Overview of The Management of Epilepsy in Adults PDF

Overview of the management of epilepsy in adults
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Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
Author
Steven C Schachter, MD
Section Editor
Timothy A Pedley, MD
Deputy Editor
April F Eichler, MD, MPH
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".)
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.
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:
Drug effectiveness for the seizure type or types (table 2)
Potential adverse effects of the drug (table 3 and table 4)
Interactions with other medications
Comorbid medical conditions, especially but not limited to hepatic and renal disease
Age and gender, including childbearing plans
Lifestyle and patient preferences
Cost
In 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.
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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:
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]
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:
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".)
Maximizing the likelihood of a successful outcome
Titration and monitoring Some general principles to consider when starting an AED include [44-46]:
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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].
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]:
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
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:
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]
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 wellcontrolled 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
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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.
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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 assaultrelated 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].
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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 studys 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:
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".)
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.
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
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
Page 7 of 32
case.
own
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:
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.
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]:
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)
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:
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.
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 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient 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)")
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.
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".)
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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.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 2220 Version 27.0
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GRAPHICS
International classification of epileptic seizures
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
Adapted from: Commission on Classification and Terminology of the International League against Epilepsy, Epilepsia 1981; 22:489.
Graphic 53661 Version 4.0
Page 13 of 32
Antiepileptic medications and seizure types

Seizure type
Antiepileptic drug
Broad spectrum: all seizure types (generalized from onset and focal onset
Clobazam, felbamate, lamotrigine, levetiracetam, rufinamide, topiramate,
seizures)
valproate, zonisamide
Narrow spectrum: focal with or without alteration in consciousness or
Carbamazepine, eslicarbazepine, ezogabine, gabapentin, lacosamide,
awareness and focal evolving to bilateral convulsive seizure
oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone,

tiagabine, vigabatrin
Absence seizure (a type of generalized seizure)
Ethosuximide
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.
Page 14 of 32
Common side effects of antiepileptic drugs

Drug
Systemic side effects
Carbamazepine
Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus
Clobazam
Increased salivation, nausea, vomiting, constipation
Eslicarbazepine
Nausea, vomiting, diarrhea, fatigue, rash
Neurotoxic side effects

Drowsiness, dizziness, blurred or double vision, lethargy,
headache
Somnolence, aggression, irritability, ataxia, insomnia
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
Dizziness, somnolence, confusion, vertigo, blurred or double
hesitancy, weight gain
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
Page 15 of 32
Rare but serious side effects of AEDs*

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,
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
neuropathy, ataxia, lupus-syndrome, hirsuitism
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.
Page 16 of 32
Pharmacologic properties of antiepileptic drugs
Carbamazepine
Metabolism and
Enzyme
Protein binding,
Half life in adults
clearance
induction/inhibition
percent*
(hours)
>90 percent metabolized by

CYP3A4 (major) and 1A2/2C8
(minor) to active (epoxide)
and inactive metabolites
Potent and broad spectrum
75
inducer of CYP, UGT-
25-65 (initial use, enzyme

inducing naive patient)
glucuronidation, and P-gp
8-22 (after several weeks due

to auto-induction)
Dose adjustment is needed in

severe renal impairment; use
is not recommended in
moderate or severe hepatic
impairment
Clobazam
Inhibits CYP2D6 (moderate)
CYPs 3A4, 2C19, 2B6 and non-
and UGT-glucuronidation
CYP transformations to active

(N-desmethylclobazam) and
Induces CYP3A4 (weak to
inactive metabolites
85
36-43 (parent drug)

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

hepatic impairment
Eslicarbazepine
Prodrug; <33 percent of active

form undergoes UGT
glucuronidation (including <5
percent metabolized to
oxcarbazepine); 66 percent is
excreted renally as unchanged
drug
Induces CYP3A4 and UGT1A1

glucuronidation (weak) but
does not induce its own
metabolism
<40
13 to 20 hours (prolonged in
renal insufficiency)
<5
40-60
Inhibits CYP2C19 (moderate)
Dose adjustment is needed for

renal impairment; not
recommended in patients with
severe hepatic impairment
Ethosuximide
Ezogabine
(retigabine)
~80 percent metabolized by

