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INTRODUCTION — Epilepsy is the syndrome of two or more unprovoked seizures that occur more than 24 hours apart . Individuals who have had two or more unprovoked epileptic seizures are more likely to continue to have seizures. Seizures are disruptive in a patient's life and can cause injury. Epilepsy is associated with disability, adverse psychosocial outcomes, higher rates of psychiatric comorbidity, and an approximately threefold increased mortality . (See "Comorbidities and complications of epilepsy in adults".)
The management of patients with epilepsy is focused on three main goals: controlling seizures, avoiding or minimizing treatment side effects, and maintaining or restoring quality of life. The initial treatment of epilepsy is with a single antiseizure drug. With an ever-expanding list of available antiseizure drugs, and no single antiseizure drug that is clearly superior in terms of efficacy or tolerability, clinicians must individualize the choice of antiseizure drug for each patient.
This topic will discuss the approach to the initial treatment of epilepsy. Other topics discuss the evaluation of patients with seizures and epilepsy, other aspects of epilepsy therapy, and features of specific antiseizure drugs. (See "Evaluation and management of the first seizure in adults" and "Overview of the management of epilepsy in adults" and "Evaluation and management of drug-resistant epilepsy" and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
WHEN TO START ANTISEIZURE DRUG THERAPY
First-time 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). Unprovoked seizures are distinct from provoked seizures: provoked seizures are due to an acute condition such as a toxic or metabolic disturbance, head trauma, or acute stroke (ie, acute symptomatic seizures).
The decision of whether or not to start antiseizure drug therapy at the time of a first unprovoked seizure in an adult should be individualized. The main factors to consider in making the decision are:
●The risk for recurrent seizures, which varies based on clinical factors discussed below (see 'Risk of seizure recurrence' below)
●The approximate benefit that can be expected from immediate antiseizure drug therapy on the risk of recurrent seizure (see 'Benefit of early versus deferred treatment' below)
●Patient values and preferences, particularly with regard to the social consequences of a recurrent seizure (eg, implications for driving or employment) (see 'Benefit of early versus deferred treatment' below)
An evidence-based guideline of the American Academy of Neurology and the American Epilepsy Society on the management of an unprovoked first seizure in adults also advocates for an individualized approach that weighs the risk of seizure recurrence against the adverse effects of antiseizure drugs and considers educated patient preferences . The guideline offers the following specific recommendations:
●Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first two years (21 to 45 percent).
●Clinical variables associated with an increased risk may include a prior brain insult, an EEG with epileptiform abnormalities, a significant brain imaging abnormality, and a nocturnal seizure.
●Immediate antiseizure drug therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first two years but may not improve quality of life. Over a longer term (>3 years), immediate antiseizure drug treatment is unlikely to improve prognosis as measured by sustained seizure remission.
●Patients should be advised that the risk of antiseizure drug adverse events may range from 7 to 31 percent and that these adverse events are likely predominantly mild and reversible.
In patients with a first unprovoked seizure who are found to have a CNS abnormality on neuroimaging (such as a brain tumor or scar tissue from an old head injury or CNS infection), the risk of seizure recurrence is high. In this instance, most clinicians would start treatment after the first unprovoked seizure. In fact, such patients likely have a sufficiently high risk of seizure recurrence to meet criteria for epilepsy according to International League Against Epilepsy (ILAE) guidelines . These criteria now consider patients with a single unprovoked seizure and an estimated risk of recurrence ≥60 percent over ten years to have epilepsy, similar to those with two unprovoked seizures occurring >24 hours apart. (See "Evaluation and management of the first seizure in adults" and 'Risk of seizure recurrence' below.)
In contrast are patients with a first unprovoked seizure who have a normal (or nonfocal) examination and normal (or nonspecific) neuroimaging. In these patients, the risk of seizure recurrence is lower, and antiseizure drug therapy may be reasonably deferred until after a second unprovoked seizure.
Patient concerns also weigh heavily in treatment decisions. If the risk of seizure recurrence is low, and the individual places a high value on avoidance of side effects, antiseizure drug therapy may be delayed. In contrast, there are some individuals who will be very concerned about seizure recurrence. In this instance, an antiseizure drug may be initiated to reduce seizure recurrence, despite what may be a low likelihood of additional seizures.
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 [4-6]. 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 [7,8].
The most replicated clinical factors associated with an increased risk for seizure recurrence after a first unprovoked seizure include [4-7,9-11]:
●Epileptiform abnormalities on EEG (see "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy")
●Remote symptomatic cause, as identified by clinical history or neuroimaging (eg, brain tumor, brain malformation, head injury with loss of consciousness, prior central nervous system infection)
●Abnormal neurologic examination, including focal findings and intellectual disability
●A first seizure that occurs during sleep (ie, a nocturnal seizure)
Each of these factors has been associated with an approximately 2- to 2.5-fold increased risk for recurrent seizure in studies that have included a mix of antiseizure drug-treated and untreated patients. There is a lack of evidence regarding interactions among various risk factors, and there is no formula available for determining additive risk .
