Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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 "Overview of the management of epilepsy in adults", section on 'Complications and comorbidities'.)
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 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 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 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 'Post-stroke 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 of the first seizure in adults", section on 'Acute symptomatic seizures' and "Evaluation of the first seizure in adults", section on 'Acute management of inpatient seizure'.)
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 [46-50].
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 [51-53]. 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 [57,58]. 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 [62,63]. 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 [65,66].
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 "Overview of the management of epilepsy in adults", section on 'Psychiatric comorbidity'.)
●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 'Post-stroke 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 [81,82]. 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".)
Comborbid 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, and pregabalin (table 2) [77,83,84]. The dose of these drugs should be lowered in the setting of renal impairment.
In patients on hemodialysis, a low dose after each dialysis may be sufficient to provide therapeutic levels of these antiseizure drugs. In addition to these antiseizure drugs, hemodialysis also efficiently removes antiseizure drugs that are water-soluble and are not highly protein-bound. As a result, supplemental doses of phenobarbital, ethosuximide, lacosamide, and levetiracetam may be required after dialysis. Antiseizure drug regimens should be individualized in hemodialysis patients based on drug levels and clinical response. The effects of peritoneal dialysis on antiseizure drug metabolism are not well studied and antiseizure drug treatment in such patients may require additional monitoring.
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 [83,86]. Many other antiseizure drugs are metabolized in the liver (table 2), requiring caution and dose adjustment when used in patients with hepatic disease. These include carbamazepine, lamotrigine, phenytoin, phenobarbital, and oxcarbazepine. Levetiracetam, gabapentin, pregabalin and vigabatrin are less problematic for use in patients with liver disease.
Psychiatric disorders — Persons with epilepsy have a higher than expected prevalence of comorbid psychiatric disorders [87-91]. The association may relate to shared perturbations in neurotransmitter action, alterations to neural networks or both [88,90,92]. 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 [94-96]. 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 [57,58]
Migraine — Some studies suggest that migraine may be more prevalent in patients with epilepsy and vice versa [98,99]. 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 [100-102]. 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 [85,103,104].
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 [105,106]. 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 [81,82]. 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) [107-109]. 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 [57,58,111]. 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 [115,116]. 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 [117,118]. (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) [119-122]. 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", section on 'Lamotrigine'.)
Catamenial epilepsy — Many women with epilepsy report an association between the occurrence of their seizures and certain phases of their menstrual cycle [124,125]. 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 [126-131] and among those with left-sided temporal epilepsy compared with right-sided, multifocal, or extratemporal epilepsy [132,133].
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 [126,134]. 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 [137-139]. 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 [127,141-143].
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 [145,146]. 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 "Overview of the management of epilepsy in adults", section on 'Complications and comorbidities'.)
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 [59,148]. (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'.)
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 topics (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.)
- Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55:475.
- Nevalainen O, Ansakorpi H, Simola M, et al. Epilepsy-related clinical characteristics and mortality: a systematic review and meta-analysis. Neurology 2014; 83:1968.
- Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2015; 84:1705.
- Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet 2005; 365:2007.
- Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. First Seizure Trial Group (FIR.S.T. Group). Neurology 1993; 43:478.
- Kim LG, Johnson TL, Marson AG, et al. Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results from the MESS trial. Lancet Neurol 2006; 5:317.
- Berg AT. Risk of recurrence after a first unprovoked seizure. Epilepsia 2008; 49 Suppl 1:13.
- Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998; 338:429.
- Hauser WA, Rich SS, Annegers JF, Anderson VE. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology 1990; 40:1163.
- Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997; 49:991.
- Ramos Lizana J, Cassinello Garciá E, Carrasco Marina LL, et al. Seizure recurrence after a first unprovoked seizure in childhood: a prospective study. Epilepsia 2000; 41:1005.
- Kho LK, Lawn ND, Dunne JW, Linto J. First seizure presentation: do multiple seizures within 24 hours predict recurrence? Neurology 2006; 67:1047.
