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Official reprint from UpToDate

www.uptodate.com 2014 UpToDate


Overview of the management of epilepsy in adults
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 (LexiInteract 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.
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

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AEDs administered as add-on therapy in patients with refractory partial epilepsy found that differences in efficacy were of too small magnitude to allow a conclusion about which AED is more effective as
adjunctive therapy [16]. In a randomized, double-blind 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]:
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

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treatment.
The physician should impress upon the patient, family, and patient's friends the critical need to follow the prescribed drug regimen. Nonadherence to AED treatment regimen is associated with increased
risk of mortality, as well as hospitalization and injury [48]. (See 'Complications of epilepsy' below.)
Written instructions on how and when to take the drugs should be provided and should explain the dosing regimen and any potential adverse effects (table 3 and table 4). The patient must also be
warned not to stop taking an AED and not to allow a prescription to run out or expire.
Patients should be urged not to start any other prescription, over-the-counter medications, dietary supplements, or herbal remedies without first contacting their physician because these might affect
serum concentrations of their AEDs [49,50]. (See "Initial treatment of epilepsy in adults", section on 'Drug interactions'.)
Seizure calendar Patients and family members should be asked to record seizures and AED doses on a calendar or diary, which can then be brought or sent to the physician for review. Seizure
triggers should be indicated. The patient and family should note on the calendar the hour at which any symptoms occur. Electronic seizure diaries are also available [51,52].
The seizure calendar helps to monitor and encourage compliance. The seizure calendar also may be used to track the patient's response to drug therapy, including possible side effects. Seizure
calendars can help identify seizure triggers. In one study of 71 patients completing daily seizure diaries, both lack of sleep and higher self-reported stress and anxiety were associated with seizure
occurrence [53]. Seizures were also associated with the patients' own prediction of the likelihood of seizure occurrence. Other reported seizure triggers include visual, olfactory, and auditory stimuli,
alcohol consumption, missed meals, and hormone fluctuations related to the menstrual cycle [54]. (See "Catamenial epilepsy".)
Physicians should be aware that patients are often unaware of their seizures and may significantly underestimate the number of seizures that occur, especially those that occur during sleep or that
disrupt consciousness [55]. Prolonged EEG recordings may be helpful in such patients, either ambulatory or in a video-EEG monitoring unit. (See "Video and ambulatory EEG monitoring in the diagnosis
of seizures and epilepsy".)
Generic substitution While definitive studies have not been performed, anecdotal reports, small case series, and patient surveys suggest that generic substitution of AEDs may be problematic
[56-59]. Using pharmacokinetic data submitted to the FDA, one group of investigators found that most generic AEDs provide total drug 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 well-controlled epilepsy [76]. Heavier
alcohol intake (three or more drinks per day) increases the risk of seizures, particularly during the withdrawal period (7 to 48 hours after the last drink), and this practice should be strongly discouraged
[77].
In an effort to enable people with epilepsy to live as normal a life as possible, it may be reasonable to advise that limited alcohol intake is acceptable, provided there is no history of alcohol or substance
abuse or a history of alcohol-related seizures. However, patients should be aware that the data are not definitive at this time. Driving or other high-risk activities should be avoided for 24 to 48 hours after
heavy alcohol intake due to the higher risk of seizures.
Nonadherence with AED therapy Up to 50 percent of patients with epilepsy may fail to take their medications as directed; over one-half of those evaluated in emergency departments for recurrent
seizures have been nonadherent [78]. Nonadherence to AED treatment regimen is not only associated with increased seizures, but also with increased risk of mortality, as well as hospitalization and
injury [48,79]. Clinicians should suspect nonadherence if a patient denies the diagnosis of epilepsy, has limited financial means to pay for AEDs, has difficulty tolerating side effects, or forgets when or
how to take medication because of memory impairment. An unexpected increase in the number or severity of seizures, or either subtherapeutic or supratherapeutic serum drug concentrations, also
suggests nonadherence. However, serum levels can 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