Other potential risk factors for seizure recurrence have been investigated and remain more uncertain. As an example, patients who have a first presentation with status epilepticus or with multiple seizures within a single day are more likely to be treated with antiseizure drugs than are those with a single short-duration seizure. However, limited data suggest that presentation with status epilepticus, in the absence of other risk factors, does not increase the risk of seizure recurrence [6,7,9,12]. Similarly, whether a history of prior febrile seizures is associated with an increased risk of seizure recurrence after a first unprovoked afebrile seizure is uncertain [6,7,9,11].
Study results have conflicted as to whether a family history of epilepsy impacts recurrence risk [5-7,9,11]. This varies according to the epilepsy syndrome, since several epilepsy syndromes have been identified as monogenetic in origin.
Benefit of early versus deferred treatment — For adults presenting with an unprovoked first seizure, immediate antiseizure drug treatment reduces the risk of seizure recurrence by about 35 percent over the next one to two years [4,5,10,13-17]. This estimate is derived from a meta-analysis of five randomized trials (n = 1600 patients) comparing immediate versus delayed antiseizure drug therapy in adults with an unprovoked first seizure .
However, studies suggest that starting an antiseizure drug has little impact on long-term outcome. At four and five years after the first seizure, patients have similar rates of complete seizure remission whether antiseizure drug treatment was initiated immediately after the first seizure or deferred until a second seizure occurred [4,5,10,13,17]. At least one randomized trial found that 20-year mortality was not impacted by immediate versus deferred treatment .
In the aggregate, quality of life outcomes, as measured in one randomized study, were not different with early versus deferred treatment . However, the questionnaires demonstrated significant tradeoffs between the adverse effects of seizures versus adverse effects of taking antiseizure drugs, suggesting that individual patient preferences should be considered. As one example, patients randomized to early antiseizure drug treatment were more likely to be able to drive than patients whose treatment was deferred. A need to drive or operate heavy machinery along with other occupational and psychological consequences of suffering a recurrent seizure are important considerations when deciding whether to start antiseizure drug therapy.
Second unprovoked seizure — Patients presenting with a second unprovoked seizure should be started on antiseizure drug therapy, since seizure recurrence indicates that the patient has a substantially increased risk for additional seizures (ie, epilepsy) [6,8].
In one prospective case series, the risk of another seizure after two unprovoked seizures was 73 percent at four years (most of these patients were treated with antiseizure drugs) . In many cases, a careful history may reveal that certain seizure types such as typical absence, myoclonic, simple or complex partial have been recurrent at the time of presentation .
Acute symptomatic seizure — Acute symptomatic seizures have a lower risk for subsequent epilepsy compared with remote symptomatic seizures . Early management decisions, including whether or not to start an antiseizure drug, 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 associated with a recurrent seizure. (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic seizures'.)
Patients with seizures that occur in the setting of acute neurologic illness or injury (eg, stroke, traumatic brain injury, meningitis, anoxic encephalopathy), particularly when severe, are often treated with antiseizure drugs in the acute setting because of the risk of prolonged recurrent seizures or aggravation of a systemic injury. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures' and "Spontaneous intracerebral hemorrhage: Treatment and prognosis", section on 'Seizure prophylaxis and treatment' and "Post-traumatic seizures and epilepsy", section on 'Early seizures'.)
A subset of acute symptomatic seizures is those that occur in the setting of an acute medical illness or metabolic disturbance (table 1). In contrast to the setting of an acute stroke or traumatic brain injury, patients with seizures provoked by metabolic derangements are generally not felt to be at risk for future epilepsy, but they are at risk for seizure recurrence in the acute setting . Short-term antiseizure drug therapy may be indicated if the metabolic disturbance is expected to persist or if the initial seizure is prolonged (as in the instance of status epilepticus). (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic seizures' and "Evaluation and management of the first seizure in adults", section on 'When to start antiseizure drug therapy'.)
SELECTION OF AN ANTISEIZURE DRUG — Epilepsy is initially treated with antiseizure drug monotherapy. Almost half of patients will become seizure-free with their first antiseizure drug trial [22,23].
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, however, and 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 a combination of drug, seizure, and patient-specific factors.
Drug-related considerations — Aspects of antiseizure drug therapy that are relevant to drug selection include efficacy, pharmacokinetics, adverse effects, and cost.
Comparative efficacy — No single antiseizure drug is clearly the most effective or best tolerated, and there are now over 20 antiseizure drugs approved for treatment of seizures in adults and/or children (table 2 and table 3). (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
Randomized trials assessing efficacy and tolerability provide the least biased evidence of efficacy. However, these typically compare active therapy to a subtherapeutic dose of the same agent and/or to placebo rather than to an effective dose of another antiseizure drug . Another limitation of most randomized trials in epilepsy is that these are usually performed testing new antiseizure drugs as add-on treatment in patients with treatment-resistant illness (see 'FDA indications' below). Such patients may not be representative of general clinical population.
