The Selection of Antiepileptic Drugs for the Treatment of Epilepsy in Children and Adults Jorge J. Asconape, MD KEYWORDS Epilepsy Seizures Antiepileptic drugs Epilepsy is one of the most common chronic neurologic conditions, affecting as many as 45 million people worldwide. The prevalence of epilepsy in the United States has been estimated at 6 to 8 per 1000 population, with an incidence of 26 to 40 per 100,000 person-years. 1 The incidence of epilepsy has a bimodal distribution, with the highest risk observed in infancy and old age. About two-thirds of the epilepsies are localization-related or partial, and a third generalized. Of the localization-related epilepsies, about two-thirds remain of unknown etiology despite an adequate workup. Approximately 60% to 70% of patients with epilepsy have an adequate response to antiepileptic drug therapy. Most patients with new-onset epilepsy that achieve complete seizure control do so with the first or second medication that they are tried on, regardless of the drug used. 2 Failure to respond to the first 2 antiepileptic drugs (AED), at adequate doses in sequential monotherapy, anticipates refractoriness to medication, and referral to an epilepsy center should not be delayed much further. The management of epilepsy is complex, including AED, hormonal therapies, diet, immunotherapy, surgery (resective or functional), neurostimulation, and behavioral modification techniques. Pharmacologic therapy is by far the most common approach, with the other modalities typically limited to patients with pharmacoresistant epilepsies. In the past 2 decades, 12 new primary AED have been approved by the Food and Drug Administration (FDA) for the treatment of epilepsy (Table 1), making the drug selection process more complex. Some of the challenges in AED selection have been addressed in several treatment guidelines from professional societies, derived from evidence-based medicine analysis, expert opinion surveys, and numerous review articles. 3 9 These guidelines provide a comprehensive review of the available Department of Neurology, Maguire Center, Stritch School of Medicine, Loyola University Chicago, Suite 2700, 2160 South, First Avenue, Maywood, IL 60153, USA E-mail address: jasconape@lumc.edu Neurol Clin 28 (2010) 843 852 doi:10.1016/j.ncl.2010.03.026 neurologic.theclinics.com 0733-8619/10/$ see front matter ª 2010 Elsevier Inc. All rights reserved.
844 Asconape Table 1 New antiepileptic drugs Drug Brand Name Year Introduced in USA Felbamate a Felbatol 1993 Gabapentin Neurontin 1994 Lamotrigine Lamictal 1994 Lacosamide Vimpat 2009 Levetiracetam Keppra 1999 Oxcarbazepine Trileptal 2000 Pregabalin Lyrica 2005 Rufinamide Banzel 2008 Tiagabine Gabitril 1997 Topiramate Topamax 1996 Vigabatrin a Sabril 2009 Zonisamide Zonegran 2000 a Restricted used due to serious safety issues. Careful risk-benefit analysis required. literature, and are a great source of information for the clinician when tailoring therapy for an individual patient. BASIC PRINCIPLES OF DRUG SELECTION AED are primarily selected based on the seizure type to be treated. AED can be divided into 2 groups: broad-spectrum and narrow-spectrum drugs (Table 2). Narrow-spectrum drugs are typically effective in partial seizures with or without secondary generalization, somewhat effective in primarily generalized tonic-clonic seizures, and ineffective or prone to worsen absence or myoclonic seizures. Broadspectrum drugs show good efficacy in partial and generalized seizure types, being very useful in situations where the seizure type or the epilepsy syndrome has not Table 2 Spectrum of action of the commonly used antiepileptic drugs Narrow-Spectrum Drugs Partial or Secondarily Generalized Tonic-Clonic Seizures Carbamazepine Gabapentin Lacosamide Oxcarbazepine Phenobarbital Phenytoin Pregabalin Primidone Tiagabine Broad-Spectrum Drugs Partial and Generalized Seizures Lamotrigine Levetiracetam Rufinamide a Topiramate Valproate Zonisamide b a Not approved by FDA for the treatment of partial seizures. No randomized, controlled studies in idiopathic generalized epilepsies. b Class IV evidence. No randomized, controlled studies in idiopathic generalized epilepsies.
