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Descripción general del tratamiento de la epilepsia en

adultos
AUTOR: Dr. Steven C Schachter
EDITOR DE SECCIÓN: Dr. Paul García
SUBEDITOR: John F Dashe, MD, PhD

Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de revisión por pares.

Revisión de la literatura actual a través de: Mayo 2023.

Este tema se actualizó por última vez: Abr 25, 2022.

INTRODUCCIÓN

El tratamiento de los pacientes con epilepsia se centra en tres objetivos principales: controlar las
convulsiones, evitar los efectos secundarios del tratamiento y mantener o restaurar la calidad de
vida. Los médicos deben ayudar a capacitar a los pacientes con epilepsia para llevar estilos de
vida consistentes con sus capacidades [1,2].

El plan de tratamiento óptimo se deriva después de un diagnóstico preciso de los tipos de

convulsiones del paciente, una medida objetiva de la intensidad y frecuencia de las
convulsiones, el conocimiento de los efectos secundarios de los medicamentos y una evaluación
de los problemas psicosociales relacionados con la enfermedad. Es esencial un conocimiento
práctico de los medicamentos anticonvulsivos (ASM) disponibles, incluidos sus mecanismos de
acción, farmacocinética, interacciones farmacológicas y efectos adversos.

Por lo general, es apropiado referir al paciente a un neurólogo al establecer un diagnóstico y

formular un curso de tratamiento. La derivación a un especialista en epilepsia puede ser
necesaria si hay dudas sobre el diagnóstico y / o si el paciente continúa teniendo convulsiones.

El enfoque general para el manejo de un paciente con convulsiones se revisa aquí. La evaluación
del paciente que ha tenido una primera convulsión y la farmacología de ASM específicas se
discuten por separado. (Ver "Evaluación y manejo de la primera convulsión en adultos" y
"Tratamiento inicial de la epilepsia en adultos" y "Medicamentos anticonvulsivos: mecanismo de
acción, farmacología y efectos adversos").
CLASIFICACIÓN

El primer paso en el diseño de un plan de tratamiento es clasificar los tipos de convulsiones del
paciente utilizando el marco de la Liga Internacional contra la Epilepsia ( tabla 1) [3-6]. Los
tipos de convulsiones y los síndromes de epilepsia se clasifican principalmente por motivos
clínicos, asistidos por estudios de laboratorio, neurofisiológicos y radiográficos. El tipo de
convulsión tiene implicaciones importantes en la elección de los ASM. La clasificación precisa
requiere una historia completa del paciente e informes de observadores que han presenciado
convulsiones reales. (Ver "Clasificación ILAE de convulsiones y epilepsia".)

Los pacientes pueden ser más capaces de describir sus síntomas de convulsiones después de
leer las descripciones de convulsiones publicadas, lo que a su vez puede mejorar la capacidad
del médico para categorizar el tipo de convulsión y planificar un enfoque terapéutico exitoso [7].
Muchos pacientes experimentan más de un tipo de convulsión (p. ej., convulsiones focales y
convulsiones secundariamente generalizadas).

Las preguntas puntuales pueden ser necesarias para revelar comportamientos o factores
ambientales que contribuyen a la incidencia de convulsiones. Estos "desencadenantes de
convulsiones", como la privación del sueño, el consumo de alcohol y el estrés, pueden ser
modificables. Por lo tanto, tomar medidas que limiten la exposición a estos desencadenantes
generalmente mejora los beneficios de la terapia ASM.

Hay dos grandes categorías de convulsiones: focales (o parciales) y generalizadas (tabla 1y

tabla 2). Las convulsiones focales involucran solo una parte del cerebro, generalmente parte
de un lóbulo de un hemisferio. Una convulsión focal puede estar asociada con deterioro de la
conciencia (anteriormente llamada convulsión parcial compleja) o ningún deterioro de la
conciencia (anteriormente llamadas convulsiones parciales simples). Una convulsión focal puede
evolucionar en segundos a una convulsión tónico-clónica bilateral, también conocida como
convulsión generalizada secundaria. (Ver "Evaluación y manejo de la primera convulsión en
adultos", sección sobre "Tipos de convulsiones").

TERAPIA CON MEDICAMENTOS ANTICONVULSIVOS

Cuándo comenzar la terapia con medicamentos anticonvulsivos : la terapia inmediata con

medicamentos anticonvulsivos (ASM) generalmente no es necesaria en individuos después de
una sola convulsión, particularmente si una primera convulsión es provocada por factores que
se resuelven. El tratamiento con ASM debe iniciarse en pacientes que tienen un riesgo
significativo de convulsiones recurrentes, como aquellos con convulsiones sintomáticas
remotas. El tratamiento de ASM generalmente se inicia después de dos o más convulsiones no
provocadas, porque la recurrencia demuestra que el paciente tiene un riesgo sustancialmente
mayor de convulsiones repetidas, muy por encima del 50 por ciento.

Las cuestiones a considerar al decidir cuándo comenzar la terapia ASM se discuten en detalle
por separado. (Ver "Tratamiento inicial de la epilepsia en adultos", sección sobre "Cuándo
comenzar la terapia con medicamentos anticonvulsivos").

La terapia ASM no es necesariamente de por vida. (Consulte "Interrupción de la terapia con

medicamentos anticonvulsivos" a continuación).

Elegir un medicamento anticonvulsivo: aproximadamente la mitad de los pacientes con un

nuevo diagnóstico de epilepsia estarán libres de convulsiones con la primera ASM prescrita [8,9].
La tolerabilidad de los efectos secundarios es tan importante como la eficacia para determinar la
efectividad general del tratamiento. Ninguna ASM es óptima para cada paciente. La selección de
una ASM específica para el tratamiento de las convulsiones debe ser individualizada
considerando:

● Eficacia farmacológica para el tipo o tipos de convulsiones (tabla 3y tabla 4) [10]

● Posibles efectos adversos del fármaco (tabla 5y tabla 6)
● Interacciones con otros medicamentos
● Condiciones médicas comórbidas, especialmente, pero no limitado a, enfermedad hepática
y renal
● Edad y sexo, incluidos los planes de maternidad
● Estilo de vida y preferencias del paciente
● Costar

In general, enzyme-inducing ASMs (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 anticancer and anti-infective drugs
( table 7). Specific interactions of ASMs with other medications may be determined using the
Lexicomp drug interactions tool.

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

Subsequent drug trials — Seizures in approximately half of patients with a new diagnosis of

epilepsy are successfully treated with the first ASM prescribed [8,9,11]. 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 [12,13]. Substantially fewer patients (approximately
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 computed tomography (CT) or magnetic resonance imaging (MRI) [13].

Similar factors are considered when a second ASM is chosen as when the first was selected (see
'Choosing an antiseizure medication' above and "Initial treatment of epilepsy in adults").
However, the clinician may also choose to select an ASM with a somewhat different mechanism
of action ( table 8) 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 [10] and to avoid drugs that may precipitate or aggravate seizures; the
latter is most relevant in patients with genetic generalized epilepsies such as juvenile myoclonic
epilepsy or absence epilepsy. (See "Juvenile myoclonic epilepsy", section on 'Antiseizure
medications to avoid' and "Childhood absence epilepsy", section on 'Drugs to avoid'.)

Except in the case of a serious adverse event from the first ASM, 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 ASM 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 ASM is subsequently tapered off.

Combination therapy — When possible, it is preferable to maintain a patient on a single ASM.

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 ASMs ( table 9A-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 [14].

● 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) [15].
 ● A randomized, double-blind study that compared carbamazepine monotherapy with
combination therapy with carbamazepine and valproate found no significant difference in
neurotoxicity between the two groups [16].

● In one epidemiologic survey, polytherapy was associated with lower quality of life and
lower rates of employment compared with patients on monotherapy [17].

There are few controlled studies comparing different drug combinations, and virtually every
possible combination of ASMs has been tried. A 2011 meta-analysis of 70 randomized controlled
trials of ASMs administered as add-on therapy in patients with refractory focal epilepsy found
that differences in efficacy were of too small magnitude to allow a conclusion about which ASM
is more effective as adjunctive therapy [18]. 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 [19].

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 8) and a different side-effect profile than the
first ASM ( table 5 and table 6) [20-22]. In this way, it is hoped that efficacy can be
maximized and side effects minimized [14]. The benefit of this approach is largely theoretical,
supported by limited observational data but not well tested prospectively [23]. However, there is
some anecdotal evidence that synergism between ASMs can occur [24-28]. As an example, a
post hoc analysis of pooled data from randomized trials suggested greater benefit and less
toxicity when lacosamide, a sodium channel-blocking drug, was used in combination with non-
sodium channel-blocking drugs [28].

Seizure remission is achieved with combination therapy in only a small percentage (10 to 15
percent) of patients whose seizures were not controlled by monotherapy [12,29,30]. One
retrospective chart review suggested that while two concurrent ASMs might provide efficacy
over monotherapy, use of three ASMs did not provide further benefit over two [27].

