Overview of the management of epilepsy in adults.pdf

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 objective 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 effects is as

important as efficacy in determining the overall effectiveness of treatment. No single AED is optimal for every patient or even most patients. 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 patients [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. It remains important to choose a drug with demonstrated efficacy 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 off.

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

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 ●

Page 1 of 32Overview of the management of epilepsy in adults

11/10/2014http://www.uptodate.com/contents/overview-of-the-management-of-epilepsy-in-adult...

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 also 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, which 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 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 trial 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 data 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 treatment occurred with a fourth or fifth drug

trial. Both studies found that the number of previous failed trials was a negative 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 patients 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 of 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 afternoon 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]:

In one large case series of 809 patients with refractory epilepsy, rates of adverse events did not differ between patients 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] ●

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 not sufficiently rigorous to refute them. A case-control study found that 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".) ●



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 medication and possible side effects, or psychosocial aspects of their disorder. It may be useful to obtain 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 patients who have

low albumin levels or who are taking other drugs that are tightly protein-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 also important 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 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 delivery

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 risk 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

history of alcohol or substance abuse or a history of alcohol-related seizures. However, patients should be aware that the data are not definitive at this time. Driving or other

high-risk activities should be avoided for 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

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

●

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] ●



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 intervention that linked intake of medication with a particular time, place, or 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 of 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 anticonvulsant 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 antiepileptic 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 of 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 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 not 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 of AEDs on oral contraceptive metabolism, oral contraceptives can increase the metabolism of 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 with 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 adults 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 follow-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

brain 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 presenting 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 patients 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 stroke 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 higher 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 (<30 years); there is no excess in mortality for older 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

for idiopathic epilepsy [127,128,130,131]. Similarly, mortality rates after an incident unprovoked seizure were found to be higher in those with symptomatic versus idiopathic

seizures, with the cause of death often attributed to the underlying cause of seizure in those with symptomatic etiologies (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].

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 that 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 of 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 controls [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 epilepsy. The most common requirements are that patients be free of 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 psychosocial interventions 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 for 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

presence 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 diagnosis 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

risk 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 saturation 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.

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

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 medication confers a perception of continuing disability ●

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

●

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 ●



own case.

There is no certain way to prospectively identify patients who will 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 different 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 patient, 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 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.)

SUMMARY AND RECOMMENDATIONS — 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.

The first study included 1013 patients with epilepsy 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 attempting 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 gradually 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, potential adverse 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".)

●



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

REFERENCES

1. Schachter SC. Advances in the assessment of refractory epilepsy. Epilepsia 1993; 34 Suppl 5:S24.

2. Schachter SC. Update in the treatment of epilepsy. Compr Ther 1995; 21:473.

3. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30:389.

4. Fountain NB, Van Ness PC, Swain-Eng R, et al. Quality improvement in neurology: AAN epilepsy quality measures: Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology. Neurology 2011; 76:94.

5. Schachter SC. Brainstorms: Epilepsy in Our Words, Raven Press, New York 1993.

6. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001; 42:1255.

7. Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007; 68:402.

8. Petrovski S, Szoeke CE, Jones NC, et al. Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology 2010; 75:1015.

9. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314.

10. Bonnett LJ, Tudur Smith C, Donegan S, Marson AG. Treatment outcome after failure of a first antiepileptic drug. Neurology 2014; 83:552.

11. 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.

12. Canevini MP, De Sarro G, Galimberti CA, et al. Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 2010; 51:797.

13. Beghi E, Gatti G, Tonini C, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res 2003; 57:1.

14. Deckers CL, Hekster YA, Keyser A, et al. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001; 42:1387.

15. Haag A, Strzelczyk A, Bauer S, et al. Quality of life and employment status are correlated with antiepileptic monotherapy versus polytherapy and not with use of "newer" versus "classic" drugs: results of the "Compliant 2006" survey in 907 patients. Epilepsy Behav 2010; 19:618.

16. Costa J, Fareleira F, Ascenção R, et al. Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 2011; 52:1280.

17. Zaccara G, Almas M, Pitman V, et al. Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: a randomized, double-blind, noninferiority trial. Epilepsia 2014; 55:1048.

18. Deckers CL, Czuczwar SJ, Hekster YA, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 2000; 41:1364.

19. Kwan P, Brodie MJ. Combination therapy in epilepsy: when and what to use. Drugs 2006; 66:1817.

20. Jonker DM, Voskuyl RA, Danhof M. Synergistic combinations of anticonvulsant agents: what is the evidence from animal experiments? Epilepsia 2007; 48:412.

21. Margolis JM, Chu BC, Wang ZJ, et al. Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action. JAMA Neurol 2014; 71:985.

22. Moeller JJ, Rahey SR, Sadler RM. Lamotrigine-valproic acid combination therapy for medically refractory epilepsy. Epilepsia 2009; 50:475.

23. Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group. Epilepsy Res 1997; 26:423.

24. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40:1141.

25. Poolos NP, Warner LN, Humphreys SZ, Williams S. Comparative efficacy of combination drug therapy in refractory epilepsy. Neurology 2012; 78:62.

26. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 2007; 62:375.

27. Callaghan BC, Anand K, Hesdorffer D, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol 2007; 62:382.

28. Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008; 70:54.

29. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4344b1_10_03_Trileptal%20Update.pdf.

30. Bell GS, Gaitatzis A, Bell CL, et al. Suicide in people with epilepsy: how great is the risk? Epilepsia 2009; 50:1933.

31. Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335.

32. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010; 363:542.

33. Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm? Epilepsia 2009; 50:978.

34. Roeder R, Roeder K, Asano E, Chugani HT. Depression and mental health help-seeking behaviors in a predominantly African American population of children and adolescents with epilepsy. Epilepsia 2009; 50:1943.

35. Mula M, Kanner AM, Schmitz B, Schachter S. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia 2013; 54:199.

36. Shneker BF, Cios JS, Elliott JO. Suicidality, depression screening, and antiepileptic drugs: reaction to the FDA alert. Neurology 2009; 72:987.

37. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428:486.

38. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16:297.

39. Wu XT, Hu FY, An DM, et al. Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China. Epilepsy Behav 2010; 19:405.

40. Yang CY, Dao RL, Lee TJ, et al. Severe cutaneous adverse reactions to antiepileptic drugs in Asians. Neurology 2011; 77:2025.

41. 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.

42. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124718.htm.

43. Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol 2011; 69:352.

44. 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.

45. Perucca E. NICE guidance on newer drugs for epilepsy in adults. BMJ 2004; 328:1273.

46. National Institute for Clinical Excellence. Newer drugs for epilepsy in adults, full guidance. Technology Appraisal Guidance 76, March 2004. www.nice.org.uk/TA076guidance (Accessed on March 3, 2005).

47. 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.

48. Faught E, Duh MS, Weiner JR, et al. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008; 71:1572.

49. 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.

50. Kaiboriboon K, Guevara M, Alldredge BK. Understanding herb and dietary supplement use in patients with epilepsy. Epilepsia 2009; 50:1927.

51. Fisher RS. Tracking epilepsy with an electronic diary. Acta Paediatr 2010; 99:516.

52. My Epilepsy Diary. Available at: http://www.epilepsy.com/seizurediary (Accessed on June 04, 2010).

53. Haut SR, Hall CB, Masur J, Lipton RB. Seizure occurrence: precipitants and prediction. Neurology 2007; 69:1905.

54. Dionisio J, Tatum WO 4th. Triggers and techniques in termination of partial seizures. Epilepsy Behav 2010; 17:210.

55. Hoppe C, Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007; 64:1595.

56. Berg MJ, Gross RA, Haskins LS, et al. Generic substitution in the treatment of epilepsy: patient and physician perceptions. Epilepsy Behav 2008; 13:693.

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.)

●



57. McAuley JW, Chen AY, Elliott JO, Shneker BF. An assessment of patient and pharmacist knowledge of and attitudes toward reporting adverse drug events due to formulation switching in patients with epilepsy. Epilepsy Behav 2009; 14:113.

58. Papsdorf TB, Ablah E, Ram S, et al. Patient perception of generic antiepileptic drugs in the Midwestern United States. Epilepsy Behav 2009; 14:150.

59. Chaluvadi S, Chiang S, Tran L, et al. Clinical experience with generic levetiracetam in people with epilepsy. Epilepsia 2011; 52:810.

60. Krauss GL, Caffo B, Chang YT, et al. Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol 2011; 70:221.

61. Liow K, Barkley GL, Pollard JR, et al. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology 2007; 68:1249.

62. Berg MJ. What's the problem with generic antiepileptic drugs?: a call to action. Neurology 2007; 68:1245.

63. Krämer G, Biraben A, Carreno M, et al. Current approaches to the use of generic antiepileptic drugs. Epilepsy Behav 2007; 11:46.