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contraceptives is increased to 3.1 per 100 woman-years in patients who concomitantly take AEDs that induce hepatic enzymes that increase the metabolism of oral contraceptives [94-97]. (See
"Overview of the use of estrogen-progestin contraceptives", section on 'Drug interactions'.)
Enzyme induction occurs with all older AEDs (including phenytoin, phenobarbital, carbamazepine, primidone) except valproate and ethosuximide. It also occurs, but to a lesser extent, with a few of the
second generation AEDs, such as felbamate, topiramate, perampanel and oxcarbazepine [98]. Enzyme-inducing AEDs are also associated with decreased estrogen and progesterone levels [96,99].
While vigabatrin is not an enzyme inducer, lower levels of ethinyl estradiol have been reported in volunteers taking this AED [100].
The World Health Organization (WHO) suggests that women taking enzyme-inducing AEDs, including lamotrigine, use a method of contraception other than hormonal pill, patch or ring contraceptives
[101]. Hormonal contraception may still be reasonable, however, if the patient understands the risks and cannot use other methods. The reported failure rate with oral contraceptives in women taking
AEDs may still be comparable with or better than other methods of contraception, such as barrier methods [102]. The United States Medical Eligibility Criteria (USMEC) for Contraceptive Use are
available online and in the table (table 9).
While as yet unconfirmed in systematic studies, the increased failure rate with oral contraceptives may be ameliorated by increasing the dose and using extended cycle regimens with shorter pill-free
intervals [103,104]. Clinicians often recommend that women on enzyme-inducing AEDs who want to take oral contraceptives receive a preparation with at least 50 mcg of the estrogen component [103].
It is expected that both the efficacy and the incidence of adverse effects associated with a higher dose of hormones used in conjunction with enzyme-inducing AEDs should be comparable with standard
doses when not combined with AEDs [103]. However, this is unproven. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Shorter pill-free interval' and "Overview of the use of
estrogen-progestin contraceptives", section on 'Continuous pill'.)
Hormone levels in patients using intrauterine hormone-releasing systems (Mirena, LNg 20) or depot injections of progesterone are not affected by AEDs; these are effective alternatives to oral
contraceptive therapy [103,105,106]. (See "Intrauterine contraception (IUD): Overview", section on 'Levonorgestrel-releasing IUDs' and "Depot medroxyprogesterone acetate for contraception".)
The efficacy of the "morning after pill" may be similarly affected by enzyme-inducing AEDs. Two doses of levonorgestrel 1.5 mg separated by 12 hours is recommended in these circumstances [103,107].
(See "Emergency contraception".)
In addition to the effect of AEDs on oral contraceptive metabolism, oral contraceptives can increase the metabolism of lamotrigine, thereby reducing the plasma drug concentration, typically by about 50
percent. Pregnancy has a similar effect on many other AEDs. (See "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and "Management of epilepsy and pregnancy", section on 'Drug levels
and dose adjustment'.)
Fertility While a number of studies have suggested that women with epilepsy have increased rates of infertility, as high as 33 to 38 percent [108,109], other studies have not confirmed this finding
[110]. It is also uncertain whether this association is linked to epilepsy itself or to AED treatment.
Potential confounding factors in assessing a possible association include lower marriage rates and a lower rate of planned pregnancies. The latter may result because the woman may be concerned
about teratogenicity, her ability to care for a child, and increased risk of epilepsy in her child [111].
There is evidence that suggests that AED use may affect fertility. In a prospective cohort study of 375 women with epilepsy, infertility was linked to polytherapy, as well as to older age, and lower
education [108]. Valproate, in particular, has been linked to an increased risk of polycystic ovary disease, a leading cause of infertility in woman [112]. (See "Epidemiology and pathogenesis of the
polycystic ovary syndrome in adults", section on 'High-risk groups'.)
Post-stroke seizures Stroke is the most common cause of seizures and epilepsy in population studies of adults over the age of 35 [113]. In one of the largest prospective studies, post-stroke
seizures occurred in 168 of 1897 patients (8.9 percent) after hemispheric stroke, including 140 of 1632 (8.6 percent) with ischemic stroke and 28 of 265 (10.6 percent) with hemorrhagic stroke [114].
However, recurrent seizures were rare during the nine months of follow-up, occurring in only 2.5 percent of patients.
Seizures occurred within 24 hours of the stroke in 43 percent of patients in the above report [114]. The pathogenesis of these early-onset seizures may be related to local ion shifts and release of high
levels of excitotoxic neurotransmitters in the area of ischemic injury [115].
In contrast, an underlying permanent lesion that leads to persistent changes in neuronal excitability appears to be responsible for late-onset seizures after stroke and other brain injuries, and probably
accounts for the fact that the risk of chronic epilepsy is higher in patients with late rather than early occurrence of seizures. In one study, for example, 118 patients who had a thrombotic stroke had a
bimodal distribution of seizures either within two weeks or from 6 to 12 months after the stroke [116]. Epilepsy developed in more patients with late than early seizures (90 and 35 percent, respectively).
The risk of late-onset seizures may increase over time. In a population-based study of over 3000 patients presenting with first stroke, post-stroke epilepsy (defined as 2 unprovoked seizures occurring
after the acute phase of stroke) developed in 213 patients (6.4 percent) after a mean follow up of four years [117]. The estimated cumulative incidence of epilepsy rose from 3.5 percent at one year,
which is similar to estimates from prior studies with shorter-term follow up, to over 12 percent at 10 years.
Among a wide range of demographic characteristics, medical comorbidities, and stroke characteristics studied, stroke severity and cortical location have been found to be most consistently associated
with the risk of acute and late seizures [117-120]. Younger age has been reported as a risk factor for late seizures in at least one large study [117]. One prospective study found that preexisting dementia
was a risk factor for late seizures (OR = 4.66, CI, 1.34-16.21) but not for early seizures [121]. Dementia is a risk factor for epilepsy in patients without stroke as well. (See "Seizures and epilepsy in the
elderly patient: Etiology, clinical presentation, and diagnosis".)
Most seizures following stroke are focal at onset, but secondary generalization is common, particularly in patients with late-onset seizures. Status epilepticus is relatively uncommon, occurring in 9
percent of 180 patients with poststroke seizures in one report [122].
When to treat Given the relatively low frequency of recurrent seizures after stroke, and an absence of absolute predictors of poststroke epilepsy, the decision of when to treat patients for a
poststroke seizure is difficult. Nevertheless, most physicians empirically treat patients who develop late-onset seizures in the setting of a stroke history within the previous two to three years [115].
The efficacy of specific AEDs for poststroke seizures has not been rigorously assessed in controlled trials, although most seizures can be controlled with a single agent [123]. Several considerations
factor into the choice of AED in this population. Studies suggest that newer AEDs have similar efficacy but a more favorable adverse event profile in older patients. (See "Pharmacology of antiepileptic
drugs" and "Treatment of seizures and epilepsy in the elderly patient".) In one prospective randomized trial, the lamotrigine treatment arm had a fewer drop-outs due to adverse events than did the
carbamazepine arm; lamotrigine was also more efficacious, although this did not reach statistical significance [124]. Gabapentin has been associated with 80 percent seizure remission in one
uncontrolled study of post-stroke epilepsy [125].
Older patients AED use in elderly patients is complicated by several factors, including age-related alterations in protein binding, reduced hepatic metabolism, and diminished renal clearance of
medications. In addition, medical comorbidities and polypharmacy are more often a concern in older adults. The selection of AED treatment in the elderly is discussed separately. (See "Treatment of
seizures and epilepsy in the elderly patient".)
Other causes The treatment of epilepsy in the setting of brain tumors and head trauma are discussed separately. (See "Seizures in patients with primary and metastatic brain tumors" and "Posttraumatic 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].

