Revista Mexicana de

Neurociencia

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Publicación oficial de la Academia Mexicana de Neurología A.C.

VOLUME 20 - NUMBER 2 / Marzo-Abril 2019 – ISSN: 1665-5044

eISSN: 2604-6180
www.revmexneurociencia.com

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Editorial
Clinical guidelines from the Priority Epilepsy Program of the public health sector in Mexico 56
J.C. Reséndiz-Aparicio

Artículos de revisión
Clinical guideline: definition and classification of epilepsy 63
J.C. Reséndiz-Aparicio, J.C. Pérez-García, E. Olivas-Peña, E. García-Cuevas, Y.L. Roque-Villavicencio, M. Hernández-Hernández,
J.I. Castro-Macías and J.D. Rayo-Mares

Clinical guideline: management of seizures in the emergency room 69

J. Visoso-Franco, L. Romero-Ocampo, J.A. Santos-Zambrano, A. Serrano-González and E. Castro-Martínez

Clinical guideline: management of the first unprovoked epileptic seizure in adults and children 76
J.A. Gien-López, R.A. Cuevas-Escalante, E. García-Cuevas, M.R. Márquez-Estudillo, B.E. Villaseñor-Anguiano, R. Leal-Cantú and R.E. Jiménez-Arredondo

Clinical guideline: antiepileptic drugs of choice for focal and generalized seizures in adult patients with epilepsy 82
L. Rivera-Castaño, H. Sentíes-Madrid, J. Berumen-Jaik and I.E. Martínez-Juárez

Clinical guideline: antiepileptic drugs of choice for epileptic syndromes and epilepsies in pediatric patients 89
J.C. Reséndiz-Aparicio, J.M. Padilla-Huicab, I.E. Martínez-Juárez, G. Hernández-Martínez, E. López-Correa, B. Vázquez-Juárez,
R. Huerta-Albarrán and C. Rivera-Acuña

Clinical guideline: febrile seizures, diagnosis and treatment 97

C. Aguirre-Velázquez, A.M. Huerta Hurtado, H. Ceja-Moreno, K. Salgado-Hernández, R. San Román-Tovar, M.A. Ortiz-Villalpando,
Avril Molina-García, G. Vargas-Ramírez, J. López-Rivera and R. Huerta-Albarrán

Clinical guideline: epilepsy in pregnancy and women of childbearing age 104

P.O. González-Vargas, Y. Matuk-Pérez, J.L. Sosa Hernández, G. Quiñones-Canales, S.E. Silva-Sánchez, G. Aguayo-Leytte, S. Medina-Benitez,
J.M. Ibarra-Puig, L.G. María del Consuelo and Elvira Castro-Martínez

Clinical guideline: status epilepticus in children and adults 110

A. Olmos-López, J. Ibarra-Aguilar, J.O. Cornelio-Nieto, L.A. Ocaña-Hernández, M.A. Márquez-Amaya, N. Luna-López, J.C. Reséndiz-Aparicio
and I. Rodríguez-Leyva

Clinical guideline: pre-operative evaluation of epilepsy surgery 116

M. Ruiz-García, M.A. Alonso-Vanegas, S.P. Pérez-Reyes, G. Quiñones-Canales, I. Rodríguez-Leyva, H.R. Martínez-Rodríguez and E. Barragán-Pérez

Clinical guide: discontinuing chronic antiepileptic drug treatment 123

M.C. Loy-Gerala, O.M. Ibarra-Bravo, M.R. Márquez-Estudillo, F. Mena-Barranco, F.J. Rogel-Ortiz, S.E. Silva-Sánchez, H. Villegas-Peña
and A. Molina-García

PERMANYER
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 Revista Mexicana de Neurociencia

Editorial

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Clinical guidelines from the Priority Epilepsy Program of the
public health sector in Mexico
J.C. Reséndiz-Aparicio
Hospital Psiquiátrico Infantil Dr. Juan N. Navarro y P.P.E, Instituto Nacional de Neurología y Neurocirugía Dr. Manuel Velasco Suárez. Mexico City,
Mexico

The Programa Prioritario de Epilepsia (PPE - Priority
Epilepsy Program) was created based on the accord
published in the Mexican Official Gazette of the Fede-
ration on October 24th, 1984. This program has labored
in an uninterrupted manner to regulate, coordinate,
methodize, and optimize the strategies in favor of pa-
tients with epilepsy, as well as their families and socie-
ty. There are currently 78 centers of integral treatment
for epilepsy in Mexico, located in various hospitals be-
longing to Mexico’s health sector.
The headquarters for the national coordination is in
the Instituto Nacional de Neurología y Neurocirugía
(National Institute of Neurology and Neurosurgery)
“Dr. Manuel Velasco Suarez” (INNN due to its acronym
in Spanish) in Mexico City, from where all actions are
No part of this publication may be reproduced or photocopying without the prior written permission o
planned for this task. The national coordination is led
by its creator and founder Francisco Rubio Donnadieu,
MD and by the author.
The development of the first Clinical Guidelines
(CGs) has been a laborious effort, one that has been
finished due to the work of all the coordinators of the
PPE, who are neurologists and pediatric neurologists
certified by the Mexican Board of Neurology and who
work in one of the many institutions of the health sec-
tor in Mexico. To elaborate the CG, all the coordinators
of the PPE met in person in two meetings, the first in
the city of Leon and the second in the city of Puebla,
where we formed workgroups for each CG. These
meetings were possible due to the support of the fe-
deral government and the contributions of the

Correspondence: Date of reception: 01-02-2019 Available online: 12-04-2019

Juan Carlos Reséndiz-Aparicio Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):56-62
E-mail: jc_doc@yahoo.com DOI: 10.24875/RMN.M19000041 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

56
 J. C. Reséndiz-Aparicio: Clinical Guidelines of the Priority Epilepsy Program

pharmaceutical laboratories that aid in training primary throughout the various institutions of the health sector;
health-care physicians. These CGs are designed to however, it is understood that the application of said
aid the primary health-care physicians and the spe- recommendations depends on many factors. It is im-

 f the publisher.   © Permanyer 2019

cialists in making adequate decisions when approa-
ching epileptic patients of different age groups and
genders. These are the culmination of the experience
of their authors, who have followed the necessary
steps for proper and updated scientific research, using
the criterion of the American Epilepsy Society 2016 to
analyze the levels of evidence and recommendations
including the benefit for the patients. To evaluate the
quality of the CG, two experts coordinated each table
and applied the Spanish version of the AGREE instru-
ment of 2001.
Due to the advances in the knowledge of epilepsy,
portant to state that there are no conflicts of interest in
these CGs due to the fact that they are editorially inde-
pendent of any external funding.
Finally, I would like to thank the INNN for their hos-
pitality and support in the coordination of the Program,
the Mexican Academy of Neurology for the publication
in their magazine, the Mexican Society of Pediatric
Neurology who supported the process of translating the
CG to English, and the authorities of the Hospital Psi-
quiátrico Infantil (Children’s Psychiatric Hospital) of
Mexico City who have allowed me to work as the ad-
junct executive member of the Priority Epilepsy Pro-

the PPE group aims to update the CG every 5 years.
These CGs constitute a series of recommendations
developed by a group of medical physicians that have
a particular interest in the field of epilepsy and work
No part of this publication may be reproduced or photocopying without the prior written permission o
gram and above all, thank you to the coordinators of
the Priority Epilepsy Program who worked on this pro-
ject; this work is dedicated to them and their families
and to which I express my most ample recognition.

