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Epilepsy articles from across Nature Portfolio

Epilepsy refers to a group of neurological disorders of varying aetiology, characterized by recurrent brain dysfunction that result from sudden excessive and disordered neuronal discharge. These episodes can manifest as epileptic seizures, but they can also occur with subtle or no behavioural signs.

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New blood biomarker of refractory epilepsy

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• Published: 17 September 2021

The pharmacological treatment of epilepsy: recent advances and future perspectives

• Emilio Perucca   ORCID: orcid.org/0000-0001-8703-223X 1 , 2  

Acta Epileptologica volume  3 , Article number:  22 ( 2021 ) Cite this article

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The pharmacological armamentarium against epilepsy has expanded considerably over the last three decades, and currently includes over 30 different antiseizure medications. Despite this large armamentarium, about one third of people with epilepsy fail to achieve sustained seizure freedom with currently available medications. This sobering fact, however, is mitigated by evidence that clinical outcomes for many people with epilepsy have improved over the years. In particular, physicians now have unprecedented opportunities to tailor treatment choices to the characteristics of the individual, in order to maximize efficacy and tolerability. The present article discusses advances in the drug treatment of epilepsy in the last 5 years, focusing in particular on comparative effectiveness trials of second-generation drugs, the introduction of new pharmaceutical formulations for emergency use, and the results achieved with the newest medications. The article also includes a discussion of potential future developments, including those derived from advances in information technology, the development of novel precision treatments, the introduction of disease modifying agents, and the discovery of biomarkers to facilitate conduction of clinical trials as well as routine clinical management.

The modern treatment of epilepsy started with the introduction of phenobarbital in 1912. The advent of phenytoin in the late thirties marked another milestone, because it was made possible by the introduction of animal models of antiseizure activity [ 1 ]. Similar models also played a key role in the subsequent development of many other antiseizure medications (ASMs). Today, the pharmacological armamentarium against epilepsy includes more than 30 drugs (Table  1 ). These drugs differ in their pharmacokinetics, efficacy, and adverse effect profile, thereby offering unprecedented opportunities to tailor treatment choices to individual needs [ 2 ]. Some of the ASMs introduced after 1985, usually referred to as second-generation drugs, have some safety advantages over older generation agents, but have not increased substantially the proportion of patients who achieve complete freedom from seizures [ 3 ]. For many of these patients, the feasibility of epilepsy surgery, or alternative therapies, should be given early consideration [ 4 , 5 ].

Despite the fact that pharmacoresistance has been little affected by the introduction of newer medications, the drug treatment of epilepsy has made major advances in the last 50 years. In particular, we learnt how to individualize drug selection based on specific patient characteristics such as age, gender, epilepsy syndrome, seizure type, comorbidities, comedications, and other factors affecting clinical response [ 6 ]. We also learnt how to optimize response by careful titration and adjustment of dosage, and use of serum drug levels whenever indicated [ 7 ]. We made major progress in understanding drug interactions, and recognizing the relative merits and indications of monotherapy and polytherapy [ 8 , 9 ]. Likewise, we improved our knowledge of the natural history of epilepsy syndromes, and characterized prognostic factors for seizure recurrence for patients in whom discontinuation of ASMs can be considered after an adequate period of freedom from seizures [ 10 ].

The purpose of the present article is to provide a concise overview of some advances in research on the drug treatment of epilepsy made in the last 5 years, and to discuss currently unmet needs as well as developments which are likely to occur in the foreseeable future.

Advances in characterizing the comparative effectiveness and safety of ASMs

A number of recent clinical trials and observational studies have provided valuable information which can assist physicians in making rational treatment selections. As a follow-up to the initial Standard and New Antiepileptic Drugs (SANAD) trials, which found lamotrigine to be superior to carbamazepine, oxcarbazepine, topiramate and gabapentin in time to treatment failure in patients with mostly focal epilepsy [ 11 ], and valproate to be superior to lamotrigine and topiramate in patients with mostly generalized and unclassified epilepsy [ 12 ], two more recent SANAD trials have been completed. In the first of these trials, 990 adults and children with newly diagnosed focal epilepsy were randomized to receive lamotrigine, levetiracetam or zonisamide, and followed-up for 2 years [ 13 ]. In the per-protocol analysis, lamotrigine was associated with a better 12-month remission from seizures compared with both levetiracetam and zonisamide. In the second SANAD-II trial, which used a similar protocol and enrolled 520 newly diagnosed adults and children, valproate was found to be more effective than levetiracetam in controlling seizures in a pooled cohort of patients with generalized or unclassified epilepsy [ 14 ]. These trials used a pragmatic design mimicking routine clinical practice, even though the possibility of assessment bias due to the open-label, unblinded design cannot be excluded. When considered together with other available lines of evidence, these findings confirm that lamotrigine should be regarded as one of the treatments of first choice for patients with focal seizures. Lamotrigine offers the advantage of being efficacious, generally devoid of adverse effects on mood and cognitive function, and with a low potential to cause adverse drug interactions, even though lamotrigine metabolisn can be affected by a variety of concurrently administered drugs [ 6 ]. One drawback of lamotrigine is the need for gradual titration in order to minimize the risk of serious skin rashes, and therefore it may not be the most appropriate drug for use in patients with frequent severe seizures requiring a prompt onset of antiseizure activity.

The findings from the SANAD studies that valproate is superior to lamotrigine, topiramate and levetiracetam in the treatment of patients with generalized epilepsy are consistent with other lines of evidence. In particular, a recent study from Denmark found that failure to achieve seizure freedom with valproate was the single most important predictor of pharmacoresistance in a cohort of 137 adults with idiopathic (genetic) generalized epilepsy [ 15 ]. The superior efficacy of valproate in controlling seizures associated with generalized epilepsy, however, creates a dilemma in the treatment of females of childbearing potential. In fact, valproate is regarded by the European Medicine Agency as contraindicated for use as first-line treatment in these women (unless the conditions of a rigorous pregnancy prevention programme are fulfilled), due to the higher risk of inducing teratogenic effects as well as impaired postnatal cognitive development in the offspring [ 16 , 17 ].

With respect to teratogenic potential of ASMs, prospective pregnancy registries have contributed greatly to characterize risks associated with individual medications. A particularly important advance was the 2018 publication of data from the international EURAP registry [ 18 ]. This study, based on analysis of 7355 prospective pregnancies exposed to 8 different ASM monotherapies provides risk estimates non only for specific ASMs, but also for different doses of the most commonly used drugs. Overall, the lowest prevalence of major congenital malformations (MCMs) in the offspring was associated with exposure to levetiracetam (2.8% prevalence), lamotrigine (2.9%) and oxcarbazepine (3.0%). Prevalence estimates were intermediate for topiramate (3.9%), carbamazepine (5.5%), phenytoin (6.4%) and phenobarbital (6.5%), and highest for valproate (10.3%). An increased risk with increasing dose was identified for lamotrigine and carbamazepine, and was most prominent for phenobarbital and valproate. In particular, the prevalence of MCMs (with 95% confidence intervals) associated with phenobarbital exposure was 2.7% (0.3–9.5%) at doses <  80 mg/day, 6.2% (3.0–11.1%) at doses > 80 to <  130 mg/day and 11.7% (4.8–22.6%) at doses > 130 mg/day. For valproate, the prevalence of MCMs was 6.3% (4.5–8.6%) at doses <  650 mg/day, 11.3% (9.0–13.9%) at doses > 650 to ≤ 1450 mg/day and 25.2% (17.6–34.2%) at doses > 1450 mg/day. These findings are important because they alert physicians about the need to consider teratogenic risks not only in relation to type of ASM prescribed, but also in relation to dose. A subsequent EURAP investigation documented a clear-cut decrease in the prevalence of MCMs over the period from 2000 to 2013 [ 19 ]. Specifically, there was a 27% decrease in prevalence of MCMs between pregnancies enrolled in the period 2010–2013 compared with those enrolled in the period 2000–2005 (Fig.  1 ). Further analysis of these data provided a strong indication that the improvement in pregnancy outcomes over time was related to changes in ASM prescription patterns, including a major decline in the proportion of pregnancies exposed to valproate. In fact, a reduction in teratogenic risk is one of the important advances associated with the introduction of second-generation ASMs [ 3 ].

Prevalence of major congenital malformations (MCMs) following prenatal exposure to monotherapy with antiseizure medications (ASMs) among cases enrolled in the EURAP international registry during three different periods. Number of exposures during each period (listed in brackets) refer to the eight most common monotherapies, which accounted for 96.7 to 98.1% of all monotherapy exposures. Based on data from Tomson et al [ 19 ].

Introduction of novel ASMs

During the last 5 years, five novel ASMs (brivaracetam, cannabidiol, cenobamate, everolimus and fenfluramine) have been introduced into the market. Key features of each of these medications are summarized in Table  2 . The history of these drugs is illustrative of different strategies being used in developing novel ASMs.

