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Abstract: Importance: Sudden unexpected death in epilepsy (SUDEP) is a common cause of mortality in patients with the disease, but it is unknown how neurologists disclose this risk when counseling patients. Objective: This study aimed at examining SUDEP discussion practices of neurologists in the U.S. and Canada. Design: An electronic, web-based survey was sent to 17,558 neurologists in the U.S. and Canada. Survey questions included frequency of SUDEP discussion, reasons for discussing/not discussing SUDEP, timing of SUDEP discussions, and perceived patient reactions. We examined factors that influence the frequency of SUDEP discussion and perceived patient response using multivariate logistic regression. Participants: The participants of this study were neurologists who completed postgraduate training and devoted >5% of their time to patient care. Results: There was a response rate of 9.3%; 1200 respondents met eligibility criteria and completed surveys. Only 6.8% of the respondents discussed SUDEP with nearly all (>90% of the time) of their patients with epilepsy/caregivers, while 11.6% never discussed it. Factors that independently predicted whether SUDEP was discussed nearly all of the time were the following: number of patients with epilepsy seen annually (OR=2.01, 95% CI=1.20–3.37, p <0.01) and if the respondent had a SUDEP case in the past 24months (OR=2.27, 95% CI=1.37–3.66, p <0.01). A majority of respondents (59.5%) reported that negative reactions were the most common response to a discussion of SUDEP. Having additional epilepsy/neurophysiology training was associated with an increased risk of a perceived negative response (OR=1.36, 95% CI=1.02–1.82, p =0.038), while years in practice (OR=0.85, 95% CI=0.77–0.95, p <0.005) and seeing both adults and children were associated with a decreased likelihood of negative response (OR=0.15, 95% CI=0.032–0.74, p =0.02). Conclusions: U.S. and Canadian neurologists rarely discuss SUDEP with all patients with epilepsy/caregivers though discussions are more likely among neurologists who frequently see patients with epilepsy or had a recent SUDEP in their practice. Perceived negative reactions to SUDEP discussions are common but not universal; more experienced neurologists may be less likely to encounter negative reactions, suggesting that there may be ways to frame the discussion that minimizes patient/caregiver distress. [Copyright &y& Elsevier]

Abstract Background Sudden Unexpected Death in Epilepsy (SUDEP) is a significant cause of death in childhood epilepsy, and causes considerable concern to patients and their families. Despite this, the condition remains poorly understood. This systematic review investigates the risk factors, pathophysiology, and circumstances associated with childhood SUDEP. It aimed to explore the etiology of SUDEP and inform clinicians approaching SUDEP risk disclosure. Methods A structured electronic database search of MEDLINE, CENTRAL, EMBASE, and ISI web of science was conducted. Studies were included if they described clinical details of one or more patients, aged 18 years of age and below, who had SUDEP. Two reviewers independently reviewed each article for data extraction and quality assessment. Results Information on 108 cases of pediatric SUDEP was extracted from 22 included studies. These comprised five cohort studies, four retrospective case control studies, seven case series, and five case reports. Factors that appeared to be linked to pediatric SUDEP included those associated with severe epilepsy (early age of onset, high seizure frequency, intellectual impairment and developmental delay, multiple antiepileptic drug therapy, and structural abnormalities). The majority of included studies was noncomparative and had significant risk of bias. Conclusions There is currently insufficient evidence to determine the etiology of pediatric SUDEP. Current best practice to prevent pediatric SUDEP is to optimize the management of epilepsy. A national SUDEP registry would provide invaluable high-quality data and insights into modifiable risk factors, genetic predispositions, and novel prevention strategies. Highlights • Very little is known about the pathophysiology, risk factors and circumstances associated with childhood SUDEP. • In this systematic review, 22 studies were included with information on 108 cases of pediatric SUDEP. • Factors which appeared to be linked to pediatric SUDEP included those associated with severe epilepsy. • This is the first systematic review of childhood SUDEP in the literature, drawn from analysis of the largest compilation of pediatric SUDEP cases. [ABSTRACT FROM AUTHOR]

• Subtle but important cognitive and behavioural changes can occur while admitted to the EMU. • Taking lessons from spaceflight, we piloted a daily psychomotor vigilance task in capturing these changes. • Task performance is associated with epileptiform activity and number of antiseizure medications administered. • Routine assessment of psychomotor vigilance can help clinicians capture important neurocognitive changes. The epilepsy monitoring unit (EMU) is a complex and dynamic operational environment, where the cognitive and behavioural consequences of medical and environmental changes often go unnoticed. The psychomotor vigilance task (PVT) has been used to detect changes in cognition and behaviour in numerous contexts, including among astronauts on spaceflight missions, pilots, and commercial drivers. Here, we piloted serial point-of-care administration of the PVT in children undergoing invasive monitoring in the EMU. Seven children completed the PVT throughout their hospital admission and their performance was associated with daily seizure counts, interictal epileptiform discharges, number of antiseizure medications (ASMs) administered, and sleep quality metrics. Using mixed-effects models, we found that PVT reaction time and accuracy were adversely affected by greater number of ASMs and interictal epileptiform activity. We show that serial point-of-care PVT is simple and feasible in the EMU and may enable greater understanding of individual patient responses to medical and environmental alterations, inform clinical decision-making, and support quality-improvement and research initiatives. [ABSTRACT FROM AUTHOR]