64. Bialer M. Generic products of antiepileptic drugs (AEDs): is it an issue? Epilepsia 2007; 48:1825.

65. Nielsen KA, Dahl M, Tømmerup E, Wolf P. Comparative daily profiles with different preparations of lamotrigine: a pilot investigation. Epilepsy Behav 2008; 13:127.

66. Zachry WM 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia 2009; 50:493.

67. Hansen RN, Campbell JD, Sullivan SD. Association between antiepileptic drug switching and epilepsy-related events. Epilepsy Behav 2009; 15:481.

68. Rascati KL, Richards KM, Johnsrud MT, Mann TA. Effects of antiepileptic drug substitutions on epileptic events requiring acute care. Pharmacotherapy 2009; 29:769.

69. Kinikar SA, Delate T, Menaker-Wiener CM, Bentley WH. Clinical outcomes associated with brand-to-generic phenytoin interchange. Ann Pharmacother 2012; 46:650.

70. LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology 2008; 70:2179.

71. Duh MS, Paradis PE, Latrémouille-Viau D, et al. The risks and costs of multiple-generic substitution of topiramate. Neurology 2009; 72:2122.

72. Labiner DM, Paradis PE, Manjunath R, et al. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology 2010; 74:1566.

73. Helmers SL, Paradis PE, Manjunath R, et al. Economic burden associated with the use of generic antiepileptic drugs in the United States. Epilepsy Behav 2010; 18:437.

74. Berg MJ, Gross RA, Tomaszewski KJ, et al. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology 2008; 71:525.

75. Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010; 70:605.

76. Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 2001; 42:1266.

77. Hauser WA, Ng SK, Brust JC. Alcohol, seizures, and epilepsy. Epilepsia 1988; 29 Suppl 2:S66.

78. Ettinger AB, Manjunath R, Candrilli SD, Davis KL. Prevalence and cost of nonadherence to antiepileptic drugs in elderly patients with epilepsy. Epilepsy Behav 2009; 14:324.

79. Manjunath R, Davis KL, Candrilli SD, Ettinger AB. Association of antiepileptic drug nonadherence with risk of seizures in adults with epilepsy. Epilepsy Behav 2009; 14:372.

80. Brown I, Sheeran P, Reuber M. Enhancing antiepileptic drug adherence: a randomized controlled trial. Epilepsy Behav 2009; 16:634.

81. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51:1069.

82. Labiner DM, Bagic AI, Herman ST, et al. Essential services, personnel, and facilities in specialized epilepsy centers--revised 2010 guidelines. Epilepsia 2010; 51:2322.

83. Tyagi A, Delanty N. Herbal remedies, dietary supplements, and seizures. Epilepsia 2003; 44:228.

84. Lee SW, Chung SS. A review of the effects of vitamins and other dietary supplements on seizure activity. Epilepsy Behav 2010; 18:139.

85. Brigo F, Del Felice A. Melatonin as add-on treatment for epilepsy. Cochrane Database Syst Rev 2012; 6:CD006967.

86. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2012; 6:CD009270.

87. Pearl PL, Drillings IM, Conry JA. Herbs in epilepsy: evidence for efficacy, toxicity, and interactions. Semin Pediatr Neurol 2011; 18:203.

88. Stavem K, Kloster R, Røssberg E, et al. Acupuncture in intractable epilepsy: lack of effect on health-related quality of life. Seizure 2000; 9:422.

89. Cheuk DK, Wong V. Acupuncture for epilepsy. Cochrane Database Syst Rev 2006; :CD005062.

90. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42:149.

91. Harden CL, Hopp J, Ting TY, et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009; 50:1229.

92. Harden CL, Meador KJ, Pennell PB, et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009; 50:1237.

93. Harden CL, Pennell PB, Koppel BS, et al. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009; 50:1247.

94. Beghi E, Cornaggia C, RESt-1 Group. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002; 43:1076.

95. Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979; 20:519.

96. Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurology 2006; 66:S37.

97. Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. Epilepsia 2011; 52:243.

98. Pennell PB, Gidal BE, Sabers A, et al. Pharmacology of antiepileptic drugs during pregnancy and lactation. Epilepsy Behav 2007; 11:263.

99. Morrell MJ, Flynn KL, Seale CG, et al. Reproductive dysfunction in women with epilepsy: antiepileptic drug effects on sex-steroid hormones. CNS Spectr 2001; 6:771.

100. 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.

101. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report (MMWR). U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition. Early release - May 28, 2010. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0528a1.htm (Accessed on May 28, 2010).

102. Thorneycroft I, Klein P, Simon J. The impact of antiepileptic drug therapy on steroidal contraceptive efficacy. Epilepsy Behav 2006; 9:31.

103. O'Brien MD, Guillebaud J. Contraception for women with epilepsy. Epilepsia 2006; 47:1419.

104. Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. FFPRHC Guidance (April 2005). Drug interactions with hormonal contraception. J Fam Plann Reprod Health Care 2005; 31:139.

105. Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs. J Fam Plann Reprod Health Care 2002; 28:78.

106. Walker SP, Permezel M, Berkovic SF. The management of epilepsy in pregnancy. BJOG 2009; 116:758.

107. http://www.fsrh.org/pdfs/CEUstatementLevonelle1500.pdf.

108. Sukumaran SC, Sarma PS, Thomas SV. Polytherapy increases the risk of infertility in women with epilepsy. Neurology 2010; 75:1351.

109. Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 1998; 352:1970.

110. Olafsson E, Hauser WA, Gudmundsson G. Fertility in patients with epilepsy: a population-based study. Neurology 1998; 51:71.

111. Pack AM. Infertility in women with epilepsy: what's the risk and why? Neurology 2010; 75:1316.

112. Verrotti A, D'Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia 2011; 52:199.

113. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993; 34:453.

114. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000; 57:1617.

115. Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol 2002; 59:195.

116. Sung CY, Chu NS. Epileptic seizures in thrombotic stroke. J Neurol 1990; 237:166.

117. Graham NS, Crichton S, Koutroumanidis M, et al. Incidence and associations of poststroke epilepsy: the prospective South London Stroke Register. Stroke 2013; 44:605.



118. Lossius MI, Rønning OM, Slapø GD, et al. Poststroke epilepsy: occurrence and predictors--a long-term prospective controlled study (Akershus Stroke Study). Epilepsia 2005; 46:1246.

119. Camilo O, Goldstein LB. Seizures and epilepsy after ischemic stroke. Stroke 2004; 35:1769.

120. Heuts-van Raak L, Lodder J, Kessels F. Late seizures following a first symptomatic brain infarct are related to large infarcts involving the posterior area around the lateral sulcus. Seizure 1996; 5:185.

121. Cordonnier C, Hénon H, Derambure P, et al. Influence of pre-existing dementia on the risk of post-stroke epileptic seizures. J Neurol Neurosurg Psychiatry 2005; 76:1649.

122. Velioğlu SK, Ozmenoğlu M, Boz C, Alioğlu Z. Status epilepticus after stroke. Stroke 2001; 32:1169.

123. Gupta SR, Naheedy MH, Elias D, Rubino FA. Postinfarction seizures. A clinical study. Stroke 1988; 19:1477.

124. Gilad R, Sadeh M, Rapoport A, et al. Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure. Clin Neuropharmacol 2007; 30:189.

125. Alvarez-Sabín J, Montaner J, Padró L, et al. Gabapentin in late-onset poststroke seizures. Neurology 2002; 59:1991.

126. Mohanraj R, Norrie J, Stephen LJ, et al. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet Neurol 2006; 5:481.

127. Cockerell OC, Johnson AL, Sander JW, Shorvon SD. Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 1997; 38:31.

128. Neligan A, Bell GS, Shorvon SD, Sander JW. Temporal trends in the mortality of people with epilepsy: a review. Epilepsia 2010; 51:2241.

129. Mu J, Liu L, Zhang Q, et al. Causes of death among people with convulsive epilepsy in rural West China: a prospective study. Neurology 2011; 77:132.

130. Trinka E, Bauer G, Oberaigner W, et al. Cause-specific mortality among patients with epilepsy: results from a 30-year cohort study. Epilepsia 2013; 54:495.

131. Callaghan B, Choi H, Schlesinger M, et al. Increased mortality persists in an adult drug-resistant epilepsy prevalence cohort. J Neurol Neurosurg Psychiatry 2014; 85:1084.

132. Benn EK, Hauser WA, Shih T, et al. Underlying cause of death in incident unprovoked seizures in the urban community of Northern Manhattan, New York City. Epilepsia 2009; 50:2296.