The development of brivaracetam followed a paradigm which has been in place for a very long time, i.e. the structural modification of an already existing medication with the aim of improving its pharmacological profile. Examples of other ASMs developed with this strategy include methylphenobarbital and primidone (both structurally related to phenobarbital), the phenytoin derivative fosphenytoin, and oxcarbazepine and eslicarbazepine acetate, which represent successive modifications of the carbamazepine structure. In fact, levetiracetam itself was originally developed with the aim of improving the pharmacological profile of piracetam, and its antiseizure activity was discovered by chance. Brivaracetam was selected for development after extensive preclinical screening of a large numbers of levetiracetam derivatives. Compared with levetiracetam, brivaracetam has higher affinity for the synaptic vesicle 2A (SV2A), and a similar pharmacological profile [ 20 ]. Brivaracetam has been found to be superior to placebo in adjunctive-therapy trials in focal epilepsy, but its activity profile in other seizure types has not yet been defined in well designed controlled trials. One limitation of brivaracetam is its lack of efficacy when added-on to levetiracetam, presumably due to competition between the two drugs for the SV2A binding site. The still unanswered question about brivaracetam is whether, and to what extent, its efficacy and tolerability profile differs from that of levetiracetam. It has been suggested that brivaracetam is less likely to cause irritability and other behavioral disturbances compared with levetiracetam [ 20 ]. However, evidence on this remains inconclusive, because to date there have been no randomized head-to-head trials comparing these two drugs [ 21 ].

Another ASM recently approved for the treatment of focal seizures is cenobamate, a carbamate derivative which is also structurally related to previously developed drugs [ 22 ]. During clinical development, three confirmed cases of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), including one fatality, were reported when cenobamate was titrated rapidly (weekly or faster titration). Consequently, a revised dosing scheme involving initiation at a small dose and slow titration at 2-week intervals has been implemented. In a safety study, no cases of DRESS were reported when 1339 patients were titrated using the slow titration scheme, and the drug has since been approved in the U.S. and Europe [ 23 ]. In the pivotal adjunctive-therapy randomized trial in patients with refractory focal seizures that led to regulatory approval, the most remarkable finding was the relatively high proportion of patients who achieved seizure freedom (21% in the 400 mg/day cenobamate group versus 1% in the placebo group) [ 24 ]. This contrasts with seizure freedom rates ranging from 0 to 6.5% in comparable trials with other second-generation ASMs [ 25 ]. Comparisons of outcome data across trials, however, should be interpreted cautiously, because of differences in clinical settings and characteristics of the patients. Moreover, seizure freedom data in randomized clinical trials refer to limited assessment periods (typically, a 12-week maintenance period) and can be inflated by the last-observation-carried-forward (LOCF) analysis, whereby patients who did not experience seizures but exited the trial prematurely are still counted as seizure-free in the final analysis. In the pivotal cenobamate trial, the proportion of randomized patients who were seizure-free during the entire 12-week maintenance period and did not exit the trial prematurely was 14%, which is still a relatively high proportion [ 24 ].

All three remaining ASMs introduced in the last 5 years share a common feature, i.e. they were approved for orphan indications. Specifically, cannabidiol was approved for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex, fenfluramine was approved for the treatment of seizures associated with Dravet syndrome, and everolimus was approved for the add-on treatment of focal seizures in patients with tuberous sclerosis complex (Table 2 ). Introduction of ASMs for orphan indications is a novel development, made possible by increased awareness of the unmet needs associated with many rare epilepsies and by regulatory incentives to develop drugs for these indications, particularly for children. In fact, only 2 of the 25 ASMs developed prior to 2015 were developed for orphan indications, compared with 3 out of 5 ASMs developed in the last 5 years.

Cannabidiol is one of the many active principles contained in the Cannabis plant, which has been used as an herbal remedy in China as early as 2000 BC. Unlike tetrahydrocannabidol (THC), cannabidiol lacks unwarranted psychoactive effects. Its antiseizure efficacy in its approved indications has been demonstrated in several adjunctive-therapy randomized placebo-controlled trials [ 26 ]. In these trials, many patients received concomitant treatment with clobazam, and the improvement in seizure control observed after adding cannabidiol could be ascribed at least in part to a drug interaction. In fact, cannabidiol is a powerful inhibitor of cytochrome CYP2C19 and by this mechanism increases more than three-fold the serum concentration of norclobazam, the active metabolite of clobazam. There is, however, also evidence that cannabidiol retains independent antiseizure activity, unrelated to its interaction with clobazam [ 27 ].

Another ASM recently introduced for the treatment of seizures associated with Dravet syndrome is fenfluramine, which was first marketed in the sixties and widely used in Europe and the U.S. for over 30 years as an appetite suppressant, either as racemic fenfluramine or as its d-enantiomer dexfenfluramine. In 1997, fenfluramine and dexfenfluramine were withdrawn from the market following the discovery of their association with cardiac valvulopathy and pulmonary hypertension. Prior to its withdrawal from the market, however, fenfluramine had been found to improve seizure control in a small cohort of patients with Dravet syndrome, who were allowed to continue treatment with the drug [ 28 ]. These observations led to recent conduction of randomized placebo-controlled adjunctive therapy trials, which demonstrated a robust seizure-suppressing effect in patients with Dravet syndrome, and subsequent regulatory approval for this indication both in Europe and the United States [ 29 ]. Recent data suggest that fenfluramine may also be useful for the treatment of seizures associated with Lennox-Gastaut syndrome [ 30 ]. To date, no evidence of cardiovascular toxicity has been found in patients with epilepsy treated with fenfluramine, possibly because the doses used for seizure protection are generally lower than those used originally for appetite suppression. Yet, there are still many unanswered questions concerning fenfluramine, including the serum levels of parent drug and its active de-ethylated metabolite norfenfluramine required for seizure suppression in children in comparison with those known to be associated with cardiovascular toxicity in adults [ 29 ]. The potential efficacy and safety advantages of developing individual enantiomers of fenfluramine and norfenfluramine should also be considered [ 29 ].

The last medication discussion in this section, everolimus, is an inhibitor of mTOR (mammalian Target Of Rapamycin). Its use in the treatment of focal seizures associated with tuberous sclerosis complex (TSC) has been prompted by evidence linking the pathogenesis of TSC to mTOR overactivation [ 31 ]. Accordingly, everolimus is an example of a novel strategy in drug development, i.e. a precision treatment targeting the etiology of the disease. Everolimus has been found to be effective in reducing tumor growth as well as drug-resistant seizures in TSC patients. Up to 40% of TSC patients show a significant improvement in seizure control when given adjunctive treatment with everolimus. In the pivotal trial that led to its regulatory approval for use as ASM, seizure frequency decreased progressively over time during treatment, suggesting a possible disease modifying effect [ 32 ]. However, a clinically relevant antiepileptogenic or disease-modifying effect has not yet been clearly demonstrated. The age at which treatment is initiated may be important for the final outcome, but controlled trials in children below 2 years of age have not yet been completed [ 31 ].

Cannabidiol, fenfluramine and everolimus are also examples of drugs approved initially for other indications. In fact, cannabidiol was first marketed in a fixed combination product with THC as a nasal spray for the treatment of spasticity associated with multiple sclerosis, fenfluramine was used initially as an appetite suppressant, and everolimus was first approved for the treatment of advanced kidney cancer, subependymal giant cell astrocytoma (SEGA) associated with TSC, pancreatic neuroendocrine tumors, and other tumors. The repurposing for use in epilepsy of drugs initially approved for other indications is one of the options being pursued in the effort to develop precision treatments (see below).

Introduction of novel formulations

Advances in epilepsy treatment can be achieved not only by developing novel drugs, but also by improving the pharmaceutical formulation of already available medications. One area where particularly significant advances have been made in the last 5 years is the development of novel formulations of ASMs for the treatment of seizure clusters and acute repetitive seizures in the out-of-hospital setting [ 33 ]. Until 2018, the only FDA-approved rescue ASM for out-of-hospital use was diazepam rectal gel. In 2019, the FDA approved two additional products for this indication, namely intranasal midazolam [ 34 ] and intranasal diazepam [ 35 ]. Use of these medications is associated with a rapid onset of antiseizure effect, thereby stopping seizures before they progress to established status epilepticus. The intranasal route is generally well accepted by patients and caregivers, as it avoids the social embarrassment associated with use of the rectal route.

Alternative non-rectal rescue formulations of benzodiazepines for out-of-hospital use have been available in other countries for a number of years. In particular, a rapidly absorbed buccal formulation of midazolam has been available in Europe since 2011 [ 36 ]. Innovative formulations of ASMs under development as potential rescue therapy for emergency use include a diazepam buccal film, and an inhaled formulation of alprazolam [ 33 ]. Oral formulations can also be used at times as a rescue treatment, but they can be associated with drawbacks in this setting, such as slower or suboptimal absorption, need for patient cooperation (which is not always feasible) and risk of aspiration [ 36 ].

Future perspectives

Extensive research is ongoing in many areas, and important advances leading to improved epilepsy outcomes are likely to occur in a not too distant future. A few relevant examples will be discussed below.

