Showing papers in "Epilepsy Currents in 2022"
TL;DR: This review will discuss progress, barriers, and next steps regarding the integration of brain network analysis into the medical and presurgical pipeline.
Abstract: Drug resistant epilepsy is a disorder involving widespread brain network alterations. Recently, many groups have reported neuroimaging and electrophysiology network analysis techniques to aid medical management, support presurgical planning, and understand postsurgical seizure persistence. While these approaches may supplement standard tests to improve care, they are not yet used clinically or influencing medical or surgical decisions. When will this change? Which approaches have shown the most promise? What are the barriers to translating them into clinical use? How do we facilitate this transition? In this review, we will discuss progress, barriers, and next steps regarding the integration of brain network analysis into the medical and presurgical pipeline.
11 citations
TL;DR: Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy, and if proven safe and effective, could be used to target lateral cortex as well as deep structures without causing damage.
Abstract: Patients with drug-resistant epilepsy (DRE) who are not surgical candidates have unacceptably few treatment options. Benefits of implanted electrostimulatory devices are still largely palliative, and many patients are not eligible to receive them. A new form of neuromodulation, low intensity focused ultrasound (LIFUS), is rapidly emerging, and has many potential intracranial applications. LIFUS can noninvasively target tissue with a spatial distribution of highly focused acoustic energy that ensures a therapeutic effect only at the geometric focus of the transducer. A growing literature over the past several decades supports the safety of LIFUS and its ability to noninvasively modulate neural tissue in animals and humans by positioning the beam over various brain regions to target motor, sensory, and visual cortices as well as frontal eye fields and even hippocampus. Several preclinical studies have demonstrated the ability of LIFUS to suppress seizures in epilepsy animal models without damaging tissue. Resection after sonication to the antero-mesial lobe showed no pathologic changes in epilepsy patients, and this is currently being trialed in serial treatments to the hippocampus in DRE. Low intensity focused ultrasound is a promising, novel, incisionless, and radiation-free alternative form of neuromodulation being investigated for epilepsy. If proven safe and effective, it could be used to target lateral cortex as well as deep structures without causing damage, and is being studied extensively to treat a wide variety of neurologic and psychiatric disorders including epilepsy.
9 citations
TL;DR: This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children.
Abstract: This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children (≥12 years and weighing ≥40 kg). Paxlovid is likely to be widely prescribed, and important considerations for patients on antiseizure medications (ASMs) include key contraindications and potential toxicity or dose adjustments while taking Paxlovid. This statement highlights concerns and provides information about their pharmacologic basis. Of particular concern, concomitant use of Paxlovid with the ASMs carbamazepine, phenobarbital, phenytoin, and primidone is contraindicated, because they are strong inducers of the CYP3A4 isozyme that metabolizes Paxlovid and thereby could cause loss of virologic response and development of resistance. Alternate oral or intravenous COVID-19 treatments should be considered. A second concern is that Paxlovid may increase the plasma concentrations of many ASMs, because it inhibits the CYP3A4 isozyme. ASMs that are metabolized, at least in part, by CYP3A4 include cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, ethosuximide, everolimus, felbamate, lacosamide, midazolam, oxcarbazepine, perampanel, stiripentol, tiagabine, and zonisamide. Patients receiving these medications may warrant closer monitoring while being treated with Paxlovid.
5 citations
TL;DR: This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid for the oral treatment of mild to moderate COVID-19 in adults and children.
Abstract: This American Epilepsy Society (AES) official statement provides information and preliminary guidance to Society members related to the U.S. Food & Drug Administration (FDA) December 22, 2021 Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children (≥12 years and weighing ≥40 kg). Paxlovid is likely to be widely prescribed, and important considerations for patients on antiseizure medications (ASMs) include key contraindications and potential toxicity or dose adjustments while taking Paxlovid. This statement highlights concerns and provides information about their pharmacologic basis. Of particular concern, concomitant use of Paxlovid with the ASMs carbamazepine, phenobarbital, phenytoin, and primidone is contraindicated, because they are strong inducers of the CYP3A4 isozyme that metabolizes Paxlovid and thereby could cause loss of virologic response and development of resistance. Alternate oral or intravenous COVID-19 treatments should be considered. A second concern is that Paxlovid may increase the plasma concentrations of many ASMs, because it inhibits the CYP3A4 isozyme. ASMs that are metabolized, at least in part, by CYP3A4 include cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, ethosuximide, everolimus, felbamate, lacosamide, midazolam, oxcarbazepine, perampanel, stiripentol, tiagabine, and zonisamide. Patients receiving these medications may warrant closer monitoring while being treated with Paxlovid.
