Since the use of bromide in the mid-nineteenth century and the introduction of phenobarbital in 1912, epilepsy has been treated by chronic administration of small-molecule antiseizure agents that reduce the occurrence of seizures and in some cases eliminate seizures—as long as a patient adheres to daily treatment. In the nearly 170 years of modern epilepsy therapy, about 30 distinct molecular entities have been introduced into practice, with a marked acceleration in introductions in the past two decades. With the possible exception of cenobamate that has demonstrated a uniquely high rate of seizure freedom (see Chapter 66, this volume; Elizebath et al., 2021), the availability of an increasing number of antiseizure agents has not led to better seizure control for the typical patient with epilepsy (Chen et al., 2018). This is the case, even though many of the newer drugs act by unique mechanisms (Sills and Rogawski, 2020). None of the available drugs specifically addresses the underlying molecular and cellular basis of any form of epilepsy, with the exception of the mTOR inhibitor everolimus, which is used in the treatment of focal seizures in the prototypic mTORopathy tuberous sclerosis complex (TSC). Many researchers believe that the failure to identify antiseizure medications with improved efficacy is because animals with spontaneous seizures and pathophysiologies relevant to human epilepsies have generally not been used for drug screening. As discussed in Chapter 64 by Metcalf et al., new models have been created that address these issues. Such models have greater construct validity in relation to the epilepsies for which treatments are sought and can be expected to play an increasing role in the identification of potential treatment agents. It remains to be determined which of these models will prove to be translationally relevant.

Ultimately, to treat any form of epilepsy and its associated comorbidities fully, a therapeutic approach should address the underlying disease mechanisms. This edition of Jasper’s Basic Mechanisms of the Epilepsies marks the beginning of a new era where credible disease-specific strategies are moving from the laboratory to the clinic. Developing such therapies requires an understanding of the molecular and cellular changes in the brain responsible for the epilepsy. This knowledge has largely come from genetics (see Section 6 of this volume). It also requires technologies to correct or abrogate the genetic defects or their consequences, and, equally important, methods to deliver those technologies to the appropriate brain regions. Since the last edition of Jasper’s, major scientific advances on all of these fronts have occurred, making it clear that the goal of treating the underlying defect is attainable, at least for certain monogenic epilepsies. For the far more common epilepsies that have polygenic inheritance or are acquired, a clear path to molecular treatments and cures is still elusive.

The Epilepsy Therapeutics section of this Jasper’s edition includes traditional topics such as methods to identify antiseizure agents and new molecular targets that could potentially be addressed with conventional small-molecule drugs or perhaps with genetic therapies. Several chapters also discuss the two major but to date unsolved problems in epilepsy therapy: first, how to identify drugs that effectively prevent seizures in patients who are deemed “pharmacoresistant” and, second, how to prevent the occurrence of epilepsy in those that are at risk as a result of environmental factors such as brain trauma or infection, or due to a genetic factor. The section also includes chapters on entirely new but highly promising approaches, including oligonucleotide and gene therapies.

Section 8 begins with the chapter by Metcalf et al. (Chapter 64) discussing various new models for therapy discovery, including models that mimic specific difficult-to-treat epilepsies. These range from zebrafish and Drosophila models to mice with genetic mutations, mice that have experienced infection with an encephalomyelitis virus, and chronic epilepsy induced by status epilepticus. The authors raise the intriguing possibility that patient-derived induced pluripotent stem cells could be used to identify personalized patient-specific therapies. Dedeurwaerdere et al. (Chapter 65) then expand on a theory of antiseizure drug pharmacoresistance, originally proposed by Rogawski and Johnson (2008) and referred to as the “intrinsic severity hypothesis,” in which it is postulated that there are neurobiological factors that cause epilepsy to be more or less severe. Empirical observations indicate that more severe epilepsies are more likely to be resistant to treatment. It therefore follows that an understanding of the factors that regulate epilepsy severity should allow the conceptualization of strategies to overcome drug refractoriness. Guignet and White (Chapter 66) next discuss various rodent models that may identify drugs with the potential to overcome antiseizure drug pharmacoresistance.

It has been a disappointment to find that the available symptomatic treatments do not in most instances alter the course of epilepsy. An encouraging exception has been the recent discovery from the EPISTOP trial in TSC that vigabatrin introduced at the start of epileptiform activity and before the onset of seizures can delay the beginning of epilepsy and prevent the occurrence of infantile spasms (Kotulska et al., 2021). Disease-modifying therapies have long been sought that interrupt the development of acquired epilepsies caused by brain insults. Löscher (Chapter 67) proposes that rationally chosen drug combinations may lead to practical antiepileptogenic therapies to prevent the occurrence of such epilepsies. Febrile status epilepticus (FSE) represents a special situation where seizures are associated with a clear risk of enduring cognitive deficits and the development of temporal lobe epilepsy. Garcia-Curran and Baram (Chapter 69) review established treatments to terminate ongoing FSE and discuss current research on the diverse mechanisms underlying the long-term consequences of the seizures. Their studies suggest treatments that could be administered after the seizures to prevent the alterations in brain circuitry responsible for the adverse long-terms effects of FSE.