Increased application of technological tools to epilepsy management

In recent years, information technology (IT)-based applications have been increasingly utilized in epilepsy management, as shown by the widespread use of smartphones to record seizures in the out-hospital setting, and the expanding opportunities offered by Internet-based services in areas such as distant education and telemedicine [ 37 ]. Smartphone applications (apps) are also being increasingly used to assist people with epilepsy to manage and cope with their disease. Most of these apps focus on issues such as treatment management, medication adherence, health care communication, and seizure tracking [ 38 ]. Other apps are aimed at assisting healthcare professionals (HCPs), on example being tools to improve epilepsy diagnosis in non-specialist settings [ 39 , 40 ]. We recently designed a smartphone app to help HCPs in selecting ASM selection for patients with seizure onset at age 10 years or above, particularly in settings where no specialized expertise is available [ 41 , 42 ]. This app is freely available on the Internet ( www.epipick.org ). In a recent validation study, selection of ASMs recommended by the app based on individual patient characteristics was found to be associated with improved seizure outcomes and fewer adverse effects compared with use of ASMs not recommended by the app [ 43 ]. In the future, individualized ASM selection is likely to empowered by more sophisticated technology, including artificial intelligence (machine learning)-based approaches. In a recent study, a machine learning approach combining clinical, genetic and clinical trial data derived from individual patients permitted to construct a computerized model that predicted response to a specific ASM [ 44 ].

In addition to facilitating treatment selection, technology will increasingly assist patients and physicians in monitoring response to treatment through a variety of tools, including seizure detection devices [ 45 ]. Efforts are also ongoing into development of sophisticated technology, including artificial intelligence, for the prediction of epileptic seizures [ 46 ]. This could pave the way to innovative treatment strategies, such as the intermittent use of ASMs prior to the time at which a seizure is predicted to occur.

Precision therapies

In recent years, our understanding of the molecular mechanisms involved in the pathogenesis of epilepsies has improved considerably. One area where advances have been greatest is the genetics of the epilepsies, and in particular the discovery of gene mutations responsible for a large proportion of patients with developmental and epileptic encephalopathies (DEEs) [ 47 ]. The elucidation of an epileptogenic mutation permits to establish the functional abnormality responsible for the epilepsy in the affected individual, and to identify (or develop) precision-therapy medications that may be able to correct such abnormality. One example of a precision therapy is the utilization of the ketogenic diet to control seizures associated with Glucose Transporter Type 1 (GLUT1) deficiency syndrome. In this condition, GLUT1 deficiency results in impaired brain uptake of glucose and consequent neuronal dysfunction, which can be overcome by supplying the brain with an alternative source of energy [ 48 ]. As discussed in recent reviews [ 49 , 50 , 51 ], precision treatments targeting the mechanisms responsible for epilepsy in individuals with specific gene mutations may involve use of drugs previously approved for other indications, a process known as drug repurposing. One example of repurposed drug is the mTOR inhibitor everolimus for the treatment of seizures associated with TSC, as discussed above in this article. Approaches to identify repurposed drugs for specific monogenic epilepsies have been described [ 52 ]. In some cases, improved outcomes can be achieved not by administering additional drugs, but by removing medications that can paradoxically aggravate seizures in these patients [ 49 ]. Importantly, precision therapies are applicable not only to genetic epilepsies, but also to epilepsies due to other etiologies, such metabolic, inflammatory or immune-mediated causes [ 53 ].

At present, application of precision therapies in the management of epilepsy is still in its early days, and will likely expand as further knowledge accrues and newer and more effective targeted treatments are introduced. For genetic epilepsies, targeted (precision) treatments have been reported to improve outcomes in a considerable proportion patients with identified gene mutations [ 54 ], although a more recent survey gave a more sober assessment of the current impact of these treatments [ 55 ].

Biomarker-guided therapies

The search for biomarkers continues to be a hot topic in epilepsy research. Biomarkers can be based on a variety of measures such as genetic, molecular, cellular, imaging, and electrophysiological measures, other clinical or laboratory data, or a combination of these [ 56 , 57 ]. Biomarkers could potentially be used for different purposes, for example to improve diagnostic accuracy, to identify ongoing epileptogenesis and its mechanisms, to predict seizure response (or lack of response) to specific treatments, to assess the probability of seizure recurrence after treatment withdrawal, or to evaluate susceptibility to adverse drug effects. Some biomarkers, such as the HLA-B*15:02 antigen to identify individuals at high risk of carbamazepine-induced serious cutaneous adverse reactions among Han Chinese and other South Asian ethnic groups, are already in routine clinical use [ 58 ].

With respect to potential therapeutic advances, identification and validation of biomarkers could improve treatment outcomes in many ways [ 56 , 57 , 59 ]. First, biomarkers could be used to identify individuals at high risk of developing epilepsy after an epileptogenic insult, thereby permitting selection of these individuals for clinical trials of potential antiepileptogenic therapies. Second, identification of biomarkers predictive of seizure recurrence could facilitate decision on whether to start or withhold ASM therapy in patients who experienced a single seizure. Third, biomarkers predictive of a favorable response to a specific medication would be valuable to select patients to be enrolled in clinical trials of that medication, thereby increasing responder rate and sparing non-responders the burden of receiving placebo or an ineffective treatment. Fourth, biomarkers could theoretically be used to monitor response to treatment, by informing physicians at an early stage on whether the prescribed medication has the required efficacy and safety in a specific individual. Lastly, and most importantly, biomarkers could in the future inform physicians on which ASM is most likely to control seizures effectively and with fewest adverse effects. This may change radically treatment paradigms: for example, the value of a drug which is effective in achieving complete seizure control in 5% of patients with pharmacoresistant epilepsy would be greatly enhanced if we had a biomarker that can identify beforehand those patients who are responsive to that drug. In that scenario, we would use that drug only in responsive patients, thereby increasing the success rate to 100%.

In practice, in most situations it is unlikely that a single biomarker will provide optimal information for any intended purpose. More realistically, breakthroughs are likely to come from algorithms that utilize a combination of biomarkers and other clinical information. The development of artificial intelligence-based tools can facilitate greatly these approaches [ 44 ].

Novel drugs and the search for disease-modifying therapies

The modest impact of second-generation ASMs on seizure outcome in patients resistant to older agents justifies continuing efforts to develop newer and potentially more effective treatments (Table  3 ). Drug development is currently benefiting from many advances, including deeper knowledge of the mechanisms of epileptogenesis and seizure generation in relation to specific etiologies, improved understanding of mechanisms of pharmacoresistance, and availability of disease-specific models as well as models of pharmacoresistance [ 53 , 60 ]. These advances are changing the paradigms used to discover and develop new drugs.

An important paradigm change is a switch from a focus on medications aimed at suppressing seizures to a focus on treatments targeting the underlying disease, i.e. specific etiologies and the molecular mechanisms associated with such etiologies [ 51 , 61 ]. Future precision treatments emerging from this approach will include repurposed drugs [ 50 , 62 ], novel small molecules, and other treatments based on innovative technologies such as antisense oligonucleotides [ 63 , 64 ] and gene therapy [ 65 ]. Some of these therapies require invasive routes of administration, which are also being explored for innovative uses of already established medications [ 66 ].

A closely related paradigm change consists in targeting specifically epileptogenesis and other manifestations of the disease [ 60 , 62 , 67 ]. Such treatment could potentially be used to prevent epilepsy, to inhibit its progression (in those syndromes showing a progressive course), or to alter the appearance or progression of comorbidities such as intellectual disability and other disorders. A wide variety of compounds have been found to possess antiepileptogenic and/or neuroprotective activity in preclinical models through antiinflammatory, antioxidant and other mechanisms [ 68 , 69 , 70 , 71 ]. In addition to novel molecules, these compounds includes naturally occurring substances such as phytocannabinnoids, melatonin, erythropoietin, vitamins and other dietary constituents [ 68 , 70 , 72 , 73 , 74 ], as well as medications already approved for other indications, such as metformin [ 75 ], montelukast [ 76 ], atorvastatin, ceftriaxone, and losartan [ 62 ]. Whether these properties documented in animal models translate into benefit in the clinical setting remains to be demonstrated. Of note, a number of precision treatments directed at specific etiologies of epilepsy could exhibit disease-modifying effects, although it is possible that any medication acting on a single molecular pathway may not address all the complex comorbidities associated with aberrant neural networks [ 61 ].

As discussed above, clinical trials of investigational new drugs could be facilitated by development of biomarkers to detect the occurrence of epileptogenesis at an early stage, to identify drug responsive patients and to monitor response to treatment. Despite claims to the contrary [ 77 ], demonstrating that a chronically administered treatment started before seizure onset prevents the occurrence of seizures in patients still receiving that treatment does not prove epilepsy prevention, because any ASM having a purely symptomatic effect could also produce such an outcome. Likewise, some comorbidities, such as progression of cognitive disability, may be prevented solely as a result of seizure suppression. Truly innovative trial designs will be required to generate unequivocal evidence that a drug is effective in preventing epilepsy, or has a direct disease modifying effect [ 78 ].

