Faculty Bibliography

Importance/UNASSIGNED:Sudden unexplained death in childhood (SUDC) is the fifth leading category of death among toddlers but remains underrecognized and inadequately studied. Objective/UNASSIGNED:To assess the potential role of febrile seizures (FS) and other risk factors associated with SUDC and describe the epidemiology, mechanisms, and prevention of SUDC. Design, Setting, and Participants/UNASSIGNED:This case series study reviewed 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to 2017 from 18 countries. Data were collected from family members of children who died suddenly; these families voluntarily registered with the SUDC Foundation. Data analysis was conducted from November 2017 to February 2019. Main Outcome Measures/UNASSIGNED:Certified manner of death characterized as accident, natural, or undetermined. Results/UNASSIGNED:A total of 391 families with decedents aged 1 to 6 years completed a comprehensive interview on medical and social histories, and circumstances of death with forensic evaluations revealing a cause of death (sudden explained death in childhood [SEDC]) or no cause of death (SUDC). Of these children, 231 (59.1%) were male, the mean (SD) age at death was 24.9 (12.8) months, and 104 (26.6%) had a history of FS. Compared with the general population FS prevalence (2%-5%), FS prevalence among SUDC (28.8%; 95% CI, 23.3%-34.2%) and SEDC (22.1%; 95% CI, 14.8%-29.3%) were elevated. The odds of death during sleep was 4.6-fold higher in SUDC than in SEDC cases (odds ratio, 4.61; 95% CI, 1.92-11.09; adjusted P = .008). The siblings of SUDC cases were followed up for 3144 life-years, and none died prematurely from SUDC. Conclusions and Relevance/UNASSIGNED:This analysis of the largest SUDC cohort confirmed an increased FS rate and found significantly increased rates of FS among SEDC. This study suggests that seizures may contribute to some SUDC and SEDC deaths. The risk of sudden death in a sibling was low. To develop and assess preventive strategies, population-based studies are needed to define the epidemiology and spectrum of risk factors and identify biomarkers of patients with FS at high risk of sudden death.

The principles underlying functional asymmetries in cortex remain debated. For example, it is accepted that speech is processed bilaterally in auditory cortex, but a left hemisphere dominance emerges when the input is interpreted linguistically. The mechanisms, however, are contested, such as what sound features or processing principles underlie laterality. Recent findings across species (humans, canines and bats) provide converging evidence that spectrotemporal sound features drive asymmetrical responses. Typically, accounts invoke models wherein the hemispheres differ in time-frequency resolution or integration window size. We develop a framework that builds on and unifies prevailing models, using spectrotemporal modulation space. Using signal processing techniques motivated by neural responses, we test this approach, employing behavioural and neurophysiological measures. We show how psychophysical judgements align with spectrotemporal modulations and then characterize the neural sensitivities to temporal and spectral modulations. We demonstrate differential contributions from both hemispheres, with a left lateralization for temporal modulations and a weaker right lateralization for spectral modulations. We argue that representations in the modulation domain provide a more mechanistic basis to account for lateralization in auditory cortex.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.

Introduction: Peri-ictal breathing dysfunction was proposed as a potential mechanism for SUDEP. We examined the incidence and risk factors for both ictal (ICA) and post-convulsive central apnea (PCCA) and their relationship with potential seizure severity biomarkers (i. e., post-ictal generalized EEG suppression (PGES) and recurrence. Methods: Prospective, multi-center seizure monitoring study of autonomic, and breathing biomarkers of SUDEP in adults with intractable epilepsy and monitored seizures. Video EEG, thoraco-abdominal excursions, capillary oxygen saturation, and electrocardiography were analyzed. A subgroup analysis determined the incidences of recurrent ICA and PCCA in patients with ≥2 recorded seizures. We excluded status epilepticus and obscured/unavailable video. Central apnea (absence of thoracic-abdominal breathing movements) was defined as ≥1 missed breath, and ≥5 s. ICA referred to apnea preceding or occurring along with non-convulsive seizures (NCS) or apnea before generalized convulsive seizures (GCS). Results: We analyzed 558 seizures in 218 patients (130 female); 321 seizures were NCS and 237 were GCS. ICA occurred in 180/487 (36.9%) seizures in 83/192 (43.2%) patients, all with focal epilepsy. Sleep state was related to presence of ICA [RR 1.33, CI 95% (1.08-1.64), p = 0.008] whereas extratemporal epilepsy was related to lower incidence of ICA [RR 0.58, CI 95% (0.37-0.90), p = 0.015]. ICA recurred in 45/60 (75%) patients. PCCA occurred in 41/228 (18%) of GCS in 30/134 (22.4%) patients, regardless of epilepsy type. Female sex [RR 11.30, CI 95% (4.50-28.34), p < 0.001] and ICA duration [RR 1.14 CI 95% (1.05-1.25), p = 0.001] were related to PCCA presence, whereas absence of PGES was related to absence of PCCA [0.27, CI 95% (0.16-0.47), p < 0.001]. PCCA duration was longer in males [HR 1.84, CI 95% (1.06-3.19), p = 0.003]. In 9/17 (52.9%) patients, PCCA was recurrent. Conclusion: ICA incidence is almost twice the incidence of PCCA and is only seen in focal epilepsies, as opposed to PCCA, suggesting different pathophysiologies. ICA is likely to be a recurrent semiological phenomenon of cortical seizure discharge, whereas PCCA may be a reflection of brainstem dysfunction after GCS. Prolonged ICA or PCCA may, respectively, contribute to SUDEP, as evidenced by two cases we report. Further prospective cohort studies are needed to validate these hypotheses.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.

Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior.

OBJECTIVE:Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS:Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS:This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE/CONCLUSIONS:In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

OBJECTIVE:Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS:Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. RESULTS:By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE/CONCLUSIONS:This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

BACKGROUND:Sleep spindles are involved in memory consolidation and other cognitive functions. Numerous automated methods for detection of spindles have been proposed; most of these rely on spectral analysis in some form. However, none of these approaches are ideal, and novel approaches to the problem could provide additional insights. NEW METHOD/UNASSIGNED:Here, we apply delay differential analysis (DDA), a time-domain technique based on nonlinear dynamics to detect sleep spindles in human intracranial sleep data, including laminar electrode, stereoelectroencephalogram (sEEG), and electrocorticogram (ECoG) recordings. RESULTS:We show that this approach is computationally fast, generalizable, requires minimal preprocessing, and provides excellent agreement with human scoring. COMPARISON WITH EXISTING METHODS/UNASSIGNED:score than all other tested methods except the automated detections published with the DREAMS data. Further, in addition to being a fast and reliable method for spindle detection, DDA also provides a novel characterization of spindle activity based on nonlinear dynamical content of the data. CONCLUSIONS:This additional, non-frequency-based perspective could prove particularly useful for certain atypical spindles, or identifying spindles of different types.

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.