Faculty Bibliography

Purpose: Assess the effect of CBD added to antiepileptic drug (AED) therapy for the treatment of drug-resistant seizures in Dravet syndrome. Method: This double-blind, placebo-controlled trial randomised 120 children aged 2-18 years with Dravet syndrome and drug-resistant seizures to receive CBD oral solution 20 mg/kg/day (n = 61) or placebo (n = 59) for 14 weeks (2 week titration; 12 week maintenance). The primary endpoint was the percentage change from baseline in convulsive seizures (tonic-clonic, tonic, clonic, and atonic) frequency over the 14-week treatment period. Results: The groups were well-balanced at baseline for demographics. Mean age was 10 years, with 29% of patients <6 years. Patients had previously tried a median 4 AEDs, and were currently taking a median 3 AEDs. Convulsive seizure frequency per month decreased from a median of 12.4 to 5.9 (median reduction of 39%) with CBD vs. 14.9 to 14.1 (median reduction of 13%) with placebo (difference between groups of 23%; p = 0.012). The proportion of patients with >=50% reduction in convulsive seizure frequency was 42.6% with CBD vs. 27.1% with placebo (OR=2.0; p = 0.078). Adverse events (AEs) occurred in 93.4% of CBD and 74.6% of placebo patients, and were mostly mild or moderate; the most common were somnolence, diarrhea, and decreased appetite. Serious AEs were reported in 16.4% of CBD and 5.1% of placebo patients, and were considered treatment-related in 8.2% of CBD patients, all of whom discontinued CBD. Some elevations in transaminases were noted without elevations of bilirubin; all were on concomitant valproate and all resolved. There were no deaths in the study. Conclusion: Results from this study suggest that CBD add-on therapy for drug-resistant seizures in Dravet syndrome may be efficacious, with more AEs 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

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.

OBJECTIVE: To determine the definite and potential frequency of seizures and epilepsy as a cause of death (COD) and how often this goes unrecognized. METHODS: Prospective determination of seizures or epilepsy and final COD for individuals aged 18-90 years with out-of-hospital sudden cardiac deaths (SCDs) from the population-based San Francisco POST SCD Study. We compared prospective seizure or epilepsy diagnosis and final COD as adjudicated by a multidisciplinary committee (pathologists, electrophysiologists, and a vascular neurologist) vs retrospective adjudication by 2 epileptologists with expertise in seizure-related mortality. RESULTS: Of 541 SCDs identified during the 37-month study period (mean age 62.8 years, 69% men), 525 (97%) were autopsied; 39/525 (7.4%) had seizures or epilepsy (mean age: 58 years, range: 27-92; 67% men), comprising 17% of 231 nonarrhythmic sudden deaths. The multidisciplinary team identified 15 cases of epilepsy, 6 sudden unexpected deaths in epilepsy (SUDEPs), and no deaths related to acute symptomatic seizures. The epileptologists identified 25 cases of epilepsy and 8 definite SUDEPs, 10 possible SUDEPs, and 5 potential cases of acute symptomatic seizures as a COD. CONCLUSIONS: Among the 25 patients identified with epilepsy by the epileptologists, they found definite or possible SUDEP in 72% (18/25) vs 24% (6/25) by the multidisciplinary group (6/15 cases they identified with epilepsy). The epileptologists identified acute symptomatic seizures as a potential COD in 5/14 patients with alcohol-related seizures. Epilepsy is underdiagnosed among decedents. Among patients with seizures and epilepsy who die suddenly, seizures and SUDEP often go unrecognized as a potential or definite COD.