Antiepileptic Drug Therapy in Patients with Drug-Resistant Epilepsy

Abstract

Antiepileptic drug (AED) therapy starts with an accurate diagnosis of epilepsy and is followed by sequential drug trials. Seizure freedom is largely achieved by the first two drug trials; thus, epilepsy that cannot be controlled after appropriately conducted trials of the first two drugs is defined as drug-resistant epilepsy (DRE). It is still unclear which mode of pharmacotherapy, among monotherapy and polytherapy, shows better outcomes in cases of DRE. However, in a recent large hospital cohort study over past two decades, combination therapy was associated with a progressive increase in seizure-free rate than monotherapy in DRE. The benefits of polytherapy in the management of DRE might be related to the recent introduction of many new AEDs with different and novel mechanisms of action and better pharmacokinetic and tolerability profiles. These new AEDs were introduced to the market after they have proven their superiority over placebos in randomized controlled trials (RCTs) on add-on therapy in patients with DRE. Therefore, polytherapy including these new AEDs in the regimen is the approved mode of treatment for cases of DRE; this has prompted physicians to try various combinations of polytherapy to optimize the clinical outcomes. In addition, the significant discrepancies in AED responder rates between RCTs and real-world practice may support the importance of judicious use of new drugs in polytherapy by experienced epileptologists. Most experts now agree to the concept of "rational polytherapy" consisting of mechanistic combinations of AEDs exerting synergistic interactions and to the importance of continuing trials of different rational polytherapy regimens to improve the outcome of the core population of epilepsy patients in the long term.

Keywords: Drug resistant epilepsy; Monotherapy; New antiepileptic drugs; Polytherapy; Real world practice.

Figure 1

Sequential drug trials in pharmacotherapy of epilepsy. Initial monotherapy is the standard mode of therapy. If it failed, either substitution monotherapy or combination therapy is conducted according to the preference of physicians. During the era of conventional drugs, most epileptologists favored substitution monotherapy and diagnosed drug-resistant epilepsy after the failure of third drug monotherapy. In the era of new AEDs, duotherapy is increasingly undertaken after the failure of initial monotherapy, especially if the first drug was at least partially effective and well tolerable. If the second drug therapy failed, duotherapy is favored. AE, adverse effects; LAEPs, Liverpool Adverse Effect Profiles; GAD-7, Generalized anxiety disorder-7; NDDI-E, neurological disease depression inventories in epilepsy; QOL-31, quality of life-31; →, indicates options in favor; ⇢, suggests less favorable options.

Figure 2

Clinical development process of conventional and new antiepileptic drugs. Conventional AEDs were introduced to the market without any rigorous RCTs and used in both monotherapy and polytherapy simultaneously. After many years of clinical experience, monotherapy was considered the preferred mode of therapy in both newly diagnosed and drug-resistant epilepsies, which was followed by comparative monotherapy trials of conventional AEDs, which promoted CBZ, PHT, and VPA as the major drugs. New AEDs were introduced to the market after rigorous RCTs of add-on therapy in patients with DRE taking 1 to 3 AEDs, which showed that the new AEDs were superior to placebo in adjunctive therapy. Thus, the indications of new AEDs were primarily for polytherapy in patients with DRE, which stimulated physicians to exercise various regimens of polytherapy resulting in the revival of polytherapy and the practice of rational polytherapy. New AEDs, after many years of use in polytherapy, underwent comparative monotherapy RCTs for their promotion as first-line drugs for partial-onset seizures, with several of them being recognized as the drugs of choice in a few specific epilepsy syndromes. Modified from reference with permission. AED, antiepileptic drug; RCT, randomized controlled trial; AE, adverse effects; CBZ, carbamazepine; PHT, phenytoin; VPA, valproate; ESM, ethosuximide; TIG, tiagabine; PGB, pregabalin; FBM, felbamate; VGB, vigabatrin; LTG, lamotrigine; TPM, topiramate; OXC, oxcarbazepine; LEV, levetiracetam; GBP, gabapentin; ZNS, zonisamide; LCM, lacosamide; STR, stiripentol; LGS, Lennox-Gastaut syndrome; PER, perampanel; DRE, drug-resistant epilepsy.

Figure 3

Pathways of epilepsy management. Epilepsy management starts with the accurate diagnosis of seizure types and epilepsy syndromes. Initial monotherapy is the standard mode of treatment resulting in 50% of prolonged seizure freedom (≥ 12 months). If initial monotherapy failed to control seizures, physicians chose a second drug for either substitution monotherapy or duotherapy with seizure-free rates of 10–20% (or 20–40% of patients who underwent second drug therapy). Thus, about 60% of patients may achieve seizure freedom by the first two drug trials. Failure to respond to adequate trials of the first two drugs satisfied the ILAE criteria for DRE, and physicians may re-evaluate the diagnostic precision of epilepsy to exclude the possibility of pseudo-pharmacoresistance or identify the cause of drug resistance as well as ensure accurate diagnosis of epilepsy syndromes. If patients were confirmed to have DRE and had a SRES, earlier referral to epilepsy surgery may carry a higher benefit-risk ratio in comparison with continuing drug trials. If patients did not have SRES, systematic trials of the third and next drugs in various combination therapies may be required with an expectation of about 30% seizure-free outcome. If the 5th to 6th drug trials failed to control seizures, chances of seizure remission by further drug trials are small and trials of alternative therapies, including VNS, DBS, or ketogenic diet therapy may be actively pursued. Modified from reference with permission. Hx, history-taking; PEx/NEx, physical and neurological examination; MRI, magnetic resonance imaging of brain; EEG, electroencephalography; Dx, diagnosis; DRE, drug-resistant epilepsy; CCTV-EEG, closed circuit video-EEG recording; SRED, surgically remediable epilepsy syndromes; NSRED, not-surgically remediable epilepsy syndromes; VNS, vagal nerve stimulation; DBS, deep brain stimulation.

Figure 4

Patient-oriented choice of antiepileptic drugs. The concept of choice of antiepileptic drugs has changed from “disease-oriented” in the past to “patient-oriented” in the era of new AEDs. Patient-oriented choice of drugs involves selecting the most suitable drug for the patient on the basis of comprehensive multi-dimensional assessment of epilepsy, AEDs, and the patient’s condition. Modified from reference with permission. Wt, body weight; QoL: quality of life; LRE, localization-related epilepsy; GE, generalized epilepsy; LGS, Lennox-Gastaut syndrome; JME, juvenile myoclonic epilepsy; EEG, electroencephalography; EBM, evidence-based medicine; RCT, randomized controlled trial; AED, antiepileptic drug.