Initial treatment of epilepsy in adults

INTRODUCTION — 

Seizures affect people in many ways. Seizures disrupt the lives of patients and can cause injury. People with epilepsy have higher rates of psychiatric comorbidity and may experience adverse psychosocial outcomes. Most worrisome is that people with epilepsy have an approximately threefold increased mortality compared with people who do not have seizures [1]. (See "Comorbidities and complications of epilepsy in adults".)

This topic will discuss the approach to the initial treatment of seizures and epilepsy. Other topics discuss the evaluation of patients with seizures and epilepsy, other aspects of epilepsy therapy, and features of specific antiseizure medications (ASMs).

●(See "Evaluation and management of the first seizure in adults".)

●(See "Evaluation and management of drug-resistant epilepsy".)

●(See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

TERMINOLOGY — 

Terms used in this topic are defined as follows [2]:

●Seizure – An epileptic seizure is a sudden transient event. The outward clinical signs and/or symptoms are caused by abnormal excessive or synchronous electrical activity of neuronal networks in the brain.

●Provoked seizure – Provoked seizures, also known as acute symptomatic seizures, are due to an acute condition such as a toxic or metabolic disturbance, immediately antecedent head trauma, concurrent cerebral infection, or a very recent/acute stroke. (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic (provoked) seizure'.)

●Unprovoked seizure – The term unprovoked seizure refers to a seizure of unknown etiology as well as one that occurs in relation to a preexisting brain lesion or progressive nervous system disorder (often referred to as a remote symptomatic seizure). (See "Evaluation and management of the first seizure in adults", section on 'Unprovoked seizure'.)

●Epilepsy – Epilepsy is a neurologic condition with an intrinsic predisposition to experience seizures. It is practically defined by the occurrence of two or more unprovoked seizures separated by more than 24 hours or by the occurrence of a single unprovoked seizure with risk factors indicating an equivalent probability of recurrence [2]. (See "Evaluation and management of the first seizure in adults", section on 'Epilepsy'.)

WHEN TO START ANTISEIZURE MEDICATION THERAPY

First-time unprovoked seizure — The decision of whether to start antiseizure medication (ASM) therapy at the time of a first unprovoked seizure in an adult should be individualized by assessing the risk of seizure recurrence, the risk of harm from seizure recurrence, and the risk of harm from treatment with ASMs in the context of patient values and preferences [3].

Immediate ASM therapy, as compared with delay of treatment pending a second seizure, reduces seizure recurrence risk during the time that the person is taking ASMs but does not improve long-term prognosis for seizure control or decrease mortality [4]. Management decisions about the use of ASMs are ideally made in consultation with neurology.

Assess risk of seizure recurrence — In prospective, randomized trials of individuals with a first unprovoked seizure, the estimated two-year recurrence risk in untreated patients ranges from 40 to 50 percent [4-7]. The risk of recurrence is highest in the first year after the seizure and diminishes with time; 80 to 90 percent of patients who have recurrent seizures do so within two years [8,9].

●High risk – The following factors are associated with a high risk of seizure recurrence in patients with a single unprovoked seizure (algorithm 1):

•Epileptiform abnormality on interictal electroencephalography (EEG) (see "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy")

•Remote symptomatic cause, as identified by clinical history or neuroimaging (eg, stroke, brain tumor, brain malformation, head injury with loss of consciousness, prior central nervous system infection, or scarring from a prior brain injury or brain surgery)

•Abnormal neurologic examination beyond the postictal period, including focal findings or intellectual disability

•A first seizure that occurs during sleep

•First presentation of an epilepsy syndrome

In studies of patients with a first unprovoked seizure, each of these factors was associated with an approximately 2- to 2.5-fold increased risk for seizure recurrence [3-6,8,10-13]; patients with one or more of these factors are at high risk of seizure recurrence and would be diagnosed with probable epilepsy according to International League Against Epilepsy (ILAE) guidelines [2]. (See "Evaluation and management of the first seizure in adults".)

●Low risk – For patients with a first unprovoked seizure who have no history of a remote brain insult and have a normal (or nonfocal) examination beyond the postictal period, an interictal EEG without epileptiform activity, and normal (or nonspecific) neuroimaging, the risk of seizure recurrence is lower.

●Uncertain risk – Other potential risk factors for seizure recurrence after single unprovoked seizure, including a history of prior febrile seizures and family history of epilepsy, have been investigated and remain more uncertain [5,6,8,10,12].

●Risk for seizure recurrence in older adults – Limited data suggest that the risk of seizure recurrence after single unprovoked seizure in older adults is similar to that of younger adults and that the predictors of recurrence are similar. In a prospective observational study of over 1000 adults presenting with a first-ever unprovoked seizure, 139 of whom were ≥65 years of age (mean 74 years), the likelihood of a seizure recurrence at one year was similar in older compared with younger adults (53 versus 48 percent) [14]. Independent predictors of seizure recurrence included remote symptomatic etiology, first seizure arising from sleep (ie, a seizure that starts when the patient is asleep), epileptiform abnormality on EEG, and focal seizures, but not age. In another prospective observational report, in which 127 of the 568 adults with a single unprovoked seizure were >60 years of age, the cumulative risk of recurrence in this age group was 83 percent over three years; however, the overall recurrence rate was higher in this study (78 percent) across all age groups [15].

