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The risk factors for SUDEP are undoubtedly heterogenous but the main factor is the frequency of generalized tonic-clonic seizures with apnoea and/or cardiac abnormalities likely precipitating the lethal event. By its very nature modelling SUDEP experimentally is challenging, yet insights into the nature of the lethal event and precipitating factors are vital in order to understand and prevent fatalities. Acute animal models, which induce status epilepticus (SE), can be used to help understand pathophysiological processes during and following seizures, which sometimes lead to death. The most commonly used method to induce seizures and status epilepticus is systemic administration of an ictogenic agent. Microinjection of such agents into restricted regions within the brain induces a more localised epileptic focus and circumvents the risk of direct actions on cardiorespiratory control centres. Both approaches have revealed substantial cardiovascular and respiratory consequences, including death as a result of apnoea, which may be of central origin, obstructive due to laryngospasm or, at least in genetically modified mice, a result of spreading depolarisation to medullary respiratory control centres. SUDEP is by definition a result of epilepsy, which in turn is diagnosed on the basis of two or more unprovoked seizures. The incidence of tonic-clonic seizures is the main risk factor, raising the possibility that repeated seizures cause cumulative pathological and/or pathophysiological changes that contribute to the risk of SUDEP. Chronic experimental models, which induce repeated seizures that in some cases lead to death, do show progressive development of pathophysiological changes in the myocardium, e.g. prolongation of QT the interval of the ECG or, over longer periods, ventricular hypertrophy. However, the currently available evidence indicates that seizure-related deaths are primarily due to apnoeas, but cardiac factors, particularly cumulative cardiac pathophysiologies due to repeated seizures, are potential contributing factors., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Debates on six controversial topics on the network theory of epilepsy were held during two debate sessions, as part of the International Conference for Technology and Analysis of Seizures, 2019 (ICTALS 2019) convened at the University of Exeter, UK, September 2-5 2019. The debate topics were (1) From pathologic to physiologic: is the epileptic network part of an existing large-scale brain network? (2) Are micro scale recordings pertinent for defining the epileptic network? (3) From seconds to years: do we need all temporal scales to define an epileptic network? (4) Is it necessary to fully define the epileptic network to control it? (5) Is controlling seizures sufficient to control the epileptic network? (6) Does the epileptic network want to be controlled? This article, written by the organizing committee for the debate sessions and the debaters, summarizes the arguments presented during the debates on these six topics., Competing Interests: Declaration of Competing Interest HZ has a grant award from the NIH (USA) on network analysis for epilepsy surgery, and is named as an inventor on patents for monitoring and modulating human brain activity., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The pathophysiology leading to the development of status epilepticus (SE) remains a topic of significant scientific interest and clinical relevance. The use of multiple experimental and computational models has shown that SE relies on a complex interaction between mechanisms that operate at both a cellular and network level. In this narrative review, we will summarise the current knowledge on the factors that play a key role in allowing SE to develop and persist. These include pathological adaptations to changing ion dynamics, neuroenergetics, receptor expression and neurotransmission, which enable the brain to meet the extensive demands required to maintain ongoing synchronous hyperexcitability. We will examine how these processes converge to enable synapses to support seizure perpetuation. Lastly, we will use the concept of a perpetuating network to highlight how connections between brain regions can provide positive feedback loops that can serve to propagate seizure activity. We hope this review will collate the findings of previous research and help fuel further studies into the mechanisms that underlie how the brain can make the transition to SE., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019. Published by Elsevier Ltd.)