDG could be performed safely in children with drug refractory epilepsy undergoing invasive EEG monitoring. SIGNIFICANCE: IODCS-SDG may be a useful adjunct to EODCS-SDG in motor mapping for children.

Drowning in epilepsy: A population-based case series.

OBJECTIVES: The risk of drowning is reported to be 15-19 times greater in people with epilepsy compared to the general population. Despite this disproportionate burden, there is limited data about the circumstances surrounding drowning deaths in people with epilepsy. This population-based case series characterizes drowning deaths in people with epilepsy. METHODS: Postmortem data from coroner-ordered autopsies conducted in Ontario between 2014 and 2016 were screened for cases of drowning in people with a history of seizures. Demographic information, epilepsy characteristics, and circumstances surrounding death were extracted from post mortem reports. The incidence of drowning in people with epilepsy was calculated using government estimates of the Ontario population and the number of people with epilepsy. RESULTS: Twenty-five people with epilepsy drowned during the three-year study period, giving an estimated incidence of 1.5 per 10,000 epilepsy person-years (95% CI: 0.98, 2.23). Decedents were mostly young (mean age 36 years) and without physical or developmental disability. Approximately one-third had psychiatric comorbidities. Epilepsy severity ranged from well-controlled to drug refractory. Only 3 people had alcohol or illicit drugs detected on toxicological analysis. Forty-four percent of deaths were the result of an unwitnessed drowning in a bathtub. CONCLUSIONS: This population-based case series confirms people with epilepsy drown at a rate nearly ten times greater than the general population (1.5 per 10,000 epilepsy person-years compared to the estimated provincial average of 0.13 per 10,000). Drowning deaths in people with epilepsy most often occur in the bathtub. These deaths are only rarely associated with intoxication. People with epilepsy should receive counseling on the increased risk of drowning, including information regarding the significant risk associated with bathtub use, the potential protective roles of anti-epileptic drug (AED) adherence and supervision when in or around water, and the fact that all people with epilepsy remain at an increased risk of drowning regardless of their apparent seizure control.

Incidence of sudden unexpected death in epilepsy in children is similar to adults.

OBJECTIVE: To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada. METHODS: Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012). Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence. RESULTS: Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval 0.68-1.88) per 1,000 pediatric epilepsy person-years. The definite/probable incidence, including definite (n = 11), definite plus (n = 2), or probable (n = 3) SUDEP cases, was 1.11 (0.63-1.79). Capture-recapture analysis indicated an estimated 21 (16-39) definite/probable SUDEP cases occurred during the study period, giving an adjusted incidence of definite/probable SUDEP of 1.45 (0.90-2.22) per 1,000 pediatric epilepsy person-years. CONCLUSION: SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer.

VXM01 is a first-in-kind orally applied tumor vaccine based on live attenuated Salmonella typhi carrying an expression plasmid encoding VEGFR2, an antigen expressed on tumor vasculature and a stable and accessible target for anti-angiogenic intervention. A recent randomized, placebo-controlled, phase I dose-escalation trial in advanced pancreatic cancer patients demonstrated safety, immunogenicity and transient, T-cell response-related anti-angiogenic activity of four priming vaccinations applied within one week. We here evaluated whether monthly boost vaccinations are safe and can sustain increased frequencies of vaccine-specific T cells. Patients with advanced pancreatic cancer were randomly assigned at a ratio of 2:1 to priming with VXM01 followed by up to six monthly boost vaccinations, or placebo treatment. Vaccinations were applied orally at two alternative doses of either 106 colony-forming units (CFU) or 107 CFU, and concomitant treatment with standard-of-care gemcitabine during the priming phase, and any treatment thereafter, was allowed in the study. Immunomonitoring involved interferon-gamma (IFNγ) ELIspot analysis with long overlapping peptides spanning the entire VEGFR2 sequence. A total of 26 patients were treated. Treatment-related adverse events preferentially associated with VXM01 were decreases in lymphocyte numbers in the blood, increased frequencies of neutrophils and diarrhea. Eight out of 16 patients who received at least one boosting vaccination responded with pronounced, i.e. at least 3-fold, increase in VEGFR2-specific T cell response over baseline levels. In the VXM01 vaccination group, VEGFR2-specific T cells peaked preferentially during the boosting phase with an average 4-fold increase over baseline levels. In conclusion, prime/boost vaccination with VXM01 was safe and immunogenic and increased vaccine specific T cell responses compared with placebo treatment.