Initial Treatment of Epilepsy in Adults - UpToDate

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Tratamiento inicial de la epilepsia en adultos

Autor: Dr. Steven Karceski
Redactor de sección: Pablo García, MD
Redactor adjunto: 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 literatura actual hasta: sep 2022. | Última actualización de este tema: 26 de abril de 2022.
INTRODUCCIÓN
La epilepsia es el síndrome de dos o más convulsiones no provocadas que ocurren con más de
24 horas de diferencia [ 1 ]. Las convulsiones afectan a las personas de muchas maneras
diferentes. Las convulsiones son disruptivas en la vida de los pacientes y pueden causar
lesiones. Las personas con epilepsia tienen tasas más altas de comorbilidad psiquiátrica y
pueden experimentar resultados psicosociales adversos. Lo más preocupante es que las
personas con epilepsia tienen una mortalidad aproximadamente tres veces mayor en
comparación con las personas que no tienen convulsiones [ 2 ]. (Ver "Comorbilidades y
complicaciones de la epilepsia en adultos" .)
Este tema discutirá el enfoque del tratamiento inicial de las convulsiones y la epilepsia. Otros
temas abordan la evaluación de pacientes con convulsiones y epilepsia, otros aspectos del
tratamiento de la epilepsia y características de medicamentos anticonvulsivos específicos.
(Consulte "Evaluación y manejo de la primera convulsión en adultos" y "Resumen del manejo de
la epilepsia en adultos" y "Evaluación y manejo de la epilepsia resistente a los medicamentos" y
"Medicamentos anticonvulsivos: mecanismo de acción, farmacología y efectos adversos" .)
CUÁNDO COMENZAR LA TERAPIA CON MEDICAMENTOS ANTICONVULSIONES
Convulsión no provocada por primera vez : el término convulsión no provocada se refiere a
una convulsión de etiología desconocida, así como a una que ocurre en relación con una lesión
cerebral preexistente o un trastorno progresivo del sistema nervioso (a menudo denominado
https://www.uptodate.com/contents/initial-treatment-of-epilepsy-in-adults/print?search=antiseizure drugs treatment&source=search_result&selectedTi… 1/61
convulsión sintomática remota). Las convulsiones no provocadas son distintas de las

convulsiones provocadas : las convulsiones provocadas se deben a una afección aguda, como
un trastorno tóxico o metabólico, un antecedente inmediato de traumatismo craneoencefálico
o un accidente cerebrovascular muy reciente/agudo (es decir, convulsiones sintomáticas
agudas).
La decisión de iniciar o no la terapia con medicamentos anticonvulsivos en el momento de una

primera convulsión no provocada en un adulto debe ser individualizada. Los principales
factores a tener en cuenta para tomar la decisión son:
● El riesgo de convulsiones recurrentes, que varía según los factores clínicos que se analizan
a continuación (consulte "Riesgo de recurrencia de convulsiones" a continuación)
● El beneficio aproximado que se puede esperar de la terapia inmediata con medicamentos

anticonvulsivos sobre el riesgo de convulsiones recurrentes (consulte "Beneficio del
tratamiento temprano versus diferido" a continuación)
● Los perfiles de efectos secundarios de varias opciones de medicamentos anticonvulsivos,

que varían según las comorbilidades y la edad de cada paciente (consulte 'Perfiles de
efectos secundarios' a continuación y 'Condiciones médicas comórbidas' a continuación)
● Valores y preferencias del paciente, particularmente con respecto a las consecuencias

sociales de una convulsión recurrente (p. ej., implicaciones para la conducción o el
empleo) (ver 'Beneficio del tratamiento temprano versus diferido' a continuación)
Una guía basada en evidencia de la Academia Estadounidense de Neurología y la Sociedad

Estadounidense de Epilepsia sobre el manejo de una primera convulsión no provocada en
adultos también aboga por un enfoque individualizado que sopese el riesgo de recurrencia de
las convulsiones frente a los posibles efectos adversos de los medicamentos anticonvulsivos. Al
mismo tiempo, el médico debe considerar las preferencias educadas del paciente [ 3 ]. La guía
ofrece las siguientes recomendaciones específicas:
● Se debe informar a los adultos con una primera convulsión no provocada que su riesgo de
recurrencia de convulsiones es mayor en los primeros dos años (21 a 45 por ciento).
● Las variables clínicas asociadas con un mayor riesgo pueden incluir una lesión cerebral
previa, un electroencefalograma (EEG) con anomalías epileptiformes, una anomalía
significativa en las imágenes cerebrales y una convulsión nocturna.
● Es probable que la terapia inmediata con medicamentos anticonvulsivos, en comparación

con la demora del tratamiento en espera de una segunda convulsión, reduzca el riesgo de
recurrencia dentro de los dos primeros años, pero puede que no altere la aparición
posterior de epilepsia (que son convulsiones recurrentes no provocadas) ni mejore la
calidad de vida. A más largo plazo (>3 años), es poco probable que el tratamiento
inmediato con medicamentos anticonvulsivos mejore el pronóstico medido por la
remisión sostenida de las convulsiones.
● Se debe informar a los pacientes que el riesgo de eventos adversos de los medicamentos
anticonvulsivos puede oscilar entre el 7 y el 31 por ciento y que estos eventos adversos
son en su mayoría leves y reversibles.
En los pacientes con una primera convulsión no provocada que presentan una anomalía del
sistema nervioso central (SNC) en las pruebas de neuroimagen (como un tumor cerebral o
tejido cicatricial de una lesión anterior en la cabeza o una infección del SNC), el riesgo de
recurrencia de la convulsión es alto. En este caso, la mayoría de los médicos comenzarían el
tratamiento después de la primera convulsión no provocada. De hecho, es probable que estos
pacientes tengan un riesgo suficientemente alto de recurrencia de convulsiones para cumplir
con los criterios de epilepsia según las pautas de la Liga Internacional contra la Epilepsia (ILAE) [
1 ]. Estos criterios ahora consideran que los pacientes con una sola convulsión no provocada y
un riesgo estimado de recurrencia ≥60 por ciento durante diez años tienen epilepsia, similar a
aquellos con dos convulsiones no provocadas que ocurren con más de 24 horas de diferencia.
(Ver "Evaluación y manejo de la primera convulsión en adultos" y "Riesgo de recurrencia de
convulsiones" a continuación).
El tratamiento de las convulsiones en este grupo de alto riesgo es muy diferente del manejo de
pacientes con una primera convulsión no provocada que tienen un examen normal (o no focal)
y una neuroimagen normal (o inespecífica). En estos pacientes, el riesgo de recurrencia de las
convulsiones es menor y la terapia con medicamentos anticonvulsivos puede posponerse
razonablemente hasta después de una segunda convulsión no provocada.
Las preocupaciones de los pacientes también pesan mucho en las decisiones de tratamiento. Si
el riesgo de recurrencia de las convulsiones es bajo y el individuo valora mucho evitar los
efectos secundarios, se puede retrasar la terapia con medicamentos anticonvulsivos. Por el
contrario, hay algunas personas que estarán muy preocupadas por la recurrencia de las
convulsiones. En este caso, se puede iniciar un medicamento anticonvulsivo para reducir la
recurrencia de las convulsiones, a pesar de lo que puede ser una baja probabilidad de
convulsiones adicionales.
Riesgo de recurrencia de las convulsiones : en ensayos prospectivos aleatorios de personas

con una primera convulsión no provocada, el riesgo estimado de recurrencia a los dos años en

pacientes no tratados oscila entre el 40 y el 50 % [ 4-6 ]. El riesgo de recurrencia es máximo

durante el primer año después de la convulsión y disminuye con el tiempo; Del 80 al 90 por
ciento de los pacientes que tienen convulsiones recurrentes lo hacen dentro de los dos años [
7,8 ].
Los factores clínicos más replicados asociados con un mayor riesgo de recurrencia de
convulsiones después de una primera convulsión no provocada incluyen [ 4-7,9-12 ]:
● Anomalías epileptiformes en el EEG (ver "Electroencefalografía (EEG) en el diagnóstico de

convulsiones y epilepsia" )
● Causa sintomática remota, identificada por la historia clínica o las neuroimágenes (p. ej.,
tumor cerebral, malformación cerebral, lesión en la cabeza con pérdida del conocimiento,
infección previa del sistema nervioso central o cicatrización de una lesión cerebral previa o
cirugía cerebral)
● Exploración neurológica anormal, incluidos hallazgos focales y discapacidad intelectual
● Una primera convulsión que ocurre durante el sueño (es decir, una convulsión nocturna)
Cada uno de estos factores se ha asociado con un riesgo aproximadamente de 2 a 2,5 veces
mayor de recurrencia de las convulsiones. Los estudios que identificaron estos factores fueron
imperfectos. Varios se realizaron en grupos mixtos de pacientes; en algunos de estos estudios,
los pacientes estaban en tratamiento con medicamentos anticonvulsivos; en otros, los
pacientes no fueron tratados. Además, falta información para guiar a los médicos sobre cómo
interactúan estos factores de riesgo [ 3 ]: si la persona tiene dos o tres de estos factores de
riesgo, ¿su riesgo es aún mayor?
Se han investigado otros factores de riesgo potenciales para la recurrencia de las convulsiones
y siguen siendo más inciertos. Como ejemplo, los pacientes que tienen una primera
presentación con estado epiléptico o con múltiples convulsiones en un solo día tienen más
probabilidades de ser tratados con medicamentos anticonvulsivos que aquellos con una sola
convulsión de corta duración. Sin embargo, datos limitados sugieren que la presentación con
estado epiléptico, en ausencia de otros factores de riesgo, no aumenta el riesgo de recurrencia
de convulsiones [ 6,7,9,13 ]. Del mismo modo, no se sabe si los antecedentes de convulsiones
febriles previas se asocian con un mayor riesgo de recurrencia de las convulsiones después de
una primera convulsión afebril no provocada [ 6,7,9,11 ].
Los resultados del estudio han entrado en conflicto en cuanto a si un historial familiar de
epilepsia afecta el riesgo de recurrencia [ 5-7,9,11 ]. Esto varía según el síndrome de epilepsia,

