Faculty Bibliography

Purpose: Evaluate efficacy of add-on CBD for the treatment of seizures associated with LGS. Method: Eligible patients were 2-55 years old with a clinical diagnosis of LGS, >=8 drop seizures during 4-week baseline, and documented failure of >=1 antiepileptic drug (AED). Patients were randomised (1:1:1) to 20 mg/kg/day CBD, 10 mg/kg/day CBD, or placebo for 14 weeks (2-week titration; 12-week maintenance). The primary efficacy endpoint was percentage change from baseline in drop seizures/month over the 14-week treatment period for CBD vs. placebo; >=50% responder rate and percentage change in total seizures were assessed. Results: 225 patients were randomised (76 CBD 20 mg/kg, 73 CBD 10 mg/kg, 76 placebo); 9 CBD 20 mg/kg, 2 CBD 10 mg/kg, and 2 placebo patients withdrew. Groups were similar at baseline; mean age was 16 years (30% of patients >=18 years) and median drop seizures/month was 85 (IQR: 44, 168). Patients had failed a median of 6 and were taking a median of 3 AEDs. Reduction in drop seizures was significantly greater for CBD 20 mg/kg (42%) and CBD 10 mg/kg (37%) than placebo (17%; p = 0.0047 and p = 0.0016), as were >=50% responder rates (40% and 36% vs. 15%; p = 0.0006 and p = 0.0030) and reductions in total seizures (38% and 36% vs. 18%; p = 0.0091 and p = 0.0015). Adverse events (AEs) occurred in 94% of CBD 20 mg/kg, 84% of CBD 10 mg/kg, and 72% of placebo patients, and were mostly mild or moderate; the most common were somnolence and decreased appetite. Treatment-related serious AEs occurred in 5 CBD 20 mg/kg, 2 CBD 10 mg/kg, and 0 placebo patients. Some elevations in transaminases were seen. There were no deaths. Of 212 completers, 99% entered the open-label extension study. Conclusion: Results suggest that add-on CBD for treatment of seizures associated with LGS may be efficacious, with more adverse events than placebo, but generally well-tolerated

Purpose: Evaluate the dose-ranging safety, tolerability, and pharmacokinetics (PK) of CBD in children with Dravet syndrome (DS). Method: Patients aged 4-10 years completed a 4-week baseline period and were randomised 4:1 to 1 of 3 CBD doses (5, 10, 20 mg/kg/day) or placebo as add-on therapy for 3 weeks. CBD (25 or 100 mg/mL oral solution) was administered BID starting at 2.5 mg/kg/day and increasing by 2.5 mg/kg QOD to randomised dose. On Days 1 and 22, PK exposures were expressed as AUC0-t. Dose proportionality was assessed on Day 22 by regression analysis. Adverse events (AEs) were recorded daily. Results: 34 patients were randomised to CBD 5 mg/kg/day (n = 10), 10 mg/kg/day (n = 8), 20 mg/kg/day (n = 9), or placebo (n = 7). Patients took a median 3 antiepileptic drugs (AEDs). On Day 22, exposures to CBD and major metabolites increased dose-proportionally; there was minimal change in clobazam levels, but concentrations of clobazam's metabolite, N-clobazam, increased independent of CBD dose, except in patients on stiripentol. There was no demonstrable effect on other AEDs (valproic acid, topiramate, stiripentol, levetiracetam). Most common AEs (CBD vs. placebo) were pyrexia (22% vs. 0%), somnolence (19% vs. 14%), decreased appetite (19% vs. 0%), and sedation (15% vs. 0%). Treatment-related serious AEs occurred in 2 patients on CBD and discontinuations due to AEs occurred in 2 patients on CBD. Increases in ALT or AST (levels >3 9 ULN) occurred in 6 patients on CBD, all on valproic acid; none had elevated bilirubin and all recovered. Conclusion: CBD was well tolerated and 20 mg/kg/day was chosen for further development. Exposure to CBD and its metabolites increased dose-proportionally. A PK interaction of CBD on N-clobazam was observed, likely mediated through CYP2C19 inhibition, except with stiripentol, presumably from prior saturated inhibition of CYP2C19 by stiripentol

BACKGROUND:Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. METHODS AND RESULTS/RESULTS:The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. CONCLUSIONS:High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

Malformations of cortical development are associated with epilepsy and cognitive dysfunction, and can occur in patients withSCN1Aion channel mutations. We report a novel and subtle bandlike subcortical heterotopia on integrated positron emission tomography-magnetic resonance imaging ( PET-MRI) in a patient with treatment-resistant epilepsy due to a de novoKCNQ1frameshift mutation. Our case highlights the potential for other channel mutations to cause both epilepsy and cortical malformations. Further scrutiny of high contrast resolution MRI studies is warranted for patients withKCNQ1and other epilepsy genes to further define their extended phenotype.

Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings has remained inconclusive. Here, we measure endogenous spindle and theta activity intracranially in humans during low-frequency tACS and find no stable entrainment of spindle power during non-REM sleep, nor of theta power during resting wakefulness. As positive controls, we find robust entrainment of spindle activity to endogenous slow-wave activity in 66% of electrodes as well as entrainment to rhythmic noise-burst acoustic stimulation in 14% of electrodes. We conclude that low-frequency tACS at common stimulation intensities neither acutely modulates spindle activity during sleep nor theta activity during waking rest, likely because of the attenuated electrical fields reaching the cortical surface.

Musical hallucinations are uncommon phenomena characterized by intrusive and frequently distressful auditory musical percepts without an external source, often associated with hypoacusis, psychiatric illness, focal brain lesion, epilepsy, and intoxication/pharmacology. Their physiological basis is thought to involve diverse mechanisms, including "release" from normal sensory or inhibitory inputs as well as stimulation during seizures, or they can be produced by functional or structural disorders in diverse cortical and subcortical areas. The aim of this review is to further explore their pathophysiology, describing the functional neuroimaging findings regarding musical hallucinations. A literature search of the PubMed electronic database was conducted through to 29 December 2015. Search terms included "musical hallucinations" combined with the names of specific functional neuroimaging techniques. A total of 18 articles, all clinical case reports, providing data on 23 patients, comprised the set we reviewed. Diverse pathological processes and patient populations with musical hallucinations were included in the studies. Converging data from multiple studies suggest that the superior temporal sulcus is the most common site and that activation is the most common mechanism. Further neurobiological research is needed to clarify the pathophysiology of musical hallucinations.

Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates, in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Delta9-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as potential contributors to these disorders.

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 muL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 muL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.