Prince and Gu (Chapter 68) provide an update on studies addressing the pathophysiological mechanisms of epileptogenesis in the undercut model of traumatic epilepsy, and they describe evidence supporting α2δ-1 and BDNF as treatment targets. Studies in transgenic mouse epilepsy models suggest that these antiepileptogenic approaches may be applicable more broadly to epilepsies than just those resulting from brain injury.

A group of chapters then considers promising molecular targets for therapies. This begins with a review by Joshi and Kapur (Chapter 70) on the roles of glutamate-mediated neurotransmission and ionotropic glutamate receptors in seizures, which leads to a proposal to study glutamate receptor antagonists, including the NMDA-receptor antagonist ketamine, in clinical trials to assess their potential to more effectively terminate acute seizures with improved long-term outcomes, including a reduction in epileptogenesis.

Staley next (Chapter 71) provides an in-depth discussion of anion dynamics in neurons as mediated by GABA_A receptors and chloride transporters, and explains the roles of anions in promoting and suppressing seizures. A key new concept is the presence of chloride microdomains, which suggests the possibility of new therapeutic strategies that are based on altering local microdomain chloride so as to tune the functional activity of GABA_A receptors in a highly selective manner.

More clinically used antiseizure medications act via modulation of voltage-gated sodium channels than by any other target. Conventional sodium channel–blocking antiseizure medications are nonselective, and because the pore domain where these drugs bind is conserved in the nine sodium channel α-subunits, it has not been possible to target specific sodium channel isoforms. As discussed in Chapter 72 by Johnson et al., it has recently been recognized that time-dependent and voltage-dependent sodium channel inhibition can be obtained by drug binding to an extracellular site on the domain IV voltage sensor (VSD4), which differs substantially in the common brain sodium channel isoform NaV1.6 from that of other sodium channel α-subunits. This breakthrough has enabled the discovery of highly selective sodium channel blockers, including a potent NaV1.6 blocker that is currently in clinical trials. This compound may have greater tolerability and improved efficacy compared with conventional sodium-channel-blocking antiseizure medications since it may be possible to achieve greater degrees of NaV1.6 block without causing adverse effects mediated by inhibition of other sodium channel isoforms that are expressed in peripheral tissues and brain. In addition, as discussed below, the compound may have utility in the treatment of SCN8A developmental and epileptic encephalopathy (DEE).

In Chapter 73, Engel and Dale discuss purinergic receptors and their, respectively, proconvulsant and anticonvulsant ligands, ATP and adenosine, whose extracellular levels in brain are increased during seizures. There is a long history of attempts to develop agonists of adenosine-sensitive P1 receptors and agents that increase adenosine availability, such as adenosine kinase antagonists, for epilepsy therapy. These attempts have been stymied by adverse peripheral actions inasmuch as P1 receptors have a prominent role in cardiovascular function. Engel and Dale focus the bulk of their attention on ATP-sensitive metabotropic P2Y and ionotropic P2X receptors, which have been proposed as antiseizure targets only in the past 10 years. Among the ATP-responsive receptors, P2X7 has been most intensively studied. While block of P2X7 may suppress seizures in some circumstances, the potential of P2X7 as an anticonvulsant target is uncertain since anticonvulsant effects of P2X7 receptor antagonists are not observed in the major translationally validated seizure models. The authors note that P2 receptors engage inflammatory mechanisms, including through effects on microglia, and that a better understanding of such actions could be relevant to the treatment of seizures and epileptogenesis.

All clinically used antiseizure medications are believed to act through effects on brain excitability mechanisms. A new direction for epilepsy therapy is proposed by Vezzani et al. in Chapter 74, which discusses potential anti-inflammatory treatment strategies. Neuroinflammation is now well recognized to be present in the epileptic brain and to potentially play a role in epileptic brain injury. Moreover, there is evidence from studies in animals that certain specific anti-inflammatory treatments can inhibit seizures, have antiepileptogenic actions, and also impact epilepsy comorbidities. The potential of anti-inflammatory strategies has been reinforced by mostly anecdotal reports of improved clinical outcomes with specific anti-inflammatory therapies in patients with focal epilepsy and refractory status epilepticus (FIRES and NORSE). Agents that have been studied include VX-765 (belnacasan), an inhibitor of IL-1β synthesis; anakinra, which binds to the IL-1R and interferes with the binding of IL-1α and IL-1β; and the anti-α4-integrin antibody natalizumab. Ongoing research is focused on assessing how these and other anti-inflammatory drugs can be applied in epilepsy treatment.