ya que varios síndromes de epilepsia han sido identificados como de origen monogenético.
Beneficio del tratamiento temprano versus diferido : para los adultos que presentan una
primera convulsión no provocada, el tratamiento inmediato con medicamentos anticonvulsivos
reduce el riesgo de recurrencia de las convulsiones en aproximadamente un 35 % durante los
próximos uno o dos años [ 4,5,10,14-18 ]. Esta estimación se deriva de un metanálisis de cinco
ensayos aleatorizados (n = 1600 pacientes) que compararon el tratamiento farmacológico
anticonvulsivo inmediato con el diferido en adultos con una primera convulsión no provocada [
3 ].
Aunque estos estudios muestran que el tratamiento reduce la recurrencia de las convulsiones,
también sugieren que comenzar con un medicamento anticonvulsivo tiene poco impacto en el
resultado a largo plazo. En otras palabras, a los cuatro y cinco años después de la primera
convulsión, los pacientes tienen tasas similares de remisión completa de las convulsiones, ya
sea que el tratamiento con medicamentos anticonvulsivos se haya iniciado inmediatamente
después de la primera convulsión o se haya pospuesto hasta que ocurra una segunda
convulsión [ 4,5,10,14,18 ]. Al menos un ensayo aleatorizado encontró que la mortalidad a los
20 años no se vio afectada por el tratamiento inmediato frente al diferido [ 19 ].
En conjunto, los resultados de calidad de vida, medidos en un estudio aleatorizado, no fueron

diferentes con el tratamiento temprano versus diferido [ 20]. Sin embargo, los cuestionarios
mostraron que había una compensación entre los efectos adversos de las convulsiones versus
los efectos adversos de tomar medicamentos anticonvulsivos. Estos hallazgos sugieren que se
deben considerar las preferencias individuales de los pacientes al decidir entre el tratamiento
temprano versus tardío de una única convulsión no provocada. A modo de ejemplo, los
pacientes asignados al azar al tratamiento temprano con medicamentos anticonvulsivos tenían
más probabilidades de poder conducir que los pacientes cuyo tratamiento se pospuso. La
necesidad de conducir u operar maquinaria pesada junto con otras consecuencias
ocupacionales y psicológicas de sufrir una convulsión recurrente son consideraciones
importantes al momento de decidir si se debe iniciar una terapia con medicamentos
anticonvulsivos.
Segunda convulsión no provocada : los pacientes que presentan una segunda convulsión no
provocada deben comenzar con una terapia con medicamentos anticonvulsivos ( algoritmo 1
), ya que la recurrencia de las convulsiones indica que el paciente tiene un riesgo
sustancialmente mayor de convulsiones adicionales (es decir, después de dos convulsiones no
provocadas, ahora tienen el diagnóstico de epilepsia) [ 6,8 ].

En una serie de casos prospectiva, el riesgo de otra convulsión después de dos convulsiones no
provocadas fue del 73 % a los cuatro años (la mayoría de estos pacientes fueron tratados con
medicamentos anticonvulsivos) [ 8 ]. Después de una sola convulsión no provocada, un historial
cuidadoso puede revelar que ciertos tipos de convulsiones ya han estado ocurriendo. Estas
convulsiones clínicas más sutiles incluyen ausencia típica, mioclónicas y parciales simples o
complejas. Es solo con un interrogatorio cuidadoso que un paciente puede revelar o incluso
darse cuenta de que algunos de los síntomas que estaba experimentando previamente eran,
de hecho, ataques epilépticos [ 7 ].
Convulsiones sintomáticas agudas : las convulsiones sintomáticas agudas tienen un riesgo

menor de epilepsia posterior en comparación con las convulsiones sintomáticas remotas [ 21 ].
Las decisiones de manejo temprano, incluso si se debe comenzar o no con un medicamento
anticonvulsivo, dependen de múltiples factores, incluida la gravedad de la enfermedad
subyacente, la causa y la duración de la convulsión, el riesgo esperado de recurrencia temprana
y los riesgos asociados con una convulsión recurrente. . (Ver "Evaluación y manejo de la primera
convulsión en adultos", sección sobre 'Convulsiones sintomáticas agudas' ).
Los pacientes con convulsiones que ocurren en el contexto de una enfermedad o lesión
neurológica grave aguda (p. ej., accidente cerebrovascular, lesión cerebral traumática,
meningitis, encefalopatía anóxica) a menudo se tratan con medicamentos anticonvulsivos en el
contexto agudo debido al riesgo de convulsiones recurrentes prolongadas o agravamiento de
una lesión sistémica. (Consulte "Resumen del tratamiento de la epilepsia en adultos", sección
sobre "Convulsiones posteriores al accidente cerebrovascular" y "Convulsiones postraumáticas
y epilepsia", sección sobre "Convulsiones tempranas" y "Hemorragia intracerebral espontánea:
tratamiento agudo y pronóstico", sección sobre "Manejo de convulsiones ' .)
Un subconjunto de convulsiones sintomáticas agudas son aquellas que ocurren en el contexto

de una enfermedad médica aguda o un trastorno metabólico ( tabla 1 ). En contraste con el
contexto de un accidente cerebrovascular agudo o una lesión cerebral traumática, los pacientes
con convulsiones provocadas por trastornos metabólicos generalmente no se consideran en
riesgo de epilepsia futura, pero sí tienen riesgo de recurrencia de convulsiones en el contexto
agudo [ 22 ]. La terapia con medicamentos anticonvulsivos a corto plazo puede estar indicada si
se espera que la alteración metabólica persista o si la convulsión inicial se prolonga (como en el
caso del estado epiléptico). La mayoría está de acuerdo en que si el tratamiento se inicia para
las convulsiones sintomáticas agudas, debe continuarse hasta que la enfermedad subyacente
se haya resuelto por completo ( algoritmo 2 ).). Sin embargo, el punto final del tratamiento
con medicamentos anticonvulsivos puede no estar del todo claro en algunos casos. (Ver
"Evaluación y manejo de la primera convulsión en adultos", sección sobre 'Convulsiones

sintomáticas agudas' y "Evaluación y manejo de la primera convulsión en adultos", sección

sobre 'Cuándo iniciar la terapia con medicamentos anticonvulsivos' ).
SELECCIÓN DE UN MEDICAMENTO ANTICONVULSIVO
La epilepsia se trata inicialmente con monoterapia con medicamentos anticonvulsivos. Casi la

mitad de los pacientes dejarán de tener convulsiones con su primera prueba de medicación
anticonvulsiva [ 23,24 ]. Sin embargo, como se analiza a continuación, los ensayos clínicos no
responden a la pregunta más importante que enfrentan los médicos y los pacientes: ¿cuál es el
mejor medicamento anticonvulsivo (más efectivo y mejor tolerado) para las convulsiones de
nueva aparición? Debido a que no se dispone de una respuesta clara, los médicos deben
individualizar la elección del medicamento anticonvulsivo para cada paciente.
Al elegir una terapia inicial, los médicos deben sopesar la eficacia relativa y el potencial de
efectos adversos de cada fármaco. Los datos comparativos de eficacia y tolerabilidad son
limitados. Los ensayos de comparación que se han realizado no han mostrado diferencias
significativas entre varios fármacos en términos de eficacia. Por lo tanto, los médicos deben
formular planes de tratamiento basados en una combinación de fármacos, convulsiones y
factores específicos del paciente.
Consideraciones relacionadas con los medicamentos : los aspectos de la terapia con
medicamentos anticonvulsivos que son relevantes para la selección de medicamentos incluyen
la eficacia, la farmacocinética, los efectos adversos y el costo.
Eficacia : ningún medicamento anticonvulsivo es claramente el más efectivo o mejor

tolerado, y ahora hay más de 25 medicamentos anticonvulsivos aprobados para el tratamiento
de convulsiones en adultos y/o niños ( tabla 2 y tabla 3 ). (Consulte "Medicamentos
anticonvulsivos: mecanismo de acción, farmacología y efectos adversos" .)
La evidencia se resume en las secciones siguientes.
● Ensayos controlados aleatorios : los ensayos controlados aleatorios (ECA) son los menos
sesgados en la evaluación de la eficacia y la tolerabilidad de los tratamientos. Sin
embargo, los ECA de medicamentos anticonvulsivos no están exentos de problemas: los
ECA generalmente comparan la terapia activa con una dosis subterapéutica del mismo
agente y/o con un placebo en lugar de con una dosis efectiva de otro medicamento
anticonvulsivo [ 25 ]. Otra limitación de la mayoría de los ensayos aleatorizados en
epilepsia es que generalmente se realizan probando nuevos medicamentos
anticonvulsivos como tratamiento adicional en pacientes con enfermedad resistente al
tratamiento (refractario) (ver "indicaciones de la FDA"abajo). Dichos pacientes pueden no

ser representativos de la población clínica general y pueden no representar con precisión
a las personas que tienen epilepsia o convulsiones de nueva aparición. Con las
convulsiones de nueva aparición, existe una brecha entre lo que se sabe y lo que se
necesita .
Ha habido un número limitado de ensayos aleatorios que compararon varios

medicamentos anticonvulsivos directamente como monoterapia inicial en adultos. Estos
han demostrado una eficacia similar entre los diferentes fármacos [ 26,27 ]. Los ensayos
de comparación aleatorizados brindan cierta información, pero incluyen una pequeña
cantidad de tratamientos actualmente disponibles:
• Carbamazepina versus fenitoína [ 28 ]