Assess risk of potential harm from seizure recurrence — The severity of the clinical features of the initial unprovoked seizure should be considered in the treatment decision. A generalized tonic-clonic seizure resulting in shoulder dislocation/fracture requiring surgery is not equivalent in its harm potential as compared with a short-duration focal seizure without impairment of awareness.

While limited data suggest that presentation with status epilepticus, in the absence of other risk factors, does not increase the overall risk of seizure recurrence [6,8,10,16], one study found that the risk of recurrence within 10 years for patients with incident idiopathic/cryptogenic status epilepticus was 25 percent [17]. Consequently, patients who present with status epilepticus or with multiple seizures within a single day are more likely to be treated with ASMs than those with a single short-duration seizure.

Assess risk of potential harm from adverse effects of treatment — The adverse effects of ASMs have the potential to negatively impact quality of life. ASMs can affect mood, cognition, weight, and balance, and the degree of impact varies depending on age and patient comorbidities. There is also a low risk of idiosyncratic side effects, including immune-mediated hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN) [18]. (See 'Special populations and medical comorbidities' below and 'Adverse effect profiles' below.)

Determine patient values and preferences — Patient concerns weigh heavily in treatment decisions, particularly regarding the psychosocial consequences of a recurrent seizure and the potential for medication side effects. If the risk of seizure recurrence is low and the risk of harm from a seizure recurrence is also low, and the patient places a high value on not taking medications, ASM therapy may be delayed. By contrast, there are some patients who will be very concerned about seizure recurrence because of the implications for driving, employment, individual living circumstances (eg, living alone or in rural/remote locations), or comorbidities (osteogenesis imperfecta, shoulder reconstruction); they may choose to initiate ASMs, despite what may be a low likelihood of additional seizures.

Choose immediate versus deferred treatment

●For high-risk patients – We suggest starting ASM therapy for patients with a first unprovoked seizure who have one or more factors associated with a high risk of seizure recurrence (algorithm 1). These factors include epileptiform abnormality on interictal EEG, a remote symptomatic cause for seizure (eg, stroke, brain tumor, brain malformation, prior brain injury or brain surgery), an abnormal neurologic examination, a first seizure that occurs during sleep, a first seizure that is focal in onset, or the first presentation of an epilepsy syndrome. (See 'Assess risk of seizure recurrence' above.)

ASM therapy is also started for most patients who present with generalized convulsive status epilepticus because of the unacceptable risk of harm from recurrence of status epilepticus. Exceptions to the need for a nonbenzodiazepine ASM may include patients who have seizures that stop with lorazepam treatment and have a rapidly reversible cause of convulsive status epilepticus that has been definitively corrected, such as severe hypoglycemia. The use of ASM therapy for patients who present with generalized convulsive status epilepticus is discussed separately. (See "Convulsive status epilepticus in adults: Management", section on 'Second therapy: Antiseizure medications'.)

●For low-risk patients – For patients with a first unprovoked short-duration seizure who have no history of a remote brain insult and have a normal (or nonfocal) examination and normal (or nonspecific) neuroimaging, the risk of seizure recurrence is lower. ASM therapy may be reasonably deferred unless there are extenuating psychosocial circumstances or comorbidities that would warrant immediate treatment (eg, driving or employment safety, living in a remote location, shoulder fracture surgery).

●Efficacy – Immediate ASM therapy, as compared with delay of treatment pending a second seizure, reduces seizure recurrence risk during the time that the person is taking ASMs but does not improve long-term prognosis for seizure control or decrease mortality [4]. In a systematic review and meta-analysis of six randomized trials that included 1634 patients presenting with an unprovoked first seizure, immediate ASM treatment compared with deferred treatment, placebo, or no treatment reduced the absolute risk of seizure recurrence at two years by approximately 13 percent (28.7 versus 41.8 percent) and the relative risk by approximately 30 percent (relative risk [RR] 0.69; 95% CI 0.59-0.80) [19]. However, early treatment had little effect on the proportion of patients achieving remission and did not reduce long-term mortality [19,20].

●Impact on quality of life – Whether early treatment improves quality of life remains uncertain. In one randomized study, aggregate quality-of-life outcomes were not different between early versus deferred treatment groups, mostly because there was a trade-off between the adverse effects of seizures and the adverse effects of taking ASMs [21]. The one exception was that the individuals randomized to early treatment were more likely to be able to drive. Note that this study was conducted in the United Kingdom, which requires 12 months of seizure freedom before reinstatement of driving privileges.

In a decision analysis model examining early versus deferred treatment, the authors considered four main factors in calculating quality-of-life adjusted year (QALY) outcomes: (1) the probability of further seizures without antiseizure medication (ASM) treatment; (2) the effectiveness of ASM treatment at preventing recurrent seizures; (3) the probability and degree of harm expected if seizures do recur; and (4) the probability and degree of harm expected from ASM-related side effects [22].

This model found that early treatment would likely improve long-term QALY in cases with a low risk of seizure recurrence if the initial seizure had a high potential for harm. By contrast, early treatment would likely reduce long-term QALY if the initial seizure had a low potential for harm, and the expected harm from ASM side effects was high even if the risk of seizure recurrence was high [22].

Second unprovoked seizure — Patients presenting with a second unprovoked seizure should be started on ASM therapy (algorithm 1). In short, the second unprovoked seizure indicates that the patient has a substantially increased risk for additional seizures [6,9].