- Leone MA, Solari A, Beghi E, FIRST Group. Treatment of the first tonic-clonic seizure does not affect long-term remission of epilepsy. Neurology 2006; 67:2227.
- Das CP, Sawhney IM, Lal V, Prabhakar S. Risk of recurrence of seizures following single unprovoked idiopathic seizure. Neurol India 2000; 48:357.
- Chandra B. First seizure in adults: to treat or not to treat. Clin Neurol Neurosurg 1992; 94 Suppl:S61.
- Gilad R, Lampl Y, Gabbay U, et al. Early treatment of a single generalized tonic-clonic seizure to prevent recurrence. Arch Neurol 1996; 53:1149.
- Leone MA, Giussani G, Nolan SJ, et al. Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unprovoked seizure. Cochrane Database Syst Rev 2016; :CD007144.
- Leone MA, Vallalta R, Solari A, et al. Treatment of first tonic-clonic seizure does not affect mortality: long-term follow-up of a randomised clinical trial. J Neurol Neurosurg Psychiatry 2011; 82:924.
- Jacoby A, Gamble C, Doughty J, et al. Quality of life outcomes of immediate or delayed treatment of early epilepsy and single seizures. Neurology 2007; 68:1188.
- Hesdorffer DC, Benn EK, Cascino GD, Hauser WA. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia 2009; 50:1102.
- Fields MC, Labovitz DL, French JA. Hospital-onset seizures: an inpatient study. JAMA Neurol 2013; 70:360.
- Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314.
- Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology 2002; 58:S2.
- French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62:1252.
- Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54:551.
- Nolan SJ, Marson AG, Weston J, Tudur Smith C. Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev 2015; :CD001911.
- Nolan SJ, Marson AG, Weston J, Tudur Smith C. Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review. Cochrane Database Syst Rev 2016; 4:CD001769.
- Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77. Neurology 1998; 51:1282.
- French J, Glue P, Friedman D, et al. Adjunctive pregabalin vs gabapentin for focal seizures: Interpretation of comparative outcomes. Neurology 2016; 87:1242.
- Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res 1999; 37:81.
- Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995; 345:476.
- Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin. Epilepsia 1999; 40:601.
- Brodie MJ, Chadwick DW, Anhut H, et al. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002; 43:993.
- Kwan P, Brodie MJ, Kälviäinen R, et al. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011; 10:881.
- Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand 2003; 107:165.
- Ramsay E, Faught E, Krumholz A, et al. Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial. Epilepsia 2010; 51:1970.
- Bill PA, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997; 27:195.
- Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997; 27:205.
- Christe W, Krämer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997; 26:451.
- Dam M, Ekberg R, Løyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989; 3:70.
- Baulac M, Brodie MJ, Patten A, et al. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012; 11:579.
- Baulac M, Patten A, Giorgi L. Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: results of a phase III, randomized, double-blind study. Epilepsia 2014; 55:1534.
- Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68:402.
- Trinka E, Marson AG, Van Paesschen W, et al. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2013; 84:1138.
- Brodie MJ, Wroe SJ, Dean AD, et al. Efficacy and Safety of Remacemide versus Carbamazepine in Newly Diagnosed Epilepsy: Comparison by Sequential Analysis. Epilepsy Behav 2002; 3:140.
- Privitera MD. Evidence-based medicine and antiepileptic drugs. Epilepsia 1999; 40 Suppl 5:S47.
- Williamson PR, Marson AG, Tudur C, et al. Individual patient data meta-analysis of randomized anti-epileptic drug monotherapy trials. J Eval Clin Pract 2000; 6:205.
- Gamble C, Williamson PR, Chadwick DW, Marson AG. A meta-analysis of individual patient responses to lamotrigine or carbamazepine monotherapy. Neurology 2006; 66:1310.
- Muller M, Marson AG, Williamson PR. Oxcarbazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2006; :CD003615.
