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P T. 2014;39(11): 776-784, 792
Perspective

Epilepsy Management: Newer Agents, Unmet Needs, and Future Treatment Strategies

C. Lee Ventola MS

INTRODUCTION

Epilepsy is a serious brain disorder with symptoms that can be treated successfully in most patients with one or more antiseizure drugs (ASDs).1 Approximately two-thirds of adults with new-onset epilepsy will achieve lasting seizure remission while taking ASDs, with about half experiencing mild-to-moderately severe adverse events (AEs) while using these agents.1 Despite the fact that drug therapy is effective for the majority of patients, significant unmet medical needs and treatment challenges remain. These include: drug-resistant epilepsy, adverse reactions, drug interactions, the need for better identification of epileptic syndromes, and a lack of anti-epileptogenic (AEG) agents that can prevent the development of epilepsy and its comorbidities.16

While many newer, second-generation ASDs cause fewer drug interactions and are better tolerated than older agents, they have not been proven to be more effective, nor have they reduced the prevalence of drug-resistant epilepsy.1 New strategies are required to fulfill these and other unmet medical needs in epilepsy management.6 Toward this goal, recent advances in drug targeting, antiepileptogenesis, and genetics have provided a better understanding of epilepsy and its management.2,3,510 Novel therapeutic approaches based on these findings are in very early stages, but they are progressing rapidly toward potentially fulfilling these unmet needs.6,7

DISEASE CHARACTERISTICS

Epidemiology

Epilepsy is one of the most common diseases of the central nervous system (CNS).4 With an estimated incidence of 34 to 76 new cases per year per 100,000 people, epilepsy affects about 70 million people worldwide.1,1013 In low- and middle-income countries, estimates of epilepsy’s prevalence are generally higher.1 The outlook for most patients with newly diagnosed epilepsy is good; around 65% to 70% achieve long-term seizure freedom with the first or second ASD prescribed.11 However, despite the availability of more than 22 ASDs, it is estimated that around 30% of newly diagnosed epilepsy patients will remain resistant to both drug monotherapy and polytherapy and will continue to experience seizures.9,10,13

Epilepsy represents a major burden for public health systems.11 In 2010, the disease burden from epilepsy was higher than that for Alzheimer’s disease and other dementias, multiple sclerosis, and Parkinson’s disease combined.1 Epilepsy also imposes a large economic burden on patients and their families, particularly in rural and remote regions where access to skilled medical care is difficult.1

Comorbidities

Epileptic seizures greatly impact patients’ quality of life, increasing risk of injury, death, and socioeconomic and educational disadvantage.9 Substantial somatic and psychiatric comorbidities are associated with epilepsy, including injury, drowning, depression, anxiety, and high suicide rates.1,10 Uncontrolled seizures and the progression of epilepsy can compromise memory, cognition, and endocrine function and can present an increased risk of morbidity.10 Mortality in patients with epilepsy, including “sudden unexplained death in epilepsy” (SUDEP), is three times the rate observed in the general population.1,10

Worldwide, epilepsy inflicts the additional hidden burden of stigmatization, prejudice, and discrimination against patients in the workplace, school, home, and community.1,13 Emotional distress, social isolation, dependence on family, poor employment opportunities, and personal injury add to the suffering of people with epilepsy.1 Because epilepsy presents serious health and psychosocial risks, the fact that the disease is often suboptimally diagnosed and managed (even in developed countries and particularly among certain socioeconomic groups) is concerning.1,9

TREATMENT

Antiseizure drugs (ASDs), also referred to as anticonvulsants or antiepileptic drugs (AEDs), are meant to prevent the occurrence of seizures in patients with epilepsy.2 Since the introduction of potassium bromide by Sir Charles Locock in 1857, ASD discovery and development have generated nearly 40 clinically effective agents.2 The proliferation of second-generation ASDs since the 1980s has provided more choices; however, since treatment is largely empirical, the number of options has also caused selection of the optimum drug for an individual patient to become a somewhat daunting process.2,14

Drug treatment and a diagnosis of epilepsy are usually recommended only after a patient has experienced two or more unprovoked seizures within a 12-month period.11 A 73% risk of seizure recurrence within four years of the two unprovoked seizures is the underlying reason for this recommendation.11 An alternative clinical definition of epilepsy that includes certain patients after their first seizure has been proposed by the International League Against Epilepsy.1 This definition includes patients with a probability of further seizures “similar to the general recurrence risk (60% or more) after two unprovoked seizures, occurring over the next 10 years,” as well as patients who have had two unprovoked seizures more than 24 hours apart, as in the previous definition.1 It is important to note that the Multicentre Study of Early Epilepsy and Single Seizures trial showed that starting an ASD after a first seizure reduces the risk of a second seizure compared with no treatment or delayed treatment.1,15

The majority of patients with new-onset epilepsy achieve seizure freedom when treated with one or more ASDs; most patients will become seizure-free on the first or second monotherapy.8,11 The response is particularly favorable for some syndromes, such as idiopathic (genetic) generalized epilepsies.5 The main factors guiding the selection of an ASD include: spectrum of activity against different seizure types and epilepsy syndromes; onset of efficacy and magnitude of clinical response; mechanism of action; patient characteristics; side-effect and drug-interaction profiles; comorbidities; convenience; availability; and medication costs.1,11,13,14 Because many of the first-line ASDs exhibit similar efficacy in new-onset epilepsy, comparative tolerability and safety are important considerations when selecting treatment.1 Special consideration is also important when treating patients who are newly diagnosed, female or elderly patients, and patients with other comorbidities.14 Unfortunately, a clear first choice for specific treatment scenarios, such as selection of the first add-on drug or use in a woman anticipating pregnancy, often does not exist.14 For these situations, there may be alternatives that are more or less optimal; however, the final choice will depend on a combination of patient factors or characteristics.14