While the chances of treatment success diminish incrementally with each successive drug trial
[31], two studies suggest a value in pursuing further drug trials [29,30]. In one center, 15 percent
of patients whose seizures continued despite two prior ASM trials subsequently became seizure
free with ASM therapy [30]. In another, 28 percent of patients with a history of uncontrolled
seizures for five or more years were subsequently controlled on ASMs [29]. 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 intellectual disability, longer duration of
epilepsy, and symptomatic epilepsy were each a negative predictor in one of the two studies.

Overall, up to 80 percent of patients can become seizure free on ASM treatment [13,29-31].

Side effects of therapy — During the first six months of treatment, systemic toxicity and
neurotoxicity cause ASM failure to the same degree as lack of efficacy against seizures
( table 5 and table 6). 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 clinician should attempt to
correlate serum drug concentrations with the patient's side effects before abandoning that
medication. Specifically, obtaining levels when a patient is experiencing side effects and
comparing them with levels obtained when the patient is free from symptoms can be helpful in
the management of some patients.

It can be also be useful 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 their morning dose of ASMs, 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 ASMs specific to individual medications are
reviewed in detail separately (see "Antiseizure medications: Mechanism of action, pharmacology,
and adverse effects"). Some severe reactions that are common to more than one medication
include the following:

● An increased risk of suicidality has been linked to several ASMs in randomized placebo-
controlled studies of patients with epilepsy, according to a January 2008 US Food and Drug
Administration (FDA) report [32]. 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 ASMs studied, and the FDA considers
this risk likely to be shared by all ASMs. A 2009 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 [33]. In addition, a 2019
Danish case-control study found that the use of ASMs was associated with an increased risk
 of suicide; the increased risk was not explained by a history of suicidality, nor by a familial
disposition to psychiatric disorders [34].

Other studies have challenged these findings. A 2021 systematic review and meta-analysis
identified five ASMs (eslicarbazepine, perampanel, brivaracetam, cannabidiol, and
cenobamate) studied in 17 randomized controlled trials and found that the risk of suicidal
ideation was not increased overall nor for any individual drug [35]. A case-control study
found that only some of the newer ASMs (levetiracetam, topiramate, vigabatrin) were
associated with a risk of self-harm or suicide, while older and other newer ASMs were not
[36]. Another study based in the United Kingdom found that the magnitude of suicide risk
associated with ASM use varied according to the underlying etiology and was not elevated
in patients with epilepsy [37]. However, the clinical studies evaluated by the FDA that led to
the original warning were performed in patients with epilepsy.

Despite being somewhat controversial, the 2008 FDA clinical advisory remains in effect.
Therefore, clinicians prescribing ASMs should identify a current or past history of
depression, anxiety, and suicidal ideation or behavior in their patients [38-40]. Patients
taking ASMs should be monitored for emergence or worsening of suicidal ideation or
depression. Patients and families should be encouraged to call their clinician if they
experience any symptoms of depression [38,41]. (See "Comorbidities and complications of
epilepsy in adults", section on 'Screening'.)

A suggested approach to the assessment of suicidality in adults is discussed separately.

(See "Suicidal ideation and behavior in adults", section on 'Suicidal ideation and behavior'.)

● 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 ASMs [42-45]. The period of highest risk is within
the first two months of use [46]. The risk may be higher in patients with HLA-B*1502 allele,
which occurs almost exclusively in patients of Asian ancestry. The FDA recommends
screening such patients for this allele prior to starting carbamazepine, oxcarbazepine, and
possibly phenytoin [47]. By extension, Asian patients starting eslicarbazepine, an active
metabolite of oxcarbazepine, should also be screened. Because cross-hypersensitivity to
other ASMs is common, patients who experience this reaction should subsequently be
treated with nonaromatic ASMs (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 ASMs to patients who experienced SJS or TEN in association with an aromatic
 ASM [45]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse
effects" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis,
clinical manifestations, and diagnosis".)

● Reduced vitamin levels have also been described in patients taking ASMs, especially
enzyme-inducing drugs. In one study, subnormal folate levels were reported in 16 percent
of patients on ASMs (primarily in patients taking carbamazepine, gabapentin, phenytoin, or
primidone) [48]. While vitamin B12 levels were lower on average in patients taking ASMs
(particularly in patients taking phenobarbital, pregabalin, primidone, or topiramate), the
frequency of subnormal B12 levels was not significantly different in patients compared with
controls. In patients with low B12 levels, vitamin supplementation yielded normal levels
within three months. Elevated plasma homocysteine occurs with increased frequency in
patients on long-term enzyme-inducing ASMs and may reflect deficiency of folate, vitamin
B6, and/or vitamin B12 [49]. (See "Clinical manifestations and diagnosis of vitamin B12 and
folate deficiency" and "Treatment of vitamin B12 and folate deficiencies".)

● Enzyme-inducing ASMs have been associated with an increased prevalence of

hyperlipidemia and other markers of vascular risk [49,50]. Lipid screening is therefore
suggested in patients who require long-term therapy with enzyme-inducing drugs. (See
"Screening for lipid disorders in adults".)

● Retrospective data suggest that people with epilepsy who use ASMs have an increased risk
of cardiovascular events [51]. However, it is unclear whether enzyme-inducing ASMs are
associated with a greater risk of cardiovascular disease than nonenzyme-inducing ASMs, as
the evidence is inconsistent [51,52].

● Bone loss has also been described in patients receiving long-term ASMs. (See "Antiseizure
medications and bone disease".)

Maximizing the likelihood of a successful outcome

Titration and monitoring — Some general principles to consider when starting an ASM

include [53-55]:

● Start treatment with a single drug (monotherapy).

● In general, the strategy is to gradually titrate to the highest dose that is tolerated and/or
produces seizure freedom (start low and go slow). The concept is to slowly titrate up to a
dose that causes persistent or recurrent side effects and then to titrate back down to a
previously tolerable dose.
 Using this approach, there is only one decision to make if breakthrough seizures occur,
which is to add a second seizure medication; raising the dose to achieve seizure control is
not a good option because the patient previously had persistent/recurrent side effects at
the next dosage level up. This strategy is especially helpful with ASMs that have easily
identified, dose-related side effects and a narrow therapeutic index.

● Monitor treatment regularly. At regular office visits, clinicians should ask and record seizure
frequency and medication side effects [3].

The recommended initial dose for individual ASMs and a potential titration schedule are
presented separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and
adverse effects".)

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 ASMs [56,57]:

● To establish an individual therapeutic concentration range when a patient's seizures are in

remission

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

● To assess adherence (see 'Nonadherence with antiseizure medication 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 approximately 90
percent protein bound. It is also important to measure free drug levels in pregnant women
taking ASMs that are bound significantly to serum proteins. (See "Management of epilepsy
during preconception, pregnancy, and the postpartum period", section on 'Antiseizure
medication monitoring 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 ASM levels at different points in the menstrual cycle
may play a role in breakthrough seizures in women with catamenial epilepsy. (See "Initial
treatment of epilepsy in adults", section on 'Catamenial epilepsy'.)

Patient education — Before treatment is initiated, the clinician 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, clinicians must
tailor discussions to clarify the impact of the condition on the specific patient's quality of life and
expectations of the treatment plan. These discussions will improve the likelihood that the patient
will comply with the plan of treatment.

The clinician should impress upon the patient, family, and patient's friends the critical need to
follow the prescribed drug regimen. Nonadherence to ASM treatment regimen is associated
with increased risk of mortality, as well as hospitalization and injury [58]. (See "Comorbidities
and complications of epilepsy in adults".)

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 5 and table 6). The patient
must also be warned not to stop taking an ASM 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 clinician because these
might affect serum concentrations of their ASMs [59,60]. (See "Initial treatment of epilepsy in
adults", section on 'Pharmacokinetics'.)

Seizure calendar — Patients and family members should be asked to record seizures and ASM
doses on a calendar or diary, which can then be brought or sent to the clinician 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 [61,62].

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 [63]. 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 [64]. (See "Initial treatment of epilepsy in adults", section on 'Catamenial
epilepsy'.)

Clinicians should recognize that patients are often unaware of their seizures and may therefore
significantly underestimate the number of seizures that occur, especially those that occur during
sleep or that disrupt consciousness [65]. Prolonged electroencephalography (EEG) recordings
may be helpful in such patients to determine seizure frequency, either ambulatory or in a video-
EEG monitoring unit. (See "Video and ambulatory EEG monitoring in the diagnosis of seizures
and epilepsy".)

Generic substitution — The use of generic versus brand-name ASMs in people with epilepsy
has attracted much attention and debate, and the evidence is mixed in terms of whether generic
substitution of ASMs has an adverse impact on seizure control and toxicity.

Using pharmacokinetic data submitted to the FDA, one study found that while most generic
ASMs provide total drug delivery similar to the reference product, differences in peak
concentrations were more common, and switches between generic products caused greater
changes in plasma drug concentrations than generic substitution of the reference product [66].
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 [67-71]. At least
for generic lamotrigine, however, such variations do not appear to cause harm [72-74].

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

● Three large case-control studies have found that changes in ASM formulation involving
generics was a risk factor for emergency or hospital-level treatment of epilepsy (odds ratio
[OR] 1.78 to 1.81) [75-77].

