8/9/2019 Overview of the Management of Epilepsy in Adults

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Official reprint from UpToDate

www.uptodate.com ©2014 UpToDate

Author 

Steven C Schachter, MD

Section Editor 

Timothy A Pedley, MD

Deputy Editor 

 April F Eichler, MD, MPH

Overview of the management of epilepsy in adults

 All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2014. | This topic last updated: Oct 14, 2014.

INTRODUCTION — The management of patients with epilepsy is focused on three main goals: controlling seizures, avoiding treatment side effects, and maintaining or restoring quality of life. Physicians

should assist in empowering patients with epilepsy to lead lifestyles consistent with their capabilities [1,2].

The optimal treatment plan is derived following an accurate diagnosis of the patient's seizure type(s), an ob jective measure of the intensity and frequency of the seizures, awareness of medication side

effects, and an evaluation of disease-related psychosocial problems. A working knowledge of available antiepileptic drugs (AEDs), including their mechanisms of action, pharmacokinetics, drug-drug

interactions, and adverse effects is essential.

It is usually appropriate to refer the patient to a neurologist, when establishing a diagnosis and formulating a course of treatment. Referral to an epilepsy specialist may be necessary if there is doubt

about the diagnosis and/or if the patient continues to have seizures.

The overall approach to management of a patient with seizures is reviewed here. Evaluation of the patient who has had a first seizure and the pharmacology of specific AEDs are discussed separately.

(See "Evaluation of the first seizure in adults" and "Initial treatment of epilepsy in adults" and "Pharmacology of antiepileptic drugs".)

CLASSIFICATION — The first step in designing a treatment plan is to classify the patient's seizure type(s) using the framework of the International League Against Epilepsy (table 1) [3,4]. Seizure types

and epilepsy syndromes are classified primarily upon clinical grounds, assisted by laboratory, neurophysiologic, and radiographic studies. Seizure type has important implications in the choice of 

antiepileptic drugs (AEDs). Accurate classification requires a full history from the patient and reports from observers who have witnessed actual seizures.

Patients may be better able to describe their seizure symptoms after reading published seizure descriptions, which in turn may improve the clinician's ability to categorize the seizure type and to plan a

successful therapeutic approach [5]. Many patients experience more than one type of seizure (eg, complex partial and secondarily generalized seizures).

Pointed questions may be necessary to reveal behaviors or environmental factors that contribute to the incidence of seizures. These "seizure triggers," such as sleep deprivation, alcohol intake, and

stress, may be modifiable. Thus, taking steps that limit exposure to these triggers usually enhances the benefits of AED therapy.

There are two broad categories of seizures: partial (or focal) and generalized (table 1). Partial seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. A complex partial

seizure (CPS) implies that consciousness is impaired, while simple partial seizures (SPS) are not associated with altered consciousness. A partial seizure can evolve over seconds into a tonic-clonic

convulsion, referred to as a secondarily generalized seizure. (See "Evaluation of the first seizure in adults".)

ANTIEPILEPTIC DRUG THERAPY

When to start AED therapy — Immediate antiepileptic drug (AED) therapy is usually not necessary in individuals after a single seizure, particularly if a first seizure is provoked by factors that resolve.

 AED therapy should be started in patients who are at significant risk for recurrent seizures, such as those with remote symptomatic seizures. AED treatment is generally started after two or more

unprovoked seizures, because the recurrence proves that the patient has a substantially increased risk for repeated seizures, well above 50 percent.

The issues to be considered in deciding when to start AED therapy are discussed in detail separately. (See "Initial treatment of epilepsy in adults", section on 'When to start AED therapy'.)

 AED therapy is not necessarily life-long. (See 'Discontinuing AED therapy' below.)

Choosing an AED — About half of patients with a new diagnosis of epilepsy will become seizure free with the first AED prescribed [6,7]. Tolerability of side e ffects is as important as efficacy in

determining the overall effectiveness of treatment. No single AED is opt imal for every patient or even most pat ients. The selection of a specific AED for treating seizures must be individualized

considering:

In general, enzyme-inducing AEDs (eg, phenytoin, carbamazepine, phenobarbital, primidone; and less so, oxcarbazepine and topiramate) are the most problematic for drug interactions with warfarin and

oral contraceptive therapy, as well as certain anti-cancer and anti-infective drugs (table 5). Specific interactions of AEDs 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.

Issues to consider in selecting a specific AED are discussed in detail separately. (See "Initial treatment of epilepsy in adults", section on 'Selection of an AED'.)

Subsequent drug trials — About half of patients with a new diagnosis of epilepsy are successfully treated with the first AED prescribed [6-8]. Treatment failure may result from breakthrough seizures or 

drug intolerance. At this point, a second drug trial should be attempted. When the initial drug failure is due to adverse effects, the second drug trial will be successful in approximately half of patien ts

[9,10]. Substantially fewer patients (about 10 to 20 percent) will have a successful second drug trial if the initial failure was due to lack of efficacy. Other factors that decrease the likelihood of success

include younger age, female gender, high generalized tonic-clonic seizure burden, and the presence of structural abnormalities on CT or MRI [10].

Similar factors are considered when a second AED is chosen as when the first was selected. (See 'Choosing an AED' above and "Initial treatment of epilepsy in adults".) However, the clinician may also

choose to select an AED with a somewhat different mechanism of action (table 6) in hopes that efficacy and/or tolerance will be improved compared with the first drug used. I t remains important to

choose a drug with demonstrated e fficacy for the patient's seizure type (table 2) [11].

Except in the case of a serious adverse event, the second medication is typically increased to therapeutic levels before the first agent is reduced in order to prevent a flurry of seizures or status

epilepticus during the switch-over period. The second antiepileptic medication is gradually titrated up slowly to effect (control of seizures) or to toxicity (side effects). However, patients should expect a

temporary increase in side effects during the overlap period that will likely abate when the first AED is subsequently tapered o ff.

Combination therapy — When possible, it is preferable to maintain a patient on a single AED. This increases the probability of compliance, provides a wider therapeutic index, and is more

cost-effective than combination drug treatment. Monotherapy is a lso associated with fewer idiosyncratic reactions and a lower incidence of teratogenic effects. Combination therapy can be associated

with drug interactions between AEDs (table 7A-C), making it difficult to dose and monitor patients.

This conventional wisdom is only partly supported by published data, wh ich give conflicting information regarding the risks and benefits of mono- versus polytherapy:

There are few controlled studies comparing different drug combinations, and virtually every possible combination of AEDs has been tried. A 2011 meta-analysis of 70 randomized controlled trials of 

®

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Partial seizures. SPS can present in a variety of ways; however, within an individual patient, the seizures are usually stereotyped. Common SPS include both visible manifestations, such as jerking

of a limb as well as subjective experiences perceived only by the patient, such as epigastric discomfort, fear, or an unpleasant smell. Such subjective feelings are commonly referred to as auras.

