1,309
Views
19
CrossRef citations to date
0
Altmetric
Review

Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies

& ORCID Icon
Pages 2229-2242 | Published online: 12 Jul 2021

Abstract

Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients’ quality of life.

Definition of Drug Resistant Epilepsy

Drug resistant epilepsy (DRE) is defined by the International League Against Epilepsy (ILAE) as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose.Citation1 According to this definition, the single variable that should be considered is whether or not the patient is seizure-free. In contrast, neither the type of seizures, the seizure frequency nor the other epilepsy-related complications are included in this definition. However, the latter drive the handicap resulting from DRE and its consequence on quality of life (QOL) at the individual patient level and will be considered in the therapeutic management of DRE.

Several issues need to be underscored:

  • The minimum duration required to evaluate the response to an ASD might vary across patients, especially depending on the baseline seizure frequency. For a patient with several seizures per week, a follow-up of several weeks will be enough to conclude on ASD failure if seizures persist. In contrast, the evaluation period will be much longer for a patient with 1–2 seizures per year.

  • The threshold of two ASD may look arbitrary: it is related to the patterns of treatment response reported in prospective cohorts of epilepsy.Citation2Citation4 The probability of seizure-freedom after two ASD failures decreases exponentially and is less than 5% after four failures.Citation4,Citation5 It should however be reminded that spontaneous or treatment-related seizure-free period of a minimum 12 months duration is reported in almost 20–25% of adult with DRE, with an annual rate of approximately 5%.Citation6,Citation7 When the analysis is limited to patients not eligible for epilepsy surgery, the cumulative probability of achieving a 12-month seizure remission period is of 33% at 7 years.Citation8 Although this remission is typically transient, with 71% of patients relapsing within 5 years,Citation8 these data might comfort the possible benefit at individual patient level of continuing to modify the ASD regimen, even after several failures. This might particularly be relevant for patients with frequent generalized-tonic seizures, especially considering the potential impact of this active management on the risk of sudden unexpected death in epilepsy (SUDEP).Citation9

  • Only half of patients with uncontrolled seizures might meet the ILAE criteria of DRE,Citation10 suggesting the importance of re-evaluating patient’s epilepsy history before conclusion. In a study evaluating the interrater agreement of the ILAE DRE definition between members of an epilepsy expert panel and individual investigators, 19% of patients were classified as having DRE by the investigators while considered to have “undefined responsiveness” by the expert panel.Citation11 These divergences were mostly related to ASD dosage and/or the choice of the previously failed ASD.

  • ASD prematurely withdrawn before having been titrated up to efficacious dose because of adverse events are not be considered as a failure for DRE criteria.

  • Distinguishing drug-resistance from “pseudo-resistance”:

    • Treatment compliance needs to be systematically evaluated.Citation12 Beliefs about medications, mood or anxiety disorders, recent uncontrolled seizures, multiple dosage schedule, poor physician–patient relationship are factors of poor adherence.Citation12

    • Psychogenic non-epileptic seizures possibly lead to 20 to 25% of pseudo-resistance.Citation13 This issue reinforces the importance of detailed diagnostic work-up in patients who develop drug-resistance, including long-term video-EEG when the description of the ictal semiology is not clear enough to exclude the occurrence of psychogenic non-epileptic seizures. This is particularly relevant in patients who suffer from both epileptic and psychogenic non-epileptic seizures.

    • Using inefficacious, or even worsening, ASD for a dedicated epilepsy syndrome can also result in “pseudo-resistance”. This issue has mostly been observed in patients with idiopathic generalized epilepsy, including childhood/adolescent absence epilepsy or juvenile myoclonic epilepsy, in whom some ASD, such as carbamazepine, phenytoin or gabapentin, can aggravate seizure frequency or precipitate status epilepticus.Citation14 Importantly, distinguishing idiopathic generalized epilepsy from focal epilepsy may not be trivial in daily clinical practice. Focal symptoms can be reported at the onset primary generalized epilepsy seizures.Citation15 Furthermore, focal EEG abnormalities can be observed in primary generalized epilepsiesCitation16 whereas generalized EEG features have been reported in 20–67% of frontal lobe seizures.Citation17

Epidemiology and Risk Factors

The prevalence of DRE is 30% (95% CI: 19–42%). Its incidence varies from 15% (95% CI: 11–19%) in children to 34% (95% CI: 6–62%) in adultsCitation18 without variation across geographic areas. Among patients with newly diagnosed epilepsy followed for at least two years in the Glasgow cohort, 36% were not seizure free the last year of follow-up.Citation5 The response to treatment was dynamic, with 37% of patients achieving immediate seizure freedom at the beginning, 22% suffering from initial relapses before persistent seizure-freedom, 16% with long-term DRE despite periods of transient remission.Citation2 Overall, 25% of patients were always drug resistant.Citation2 Despite the increasing number of available ASD, this picture has remained unchanged. The long-term follow-up of the Glasgow cohort thus showed that the proportion of newly diagnosed patients who developed DRE has not been modified over the past twenty years, at 64% in 2000 and 63.7% in 2018, despite the continual increase in the use of the new ASDs.Citation5

As shown in , several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy. Although a lot of variations in the definitions of the risk factors across studies limit the interpretation of available epidemiological data, the factors with the strongest association with DRE are epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam.Citation18 Although number of seizures before treatment initiation has been suggested to be a risk factor for DRE, delaying treatment initiation in patients who have presented one or two seizures does not modify the probability of achieving seizure freedom.Citation19 Better identification of patients at high risk of DRE at treatment initiation remains an important challenge. A machine learning approach identified patients at high risk of DRE two years earlier than the current practice.Citation20 However, patterns of evolution vary among patients, with in some patients DRE present at onset;Citation3 but other experience a relapse-remitting pattern.Citation2

Table 1 Risk Factors for Developing Drug Resistant Epilepsy

DRE can occur in all types of epilepsy syndromes, though the risk differs across them. In particular, although idiopathic generalized epilepsies are often considered as drug responsive, the long-term remission rates ranges from 64% to 82% of treated patients.Citation21,Citation22 Long-term follow-up data thus shows that the proportion of patients who suffer from seizures despite ASD, even at low annual rate, is almost similar as the proportion of drug-resistance in adult focal epilepsy.Citation23,Citation24 Poor outcome factors for idiopathic generalized epilepsies were recently evaluatedCitation25 and were early seizure onset (before 13 years), multiple types of generalized seizures, history of status epilepticus, EEG with epileptiform activity (mainly polyspikes) and side effects of ASD. Resistance to sodium valproate was found to be the most important prognostic factor for refractory seizuresCitation26 and suggest that “drug resistant idiopathic generalized epilepsies” may not be considered unless patients have been treated with sodium valproate.

In patients with epilepsy related to a genetic etiology, drug-resistance is particularly frequent, especially in those with severe developmental and epileptic encephalopathies. For instance, drug-resistance is virtually observed in all patients with Dravet Syndrome.Citation27,Citation28 However, SCN1A mutations, which are associated with Dravet syndrome, can also be associated with Genetic Epilepsy with Febrile Seizures Plus (GEFS+),Citation29 resulting in potential implications for treatment specially to avoid pseudo-resistance. In addition, some Single Nucleotide Polymorphisms (SNPs) of the intronic regions of the SCN1A genes are significantly associated with drug resistance,Citation30 thus emerging as potential risk factors for drug resistance.

Concerning adult focal epilepsies, a great variability exists across the underlying etiologies. A diagnosis in the second decade of life, with more than one seizure with impaired awareness per month, mesial temporal sclerosis and bitemporal epilepsy are risk factors for DRE in focal epilepsy.Citation31 The drug resistance risk is higher in patients with cortical dysgenesis or hippocampal atrophy.Citation32

Pharmacological Management

Alternative Monotherapy or Adjunctive Therapy?