Selection of Antiepileptic Drugs 845 been well established. Pediatricians and primary care physicians ought to consider using broad-spectrum drugs rather than drugs such as phenobarbital and phenytoin, especially in children and adolescents, given the high incidence of generalized epilepsy syndromes in these age groups. Epilepsies starting in old age, on the other hand, are practically always localization-related (partial or focal). In the selection process of an AED several factors are considered, including its relative efficacy, tolerability, serious toxicity, ease of use (determined by the pharmacokinetic profile and the drug-drug interaction potential), the presence of comorbid conditions, and cost. Age and gender are also important considerations. Relative Efficacy A large body of literature including head-to-head and pivotal clinical trials suggests that AED have a fairly similar relative efficacy against partial seizures. 3 5,10 With the exception of gabapentin and tiagabine, which appear to be less potent, the rest of the drugs including the classic ones are more or less equally effective. In a given patient, however, important differences can be noted among the different AED, making the finding of the most effective drug essentially a trial and error process. Therefore, in patients with partial seizures, relative efficacy is not a useful factor in selecting a particular drug. This is not the case, however, in patients with idiopathic generalized epilepsy, where some important differences in the relative efficacy of the AED have been noted. In a recent large, pragmatic, randomized study of patients with new-onset generalized seizures, valproate was found to be more successful in retaining patients than lamotrigine and topiramate. 11 Patient retention is mostly determined by 2 factors, tolerability and efficacy. Patients on lamotrigine had almost twice the failure rate of those on valproate, mostly due to lack of efficacy, whereas patients on topiramate had a significantly higher failure rate mostly because of side effects. Unfortunately, this study did not include levetiracetam because the drug was not available at the time. Tolerability Tolerability of a drug is one of the most important factors in selecting an AED. Cognitive, behavioral, or sedative side effects frequently complicate the use of these drugs and can have a significant detrimental effect on the quality of life of the patient. These side effects tend to be slightly more common with the classic AED. The relative cognitive effects of the AED are summarized in Table 3. Behavioral reactions are most commonly observed with levetiracetam, phenobarbital, and primidone. AED with the most favorable tolerability profile include lamotrigine and oxcarbazepine. The most common side effects of the AED are shown in Table 4. Table 3 Relative cognitive effects of the antiepileptic drugs None or Minimal Some Significant Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Vigabatrin Carbamazepine Phenytoin Valproate Zonisamide Phenobarbital Primidone Topiramate
846 Asconape Table 4 Side effects of the commonly used antiepileptic drugs Drug Common Side Effects Serious Side Effects Carbamazepine Dizziness, diplopia, blurred vision, ataxia, sedation, nausea, neutropenia, rash, a hyponatremia Agranulocytosis, aplastic anemia, hepatic failure, Stevens-Johnson syndrome Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Pregabalin Rufinamide Topiramate Valproate Zonisamide Dizziness, diplopia, blurred vision, headache, nausea Dizziness, diplopia, blurred vision, insomnia, headache, rash Fatigue, dizziness, somnolence, irritability, mood swings Dizziness, diplopia, blurred vision, headache, nausea, hyponatremia Fatigue, dizziness, ataxia, nausea, confusion, gingival hyperplasia, hirsutism, osteopenia, rash Fatigue, dizziness, ataxia, diplopia, weight gain, edema Somnolence, headache, dizziness, diplopia, fatigue, nausea Drowsiness, ataxia, word-finding difficulty, difficulty concentrating, anorexia, weight loss, paresthesias, metabolic acidosis, oligohydrosis, nephrolithiasis Drowsiness, ataxia, tremor, weight gain, hair loss, thrombocytopenia, hyperammonemia