SPS may be immediately followed by CPS; these are usually manifested by a clouding of consciousness, staring, and repetitive motor behaviors, termed automatisms, such as swallowing,

chewing, or lip smacking. After a CPS, the patient may experience confusion, fatigue, and a throbbing headache. When individuals are told of their behavior during CPS, they often express

disbelief, as they have no recollection. In fact, some patients are completely unaware of all of their seizures.

●

Generalized seizures. Generalized seizures are those in which the first clinical and electroencephalographic changes indicate that large parts of both hemispheres of the brain are involved at the

onset of the seizure. There is nearly always impaired consciousness except for the very brief myoclonic seizures. The most common subtypes of generalized seizures are tonic-clonic seizures

(grand mal), absence seizures (petit mal), and myoclonic seizures.

●

Drug effectiveness for the seizure type or types (table 2)●

Potential adverse effects of the drug (table 3 and table 4)●

Interactions with other medications●

Comorbid medical conditions, especially but not limited to hepatic and renal disease●

 Age and gender, including childbearing plans●

Lifestyle and patient preferences●

Cost●

In one large case series of 809 patients with refractory epilepsy, rates of adverse events did not differ between pa tients on poly- versus monotherapy [12]●

In one clinical trial, rates of adverse events were similar among 157 patients randomized to adjunctive treatment versus alternative monotherapy, and rates of seizure remission were also similar 

(16 versus 14 percent) [13]

●

 A randomized, double-blind study that compared carbamazepine monotherapy to combination therapy with carbamazepine and valproate found no significant difference in neurotoxicity between the

two groups [14]

●

In one epidemiologic survey, polytherapy was associated with lower quality of life and lower rates of employment compared with patients on monotherapy [15]●

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 AEDs administered as add-on therapy in patients with refractory partial epilepsy found that differences in efficacy were of too small magnitude to allow a conclusion about which AED is more effective as

adjunctive therapy [16]. In a randomized, double-blind t rial of pregabalin versus levetiracetam as add-on therapy in 509 patients with refractory focal seizures published subsequent to this analysis, 60

percent of patients in each arm achieved a ≥50 percent reduction in 28-day seizure rate, and tolerability was similar [17].

In the absence of comparative da ta from clinical trials, it makes sense to choose an add-on drug that has a different mechanism of action (table 6) and a different side-effect profile than the first AED

(table 3 and table 4) [18-20]. In this way, it is hoped that efficacy can be maximized and side effects minimized [12]. The benefit of this approach is largely theoretical, supported by limited observational

data but not well tested prospectively [21]. However, there is some anecdotal evidence that synergism between AEDs can occur. As an example, the combination of lamotrigine and valproate has been

reported in some cases to have dramatic efficacy even when patients had previously failed treatment with one or both drugs in monotherapy [22-24]. A retrospective chart review of 148 developmentally

disabled adults with drug-resistant epilepsy also suggested that the combination of lamotrigine and valproate may have superior efficacy over other combinations, but this was a nonrandomized study

[25].

Seizure remission is achieved with combination therapy in only a small percentage (10 to 15 percent) of patients who have failed monotherapy [9,26,27]. One retrospective chart review suggested that

while two concurrent AEDs might provide efficacy over monotherapy, use of three AEDs did not provide further benefit over two [25].

While the chances of treatment success diminish incrementally with each successive drug trial [28], two studies suggest a value in pursuing further drug trials [26,27]. In one center, 15 percent of 

patients who had failed at least two prior AED trials subsequently became seizure free with AED therapy [27]. In another, 28 percent of patients with a history of uncontrolled seizures for five or more

years were subsequently controlled on AEDs [26]. In some cases, response to t reatment occurred with a fourth or fifth drug trial. Both studies found that the number of previous failed trials was anegative prognostic indicator, and a history of status epilepticus, younger age at intractability, underlying mental retardation, longer duration of epilepsy, and symptomatic epilepsy were each negative

predictors in one of the two studies.

Overall, up to 80 percent of pa tients can become seizure free on AED treatment [10,26-28].

Side effects of therapy — During the first six months of treatment, systemic toxicity and neurotoxicity cause AED failure to the same degree as lack of efficacy against seizures (table 3 and table 4).

Serum levels that are associated with neurotoxicity vary from patient to patient, and toxicity can occur even when measured levels are considered to be within the appropriate therapeutic range.

The usual strategy in patients experiencing peak-level side effects from a specific drug is to alter the medication regimen or treatment schedule to minimize side effects; one alteration may be to spread

the medication over more doses throughout the day. The physician should attempt to correlate serum drug concentrations with the patient's side effects before abandoning that medication. Specifically,

levels should be obtained when a patient is experiencing side effects compared with levels when the patient is free from symptoms can be helpful in the management o f some patients.

I find it helpful to refer to the patient's seizure calendar in planning the timing of drug levels in an attempt to prove a cause-and-effect relationship between peak levels and side effects. As an example, in

a patient who experiences seizures only at night but who has side effects in the a fternoon from his or her morning dose of antiepileptic, shifting part of the morning dose to the bedtime dose may

eliminate these side effects while improving seizure control.

Specific adverse reactions — Many side effects of AEDs specific to individual medications are reviewed in detail separately. (See "Pharmacology of antiepileptic drugs".) Some severe reactions

that are common to more than one medication include the following:

Maximizing the likelihood of a successful outcome

Titration and monitoring — Some general principles to consider when starting an AED include [44-46]:

The recommended initial dose for individual AEDs and a potential titration schedule are presented separately. (See "Pharmacology of antiepileptic drugs".)

Regular follow-up visits should be scheduled to check drug concentrations, blood counts, and hepatic and renal function, when indicated. These visits are also used to address concerns the patient may

have about taking the med ication and possible side effects, or psychosocial aspects of their disorder. It may be useful to ob tain drug levels at least yearly, including in patients who are not having

seizures and not undergoing medication dose changes.

Drug levels can be helpful in the management of AEDs [47]:

Total serum levels alone should not necessarily be taken at face value. As an example, unbound ("free") serum levels of phenytoin, must be checked in pa tients who have low albumin levels or who are

taking other drugs that are tightly prote in-bound; free levels should be multiplied by 10 to approximate the desired total serum level for agents that are typically about 90 percent protein bound. It is alsoimportant to measure free drug levels in pregnant women taking AEDs that are bound significantly to serum proteins. (See "Management of epilepsy and pregnancy", section on 'Drug levels and dose

adjustment'.)