Although polytherapy is frequently used in patients with DRE, few evidences support a significant benefit of adjunctive therapy in comparison with alternative monotherapy. It should however be reminded that all ASDs are first evaluated as adjunctive therapy in Phase III studies conducted in patients with DRE.Citation33 Accordingly, the level of evidence about the efficacy of available ASDs in the add-on therapy in DRE is high. Rare studies compared efficacy of alternative monotherapy versus adjunctive therapy in patients who had not responded to ASD. In two studies conducted in Italy, no difference was observed between the two arms.Citation34,Citation35 However, a large majority of patients included in these studies failed only one monotherapy, and therefore did not fulfil criteria of DRE. Patients were randomized in one study, whereas the other was observational. However, because the randomized study needed to be pragmatic and adapted to clinical practice, no blinding procedure was used. Most importantly, the seizure freedom rate was very different between the two studies, suggesting different patient populations. While remission was observed whatever the treatment strategy in 72% of patients in one study,Citation35 the 12-month probability of remaining seizure-free was about 15% in the other.Citation34

On the other hand, the benefit of polytherapy in comparison with monotherapy has been indirectly shown in other studies, especially when one considers the positive impact of the association of lamotrigine and sodium valproate in patients with DRECitation36 or of clobazam with stiripentol of cannabidiol in Dravet Syndrome.Citation37,Citation38

However, there are also a large amount of data demonstrating the consequences of ASD-related adverse events on patients’ quality of life.Citation39 In patients with DRE, it has been shown that the negative impact on daily quality of life of ASD-related adverse events is greater than seizure frequency,Citation40 especially when ASDs alter cognitive functioning, mood or coordination.Citation41 In this context, reducing ASD load might be beneficial in some patients, though seizure freedom is not achieved.

Overall, the choice between monotherapy and polytherapy should probably vary across patients, depending on types of seizure, seizure frequency, underlying epileptic syndrome and ASD tolerability.

Choosing ASD Upon Its Efficacy Data in DRE?

As discussed above, one of the main principles is to use ASDs adapted to the patient’s epilepsy syndrome. All licensed ASDs, but ethosuximide, stiripentol and cannabidiol, can be used in drug-resistant focal epilepsy. In idiopathic generalized epilepsy as well as in some developmental epileptic encephalopathies,Citation42 some ASDs should be used with caution, whereas broad-spectrum medications, such as levetiracetam, sodium valproate, topiramate, perampanel, barbiturates or zonisamide, may be preferred.

Beyond this principle, basing the choice of ASD on a hierarchy of efficacy between them is difficult to achieve, both in primary generalized epilepsyCitation43 and in focal epilepsies.Citation44 In the absence of head-to-head trials comparing ASDs in DRE, efficacy evaluation relies on indirect comparisons of phase III randomized placebo-controlled trials. Using this approach, no significant difference in efficacy was observed between ASD available in drug-resistant focal epilepsyCitation44 or in primary generalized epilepsy.Citation43 Another methodological approach is to compare data of the same randomized studies using network meta-analyses.Citation45 However, results were similar and mostly showed no statistically significant differences between ASDs for adjunctive therapy.Citation45 However, all these systematic reviews suffered from similar limitations.Citation44,Citation45 Because all ASDs are compared to placebo, a key issue is to assume that response to placebo is similar across studies. However, as demonstrated in other diseases, this proved to be wrong. In epilepsy, it has been shown that response to placebo is greater in children than in adultsCitation46 and, in the latter, has progressively increased over the last 20 years.Citation44 The reasons underlying this evolution are unclear but they are probably multifactorial, including variation in the regression to the mean effect, placebo effect and Hawthorne effect.Citation44 Whether or not the evolution of how the studies are coordinated, with increased number of study sites and involvement of a very large number of countries in a single trial, has also played a role remains to be determined. However, the validity of comparing placebo-controlled studies performed in the 90s with studies performed more recently is highly debatable.Citation44

Another important issue is the primary outcome of the phase III randomized placebo-controlled trials and therefore of their meta-analyses. According to the FDA and the EMA guidelines, the primary outcome of these trials is the decrease of the median monthly seizure frequency or the 50% responder rate (ie, the number of patients who achieve 50% decrease in seizure frequency during the treatment period in comparison with the baseline period), respectively. In contrast, the evaluation of the seizure freedom rate is rarely informative because of methodological issuesCitation47 and because patients included in these studies typically do not achieve period of seizure remission. Accordingly, no difference in seizure freedom rate is usually observed between ASD and placebo.Citation44 It should however be noted that a recent study evaluating a new ASD, Cenobamate, reported that 21% of patients allocated to the 400 mg arm were seizure free in comparison with 1% in the placebo group.Citation48 Although a patient can suffer from different seizure types, the data of phase III randomized placebo-controlled trials are usually informative for only one of them, corresponding to the primary outcome. For instance, patients with drug-resistant focal epilepsy can present focal seizures and focal to bilateral tonic-clonic seizures. However, phase III studies are not designed to evaluate focal to bilateral tonic-clonic seizures.Citation49 Similarly, studies evaluating ASD in drug-resistant idiopathic generalized epilepsies are typically designed to evaluate tonic-clonic seizures but are less informative for other seizure types, including absence or myoclonic seizures. The same issue has also been raised in epileptic encephalopathies, such as Lennox–Gastaut syndrome.Citation50

Improving Antiseizure Efficacy with Drugs Acting on Disease-Specific Pharmacological Targets?

The primary mechanism of action of the drugs currently available in the treatment of epilepsy can be grouped into five broad categories:Citation51 (i) Modulation of voltage-gated ion channels, (ii) modulation of neurotransmitter release, (iii) potentiation of GABAergic transmission, (iv) blockade of glutamatergic transmission, and (v) ASD with a different mechanism of action. Apart from few exceptions discussed below, these mechanisms of action share a similar effect on the epileptic networks: through modification of the excitation/inhibition balance, they decrease the excitability of the neuronal network and consequently the risk of seizure initiation or propagation. In contrast, they do not alter the pathophysiological process involved in the epileptogenesis. Accordingly, they can lead to seizure control, but none has showed an antiepileptogenic efficacyCitation52 and can be considered as a curative treatment of epilepsy.

True disease-specific treatments remain therefore very rare in DRE. A recent reviewCitation53 presented patient and etiology-adapted treatments. This approach is attractive but relies on identification of a specific etiology mainly genetic and/or metabolic. Inhibition of the mTOR pathway for the treatment of seizures in Tuberous Sclerosis Complex (TSC) could be considered as the prototypic example. Mutations of TSC1 or TSC2 genes are detected in more than 95% of patients and cause suppression of mTOR (mechanistic target of rapamycin) inhibition, producing an excessive activation of the mTOR signaling pathway and several abnormalities in cell cycle regulation. Beyond decreasing the volume of TSC-related tumors, especially giant astrocytoma or angiomyolipoma, everolimus, a drug inhibiting the mTOR pathway, significantly reduces seizure frequency in patients with TSC.Citation54 Because of the role of abnormalities in the mTOR pathways of some focal cortical dysplasia,Citation55,Citation56 antiseizure efficacy of everolimus might not be restricted to tuberous sclerosis,Citation57 but clinical data are lacking.Citation58 Few other examples of disease-specific treatments can be discussed. In patients with GLUT1 deficiency, ketogenic diet represents the standard choice because it provides ketone bodies for brain energy metabolism and thus compensates the brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers.Citation59(p1) Fenfluramine, a serotonin agonist acting on 5HT2B/C receptor, has recently been shown to have a strong antiseizure efficacy in Dravet syndrome,Citation60 in which preclinical data suggesting involvement of serotonin dysfunction in the pathogenesis of epilepsy in this syndrome.Citation61Citation63 In the future, other similar gene-specific therapy might be developed, such as the glutamatergic drug memantine in patients with mutation of GRIN2A geneCitation64 or drug acting on voltage-gated potassium channels, including Retigabine, in patients with severe epileptic encephalopathies due to mutation of KCNQ genes.Citation65