4 citations
TL;DR: In this paper, the authors highlight how AI has been applied to neuroimaging in patients with epilepsy to enhance classification of clinical diagnosis, prediction of treatment outcomes, and the understanding of cognitive comorbidities.
Abstract: Artificial intelligence (AI) is increasingly used in medical image analysis and has accelerated scientific discoveries across fields of medicine. In this review, we highlight how AI has been applied to neuroimaging in patients with epilepsy to enhance classification of clinical diagnosis, prediction of treatment outcomes, and the understanding of cognitive comorbidities. We outline the strengths and shortcomings of current AI research and the need for future studies using large datasets that test the reproducibility and generalizability of current findings, as well as studies that test the clinical utility of AI approaches.
4 citations
TL;DR: It is argued that an increase in dendritic excitability, coordinated across the population of pyramidal cells, is a key stage in ictogenesis.
Abstract: Investigations into seizure initiation, in recent years, have focused almost entirely upon alterations of interneuronal function, chloride homeostasis, and extracellular potassium levels. In contrast, little attention has been directed toward a possible role of dendritic plateau potentials in the actual ictogenic transition, despite a substantial literature dating back 40 years regarding its importance generally in epilepsy. Here, we argue that an increase in dendritic excitability, coordinated across the population of pyramidal cells, is a key stage in ictogenesis.
3 citations
TL;DR: The histopathological and electroclinical features of existing FCD type II animal models are reviewed and the scientific and technical considerations, clinical applications, and limitations of current models are discussed.
Abstract: Focal cortical dysplasia (FCD) is a malformation of cortical development that is a prevalent cause of intractable epilepsy in children. Of the three FCD subtypes, understanding the etiology and pathogenesis of FCD type II has seen the most progress owing to the recent advances in identifying gene mutations along the mTOR signaling pathway as a frequent cause of this disorder. Accordingly, numerous animal models of FCD type II based on genetic manipulation of the mTOR signaling pathway have emerged to investigate the mechanisms of epileptogenesis and novel therapeutics for epilepsy. These include transgenic and in utero electroporation-based animal models. Here, we review the histopathological and electroclinical features of existing FCD type II animal models and discuss the scientific and technical considerations, clinical applications, and limitations of current models. We also highlight other models of FCD based on early life acquired factors.
2 citations
TL;DR: The hazard of incident cardiovascular disease is higher in those receiving eiASMs and the association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.
Abstract: Importance: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. Objective: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. Design, Setting, and Participants: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4–15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Exposures: Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Main Outcomes and Measures: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Results: Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19–50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06–1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28–1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52–3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. Conclusions and Relevance: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.
2 citations
TL;DR: Physicians should screen for AAS not only to assess the impact of epilepsy on daily life, but also as an interictal biomarker of ictal semiology and emotional network involvement at seizure onset.
Abstract: Anticipatory Anxiety of Seizures is Associated With Ictal Emotional Distress and Amygdala Onset Seizures Tarrada A, Aron O, Vignal JP, Ertan D, Maillard L, Hingray C. Epilepsia. 2022;63(5):1130-1140. doi:10.1111/epi.17215. Objective: Anxiety disorders are a frequent psychiatric condition in patients with epilepsy. Anticipatory anxiety of seizures (AAS) is described as a daily persistent fear or excessive worry of having a seizure. AAS seems to be related to “subjective ictal anxiety” reported by patients. The current study aimed to assess the association between objective ictal features and the presence of AAS. Methods: Ninety-one patients with drug-resistant focal epilepsy underwent a standardized psychiatric assessment, specific for epilepsy, and presurgical long-term video-electroencephalography (EEG) or stereo-EEG (SEEG). We compared seizure semiology and epilepsy features of patients with AAS (n = 41) to those of patients without AAS (n = 50). We analyzed emotional and motor behavior ictal signs as well as ictal consciousness. We further assessed amygdala ictal involvement in seizures recorded with SEEG (n = 28). Results: AAS was significantly associated with the presence of ictal emotional distress; negative emotional behavior (P < .01) and negative emotion were explicitly reported to the examiner during recording (P = .015), regardless of the ictal level of consciousness. Among the patients recorded with SEEG, we found a significant involvement of amygdala within the seizure onset zone (P < .01) for patients with AAS. Significance: Higher risk of developing AAS is associated with seizures expressing negative emotional symptoms, independently of ictal consciousness level. Persistent interictal fear of seizures might be viewed as the consequence of a reinforcement of the emotional networks secondary to amygdala involvement in seizures of temporal origin. Physicians should screen for AAS not only to assess the impact of epilepsy on daily life, but also as an interictal biomarker of ictal semiology and emotional network involvement at seizure onset.