CYP3A4 (major) and non-CYP
transformations to inactive
metabolites
~60 percent metabolized by
non-CYP transformations
(UGT-glucuronidation, Nacetylation) to active (NAMR)
and inactive metabolites
None
NAMR seems to inhibit P-gp
80 (parent drug)
45 (NAMR)
7-11 (prolonged in renal

insufficiency and in older
adults)

moderate or severe hepatic or
renal impairment
Felbamate
50 percent metabolized by
CYP3A4 and 2E1 (minor); ~50
percent renally excreted as
unchanged drug
25

insufficiency)
None
<5

insufficiency; >130 hours in
anuria)
Inhibits 2C19 (minor)
<15
13
May induce its own metabolism

by UGT-glucuronidation
(minor)
55
12-62
None
<10
6-8
Induces CYP3A4 (moderate)

Inhibits CYP2C19 (minor)

renal impairment
Gabapentin
>95 percent renally excreted

as unchanged drug (ie, does
not undergo hepatic
metabolism)
renal impairment
Lacosamide
40 percent renally excreted as

unchanged drug; 30 percent
metabolized by non-CYP
transformations (including
methylation) to inactive
metabolite
hepatic and renal impairment
Lamotrigine

UGT glucuronidation and other
non-CYP transformations to
inactive metabolites
moderate to severe renal or
hepatic impairment
Levetiracetam
>65 renally excreted as

unchanged drug; 24 percent
metabolized by non-CYP
transformation (including
Page 17 of 32
amidase hydrolysis) to inactive

metabolites
renal impairment
Oxcarbazepine
Prodrug; 70 percent of active

(MHD) form undergoes UGT
glucuronidation; 30 percent is
renally excreted as unchanged
Induces CYP3A4 (moderate to
40
9 (active metabolite,
severe) and UGT-
prolonged in renal
glucuronidation but does not

induce its own metabolism
insufficiency)
active drug
severe renal impairment
Perampanel

CYPs 3A4, 3A5 and non-CYP
metabolites
Appears to induce metabolism
95
105
55
75-110

inducer of CYP and UGTglucuronidation
90-95
9- >42 (dose dependent)
None
<5

inducer of CYP
0-20
of progestin-containing
hormonal contraceptives

mild or moderate hepatic
impairment
Phenobarbital
CYPs 2C19, 2C9 (minor) and
glucosidase hydrolysis and 2E1
(minor) to inactive
metabolites; 25 percent
drug

inducer of CYP and UGTglucuronidation

severe renal or hepatic
impairment
Phenytoin

CYPs 2C9, 2C19 and 3A4
(minor) and non-CYP
metabolites; clearance is dose
dependent, saturable, and may
be subject to genetic
polymorphism
severe renal or hepatic
insufficiency; monitoring of
free (unbound) concentrations
also suggested
Pregabalin
>95 excreted renally as

unchanged drug
renal impairment
Primidone
CYPs 2C19, 2C9 (minor) and
2E1 (minor) to active
intermediates; ~25 percent
drug
10-15 (parent)
29-100 (active metabolite)

moderate and severe renal or
hepatic impairment; close
monitoring of plasma levels
suggested
Rufinamide
Tiagabine
Topiramate

(hydrolysis) to inactive
metabolites
Induces CYP3A4 (minor)
35
6-10
Inhibits CYP2E1 (minor)

CYP3A4 and non-CYP
metabolites
None
>65 percent excreted renally

as unchanged drug; <30
percent metabolized by nonCYP transformations to inactive
metabolites; extent of
metabolism is increased ~50
percent in patients receiving
enzyme inducing AEDs
Inhibits CYP2C19 (minor)
95
7-9
2-5 (with enzyme-inducing
AEDs)
9-17
12-24
80-95
7-16
Induces CYP3A4 (minor)

moderate and severe renal or
hepatic impairment
Valproate
>95 percent undergoes
Moderate broad spectrum
complex transformations
inhibitor including CYP2A6,
including CYPs 2C9, 2C19,
2B6, 2C9, 2C19, 2E1 and UGT-
2A6, UGT-glucuronidation and

other non-CYP transformation
glucuronidation
CYP2A6
Page 18 of 32
Minor or moderate inducer of
hepatic impairment
Vigabatrin
>90 percent excreted renally
Induces CYP2C9
5-13 (unrelated to duration of

action)
as unchanged drug
renal impairment
Zonisamide
None
50
63
CYPs 3A4, 2C19 (minor) and