In addition to these few true disease-specific treatments, it has been suggested that some molecules might be used to target epilepsy-related pathological process that might participate to drug-resistance. Drug-resistance might partly be related to overexpression of ABC transporters, especially P-glycoprotein.Citation66 Verapamil being a competitive inhibitor of ABC transporters,Citation67 its efficacy an adjunctive treatment to ASD has been evaluated in an open-label pilot study.Citation68 However, controlled studies are required to formally evaluate its efficacy. The potential interest of diuretics in the treatment of seizures was raised several years ago.Citation69 It has been reported very often over the last twenty years that during the period of brain development and during epileptogenesis the inhibitory action of GABAergic transmission could be reversed towards an excitatory action.Citation70 This reversal of the effect of GABAergic transmission would depend on the intracellular accumulation of chlorine linked to a modification of the expression of certain membrane transporters of the latter.Citation70 Thus, whereas in the adult brain the regulation of chlorine is mainly ensured by the KCC2 transporter, which maintains a low intracellular chlorine concentration and thus a hyperpolarizing GABAergic transmission, the situation is different in the immature brain and in immatureCitation71 and adultCitation72 epileptic networks. Indeed, the sodium/potassium/chlorine exchanger NKCC1 is expressed in a pre-dominant manner, favoring the accumulation of intracellular chlorine and consequently modifying the effect of GABAergic transmission towards a depolarizing, potentially pro-epileptogenic action.Citation70 Because of its antagonistic action on NKCC1, bumetanide could be a pathway for regulating pathological network activity. Despite encouraging animal studies,Citation73 a therapeutic trial in the management of refractory seizures in neonates failed to show an antiseizure efficacy of bumetanide.Citation74 However, other NKCC1 antagonists might be developed in the future.Citation75 Numerous data have shown the importance of the inflammatory reaction during the epileptogenic process.Citation76 Accordingly, drugs with anti-inflammatory properties and/or targeting the immune system might be of interest in DRE. Blocking the interleukin 1-β pathway has thus been proposed has thus been proposed, using an antagonist of the caspase 1, VX765. Despite interesting data in rodentsCitation77 and in a phase 2a study in patients,Citation78 the phase 2b trial was stopped because of lack of efficacy. It should however be noted that in several situations, including DRE associated with limbic encephalitis.Citation79 New Onset Refractory Status Epilepticus (NORSE) or febrile infection-related epilepsy syndrome,Citation80 anti-inflammatory and/or immunosuppressive drugs must be considered.

Choosing ASD Upon Their Safety Profile?

It is clear that the factors underlying the ASD choice cannot be limited to efficacy data alone. Safety of ASD can be influenced by several factors: (i) patient’s age; (ii) patient’s gender; (iii) risk of drug–drug interactions, between ASDs and/or with non-ASD molecules; and (iv) patients’ comorbidities.

Risk of drug-related adverse effects varies across patients’ age. In children, a specific attention needs to be paid to the impact of ASD on cognitive functioning. Some ASD, including sodium valproate, can aggravate attention deficit,Citation81 which is very frequent in DRECitation82 and associated a greater risk of academic difficulties.Citation81 Nevertheless, this parameter must also be considered in adults, with particular attention to the elderly. In the later, ASD tolerability might be lower than in young adults because of decrease in drug clearanceCitation83 and/or of greater susceptibility to non-specific central nervous system side effects. The risk of fall and injury is thus greater, especially with ASD associated with increased risk of imbalance, such as sodium-channel blockers,Citation84 or of impaired alertness, including benzodiazepines.Citation85

Another important factor to consider in the elderly is drug–drug interactions, which often lead to the avoidance of enzyme inducers. This issue of drug interaction should also be anticipated regardless of age in the setting of a tumor-related epilepsy where the use of an enzyme-inducing ASD may result in a decrease in the efficacy of the chemotherapy or in women in childbearing age with oral contraception. Furthermore, the long-term association between enzyme inducers and atherosclerosis and risk of cardiovascular events might result in considering limiting the use of enzyme inducers in most patients with DRE, especially in those with additional cardiovascular risk factors.

Anticipating the safety issues related to the risk of malformations and/or cognitive deficit in children after in-utero exposition to ASD is a key rule in women of childbearing age with new-onset epilepsy.Citation86 This aspect remains mandatory in patients with DRE. Polytherapy has traditionally been considered to be associated with a higher risk of major congenital malformations than monotherapy. However, it has been shown the risks are primarily driven by the type of ASD included as polytherapy than the number of ASDs.Citation86 As a matter of fact, combination of sodium of valproate or topiramate is an independent risk factor of major congenital malformations.Citation87

Lastly, patients’ comorbidities must carefully be screened. Without going into an exhaustive list, some frequent examples can be highlighted. Psychiatric comorbidity, either depressive or anxious, is frequent in patients with DRE.Citation88 Several drugs are associated with a greater risk of psychiatric complications, including levetiracetam, topiramate, zonisamide or perampanel,Citation89,Citation90 and should be used with cautious in these patients. In contrast, other drugs, such as carbamazepine, lamotrigine or sodium valproate, are approved in the treatment of mood disorders. Some treatments are associated with weight gain and should be avoided in overweight patients. Conversely, others, such as topiramate and zonisamide, are associated with weight loss and should be used with caution in patients with eating disorders. Lamotrigine may cause sleep disturbances or be associated with headache, which is important in the context of frequent migraine comorbidity.

Using Efficacy and Safety Data to Choose ASD Upon a Rational Polytherapy Approach?

Rational polytherapy has frequently been advocated. It is typically viewed as a way to optimize the efficacy of the association of two ASDs through the complementarity of their mechanisms of action.Citation91,Citation92 However, as discussed below, this concept might primarily apply to the choice of the most appropriate balance between the expected benefit of the ASDs combination on seizure frequency and the safety profile of the later.

In theory, three situations can be encountered when two drugs are associated: (i) Additive effect, the effect of the association being the addition of each drug apart; (ii) an antagonist or infra-additive effect; or (iii) a synergistic effect corresponding to a supra-additive effect. Synergistic association is the most interesting, but the majority of preclinical and clinical studies are not designed to distinguish synergic, additive or antagonist associations.Citation51

A systematic reviewCitation93 evaluated published preclinical data with a possible synergistic effect of the association of ASD. A total of 107 studies were included, with a synergistic effect reported in 54%. However, only 65 studies had appropriate methods and only 27 had considered pharmacokinetic intracerebral variations. Accordingly, the majority of preclinical studies were not performed to distinguish synergistic, additive, and antagonistic activities of ASD.Citation93,Citation94 When restricted to studies with appropriate methods, as many synergic and antagonistic associations were observed, without correlation with the mechanisms of the ASD.Citation93

Similarly, no clinical data formally support a synergistic association between ASD. However, rare exceptions must be noticed. The most important is the association of lamotrigine and sodium valproate which proved to be better that combination of lamotrigine with carbamazepine or phenytoin. The value of this association was since reported in other studies.Citation95 As discussed above, the other exceptions have been reported in Dravet syndrome with association of stiripentol with sodium valproate and clobazamCitation37 or with association of cannabidiol and clobazam.Citation38

However, a key aspect of rational polytherapy is that it should not be only viewed as a way to improve efficacy but also as an important factor for ASD tolerability.Citation51 Associations of ASDs can favor the occurrence of adverse events.Citation92 This is particularly true for sodium channel blockers which associations can increase the risk of vertigo, ataxia, diplopia. In a pooled analysis of lacosamide data, the adverse event rate doubled when this ASD was associated another sodium channel blocker compared with association with an ASD with other mechanism of action.Citation96 Similar observations were reported for association of carbamazepine with lamotrigine.Citation97