In one prospective case series, the risk of another seizure after two unprovoked seizures was 73 percent (95% CI 59 to 87 percent) at four years (most of these patients were treated with ASMs) [9]. While most seizures are transient events without sequelae, even a single seizure is associated with an increased risk of morbidity and mortality (see "Comorbidities and complications of epilepsy in adults"), and most patients can be treated successfully with ASM therapy. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy'.)

Acute symptomatic (provoked) seizure — Acute symptomatic seizures (ie, seizures due to an acute brain insult such as a toxic or metabolic disturbance, immediately antecedent head trauma, or very recent/acute stroke) generally have a lower risk for subsequent epilepsy compared with remote symptomatic seizures [23]. Early management decisions, including whether to start an ASM, depend upon multiple factors, including the severity of the underlying illness, the cause and duration of the seizure, the expected risk of early recurrence, and the risks of potential harm associated with a recurrent seizure. These are reviewed in the algorithm (algorithm 2) and discussed in greater detail separately. (See "Evaluation and management of the first seizure in adults", section on 'With acute symptomatic seizures' and "Evaluation and management of the first seizure in adults", section on 'Acute brain injury'.)

SELECTION OF AN ANTISEIZURE MEDICATION

Choice should be individualized — Epilepsy is initially treated with antiseizure medication (ASM) monotherapy. Almost half of patients will become seizure-free with their first ASM trial [24,25]. However, as discussed below, clinical trials do not answer the most important question facing clinicians and patients: Which is the best (most effective and best tolerated) ASM for new-onset seizures? Because no clear answer is at hand, clinicians must individualize the choice of ASM for each patient.

In choosing an initial therapy, clinicians must weigh relative efficacy and potential for adverse effects of each drug. Comparative efficacy and tolerability data are limited. Head-to-head comparison trials that have been performed have not shown significant differences among various drugs in terms of efficacy. Clinicians must therefore formulate treatment plans based upon the type of seizure(s), patient-specific factors, and individual drug-specific factors.

Focal versus generalized seizures/epilepsy — In selecting an ASM for a patient, it is important to determine the type of seizures the patient is experiencing and, if possible, to classify the epilepsy syndrome [26]. ASMs are classified as either broad- or narrow-spectrum agents (table 1). While broad-spectrum agents treat both focal and generalized seizures, narrow-spectrum agents treat specific seizure subtypes [27]. (See "Evaluation and management of the first seizure in adults", section on 'Types of seizures'.)

Based upon data from the major trials [28-32], comprehensive reviews [27,33,34], expert opinion [33,35-37], and clinical experience of the contributors to this topic, reasonable initial ASM choices include the following:

●For focal seizures and secondarily generalized seizures – Lamotrigine, levetiracetam, oxcarbazepine, carbamazepine, or lacosamide

●For absence seizures – Ethosuximide, valproate, or lamotrigine

●For genetically mediated generalized tonic-clonic seizures – Lamotrigine, levetiracetam, valproate, topiramate, and zonisamide

●For myoclonic seizures – Levetiracetam, valproate, zonisamide, and clonazepam

●For tonic/atonic seizures – Valproate, lamotrigine, clobazam, zonisamide, levetiracetam

●For focal motor seizures/epilepsia partialis continua – Phenytoin, carbamazepine, oxcarbazepine

Special populations and medical comorbidities — Patient age, sex, and medical comorbidities are important to consider when selecting an ASM. Many ASMs are either metabolized by the liver, excreted by the kidneys, or both (table 2). When a person has hepatic or renal disease, it may be necessary to avoid certain ASMs or to adjust the dose. Some comorbidities can be problematic because of potential drug side effects or drug interactions, while others may represent an opportunity to choose an ASM that has efficacy in both conditions. Specific interactions of ASMs with other medications may be determined using the UpToDate drug interactions program.

Older adults — The use of ASMs in older patients is complicated by several factors, including altered pharmacokinetics and increased risk for both common and rare adverse effects (table 3 and table 4) and drug-drug interactions [38]. Compared with younger adults, older adults appear to be more sensitive to the adverse effects of ASMs, experiencing them more frequently and with lower doses. General dose-dependent side effects of ASMs that can be particularly problematic in older patients include falls, confusion, impaired gait, sedation, tremor, dizziness, and visual disturbance.

The choice of a specific ASM in an older patient should take into account the types of seizures the patient is experiencing (eg, focal seizure, myoclonic seizures, generalized tonic-clonic seizures), the potential for drug-drug interactions, comorbid medical conditions, and the mode of administration (swallowed completely versus crushed versus gastrostomy tube) [38].

●With focal seizures – Focal seizures with impairment of awareness are the most common types of new-onset seizures in older adults.

We prefer to use lamotrigine or levetiracetam as first-line medications for focal seizures because of the relative lack of sedation and absence of bidirectional drug interactions encountered with these two ASMs compared with other choices. Lamotrigine is appropriate if the clinical scenario does not require an immediate therapeutic level (eg, seizures are infrequent and/or mild). Levetiracetam is appropriate if there is a more urgent need to reach therapeutic dosing more quickly; it is available in both tablet and liquid formulations.