133. Day SM, Wu YW, Strauss DJ, et al. Causes of death in remote symptomatic epilepsy. Neurology 2005; 65:216.

134. Bell GS, Gaitatzis A, Bell CL, et al. Drowning in people with epilepsy: how great is the risk? Neurology 2008; 71:578.

135. Fazel S, Wolf A, Långström N, et al. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet 2013; 382:1646.

136. St Germaine-Smith C, Liu M, Quan H, et al. Development of an epilepsy-specific risk adjustment comorbidity index. Epilepsia 2011; 52:2161.

137. Annegers JF, Coan SP. SUDEP: overview of definitions and review of incidence data. Seizure 1999; 8:347.

138. Leestma JE, Walczak T, Hughes JR, et al. A prospective study on sudden unexpected death in epilepsy. Ann Neurol 1989; 26:195.

139. Nilsson L, Farahmand BY, Persson PG, et al. Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 1999; 353:888.

140. Walczak TS, Leppik IE, D'Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001; 56:519.

141. Annegers JF, Melton LJ 3rd, Sun CA, Hauser WA. Risk of age-related fractures in patients with unprovoked seizures. Epilepsia 1989; 30:348.

142. Kirby S, Sadler RM. Injury and death as a result of seizures. Epilepsia 1995; 36:25.

143. Vestergaard P, Tigaran S, Rejnmark L, et al. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999; 99:269.

144. Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia 2002; 43:768.

145. Friedman DE, Tobias RS, Akman CI, et al. Recurrent seizure-related injuries in people with epilepsy at a tertiary epilepsy center: a 2-year longitudinal study. Epilepsy Behav 2010; 19:400.

146. Kwon CS, Liu M, Quan H, et al. The incidence of injuries in persons with and without epilepsy--a population-based study. Epilepsia 2010; 51:2247.

147. Lawn ND, Bamlet WR, Radhakrishnan K, et al. Injuries due to seizures in persons with epilepsy: a population-based study. Neurology 2004; 63:1565.

148. Bowman SM, Aitken ME, Sharp GB. Disparities in injury death location for people with epilepsy/seizures. Epilepsy Behav 2010; 17:369.

149. Kwon C, Liu M, Quan H, et al. Motor vehicle accidents, suicides, and assaults in epilepsy: a population-based study. Neurology 2011; 76:801.

150. Shackleton DP, Kasteleijn-Nolst Trenité DG, de Craen AJ, et al. Living with epilepsy: long-term prognosis and psychosocial outcomes. Neurology 2003; 61:64.

151. Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012; 380:1180.

152. Strine TW, Kobau R, Chapman DP, et al. Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia 2005; 46:1133.

153. Schachter SC, Shafer PO, Murphy W. The personal impact of epilepsy: Correlations with seizure frequency, employment, cost of medical care, and satisfaction with physician care. J Epilepsy 1993; 6:224.

154. Holland P, Lane S, Whitehead M, et al. Labor market participation following onset of seizures and early epilepsy: Findings from a UK cohort. Epilepsia 2009; 50:1030.

155. Jennum P, Gyllenborg J, Kjellberg J. The social and economic consequences of epilepsy: a controlled national study. Epilepsia 2011; 52:949.

156. Gauffin H, Landtblom AM, Räty L. Self-esteem and sense of coherence in young people with uncomplicated epilepsy: a 5-year follow-up. Epilepsy Behav 2010; 17:520.

157. Hinnell C, Williams J, Metcalfe A, et al. Health status and health-related behaviors in epilepsy compared to other chronic conditions--a national population-based study. Epilepsia 2010; 51:853.

158. Samokhvalov AV, Irving H, Mohapatra S, Rehm J. Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51:1177.

159. Devinsky O. Clinical uses of the quality-of-life in epilepsy inventory. Epilepsia 1993; 34 Suppl 4:S39.

160. Ramaratnam S, Baker GA, Goldstein L. Psychological treatments for epilepsy. Cochrane Database Syst Rev 2001; :CD002029.

161. Layne Moore J, Elliott JO, Lu B, et al. Serious psychological distress among persons with epilepsy based on the 2005 California Health Interview Survey. Epilepsia 2009; 50:1077.

162. Fuller-Thomson E, Brennenstuhl S. The association between depression and epilepsy in a nationally representative sample. Epilepsia 2009; 50:1051.

163. Tellez-Zenteno JF, Patten SB, Jetté N, et al. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007; 48:2336.

164. Seminario NA, Farias ST, Jorgensen J, et al. Determination of prevalence of depression in an epilepsy clinic using a brief DSM-IV-based self-report questionnaire. Epilepsy Behav 2009; 15:362.

165. Fiest KM, Dykeman J, Patten SB, et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology 2013; 80:590.

166. Rai D, Kerr MP, McManus S, et al. Epilepsy and psychiatric comorbidity: a nationally representative population-based study. Epilepsia 2012; 53:1095.

167. Reisinger EL, DiIorio C. Individual, seizure-related, and psychosocial predictors of depressive symptoms among people with epilepsy over six months. Epilepsy Behav 2009; 15:196.

168. Adelöw C, Andersson T, Ahlbom A, Tomson T. Hospitalization for psychiatric disorders before and after onset of unprovoked seizures/epilepsy. Neurology 2012; 78:396.

169. Hesdorffer DC, Ishihara L, Mynepalli L, et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 2012; 72:184.

170. Szaflarski M, Meckler JM, Privitera MD, Szaflarski JP. Quality of life in medication-resistant epilepsy: the effects of patient's age, age at seizure onset, and disease duration. Epilepsy Behav 2006; 8:547.

171. Kwan P, Yu E, Leung H, et al. Association of subjective anxiety, depression, and sleep disturbance with quality-of-life ratings in adults with epilepsy. Epilepsia 2009; 50:1059.

172. Park SP, Song HS, Hwang YH, et al. Differential effects of seizure control and affective symptoms on quality of life in people with epilepsy. Epilepsy Behav 2010; 18:455.

173. Taylor RS, Sander JW, Taylor RJ, Baker GA. Predictors of health-related quality of life and costs in adults with epilepsy: a systematic review. Epilepsia 2011; 52:2168.

174. Kanner AM, Barry JJ, Gilliam F, et al. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia 2012; 53:1104.

175. Stefanello S, Marín-Léon L, Fernandes PT, et al. Suicidal thoughts in epilepsy: a community-based study in Brazil. Epilepsy Behav 2010; 17:483.

176. Hesdorffer DC, French JA, Posner K, et al. Suicidal ideation and behavior screening in intractable focal epilepsy eligible for drug trials. Epilepsia 2013; 54:879.

177. Christensen J, Vestergaard M, Mortensen PB, et al. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol 2007; 6:693.

178. 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.

179. Rathore JS, Jehi LE, Fan Y, et al. Validation of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adults with epilepsy. Epilepsy Behav 2014; 37:215.



180. Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001; 357:216.

181. Meador KJ. Cognitive outcomes and predictive factors in epilepsy. Neurology 2002; 58:S21.

182. Aldenkamp AP, Bodde N. Behaviour, cognition and epilepsy. Acta Neurol Scand Suppl 2005; 182:19.

183. Taylor J, Kolamunnage-Dona R, Marson AG, et al. Patients with epilepsy: cognitively compromised before the start of antiepileptic drug treatment? Epilepsia 2010; 51:48.

184. Hermann BP, Seidenberg M, Dow C, et al. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol 2006; 60:80.

185. Baker GA, Taylor J, Aldenkamp AP, SANAD group. Newly diagnosed epilepsy: cognitive outcome after 12 months. Epilepsia 2011; 52:1084.

186. Sander JW. Comorbidity and premature mortality in epilepsy. Lancet 2013; 382:1618.

187. Ottman R, Lipton RB, Ettinger AB, et al. Comorbidities of epilepsy: results from the Epilepsy Comorbidities and Health (EPIC) survey. Epilepsia 2011; 52:308.

188. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2013; 62.

189. Gaitatzis A, Sisodiya SM, Sander JW. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 2012; 53:1282.

190. Vendrame M, Jackson S, Syed S, et al. Central sleep apnea and complex sleep apnea in patients with epilepsy. Sleep Breath 2014; 18:119.

191. Phillips MC, Costello CA, White EJ, et al. Routine polysomnography in an epilepsy monitoring unit. Epilepsy Res 2013; 105:401.

192. Pornsriniyom D, Shinlapawittayatorn K, Fong J, et al. Continuous positive airway pressure therapy for obstructive sleep apnea reduces interictal epileptiform discharges in adults with epilepsy. Epilepsy Behav 2014; 37:171.

193. Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia 2008; 49:455.

194. Randomised study of antiepileptic drug withdrawal in patients in remission. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet 1991; 337:1175.