While in newly diagnosed epilepsy, quality of life primarily associated with complete seizure control, the quality of life of patients suffering from DRE is primarily driven by the occurrence of ASD-related adverse events,Citation40 especially those affecting mood, cognition and coordination.Citation41 Anticipating the risk of occurrence of ASD-related adverse events is therefore of paramount importance. Accordingly, limiting the association of ASD with the same mechanism of action may be important.Citation51

More generally, in patients who have failed several ASDs, the decision to substitute ASD regimen to another should always be individualized in order to balance at the patient individual level the expected efficacy of the new ASD and its safety profile. Accordingly, a combination might be useful in a given patient but not pertinent in another because the risk of adverse events resulting from her/his comorbidities overcomes the potential benefit of that combination. Maintaining the same ASD regimen despite persistent seizures might thus be the best options in certain patients. However, the benefit in terms of efficacy might vary across seizure types. In patients with frequent tonic-clonic seizures, the risks of seizure-related complications, including the risk of SUDEP,Citation9 might justify pursuing active treatment revision.

Non-Pharmacological Management

Every patient with DRE should be referred to a reference tertiary center, especially in the perspective of discussing eligibility for epilepsy surgery or neurostimulation. Despite accumulating evidence about the efficacy of epilepsy surgery and the release of specific guidelines,Citation98 delay before referring to a tertiary center seems to remain stable, around 15–20 years in North America and Europe.Citation99

Epilepsy Surgery

Epilepsy surgery should primarily be considered in patients with drug-resistant focal epilepsy.Citation100 There are class I evidences showing superiority of epilepsy surgery over medical management in adults with drug-resistant temporal lobe epilepsyCitation101,Citation102 and whatever the localization in children with drug-resistant focal epilepsy.Citation103 In addition, successful surgery for epilepsy due to early brain lesions despite generalized EEG has been reported in children.Citation104

The presurgical evaluation aims to delineate the epileptogenic zone, a benefit/risk balance between resection, disconnection or destruction of a brain region and the minimum neurological deficit.Citation100 The minimal examination should include interictal scalp EEG, a dedicated MRI protocol for epilepsy, neuropsychological assessment, completed if required by functional neuroimaging.Citation100 Long-term video-EEG to capture seizures is strongly recommended.Citation100 Functional MRI is increasingly used to lateralize language and has mainly replaced Wada test in temporal lobe epilepsy.Citation105 When data at the end of this first phase are not strong enough to delineate the brain region that needs to be resected or if this latter involves eloquent cortex, invasive video-EEG recordings with intracranial electrodes, strips or grids are used.Citation106 Stereo-electro-encephalography is now the principal method for intracranial EEG monitoring in the majority of epilepsy surgery centers in Europe and in the US.Citation107

Overall, seizure freedom following epilepsy surgery is achieved by 60–80% in patients with temporal lobe epilepsy and 40–75% in patients with extra-temporal lobe epilepsy.Citation100 Moreover, the benefit on quality of life, cognitive evolution, particularly for children, and psychiatric comorbidities is positive.Citation108Citation110 This global benefit is also stated in more specific populations, including children with autism spectrum disordersCitation111 or older adults (more than 60 years).Citation112 It should be emphasized that lesion on MRI is not a prerequisite for epilepsy surgery.Citation108 In patients with MRI-negative temporal lobe epilepsy, long-term postoperative seizure-free rates vary from 40% to 60%.Citation100 Similarly, the presence of a focal MRI abnormality has not been significantly associated with outcome in extra-temporal lobe epilepsy.Citation113 However, the best results have been reported in focal cortical dysplasia type 2B, with up to 92% of patients achieving seizure freedom after a mean follow-up of 4 years, and no difference between MRI-positive and MRI-negative patients.Citation114

Magnetic resonance imaging-guided laser interstitial thermal therapy (MR-guided LiTT) is an alternative to cortical resection. Because of its minimal postoperative morbidity,Citation115,Citation116 its use is growing in mesial temporal lobe epilepsy. MR-guided LiTT as well as stereo-EEG-guided radiofrequency thermocoagulation might also be useful in patients not eligible for cortical resection including those with periventricular nodular heterotopia or hypothalamic hamartomas. About 50% of patients with periventricular nodular heterotopia can achieve seizure remission following stereo-EEG-guided radiofrequency thermocoagulation.Citation117

Neurostimulation

Neurostimulation can be separated into two groups, vagus nerve stimulation (VNS) and brain stimulation, including Deep Brain Stimulation (DBS) and Responsive neurostimulation (RNS). These approaches showed similar efficacy.Citation118

VNS is frequently proposed in patients not eligible for epilepsy surgery. The probability to achieve seizure freedom is low,Citation119 but there is a positive impact on QOL in 50% of patients.Citation120 Adverse events are not rare, with intraoperative abnormal heart rhythm, dysphonia, dysphagia, surgical site infection and sleep apnea.Citation120 Initially validated in focal epilepsy, other studies demonstrated interest of VNS in generalized epilepsies,Citation119 such as Lennox Gastaut or Dravet syndromes.

DBS proved to decrease seizure frequency in DRE. The highest level of evidence has been reported for stimulation of the anterior nucleus of the thalamus.Citation121 Long-term study reported 69% reduction in seizure frequency at five years, with two-third of 50% responders.Citation122 Other targets, including centromedian thalamus nucleus, may also be associated with antiseizure efficacy, especially in Lennox-Gastaut syndrome.Citation123

RNS is a closed-loop cortical stimulation device. Cortical strips and/or depth electrodes deliver customized neurostimulation in the seizure onset zone and prevent seizure propagation based on the electrocorticographic detection of abnormalities.Citation124 In a pivotal double-blind sham-controlled parallel-group RCT which included 191 adult patients with focal DRE, RNS system therapy showed showing an overall 29% responder rate at the end of the double-blind phase and 45% at 2 years in the open-label extension.Citation125

Diets

Ketogenic diet has proven its usefulness in children and adolescents with DRE.Citation126,Citation127 In adults, the use of ketogenic diet remains uncertain and needs further research. In case of ketogenic diet, ASD concentrations have to be monitored, due to pharmacokinetic interactions between diet and ASD.Citation128 A potential beneficial effect of probiotics in DRE has been assessed by a pilot study.Citation129 Thirty percent of patients with the probiotic mixture for four months experienced for a greater than 50% of seizure reduction, but further investigations are needed.

Comprehensive Care Adaptations

As mentioned above, the main goals in patients with DRE is to optimize quality of life. QOL determinant in DRE are multifactorial. The relation between seizure frequency and QOL is blurry, some authors showing a statistically significative association,Citation130Citation132 whereas others do not.Citation40 Conversely, poor tolerance of ASD has a negative impact on QOL, adverse events of treatment being a strong prognostic variable for QOL.Citation40

Furthermore, the existence of a psychiatric comorbidity – anxiety or depression – is independently associated with QOL alteration.Citation40,Citation133,Citation134 The burden of epilepsy could also vary according to the type of seizure, given that generalized tonic-clonic seizures, even though less frequent, are associated with more severe seizure-related complications and are associated with increased risk of depression and anxiety.Citation135 For children and adolescents, a close relation exists between QOL and cognitive impairment, particularly attention deficit.Citation82,Citation136 In adults, specific data are scarce but point to the same direction,Citation137 particularly the relation with cognitive impairment and treatment adverse events.Citation41 In patients older than 50 with drug resistant temporal epilepsy, an impaired cognitive profile (verbal memory performance) was assessed in half of patients by neuropsychological examinations.Citation138