- Tudur Smith C, Marson AG, Clough HE, Williamson PR. Carbamazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2002; :CD001911.
- Marson AG, Appleton R, Baker GA, et al. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial. Health Technol Assess 2007; 11:iii.
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369:1000.
- Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369:1016.
- Chadwick D, Marson T. Choosing a first drug treatment for epilepsy after SANAD: randomized controlled trials, systematic reviews, guidelines and treating patients. Epilepsia 2007; 48:1259.
- Jacoby A, Sudell M, Tudur Smith C, et al. Quality-of-life outcomes of initiating treatment with standard and newer antiepileptic drugs in adults with new-onset epilepsy: findings from the SANAD trial. Epilepsia 2015; 56:460.
- French JA. First-choice drug for newly diagnosed epilepsy. Lancet 2007; 369:970.
- Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2003; 2:473.
- Patsalos PN, Fröscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43:365.
- Gidal BE, French JA, Grossman P, Le Teuff G. Assessment of potential drug interactions in patients with epilepsy: impact of age and sex. Neurology 2009; 72:419.
- Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology 2009; 72:1223.
- Hessen E, Lossius MI, Gjerstad L. Antiepileptic monotherapy significantly impairs normative scores on common tests of executive functions. Acta Neurol Scand 2009; 119:194.
- Motamedi G, Meador K. Epilepsy and cognition. Epilepsy Behav 2003; 4 Suppl 2:S25.
- Meador KJ. Cognitive and memory effects of the new antiepileptic drugs. Epilepsy Res 2006; 68:63.
- Koch MW, Polman SK. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database Syst Rev 2009; :CD006453.
- Yang CY, Dao RL, Lee TJ, et al. Severe cutaneous adverse reactions to antiepileptic drugs in Asians. Neurology 2011; 77:2025.
- Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 2005; 64:1134.
- Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011; 52:2133.
- French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia 2010; 51:1936.
- French JA, Temkin NR, Shneker BF, et al. Lamotrigine XR conversion to monotherapy: first study using a historical control group. Neurotherapeutics 2012; 9:176.
- Chung S, Ceja H, Gawłowicz J, et al. Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study. Epilepsy Res 2012; 101:92.
- French J, Kwan P, Fakhoury T, et al. Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial. Neurology 2014; 82:590.
- Wechsler RT, Li G, French J, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study. Epilepsia 2014; 55:1088.
- Sperling MR, French J, Jacobson MP, et al. Conversion to eslicarbazepine acetate monotherapy: A pooled analysis of 2 phase III studies. Neurology 2016; 86:1095.
- Perucca E. Treatment of epilepsy in developing countries. BMJ 2007; 334:1175.
- Lüders HO, Turnbull J, Kaffashi F. Are the dichotomies generalized versus focal epilepsies and idiopathic versus symptomatic epilepsies still valid in modern epileptology? Epilepsia 2009; 50:1336.
- Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756.
- Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39:5.
- Gelisse P, Genton P, Kuate C, et al. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsia 2004; 45:1282.
- Ryvlin P, Montavont A, Nighoghossian N. Optimizing therapy of seizures in stroke patients. Neurology 2006; 67:S3.
- Vecht CJ, van Breemen M. Optimizing therapy of seizures in patients with brain tumors. Neurology 2006; 67:S10.
- Michelucci R. Optimizing therapy of seizures in neurosurgery. Neurology 2006; 67:S14.
- Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006; 67:S28.
- Israni RK, Kasbekar N, Haynes K, Berns JS. Use of antiepileptic drugs in patients with kidney disease. Semin Dial 2006; 19:408.
- Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004; 63:S24.
- Ahmed SN, Siddiqi ZA. Antiepileptic drugs and liver disease. Seizure 2006; 15:156.
- Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005; 7 Suppl 1:S1.
- Gabbs MG, Barry JJ. The link between mood disorders and epilepsy: why is it important to diagnose and treat?. Adv Stud Med 2005; 5:S572.