195. Specchio LM, Tramacere L, La Neve A, Beghi E. Discontinuing antiepileptic drugs in patients who are seizure free on monotherapy. J Neurol Neurosurg Psychiatry 2002; 72:22.

196. Britton JW. Antiepileptic drug withdrawal: literature review. Mayo Clin Proc 2002; 77:1378.

197. Callaghan N, Garrett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two years. A prospective study. N Engl J Med 1988; 318:942.

198. Cardoso TA, Coan AC, Kobayashi E, et al. Hippocampal abnormalities and seizure recurrence after antiepileptic drug withdrawal. Neurology 2006; 67:134.

199. Aktekin B, Dogan EA, Oguz Y, Senol Y. Withdrawal of antiepileptic drugs in adult patients free of seizures for 4 years: a prospective study. Epilepsy Behav 2006; 8:616.

200. Koepp MJ, Farrell F, Collins J, Smith S. The prognostic value of long-term ambulatory electroencephalography in antiepileptic drug reduction in adults with learning disability and epilepsy in long-term remission. Epilepsy Behav 2008; 13:474.

201. Ranganathan LN, Ramaratnam S. Rapid versus slow withdrawal of antiepileptic drugs. Cochrane Database Syst Rev 2006; :CD005003.

202. Azar NJ, Wright AT, Wang L, et al. Generalized tonic-clonic seizures after acute oxcarbazepine withdrawal. Neurology 2008; 70:2187.

Topic 2220 Version 27.0



GRAPHICS

International classification of epileptic seizures

Adapted from: Commission on Classification and Terminology of the International League against Epilepsy, Epilepsia 1981; 22:489.

Graphic 53661 Version 4.0

Partial (focal, local) seizures

Simple partial seizures (conciousness not impaired)

With motor symptoms

Focal motor without march

Focal motor with march (Jacksonian)

Versive

Postural

Phonatory (vocalization or arrest of speech)

With somatosensory or special sensory symptoms

Somatosensory

Visual

Auditory

Olfactory

Gustatory

Vertiginous

With autonomic symptoms or signs (including epigastric, pallor, sweating, etc)

With psychic symptoms (disturbance of higher cerebral function). Usually occur with impairment of consciousness and classified as complex partial.

Dysphasic

Cognitive (eg, distortions of time sense)

Dysmnesic (eg, deja-vu)

Affective (eg, fear)

Illusions

Hallucinations

Complex partial (with impairment of consciousness)

Simple partial onset followed by impairment of consciousness

Impairment of consciousness at onset

With impairment of consciousness only

With automatisms

Partial seizures (simple or complex) evolving to secondarily generalized seizures

Generalized seizures

Nonconvulsive (absence)

Typical (3/sec spike and slow wave complexes on EEG)

Atypical (<3/sec spike and slow wave complexes on EEG)

Convulsive

Myoclonic seizures

Clonic seizures

Tonic seizures

Tonic-clonic seizures

Atonic ("drop attacks")

Unclassified seizure



Antiepileptic medications and seizure types

Note that although there is evidence to support the use of these medications for these seizure types, the medication may not be indicated for this use by the United States Food and Drug Administration.


Seizure type Antiepileptic drug

Broad spectrum: all seizure types (generalized from onset and focal onset seizures)

Clobazam, felbamate, lamotrigine, levetiracetam, rufinamide, topiramate, valproate, zonisamide

Narrow spectrum: focal with or without alteration in consciousness or awareness and focal evolving to bilateral convulsive seizure

Carbamazepine, eslicarbazepine, ezogabine, gabapentin, lacosamide, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, vigabatrin

Absence seizure (a type of generalized seizure) Ethosuximide



Common side effects of antiepileptic drugs


Drug Systemic side effects Neurotoxic side effects

Carbamazepine Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus Drowsiness, dizziness, blurred or double vision, lethargy, headache

Clobazam Increased salivation, nausea, vomiting, constipation Somnolence, aggression, irritability, ataxia, insomnia

Eslicarbazepine Nausea, vomiting, diarrhea, fatigue, rash Dizziness, drowsiness, headache, diplopia, vertigo, ataxia, attention disturbance, blurred vision, tremor

(Note: Dizziness, diplopia and ataxia reported more frequently in combination with carbamazepine)

Ethosuximide Nausea, vomiting Sleep disturbance, drowsiness, hyperactivity

Ezogabine Nausea, fatigue, change in color of urine, dysuria, urinary hesitancy, weight gain

Dizziness, somnolence, confusion, vertigo, blurred or double vision, tremor, abnormal coordination, inattention, memory impairment

Felbamate Nausea, vomiting, anorexia, weight loss Insomnia, dizziness, headache, ataxia

Gabapentin Infrequent Somnolence, dizziness, ataxia

Lacosamide Nausea, vomiting, fatigue Ataxia, dizziness, headache, diplopia

Lamotrigine Rash, nausea Dizziness, tremor, diplopia

Levetiracetam Infection Fatigue, somnolence, dizziness, agitation, anxiety, irritability, depression

Oxcarbazepine Nausea, rash, hyponatremia Sedation, headache, dizziness, vertigo, ataxia, diplopia

Perampanel Weight gain, fatigue, nausea Dizziness, somnolence, irritability, gait disturbance, falls, aggression, mood alteration

Phenytoin Gingival hypertrophy, rash Confusion, slurred speech, double vision, ataxia

Pregabalin Weight gain, peripheral edema, dry mouth Dizziness, somnolence, ataxia, tremor

Primidone, phenobarbital Nausea, rash Alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence

Rufinamide Nausea, vomiting, fatigue Dizziness, somnolence, headache

Tiagabine Abdominal pain Dizziness, lack of energy, somnolence, nausea, nervousness, tremor, difficulty concentrating

Topiramate Weight loss, paresthesias Fatigue, nervousness, difficulty concentrating, confusion, depression, anorexia, language problems, anxiety, mood problems, tremor

Valproate Weight gain, nausea, vomiting, hair loss, easy bruising Tremor, dizziness

Vigabatrin Vision loss Drowsiness, fatigue, dizziness

Zonisamide Nausea, anorexia Somnolence, dizziness, ataxia, confusion, difficulty concentrating, depression



Rare but serious side effects of AEDs*

AEDs: antiepileptic drugs; SJS: Stevens-Johnson sydrome; TEN: toxic epidermal necrolysis. * As a class, AEDs have been associated with an increased risk of suicidal ideation and suicidal behavior.


Drug Side effects*

Carbamazepine Agranulocytosis, aplastic anemia, SJS/TEN, hepatic failure, dermatitis/rash, serum sickness, pancreatitis, lupus syndrome

Clobazam Respiratory depression, SJS/TEN

Eslicarbazepine Prolonged PR interval, atrioventricular block, hyponatremia (rarely severe), SJS/TEN

Ethosuximide Agranulocytosis, SJS/TEN, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness

Ezogabine Urinary retention, urinary tract infection, QT prolongation, psychosis

Felbamate Aplastic anemia, liver failure

Gabapentin Multiorgan hypersensitivity

Lacosamide Prolonged PR interval, atrioventricular block, multiorgan hypersensitivity, neutropenia

Lamotrigine SJS/TEN, multiorgan hypersensitivity, aseptic meningitis

Levetiracetam SJS/TEN, pancytopenia, psychosis

Oxcarbazepine SJS/TEN, multiorgan hypersensitivity, agranulocytosis, pancytopenia, leukopenia

Phenytoin Agranulocytosis, SJS/TEN, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness, adenopathy, pseudolymphoma, neuropathy, ataxia, lupus-syndrome, hirsuitism

Pregabalin Angioedema, hypersensitivity reactions, rhabdomyolysis

Primidone, phenobarbital Agranulocytosis, SJS/TEN, hepatic failure, dermatitis/rash, serum sickness, connective tissue contractures (eg, Duputrens)

Rufinamide SJS/TEN, dermatitis/rash, shortened QT interval

Tiagabine SJS/TEN, nonconvulsive status epilepticus

Topiramate Acute myopia and glaucoma; kidney stones; oligohydrosis and hyperthermia which primarily occur in children

Valproate Agranulocytosis, SJS/TEN, aplastic anemia, hepatic failure, dermatitis/rash, serum sickness, pancreatitis, polycystic ovary syndrome

Vigabatrin MRI abnormalities, depression, weight gain

Zonisamide Rash, SJS/TEN, aplastic anemia, agranulocytosis, nephrolithiasis; in children, fever and hyperhidrosis



Pharmacologic properties of antiepileptic drugs

Metabolism and

clearanceEnzyme

induction/inhibitionProtein binding,

percent*Half life in adults

(hours)