Drowsiness, ataxia, difficulty concentrating, anorexia, weight loss, nausea, nephrolithiasis, oligohydrosis PR interval prolongation, atrial fibrillation, atrial flutter, multiorgan hypersensitivity Stevens-Johnson syndrome, toxic epidermal necrolysis, multiorgan failure, hepatic failure Psychosis Stevens-Johnson syndrome, toxic epidermal necrolysis Stevens-Johnson syndrome, toxic epidermal necrolysis, blood dyscrasia, pseudolymphoma, lupus-like syndrome None reported Shortened QT interval (no known clinical risk), multiorgan hypersensitivity Acute close angle glaucoma, heat stroke Hepatic failure, pancreatitis, aplastic anemia, blood dyscrasias, lupus-like syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis Aplastic anemia, rash, Stevens- Johnson syndrome, toxic epidermal necrolysis, heat stroke a HLA-B*1502 testing recommended in patients of Asian descent (haplotype associated with higher risk of Stevens-Johnson syndrome). Serious Toxicity Serious idiosyncratic reactions have been observed with practically every AED, but fortunately are rare, with some notable exceptions. Felbamate use has been associated with a high incidence of idiosyncratic reactions including aplastic anemia and liver failure. The risk of aplastic anemia is higher in females, adults, and those with a history of cytopenia or a prior allergic reaction to AED. Vigabatrin, recently approved in the United States for adjuvant therapy for partial seizures and infantile spasms, is
Selection of Antiepileptic Drugs 847 associated with an irreversible retinopathy. After an average exposure of 6 to 9 months, a gradual, progressive constriction of the visual fields has been detected, with a prevalence of 25% to 50% in adults and 15% to 30% in infants. These 2 AED have a very limited role in the therapy for epilepsy, and should only be used after a very careful risk-benefit analysis. The risk of valproate-associated hepatotoxicity is about 1 in 20,000 to 100,000, but has been found to be considerably higher in children younger than 2 years, in the presence of polytherapy or developmental problems. When all 3 risk factors are present, the risk of liver failure approaches 1 in 500. 12 Valproate should be used with caution in this age group. The risk of Stevens-Johnson syndrome or toxic epidermal necrolysis with the use of carbamazepine is significantly increased in patients with the HLA allele HLA-B*1502, found almost exclusively in people of Asian descent. 13 It has been recommended that patients of Asian ancestry be screened for this allele before initiating treatment with carbamazepine. Rash is the most common, potentially serious idiosyncratic reaction that the clinician faces in daily practice. Rash has been reported with almost every AED, but is more commonly observed with drugs such as carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and zonisamide. When facing a patient with prior history of rash, the following AED are considered safer: levetiracetam, gabapentin, pregabalin, topiramate, and valproate. Ease of Use One of the clearest advantages of the newer AED over the classic ones has been their more favorable pharmacokinetic and drug-drug interaction profiles. The older AED such as phenytoin, carbamazepine, phenobarbital, and primidone are potent inducers of the cytochrome P450 enzymatic system, resulting in significant drug-drug interactions with a long list of medications commonly used in clinical practice (Fig. 1; Table 5). 14 This enzyme-inducing effect seems to be in part responsible for the high incidence of osteopenia observed in patients taking these AED, presumably by accelerating the metabolism of vitamin D. The newer AED have much more favorable pharmacokinetics, with generally good oral bioavailability, low protein binding, linear kinetics, lack of active metabolites and low potential for drug-drug interactions (Table 6). Box 1 lists some of the shortcomings of the older AED. Comorbidities The presence of hepatic or renal insufficiency can impair the elimination of the AED, leading to accumulation of the parent drug and clinical toxicity. Avoiding drugs that Fig. 1. Effects of antiepileptic drugs on the cytochrome P450.