Juan Carlos Reséndiz Aparicio, MD, Adjunct Executive Member

American Epilepsy Society 2016

Article Classification: Evidence

 randomized, prospective and controlled clinical trial with masked outcome assessment, in a repre-
Class I: A
sentative population. The following are required:
a. No more than two specified primary results.
b. Blind allocation of subjects.
c. Exclusion/inclusion criteria are clearly defined.
d. Relevant baseline characteristics are presented and substantially equivalent among treatment
groups or there is appropriate statistical adjustment for differences.
e. Adequate accounting for dropouts with numbers sufficiently low to have a minimal potential for
bias. (study was completed with at least 80% of the enrolled subjects).
f. Demonstration of superior design of the studies or demonstration of non-inferiority with a 10%
non- inferior design margin.
 randomized, prospective and controlled clinical trial with masked outcome assessment that lacks
Class II: A
one or two criteria of Class I a-e above, or a prospective matched cohort study with masked objec-
tive outcome assessment in a representative population that meets a-e.
Class III: All other control trials in a representative population, where outcome was independently assessed
by objective outcome measurement.
Class IV: Evidence from non-controlled trials, including series reports, case reports, consensus, or expert
opinion.

57
 Rev Mex Neuroci. 2019;20

Evidence for the Conclusion and Recommendation

Recommendation Conclusion, Level A
Level A Established as effective, ineffective, or harmful for the given condition in

 f the publisher.   © Permanyer 2019

One or more Class I trials or
two or more Class II trials.
Level B
One or more Class II trials or
three or more class III trials.
Level C
Two or more Class III trials.
Level U
Absence of trails that com-
plement levels A, B, or C.
Level R-PPE
the specified population.
Recommendation:
Must be done or must not be done.
Conclusion, Level B
Probably effective, ineffective, or harmful for the given condition in the
specified population.
Recommendation:
It must be considered or must not be considered.
Conclusion, Level C
Possibly effective, ineffective, or harmful for the given condition in the
specified population.
Recommendation:

No part of this publication may be reproduced or photocopying without the prior written permission o
It could be considered or should not be considered.
Conclusion, Level U
Data is insufficient or inadequate given current knowledge, treatment is
unproven
Recommendation: Should not be performed
Conclusion, Level R-PPE
No evidence from levels A, B, or C, but it is a recommendation by con-
sensus of the group that elaborated the Clinical Guidelines of the PPE.

In all of the CGs of the Priority Epilepsy Program Seizure

(PPE), the abbreviations we published are the same as
ES: epileptic seizure
the book “Epilepsia” by authors Rubio, Reséndiz, Alon-
GS: generalized seizure
so, and Sentíes, by the editorial Alfil in 2016, page GTCS: generalized tonic-clonic seizure
numbers IX, X y XI; ISBN 978-607-741-168-0. FS: focal seizure
FIAS: focal impaired awareness seizures (or discon-
Glossary and Abbreviations nection from medium)
FAS: focal aware seizure/simple partial seizure
FBTCS: focal to bilateral tonic-clonic seizure
Channelopathies
SE: status epilepticus
SCN4A, SCN2A, SCN1B FeS: febrile seizure
KCNA1, KCNQ2, KCNQ3
CACNA1A Electrolytes and neurotransmitters
CHRNA4, CHRNB2
GLRA1 Ca++: calcium
Cl−: chlorine
GABRG2
K+: potassium
Ion: NA: sodium; K: potassium; CA: calcium;
Mg++: magnesium
CH: acetylcholine; GL: glycine; GABA: gamma-ami- Na+: sodium
nobutyric acid GABA: gamma-aminobutyric acid
Channel or receptor: CN: channel; R: receptor; NMDA: N-methyl-D-aspartate
N: nicotinic AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazolepro-
Subunit: A: α; B: β: Q: M; G: γ pionic acid

58
 J. C. Reséndiz-Aparicio: Clinical Guidelines of the Priority Epilepsy Program

Neurologic structures GPC-PPE: G

 uía de Práctica Clínica del Programa
Prioritario de Epilepsia or Clinical Guide-
BBB: blood–brain barrier lines of the Priority Epilepsy Program

 f the publisher.   © Permanyer 2019

CSF: cerebrospinal fluid
CNS: central nervous system
Additional neurological disorders
Diagnostic tests CVD: cerebrovascular disease
TBI: traumatic brain injury
fMRI: functional magnetic resonance imaging
MRI: magnetic resonance imaging
PET: positron emission tomography Drug administration routes
SPECT: single-photon emission computed tomography IM: intramuscular
CT: computed tomography scan IV: intravenous
ECoG: electrocorticography/intracranial PO: oral
electroencephalography S/C: subcutaneous
EEG: electroencephalogram

