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Cannabinoid treatments in epilepsy and seizure disorders

Devinsky, Orrin; Jones, Nicholas A; Cunningham, Mark O; Jayasekera, B Ashan P; Devore, Sasha; Whalley, Benjamin J
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.
PMID: 37882730
ISSN: 1522-1210
CID: 5628142

Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

O'Neill, Kimberly A; Dugue, Andrew; Abreu, Nicolas J; Balcer, Laura J; Branche, Marc; Galetta, Steven; Graves, Jennifer; Kister, Ilya; Magro, Cynthia; Miller, Claire; Newsome, Scott D; Pappas, John; Rucker, Janet; Steigerwald, Connolly; William, Christopher M; Zamvil, Scott S; Grossman, Scott N; Krupp, Lauren B
A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.
PMID: 38181317
ISSN: 2332-7812
CID: 5628442

Proteomic profiling of interferon-responsive reactive astrocytes in rodent and human

Prakash, Priya; Erdjument-Bromage, Hediye; O'Dea, Michael R; Munson, Christy N; Labib, David; Fossati, Valentina; Neubert, Thomas A; Liddelow, Shane A
Astrocytes are a heterogeneous population of central nervous system glial cells that respond to pathological insults and injury by undergoing a transformation called "reactivity." Reactive astrocytes exhibit distinct and context-dependent cellular, molecular, and functional state changes that can either support or disturb tissue homeostasis. We recently identified a reactive astrocyte sub-state defined by interferon-responsive genes like Igtp, Ifit3, Mx1, and others, called interferon-responsive reactive astrocytes (IRRAs). To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this reactive sub-state. We induced IRRAs in immunopanned rodent astrocytes and human iPSC-differentiated astrocytes using TNF, IL1α, C1Q, and IFNβ and characterized their proteomic profile (both cellular and secreted) using unbiased quantitative proteomics. We identified 2335 unique cellular proteins, including IFIT2/3, IFITM3, OASL1/2, MX1/2/3, and STAT1. We also report that rodent and human IRRAs secrete PAI1, a serine protease inhibitor which may influence reactive states and functions of nearby cells. Finally, we evaluated how IRRAs are distinct from neurotoxic reactive astrocytes (NRAs). While NRAs are described by expression of the complement protein C3, it was not upregulated in IRRAs. Instead, we found ~90 proteins unique to IRRAs not identified in NRAs, including OAS1A, IFIT3, and MX1. Interferon signaling in astrocytes is critical for the antiviral immune response and for regulating synaptic plasticity and glutamate transport mechanisms. How IRRAs contribute to these functions is unknown. This study provides the basis for future experiments to define the functional roles of IRRAs in the context of neurodegenerative disorders.
PMID: 38031883
ISSN: 1098-1136
CID: 5616902

Video Analyses of Sudden Unexplained Deaths in Toddlers

Gould, Laura; Reid, Codi-Ann; Rodriguez, Alcibiades J; Devinsky, Orrin; ,
BACKGROUND AND OBJECTIVES/OBJECTIVE:More than 2,900 US children aged younger than 4 years die from unknown causes each year, accounting for more than 219,000 life years lost annually. They are mostly sleep-related and unwitnessed with unremarkable autopsies, limiting our understanding of death mechanisms. We sought to understand potential mechanisms of death by evaluating videos of sudden deaths in toddlers. METHODS:In our registry of 301 sudden unexplained child deaths, a series of 7 consecutively enrolled cases with home video recordings of the child's last sleep period were independently assessed by 8 physicians for video quality, movement, and sound. RESULTS:Four boys and 3 girls (13-27 months at death) with terminal videos shared similar demographic features to the 293 other registry cases without video recordings. Five video recordings were continuous and 2 were triggered by sound or motion. Two lacked audio. All continuous recordings included a terminal convulsive event lasting 8-50 seconds; 4 children survived for >2.5 minutes postconvulsion. Among discontinuous videos, time lapses limited review; 1 suggested a convulsive event. Six were prone with face down, and 1 had autopsy evidence of airway obstruction. Primary cardiac arrhythmias were not supported; all 7 children had normal cardiac pathology and whole-exome sequencing identified no known cardiac disease variants. DISCUSSION/CONCLUSIONS:Audio-visual recordings in 7 toddlers with unexplained sudden deaths strongly implicate that deaths were related to convulsive seizures, suggesting that many unexplained sleep-related deaths may result from seizures.
PMID: 38175965
ISSN: 1526-632x
CID: 5628382

