Neonatal Seizures.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures.

Selective Neuronal Knockout of STAT3 Function Inhibits Epilepsy Progression, Improves Cognition, and Restores Dysregulated Gene Networks in a Temporal Lobe Epilepsy Model.

OBJECTIVE: Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and hippocampal neural circuit remodeling that results in spontaneous seizures and cognitive dysfunction. Targeting these cascades may provide disease-modifying treatments for TLE patients. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors have emerged as potential disease-modifying therapies; a more detailed understanding of JAK/STAT participation in epileptogenic responses is required, however, to increase the therapeutic efficacy and reduce adverse effects associated with global inhibition. METHODS: We developed a mouse line in which tamoxifen treatment conditionally abolishes STAT3 signaling from forebrain excitatory neurons (nSTAT3KO). Seizure frequency (continuous in vivo electroencephalography) and memory (contextual fear conditioning and motor learning) were analyzed in wild-type and nSTAT3KO mice after intrahippocampal kainate (IHKA) injection as a model of TLE. Hippocampal RNA was obtained 24 h after IHKA and subjected to deep sequencing. RESULTS: Selective STAT3 knock-out in excitatory neurons reduced seizure progression and hippocampal memory deficits without reducing the extent of cell death or mossy fiber sprouting induced by IHKA injection. Gene expression was rescued in major networks associated with response to brain injury, neuronal plasticity, and learning and memory. We also provide the first evidence that neuronal STAT3 may directly influence brain inflammation. INTERPRETATION: Inhibiting neuronal STAT3 signaling improved outcomes in an animal model of TLE, prevented progression of seizures and cognitive co-morbidities while rescuing pathogenic changes in gene expression of major networks associated with epileptogenesis. Specifically targeting neuronal STAT3 may be an effective disease-modifying strategy for TLE. ANN NEUROL 2023;94:106-122.

Down-regulation of AMPA receptors and long-term potentiation during early epileptogenesis.

Epilepsy is a brain disorder characterized by the occurrence of recurrent spontaneous seizures. Behavioral disorders and altered cognition are frequent comorbidities affecting the quality of life of people with epilepsy. These impairments are undoubtedly multifactorial and the specific mechanisms underlying these comorbidities are largely unknown. Long-lasting alterations in synaptic strength due to changes in expression, phosphorylation, or function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) have been associated with alterations in neuronal synaptic plasticity. In particular, alterations in hippocampal long-term potentiation (LTP), a well-accepted model of learning and memory, have been associated with altered cognition in epilepsy. Here, we analyzed the effects of pilocarpine-induced status epilepticus (SE) on AMPARs to determine if alterations in AMPAR signaling might be one of the mechanisms contributing to altered cognition during epilepsy. We found alterations in the phosphorylation and plasma membrane expression of AMPARs. In addition, we detected altered expression of GRIP, a key scaffolding protein involved in the proper distribution of AMPARs at the neuronal cell surface. Interestingly, a functional analysis revealed that these molecular changes are linked to impaired LTP. Together, these observations suggest that seizure-induced alterations in the molecular machinery regulating AMPARs likely impact the neuron's ability to support synaptic plasticity that is required for learning and memory.

Altered Protein Profiles During Epileptogenesis in the Pilocarpine Mouse Model of Temporal Lobe Epilepsy.

Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor to the global burden of neurological disease. Although epilepsy can result from a variety of brain insults, in many cases the cause is unknown and, in a significant proportion of cases, seizures cannot be controlled by available treatments. Understanding the molecular alterations that underlie or are triggered by epileptogenesis would help to identify therapeutics to prevent or control progression to epilepsy. To this end, the moderate throughput technique of Reverse Phase Protein Arrays (RPPA) was used to profile changes in protein expression in a pilocarpine mouse model of acquired epilepsy. Levels of 54 proteins, comprising phosphorylation-dependent and phosphorylation-independent components of major signaling pathways and cellular complexes, were measured in hippocampus, cortex and cerebellum of mice at six time points, spanning 15 min to 2 weeks after induction of status epilepticus. Results illustrate the time dependence of levels of the commonly studied MTOR pathway component, pS6, and show, for the first time, detailed responses during epileptogenesis of multiple components of the MTOR, MAPK, JAK/STAT and apoptosis pathways, NMDA receptors, and additional cellular complexes. Also noted are time- and brain region- specific changes in correlations among levels of functionally related proteins affecting both neurons and glia. While hippocampus and cortex are primary areas studied in pilocarpine-induced epilepsy, cerebellum also shows significant time-dependent molecular responses.

Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

The path from scientific discovery to cures for epilepsy.

The epilepsies are a complex group of disorders that can be caused by a myriad of genetic and acquired factors. As such, identifying interventions that will prevent development of epilepsy, as well as cure the disorder once established, will require a multifaceted approach. Here we discuss the progress in scientific discovery propelling us towards this goal, including identification of genetic risk factors and big data approaches that integrate clinical and molecular 'omics' datasets to identify common pathophysiological signatures and biomarkers. We discuss the many animal and cellular models of epilepsy, what they have taught us about pathophysiology, and the cutting edge cellular, optogenetic, chemogenetic and anti-seizure drug screening approaches that are being used to find new cures in these models. Finally, we reflect on the work that still needs to be done towards identify at-risk individuals early, targeting and stopping epileptogenesis, and optimizing promising treatment approaches. Ultimately, developing and implementing cures for epilepsy will require a coordinated and immense effort from clinicians and basic scientists, as well as industry, and should always be guided by the needs of individuals affected by epilepsy and their families. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

Evidence for a non-canonical JAK/STAT signaling pathway in the synthesis of the brain's major ion channels and neurotransmitter receptors.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells. RESULTS: Here, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α). CONCLUSIONS: These findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease.

From molecules to medicines: the dawn of targeted therapies for genetic epilepsies.

Precision medicine is the treatment of patients with therapy targeted to their specific pathophysiology. This lofty ideal currently has limited application in clinical practice. However, new technological advances in epilepsy models and genomics suggest that the precision medicine revolution is closer than ever before. We are gaining an improved understanding of the true complexity underlying the pathophysiology of genetic epilepsies and the sources of phenotypic variation that continue to frustrate efforts at genotype-phenotype correlation. Conventional experimental models of epilepsy, such as mouse models and heterologous expression systems, have provided many of the advances in our understanding of genetic epilepsies, but fail to account for some of these complexities. Novel high-throughput models of epilepsy such as zebrafish and induced pluripotent stems cells can be combined with CRISPR-Cas9 gene editing techniques to explore the pathogenesis of a specific gene change and rapidly screen drug libraries for potential therapeutics. The knowledge gained from these models must be combined with thorough natural history studies to determine appropriate patient populations for pragmatic clinical trials. Advances in the 'omics', genetic epilepsy models and deep-phenotyping techniques have revolutionary translational research potential that can bring precision medicine to the forefront of clinical practice in the coming decade.

Nuclear Respiratory Factor 1 (NRF-1) Controls the Activity Dependent Transcription of the GABA-A Receptor Beta 1 Subunit Gene in Neurons.

While the exact role of ß1 subunit-containing GABA-A receptors (GABARs) in brain function is not well understood, altered expression of the ß1 subunit gene (GABRB1) is associated with neurological and neuropsychiatric disorders. In particular, down-regulation of ß1 subunit levels is observed in brains of patients with epilepsy, autism, bipolar disorder and schizophrenia. A pathophysiological feature of these disease states is imbalance in energy metabolism and mitochondrial dysfunction. The transcription factor, nuclear respiratory factor 1 (NRF-1), has been shown to be a key mediator of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Using a variety of molecular approaches (including mobility shift, promoter/reporter assays, and overexpression of dominant negative NRF-1), we now report that NRF-1 regulates transcription of GABRB1 and that its core promoter contains a conserved canonical NRF-1 element responsible for sequence specific binding and transcriptional activation. Our identification of GABRB1 as a new target for NRF-1 in neurons suggests that genes coding for inhibitory neurotransmission may be coupled to cellular metabolism. This is especially meaningful as binding of NRF-1 to its element is sensitive to the kind of epigenetic changes that occur in multiple disorders associated with altered brain inhibition.

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Identification and characterization of outcome measures reported in animal models of epilepsy: Protocol for a systematic review of the literature-A TASK2 report of the AES/ILAE Translational Task Force of the ILAE.