● Some, but not all [78,79], studies using medical and pharmacy claims databases have
found that generic switching of ASMs is associated with higher epilepsy-related medical
utilization rates (eg, hospitalizations) and seizure-related injuries [80-84].

● A retrospective study of breakthrough seizures that occurred in association with generic

substitution found that ASM blood levels at the time of the seizure were on average 33
percent lower than previous levels obtained when the patient was using brand-name ASMs
[85].
 ● Additional anecdotal reports, small case series, and patient surveys [86-89].

By contrast, a systematic review and meta-analysis of seven trials in which the frequency of
seizures was compared between a brand-name ASM and a generic alternative found no
difference in the odds of seizures between treatment regimens [90]. The FDA maintains that
there is no convincing evidence that people with epilepsy have lessened seizure control when
taking generic medications. In addition, an analysis of generic oral ASMs approved in Europe
concluded that the risk of non-bioequivalence between individual generic products was small
and that switching across generic products was unlikely to cause clinically important changes in
plasma drug levels [91].

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 clinician 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 breakthrough seizures or toxicity along
with other possible explanations, including differences in pharmacokinetics or appearance,
which can influence adherence.

Alcohol intake — Alcohol consumption in small amounts (one to two drinks per day) may not
affect seizure frequency or serum levels of ASMs in patients with well-controlled epilepsy [92].
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 [93].

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. Patients who are otherwise medically cleared
to drive should nevertheless avoid driving and other high-risk activities for 24 to 48 hours after
heavy alcohol intake due to the higher risk of seizures.

Nonadherence with antiseizure medication therapy — Up to 50 percent of patients with

epilepsy may not take their medications as directed; over one-half of those evaluated in
emergency departments for recurrent seizures have been nonadherent [94]. Nonadherence to
ASM treatment regimen is not only associated with increased seizures, but also with increased
risk of mortality, as well as hospitalization and injury [58,95].

Clinicians should suspect nonadherence if a patient denies the diagnosis of epilepsy, has limited
financial means to pay for ASMs, 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.

Adherence diminishes when intervals between office visits grow longer and when medication
regimens grow increasingly complex and expensive. Clinicians should be attuned to out-of-
pocket costs and strive to use the simplest regimen possible, with generic substitutions when
appropriate. (See 'Generic substitution' above and "Patient education: Coping with high
prescription drug prices in the United States (Beyond the Basics)".)

Nonadherence also often results from a failure to effectively communicate. Written information
about medications and changes in dosing should be provided in simple language. Improving the
patient's understanding of their disorder and the need for regular intake of medications may
also improve motivation and adherence. 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 [96]. Another found that three sessions of motivational interviewing and
behavior-change techniques improved not only medication adherence but also self-perceptions
of control and coping [97].

DRUG-RESISTANT EPILEPSY

There is no standardized definition of drug-resistant epilepsy, previously referred to as 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 antiseizure medication (ASM) schedules (whether as
monotherapies or in combination) to achieve sustained seizure freedom [98]. (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 ASM trials. In particular, video-electroencephalography (EEG) monitoring to
confirm the epileptic nature of spells should be considered in anyone still having seizures after
two ASM 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 (see "Surgical treatment of epilepsy in adults" and "Vagus
nerve stimulation therapy for the treatment of epilepsy"). Deep brain stimulation and responsive
cortical stimulation are emerging valid treatment options for select patients with drug-resistant
epilepsy (see "Evaluation and management of drug-resistant epilepsy", section on 'Deep brain
stimulation' and "Evaluation and management of drug-resistant epilepsy", section on
'Responsive cortical stimulation'). The ketogenic or modified Atkins diet may be helpful in
selected patients. (See "Surgical treatment of epilepsy in adults" and "Ketogenic dietary
therapies for the treatment of epilepsy" 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 [99].

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

ALTERNATIVE THERAPIES

Several randomized trials have demonstrated modest efficacy of a standardized preparation of

cannabidiol oil in specific patient groups (eg, Dravet syndrome, Lennox-Gastaut syndrome).
However, unregulated formulations containing lower concentrations of CBD have only anecdotal
evidence in support of their efficacy. The randomized trial data are reviewed separately. (See
"Evaluation and management of drug-resistant epilepsy", section on 'Cannabinoids' and
"Seizures and epilepsy in children: Refractory seizures", section on 'Cannabinoids' and "Dravet
syndrome: Management and prognosis" and "Epilepsy syndromes in children", section on
'Lennox-Gastaut syndrome'.)

Some other herbal medicines and dietary supplements, including melatonin, may have
anticonvulsant effects, but few have been tested in rigorous trials [100-102]. Other herbal
medicines and dietary supplements may instead be proconvulsant [103]. In addition, as with
other drugs, alternative medications and supplements can affect the metabolism of antiseizure
medications (ASMs) 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 ASM levels in such patients.

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
[104,105].

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 [106-109]. Clinicians
should regularly review these issues with their female patients with epilepsy [3]. Pregnancies
should be planned, and women with epilepsy require close follow-up in pregnancy. (See
"Management of epilepsy during preconception, pregnancy, and the postpartum period".)

Effect of antiseizure medications on the fetus — There is an increased risk of both major and
minor malformations in fetuses exposed to antiseizure medications (ASMs). 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 during pregnancy and postpartum
period", section on 'Effect of ASMs on the fetus and neonate'.)

ASM therapy should be optimized before conception, if possible, to minimize exposure of the
fetus to potential teratogenic effects of ASMs. Because there is no agreement as to which ASM is
least teratogenic, the ASM that stops seizures in an individual patient is the one that should be
used. An exception is valproate, for which there are strong data regarding increased risk of
malformations and adverse developmental outcomes. Where possible, valproate should be
avoided in women of childbearing potential and should not be prescribed as first-line therapy
for focal epilepsy in these patients, given the availability of numerous other ASMs with similar
efficacy and lower fetal risks [110]. For seizure or epilepsy types where valproate is the most
effective treatment (eg, some genetic generalized epilepsies), a process of shared decision
making is particularly important when choosing first-line therapy, accounting for the fetal risks
associated with valproate as well as the risks and benefits of alternative therapies. (See
"Management of epilepsy during preconception, pregnancy, and the postpartum period",
section on 'Choice of antiseizure medication'.)

Folic acid supplementation — Folate should be routinely prescribed to all women of

childbearing age taking ASMs. Patients taking valproate or carbamazepine should receive daily
folic acid supplementation (up to 4 mg/day) for one to three months prior to conception. Women
who are taking other ASMs should take the more standard lower dose of folic acid (0.4 to 0.8
mg/day). (See "Management of epilepsy during preconception, pregnancy, and the postpartum
period", section on 'Folic acid supplementation'.)

Contraception — Enzyme-inducing ASMs lower the efficacy of hormonal contraceptives (eg,

oral contraceptive pills, vaginal ring, etonogestrel implant). Thus, for patients taking enzyme-
inducing ASMs, long-acting reversible contraceptive (LARC) choices of intrauterine devices or
intramuscular depot medroxyprogesterone acetate are suggested. Alternatively, a higher-dose
combined oral contraceptive pill may be effective if one of the LARC options is not used,
although precise studies are lacking. This issue is discussed in greater detail separately. (See
"Management of epilepsy during preconception, pregnancy, and the postpartum period",
section on 'Birth control'.)

Fertility — While a number of studies have suggested that women with epilepsy have
increased rates of infertility, as high as 33 to 38 percent [111,112], other studies have not
confirmed this finding [113]. It is also uncertain whether this association is linked to epilepsy
itself or to ASM 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 [114].

There is evidence that suggests that ASM 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 [111]. Valproate, in particular, has been linked to an increased risk of polycystic ovary
disease, a leading cause of infertility in woman [115]. (See "Epidemiology, phenotype, and
genetics of the polycystic ovary syndrome in adults", section on 'High-risk groups'.)

Poststroke seizures — Stroke is the most common cause of seizures and epilepsy in population
studies of adults over the age of 35 [116]. A 2020 systematic review and meta-analysis of
seizures occurring after acute ischemic stroke reperfusion therapy (intravenous thrombolysis
and/or mechanical thrombectomy) included 25 studies with 13,573 patients [117]. The pooled
incidence of poststroke seizures was 5.9 percent. Among studies reporting the time of seizure
onset, the incidence of early poststroke seizures (occurring within seven days) was 3.2 percent,
while the incidence of late poststroke seizures (occurring after seven days) was 6.7 percent. In an
international, multicenter prospective study from 2000, poststroke 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 [118]. 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 international
prospective study [118]. 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 [119].

By 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 [120]. 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, poststroke 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 [121]. 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.

The most consistently identified risk factors for acute and late poststroke seizures are worse
stroke severity, cortical location, and hemorrhagic lesions [118,121-125]. For primary
intracerebral hemorrhage, subcortical hematoma location may actually pose higher risk for late
seizures than cortical location [126]. Younger age has been reported as a risk factor for late
seizures in at least one large study [121]. One prospective study found that preexisting dementia
was a risk factor for late seizures (odds ratio [OR] 4.66, CI 1.34-16.21) but not for early seizures
[127]. Dementia is a risk factor for epilepsy in patients without stroke as well. (See "Seizures and
epilepsy in older adults: 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 [128].