2 citations
TL;DR: It is found that COVID-19 vaccination does not increase seizures in the majority of PWE and does not produce a pathognomonic EEG or seizure phenotype, but rather 1 that can be seen in other types of encephalopathy.
Abstract: Coronavirus 19 (COVID-19) has infected over 400 million people worldwide. Although COVID-19 causes predominantly respiratory symptoms, it can affect other organs including the brain, producing neurological symptoms. People with epilepsy (PWE) have been particularly impacted during the pandemic with decreased access to care, increased stress, and worsening seizures in up to 22% of them probably due to multiple factors. COVID-19 vaccines were produced in a record short time and have yielded outstanding protection with very rare serious side effects. Studies have found that COVID-19 vaccination does not increase seizures in the majority of PWE. COVID-19 does not produce a pathognomonic EEG or seizure phenotype, but rather 1 that can be seen in other types of encephalopathy. COVID-19 infection and its complications can lead to seizures, status epilepticus and post-COVID inflammatory syndrome with potential multi-organ damage in people without pre-existing epilepsy. The lack of access to care during the pandemic has forced patients and doctors to rapidly implement telemedicine. The use of phone videos and smart telemedicine are helping to treat patients during this pandemic and are becoming standard of care. Investment in infrastructure is important to make sure patients can have access to care even during a pandemic.
2 citations
TL;DR: In comatose survivors of cardiac arrest, the incidence of a poor neurologic outcome at 3 months did not differ significantly between a strategy of suppressing rhythmic and periodic EEG activity with the use of antiseizure medication for at least 48 hours plus standard care and standard care alone.
Abstract: Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J. N Engl J Med. 2022;386(8):724-734. doi:10.1056/NEJMoa2115998 Background: Whether the treatment of rhythmic and periodic electroencephalographic (EEG) patterns in comatose survivors of cardiac arrest improves outcomes is uncertain. Methods: We conducted an open-label trial of suppressing rhythmic and periodic EEG patterns detected on continuous EEG monitoring in comatose survivors of cardiac arrest. Patients were randomly assigned in a 1:1 ratio to a stepwise strategy of antiseizure medications to suppress this activity for at least 48 consecutive hours plus standard care (antiseizure-treatment group) or to standard care alone (control group); standard care included targeted temperature management in both groups. The primary outcome was neurologic outcome according to the score on the Cerebral Performance Category (CPC) scale at 3 months, dichotomized as a good outcome (CPC score indicating no, mild, or moderate disability) or a poor outcome (CPC score indicating severe disability, coma, or death). Secondary outcomes were mortality, length of stay in the intensive care unit (ICU), and duration of mechanical ventilation. Results: We enrolled 172 patients, with 88 assigned to the antiseizure-treatment group and 84 to the control group. Rhythmic or periodic EEG activity was detected a median of 35 hours after cardiac arrest; 98 of 157 patients (62%) with available data had myoclonus. Complete suppression of rhythmic and periodic EEG activity for 48 consecutive hours occurred in 49 of 88 patients (56%) in the antiseizure-treatment group and in 2 of 83 patients (2%) in the control group. At 3 months, 79 of 88 patients (90%) in the antiseizure-treatment group and 77 of 84 patients (92%) in the control group had a poor outcome (difference, 2 percentage points; 95% confidence interval, −7 to 11; P = 0.68). Mortality at 3 months was 80% in the antiseizure-treatment group and 82% in the control group. The mean length of stay in the ICU and mean duration of mechanical ventilation were slightly longer in the antiseizure-treatment group than in the control group. Conclusions: In comatose survivors of cardiac arrest, the incidence of a poor neurologic outcome at 3 months did not differ significantly between a strategy of suppressing rhythmic and periodic EEG activity with the use of antiseizure medication for at least 48 hours plus standard care and standard care alone.
TL;DR:
Abstract: Epileptic encephalopathy (EE) is characterized by seizures that respond poorly to antiseizure drugs, psychomotor delay, and cognitive and behavioral impairments. One of the frequently mutated genes in EE is KCNQ2, which encodes the Kv7.2 subunit of voltage-gated Kv7 potassium channels. Kv7 channels composed of Kv7.2 and Kv7.3 are enriched at the axonal surface, where they potently suppress neuronal excitability. Previously, we reported that the de novo dominant EE mutation M546V in human Kv7.2 blocks calmodulin binding to Kv7.2 and axonal surface expression of Kv7 channels via their intracellular retention. However, whether these pathogenic mechanisms underlie epileptic seizures and behavioral comorbidities remains unknown. Here, we report conditional transgenic cKcnq2+/M547V mice, in which expression of mouse Kv7.2-M547V (equivalent to human Kv7.2-M546V) is induced in forebrain excitatory pyramidal neurons and astrocytes. These mice display early mortality, spontaneous seizures, enhanced seizure susceptibility, memory impairment, and repetitive behaviors. Furthermore, hippocampal pathology shows widespread neurodegeneration and reactive astrocytes. This study demonstrates that the impairment in axonal
TL;DR: Cain et al. as mentioned in this paper showed that optogenetic stimulation of the superior/inferior colliculus in Cacna1aS218L mice induces severe seizures, and resulting spreading depolarization in the superior and inferior colliculi that propagates to the brainstem and correlates with the respiratory arrest followed by cardiac arrest.