Seizure control is the primary goal of therapy and many ASDs treat only certain syndromes, so diagnosis of the epilepsy syndrome is often the primary factor considered.13,14 Narrow-spectrum ASDs are often much more effective at treating specific epileptic syndromes or categories of seizures (i.e., partial versus generalized), while broad-spectrum agents are more often selected to treat patients with both partial and generalized seizures or undiagnosed epileptic syndromes.14 A clear diagnosis of epilepsy syndrome or seizure classification (i.e., partial or generalized) can be made about half of the time.14 If the diagnosis is unclear, treatment with a broad-spectrum ASD is preferred.14

Recent treatment guidelines issued by the American Academy of Neurology recommend that standard first-generation ASDs or newer agents such as oxcarbazepine, gabapentin, lamotrigine, or topiramate be used as first-line agents for patients with newly diagnosed epilepsy.13 About 50% of patients with new-onset focal or generalized seizures become seizure-free with the initial appropriately selected and dosed first-line ASD.1,14 Choice of first-line therapy can also be critical because many patients will remain on the initial prescribed therapy for the long term.14 A seizure-free patient may be unwilling to change therapies even if experiencing side effects.14

Many ASDs have a narrow therapeutic index and significant variations among individuals in dose requirements.13 If dosage adjustments are required, they should be made carefully with the aid of therapeutic drug monitoring to minimize potent adverse effects.13 If seizures cannot be controlled at the target dosage, the dose is gradually increased until seizure freedom is attained or unbearable AEs occur.13 If the initially prescribed drug cannot control seizures, most clinicians will substitute monotherapy treatment with an alternative ASD.13 It should be noted that ASD dose reduction can trigger a withdrawal response, seizure clusters, or status epilepticus.14 Therefore, dose reduction or removal should be performed gradually, often over many weeks.14

Combination or “add-on” therapy may be tried after a patient has been observed to be refractory to two or three ASDs that have been administered as monotherapy at maximum tolerated doses.1,13 Some drug combinations have demonstrated substantial synergy and are markedly more effective in models of seizure and epilepsy than each compound when administered alone.10 However, it should be noted that combination therapy can expose the patient to a greater risk of drug interactions, side effects, poor prognosis, and poor compliance.13 For patients with drug-resistant epilepsy, short-term randomized, controlled trials have shown that freedom from seizures declines with successive drug regimens, most markedly from the first to the third AED, especially in patients with localization-related epilepsies.1 Although substitution is preferable for patients who experience serious idiosyncratic side effects from the first drug, many physicians prefer add-on polytherapy treatment.1 It should be noted that add-on treatment has become easier to implement and maintain with the availability of second-generation, non–enzyme-inducing ASDs.1

TREATMENT CHALLENGES

Despite the introduction of many second-generation ASDs, challenges persist in several areas of epilepsy treatment, such as the lack of effective agents for refractory or drug-resistant epilepsy; the inability to treat substantial comorbidities that are present with epilepsy; the need for studies regarding targeted, optimized intervention for specific epileptic subtypes; the lack of antiepileptogenic (AEG), or “disease-modifying,” effects among available ASDs; and the persistence of AEs and drug interactions.1,26 A discussion of these challenges follows.

Drug-Resistant Epilepsy

Drug-resistant epilepsy is one of the most important challenges in epilepsy management.1 Traditionally, drug resistance is defined as the failure of seizures to respond to at least two ASDs that are appropriately chosen, adequately dosed, and used for an appropriate period.1,9 A patient may experience complete resistance to ASD treatment or may be deemed only partially responsive if seizures are reduced in frequency and/ or intensity but not eliminated.9 As previously noted, about a third of patients with newly diagnosed epilepsy experience resistance to ASD therapy.1,4,12 A recent study of the outcomes observed for newly diagnosed patients with epilepsy showed that 37% experienced early, sustained seizure freedom; 22% had delayed but sustained seizure freedom; 16% fluctuated between periods of seizure freedom and relapse; and 25% never attained seizure freedom.12 Overall, 68% of patients were seizure-free, with 62% on monotherapy.12

Pharmacoresistant epilepsy can also be defined according to the number of ASDs that a patient has tried unsuccessfully, the duration of the seizure disorder, seizure frequency, and the extent of any remission(s).3 For example, epilepsy may be considered drug-resistant if, for any reason, treatment does not stop seizures for 12 months.1 According to this broader definition, which is increasingly being used in the U.S., 36% of newly treated patients have drug-resistant seizures.1 A diagnosis of absolute drug resistance may require failure of at least six AEDs, since about 17% of patients can become seizure-free even after two to five drugs have previously failed to control their seizures.1 The mechanisms underlying drug-resistant epilepsy are still not fully understood.1 This suggests that better strategies are needed for finding more effective ASDs for the treatment of refractory epilepsy.1