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A population-based study in Europe found that seizure-related accidents occurred in only 6.5 percent of the cohort at two years of follow-up; risk was largely determined by higher seizure frequency [94].
Similarly, a subsequent population-based study in the United States found that the risk of seizure-related injury was low and that most injuries were minor and without adverse social or occupational
consequences [147]. Seizure frequency was the only significant risk factor for seizure-related injury.
Patients with poorly controlled seizures are at the highest risk for seizure-related injury. However, for most patients with epilepsy, excessive restriction of activities for the purpose of avoiding injury is
unnecessary [147]. Supervision of swimming is a reasonable precaution.
A few studies have suggested that people with epilepsy may be at higher risk of violent assault. In one report, death from homicide in the home was more common in patients with epilepsy compared
with controls (RR = 2.3) [148]. One population-based study in Canada found that individuals with epilepsy were more likely to suffer assault-related injuries compared with normal controls [149].
It is recommended that clinicians regularly review relevant safety issues with their patients with epilepsy [4].
Motor vehicle accidents The relative risk of a motor vehicle accident (MVA) in a person with epilepsy compared with other drivers has been variously estimated and may be as high as 2.0. The
seizure-free interval (time since last seizure) is believed to be an important factor in assessing the risk of a MVA. (See "Driving restrictions for patients with seizures and epilepsy".)
Driving restrictions States vary widely in driver licensing requirements for patients with epilepsy. The most common requirements are that patients be free of seizures for a specified period of
time and that they submit a physician's evaluation of their ability to drive safely.
Physicians should also consider the potential neurotoxic side effects of AEDs (eg, sedation, double vision) (table 3), when counseling patients about driving.
A listing of individual state driving requirements can be found on the Epilepsy Foundation Website at http://www.epilepsyfoundation.org/resources/drivingandtravel.cfm.
Additional details about driving restrictions in patients with epilepsy are discussed separately. (See "Driving restrictions for patients with seizures and epilepsy".)
Psychosocial issues Management of patients with epilepsy must include consideration of the psychosocial dimensions of the disorder [150,151]. Among over 30,000 respondents, the National
Health Interview Survey found increased odds of psychological symptoms, medical symptoms and diagnoses, and decreased leisure time physical activity in patients with seizures [152].
Employment status is often negatively impacted by epilepsy, even when seizures are infrequent [153-155]. In one survey, over 40 percent of college-educated people with "well-controlled" seizures were
unemployed [153].
Newly diagnosed patients with epilepsy are commonly affected by the loss of independence that is most obvious in their inability to drive. They may also have problems obtaining insurance and finding or
maintaining suitable employment. Their self-esteem may also suffer [156]. As the treatment plan is formulated, psychosocial issues must be systematically explored with patients so that appropriate
referrals for additional help and counseling can be initiated.
Patients with epilepsy are more likely to have a poor pattern of health-related behaviors (increased smoking, higher alcohol consumption, less physical activity) compared with the general population
[136,157,158]. Counselling regarding these issues may improve health and quality of life.
A complete psychosocial history includes inquiries about educational background, employment, driving, insurance, interpersonal relationships, previous psychiatric illness (especially depression), and
attitude toward having epilepsy. Questionnaires for this purpose are available, and they provide a measurable way of assessing and following patients as pharmacotherapeutic and psychosocial
interventions are implemented [159].
Identifying sources of psychosocial stress should lead to the development of strategies to minimize the impact of those stresses on the patient. Stress reduction can, in turn, help reduce seizure
frequency, although this has not been proved definitively [160]. Patients are often deeply concerned about health, independence, personal growth, relationships, well-being, and security; those with
stress-induced seizures may be candidates for stress reduction, biofeedback, or relaxation training. Many resources are available to help patients. In the absence of a local epilepsy group, patients
should be encouraged to call the Epilepsy Foundation at 1-800-EFA-1000 or to visit their website at www.epilepsyfoundation.org.
Depression and psychiatric disease Mood disorders, particularly anxiety and depression, are common in patients with epilepsy [136,161-164]. The reported prevalence of depression in patients
with epilepsy ranges from 13 to 35 percent, with much of the variability explained by differences in methods of ascertaining depression [165]. In one community health survey, epilepsy was associated
with 43 percent higher odds of depression after adjustment for other demographic factors [162]. Results from surveys in Canada and England have also reported higher odds of anxiety, depression, and
suicidal ideation among those with epilepsy [163,166].
Epilepsy-related disability, including unemployment and activity restriction, along with impaired social support and a perceived stigma associated with the diagnosis are risk factors for depression in these
patients [167]. Other reports that find a high rate of psychiatric comorbidity (including depression, bipolar disease, psychosis, anxiety, and suicidality) predating seizure onset suggest a bidirectional
relationship and perhaps a common underlying mechanism for psychiatric disorders and epilepsy [168,169].
Mood disturbances are important contributors to decreased health-related quality of life in persons with epilepsy [161,170-173]. One 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