There have been a limited number of randomized trials comparing various antiseizure drugs head-to-head as initial monotherapy in adults, all of which have shown similar efficacy between drugs [24,25]:
Although these trials have not shown significant differences between antiseizure drugs, the quality of the data remains limited by the fact that they were generally of short duration (24 or 48 weeks). Such studies can compare the incidence of short-term side effects between drugs, but they have limited power to assess relative efficacy. In general, but with some exceptions, the newer antiseizure drugs are superior with respect to tolerability .
Meta-analyses of randomized trials can potentially overcome some of the limitations of individual trials, but even these studies can be problematic, since patient populations and drug doses often vary between trials; this substantively limits the ability to compare the studied treatments. In general, such studies have lacked power either to refute or substantively confirm results of individual trials [47-51].
The largest individual randomized trial examining different antiseizure drugs as monotherapy for the initial treatment of epilepsy was the Standard and New Antiepileptic Drugs (SANAD) trial [52-54]. The SANAD trial included 1721 patients with focal epilepsy and 716 patients with generalized seizures. In an effort to balance methodologic rigor and practicality, the trial was not blinded . 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 mean follow-up time exceeded three years. The main findings were:
●For patients treated for focal epilepsy, lamotrigine and oxcarbazepine had the longest time to treatment failure compared with carbamazepine, gabapentin, and topiramate . Lamotrigine and carbamazepine were associated with the shortest times to 12-month seizure remission.
●For patients treated for generalized epilepsy, valproate and lamotrigine were superior to topiramate in regard to time to treatment failure . For time to 12-month seizure remission, valproate and topiramate were more efficacious compared with lamotrigine.
●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 . The strongest predictor of improved quality of life outcomes was achievement of a 12-month seizure remission.
The investigators concluded that lamotrigine should be considered the drug of first choice for focal epilepsy and valproate for generalized epilepsy. Because the SANAD trial was unblinded, however, there was potential for bias. Also, it provided only sparse data regarding the potential of rare, often idiosyncratic, serious adverse events (eg, potential for teratogenicity with valproate). These results also do not account for other patient-specific preferences regarding the likelihood of different side effects, need for drug monitoring, potential for drug interactions, and dosing frequency .
Pharmacokinetics — Important pharmacologic features of individual antiseizure drugs are summarized in the table and reviewed in more detail separately (table 2). (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
Some of the more important considerations when choosing a first-line antiseizure drug include the following:
●Dosing frequency – The half-lives of antiseizure drugs vary considerably (table 2). For many individuals, the frequency with which a drug must be taken is an important factor in compliance and/or seizure control. Optimal dose frequency for individual drugs can vary between patients.
Most antiseizure drugs are prescribed in two daily doses. Antiseizure drugs 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, extended-release valproate, zonisamide, eslicarbazepine, perampanel, and extended-release formulations of levetiracetam and lamotrigine.
●Drug interactions – The selection of an antiseizure drug should consider other prescribed medications for potential drug interactions. Clinicians should review each item on a patient's medication list for potential drug interactions [58,59]. Specific interactions of antiseizure drugs with other medications may be determined using the drug interactions tool (Lexi-Interact online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.
In general, antiseizure drugs with hepatic enzyme induction or inhibitory properties have the greatest potential for interactions. Enzyme induction occurs with all older antiseizure drugs (phenytoin, phenobarbital, carbamazepine) except valproate and ethosuximide. Enzyme induction also occurs with a few of the more recently approved antiseizure drugs such as felbamate, topiramate, and oxcarbazepine (table 2) .
Antiseizure drugs 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 antiseizure drugs include statins, calcium channel blockers, serotonin reuptake inhibitors, antipsychotics, tricyclic antidepressants, hormonal contraceptive therapy, warfarin, and many anticancer drugs .
In contrast, valproate is a hepatic enzyme inhibitor and may cause significant increases in serum concentrations of medications that are metabolized in the liver.
Other drug interactions relate to protein binding. Addition of a drug that is highly protein-bound will displace another protein-bound drug, increasing its free fraction. In the setting of reduced serum albumin, this effect is amplified. Lamotrigine concentrations are reduced by estrogen-containing hormonal contraceptives. (See 'Hormonal contraception' below.)
●Aging – Antiseizure drug use in older adult patients is complicated by several factors, including age-related alterations in protein binding, reduced hepatic metabolism, and diminished renal clearance of medications. In addition, polypharmacy is more often a concern in older adults. These and other factors related to antiseizure drug selection in older adults are discussed separately. (See "Treatment of seizures and epilepsy in older adults".)
Side effect profiles — The adverse effects of antiseizure drugs make a significant contribution to reduced quality of life in individuals with epilepsy . While many antiseizure drug side effects (eg, drowsiness, dizziness, diplopia, and imbalance) seem to be common to this entire class of medicines, others are more specific to an individual drug. These should be considered in selecting an antiseizure drug since certain side effects are either more likely or more problematic in certain patients.
