Faculty Bibliography

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

OBJECTIVE:Epilepsy patients often report memory deficits despite normal objective testing, suggesting that available measures are insensitive or that non-mnemonic factors are involved. The Visual Paired Comparison Task (VPCT) assesses novelty preference, the tendency to fixate on novel images rather than previously viewed items, requiring recognition memory for the "old" images. As novelty preference is a sensitive measure of hippocampal-dependent memory function, we predicted impaired VPCT performance in epilepsy patients compared to healthy controls. METHODS:We assessed 26 healthy adult controls and 31 epilepsy patients (16 focal-onset, 13 generalized-onset, 2 unknown-onset) with the VPCT using delays of 2 or 30 s between encoding and recognition. Fifteen healthy controls and 17 epilepsy patients (10 focal-onset, 5 generalized-onset, 2 unknown-onset) completed the task at 2-, 5-, and 30-minute delays. Subjects also performed standard memory measures, including the Medical College of Georgia (MCG) Paragraph Test, California Verbal Learning Test-Second Edition (CVLT-II), and Brief Visual Memory Test-Revised (BVMT-R). RESULTS:The epilepsy group was high functioning, with greater estimated IQ (p = 0.041), greater years of education (p = 0.034), and higher BVMT-R scores (p = 0.024) compared to controls. Both the control group and epilepsy cohort, as well as focal- and generalized-onset subgroups, had intact novelty preference at the 2- and 30-second delays (p-values ≤ 0.001) and declined at 30 min (p-values > 0.05). Only the epilepsy patients had early declines at 2- and 5-minute delays (controls with intact novelty preference at p = 0.003 and p ≤ 0.001, respectively; epilepsy groups' p-values > 0.05). CONCLUSIONS:Memory for the "old" items decayed more rapidly in overall, focal-onset, and generalized-onset epilepsy groups. The VPCT detected deficits while standard memory measures were largely intact, suggesting that the VPCT may be a more sensitive measure of temporal lobe memory function than standard neuropsychological batteries.

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.

Substantial efforts are underway towards optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trials execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, while seizures represent one critical therapeutic target, targeting non-seizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves as well as other non-seizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics from drug discovery to translational application.

Many developmental and epileptic encephalopathies (DEEs) result from variants in cation channel genes. Using mRNA transfection, we generated and characterised an induced pluripotent stem cell (iPSC) line from the fibroblasts of a male late-onset DEE patient carrying a heterozygous missense variant (E1211K) in Na_v1.2(SCN2A) protein. The iPSC line displays features characteristic of the human iPSCs, colony morphology and expression of pluripotency-associated marker genes, ability to produce derivatives of all three embryonic germ layers, and normal karyotype without SNP array-detectable abnormalities. We anticipate that this iPSC line will aid in the modelling and development of precision therapies for this debilitating condition.

Contextual embeddings, derived from deep language models (DLMs), provide a continuous vectorial representation of language. This embedding space differs fundamentally from the symbolic representations posited by traditional psycholinguistics. We hypothesize that language areas in the human brain, similar to DLMs, rely on a continuous embedding space to represent language. To test this hypothesis, we densely record the neural activity patterns in the inferior frontal gyrus (IFG) of three participants using dense intracranial arrays while they listened to a 30-minute podcast. From these fine-grained spatiotemporal neural recordings, we derive a continuous vectorial representation for each word (i.e., a brain embedding) in each patient. Using stringent zero-shot mapping we demonstrate that brain embeddings in the IFG and the DLM contextual embedding space have common geometric patterns. The common geometric patterns allow us to predict the brain embedding in IFG of a given left-out word based solely on its geometrical relationship to other non-overlapping words in the podcast. Furthermore, we show that contextual embeddings capture the geometry of IFG embeddings better than static word embeddings. The continuous brain embedding space exposes a vector-based neural code for natural language processing in the human brain.

OBJECTIVE:New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. METHODS:Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. RESULTS:Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. SIGNIFICANCE/CONCLUSIONS:Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.

INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.