Conclusions

Despite the fact that second-generation ASMs have not reduced substantially the burden of pharmacoresistance, advances in the drug treatment of epilepsy continue to be made. These advances result mostly from improved understanding of the comparative efficacy and safety of existing ASMs and from the introduction of newer medicines and innovative formulations. Further advances can be ascribed to technological tools for distant education, telemedicine, and patient empowerment made possible by self-management smartphone-based apps.

It likely that further important therapeutic advances will occur in the coming years. Thanks to ongoing multidisciplinary efforts, clinical outcome for people with epilepsy is likely to improve due to advances in IT technology, development of novel precision therapies, identification of biomarkers to guide drug development as well as routine clinical management, and, ultimately, introduction of truly innovative disease modifying therapies.

Availability of data and materials

Not applicable.

Abbreviations

Antiseizure medication

Developmental and epileptic encephalopathy

Cerebrospinal fluid

Drug Reaction with Eosinophilia and Systemic Symptoms

Dravet syndrome

Cytochrome P450

Electroencephalography

International Registry of Antiepileptic Drugs and Pregnancy

Food and Drug Administration (United States)

Healthcare professional

Gamma-aminobutyric acid

G protein-coupled receptor 55

Information technology

Lennox-Gastaut syndrome

Major congenital malformation

Last-observation-carried-forward

Mammalian Target Of Rapamycin

P-glycoprotein

Standard and New Antiepileptic Drugs

Subependymal giant cell astrocytoma

Synaptic vesicle 2A

Transient receptor potential vanilloid type 1

Tuberous sclerosis complex

Uridine 5′-diphospho-glucuronosyltransferase

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Perucca, E. The pharmacological treatment of epilepsy: recent advances and future perspectives. Acta Epileptologica 3 , 22 (2021). https://doi.org/10.1186/s42494-021-00055-z

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Epilepsy research: a window onto function and dysfunction of the human brain

Investigación en epilepsia: una ventana hacia la función y disfunción del cerebro humano, recherche sur l'épilepsie: une fenêtre sur le fonctionnement et le dysfonctionnement du cerveau humain, christian e. elger.

Department of Epileptology, University of Bonn Medical Center, Bonn, Germany

As one of the most common neurological disorders, epilepsy has devastating behavioral, social, and occupational consequences and is associated with accumulating brain damage and neurological deficits. Epilepsy comprises a large number of syndromes, which vary greatly respect to their etiology and clinical features, but share the characteristic clinical hallmark of epilepsy recurrent spontaneous seizures. Research aimed at understanding the genetic, molecular, and cellular basis of epilepsy has to integrate various research approaches and techniques ranging from clinical expertise, functional analyses of the system and cellular levels, both in human subjects and rodent models of epilepsy, to human and mouse genetics. This knowledge may then be developed into novel treatment options with better control of seizures andlor fewer side effects. In addition, the study of epilepsy has frequently shed light on basic mechanisms underlying the function and dysfunction of the human brain.

La epilepsia es uno de los trastornos neurológicos más comunes y tiene consecuencias conductuales, sociales y ocupacionales devastadoras, y se asocia con daño cerebral acumulaiivo y déficit neurológicos. La epilepsia incluye un gran núméro de síndromes, que varían ampliamente en relación con la etiología y los aspectos clínicos, pero que comparten el sello clínico característico de la epilepsia: las crisis espontáneas recurrentes. La investigación orientada a la comprensión de las bases genéticas, moleculares y celulares de la epilepsia ha integrado varias aproximaciones y técnicas de investigación que van desde la habílidad clínica, los análisis funcionales de los sisiemas y el nivel celular, tanto en modelos de epilepsia en humanos como en roedores, hasia la genética en ratones. Este conocimienio entonces puede dar origen a nuevas opciones terapéuticas con mejor control de las convulsiones ylo menores efectos secundarios. Además, el estudio de la epilepsia frecuentemenie ha dado luces acerca de los mécanismes básicos que subyacen a la función y disfunción del cerebro humano.

Les conséquences comportementales, sociales et professionnelles de l'épilepsie, l'un des troubles neurologiques les plus courants, sont dévastatrices. L'épilepsie est associée à une accumulation d'altérations cérébrales et de déficits neurologiques. Ses syndromes sont nombreux et varient beaucoup selon leur étiologie et leurs particularités cliniques, mais partagent l'aspect clinique caractéristique de l'épilepsie : les crises spontanées récidivantes. La recherche s'est efforcée de comprendre les bases génétiques, moléculaires et cellulaires de l'épilepsie en intégrant diverses approches et techniques allant de l'expertise clinique, de l'analyse fonctionnelle des systèmes à un niveau cellulaire, à la fois chez les humains et dans des modèles murins d'épilepsie, jusqu'à la génétique humaine et la génétique murine. Grâce à cette connaissance, de nouveaux traitements pourraient être développés, les crises mieux contrôlées et/ou les effets indésirables plus restreints. L'étude de l'épilepsie a, en outre, fréquemment permis d'éclairer les mécanismes de base du fonctionnement et du dysfonctionnement du cerveau humain.

Epilepsy is one of the most common neurological disorders (~8 000 000 patients in the European Union). It has devastating behavioral, social, and occupational consequences, and is associated with accumulating brain damage and neurological deficits. Epilepsy comprises a large number of syndromes, which vary greatly with respect to their clinical features, treatment, and prognosis. However, all of these syndromes share the characteristic clinical hallmark of epilepsy - recurrent spontaneous seizures.

Even though the key manifestation of all epilepsies is recurrent seizures, the etiologies that can give rise to an increased propensity of the human brain to generate synchronized neuronal activity and seizures are diverse. Epileptic seizures are associated with overt causes, such as certain central nervous system (CNS) tumors or neurodevelopmental abnormalities, CNS trauma, or inflammation (symptomatic epilepsies). In a small number of epilepsy patients, a mutation in a single gene suffices to cause chronic seizures. Additionally, a large group of epilepsies has a yet-unknown etiology (idiopathic epilepsies). Studies of the genetic or molecular and cellular causes of epilepsy have to take account of the fact that epilepsy is not a uniform disorder, but a mixture of many different entities. A precise analysis of the clinical, neurophysiological, and neuropathological phenotype of human epilepsies with a definition of homogenous subgroups/syndromes is a prerequisite not only for genetic studies, but also for the development of appropriate animal models to study the cellular basis of seizures and epilepsy. Because of the etiological diversity of epilepsy, modern approaches to epilepsy research involve many different fields. These include clinical fields such as clinical epileptology and neurosurgery, neurology, psychiatry, and neuropathology, but also basic research areas such as human genetics, neuropsychology, immunology, neurophysiology, neurophysics, molecular biology and transgenics, developmental neurobiology, and neuropharmacology.

The ultimate goal of studies into the molecular and cellular mechanisms of epilepsy is to develop novel, and more effective, therapies. This may be approached in several ways. Firstly, a better understanding of the underlying disease mechanisms may in some instances lead to the identification of novel treatment options. Secondly, it is important to understand why currently available therapies do not help certain patients, while they are very effective in others. Finally, another goal of epilepsy research is to identify mechanisms underlying side effects of drug therapy, because these often limit drug therapy. In addition to the intrinsic value of studying disease processes in one of the most common neurological disorders, epilepsy research is an excellent model for understanding basic mechanisms of CNS function and plasticity, in particular in the human brain, for several reasons. Firstly, seizures are known to initiate a large number of plastic changes on a molecular and cellular level in the brain. Many of these plasticity mechanisms have been recognized as key components of normal brain function (ic, brain development or learning and memory) or in other neurological disorders. Secondly, understanding the cellular basis of aberrant synchronized discharges of neurons during epileptic seizures also yields insights into the mechanisms of normal synchronization in the brain. Finally, the necessity to perform invasive electrode (depth and subdural) recordings in patients with epilepsy results in unique opportunities to study human cognitive processes at extremely high time resolution by recording field or even single unit potentials during cognitive tasks. This technique can be combined with different functional imaging techniques, which ideally complement invasive recordings from the human brain by providing excellent spatial resolution.

Research into the basic mechanisms of epilepsy

The study of idiopathic genetic epilepsies : how do single gene mutations cause epilepsy.