Adverse Events

AEs are common in ASD therapy and have been estimated to adversely affect the quality of life for 30% to 60% of patients.1,5 The patterns of AEs can differ considerably from one ASD to another.5 Many available therapies are associated with CNS effects, such as ataxia, incoordination, dizziness, sedation, irritability, agitation, cognitive disturbance, and depression.5 Other AEs observed with ASDs include metabolic effects, idiosyncratic reactions, drug interactions, and teratogenic effects, among others.5

Many ASDs can cause significant toxicity at therapeutic doses.5 Intolerable dose-related AEs can negatively influence drug efficacy, since they may prevent the achievement of efficacious doses.5 In fact, reaching a dose that is both fully efficacious and devoid of AEs sometimes cannot be achieved.5 The development of AEs also depends on the rate of dose titration, dosage and dosing schedule, formulation, treatment duration, and patient-specific factors such as age, gender, comorbidities, comedications, and genetic factors.5 Because AEs can limit the usefulness of a potentially highly effective ASD, more effort is needed to identify preclinical animal models that can predict and eliminate common dose-related and dose-limiting toxicities.5

Drug Interactions

A risk of both pharmacokinetic and pharmacodynamic interactions often exists when drugs are combined.1 When ASDs and other medications are taken concurrently, introduced, or withdrawn, AEs and changes in efficacy can occur due to pharmacokinetic interactions between drugs that alter serum concentrations.1 Interference with hepatic drug-metabolizing enzymes can continue as long as the patient is taking an ASD, which can affect subsequent drugs that the patient is prescribed.1 Sequential monotherapy with ASDs is strongly preferred for this reason, since AEs can occur when many of these agents are combined.14

However, newer ASDs do not cause as many AEs as first-generation ASDs when they are combined.14 Therefore, it is now not uncommon for drug-resistant patients to be maintained on two, three, or even four second-generation agents.14 Still, when using any ASD drugs in polytherapy, pharmacokinetic interactions must be considered, doses should be appropriately altered, and combinations that are known to produce more AEs should be avoided.14 Ineffective drugs should be eliminated from the regimen in order to avoid drug interactions, reduce AEs, allow other drugs to be added, and/or diminish the overall drug burden on a patient’s body.14

Syndrome Diversity

Epilepsy is diverse; 30 epileptic syndromes and more than 15 seizure types have been identified.1,5,10 Although all epilepsy syndromes have seizures in common, they differ dramatically in terms of etiology, symptoms, history, and sensitivity to treatments.5,6 While drug response may be related to genetic polymorphisms, it may also be true that specific types of epilepsy respond to different drugs.7

In some cases, current medications work with exceptional success and can prevent seizures until the underlying tendency to seize disappears.7 For instance, childhood absence epilepsy responds well to several current drugs and often resolves entirely as children pass through puberty.7 This is in contrast to the many epilepsy syndromes that show varying degrees of drug resistance.7 For example, up to 30% of patients with temporal lobe epilepsy do not respond to available drugs, and when they do, patients must often be concerned about side effects. 7 For instance, choosing between topiramate and sodium valproate may also involve a choice between potential deleterious cognitive effects and weight gain, respectively.7

Several new ASDs have been shown to have highly selective efficacy, such as stiripentol (Diacomit, Biocodex) for Dravet syndrome, vigabatrin (Sabril, Lundbeck) for West syndrome, or rapamycin for seizures that occur in tuberous sclerosis complex.10 Because varying mechanisms and etiologies may underlie different epilepsy syndromes and seizure types, concern is growing that use of a broad-spectrum agent may not be the best approach to achieving higher efficacy in difficult-to-treat patient populations.10 Additionally, clinical trial designs often don’t acknowledge disease heterogeneity among patients with drug-resistant epilepsy, since experimental ASDs are not usually evaluated according to specific epilepsy syndromes in these patients.10 Better identification of the pathophysiology of the underlying epilepsy syndromes will enable clinicians to effectively identify and individualize treatment in drug-resistant patients.5

NEED FOR DISEASE-MODIFYING TREATMENTS

The need for treatments that prevent epilepsy in patients who are at risk of developing seizures—for example, those with traumatic brain injury or stroke—presents another treatment challenge.10 Typically, following a brain insult, there is a seizure-free interval (known as a latent period) that lasts from a few months to several years before the onset of spontaneous recurring epileptic seizures.10 This latent period is also typical for genetic epilepsies.10

The processes that occur during the latent period, which ultimately lead to chronic epilepsy, are referred to as “epileptogenesis.” 10 The latent period, which varies in length among different patients, may offer a window of opportunity during which an appropriate treatment may prevent or modify the epileptogenic process.10 However, the concept of a seizure-free, pre-epileptic latent period preceding clinical epilepsy has also been criticized.10 Some investigators suggest that the anti-epileptogenic (AEG) therapeutic window may be narrower than believed and that treatment may only be effective during the first few days after traumatic injury.10 Nevertheless, according to clinical observation, the development of epilepsy after a brain trauma has been seen to take months or even years; therefore, it is possible that an opportunity for disease modification may be available for a considerable period.10