848 Asconape Table 5 Increased clearance of commonly used drugs in the presence of enzyme-inducing antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, and primidone) Drug Type Antiepileptic Psychiatric Cardiac Antineoplastic Anti-infective Immunosuppressants Other Increased Clearance (Higher Doses Needed) Lacosamide, lamotrigine, oxcarbazepine, rufinamide, tiagabine, topiramate, valproate, zonisamide, diazepam Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, citalopram, paroxetine, buproprion, haloperidol, chlorpromazine, clozapine, olanzapine, risperidone, quetiapine Mexiletine, quinidine, amiodarone, propranolol, metoprolol, nifedipine, felodipine, nimodipine, digoxin, lovastatin, simvastatin, dicumarol, warfarin Cyclophosphamide, busulfan, etoposide, methotrexate, teniposide, some vinca alkaloids Praziquantel, albendazole, doxycycline, nevirapine, efavirenz, delavirdine, indinavir, ritonavir, saquinavir Cyclosporine, tacrolimus Oral contraceptive pills, prednisone, theophylline, methadone Modified from Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interaction between antiepileptic drugs and other drugs. Lancet Neurol 2003;2:473 81; with permission. are eliminated predominantly by the affected organ has obvious benefits. The classic AED are mostly dependent on hepatic metabolism for their elimination and may be problematic in patients with liver disease. The relative contribution of the liver and kidney in the elimination of the newer AED is summarized in Fig. 2. Comorbid conditions in patients with epilepsy often are determinant in the selection of an AED. Certain comorbid conditions may benefit or worsen, directly or indirectly, from a particular AED. In patients with obesity, drugs such as topiramate and zonisamide are often used because of their tendency to promote weight loss. Other AED can promote weight gain. Valproate and pregabalin are associated with significant weight gain, whereas gabapentin and carbamazepine have a more modest effect. Table 6 Relative drug-drug interaction potential of the antiepileptic drugs None Low a High Ethosuximide Gabapentin Levetiracetam Pregabalin Vigabatrin Lacosamide Lamotrigine Oxcarbazepine b Rufinamide Topiramate b Tiagabine Zonisamide Carbamazepine Felbamate Phenytoin Phenobarbital Primidone Valproate a These drugs generally do not affect other drugs, but are usually targets of the High potential group. b These drugs inhibit the CYP 2C19 and may increase serum levels of phenytoin. They also have a mild, dose-dependent inducing effect on the metabolism of oral contraceptives.
Selection of Antiepileptic Drugs 849 Box 1 Pharmacokinetic issues with the older antiepileptic drugs High protein bound fraction (phenytoin, valproate) Nonlinear kinetics Saturable metabolism (phenytoin) Autoinduction (carbamazepine) Active metabolites (carbamazepine, primidone) P450 enzyme induction (phenytoin, carbamazepine, primidone, phenobarbital) P450 enzyme inhibition (valproate) Numerous drug interactions (phenytoin, carbamazepine, valproate, phenobarbital, primidone) The incidence of migraine in patients with epilepsy is higher than in the general population. Certain AED have shown good efficacy for the prophylaxis of migraine for several decades (Box 2), and often a single drug can treat both conditions effectively. Psychiatric comorbidities are extremely common in patients with epilepsy. Depression, anxiety disorders, panic disorder, psychosis, attention deficit disorders, and autistic disorders are overrepresented in patients with epilepsy. AED can have significant, either positive or negative, effects on mood. AED associated with a higher risk of depression include levetiracetam, phenobarbital, primidone, topiramate, vigabatrin, and zonisamide. AED with a positive psychotropic effect include carbamazepine, lamotrigine, oxcarbazepine, and valproate. Almost every AED can cause or worsen attention deficit disorders, but the most common offenders include phenobarbital, primidone, benzodiazepines, and vigabatrin. SELECTION OF AED IN WOMEN In young females, valproate has been associated with a higher incidence of polycystic ovarian syndrome, presenting with dysmenorrhea, anovulatory cycles, hyperandrogenism, and weight gain. The mechanism is not well understood, but the drug appears to play an important role. Enzyme-inducing AED such as phenobarbital, phenytoin, and carbamazepine increase the clearance of oral contraceptives, and may result in a pill failure unless Fig. 2. Routes of elimination of the newer antiepileptic drugs.