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
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:
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.
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.
Page 19 of 32
Common mechanisms of antiepileptic drug action

Drug
Na+ channels
Ca+ channels
K+ channels
Benzodiazepines
Carbamazepine
Inhibitory transmission
+++
+++
Clobazam
+++
Ethosuximide
+++
Ezogabine
++
Felbamate
++
++
Gabapentin
++
Lacosamide
+++
Lamotrigine
+++
Levetiracetam
Oxcarbazepine
Excitatory transmission
+++
++
+
+
Perampanel
+++
Phenobarbital
Phenytoin
+++
Rufinamide
+++
+++
Tiagabine
+++
Topiramate
++
++
++
++
Valproate
++
Vigabatrin
Zonisamide
+++
++
++
+++: 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.
Page 20 of 32
Some interactions between carbamazepine and other antiepileptic drugs*

Interacting drugs
Effects (probable mechanism)
Management
Carbamazepine, with:
Clonazepam
Eslicarbazepine
Decreased clonazepam effect (increased metabolism)

Increased risk of diplopia, abnormal coordination, and
dizziness (pharmacodynamic interaction)
Monitor clinical status

Monitor clinical status; eslicarbazepine or carbamazepine
dosage may need to be adjusted
Decreased plasma concentration of eslicarbazepine

(increased metabolism)
Lamotrigine
Carbamazepine toxicity (mechanism not established)
Monitor clinical status; serum carbamazepine measurements

alone may not predict toxicity
Levetiracetam
Decreased lamotrigine effect (increased metabolism;
Lamotrigine dosage may need to be adjusted; monitor
glucuronidation)
lamotrigine concentration and clinical status
Possible increased risk of carbamazepine toxicity (mechanism
Monitor for clinical evidence of carbamazepine toxicity
not established)
Oxcarbazepine
Possible decreased oxcarbazepine effect (increased
Monitor oxcarbazepine concentrations and clinical status
metabolism)
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)
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
Decreased zonisamide effect (increased metabolism by

CYP3A4)
Monitor zonisamide concentrations and clinical status;

zonisamide dosage may need to be adjusted
Zonisamide
* 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.
Page 21 of 32
Some interactions between phenytoin and other antiepileptic drugs*

Interacting drugs
Management
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
Monitor phenytoin concentrations
established)
Eslicarbazepine
Decreased eslicarbazepine concentrations (increased

metabolism)
Possible phenytoin toxicity (decreased metabolism by
Eslicarbazepine dose may need to be increased

Monitor phenytoin concentrations and clinical status
CYP2C19)
Lamotrigine
Oxcarbazepine
Decreased lamotrigine serum concentrations (increased
Monitor lamotrigine serum concentrations and clinical status;
metabolism; induction of glucuronidation by phenytoin)
lamotrigine dosage may need to be adjusted
Possible decreased oxcarbazepine effect (increased
Monitor clinical status and serum concentration
metabolism)
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)
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)
Possible phenytoin toxicity (displacement from binding)

(unbound concentrations may be more helpful than total)
Possible decreased valproate effect and increased toxicity

Monitor clinical status and valproate serum concentrations
Decreased zonisamide effect (increased metabolism by

CYP3A4)
Monitor zonisamide concentrations and clinical status;

zonisamide dosage may need to be adjusted
Valproate
Zonisamide
Adapted with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright 2008 The Medical Letter.
Page 22 of 32
Some interactions between valproate and other antiepileptic drugs*