COMPARISON OF NEWER VERSUS OLDER EPILEPSY DRUGS

Prior to 1993, the choice of ASDs in the U.S. was limited to phenobarbital, primidone, phenytoin, carbamazepine, valproate, and ethosuximide.13 Although these first-generation ASDs are familiar and often effective, many patients treated with them experience refractory seizures and intolerable AEs.13 Since 1975, the anticonvulsant screening program of the National Institute for Neurological Disorders and Stroke (NINDS) has tested more than 30,000 potential drugs, identifying or contributing to the identification of at least nine new ASDs.6,13 Screening programs based on classic acute-seizure models (maximal electroshock seizure and pentylenetetrazol), integrated with kindling and 6-Hz electrical stimulation models, have also continued to identify new ASDs.6

Since 1993, many second-generation ASDs have been introduced in the U.S. and Europe, each differing in efficacy spectrum, mechanism of action, pharmacokinetics, and safety and tolerability profiles.13 These include: eslicarbazepine, ezogabine/retigabine, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.13 Many of the newer agents have proven safer, better tolerated, and easier to use, with broader spectrums and reduced drug interactions than the first-generation drugs.12 However, despite these advances, overall efficacy of these ASD agents has not improved, and any advantage they provide in treating drug-resistant epilepsy is modest at best.3,13 Therefore, novel approaches to epilepsy treatment are still greatly needed.12 A representative overview of the characteristics of newer ASDs is presented in Table 1.

Efficacy of New Versus Old AEDs

A particularly disappointing aspect of epilepsy research is the lack of substantial progress in seizure control over the past 40 to 50 years.3,10 Second-generation drugs demonstrate similar efficacy to their older counterparts and have not significantly decreased the proportion of patients with drug-resistant epilepsy.6,13 This suggests that the newer drugs, using current screening practices, are likely to have only an incremental value for drug-resistant patients.6,10,11 However, the newer drugs present fewer pharmacokinetic and tolerability issues, possibly making them more useful in the long term.10,11

Many studies have compared the efficacy of new AEDs with that of older agents.13 Although the newer agents do not show superior efficacy when compared to older drugs, some have proven to be “noninferior.” 13,14 Second-generation ASDs that have undergone head-to-head trials with older agents confirming similar efficacy and equal or better tolerability in focal epilepsy include: levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide.14 Oxcarbazepine has demonstrated equivalent efficacy in comparison to carbamazepine, valproic acid, and phenytoin.13 Topiramate (100 mg and 200 mg) has demonstrated equivalent efficacy and safety when compared with 600 mg twice-daily carbamazepine for partial seizures, as well as with 1,250 mg valproic acid for idiopathic generalized seizures.13

Unfortunately, for patients with drug-resistant seizures, newer ASDs appear to provide only minimally improved outcomes, if that.5 In a recent study of newer ASDs, the proportion of patients achieving freedom from seizures rose only from 64% to 68%.5 Similarly, in a recent meta-analysis of 54 randomized, controlled, add-on trials in 11,106 patients with refractory epilepsy, the increased benefit with respect to overall efficacy when adding a newer ASD compared with placebo was 21% (defined by a 50% reduction in seizure frequency), but was only 6% for freedom from seizure.1

This lack of progress in developing more effective drugs for the treatment of epilepsy has several consequences.10 Physicians and patients don’t perceive newer ASDs to be more efficacious than older agents, so they have become less interested in prescribing or trying them, particularly since they are more costly.5,10 Payers are also hesitant to pay a premium for new drugs that aren’t any more effective than low-cost generic versions of established medications.10 Consequently, the pharmaceutical industry could potentially abandon pursuing the development of new compounds for epilepsy treatment.10

Safety and Tolerability of New Versus Old AEDs

Many studies comparing the safety and tolerability of newer versus older ASDs have found that the newer agents are often safer and better tolerated.13 One group of investigators reported that the discontinuation rate due to AEs in newly diagnosed adolescents and adults with partial or generalized epilepsy was lower in patients treated with higher doses of gabapentin (13.5%) than in patients treated with carbamazepine (24%).13 In addition, patients in the carbamazepine-treated group more frequently reported dizziness, fatigue, and somnolence.13 Gabapentin and levetiracetam also do not alter hepatic enzyme function and have been observed to cause fewer or no dermatologic hypersensitivity reactions.1,10

Another study compared treatment with lamotrigine and phenytoin in patients 14 to 75 years of age.13 A higher incidence of asthenia (29% versus 16%), somnolence (28% versus 7%), and ataxia (11% versus 0%) was observed in the phenytoin-treated group.13 However, more patients had a rash in the lamotrigine group (14%) compared with phenytoin (9%).13 In another comparison between lamotrigine and valproate monotherapy, lamotrigine was not associated with weight gain or higher androgen levels in women 15 to 50 years of age with epilepsy.13 Oxcarbazepine also exhibited few dose-related AEs in children and adolescents with epilepsy when compared with carbamazepine, valproic acid, and phenytoin.13 In another study in adult patients with previously untreated, newly diagnosed epilepsy, the discontinuation rate due to AEs was significantly lower among patients treated with oxcarbazepine (14%) than those on carbamazepine (26%).13

In another study of patients 15 to 64 years of age with partial seizures and/or generalized tonic–clonic seizures, monotherapy with vigabatrin was found to be effective and safe, with fewer cognitive side effects than carbamazepine.13 Vigabatrin was also found to be better tolerated than carbamazepine in children with newly diagnosed partial seizures.13 A representative overview of AEs commonly reported with older and newer ASDs is presented in Table 2.13