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 clinicians empirically treat patients who
develop late-onset seizures in the setting of a stroke history within the previous two to three
years [119].

The efficacy of specific ASMs for poststroke seizures has not been rigorously assessed in
controlled trials, although most seizures can be controlled with a single agent [129]. The
evidence does not support one specific ASM over another [130]. Several considerations factor
into the choice of ASM in this population. Studies suggest that newer ASMs have similar efficacy
but a more favorable adverse event profile in older patients (see "Antiseizure medications:
Mechanism of action, pharmacology, and adverse effects" and "Seizures and epilepsy in older
adults: Treatment and prognosis"). In one prospective randomized trial, the lamotrigine
treatment arm had fewer dropouts due to adverse events than did the carbamazepine arm;
lamotrigine was also more efficacious, although this did not reach statistical significance [131].
Gabapentin has been associated with 80 percent seizure remission in one uncontrolled study of
poststroke epilepsy [132].

Older patients — ASM use in older adult patients is complicated by several factors, including
age-related alterations in protein binding, reduced hepatic metabolism, and diminished renal
clearance of medications. In addition, medical comorbidities and polypharmacy are more often a
concern in older adults. The selection of ASM treatment in older adults is discussed separately.
(See "Seizures and epilepsy in older adults: Treatment and prognosis".)

Sleep-related epilepsy — Several epilepsy syndromes manifest with seizures that occur

exclusively or predominantly during sleep. Most are focal epilepsy syndromes with genetic or
structural etiologies. The most common of these is nocturnal frontal lobe epilepsy (NFLE), also
referred to as "sleep-related hypermotor epilepsy." Nocturnal temporal, parietal, and occipital
lobe epilepsies also occur but are less common and have overlapping clinical features with NFLE.
Most have an onset in adolescence or early adulthood. The clinical features, diagnosis,
differential diagnosis, and management of sleep-related epilepsy are discussed separately. (See
"Sleep-related epilepsy syndromes", section on 'Sleep-related focal epilepsies'.)

Other causes — The treatment of epilepsy in the setting of brain tumors and head trauma is
discussed separately. (See "Seizures in patients with primary and metastatic brain tumors" and
"Posttraumatic seizures and epilepsy".)

COMPLICATIONS AND COMORBIDITIES

Epilepsy is a chronic disease associated with an increased risk of a variety of psychiatric and
medical comorbidities that can adversely impact quality of life as well as life expectancy.
Comorbidities can arise due to common underlying predispositions, direct effects of seizures,
underlying epilepsy etiologies, and adverse effects of antiseizure medications (ASMs) and other
therapies. Depression and anxiety are particularly common in adults with epilepsy, and
screening should be a routine part of long-term follow-up.

These and other comorbidities and complications of epilepsy in adults are discussed separately.
(See "Comorbidities and complications of epilepsy in adults".)

DISCONTINUING ANTISEIZURE MEDICATION THERAPY

After a two- to four-year seizure-free interval, it is reasonable to begin a discussion about
continued antiseizure medication (ASM) therapy versus a trial of discontinuation. This decision
must be individualized and weighs the risks of seizure recurrence against the possible benefits
of drug withdrawal, all of which may vary significantly across patients.

Risks and benefits of drug withdrawal — There are several reasons to consider discontinuing
ASMs in appropriate patients.

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

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

● Cognitive and behavioral side effects of ASMs may be subtle and not fully recognized until
drugs are discontinued [133].

● Some ASMs 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 ASM therapy.

The main disadvantage is the possibility that seizures will recur. The psychosocial implications
may be particularly significant for adults who are employed, who drive, and whose lifestyle
would be adversely affected by recurrent seizures. There is also a potential risk that seizure
control will not be regained to the same degree when therapy is resumed compared with before
discontinuation. The risk of this scenario appears to be small, however [134,135].

Estimating risk of seizure recurrence — There is no certain way to prospectively identify

patients who will remain seizure free after they discontinue ASM therapy and no high-quality
studies to guide decision making. In addition to confirming the time elapsed since the last
seizure, clinicians should review the epilepsy history and most recent neuroimaging studies. An
electroencephalogram (EEG) is often obtained to help with risk stratification, as epileptiform
abnormalities are a risk factor for seizure recurrence [134]. However, their contribution appears
to be quite modest beyond what is derived from other clinical factors, and we do not routinely
obtain an EEG in all patients who are considering drug discontinuation.

Based on a meta-analysis of observational studies with varying entry criteria and patient
characteristics at the time of drug discontinuation in nearly 10,000 patients, the cumulative
seizure recurrence rate after drug withdrawal in patients with epilepsy is approximately 35
percent [136]. In nonsurgical cohorts, approximately two-thirds of recurrences occur within the
first year after drug discontinuation; in surgical cohorts, only half of eventual recurrences occur
within the first year. (See "Surgical treatment of epilepsy in adults", section on 'Antiseizure
medication management after surgery'.)

Prospective studies comparing continued ASM treatment with drug withdrawal 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 ASM treatment or slow withdrawal [137]. By two years after randomization, 22
and 41 percent of patients, respectively, experienced seizure relapse. 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 ASM (which increased recurrence).

● The second study included 330 patients with epilepsy who were also seizure free for two
years on a single ASM and had consented to drug withdrawal [138]. Approximately two-
thirds of the patients elected to proceed with drug withdrawal, and the remaining one-
third continued therapy. The overall rate of seizure relapse was higher among those who
discontinued therapy (50 versus 28 percent). Among those who discontinued therapy, the
probabilities of relapse at one, two, three, and five years were 26, 43, 49, and 52 percent,
respectively. Duration of active disease and length of remission before ASM withdrawal
influenced the risk of relapse.

● A third study enrolled patients who were seizure-free on ASM monotherapy and randomly
assigned them to ASM withdrawal (n = 79) or no withdrawal (n = 81) [133]. At 12 months,
there was a trend toward a higher seizure relapse rate in the withdrawal group (15 percent
versus 7 percent, RR 2.46, 95% CI 0.85-7.08). While the difference was not statistically
significant, this may be due to the small number of participants, leading to wide confidence
intervals around the estimate of effect.

More than 20 different variables have been associated with risk of seizure recurrence upon ASM
discontinuation in individual studies [136]. In a meta-analysis of individual patient data from 10
studies and 1769 patients examining risk of seizure recurrence after drug discontinuation, the
following factors were independent predictors of seizure recurrence [134]:

● Epilepsy duration before remission (longer duration associated with higher risk)
● Seizure-free interval before ASM withdrawal (shorter interval associated with higher risk)
● Age at onset of epilepsy (onset in adulthood associated with higher risk)
 ● History of febrile seizures
● Number of seizures before remission (≥10 associated with higher risk)
● Absence of a self-limiting epilepsy syndrome (eg, absence epilepsy, benign epilepsy with
centrotemporal spikes)
● Epileptiform abnormality on EEG before withdrawal

The magnitude of risk for any one of these variables ranged from 1.3 to 1.5 times the risk of
recurrence compared with the absence of the variable. A history of seizure recurrence with past
attempts at drug withdrawal was not an independent predictor of future failure.

A nomogram for individualized prediction of recurrence risk derived from the patient-level data
in this meta-analysis is available at http://epilepsypredictiontools.info [134]. The nomogram
should not be used as a substitute for an individualized discussion of a full range of potential
risks and benefits. It does not apply to patients with acute symptomatic seizures or neonatal
seizures, as these populations were not included in the study, or to patients with juvenile
myoclonic epilepsy, who were underrepresented and who are known to have a high rate of
seizure relapse (>80 percent) with attempted ASM withdrawal. Patients who have had epilepsy
surgery were also underrepresented in the study. (See "Juvenile myoclonic epilepsy", section on
'Prognosis'.)

Other factors that may increase risk but for which the data are less consistent include [133,139-
144]:

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

● Intellectual disability
● Abnormal neurologic examination
● Multiple seizure types
● Poor initial response to treatment
● Combination therapy at the time of withdrawal
● Family history of epilepsy
● Hippocampal atrophy or abnormal hippocampal signal on magnetic resonance imaging
(MRI)

Thus, the choice to taper ASMs must be made on an individual basis, weighing the potential risk
of seizure recurrence after discontinuing therapy against that of continuing therapy. 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 their own case. As an example, one may have quite different recommendations regarding
ASM 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 approximately a 20 to 25 percent risk of seizure recurrence after ASM
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 ASM therapy rather than risk
having seizures recur. However, one should also keep in mind that the risk is not zero even with
continued ASMs.

Recommendations of others — A 2021 practice advisory from the American Academy of

Neurology (AAN) for ASM withdrawal in seizure-free patients recommended that the decision
should incorporate individual patient characteristics and preferences [145]. The AAN concluded
that it is unknown if EEG or imaging studies inform the decision to withdraw ASMs. Based upon
low-quality evidence, the AAN found no difference in quality of life for patients with well-
controlled epilepsy who stop ASMs compared with those who continue taking ASMs. In addition,
the evidence review did not suggest an increased risk of status epilepticus or death after ASM
withdrawal.