Interacting drugs
Management
Valproate, with:
Carbamazepine
Decreased valproate effect and possible increased toxicity
Monitor valproate concentrations and clinical status
Clonazepam
Carbamazepine toxicity (decreased metabolism of
Monitor carbamazepine and carbamazepine epoxide
carbamazepine epoxide and displacement from binding)
concentrations
Clonazepam may precipitate absence status (mechanism not
established)
Ethosuximide
Possible ethosuximide toxicity (decreased metabolism)
Monitor ethosuximide concentration
Possible decreased valproate effect (mechanism not
Monitor valproate concentration
established)
Lamotrigine
Oxcarbazepine
Possible lamotrigine toxicity (decreased metabolism;
Decrease lamotrigine dose; monitor lamotrigine
glucuronidation)
concentrations and clinical status
Possible decreased oxcabazepine concentration (increased
Monitor oxcarbazepine concentrations and clinical status
metabolism)
Phenytoin
Topiramate
Phenytoin toxicity (displacement from binding and decreased
metabolism)
(unbound concentrations may be more helpful than total)
Possible decreased valproate effect and increased toxicity

Monitor clinical status and valproate serum concentrations
Possible increased hepatotoxic effect of valproate

(mechanism not established)
Reproduced with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright 2008 The Medical Letter.
Page 23 of 32
General guidelines to improve patient adherence to antihypertensive therapy

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
* 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:
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.
Page 24 of 32
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 to
classifications 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
Not applicable*
Not applicable*
Not applicable*
Not applicable*
4*
Menarche to
Menarche to
Menarche to
Menarche to
Menarche to
Personal characteristics and reproductive history

Pregnancy
Age
<40 years = 1
<18 years = 1
<18 years = 2
<18 years = 1
<20 years = 2
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
b. Parous
Postpartum (nonbreastfeeding women)

a. <21 days
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)
ii. Without other risk
factors for VTE
c. >42 days
Postpartum (breastfeeding women )
a. <21 days
b. 21 to <30 days
i. With other risk
as age 35 years,
previous VTE,
thrombophilia,
at delivery, BMI 30
kg/m 2, postpartum
hemorrhage,
preeclampsia, or
smoking)
factors for VTE
c. 30 to 42 days
i. With other risk
as age 35 years,
previous VTE,
thrombophilia,
at delivery, BMI 30,
postpartum
hemorrhage,
preeclampsia, or
smoking)
factors for VTE
d. >42 days
Postpartum (breastfeeding or nonbreastfeeding women, including postcesarean delivery)
Page 25 of 32
a. <10 min after delivery
of the placenta
b. 10 min after delivery
of the placenta to <4

weeks
c. 4 weeks
d. Puerperal sepsis
Postabortion
a. First trimester
1*
1*
1*
1*
1*
b. Second trimester
1*
1*
1*
1*
c. Immediate postseptic
1*
1*
1*
1*
Past ectopic pregnancy
History of pelvic surgery
i. <15 Cigarettes/day
ii. 15 Cigarettes/day
a. 30 kg/m 2 BMI
b. Menarche to <18 years

and 30 kg/m 2 BMI
3/4*
2*
3*
2*
3*
1*
2*
1*
abortion
(see Postpartum,
breastfeeding or
nonbreastfeeding women,
including postcesarean
delivery)
Smoking
a. Age <35 years
b. Age 35 years
Obesity
History of bariatric surgery

a. Restrictive procedures:
decrease storage capacity
of the stomach (vertical
banded gastroplasty,
laparoscopic adjustable
gastric band, laparoscopic
sleeve gastrectomy)
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
Cardiovascular disease
Multiple risk factors for
arterial cardiovascular
disease (such as older age,
smoking, diabetes, and
hypertension)
Hypertension
a. Adequately controlled
hypertension
b. Elevated blood pressure levels (properly taken measurements)

i. Systolic 140 to 159
mmHg or diastolic 90
to 99 mmHg
ii. Systolic 160

mmHg or diastolic
100 mmHg
c. Vascular disease
History of high blood
pressure during
pregnancy (where current
blood pressure is
measurable and normal)
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)
Page 26 of 32
History of estrogenassociated DVT/PE
Pregnancyassociated DVT/PE
Idiopathic DVT/PE
Known
thrombophilia,
including
antiphospholipid
syndrome
Active cancer
(metastatic, on
therapy, or
within six months
after clinical
remission),
excluding nonmelanoma skin
cancer
History of recurrent
DVT/PE
ii. Lower risk for
recurrent DVT/PE (no

risk factors)
b. Acute DVT/PE
c. DVT/PE and established on anticoagulant therapy for at least three months