Abstract Heterozygous mutations in syntaxin-binding protein 1 (STXBP1) gene are associated with early infantile epileptic encephalopathy 4 (EIEE4). This condition is characterized by epilepsy, developmental delay (DD), and various movement disorders. Herein, we will report 5 unrelated patients with different de novo mutations in STXBP1. In addition, we conducted an online survey through Facebook to identify the incidence of bruxism (BRX) in these patients. Four out of 5 patients (80%) presented with awake BRX (A-BRX). Bruxism was also reported in 81.4% (57/70) of the patients with STXBP1 encephalopathy through the online questionnaire. No consistent correlation was identified between the type of mutation and development of movement disorders or BRX. This is the first study to demonstrate A-BRX in patients with STXBP1 mutation. Given the role of STXBP1 in exocytosis of neurotransmitters and other manifestations of dopamine dysregulation in patients with STXBP1 -EIEE4, we suggest that in patients with STXBP1 encephalopathy, A-BRX might be the result of the involvement of dopaminergic circuits. Highlights • In patients with STXBP1 encephalopathy, bruxism during wakefulness is more common than during sleep. • Awake bruxism occurs in 80% of patients with STXBP1 mutations. • The role of STXBP1 in dopamine activity may explain awake bruxism in these patients. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • Evaluates the efficacy of AED tapering in a pediatric EMU setting • Fully tapering AED(s) in EMU patients was not associated with seizure likelihood. • Associated factors: MRI findings, presurgical referral, and time since last seizure [ABSTRACT FROM AUTHOR]

The North American SUDEP Registry (NASR) is a repository of clinical data and biospecimens in cases of sudden unexpected death in epilepsy (SUDEP), a leading cause of epilepsy-related deaths. We assessed whether bereaved families were aware of SUDEP before their family member's death and their preferences for SUDEP disclosure. At enrollment, next-of-kin of SUDEP cases completed an intake interview, including questions assessing premorbid SUDEP discussions. Only 18.1% of the 138 next-of-kin recalled a previous discussion of SUDEP with a healthcare provider or support resource. Of the 112 who did not recall such a discussion, 72.3% wished it was discussed, 10.7% were satisfied it was not discussed, and 17% were unsure. A history of status epilepticus predicted SUDEP discussion. Rates of SUDEP discussion were not significantly higher among SUDEPs after 2013 (the approximate study midpoint) compared with those before then. Our study suggests that SUDEP remains infrequently discussed with family members of persons with epilepsy. Nearly three-quarters of family members wished they had known of SUDEP before the death. However, some were indifferent or were satisfied that this discussion had not occurred. We must balance more systematic education of patients and families about SUDEP while respecting individual preferences about having this discussion. [ABSTRACT FROM AUTHOR]

Although developmental outcomes may improve following functional hemispherotomy for lateralized, catastrophic childhood epilepsy, the neuronal processes mediating these improvements are unknown. We report the case of a 14-year-old child with neurocognitive impairment who underwent functional hemispherotomy with longitudinal resting-state fMRI. Compared with preoperative fMRI, we report significantly more robust thalamo-default mode network connectivity on postoperative neuroimaging. Furthermore, we show decreased connectivity to nodes within the disconnected hemisphere, providing direct evidence that functional interactions are dependent upon structural connectivity. Since the vascular supply to these nodes remains intact, although they are disconnected from the remainder of the brain, these findings also confirm that blood-oxygen level dependent oscillations are driven primarily by neuronal activity. The current study highlights the importance of thalamocortical interactions in the understanding of neural oscillations and cognitive function, and their impairment in childhood epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: Accurate localization of language function is critical in children undergoing epilepsy surgery. Functional magnetic resonance imaging (fMRI) is a noninvasive mapping method that has begun to replace electrocortical stimulation mapping (ESM) and the intracarotid amytal test (IAT). We used both quantitative and qualitative methods to evaluate the concordance of fMRI with ESM and IAT in 20 children using a panel of language tasks. In no cases did fMRI assessment of language hemisphere dominance identify the opposite hemisphere from assessment by IAT or ESM. Concordance with IAT and ESM was higher using fMRI visual inspection than an fMRI laterality index, which failed to lateralize language in a number of the subjects. We have demonstrated that fMRI has good concordance with more traditional methods of language mapping. When fMRI demonstrates bilateral language activations, however, we continue to recommend confirmatory testing by either IAT or ESM prior to resection in classic language regions. [Copyright &y& Elsevier]