Abstract: Hyperexcitable Superior Colliculus and Fatal Brainstem Spreading Depolarization in a Model of Sudden Unexpected Death in Epilepsy Cain SM, Bernier LP, Zhang Y, Yung AC, Kass J, Bohnet B, Yang Y, Gopaul R, Kozlowski P, MacVicar BA, Snutch TP. Brain Commun. 2022;4(2):fcac006. doi:10.1093/braincomms/fcac006 Cardiorespiratory arrest and death in mouse models of sudden unexpected death in epilepsy occur when spreading depolarization (SD) is triggered by cortical seizures and then propagates to the brainstem. However, the critical brain regions and the specific changes required to allow SD to propagate to the brainstem under the relatively rare circumstances leading to a fatal seizure are unknown. We previously found that following cortical seizure-inducing electrical stimulation, SD could occur in both the superior and inferior colliculi in Cacna1aS218L mice, but was never observed in wild-type animals or following non-seizure-inducing stimuli in Cacna1aS218L mice. Here, we show that optogenetic stimulation of the superior/inferior colliculi in Cacna1aS218L mice induces severe seizures, and resulting SD in the superior/inferior colliculi that propagates to the brainstem and correlates with the respiratory arrest followed by cardiac arrest. Further, we show that neurons of the superior colliculus in Cacna1aS218L mice exhibit hyperexcitable properties that we propose underlie a distinct susceptibility to SD. Our data suggest that the susceptibility of the superior colliculus to elicit fatal SD is a result of either genetic or seizure-related alterations within the superior colliculus that may involve changes to structure, connectivity and/or excitability.
TL;DR: Dahlin et al. as mentioned in this paper found that children with drug-resistant epilepsy are more likely to benefit from KD treatment when specific Bifidobacteria and TNF are elevated.
Abstract: Higher Levels of Bifidobacteria and Tumor Necrosis Factor in Children With Drug-Resistant Epilepsy Are Associated With Anti-Seizure Response to the Ketogenic Diet Dahlin M, Singleton SS, David JA, Basuchoudhary A, Wickström R, Mazumder R, Prast-Nielsen S. EBioMedicine. 2022;80:104061. doi:10.1016/j.ebiom.2022.104061 Background: Recently, studies have suggested a role for the gut microbiota in epilepsy. Gut microbial changes during ketogenic diet (KD) treatment of drug-resistant epilepsy have been described. Inflammation is associated with certain types of epilepsy and specific inflammation markers decrease during KD. The gut microbiota plays an important role in the regulation of the immune system and inflammation. Methods: 28 children with drug-resistant epilepsy treated with the ketogenic diet were followed in this observational study. Fecal and serum samples were collected at baseline and three months after dietary intervention. Findings: We identified both gut microbial and inflammatory changes during treatment. KD had a general anti-inflammatory effect. Novel bioinformatics and machine learning approaches identified signatures of specific Bifidobacteria and TNF (tumor necrosis factor) associated with responders before starting KD. During KD, taxonomic and inflammatory profiles between responders and non-responders were more similar than at baseline. Interpretation: Our results suggest that children with drug-resistant epilepsy are more likely to benefit from KD treatment when specific Bifidobacteria and TNF are elevated. We here present a novel signature of interaction of the gut microbiota and the immune system associated with anti-epileptic response to KD treatment. This signature could be used as a prognostic biomarker to identify potential responders to KD before starting treatment. Our findings may also contribute to the development of new anti-seizure therapies by targeting specific components of the gut microbiota. Funding: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Stiftelsen Sunnerdahls Handikappfond, Linnea & Josef Carlssons Foundation, and The McCormick Genomic & Proteomic Center.
TL;DR: This review explains how the scientific progress and clinical applications of metabolomics remain hampered by biological and technical challenges, and proposes best practices to overcome these challenges so that metabolomics can be used in a rigorous and effective manner to further epilepsy research.