Carbamazepine>90 percent metabolized by CYP3A4 (major) and 1A2/2C8 (minor) to active (epoxide) and inactive metabolites

Dose adjustment is needed in severe renal impairment; use is not recommended in moderate or severe hepatic impairment

Potent and broad spectrum inducer of CYP, UGT-glucuronidation, and P-gp

7525-65 (initial use, enzyme inducing naive patient)

8-22 (after several weeks due to auto-induction)

Clobazam>90 percent metabolized by CYPs 3A4, 2C19, 2B6 and non-CYP transformations to active (N-desmethylclobazam) and inactive metabolites

Dose adjustment is needed in hepatic impairment

Inhibits CYP2D6 (moderate) and UGT-glucuronidation

Induces CYP3A4 (weak to moderate)

8536-43 (parent drug)

72-82 (N-desmethylclobazam metabolite [active])

EslicarbazepineProdrug; <33 percent of active form undergoes UGT glucuronidation (including <5 percent metabolized to oxcarbazepine); 66 percent is excreted renally as unchanged drug

Dose adjustment is needed for renal impairment; not recommended in patients with severe hepatic impairment

Induces CYP3A4 and UGT1A1 glucuronidation (weak) but does not induce its own metabolism

Inhibits CYP2C19 (moderate)

<40 13 to 20 hours (prolonged in renal insufficiency)

Ethosuximide ~80 percent metabolized by CYP3A4 (major) and non-CYP transformations to inactive metabolites

None <5 40-60

Ezogabine (retigabine) ~60 percent metabolized by

non-CYP transformations (UGT-glucuronidation, N-acetylation) to active (NAMR) and inactive metabolites

Dose adjustment is needed in moderate or severe hepatic or renal impairment

NAMR seems to inhibit P-gp80 (parent drug)

45 (NAMR)

7-11 (prolonged in renal insufficiency and in older adults)

Felbamate50 percent metabolized by CYP3A4 and 2E1 (minor); ~50 percent renally excreted as unchanged drug

Dose adjustment is needed in renal impairment

Induces CYP3A4 (moderate)

Inhibits CYP2C19 (minor)

25 13-22 (prolonged in renal insufficiency)

Gabapentin>95 percent renally excreted as unchanged drug (ie, does not undergo hepatic metabolism)


None <5 5-7 (prolonged in renal insufficiency; >130 hours in anuria)

Lacosamide40 percent renally excreted as unchanged drug; 30 percent metabolized by non-CYP transformations (including methylation) to inactive metabolite

Dose adjustment is needed in hepatic and renal impairment

Inhibits 2C19 (minor) <15 13

Lamotrigine>90 percent metabolized by UGT glucuronidation and other non-CYP transformations to inactive metabolites

Dose adjustment is needed in moderate to severe renal or hepatic impairment

May induce its own metabolism by UGT-glucuronidation (minor)

55 12-62

Levetiracetam>65 renally excreted as unchanged drug; 24 percent metabolized by non-CYP transformation (including

None <10 6-8



amidase hydrolysis) to inactive metabolites


OxcarbazepineProdrug; 70 percent of active (MHD) form undergoes UGT glucuronidation; 30 percent is renally excreted as unchanged active drug

Dose adjustment is needed in severe renal impairment

Induces CYP3A4 (moderate to severe) and UGT-glucuronidation but does not induce its own metabolism

40 9 (active metabolite, prolonged in renal insufficiency)

Perampanel>70 percent metabolized by CYPs 3A4, 3A5 and non-CYP transformations to inactive metabolites

Dose adjustment is needed in mild or moderate hepatic impairment

Appears to induce metabolism of progestin-containing hormonal contraceptives

95 105

Phenobarbital75 percent metabolized by CYPs 2C19, 2C9 (minor) and glucosidase hydrolysis and 2E1 (minor) to inactive metabolites; 25 percent excreted renally as unchanged drug

Dose adjustment is needed in severe renal or hepatic impairment

Potent and broad spectrum inducer of CYP and UGT-glucuronidation

55 75-110

Phenytoin>90 percent metabolized by CYPs 2C9, 2C19 and 3A4 (minor) and non-CYP transformations to inactive metabolites; clearance is dose dependent, saturable, and may be subject to genetic polymorphism

Dose adjustment is needed in severe renal or hepatic insufficiency; monitoring of free (unbound) concentrations also suggested

Potent and broad spectrum inducer of CYP and UGT-glucuronidation

90-95 9- >42 (dose dependent)

Pregabalin>95 excreted renally as unchanged drug


None <5 6

Primidone75 percent metabolized by CYPs 2C19, 2C9 (minor) and 2E1 (minor) to active intermediates; ~25 percent excreted renally as unchanged drug

Dose adjustment is needed in moderate and severe renal or hepatic impairment; close monitoring of plasma levels suggested

Potent and broad spectrum inducer of CYP

0-2010-15 (parent)

29-100 (active metabolite)

Rufinamide >90 percent metabolized by non-CYP transformations (hydrolysis) to inactive metabolites

Induces CYP3A4 (minor)

Inhibits CYP2E1 (minor)

35 6-10

Tiagabine >90 percent metabolized by CYP3A4 and non-CYP transformations to inactive metabolites

None 957-9

2-5 (with enzyme-inducing AEDs)

Topiramate>65 percent excreted renally as unchanged drug; <30 percent metabolized by non-CYP transformations to inactive metabolites; extent of metabolism is increased ~50 percent in patients receiving enzyme inducing AEDs

Dose adjustment is needed in moderate and severe renal or hepatic impairment

Inhibits CYP2C19 (minor)

Induces CYP3A4 (minor)

9-17 12-24

Valproate>95 percent undergoes Moderate broad spectrum

80-95 7-16



AEDs: antiepileptic drugs; CYP: cytochrome P450; MHD: monohydroxy derivative active form of oxcarbazepine; P-gp: membrane P-glycoprotein multidrug resistance transporter; UGT-glucuronidation: metabolism by uridine 5'diphosphate-glucuronyltransferases. * Highly protein-bound AEDs exhibit altered pharmacokinetics, including greater therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum albumin or protein binding affinity (eg, due to nephrotic syndrome or acidosis). Dose alteration is needed and monitoring of unbound (free) AED serum concentrations is suggested. Refer to UpToDate topic for additional information.

Modified from:

Additional data from: Anderson GD and Hakimian S. Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment. Clin Pharmacokinet 2014; 53:29 and Lexicomp Online. Copyright © 1978-2014 Lexicomp, Inc. All Rights Reserved.


complex transformations including CYPs 2C9, 2C19, 2A6, UGT-glucuronidation and other non-CYP transformation

Dose adjustment is needed in hepatic impairment

inhibitor including CYP2A6, 2B6, 2C9, 2C19, 2E1 and UGT-glucuronidation

Minor or moderate inducer of CYP2A6

Vigabatrin>90 percent excreted renally as unchanged drug


Induces CYP2C9 0 5-13 (unrelated to duration of action)

Zonisamide>65 percent metabolized by CYPs 3A4, 2C19 (minor) and non-CYP transformations

Dose adjustment and/or slower titration is needed in mild renal impairment or hepatic impairment; not recommended in patients with moderate or severe renal impairment

None 50 63

1. Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756. 2. Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006; 67:S28.



Common mechanisms of antiepileptic drug action

+++: primary action; ++: probable action; +: possible action.

Adapted with permission from: Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology 2002; 58:S2. Copyright © 2002 Lippincott Williams & Wilkins.


Drug Na+ channels Ca+ channels K+ channels Inhibitory transmission Excitatory transmission

Benzodiazepines +++

Carbamazepine +++ +

Clobazam +++

Ethosuximide +++

Ezogabine ++

Felbamate ++ + ++ ++

Gabapentin + + ++

Lacosamide +++

Lamotrigine +++ +

Levetiracetam + + + +

Oxcarbazepine +++ + +

Perampanel +++

Phenobarbital + +++ +

Phenytoin +++ +

Rufinamide +++

Tiagabine +++

Topiramate ++ ++ ++ ++

Valproate + + ++ +

Vigabatrin +++

Zonisamide ++ ++



Some interactions between carbamazepine and other antiepileptic drugs*

* NOTE: Not all potential interactions are listed. Additional interactions of antiepileptic drugs and management suggestions may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. The Lexi-Interact program can be accessed from the UpToDate new search tab or through the individual drug information topics in the section on Drug interactions.

Adapted with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright © 2008 The Medical Letter.