Serum drug concentrations may fluctuate in compliant patients due to laboratory error, change in drug formulation (generic to brand, reverse, or generic to generic switch), drug interactions, variable

absorption, and variable pill potency (eg, some pills stored in warm, humid places may have reduced effectiveness). Fluctuating AED levels at different points in the menstrual cycle may play a role in

breakthrough seizures in women with catamenial epilepsy. (See "Catamenial epilepsy".)

Patient education — Before treatment is initiated, the physician needs to begin a dialogue with the patient and family to increase their understanding of epilepsy and their ability to report necessary

and relevant information. Epilepsy affects each patient in a unique way, and patients differ in their capacity to understand various aspects of the disorder. As a result, physicians must tailor discussions to

clarify the impact of the condition on the specific patient's quality of life and expectations of the treatment plan. These discussions will improve the likelihood that the patient will comply with the plan of 

 An increased risk of suicidality has been linked to several AEDs in randomized placebo-controlled studies of patients with epilepsy, according to a January 2008 United States Food and Drug Administration (FDA) report [29]. The elevated risk (0.43 versus 0.22 percent) was observed as early as one week after starting medication and continued through the 24 weeks of study

observation. The effect was consistent in the 11 AEDs studied, and the FDA considers this risk likely to be shared by all AEDs. A literature review estimated that the overall standardized mortality

ratio for suicide was 3.3; and that this increased risk appeared to be present among most subgroups of individuals with epilepsy [30].

While observational studies have challenged these findings, these studies are no t sufficiently rigorous to refute them. A case-control study found tha t only some of the newer AEDs (levetiracetam,

topiramate, vigabatrin) were associated with a risk of self-harm or suicide, while older and other newer AEDS were not [31]. Another study based in the United Kingdom found that the magnitude of 

suicide risk associated with AED use varied according to the underlying etiology and was not elevated in patients with epilepsy [32]. However, the clinical studies evaluated by the FDA that led to

the original warning were performed in patients with epilepsy.

While this clinical advisory is somewhat controversial, clinicians prescribing AEDs should identify a current or past history of depression, anxiety, and suicidal ideation or behavior in their patients

[33-35]. A suggested approach to the assessment of suicidality in adults is discussed separately. (See "Suicidal ideation and behavior in adults", section on 'Suicidal ideation'.)

Patients taking AEDs should be monitored for emergence or worsening of suicidal ideation or depression. Patients and families should be encouraged to call their physician if they experience any

symptoms of depression [33,36]. (See 'Depression and psychiatric disease' below.)

●

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 that have been associated with the use of carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, zonisamide, lamotrigine, and (less commonly)

other AEDs [37-40]. The period of highest risk is within the first two months of use [41]. The risk may be higher in patients with HLA-B*1502 allele, which occurs almost exclusively in patients of 

 Asian ancestry, including South Asian Indians. The FDA recommends screening such patients for this allele prior to starting carbamazepine, oxcarbazepine, and possibly phenytoin [42]. Because

cross-hypersensitivity to other AEDs is common, patients who experience this reaction should subsequently be treated with nonaromatic AEDs (eg, valproate, topiramate) which have a lower risk of 

this reaction. In one case series, the latter medications were well-tolerated when prescribed as alternative AEDs to patients who experienced SJS or TEN in association with an aromatic AED [40].

 (See "Pharmacology of antiepileptic drugs" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●

Reduced vitamin levels have also been described in patients taking AEDs. In one study, subnormal folate levels were reported in 16 percent of patients on AEDs (primarily in patients taking

carbamazepine, gabapentin, phenytoin, or primidone) [43]. While vitamin B12 levels were lower on average in patients taking AEDs (particularly in patients taking phenobarbital, pregabalin,

primidone, or topiramate), the frequency of subnormal B12 levels was not significantly different in patients compared with controls. Vitamin supplementation yielded normal levels in patients with

subnormal levels within three months.

●

Bone loss has also been described in patients receiving long-term AEDs. (See "Antiepileptic drugs and bone disease".)●

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 seizure freedom (start low and go slow).●

Treatment should be monitored regularly. At regular office visits, physicians should ask and record seizure frequency and medication side effects [4].●

To establish an individual therapeutic concentration range when a patient is in remission●

To assist in the diagnosis of clinical AED toxicity (see 'Side effects of therapy' above)●

To assess adherence (see 'Nonadherence with AED therapy' below)●

To guide dose adjustments, particularly in the setting of drug formulation changes, breakthrough seizures, when an interacting medication is added to or removed from a patient's regimen, or during

pregnancy

●

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treatment.

The physician should impress upon the patient, family, and patient's friends the critical need to follow the prescribed drug regimen. Nonadherence to AED treatment regimen is associated with increased

risk of mortality, as well as hospitalization and injury [48]. (See 'Complications of epilepsy' below.)

Written instructions on how and when to take the drugs should be provided and should explain the dosing regimen and any potential adverse effects (table 3 and table 4). The patient must also be

warned not to stop taking an AED 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 AEDs [49,50]. (See "Initial treatment of epilepsy in adults", section on 'Drug interactions'.)

Seizure calendar  — Patients and family members should be asked to record seizures and AED doses on a calendar or diary, which can then be brought or sent to the physician for review. Seizure

triggers should be indicated. The patient and family should note on the calendar the hour at which any symptoms occur. Electronic seizure diaries are also available [51,52].

The seizure calendar helps to monitor and encourage compliance. The seizure calendar also may be used to track the patient's response to drug therapy, including possible side effects. Seizure

calendars can help identify seizure triggers. 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 [53]. Seizures were also associated with the patients' own prediction of the likelihood of seizure occurrence. Other reported seizure triggers include visual, olfactory, and auditory stimuli,

alcohol consumption, missed meals, and hormone fluctuations related to the menstrual cycle [54]. (See "Catamenial epilepsy".)

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 [55]. Prolonged EEG recordings may be helpful in such patients, either ambulatory or in a video-EEG monitoring unit. (See "Video and ambulatory EEG monitoring in the diagnosis

of seizures and epilepsy".)

Generic substitution — While definitive studies have not been performed, anecdotal reports, small case series, and patient surveys suggest that generic substitution of AEDs may be problematic

[56-59]. Using pharmacokinetic data submitted to the FDA, one group of investigators found that most generic AEDs provide total drug de livery similar to the reference product [60]. Differences in peak

concentrations were more common, with switches between generic products causing greater changes in plasma drug concentrations than generic substitution of the reference product. It is possible that

the small, FDA-allowed variations in pharmacokinetics between a name brand and its generic equivalent (and between generic equivalents) can lead to either toxicity or seizures in some patients who,

for unknown reasons, are particularly vulnerable [61-65].

Examples of published reports with indirect evidence that this is a potential problem include:

In contrast, a systematic review and meta-analysis of seven trials in which the frequency of seizures were compared between a brand name AED and a generic alternative found no difference in the

odds of seizures between treatment regimens [75]. The FDA also maintains that there is no convincing evidence that people with epilepsy have lessened seizure control when taking generic

medications.