4*
3*
i. With prolonged
immobilization
ii. Without prolonged

immobilization
f. Minor surgery without

immobilization
4*
2*
2*
2*
2*
a. Varicose veins
b. Superficial
thrombophlebitis
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 nonmelanoma skin
cancer
History of recurrent
DVT/PE
ii. Lower risk for

recurrent DVT/PE (no
risk factors)
d. Family history (firstdegree relatives)
e. Major surgery
Known thrombogenic
mutations (eg, factor V
Leiden; prothrombin
mutation; protein S, protein
C, and antithrombin
deficiencies)
Superficial venous thrombosis
Current and history of

ischemic heart disease
Stroke (history of
cerebrovascular accident)
Known hyperlipidemias
Initiation
4
Continuation
Initiation
Continuation
Initiation
3
Continuation
Initiation
Continuation
Initiation
Continuation
2/3*
2*
2*
2*
2*
a. Uncomplicated
b. Complicated
(pulmonary hypertension,
risk for atrial fibrillation,
Valvular heart disease
Page 27 of 32
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, mild
activity)
i. <6 months
ii. 6 months
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)
Rheumatic diseases
Systemic lupus
Initiation
Continuation
Init
erythematosus
a. Positive (or unknown)
antiphospholipid
antibodies
b. Severe
thrombocytopenia
2*
c. Immunosuppressive
treatment
d. None of the above
a. On immunosuppressive
therapy
2/3*
b. Not on
immunosuppressive
therapy
Rheumatoid arthritis
Initiation
Continuation
Init
Neurologic conditions
Headaches
Initiation
Continuation
Initiation
Continuation
Initiation
Continuation
Initiation
Continuation
Initiation
Continuation
1*
2*
1*
1*
1*
1*
1*
1*
1*
1*
- 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*
a. Non-migrainous (mild
or severe)
b. Migraine
i. Without aura
Epilepsy
1*
1*
1*
1*
1*
1*
1*
1*
Initiation
Continuation
1*
2*
2*
2*
1*
2*
Initiation
Continuation
If on treatment, see Drug interactions section below

Depressive disorders
Depressive disorders
1*
Reproductive tract infections and disorders

Vaginal bleeding patterns
a. Irregular pattern
without heavy bleeding
b. Heavy or prolonged
bleeding (includes regular
and irregular patterns)
Unexplained vaginal
bleeding (suspicious for
serious condition)
2*
2*
3*
3*
Endometriosis
Before evaluation
4*
1
2*
Benign ovarian tumors

(including cysts)
Severe dysmenorrhea
a. Decreasing or
undetectable beta-hCG
levels
b. Persistently elevated
beta-hCG levels or
malignant disease
Init
Gestational trophoblastic disease
Cervical ectropion
Cervical intraepithelial
Page 28 of 32
neoplasia
Cervical cancer (awaiting
treatment)
Initiation
Continuation
Init
Breast disease
a. Undiagnosed mass
2*
2*
2*
2*
b. Benign breast disease
c. Family history of
i. Current
ii. Past and no
cancer
d. Breast cancer
evidence of current
disease for five years
Endometrial hyperplasia
Endometrial cancer
1
Initiation
Continuation
Ovarian cancer
Uterine fibroids
Init
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)
b. Other abnormalities
(including cervical
stenosis or cervical
lacerations) not distorting
the uterine cavity or
interfering with IUD
insertion
Pelvic inflammatory disease (PID)

a. Past PID (assuming no
current risk factors of
STIs)
Initiation
Continuation
i. With subsequent
pregnancy
ii. Without subsequent

pregnancy
b. Current PID
STIs
2*
Initiation
Continuation
a. Current purulent
cervicitis or chlamydial
infection or gonorrhea
2*
b. Other STIs (excluding