No part of this publication may be reproduced or photocopying without the prior written permission o
S/L: sublingual
MEG: magnetoelectroencephalogram
Video-EEG: video electroencephalogram
PSG: polysomnogram Syndromes and types of epilepsy
EKG: electrocardiogram BECTS: b  enign epilepsy with centrotemporal spikes
LP: lumbar puncture/spinal tap (Rolandic Epilepsy)
IGE: idiopathic generalized epilepsy
Genetics PME: progressive myoclonus epilepsy
JME: juvenile myoclonus epilepsy
AD: autosomal dominant MTS: mesial temporal sclerosis
AR: autosomal recessive. LGS: Lennox-Gastaut syndrome
p: short arm of a chromosome DRE: difficult to treat seizures/drug-resistant epilepsy
q: long arm of a chromosome
DNA: deoxyribonucleic acid
RNA: ribonucleic acid Miscellaneous
NB: newborn/neonate AED: antiepileptic drugs/anti-seizure medications
BZD: benzodiazepines
Organizations
AAN: American Academy of Neurology Antiepileptic drugs
AES: American Epilepsy Society ACZ: acetazolamide
AAP: American Academy of Pediatrics ACTH : adrenocorticotropic hormone
CAIE: Centros de Atención Integral para la Epilepsia NE: barbexaclone
or Comprehensive Care Centers for Epilepsy NE: beclamide
FDA: Food and Drug Administration CBZ: carbamazepine
IBE: International Bureau for Epilepsy CLB: clobazam
ILAE: International League Against Epilepsy CZP: clonazepam
INNN: Instituto Nacional de Neurología y Neurocirugía CLP: clorazepate
or National Institute for Neurology and DZP: diazepam
Neurosurgery. ESM: ethosuximide
WHO: World Health Organization FBM: felbamate
PAHO: Pan American Health Organization GBP: gabapentin
PPE: Programa Prioritario de Epilepsia or Priority LTG: lamotrigine
Epilepsy Program LEV: levetiracetam
SAdE: Sociedad Andaluza de Epilepsia or Andalusian LZP: lorazepam
Epilepsy Society MDL: midazolam
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 Rev Mex Neuroci. 2019;20

MPH: methylphenidate CBT: carabersat (SB-204269)

MPB: methylphenobarbital TBT: tonabersat (SB-220453)
MSM: mesuximide/methsuximide SFM: safinamide (PNU-151774E)

 f the publisher.   © Permanyer 2019

NTZ: nitrazepam RUF: rufinamide (SGP33101)
OXC: oxcarbazepine STL: soretolide (D-2916)
PAC: phenacemide TLP: talampanel (GYKI 53773)
PTR: pheneturide HUP: huperzine A
PB: phenobarbital ATM: atipamezole
PSM: phensuximide VLR: valrocemide (TV1901)
PHT: phenytoin IVR: isovaleramide
NE: fosphenytoin VPG: valproyl glycinamide
PGB: pregabalin VLT: valnoctamide
PRM: primidone VPD: valpromide
PRO: progabide VCD: valrocemide
STM: sultiame/sulthiame PID: propylisopropylacetamide

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TGB: tiagabine LiCBZ: licarbazepine
TPM: topiramate EsliCBZ: eslicarbazepine (BIA 2-093)
NE: trimethadione FI-FBM: fluorofelbamate
VPA: valproic acid NA: ganaxolone
VGB: vigabatrin carisbamate (RWJ-333369)
ZNS: zonisamide perampanel
NE: 4-amino-3-hydroxibutiric Acid ELB-139
FLN: flunarizine JZP-4
LSG: losigamone NS-1209
RLT: ralitoline (Cl-946) CGX-1007
REM: remacemide SPD-421
STP: stiripentol ICA27243
HRK: harkoseride T2000
LCM: lacosamide XP-13512*
RET: retigabine (D-23129) YKP3089
BRV: brivaracetam NE: not established
STM: seletracetam (ucb 44212) NA: not applicable

60
 Centers of integral care for epilepsy “CAIE” in Mexico
J. C. Reséndiz-Aparicio: Clinical Guidelines of the Priority Epilepsy Program

61
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 Rev Mex Neuroci. 2019;20

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No part of this publication may be reproduced or photocopying without the prior written permission o
Thanks to Jetzabel Fragoso and Dr. Francisco López for their support in all the activities of the Priority Epilepsy
Program.

62
Revista Mexicana de Neurociencia

REVIEW ARTICLE

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Clinical guideline: definition and classification of epilepsy
Juan C. Reséndiz-Aparicio1, Juan C. Pérez-García2, Efraín Olivas-Peña3, Enrique García-Cuevas4, Yuridia
L. Roque-Villavicencio5, Marisela Hernández-Hernández6, Jaime I. Castro-Macías7 and
Jesús D. Rayo-Mares8
1PPE, Instituto
Nacional de Neurología y Neurocirugía Dr. Manuel Velasco Suárez y Hospital Psiquiátrico Infantil Dr. Juan N. Navarro, Mexico City;
2HospitalChristus Muguerza UPAEP, Puebla; 3Hospital de la Mujer, Yautepec, Morelos; 4Hospital General Acapulco, Guerrero; 5Hospital Civil de
Guadalajara, Jalisco; 6Hospital Central Sur de Alta Especialidad Pemex, Mexico City; 7Hospital Regional de Alta Especialidad del Bajío, León,
Guanajuato; 8Hospital de Pediatría del Centro Médico Nacional Siglo XXI IMSS, Mexico City. Mexico

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
The current definition of epilepsy proposes three possibilities to consider this diagnosis, the first when a patient has two or
more unprovoked or reflex seizures in >24 h; the second, an unprovoked or reflex seizure with at least a 60% probability of
continuing to present seizures; and the third, the presence of an epileptic syndrome. The classification of the type of seizure
divides them into three possibilities depending on how they begin; they can be of focal, generalized, or unknown onset. Focal
seizures can be subclassified into those that have or have not lost consciousness, then categorized as to whether the symp-
toms are motor or non-motor, and further give a descriptor of the event, which is nothing else but the description of symptoms
and signs presented by the patient during his seizure. The classification of the type of epilepsy, proposes three diagnostic
levels, the first related to the type of seizure, the second to the type of epilepsy, and the third to the type of epileptic syndrome,
without forgetting etiology and comorbidity. These concepts are basic for the approach of any patient who presents epilepsy.

Key words: Epilepsy. Definition. Classification.

Introduction and not a review of the available evidence. The ILAE

This being a clinical guide, it is developed based on
research questions under the PICO method; answers
are presented, and it concludes with recommendations.
In this clinical guide, we do not mention levels of evi-
dence since the references used are current articles
from the International League Against Epilepsy (ILAE)1-3,
which is the official agency for this disease worldwide,
and its workgroups have strived to provide a standard
terminology to be used worldwide.
Question 1. What is an epileptic seizure?
An epileptic seizure is defined as the transitory ma-
nifestation of signs and/or symptoms caused by an
anomalous excessive neuronal activity in the brain4.