Idiopathic Generalized Epilepsy: Misunderstandings, Challenges, and Opportunities

Devinsky, Orrin; Elder, Christopher; Sivathamboo, Shobi; Scheffer, Ingrid E; Koepp, Matthias J
The idiopathic generalized epilepsies (IGE) make up a fifth of all epilepsies, but <1% of epilepsy research. This skew reflects misperceptions: diagnosis is straightforward, pathophysiology is understood, seizures are easily controlled, epilepsy is outgrown, morbidity and mortality are low, and surgical interventions are impossible. Emerging evidence reveals that patients with IGE may go undiagnosed or misdiagnosed with focal epilepsy if EEG or semiology have asymmetric or focal features. Genetic, electrophysiologic, and neuroimaging studies provide insights into pathophysiology, including overlaps and differences from focal epilepsies. IGE can begin in adulthood and patients have chronic and drug-resistant seizures. Neuromodulatory interventions for drug-resistant IGE are emerging. Rates of psychiatric and other comorbidities, including sudden unexpected death in epilepsy, parallel those in focal epilepsy. IGE is an understudied spectrum for which our diagnostic sensitivity and specificity, scientific understanding, and therapies remain inadequate.
PMID: 38165295
ISSN: 1526-632x
CID: 5625962

Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis

Ziaei, Amin; Solomon, Olivia; Casper, T Charles; Waltz, Michael; Weinstock-Guttman, Bianca; Aaen, Greg; Wheeler, Yolanda; Graves, Jennifer; Benson, Leslie; Gorman, Mark; Rensel, Mary; Mar, Soe; Lotze, Tim; Greenberg, Benjamin; Chitnis, Tanuja; Waldman, Amy T; Krupp, Lauren; James, Judith A; Hart, Janace; Barcellos, Lisa F; Waubant, Emmanuelle
BACKGROUND AND OBJECTIVE/UNASSIGNED:Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS/UNASSIGNED:Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS/UNASSIGNED:(AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION/UNASSIGNED:POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.
PMID: 38332747
ISSN: 1477-0970
CID: 5632482

Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders

Liddelow, Shane A; Olsen, Michelle L; Sofroniew, Michael V
In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond to CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is a heterogeneous spectrum of potential changes that occur in a context-specific manner. These changes are determined by diverse signaling events and vary not only with the nature and severity of different CNS insults but also with location in the CNS, genetic predispositions, age, and potentially also with "molecular memory" of previous reactivity events. Astrocyte reactivity can be associated with both essential beneficial functions as well as with harmful effects. The available information is rapidly expanding and much has been learned about molecular diversity of astrocyte reactivity. Emerging functional associations point toward central roles for astrocyte reactivity in determining the outcome in CNS disorders.
PMID: 38316554
ISSN: 1943-0264
CID: 5632792

Reliable Prediction of Discharge Disposition Following Cervical Spine Surgery With Ensemble Machine Learning and Validation on a National Cohort