●Neurocognitive side effects – Most antiseizure drugs are associated with a negative impact on cognition, but some are more problematic than others . Among the older antiseizure drugs, studies suggest that phenobarbital is associated with greater impairments compared with carbamazepine, valproate, and phenytoin, which have similar, but more modest negative effects [63,64]. Among the newer antiseizure drugs, 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 . Finally, a significant minority of patients taking topiramate discontinue the drug because of clinically apparent cognitive difficulties. In direct comparison studies, cognitive profiles in patients taking topiramate were worse than those taking valproate, lamotrigine, or gabapentin .
●Hypersensitivity reactions – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash 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 carbamazepine, oxcarbazepine, phenytoin, lamotrigine, and phenobarbital (table 5), and less commonly with valproate and topiramate; however, they have been described with almost all antiseizure drugs [66,67].
The period of highest risk is within the first two months of use. For carbamazepine (and possibly phenytoin and oxcarbazepine), the risk may be higher in patients with the HLA-B*1502 or HLA-A*3101 alleles. The former occurs almost exclusively in patients of Asian ancestry, including South Asian Indians. The US Food and Drug Administration (FDA) recommends screening such patients for the HLA-B*1502 allele prior to starting carbamazepine and possibly phenytoin. This is discussed in more detail separately. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Role of HLA testing' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Suicidality – Antiseizure drugs as a class have been associated with an approximately twofold increased relative risk of suicidal behavior or ideation based on pooled analyses of placebo-controlled trials (0.43 versus 0.22 percent) . Some experts advise screening for depression at diagnosis of epilepsy and at each follow-up visit . This is discussed in more detail separately. (See "Overview of the management of epilepsy in adults", section on 'Specific adverse reactions' and "Comorbidities and complications of epilepsy in adults", section on 'Psychiatric disorders'.)
●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.
FDA indications — The FDA indication for use of antiseizure drugs may influence physician prescribing habits. For many newer antiseizure drugs, the FDA indications are based on studies that showed effectiveness as add-on treatment in persons with refractory epilepsy. Monotherapy trials are performed infrequently because most physicians and patients are reluctant to be treated with placebo when effective treatments exist . As a result, many antiseizure drugs are not FDA-approved as initial monotherapy. Some physicians may be initially reluctant to use newer antiseizure drugs as monotherapy in the initial treatment of epilepsy pending advice from colleagues and/or published expert opinion.
A historical-controlled treatment discontinuation trial design is being increasingly used in an attempt to evaluate the effectiveness of various antiseizure drugs as conversion to monotherapy in patients with drug-resistant epilepsy, since randomizing patients with active seizures to a placebo conversion presents ethical concerns. The primary outcome measure is the predicted exit percentage, defined as the proportion of patients meeting a seizure-related exit criterion (eg, withdrawal due to inadequate seizure control or adverse effects) at four months, compared with a pooled historical benchmark of 65 percent (compiled from older trials that did use a placebo or subtherapeutic antiseizure drug dose) . Drugs shown to be more effective than this historical benchmark in prospective trials include lamotrigine extended release , levetiracetam extended release , pregabalin , lacosamide , and eslicarbazepine . The exit rate in these trials has ranged from 20 to 40 percent at four months.
Cost of medications — For many patients, the cost of their medication is also an issue and whether a specific antiseizure drug is on a list of preferred medications approved by a third party payer may also be influential in the choice of antiseizure drug. When cost is taken into account, for areas of the world and for individual patients with restricted resources, phenobarbital may be the treatment of choice for partial epilepsy . Generic substitution can lower cost of many antiseizure drugs but is occasionally associated with a change in seizure control or tolerability, although the magnitude of this risk has been debated. (See 'Generic substitutions' below.)
Focal versus generalized epilepsy — In selecting an antiseizure drug for a patient with new onset epilepsy, it is important to differentiate between a focal versus generalized epilepsy syndrome . Antiseizure drugs are classified as either broad or narrow spectrum agents (table 3). While broad spectrum agents treat both focal and generalized epilepsy syndromes, narrow spectrum agents treat one or the other .
Most of the narrow spectrum agents are effective for localization-related or focal epilepsies. As an example, gabapentin (a narrow spectrum agent) may work well for a patient with temporal lobe epilepsy (a focal epilepsy), but is unlikely to be effective in juvenile myoclonic epilepsy (a generalized epilepsy). Ethosuximide is another narrow spectrum agent used for absence seizures (a generalized epilepsy), which is generally ineffective for focal seizures. Broad spectrum agents are effective for both types of epilepsies . If the clinician is unsure whether the epilepsy syndrome is focal or generalized, a broad spectrum agent is usually chosen (table 3).
Identifying the correct epilepsy syndrome is critical to selecting an optimal treatment. For instance, a few of the narrow spectrum agents have been reported to worsen certain seizures that occur in the primary generalized epilepsy syndromes. Oxcarbazepine , carbamazepine, phenytoin, vigabatrin, and gabapentin  have all been reported to worsen certain seizures types in generalized epilepsy syndromes.
Specific etiologies — In addition to the distinction between generalized and focal epilepsy discussed above, specific etiologies of epilepsy may impact the treatment choice.