• Fenitoína versus valproato [ 29 ]
• Gabapentina versus carbamazepina [ 30 ] o pregabalina [ 31 ]
• Lamotrigina versus carbamazepina [ 32,33 ] o fenitoína [ 34 ] o gabapentina [ 35 ] o
pregabalina [ 36 ]
• Topiramato versus valproato y carbamazepina [ 37 ] o fenitoína [ 38 ]
• Oxcarbazepine versus phenytoin [39,40] or valproate [41] or carbamazepine [42]
• Zonisamide versus carbamazepine [43,44]
• Levetiracetam versus carbamazepine or valproate [45-47]
• Lacosamide versus carbamazepine [48]
• Carbamazepine extended-release versus levetiracetam, zonisamide, lacosamide, or
eslicarbazepine [49]
Although these trials have not shown significant differences between antiseizure
medications, the quality of the data remains limited by the fact that they were generally of
short duration (24 or 48 weeks). Such studies can compare the incidence of short-term
side effects between drugs, but they have limited power to assess relative long-term
efficacy. In general, but with some exceptions, these trials suggest that the newer
antiseizure medications are superior with respect to tolerability [27,50]. There has never
been a randomized trial that includes all available treatments. Such a trial would be
massive, likely impractical, and obsolete as soon as a new drug (or treatment) became
available
A meta-analysis of randomized trials can potentially overcome some of the limitations of

individual trials, but even these studies can be problematic, since patient populations and
drug doses often vary between trials; this substantively limits the ability to compare the

studied treatments. In general, such studies have lacked power either to refute or
substantively confirm results of individual trials [51-55].
● SANAD trials – The largest individual randomized trials examining different antiseizure
medications as monotherapy for the initial treatment of epilepsy were the Standard and
New Antiepileptic Drugs (SANAD) trials [56-58]. The first SANAD trials included 1721
patients with focal epilepsy and 716 patients with generalized and unclassifiable epilepsy;
the SANAD II trial included 990 patients with focal epilepsy and 520 patients with
generalized or unclassifiable epilepsy [59,60]. In an effort to balance methodologic rigor
and practicality, the trials were not blinded [61]. The treating physician determined how
quickly to titrate the medication, instead of following a standardized blinded protocol. This
approach may have better approximated the "real life" use of these drugs than would a
blinded trial. Outcome measures were time to treatment failure (for either inadequate
seizure control or intolerable side effects) and time to achievement of a 12-month seizure
remission. The main findings were:
• For patients treated for focal epilepsy, the first SANAD trail found that lamotrigine and
oxcarbazepine had the longest time to treatment failure compared with
carbamazepine, gabapentin, and topiramate [57]. Lamotrigine and carbamazepine
were associated with the shortest times to 12-month seizure remission. In the SANAD II
trial, by intention-to-treat analysis, levetiracetam did not meet noninferiority criteria
compared with lamotrigine for time to 12-month seizure remission and was inferior for
time to treatment failure for any reason; in contrast, zonisamide did meet the criteria
for noninferiority compared with lamotrigine for time to 12-month seizure remission,
but was also inferior for time to treatment failure [59]. Both levetiracetam and
zonisamide were more likely to fail than lamotrigine due to adverse reactions, but not
because of inadequate control of seizures.
• For patients treated for generalized and unclassifiable epilepsy, the first SANAD trial
found that valproate and lamotrigine were superior to topiramate in regard to time to
treatment failure [58]. For time to 12-month seizure remission, valproate and
topiramate were more efficacious compared with lamotrigine. In the SANAD II trial, by
intention-to-treat analysis, levetiracetam did not meet noninferiority criteria compared
with valproate for time to 12-month seizure remission [60].
• In the first SANAD trial, quality of life outcomes were largely similar across treatment
groups over a two-year period and did not show a clear advantage for any specific drug
[62]. The strongest predictor of improved quality of life outcomes was achievement of a
12-month seizure remission.
The investigators concluded that lamotrigine should be considered the drug of first choice
for focal epilepsy and valproate for generalized epilepsy [57-60]. Because the SANAD trials
were unblinded, however, there was potential for bias. Also, they provided only sparse
data regarding the potential of rare, often idiosyncratic, serious adverse events (eg,
potential for teratogenicity with valproate). These results also do not account for other
patient-specific preferences regarding the likelihood of different side effects, need for
drug monitoring, potential for drug interactions, and dosing frequency [63].
● Expert opinion – Several articles have reviewed expert opinion and performed statistical
analysis to summarize the recommendations regarding the choice of antiseizure
medication for the treatment of adults and children with epilepsy [64-67]. As an example,
a 2017 report summarized expert opinion regarding all available antiseizure medications
(as of 2016) for the initial treatment of focal and generalized epilepsies [65]. In addition,
the experts provided recommendations on special patient populations such as females of
childbearing age, older adults, and those with intellectual challenges. Based upon data
from the major trials [56-60], comprehensive reviews [65], and clinical experience of the
contributors to this topic, the following antiseizure medications are reasonable choices for
different clinical situations, with the exception that valproate should be avoided for
females of childbearing age:
• Initial treatment of focal epilepsy: Lamotrigine, levetiracetam, oxcarbazepine,

carbamazepine, lacosamide
• Genetically mediated generalized epilepsies syndrome with mainly generalized tonic-

clonic seizures: Lamotrigine, levetiracetam, valproate, topiramate, zonisamide
• Absence seizures: Ethosuximide, valproate, lamotrigine
• Genetically mediated generalized epilepsy syndrome with myoclonic seizures:

Levetiracetam, valproate, zonisamide
• Female of childbearing age with either genetic generalized epilepsy or focal epilepsy:
Lamotrigine, levetiracetam
• Older adult with focal epilepsy: Lamotrigine, levetiracetam, lacosamide
• Comorbid depression with focal epilepsy: Lamotrigine, lacosamide, oxcarbazepine
• Comorbid depression with genetically mediated generalized epilepsy: Lamotrigine,

valproate
https://www.uptodate.com/contents/initial-treatment-of-epilepsy-in-adults/print?search=antiseizure drugs treatment&source=search_result&selected… 10/61

• Hepatic failure or after organ transplantation: Levetiracetam, gabapentin, lacosamide
• Renal failure on hemodialysis: Lamotrigine, oxcarbazepine, levetiracetam
We can look to the experts for guidance in choosing initial antiseizure therapy. These
expert opinion reports can be viewed as similar to a consultation, but one that distills the
opinions of a large group of epilepsy experts.
Pharmacokinetics — Important pharmacologic features of individual antiseizure medications

are summarized in the table and reviewed in more detail separately ( table 2). (See
"Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
Some of the more important considerations when choosing a first-line antiseizure medication
include the following:
● Dosing frequency – The half-lives of antiseizure medications vary considerably

( table 2). For many individuals, the frequency with which a drug must be taken is an
important factor in compliance (ie, adherence) and/or seizure control [68]. Optimal dose
frequency for individual drugs can vary between patients.
Most antiseizure medications are prescribed in two daily doses. Antiseizure medications
that often require more frequent dosing include immediate-release carbamazepine,
tiagabine, regular and delayed-release valproate, gabapentin, and pregabalin. Once daily
dosing may be possible with phenobarbital, phenytoin, zonisamide, eslicarbazepine,
perampanel, and extended-release formulations of levetiracetam, valproate,
oxcarbazepine, topiramate, and lamotrigine.
● Drug interactions – The selection of an antiseizure medication should consider other

prescribed medications for potential drug interactions. Clinicians should review each item
on a patient's medication list for potential drug interactions [69,70]. Specific interactions of
antiseizure medications with other medications may be determined using the Lexicomp
drug interactions tool.
In general, antiseizure medications with hepatic enzyme induction or inhibitory properties

have the greatest potential for interactions. Induction of cytochrome P450 (CYP) enzymes
occurs with all older antiseizure medications (phenobarbital, carbamazepine, and
phenytoin) except valproate and ethosuximide. Enzyme induction also occurs with a few of
the newer approved antiseizure medications such as eslicarbazepine, oxcarbazepine,
primidone, rufinamide, and topiramate ( table 2) [61,71].