Recent advances in epilepsy genetics have made it possible to devise therapies to correct the causative molecular defects in certain genetic epilepsies. Such targeted therapies were inconceivable only a few years ago but are now routinely studied in the laboratory and several have entered clinical trials. Some targeted therapies are small molecules that act on neuronal ion channels as do many conventional antiseizure drugs. However, unlike conventional agents that are used without consideration of the underlying pathophysiology, the targeted drugs are intended to modify ion channel function to specifically address disease mechanisms. For example, in KCNQ2 DEE, Kv7 (encoded by KCNQ) potassium channel opener drugs are being investigated based on their potential to functionally reverse the loss of function in Kv7.2 caused by certain KCNQ mutations. In a similar vein, in SCN8A DEE caused by gain-of-function Nav1.6 mutations, selective Nav1.6 sodium channel blockers may functionally correct the disease pathophysiology (Meisler, 2019). Other targeted therapies address the genetic basis of the epilepsy. Such therapies range from oligonucleotides that require periodic dosing to engineered viral gene therapies that are potentially curative following a single dose. A series of chapters considers these approaches, which are expected to be actively investigated in the years ahead.

Isom and Knupp (Chapter 75) consider the TANGO antisense oligonucleotide (ASO) approach to treating Dravet syndrome associated with haploinsufficiency of the Nav1.1 voltage-activated sodium channel encoded by the SCN1A gene. TANGO ASOs have been devised that bind to pre-RNA transcribed from the functional copy of the gene to enhance the abundance of productive SCN1A mRNAs and increase Nav1.1 protein expression. Intrathecal lumbar bolus administration of a TANGO ASO in nonhuman primates has been shown to variably enhance Nav1.1 expression in different brain regions, and early results following monthly intrathecal administration in children with Dravet syndrome have been promising.

Goodspeed et al. (Chapter 76) discuss the implications of genetic diagnosis for the selection of therapies and the various approaches to gene therapy with viral vectors, including gene replacement, gene silencing, and gene editing. They explain the function of recombinant AAV (rAAV), which is currently the most widely used vector for gene delivery to the central nervous system due to its safety and high efficiency. In addition to gene therapies intended to correct specific genetic defects, Goodspeed et al. consider the potential of gene therapy to deliver neuroactive substances that suppress seizures, including adenosine, galanin, and neuropeptide Y. These approaches have been found to be effective in animal models but have not been applied in the clinic.

Kullmann (Chapter 77) further expands on gene therapies with viral vectors. The chapter considers how cell-specific expression can be achieved and discusses strategies to alter ion channel expression to reduce epileptic hyperexcitability, including overexpressing voltage-activated potassium channels or inhibiting the expression of NMDA receptors. Kullmann further considers methods to regulate the expression of the relevant ion channel such as with chemogenetics so as to optimize excitation/inhibition balance to produce the desired therapeutic effect and avoid side effects.

Cell transplantation therapies are considered by Bröer and Vogt (Chapter 78). The authors focus on interneurons derived from the medial ganglionic eminence (MGE), which in animal models were demonstrated to integrate into epileptic networks, form synapses with host neurons, increase inhibitory tone, and effectively reduce seizure frequency for extended periods. To advance this approach to a treatment for human pharmacoresistant epilepsy, protocols were developed for in vitro differentiation of human pluripotent stem cells to produce allogeneic GABA-secreting interneurons. Transplantation of these cells into rodents produced similar effects as was obtained with MGE interneurons. A human clinical trial in mesial temporal lobe epilepsy with hippocampal sclerosis is underway.

Extensive clinical evidence reviewed by Williams et al. (Chapter 79) supports the effectiveness of the ketogenic diet in controlling seizures in patients who have failed to respond to conventional antiseizure medications. With the expectation that an understanding of the therapeutic mechanisms would permit the development of more practical treatment approaches for refractory epilepsy, there has been keen interest in the physiological and biological actions of the traditional ketogenic diet and related dietary therapies that have shown efficacy in epilepsy treatment, including the medium chain triglyceride diet, modified Atkins diet, and low-glycemic index diet. The authors review research on the effects of ketosis and circulating ketone bodies; the role of glycolytic restriction; the actions on purinergic and GABAergic neurotransmission; fatty acid modulation of ion channel function; the role of improved cellular and mitochondrial bioenergetics; and the impact on oxidative stress. An intriguing new development is the potential that the dietary therapies act to some extent through effects on the gut microbiome. While it is apparent that dietary therapies cause a myriad of metabolic actions, an understanding of how the diets treat refractory epilepsy is still elusive. Nevertheless, the progress made in recent years has opened many new directions for research that will be pursued in the decade ahead with the objective of defining superior treatment strategies.