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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 own case.
There is no certain way to prospectively identify patients who will remain seizure free after they discontinue AED therapy. At least two studies have compared continued AED treatment with drug
withdrawal and reported the following results:
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".)
AED discontinuation can be considered in patients who have been seizure free for more than two years. Such decisions are individualized based on an evaluation of the individual's risk of seizure
recurrence, adverse effects of AED treatment, and the medical and psychosocial consequences of a recurrent seizure. AED drug withdrawal should be slow, over a few to several months. (See
'Discontinuing AED therapy' above.)

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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

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Antiepileptic medications and seizure types


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

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

Narrow spectrum: focal with or without alteration in consciousness or awareness and


focal evolving to bilateral convulsive seizure

Carbamazepine, eslicarbazepine, ezogabine, gabapentin, lacosamide, oxcarbazepine,


perampanel, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, vigabatrin

Absence seizure (a type of generalized seizure)

Ethosuximide

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.
Graphic 78021 Version 6.0

12 of 29

Common side effects of antiepileptic drugs


Drug

Systemic side effects

Neurotoxic side effects

Carbamazepine

Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus

Drowsiness, dizziness, blurred or double vision, lethargy, headache

Clobazam

Increased salivation, nausea, vomiting, constipation

Somnolence, aggression, irritability, ataxia, insomnia

Eslicarbazepine

Nausea, vomiting, diarrhea, fatigue, rash

Dizziness, drowsiness, headache, diplopia, vertigo, ataxia, attention


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

Ethosuximide

Nausea, vomiting

Sleep disturbance, drowsiness, hyperactivity

Ezogabine

Nausea, fatigue, change in color of urine, dysuria, urinary hesitancy,

Dizziness, somnolence, confusion, vertigo, blurred or double vision,

weight gain

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,

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

mood alteration

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

Graphic 59755 Version 11.0

13 of 29

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, neuropathy, ataxia,
lupus-syndrome, hirsuitism

Pregabalin

Angioedema, hypersensitivity reactions, rhabdomyolysis

Primidone, phenobarbital

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

Rufinamide

SJS/TEN, dermatitis/rash, shortened QT interval

Tiagabine

SJS/TEN, nonconvulsive status epilepticus

Topiramate

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

Valproate

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

Vigabatrin

MRI abnormalities, depression, weight gain

Zonisamide

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

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.
Graphic 78896 Version 11.0

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Pharmacologic properties of antiepileptic drugs


Metabolism and clearance

Carbamazepine

Enzyme
induction/inhibition

>90 percent metabolized by CYP3A4

Potent and broad spectrum inducer

(major) and 1A2/2C8 (minor) to


active (epoxide) and inactive
metabolites

of CYP, UGT-glucuronidation, and


P-gp

Protein binding, percent*

75

Half life in adults (hours)

25-65 (initial use, enzyme inducing


naive patient)
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

>90 percent metabolized by CYPs


3A4, 2C19, 2B6 and non-CYP
transformations to active
(N-desmethylclobazam) and inactive
metabolites

Inhibits CYP2D6 (moderate) and


UGT-glucuronidation

85

36-43 (parent drug)


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

Induces CYP3A4 (weak to moderate)

Dose adjustment is needed in


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

<40

glucuronidation (weak) but does not


induce its own metabolism

13 to 20 hours (prolonged in renal


insufficiency)

Inhibits CYP2C19 (moderate)

Dose adjustment is needed for renal


impairment; not recommended in
patients with severe hepatic
impairment
Ethosuximide

~80 percent metabolized by CYP3A4


(major) and non-CYP
transformations to inactive

None

<5

40-60

80 (parent drug)