A specific period with higher risk for these complications is the transition between adolescence and adulthood. Patients and their families face several issues, including the change from childhood neurologist to adult neurologist. Over the past years, several studies have emphasized the importance of adequately manage this critical period, especially with dedicated transitions clinics in the most difficult situations.Citation139

Psychologic Care

Epilepsy is associated with 2 or 3-fold more psychiatric comorbidities than population and about a third of drug resistant patients are affected by these latter.Citation88,Citation140 Psychiatric comorbidities include mood disorders, anxiety and some psychotic disorders. Depression prevalence is higher in epileptic population, notably in DRE, and suicide risk is three times higher than the risk in general population.Citation141 Anxiety comes next,Citation140 with panic disorder, social phobia, obsessive disorder, generalized anxiety.Citation142 More than a third of children undergoing epilepsy surgery evaluation reported unmet overall healthcare needs,Citation143 with greater risk if the patient presented depressive symptoms or with young or unemployed caregivers. In this context, monitoring and care of psychiatric comorbidities is important, especially using dedicated screening scales validated in epilepsy such as the neurological disorders depression inventory for epilepsy (NDDI-E).Citation144 Importantly, if a specific treatment is needed, epilepsy does not represent a contraindication for antidepressants, with a selective serotonin reuptake inhibitor as a first line.Citation145 VNS is also approved for refractory depression and might be useful for patients DRE and comorbid depression.Citation146 Mindfulness therapy is also associated with greater benefits than short-term psychotherapy in QOL, mood, seizure frequency, and verbal memory.Citation147

Cognitive Impairment

Many factors contribute to cognitive impairments in PWE: epilepsy etiology, seizure type, frequency, age of beginning, medical treatment. Moreover, all cognitive functions can be impact to several degrees, such as attention, language, memory, emotions, gestures, executive functions, logic, visuospatial capacities. Given the increased handicap associated with these cognitive difficulties, particularly for formation or professional projects, their early detection is a fundamental element in the ILAE care.Citation148

Education and Professional Impacts

Because occurrence of a seizure at work may expose to a risk of injury, some professional activities are not compatible with DRE. Conversely, some patients suffer from difficulties to achieve their professional objectives not because of seizures per se but because stigmatization. In order to better accompany the patients, several epilepsy centers have created epileptological and occupational physician combined consultations. In children, an individualized host project allows education in ordinary schools or with auxiliary, or adapted education.

Abbreviations

ABC transporter, adenosine triphosphate binding cassette; ASD, antiseizure drug; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; DBS, deep brain stimulation; DRE, drug resistant epilepsy; GABA, Gamma-aminobutyric acid; GEFS+, Genetic Epilepsy with Febrile Seizures Plus; GGE, genetic generalized epilepsy; ILAE, International League Against Epilepsy; MR-guided LiTT, magnetic resonance imaging-guided laser interstitial thermal therapy; NMDR, N-Methyl-d-aspartic acid receptor; mTOR, Mammalian target of rapamycin; QOL, quality of life; RNS, responsive neurostimulation; SNPs, single nucleotide polymorphisms; SUDEP, sudden unexpected death in epilepsy; TMS, transcranial repetitive stimulation; VNS, vagus nerve stimulation.

Disclosure

D.G reports has nothing to disclose.

S.R received speaker and/or consulting fees from UCB Pharma, EISAI, GW Pharma, Idiorsia, Livanova, Arvelle Therapeutics.