Interacting drugs Effects (probable mechanism) Management

Carbamazepine, with:

Clonazepam Decreased clonazepam effect (increased metabolism) Monitor clinical status

Eslicarbazepine Increased risk of diplopia, abnormal coordination, and dizziness (pharmacodynamic interaction)

Decreased plasma concentration of eslicarbazepine (increased metabolism)

Monitor clinical status; eslicarbazepine or carbamazepine dosage may need to be adjusted

Lamotrigine Carbamazepine toxicity (mechanism not established) Monitor clinical status; serum carbamazepine measurements alone may not predict toxicity

Decreased lamotrigine effect (increased metabolism; glucuronidation)

Lamotrigine dosage may need to be adjusted; monitor lamotrigine concentration and clinical status

Levetiracetam Possible increased risk of carbamazepine toxicity (mechanism not established)

Monitor for clinical evidence of carbamazepine toxicity

Oxcarbazepine Possible decreased oxcarbazepine effect (increased metabolism)

Monitor oxcarbazepine concentrations and clinical status

Perampanel Decreased perampanel effect (increased metabolism by CYP3A4)

Monitor clinical status; perampanel dosage may need to be adjusted

Phenytoin Decreased carbamazepine effect (increased metabolism) Monitor carbamazepine and phenytoin concentrations

Altered phenytoin effect (mechanism not established)

Tiagabine Decreased tiagabine effect (increased metabolism) Monitor clinical status

Topiramate Possible decreased topiramate effect (increased metabolism) Monitor topiramate concentrations and clinical status; may need higher doses of topiramate

Valproate Decreased valproate effect and possible increased toxicity (increased metabolism and formation of toxic metabolite)

Monitor valproate concentrations and clinical status

Carbamazepine toxicity (decreased metabolism of carbamazepine epoxide and displacement from binding)

Monitor carbamazepine and carbamazepine epoxide concentrations

Zonisamide Decreased zonisamide effect (increased metabolism by CYP3A4)

Monitor zonisamide concentrations and clinical status; zonisamide dosage may need to be adjusted



Some interactions between phenytoin and other antiepileptic drugs*


Adapted with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright © 2008 The Medical Letter.



Phenytoin, with:

Carbamazepine Decreased carbamazepine effect (increased metabolism) Monitor carbamazepine and phenytoin concentrations

Altered phenytoin effect (mechanism not established)

Clonazepam Decreased clonazepam effect (increased metabolism) Monitor clonazepam effect or concentrations

Variable effects on phenytoin concentrations (mechanism not established)

Monitor phenytoin concentrations

Eslicarbazepine Decreased eslicarbazepine concentrations (increased metabolism) Eslicarbazepine dose may need to be increased

Possible phenytoin toxicity (decreased metabolism by CYP2C19)

Monitor phenytoin concentrations and clinical status

Lamotrigine Decreased lamotrigine serum concentrations (increased metabolism; induction of glucuronidation by phenytoin)

Monitor lamotrigine serum concentrations and clinical status; lamotrigine dosage may need to be adjusted

Oxcarbazepine Possible decreased oxcarbazepine effect (increased metabolism)

Monitor clinical status and serum concentration

Possible phenytoin toxicity with oxcarbazepine doses of 1200 mg/day or higher (decreased metabolism)

Monitor phenytoin concentrations especially when oxcarbazepine dosage is 1200 mg/day or higher

Perampanel Decreased perampanel effect (increased metabolism by CYP3A4)

Monitor clinical status; perampanel dosage may need to be adjusted

Tiagabine Decreased tiagabine effect (increased metabolism) Monitor clinical status

Topiramate Possible decreased topiramate effect (increased metabolism) Monitor topiramate concentrations and clinical status; may need to increase topiramate dose

Possible phenytoin toxicity (decreased metabolism by CYP2C19)

Monitor phenytoin concentrations and clinical status

Valproate Possible phenytoin toxicity (displacement from binding) Monitor phenytoin concentrations and clinical status (unbound concentrations may be more helpful than total)

Possible decreased valproate effect and increased toxicity (increased metabolism and formation of toxic metabolite)

Monitor clinical status and valproate serum concentrations

Zonisamide Decreased zonisamide effect (increased metabolism by CYP3A4)

Monitor zonisamide concentrations and clinical status; zonisamide dosage may need to be adjusted



Some interactions between valproate and other antiepileptic drugs*


Reproduced with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright © 2008 The Medical Letter.



Valproate, with:

Carbamazepine Decreased valproate effect and possible increased toxicity (increased metabolism and formation of toxic metabolite)

Monitor valproate concentrations and clinical status

Carbamazepine toxicity (decreased metabolism of carbamazepine epoxide and displacement from binding)

Monitor carbamazepine and carbamazepine epoxide concentrations

Clonazepam Clonazepam may precipitate absence status (mechanism not established)

Monitor clinical status

Ethosuximide Possible ethosuximide toxicity (decreased metabolism) Monitor ethosuximide concentration

Possible decreased valproate effect (mechanism not established)

Monitor valproate concentration

Lamotrigine Possible lamotrigine toxicity (decreased metabolism; glucuronidation)

Decrease lamotrigine dose; monitor lamotrigine concentrations and clinical status

Oxcarbazepine Possible decreased oxcabazepine concentration (increased metabolism)

Monitor oxcarbazepine concentrations and clinical status

Phenytoin Phenytoin toxicity (displacement from binding and decreased metabolism)

Monitor phenytoin concentrations and clinical status (unbound concentrations may be more helpful than total)

Possible decreased valproate effect and increased toxicity (increased metabolism and formation of toxic metabolite)

Monitor clinical status and valproate serum concentrations

Topiramate Possible increased hepatotoxic effect of valproate (mechanism not established)

Monitor clinical status



General guidelines to improve patient adherence to antihypertensive therapy

* For a comprehensive list of cost-lowering strategies for patients, refer to UpToDate patient information topics on reducing the costs of medicines: Beyond the basics.

Courtesy of authors with additional data from:


Be aware of the problem and be alert to signs of patient nonadherance

Establish the goal of therapy: to reduce blood pressure to near normotensive levels with minimal or no side effects

Educate the patient about the disease and its treatment

Involve the patient in decision making

Encourage family support

Maintain contact with the patient

Encourage visits and calls to allied health personnel

Allow pharmacist to monitor therapy

Give feedback to the patient via home BP readings

Ask about adherence

Make contact with patients who do not return

Keep care inexpensive and simple

Do the least workup needed to rule out secondary causes

Obtain follow-up laboratory data only yearly unless indicated more often

Use home blood pressure readings

Use nondrug, no-cost therapies

Use the fewest daily doses of drugs needed

Tailor medication to daily routines

Use generic drugs

Ask patient to provide list of preferred drugs from insurance

Have pharmacist suggest low-cost alternatives*

If appropriate, use combination tablets (eg, ACE or ARB with CCB and/or low-dose HCTZ)

Use pill box(es), blister packaging, or electronic reminders (eg, smartphone app)

Prescribe according to pharmacological principles

Add one drug at a time

Use longer-acting drugs with less peak-trough BP lowering variation

Use moderately dosed combinations to minimize side effects (eg, ACE or ARB with low-dose diuretic and/or amlodipine)

Other

Start with small doses, aiming for 5 to 10 mmHg reductions at each step

Have medication taken immediately upon awakening in the morning or after 4 am if patient awakens to void

Prevent volume overload with adequate diuretic and sodium restriction

Titrate gradually, particularly beta blockers

Be willing to stop unsuccessful therapy and try a different approach

Anticipate side effects

Adjust therapy to ameliorate side effects that do not spontaneously disappear

Continue to add effective and tolerated drugs, stepwise, in sufficient doses to achieve the goal of therapy

Have case manager, pharmacist, or nurse identify and suggest solutions to barriers to adherence

1. Morgado MP, et al. Pharmacist interventions to enhance blood pressure control and adherence to antihypertensive therapy: Review and meta-analysis. Am J Health Syst Pharm. 2011; 68:241.

2. Viswanathan M, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Ann Intern Med. 2012; 157(11):785.



US Medical Eligibility Criteria for Contraceptive Use: Summary of classifications for hormonal contraceptive methods and intrauterine devices

Healthcare providers can use the summary table as a quick reference guide to the classifications for hormonal contraceptive methods and intrauterine contraception and toclassifications across these methods. See the full appendix for each method for clarifications to the numeric categories, as well as for summaries of the evidence and addit

BOX. Categories for classifying hormonal contraceptives and IUDs

1 = A condition for which there is no restriction for the use of the contraceptive method.

2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks.

3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method.

4 = A condition that represents an unacceptable health risk if the contraceptive method is used.