Antiseizure medications that are hepatic-enzyme inducers increase the metabolism of

other medications that are broken down by the same pathway. As an example, phenytoin
induces the metabolism of warfarin, potentially leading to subtherapeutic international
normalized ratio (INR) and/or an increased dose requirement of warfarin. Commonly
prescribed drugs with the potential to interact with enzyme-inducing antiseizure
medications include statins, calcium channel blockers, serotonin reuptake inhibitors,
antipsychotics, tricyclic antidepressants, hormonal contraceptive therapy, warfarin, and
many anticancer drugs [72].
In contrast, valproate is a hepatic enzyme inhibitor and may cause significant increases in
serum concentrations of medications that are metabolized in the liver. Similarly,
stiripentol, which is approved for Dravet syndrome, is a potent hepatic enzyme inhibitor. It
is known to increase levels of the main metabolite of carbamazepine (the 10,11 epoxide)
[73].
Other drug interactions relate to protein binding. Addition of a drug that is highly protein-
bound will displace another protein-bound drug, increasing its free fraction. In the setting
of reduced serum albumin, this effect is amplified. Hormones can also affect the levels of
some antiseizure medications. For instance, lamotrigine concentrations are reduced by
estrogen-containing hormonal contraceptives. (See 'Hormonal contraception' below.)
● Aging – Antiseizure medication 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, polypharmacy is more often a
concern in older adults. These and other factors related to antiseizure medication
selection in older adults are discussed separately. (See "Seizures and epilepsy in older
adults: Treatment and prognosis".)
Side effect profiles — The adverse effects of antiseizure medications make a significant

contribution to reduced quality of life in individuals with epilepsy [74]. While many antiseizure
medication side effects (eg, drowsiness, dizziness, diplopia, and imbalance) seem to be
common to this entire class of medicines, others are more specific to an individual drug. These
should be considered in selecting an antiseizure medication since certain side effects are either
more likely or more problematic in certain patients.
Common neurotoxic and systemic side effects are summarized in the table ( table 4). Less
common, often idiosyncratic, but potentially serious adverse events are summarized separately
( table 5).

● Neurocognitive side effects – Most antiseizure medications are associated with a

negative impact on cognition, but some are more problematic than others [75]. Among
the older antiseizure medications, studies suggest that phenobarbital is associated with
greater impairments compared with carbamazepine, valproate, and phenytoin, which
have similar, but more modest negative effects [76,77]. Among the newer antiseizure
medications, gabapentin and lamotrigine have been found to be less problematic than
carbamazepine in their effects on cognition. Negative cognitive effects are similar with
oxcarbazepine and carbamazepine [78]. Finally, a significant minority of patients taking
topiramate discontinue the drug because of clinically apparent cognitive difficulties. In
direct comparison studies, cognitive profiles in patients taking topiramate were worse
than those taking valproate, lamotrigine, or gabapentin [77].
● Hypersensitivity reactions – 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. SJS and TEN
have been most often associated with the use of carbamazepine, oxcarbazepine,
phenytoin, lamotrigine, and phenobarbital ( table 5), and less commonly with valproate
and topiramate; however, they have been described with almost all antiseizure
medications [79,80].
The period of highest risk is within the first two months of use. For carbamazepine,
oxcarbazepine, and possibly phenytoin, the risk is higher in patients with the HLA-B*1502
allele, which occurs almost exclusively in patients of Asian ancestry, including Indian. The
US Food and Drug Administration (FDA) recommends screening such patients for the HLA-
B*1502 allele prior to starting carbamazepine and oxcarbazepine. This is discussed in
more detail separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Pathogenesis, clinical manifestations, and diagnosis", section on 'HLA types' and
"Antiseizure medications: Mechanism of action, pharmacology, and adverse effects",
section on 'Carbamazepine' and "Antiseizure medications: Mechanism of action,
pharmacology, and adverse effects", section on 'Oxcarbazepine'.)
● Suicidality – Antiseizure medications as a class have been associated with an

approximately twofold increased relative risk of suicidal behavior or ideation based on
pooled analyses of placebo-controlled trials (0.43 versus 0.22 percent) [81]. Some experts
advise screening for depression at diagnosis of epilepsy and at each follow-up visit [82].
This is discussed in more detail separately. (See "Overview of the management of epilepsy
in adults", section on 'Specific adverse reactions' and "Comorbidities and complications of
epilepsy in adults", section on 'Psychiatric disorders'.)

● Weight gain or loss – Weight gain is associated with valproate, gabapentin,

carbamazepine, vigabatrin, pregabalin, and perampanel. Weight loss has been reported
with felbamate, topiramate, and zonisamide.
FDA indications — The FDA indication for use of antiseizure medications may influence
physician prescribing habits. For many newer antiseizure medications, the FDA indications are
based on studies that showed effectiveness as add-on treatment in persons with refractory
epilepsy. Monotherapy trials are performed infrequently because most physicians and patients
are reluctant to be treated with placebo when effective treatments exist [25]. As a result, many
antiseizure medications are not FDA-approved as initial monotherapy. Some physicians may be
initially reluctant to use newer antiseizure medications as monotherapy in the initial treatment
of epilepsy pending advice from colleagues and/or published expert opinion.
A historical-controlled treatment discontinuation trial design is being increasingly used in an

attempt to evaluate the effectiveness of various antiseizure medications as conversion to
monotherapy in patients with drug-resistant epilepsy, since randomizing patients with active
seizures to a placebo conversion presents ethical concerns. The primary outcome measure is
the predicted exit percentage, defined as the proportion of patients meeting a seizure-related
exit criterion (eg, withdrawal due to inadequate seizure control or adverse effects) at four
months, compared with a pooled historical benchmark of 65 percent (compiled from older trials
that did use a placebo or subtherapeutic antiseizure medication dose) [83]. Drugs shown to be
more effective than this historical benchmark in prospective trials include lamotrigine
extended-release [84], levetiracetam extended-release [85], pregabalin [86], lacosamide [87],
and eslicarbazepine [88]. The exit rate in these trials has ranged from 20 to 40 percent at four
months.
Cost of medications — For many patients, the cost of their medication is also an issue and
whether a specific antiseizure medication is on a list of preferred medications approved by a
third-party payer may also be influential in the choice of antiseizure medication. When cost is
taken into account, for areas of the world and for individual patients with restricted resources,
older, less expensive medications such as phenobarbital or phenytoin may be the treatment of
choice for partial epilepsy [89]. Generic substitution can lower cost of many antiseizure
medications. In rare instances, use of a generic may be associated with a change in seizure
control or tolerability, although the magnitude of this risk has been debated. (See 'Generic
substitutions' below.)
Seizure and epilepsy syndrome-related considerations

Focal versus generalized seizures/epilepsy — In selecting an antiseizure medication for a

patient with new onset epilepsy, it is important to differentiate between a focal versus
generalized epilepsy syndrome [90]. Antiseizure medications are classified as either broad or
narrow spectrum agents ( table 3). While broad spectrum agents treat both focal and
generalized epilepsy syndromes, narrow spectrum agents treat one or the other [91].
Most of the narrow spectrum agents are effective for localization-related or focal epilepsies. As
an example, gabapentin (a narrow spectrum agent) may work well for a patient with temporal
lobe epilepsy (a focal epilepsy) but is unlikely to be effective in juvenile myoclonic epilepsy (a
generalized epilepsy). Ethosuximide is another narrow spectrum agent used for absence
seizures (a generalized epilepsy), which is generally ineffective for focal seizures. Broad
spectrum agents are effective for both types of epilepsies [92]. If the clinician is unsure whether
the epilepsy syndrome is focal or generalized, a broad spectrum agent is usually chosen
( table 3).
Identifying the correct epilepsy syndrome is critical to selecting an optimal treatment. For
instance, a few of the narrow spectrum agents have been reported to worsen certain seizures
that occur in the primary generalized epilepsy syndromes. Oxcarbazepine [93], carbamazepine,
phenytoin, vigabatrin, and gabapentin [92] have all been reported to worsen certain seizures
types in generalized epilepsy syndromes.
Specific etiologies — In addition to the distinction between generalized and focal epilepsy
discussed above, specific etiologies of epilepsy may impact the treatment choice.
● Post-stroke epilepsy is generally easily controlled with antiseizure medication

monotherapy [94]. The choice of antiseizure medication may be influenced by specific
concerns, such as potential impact of the antiseizure medication on post-stroke functional
recovery and the potential for drug interactions with warfarin and salicylates (see
'Pharmacokinetics' above) [95]. The treatment of post-stroke epilepsy is discussed in detail
separately. (See "Overview of the management of epilepsy in adults", section on
'Poststroke seizures'.)
● Brain tumors are associated with epilepsy in 30 to 70 percent of patients, depending on

the tumor type. The choice of antiseizure medication in this setting is influenced by
potential drug interactions with chemotherapeutic agents leading to decreased efficacy of
both treatments, as well as the increased potential for allergic cutaneous reactions when
antiseizure medications are used during radiotherapy [96,97]. Both of these factors
contribute to a strong preference for non-enzyme inducing antiseizure medications in

brain tumor patients when possible. (See "Seizures in patients with primary and metastatic
brain tumors".)
Comorbid medical conditions — Medical comorbidities are important to consider when