• Seizure outcomes following ablation of hypothalamic hamartomas are heterogeneous. • Differences in surgical targeting contribute to variability in postoperative outcomes. • A preoperative high-resolution hypothalamic atlas can inform surgical targeting. Large hypothalamic hamartomas (HH) are often associated with difficult-to-treat, refractory seizures. Although magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a useful tool to treat these challenging lesions, postoperative outcomes are variable and potentially related to differences in surgical targeting. We sought to identify differences in the anatomic localization of laser ablations that either did or did not result in seizure freedom. Four children who underwent MRgLITT for large HH (3 seizure-free and 1 not seizure-free) were included in the analysis. Ablation volumes were segmented, normalized, and overlaid on a high-resolution hypothalamic atlas. For each lesion, the size, spatial extent, and degree of overlap with key hypothalamic nuclei and surrounding brain regions were computed and compared between ablations that did and did not result in seizure freedom. Ablation masks that resulted in seizure freedom were smaller and located more centrally than the ablation mask that did not. In addition, ablation masks that resulted in seizure freedom overlapped with regions including the paraventricular nucleus, the posterior hypothalamus and the zona incerta, fornix, and mammillothalamic tract, whereas the single non-seizure-free ablation did not. Differences in the size, position, and anatomical localization of ablation volumes may be a potential contributor to the variability in postoperative outcomes of large HH treated with MRgLITT. A novel, high-resolution MRI atlas of the hypothalamus identifies a number of regions at the interface of large HH that are preferentially disconnected in seizure-free patients. This method of anatomical localization not only serves as a potential clinical tool for surgical targeting but may also provide novel insights into the mechanisms of epileptogenesis in hypothalamic hamartomas. [ABSTRACT FROM AUTHOR]

Postictal generalized electroencephalographic suppression (PGES) has been associated with sudden unexpected death in epilepsy (SUDEP) in adults. Decreased heart rate variability (HRV) is one clinical marker of SUDEP in adults with epilepsy. The objective of this study was to analyze the characteristics of HRV associated with generalized convulsive seizures (GCS) ± PGES in children. Nine hundred and seventy-seven consecutive children who underwent prolonged scalp video-EEG (vEEG) and 1-lead electrocardiogram (ECG) monitoring at the Hospital for Sick Children, Toronto, Ontario, Canada were reviewed retrospectively from 2009 to 2011. Thirty-five children had GCS captured during their vEEG with or without PGES and met inclusion criteria. Children were subdivided into three age groups and compared with age-matched controls: 3–6 years; 7–12 years; and 13–18 years. Interictal HRV was measured at 5 min during N2 sleep. Preictal HRV was measured at 1 h prior to GCS onset, and postictal HRV was measured at 3 min post-GCS cessation. Low frequency (LF: ms2, 0.04–0.15 Hz) and high frequency (HF: ms2, 0.15–0.4 Hz) bands of heart rate oscillations were analyzed during the interictal and preictal periods. The root mean square of successive differences (RMSSDs) was analyzed during the following time points: interictal; preictal; and postictal. Thirty-five children had GCS: 18 children with PGES [3–6 years (n = 2); 7–12 years (n = 6); 13–18 years (n = 10)] and 17 children without PGES [3–6 years (n = 6); 7–12 years (n = 5); 13–18 years (n = 6)]. Seventeen additional age-matched controls were identified [3–6 years (n = 3); 7–12 years (n = 5); 13–18 years (n = 9)]. Seventy-four GCS were captured consisting of 36 GCS + PGES and 38 GCS − PGES. There was no difference of interictal HRV among children with GCS ± PGES and controls. The preictal LF and HF in 36 GCS + PGES were significantly higher compared with 38 GCS − PGES (p < 0.01). The postictal RMSSD in 36 GCS + PGES was significantly higher compared with 38 GCS − PGES (p < 0.01). The pre- to postictal RMSSD change was significantly lower in children with GCS + PGES than in those with GCS − PGES (p = 0.035). In summary, the preictal HRV in GCS + PGES was significantly higher than in children with GCS − PGES. The higher remaining postictal RMSSD in children with GCS + PGES is a potential indicator of autonomic dysregulation. In certain children with epilepsy, autonomic dysregulation may contribute to poor recovery from a GCS with subsequent PGES, thereby contributing to SUDEP. Heart rate variability and autonomic regulation in children with epilepsy should be further studied prospectively in order to better understand the mechanism by which PGES may lead to SUDEP. • Preictal LF and HF in GCS + PGES were significantly higher than those in GCS − PGES. • Postictal RMSSD in GCS + PGES was significantly higher than that of GCS − PGES. • Pre- to postictal RMSSD change was significantly lower in GCS + PGES than in GCS – PGES. • Patients with GCS + PGES may have potential autonomic dysregulation. • Autonomic dysregulation leading to GCS results in PGES and possible SUDEP. [ABSTRACT FROM AUTHOR]