7-11 (prolonged in renal


insufficiency and in older adults)

metabolites
Ezogabine (retigabine)

~60 percent metabolized by


non-CYP transformations

NAMR seems to inhibit P-gp

45 (NAMR)

(UGT-glucuronidation, N-acetylation)
to active (NAMR) and inactive
metabolites
Dose adjustment is needed in
moderate or severe hepatic or renal
impairment
Felbamate

50 percent metabolized by CYP3A4

Induces CYP3A4 (moderate)

and 2E1 (minor); ~50 percent


renally excreted as unchanged drug

Inhibits CYP2C19 (minor)

25

13-22 (prolonged in renal


insufficiency)

Dose adjustment is needed in renal


impairment
Gabapentin

>95 percent renally excreted as

None

<5

5-7 (prolonged in renal insufficiency;


>130 hours in anuria)

unchanged drug (ie, does not


undergo hepatic metabolism)
Dose adjustment is needed in renal
impairment
Lacosamide

40 percent renally excreted as


unchanged drug; 30 percent
metabolized by non-CYP

Inhibits 2C19 (minor)

<15

13

May induce its own metabolism by


UGT-glucuronidation (minor)

55

12-62

None

<10

6-8

Prodrug; 70 percent of active (MHD)

Induces CYP3A4 (moderate to

40

9 (active metabolite, prolonged in

form undergoes UGT


glucuronidation; 30 percent is

severe) and UGT-glucuronidation but


does not induce its own metabolism

transformations (including
methylation) to inactive metabolite
Dose adjustment is needed in
hepatic and renal impairment
Lamotrigine

>90 percent metabolized by UGT


glucuronidation and other non-CYP
transformations to inactive
metabolites
Dose adjustment is needed in
moderate to severe renal or hepatic
impairment

Levetiracetam

>65 renally excreted as unchanged


drug; 24 percent metabolized by
non-CYP transformation (including
amidase hydrolysis) to inactive
metabolites
Dose adjustment is needed in renal
impairment

Oxcarbazepine

renally excreted as unchanged


active drug
Dose adjustment is needed in severe
renal impairment

15 of 29

renal insufficiency)

Perampanel

>70 percent metabolized by CYPs

Appears to induce metabolism of

3A4, 3A5 and non-CYP


transformations to inactive

progestin-containing hormonal
contraceptives

95

105

Potent and broad spectrum inducer


of CYP and UGT-glucuronidation

55

75-110

Potent and broad spectrum inducer


of CYP and UGT-glucuronidation

90-95

9- >42 (dose dependent)

None

<5

Potent and broad spectrum inducer


of CYP

0-20

10-15 (parent)

>90 percent metabolized by

Induces CYP3A4 (minor)

35

6-10

non-CYP transformations
(hydrolysis) to inactive metabolites

Inhibits CYP2E1 (minor)

>90 percent metabolized by CYP3A4

None

95

7-9

metabolites
Dose adjustment is needed in mild
or moderate hepatic impairment
Phenobarbital

75 percent metabolized by CYPs


2C19, 2C9 (minor) and glucosidase
hydrolysis and 2E1 (minor) to
inactive metabolites; 25 percent
excreted renally as unchanged drug
Dose adjustment is needed in severe
renal or hepatic impairment

Phenytoin

>90 percent metabolized by CYPs


2C9, 2C19 and 3A4 (minor) and
non-CYP transformations to inactive
metabolites; clearance is dose
dependent, saturable, and may be
subject to genetic polymorphism
Dose adjustment is needed in severe
renal or hepatic insufficiency;
monitoring of free (unbound)
concentrations also suggested

Pregabalin

>95 excreted renally as unchanged


drug
Dose adjustment is needed in renal
impairment

Primidone

75 percent metabolized by CYPs


2C19, 2C9 (minor) and 2E1 (minor)
to active intermediates; ~25 percent

29-100 (active metabolite)

excreted renally as unchanged drug


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

Tiagabine

and non-CYP transformations to


inactive metabolites
Topiramate

>65 percent excreted renally as


unchanged drug; <30 percent
metabolized by non-CYP
transformations to inactive

2-5 (with enzyme-inducing AEDs)

Inhibits CYP2C19 (minor)

9-17

12-24

80-95

7-16

Induces CYP2C9

5-13 (unrelated to duration of


action)

None

50

63

Induces CYP3A4 (minor)

metabolites; extent of metabolism is


increased ~50 percent in patients
receiving enzyme inducing AEDs
Dose adjustment is needed in
moderate and severe renal or
hepatic impairment
Valproate

>95 percent undergoes complex

Moderate broad spectrum inhibitor

transformations including CYPs 2C9,


2C19, 2A6, UGT-glucuronidation and
other non-CYP transformation

including CYP2A6, 2B6, 2C9, 2C19,


2E1 and UGT-glucuronidation

Dose adjustment is needed in

Minor or moderate inducer of


CYP2A6

hepatic impairment
Vigabatrin

>90 percent excreted renally as


unchanged drug
Dose adjustment is needed in renal
impairment

Zonisamide

>65 percent metabolized by CYPs


3A4, 2C19 (minor) and non-CYP
transformations
Dose adjustment and/or slower
titration is needed in mild renal
impairment or hepatic impairment;
not recommended in patients with
moderate or severe renal
impairment

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.