Genetic factors are the major determinants in at least 40% of all epilepsies; these are designated as “idiopathic epilepsies.” Only about 2% of these idiopathic epilepsies are inherited as monogenic disorders, in which one gene conveys the major heritable impact, while environment and lifestyle play a limited role. Genetic studies have allowed identification of the first disease genes that define monogenic idiopathic epilepsies. 1 , 2 In these cases, genetic studies have identified causal gene variants, many of them neuronal ion channels, receptors, or associated proteins. Subsequently, the function of these variants was examined carefully in expression systems, and specific functional changes were found. These analyses, while compelling in implicating specific genes in idiopathic epilepsies, are not the last word in understanding how a gene mutation leads to a behavioral and clinical phenotype. We are beginning to obtain such an understanding in some instances from transgenic mouse models that carry disease-associated gene variants. 3 The advantage of such models is that they harbor human disease-associated gene variants, and can be examined at various points during the development of epilepsy with in vitro and molecular techniques. The limitation of such models is that the mechanisms of epileptogenesis may not be the same in mice and humans, and that disease-associated human gene variants are expressed on a background of mouse genes that may interact in unexpected ways with the human ortholog. Nevertheless, such studies are increasingly part of an integrated strategy to understand the mechanisms of monogenic epilepsies involving both human genetics and physiological, and molecular studies in transgenic mouse models.

The study of focal epilepsy

What are the mechanisms of seizures.

By far most types of epilepsies, however, are not monogenic. Rather, they most probably involve both the effects of various combinations of gene variants, environmental factors, and precipitating injuries early during development. The relative importance of these factors in common focal epilepsies such as temporal lobe epilepsy (TLE) is unknown. For obvious reasons, it is difficult to investigate how these epilepsies develop over time prior to the first clinical manifestation. This is probably why research in the field has focused more on identifying key mechanisms that govern abnormal excitability and synchronization in chronic epilepsy, in particular those which might be potential targets for therapeutic manipulation. Animal models generated for this goal have been selected with the rationale that they should reproduce the neuropathologies, clinical, and physiological features of the chronic stage of epilepsy. This has been achieved to some extent for temporal lobe epilepsy. Models of temporal lobe epilepsy (TLE) include the kainate model, 4 the pilocarpine model, 5 and the self-sustaining limbic status model. 6 All rely on the induction of status epilepticus (SE) either pharmacologically (with the ionotropic glutamate receptor agonist kainate or the muscarinic agonist pilocarpine), or via electrical stimulation (self-sustaining limbic status model). After a period of a few weeks, animals that have experienced SE exhibit several hallmarks of temporal lobe epilepsy, including (i) spontaneous seizures; (ii) a pattern of neuropathological damage similar to a subset of temporal lobe epilepsy patients with segmental hippocampal cell loss, gliosis and axonal reorganization; and (iii) dispersion of granule cells. In TLE, we have the unique possibility of validating such animal models because tissue from TLE patients is available from epilepsy surgery. From comparative neuropathological studies, we know that the pattern of damage in the abovementioned models is surprisingly close to that seen in a subgroup of TLE patients with so-called Ammon's horn sclerosis (AHS). Patients with AHS also display severe segmental neuron loss, axonal reorganization, and gliosis, along with dispersion of granule neurons. 7 - 9 It should be noted that in other instances, these epilepsy models differ from the human condition. For instance, damage in the pilocarpine model is not restricted to the hippocampus, involving instead many other brain regions. Nevertheless, these and similar models have been used extensively to study cellular and molecular changes in chronic epilepsy, and how these might lead to seizure generation. These changes have in some cases been compared with data obtained from human neurons obtained from epilepsy surgical specimens. 10

A further group of TLE patients docs not display the neuropathological features of AHS, even though they experience seizures originating from the mesial temporal lobe. 7 - 9 In this group of TLE. patients, epilepsy is often a consequence of a mesial temporal lobe tumor or developmental malformation. An animal model that is thought to replicate some features of these human patients is the kindling model. In this model, repeated application of subthreshold electrical stimulation to limbic structures results in the expression of permanent limbic hyperexcitability. In this model, significant neuropathological damage is largely absent. In comparison with studies on human and experimental TLE, work on models of epilepsies with neocortical seizure foci has been relatively scarce, even though such models can also be validated in human in vitro studies.

Models of TLE have proven useful as a complementary strategy to investigations on human epileptic brain tissue. In experiments on human tissue, a fundamental problem is the lack of living control tissue. Very rarely, nonepileptic human control tissue is available from the penumbra of tumor resections in the temporal lobe. Other than this rare commodity, experimenters are left with the option of comparing epileptic tissue with autopsy control tissue, which is impossible for physiological and some molecular biological approaches. A further, commonly used approach is to compare tissue from patients with AHS vs lesion-associated epilepsy. This strategy has allowed the investigation of the expression of candidate molecules associated with changes present only in one of these patient groups. For instance, molecules important in synaptic reorganization would be expected to be present in specific areas in AHS, but not in lesion-associated epilepsy. Studies in animal models, on the other hand, always require validation with studies on human tissue to demonstrate their relevance to the human disorder unequivocally 11 However, animal models do complement human studies in important ways. Firstly, animal models allow molecular and functional changes to be studied in detail without the constraints imposed by the lack of control material in experiments with human tissue. Further, having identified clear molecular changes, animal models allow us to determine the importance of such changes for hyperexcitability and epileptogenesis. This question is important because a large number of regulated candidate molecules have been identified, all of which may be potentially important in the development of epilepsy. A major challenge will be to determine which of these manifold changes are functionally important in common forms of epilepsy. To decipher the causal role of candidate genes, it has become increasingly accepted that it is necessary to generate cell-specific and inducible gain - as well as loss-of-function models on a more systematic scale than previously attempted. Such approaches may be realized using viral transfer of small interfering RNAs (siRNAs), or transgenic models that allow cell-specific and inducible genetic modifications. Finally, animal models allow to study some aspects of epileptogenesis, which is virtually impossible in human tissue, because specimens are only obtained late during the disease course.

What are the mechanisms of epileptogenesis?

Broadly speaking, epileptogenesis can be defined as a plastic process leading from a normal to a chronically epileptic brain. Precipitating brain insults (ie, febrile seizures, local infections, SE, ischemia, or trauma) in concert with genetic susceptibility factors are thought to trigger such persistent changes. As explained above, to directly address this issue in human subjects is extremely difficult. In recent years, investigators have therefore increasingly turned to animal models for this purpose. In the case of TLE, most investigators have studied epileptogenesis after an initial SE. It is important to realize that TLE models replicate the chronic features of TLE reasonably well. It is however not clear how much the mechanisms underlying SE-induced epileptogenesis overlap with the mechanisms underlying epileptogenesis in TLE patients, in whom this process is likely multifactorial and not triggered by SE. Nevertheless, studies of epileptogenesis in SE models have been worthwhile because they have resulted in an increased understanding of the basic mechanisms underlying key features of AHS, such as sprouting, cell death, and gliosis.

It may seem easier to establish models of epileptogenesis in symptomatic epilepsies, for instance epilepsy associated with CNS tumors, developmental malformations, or CNS trauma, for the simple reason that the initial precipitating injury is known, and can be replicated quite well in many cases. However, developing such models has proven surprisingly elusive. Models for tumor-associated epilepsy are scarce, and have relied on the injection of rapidly proliferating tumor cell lines into the brain of rodents. 12 While potentially valuable to assess the consequences of a rapidly growing malignancy in the CNS, these models are probably not that informative on mechanisms of epileptogenesis and seizure generation involved in human epilepsy patients. This is mainly because the tumors that are likely to cause epilepsy are mostly low-grade tumors with slow proliferation. The reasons for this association are unknown. It will be necessary to create additional models aimed at replicating features of these tumors. Regarding developmental malformations, there are several models in which the proper formation of cortical structures has been disrupted. These include models in which drugs are applied during cortical development that arrest neuronal migration, or in which lesions are applied to the cortex during cortex formation, which also lead to formation of a cortex with a disturbed laminar organization. 13 In trauma models, fluid percussion injury results in a circumscribed traumatic cortical injury zone. 14 These models have been informative because they have revealed manifold changes in excitability in and surrounding the abnormal cortical areas, and address the underlying mechanisms. However, it is not yet clear if these models lead to symptomatic epilepsy. More recently, genetic models of cortical malformations have been introduced. These models rely on the temporally selective and cell-type specific disruption of genes important in neuronal differentiation and migration. A further intriguing model that may address a common mechanism in many epilepsies is disruption of the blood-brain barrier. It has been recently shown that focal disruption of the blood-brain barrier results in development of a hyperexcitablc focus. 15 , 16 Since blood-brain barrier disruption is a common feature of status epilepticus, ischemia, trauma, and CNS tumors, it may be that this is a common mechanism for hyperex citability in these models. The proliferation of these and other models has led to an intense discussion in the field regarding the validity of such models for the human condition. A worthwhile aspect of this discussion is that it has led to an awareness that animal models only replicate specific aspects of any human condition, and it is paramount to be aware of the areas where a specific model is informative versus the ones where it is not.

