Cannabidiol Modulates Excitatory-Inhibitory Ratio to Counter Hippocampal HyperactivityRosenberg EC, Chamberland S, Bazelot M, Nebet ER, Wang X, McKenzie S, Jain S, Greenhill S, Wilson M, Marley N, Salah A, Bailey S, Patra PH, Rose R, Chenouard N, Sun SD, Jones D, Buzsaki G, Devinsky O, Woodhall G, Scharfman HE, Whalley BJ, Tsein RW. Neuron. 2023;111:1-19. doi:10.1016/j.neuron.2023.01.018Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARg2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI’s pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI’s synaptic effects and dampening hyperexcitability.

Hidden Behavioral Fingerprints in EpilepsyGschwind T, Zeine A, Raikov I, Markowitz JE, Gillis WF, Felong S, Isom LL, Datta SR, Soltesz I. Neuron. 2023;111(9):1440-1452.e5. doi:10.1016/j.neuron.2023.02.003. PMID: 36841241; PMCID: PMC10164063Epilepsy is a major disorder affecting millions of people. Although modern electrophysiological and imaging approaches provide high-resolution access to the multi-scale brain circuit malfunctions in epilepsy, our understanding of how behavior changes with epilepsy has remained rudimentary. As a result, screening for new therapies for children and adults with devastating epilepsies still relies on the inherently subjective, semi-quantitative assessment of a handful of pre-selected behavioral signs of epilepsy in animal models. Here, we use machine learning-assisted 3D video analysis to reveal hidden behavioral phenotypes in mice with acquired and genetic epilepsies and track their alterations during post-insult epileptogenesis and in response to anti-epileptic drugs. These results show the persistent reconfiguration of behavioral fingerprints in epilepsy and indicate that they can be employed for rapid, automated anti-epileptic drug testing at scale.

[Box: see text]

[Box: see text]

Management of Refractory Status Epilepticus: An International Cohort Study (MORSE CODe) Analysis of Patients Managed in the ICUChiu WT, Campozano V, Schiefecker A, Rodriguez DR, Ferreira D, Headlee A, Zeidan S, Grinea A, Huang YH, Doyle K, Shen Q, Gómez D, Hocker SE, Rohaut B, Sonneville R, Hong C-T, Demeret S, Kurtz P, Maldonado N, Helbok R, Fernandez T, Claassen J. Neurology. 2022;99(11):e1191-e1201. doi:10.1212/WNL.0000000000200818Background and Objectives:Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings.Methods:Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge.Results:Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and >24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG <1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge.Discussion:Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE.Ketamine for Management of Neonatal and Pediatric Refractory Status EpilepticusJacobwitz M, Mulvihill C, Kaufman MC, Gonzalez AK, Resendiz K, MacDonald JM, Francoeur C, Helbig I, Topjian AA, Abend NS. Neurology. 2022;99(12):e1227-e1238. doi:10.1212/WNL.0000000000200889Background and Objectives:Few data are available regarding the use of anesthetic infusions for refractory status epilepticus (RSE) in children and neonates, and ketamine use is increasing despite limited data. We aimed to describe the impact of ketamine for RSE in children and neonates.Methods:Retrospective single-center cohort study of consecutive patients admitted to the intensive care units of a quaternary care children’s hospital treated with ketamine infusion for RSE.Results:Sixty-nine patients were treated with a ketamine infusion for RSE. The median age at onset of RSE was 0.7 years (interquartile range 0.15-7.2), and the cohort included 13 (19%) neonates. Three patients (4%) had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in 2 patients and delirium in 1 patient. Ketamine infusion was followed by seizure termination in 32 patients (46%), seizure reduction in 19 patients (28%), and no change in 18 patients (26%).Discussion:Ketamine administration was associated with few adverse events, and seizures often terminated or improved after ketamine administration. Further data are needed comparing first-line and subsequent anesthetic medications for treatment of pediatric and neonatal RSE.

[Box: see text]

[Box: see text]

Development and Application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE): Initial Results From a Multi-Center Study of Adults With Temporal Lobe EpilepsyMcDonald CR, Busch RM, Reyes A, Arrotta K, Barr W, Block C, Hessen E, Loring DW, Drane DL, Hamberger MJ, Wilson SJ, Baxendale S, Hermann BP. Neuropsychology. 2022. doi:10.1037/neu0000792Objective:To describe the development and application of a consensus-based, empirically driven approach to cognitive diagnostics in epilepsy research-The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) and to assess the ability of the IC-CoDE to produce definable and stable cognitive phenotypes in a large, multi-center temporal lobe epilepsy (TLE) patient sample.Method:Neuropsychological data were available for a diverse cohort of 2,485 patients with TLE across seven epilepsy centers. Patterns of impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) using two impairment thresholds (≤1.0 and ≤1.5 standard deviations below the normative mean). Cognitive phenotypes were derived across samples using the IC-CoDE and compared to distributions of phenotypes reported in existing studies.Results:Impairment rates were highest on tests of language, followed by memory, executive functioning, attention/processing speed, and visuospatial ability. Application of the IC-CoDE using varying operational definitions of impairment (≤1.0 and ≤1.5 SD) produced cognitive phenotypes with the following distribution: cognitively intact (30%-50%), single-domain (26%-29%), bi-domain (14%-19%), and generalized (10%-22%) impairment. Application of the ≤1.5 cutoff produced a distribution of phenotypes that was consistent across cohorts and approximated the distribution produced using data-driven approaches in prior studies.Conclusions:The IC-CoDE is the first iteration of a classification system for harmonizing cognitive diagnostics in epilepsy research that can be applied across neuropsychological tests and TLE cohorts. This proof-of-principle study in TLE offers a promising path for enhancing research collaborations globally and accelerating scientific discoveries in epilepsy.