Drug-Interaction Profiles for New and Old AEDs

Although drug interactions caused by older ASDs can greatly lower the efficacy of other drugs, this is often not a problem with many newer agents that don’t induce hepatic drug-metabolizing enzymes.1 Among older-generation ASDs, carbamazepine, phenytoin, phenobarbital, and primidone are known hepaticenzyme inducers, causing a decreased plasma concentration and reduced pharmacological effect for many ASDs (e.g., tiagabine, valproic acid, lamotrigine, and topiramate) that are given concomitantly, as well as other drugs that are substrates of the same metabolic enzymes.10,13 Most of the newer ASDs interact less; for example, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other ASDs.13 With respect to interactions with other types of drugs, gabapentin and levetiracetam have the lowest potential among the newer ASD agents, while lamotrigine and topiramate are the most likely to interact.13 A representative overview of drug interactions observed with older and newer ASDs is presented in Table 3.

FUTURE TREATMENT TRENDS

New Target-Driven Approaches

In light of the persistent challenges faced in epilepsy treatment, it seems advisable to rethink conventional approaches to ASD discovery and development.10 Even with the introduction of a new generation of ASDs, a substantial population of pharmacoresistant patients remains, and although tolerability has improved, patients still experience AEs that can contribute to a poor quality of life.10 There is an urgent need for the development of new strategies that can address the remaining unmet medical needs in epilepsy management.9,10

Devising better ASDs will require applying the techniques of 21st-century drug design to this ancient disease.3 Although there are some notable exceptions, such as valproate and gabapentin, the majority of anticonvulsant agents contain an amide functional group and one or more aromatic phenyl rings (C6H5) (Figure 1).3 A wide range of anticonvulsant agents (phenobarbital, phenytoin, carbamazepine, clobazam, zonisamide, felbamate) contain these structural commonalities for good reason—these compounds work and are easy to synthesize.3 However, the continued development of drugs with this structural motif will likely result in agents that do “more of the same” and have no effect on overcoming treatment challenges.3 Therefore, the development of truly innovative agents will require the identification of novel chemical structures, as well as new pharmacological receptors.3 It has been conservatively estimated that 6 × 1015 molecules may potentially be neuroactive; some of these molecular structures should be evaluated as possible epilepsy therapeutics.3

The principal targets for ASD drugs have also historically comprised voltage-dependent sodium, potassium, and calcium channels, γ-aminobutyric acid (GABA)–metabolizing enzymes, GABAA receptors, and GABA transporters.3,8,10 To date the development of new ASDs has been based mostly on the previously presumed mechanisms of seizure generation: that is, impaired GABA-ergic inhibition and increased glutamatergic excitation.8,10 Use of these targets has resulted in ASDs that either potentiate GABA transmission (such as vigabatrin and tiagabine) or inhibit glutamate receptors (such as peram-panel).8,10 However, the view that epilepsy or seizures are due to an imbalance between GABA-ergic inhibition and glutamatergic excitation ignores the complexity of the neurotransmitter systems in the brains of patients with epileptic seizures.10

For example, new data have shown that GABA and glutamatergic neurons in the CNS have both excitatory and inhibitory roles.8 Moreover, besides synaptic glutamatergic (N-methyl-D-aspartate, kainate, aminomethylphosphonic acid) and GABA receptors, extrasynaptic receptors for amino acid transmitters have been implicated in the pathogenesis of seizures.8,10,12,14 Excitatory amino acid receptors and some synaptic proteins may also be involved in the mechanism of ASD action.8 Significant progress has been made in elucidating the role of various kinds of potassium ion channels, amino acid receptor subunits, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, gap junctions, and acid-sensing ion channels in the regulation of neuronal excitability and seizures.8 Changes in gene expression, loss-of-function or gain-of-function mutation, polymorphisms, and cellular energetic imbalance may also contribute to disturbed ligand- and voltage-dependent sodium, potassium, chloride, and calcium channel function, resulting in seizure activity.8

With respect to future directions of treatment, new molecularly characterized drug targets and direct drug delivery to the seizure focus are also expected to be significant.8 The introduction of new compounds acting through these novel pharmacological mechanisms provides hope that more effective ASDs will be discovered and that the proportion of patients with uncontrolled epilepsy will decrease substantially.8

Antiepileptogenic Drugs

An intensive research effort is focused on understanding the scientific basis of epileptogenesis.2 A therapeutic antiepileptogenic (AEG) agent must successfully intervene in the epileptogenic process, preventing the development of seizures and altering the course of the disease following treatment.2,3,5,6 ASD drugs currently marketed for the management of seizures are antiictogenic, not antiepileptogenic.3 Rather than developing new, “improved” ASDs that suppress existing seizures, a better approach might be to invent pioneering AEG agents that will nullify the need for a patient to commit to lifelong symptomatic treatment.2 Such disease-modifying therapies would ideally prevent or delay the onset of spontaneous recurrent seizures in an at-risk individual; reverse established epilepsy; and prevent or ameliorate accompanying comorbidities, such as depression and learning difficulties.2,7