Patients should be aware that pharmacists or mail-order pharmacies sometimes make generic substitutions at the point of sale, and that they should check with their physician prior to accepting this

substitution. Additional clinical and laboratory monitoring with plasma drug levels may be advisable with changes in drug formulation. Clinicians should consider the possibility of change in drug

formulation as a cause of unexpected break-through seizures or toxicity along with other possible explanations.

Alcohol intake — Alcohol consumption in small amounts (one to two drinks per day) may not affect seizure frequency or serum levels of AEDs in patients with well-controlled epilepsy [76]. Heavier 

alcohol intake (three or more drinks per day) increases the r isk of seizures, particularly during the withdrawal period (7 to 48 hours after the last drink), and this practice should be strongly discouraged

[77].

In an effort to enable people with epilepsy to live as normal a life as possible, it may be reasonable to advise that limited alcohol intake is acceptable, provided there is no h istory of alcohol or substance

abuse or a history of alcohol-related seizures. However, patients should be aware tha t the data are no t definitive at this time. Driving or other high-risk activities should be avoided fo r 24 to 48 hours after 

heavy alcohol intake due to the higher risk of seizures.

Nonadherence with AED therapy — Up to 50 percent of patients with epilepsy may fail to take their medications as directed; over one-half of those evaluated in emergency departments for recurrent

seizures have been nonadherent [78]. Nonadherence to AED treatment regimen is not only associated with increased seizures, but also with increased risk of mortality, as well as hospitalization and

injury [48,79]. Clinicians should suspect nonadherence if a patient denies the diagnosis of epilepsy, has limited financial means to pay for AEDs, has difficulty tolerating side effects, or forgets when or 

how to take medication because of memory impairment. An unexpected increase in the number or severity of seizures, or either subtherapeutic or supratherapeutic serum drug concentrations, also

suggests nonadherence. However, serum levels can fluctuate due to a number of factors; thus, they should be interpreted with some caution.

Compliance diminishes when intervals between office visits grow longer and when medication regimens grow increasingly complex. Nonadherence also often results from a failure to communicate. Thus,

improving the patient's understanding of his or her disorder and the need for regular intake of medications usually improves compliance. Some of the guidelines proposed to improve patient adherence to

antihypertensive therapy may also be relevant to the patient with epilepsy (table 8). One randomized study showed that at least short-term compliance was improved with an inte rvention that linked

intake of medication with a particular time, place, o r activity [80].

DRUG-RESISTANT EPILEPSY — There is no standardized definition of medically intractable epilepsy. A task force of the International League Against Epilepsy proposed that drug-resistant epilepsy

may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [81].

(See "Evaluation and management of drug-resistant epilepsy", section on 'Definition'.)

The diagnosis and classification of epilepsy should be reconsidered in patients whose seizures do not respond to AED trials. In particular, video-EEG monitoring to confirm the epileptic nature o f spells

should be considered in anyone still having seizures after two AED trials or more than one year of treatment. (See "Video and ambulatory EEG monitoring in the diagnosis of seizures and epilepsy".)

Established treatment options for medically refractory epilepsy in adults include epilepsy surgery and vagus nerve stimulation. The ketogenic or modified Atkins diet may be helpful in selected patients.

Therapeutic strategies that employ various forms of brain stimulation are in development. (See "Surgical treatment of epilepsy in adults" and "The ketogenic diet" and "Vagus nerve stimulation therapy for 

the treatment of epilepsy".)

One published guideline suggests that patients whose seizures are uncontrolled after 12 months should be referred to a specialized epilepsy center when possible [82].

The evaluation and management of patients with medically refractory epilepsy is discussed separately. (See "Evaluation and management of drug-resistant epilepsy".)

ALTERNATIVE THERAPIES — Some herbal medicines and dietary supplements, including melatonin and cannabis, may have an ticonvulsant effects, but none has been tested in randomized, blinded,

controlled trials [83-86]. Some herbal medicines and dietary supplements may instead be proconvulsant [87]. In addition, as with other drugs, alternative medications supplements can affect the

metabolism of antiepileptic drugs (AEDs) and can thus alter drug levels. In addition, patients should be asked about their use of alternative medications and supplements, and consideration should be

given to additional monitoring of AED levels in such patients. (See "Evaluation and management of drug-resistant epilepsy", section on 'Cannabinoids'.)

In one trial, acupuncture therapy was compared with a sham procedure in 34 patients with epilepsy and found no benefit for seizure frequency, seizure-free weeks, or quality of life [88,89].

SPECIAL POPULATIONS

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 [90-93]. Clinicians should regularly

review these issues with their female patients with epilepsy [4]. Pregnancies should be planned, and women with epilepsy require close follow-up in pregnancy. (See "Management of epilepsy and

pregnancy".)

Effect of antiepileptic drugs on the fetus — There is an increased risk of both major and minor malformations in fetuses exposed to antiepileptic drugs (AEDs). In addition, there is accumulating

evidence from observational studies that anticonvulsant therapy during pregnancy may have deleterious effects on cognitive and developmental outcomes of exposed children later in life. (See "Risks

associated with epilepsy and pregnancy", section on 'Effect of antiepileptic drugs on the fetus'.)

 AED therapy should be optimized prior to conception, if possible, before exposure of the fetus to potential teratogenic effects of AEDs. Since there is no agreement as to which AED is most or least

teratogenic, the AED that stops seizures in a given patient is the one that should be used. An exception is valproate, for which there are the strongest data regarding increased risk of malformations and

adverse developmental outcomes. (See "Management of epilepsy and pregnancy", section on 'Choice of antiepileptic drug' .)

Folic acid supplementation — Folate should be routinely prescribed to all women of childbearing age taking an tiepileptic drugs (AEDs). 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 AEDs should take the more standard lower dose o f folic acid (0.4 to 0.8 mg per day).

(See "Management of epilepsy and pregnancy", section on 'Folic acid supplementation'.)

Contraception — Women should be educated on the interactions between AED therapies and oral contraceptives. The expected contraceptive failure rate of 0.7 per 100 woman-years using oral

Three large case-control studies have found that changes in AED formulation involving generics was a risk factor for emergency or hospital-level treatment of epilepsy (OR: 1.78 to 1.81) [66-68]●

Many, but not all [69], studies using medical and pharmacy claims databases have found that generic switching of AEDs is associated with higher epilepsy-related medical utilization rates (eg,

hospitalizations) and seizure-related injuries [70-73]

●

 A retrospective study of breakthrough seizures that occurred in association with generic substitution found that AED blood levels at the time of the seizure were on average 33 percent lower than

previous levels obtained when the patient was using branded AEDs [74]

●

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contraceptives is increased to 3.1 per 100 woman-years in patients who concomitantly take AEDs that induce hepatic enzymes that increase the metabolism of oral contraceptives [94-97]. (See

"Overview of the use of estrogen-progestin contraceptives", section on 'Drug interactions'.)