●Post-stroke epilepsy is generally easily controlled with antiseizure drug monotherapy. The choice of antiseizure drug may be influenced by specific concerns, such as potential impact of the antiseizure drug on post-stroke functional recovery and the potential for drug interactions with warfarin and salicylates (see 'Pharmacokinetics' above) . The treatment of post-stroke epilepsy is discussed in detail separately. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.)
●Brain tumors are associated with epilepsy in 30 to 70 percent of patients, depending on the tumor type. The choice of antiseizure drug in this setting is influenced by potential drug interactions with chemotherapeutic agents leading to decreased efficacy of both treatments, as well as the increased potential for allergic cutaneous reactions when antiseizure drugs are used during radiotherapy [82,83]. Both of these factors contribute to a strong preference for non-enzyme inducing antiseizure drugs in brain tumor patients when possible. (See "Seizures in patients with primary and metastatic brain tumors".)
Comorbid medical conditions — Medical comorbidities are important to consider when selecting an antiseizure drug. Many antiseizure drugs 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 antiseizure drugs or to adjust the dose. Other comorbidities can be problematic because of potential drug side effects or drug interactions, while others may represent an opportunity to choose an antiseizure drug that has efficacy in both conditions.
Renal disease — Renally excreted drugs include gabapentin, topiramate, zonisamide, lacosamide, levetiracetam, oxcarbazepine, and pregabalin (table 2) [78,84,85]. The dose of these drugs should be adjusted based on the severity of renal impairment (table 6).
In patients on hemodialysis, antiseizure drug 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 antiseizure drug metabolism are not well studied, and antiseizure drug treatment in such patients may require additional monitoring. (See "Seizures in patients undergoing hemodialysis", section on 'Dosing'.)
Albuminuria (causing low serum albumin) and acidosis reduce protein binding fractions and binding affinity, leading to increased fractions of free drug . For highly protein-bound antiseizure drugs (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 antiseizure drugs.
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 "Risk factors for calcium stones in adults"). Renal tubular acidosis can also occur with these antiseizure drugs; 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 .
In the setting of renal transplantation, potential drug interactions between antiseizure drugs and immunosuppressive therapy should be considered. Enzyme-inducing antiseizure drugs may lower serum immunosuppressant levels, while enzyme-inhibitors may increase levels.
Hepatic disease — Some antiseizure drugs are associated with hepatic toxicity and should be avoided in patients with preexisting liver disease. These include valproate and felbamate, and to a lesser extent, phenytoin and carbamazepine [84,87]. Many other antiseizure drugs 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 carbamazepine, lamotrigine, phenytoin, phenobarbital, clobazam, valproate, felbamate, zonisamide, topiramate, oxcarbazepine, eslicarbazepine, and brivaracetam. Levetiracetam, gabapentin, pregabalin, and vigabatrin do not undergo hepatic metabolism and are less problematic for use in patients with chronic liver disease.
Psychiatric disorders — Persons with epilepsy have a higher than expected prevalence of comorbid psychiatric disorders [88-92]. The association may relate to shared perturbations in neurotransmitter action, alterations to neural networks or both [89,91,93]. In persons with epilepsy, the presence of depression correlates more strongly with a poor quality of life than the frequency of the seizures .
Some antiseizure drugs (valproate, lamotrigine, carbamazepine, oxcarbazepine) appear to have mood stabilizing properties [95-97]. Their efficacy in this regard is best established for bipolar disorder. However, many physicians view these medications as attractive in patients with comorbid anxiety and depression.
In contrast, some antiseizure drugs, in particular those that potentiate gamma-aminobutyric acid (GABA) neurotransmission (phenobarbital, tiagabine, vigabatrin, topiramate), have been reported to cause or exacerbate a depressed mood and perhaps should be avoided in patients with comorbid depression . 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.
Use of one of the antiseizure drugs thought to be effective in mood stabilization 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, antiseizure drugs are associated with an increased risk of suicide. All patients with epilepsy treated with antiseizure drugs should be monitored for changes in mood and suicidality. (See "Overview of the management of epilepsy in adults", section on 'Specific adverse reactions'.)
Drug interactions are also a potential concern in patients with psychiatric disorders. Enzyme-inducing antiseizure drugs (table 2) can decrease the plasma concentration of many antidepressants including tricyclic agents and selective serotonin reuptake inhibitors, as well as antipsychotic drugs and benzodiazepines [58,59]
Migraine — Some studies suggest that migraine may be more prevalent in patients with epilepsy and vice versa [99,100]. Valproate, gabapentin, and topiramate are antiseizure drugs that have demonstrated efficacy for migraine prevention in placebo-controlled trials (see "Preventive treatment of migraine in adults", section on 'Anticonvulsants'). This may provide an opportunity to limit polypharmacy in individuals with both migraine and epilepsy.