What are the key questions that have been addressed in studies of epileptogenesis? Firstly, experiments primarily in post-status models of epileptogenesis have addressed the role of changes in voltage-and transmitter-operated ion channels in epileptogenesis. Generally, activity-dependent changes in neuronal function can be subdivided into changes in synaptic communication between neurons (termed synaptic plasticity), and changes in intrinsic membrane properties of neurons (termed intrinsic plasticity) that govern how synaptic input is integrated. Work on synaptic plasticity has focused on changes in the expression and function of neurotransmitter receptors at synapses, as well as changed properties of presynaptic neurotransmitter release. Research on intrinsic plasticity has addressed changes in voltage-gated ion channels in the somatic, dendritic, and axonal membrane of neurons. 17 There have been multiple such changes described convincingly in the literature. A crucial question is how to evaluate the role of individual molecular changes seen in animal models in the development of epilepsy. There are several strategies that could be used to this end. Perhaps the most straightforward of these is to specifically interfere genetically or pharmacologically with ion channel regulation. Due to the novel genetic tools available in recent years, this is becoming more and more feasible. To transfer these types of studies to the human is more difficult. As stated above, human tissue obtained from epilepsy patients reflects the end stage of chronic epilepsy in most cases. It is therefore doubtful that human tissue can serve as a useful control for animal models at an early stage of epileptogenesis. One avenue which may provide a useful link between animal models and human epilepsy, however, is the use of genetic techniques to address whether polymorphisms in ion channel genes, associated proteins, or relevant transcription factors are associated with an increased propensity to develop epilepsy.

What causes changes in ion-channel function? The underlying molecular mechanisms are just beginning to be unraveled. One feature of epileptogenesis is the selective and coordinated regulation of transcription. This regulation affects mRNA levels encoding for groups of ion channels. The mechanisms that drive altered transcription have been identified in only few cases. Identification of the responsible transcription factors is one possible avenue to inhibit specific features of epileptogenesis. Persistent changes in transcription, however, are not only determined by a persistent activation of transcription factors, but can also be caused by changes in the chromatin state or autoregulatory feedback loops involving key transcription factors. Following transcription, alterations at the post-transcriptional level may be caused by changes in translational regulation. Finally, trafficking of ion-channel subunit proteins, as well as post-translational modifications, are important determinants of function that may be altered in chronic epilepsy. Understanding changes in intrinsic neuronal properties and synaptic function are also relevant for understanding mechanisms of drug actions, as well as why resistance to these drugs occurs. A large number of voltage-gated ion channels and some presynaptic proteins are targets for antiepilcptic drugs, and changes in these targets may cause reduced drug sensitivity (explained in more detail below).

In addition to changes in membrane-bound ion channels, epileptogenesis is associated with large changes in mitochondrial function, including mitochondrial DNA depletion, failure of energy supply, and production of reactive oxygen species. 18 , 19 Such changes play a large role in the initiation of cell death cascades. Studies on mitochondrial function have been conducted in chronic experimental and human epilepsy. As above, studies on the mechanisms underlying the development of mitochondrial dysfunction are difficult in human tissue obtained at chronic stages. Here also, genetic studies provide an important link to epileptogenesis. An increasing number of studies have addressed whether genetic variability in genes encoding mitochondrial proteins confers susceptibility to epileptogenesis. 20

An intriguing novel facet of epileptogenesis, that will likely necessitate the development of new model systems, is the involvement of immune cells in the development of epilepsy. Immune cells profoundly influence processes in the normal brain, such as neurogenesis or synaptic plasticity. The link between neuroimmunological processes and epilepsy is highlighted by inflammatory/autoinflammatory epileptic syndromes (eg, Rasmussen encephalitis or limbic encephalitis). Innate immune cells may not only play a role in the pathogenesis of these relatively rare epileptic syndromes, but also in the process of epileptogenesis in common chronic epilepsies which were not previously considered to have “encephalitic” components. 21 - 23

How does epilepsy research lead to improved therapies?

In many patients with epilepsy, seizures are well-controlled with currently available antiepilcptic drugs. However, seizures persist in a considerable proportion of these patients. 24 The exact fraction of epilepsy patients that are considered refractory varies in the literature, mostly because the criteria for classification as pharmacoresistant have varied. Nevertheless, a substantial fraction (~30%) of epilepsy patients does not respond to any of two to three first-line antiepilcptic drugs (AEDs), despite administration in an optimally monitored regimen. 25 Despite the clinical relevance of this phenomenon, the cellular basis of pharmacoresistance has remained elusive. However, integrated strategics integrating clinical, genetic, and molecular physiological techniques are providing some insight into possible mechanisms. What are the key strategies that can be used to unravel mechanisms of pharmacoresistance?

The first approach is pharmacogenomic. The ultimate goal of pharmacogenomics is to define the contributions of genetic differences in drug response. 26 The variability of an individual's response to a given drug can be considerable, and identifying causal genetic factors is expected to lead to improved safety and efficacy of drug therapy through use of genetically guided, individualized treatment. Pharmacogenomic approaches require both substantial clinical and genetic expertise. Following delineation of pharmacoresistant and pharmacoresponsive patient groups, powerful tools for disease gene mapping and identification afforded by the human genome project can be exploited. These tools, which include a large number of catalogued sequence variants, permit genomewide studies for the identification of genetic loci underlying diseases and related phenotypes, including the response to drug treatment. These studies may allow identification of novel gene variations conferring risk for the development of epilepsy and pharmacoresistance. While this approach sounds straightforward, it is far from simple in practice. This is also clear from the large number of polymorphisms found in such association studies which could not be reproduced in replication studies. Major problems that still have to be overcome are firstly, that pharmacoresponse may not be determined by a single gene polymorphisms, rather, it may be the result of a combination of polymorphisms. Accordingly, the impact of single genes may be rather small, requiring large patient cohorts. In addition, gathering large patient cohorts prospectively, which are carefully matched according to their drug response, is extremely difficult and requires collaboration between epilepsy centers. Finally, it will be necessary to address experimentally in those cases in which polymorphisms are found in association studies whether they have biologically plausible effects that may result in pharmacoresistance. It is clearly worthwhile to exploit such strategies to the utmost, because genetic approaches can nowadays provide a genome-wide analysis at comparatively low cost. Thus, we are not limited by our preconceptions regarding the specific molecules important in pharmacoresistance.

An alternate approach to the problem of pharmacoresistance has been to examine directly the response of drug targets in epileptic tissue. This work has focused on targets such as voltage-gated sodium channels, for which AFT) responsiveness is well established. 27 Subsequently, the response of channels to AEDs was investigated in both animal models of TLE and human epilepsy. 10 In some cases, as for voltage-gated sodium channels, a loss of sensitivity of the channel complex to AEDs was found, both in experimental and human epilepsy. Importantly, such in-vitro data can be correlated with the clinical phenotype. Indeed, in the case of carbamazepine, pharmacoresistance observed clinically was found to correlate with a loss of carbamazepine sensitivity of voltage-gated sodium channels. This strategy may be integrated with genetic approaches to provide a potentially very informative approach to pharmacoresistance. The increasing availability of genetic information also on epilepsy patients who undergo epilepsy surgery opens the possibility to perform genetic analyses on key molecules implicated in the response to AEDs (ie, ion channels, presynaptic proteins, or drug transporters). Subsequent to the epilepsy surgery, a number of experiments can be done on human tissue from these patients. Firstly, ion channel or drug transporter function can be assessed directly. Secondly, seizure activity can be elicited in human brain slices, and the pharmacoresponse of this activity can be quantitatively determined. In both cases, a correlation with genetic information can provide useful information on the functional relevance of genetic variability.

The analyses in human tissue - while potentially very useful - are hampered by the fact that human tissue is only available from a subgroup of epilepsy patients. This has sparked a quest for other suitable human model systems. One possibility is to use cells generated from human embryonic stem cells and differentiated into either neurons or glial cells in vitro. This approach would permit to test the effects of antiepilcptic drugs in a cell model with a human background. Alternatively, it may be possible to isolate adult human stem cells from epilepsy surgical specimens, amplify them and generate appropriate neural populations. The latter approach has the advantage that the genetic phenotype of the patient is available for individual interpretation of differential drug responses. In addition to experiments aimed at understanding mechanisms of drug resistance, and the development of new drugs, other avenues for treatment of epilepsy have been explored. One of these avenues is the transplantation of defined neuronal populations into either the epileptic focus itself or into sites that contribute to seizure generalization. It has been shown that such approaches can ameliorate seizure activity. 28 An alternate approach is to predict and prevent seizures with invasive recording and stimulation techniques. 29 Seizure prediction is a field of great interest in the clinical and basic neuroscience communities. This is not only because of its potential clinical application in warning and therapeutic antiepilcptic devices, but also for its promise of increasing our understanding of the mechanisms underlying epilepsy and seizure generation.