850 Asconape Box 2 AED use in migraine prophylaxis FDA-approved indication Valproate a Topiramate a AED without FDA-approved indication Gabapentin a Lamotrigine Levetiracetam Pregabalin Zonisamide a Class I level of evidence. higher doses are used (at least 50 mg of ethinyl estradiol). Oxcarbazepine and topiramate may also decrease the effectiveness of oral contraceptives, but they have a weaker, dose-dependent effect. Oral contraceptives increase the clearance of lamotrigine and adjustments to the dose of lamotrigine can be necessary. An increased rate of congenital malformations has been observed in the offspring of women taking AED during pregnancy. These drugs are relatively weak teratogens, and for the majority of women with epilepsy the benefits of AED therapy offset the potential risks. Information on the relative teratogenic risk of each AED is limited, and no drug can be considered safe. Valproate and phenobarbital, however, have consistently shown significantly higher malformation rates than the other AED and should be avoided whenever possible. Children exposed to valproate in utero have shown lower IQ scores and higher rates of developmental delay. Phenobarbital probably has a similar effect. The risk appears maximal with exposure during the third trimester of pregnancy. EPILEPSY IN THE ELDERLY The incidence of epilepsy increases dramatically after the age of 60 years. When the epilepsy starts late in life, it is almost always localization-related, seizures can be subtle or atypical, response to therapy is usually good, and the condition does not remit, so life-long therapy is usually required. Elderly patients with epilepsy typically have several comorbid conditions and frequently take several other drugs. AED with no drug interaction potential should be selected whenever possible. The elderly are more susceptible to some of the common side effects of AED such as dizziness or ataxia. Drugs such as carbamazepine, phenytoin, or oxcarbazepine tend to be poorly tolerated, and may increase the risk of falls in this population. Cognitive issues are also a concern, making phenytoin, phenobarbital, topiramate, or zonisamide less desirable choices. AED with a favorable profile for an elderly patient include lamotrigine, pregabalin, and levetiracetam. A slow titration and conservative maintenance doses are especially important in the elderly. DRUG OF CHOICE FOR NEWLY DIAGNOSED EPILEPSY The tradition of recognizing a first-choice drug for a certain seizure type or epilepsy syndrome is no longer practical. With so many AED available, depending on several
Selection of Antiepileptic Drugs 851 factors such age, gender, comorbidities, and cost, different patients with a similar type of epilepsy may be prescribed different AED. The following are some general practical recommendations for a hypothetical patient with no confounding factors (ie, a young male with epilepsy, otherwise healthy). New-Onset Partial Epilepsy (Partial and Secondary Generalized Tonic-Clonic Seizures) First tier: these drugs have the most favorable tolerability and pharmacokinetic profiles: Lamotrigine or oxcarbazepine are good initial choices for adults. In children, due to the increased risk of serious rash with lamotrigine, oxcarbazepine would be first choice. If cost is an overriding issue, carbamazepine is a reasonable first choice. Second tier: these drugs have some tolerability or pharmacokinetic issues: Levetiracetam (behavioral side effects), topiramate (cognitive side effects), pregabalin (weight gain), valproate (weight gain, women s issues, drug interactions), zonisamide (cognitive side effects). Obsolete: due to most unfavorable pharmacokinetic and tolerability profiles: Phenytoin, phenobarbital, primidone. New-Onset Generalized Epilepsy Childhood absence First tier: Ethosuximide, valproate, lamotrigine Second tier: Levetiracetam, zonisamide, topiramate, clonazepam Idiopathic generalized epilepsy of adolescence (includes juvenile myoclonic, juvenile absence epilepsy, idiopathic generalized epilepsy with generalized tonic-clonic seizures on awakening, photosensitive epilepsy): In this group of very common epilepsies, valproate remains the most effective agent. However, in women of child-bearing age, due to its adverse side effect profile, it is only recommended when other drugs have failed. In nonobese men it remains as a reasonable first choice. First tier: Valproate, lamotrigine, levetiracetam, topiramate Second tier: Zonisamide, benzodiazepines Lennox-Gastaut syndrome: this syndrome is often refractory to pharmacologic therapy, with multiple drug combinations or nonpharmacologic therapies usually needed. Broad-spectrum drugs are preferred initially. First tier: Lamotrigine, levetiracetam, rufinamide, topiramate, valproate, zonisamide Second tier: Felbamate, benzodiazepines SUMMARY Clinicians practice in an era of abundance of AED, making the selection of a drug a more complex process, but at the same time providing an opportunity to better meet the needs of more patients. The newer AED have shown no better efficacy than the classic drugs, but they are easier to use, with much better pharmacokinetic profiles and fewer drug interactions. AED have also expanded the availability of broadspectrum drugs, a major benefit for patients with generalized epilepsies. The long list
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