16 of 29

Copyright 1978-2014 Lexicomp, Inc. All Rights Reserved.


Graphic 60182 Version 11.0

17 of 29

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.
Graphic 71274 Version 11.0

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Some interactions between carbamazepine and other antiepileptic drugs*


Interacting drugs

Effects (probable mechanism)

Management

Carbamazepine, with:
Clonazepam

Decreased clonazepam effect (increased metabolism)

Monitor clinical status

Eslicarbazepine

Increased risk of diplopia, abnormal coordination, and dizziness


(pharmacodynamic interaction)

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

Decreased lamotrigine effect (increased metabolism; glucuronidation)

Lamotrigine dosage may need to be adjusted; monitor lamotrigine


concentration and clinical status

Levetiracetam

Possible increased risk of carbamazepine toxicity (mechanism not


established)

Monitor for clinical evidence of carbamazepine toxicity

Oxcarbazepine

Possible decreased oxcarbazepine effect (increased metabolism)

Monitor oxcarbazepine concentrations and clinical status

Perampanel

Decreased perampanel effect (increased metabolism by CYP3A4)

Monitor clinical status; perampanel dosage may need to be adjusted

Decreased carbamazepine effect (increased metabolism)

Monitor carbamazepine and phenytoin concentrations

Phenytoin

Altered phenytoin effect (mechanism not established)


Tiagabine

Decreased tiagabine effect (increased metabolism)

Topiramate

Possible decreased topiramate effect (increased metabolism)

Monitor clinical status


Monitor topiramate concentrations and clinical status; may need higher
doses of topiramate

Valproate

Decreased valproate effect and possible increased toxicity (increased

Monitor valproate concentrations and clinical status

metabolism and formation of toxic metabolite)

Zonisamide

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

* NOTE: Not all potential interactions are listed. Additional interactions of antiepileptic drugs and management suggestions may be determined using the drug interactions tool (LexiInteract 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.
Graphic 80801 Version 6.0

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Some interactions between phenytoin and other antiepileptic drugs*


Interacting drugs

Effects (probable mechanism)

Management

Phenytoin, with:
Carbamazepine

Decreased carbamazepine effect (increased metabolism)

Monitor carbamazepine and phenytoin concentrations

Altered phenytoin effect (mechanism not established)


Clonazepam

Eslicarbazepine

Lamotrigine

Oxcarbazepine

Decreased clonazepam effect (increased metabolism)

Monitor clonazepam effect or concentrations

Variable effects on phenytoin concentrations (mechanism not


established)

Monitor phenytoin concentrations

Decreased eslicarbazepine concentrations (increased metabolism)

Eslicarbazepine dose may need to be increased

Possible phenytoin toxicity (decreased metabolism by CYP2C19)

Monitor phenytoin concentrations and clinical status

Decreased lamotrigine serum concentrations (increased metabolism;

Monitor lamotrigine serum concentrations and clinical status;

induction of glucuronidation by phenytoin)

lamotrigine dosage may need to be adjusted

Possible decreased oxcarbazepine effect (increased metabolism)

Monitor clinical status and serum concentration

Possible phenytoin toxicity with oxcarbazepine doses of 1200 mg/day or


higher (decreased metabolism)

Monitor phenytoin concentrations especially when oxcarbazepine dosage


is 1200 mg/day or higher

Perampanel

Decreased perampanel effect (increased metabolism by CYP3A4)

Monitor clinical status; perampanel dosage may need to be adjusted

Tiagabine

Decreased tiagabine effect (increased metabolism)

Monitor clinical status

Topiramate

Possible decreased topiramate effect (increased metabolism)

Monitor topiramate concentrations and clinical status; may need to


increase topiramate dose

Possible phenytoin toxicity (decreased metabolism by CYP2C19)

Monitor phenytoin concentrations and clinical status

Valproate

Possible phenytoin toxicity (displacement from binding)

Monitor phenytoin concentrations and clinical status (unbound


concentrations may be more helpful than total)

Possible decreased valproate effect and increased toxicity (increased

Monitor clinical status and valproate serum concentrations

metabolism and formation of toxic metabolite)


Zonisamide

Decreased zonisamide effect (increased metabolism by CYP3A4)

Monitor zonisamide concentrations and clinical status; zonisamide


dosage may need to be adjusted

* NOTE: Not all potential interactions are listed. Additional interactions of antiepileptic drugs and management suggestions may be determined using the drug interactions tool (LexiInteract 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.
Graphic 55399 Version 6.0

20 of 29

Some interactions between valproate and other antiepileptic drugs*


Interacting drugs

Effects (probable mechanism)

Management

Valproate, with:
Carbamazepine

Decreased valproate effect and possible increased toxicity (increased


metabolism and formation of toxic metabolite)

Monitor valproate concentrations and clinical status

Carbamazepine toxicity (decreased metabolism of carbamazepine

Monitor carbamazepine and carbamazepine epoxide concentrations

epoxide and displacement from binding)