Feng, Rui; Valliani, Aly A; Martini, Michael L; Gal, Jonathan S; Neifert, Sean N; Kim, Nora C; Geng, Eric A; Kim, Jun S; Cho, Samuel K; Oermann, Eric K; Caridi, John M
STUDY DESIGN/METHODS:A retrospective cohort study. OBJECTIVE:The purpose of this study is to develop a machine learning algorithm to predict nonhome discharge after cervical spine surgery that is validated and usable on a national scale to ensure generalizability and elucidate candidate drivers for prediction. SUMMARY OF BACKGROUND DATA/BACKGROUND:Excessive length of hospital stay can be attributed to delays in postoperative referrals to intermediate care rehabilitation centers or skilled nursing facilities. Accurate preoperative prediction of patients who may require access to these resources can facilitate a more efficient referral and discharge process, thereby reducing hospital and patient costs in addition to minimizing the risk of hospital-acquired complications. METHODS:Electronic medical records were retrospectively reviewed from a single-center data warehouse (SCDW) to identify patients undergoing cervical spine surgeries between 2008 and 2019 for machine learning algorithm development and internal validation. The National Inpatient Sample (NIS) database was queried to identify cervical spine fusion surgeries between 2009 and 2017 for external validation of algorithm performance. Gradient-boosted trees were constructed to predict nonhome discharge across patient cohorts. The area under the receiver operating characteristic curve (AUROC) was used to measure model performance. SHAP values were used to identify nonlinear risk factors for nonhome discharge and to interpret algorithm predictions. RESULTS:A total of 3523 cases of cervical spine fusion surgeries were included from the SCDW data set, and 311,582 cases were isolated from NIS. The model demonstrated robust prediction of nonhome discharge across all cohorts, achieving an area under the receiver operating characteristic curve of 0.87 (SD=0.01) on both the SCDW and nationwide NIS test sets. Anterior approach only, age, elective admission status, Medicare insurance status, and total Elixhauser Comorbidity Index score were the most important predictors of discharge destination. CONCLUSIONS:Machine learning algorithms reliably predict nonhome discharge across single-center and national cohorts and identify preoperative features of importance following cervical spine fusion surgery.
PMID: 38285429
ISSN: 2380-0194
CID: 5627372

"Count on Sleep": an OSA awareness project update

Martin, Jennifer L; Rowley, James; Goel, Namni; Heller, H Craig; Gurubhagavatula, Indira; DelRosso, Lourdes M; Rodriguez, Alcibiades; Clark, Melissa; Rice-Conboy, Liz; ,
UNLABELLED:Obstructive sleep apnea (OSA) is a common, chronic sleep-related breathing disorder that affects approximately 12% of the US adult population. Greater public awareness of OSA is necessary to decrease the number of people with undiagnosed or untreated OSA and reduce the negative health consequences of unrecognized OSA. In 2021, the American Academy of Sleep Medicine initiated the "Count on Sleep" project in partnership with key stakeholders with the objective of raising the awareness of OSA among the public, health care providers, and public health officials. Four workgroups implemented strategies and completed tasks focused on increasing OSA awareness in their targeted areas to address the objectives of the project including (1) Public Awareness and Communications, (2) Provider Education, (3) Tool Development and Surveillance, and (4) a Strategic Planning workgroup that coordinated efforts across the project. Over the first 2 years, workgroups made substantial progress toward project goals including holding "listening sessions" with representatives of communities disproportionately affected by OSA and its consequences, developing resources for primary care providers that can be easily accessed and used in practice, and developing a brief survey for use in estimating and tracking OSA risk across the population. Over the first 2 project years, workgroups made significant progress in advancing efforts to increase awareness of OSA in US communities. The third year of the project will focus on dissemination of campaign materials and resources for all targeted groups, including the public, health care professionals, and public health professionals. CITATION/BACKGROUND:2024;20(2):303-307.
PMCID:10835781
PMID: 37861414
ISSN: 1550-9397
CID: 5633022

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis

Covey, Thomas J; Golan, Daniel; Sergott, Robert; Wilken, Jeffrey; Zarif, Myassar; Bumstead, Barbara; Buhse, MariJean; Kaczmarek, Olivia; Doniger, Glen M; Penner, Iris-Katharina; Hancock, Laura M; Bogaardt, Hans; Barrera, Marissa A; Morrow, Sarah A; Galetta, Steve; Gudesblatt, Mark
BACKGROUND:Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. OBJECTIVE:We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. RESULTS:Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. CONCLUSION/CONCLUSIONS:Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.
PMID: 38091086
ISSN: 1432-1459
CID: 5589302