Although appealing, AEG agents with these qualities are elusive in practice and remain theoretical.3 Unfortunately, there are no clinically proven AEG agents.2,3,10 Many clinical trials studying the use of available ASDs as AEG agents have yielded negative results.5 Phenytoin, phenobarbital, carbamazepine, and valproate have been rigorously studied in clinical trials for the ability to prevent the development of post-traumatic epilepsy, and none has been found to have any AEG effects.2 However, long-term treatment with ethosuximide and levetiracetam has recently demonstrated a compelling ability to reduce the development of seizures in genetic animal models of absence epilepsy, so clinical trials with these agents may be warranted.2 There is also some evidence that levetiracetam may cause a delay in kindling acquisition that persists beyond the period of drug exposure, suggesting an antiepileptogenic action.2 Topiramate has also displayed AEG qualities in animal studies.2

In addition, it is suspected that many treatments that are indicated for other diseases may be antiepileptogenic.2 Among the epileptogenic mechanisms that have been postulated are neurodegeneration, inflammation, disruption of the blood– brain barrier, and acquired and genetically encoded changes in the functional activity or expression of ion channels or transporters.2 Therefore, AEGs may potentially be found among drugs that reduce oxidative stress; modulate immune and inflammatory mechanisms; activate certain secondary messenger systems; influence thrombolysis, hematopoiesis, and angiogenesis targets; inhibit 3-methylglutaryl-coenzyme A (HMG-CoA) reductase and brain-derived neurotrophic factor (BDNF) signaling; block α2 adrenergic and cannabinoid receptors; and influence Cl− homeostasis.2

A wide range of new molecular targets with AEG activity has been identified.2 In many cases, these targets are entirely different than those that have been defined through studies of the mechanisms of action of ASDs.2 Promising strategies include the inhibition of interleukin 1β signaling by VX-765; modulation of sphingosine 1-phosphate signaling by fingolimod; activation of the mammalian target of rapamycin by rapamycin; treatment with the hormone erythropoietin; and, paradoxically, treatment with the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity.2 The fact that many of these agents are already approved for use in other diseases will facilitate the evaluation of these novel strategies in human clinical studies, which are expected.2,5

Pharmacogenomics

Large research programs are under way in the U.S. and Europe to search for genetic biomarkers that can diagnose epileptogenesis (that is, identify individuals who are at a high risk of developing epilepsy); predict the severity of epilepsy; and predict therapeutic responses.10 To advance therapeutic treatment from palliative, symptomatic seizure reduction to treatment of the underlying disease, researchers will likely have to utilize biomarker-based predictions of epileptogenesis.7 Given the complexity of epilepsy, it is unlikely that a single biomarker will be sufficient for predicting epileptogenesis; rather, a combined approach may be necessary to identify appropriate biomarkers at different stages of the disease as it evolves.10 To this end, advances in genetics have identified a number of mutations and proteins that are closely associated with an increased risk of developing epilepsy.7 In models of acquired epilepsy, alterations in gene expression that underlie various processes linked to epileptogenesis, such as cell death and survival, neuronal plasticity, or immune responses, appear to be time-specific.10

Genetic and epigenetic alterations in epilepsy are interesting sources for the identification of new targets for both seizure suppression and antiepileptogenesis.10 Given the complex pathophysiology of epilepsy, targeting transcription factors and the epigenetic mechanisms involved in transcriptional regulation seems to be a potentially effective option for therapeutic intervention.10 Other potential biomarkers that need to be validated experimentally and clinically include blood biomarkers of brain injury, inflammation, blood–brain barrier damage, and microRNA and epigenetic factors.10 Network-based systems biology approaches and bioinformatics already used in neurotrauma and Alzheimer’s disease research must be applied to identify the most predictive combinations of biomarkers for various types of epilepsy.10

There is also interest in using genetic biomarkers to determine which patients will benefit most from different drug treatments.7 It is possible that as the underlying genetic causes of different epilepsy syndromes are determined, new treatments may be designed to target them.7 For example, approximately 10% of patients with early-onset absence epilepsy may have mutations in the glucose transporter gene SLC2A1.7 Once these patients are identified through genetic sequencing, a ketogenic diet may be an effective treatment.7 Genetic screening would also avoid unnecessary trials of diet and other therapies in patients with epilepsy syndromes that have been determined to have a different etiology.7 Illustratively, focal neocortical epilepsy is more likely to require gene therapy or device implantation rather than dietary therapy.7

Ongoing advances in pharmacogenomics should help to identify novel targets for therapeutic intervention, improve our understanding of drug-resistant epilepsy, and perhaps ultimately lead to personalized prescribing of both existing ASDs and novel agents that optimize therapy for the individual patient.9 The identification of valid, predictive biomarkers will enable trials of AEG agents, reduce the risks and costs involved in drug development, and allow smaller trials in various epilepsy syndromes.5,6

CONCLUSION

Novel approaches are emerging for the development of new ASD and AEG treatment strategies.1 These offer hope for finding ASDs that have improved tolerability and drug-interaction profiles and are more effective in treating drug-resistant epilepsy, as well as AEGs that prevent the development of epilepsy before the first seizure.1,10 Our expanding knowledge regarding the pathophysiological mechanisms underlying epilepsy, the causes of drug resistance, new molecular-target-driven approaches, and the emerging role of pharmacogenomics over the past decade is expected to guide the discovery of new epilepsy treatments.1 The scientific information base is expanding rapidly, so despite some hurdles, there is cause for cautious optimism that improved ASD therapies and AEG treatments will emerge, ushering in a new era in epilepsy management.2

Figure and Tables

The structures of these six first- and second-generation ASDs all include a phenyl-amide region as a common structural feature.1722