Correspondence:
Juan Carlos Reséndiz-Aparicio
PPE, Instituto Nacional de Neurología y
Neurocirugía Dr. Manuel Velasco Suárez
Hospital Psiquiátrico Infantil Dr. Juan N. Navarro Date of reception: 21-01-2019 Disponible en internet: 12-04-2019
Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):63-68
E-mail: jc_doc@yahoo.com DOI: 10.24875/RMN.M19000024 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

63
 Rev Mex Neuroci. 2019;20
Question 2. What is an unprovoked
seizure?
The term unprovoked implies the absence of a
temporal or reversible factor that reduces the convulsive
threshold and provokes a seizure at that moment. The
opposite of this type of phenomenon is an acute symp-
tomatic seizure, defined as a seizure that occurs in tem-
poral relation during cerebral injury, which can be meta-
bolic, infectious, toxic, structural, or inflammatory4,5.
Question 3. What is the current definition
of epilepsy?
A diagnosis of epilepsy is established after any of the
following situations4:
1. Two or more unprovoked or reflex seizures occurring
with >24 h difference.
2. An unprovoked or reflex seizure with a probability of at
least 60% of presenting a future seizure (similar range
as the general risk of recurrence, after two unprovoked
seizures that appear in the following 10 years).
3. Diagnosed epileptic syndrome.
Question 4. How is the risk of recurrence
of an epileptic seizure defined?
The events that have been documented to increase
the risk of recurrence of an epileptic seizure are cere-
brovascular disease, both ischemic and hemorrhagic,
cranioencephalic trauma, abnormal electric activity in
an EEG compatible with an epileptic seizure, or a cranial
magnetic resonance showing a lesion compatible with
a diagnosis of epilepsy5. If a patient, after a first unpro-
voked seizure is predisposed to continued generation
of seizures of at least 60%, a diagnosis of epilepsy must
be considered4. If this is not the case, to establish a
diagnosis of epilepsy one must consider option one (two
or more unprovoked seizures >24 h apart).
Epilepsy is considered as resolved in those patients
that have an age-dependent epileptic syndrome but
have grown older than the corresponding age for the
specific syndrome or in patients that have remained
seizure-free for the past ten, without taking antiepileptic
drugs in the last 5 years4.
Question 5. What is the current
classification by type of epileptic seizure?
The ILAE decided to modify the classification system
for epileptic seizures in 19816, and update it in 20107.
64
The classification is divided into three, depending on
the patient’s symptoms at seizure onset:
Focal onset seizure/Generalized onset seizure/Unk-
 f the publisher.   © Permanyer 2019
nown onset seizure.
Focal onset seizures originate within a network limi-
ted to one hemisphere; they can be localized or more
widely distributed. Generalized seizures are those that
originate at one point with wide and rapid participation
of bilaterally distributed networks. Those seizures whe-
re it cannot be distinguished whether they are of focal
or generalized onset with a confidence level of 80%,
must be considered of unknown onset (Fig. 1).
Question 6. How are focal onset epileptic
seizures currently classified?
No part of this publication may be reproduced or photocopying without the prior written permission o
The state of awareness is a differentiating factor for
the type of seizure in focal seizures1,2. Awareness refers
to the relationship between oneself and the external
environment. In epilepsy, we establish awareness as the
mental state, with both subjective and objective aspects,
that encompasses the sense of self as a unique entity,
capable of response, and memory. A  focal seizure is
classified by the degree of awareness during onset,
which can be altered at any time during the event.
Focal seizures, with or without impaired awareness, can
be subclassified depending on whether they initiate with
motor or non-motor symptoms. In addition, the 2017 clas-
sification recommends adding what they call “descriptors,”
which are symptoms and signs that the patient presents
during the seizure1,2. Descriptors have been divided into
six groups: motor, automatisms, sensory, emotional, cog-
nitive, or autonomic. To remember these descriptors more
easily, you can use the mnemotechny MASECA, which is
the most famous brand of tortilla dough in Mexico8.
Question 7. How are the symptoms and
signs divided into focal seizures?
Motor
Involvement of the musculature in any way. An in-
crease (positive) or decrease (negative) in muscular
contraction to produce movement. The most frequent
are: motor arrest, astatic, clonic, dysarthria, dystonic,
pelvic thrusting, figure-of-4, hypokinetic, hyperkinetic,
incoordination, Jacksonian, myoclonic, paralysis, pare-
sis, pedaling, fencer’s posture, and versive.
The most frequent clinical confusion is in differentia-
ting clonic seizures from myoclonic seizures. A  clonic
seizure is a repetitive, regular movement that can be
 J.C. Reséndiz-Aparicio, et al.: Definition and classification of epilepsy

 f the publisher.   © Permanyer 2019

Focal Onset Generalized Onset Unknown Onset

Aware Impaired
Awareness
MOTOR MOTOR
tonic-clonic tonic-clonic
clonic epileptic spasms
tonic NON- MOTOR
myoclonic Behavior arrest
MOTOR ONSET
myoclonic-tonic-clonic
automatisms
myoclonic-atonic
atonic*

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atonic
clonic
epileptic spasms*
epileptic spasms*
ABSENCE
hyperkinetic
typical
myoclonic
atypical
tonic
myoclonic
NON-MOTOR ONSET
palpebral myoclonia
Behavior arrest
autonomic
sensory
emotional
cognitive

Focal to bilateral Unclassified†

tónico-clónica

* Can be focal or generalized, with or without alteration of awareness

†
Due to inadequate information or inability to be included in another category

Figure 1. Classification by type of seizure. ILAE, 2017.