Enzyme induction occurs with all older AEDs (including phenytoin, phenobarbital, carbamazepine, primidone) except valproate and ethosuximide. It also occurs, but to a lesser extent, with a few of the

second generation AEDs, such as felbamate, topiramate, perampanel and oxcarbazepine [98]. Enzyme-inducing AEDs are also associated with decreased estrogen and progesterone levels [96,99].

While vigabatrin is not an enzyme inducer, lower levels of ethinyl estradiol have been reported in volunteers taking this AED [100].

The World Health Organization (WHO) suggests that women taking enzyme-inducing AEDs, including lamotrigine, use a method of contraception other than hormonal pill, patch or ring contraceptives

[101]. Hormonal contraception may still be reasonable, however, if the patient understands the risks and cannot use other methods. The reported failure rate with oral contraceptives in women taking

 AEDs may still be comparable with or better than other methods of contraception, such as barrier methods [102]. The United States Medical Eligibility Criteria (USMEC) for Contraceptive Use are

available online and in the table (table 9).

While as yet unconfirmed in systematic studies, the increased failure rate with oral contraceptives may be ameliorated by increasing the dose and using extended cycle regimens with shorter pill-free

intervals [103,104]. Clinicians often recommend that women on enzyme-inducing AEDs who want to take oral contraceptives receive a preparation with at least 50 mcg of the estrogen component [103].

It is expected that both the efficacy and the incidence of adverse effects associated with a higher dose of hormones used in conjunction with enzyme-inducing AEDs should be comparable with standard

doses when not combined with AEDs [103]. However, this is unproven. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Shorter pill-free interval' and "Overview of the use of 

estrogen-progestin contraceptives", section on 'Continuous pill'.)

Hormone levels in patients using intrauterine hormone-releasing systems (Mirena®, LNg 20) or depot injections of progesterone are no t affected by AEDs; these are effective alternatives to oral

contraceptive therapy [103,105,106]. (See "Intrauterine contraception (IUD): Overview", section on 'Levonorgestrel-releasing IUDs' and "Depot medroxyprogesterone acetate for contraception".)

The efficacy of the "morning after pill" may be similarly affected by enzyme-inducing AEDs. Two doses of levonorgestrel 1.5 mg separated by 12 hours is recommended in these circumstances [103,107].

(See "Emergency contraception".)

In addition to the effect o f AEDs on oral contraceptive metabolism, oral contraceptives can increase the metabolism o f lamotrigine, thereby reducing the plasma drug concentration, typically by about 50

percent. Pregnancy has a similar effect on many other AEDs. (See "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and "Management of epilepsy and pregnancy", section on 'Drug levels

and dose adjustment'.)

Fertility — While a number of studies have suggested that women w ith epilepsy have increased rates of infertility, as high as 33 to 38 percent [108,109], other studies have not confirmed this finding

[110]. It is also uncertain whether this association is linked to epilepsy itself or to AED treatment.

Potential confounding factors in assessing a possible association include lower marriage rates and a lower rate of planned pregnancies. The latter may result because the woman may be concerned

about teratogenicity, her ability to care for a child, and increased risk of epilepsy in her child [111].

There is evidence that suggests that AED use may affect fertility. In a prospective cohort study of 375 women with epilepsy, infertility was linked to polytherapy, as well as to older age, and lower 

education [108]. Valproate, in particular, has been linked to an increased risk of polycystic ovary disease, a leading cause of infertility in woman [112]. (See "Epidemiology and pathogenesis of the

polycystic ovary syndrome in adults", section on 'High-risk groups'.)

Post-stroke seizures — Stroke is the most common cause of seizures and epilepsy in population studies of adu lts over the age of 35 [113]. In one of the largest prospective studies, post-stroke

seizures occurred in 168 of 1897 patients (8.9 percent) after hemispheric stroke, including 140 of 1632 (8.6 percent) with ischemic stroke and 28 of 265 (10.6 percent) with hemorrhagic stroke [114].

However, recurrent seizures were rare during the nine months of fo llow-up, occurring in only 2.5 percent of patients.

Seizures occurred within 24 hours of the stroke in 43 percent of patients in the above report [114]. The pathogenesis of these early-onset seizures may be related to local ion shifts and release of high

levels of excitotoxic neurotransmitters in the area of ischemic injury [115].

In contrast, an underlying permanent lesion that leads to persistent changes in neuronal excitability appears to be responsible for late-onset seizures after stroke and other b rain injuries, and probably

accounts for the fact that the risk of chronic epilepsy is higher in patients with late rather than early occurrence of seizures. In one study, for example, 118 patients who had a thrombotic stroke had a

bimodal distribution of seizures either within two weeks or from 6 to 12 months after the stroke [116]. Epilepsy developed in more patients with late than early seizures (90 and 35 percent, respectively).

The risk of late-onset seizures may increase over time. In a population-based study of over 3000 patients p resenting with first stroke, post-stroke epilepsy (defined as ≥2 unprovoked seizures occurring

after the acute phase of stroke) developed in 213 patients (6.4 percent) after a mean follow up of four years [117]. The estimated cumulative incidence of epilepsy rose from 3 .5 percent at one year,

which is similar to estimates from prior studies with shorter-term follow up, to over 12 percent at 10 years.

 Among a wide range of demographic characteristics, medical comorbidities, and stroke characteristics studied, stroke severity and cortical location have been found to be most consistently associated

with the risk of acute and late seizures [117-120]. Younger age has been reported as a risk factor for late seizures in at least one large study [117]. One prospective study found that preexisting dementia

was a risk factor for late seizures (OR = 4.66, CI, 1.34-16.21) but not for early seizures [121]. Dementia is a risk factor for epilepsy in pa tients without stroke as well. (See "Seizures and epilepsy in the

elderly patient: Etiology, clinical presentation, and diagnosis".)

Most seizures following stroke are focal at onset, but secondary generalization is common, particularly in patients with late-onset seizures. Status epilepticus is relatively uncommon, occurring in 9

percent of 180 patients with poststroke seizures in one report [122].

When to treat — Given the relatively low frequency of recurrent seizures after stroke, and an absence of absolute predictors of poststroke epilepsy, the decision of when to treat patients for a

poststroke seizure is difficult. Nevertheless, most physicians empirically treat patients who develop late-onset seizures in the setting of a st roke history within the previous two to three years [115].

