Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

Direct recordings from the human brain have historically involved epilepsy patients undergoing invasive electroencephalography (iEEG) for surgery. However, these measurements are temporally limited and affected by clinical variables. The RNS System (NeuroPace, Inc.) is a chronic, closed-loop electrographic seizure detection and stimulation system. When adapted by investigators for research, it facilitates cognitive testing in a controlled ambulatory setting, with measurements collected over months to years. We utilized an associative learning paradigm in 5 patients with traditional iEEG and 3 patients with chronic iEEG, and found increased hippocampal gamma (60-100 Hz) sustained at 1.3-1.5 seconds during encoding in successful versus failed trials in surgical patients, with similar results in our RNS System patients (1.4-1.6 seconds). Our findings replicate other studies demonstrating that sustained hippocampal gamma supports encoding. Importantly, we have validated the RNS System to make sensitive measurements of hippocampal dynamics during cognitive tasks in a chronic ambulatory research setting.

Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.

PURPOSE OF REVIEW/OBJECTIVE:To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy. RECENT FINDINGS/RESULTS:Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (>99% of CBD and <0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data. SUMMARY/CONCLUSIONS:Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

OBJECTIVE:To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. METHODS:This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed. RESULTS:= 0.009). CONCLUSIONS:PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.

BACKGROUND:Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD/METHODS:We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS:The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS/UNASSIGNED:Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales simultaneously. CONCLUSIONS:This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

BACKGROUND AND PURPOSE/OBJECTIVE:-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. EXPERIMENTAL APPROACH/METHODS:Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography-telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats, and treatment-naïve rat, mouse, chicken, dog and human tissue. KEY RESULTS/RESULTS:-THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than a species that did not (dog). CONCLUSION AND IMPLICATIONS/CONCLUSIONS:Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models.

Sudden unexpected death of an individual with epilepsy (SUDEP) can pose a challenge to death investigators, as most deaths are unwitnessed and the individual is commonly found dead in bed. Anatomic findings (e.g., tongue/lip bite) are commonly absent and of varying specificity, limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus, it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention convened an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden, unexpected death in a person with epilepsy is encountered.