symmetrical or asymmetrical and that involves the same
muscle groups. A myoclonic seizure is a brief (< 100 ms),
sudden, involuntary, single or multiple contractions of
the muscles or muscle groups, with variable topography
(axial, proximal, or distal extremities). The myoclonic
seizure is less repetitive and sustained.
Automatisms
Motor activity, which is more or less coordinated, that
generally occurs when awareness is deteriorated and
after which the subject is generally (but not always)
amnesiac. It commonly resembles a voluntary move-
ment. The most frequent include: aggression, manual,
oral-facial, perseveration, sexual, undressing, vocaliza-
tion, walking, or running.
Sensory
Related with the senses, thus, in this case, are not
signs but symptoms. The most frequently reported
symptoms are: auditory, gustatory, olfactory, somato-
sensory, vestibular, visual, and pain.
Emotional
These are seizures that present as having an emotion
as a prominent initial feature, such as fear, pleasure or
65
 Rev Mex Neuroci. 2019;20
spontaneous euphoria, laughter, crying, expressed in
bursts, or flares.
Cognitive
The most frequently reported data from this group
are: acalculia, aphasia, attention impairment, déjà vu
or jamais vu phenomena, dysphasia, illusions, memory
impairment, forced thinking, altered responsiveness, or
hallucinations.
Autonomic
Alteration of the autonomic nervous system function,
which may involve the cardiovascular system, pupils,
diaphoresis, the gastrointestinal tract, vasomotor and
thermoregulation functions.
In focal seizures, there are two sections that were not
included in previous classifications, the epileptic spasm
(previously only classified within generalized seizures)
and behavior arrest1,2.
A focal onset seizure, with or without impaired awa-
reness, motor or non-motor, can progress to a bilateral
tonic-clonic activity. The term previously used for this
type of seizure was a secondary generalized partial
seizure. At present, we must classify it as a focal onset
seizure that evolves into a bilateral tonic-clonic
seizure.
The term bilateral tonic-clonic is used for focal seizu-
res that propagate to both cerebral hemispheres, while
generalized is for seizures that originate simultaneously
in both cerebral hemispheres.
Question 8. ¿How are generalized
epileptic seizures currently classified?
They are divided into seizures with motor or
non-motor symptoms. Among those with motor, symp-
toms are the generalized tonic-clonic, clonic, tonic,
myoclonic, myoclonic-tonic-clonic, myoclonic-atonic
seizures, and the epileptic spasm. For non-motor,
there are absence seizures1,2. A myoclonic-tonic-clo-
nic is a type of generalized seizure that was not in-
cluded in the previous classification. These seizures
imply one or various bilateral jerks (myoclonic) of the
extremities, followed by a tonic-clonic seizure1,2,8. Ato-
nic seizures present sudden loss or reduction in mus-
cle tone involving musculature of the head, trunk,
mandible, or extremities.
The epileptic spasm is usually more sustained than
a myoclonic movement, but not as sustained as a tonic
66
seizure. It frequently occurs in clusters or bursts. Epi-
leptic spasms are more frequent in children but can
occur at all ages.
 f the publisher.   © Permanyer 2019
Absence seizures can be divided into four types:
Typical absence, atypical absence, myoclonic absence,
and absence with palpebral myoclonus. Typical absen-
ce seizures are of sudden onset, interrupting ongoing
activities, blank stare, does not respond when spoken
to, lasting from seconds to half a minute, and with very
quick recovery. It’s important to remember that the
word “absence” is not synonymous with blank stare
since this can also be encountered in focal onset
seizures2.
Atypical absence seizures show changes in tone that
are more pronounced than in typical absence; the on-
No part of this publication may be reproduced or photocopying without the prior written permission o
set and cessation are not abrupt. Myoclonic absence
presents with sudden, brief (<100 ms), involuntary,
non-repetitive nor sustained, and absence. In absence
with palpebral myoclonus, we observe eyelids jerking
at a frequency under 3 per second, eyes commonly
deviated upward, generally lasting <10 s, frequently
precipitated by ocular closure, with high possibility of
photosensitivity.
Question 9. When do we classify an
epileptic seizure under the heading of
unknown onset or unclassified?
When there is no evidence about the onset of the
seizure, focal or generalized, it may be classified under
the heading of unknown onset seizure, and in this case,
a limited classification can be carried out with the fin-
dings that were observed.
The heading “Unclassified” applies to the type of
seizure when there are no data described in the ILAE
classification of 2017, either because the information is
inadequate or because of unusual characteristics1,2.
Question 10. How are epilepsy and
epileptic syndromes classified?
Since April 2017 the epilepsy classification set forth
by the ILAE establishes three levels of diagnosis: the
first level is the type of seizure, which incorporates all
of the concepts in all diagnostic levels revised pre-
viously, focal, generalized or of unknown onset, and
now we have added two important concepts at all
diagnostic levels: patient comorbidities (associated
pathological entities) and etiology. Some patients can
only stay at this diagnostic level because it is not pos-
sible to study more, and this can be valid or be the
 J.C. Reséndiz-Aparicio, et al.: Definition and classification of epilepsy

Type of seizure Etiology

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Focal Generalized Unknown
Structural

Genetic
Comorbidities

Type of Epilepsy Infectious

Combined,
generalized
Focal Generalized and focal Unknown Metabolic

Immune

Unknown
Epileptic Syndrome

No part of this publication may be reproduced or photocopying without the prior written permission o
Figure 2. Classification of Epilepsy. ILAE 2017.

first step in their evaluation. The second diagnostic
level applies when there is at least one encephalo-
gram and a cerebral imaging study. At this level one
must establish the type of epilepsy, which can be fo-
cal, generalized, or combined; this is for focal, gene-
ralized (which is common in various epileptic syndro-
mes) or unknown type seizures. The etiologic diagnosis
can be in any of the following fields: structural, gene-
tic, infectious, metabolic, immune, or unknown. On
occasion there can be >1 etiology in the same patient,
for example, a patient with tuberous sclerosis that has
cortical tubers would suggest a structural etiology, but
also genetic due to the base disease. The third diag-
nostic level constitutes an epileptic syndrome. A group
of characteristics that incorporates types of seizure,
specific EEG findings, characteristics form imaging
studies, age-dependent frequency, age at onset, and
remission when applicable, specific triggers, varia-
tions during the day, on occasion prognosis, distincti-
ve comorbidities both intellectual and psychiatric, and
all can have implications on etiology and treatment.
This classification eliminates the term benign which
has been substituted by the terms autolimited or drug
responsive (Fig. 2).
Epileptic syndromes can be classified by age groups,
as was established by the ILEA classification of 20107,
but that is subject for another Guide.
Question 11. How are seizures and
epilepsy in the newborn classified?
There are various classifications for neonatal seizu-
res. The Volpe classification9 considers the clinical fin-
dings (mostly used by pediatricians and neonatologists)
and the Mizrahi classification10 considers the physiopa-
thologic origin, be it epileptic or non-epileptic. In 2018,
the ILAE issued a new proposal to classify seizures in
the newborn (Fig. 3) that includes four parts: the pre-
sentation, established in the critically ill newborn who
must be under vigilance in view of the possibility of a
seizure; diagnosis, by performing a video-EEG; mani-
festation, which could be by clinical signs or only elec-
troencephalographic data; and fourth, the type of sei-
zure, which could be with motor symptoms. It is called
sequential when the symptoms in the newborn show a
motor sequence and the seizure is of a non-motor type.
Recommendation Level of recommendation
It’s desirable for health R‑PPE
professionals to know the
current definition of epilepsy to
be able to apply it
It’s desirable that health R‑PPE
professionals know and apply
the current classification of the
types of epileptic seizures and
epilepsies

67
 Rev Mex Neuroci. 2019;20

Critically ill or with clinical suspicion Presentation

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No seizure
Video EEG
(without EEG correlate) Diagnosis

Seizure
(with EEG correlate)

Without clinical signs

with clinical science (only electrographic)
Manifestation

MOTOR
automatisms
clonic
epileptic spasms
myoclonic

No part of this publication may be reproduced or photocopying without the prior written permission o
tonic
sequential
Seizure type
NON-MOTOR
Behavior arrest
autonomic
UNCLASSIFIED

Figure 3. Diagram of the proposed classification for seizures in the newborn.