Withdrawal schedule — There are no data that indicate an optimal tapering regimen when the
decision is made to discontinue ASM therapy [146]. The following considerations may be helpful:

● Rapid changes in drug treatment increase the risk of more severe seizures [147]. Slow rates
of ASM taper (six months) were relatively similar to more moderate rates (two to three
months) in one large study [137].

● 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.

● There are no guidelines or general consensus regarding driving restrictions during and
after ASM withdrawal. (See "Driving restrictions for patients with seizures and epilepsy",
section on 'Discontinuing medication'.)

DRIVING AND OTHER 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 clinician's evaluation of their ability to drive safely.

Clinicians should also consider the potential neurotoxic side effects of antiseizure medications
(ASMs), such as sedation and double vision ( table 5) when counseling patients about driving.

A listing of individual state driving requirements can be found on the Epilepsy Foundation
website at https://www.epilepsy.com/driving-laws. Additional details about driving
restrictions in patients with epilepsy are discussed separately. (See "Driving restrictions for
patients with seizures and epilepsy".)

Questions may arise about participation in sports and other activities, and clinicians may be
asked to provide medical clearance before a patient can participate. These decisions should be
individualized, weighing not only the potential risks of participation but also the benefits of
physical exercise and social engagement [148].

Factors to consider include the type of sport or activity, the probability of a seizure occurring
during the activity and related implications, the amount of supervision available during the
activity, the patient's seizure type and severity, the consistency of any prodromal symptoms,
relevant seizure precipitants, a history of seizure-related accidents or injuries, recent seizure
control, degree of adherence to therapy, and the willingness of the patient and parents to take
on risk. The International League Against Epilepsy has published a consensus-based guideline
on sports participation in patients with epilepsy, which divides sports into three risk categories
and proposes a decision-making framework for each risk category [148].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in
adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

● Beyond the Basics topic (see "Patient education: Seizures in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Goals – 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. (See 'Introduction' above.)

● Need for ASM – Immediate antiseizure medication (ASM) 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 antiseizure medication
therapy'.)

• We recommend initiating an ASM in monotherapy in individuals who are at high risk of

recurrent seizures (Grade 1A). Selection of an ASM 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 antiseizure medication'.)

• If the first ASM trial is unsuccessful, a second ASM trial is recommended (Grade 1A).
ASM therapy is as likely to fail from adverse effects of medication as from lack of
efficacy. The chance of successful ASM treatment diminishes if the preceding ASM trial
failure was due to lack of efficacy. However, treatment failure caused by adverse effects
 does not diminish the likelihood of success with subsequent ASM treatments. (See
'Subsequent drug trials' above.)

● Measures to improve outcome – 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 and ASMs – Women of childbearing age should be counseled regarding possible
teratogenic effects of ASMs and should consider taking supplemental folate to limit the
risk. Enzyme-inducing ASMs can limit the effectiveness of oral contraception; alternative
forms of birth control should be considered in women taking these ASMs. (See 'Women of
childbearing age' above.)

● Specific adverse reactions of ASMs – Mood problems, anxiety, and depression are more
prevalent in persons with epilepsy than in the general population. In addition, ASM
treatment has been associated with suicidality. Patients treated with ASMs should be
monitored for changes in mood and suicidality. (See 'Specific adverse reactions' above.)

● Comorbidities and complications – 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 "Comorbidities and complications of epilepsy in adults".)

● Driving restrictions – Individuals who have had a recent epileptic seizure may be
restricted from driving. Patients who are experiencing substantial neurotoxic side effects
from ASMs should also be counseled about their appropriateness for driving until such side
effects abate. (See 'Driving and other restrictions' above.)

● ASM discontinuation – Stopping ASMs 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 ASM treatment,
and the medical and psychosocial consequences of a recurrent seizure. ASM withdrawal
should be slow, over a few to many months. (See 'Discontinuing antiseizure medication
therapy' above.)

Use of UpToDate is subject to the Terms of Use.

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Topic 2220 Version 68.0
GRAPHICS

International League Against Epilepsy (ILAE) classification of seizure types

Generalized onset seizures

Motor Nonmotor (absence)

Tonic-clonic Typical
Clonic Atypical
Tonic Myoclonic
Myoclonic Eyelid myoclonia
Myoclonic-tonic-clonic
Myoclonic-atonic
Atonic
Epileptic spasms

Focal onset seizures

Motor onset Nonmotor onset

Aware Aware
Impaired awareness Impaired awareness
Unknown awareness Unknown awareness

Automatisms Autonomic
Atonic* Behavior arrest
Clonic Cognitive
Epileptic spasms* Emotional
Hyperkinetic Sensory
Myoclonic
Tonic

Focal to bilateral tonic-clonic Focal to bilateral tonic-clonic

Unknown onset seizures

Motor Nonmotor

Tonic-clonic Behavior arrest

Epileptic spasms

Unclassified seizures ¶

ILAE: International League Against Epilepsy.

* Degree of awareness usually is not specified.

​¶ Due to inadequate information or inability to place in other categories.

Adapted from: Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League
Against Epilepsy: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017.

Graphic 91409 Version 4.0

Common descriptors of behaviors during focal seizures (alphabetically)

Cognitive Automatisms

Acalculia Aggression
Aphasia Eye-blinking
Attention impairment Head-nodding
Déjà vu or jamais vu Manual
Dissociation Oral-facial
Dysphasia Pedaling
Hallucinations Pelvic thrusting
Illusions Perseveration
Memory impairment Running (cursive)
Neglect Sexual
Forced thinking Undressing
Responsiveness impairment Vocalization/speech
Walking

Emotional or affective Motor

Agitation Dysarthria
Anger Dystonic
Anxiety Fencer's posture (figure-of-4)
Crying (dacrystic) Incoordination
Fear Jacksonian
Laughing (gelastic) Paralysis
Paranoia Paresis
Pleasure Versive

Autonomic Sensory

Asystole Auditory
Bradycardia Gustatory
Erection Hot-cold sensations
Flushing Olfactory
Gastrointestinal Somatosensory
Hyper/hypoventilation Vestibular
Nausea or vomiting Visual
Pallor
Laterality
Palpitations
Piloerection Left
Respiratory changes Right
Tachycardia Bilateral
From: Fisher RS, Cross JH, D'Souza C, et al. Instruction manual for the ILAE 2017 operational classification of seizure types.
Epilepsia 2017. DOI: 10.1111/epi.13671. http://onlinelibrary.wiley.com/wol1/doi/10.1111/epi.13671/abstract. Copyright ©
2017 The International League Against Epilepsy. Reproduced with permission of John Wiley & Sons Inc. This image has been
provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared
or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink
service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library
(http://onlinelibrary.wiley.com).

Graphic 94645 Version 3.0

Therapeutic spectrum of antiseizure medications

Broad spectrum:

Drugs used to treat a broad range of seizure types (both focal and generalized onset)

Brivaracetam
Clobazam
Felbamate
Lamotrigine*
Levetiracetam
Perampanel
Rufinamide
Topiramate
Valproate
Zonisamide

Narrow spectrum (focal):

Drugs used primarily for focal-onset seizures (including focal evolving to bilateral convulsive seizures ¶ )

Carbamazepine Δ
Cenobamate
Eslicarbazepine ◊
Gabapentin ◊
Lacosamide
Oxcarbazepine ◊
Phenobarbital Δ
Phenytoin Δ
Pregabalin
Primidone Δ
Stiripentol
Tiagabine ◊
Vigabatrin ◊
 Narrow spectrum (absence):

Absence seizures only (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 US Food and Drug Administration.

* May worsen or precipitate myoclonic seizures.

¶ Previously referred to as secondary generalized seizures.

Δ Some evidence of efficacy for generalized-onset tonic-clonic seizures, but may also worsen certain
generalized seizure types.

◊ Potential to worsen certain generalized seizure types.

Graphic 78021 Version 17.0

Antiseizure medications with the potential to worsen generalized seizure
types

Medications with potential to

Seizure type and patient population
precipitate or aggravate seizures*

Generalized-onset tonic-clonic seizures in children Carbamazepine, phenytoin

and adults

Absence seizures in children Carbamazepine, oxcarbazepine, phenobarbital,

phenytoin, tiagabine, and vigabatrin

Absence seizures, myoclonic seizures, and in Carbamazepine, gabapentin, lamotrigine,

some cases generalized-onset tonic-clonic oxcarbazepine, phenytoin, tiagabine, vigabatrin ¶
seizures in patients with juvenile myoclonic
epilepsy

* Low-quality evidence, based primarily on scattered reports.

¶ Myoclonic seizures only, also reported in other generalized epilepsy syndromes.

Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness
as initial monotherapy for epileptic seizures and syndromes. Epilepsia 54:551-63; 2013.