The efficacy of specific AEDs for poststroke seizures has not been rigorously assessed in controlled trials, although most seizures can be controlled with a single agent [123]. Several considerations

factor into the choice of AED in this population. Studies suggest that newer AEDs have similar efficacy but a more favorable adverse event profile in older patients. (See "Pharmacology of antiepileptic

drugs" and "Treatment of seizures and epilepsy in the elderly patient".) In one prospective randomized trial, the lamotrigine treatment arm had a fewer drop-outs due to adverse events than did the

carbamazepine arm; lamotrigine was also more efficacious, although this did not reach statistical significance [124]. Gabapentin has been associated with 80 percent seizure remission in one

uncontrolled study of post-stroke epilepsy [125].

Older patients — AED use in elderly patients is complicated by several factors, including age-related alterations in protein binding, reduced hepatic metabolism, and diminished renal clearance of 

medications. In addition, medical comorbidities and polypharmacy are more often a concern in older adults. The selection of AED treatment in the elderly is discussed separately. (See "Treatment of 

seizures and epilepsy in the elderly patient".)

Other causes — The treatment of epilepsy in the setting of brain tumors and head trauma are discussed separately. (See "Seizures in patients with primary and metastatic brain tumors" and "Post-

traumatic seizures and epilepsy".)

COMPLICATIONS OF EPILEPSY

Mortality — Mortality rates in general are h igher in people with chronic epilepsy compared with age- and sex-matched cohorts [126-130]. The standardized mortality ratio (SMR) for chronic epilepsy

ranges from two to three [126,131]. The SMR is highest in the initial year after diagnosis and subsequently decreases [128]. The greatest excess in mortality is seen in younger patients (60 years) [126,129].

Population-based studies have found that the standardized mortality ratios could be stratified according to etiology and are higher for remote symptomatic epilepsy and lower fo r idiopathic epilepsy

[127,128,130,131]. Similarly, mortality rates after an incident unprovoked seizure were found to be h igher in those with symptomatic versus idiopathic seizures, with the cause of death often attributed to

the underlying cause of seizure in those with symptomatic e tiologies (eg, malignant neoplasm) [132].

 Accidental death may be the largest contributor to this excess mortality. This observation is supported by epidemiologic studies, which find that death rates for persons with epilepsy are about threefold

higher for accidental death compared with persons without epilepsy [129,133]. The risk of a drowning death, in particular, is higher in patients with epilepsy, with an estimated relative risk ranging from 13

to 19-fold [129,133,134].

Psychiatric comorbidity may be another important contributing factor. In a population-based cohort study in Sweden, the premature death rate in patients with epilepsy was 9 percent, compared with 0.7

percent in the general population [135]. External causes (eg, accidents, poisonings, suicide, assaults) accounted for 16 percent of epilepsy deaths, approximately half of which were from suicide. Among

those who died from external causes, 75 percent had comorbid psychiatric disorders, and comorbid depression and substance misuse were the strongest risk factors for death (adjusted odds ratios 13

and 22, respectively).

In addition to deaths from external causes such as accidents or suicide, deaths attributed to other causes (eg, respiratory disorders, cancer, cerebrovascular disease) may also be higher in patients with

chronic epilepsy [126]. One database study found that patients with epilepsy had high rates of comorbid illness, including pulmonary disease, hypertension, cerebrovascular disease, depression, and

alcohol abuse [136]. A comorbidity index score predicted the risk of mortality.

Patients with epilepsy have a small risk of sudden unexpected death, a condition referred to as sudden unexpected death in epilepsy (SUDEP) [137]. Risk factors for SUDEP include early age of 

epilepsy onset, frequent generalized tonic-clonic seizures, and intractable epilepsy [137-140]. SUDEP is discussed in detail separately. (See "Sudden unexpected death in epilepsy".)

Personal injury — Several studies have demonstrated that the risk of seizure-related personal injury, such as falls, bone fractures, drowning, and other accidents is significantly elevated compared with

control subjects [134,141-146]. However, most of these studies selected preferentially for patients with injuries or more severe seizures, as most subjects were evaluated in emergency departments or 

tertiary centers [147].

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 A population-based study in Europe found that seizure-related accidents occurred in only 6.5 percent of the cohort at two years of follow-up; risk was largely determined by higher seizure frequency [94].

Similarly, a subsequent population-based study in the United States found tha t the risk of seizure-related injury was low and that most injuries were minor and without adverse social or occupational

consequences [147]. Seizure frequency was the only significant risk factor for seizure-related injury.

Patients with poorly controlled seizures are at the highest risk for seizure-related injury. However, for most patients with epilepsy, excessive restriction of activities for the purpose o f avoiding injury is

unnecessary [147]. Supervision of swimming is a reasonable precaution.

 A few studies have suggested that people with epilepsy may be at higher risk of violent assault. In one report, death from homicide in the home was more common in patients with epilepsy compared

with controls (RR = 2.3) [148]. One population-based study in Canada found that individuals with epilepsy were more likely to suffer assault-related injuries compared with normal con trols [149].

It is recommended that clinicians regularly review relevant safety issues with their patients with epilepsy [4].

Motor vehicle accidents — The relative risk of a motor vehicle accident (MVA) in a person with epilepsy compared with other drivers has been variously estimated and may be as high as 2.0. The

seizure-free interval (time since last seizure) is believed to be an important factor in assessing the risk of a MVA. (See "Driving restrictions for patients with seizures and epilepsy".)

Driving restrictions — States vary widely in driver licensing requirements for patients with ep ilepsy. The most common requ irements are that patients be free o f seizures for a specified period of 

time and that they submit a physician's evaluation of their ability to drive safely.

Physicians should also consider the potential neurotoxic side effects of AEDs (eg, sedation, double vision) (table 3), when counseling patients about driving.

 A listing of individual state driving requirements can be found on the Epilepsy Foundation Website at http://www.epilepsyfoundation.org/resources/drivingandtravel.cfm.

 Additional details about driving restrictions in patients with epilepsy are discussed separately. (See "Driving restrictions for patients with seizures and epilepsy".)

Psychosocial issues — Management of patients with epilepsy must include consideration of the psychosocial dimensions of the disorder [150,151]. Among over 30,000 respondents, the National

Health Interview Survey found increased odds of psychological symptoms, medical symptoms and diagnoses, and decreased leisure time physical activity in patients with seizures [152].

Employment status is often negatively impacted by epilepsy, even when seizures are infrequent [153-155]. In one survey, over 40 percent of college-educated people with "well-controlled" seizures were

unemployed [153].

Newly diagnosed patients with epilepsy are commonly affected by the loss of independence that is most obvious in their inability to drive. They may also have problems obtaining insurance and finding or 

maintaining suitable employment. Their self-esteem may also suffer [156]. As the treatment plan is formulated, psychosocial issues must be systematically explored with patients so that appropriate

referrals for additional help and counseling can be initiated.

Patients with epilepsy are more likely to have a poor pattern of health-related behaviors (increased smoking, higher alcohol consumption, less physical activity) compared with the general population

[136,157,158]. Counselling regarding these issues may improve health and quality of life.