selecting an antiseizure medication. Many antiseizure medications are either metabolized by
the liver, excreted by the kidneys, or both ( table 2). When a person has hepatic or renal
disease, it may be necessary to avoid certain antiseizure medications or to adjust the dose.
Other comorbidities can be problematic because of potential drug side effects or drug
interactions, while others may represent an opportunity to choose an antiseizure medication
that has efficacy in both conditions. Specific interactions of antiseizure medications with other
medications may be determined using the Lexicomp drug interactions tool.
Renal disease — Renally excreted drugs include gabapentin, topiramate, zonisamide,

lacosamide, levetiracetam, oxcarbazepine, and pregabalin ( table 2) [91,98,99]. The dose of
these drugs should be adjusted based on the severity of renal impairment ( table 6).
In patients on hemodialysis, antiseizure medication regimens should be individualized based on

drug levels and clinical response. The renally excreted drugs and some others (eg,
phenobarbital, lamotrigine) are removed by hemodialysis, and a low dose should be
supplemented after dialysis to maintain therapeutic levels. The effects of peritoneal dialysis on
antiseizure medication metabolism are not well studied, and antiseizure medication treatment
in such patients may require additional monitoring. (See "Seizures in patients undergoing
hemodialysis", section on 'Dosing'.)
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). Albuminuria (causing low serum albumin) and acidosis reduce protein binding
fractions and binding affinity, leading to increased fractions of free drug [98]. For highly protein-
bound antiseizure medications ( table 2), subtherapeutic total drug levels may be both
sufficient for efficacy and required to avoid toxicity in this setting. Free drug levels of phenytoin
may be monitored, but such tests are less routinely available for other antiseizure medications.
Topiramate and zonisamide are associated with nephrolithiasis and should probably be avoided
in patients with a history of or who are prone to this condition (see "Kidney stones in adults:
Epidemiology and risk factors"). Renal tubular acidosis can also occur with these antiseizure
medications; patients with preexisting conditions that make them prone to metabolic acidosis
(eg, severe respiratory disorders, diarrhea) should also consider avoiding these drugs or have
more frequent monitoring of serum bicarbonate levels [100].

In the setting of renal transplantation, potential drug interactions between antiseizure

medications and immunosuppressive therapy should be considered. Enzyme-inducing
antiseizure medications may lower serum immunosuppressant levels, while enzyme-inhibitors
may increase levels.
Hepatic disease — Some antiseizure medications are associated with hepatic toxicity and
should be avoided in patients with preexisting liver disease. These include valproate and
felbamate, and to a lesser extent, phenytoin and carbamazepine [98,101]. Many other
antiseizure medications are metabolized fully or partially in the liver ( table 2), requiring
caution and dose adjustment when used in patients with chronic liver disease. These include
carbamazepine, lamotrigine, phenytoin, phenobarbital, clobazam, valproate, felbamate,
zonisamide, topiramate, oxcarbazepine, eslicarbazepine, and brivaracetam. Levetiracetam,
gabapentin, pregabalin, and vigabatrin do not undergo hepatic metabolism and are less
problematic for use in patients with chronic liver disease.
Psychiatric disorders — Persons with epilepsy have a higher than expected prevalence of

comorbid psychiatric disorders [64,102-105]. The association may relate to shared
perturbations in neurotransmitter action, alterations to neural networks or both [102,104,106].
In persons with epilepsy, the presence of depression correlates more strongly with a poor
quality of life than the frequency of the seizures [107].
Some antiseizure medications (valproate, lamotrigine, carbamazepine, oxcarbazepine) appear

to have mood-stabilizing properties [108-110]. Their efficacy in this regard is best established
for bipolar disorder. However, many physicians view these medications as attractive in patients
with comorbid anxiety and depression.
In contrast, some antiseizure medications, in particular those that potentiate gamma-

aminobutyric acid (GABA) neurotransmission (phenobarbital, tiagabine, vigabatrin, topiramate),
have been reported to cause or exacerbate a depressed mood and perhaps should be avoided
in patients with comorbid depression [111]. Similarly, drugs that have been reported to provoke
psychosis (levetiracetam, topiramate, vigabatrin, zonisamide, ethosuximide, and perampanel)
may be less desirable in patients with that history. In the Columbia-Yale study, neuropsychiatric
side effects were reported in 17 percent of patients taking antiseizure medications.
Levetiracetam was associated with the highest rate (22 percent) while zonisamide had the
second highest rate (9.7 percent) of neuropsychiatric side effects. In comparison,
carbamazepine, clobazam, gabapentin, lamotrigine, oxcarbazepine, phenytoin, and valproate
were significantly associated with a decreased rate of psychiatric or behavioral side effects
[112].

Use of one of the antiseizure medications thought to be effective in mood stabilization does not
substitute for a full psychiatric evaluation and independent treatment of a coexisting psychiatric
disorder. Further impetus for this comes from the fact that as a class, antiseizure medications
are associated with an increased risk of suicide. All patients with epilepsy treated with
antiseizure medications should be monitored for changes in mood and suicidality. (See
"Overview of the management of epilepsy in adults", section on 'Specific adverse reactions'.)
Drug interactions are also a potential concern in patients with psychiatric disorders. Enzyme-
inducing antiseizure medications ( table 2) can decrease the plasma concentration of many
antidepressants including tricyclic agents and selective serotonin reuptake inhibitors, as well as
antipsychotic drugs and benzodiazepines [69,70].
Migraine — Some studies suggest that migraine may be more prevalent in patients with
epilepsy and vice versa [113,114]. Valproate, gabapentin, and topiramate are antiseizure
medications that have demonstrated efficacy for migraine prevention in placebo-controlled
trials (see "Preventive treatment of episodic migraine in adults", section on 'Anticonvulsants').
This may provide an opportunity to limit polypharmacy in individuals with both migraine and
epilepsy.
Osteoporosis risk — Antiseizure medications in chronic use have been associated with bone
loss. Initially this association was observed for enzyme-inducing antiseizure medications
( table 2), but later was found to extend to valproate as well as to some of the newer
nonenzyme-inducing antiseizure medications [115-117]. The evidence associating osteoporosis
and antiseizure medication therapy may be strongest for phenytoin. Osteoporosis is particularly
problematic for patients with epilepsy, as seizures are associated with falls and bone fractures
[100,118,119].
While phenytoin should perhaps be avoided in patients in whom there is concern for bone loss,
there are insufficient data to recommend avoiding or choosing any other specific antiseizure
medication in order to limit the risk of osteoporosis [100]. Rather, monitoring of bone density,
routine supplementation of calcium and vitamin D, and a consistent exercise regimen are
suggested for all patients on chronic antiseizure medication therapy. (See "Antiseizure
medications and bone disease".)
Others
● Diabetes – Because of its association with weight gain, insulin resistance, and polycystic
ovarian syndrome, use of valproate in individuals with diabetes or obesity should be
carefully considered [120]. Carbamazepine, vigabatrin, gabapentin, and pregabalin are

also, but much less frequently, associated with weight gain. (See 'Side effect profiles'
above.)
Some antiseizure medications (gabapentin, pregabalin, and possibly carbamazepine) have

efficacy in treating pain associated with diabetic neuropathy. (See "Management of
diabetic neuropathy", section on 'Pain management'.)
● Thyroid disease – While many antiseizure medications, in particular the enzyme-inducing

agents, can alter thyroid hormone levels, this is generally subclinical and should not
impact drug choice [120,121]. Enzyme-inducing agents should probably be avoided in
patients with severe thyroid dysfunction.
● Cancer – The choice of antiseizure medication in patients being treated for systemic
cancer is influenced by potential drug interactions between enzyme-inducing antiseizure
medications ( table 2) and chemotherapeutic agents that can lead to decreased efficacy
of both treatments [96,97]. By inhibiting their metabolism, valproate may increase the
toxicity of certain cancer chemotherapy agents. There also may be an increased potential
for allergic cutaneous reactions when antiseizure medications are used during
radiotherapy; however, there is no way to predict which patients are more at risk for this
particular side effect.
● HIV – Enzyme-inducing antiseizure medications and those that are highly protein-bound
( table 2) may interact with antiretroviral therapy (ART) [122-124]. Of particular concern
is that these drug interactions may cause minor reductions in the levels of protease
inhibitors that could lead to loss of viral suppression and the emergence of drug
resistance. There are also concerns that phenytoin-associated skin rash may be more
common in HIV-positive patients. Lamotrigine doses may need to be increased with
certain medications including ritonavir and atazanavir. While early in vitro studies
suggested that valproate might increase viral replication, a series of patients treated with
valproate maintained excellent control of both seizures and HIV [125].
● Cardiovascular disease – Clinicians should consider potential drug interactions between

cytochrome P450 (CYP) enzyme-inducing antiseizure medications (ie, carbamazepine,
eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, and
topiramate) and statins, calcium channel blockers, and warfarin [69,70,126]. While
carbamazepine has been associated with heart block and other bradyarrhythmias in
susceptible individuals [127], clinically significant electrocardiography (ECG) changes are
uncommon with carbamazepine in older adult patients who do not have a preexisting
conduction defect [128].