- Ettinger AB, Reed ML, Goldberg JF, Hirschfeld RM. Prevalence of bipolar symptoms in epilepsy vs other chronic health disorders. Neurology 2005; 65:535.
- Kanner AM. Depression in epilepsy: a neurobiologic perspective. Epilepsy Curr 2005; 5:21.
- Beyenburg S, Mitchell AJ, Schmidt D, et al. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav 2005; 7:161.
- Karceski SC. Exploring the connection between mood disorders and epilepsy. Pract Neurol 2005; 4:24.
- Gilliam FG, Mendiratta A, Pack AM, Bazil CW. Epilepsy and common comorbidities: improving the outpatient epilepsy encounter. Epileptic Disord 2005; 7 Suppl 1:S27.
- Brodtkorb E, Mula M. Optimizing therapy of seizures in adult patients with psychiatric comorbidity. Neurology 2006; 67:S39.
- García-Morales I, de la Peña Mayor P, Kanner AM. Psychiatric comorbidities in epilepsy: identification and treatment. Neurologist 2008; 14:S15.
- Labiner DM, Ettinger AB, Fakhoury TA, et al. Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy. Epilepsia 2009; 50:434.
- Mula M, Hesdorffer DC, Trimble M, Sander JW. The role of titration schedule of topiramate for the development of depression in patients with epilepsy. Epilepsia 2009; 50:1072.
- De Simone R, Ranieri A, Marano E, et al. Migraine and epilepsy: clinical and pathophysiological relations. Neurol Sci 2007; 28 Suppl 2:S150.
- Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine. Epilepsy Behav 2003; 4 Suppl 2:S13.
- Pack AM, Morrell MJ, Marcus R, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol 2005; 57:252.
- Pack A. Effects of Treatment on Endocrine Function in Patients with Epilepsy. Curr Treat Options Neurol 2005; 7:273.
- Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008; 70:1586.
- Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav 2004; 5 Suppl 2:S36.
- Tomson T, Beghi E, Sundqvist A, Johannessen SI. Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Res 2004; 60:1.
- Steinhoff BJ. Optimizing therapy of seizures in patients with endocrine disorders. Neurology 2006; 67:S23.
- Lossius MI, Taubøll E, Mowinckel P, Gjerstad L. Reversible effects of antiepileptic drugs on thyroid hormones in men and women with epilepsy: a prospective randomized double-blind withdrawal study. Epilepsy Behav 2009; 16:64.
- Bhigjee AI, Rosemberg S. Optimizing therapy of seizures in patients with HIV and cysticercosis. Neurology 2006; 67:S19.
- Birbeck GL, French JA, Perucca E, et al. Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN. Epilepsia 2012; 53:207.
- Birbeck GL, French JA, Perucca E, et al. Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. Neurology 2012; 78:139.
- Yacoob Y, Bhigjee AI, Moodley P, Parboosing R. Sodium valproate and highly active antiretroviral therapy in HIV positive patients who develop new onset seizures. Seizure 2011; 20:80.
- Bullman J, Nicholls A, Van Landingham K, et al. Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers. Epilepsia 2011; 52:1351.
- Kennebäck G, Bergfeldt L, Tomson T, et al. Carbamazepine induced bradycardia--a problem in general or only in susceptible patients? A 24-h long-term electrocardiogram study. Epilepsy Res 1992; 13:141.
- Saetre E, Abdelnoor M, Amlie JP, et al. Cardiac function and antiepileptic drug treatment in the elderly: a comparison between lamotrigine and sustained-release carbamazepine. Epilepsia 2009; 50:1841.
- Mintzer S, Skidmore CT, Abidin CJ, et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol 2009; 65:448.
- Erdemir A, Cullu N, Yiş U, et al. Evaluation of serum lipids and carotid artery intima media thickness in epileptic children treated with valproic acid. Brain Dev 2009; 31:713.
- Chuang YC, Chuang HY, Lin TK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia 2012; 53:120.