The available evidence, although limited by a paucity of head-to-head comparisons, suggests that the more commonly used ASMs (ie, lamotrigine, levetiracetam, valproate, gabapentin) have similar efficacy and tolerability for older patients with epilepsy [39,40]. One analysis suggested that probability of seizure freedom was more likely with levetiracetam compared with lamotrigine (risk ratio [RR] 0.83, 95% CI 0.68-0.97), but the statistical significance was marginal [40].

Carbamazepine and phenytoin have multiple drug-drug interactions (table 5 and table 6). In older patients who may be taking many medications (polypharmacy), these drug interactions may result in greater side effects and, therefore, a reduced quality of life.

Older adults appear to be more sensitive to side effects of ASMs, experiencing them more frequently and with lower doses than do younger patients. General dose-dependent side effects of ASMs that can be particularly problematic in older patients include falls, confusion, impaired gait, sedation, tremor, dizziness, and visual disturbance. Two analyses suggested that carbamazepine is least well tolerated in older patients and is more likely to be discontinued (pooled weighted risk ratio [RR] 1.83, 95% CI 1.23-2.43) [39,40].

●With myoclonic seizures – Rarely, in patients with Alzheimer disease or other neurodegenerative conditions, the primary seizure subtype may be myoclonic seizures [41-44]. Levetiracetam and valproate are efficacious [45,46].

●With generalized seizures – New-onset generalized seizures are unlikely in older adults; observed generalized seizures are more likely to be focal seizures with secondary generalization. Therefore, the approach to therapy is the same as stated above for focal seizures.

Females of childbearing potential — Several issues are important in women of childbearing age, including family planning/contraception and pregnancy. For females with either genetic generalized epilepsy or focal epilepsy, lamotrigine or levetiracetam are reasonable choices.

Valproate should be avoided in females of childbearing potential if possible since valproate monotherapy is associated with the highest rate of teratogenicity of all marketed ASMs. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

●Folate supplementation – Folate should be prescribed to all women of childbearing age who are taking ASMs. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Folic acid supplementation'.)

●Choice of ASM in pregnancy – Seizures, particularly convulsive seizures, are believed to be harmful to the fetus. At the same time, both major and minor malformations are more common in fetuses exposed to ASMs in utero.

Issues regarding initiating and selecting ASM for a first seizure in pregnancy are discussed separately. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Approach to a first seizure in pregnancy'.)

●Management of contraception – Women should be informed about the interactions between ASM therapies and hormonal pill, patch, or ring contraception to avoid contraceptive failure and unplanned pregnancy. Long-acting reversible contraception (LARC) is highly effective and avoids most if not all drug-drug interactions, depending on the specific method. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Preconception management'.)

In addition to the effect of ASMs on hormonal contraceptive metabolism, combined hormonal contraceptives can increase the metabolism of lamotrigine, thereby reducing the plasma drug concentration. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'.)

Kidney disease — Renally excreted drugs include the following (table 2) [47,48]:

●Gabapentin

●Lacosamide

●Levetiracetam

●Oxcarbazepine

●Pregabalin

●Topiramate

●Zonisamide

The dose of these drugs should be adjusted based on the severity of renal impairment (table 7).

●Hemodialysis – For patients on hemodialysis, lamotrigine, oxcarbazepine, or levetiracetam are reasonable choices for initial ASM therapy. ASM regimens should be individualized based on drug levels and clinical response. The renally excreted drugs and some others (eg, phenobarbital, lamotrigine) are removed by hemodialysis, and a low dose should be supplemented after dialysis to maintain therapeutic levels. The effects of peritoneal dialysis on ASM metabolism are not well studied, and ASM treatment in such patients may require additional monitoring. (See "Seizures in patients undergoing hemodialysis", section on 'Dosing'.)

●Nephrolithiasis – Topiramate and zonisamide are associated with nephrolithiasis and should probably be avoided in patients with a history of or who are prone to this condition. (See "Kidney stones in adults: Epidemiology and risk factors".)

●Renal tubular acidosis – Topiramate and zonisamide are also associated with an increased risk of renal tubular acidosis; patients with preexisting conditions that make them prone to metabolic acidosis (eg, severe respiratory disorders, diarrhea) should also consider avoiding these drugs or have more frequent monitoring of serum bicarbonate levels [49].

Hepatic disease — For patients with hepatic failure or after organ transplantation, levetiracetam, gabapentin, or pregabalin are reasonable choices for initial ASM therapy. These ASMs do not undergo hepatic metabolism and are less problematic for use in patients with chronic liver disease.

Some ASMs are associated with hepatic toxicity and should be avoided in patients with preexisting liver disease. These include [47,50]:

●Carbamazepine

●Felbamate

●Phenytoin

●Valproate

Many other ASMs are metabolized fully or partially in the liver (table 2), requiring caution and dose adjustment when used in patients with chronic liver disease. These include lamotrigine, phenobarbital, clobazam, zonisamide, topiramate, oxcarbazepine, eslicarbazepine, and brivaracetam.

Organ transplantation — In the setting of organ transplantation, potential drug interactions between ASMs and immunosuppressive therapy should be considered. Enzyme-inducing ASMs may lower serum immunosuppressant levels, while enzyme inhibitors may increase levels. (See 'Pharmacologic aspects' below.)