Abstract: Metabolomics is the laboratory analysis and scientific study of the metabolome—that is, the entire collection of small molecule chemicals in an organism. The metabolome represents the functional state of an organism and provides a multifaceted readout of the aggregate activity of endogenous (cellular) and exogenous (environmental) processes. In this review, we discuss how the integrative and dynamic properties of the metabolome create unique opportunities to study complex pathologies that evolve and oscillate over time, like epilepsy. We explain how the scientific progress and clinical applications of metabolomics remain hampered by biological and technical challenges, and we propose best practices to overcome these challenges so that metabolomics can be used in a rigorous and effective manner to further epilepsy research.
TL;DR: Eleven patients from 8 families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations are identified, demonstrating crucial roles for Neurod2 in neocortical development, whose alterations can cause neuro developmental disorders including intellectual disabilities and ASD.
Abstract: Although the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KOmice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from 8 families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
TL;DR: The history of chemogenetics, their applications to date in epilepsy, and the potential (and potential hurdles to overcome) for future translation are highlighted.
Abstract: The fundamental commonality across pharmacotherapies for the epilepsies is the modulation of neuronal excitability. This poses a clear challenge—patterned neuronal excitation is essential to normal function, thus disrupting this activity leads to side effects. Moreover, the efficacy of current pharmacotherapy remains incomplete despite decades of drug development. Approaches that allow for the selective targeting of critical populations of cells and particular pathways in the brain have the potential to both avoid side effects and improve efficacy. Chemogenetic methods, which combine the selective expression of designer receptors with designer drugs, have rapidly grown in use in the neurosciences, including in epilepsy. This review will briefly highlight the history of chemogenetics, their applications to date in epilepsy, and the potential (and potential hurdles to overcome) for future translation.
TL;DR: In this article , the authors address the question "What causes seizures in NCC?" by summarizing and discussing the major theories that seek to explain the seizurogenic and epileptogenic processes in this disorder, and highlight the potential for recent advances in disease modeling to help accelerate progress in this area.
Abstract: Neurocysticercosis (NCC) is the most prevalent parasitic infection of the central nervous system. It is caused by the presence of larvae of the cestode Taenia solium in the brain. The most common symptom of NCC is seizures, and it is widely considered the world’s leading cause of preventable epilepsy. Despite the prevalence and impact of NCC, a thorough, mechanistic understanding of seizure generation is still lacking. In this review, we address the question “What causes seizures in NCC?” by summarizing and discussing the major theories that seek to explain the seizurogenic and epileptogenic processes in this disorder. In addition, we highlight the potential for recent advances in disease modeling to help accelerate progress in this area.
TL;DR: The rate of breastfeeding initiation in WWE was lower than in healthy women without epilepsy, and WWE were less likely to maintain breastfeeding at 6 weeks and 3 months postpartum.
Abstract: breastfeeding Objective: This study aimed to compare rates of breastfeeding initiation and maintenance in women with epilepsy (WWE) with those of the general population and to identify factors affecting breastfeeding patterns in WWE. Methods: We retrospectively reviewed data for the following variables in pregnant WWE (n = 102) and healthy women without epilepsy (n = 112): de-mographic characteristics (age, race, and ethnicity), epilepsy type (focal or generalized onset), anti-seizure medication(s), psychiatric comorbidities, postpartum seizure control, breastfeeding counseling, and lactation consultation. Fisher exact test and logistic regression analyses were performed to compare the rates of breastfeeding initiation and continuation in pregnant WWE with those of healthy pregnant women and to determine factors associated with rates of breastfeeding initiation and maintenance. Results: The rate of breastfeeding initiation in WWE was signi fi cantly lower than in healthy women without epilepsy (50.9% vs 87.6%), and WWE were less likely to maintain breastfeeding at 6 weeks (38.2%) and 3 months (36%) postpartum. Nearly half (53%) of WWE received antepartum breastfeeding counseling by their neurologists, and these women had higher odds of breastfeeding initiation and continuation (odds ratio [OR] = 2.53, 95% con fi dence interval [CI] = 1.14 – 5.72, P = .02). Postpartum consultation with a board-certi fi ed lactation consultant was associated
TL;DR: Puhahn-Schmeiser et al. as discussed by the authors investigated the role of Cajal-Retzius cells in the regulation of hippocampal microcircuits and specific types of behaviors.