Because the CYP enzymes are involved in cholesterol synthesis, it is possible that enzyme-
inducing antiseizure medications may thereby affect vascular risk. In one small series,
switching patients from carbamazepine or phenytoin to noninducing antiseizure
medications levetiracetam or lamotrigine was associated with improvements in serologic
markers of vascular risk (eg, total cholesterol, triglycerides, C-reactive protein) [129]. Some
studies have found that long-term monotherapy with carbamazepine, phenytoin, or
valproate, is associated with markers of increased cardiovascular risk, such as carotid
intimal thickening, abnormal cholesterol, homocysteine, and folate metabolism, and
elevated levels of C-reactive protein [130,131]. However, it is unclear whether enzyme-
inducing antiseizure medications are associated with a greater risk of cardiovascular
disease than nonenzyme-inducing antiseizure medications, as the evidence is inconsistent
[132,133].
● Blood disorders – Certain antiseizure medications (carbamazepine, phenytoin,

ethosuximide, valproate) are associated with neutropenia and agranulocytosis, and should
be avoided in patients with blood disorders [134,135]. (See "Drug-induced neutropenia
and agranulocytosis".)
Similarly, drugs associated with thrombocytopenia (eg, carbamazepine, valproate,

phenytoin) should be avoided in patients with a low platelet count or a history of other
bleeding diatheses. (See "Drug-induced immune thrombocytopenia".)
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.
Folate should be prescribed to all women of childbearing age who are taking antiseizure
medications. (See "Management of epilepsy during preconception, pregnancy, and the
postpartum period", section on 'Folic acid supplementation'.)
Hormonal contraception — Women should be informed about the interactions between

antiseizure medication therapies and hormonal pill, patch, or ring contraception and the
availability of long-acting reversible contraception (LARC), which is highly effective and avoids
most if not all drug-drug interactions, depending on the specific method. (See "Management of
epilepsy during preconception, pregnancy, and the postpartum period", section on
'Preconception management' and "Contraception: Counseling and selection".)
The expected contraceptive failure rate of 0.7 per 100 woman-years using oral contraceptives is
increased to 3.1 per 100 woman-years in patients who concomitantly take enzyme-inducing
antiseizure medications ( table 2) [136-139]. While vigabatrin is not an enzyme inducer, lower
levels of ethinyl estradiol have been reported in volunteers taking this antiseizure medication
[140] (see "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and
use", section on 'Drug interactions'). If an enzyme-inducing antiseizure medication is
nonetheless deemed to be the drug of choice in a woman taking combined hormonal pill,
patch, or ring contraception, alternative regimens or forms of contraception should be
considered. (See "Overview of the management of epilepsy in adults", section on
'Contraception'.)
In addition to the effect of antiseizure medications on hormonal contraceptive metabolism,

combined hormonal contraceptives can increase the metabolism of lamotrigine, thereby
reducing the plasma drug concentration. In other words, higher doses of lamotrigine may be
needed in women taking combined estrogen-progesterone contraception, and continuous
dosing may be preferable to avoid increased lamotrigine levels during pill-free intervals. (See
"Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on
'Lamotrigine'.)
Catamenial epilepsy — Many women with epilepsy report an association between the

occurrence of their seizures and certain phases of their menstrual cycle [141,142]. Catamenial
seizure clustering can occur in women with any seizure type and epilepsy syndrome but may be
more common among women with focal compared with generalized epilepsy [143-148] and
among those with left-sided temporal epilepsy compared with right-sided, multifocal, or
extratemporal epilepsy [149,150].
In general, research suggests that catamenial seizure patterns result from cyclic changes in
hormone levels during the menstrual cycle; changes in antiseizure medication levels due to
endogenous metabolic effects may also contribute. Estrogen levels peak mid-cycle and then, in
women who do not conceive, fall through the onset of menses. It is during the late part of the
menstrual cycle (just before the onset of menses), during a relative drop in estrogen levels, that
seizures most often cluster [143,151]. Periovulatory (mid-cycle) seizure clustering can also
occur.
The mainstay of treatment of catamenial seizures is an antiseizure medication that is most

effective for the woman's epilepsy syndrome. However, when catamenial seizures are not
controlled with antiseizure medications, clinicians may consider use of a continuous estrogen-
progestin contraceptive on the theoretical basis that suppressing estrogen fluctuations will lead
to better seizure control. The rationale and use of hormonal prophylaxis for catamenial epilepsy
is similar to that in estrogen-associated migraine, which is reviewed separately. (See "Estrogen-
associated migraine, including menstrual migraine".)

Intermittent benzodiazepine treatment timed according to the vulnerable phase of the

menstrual cycle is also a common strategy. Clobazam is the only benzodiazepine studied
systematically for this purpose. In a double-blind cross-over study, clobazam (20 to 30 mg/day)
was administered for 10 days in the high-risk phase of the menstrual cycle in 18 women with
catamenial epilepsy [152]. Fourteen patients reported better seizure control with clobazam than
placebo. Long-term follow-up of patients who continued to use this treatment strategy revealed
seizure remission and/or significant reduction of seizures in five of nine patients [153]. These
limited data support a fairly common practice of treating catamenial seizure exacerbations with
intermittent benzodiazepines with a long-acting agent such as lorazepam. A reasonable dose of
lorazepam in this setting is 0.5 to 1 mg two to three times daily.
Very limited data suggest that appropriately timed acetazolamide may have some benefit in
catamenial epilepsy [154-156]. Although cyclic natural progesterone has been reported to
reduce seizure frequency in observational studies, a randomized trial failed to confirm a benefit
in 294 women with poorly controlled seizures [157]. Other investigational strategies include
gonadotropin analogs and neurosteroids such as ganaxolone [144,158-160].
Pregnancy and postpartum — Treatment of epilepsy during pregnancy must balance

competing risks. Seizures, particularly convulsive seizures, are believed to be harmful to the
fetus. At the same time, both major and minor malformations are more common in fetuses
exposed to antiseizure medications in utero compared with offspring of untreated women with
epilepsy and women without epilepsy. The overall risk of major malformations is 4 to 6 percent
in exposed infants; valproate is a major contributor to this risk. Polypharmacy increases the
risk. The timing (early versus late in gestation) and dose of exposure are also likely to be
important. While no antiseizure medication has been definitively shown to be safe in
pregnancy, the evidence linking valproate to fetal malformations is sufficiently convincing to
recommend avoiding its initiation and use in most women of childbearing potential [161]. (See
"Risks associated with epilepsy during pregnancy and postpartum period".)
The management of epilepsy in pregnancy and during breastfeeding is discussed separately.

(See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)
INITIATION OF ANTISEIZURE MEDICATION THERAPY
Patient education — The management of patients with epilepsy is focused on three main

goals: controlling seizures, avoiding, or minimizing treatment side effects, and maintaining or
restoring quality of life. Successful treatment can be optimized by a systematic approach that
includes patient education [162,163]. Before treatment is initiated, the physician needs to

counsel the patient and family to increase their understanding of epilepsy and their ability to
report necessary and relevant information. These discussions will improve the likelihood that
the patient will comply with the plan of treatment.
The physician should impress upon the patient, family, and patient's friends the critical need to
follow the prescribed drug regimen. Nonadherence to antiseizure medication treatment
regimen is associated with increased risk of mortality, as well as hospitalization and injury [164].
(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 or drug-drug interactions. The patient
must also be warned not to stop taking an antiseizure medication on their own initiative, and
not to allow a prescription to run out or expire.
Patients should be urged not to start any other prescription, over-the-counter medications,
dietary supplements, or herbal remedies without first contacting their physician because these
might affect serum concentrations of their antiseizure medications [72,165]. (See
'Pharmacokinetics' above.)
Drug administration and dosing — Treatment should be started with a single drug

(monotherapy). In general, the strategy is to gradually titrate the dosage to that which is
maximally tolerated and/or produces optimal seizure control (start low and go slow). Pooled
analysis from two large prospective studies found that with this approach, adverse event
reporting was no higher in treated versus untreated patients [166]. Variables other than
antiseizure medication treatment were found to be associated with adverse event reporting,
most notably comorbid depression. The recommended initial dose and suggested titration
schedule is presented separately. (See "Antiseizure medications: Mechanism of action,
pharmacology, and adverse effects".)
Seizure calendar — Patients and family members should be asked to record seizures and
antiseizure medication doses on a calendar, which can then be brought or sent to the physician
for review. Seizure triggers (eg, stress, sleep deprivation, alcohol, menses) should be indicated.
The patient and family should note on the calendar the hour at which any symptoms occur.
The seizure calendar helps to monitor and encourage compliance, as well as identify triggers.
The seizure calendar also may be used to track the patient's response to drug therapy, including
possible side effects. 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
[167]. Seizures were also associated with the patients' own prediction of the likelihood of
seizure occurrence. Physicians should be aware that patients are often unaware of their
seizures and may significantly underestimate the number of seizures that occur, especially
those that occur during sleep or that disrupt consciousness [168].
Laboratory monitoring — A complete blood count, liver function tests, blood urea nitrogen
(BUN), and measurement of creatinine and electrolytes levels should be done prior to starting
antiseizure medication therapy. Albumin levels should also be obtained prior to starting
treatment with one of the highly protein-bound antiseizure medications.
Regular follow-up visits should be scheduled to check drug concentrations, blood counts, and
hepatic and renal function. 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.
Drug levels should be checked at least yearly in patients who are not having seizures and not
undergoing medication dose changes. Chemistry and hematology studies are usually checked
in association with drug levels.
Drug levels can be helpful in the management of antiseizure medications [169]:
● To establish an individual therapeutic concentration when a patient is in remission