Cancer — Levetiracetam, lacosamide, and lamotrigine are reasonable choices in this setting [27]. The choice of ASM in patients being treated for systemic cancer is influenced by potential drug interactions between enzyme-inducing ASMs (table 2) and chemotherapeutic agents that can lead to decreased efficacy of both treatments [51,52]. By inhibiting their metabolism, valproate may increase the toxicity of certain cancer chemotherapy agents. There also may be an increased potential for allergic cutaneous reactions when ASMs are used during radiotherapy or when patients are receiving immune checkpoint inhibitors; however, there is no way to predict which patients are more at risk for this adverse effect.

HIV — Enzyme-inducing ASMs and those that are highly protein-bound (table 2) may interact with antiretroviral therapy (ART) [53-55]. Of particular concern is that these drug interactions may cause minor reductions in the levels of protease inhibitors that could lead to loss of viral suppression and the emergence of drug resistance. There are also concerns that phenytoin-associated skin rash may be more common in human immunodeficiency virus (HIV)-positive patients. Lamotrigine doses may need to be increased with certain medications including ritonavir and atazanavir. While early in vitro studies suggested that valproate might increase viral replication, a series of patients treated with valproate maintained excellent control of both seizures and HIV [56].

Psychiatric disorders — Persons with epilepsy have a higher than expected prevalence of comorbid psychiatric disorders [35,57-60]. The association may relate to shared perturbations in neurotransmitter action, alterations to neural networks, or both [57,59,61].

For patients with comorbid depression and focal epilepsy, lamotrigine, lacosamide, or oxcarbazepine are reasonable choices. For those with genetically mediated generalized epilepsy, lamotrigine or valproate are reasonable choices.

Some ASMs (valproate, lamotrigine, carbamazepine, oxcarbazepine) appear to have efficacy for bipolar disorder [62-64]. Some clinicians view these medications as attractive in patients with comorbid anxiety and/or depression.

By contrast, some ASMs, in particular those that potentiate gamma-aminobutyric acid (GABA) neurotransmission (phenobarbital, tiagabine, vigabatrin, topiramate), have been reported to cause or exacerbate depression and perhaps should be avoided in patients with comorbid depression [65]. Similarly, drugs that have been reported to provoke psychosis (levetiracetam, topiramate, vigabatrin, zonisamide, ethosuximide, and perampanel) may be less desirable in patients with that history. In the Columbia-Yale study, neuropsychiatric side effects (including depressive mood, psychosis, anxiety, suicidal ideation, irritability, aggression, and tantrum) were reported in 17 percent of patients taking ASMs. Levetiracetam was associated with the highest rate (22 percent) while zonisamide had the second-highest rate (9.7 percent) of neuropsychiatric side effects. By comparison, carbamazepine, clobazam, gabapentin, lamotrigine, oxcarbazepine, phenytoin, and valproate were significantly associated with a decreased rate of psychiatric or behavioral side effects [66].

Use of one of the ASMs thought to be effective in bipolar, depressive, or anxiety disorders does not substitute for a full psychiatric evaluation and independent treatment of a coexisting psychiatric disorder. Further impetus for this comes from the fact that as a class, ASMs are associated with an increased risk of suicide. All patients with epilepsy treated with ASMs should be monitored for changes in affect and for suicidal ideation and behavior. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Rare but potentially serious adverse effects'.)

Drug interactions are also a potential concern in patients with psychiatric disorders. Enzyme-inducing ASMs (table 2) can decrease the plasma concentration of many antidepressants including tricyclic agents and selective serotonin reuptake inhibitors (SSRIs), as well as antipsychotic drugs and benzodiazepines [67,68].

Migraine — Some studies suggest that migraine may be more prevalent in patients with epilepsy and vice versa [69,70]. Valproate, gabapentin, and topiramate are ASMs that have demonstrated efficacy for migraine prevention in placebo-controlled trials (see "Preventive treatment of episodic migraine in adults", section on 'Anticonvulsants'). This may provide an opportunity to limit polypharmacy in individuals with both migraine and epilepsy.

Cardiovascular disease — Levetiracetam and topiramate are reasonable choices in this setting [27]. Clinicians should consider potential drug interactions between cytochrome P450 (CYP) enzyme-inducing ASMs (ie, carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, and topiramate) and statins, calcium channel blockers, and warfarin [67,68,71]. While carbamazepine has been associated with heart block and other bradyarrhythmias in susceptible individuals [72], clinically significant electrocardiography (ECG) changes are uncommon with carbamazepine in older adult patients who do not have a preexisting conduction defect [73].

Because the CYP enzymes are involved in cholesterol synthesis, it is possible that enzyme-inducing ASMs may thereby affect vascular risk. In one small series, switching patients from carbamazepine or phenytoin to noninducing ASMs levetiracetam or lamotrigine was associated with improvements in serologic markers of vascular risk (eg, total cholesterol, triglycerides, C-reactive protein) [74]. Some studies have found that long-term monotherapy with carbamazepine, phenytoin, or valproate is associated with markers of increased cardiovascular risk, such as carotid intimal thickening, abnormal cholesterol, homocysteine, and folate metabolism, as well as elevated levels of C-reactive protein [75,76]. However, it is unclear whether enzyme-inducing ASMs are associated with a greater risk of cardiovascular disease than nonenzyme-inducing ASMs as the evidence is inconsistent [77,78].