HIV and hepatitis)
c. Vaginitis (including
2/3*
Initiation
Continuation
High risk for HIV
HIV infection
AIDS
Init
Init
Trichomonas vaginalis
and bacterial vaginosis)
d. Increased risk for STIs
2/
HIV/AIDS
NOTE: If on treatment, drug interactions might exist between hormonal contraceptives, including LNGIUD, and antiretroviral drugs; refer to the section on drug interactions below as there may be
limitations to use of the method.
Init
Other infections
Schistosomiasis
a. Uncomplicated
b. Fibrosis of the liver (if

severe, see Cirrhosis)
1*
1*
1*
1*
Tuberculosis
a. Nonpelvic
Initiation
Continuation
Init
b. Pelvic
1*
Page 29 of 32
1*
1*
1*
If on treatment, see Drug interactions section below

Malaria
Endocrine conditions
Diabetes
a. History of gestational
disease
b. Nonvascular disease
i. Noninsulindependent
ii. Insulin-dependent
3/4*
3/4*
a. Simple goiter
b. Hyperthyroid
c. Hypothyroid
2/3*
i. Treated by
cholecystectomy
ii. Medically treated
iii. Current
b. Asymptomatic
a. Pregnancy-related
b. Past COC-related
c.
Nephropathy/retinopathy/
neuropathy
d. Other vascular disease
or diabetes of >20 years'
duration
Thyroid disorders
Gastrointestinal conditions
Inflammatory bowel
disease (IBD) (ulcerative
colitis, Crohn disease)
Gallbladder disease
a. Symptomatic
History of cholestasis
Viral hepatitis
a. Acute or flare
Initiation
Continuation
3/4*
b. Carrier
c. Chronic
Cirrhosis
a. Mild (compensated)
b. Severe
i. Focal nodular
hyperplasia
ii. Hepatocellular
adenoma
Thalassemia
Sickle cell disease
Iron-deficiency anemia
(decompensated)
Liver tumors
a. Benign
b. Malignant (hepatoma)
Anemias
Solid organ transplantation

Solid organ
transplantation
a. Complicated: graft
failure (acute or chronic),
rejection, cardiac
allograft vasculopathy
b. Uncomplicated
2*
1*
Initiation
Continuation
Init
Drug interactions
Antiretroviral therapy
a. Nucleoside reverse
Initiation
Continuation
2/3*
2*
Init
2/
Page 30 of 32
transcriptase inhibitors
(NRTIs)
b. Non-nucleoside
2*
2*
2*
2/3*
2*
2/
3*
3*
2*
2/3*
2*
2/
3*
3*
2*
3*
b. Antifungals
c. Antiparasitics
3*
3*
2*
reverse transcriptase
inhibitors (NNRTIs)
c. Ritonavir-boosted
protease inhibitors
Anticonvulsant therapy
a. Certain anticonvulsants
(phenytoin,
carbamazepine,
barbiturates, primidone,
topiramate,
oxcarbazepine)
b. Lamotrigine
Antimicrobial therapy
a. Broad-spectrum
antibiotics
d. Rifampicin or rifabutin
therapy
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 2]); 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.
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:
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.
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.
Page 31 of 32
PHQ-9 depression questionnaire

Name:
Date:
Over the last two weeks, how often have you been bothered by any of the following
Not at all
problems?
Several
More than
Nearly
days
half the
every day
days
Little interest or pleasure in doing things
Feeling down, depressed, or hopeless
Trouble falling or staying asleep, or sleeping too much
Feeling tired or having little energy
Poor appetite or overeating
Feeling bad about yourself, or that you are a failure, or have let yourself or your family
Trouble concentrating on things, such as reading the newspaper or watching television
Moving or speaking so slowly that other people could have noticed? Or the opposite, being
Thoughts that you would be better off dead or of hurting yourself in some way
Total ___ =
___
+ ___
+ ___
+ ___
Not difficult
at all
Somewhat
difficult
Very difficult
Extremely
difficult
___
___
down
so fidgety or restless that you have been moving around a lot more than usual.
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?
___
___
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.
Page 32 of 32
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

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