Conflicts of interest 4. Fisher R, Acevedo C, Arzimanoglou A, et al. Definición clínica practica

In this article, there are no conflicts of interest by the
authors or the source of funding.
References
1. Fisher RS, Cross JH, French JA, et al. Operational classification of sei-
zure types by the international league against epilepsy: position paper of
the ILAE commission for classification and terminology. Epilepsia.
2017;58:522-30.
2. Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE
2017 operational classification of seizure types. Epilepsia. 2017;58:531-42.
3. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the
epilepsies: position paper of the ILAE commission for classification and
terminology. Epilepsia. 2017;58:512-21.
de la Epilepsia. Epilepsia. 2014;55:475-82.
5. Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic
studies and surveillance of epilepsy. Epilepsia. 2011;52 Suppl 7:2-6.
6. Bancaud J, Rubio-Donnadieu F, Seino M, Dreifuss F, Penry K. Proposal
for revised clinical and electroencephalographic classification of epileptic
seizures. From the commission on classification and terminology of the
international league against epilepsy. Epilepsia. 1981;22:489-501.
7. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and con-
cepts for organization of seizures and epilepsies: report of the ILAE
commission on classification and terminology, 2005-2009. Epilepsia.
2010;51:676-85.
8. Rubio F, Resendiz JC, Alonso MA, Senties H. Epilepsia. 1st ed. México:
Editorial Alfil; 2016. p. 27-42.
9. Volpe JJ. Neonatal seizures: current concepts and revised classification.
Pediatrics. 1989;84:422-8.
10. Mizrahi EM, Kellaway P. Characterization and classification of neonatal
seizures. Neurology. 1987;37:1837-44.

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Revista Mexicana de Neurociencia

REVIEW ARTICLE

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Clinical guideline: management of seizures in the emergency
room
José Visoso-Franco1, Liliana Romero-Ocampo2, José A. Santos-Zambrano3, Alberto Serrano-González4
and Elvira Castro-Martínez5
1Hospital Regional de Especialidades ISSSTE, León, Guanajuato; 2Hospital Central Norte PEMEX y Hospital General de La Raza CMN, Especialidades

IMSS; 3Instituto Nacional de Neurología y Neurocirugía; 4Hospital Pediátrico Legaria; 5Hospital General “Dr.  Manuel Gea González” e Instituto
Nacional de Neurología y Neurocirugía. Mexico City, Mexico.

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
This clinical guideline on epilepsy contains levels of evidence and recommendations based on the scientific method. Its
primary function is to provide emergency medicine physicians a clear diagnostic approach when faced with a pediatric or
adult patient with epileptic seizures (ES) or epilepsy. The objective is to unify criteria that will guarantee integral health care,
based on adequate decision-making, benefiting the patient through the individualized analysis of proper anamnesis, physical
examination, precise indication of laboratory, and image diagnostic tests that yield the pertinent clinical and pharmacological
treatment for opportune interventions, avoiding complications, and whenever possible, the recurrence of the ES.

Key words: Seizures. Epilepsy. Treatment in the emergency room.

Introduction to be 1 billion dollars. Clinical guidelines attempt to

Epilepsy is one of the diseases that affect the quality
of life of patients the most, due to its neurological, psy-
chological, and social implications. Epileptic seizures
(ES) are a common cause of admittance to the emer-
gency room (ER), and they are responsible for 1 million
or 1% of all the ER consults. The annual cost of care,
prehospital and within the ER, to treat ES is estimated
direct and guarantee the assertiveness of medical at-
tention to improve the diagnosis and treatment of this
disease1-3.
Recommendations for scientific research were based
on the selective location of keywords in PubMed-MED-
LINE, The Cochrane Library, and other clinical practice
guidelines, as well as recommendations by other scien-
tific societies.

Correspondence:
Elvira Castro Martínez
Hospital General “Dr. Manuel Gea González” e
Instituto Nacional de Neurología y Neurocirugía Date of reception: 01-02-2019 Disponible en internet: 12-04-2019
Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2018;20(2):69-75
E-mail: elviracastrom@yahoo.com.mx DOI: 10.24875/RMN.M19000025 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

69
 Rev Mex Neuroci. 2019;20

Questions addressed within this guideline

1. What clinical data must be purposefully investigated during the anamnesis of a patient with ES in the ER?
2. Which laboratory tests must be performed in the ER on a patient with a first ES?

 f the publisher.   © Permanyer 2019

3. Under which conditions must electroencephalography be performed on a patient with ES in the ER?
4. Under which conditions must a neuroimaging test (CT or MRI) be performed on a patient with ES in the ER?
5. Under which conditions must anti‑epileptic drugs be initiated on patients with a first ES in the ER?

ES: epileptic seizures; ER: emergency room; CT: computerized tomography; MRI: magnetic resonance imaging.

What clinical data must be purposefully investigated during the anamnesis of a

patient with ES in the ER?

Recommendation (Figures 1-3) Level of recommendation

No part of this publication may be reproduced or photocopying without the prior written permission o
Identification of all possible triggering factors for the seizure: D
− Fever, concomitant systemic infection or disease NICE, 20124
− History of previous neurological disease R‑ Solari F, 20115
− Trauma
− Ingestion of drugs or toxic substances
− Recent vaccinations
− Family history of ES

Medical personnel performing an initial examination on a patient in the ER must identify and interrogate: D
− Alteration of the level of consciousness NICE, 20124
− Type and topography of altered motor activity R‑ SAdE, 20156
− Sensory symptoms
− Autonomic symptoms
− Cognitive symptoms
− Behavior during the preictal, ictal, and postictal periods

Additional information must be gathered for the diagnosis, including: 3

− Perinatal pathologies NICE, 20124
− Characteristics of psychomotor development timeline R‑ SAdE, 20156
− Learning disabilities
− Other neurological or psychiatric diseases

A directed neurological examination is recommended in search of signs and symptoms of: D

− Intracranial hypertension NICE, 20124
− Signs of meningeal irritation R‑ SAdE, 20156
− Focal neurological deficit
− Neurological emergency

ES: epileptic seizures; ER: emergency room.

Which laboratory tests must be performed in the ER on a patient with a first ES?