Abstract: Granule Cell Dispersion in Two Mouse Models of Temporal Lobe Epilepsy and Reeler Mice Is Associated With Changes in Dendritic Orientation and Spine Distribution Puhahn-Schmeiser B, Kleemann T, Jabbarli R, Bock HH, Beck J, Freiman TM [published online ahead of print May 27, 2022]. Hippocampus. 2022. doi:10.1002/hipo.23447 Temporal lobe epilepsy is characterized by hippocampal neuronal death in CA1 and hilus. Dentate gyrus granule cells survive but show dispersion of the compact granule cell layer. This is associated with decrease of the glycoprotein Reelin, which regulates neuron migration and dendrite outgrow. Reelin-deficient (reeler) mice show no layering, their granule cells are dispersed throughout the dentate gyrus. We studied granule cell dendritic orientation and distribution of postsynaptic spines in reeler mice and two mouse models of temporal lobe epilepsy, namely the p35 knockout mice, which show Reelin-independent neuronal migration defects, and mice with unilateral intrahippocampal kainate injection. Granule cells were Golgi-stained and analyzed, using a computerized camera lucida system. Granule cells in naive controls exhibited a vertically oriented dendritic arbor with a small bifurcation angle if positioned proximal to the hilus and a wider dendritic bifurcation angle, if positioned distally. P35 knockout- and kainate-injected mice showed a dispersed granule cell layer, granule cells showed basal dendrites with wider bifurcation angles, which lost position-specific differences. Reeler mice lacked dendritic orientation. P35 knockout- and kainate-injected mice showed increased dendritic spine density in the granule cell layer. Molecular layer dendrites showed a reduced spine density in kainate-injected mice only, whereas in p35 knockouts no reduced spine density was seen. Reeler mice showed a homogenous high spine density. We hypothesize that granule cells migrate in temporal lobe epilepsy, develop new dendrites which show a spread of the dendritic tree, create new spines in areas proximal to mossy fiber sprouting, which is present in p35 knockout- and kainate-injected mice and loose spines on distal dendrites if mossy cell death is present, as it was in kainate-injected mice only. These results are in accordance with findings in epilepsy patients. Glutamate Released by Cajal-Retzius Cells Impacts Specific Hippocampal Circuits and Behaviors Anstötz M, Lee SK, Maccaferri G. Cell Rep. 2022;39(7):110822. doi:10.1016/j.celrep.2022.110822 The impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.
TL;DR: It is shown that retrovirus-driven expression of Ascl1 and Dlx2 in reactive hippocampal glia in situ, or in cortical astroglia grafted in the epileptic hippocampus, causes efficient reprogramming into iNs exhibiting hallmarks of interneurons, which show a significant reduction in both the number and cumulative duration of spontaneous recurrent hippocampal seizures.
Abstract: Reprogramming brain-resident glial cells into clinically relevant induced neurons (iNs) is an emerging strategy toward replacing lost neurons and restoring lost brain functions. A fundamental question is now whether iNs can promote functional recovery in pathological contexts. We addressed this question in the context of therapy-resistant mesial temporal lobe epilepsy (MTLE), which is associated with hippocampal seizures and degeneration of hippocampal GABAergic interneurons. Using a MTLE mouse model, we show that retrovirus-driven expression of Ascl1 and Dlx2 in reactive hippocampal glia in situ, or in cortical astroglia grafted in the epileptic hippocampus, causes efficient reprogramming into iNs exhibiting hallmarks of interneurons. These induced interneurons functionally integrate into epileptic networks and establish GABAergic synapses onto dentate granule cells. MTLE mice with GABAergic iNs show a significant reduction in both the number and cumulative duration of spontaneous recurrent hippocampal seizures. Thus glia-to-neuron reprogramming is a potential disease-modifying strategy to reduce seizures in therapy-resistant epilepsy.
TL;DR: The results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition.
Abstract: Patients with epilepsy report that sleep deprivation is a common trigger for breakthrough seizures. The basic mechanism of this phenomenon is unknown. In the Kv1.1 / mouse model of epilepsy, daily sleep deprivation indeed exacerbated seizures though these effects were lost after the third day. Sleep deprivation also accelerated mortality in ∼ 52% of Kv1.1 / mice, not observed in controls. Voltage-clamp experiments on the day after recovery from sleep deprivation showed reductions in GABAergic tonic inhibition in dentate granule cells in epileptic Kv1.1 / mice. Our results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition.
TL;DR: An optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats is developed and a core of slow-migrating hippocampal activity was identified in both non-kindled and kindled seizures, revealing a novel mechanism of seizure sustainment and propagation.
Abstract: Repeated seizure activity can lead to long-term changes in seizure dynamics and behavior. However, resulting changes in brain-wide dynamics remain poorly understood. This is due partly to technical challenges in precise seizure control and in vivo whole-brain mapping of circuit dynamics. Here, we developed an optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats. We then combined fMRI with electrophysiology to track brain-wide circuit dynamics resulting from nonafterdischarge (AD)-generating stimulations and individual convulsive seizures. Kindling induced widespread increases in nonADgenerating stimulation response and ipsilateral functional connectivity and elevated anxiety. Individual seizures in kindled animals showed more significant increases in brain-wide activity and bilateral functional connectivity. Onset time quantification provided evidence for kindled seizure propagation from the ipsilateral to the contralateral hemisphere. Furthermore, a core of slow-migrating hippocampal activity was identified in both non-kindled and kindled seizures, revealing a novel mechanism of seizure sustainment and propagation.