References

  • Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE commission on therapeutic strategies: definition of drug resistant epilepsy. Epilepsia. 2009;51(6):1069–1077. doi:10.1111/j.1528-1167.2009.02397.x19889013
  • Brodie MJ, Barry SJE, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548–1554. doi:10.1212/WNL.0b013e3182563b1922573629
  • Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314–319. doi:10.1056/NEJM20000203342050310660394
  • Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology. 2008;70(1):54–65. doi:10.1212/01.wnl.0000286959.22040.6e18166707
  • Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75(3):279. doi:10.1001/jamaneurol.2017.394929279892
  • Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62(4):382–389. doi:10.1002/ana.2116617880009
  • Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol. 2007;62(4):375–381. doi:10.1002/ana.2106417253624
  • Callaghan B, Schlesinger M, Rodemer W, et al. Remission and relapse in a drug-resistant epilepsy population followed prospectively: drug-resistant epilepsy population. Epilepsia. 2011;52(3):619–626. doi:10.1111/j.1528-1167.2010.02929.x21269287
  • Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 2011;10(11):961–968. doi:10.1016/S1474-4422(11)70193-421937278
  • Choi H, Hayat MJ, Zhang R, et al. Drug-resistant epilepsy in adults: outcome trajectories after failure of two medications. Epilepsia. 2016;57(7):1152–1160. doi:10.1111/epi.1340627265407
  • Zaccara G, Mula M, Ferrò B, et al. Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy? Epilepsia. 2019;60(1):175–183. doi:10.1111/epi.1462230585315
  • O’ Rourke G, O’ Brien JJ. Identifying the barriers to antiepileptic drug adherence among adults with epilepsy. Seizure. 2017;45:160–168. doi:10.1016/j.seizure.2016.12.00628063375
  • Anzellotti F, Dono F, Evangelista G, et al. Psychogenic non-epileptic seizures and pseudo-refractory epilepsy, a management challenge. Front Neurol. 2020;11:461. doi:10.3389/fneur.2020.0046132582005
  • Thomas P, Valton L, Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain. 2006;129(5):1281–1292. doi:10.1093/brain/awl04716513683
  • Boylan LS, Labovitz DL, Jackson SC, Starner K, Devinsky O. Auras are frequent in idiopathic generalized epilepsy. Neurology. 2006;67(2):343–345. doi:10.1212/01.wnl.0000225185.37081.9716864837
  • Lombroso CT. Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades. Epilepsia. 1997;38(7):797–812. doi:10.1111/j.1528-1157.1997.tb01467.x9579907
  • Kellinghaus C, Lüders HO. Frontal lobe epilepsy. Epileptic Disord. 2004;6(4):223–239.15634619
  • Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia. 2018;59(12):2179–2193. doi:10.1111/epi.1459630426482
  • Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet. 2005;365(9476):2007–2013. doi:10.1016/S0140-6736(05)66694-915950714
  • An S, Malhotra K, Dilley C, et al. Predicting drug-resistant epilepsy — a machine learning approach based on administrative claims data. Epilepsy Behavior. 2018;89:118–125. doi:10.1016/j.yebeh.2018.10.01330412924
  • Mohanraj R, Brodie MJ. Outcomes of newly diagnosed idiopathic generalized epilepsy syndromes in a non-pediatric setting. Acta Neurol Scand. 2007;115(3):204–208. doi:10.1111/j.1600-0404.2006.00791.x17295717
  • Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Seizure control in patients with idiopathic generalized epilepsies: EEG determinants of medication response. Epilepsy Behavior. 2010;17(4):525–530. doi:10.1016/j.yebeh.2010.02.00520227351
  • Holtkamp M, Kowski AB, Merkle H, Janz D. Long-term outcome in epilepsy with grand mal on awakening: forty years of follow-up. Ann Neurol. 2014;75(2):298–302. doi:10.1002/ana.2410324395517
  • Senf P, Schmitz B, Holtkamp M, Janz D. Prognosis of juvenile myoclonic epilepsy 45 years after onset: seizure outcome and predictors. Neurology. 2013;81(24):2128–2133. doi:10.1212/01.wnl.0000437303.36064.f824212391
  • Gomez-Ibañez A, McLachlan RS, Mirsattari SM, Diosy DC, Burneo JG. Prognostic factors in patients with refractory idiopathic generalized epilepsy. Epilepsy Res. 2017;130:69–73. doi:10.1016/j.eplepsyres.2017.01.01128157601
  • Gesche J, Khanevski M, Solberg C, Beier CP. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies. Epilepsia. 2017;58(4):e64–e69. doi:10.1111/epi.1370228230254
  • Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain. 2011;134(10):2982–3010. doi:10.1093/brain/awr12921719429
  • Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome: long-term outcome. Epilepsia. 2011;52:44–49. doi:10.1111/j.1528-1167.2011.03001.x21463279
  • Singh R, Scheffer IE, Crossland K, Berkovic SF. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol. 1999;45(1):75–81. doi:10.1002/1531-8249(199901)45:1<75::aid-art13>3.0.co;2-w9894880
  • Margari L, Legrottaglie AR, Vincenti A, et al. Association between SCN1A gene polymorphisms and drug resistant epilepsy in pediatric patients. Seizure. 2018;55:30–35. doi:10.1016/j.seizure.2018.01.00229353705
  • Roy PL, Ronquillo LH, Ladino LD, Tellez-Zenteno JF. Risk factors associated with drug resistant focal epilepsy in adults: a case control study. Seizure. 2019;73:46–50. doi:10.1016/j.seizure.2019.10.02031734466
  • Semah F, Picot M-C, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998;51(5):1256–1262. doi:10.1212/WNL.51.5.12569818842
  • Perucca E, French J, Bialer M. Development of new antiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol. 2007;6(9):793–804. doi:10.1016/S1474-4422(07)70215-617706563
  • Beghi E, Gatti G, Tonini C, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res. 2003;57(1):1–13. doi:10.1016/j.eplepsyres.2003.09.00714706729
  • Millul A, Iudice A, Adami M, et al. Alternative monotherapy or add-on therapy in patients with epilepsy whose seizures do not respond to the first monotherapy: an Italian multicenter prospective observational study. Epilepsy Behav. 2013;28(3):494–500. doi:10.1016/j.yebeh.2013.05.03823892580
  • Brodie MJ, Yuen AWC. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res. 1997;26(3):423–432. doi:10.1016/S0920-1211(96)01007-89127723
  • Chiron C, Marchand M, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet. 2000;356(9242):1638–1642. doi:10.1016/S0140-6736(00)03157-311089822
  • Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020. doi:10.1056/NEJMoa161161828538134
  • Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):792–802. doi:10.1016/S1474-4422(12)70153-922832500
  • Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology. 2004;62(1):23–27. doi:10.1212/WNL.62.1.2314718691
  • Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology. 2009;72(14):1223–1229. doi:10.1212/01.wnl.0000345667.45642.6119349601
  • Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998;39(1):5–17. doi:10.1111/j.1528-1157.1998.tb01268.x9578007
  • Rheims S, Ryvlin P. Pharmacotherapy for tonic–clonic seizures. Expert Opin Pharmacother. 2014;15(10):1417–1426. doi:10.1517/14656566.2014.91502924798217
  • Rheims S, Perucca E, Cucherat M, Ryvlin P. Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis: response to AEDs in Randomized Trials. Epilepsia. 2011. doi:10.1111/j.1528-1167.2010.02915.x
  • Thieffry S, Klein P, Baulac M, et al. Understanding the challenge of comparative effectiveness research in focal epilepsy: a review of network meta‐analyses and real‐world evidence on antiepileptic drugs. Epilepsia. 2020;61(4):595–609. doi:10.1111/epi.1647632201951
  • Rheims S, Cucherat M, Arzimanoglou A, Ryvlin P. Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy. PLoS Med. 2008;5(8):e166. doi:10.1371/journal.pmed.005016618700812
  • Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs. Epilepsia. 2007;48(7):1303–1307. doi:10.1111/j.1528-1167.2007.01136.x17521343
  • Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19(1):38–48. doi:10.1016/S1474-4422(19)30399-031734103
  • Hemery C, Ryvlin P, Rheims S. Prevention of generalized tonic-clonic seizures in refractory focal epilepsy: a meta-analysis. Epilepsia. 2014;55(11):1789–1799. doi:10.1111/epi.1276525182978
  • Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82–93. doi:10.1016/S1474-4422(08)70292-819081517
  • Guery D, Rheims S. Is the mechanism of action of antiseizure drugs a key element in the choice of treatment? Fundam Clin Pharmacol. 2020;fcp.12614. doi:10.1111/fcp.12614
  • Trinka E, Brigo F. Antiepileptogenesis in humans: disappointing clinical evidence and ways to move forward. Curr Opin Neurol. 2014;27(2):227–235. doi:10.1097/WCO.000000000000006724556736
  • Perucca P, Perucca E. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res. 2019;152:18–30. doi:10.1016/j.eplepsyres.2019.03.00130870728