 A complete psychosocial history includes inquiries about educational background, employment, driving, insurance, interpersonal relationships, previous psychiatric illness (especially depression), and

attitude toward having epilepsy. Questionnaires for this purpose are available, and they provide a measurable way of assessing and following patients as pharmacotherapeutic and psychosocialinterventions are implemented [159].

Identifying sources of psychosocial stress should lead to the development of strategies to minimize the impact of those stresses on the patient. Stress reduction can, in turn, help reduce seizure

frequency, although this has not been proved definitively [160]. Patients are often deeply concerned about health, independence, personal growth, relationships, well-being, and security; those with

stress-induced seizures may be candidates for stress reduction, biofeedback, or relaxation training. Many resources are available to help patients. In the absence of a local epilepsy group, patients

should be encouraged to call the Epilepsy Foundation at 1-800-EFA-1000 or to visit their website at www.epilepsyfoundation.org.

Depression and psychiatric disease — Mood disorders, particularly anxiety and depression, are common in patients with epilepsy [136,161-164]. The reported prevalence of depression in patients

with epilepsy ranges from 13 to 35 percent, with much of the variability explained by differences in methods of ascertaining depression [165]. In one community health survey, epilepsy was associated

with 43 percent higher odds of depression after adjustment for other demographic factors [162]. Results from surveys in Canada and England have also reported higher odds of anxiety, depression, and

suicidal ideation among those with epilepsy [163,166].

Epilepsy-related disability, including unemployment and activity restriction, along with impaired social support and a perceived stigma associated with the diagnosis are risk factors for depression in these

patients [167]. Other reports that find a high rate of psychiatric comorbidity (including depression, bipolar disease, psychosis, anxiety, and suicidality) predating seizure onset suggest a bidirectional

relationship and perhaps a common underlying mechanism fo r psychiatric disorders and epilepsy [168,169].

Mood disturbances are important contributors to decreased health-related quality of life in persons with epilepsy [161,170-173]. One study’s results suggested that the p resence of a mood disorder also

increases the likelihood of an AED-related adverse event, which may, in turn, contribute to drug intolerance and noncompliance as well [174].

Suicide risk is a particular concern in patients with epilepsy [175,176]. A population-based study in Denmark demonstrated a three-times higher risk for suicide in epileptic patients compared with

controls [177]. Similar risk was demonstrated in a separate population-based study both in the three years before and after a d iagnosis of epilepsy [169]. Other studies have not found a higher risk of 

suicide among individuals with epilepsy after adjustment for psychiatric comorbidity [149]. Suicidality has also been linked to AED treatment. (See 'Side effects of therapy' above.)

 An international consensus group published guidelines in 2011 for the management of depression and other psychiatric conditions associated with epilepsy [178]. Their recommendations included:

Cognitive impairment — Impaired cognition appears to be a comorbidity of epilepsy [178].

The causes are likely multifactorial and include the impact of the underlying etiology, side effects of medications or other treatments, the effects of recurrent seizures, as well as psychosocial factors

[151,180-182]. Studies suggest that some patients are already impaired at the time of their diagnosis and also follow a different cognitive trajectory after diagnosis compared with control groups and/or 

the general population [183-185]. Clinical neuropsychological evaluation and cognitive rehabilitation may be helpful for some patients with cognitive complaints [178].

Medical comorbidities — Adults with epilepsy have increased rates of medical as well as psychiatric comorbidities that can complicate epilepsy management, contribute to decreased health-related

quality of life, increase health-care costs, and shorten lifespan [186-189]. These associations might result from a variety of factors, including shared r isk factors, treatment side effects (eg, weight gain,

altered lipid profiles), or shared genetic, environmental, or other factors [186,188].

In an analysis of data from the 2010 U.S. National Health Interview Survey, adults with epilepsy had an increased prevalence of cardiovascular, respiratory, inflammatory, and pain disorders than adults

without epilepsy [188]. This included increased rates of self-reported heart disease (18 versus 11 percent), high blood pressure (34 versus 29 percent), stroke (14 versus 2 percent), and obesity (34

versus 28 percent).

Sleep-related breathing disorders, including obstructive sleep apnea and central sleep apnea, have been reported with increased frequency in patients with epilepsy [190,191]. In one small study,

treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) therapy reduced interictal discharges in addition to improving oxygen saturat ion and sleep quality in nine adults

with epilepsy [192]. The clinical significance of interictal discharges is uncertain, however.

Recognition of medical comorbidities can facilitate treatment of epilepsy and is particularly important when selecting AED therapy. (See "Initial treatment of epilepsy in adults", section on 'Concurrent

Illnesses'.)

DISCONTINUING AED THERAPY — After a two to four-year seizure free interval, it is reasonable to consider discontinuing antiepileptic drugs (AEDs). This decision must weigh the risk of seizure

recurrence against the possible benefits of drug withdrawal.

There are several reasons to consider discontinuing AEDs in appropriate patients.

Screening for depression at diagnosis of epilepsy and on annual follow-up. The Patient Health Questionnaire-9 (table 10) and Neurologic Disorders Depression Inventory for Epilepsy were

suggested tools. Both have been validated in adults with epilepsy and found to have excellent accuracy [179]. (See "Using scales to monitor symptoms and treat depression (measurement based

care)" and "Screening for depression", section on 'Screening instruments'.)

●

Because of the risk of suicide as well as the adverse impact of depression on quality of life and seizure control, they advised against watchful waiting but rather appropriate referral and/or treatment

of depression. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)

●

Patients with epilepsy should be advised about the risk of suicide associated with AED therapy. Patients with suicidal ideation should be referred for appropriate intervention. (See "Suicidal ideation

and behavior in adults".)

●

 Anxiety is also a common comorbid condition in patients with epilepsy and may benefit from specific treatment. While psychoses and neurobehavioral disorders are less frequent, they can be

troublesome and associated with significant risks. Formal psychiatric assessment and treatment should be arranged for such patients as well. (See "Generalized anxiety disorder: Epidemiology,

pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Pharmacotherapy for generalized anxiety disorder" and "Clinical manifestations, differential diagnosis, and initial

management of psychosis in adults".)

●

It offers patients a sense of being "cured," whereas the need for chronic med ication confers a perception of continuing disability●

No drug is entirely benign, and adverse effects associated with chronic therapy may take years to become evident●

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The main disadvantage is the possibility that seizures will recur. The psychosocial implications may be particularly significant for adults who are employed, drive, and whose lifestyle would be adversely

affected by recurrent seizures. The recommendation to withdraw AEDs must be made on an individual basis, and the approach should be neither dogmatic nor inflexible. Each patient should have a

reasonable understanding of the possible risks and benefits related to discontinuing drugs that are relevant to his or her own case.