Recommendation Level of recommendation

Laboratory tests on a patient that has complete recovery after a first ES are not considered necessary, 3
unless there are specific findings that justify them NICE, 20124
R‑SAdE, 20156

Laboratory tests recommended for patients with ES that present with dehydration due to vomiting or D
diarrhea and demonstrate a progressive or persistent deterioration of consciousness are: NICE, 20124
− Complete blood count R‑SAdE, 20156
− Blood glucose, sodium, and electrolytes
− Serum pregnancy (qualitative hCG) test

70
 J. Visoso-Franco, et al.: Management of seizures in the emergency room

Diagnosis of UES

 f the publisher.   © Permanyer 2019

Yes Non-epileptic
No
paroxysmal event

Diagnostic support with Confirmed ES

EEG or VEEG is
suggested

Recurrence risk assessment:

No part of this publication may be reproduced or photocopying without the prior written permission o
1. Family history of epilepsy
2. Abnormal neurological
A doubtful or uncertain diagnosis examination
merits a referral to a specialist 3. Abnormal EEG
(Psychiatrist or Neurologist) 4. Brain injury visible on
cranial CT or MRI
5. FS (focal epileptic seizures)
6. ES during sleep
7. Epileptic Syndrome

Commence individualized
AED therapy

Figure 1. Unprovoked Epileptic Seizure.

LP is recommended for any patient with a first ES and suspicion of CNS infection, subarachnoid D
hemorrhage determined by a non‑diagnostic CT image, suspicion of HIV infection, or children under 6 NICE, 20124
months of age R‑ SAdE, 20156

A LP is not indicated on patients who show complete recovery of their neurological basal state after a R‑ SAdE, 20156
first ES

To establish a differential diagnosis of non‑epileptic paroxysmal events, individualization of cases is D

recommended when considering complementary tests NICE, 20124
R‑SAdE, 20156

If substance abuse of psychoactive drugs or exposure to toxic substances is suspected, a toxicology D

screen is recommended NICE, 20124
R‑ SAdE, 20156

Complementary diagnostic tests after a new ES on patients with a known history of epilepsy are not R‑SAdE, 20156
necessary, unless there is suspicion of lack of pharmaceutical efficacy, intoxication, adherence to
treatment, or change in seizure pattern

LP: lumbar puncture; ES: epileptic seizures; CNS: central nervous system; CT: computerized tomography.

71
 Rev Mex Neuroci. 2019;20

 f the publisher.   © Permanyer 2019

No part of this publication may be reproduced or photocopying without the prior written permission o
Figure 2. Acute symptomatic epileptic seizure (provoked).

Under which conditions must electroencephalography be performed on a patient with

ES in the ER?

Recommendation Level of recommendation

There is no evidence that an emergency EEG has any implication on immediate therapy; therefore, there IV
are few indications such as: SAdE, 20156
− Suspicion of subtle or non‑convulsive status epilepticus
− Comatose state of unknown origin
− Suspicion of herpetic encephalitis

A routine EEG in the ER is not recommended for previously healthy patients (pediatric or adult) that R‑SAdE, 20156
present a first ES and have returned to their basal state

An EEG is a useful diagnostic test in stabilized patients in the ER to: 2+

− Support the diagnosis of epilepsy SIGN, 20157
− Determine the type of epilepsy and epileptic syndrome, in concordance with clinical findings and 3
ictal activity NICE, 20124
− Asses the risk of seizure recurrence R‑ SAdE, 20156
− Support therapeutic decisions

EEG: electroencephalography; ES: epileptic seizures, ER: emergency room.

72
 J. Visoso-Franco, et al.: Management of seizures in the emergency room

ES on patients
previously diagnosed

 f the publisher.   © Permanyer 2019

with epilepsy

Typical ES
No presentation Yes

Repeat initial diagnostic Identification of trigger factors

tests: for uncontrolled seizures:

No part of this publication may be reproduced or photocopying without the prior written permission o
1. Blood glucose • Lack of AED treatment
and sodium adherence
2. Cranial CT • AED cessation due to
adverse effects
• AED drug interaction with
concomitant treatment
• Insufficient AED dosage
• Sleep hygiene alteration
Hospitalization • Underlying infection
assessment • Alcohol or toxin ingestion

Correction of uncontrolled
seizure trigger factors

Adjustment or modification
of AED treatment

Outpatient consult follow-up

Figure 3. Epileptic seizure on patients previously diagnosed with epilepsy.

Under which conditions must a neuroimaging test (CT or MRI) be performed on a

patient with ES in the ER?

Recommendation Level of recommendation

A cranial CT must be performed on all emergency cases; however, it does B

not substitute a programmed cranial MRI SAdE, 20156

An emergency cranial CT may be considered for previously healthy R‑SAdE, 20156

patients (pediatric or adult) if a programmed MRI cannot be performed within
the following 3 days

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 Rev Mex Neuroci. 2019;20

Neuroimaging tests (cranial CT or MRI, the latter being the first choice) are B
recommended for patients who present a first ES under the following SAdE, 20156
circumstances: C
− Focal seizures

 f the publisher.   © Permanyer 2019

NICE, 20124
− Focal neurological deficit R‑Ghofrani M, 20138
− Persistent alteration in the level of consciousness R‑Aprahamian N, 20149
− Recent traumatic brain injury R‑Michoulas AS, 201110
− Cancer
− Suspicion of HIV infection/immunosuppression
− Hemorrhagic diathesis
− Children under 2 years of age
− Persistent cephalea (headache)
− Meningeal signs
− Signs of intracranial hypertension

Neuroimaging tests are not useful under the following circumstances: R‑SAdE, 20156
− Febrile seizures
− Focal impaired awareness seizures
− ES with a proven metabolic origin

CT: computerized tomography; MRI: magnetic resonance imaging.

No part of this publication may be reproduced or photocopying without the prior written permission o
Under which conditions must anti-epileptic drugs be initiated on patients with a first
ES in the ER?

Recommendation Level de recommendation

Before initiating treatment with AED on a patient with a first ES, it is recommended to consider: C
− The probability of recurrence NICE, 20124
− The drugs efficacy and toxicity R‑Bergey G, 201611

Treatment with AED after a first ES must be individualized and assessed by a qualified professional A
NICE, 20124
R‑ Leone MA, 201612
C
NICE, 20124
R‑Bergey G, 201611

It is recommended that AED treatment be initiated on patients with one or more of the following risk
factors: C
− History of previous brain injury with remote symptomatic seizures NICE, 20124
− Focal ES R‑Michoulas AS, 201110
− ES during sleep R‑Bergey G, 201611
− Family history of ES R‑Ghofrani M, 20138
− Abnormal neurological examination R‑Krumholz A, 201513
− Psychomotor delay
− Status epilepticus
− Abnormal EEG
− Neuroimaging abnormalities

During the initiation of AED treatment, it is recommended to consider the risk of seizure aggravation: D
− Phenytoin aggravates absence and myoclonic seizures NICE, 20124
− Carbamazepine and oxcarbamazepine exacerbate absence, myoclonic, and atonic seizures R‑SAdE, 20156

AED: anti‑epileptic drug; EEG: electroencephalography.