  • French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a Phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153–2163. doi:10.1016/S0140-6736(16)31419-227613521
  • Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73(7):836. doi:10.1001/jamaneurol.2016.036327159400
  • Baldassari S, Ribierre T, Marsan E, et al. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol. 2019;138(6):885–900. doi:10.1007/s00401-019-02061-531444548
  • Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 2018;13(2):49–58. doi:10.2217/fnl-2018-000130505235
  • Guerrini R, Duchowny M, Jayakar P, et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia. 2015;56(11):1669–1686. doi:10.1111/epi.1320026434565
  • Klepper J, Akman C, Armeno M, et al. Glut1 Deficiency Syndrome (Glut1DS): state of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open. 2020;5(3):354–365. doi:10.1002/epi4.1241432913944
  • Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243–2254. doi:10.1016/S0140-6736(19)32500-031862249
  • Hatini PG, Commons KG. Serotonin abnormalities in Dravet syndrome mice before and after the age of seizure onset. Brain Res. 2019;1724:146399. doi:10.1016/j.brainres.2019.14639931445030
  • Griffin AL, Jaishankar P, Grandjean J-M, Olson SH, Renslo AR, Baraban SC. Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome. Brain Commun. 2019;1(1):fcz008. doi:10.1093/braincomms/fcz00831667472
  • Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017;aww342. doi:10.1093/brain/aww342
  • Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early‐onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190–198. doi:10.1002/acn3.3924839611
  • Ihara Y, Tomonoh Y, Deshimaru M, et al. Retigabine, a Kv7.2/Kv7.3-channel opener, attenuates drug-induced seizures in knock-in mice harboring Kcnq2 Mutations. PLoS One. 2016;11(2):e0150095. doi:10.1371/journal.pone.015009526910900
  • Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6(8):591–602. doi:10.1038/nrn172816025095
  • Leandro K, Bicker J, Alves G, Falcão A, Fortuna A. ABC transporters in drug-resistant epilepsy: mechanisms of upregulation and therapeutic approaches. Pharmacol Res. 2019;144:357–376. doi:10.1016/j.phrs.2019.04.03131051235
  • Asadi-Pooya AA, Razavizadegan SMA, Abdi-Ardekani A, Sperling MR. Adjunctive use of verapamil in patients with refractory temporal lobe epilepsy: a pilot study. Epilepsy Behavior. 2013;29(1):150–154. doi:10.1016/j.yebeh.2013.07.00623973639
  • Hesdorffer DC, Stables JP, Hauser WA, Annegers JF, Cascino G. Are certain diuretics also anticonvulsants? Ann Neurol. 2001;50(4):458–462. doi:10.1002/ana.113611601497
  • Ben-Ari Y, Gaiarsa J-L, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87(4):1215–1284. doi:10.1152/physrev.00017.200617928584
  • Khalilov I, Holmes GL, Ben-Ari Y. In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat Neurosci. 2003;6(10):1079–1085. doi:10.1038/nn112514502289
  • Cohen I. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298(5597):1418–1421. doi:10.1126/science.107651012434059
  • Dzhala VI, Talos DM, Sdrulla DA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11(11):1205–1213. doi:10.1038/nm130116227993
  • Pressler RM, Boylan GB, Marlow N, et al. Bumetanide for neonatal seizures-back from the cotside. Nat Rev Neurol. 2015;11(12):724. doi:10.1038/nrneurol.2015.11626526530
  • Hampel P, Römermann K, Gramer M, Löscher W. The search for brain-permeant NKCC1 inhibitors for the treatment of seizures: pharmacokinetic-pharmacodynamic modelling of NKCC1 inhibition by azosemide, torasemide, and bumetanide in mouse brain. Epilepsy Behav. 2021;114(PtA):107616. doi:10.1016/j.yebeh.2020.10761633279441
  • Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7(1):31–40. doi:10.1038/nrneurol.2010.17821135885
  • Ravizza T, Lucas S-M, Balosso S, et al. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia. 2006;47(7):1160–1168. doi:10.1111/j.1528-1167.2006.00590.x16886979
  • Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013;103(1):2–30. doi:10.1016/j.eplepsyres.2012.10.00123219031
  • Vogrig A, Joubert B, André-Obadia N, Gigli GL, Rheims S, Honnorat J. Seizure specificities in patients with antibody-mediated autoimmune encephalitis. Epilepsia. 2019;60(8):1508–1525. doi:10.1111/epi.1628231283859
  • Hirsch LJ, Gaspard N, van Baalen A, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia. 2018;59(4):739–744. doi:10.1111/epi.1401629399791
  • Rheims S, Auvin S. Attention deficit/hyperactivity disorder and epilepsy. Curr Opin Neurol. 2021;34(2):219–225. doi:10.1097/WCO.000000000000090333464761
  • Sherman EMS, Slick DJ, Connolly MB, Eyrl KL. ADHD, Neurological correlates and health-related quality of life in severe pediatric epilepsy. Epilepsia. 2007;48(6):1083–1091. doi:10.1111/j.1528-1167.2007.01028.x17381442
  • Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet. 2006;45(4):351–363. doi:10.2165/00003088-200645040-0000216584283
  • Sirven JI, Fife TD, Wingerchuk DM, Drazkowski JF. Second-generation antiepileptic drugs’ impact on balance: a meta-analysis. Mayo Clin Proc. 2007;82(1):40–47. doi:10.4065/82.1.4017285784
  • Finkle WD, Der JS, Greenland S, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc. 2011;59(10):1883–1890. doi:10.1111/j.1532-5415.2011.03591.x22091502
  • Tomson T, Battino D, Bromley R, et al. Management of epilepsy in pregnancy: a report from the International league against epilepsy task force on women and pregnancy. Epileptic Disord. 2019;21(6):497–517. doi:10.1684/epd.2019.110531782407
  • Keni RR, Jose M, Sarma PS, Thomas SV. For the Kerala Registry of Epilepsy and Pregnancy Study Group. Teratogenicity of antiepileptic dual therapy: dose-dependent, drug-specific, or both? Neurology. 2018;90(9):e790–e796. doi:10.1212/WNL.000000000000503129429975
  • Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol. 2016;12(2):106–116. doi:10.1038/nrneurol.2015.24326782334
  • Chen Z, Lusicic A, O’Brien TJ, Velakoulis D, Adams SJ, Kwan P. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain. 2016;139(10):2668–2678. doi:10.1093/brain/aww19627503872
  • Mula M. The pharmacological management of psychiatric comorbidities in patients with epilepsy. Pharmacol Res. 2016;107:147–153. doi:10.1016/j.phrs.2016.03.02227001226
  • Verrotti A, Tambucci R, Di Francesco L, et al. The role of polytherapy in the management of epilepsy: suggestions for rational antiepileptic drug selection. Expert Rev Neurother. 2020;20(2):167–173. doi:10.1080/14737175.2020.170766831855066
  • Stephen LJ, Forsyth M, Kelly K, Brodie MJ. Antiepileptic drug combinations—Have newer agents altered clinical outcomes? Epilepsy Res. 2012;98(2–3):194–198. doi:10.1016/j.eplepsyres.2011.09.00821982026
  • Jonker DM, Voskuyl RA, Danhof M. Synergistic Combinations of Anticonvulsant Agents: what Is the Evidence from Animal Experiments? Epilepsia. 2007;48(3):412–434. doi:10.1111/j.1528-1167.2006.00952.x17346245
  • Stafstrom CE. Mechanisms of action of antiepileptic drugs: the search for synergy. Curr Opin Neurol. 2010;23(2):157–163. doi:10.1097/WCO.0b013e32833735b520125013
  • Poolos NP, Warner LN, Humphreys SZ, Williams S. Comparative efficacy of combination drug therapy in refractory epilepsy. Neurology. 2012;78(1):62–68. doi:10.1212/WNL.0b013e31823ed0dd22170887
  • Sake J-K, Hebert D, Isojärvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs. 2010;24(12):1055–1068. doi:10.2165/11587550-000000000-0000021090839
  • Besag FMC, Berry DJ, Pool F, Newbery -J-JE, Subel B. Carbamazepine Toxicity with Lamotrigine: pharmacokinetic or Pharmacodynamic Interaction? Epilepsia. 1998;39(2):183–187. doi:10.1111/j.1528-1157.1998.tb01356.x9577998
  • Engel J, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in Association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology. 2003;60(4):538–547. doi:10.1212/01.WNL.0000055086.35806.2D12601090
  • Haneef Z, Stern J, Dewar S, Engel J. Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology. 2010;75(8):699–704. doi:10.1212/WNL.0b013e3181eee45720733145
  • Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol. 2014;13(11):1114–1126. doi:10.1016/S1474-4422(14)70156-525316018
  • Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311–318. doi:10.1056/NEJM20010802345050111484687
  • Engel J. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922. doi:10.1001/jama.2012.22022396514
  • Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. N Engl J Med. 2017;377(17):1639–1647. doi:10.1056/NEJMoa161533529069568
  • Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology. 2007;69(4):389–397. doi:10.1212/01.wnl.0000266386.55715.3f17646632