Graphic 106663 Version 3.0

Common side effects of antiseizure medications

Antiseizure
Systemic side effects Neurologic side effects
medication

Brivaracetam* Nausea, vomiting, constipation, fatigue Headache, somnolence, dizziness,

ataxia, abnormal coordination,
nystagmus

Cannabidiol Anemia, decreased appetite, diarrhea, CNS depression (eg, drowsiness,

infection, dose-related elevations of lethargy, sedation), malaise, insomnia,
liver transaminases (ALT and/or AST), sleep disturbance
rash, fatigue

Carbamazepine Nausea, vomiting, diarrhea, Drowsiness, dizziness, blurred or

hyponatremia, rash, pruritus double vision, lethargy, headache

Cenobamate Fatigue Somnolence, dizziness, headache,

diplopia

Clobazam Increased salivation, nausea, vomiting, Somnolence, aggression, irritability,

constipation ataxia, insomnia

Eslicarbazepine Nausea, vomiting, diarrhea, fatigue, Dizziness, drowsiness, headache,

hyponatremia, rash 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

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

loss

Gabapentin Infrequent Somnolence, dizziness, ataxia

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

Lamotrigine Rash, nausea Dizziness, tremor, diplopia

Levetiracetam Fatigue, infection Somnolence, dizziness, agitation,

anxiety, irritability, depression

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

ataxia, diplopia

Perampanel Weight gain, fatigue, nausea Dizziness, somnolence, irritability, gait

disturbance, falls, aggression, mood
alteration
 Phenobarbital Nausea, rash Alteration of sleep cycles, sedation,
lethargy, behavioral changes,
hyperactivity, ataxia, tolerance,
dependence

Phenytoin Gingival hypertrophy, rash Confusion, slurred speech, double

vision, ataxia

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

Primidone Nausea, rash Alteration of sleep cycles, sedation,

lethargy, behavioral changes,
hyperactivity, ataxia, tolerance,
dependence

Rufinamide Nausea, vomiting, fatigue Dizziness, somnolence, headache

Stiripentol Nausea, decreased appetite, weight Somnolence, agitation, ataxia,

loss hypotonia, tremor, dysarthria,
insomnia

Tiagabine Abdominal pain, nausea, lack of energy Dizziness, somnolence, nervousness,

tremor, difficulty concentrating

Topiramate Weight loss, paresthesia, fatigue Nervousness, difficulty concentrating,

confusion, depression, anorexia,
language problems, anxiety, mood
problems, tremor

Valproate Weight gain, nausea, vomiting, hair Tremor, dizziness

loss, easy bruising

Vigabatrin Vision loss, fatigue Drowsiness, dizziness

Zonisamide Nausea, anorexia Somnolence, dizziness, ataxia,

confusion, difficulty concentrating,
depression

ALT: alanine aminotransferase; AST: aspartate aminotransferase; CNS: central nervous system.

* Based upon limited experience from preapproval clinical trials.

Graphic 59755 Version 19.0

Rare but serious side effects of antiseizure medications

Drug Side effects*

Brivaracetam ¶ Hypersensitivity reactions including bronchospasm and angioedema, leukopenia,

neutropenia, psychosis

Cannabidiol Hypersensitivity reactions (including angioedema, erythema, and pruritus),

suicidal ideation

Carbamazepine Agranulocytosis, aplastic anemia, SJS/TEN, hepatic failure, DRESS, dermatitis/rash,

serum sickness, pancreatitis, lupus syndrome, hypogammaglobulinemia

Cenobamate QT interval shortening, DRESS/multiorgan hypersensitivity

Clobazam Respiratory depression, SJS/TEN, DRESS

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

SJS/TEN

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

sickness, drug-induced immune thrombocytopenia

Felbamate Aplastic anemia, liver failure

Gabapentin Multiorgan hypersensitivity, respiratory depression

Lacosamide Prolonged PR interval, atrioventricular block, multiorgan hypersensitivity,

neutropenia

Lamotrigine SJS/TEN, DRESS/multiorgan hypersensitivity, aseptic meningitis,

hypogammaglobulinemia, cardiac rhythm and conduction abnormalities

Levetiracetam SJS/TEN, anaphylaxis and angioedema, pancytopenia, psychosis,

hypogammaglobulinemia

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

leukopenia

Perampanel Severe neuropsychiatric effects (eg, hostility, aggression)

Phenobarbital Agranulocytosis, SJS/TEN, hepatic failure, dermatitis/rash, serum sickness,

connective tissue contractures (eg, Dupuytren), complex regional pain syndrome

Phenytoin Agranulocytosis, SJS/TEN, DRESS, aplastic anemia, hepatic failure, dermatitis/rash,

serum sickness, adenopathy, pseudolymphoma, neuropathy, ataxia, lupus
syndrome, hirsutism

Pregabalin Angioedema, hypersensitivity reactions, rhabdomyolysis

Primidone Acute toxic reaction (sedation, dizziness, ataxia, nausea, and vomiting),
agranulocytosis, SJS/TEN, hepatic failure, dermatitis/rash, serum sickness,
connective tissue contractures (eg, Dupuytren)

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

 Stiripentol Limited information: severe somnolence, marked weight loss, neutropenia and
thrombocytopenia, suicidal ideation and behavior

Tiagabine SJS/TEN, nonconvulsive status epilepticus

Topiramate Acute myopia and glaucoma, kidney stones, oligohidrosis and hyperthermia
(which primarily occur in children)

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

sickness, pancreatitis, polycystic ovary syndrome, hypogammaglobulinemia

Vigabatrin MRI abnormalities, depression, weight gain

Zonisamide Rash, SJS/TEN, aplastic anemia, agranulocytosis, nephrolithiasis; acute myopia

and secondary angle closure glaucoma, hyperammonemia and encephalopathy;
in children, fever and hyperhidrosis

SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; DRESS: drug reaction with
eosinophilia and systemic symptoms; MRI: magnetic resonance imaging.

* As a class, antiseizure medications have been associated with an increased risk of suicidal ideation
and suicidal behavior.

¶ Based upon limited experience from preapproval clinical trials.

Graphic 78896 Version 28.0

Pharmacologic properties of antiseizure medications

Enzyme or
Metabolism and Protein binding Half-lif
  transporter
clearance (%) ¶ adults (h
induction/inhibition*

Brivaracetam Metabolized Inhibits epoxide ≤20 9

primarily by CYP- hydroxylase Δ
independent
hydrolysis (60%) and
CYP2C19 (30%)

Dose adjustment is
needed in hepatic
impairment

Cannabidiol Hepatic (primarily) Inhibits BCRP/ABCG2, >94 56 to 61

and gut by BSEP/ABCB11, CYP2C19
CYP2C19, CYP3A4, (moderate)
UGT1A7, UGT1A9,
May increase serum
and UGT2B7 to
concentration of
active metabolite 7-
clobazam and the active
OH-CBD and then to
metabolite(s) of clobazam
inactive metabolite
7-COOH-CBD

Dose adjustment is
needed in moderate
to severe hepatic
impairment

Carbamazepine >90% metabolized Potent and broad- 75 25 to 65 (init

by CYPs 3A4 (major) spectrum inducer of CYP, enzyme-ind
and 1A2/2C8 (minor) UGT-glucuronidation, and naive patien
to active (epoxide) P-gp
8 to 22 (afte
and inactive
weeks due t
metabolites
induction)
Dose adjustment is
needed in severe
renal impairment;
use is not
recommended in
moderate or severe
hepatic impairment

Cenobamate Primarily May increase serum 60 50 to 60 hou

metabolized by concentrations of
glucuronidation via clobazam, phenobarbital,
 UGT2B7 and to a phenytoin, and CYP2C19
lesser extent by substrates
UGT2B4, and by
May decrease serum
oxidation via
concentrations of
CYP2E1, CYP2A6,
carbamazepine,
CYP2B6, and to a
lamotrigine, and CYP2B6
lesser extent by
and CYP3A substrates
CYP2C19 and
CYP3A4/5

Dose adjustment is
needed for hepatic
impairment; not
recommended for
patients with severe
hepatic impairment
or end-stage renal
disease

Clobazam >90% metabolized Inhibits CYP2D6 (weak) 80 to 90 (clobazam, 36 to 42 (clo

by CYPs 3A4, 2C19, parent drug) parent drug
2B6 and non-CYP
70 (N- 71 to 82 (N-
transformations to
desmethylclobazam, desmethylcl
active (N-
active metabolite) active metab
desmethylclobazam)
and inactive
metabolites

Active metabolite is
primarily
metabolized by
CYP2C19

Dose adjustment is
needed in hepatic
impairment

Eslicarbazepine Prodrug; <33% of Induces CYP3A4 <40 13 to 20 (pro

active form (moderate) in renal
undergoes UGT- insufficiency
Inhibits CYP2C19 (weak)
glucuronidation
(including <5%
metabolized to
oxcarbazepine); 66%
is excreted renally
as unchanged drug