Mechanisms of cognitive deficits associated with epilepsy

Epilepsy is frequently associated with cognitive deficits that may be due to an a-priori brain pathology, plastic changes induced by the epilepsy, adverse effects of drug treatment, or epilepsy surgery. The prevalence and clinical importance of cognitive deficits has triggered intense research activity in this field, in particular concerning preand postsurgical memory and language impairments. However, epilepsy and the employed invasive diagnostic and therapeutic procedures also provide neuroscientists with a unique and unprecedented opportunity to study the neurophysiological basis of cognition and emotions in vivo. The specific techniques that can be used for such clinical and cognitive analyses are, for instance, recordings from implanted depth electrodes, which provide a high temporal resolution of activity in the cortex or deeper brain structures, in particular the hippocampus. 30 - 32 In addition to recording activity from collective neuronal behavior, single unit activity from temporal lobe neurons can be analyzed, thereby enabling the analysis of cognitive functions at the single cell level. 33 Complementing these techniques, functional imaging techniques offer high spatial resolution but less precise temporal information about neuronal activity. They also permit functional analysis of areas in which electrode placement is clinically unnecessary, and allow the analysis of structural and functional changes of connectivity. The combination of these techniques is of considerable interest, primarily because they are complementary with regard to spatial and temporal resolution. It will therefore constitute a fundamental advance to acquire combined (ic, simultaneous) intracranial electroencephalogram (EEG)/single unit and functional magnetic resonance imaging (fMRT) data during cognitive tasks. While this will also contribute significantly to resolving the current debate about the neuronal correlate of fMRI signals in humans, combining these technologies will enable the investigation of the “brain at work” at an unprecedented degree of accuracy. A clinical demand also exists for such combined recordings (ie, the detection of seizure foci with spike-triggered fMRI). A simultaneous recording of intracranial EEG/single units and fMRI is in principle possible. Several companies are currently performing safety evaluations with pending applications for approval of their intracranial electrodes for use within fMRI scanners.

So far, analyses utilizing intracranial EEG recordings have allowed important insights into the function of mesial temporal lobe structures in the human, and have allowed to directly study mechanisms underlying episodic memory processes and their plasticity due to hippocampal dysfunction in the human. They have also resulted in an increased understanding of the perception and production of language, and declarative memory functions related to language. Interesting areas that can be studied using such techniques are also those aimed at understanding how the human amygdala and hippocampus process fear and emotional stimuli. Interaction with researchers of other disciplines, such as economy and social sciences, may permit the investigation of human problem-solving mechanisms employing realistic paradigms. A further interesting avenue is to conduct pharmacological in-vivo studies, in which pharmacological manipulations are performed in healthy subjects and epilepsy patients (ie, N-methyl-D-aspartate [NMDA] receptor antagonists), both during invasive depth electrode recordings and fMRI experiments. 34 These approaches have proven important to dissect out the contribution of specific neurotransmitter systems to cognitive functions. They also potentially provide an endophenotype that may predict drug efficacy or side effects.

Apart from functional imaging techniques, modem imaging technologies provide an unprecendented look at structural changes in the human brain associated with epilepsy. It has become increasingly clear that both functional (ie, an hyperexcitablc focus) or structural lesions can lead to shifts in the local representation of function in the brain, and to substantial changes in functional and structural connectivity between brain areas. Using modern structural and functional MRI techniques, such as diffusion tensor imaging or dynamic causal modeling, allows analysis of such changes in human subjects with excellent spatial resolution, with respect to the functions described above. Such experiments will reveal the properties and time course of structural and functional disease associated plasticity, as well as which aspects of this plasticity can be influenced (ie, by seizure suppression or epilepsy surgery).

Relationship of epilepsy to other neurological disorders

It is becoming increasingly clear that key molecules and mechanisms responsible for the development of epilepsy may also be pivotal in other neurological disorders. For instance, evidence from animal studies suggests that mechanisms of neuronal degeneration may be very similar in models of epilepsy, trauma, ischemia, and perhaps other chronic neurodegenerative disorders. Furthermore, the conversion of glial cells to a reactive phenotype occurs not only in epilepsy, but also in a wide range of neurological disorders. There are numerous other examples for stereotypical, disease-associated plastic changes in neurons in different neurological disorders. In addition to these similarities, genetic studies also suggest shared susceptibility factors. These shared molecular mechanisms are thought to underlie the phenomenon of comorbidity (ie, an epidemiological association of epilepsy with other disorders). Since it is likely that comorbidity results from a shared genetic susceptibility, genetic approaches are well-suited for identifying these common pathways. An important further aspect is the availability of human brain tissue in the context of an epilepsy surgical center for cellular and molecular analyses, as well as in-vitro physiology and pharmacology experiments. These human brain materials represent a unique resource for the assessment of specific pathophysiological hypotheses, especially in combination with tissues from appropriate animal models. Furthermore, frequent comorbid disorders, such as depression, occur often enough within epilepsy patient collectives to allow relevant numbers of experiments using a combination of in-vivo physiology and fMRI, on matched groups of epilepsy patients with and without comorbid disorders. In contrast to electrophysiological recordings, which can only be done on epilepsy patients, fMRI studies can be performed on both epilepsy patients, nonepileptic patients with comorbidity (ie, depression or migraine), and control subjects. These experiments will yield unique insights as to the relationship between epilepsy, comorbid disorders, and cognitive processes. They will also allow us to examine the effects of drugs used in other CNS disorders on cognitive processes with high resolution.

In summary, the study of the neurobiological basis of epilepsy using approaches that integrate genetic, human functional and behavioral studies, and work on animal models, is important for developing novel therapeutic strategies. It is also one of the few existing research approaches that can be utilized to examine the function of the human brain at high temporal, spatial, and cellular resolution.

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The inside experience of epilepsy: An essay about the importance of subjectivity

Affiliation.

• 1 Danish Epilepsy Centre Filadelfia, Dianalund, Denmark; Programa de Pós-Graduação em Ciências Médicas, Universidad Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: [email protected].
• PMID: 33531199
• DOI: 10.1016/j.seizure.2021.01.006

This essay addresses three aspects of the inside experience of epilepsy, i) the high semiological significance of subjective seizure symptoms, ii) the therapeutic consequences, both positive and negative, of subjective seizure experiences, and iii) the importance of recognizing the patient as the 'inside expert' of epilepsy. Subjective symptoms are often not spontaneously reported but ignoring them may be associated with serious risks. They can be experienced as neutral, negative or positive, and this can have important consequences for therapy. Only patients have full and first-hand knowledge of subjective symptoms but an understanding of these symptoms and an adequate response to them requires expert assistance. The inside and outside views of seizures are different but of equal importance. To get the full picture, both are needed to supplement each other.

Keywords: Epilepsy surgery; Isolated aura; Patient-doctor relation; Psychoeducation; Seizure arrest; Seizure semiology.

Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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Epilepsy Society

Research papers

Please find below a lay summary of research recently published in open access journal by staff based at the Chalfont Centre for Epilepsy.

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Published on 23 February 2020

Updated: 12 July 2022

Authored by Anonymous

Perampanel in routine clinical use across Europe: Pooled, multicenter, observational data.

Authors Rohracher A, Zimmermann G, Villanueva V, Garamendi I, Sander JW, et al.

Journal details Epilepsia. 2018; 59:1727-1739.

Lay summary One of the limitations of clinical trials is related to the difficulty to interpret or generalize the results because the studied population is very different from the population treated in normal life. In this report the researchers aimed to generate real-world evidence of health information from data reflecting routine clinical use over the past 4 years; from a wide variety of people with epilepsy, including those typically underrepresented such as the elderly members of the population who are being treated with the antiepileptic drug Perampanel (sold under the trade name Fycompa). Information was collected from over 2300 patients who had been prescribed this medicine from over 45 centres across Europe. The Perampanel related adverse side effects found in this study were similar to previous reports documenting routine clinical use, no new Perampanel related side effects were found in this study, adverse side effects such as dizziness were less frequent in people, than those events reported in the clinical trials. It was concluded that Perampanel was effective in routine clinical use in a wide variety of people whose epilepsy was not controlled.

The landscape of epilepsy-related GATOR1 variants

Authors  Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez- Hernandez L, Krithika S, et al

Journal details Genet Med. 2019; 21:398-408

Lay summary The objective of this study was to gain further understanding of the three genes that are involved in forming the GATOR1 protein complex (GAP activity towards rags complex 1); mutations in these genes are known to play a role in causing focal epilepsies. The researchers extracted DNA of 73 people with focal epilepsy and looked for changes in these three genes.  The results of this study enabled detailed characterisation of epilepsy features related to GATOR1 protein complex. Additionally, it provided updated information to researchers and clinicians on all previously reported and novel GATOR1 epilepsy-related gene changes complete with new guidance for their clinical interpretation.

Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug- resistant epilepsy.

Authors Schoeler NE, Leu C, Balestrini S, Mudge JM, Steward CA, Frankish A, Leung MA, Mackay M, Scheffer I, Williams R, Sander JW, Cross JH, Sisodiya SM.

Journal details  Epilepsia. 2018; 59:1557-1566.

Lay summary Ketogenic dietary therapies (KDTs) are a group of high‐fat, low‐carbohydrate diets that have been used effectively as treatment options for people with drug resistant epilepsy since the early 1900s. We know that certain epilepsies, such as epilepsy with myoclonic‐atonic seizures, tuberous sclerosis complex, and Dravet syndrome, generally respond well to KDTs. However, KDTs are resource‐intensive, require dietary restriction, and can cause adverse side effects. Therefore the aim of this study was to identify a way to predict those who are likely to respond well and those who will not respond to KDTs in order to enable this dietary treatment earlier in the course of epilepsy.