  • Janecek JK, Swanson SJ, Sabsevitz DS, et al. Language lateralization by fMRI and Wada testing in 229 patients with epilepsy: rates and predictors of discordance. Epilepsia. 2013;54(2):314–322. doi:10.1111/epi.1206823294162
  • Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. Lancet. 2019;393(10172):689–701. doi:10.1016/S0140-6736(18)32596-030686584
  • Gavvala J, Zafar M, Sinha SR, Kalamangalam G, Schuele S. Stereotactic EEG practices: a survey of United States tertiary referral epilepsy centers. J Clin Neurophysiol. 2020. doi:10.1097/WNP.0000000000000794
  • Ryvlin P, Rheims S. Predicting epilepsy surgery outcome. Curr Opin Neurol. 2016;29(2):182–188. doi:10.1097/WCO.000000000000030626886359
  • Jain P, Smith ML, Speechley K, et al. Seizure freedom improves health‐related quality of life after epilepsy surgery in children. Dev Med Child Neurol. 2020;62(5):600–608. doi:10.1111/dmcn.1439031709524
  • Ramos-Perdigués S, Baillés E, Mané A, et al. A prospective study contrasting the psychiatric outcome in drug-resistant epilepsy between patients who underwent surgery and a control group. Epilepsia. 2016;57(10):1680–1690. doi:10.1111/epi.1349727562413
  • Morrison-Levy N, Go C, Ochi A, et al. Children with autism spectrum disorders and drug-resistant epilepsy can benefit from epilepsy surgery. Epilepsy Behavior. 2018;85:200–204. doi:10.1016/j.yebeh.2018.06.02330032808
  • Lang JD, Grell L, Hagge M, et al. Long-term outcome after epilepsy surgery in older adults. Seizure. 2018;57:56–62. doi:10.1016/j.seizure.2018.02.01229604610
  • Lazow SP, Thadani VM, Gilbert KL, et al. Outcome of frontal lobe epilepsy surgery: outcome of Frontal Lobe Epilepsy Surgery. Epilepsia. 2012;53(10):1746–1755. doi:10.1111/j.1528-1167.2012.03582.x22780836
  • Chassoux F, Landré E, Mellerio C, et al. Type II focal cortical dysplasia: electroclinical phenotype and surgical outcome related to imaging: phenotype and Imaging in TTFCD. Epilepsia. 2012;53(2):349–358. doi:10.1111/j.1528-1167.2011.03363.x22221288
  • Kang JY, Sperling MR. Magnetic resonance imaging-guided laser interstitial thermal therapy for treatment of drug-resistant epilepsy. Neurotherapeutics. 2017;14(1):176–181. doi:10.1007/s13311-016-0498-327905093
  • Shimamoto S, Wu C, Sperling MR. Laser interstitial thermal therapy in drug-resistant epilepsy. Curr Opin Neurol. 2019;32(2):237–245. doi:10.1097/WCO.000000000000066230694919
  • Bourdillon P, Cucherat M, Isnard J, et al. Stereo-electroencephalography-guided radiofrequency thermocoagulation in patients with focal epilepsy: a systematic review and meta-analysis. Epilepsia. 2018;59(12):2296–2304. doi:10.1111/epi.1458430345535
  • Benbadis SR, Geller E, Ryvlin P, et al. Putting it all together: options for intractable epilepsy. Epilepsy Behavior. 2018;88:33–38. doi:10.1016/j.yebeh.2018.05.03030216929
  • Orosz I, McCormick D, Zamponi N, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia. 2014;55(10):1576–1584. doi:10.1111/epi.1276225231724
  • Ryvlin P, Gilliam FG, Nguyen DK, et al. The long‐term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long‐term Effectiveness) trial. Epilepsia. 2014;55(6):893–900. doi:10.1111/epi.1261124754318
  • Bouwens van der Vlis TAM, Schijns OEMG, Schaper FLWVJ, et al. Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy. Neurosurg Rev. 2019;42(2):287–296. doi:10.1007/s10143-017-0941-x29306976
  • Salanova V, Witt T, Worth R, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84(10):1017–1025. doi:10.1212/WNL.000000000000133425663221
  • Velasco AL, Velasco F, Jimenez F, et al. Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with lennox–gastaut syndrome. Epilepsia. 2006;47(7):1203–1212. doi:10.1111/j.1528-1167.2006.00593.x16886984
  • Skarpaas TL, Jarosiewicz B, Morrell MJ. Brain-responsive neurostimulation for epilepsy (RNS® System). Epilepsy Res. 2019;153:68–70. doi:10.1016/j.eplepsyres.2019.02.00330850259
  • Nune G, Arcot Desai S, Razavi B, et al. Treatment of drug-resistant epilepsy in patients with periventricular nodular heterotopia using RNS® System: efficacy and description of chronic electrophysiological recordings. Clin Neurophysiol. 2019;130(8):1196–1207. doi:10.1016/j.clinph.2019.04.70631163364
  • Lambrechts DAJE, de Kinderen RJA, Vles JSH, de Louw AJA, Aldenkamp AP, Majoie HJM. A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy. Acta Neurol Scand. 2017;135(2):231–239. doi:10.1111/ane.1259227027847
  • Martin-McGill KJ, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Systematic Rev. 2020. doi:10.1002/14651858.CD001903.pub5
  • Kverneland M, Taubøll E, Molteberg E, et al. Pharmacokinetic interaction between modified Atkins diet and antiepileptic drugs in adults with drug‐resistant epilepsy. Epilepsia. 2019;60(11):2235–2244. doi:10.1111/epi.1636431602644
  • Gómez-Eguílaz M, Ramón-Trapero JL, Pérez-Martínez L, Blanco JR. The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study. Benef Microbes. 2018;9(6):875–881. doi:10.3920/BM2018.001830198325
  • Leidy NK, Elixhauser A, Vickrey B, Means E, Willian MK. Seizure frequency and the health-related quality of life of adults with epilepsy. Neurology. 1999;53(1):162. doi:10.1212/WNL.53.1.16210408553
  • Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. Community Study. Epilepsia. 1996;37(2):148–161. doi:10.1111/j.1528-1157.1996.tb00006.x8635425
  • Guekht AB, Mitrokhina TV, Lebedeva AV, et al. Factors influencing on quality of life in people with epilepsy. Seizure. 2007;16(2):128–133. doi:10.1016/j.seizure.2006.10.01117157536
  • Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia. 2004;45(5):544–550. doi:10.1111/j.0013-9580.2004.47003.x15101836
  • Cramer J. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behavior. 2003;4(2):124–132. doi:10.1016/S1525-5050(03)00005-212697136
  • Sheikh SR, Thompson N, Frech F, Malhotra M, Jehi L. Quantifying the burden of generalized tonic‐clonic seizures in patients with drug‐resistant epilepsy. Epilepsia. 2020;61(8):1627–1637. doi:10.1111/epi.1660332658343
  • Sherman EMS, Slick DJ, Eyrl KL. Executive dysfunction is a significant predictor of poor quality of life in children with epilepsy. Epilepsia. 2006;47(11):1936–1942. doi:10.1111/j.1528-1167.2006.00816.x17116035
  • Giovagnoli AR, Parente A, Tarallo A, Casazza M, Franceschetti S, Avanzini G. Self-rated and assessed cognitive functions in epilepsy: impact on quality of life. Epilepsy Res. 2014;108(8):1461–1468. doi:10.1016/j.eplepsyres.2014.06.00225060995
  • Sarkis RA, McGinnis S, Rushia SN, Park S, Ansari EE, Willment KC. Growing older with drug-resistant epilepsy: cognitive and psychosocial outcomes. J Neurol. 2018;265(5):1059–1064. doi:10.1007/s00415-018-8805-z29478222
  • Camfield PR, Andrade D, Camfield CS, et al. How can transition to adult care be best orchestrated for adolescents with epilepsy? Epilepsy Behavior. 2019;93:138–147. doi:10.1016/j.yebeh.2018.12.01530642688
  • Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007. doi:10.1111/j.1528-1167.2007.01222.x
  • Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: a population-based case–control study. Lancet Neurol. 2007;6(8):693–698. doi:10.1016/S1474-4422(07)70175-817611160
  • Beyenburg S, Mitchell AJ, Schmidt D, Elger CE, Reuber M. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behavior. 2005;7(2):161–171. doi:10.1016/j.yebeh.2005.05.01416054870
  • Almanza-Sepulveda ML, Smith ML, Widjaja E. Influence of patient, caregiver, and family factors on unmet healthcare needs in children with drug-resistant epilepsy undergoing epilepsy surgery evaluation. Epilepsy Behavior. 2019;99:106502. doi:10.1016/j.yebeh.2019.10650231493734
  • Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM. Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurol. 2006;5(5):399–405. doi:10.1016/S1474-4422(06)70415-X16632310
  • Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: a review of the evidence. Epilepsy Behavior. 2016;61:282–286. doi:10.1016/j.yebeh.2016.03.02227236241
  • Conway CR, Udaiyar A, Schachter SC. Neurostimulation for depression in epilepsy. Epilepsy Behavior. 2018;88:25–32. doi:10.1016/j.yebeh.2018.06.00730212725
  • Tang V, Poon WS, Kwan P. Mindfulness-based therapy for drug-resistant epilepsy: an assessor-blinded randomized trial. Neurology. 2015;85(13):1100–1107. doi:10.1212/WNL.000000000000196726333801
  • Wilson S. the Task Force members. In response: indications and expectations for neuropsychological assessment in routine epilepsy care: report of the ILAE Neuropsychology Task Force, Diagnostic Methods Commission, 2013–2017. Epilepsia. 2015;56(8):1316–1317. doi:10.1111/epi.1305526235735