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

Ethosuximide ~80% metabolized None <5 40 to 60

by CYP3A4 (major)
and non-CYP
transformations to
inactive metabolites

Felbamate 50% metabolized by Increases conversion of 25 13 to 22 (pro

CYPs 3A4, 2E1 carbamazepine to active in renal
(minor); ~50% epoxide metabolite; insufficiency
renally excreted as mechanism not
unchanged drug established

Dose adjustment is Inhibits CYP2C19 (weak)

needed in renal
impairment

Gabapentin >95% renally None <5 5 to 7 (prolo

excreted as renal insuffi
unchanged drug (ie, >130 hours
does not undergo anuria)
hepatic metabolism)

Dose adjustment is
needed in renal
impairment

Lacosamide 40% renally excreted None <15 13

as unchanged drug;
30% metabolized by
non-CYP
transformations
(including
methylation) to
inactive metabolite

Dose adjustment is
needed in hepatic
and renal
impairment

Lamotrigine >90% metabolized May induce its own 55 12 to 62

by UGT- metabolism by UGT-
glucuronidation and glucuronidation (minor)
other non-CYP
transformations to
inactive metabolites
 Dose adjustment is
needed in moderate
to severe renal or
hepatic impairment

Levetiracetam >65% renally None <10 6 to 8

excreted as
unchanged drug;
24% metabolized by
non-CYP
transformation
(including amidase
hydrolysis) to
inactive metabolites

Dose adjustment is
needed in renal
impairment

Oxcarbazepine Prodrug; 70% of Induces CYP3A4 (weak) 40 9 (active me

active (MHD) form and UGT-glucuronidation prolonged in
undergoes UGT- but does not induce its insufficiency
glucuronidation; own metabolism
30% is renally
excreted as
unchanged active
drug

Dose adjustment is
needed in severe
renal impairment

Perampanel >70% metabolized Appears to induce 95 105

by CYPs 3A4, 3A5 metabolism of progestin-
and non-CYP containing hormonal
transformations to contraceptives
inactive metabolites

Dose adjustment is
needed in mild or
moderate hepatic
impairment

Phenobarbital 75% metabolized by Potent and broad- 55 75 to 110

CYPs 2C19, 2C9 spectrum inducer of CYP
(minor) and and UGT-glucuronidation
glucosidase
hydrolysis and 2E1
(minor) to inactive
metabolites; 25%
 excreted renally as
unchanged drug

Dose adjustment is
needed in severe
renal or hepatic
impairment

Phenytoin >90% metabolized Potent and broad- 90 to 95 9 to >42 (do

by CYPs 2C9, 2C19, spectrum inducer of CYP dependent)
3A4 (minor) and and UGT-glucuronidation
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 None <5 6

renally as
unchanged drug

Dose adjustment is
needed in renal
impairment

Primidone 75% metabolized by Potent and broad- 0 to 20 10 to 15 (pa

CYPs 2C19, 2C9 spectrum inducer of CYP
29 to 100 (ac
(minor) and 2E1
metabolite)
(minor) to active
intermediates; ~25%
excreted renally as
unchanged drug

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

Rufinamide >90% metabolized Induces CYP3A4 (weak) 35 6 to 10

by non-CYP
transformations
(hydrolysis) to
inactive metabolites

Stiripentol Metabolized Inhibits CYP3A4, 99 4.5 to 13

primarily in the liver CYP2C19, P-gp, and BCRP
by CYP450 enzymes
CYP2C19, CYP3A4,
and glucuronidation

Tiagabine >90% metabolized None 95 7 to 9

by CYP3A4 and non-
2 to 5 (with
CYP transformations
inducing an
to inactive
medications
metabolites

Topiramate >65% excreted None 9 to 17 12 to 24

renally as
unchanged drug;
<30% metabolized
by non-CYP
transformations to
inactive
metabolites; extent
of metabolism is
increased ~50% in
patients receiving
enzyme-inducing
antiseizure
medications

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

Valproate >95% undergoes None 80 to 95 7 to 16

complex
transformations
including CYPs 2C9,
2C19, 2A6, UGT-
glucuronidation and
other non-CYP
transformation
 Dose adjustment is
needed in hepatic
impairment

Vigabatrin >90% excreted None 0 5 to 13 (unre

renally as duration of
unchanged drug

Dose adjustment is
needed in renal
impairment

Zonisamide >65% metabolized None 50 63

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

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.

* The inhibitors and inducers of CYP or UGT drug metabolism and P-gp transporters listed in this
table can alter serum concentrations of drugs that are dependent upon these enzymes or
transporters for elimination, activation, or bioavailability. Classifications are based on US Food and
Drug Administration guidance [4, 5]. Other sources may use a different classification system resulting
in some agents being classified differently. Specific interactions should be assessed using a drug
interaction program such as Lexicomp interactions included within UpToDate.

¶ Highly protein-bound antiseizure medications 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) antiseizure medication serum concentrations
is suggested. Refer to UpToDate topic for additional information.

Δ Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and
active metabolite of carbamazepine; refer to UpToDate topic.

Data from: Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.

Additional data 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.
3. Anderson GD, Hakimian S. Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment. Clin
Pharmacokinet 2014; 53:29.
4. US Food and Drug Administration. Clinical drug interaction studies – Cytochrome P450 enzyme- and transporter-
mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-
transporter-mediated-drug-interactions (Accessed on June 5, 2020).
5. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and
Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers (Accessed on June 12, 2019).

Graphic 60182 Version 35.0

Common mechanisms of antiseizure medication action

Na+ Ca+ K+ Inhibitory Excitatory SV2A

Drug
channels channels channels transmission transmission bindin

Benzodiazepines       +++    

Brivaracetam             +++

Cannabidiol       ++    

Carbamazepine +++ +        

Cenobamate ++     +    

Clobazam       +++    

Eslicarbazepine +++           

Ethosuximide   +++        

Felbamate ++ +   ++ ++  

Gabapentin   ++   ++    

Lacosamide +++          

Lamotrigine +++ +        

Levetiracetam   + + + + +++ 

Oxcarbazepine +++ + +      

Perampanel          +++   

Phenobarbital   +   +++ +  

Phenytoin +++ +        

Pregabalin   ++   ++    

Primidone   +   +++  +  

Rufinamide +++          

Stiripentol       +++    

Tiagabine       +++    

Topiramate ++ ++   ++ ++  

Valproate + +   ++ +  

Vigabatrin       +++    

Zonisamide ++ ++        

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

SV2A: synaptic vesicle protein 2A.

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 18.0

Some interactions between carbamazepine and other antiseizure
medications*
Interacting
Effects (probable mechanism)
drugs
Carbamazepine, with:
Brivaracetam Possible carbamazepine toxicity
(decreased metabolism of active
epoxide metabolite ¶ )
Decreased brivaracetam effect
(increased metabolism by CYP2C19)
Clonazepam Decreased clonazepam effect
(increased metabolism by CYP3A4)
Felbamate Possible carbamazepine toxicity
(increased concentration of active
epoxide metabolite ¶ )
Decreased felbamate effect (increased
metabolism by CYP3A4)
Lamotrigine Carbamazepine toxicity (increased
concentration of active epoxide
metabolite ¶ )
Decreased lamotrigine effect
(increased metabolism;
glucuronidation)
Levetiracetam Possible increased risk of
carbamazepine toxicity (mechanism
not established)
Possible decreased levetiracetam
concentrations (increased metabolism)
Perampanel Decreased perampanel effect
(increased metabolism by CYP3A4)
Management
Monitor clinical status; reduction of
carbamazepine dose may be needed
Monitor clinical status; brivaracetam
dose may need to be adjusted
Monitor clinical status
Monitor clinical status; felbamate and
carbamazepine dose may need to be
adjusted
A reduction in carbamazepine dose is
recommended when felbamate is
added to carbamazepine therapy.
Specific dose adjustment
recommendations are provided in the
Lexicomp monograph.
Monitor clinical status; serum
carbamazepine measurements alone
may not predict toxicity
Monitor clinical status and lamotrigine
concentrations; lamotrigine dose may
need to be increased. Specific
lamotrigine dose adjustment
recommendations are provided in the
Lexicomp monograph.
Monitor for clinical evidence of
carbamazepine toxicity
Monitor clinical effect
Monitor clinical status; perampanel
dosage may need to be adjusted
 Phenytoin Decreased carbamazepine effect Monitor clinical status and
(increased metabolism) carbamazepine and phenytoin
concentrations
Altered phenytoin effect may include
decreased or increased phenytoin
levels (mechanism not established)

Tiagabine Decreased tiagabine effect (increased Monitor clinical status

metabolism by CYP3A4)

Topiramate Possible decreased topiramate effect Monitor clinical status; may need
(increased metabolism); possible higher doses of topiramate
additive CNS side effects (mechanism
not established)

Valproate Decreased valproate effect and Monitor clinical status and valproate
possible increased toxicity (increased concentrations
metabolism by CYP 2C9, 2C19,
glucuronidation, and formation of toxic
metabolite)

Carbamazepine toxicity (increased Monitor clinical status, carbamazepine,

concentration of active epoxide and carbamazepine epoxide
metabolite and displacement from concentrations; carbamazepine dose
binding sites) ¶ may need to be adjusted

Zonisamide Decreased zonisamide effect Monitor zonisamide concentrations

(increased metabolism by CYP3A4) and clinical status; zonisamide dosage
may need to be adjusted

Carbamazepine is a strong inducer of multiple hepatic enzymes; it can reduce serum concentrations
of other drugs, including antiseizure medications. Carbamazepine is metabolized by CYP3A4 and
induces its own metabolism; serum concentrations of carbamazepine fall after first few weeks of
initial therapy. Other drugs that are inducers or inhibitors of CYP3A4 can alter serum concentrations
of carbamazepine and epoxide active metabolite. A list of CYP3A4 inhibitors and inducers is available
in a separate table in UpToDate.