Clonazepam

Ethosuximide

Lamotrigine

Clonazepam may precipitate absence status (mechanism not


established)

Monitor clinical status

Possible ethosuximide toxicity (decreased metabolism)

Monitor ethosuximide concentration

Possible decreased valproate effect (mechanism not established)

Monitor valproate concentration

Possible lamotrigine toxicity (decreased metabolism; glucuronidation)

Decrease lamotrigine dose; monitor lamotrigine concentrations and


clinical status

Oxcarbazepine

Possible decreased oxcabazepine concentration (increased metabolism)

Monitor oxcarbazepine concentrations and clinical status

Phenytoin

Phenytoin toxicity (displacement from binding and decreased

Monitor phenytoin concentrations and clinical status (unbound

Topiramate

metabolism)

concentrations may be more helpful than total)

Possible decreased valproate effect and increased toxicity (increased


metabolism and formation of toxic metabolite)

Monitor clinical status and valproate serum concentrations

Possible increased hepatotoxic effect of valproate (mechanism not

Monitor clinical status

established)
* NOTE: Not all potential interactions are listed. Additional interactions of antiepileptic drugs and management suggestions may be determined using the drug interactions tool (LexiInteract 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.
Reproduced with permission from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright 2008 The Medical Letter.
Graphic 53463 Version 6.0

21 of 29

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.
Graphic 77847 Version 7.0

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

23 of 29

Healthcare providers can use the summary table as a quick reference guide to the classifications for hormonal contraceptive methods and intrauterine contraception and to compare
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 additional comments.
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

Cu-IUD

Not applicable*

Not applicable*

Not applicable*

Not applicable*

4*

4*

Menarche to

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

<20 years = 2

40 years = 2

18 to 45 years = 1

18 to 45 years = 1

18 to 45 years = 1

20 years = 1

20 years = 1

>45 years = 1

>45 years = 2

>45 years = 1

Parity
a. Nulliparous

b. Parous

b. 10 min after delivery


of the placenta to <4
weeks

c. 4 weeks

d. Puerperal sepsis

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
factors for VTE (such
as age 35 years,
previous VTE,
thrombophilia,
immobility, transfusion
at delivery, BMI 30
kg/m 2, postpartum
hemorrhage,
postcesarean delivery,
preeclampsia, or
smoking)
ii. Without other risk
factors for VTE
c. 30 to 42 days
i. With other risk
factors for VTE (such
as age 35 years,
previous VTE,
thrombophilia,
immobility, transfusion
at delivery, BMI 30,
postpartum
hemorrhage,
postcesarean delivery,
preeclampsia, or
smoking)
ii. Without other risk
factors for VTE
d. >42 days

Postpartum (breastfeeding or nonbreastfeeding women, including postcesarean delivery)


a. <10 min after delivery
of the placenta

Postabortion

24 of 29

a. First trimester

1*

1*

1*

1*

1*

b. Second trimester

1*

1*

1*

1*

1*
2

c. Immediate postseptic
abortion

1*

1*

1*

1*

Past ectopic pregnancy

History of pelvic surgery

(see Postpartum,
breastfeeding or
nonbreastfeeding women,
including postcesarean
delivery)
Smoking
a. Age <35 years
b. Age 35 years
i. <15 Cigarettes/day

ii. 15 Cigarettes/day

Obesity
a. 30 kg/m 2 BMI

b. Menarche to <18 years


and 30 kg/m 2 BMI

COCs: 3

3/4*

2*

3*

2*

3*

1*

2*

1*

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

P/R: 1

shortening the functional


length of the small
intestine (Roux-en-Y
gastric bypass,
biliopancreatic diversion)
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)
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
non-melanoma skin
cancer

25 of 29

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*

ii. Without prolonged


immobilization

f. Minor surgery without


immobilization

4*

2*

2*

2*

2*

1*

i. Higher risk for


recurrent DVT/PE (1
risk factors)
Known
thrombophilia,
including
antiphospholipid
syndrome
Active cancer
(metastatic, on
therapy, or
within six months
after clinical
remission),
excluding
non-melanoma skin
cancer
History of recurrent
DVT/PE
ii. Lower risk for
recurrent DVT/PE (no
risk factors)
d. Family history (firstdegree relatives)
e. Major surgery
i. With prolonged
immobilization

Known thrombogenic
mutations (eg, factor V
Leiden; prothrombin
mutation; protein S, protein
C, and antithrombin
deficiencies)
Superficial venous thrombosis
a. Varicose veins

b. Superficial
thrombophlebitis

Current and history of


ischemic heart disease

Stroke (history of
cerebrovascular accident)
Known hyperlipidemias

4
2/3*

Initiation

Continuation

Initiation

Continuation

2*

Initiation

Continuation

Initiation

Continuation

Initiation

Continuation

2*

3
2*

2*

1*

Valvular heart disease


a. Uncomplicated

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

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 limitation of
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
erythematosus
a. Positive (or unknown)
antiphospholipid
antibodies