● To assist in the diagnosis of clinical antiseizure medication toxicity
● To assess compliance
● To guide dose adjustments, particularly in the setting of drug formulation changes, when
an interacting medication is added to or removed from a patient's regimen, or during
pregnancy
Generic substitutions — The use of generic medications as a treatment for people with

epilepsy has attracted much attention and debate, and the evidence is mixed in terms of
whether generic substitution of antiseizure medications has an adverse impact on seizure
control and toxicity. Clinicians should consider the possibility of generic substitution as a cause
of unexpected breakthrough seizures or toxicity, along with other possible explanations. In
addition, clinicians may wish to obtain laboratory monitoring with plasma drug levels when a
change is made in drug formulation. This topic is reviewed in more detail separately. (See
"Overview of the management of epilepsy in adults", section on 'Generic substitution'.)
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)")
● Beyond the Basics topic (see "Patient education: Seizures in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
When the diagnosis of epilepsy is made, the initial treatment is a single antiseizure medication.
When to start treatment, and with what agent, is a complex decision that is individualized in
order to optimize both efficacy and tolerability.
● When to start antiseizure medication
• First unprovoked seizure – The decision of whether to start antiseizure medication

therapy at the time of a first unprovoked seizure in an adult should be individualized.
The decision is based on several factors: an assessment of the risk for recurrent
seizure, the potential benefits of immediate antiseizure medication therapy in reducing
the risk of recurrent seizure, the side effects of antiseizure medications, and patient
preferences. (See 'First-time unprovoked seizure' above.)
Antiseizure medication treatment is reasonable in patients after a single unprovoked

seizure if they also have a potential symptomatic cause of epilepsy (eg, stroke or
trauma history, brain tumor), epileptiform features on electroencephalogram, a
relevant abnormality on neuroimaging study (computed tomography [CT] or magnetic
resonance imaging [MRI]), or an abnormal neurologic examination. Many of these

patients likely meet criteria for epilepsy according to the International League Against
Epilepsy (ILAE) definition, which considers patients with a single unprovoked seizure
and an estimated risk of recurrence ≥60 percent over ten years to have epilepsy, similar
to those with two unprovoked seizures occurring >24 hours apart. (See 'Risk of seizure
recurrence' above.)
Antiseizure medication treatment after a single unprovoked seizure in patients may be

deferred depending on the presence or absence of other risk factors and on individual
patient preferences. (See 'Benefit of early versus deferred treatment' above.)
• Second unprovoked seizure – We recommend initiating antiseizure medication

therapy in individuals who have had two or more unprovoked seizures (Grade 1A).
Such patients are at high risk for further unprovoked seizures. (See 'Second
unprovoked seizure' above.)
● Selection of antiseizure medication – The selection of antiseizure medication considers

the type of epilepsy or epilepsy syndrome ( table 3) and potential side effects ( table 4
and table 5), as well as other prescribed medications and comorbidities. Patient age,
patient sex, and cost and availability of medication may also be relevant factors. (See
'Drug-related considerations' above and 'Seizure and epilepsy syndrome-related
considerations' above.)
• Consider drug interactions – In general, enzyme-inducing antiseizure medications

(eg, phenytoin, carbamazepine, phenobarbital, oxcarbazepine) are the most
problematic for interactions with drugs such as warfarin, hormonal contraception, anti-
cancer drugs, and anti-infective drugs. Specific interactions of antiseizure medications
with other medications may be determined using the Lexicomp drug interactions tool.
(See 'Pharmacokinetics' above.)
• Impact of kidney and liver disease – Because antiseizure medications are either
metabolized by the liver or excreted by the kidneys, renal and hepatic disease impacts
on both the choice of antiseizure medication as well as the prescribing regimen. (See
'Renal disease' above and 'Hepatic disease' above.)
• Teratogenic effects – Women of childbearing age should be counseled regarding

possible teratogenic effects of antiseizure medications. Folic acid supplementation is
recommended for all women of child-bearing potential. Valproate should be avoided
and only prescribed if no other antiseizure medication is effective for that particular
patient. (See 'Women of childbearing age' above.)
• Consider comorbid psychiatric disorders – Patients with epilepsy have a higher-than-

expected incidence of mood problems, anxiety, and depression. Antiseizure
medications as a class have been associated with suicidality. Some antiseizure
medications appear to have mood-stabilizing properties, while others may cause or
exacerbate a depressed mood or provoke psychosis. Patients treated with antiseizure
medications should be monitored for changes in mood and suicidality. (See 'Psychiatric
disorders' above.)
● Patient education and follow-up – Successful treatment can be optimized by a

systematic approach that includes patient education. The physician should emphasize the
critical need to follow the prescribed drug regimen. Nonadherence to antiseizure
medication treatment regimen is associated with increased risk of mortality, as well as
hospitalization and injury. Regular outpatient follow-up appointments and the use of
seizure calendars can help maximize the success of epilepsy treatment. (See 'Initiation of
antiseizure medication therapy' above.)
Use of UpToDate is subject to the Terms of Use.
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Topic 2212 Version 55.0

GRAPHICS
Management of a first unprovoked seizure in an adult
CNS: central nervous system; EEG: electroencephalography; ASM: antiseizure

medication.
* Coexisting medical conditions likely to be worsened by a seizure (eg, osteogenesis

imperfecta, shoulder reconstruction) may warrant treatment for low-risk patients.
¶ ASM decision made in consultation with neurology; treatment should be

individualized; patient preference may reasonably lead high-risk patients to defer ASM
until they have a second seizure.
Graphic 134331 Version 1.0

Causes of provoked seizures
Alcohol & drug withdrawal
Drug intoxication
Hyponatremia, hypernatremia
Hypomagnesium
Hypocalcemia
Hypoglycemia
Nonketotic hyperglycemia
Uremia
Hypoxia
Hyperthyroidism
Dialysis disequilibrium syndrome
Porphyria

Management of first provoked seizure in an adult
ASM: antiseizure medication.
* ASM started in consultation with neurology; treatment should be individualized.
¶ Consult with neurologist; continued ASM treatment may be warranted for patients with a
higher risk of recurrent seizure (eg, those with encephalitis, hemorrhagic stroke, or other
acute intracranial lesions).

Pharmacologic properties of antiseizure medications
Enzyme or
Metabolism and Protein binding Half-l
transporter
clearance (%)¶ adults (
induction/inhibition*
Brivaracetam Metabolized Inhibits epoxide ≤20 9

primarily by CYP- hydroxylaseΔ
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 CYP2C19, BSEP/ABCB11, CYP2C19
CYP3A4, UGT1A7, (moderate)
UGT1A9, and
May increase serum
UGT2B7 to active
concentration of
metabolite 7-OH-
clobazam and the active
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 (in

by CYPs 3A4 (major) spectrum inducer of CYP, enzyme-ind
and 1A2/2C8 (minor) UGT-glucuronidation, and naive patie
to active (epoxide) P-gp
8 to 22 (aft
and inactive
weeks due
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 ho

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 (cl

by CYPs 3A4, 2C19, parent drug) parent dru
2B6 and non-CYP
70 (N- 71 to 82 (N
transformations to
desmethylclobazam, desmethylc
active (N-
active metabolite) active meta
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 (p

active form (moderate) in renal
undergoes UGT- insufficienc
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 (p

CYPs 3A4, 2E1 carbamazepine to active in renal
(minor); ~50% epoxide metabolite; insufficienc
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 (prol

excreted as renal insuf
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

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
Dose adjustment is
needed in renal
impairment
Oxcarbazepine Prodrug; 70% of Induces CYP3A4 (weak) 40 9 (active m

active (MHD) form and UGT-glucuronidation prolonged
undergoes UGT- but does not induce its insufficienc
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
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 (d

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 (p

CYPs 2C19, 2C9 spectrum inducer of CYP
29 to 100 (a
(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
Stiripentol Metabolized Inhibits CYP3A4, CYP2C19, 99 4.5 to 13

primarily in the liver 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 a
to inactive
medication
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 (un

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 © 1978-2022 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.
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).

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¶ )
CarbamazepineΔ
Cenobamate
Eslicarbazepine◊
Gabapentin◊
Lacosamide
Oxcarbazepine◊
PhenobarbitalΔ
PhenytoinΔ
Pregabalin
PrimidoneΔ
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.

Common side effects of antiseizure medications
Antiseizure
Systemic side effects Neurologic side effects
medication
Brivaracetam* Nausea, vomiting, constipation, Headache, somnolence, dizziness,

fatigue 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 Dizziness, somnolence, nervousness,

energy 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.

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,

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)
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,
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.