In this study the researchers used a technique called genotyping in 272 patients to look for any specific signals such as changes in the DNA potentially associated with their responses to KDTs. A specific change in a gene called chromodomain Y like (CDYL) was found to be associated in individuals with poor response to KDT, where seizures were not under control. The CDYL gene is known to play a role in neural activities such as migration and therefore is a good candidate to study in more detail.

Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.

Authors Xiao F, Caciagli L, Wandschneider B, Sander JW, Sidhu M, Winston G, Burdett J, Trimmel K, Hill A, Vollmar C, Vos SB, Ourselin S, Thompson PJ, Zhou D, Duncan JS, Koepp MJ.

Journal details Epilepsia. 2018; 59:1362-1371

Lay summary This investigation took an imaging approach to study the effects of three antiepileptic drugs, Carbamazepine, Lamotrigine and Levetiracetam, on cognitive abilities of people with epilepsy. The 7 year records of functional magnetic resonance imaging (fMRI) brain scans of adult patients, who were fluent in English, were evaluated as part of their pre-surgical evaluation at the National Hospital for Neurology and Neurosurgery and Chalfont Centre for Epilepsy (UK). Activities in brain regions of patients and healthy volunteers were measured using their fMRI scans. Researchers found changes in patterns of activities involved in language tasks in patients on Lamotrigine and those on Carbamazepine showed more pronounced impairment of performance than those on lamotrigine. This study indicated that patients on Carbamazepine perform less well on a verbal fluency tests than those taking Lamotrigine and Levetiracetam. These important findings enhanced understanding of the effects of these medicines on the cognition of people with epilepsy.

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Authors Sander JW, Sisodiya SM.

Journal details International League Against Epilepsy Consortium on Complex Epilepsies. Nat Communications. 2018; 9:5269.

Lay summary This large study was conducted by the International League Against Epilepsy Consortium to help further the understanding of the genetics of the both focal and generalised epilepsies. The researchers compared the genomes of over 15,000 people with epilepsy with the genomes from over 29,000 healthy controls using a technique called genotyping.

Results of this study confirmed association of 16 regions of the genome with common epilepsies. One of these regions was a new association with juvenile myoclonic epilepsy and two novel regions were shown to be associated with focal epilepsy with hippocampal sclerosis. A total of 21 candidate epilepsy genes detected in these regions were studied further, to understand specific variants in these genes and the underlying biological mechanisms, and found a wide range of functions carried out by the products of these genes in the brain. Collectively, their findings provide new therapeutic leads that could  potentially develop into drugs for treating common types of epilepsy.

MRI PhD theses

The following are PhD theses from the ES MRI Epilepsy Imaging Group:

• Vejay Vakharia.  Computer assisted planning and robotics in epilepsy surgery.
• Bianca DeBlasi. Multi-parametric Imaging Using Hybrid PET/MR to Investigate the Epileptogenic Brain
• Lorenzo Caciagli - Neuroimaging of epilepsy: disease severity, cognitive comorbidities and endophenotypes
• Mark Nowell - Novel multimodality imaging in the planning and surgical treatment of epilepsy
• Christian Vollmar - Neuroimaging of functional and structural alterations in juvenile myoclonic epilepsy and frontal lobe epilepsy
• Britta Wandschneider - The effects of genes, antiepileptic drugs and risk of death on functional anatomy and cognitive networks in epilepsy
• Maria Feldmann - Imaging p-glycoprotein function: prediction of treatment response in mesial temporal lobe epilepsy
• Meneka Sidhu - Episodic memory in temporal lobe epilepsy
• Silvia Bonelli-Nauer - Cognitive functional MRI in temporal lobe epilepsy
• Helmut Laufs - EEG-fMRI signatures of spontaneous brain activity in healthy volunteers and epilepsy patients
• Rachel Thornton - Imaging brain networks in focal epilepsy : a prospective study of the clinical application of simultaneous EEG-fMRI in pre-surgical evaluation
• Gavin Winston - Translation of novel imaging techniques into clinical use for patients with epilepsy
• Mahinda Yogarajah - Imaging structural connections of the brain in epilepsy
• Umair Chaudhary - Haemodynamic correlates of interictal and ictal epileptic discharges and ictal semiology using simultaneous scalp video-EEG-fMRI and intracranial EEG-fMRI
• Robert Simister - Magnetic Resonance Spectroscopy as applied to epilepsy
• Serge Vulliemoz - Imaging functional and structural networks in the human epileptic brain
• Beate Diehl - Imaging correlates of the epileptogenic zone and functional deficit zone using diffusion tensor imaging (DTI)
• Khalid Hamandi - Functional MRI of focal and generalised interictal epileptiform discharges
• Afraim Salek-Haddadi - EEG-correlated functional MRI in epilepsy
• Rebecca Samson - Optimisation of quantitative magnetisation transfer (qMT) MRI to study restricted protons in the living human brain
• Robert Powell - Investigating brain structure and function in temporal lobe epilepsy
• Karsten Krakow - Imaging of epileptic activity using EEG-correlated functional MRI
• Rebecca Liu - Investigation of secondary cerebral damage in epilepsy
• Tejal Mitchell - Quantitative MRI in cerebral development disorders and epilepsy
• Fergus Rugg-Gunn - Imaging the neocortex in epilepsy with advanced MRI techniques
• Alex Everitt - The structural basis of the epilepsies: MRI and epidemiological studies
• Alexander Hammers - PET investigations in focal epilepsy
• Udo Wieshmann - New MR imaging techniques in epilepsy
• Matthias Koepp - Central benzodiazepine receptors in hippocampal sclerosis and idiopathic generalised epilepsies and opioid receptors in reading epilepsy
• Mark Richardson - Positron emission tomography investigation of cortical malformations causing epilepsy
• Wim van Paesschen - Quantitative MRI and hippocampal neuropathology of temporal lobe epilepsy
• Sanjay Sisodiya - Qualitative and quantitative analysis of MRI data from patients with epilepsy

Read how we are working to understand the genetic architecture of each individual person's epilepsy through our world leading genomics research programme.

Neuroimaging

Neuroimaging enables us to look deep inside the brain to learn more about the impact of seizures on its structure and function.

Neuropathology

The Epilepsy Society Brain and Tissue Bank is the first of its kind in the UK. It is dedicated to the study of epilepsy through brain and other tissue samples.

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Heat waves may increase the likelihood of seizures in people with epilepsy

by University College London

Heat waves can worsen abnormal excitability of the brain in people with epilepsy, finds a new small-scale patient study by clinical scientists at UCL.

The research , published in Brain Communications , used intracranial electroencephalography (icEEG) tests.

Small electrodes were inserted into the substance of the brain to measure electrical impulses to track the brain activity of nine patients being evaluated for surgical treatment of medication-resistant epilepsy at the National Hospital for Neurology and Neurosurgery in the summer months (May–August) of 2015–2022.

Genomic testing showed that none of the participants had known genetic epilepsies that are already associated with worsening of seizures during heat waves.

In London, a heat wave is defined as three or more consecutive days with daily maximum temperatures of more than 28°C.

The nine patients involved in the study were, by chance, having icEEG recordings taken during spontaneous heat waves in London, allowing the researchers to directly examine their brain activity during periods of unusually hot weather.

The researchers then compared this data to icEEG recordings taken from the patients during non–heat wave periods, while ensuring that all other conditions (apart from temperature) remained the same.

For each participant, the team logged any abnormal electrical activity across four 10-minute segments within and outside of heat waves. They also tracked all seizures.

They found that, overall, more seizures were recorded by the icEEG during heat waves compared with the non-heat wave period. Meanwhile, three patients also had more abnormal electrical brain activity aside from seizures during heat waves.

Senior author, Professor Sanjay Sisodiya (UCL Queen Square Institute of Neurology), said, "Our research shows that for some people with epilepsy—in particular those with the most severe epilepsies—higher ambient temperatures increase the likelihood of having seizures.

"This is an important finding, providing some of the first evidence that for some people who already have epilepsy, higher temperatures seen during heat waves can make their condition worse.

"Such information is important for the care of individual people with epilepsy, and also for broader efforts to ensure people with epilepsy can be kept safe as the climate changes."

The current study sample size is relatively small as icEEG is not commonly undertaken and a heat wave had to have happened, by chance, during the recording.

However, the team now hope to have a bigger prospective study, and data are currently being collected.

Professor Sisodiya said, "Despite the study's limited sample size, our findings remain valuable in the context of climate change. As global temperatures rise and extreme weather events become more frequent, understanding the effects of heat waves on brain activity is crucial."

Professor Sisodiya recently led to a review of 332 papers published across the world, that explored the scale of potential effects of climate change on neurological diseases.

The researchers found that the effect of climate change on weather patterns and adverse weather events is likely to negatively affect the health of people with brain conditions, including stroke, migraine, Alzheimer's, meningitis, epilepsy and multiple sclerosis. The new research adds to this analysis.

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