The Association Between Early Childhood Onset Epilepsy and Attention-DeficitHyperactivity Disorder (ADHD) in 3237 Children and Adolescents With Autism SpectrumDisorder (ASD): A Historical Longitudinal Cohort Data Linkage StudyCarson L, Parlatini V, Safa T, Baig B, Shetty H, Phillips-Owen J, Prasad V, Downs J.Eur Child Adolesc Psychiatry. 2022. doi:10.1007/s00787-022-02041-3Children and young people with Autism Spectrum Disorder (ASD) have an increased riskof comorbidities, such as epilepsy and Attention-Deficit/Hyperactivity Disorder(ADHD). However, little is known about the relationship between early childhoodepilepsy (below age 7) and later ADHD diagnosis (at age 7 or above) in ASD. In thishistorical cohort study, we examined this relationship using an innovative datasource, which included linked data from routinely collected acute hospital paediatricrecords and childhood community and inpatient psychiatric records. In a large sampleof children and young people with ASD (N = 3237), we conducted a longitudinal analysisto examine early childhood epilepsy as a risk factor for ADHD diagnosis whileadjusting for potential confounders, including socio-demographic characteristics,intellectual disability, family history of epilepsy and associated physicalconditions. We found that ASD children and young people diagnosed with early childhoodepilepsy had nearly a twofold increase in risk of developing ADHD later in life, anassociation which persisted after adjusting for potential confounders (adjusted OR =1.72, CI95% = 1.13-2.62). This study suggests that sensitive monitoring of ADHDsymptoms in children with ASD who have a history of childhood epilepsy may beimportant to promote early detection and treatment. It also highlights how linkedelectronic health records can be used to examine potential risk factors over time formultimorbidity in neurodevelopmental conditions.

Development and Validation of the 5-SENSE Score to Predict Focality of theSeizure-Onset Zone as Assessed by StereoelectroencephalographyAstner-Rohracher A, Zimmermann G, Avigdor T, Abdallah C, Barot N, Brázdil M,Doležalová I, Gotman J, Hall JA, Ikeda K, Kahane P, Kalss G, Kokkinos V, Leitinger M,Mindruta I, Minotti L, Mizera MM, Oane I, Richardson M, Schuele SU, Trinka E, Urban A,Whatley B, Dubeau F, Frauscher B. JAMA Neurol. 2022;79(1):70-79.doi:10.1001/jamaneurol.2021.4405Importance:Stereoelectroencephalography (SEEG) has become the criterion standard in case ofinconclusive noninvasive presurgical epilepsy workup. However, up to 40% of patientsare subsequently not offered surgery because the seizure-onset zone is less focalthan expected or cannot be identified.Objective:To predict focality of the seizure-onset zone in SEEG, the 5-point 5-SENSE scorewas developed and validated.Design, Setting, and Participants:This was a monocentric cohort study for score development followed by multicentervalidation with patient selection intervals between February 2002 to October 2018and May 2002 to December 2019. The minimum follow-up period was 1 year. Patientswith drug-resistant epilepsy undergoing SEEG at the Montreal Neurological Institutewere analyzed to identify a focal seizure-onset zone. Selection criteria were 2 ormore seizures in electroencephalography and availability of completeneuropsychological and neuroimaging data sets. For validation, patients from 9epilepsy centers meeting these criteria were included. Analysis took place betweenMay and July 2021.Main Outcomes and Measures:Based on SEEG, patients were grouped as focal and nonfocal seizure-onset zone.Demographic, clinical, electroencephalography, neuroimaging, and neuropsychologydata were analyzed, and a multiple logistic regression model for developing a scoreto predict SEEG focality was created and validated in an independent sample.Results:A total of 128 patients (57 women [44.5%]; median [range] age, 31 [13-58] years)were analyzed for score development and 207 patients (97 women [46.9%]; median[range] age, 32 [16-70] years) were analyzed for validation. The score comprised thefollowing 5 predictive variables: focal lesion on structural magnetic resonanceimaging, absence of bilateral independent spikes in scalp electroencephalography,localizing neuropsychological deficit, strongly localizing semiology, and regionalictal scalp electroencephalography onset. The 5-SENSE score had an optimal mean (SD)probability cutoff for identifying a focal seizure-onset zone of 37.6 (3.5). Areaunder the curve, specificity, and sensitivity were 0.83, 76.3% (95%CI, 66.7-85.8),and 83.3% (95%CI, 72.30-94.1), respectively. Validation showed 76.0% (95%CI,67.5-84.0) specificity and 52.3% (95%CI, 43.0-61.5) sensitivity.Conclusion and Relevance:High specificity in score development and validation confirms that the 5-SENSEscore predicts patients where SEEG is unlikely to identify a focal seizure-onsetzone. It is a simple and useful tool for assisting clinicians to reduce unnecessaryinvasive diagnostic burden on patients and overutilization of limited health careresources.