Condition COC/P/R POP DMPA Implants LNG-IUD

Personal characteristics and reproductive history

Pregnancy Not applicable* Not applicable* Not applicable* Not applicable* 4*

Age Menarche to <40 years = 1

Menarche to <18 years = 1




≥40 years = 2 18 to 45 years = 1 18 to 45 years = 1 18 to 45 years = 1 ≥20 years = 1

>45 years = 1 >45 years = 2 >45 years = 1

Parity

a. Nulliparous 1 1 1 1 2

b. Parous 1 1 1 1 1

Postpartum (nonbreastfeeding women)

a. <21 days 4 1 1 1

b. 21 to 42 days

i. With other risk factors for VTE (such as age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, BMI ≥30, postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)

3 1 1 1

ii. Without other risk factors for VTE

2 1 1 1

c. >42 days 1 1 1 1

Postpartum (breastfeeding women )

a. <21 days 4 2 2 2

b. 21 to <30 days

i. With other risk factors for VTE (such as age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, BMI ≥30 kg/m , postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)

3 2 2 2


3 2 2 2

c. 30 to 42 days

i. With other risk factors for VTE (such as age ≥35 years, previous VTE, thrombophilia, immobility, transfusion at delivery, BMI ≥30, postpartum hemorrhage, postcesarean delivery, preeclampsia, or smoking)

3 1 1 1


2 1 1 1

d. >42 days 2 1 1 1

Postpartum (breastfeeding or nonbreastfeeding women, including postcesarean delivery)

Δ

◊

2

Δ

Δ



a. <10 min after delivery of the placenta

2

b. 10 min after delivery of the placenta to <4 weeks

2

c. ≥4 weeks 1

d. Puerperal sepsis 4

Postabortion

a. First trimester 1* 1* 1* 1* 1*

b. Second trimester 1* 1* 1* 1* 2

c. Immediate postseptic abortion

1* 1* 1* 1* 4

Past ectopic pregnancy 1 2 1 1 1

History of pelvic surgery (see Postpartum, breastfeeding or nonbreastfeeding women, including postcesarean delivery)

1 1 1 1 1

Smoking

a. Age <35 years 2 1 1 1 1

b. Age ≥35 years

i. <15 Cigarettes/day 3 1 1 1 1

ii. ≥15 Cigarettes/day 4 1 1 1 1

Obesity

a. ≥30 kg/m BMI 2 1 1 1 1

b. Menarche to <18 years and ≥30 kg/m BMI

2 1 2 1 1

History of bariatric surgery

a. Restrictive procedures: decrease storage capacity of the stomach (vertical banded gastroplasty, laparoscopic adjustable gastric band, laparoscopic sleeve gastrectomy)

1 1 1 1 1

b. Malabsorptive procedures: decrease absorption of nutrients and calories by shortening the functional length of the small intestine (Roux-en-Y gastric bypass, biliopancreatic diversion)

COCs: 3

P/R: 1

3 1 1 1

Cardiovascular disease

Multiple risk factors for arterial cardiovascular disease (such as older age, smoking, diabetes, and hypertension)

3/4* 2* 3* 2* 2

Hypertension

a. Adequately controlled hypertension

3* 1* 2* 1* 1

b. Elevated blood pressure levels (properly taken measurements)

i. Systolic 140 to 159 mmHg or diastolic 90 to 99 mmHg

3 1 2 1 1

ii. Systolic ≥160 mmHg or diastolic ≥100 mmHg

4 2 3 2 2

c. Vascular disease 4 2 3 2 2

History of high blood pressure during pregnancy (where current blood pressure is measurable and normal)

2 1 1 1 1

Deep venous thrombosis (DVT)/pulmonary embolism (PE)

a. History of DVT/PE, not on anticoagulant therapy

i. Higher risk for recurrent DVT/PE (≥1 risk factors)

4 2 2 2 2

2

2

§

§



History of estrogen-associated DVT/PE

Pregnancy-associated DVT/PE

Idiopathic DVT/PE Known

thrombophilia, including antiphospholipid syndrome

Active cancer (metastatic, on therapy, or within six months after clinical remission), excluding non-melanoma skin cancer

History of recurrent DVT/PE

ii. Lower risk for recurrent DVT/PE (no risk factors)

3 2 2 2 2

b. Acute DVT/PE 4 2 2 2 2

c. DVT/PE and established on anticoagulant therapy for at least three months

i. Higher risk for recurrent DVT/PE (≥1 risk factors)

Known thrombophilia, including antiphospholipid syndrome

Active cancer (metastatic, on therapy, or within six months after clinical remission), excluding non-melanoma skin cancer

History of recurrent DVT/PE

4* 2 2 2 2

ii. Lower risk for recurrent DVT/PE (no risk factors)

3* 2 2 2 2

d. Family history (first-degree relatives)

2 1 1 1 1

e. Major surgery

i. With prolonged immobilization

4 2 2 2 2

ii. Without prolonged immobilization

2 1 1 1 1

f. Minor surgery without immobilization

1 1 1 1 1

Known thrombogenic mutations (eg, factor V Leiden; prothrombin mutation; protein S, protein C, and antithrombin deficiencies)

4* 2* 2* 2* 2*

Superficial venous thrombosis

a. Varicose veins 1 1 1 1 1

b. Superficial thrombophlebitis

2 1 1 1 1

Current and history of ischemic heart disease

Initiation Continuation Initiation Continuation Initiation Continuation

4 2 3 3 2 3 2 3

Stroke (history of cerebrovascular accident)

Initiation Continuation Initiation Continuation

4 2 3 3 2 3 2

Known hyperlipidemias 2/3* 2* 2* 2* 2*

Valvular heart disease

a. Uncomplicated 2 1 1 1 1

b. Complicated (pulmonary hypertension, risk for atrial fibrillation,

4 1 1 1 1

§

§

§

§



history of subacute bacterial endocarditis)

Peripartum cardiomyopathy

a. Normal or mildly impaired cardiac function (New York Heart Association Functional Class I or II: patients with no limitation of activities or patients with slight, mildactivity)

i. <6 months 4 1 1 1 2

ii. ≥6 months 3 1 1 1 2

b. Moderately or severely impaired cardiac function (New York Heart Association Functional Class III or IV: patients with marked limitation of activity or patients who should be at complete rest)

4 2 2 2 2

Rheumatic diseases

Systemic lupus erythematosus

Initiation Continuation Init

a. Positive (or unknown) antiphospholipid antibodies

4 3 3 3 3 3

b. Severe thrombocytopenia

2 2 3 2 2 2* 3

c. Immunosuppressive treatment

2 2 2 2 2 2

d. None of the above 2 2 2 2 2 2

Rheumatoid arthritis Initiation Continuation Init

a. On immunosuppressive therapy

2 1 2/3* 1 2 1

b. Not on immunosuppressive therapy

2 1 2 1 1

Neurologic conditions

Headaches Initiation Continuation Initiation Continuation Initiation Continuation Initiation Continuation Initiation Continuation

a. Non-migrainous (mild or severe)

1* 2* 1* 1* 1* 1* 1* 1* 1* 1*

b. Migraine

i. Without aura

- Age <35 years 2* 3* 1* 2* 2* 2* 2* 2* 2* 2*

- Age ≥35 years 3* 4* 1* 2* 2* 2* 2* 2* 2* 2*

ii. With aura (at any age)

4* 4* 2* 3* 2* 3* 2* 3* 2* 3*

Epilepsy 1* 1* 1* 1* 1

If on treatment, see Drug interactions section below

Depressive disorders

Depressive disorders 1* 1* 1* 1* 1*

Reproductive tract infections and disorders

Vaginal bleeding patterns Initiation Continuation

a. Irregular pattern without heavy bleeding

1 2 2 2 1 1

b. Heavy or prolonged bleeding (includes regular and irregular patterns)

1* 2* 2* 2* 1* 2*

Unexplained vaginal bleeding (suspicious for serious condition)


Before evaluation 2* 2* 3* 3* 4* 2* 4

Endometriosis 1 1 1 1 1

Benign ovarian tumors (including cysts)

1 1 1 1 1

Severe dysmenorrhea 1 1 1 1 1

Gestational trophoblastic disease

a. Decreasing or undetectable beta-hCG levels

1 1 1 1 3

b. Persistently elevated beta-hCG levels or malignant disease

1 1 1 1 4

Cervical ectropion 1 1 1 1 1

§

§

§

§



Cervical intraepithelial neoplasia

2 1 2 2 2

Cervical cancer (awaiting treatment)


2 1 2 2 4 2

Breast disease

a. Undiagnosed mass 2* 2* 2* 2* 2

b. Benign breast disease 1 1 1 1 1

c. Family history of cancer

1 1 1 1 1

d. Breast cancer

i. Current 4 4 4 4 4

ii. Past and no evidence of current disease for five years

3 3 3 3 3

Endometrial hyperplasia 1 1 1 1 1

Endometrial cancer Initiation Continuation Init

1 1 1 1 4 2

Ovarian cancer 1 1 1 1 1

Uterine fibroids 1 1 1 1 2

Anatomical abnormalities

a. Distorted uterine cavity (any congenital or acquired uterine abnormality distorting the uterine cavity in a manner that is incompatible with IUD insertion)