CYP: cytochrome P450.

* Not all potential interactions are listed. Additional interactions of antiseizure medications and
management suggestions may be determined by using the drug interactions program included
within UpToDate.

¶ Routine carbamazepine serum measurements do not assess for accumulation of the active
carbamazepine-epoxide metabolite, but this metabolite can be measured as a separate test; refer to
accompanying text.

Data from: Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.
Graphic 80801 Version 19.0
Some interactions between phenytoin or fosphenytoin and other antiseizure
medications*

Interacting drugs Effects (probable mechanism) Management

Phenytoin or fosphenytoin, with:

Brivaracetam Decreased brivaracetam effect Monitor clinical status

(increased metabolism by CYP2C19)

Possible phenytoin toxicity Monitor clinical status and phenytoin

(decreased metabolism by CYP2C19) concentrations

Carbamazepine Decreased carbamazepine effect Monitor carbamazepine and

(increased metabolism) phenytoin concentrations

Altered phenytoin effect may include

decreased or increased phenytoin
levels (mechanism not established)

Clonazepam Decreased clonazepam effect Monitor clinical status

(increased metabolism)

  Monitor phenytoin concentrations

Eslicarbazepine Decreased eslicarbazepine Monitor clinical status;

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

Possible phenytoin toxicity Monitor clinical status and phenytoin

(decreased metabolism by CYP2C19) concentrations

Felbamate Decreased felbamate effect Monitor felbamate effect; dose may

(increased metabolism) need to be increased

Possible phenytoin toxicity Phenytoin dose reduction may be

(mechanism not established) needed; refer to Lexicomp for detail.
Monitor clinical status and phenytoin
concentrations.

Lamotrigine Decreased lamotrigine serum Monitor clinical status and

concentrations (increased lamotrigine serum concentrations;
metabolism; induction of lamotrigine dose may need to be
glucuronidation by phenytoin) adjusted

Levetiracetam Possible decreased levetiracetam Monitor clinical effect

concentrations (increased
metabolism)

Oxcarbazepine Possible decreased oxcarbazepine Monitor clinical status and

effect (increased metabolism) oxcarbazepine concentration
 Possible phenytoin toxicity with
oxcarbazepine doses of 1200 mg/day
or higher (decreased metabolism by
CYP2C19)
Monitor phenytoin concentrations
especially when oxcarbazepine
dosage is 1200 mg/day or higher;
reduction of phenytoin dose may be
needed

Perampanel Decreased perampanel effect Monitor clinical status; perampanel

(increased metabolism by CYP3A4) dose may need to be adjusted

Tiagabine Decreased tiagabine effect (increased Monitor clinical status

metabolism by CYP3A4)

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

Possible phenytoin toxicity Monitor clinical status and phenytoin

(decreased metabolism by CYP2C19) concentrations
with high doses of topiramate

Valproate Possible phenytoin toxicity Monitor clinical status and phenytoin

(displacement from binding and concentrations (unbound
decreased metabolism, complex time concentrations may be more helpful
course) than total)

Possible decreased valproate effect Monitor clinical status and valproate

and increased toxicity (increased serum concentrations
metabolism and formation of toxic
metabolite)

Zonisamide Decreased zonisamide effect Monitor clinical status and

(increased metabolism by CYP3A4) zonisamide concentrations;
zonisamide dose may need to be
adjusted

The pharmacokinetics of phenytoin are distinctive in that its metabolism by CYP2C9 and 2C19 is
saturable and half-life variable (ie, from 12 hours to up to 10 days or more) depending upon serum
levels. The magnitude of effect due to a drug interaction can vary widely based upon phenytoin
serum level, and a new steady-state phenytoin level may not occur until 2 to 3 weeks following an
alteration of therapy. Refer to accompanying text.

CYP: cytochrome P450.

* Not all potential interactions are listed. Additional interactions of antiseizure medications and
management suggestions may be determined using the drug interactions program included within
UpToDate.

Data from: Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.

Graphic 55399 Version 18.0

Some interactions between valproate and other antiseizure medications*
Interacting drugs Effects (probable mechanism)
Valproate, with:
Carbamazepine Decreased valproate effect and
possible increased toxicity (increased
metabolism by CYP 2C9, 2C19,
glucuronidation, and formation of
toxic metabolite)
Carbamazepine toxicity (increased
concentration of active epoxide
metabolite and displacement from
binding sites) ¶
Ethosuximide Possible ethosuximide toxicity
(decreased metabolism)
Possible decreased valproate effect
(mechanism not established)
Felbamate Possible decreased felbamate effect
(mechanism unknown)
Possible valproate toxicity (decreased
metabolism by CYP2C19)
Lamotrigine Lamotrigine toxicity (decreased
metabolism; glucuronidation)
Oxcarbazepine Possible decreased oxcarbazepine
effect (increased metabolism)
Phenobarbital Possible phenobarbital toxicity
(decreased metabolism by CYP2C9
and glucuronidation)
Management
Monitor clinical status and valproate
concentrations
Monitor clinical status and
carbamazepine and carbamazepine
epoxide concentrations;
carbamazepine dose may need to be
adjusted
Monitor clinical status and
ethosuximide concentrations
Monitor clinical status and valproate
concentrations
Monitor clinical status
Monitor clinical status and valproate
concentrations. A reduction in
valproate dose is recommended
when initiating felbamate. Specific
dose adjustment recommendations
are provided in the Lexicomp
monograph.
Decrease lamotrigine dose by
approximately 50%; monitor clinical
status and lamotrigine
concentrations. Specific lamotrigine
dose adjustment recommendations
for use with valproate are provided
in the Lexicomp monograph.
Monitor clinical status and
oxcarbazepine concentrations
Monitor clinical status and
phenobarbital concentrations
 Possible decreased valproate effect Monitor clinical status and valproate
(increased metabolism by concentrations
glucuronidation and CYP oxidation)

Phenytoin Possible phenytoin toxicity Monitor clinical status and phenytoin

(displacement from binding sites and concentrations (unbound
decreased metabolism; complex time concentrations may be more helpful
course) than total)

Possible decreased valproate effect Monitor clinical status and valproate

and increased toxicity (increased serum concentrations
metabolism and formation of toxic
valproate metabolites)

Rufinamide Possible increased rufinamide Monitor clinical status; a decrease in

toxicity (decreased metabolism)
initial rufinamide dose is
recommended. Specific rufinamide
dose adjustment recommendations
for use with valproate are provided
in the Lexicomp monograph.

Topiramate Possible increased hepatotoxic effect Monitor clinical status

of valproate and increased risk for
hypothermia (mechanism not
established)

Valproate is highly bound to plasma proteins and undergoes complex hepatic metabolism
including glucuronidation (30 to 50%); the unbound fraction of valproate increases as valproate
serum concentrations rise, causing wide inter-individual variability in the observed effect(s) of
drug interactions.
Valproate effects can be altered by other antiseizure medications via multiple mechanisms, eg,
altered protein binding and competitive inhibition at sites of hepatic drug metabolism (ie,
glucuronidation).

CYP: cytochrome P450.

* Not all potential interactions are listed. Additional interactions of antiseizure medications and
management suggestions may be determined using the drug interactions tool (Lexi-Interact)
included within UpToDate.

¶ Routine carbamazepine serum measurements do not assess for accumulation of the active
carbamazepine-epoxide metabolite, but this metabolite can be measured as a separate test; refer to
accompanying text.

Adapted from: Drugs for Epilepsy. Treatment guidelines from The Medical Letter 2008; 6(70):37-46. Copyright © 2008 The
Medical Letter. Additional data from: Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved and Drugs
for Epilepsy. Treatment guidelines from The Medical Letter 2013; 11(126):9-11. Copyright © 2013 The Medical Letter.

Graphic 53463 Version 16.0

Contributor Disclosures
Steven C Schachter, MD Patent Holder: Supernus Pharmaceuticals [Epilepsy]. Consultant/Advisory
Boards: Supernus Pharmaceuticals [Epilepsy]. All of the relevant financial relationships listed have been
mitigated. Paul Garcia, MD Equity Ownership/Stock Options: EnlitenAI Inc [Epilepsy]. Consultant/Advisory
Boards: Biogen [Epilepsy]; EnlitenAI Inc [Epilepsy]; Medtronics [Epilepsy]; Moon Creative Lab [Epilepsy];
Otsuka [Epilepsy]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD,
PhD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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