Others

●Diabetes – Because of its association with weight gain, insulin resistance, and polycystic ovarian syndrome, use of valproate in individuals with diabetes or obesity should be carefully considered [79]. Carbamazepine, vigabatrin, gabapentin, and pregabalin are also, but much less frequently, associated with weight gain. (See 'Adverse effect profiles' below.)

Topiramate and zonisamide are associated with increased rates of metabolic acidosis, especially if administered in conjunction with metformin [49].

Some ASMs (gabapentin, pregabalin, and possibly carbamazepine) have efficacy in treating pain associated with diabetic neuropathy. (See "Management of diabetic neuropathy", section on 'Pain management'.)

●Advanced dementia – Gabapentin and oxcarbazepine can rarely precipitate or induce myoclonic seizures in older patients with advanced dementia.

●Thyroid disease – While many ASMs, in particular the enzyme-inducing agents, can alter thyroid hormone levels, this is generally subclinical and should not impact drug choice [79,80]. Enzyme-inducing agents should probably be avoided in patients with severe thyroid dysfunction.

●Patients at risk for hyponatremia – Carbamazepine, oxcarbazepine, and eslicarbazepine increase the risk of symptomatic hyponatremia, especially in patients receiving SSRIs and/or diuretics [81].

●Blood disorders – Certain ASMs (carbamazepine, phenytoin, ethosuximide, valproate) are associated with neutropenia and agranulocytosis, and they should be avoided in patients with blood disorders [82,83]. (See "Drug-induced neutropenia and agranulocytosis".)

Similarly, drugs associated with thrombocytopenia (eg, carbamazepine, valproate, phenytoin) should be avoided in patients with a low platelet count or a history of other bleeding diatheses. (See "Drug-induced immune thrombocytopenia".)

Drug-related considerations — Aspects of ASM therapy that are relevant to drug selection include efficacy, pharmacokinetics, drug-drug interactions, adverse effects, and cost.

Efficacy — No single ASM is clearly the most effective or best tolerated, and there are over 25 ASMs approved for treatment of seizures in adults and/or children (table 1 and table 2). (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

●Randomized controlled trials – There have been a number of randomized trials comparing various ASMs head-to-head as initial monotherapy in adults. These have generally shown a similar effectiveness between the different drugs [84,85]. In general, but with some exceptions, these trials suggest that the newer ASMs (ie, lamotrigine, levetiracetam, oxcarbazepine, lacosamide) are superior with respect to tolerability and similar with respect to efficacy as compared with older ASMs (phenytoin, carbamazepine, valproate) [85,86]. There has never been a randomized trial that includes all available treatments.

●SANAD trials – The largest individual randomized trials examining different ASMs as monotherapy for the initial treatment of epilepsy were the Standard and New Antiepileptic Drugs (SANAD) trials [28-32]. The first SANAD trial included 1721 patients with focal seizures/epilepsy and 716 patients with generalized/unclassifiable seizures/epilepsy [28,29]; the SANAD II trial included 990 patients with focal seizures/epilepsy and 520 patients with generalized/unclassifiable seizures/epilepsy [31,32]. To balance methodologic rigor and practicality, the trials were not blinded [87]. The treating physician determined how quickly to titrate the medication instead of following a standardized blinded protocol. This approach may have better approximated the "real-life" use of these drugs than would a blinded trial. Outcome measures were time to treatment failure (for either inadequate seizure control or intolerable side effects) and time to achievement of a 12-month seizure remission.

The main findings were:

•For patients treated for focal seizures/epilepsy, the first SANAD trial found that lamotrigine and oxcarbazepine had the longest time to treatment failure compared with carbamazepine, gabapentin, and topiramate [29]. Lamotrigine and carbamazepine were associated with the shortest times to 12-month seizure remission. In the SANAD II trial, by intention-to-treat analysis, levetiracetam did not meet noninferiority criteria compared with lamotrigine for time to 12-month seizure remission and was inferior for time-to-treatment failure for any reason; by contrast, zonisamide did meet the criteria for noninferiority compared with lamotrigine for time to 12-month seizure remission but was also inferior for time-to-treatment failure [31]. Both levetiracetam and zonisamide were more likely to fail than lamotrigine due to adverse reactions but not because of inadequate control of seizures.

•For patients treated for generalized and unclassifiable epilepsy, the first SANAD trial found that valproate and lamotrigine were superior to topiramate with regard to time-to-treatment failure [30]. For time to 12-month seizure remission, valproate and topiramate were more efficacious compared with lamotrigine. In the SANAD II trial, by intention-to-treat analysis, levetiracetam did not meet noninferiority criteria compared with valproate for time to 12-month seizure remission [32].

•In the first SANAD trial, quality-of-life outcomes were largely similar across treatment groups over a two-year period and did not show a clear advantage for any specific drug [88]. The strongest predictor of improved quality-of-life outcomes was achievement of a 12-month seizure remission.

•In the second SANAD trial, the investigators concluded that lamotrigine should be considered the drug of first choice for focal epilepsy and valproate for generalized epilepsy [29-32].

Because the SANAD trials were unblinded, however, there was potential for bias [89].

Pharmacologic aspects — Important pharmacologic features of individual ASMs are summarized in the table and reviewed in more detail separately (table 2). (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Some of the more important considerations when choosing a first-line ASM include the following:

●Dosing frequency – The half-lives of ASMs vary considerably (table 2). For many individuals, the frequency with which a drug must be taken is an important factor in compliance (ie, adherence) and/or seizure control [90]. Optimal dose frequency for individual drugs can vary between patients.