4

b. Other abnormalities (including cervical stenosis or cervical lacerations) not distorting the uterine cavity or interfering with IUD insertion

2

Pelvic inflammatory disease (PID)

a. Past PID (assuming no current risk factors of STIs)


i. With subsequent pregnancy

1 1 1 1 1 1

ii. Without subsequent pregnancy

1 1 1 1 2 2

b. Current PID 1 1 1 1 4 2*

STIs Initiation Continuation Init

a. Current purulent cervicitis or chlamydial infection or gonorrhea

1 1 1 1 4 2*

b. Other STIs (excluding HIV and hepatitis)

1 1 1 1 2 2

c. Vaginitis (including Trichomonas vaginalis and bacterial vaginosis)

1 1 1 1 2 2

d. Increased risk for STIs 1 1 1 1 2/3* 2 2/

HIV/AIDS


High risk for HIV 1 1 1 1 2 2

HIV infection 1 1 1 1 2 2

AIDS 1 1 1 1 3 2

NOTE: If on treatment, drug interactions might exist between hormonal contraceptives, including LNG-IUD, and antiretroviral drugs; refer to the section on drug interactions below as there may be limitations to use of the method.

2 2

Other infections

Schistosomiasis

a. Uncomplicated 1 1 1 1 1

b. Fibrosis of the liver (if severe, see Cirrhosis)

1 1 1 1 1

Tuberculosis Initiation Continuation Init

a. Nonpelvic 1* 1* 1* 1* 1 1

§

§

§

￥

§

§

§

§



b. Pelvic 1* 1* 1* 1* 4 3

If on treatment, see Drug interactions section below

Malaria 1 1 1 1 1

Endocrine conditions

Diabetes

a. History of gestational disease

1 1 1 1 1

b. Nonvascular disease

i. Noninsulin-dependent

2 2 2 2 2

ii. Insulin-dependent 2 2 2 2 2

c. Nephropathy/retinopathy/ neuropathy

3/4* 2 3 2 2

d. Other vascular disease or diabetes of >20 years' duration

3/4* 2 3 2 2

Thyroid disorders

a. Simple goiter 1 1 1 1 1

b. Hyperthyroid 1 1 1 1 1

c. Hypothyroid 1 1 1 1 1

Gastrointestinal conditions

Inflammatory bowel disease (IBD) (ulcerative colitis, Crohn disease)

2/3* 2 2 1 1

Gallbladder disease

a. Symptomatic

i. Treated by cholecystectomy

2 2 2 2 2

ii. Medically treated 3 2 2 2 2

iii. Current 3 2 2 2 2

b. Asymptomatic 2 2 2 2 2

History of cholestasis

a. Pregnancy-related 2 1 1 1 1

b. Past COC-related 3 2 2 2 2

Viral hepatitis Initiation Continuation

a. Acute or flare 3/4* 2 1 1 1 1

b. Carrier 1 1 1 1 1 1

c. Chronic 1 1 1 1 1 1

Cirrhosis

a. Mild (compensated) 1 1 1 1 1

b. Severe (decompensated)

4 3 3 3 3

Liver tumors

a. Benign

i. Focal nodular hyperplasia

2 2 2 2 2

ii. Hepatocellular adenoma

4 3 3 3 3

b. Malignant (hepatoma) 4 3 3 3 3

Anemias

Thalassemia 1 1 1 1 1

Sickle cell disease 2 1 1 1 1

Iron-deficiency anemia 1 1 1 1 1

Solid organ transplantation

Solid organ transplantation


a. Complicated: graft failure (acute or chronic), rejection, cardiac allograft vasculopathy

4 2 2 2 3 2

b. Uncomplicated 2* 2 2 2 2

Drug interactions

Antiretroviral therapy Initiation Continuation Init

a. Nucleoside reverse 1* 1 1 1 2/3* 2* 2/

§

§

§

§

§

§

§

§



COC: combined oral contraceptive; P: combined hormonal contraceptive patch; R: combined hormonal vaginal ring; POP: progestin-only pill; DMPA: depot medroxyprogesterone acetate; IUD: intrauterine device; LNG-IUD: levonorgestrel-releasing IUD; Cu-IUD: copper IUD; BMI: body mass index (weight [kg]/height [m ]); DVT: deep venous thrombosis; VTE: venous thromboembolism; CHC: combined hormonal contraceptive; PE: pulmonary embolism; hCG: human chorionic gonadotropin; PID: pelvic inflammatory disease; STI: sexually transmitted infection; HIV: human immunodeficiency virus; AIDS: acquired immunodeficiency syndrome; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase. * Consult the appendix for this contraceptive method for a clarification to this classification. Initiation refers to a condition already present when the contraceptive is begun. Continuation refers to a condition that develops after initiation of the method. Δ Clarification: For women with other risk factors for VTE, these risk factors might increase the classification to a "4"; for example, smoking, deep venous thrombosis/pulmonary embolism, known thrombogenic mutations, and peripartum cardiomyopathy. ◊ The breastfeeding recommendations are divided by month in US Medical Eligibility Criteria for Contraceptive Use, 2010. They have been divided by days for purposes of integration with the postpartum recommendations. § Condition that exposes a woman to increased risk as a result of unintended pregnancy. ￥ Some studies suggest that women using progestin-only injectable contraception might be at increased risk for HIV acquisition; other studies do not show this association. CDC reviewed all available evidence and agreed that the data were not sufficiently conclusive to change current guidance. However, because of the inconclusive nature of the body of evidence on possible increased risk for HIV acquisition, women using progestin-only injectable contraception should be strongly advised to also always use condoms (male or female) and take other HIV preventive measures.

References:

Reproduced with permission from: US Medical Eligibility Criteria for Contraceptive Use 2010, with data adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th edition.


transcriptase inhibitors (NRTIs)

b. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

2* 2* 1 2* 2/3* 2* 2/

c. Ritonavir-boosted protease inhibitors

3* 3* 1 2* 2/3* 2* 2/

Anticonvulsant therapy

a. Certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine)

3* 3* 1 2* 1

b. Lamotrigine 3* 1 1 1 1

Antimicrobial therapy

a. Broad-spectrum antibiotics

1 1 1 1 1

b. Antifungals 1 1 1 1 1

c. Antiparasitics 1 1 1 1 1

d. Rifampicin or rifabutin therapy

3* 3* 1 2* 1

1. Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Revised Recommendations for the Use of Contraceptive Methods During the Postpartum Period. MMWR Morb Mortal Wkly Rep 2011; 60:878.

2. Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Revised Recommendations for the Use of Hormonal Contraception Among Women at High Risk for HIV Infection or Infected with HIV. MMWR Morb Mortal Wkly Rep 2012; 61:449.

2



PHQ-9 depression questionnaire

Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke and colleagues, with an educational grant from Pfizer Inc. No permission required to reproduce, translate, display or distribute.


Name: Date:

Over the last two weeks, how often have you been bothered by any of the following problems?

Not at all Several days

More than half the days

Nearly every day

Little interest or pleasure in doing things 0 1 2 3

Feeling down, depressed, or hopeless 0 1 2 3

Trouble falling or staying asleep, or sleeping too much 0 1 2 3

Feeling tired or having little energy 0 1 2 3

Poor appetite or overeating 0 1 2 3

Feeling bad about yourself, or that you are a failure, or have let yourself or your family down

0 1 2 3

Trouble concentrating on things, such as reading the newspaper or watching television 0 1 2 3

Moving or speaking so slowly that other people could have noticed? Or the opposite, being so fidgety or restless that you have been moving around a lot more than usual.

0 1 2 3

Thoughts that you would be better off dead or of hurting yourself in some way 0 1 2 3

Total ___ = ___ + ___ + ___ + ___

PHQ-9 Score ≥10: Likely major depression.

Depression score ranges:

5 to 9: mild

10 to 14: moderate

15 to 19: moderately severe

≥20: severe

If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people? Not difficult

at all

___

Somewhat difficult

___

Very difficult

___

Extremely difficult

___



Disclosures

Disclosures: Steven C Schachter, MD Nothing to disclose. Timothy A Pedley, MD Other Financial Interest: American Academy of Neurology (President). April F Eichler, MD, MPH Equity Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)]. Employment: Employee of UpToDate, Inc. 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. Conflict of interest policy



Documents

Overview of the management of epilepsy in adults.pdf