- French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl J Med 2008; 359:166.
- Rahman A, Mican LM, Fischer C, Campbell AH. Evaluating the incidence of leukopenia and neutropenia with valproate, quetiapine, or the combination in children and adolescents. Ann Pharmacother 2009; 43:822.
- Morrell MJ, Sarto GE, Shafer PO, et al. Health issues for women with epilepsy: a descriptive survey to assess knowledge and awareness among healthcare providers. J Womens Health Gend Based Med 2000; 9:959.
- Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42:149.
- Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979; 20:519.
- Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurology 2006; 66:S37.
- ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107:1453.
- Herzog AG. Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Seizure 2008; 17:151.
- Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysiology, diagnosis, and management. Neurology 2003; 61:S2.
- Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997; 38:1082.
- Reddy DS. The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. Epilepsy Res 2009; 85:1.
- El-Khayat HA, Soliman NA, Tomoum HY, et al. Reproductive hormonal changes and catamenial pattern in adolescent females with epilepsy. Epilepsia 2008; 49:1619.
- Morrell, MJ, Hamdy, SF, Seale, CG, Springer, EA. Self-reported reproductive history in women with epilepsy: puberty onset and effects of menarche and menstrual cycle on seizures. Neurology 1998; 50:448.
- Marques-Assis L. [Influence of menstruation on epilepsy]. Arq Neuropsiquiatr 1981; 39:390.
- Herzog AG, Fowler KM, Sperling MR, et al. Variation of seizure frequency with ovulatory status of menstrual cycles. Epilepsia 2011; 52:1843.
- Kalinin VV, Zheleznova EV. Chronology and evolution of temporal lobe epilepsy and endocrine reproductive dysfunction in women: relationships to side of focus and catameniality. Epilepsy Behav 2007; 11:185.
- Quigg M, Smithson SD, Fowler KM, et al. Laterality and location influence catamenial seizure expression in women with partial epilepsy. Neurology 2009; 73:223.
- Herzog AG, Fowler KM, Sperling MR, et al. Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia 2015; 56:e58.
- Feely M, Calvert R, Gibson J. Clobazam in catamenial epilepsy. A model for evaluating anticonvulsants. Lancet 1982; 2:71.
- Feely M, Gibson J. Intermittent clobazam for catamenial epilepsy: tolerance avoided. J Neurol Neurosurg Psychiatry 1984; 47:1279.
- Lim LL, Foldvary N, Mascha E, Lee J. Acetazolamide in women with catamenial epilepsy. Epilepsia 2001; 42:746.
- Ansell, B, Clarke, E. Acetazolamide in treatment of epilepsy. BMJ 1956; 1:650.
- Poser CH. Letter: Modification of therapy for exacerbation of seizures during menstruation. J Pediatr 1974; 84:779.
- Herzog AG, Fowler KM, Smithson SD, et al. Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology 2012; 78:1959.
- Reddy DS, Rogawski MA. Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 2009; 6:392.
- Nohria V, Giller E. Ganaxolone. Neurotherapeutics 2007; 4:102.
- Haider Y, Barnett DB. Catamenial epilepsy and goserelin. Lancet 1991; 338:1530.
- Tomson T, Marson A, Boon P, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 2015; 56:1006.
- Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47:1094.
- Perucca E. NICE guidance on newer drugs for epilepsy in adults. BMJ 2004; 328:1273.
- Faught E, Duh MS, Weiner JR, et al. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008; 71:1572.
- Kaiboriboon K, Guevara M, Alldredge BK. Understanding herb and dietary supplement use in patients with epilepsy. Epilepsia 2009; 50:1927.
- Perucca P, Jacoby A, Marson AG, et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology 2011; 76:273.
- Haut SR, Hall CB, Masur J, Lipton RB. Seizure occurrence: precipitants and prediction. Neurology 2007; 69:1905.
- Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007; 64:1595.
- Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008; 49:1239.