Most ASMs are prescribed in two daily doses. ASMs that often require more frequent dosing include immediate-release carbamazepine, tiagabine, regular and delayed-release valproate, gabapentin, and pregabalin.

Once-daily dosing may be possible with phenobarbital, phenytoin, zonisamide, eslicarbazepine, perampanel, and extended-release formulations of levetiracetam, valproate, oxcarbazepine, topiramate, and lamotrigine.

●Drug interactions – The selection of an ASM should include consideration of other prescribed medications for potential drug interactions. Clinicians should review each item on a patient's medication list for potential drug interactions [67,68]. Specific interactions of ASMs with other medications may be determined using the UpToDate drug interactions program.

•Enzyme induction or inhibition – In general, ASMs with hepatic enzyme induction or inhibitory properties have the greatest potential for interactions. Induction of CYP enzymes occurs with all older ASMs (phenobarbital, carbamazepine, and phenytoin) except valproate and ethosuximide. Enzyme induction also occurs with a few of the newer approved ASMs such as eslicarbazepine, oxcarbazepine, primidone, rufinamide, and topiramate (table 2) [27,91].

ASMs that are hepatic-enzyme inducers increase the metabolism of other medications that are broken down by the same pathway. As an example, phenytoin induces the metabolism of warfarin, potentially leading to subtherapeutic international normalized ratio (INR) and/or an increased dose requirement of warfarin. Commonly prescribed drugs with the potential to interact with enzyme-inducing ASMs include statins, calcium channel blockers, serotonin reuptake inhibitors, antipsychotics, tricyclic antidepressants, hormonal contraceptive therapy, warfarin, and many anticancer drugs [92].

By contrast, valproate is a hepatic enzyme inhibitor and may cause significant increases in serum concentrations of medications that are metabolized in the liver. Similarly, stiripentol, which is approved for Dravet syndrome, is a potent hepatic enzyme inhibitor. It is known to increase levels of the main metabolite of carbamazepine (the 10,11 epoxide) [93].

•Protein binding – Other drug interactions relate to protein binding. Highly protein-bound ASMs exhibit altered pharmacokinetics, including greater therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum albumin or protein-binding affinity (eg, due to nephrotic syndrome or acidosis). Addition of a drug that is highly protein-bound will displace another protein-bound drug, increasing its free fraction. Albuminuria (causing low serum albumin) and acidosis reduce protein binding fractions and binding affinity, leading to increased fractions of free drug [47]. For highly protein-bound ASMs (table 2), subtherapeutic total drug levels may be both sufficient for efficacy and required to avoid toxicity in this setting. Free drug levels of phenytoin may be monitored, but such tests are less routinely available for other ASMs.

Hormones can also affect the levels of some ASMs. For instance, lamotrigine concentrations are reduced by estrogen-containing hormonal contraceptives.

Adverse effect profiles — Adverse effects should be considered in selecting an ASM since some side effects are either more likely or more problematic in certain patients.

Common neurotoxic and systemic side effects are summarized in the table (table 3). Less common, often idiosyncratic, but potentially serious adverse events are summarized separately (table 4).

●Neurocognitive side effects – Most ASMs are associated with a negative impact on cognition, but some are more problematic than others [94]. Among the older ASMs, studies suggest that phenobarbital is associated with greater impairments compared with carbamazepine, valproate, and phenytoin, which have similar but more modest negative effects [95,96]. Among the newer ASMs, gabapentin and lamotrigine have been found to be less problematic than carbamazepine in their effects on cognition. Negative cognitive effects are similar with oxcarbazepine and carbamazepine [97]. Finally, a significant minority of patients taking topiramate discontinue the drug because of clinically apparent cognitive difficulties. In head-to-head comparison studies, cognitive profiles in patients taking topiramate were worse than those taking valproate, lamotrigine, or gabapentin [96].

●Hypersensitivity reactions – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are rare but severe idiosyncratic reactions, characterized by fever and mucocutaneous lesions. SJS and TEN have been most often associated with the use of the following (table 4):

•Carbamazepine

•Oxcarbazepine

•Phenytoin

•Lamotrigine

•Phenobarbital

These reactions are less commonly associated with valproate and topiramate; however, they have been described with almost all ASMs [98,99].

The period of highest risk is within the first two months of use. For carbamazepine, oxcarbazepine, and possibly phenytoin, the risk is higher in patients with the HLA-B*1502 allele, which occurs almost exclusively in patients of Asian ancestry, including Indian. The US Food and Drug Administration (FDA) recommends screening such patients for the HLA-B*1502 allele prior to starting carbamazepine and oxcarbazepine. This is discussed in more detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Oxcarbazepine' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA polymorphism and pharmacogenetics'.)

●Suicidal ideation and behavior – ASMs as a class have been associated with an increased relative risk of suicidal ideation or behavior. Universal screening for depression is endorsed by the United States Preventive Services Task Force. This is discussed in more detail separately. (See "Comorbidities and complications of epilepsy in adults", section on 'Psychiatric disorders' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Rare but potentially serious adverse effects'.)

●Weight gain or loss – Weight gain is associated with valproate, gabapentin, carbamazepine, vigabatrin, pregabalin, and perampanel. Weight loss has been reported with felbamate, topiramate, and zonisamide.