Overview of the Characteristics of Newer ASDs1,10,14,16

Drug* Presumed Main Mechanism of Action Approved Use (FDA, EMA) Main Uses Main Limitations
Vigabatrin (1989, U.K.; 2009, U.S.) GABA potentiation Infantile spasms, complex partial seizures (currently for adjunctive use only) No clinical hepatotoxicity; use for infantile spasms, focal and generalized seizures with focal onset Not useful for absence or myoclonic seizures; causes a visual field defect and weight gain; not as efficacious as carbamazepine for focal seizures
Lamotrigine (1990, Ireland; 1994, U.S.) Na+ channel blocker Partial and generalized convulsive seizures, Lennox-Gastaut syndrome, bipolar disorder First-line drug for focal and generalized seizures Enzyme inducer, skin hypersensitivity; not as effective as valproate for new-onset absence seizures
Oxcarbazepine (1990, Denmark; 2000, U.S.) Na+ channel blocker Partial seizures First-line drug for focal and generalized seizures with focal onset Enzyme inducer, hyponatremia, skin hypersensitivity; not useful for absence or myoclonic seizures
Gabapentin (1993) Ca2+ blocker (α28 subunit) Partial and generalized convulsive seizures, postherpetic and diabetic neuralgia, restless legs syndrome No clinical hepatotoxicity; use for focal and generalized seizures with focal onset Currently adjunctive use only; not useful for absence or myoclonic seizures, and can cause weight gain; not as effective as carbamazepine for new-onset focal seizures
Topiramate (1995) Multiple (GABA potentiation, glutamate [AMPA] inhibition, sodium and calcium channel blockade) Partial and generalized convulsive seizures, Lennox-Gastaut syndrome, migraine prophylaxis First-line drug for focal and generalized seizures; no clinical hepatotoxicity Cognitive side effects, kidney stones, speech problems, weight loss; not as effective as carbamazepine for new-onset focal seizures
Tiagabine (1996 Europe, 1997 U.S.)10 GABA potentiation Adjunctive therapy in adults and children 12 years of age and older in the treatment of partial seizures16 No clinical hepatotoxicity; adjunctive use for partial seizures10 Currently for adjunctive use only; narrow spectrum, may exacerbate generalized myoclonic and absence seizures10,14
Levetiracetam (2000) SV2A modulation Partial and generalized convulsive seizures, partial seizures, GTCS, juvenile myoclonic epilepsy First-line drug (IV) for focal and generalized seizures with focal onset and myoclonic seizures; no clinical hepatotoxicity; as efficacious as carbamazepine for new-onset focal seizures Not useful for absence or myoclonic seizures; psychiatric side effects
Zonisamide (2000) Na+ channel blocker Partial seizures First-line drug for focal and generalized seizures; no clinical hepatotoxicity; non-inferior to carbamazepine for new-onset focal seizures Cognitive side effects, kidney stones, sedative, weight loss
Stiripentol (2002) GABA potentiation, Na+ channel blocker Dravet syndrome Use for seizures in Dravet syndrome; no clinical hepatotoxicity Currently for adjunctive use only
Pregabalin (2004) Ca2+ blocker (α28 subunit) Partial seizures, neuropathic pain, generalized anxiety disorder, fibromyalgia Use for focal and generalized seizures with focal onset; no clinical hepatotoxicity Currently for adjunctive use only; not useful for absence or myoclonic seizures; weight gain
Rufinamide (2004) Na+ channel blocker Lennox-Gastaut syndrome Use for seizures in Lennox-Gastaut syndrome; no clinical hepatotoxicity Currently for adjunctive use only
Lacosamide (2008) Enhanced slow inactivation of voltage-gated Na+ channels Partial seizures Use (IV) for focal and generalized seizures with focal onset; no clinical hepatotoxicity Currently for adjunctive use only
Eslicarbazepine (2009) Na+ channel blocker Partial seizures Use for focal and generalized seizures with focal onset Currently for adjunctive use only; enzyme inducer, hyponatremia
Perampanel (2012) Glutamate (AMPA) antagonist Partial seizures Use for focal and generalized seizures with focal onset Currently for adjunctive use only; not useful for absence or myoclonic seizures

AMPA = α-amino-3-hydroxy-methyl-4-isoxazolepropionic acid subtype of glutamate receptors; EMA = European Medicines Agency; FDA = U.S. Food and Drug Administration; GABA = γ-aminobutyric acid; GTCS = generalized tonic–clonic seizures on awakening; IV = intravenous; SV2A = synaptic vesicle protein

*Year in which the drug was first approved or marketed in the U.S. or Europe

Adapted with permission from BMJ,1 which is the source for all information except as otherwise noted