Typical maintenance dosing of antiseizure medications in adults with

chronic kidney disease*
CKD stage 3
CKD stage 4
CKD stage 5
GFR >60
Antiseizure GFR 30 to 59 GFR 15 to 29 GFR <15
mL/minute/1.73
medication mL/minute/1.73 mL/minute/1.73 mL/minute/1.73
m2
m2 m2 m2
Carbamazepine 400 to 1600 mg No adjustment No adjustment No adjustment

orally per day in necessary. necessary. necessary.
two or three
divided doses.
Gabapentin¶ 900 to 3600 mg 400 to 1400 mg 200 to 700 mg 100 to 300 mg

orally per day in orally per day in orally once per day. orally once per day.
three divided two divided doses.
Use with caution.
doses.
Lacosamide 100 to 400 mg No adjustment Gradually titrate Gradually titrate

orally per day in necessaryΔ . from low initial from low initial
two divided doses. dose. dose.
Maximum 300 mg Maximum 300 mg

per day in divided per day in divided
dosesΔ . dosesΔ .
Lamotrigine Varies due to Use with caution; Use with caution; Use with caution;
indication and dose reduction may dose reduction may dose reduction may
concomitant be needed. be needed. be needed.
antiseizure
medications (eg,
without enzyme-
inducing drug: 225
to 375 mg orally
per day in two
divided doses).
Levetiracetam 1000 to 3000 mg 500 to 1500 mg 500 to 1000 mg 500 to 1000 mg

orally per day in orally per day in orally per day in orally per day in
two divided doses. two divided doses. two divided doses. two divided doses.
Oxcarbazepine 600 to 2400 mg No adjustment Initiate at half of Initiate at half of

orally per day in necessary. usual daily dose. usual daily dose.
two divided doses.
Phenobarbital 120 to 300 mg Use with caution; Use with caution; Use with caution;

orally per day in dose reduction may dose reduction may dose reduction may
two or three be needed. be needed. be needed.
divided doses.
Carefully
individualize dose
according to
seizure control and
serum
concentrations,
refer to clinical
topic for detail.
Phenytoin 300 to 600 mg No change. No change. No change.

orally per day in
Oral loading dose Oral loading dose Oral loading dose
two or three
usually not given. usually not given. usually not given.
divided doses.
Protein binding
Carefully
may be decreased;
individualize dose
consider assessing
according to
free phenytoin
seizure control and
levels.
serum
concentrations,
refer to clinical
topic for detail.
Pregabalin¶ 150 to 600 mg 75 to 300 mg orally 25 to 150 mg orally 25 to 75 mg orally

orally per day in per day in two or once per day in a once per day.
two or three three divided single or two
divided doses. doses. divided doses.
Topiramate 200 to 400 mg 50% dose 50% dose 50% dose

orally per day in reduction. reduction. reduction.
two divided doses.
Valproic acid 15 to 60 mg/kg No adjustment No adjustment No adjustment

(valproate) orally per day in necessary. necessary. necessary.
two or three
divided doses.
Standard dose
(usual upper limit
of weight-based
dosing): ≤2500 mg
per day.

Zonisamide 100 to 400 mg No adjustment Unclear. Unclear.

orally once per day. necessary.
Gradually titrate Gradually titrate
Gradually titrate from low initial from low initial
from low initial dose. dose.
dose.
Typical adult maintenance dosing in epilepsy (ie, not for status epilepticus or other indications) of
oral immediate-release formulations; initial dosing is usually the lowest maintenance dose, which
may need to be titrated to improve tolerability and according to seizure control. Details for initiating
and adjustment of dose vary by each agent. Refer to the Lexicomp drug monographs and
appropriate UpToDate clinical reviews for detailed information on individual agents.
GFR: glomerular filtration rate; CKD: chronic kidney disease; ESRD: end-stage renal disease; IHD:
intermittent hemodialysis; PD: peritoneal dialysis.
* Dose is adjusted according to seizure control. Drug levels may be useful for establishing an
individual therapeutic range when the patient is in remission and for guiding dose adjustments (eg,
when renal function is changing or there is an alteration in drug formulation or change in regimen
involving an interacting medication). Refer to UpToDate clinical reviews of epilepsy treatment.
¶ Clearance dependent upon kidney function; low protein binding, low volume of distribution (Vd),
and cleared efficiently by dialysis. Post-dialysis supplemental dosing is necessary.
Δ Patients with CKD who are taking medications that are strong CYP3A4 and CYP2C9 inhibitors may
have increased exposure to lacosamide; a further dose reduction may be needed. Specific
interactions may be determined by using the Lexi-Interact program included within UpToDate.
◊ Seizures have been reported in a small number of patients after high-flux IHD. Individualized
supplementation may be needed.
Adapted from: Bansal AD, Hill CE, Berns JB. Use of antiepileptic drugs in patients with chronic kidney disease and end stage
renal disease. Semin Dial 2015; 28:404.
Additional data from:

1. Israni R, Kasbekar N, Haynes K, Berns J. Use of antiepileptic drugs in patients with kidney disease. Semin Dial 2006;
19:408.
2. Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001;
15:405.
3. Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol 2014; 119:417.
4. Diaz A, Deliz B, Benbadis S. The use of newer antiepileptic drugs in patients with renal failure. Expert Rev Neurother
2014; 12:99.
5. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.


Contributor Disclosures
Steven Karceski, MD Speaker's Bureau: LivaNova [Patient education].
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];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.
El grupo editorial revisa las divulgaciones de los contribuyentes en busca de conflictos de intereses.
Cuando se encuentran, estos se abordan mediante la investigación a través de un proceso de revisión de
múltiples niveles y mediante los requisitos para que se proporcionen referencias para respaldar el
contenido. Se requiere que todos los autores tengan contenido referenciado de manera adecuada y debe
cumplir con los estándares de evidencia de UpToDate.
Política de conflicto de intereses

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5/10/22, 22:04 Initial treatment of epilepsy in adults - UpToDate

Reimpresión oficial de UpToDate ®

Tratamiento inicial de la epilepsia en adultos

CUÁNDO COMENZAR LA TERAPIA CON MEDICAMENTOS ANTICONVULSIONES

convulsión sintomática remota). Las convulsiones no provocadas son distintas de las

La decisión de iniciar o no la terapia con medicamentos anticonvulsivos en el momento de una

● El beneficio aproximado que se puede esperar de la terapia inmediata con medicamentos

● Los perfiles de efectos secundarios de varias opciones de medicamentos anticonvulsivos,

● Valores y preferencias del paciente, particularmente con respecto a las consecuencias

Una guía basada en evidencia de la Academia Estadounidense de Neurología y la Sociedad

● Es probable que la terapia inmediata con medicamentos anticonvulsivos, en comparación

Riesgo de recurrencia de las convulsiones : en ensayos prospectivos aleatorios de personas

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pacientes no tratados oscila entre el 40 y el 50 % [ 4-6 ]. El riesgo de recurrencia es máximo

● Anomalías epileptiformes en el EEG (ver "Electroencefalografía (EEG) en el diagnóstico de

● Exploración neurológica anormal, incluidos hallazgos focales y discapacidad intelectual

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En conjunto, los resultados de calidad de vida, medidos en un estudio aleatorizado, no fueron

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Convulsiones sintomáticas agudas : las convulsiones sintomáticas agudas tienen un riesgo

Un subconjunto de convulsiones sintomáticas agudas son aquellas que ocurren en el contexto

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sintomáticas agudas' y "Evaluación y manejo de la primera convulsión en adultos", sección

SELECCIÓN DE UN MEDICAMENTO ANTICONVULSIVO

La epilepsia se trata inicialmente con monoterapia con medicamentos anticonvulsivos. Casi la

Eficacia : ningún medicamento anticonvulsivo es claramente el más efectivo o mejor

La evidencia se resume en las secciones siguientes.

tratamiento (refractario) (ver "indicaciones de la FDA"abajo). Dichos pacientes pueden no

Ha habido un número limitado de ensayos aleatorios que compararon varios

• Carbamazepina versus fenitoína [ 28 ]

A meta-analysis of randomized trials can potentially overcome some of the limitations of

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• Initial treatment of focal epilepsy: Lamotrigine, levetiracetam, oxcarbazepine,

• Genetically mediated generalized epilepsies syndrome with mainly generalized tonic-

• Absence seizures: Ethosuximide, valproate, lamotrigine

• Genetically mediated generalized epilepsy syndrome with myoclonic seizures:

• Older adult with focal epilepsy: Lamotrigine, levetiracetam, lacosamide

• Comorbid depression with focal epilepsy: Lamotrigine, lacosamide, oxcarbazepine

• Comorbid depression with genetically mediated generalized epilepsy: Lamotrigine,

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• Hepatic failure or after organ transplantation: Levetiracetam, gabapentin, lacosamide

• Renal failure on hemodialysis: Lamotrigine, oxcarbazepine, levetiracetam

Pharmacokinetics — Important pharmacologic features of individual antiseizure medications

● Dosing frequency – The half-lives of antiseizure medications vary considerably

● Drug interactions – The selection of an antiseizure medication should consider other

In general, antiseizure medications with hepatic enzyme induction or inhibitory properties

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Antiseizure medications that are hepatic-enzyme inducers increase the metabolism of

● Aging – Antiseizure medication use in older adult patients is complicated by several

Side effect profiles — The adverse effects of antiseizure medications make a significant

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● Neurocognitive side effects – Most antiseizure medications are associated with a

● Hypersensitivity reactions – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis

● Suicidality – Antiseizure medications as a class have been associated with an

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● Weight gain or loss – Weight gain is associated with valproate, gabapentin,

A historical-controlled treatment discontinuation trial design is being increasingly used in an

Seizure and epilepsy syndrome-related considerations

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Focal versus generalized seizures/epilepsy — In selecting an antiseizure medication for a

● Post-stroke epilepsy is generally easily controlled with antiseizure medication

● Brain tumors are associated with epilepsy in 30 to 70 percent of patients, depending on

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