●Bone loss – ASMs in chronic use have been associated with bone loss. Phenytoin, phenobarbital, primidone, and carbamazepine are most commonly implicated as affecting bone and mineral metabolism. Issues regarding this association, as well as screening, treatment, and prevention of ASM-related bone disease, are discussed in detail elsewhere. (See "Antiseizure medications and bone disease".)

Cost of medications — For many patients, the cost of their medication is also an issue, and whether a specific ASM is on a list of preferred medications approved by a third-party payer may be influential in the choice of ASM. When cost is taken into account, for areas of the world and for individual patients with restricted resources, older, less expensive medications such as phenobarbital or phenytoin may be the treatment of choice for partial epilepsy [100]. Generic substitution can lower the cost of many ASMs. In rare instances, use of a generic ASM may be associated with a change in seizure control or tolerability, although the magnitude of this risk has been debated. (See "Antiseizure medication maintenance therapy and drug monitoring", section on 'Generic substitution'.)

ANTISEIZURE MEDICATION INITIATION AND MONITORING — 

The approach to antiseizure medication (ASM) use, including patient education, ASM titration, monitoring, nonadherence, generic substitution, and breakthrough seizures, is reviewed separately. (See "Antiseizure medication maintenance therapy and drug monitoring".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Seizures (The Basics)" and "Patient education: Epilepsy in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Seizures in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●When to start antiseizure medication – When the diagnosis of epilepsy is made, the initial treatment is a single antiseizure medication (ASM). When to start treatment, and with what agent, is a complex decision that is individualized to optimize efficacy, tolerability, and patient values and preferences. (See 'When to start antiseizure medication therapy' above.)

•First unprovoked seizure – The term "unprovoked seizure" refers to a seizure of unknown etiology as well as one that occurs in relation to a preexisting brain lesion or progressive nervous system disorder (often referred to as a remote symptomatic seizure). The decision of whether to start ASM therapy at the time of a first unprovoked seizure in an adult should be individualized. The decision is based on several factors: an assessment of the risk for recurrent seizure, the potential benefits of immediate ASM therapy in reducing the risk of recurrent seizure, the side effects of ASMs, and patient preferences (algorithm 1). (See 'First-time unprovoked seizure' above.)

For patients with a single unprovoked seizure who have one or more of the following factors consistent with a high risk of seizure recurrence, we suggest starting ASM without delay (Grade 2B):

-A remote symptomatic cause of seizure (eg, stroke, head trauma, brain tumor)

-Epileptiform features on EEG

-A relevant abnormality on neuroimaging study (computed tomography [CT] or magnetic resonance imaging [MRI])

-An abnormal neurologic examination

-A first seizure that occurs in sleep

This approach is supported by evidence from randomized controlled trials that immediate ASM treatment after a single unprovoked seizure reduces the risk of seizure recurrence within the first two years. However, it does not change the long-term risk for seizure control or reduce mortality. Thus, ASM treatment may be deferred depending on the presence or absence of other risk factors and on individual patient preferences. (See 'Choose immediate versus deferred treatment' above.)

•Second unprovoked seizure – For patients who have had two or more unprovoked seizures, we recommend initiating ASM therapy (Grade 1A). Such patients are at elevated risk for further unprovoked seizures (ie, epilepsy). (See 'Second unprovoked seizure' above.)

●Selection of antiseizure medication – The selection of ASM considers the type of seizure and epilepsy syndrome (table 1) and potential side effects (table 3 and table 4), as well as other prescribed medications and comorbidities. Patient age, patient sex, and cost and availability of medication may also be relevant factors. (See 'Selection of an antiseizure medication' above.)

•Consider drug interactions – In general, hepatic enzyme-inducing ASMs (eg, phenytoin, carbamazepine, phenobarbital, oxcarbazepine) are the most problematic for interactions with drugs such as warfarin, hormonal contraception, anti-cancer drugs, and anti-infective drugs. Specific interactions of ASMs with other medications may be determined using the UpToDate drug interactions program. (See 'Pharmacologic aspects' above.)

•Impact of kidney and liver disease – Because ASMs are either metabolized by the liver or excreted by the kidneys, renal and hepatic disease impacts both the choice of ASM as well as the prescribing regimen. (See 'Kidney disease' above and 'Hepatic disease' above.)

•Teratogenic effects – Women of childbearing age should be counseled about possible teratogenic effects of ASMs. Folic acid supplementation is recommended for all women of child-bearing potential. Valproate should be avoided and only prescribed if no other ASM is effective for that particular patient. (See 'Females of childbearing potential' above.)

•Consider comorbid psychiatric disorders – Patients with epilepsy have a higher-than-expected incidence of depressive, anxiety, and bipolar disorders. ASMs as a class have been associated with suicidal ideation and behavior. Some ASMs appear to have antimanic properties, while others may cause or exacerbate depression or provoke psychosis. Patients treated with ASMs should be monitored for changes in affect and for suicidal ideation and behavior. (See 'Psychiatric disorders' above.)

●Patient education and follow-up – Successful treatment can be optimized by a systematic approach. Issues related to patient education, ASM titration, monitoring, nonadherence, generic substitution, and breakthrough seizures are reviewed separately. (See "Antiseizure medication maintenance therapy and drug monitoring".)