Adverse Effects Observed With Newer and Older ASDs14

Antiepileptic Drug Potential Adverse Effects (Not Fully Inclusive)
Bromides Drowsiness; restlessness; headache; delirium; acneiform rashes; granulomatous skin lesions; loss of appetite; pyschosis
Phenobarbital and other barbiturates Sedation, depression, and paradoxical hyperactivity in children; neurological toxicity (such as dysarthria, ataxia, and nystagmus) with increasing doses; rare hematological toxicity
Phenytoin Nystagmus; ataxia; diplopia; drowsiness; impaired concentration; gingival hyperplasia; hirsutism; hepatotoxicity and idiosyncratic reactions, including lupus-like reactions and aplastic anemia
Ethosuximide Nausea; abdominal discomfort; anorexia; drowsiness; dizziness; numerous idiosyncratic reactions; rarely, hematological toxicity
Carbamazepine Nausea; dizziness; drowsiness; diplopia; weight gain; rash; Stevens-Johnson syndrome; toxic epidermal necrolysis; hyponatremia; leucopenia; rare cases of hepatotoxicity; other idiosyncratic reactions
Valproate Dose-limiting tremor (less with controlled-release formulations); hair loss; weight gain; nausea; vomiting; hepatotoxicity; acute hemorrhagic pancreatitis; thrombocytopenia; hyperammonemia; less commonly, lethargy
Vigabatrin Headache; fatigue; dizziness; depression; permanent visual-field deficits
Felbamate Headache; nausea; dizziness; weight loss; fulminant hepatic failure; aplastic anemia
Gabapentin Somnolence; dizziness; fatigue; weight gain
Lamotrigine Hypersensitivity reactions; Stevens-Johnson syndrome (increased occurrence with rapid titration); dizziness; nausea; insomnia; headache
Tiagabine Dizziness; tremor; abnormal thinking; nervousness; abdominal pain; rare psychosis; rare convulsive status epilepticus
Topiramate Drowsiness; paresthesia; metabolic acidosis; oligohidrosis; renal calculi (most commonly reported idiosyncratic reaction); rare hepatic failure; impaired language fluency and cognition; weight loss; rarely, acute glaucoma
Levetiracetam Dizziness; somnolence; asthenia; headache; irritability; behavioral problems; depression; psychosis
Oxcarbazepine Fatigue; headache; dizziness; ataxia; diplopia; nausea; vomiting; rash; hyponatremia; Stevens-Johnson syndrome
Zonisamide Fatigue; dizziness; somnolence; anorexia; abnormal thinking; rash; Stevens-Johnson syndrome; renal calculi; aplastic anemia; oligohidrosis
Pregabalin Dizziness; somnolence; weight gain
Rufinamide Fatigue; vomiting; loss of appetite; somnolence; headache; aggravated seizures; status epilepticus
Lacosamide Dizziness; headache; nausea; diplopia
Ezogabine* Urinary retention; dizziness; somnolence; fatigue; confusion; vertigo; tremor; abnormal coordination
Perampanel Dizziness; somnolence; irritability; falls; ataxia; risk of severe changes in mood and behavior, including aggression, hostility, anger, and homicidal ideation and threats

*U.S. adopted name; known in rest of world as retigabine

Adapted with permission from Wolters Kluwer Health14

This table provides a representative sample and is not comprehensive.

Drug Interactions Observed With Newer and Older ASDs1

Drug Clinically Relevant Interactions When Added to Other Drugs, Including Antiepileptic Drugs Clinically Relevant Interactions When Other Drugs Are Added
Carbamazepine Lowers plasma concentrations of lamotrigine, tiagabine, and valproate; lowers efficacy of drugs for other disorders* Plasma concentration increased by a variety of drugs, including erythromycin, propoxyphene, isoniazid, cimetidine, verapamil, diltiazem, and fluoxetine
Clobazam No relevant change No relevant change
Eslicarbazepine Lowers plasma concentrations and lowers efficacy of other drugs* Plasma concentration reduced by enzyme inducers
Ethosuximide Uncertain Plasma concentration reduced by enzyme inducers
Felbamate Increases plasma concentrations of valproate, phenytoin, phenobarbital, and carbamazepine epoxide Plasma concentration reduced by enzyme inducers
Gabapentin No relevant change No relevant change
Lacosamide No relevant change Plasma concentration reduced by enzyme inducers
Lamotrigine No relevant change Plasma concentration increased by valproate and reduced by enzyme inducers
Levetiracetam No relevant change No relevant change
Oxcarbazepine Lowers plasma concentrations of lamotrigine, phenytoin, tiagabine, and valproate; lowers efficacy of drugs for other disorders* at doses of > 900 mg oxcarbazepine Plasma concentration reduced by enzyme inducers
Perampanel No relevant change Plasma concentration reduced by enzyme inducers
Phenobarbital Lowers plasma concentrations of lamotrigine, oxcarbazepine, phenytoin, tiagabine, and valproate; lowers efficacy of drugs for other disorders* Plasma concentration increased by valproate and felbamate
Phenytoin Lowers plasma concentrations of lamotrigine, tiagabine, and valproate; lowers efficacy of drugs for other disorders* Valproate competes for protein binding
Pregabalin No relevant change No relevant change
Primidone Lowers plasma concentrations of lamotrigine, oxcarbazepine, phenytoin, tiagabine, valproate, and others; lowers efficacy of drugs for other disorders* Plasma concentration reduced by enzyme inducers
Retigabine No relevant change No relevant change
Topiramate No relevant change Plasma concentration reduced by enzyme inducers
Valproate Higher toxicity of phenytoin, phenobarbital, and primidone (which is mainly metabolized to phenobarbital) Plasma concentration reduced by enzyme inducers
Vigabatrin No relevant change No relevant change
Zonisamide No relevant change Plasma concentration reduced by enzyme inducers

*Inducers of cytochrome P450 system

Need to monitor serum concentrations

This table provides a representative sample and is not comprehensive.

Reproduced with permission from BMJ1

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