TL;DR: Mortality is increased in epilepsy, but the important issue is that a proportion of epilepsy-related death is potentially preventable by optimized therapy and therefore needs to be identi fi ed.
Abstract: Objective: This study was undertaken to investigate the trends and mechanisms of epilepsy-related deaths in Scotland, highlighting the proportion that were potentially avoidable. Methods: This was a retrospective observational data-linkage study of administrative data from 2009 to 2016. We linked nationwide data encompassing mortality records, hospital admissions, outpatient attendance, antiepileptic drug (AED) prescriptions and regional primary care attendances. Adults (aged ≥ 16 years) suffering epilepsy-related death were identi fi ed for study using International Classi fi cation of Diseases, 10th Revision coding combined with AED prescriptions. We reported epilepsy-related mortality rate (MR), age-speci fi c mortality ratios, multiple cause-of-death frequencies and the proportion of potentially avoidable deaths (identi fi ed as those with an underlying cause listed as avoidable by the Of fi ce for National Statistics). Results: A total of 1921 epilepsy-related deaths were identi fi ed across Scotland; 1185 (62%) decedents were hospitalized for seizures in the years leading up to death, yet only 518 (27%) were seen in a neurology clinic during the same period. MR remained unchanged over time, ranging from 5.9 to 8.7 per 100 000 Scottish population (95% con fi dence interval [CI] = (cid:1) .05 to .66 per 100 000 for annual change in MR). Mortality ratios were signi fi cantly increased in young adults aged 1654 years (2.3, 95% CI = 1.82.8), peaking at age 1624 years (5.3, 95% CI = 1.88.8). Sudden unexpected death in epilepsy (SUDEP) constituted 30% of the 553 young adult epilepsy-related deaths, with several other non-SUDEP fatal mechanisms identi fi ed including aspiration pneumonia, cardiac arrest, AED or narcotic poisoning, drowning and alcohol dependence. Seventy-six percent of young adult epilepsy-related deaths were potentially avoidable. Signi fi cance: Epilepsy-related deaths are a major public health problem in Scotland, given that they are not reducing, people are dying young and many deaths are potentially avoidable. SUDEP is only one of several important mechanisms by which epilepsy-related deaths are occurring in young adults. Services may need to be re-evaluated to improve specialist referral following seizure-related hospital admissions. Background and Objectives: Mortality is increased in epilepsy, but the important issue is that a proportion of epilepsy-related death is potentially preventable by optimized therapy and therefore needs to be identi fi ed. A new systematic classi fi cation of epilepsy-related mortality has been suggested to identify these preventable deaths. We applied this classi fi cation to an analysis of premature mortality in persons with epilepsy who were < 50 years of age. Methods: The study was a population-based retrospective cohort of all Danish citizens with and without epilepsy 1 to 49 years of age during 2007 to 2009. Information on all deaths was retrieved from the Danish Cause of Death Registry, autopsy reports, death certi fi cates and the Danish National Patient Registry. The primary cause of death in persons with epilepsy was evaluated independently by 3 neurologists, 1 neuro-paediatrician and 2 cardiologists. In case of uncertainty, a pathologist was consulted. All deaths were
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TL;DR: Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles.
Abstract: Thalamic Deep Brain Stimulation Modulates Cycles of Seizure Risk in Epilepsy Gregg NM, Sladky V, Nejedly P, et al. Sci Rep. 2021;11:24250. doi:10.1101/2021.08.25.21262616. Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and multiday cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and multiday IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and multiday (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.
TL;DR: Unsupervised machine learning is utilized to estimate latent relations (or disease factors) from 3T multimodal MRI features representing whole-brain patterns of structural pathology in 82 TLE patients, providing a novel appraisal of the continuum of interindividual variability.
Abstract: In drug-resistant temporal lobe epilepsy (TLE), precise predictions of drug response, surgical outcome, and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant “one-size-fits-all” group-level analytical approaches that do not allow parsing interindividual variations along the disease spectrum. Conversely, analyzing interpatient heterogeneity is increasingly recognized as a step toward person-centered care. Here, we utilized unsupervised machine learning to estimate latent relations (or disease factors) from 3T multimodal MRI features (cortical thickness, hippocampal volume, FLAIR, T1/FLAIR, and diffusion parameters) representing whole-brain patterns of structural pathology in 82 TLE patients. We assessed the specificity of our approach against ageand sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably coexpressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor-1), bilateral paralimbic and hippocampal gliosis (Factor-2), bilateral neocortical atrophy (Factor-3), and bilateral white matter microstructural alterations (Factor-4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is likely determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics.
