Seizure Mechanisms
There remains a pressing need to understand the initiation, propagation, and termination of seizures at the network level in different forms of epilepsy in order to devise better treatment strategies. Understanding how neuronal synchrony within a microcircuit reaches a critical threshold, subsequently allowing it to entrain larger populations of neurons, could suggest novel mechanisms that can be engaged to terminate a seizure. Although there are volumes of work on this topic over the decades,9-11 new advances in stratification of epilepsies through pharmacogenomics12 and genetic analysis13 could provide new understanding of mechanisms in models relevant for human disease. Advances in computational models have reached the point where both interictal and ictal activities can be reliably generated from the same network. The predictions of these models can now be practically verified.14,15 Additional insights may also follow from a determination of the relative contribution of shared cellular and network mechanisms to different models. Similarly, advances in modeling the process of epileptogenesis suggest interesting new mechanisms, yet highlight the complexity of the problem.16 These mechanisms could lead to the testing of more effective therapies.
Status epilepticus remains a clinical challenge, with a subset of patients proving refractory to multiple treatments17 despite the development and approval of new antiseizure medications (ASMs). The persistent seizures associated with this condition focus attention on how little we understand about the processes of seizure initiation, maintenance, and termination. Thus, insight into mechanisms that maintain hypersynchronous firing for prolonged durations in the face of adaptive changes, exhaustion of energy stores, and mounting inflammatory cascades may allow improved treatments that can stop ongoing seizures and status epilepticus. Although a variety of processes are considered relevant to status epilepticus,18-20 we still lack a clear assessment of the relative contributions of each one. New mechanism-based targets would improve our ability to effectively terminate status epilepticus.
An impressive amount of electrophysiological analysis of mechanisms that can lead to hypersynchronous firing has been performed either in vivo in adult animals or ex vivo in brain slices from rodents that range in age from adolescence to young adulthood. There is a growing opportunity to complement animal tissue work with acute and organotypic human brain slices obtained following surgical resection21,22 as well as in vivo recordings from depth electrode–implanted patients.23 However, there is a stark lack of information in some areas, for example, related to features of the neonatal brain that contribute to hypersynchronous activity, apart from changes in chloride (Cl−) gradients that render GABAergic transmission excitatory.24,25 Early-life seizures are an important therapeutic target because many epileptic encephalopathies become apparent early in life. In particular, understanding the mechanisms underlying hypersynchronous firing in neonatal brain could lead to the development of therapies that are more effective for neonatal seizures as opposed to simply modifying the dosing of drugs that showed a positive signal in clinical trials in adults with epilepsy. Strategies could involve use of repurposed drugs, specific combinations of therapies, or the development of new therapies, noting, however, the substantial hurdles for bringing to market drugs for a pediatric population. Although the first uncontrolled trial of the repurposed drug bumetanide did not show efficacy,26 this finding was controversial,27,28 and the results of a subsequent blinded controlled trial of bumetanide is reported to be more promising (clinicaltrials.govNCT00830531). To this end, new genetic models of ultrarare variants in genes capable of producing seizures and hyperexcitability may provide new models of mechanisms underlying development of an epileptic focus in neonatal animals. Indeed, multiple animal models of genetic epilepsies show seizure activity at an early age, providing an opportunity to study epilepsy in the developing brain.
The role of inflammation has been increasingly recognized in a wide range of neurological diseases, including epilepsy and status epilepticus.29-31 Neuroinflammation can impact network excitability in several ways, including activating microglia, reshaping synaptic input, and altering ion channel function. Thus, there is the potential to explore anti-inflammatory therapies for use in conjunction with conventional ASMs in the chronic therapy of epilepsies that are thought to be inflammatory in nature, such as Rasmussen encephalitis.32 In addition, the utility of some treatments for seizure categories not conventionally believed to be related to inflammatory mechanisms should be explored. This has the potential to perhaps reduce the refractory rate, or increase seizure control, for some groups of patients.
There is an emerging appreciation of autoimmune encephalitis33 that involves antibodies against epitopes in proteins that control neuronal excitability, such as the NMDA receptor,34 GAD65,35 and GABAB receptor subunits.36,37 Patients with antibody-mediated encephalitis often exhibit nonconvulsive seizures, in addition to memory loss, psychiatric symptoms, and other features. For some epitopes, preclinical data validate the immunoglobulin G fraction as causative for seizures. Treatment with immunotherapy can be effective, but additional therapeutic strategies are needed.36,38 The full extent of this clinical condition is just now becoming appreciated, and it remains almost certainly underdiagnosed at this point. Thus, future work should focus on earlier recognition of these presentations and early and robust diagnosis in order to achieve potentially effective treatment before the development of irreversible sequelae of neuroinflammation.