Osteoporosis risk — Antiseizure drugs in chronic use have been associated with bone loss. Initially this association was observed for enzyme-inducing antiseizure drugs (table 2), but later was found to extend to valproate as well as to some of the newer nonenzyme-inducing antiseizure drugs [101-103]. The evidence associating osteoporosis and antiseizure drug therapy may be strongest for phenytoin. Osteoporosis is particularly problematic for patients with epilepsy, as seizures are associated with falls and bone fractures [86,104,105].
While phenytoin should perhaps be avoided in patients in whom there is concern for bone loss, there are insufficient data to recommend avoiding or choosing any other specific antiseizure drug in order to limit the risk of osteoporosis . Rather, monitoring of bone density, routine supplementation of calcium and vitamin D, and a consistent exercise regimen are suggested for all patients on chronic antiseizure drug therapy. (See "Antiepileptic drugs and bone disease".)
●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 . Carbamazepine, vigabatrin, gabapentin, and pregabalin are also, but less frequently, associated with weight gain. (See 'Side effect profiles' above.)
Some antiseizure drugs (gabapentin, pregabalin, and possibly carbamazepine and topiramate) have efficacy in treating pain associated with diabetic neuropathy. (See "Treatment of diabetic neuropathy", section on 'Anticonvulsants'.)
●Thyroid disease – While many antiseizure drugs, in particular the enzyme-inducing agents, can alter thyroid hormone levels, this is generally subclinical and should not impact drug choice [106,107]. Enzyme-inducing agents should probably be avoided in patients with severe thyroid dysfunction.
●Cancer – The choice of antiseizure drug in patients being treated for systemic cancer is influenced by potential drug interactions between enzyme-inducing antiseizure drugs (table 2) and chemotherapeutic agents that can lead to decreased efficacy of both treatments [82,83]. 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 antiseizure drugs are used during radiotherapy.
●HIV – Enzyme-inducing antiseizure drugs and those that are highly protein-bound (table 2) may interact with antiretroviral therapy (ART) [108-110]. 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 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 .
●Cardiovascular disease – Clinicians should consider potential drug interactions between enzyme-inducing antiseizure drugs and statins, calcium channel blockers, and warfarin [58,59,112]. While, carbamazepine has been associated with heart block and other bradyarrhythmias in susceptible individuals , clinically significant ECG changes are uncommon with carbamazepine in older adult patients who do not have a preexisting conduction defect .
Because the cytochrome P450 enzymes are involved in cholesterol synthesis, it is possible that enzyme-inducing antiseizure drugs may thereby affect vascular risk. In one small series, switching patients from carbamazepine or phenytoin to noninducing antiseizure drugs levetiracetam or lamotrigine was associated with improvements in serologic markers of vascular risk (eg, total cholesterol, triglycerides, C-reactive protein) . 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, and elevated levels of C-reactive protein [116,117]. However, no studies have clearly linked any specific antiseizure drugs to a higher or lower risk of vascular events.
●Blood disorders – Certain antiseizure drugs (carbamazepine, phenytoin, ethosuximide, valproate) are associated with neutropenia and agranulocytosis, and should be avoided in patients with blood disorders [118,119]. (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".)
Women of childbearing age — A number of issues are important in women of childbearing age, especially if they are considering becoming or are already pregnant.
Folate should be prescribed to all women of childbearing age who are taking antiseizure drugs. Patients taking valproate or carbamazepine should receive daily folic acid supplementation (4 mg/day) for one to three months prior to conception. Women who are taking other antiseizure drugs should take the more standard lower dose of folic acid (0.4 to 0.8 mg per day). (See "Management of epilepsy and pregnancy", section on 'Folic acid supplementation'.)
Hormonal contraception — Women should be informed about the interactions between antiseizure drug therapies and hormonal pill, patch, or ring contraception and the availability of long-acting reversible contraception (LARC), which is highly effective and avoids most if not all drug-drug interactions, depending on the specific method. (See "Contraceptive counseling and selection".)
The expected contraceptive failure rate of 0.7 per 100 woman-years using oral contraceptives is increased to 3.1 per 100 woman-years in patients who concomitantly take enzyme-inducing antiseizure drugs (table 2) [120-123]. While vigabatrin is not an enzyme inducer, lower levels of ethinyl estradiol have been reported in volunteers taking this antiseizure drug  (see "Overview of the use of estrogen-progestin contraceptives", section on 'Drug interactions'). If an enzyme-inducing antiseizure drug is nonetheless deemed to be the drug of choice in a woman taking combined hormonal pill, patch, or ring contraception, alternative regimens or forms of contraception should be considered. (See "Overview of the management of epilepsy in adults", section on 'Contraception'.)
In addition to the effect of antiseizure drugs on hormonal contraceptive metabolism, combined hormonal contraceptives can increase the metabolism of lamotrigine, thereby reducing the plasma drug concentration. In other words, higher doses of lamotrigine may be needed in women taking combined estrogen-progesterone contraception, and continuous dosing may be preferable to avoid increased lamotrigine levels during pill-free intervals. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
Catamenial epilepsy — Many women with epilepsy report an association between the occurrence of their seizures and certain phases of their menstrual cycle [125,126]. Catamenial seizure clustering can occur in women with any seizure type and epilepsy syndrome but may be more common among women with focal compared with generalized epilepsy [127-132] and among those with left-sided temporal epilepsy compared with right-sided, multifocal, or extratemporal epilepsy [133,134].