There is no certain way to prospectively identify patients who w ill remain seizure free after they discontinue AED therapy. At least two studies have compared continued AED treatment with drug

withdrawal and reported the following results:

Risk factors for seizure recurrence — Factors that have been associated with an increased risk of seizure recurrence after discontinuation of AED therapy include the following [193,196-200]:

Thus, the physician must make the choice to taper AEDs on an individual basis, weighing the potential risk of seizure recurrence after discontinuing therapy against that of continuing therapy. As an

example, one may have quite d ifferent recommendations regarding AED withdrawal in a 25-year-old woman who wishes to become pregnant than in a 25-year-old man whose livelihood depends on

driving.

Even patients who are seizure free for several years and have none of the risk factors listed above still have about a 20 to 25 percent risk of seizure recurrence after AED withdrawal, a much higher risk

of seizures than the general population. Because this risk cannot be known exactly for any given pat ient, and as the timing of a seizure recurrence cannot be predicted, many patients elect to continue

 AED therapy rather than risk having seizures recur. However, one should also keep in mind that the risk is not zero even with continued AEDs; in most studies, the risk is halved if AEDs are continued.

Withdrawal schedule — There are no data that indicate an optimal tapering regimen [201]. The following considerations may be helpful:

Driving — There are no guidelines or general consensus regarding driving restrictions during and after AED withdrawal. (See "Driving restrictions for patients with seizures and epilepsy", section on

'Discontinuing medication'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at

the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who

prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 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 a rticles 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.)

SUMMARY AND RECOMMENDATIONS — The management of patients with epilepsy is focused on th ree main goals: controlling seizures, avoiding treatment side effects, and maintaining or restoring

quality of life.

Use of UpToDate is subject to the Subscription and License Agreement.

Cognitive and behavioral side effects of AEDs may be subtle and not fully recognized until drugs are discontinued [193]●

The newer AEDs are expensive and pose a significant financial burden for many patients●

There may be special circumstances, such as pregnancy or serious coexisting medical conditions, in which outcomes may be improved and management simplified in the absence of unnecessary

 AED therapy

●

The first study included 1013 patients with ep ilepsy who had been seizure free for at least two years (range two to six years); these patients were randomly assigned to either continued AED

treatment or slow withdrawal of drug therapy [194]. By two years after randomization, 78 and 59 percent of patients, respectively, remained seizure free. The most important factors predicting

outcome were longer seizure-free periods before attempt ing drug withdrawal (which reduced seizure recurrence) and a history of tonic-clonic seizures treated with more than one AED (which

increased recurrence).

●

The second study included 330 patients with epilepsy who were also seizure free for two years on a single AED and had consented to drug withdrawal [195]. The proportion of those with persistent

seizure remission for those who continued and discontinued therapy (82 and 57 percent, respectively) were remarkably similar to those found in the first study. Duration of active disease and length

of remission before AED withdrawal also influenced the risk of relapse.

●

Identifiable brain disease (eg, brain tumor, congenital malformation, encephalomalacia)●

Mental retardation●

 Abnormal neurologic examination●

Seizure onset after the first decade●

Multiple seizure types●

Poor initial response to treatment●

Combination therapy at the time of withdrawal●

Selected epilepsy syndromes (especially juvenile myoclonic epilepsy) (see "Juvenile myoclonic epilepsy", section on 'Prognosis')●

Epileptiform discharges on electroencephalogram (EEG)●

Family history of epilepsy●

Hippocampal atrophy or abnormal hippocampal signal on magnetic resonance imaging (MRI)●

Rapid changes in drug treatment increase the risk of provoking seizures, especially with carbamazepine and oxcarbazepine [202]. Slow rates of AED taper (six months) were relatively similar to

more moderate rates (two to three months) in one large study [194].

●

Exceptions are benzodiazepines and barbiturates, which should be discontinued very gradua lly to avoid withdrawal seizures.●

Taper one drug at a time in patients on combination therapy.●

th th

th th

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

Beyond the Basics topics (see "Patient information: Seizures in adults (Beyond the Basics)")●

Immediate antiepileptic drug (AED) therapy is usually not necessary in individuals after a single seizure and is typically reserved for individuals who are at high risk of recurrent seizures or those

who have had two or more unprovoked seizures. (See "Initial treatment of epilepsy in adults", section on 'When to start AED therapy'.)

●

We recommend initiating an AED in monotherapy in individuals who are at high risk of recurrent seizures (Grade 1A). Selection of AED is individualized based upon the seizure type, po tentialadverse effects, interactions with other medications, comorbid medical conditions, age and gender, including childbearing plans, lifestyle and patient preferences, and cost. (See "Initial treatment of 

epilepsy in adults", section on 'Selection of an AED'.)

●

If the first AED trial is unsuccessful, a second AED trial is recommended (Grade 1A). AED therapy is as likely to fail from adverse effects of medication as from lack of efficacy. The chance of 

successful AED treatment diminishes with each unsuccessful drug trial. (See 'Subsequent drug trials' above.)

●

Regular outpatient office visits that include patient education, review of adverse medication effects, seizure calendar, and drug monitoring are suggested to improve compliance and the likelihood of 

a successful outcome. (See 'Maximizing the likelihood of a successful outcome' above.)

●

Women of childbearing age should be counseled regarding possible teratogenic effects of AEDs and should consider taking supplemental folate to limit the risk.

Enzyme-inducing AEDs can limit the effectiveness of oral contraception; alternative forms of birth control should be considered in women taking these AEDs. (See 'Women of childbearing age'

above.)

●

Mood problems, anxiety, and depression are more prevalent in persons with epilepsy than in the general population. In addition, AED treatment has been associated with suicidality. Patients treated

with AEDs should be monitored for changes in mood and suicidality. (See 'Specific adverse reactions' above and 'Psychosocial issues' above.)

●

Patients with epilepsy have a higher than expected risk of mortality (including sudden death), injury, and motor vehicle accidents. Seizure frequency is a major risk factor for these complications. It

is reasonable to counsel patients regarding these risks when discussing compliance issues or aggressive treatment for medically refractory epilepsy. (See 'Complications of epilepsy' above.)

Individuals who have had a recent epileptic seizure may be restricted from driving. Patients who are experiencing substantial neurotoxic side effects from AEDs should also be counseled about

their appropriateness for driving until such side effects abate. (See "Driving restrictions for patients with seizures and epilepsy".)

●

 AED discontinuation can be considered in patients who have been seizure free for more than two years. Such decisions are individualized based on an evaluation of the individual's risk of seizure

recurrence, adverse effects of AED treatment, and the medical and psychosocial consequences of a recurrent seizure. AED drug withdrawal should be slow, over a few to several months. (See

'Discontinuing AED therapy' above.)

●

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