Current antiseizure therapy is ineffective in approximately one third of people with epilepsy and is often associated with substantial side effects. In addition, most current therapeutic paradigms offer treatment, but not cure, and no therapies are able to modify the underlying disease, that is, can prevent or halt the process of epileptogenesis or alleviate the cognitive and psychiatric comorbidities. Preclinical research in the field of epilepsy has been extensive, but unfortunately, not all the animal models being used have been validated for their predictive value. The overall goal of TASK2 of the AES/ILAE Translational Task Force is to organize and coordinate systematic reviews on selected topics regarding animal research in epilepsy. Herein we describe our strategy. In the first part of the paper we provide an overview of the usefulness of systematic reviews and meta-analysis for preclinical research and explain the essentials for their conduct. Then we describe in detail the protocol for a first systematic review, which will focus on the identification and characterization of outcome measures reported in animal models of epilepsy. The specific goals of this study are to define systematically the phenotypic characteristics of the most commonly used animal models, and to effectively compare these with the manifestations of human epilepsy. This will provide epilepsy researchers with detailed information on the strengths and weaknesses of epilepsy models, facilitating their refinement and future research. Ultimately, this could lead to a refined use of relevant models for understanding the mechanism(s) of the epilepsies and developing novel therapies.

WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities.

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery.

Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABAA receptor α1 subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in astrocytes. Analysis of the proteolytic machinery that cleaves proBDNF to produce mature BDNF demonstrates that acutely after SE there is a decrease in tissue plasminogen activator and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, which normalizes over the first week after SE. In vitro treatment of hippocampal slices from animals 24 h after SE with a PAI-1 inhibitor reduces proBDNF levels. These findings suggest that rapid proBDNF increases following SE are due in part to reduced cleavage, and that proBDNF may be part of the initial neurotrophin response driving intracellular signaling during the acute phase of epileptogenesis.

JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.

Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery.

Seizure-related regulation of GABAA receptors in spontaneously epileptic rats.

In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥24h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into the molecular changes that might help to explain how alterations in GABAAR function can be associated with differential seizure burden. Our findings also suggest that increased plasma membrane levels of GABAAR might act as a compensatory mechanism to more effectively maintain inhibitory function, repress hyperexcitability and reduce seizure burden. This study is an initial step towards a fuller characterization of the molecular events that trigger alterations in GABAergic neurotransmission during chronic epilepsy.

Effect of spontaneous seizures on GABAA receptor α4 subunit expression in an animal model of temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is frequently medically intractable and often progressive. Compromised inhibitory neurotransmission due to altered γ-aminobutyric acid (GABA)A receptor α4 subunit (GABAA Rα4) expression has been emphasized as a potential contributor to the initial development of epilepsy following a brain insult (primary epileptogenesis), but the regulation of GABAA Rα4 during chronic epilepsy, specifically, how expression is altered following spontaneous seizures, is less well understood. METHODS: Continuous video-electroencephalography (EEG) recordings from rats with pilocarpine-induced TLE were used to capture epileptic animals within 3 h of a spontaneous seizure (SS), or >24 h after the last SS, to determine whether recent occurrence of a seizure was associated with altered levels of GABAA Rα4 expression. We further evaluated whether this GABAA Rα4 plasticity is regulated by signaling mechanisms active in primary epileptogenesis, specifically, increases in brain-derived neurotrophic factor (BDNF) and early growth response factor 3 (Egr3). RESULTS: Elevated levels of GABAA Rα4 messenger RNA (mRNA) and protein were observed following spontaneous seizures, and were associated with higher levels of BDNF and Egr3 mRNA. SIGNIFICANCE: These data suggest that spontaneous, recurrent seizures that define chronic epilepsy may influence changes in GABAA Rα4 expression, and that signaling pathways known to regulate GABAA Rα4 expression after status epilepticus may also be activated after spontaneous seizures in chronically epileptic animals.

Effects of JAK2-STAT3 signaling after cerebral insults.

The JAK2-STAT3 signaling pathway has been shown to regulate the expression of genes involved in cell survival, cell proliferation, cell-cycle progression, and angiogenesis in development and after cerebral insults. Until recently, little has been known about the effects of this pathway activation after cerebral insults and if blocking this pathway leads to better recovery. This review exams the role of this pathway after 3 cerebral insults (traumatic brain injury, stroke, and status epilepticus).

The challenge and promise of anti-epileptic therapy development in animal models.

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies-complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.