Faculty Bibliography

OBJECTIVE:To develop and validate a tool for individualised prediction of Sudden Unexpected Death in Epilepsy (SUDEP) risk, we re-analysed data from one cohort and three case-control studies undertaken 1980-2005. METHODS:We entered 1273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model. RESULTS:Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalised tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM +/-12.5, and 22.9, SEM +/-11.0 respectively). The mean cross-validated (95% Credibility Interval) Area Under the Receiver Operating Curve was 0.71 (0.68 to 0.74) for our model versus 0.38 (0.33 to 0.42) and 0.63 (0.59 to 0.67) for the baseline average and generalised tonic-clonic seizure frequency models respectively. Model performance was weaker when applied to non-represented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age of epilepsy onset and family history of epilepsy. Anti-seizure medication adherence was associated with lower risk. CONCLUSIONS:Even when generalised to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not only focus on the frequency of convulsions.

OBJECTIVE:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients. METHODS:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. CONCLUSION/CONCLUSIONS:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

We describe the spatiotemporal course of cortical high-gamma activity, hippocampal ripple activity and interictal epileptiform discharges during an associative memory task in 15 epilepsy patients undergoing invasive EEG. Successful encoding trials manifested significantly greater high-gamma activity in hippocampus and frontal regions. Successful cued recall trials manifested sustained high-gamma activity in hippocampus compared to failed responses. Hippocampal ripple rates were greater during successful encoding and retrieval trials. Interictal epileptiform discharges during encoding were associated with 15% decreased odds of remembering in hippocampus (95% confidence interval 6-23%). Hippocampal interictal epileptiform discharges during retrieval predicted 25% decreased odds of remembering (15-33%). Odds of remembering were reduced by 25-52% if interictal epileptiform discharges occurred during the 500-2000-ms window of encoding or by 41% during retrieval. During encoding and retrieval, hippocampal interictal epileptiform discharges were followed by a transient decrease in ripple rate. We hypothesize that interictal epileptiform discharges impair associative memory in a regionally and temporally specific manner by decreasing physiological hippocampal ripples necessary for effective encoding and recall. Because dynamic memory impairment arises from pathological interictal epileptiform discharge events competing with physiological ripples, interictal epileptiform discharges represent a promising therapeutic target for memory remediation in patients with epilepsy.

Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K⁺) concentration via K⁺ ion channels. Seizures may disrupt the regulation of inwardly rectifying K⁺ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K⁺ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K⁺ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.

Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics. Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD. Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.

Objective/UNASSIGNED:-related neurodevelopmental disorder in 33 individuals. Methods/UNASSIGNED:using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results/UNASSIGNED:-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions/UNASSIGNED:-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

OBJECTIVE:People with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. METHODS:89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). RESULTS:Of 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4-26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4-44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SIGNIFICANCE/CONCLUSIONS:Our study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.