In general, research suggests that catamenial seizure patterns result from cyclic changes in hormone levels during the menstrual cycle; changes in antiseizure drug levels due to endogenous metabolic effects may also contribute. Estrogen levels peak mid-cycle and then, in women who do not conceive, fall through the onset of menses. It is during the late part of the menstrual cycle (just before the onset of menses), during a relative drop in estrogen levels, that seizures most often cluster [127,135]. Periovulatory (mid-cycle) seizure clustering can also occur.
The mainstay of treatment of catamenial seizures is an antiseizure drug that is most effective for the woman's epilepsy syndrome. However, when catamenial seizures are not controlled with antiseizure drugs, clinicians may consider use of a continuous estrogen-progestin contraceptive on the theoretical basis that suppressing estrogen fluctuations will lead to better seizure control. The rationale and use of hormonal prophylaxis for catamenial epilepsy is similar to that in estrogen-associated migraine, which is reviewed separately. (See "Estrogen-associated migraine", section on 'Hormone-based interventions'.)
Intermittent benzodiazepine treatment timed according to the vulnerable phase of the menstrual cycle is also a common strategy. Clobazam is the only benzodiazepine studied systematically for this purpose. In a double-blind cross-over study, clobazam (20 to 30 mg/day) was administered for 10 days in the high risk phase of the menstrual cycle in 18 women with catamenial epilepsy . Fourteen patients reported better seizure control with clobazam than placebo. Long term follow-up of patients who continued to use this treatment strategy revealed seizure remission and/or significant reduction of seizures in five of nine patients . These limited data support a fairly common practice of treating catamenial seizure exacerbations with intermittent benzodiazepines with a long-acting agent such as lorazepam. A reasonable dose of lorazepam in this setting is 0.5 to 1 mg two to three times daily.
Very limited data suggest that appropriately timed acetazolamide may have some benefit in catamenial epilepsy [138-140]. Although cyclic natural progesterone has been reported to reduce seizure frequency in observational studies, a randomized trial failed to confirm a benefit in 294 women with poorly controlled seizures . Other investigational strategies include gonadotropin analogs and neurosteroids such as ganaxolone [128,142-144].
Pregnancy and postpartum — Treatment of epilepsy during pregnancy must balance competing risks. 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 antiseizure drugs in utero compared with offspring of untreated women with epilepsy and women without epilepsy. The overall risk of major malformations is 4 to 6 percent in exposed infants; valproate is a major contributor to this risk. Polypharmacy increases the risk. The timing (early versus late in gestation) and dose of exposure are also likely to be important. While no antiseizure drug has been definitively shown to be safe in pregnancy, the evidence linking valproate to fetal malformations is sufficiently convincing to recommend avoiding its initiation and use in most women of childbearing potential . (See "Risks associated with epilepsy and pregnancy".)
The management of epilepsy in pregnancy and during breastfeeding is discussed separately. (See "Management of epilepsy and pregnancy".)
INITIATION OF ANTISEIZURE DRUG THERAPY
Patient education — Successful treatment can be optimized by a systematic approach that includes patient education [146,147]. Before treatment is initiated, the physician needs to counsel the patient and family to increase their understanding of epilepsy and their ability to report necessary and relevant information. These discussions will improve the likelihood that the patient will comply with the plan of treatment.
The physician should impress upon the patient, family, and patient's friends the critical need to follow the prescribed drug regimen. Nonadherence to antiseizure drug treatment regimen is associated with increased risk of mortality, as well as hospitalization and injury . (See "Comorbidities and complications of epilepsy in adults".)
Written instructions on how and when to take the drugs should be provided and should explain the dosing regimen and any potential adverse effects or drug-drug interactions. The patient must also be warned not to stop taking an antiseizure drug on their own initiative, and not to allow a prescription to run out or expire.
Patients should be urged not to start any other prescription, over-the-counter medications, dietary supplements, or herbal remedies without first contacting their physician because these might affect serum concentrations of their antiseizure drugs [60,149]. (See 'Pharmacokinetics' above.)
Drug administration and dosing — Treatment should be started with a single drug (monotherapy). In general, the strategy is to gradually titrate the dosage to that which is maximally tolerated and/or produces optimal seizure control (start low and go slow). Pooled analysis from two large prospective studies found that with this approach, adverse event reporting was no higher in treated versus untreated patients . Variables other than antiseizure drug treatment were found to be associated with adverse event reporting, most notably comorbid depression. The recommended initial dose and suggested titration schedule is presented separately. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
Seizure calendar — Patients and family members should be asked to record seizures and antiseizure drug doses on a calendar, which can then be brought or sent to the physician for review. Seizure triggers (eg, stress, sleep deprivation, alcohol, menses) should be indicated. The patient and family should note on the calendar the hour at which any symptoms occur.