Initiation

Continuation

Initiation

Continuation

26 of 29

b. Severe
thrombocytopenia

2*

3*

2*

c. Immunosuppressive
treatment

d. None of the above

Rheumatoid arthritis
a. On immunosuppressive

2/3*

Initiation

Continuation

Initiation

Continuation

therapy
b. Not on

immunosuppressive
therapy
Neurologic conditions
Headaches

Initiation

Continuation

Initiation

Continuation

Initiation

Continuation

Initiation

Continuation

Initiation

Continuation

1*

2*

1*

1*

1*

1*

1*

1*

1*

1*

1*

- Age <35 years

2*

3*

1*

2*

2*

2*

2*

2*

2*

2*

1*

- Age 35 years

3*

4*

1*

2*

2*

2*

2*

2*

2*

2*

1*

ii. With aura (at any


age)

4*

4*

2*

3*

2*

3*

2*

3*

2*

3*

1*

a. Non-migrainous (mild
or severe)
b. Migraine
i. Without aura

Epilepsy

1*

1*

1*

1*

1*

1*

1*

1*

1*

Initiation

Continuation

1*

2*

2*

2*

1*

2*

2*

Initiation

Continuation

Initiation

2*

4*

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)
Before evaluation

4*

Continuation

2*

2*

3*

3*

Endometriosis

2*

Benign ovarian tumors

Cervical ectropion

Cervical intraepithelial

(including cysts)
Severe dysmenorrhea
Gestational trophoblastic disease
a. Decreasing or
undetectable beta-hCG
levels
b. Persistently elevated
beta-hCG levels or
malignant disease

neoplasia
Cervical cancer (awaiting
treatment)

Initiation

Continuation

Initiation

Continuation

Breast disease
a. Undiagnosed mass

2*

2*

2*

2*

b. Benign breast disease

c. Family history of
cancer

d. Breast cancer
i. Current

ii. Past and no


evidence of current

disease for five years


Endometrial hyperplasia
Endometrial cancer

Initiation

Continuation

Initiation

Continuation

Ovarian cancer

Uterine fibroids

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

Initiation

Continuation

Initiation

Continuation

current risk factors of


STIs)
i. With subsequent
pregnancy

ii. Without subsequent


pregnancy

b. Current PID
STIs
a. Current purulent
cervicitis or chlamydial

2*

2*

Initiation

Continuation

Initiation

Continuation

2*

2*

b. Other STIs (excluding


HIV and hepatitis)

c. Vaginitis (including

2/3*

2/3*

Initiation

Continuation

Initiation

Continuation

High risk for HIV

HIV infection

AIDS

2*

infection or gonorrhea

Trichomonas vaginalis
and bacterial vaginosis)
d. Increased risk for STIs
HIV/AIDS

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

b. Fibrosis of the liver (if


severe, see Cirrhosis)

Initiation

Continuation

Initiation

a. Nonpelvic

1*

1*

1*

1*

b. Pelvic

1*

1*

1*

1*

Tuberculosis

Continuation

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
c.
Nephropathy/retinopathy/

3/4*

3/4*

neuropathy
d. Other vascular disease
or diabetes of >20 years'
duration
Thyroid disorders
a. Simple goiter

b. Hyperthyroid

c. Hypothyroid

2/3*

Gastrointestinal conditions
Inflammatory bowel
disease (IBD) (ulcerative
colitis, Crohn disease)
Gallbladder disease
a. Symptomatic
i. Treated by
cholecystectomy
ii. Medically treated

iii. Current

b. Asymptomatic

History of cholestasis

27 of 29

a. Pregnancy-related

b. Past COC-related

Viral hepatitis
a. Acute or flare

Initiation

Continuation

3/4*

b. Carrier

c. Chronic

Cirrhosis
a. Mild (compensated)

b. Severe
(decompensated)

Thalassemia

Sickle cell disease

Iron-deficiency anemia

Liver tumors
a. Benign
i. Focal nodular
hyperplasia
ii. Hepatocellular
adenoma
b. Malignant
(hepatoma)
Anemias

Solid organ transplantation


Solid organ
transplantation
a. Complicated: graft
failure (acute or chronic),

Initiation

Continuation

Initiation

Continuation

2*

Initiation

Continuation

Initiation

Continuation

1*

2/3*

2*

2/3*

2*

2*

2*

2*

2/3*

2*

2/3*

2*

3*

3*

2*

2/3*

2*

2/3*

2*

3*

3*

2*

3*

rejection, cardiac
allograft vasculopathy
b. Uncomplicated

Drug interactions
Antiretroviral therapy
a. Nucleoside reverse
transcriptase inhibitors
(NRTIs)
b. Non-nucleoside
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
b. Antifungals

c. Antiparasitics

3*

3*

2*

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.
Graphic 74890 Version 16.0

28 of 29

PHQ-9 depression questionnaire


Name:

Date:

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

Not at all

Several days

More than half


the days

Nearly every
day

Little interest or pleasure in doing things

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 down

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 so fidgety or
restless that you have been moving around a lot more than usual.

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

___

___

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.
Graphic 59307 Version 5.0

29 of 29