TL;DR: Hakeem et al. as discussed by the authors developed and validated a deep learning model using readily available clinical information to predict treatment success with the first antiseizure medication for individual patients, which is defined as complete seizure freedom for the first year of treatment while taking the first ASM.
Abstract: Development and Validation of a Deep Learning Model for Predicting Treatment Response in Patients With Newly Diagnosed Epilepsy Hakeem H, Feng W, Chen Z, Choong J, Brodie MJ, Fong SL, Lim KS, Wu J, Wang X, Lawn N, Ni G. JAMA Neurol. 2022;79(10):986-996. doi:10.1001/jamaneurol.2022.2514 Importance: Selection of antiseizure medications (ASMs) for epilepsy remains largely a trial-and-error approach. Under this approach, many patients have to endure sequential trials of ineffective treatments until the “right drugs” are prescribed. Objective: To develop and validate a deep learning model using readily available clinical information to predict treatment success with the first ASM for individual patients. Design, Setting, and Participants: This cohort study developed and validated a prognostic model. Patients were treated between 1982 and 2020. All patients were followed up for a minimum of 1 year or until failure of the first ASM. A total of 2404 adults with epilepsy newly treated at specialist clinics in Scotland, Malaysia, Australia, and China between 1982 and 2020 were considered for inclusion, of whom 606 (25.2%) were excluded from the final cohort because of missing information in 1 or more variables. Exposures: One of 7 antiseizure medications. Main Outcomes and Measures: With the use of the transformer model architecture on 16 clinical factors and ASM information, this cohort study first pooled all cohorts for model training and testing. The model was trained again using the largest cohort and externally validated on the other 4 cohorts. The area under the receiver operating characteristic curve (AUROC), weighted balanced accuracy, sensitivity, and specificity of the model were all assessed for predicting treatment success based on the optimal probability cutoff. Treatment success was defined as complete seizure freedom for the first year of treatment while taking the first ASM. Performance of the transformer model was compared with other machine learning models. Results: The final pooled cohort included 1798 adults (54.5% female; median age, 34 years [IQR, 24-50 years]). The transformer model that was trained using the pooled cohort had an AUROC of 0.65 (95% CI, 0.63-0.67) and a weighted balanced accuracy of 0.62 (95% CI, 0.60-0.64) on the test set. The model that was trained using the largest cohort only had AUROCs ranging from 0.52 to 0.60 and a weighted balanced accuracy ranging from 0.51 to 0.62 in the external validation cohorts. Number of pretreatment seizures, presence of psychiatric disorders, electroencephalography, and brain imaging findings were the most important clinical variables for predicted outcomes in both models. The transformer model that was developed using the pooled cohort outperformed 2 of the 5 other models tested in terms of AUROC. Conclusions and Relevance: In this cohort study, a deep learning model showed the feasibility of personalized prediction of response to ASMs based on clinical information. With improvement of performance, such as by incorporating genetic and imaging data, this model may potentially assist clinicians in selecting the right drug at the first trial.
TL;DR: Findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection, and Regulation of SynGap-αexpression or function may be a viable therapeutic strategy to broadly improve cognitivefunction and mitigate seizure.
Abstract: Endogenous Syngap Alpha Splice Forms Promote Cognitive Function and Seizure Protection M Kilinc, V Arora, TK Creson, et al. eLife. 2022;11:e75707. doi:10.7554/eLife.75707. Loss-of-function variants in SYNGAP cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-αexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.
TL;DR: The results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of manyFastigial output channels, and selective modulation of the fastigual output channel to the central lateral thalamus, specifically, is sufficient for seizure control.
Abstract: Distinct Fastigial Output Channels and Their Impact on Temporal Lobe Seizures Streng ML, Tetzlaff MR, Krook-Magnuson E. 2021. J. Neurosci. 41(49):10091-10107. doi:10.1523/JNEUROSCI.0683-21.2021. Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with important consequences for therapeutic interventions.
TL;DR: Madar et al. as mentioned in this paper showed that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model).
Abstract: Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy Madar AD, Pfammatter JA, Bordenave J, Plumley EI, Ravi S, Cowie M, Wallace EP, Hermann BP, Maganti RK, Jones MV. J Neurosci. 2021;41(46):9669-9686. doi:10.1523/JNEUROSCI.2439-20.2021 In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.