The seizure calendar helps to monitor and encourage compliance, as well as identify triggers. The seizure calendar also may be used to track the patient's response to drug therapy, including possible side effects. In one study of 71 patients completing daily seizure diaries, both lack of sleep and higher self-reported stress and anxiety were associated with seizure occurrence . Seizures were also associated with the patients' own prediction of the likelihood of seizure occurrence. Physicians should be aware that patients are often unaware of their seizures and may significantly underestimate the number of seizures that occur, especially those that occur during sleep or that disrupt consciousness .
Laboratory monitoring — A complete blood count, liver function tests, blood urea nitrogen (BUN), and measurement of creatinine and electrolytes levels should be done prior to starting antiseizure drug therapy. Albumin levels should also be obtained prior to starting treatment with one of the highly protein bound antiseizure drugs.
Regular follow-up visits should be scheduled to check drug concentrations, blood counts, and hepatic and renal function. These visits are also used to address concerns the patient may have about taking the medication and possible side effects, or psychosocial aspects of their disorder. Drug levels should be checked at least yearly in patients who are not having seizures and not undergoing medication dose changes. Chemistry and hematology studies are usually checked in association with drug levels.
Drug levels can be helpful in the management of antiseizure drugs :
●To establish an individual therapeutic concentration when a patient is in remission
●To assist in the diagnosis of clinical antiseizure drug toxicity
●To assess compliance
●To guide dose adjustments, particularly in the setting of drug formulation changes, when an interacting medication is added to or removed from a patient's regimen, or during pregnancy
Generic substitutions — The use of generic medications as a treatment for people with epilepsy has attracted much attention and debate, and the evidence is mixed in terms of whether generic substitution of antiseizure drugs has an adverse impact on seizure control and toxicity. Clinicians should consider the possibility of generic substitution as a cause of unexpected breakthrough seizures or toxicity, along with other possible explanations. In addition, clinicians may wish to obtain laboratory monitoring with plasma drug levels when a change is made in drug formulation. This topic is reviewed in more detail separately. (See "Overview of the management of epilepsy in adults", section on 'Generic substitution'.)
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 5th to 6th 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 10th to 12th 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 — Epilepsy is usually managed initially with antiseizure drug monotherapy. When to start treatment and with what agent is individualized in order to optimize both efficacy and tolerability.
●The decision of whether or not to start antiseizure drug therapy at the time of a first unprovoked seizure in an adult should be individualized based on an assessment of the risk for recurrent seizure, the potential benefits of immediate antiseizure drug therapy in reducing the risk of recurrent seizure, the side effects of antiseizure drugs, and patient preferences. (See 'First-time unprovoked seizure' above.)
•Antiseizure drug treatment is reasonable in patients after a single unprovoked seizure if they also have a potential symptomatic cause of epilepsy (eg, stroke or trauma history, brain tumor), epileptiform features on electroencephalogram, a relevant abnormality on neuroimaging study (CT or MRI), or an abnormal neurologic examination. Many of these patients likely meet criteria for epilepsy according to the International League Against Epilepsy (ILAE) definition, which considers patients with a single unprovoked seizure and an estimated risk of recurrence ≥60 percent over ten years to have epilepsy, similar to those with two unprovoked seizures occurring >24 hours apart. (See 'Risk of seizure recurrence' above.)
•Antiseizure drug treatment after a single unprovoked seizure in patients may be deferred depending on the presence or absence of other risk factors and on individual patient preferences. (See 'Benefit of early versus deferred treatment' above.).
●We recommend initiating antiseizure drug therapy in individuals who have had two or more unprovoked seizures (Grade 1A). Such patients are at high risk for further unprovoked seizures. (See 'Second unprovoked seizure' above.)
●The selection of antiseizure drug considers the type of epilepsy or epilepsy syndrome (table 3) and potential side effects (table 4 and table 5), as well as other prescribed medications and comorbidities. Gender and patient age, and cost and availability of medication may also be relevant factors. (See 'Drug-related considerations' above and 'Seizure-related considerations' above.)
●In general, enzyme-inducing antiseizure drugs (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. (See 'Pharmacokinetics' above.)
●Because antiseizure drugs are either metabolized by the liver or excreted by the kidneys, renal and hepatic disease impacts on both the choice of antiseizure drug as well as the prescribing regimen. (See 'Renal disease' above and 'Hepatic disease' above.)
●Women of childbearing age should be counseled regarding possible teratogenic effects of antiseizure drugs and should consider taking supplemental folate to limit the risk. Initiation of valproate should be avoided in pregnancy. (See 'Women of childbearing age' above.)
●Regular outpatient follow-up appointments and the use of seizure calendars can help maximize the success of epilepsy treatment. (See 'Initiation of antiseizure drug therapy' above.)
●Patients with epilepsy have a higher than expected incidence of mood problems, anxiety, and depression. Antiseizure drugs have been associated with suicidality. Patients treated with antiseizure drugs should be monitored for changes in mood and suicidality. (See 'Psychiatric disorders' above.)
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