This article and its authors do not present any conflict of interest or source of financing.

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 J. Visoso-Franco, et al.: Management of seizures in the emergency room

Algorithm: Management of ES in the ER

 f the publisher.   © Permanyer 2019

ES in ER

Unprovoked Acute
ES on patients Status
ES Symptomatic
previously diagnosed Epilepticus
ES
with epilepsy

No part of this publication may be reproduced or photocopying without the prior written permission o
Refer to status
Figure 1 Figure 2 Figure 3 epilepticus
guidelines

References
1. Cerdá JM, Argani MT, Llerda JA, et al. Guía oficial de la sociedad española de neurología de práctica clínica en epilepsia. Neurología. 2016;31:121-9.
2. Pallin DJ, Goldstein JN, Moussally JS, et al. Seizure visits in US emergency departments: epidemiology and potential disparities in care. Int J Emerg Med.
2008;1:97-105.
3. Martindale JL, Goldstein JN, Pallin DJ. Emergency department seizure epidemiology. Emerg Med Clin North Am. 2011;29:15-27.
4. National Clinical Guideline Centre (UK). The Epilepsies: the Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary
Care: pharmacological Update of Clinical Guideline 20. London: Royal College of Physicians (UK) (NICE Clinical Guidelines, No. 137); 2012.
5. Solari BF. Crisis epilépticas en la población infantil. Rev Med Clin Condes. 2011;22:647-54.
6. Sociedad Andaluza de Epilepsia. Guía Andaluza de Epilepsia. Barcelona: Sociedad Andaluza de Epilepsia; 2015. p. 484.
7. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and Management of Epilepsy in Adults. Edinburgh: Scottish Intercollegiate Guidelines Network;
2015.
8. Ghofrani M. Approach to the first unprovoked seizure-PART I. Iran J Child Neurol. 2013;7:1-5.
9. Aprahamian N, Harper MB, Prabhu SP, et al. Pediatric first time non-febrile seizure with focal manifestations: is emergent imaging indicated? Seizure.
2014;23:740-5.
10. Michoulas A, Farrell K, Connolly M. Approach to a child with a first afebrile seizure. BCMJ. 2011;53:274-7.
11. Bergey GK. Management of a first seizure. Continuum (Minneap Minn). 2016;22:38-50.
12. Leone MA, Giussani G, Nolan SJ, Marson AG, Beghi E. Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unpro-
voked seizure. Cochrane Database Syst Rev. 2016;5:CD007144.
13. Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: management of an unprovoked first seizure in adults: report of the guideline deve-
lopment subcommittee of the American academy of neurology and the American epilepsy society. Epilepsy Curr. 2015;15:144-52.

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 Revista Mexicana de Neurociencia

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Clinical guideline: management of the first unprovoked
epileptic seizure in adults and children
José A. Gien-López1, Raymundo A. Cuevas-Escalante2, Enrique García-Cuevas3, María R. Márquez-Estudillo4,
Blanca E. Villaseñor-Anguiano5, Raúl Leal-Cantú6 and Ramón E. Jiménez-Arredondo7
1HospitalRegional No. 1. IMSS, Mérida, Yucatán; 2Hospital Infantil de Tlaxcala, Tlaxcala; 3Hospital General Acapulco Guerrero; 4Hospital Regional
de Puebla, ISSSTE, Puebla; 5Hospital General de Zona No.  1. Colima, Colima; 6Hospital Civil “Dr.  Miguel Silva”, Morelia, Michoacán; 7Hospital
General de Zona No. 1. “Luis Ernesto Miramontes Cárdenas”, IMSS Tepic, Nayarit, Mexico City. Mexico.

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
Unprovoked seizures represent a challenge in the neurological clinical consult. Identifying a first unprovoked seizure is the
first step for an adequate medical approach, for which there are different diagnostic tools that help establish the risk of a
second seizure, as well as recurrence factors for a first unprovoked epileptic seizure (UES) or diagnose epilepsy. Pharma-
cological treatment for a first UES and key points for referral to specialists are similarly established, and we move forward to
the reference for the next level of medical attention. In this section we also describe nonmedical recommendation for patients
and family members after a first UES. This Mexican Guideline was elaborated accounting for the resources and diagnostic
tools available in both public and private hospitals in Mexico.

Key words: Epilepsy. Unprovoked. Guidelines.

Introduction suffered an epileptic seizure (ES) and to make deci-

This guideline was developed based on research
questions under the PICO method, where questions are
presented with their corresponding answer, establishing
levels of evidence to offer specific orientation regarding
the international recommendations on the related sub-
ject matter, seeking the exposure and application of
these same management criteria for first unprovoked
seizures in children and adults. The final objective of
this guide is to aid health-care professionals in solving
the initial questions when faced with a patient who has
sions based on the best evidence available.
1. What are the characteristics of acute
symptomatic ESs and unprovoked ESs
(UES)?
An acute symptomatic ES, provoked or reactive, can
be defined as seizures presented during the course of
a disease which temporarily lowers the threshold of an
ES; this type of seizure is not considered epilepsy1.

Correspondence:
Jose Antonio Gien-López
Hospital Regional No. 1. IMSS Date of reception: 31-01-2019 Disponible en internet: 12-04-2019
Mérida, Yucatán, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):76-81
E-mail: neurologiamerida@gmail.com DOI: 10.24875/RMN.M19000026 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

76
 J. A. Gien-López, et al.: First unprovoked epileptic seizure
For the condition to be considered a provoked ES,
the required time span between a cerebral injury and
onset of the seizure is 7 days for injuries such as trau-
matic brain injury (TBI), brain surgery, cerebrovascular
disease, and cerebral anoxia and for the acute phase
of infections of the central nervous system (CNS); 24 h
for patients with metabolic disorders; and 7-48 h after
the last ingestion of alcohol in patients with
abstinence2.
An UES is characterized by the lack of temporary or
reversible risk factors that lower the threshold to pre-
sent an ES3. The diagnosis of an ES and epilepsy is
based on the patient’s medical history, the information
obtained during direct questioning when the patient’s
consciousness is preserved and is able to describe the
seizure, or indirect questioning when information is ob-
tained from a first-hand witness of the seizure. A tho-
rough medical history must be obtained to allow the
clinician to identify if the event is an ES as well as the
type of seizure. This information will also be useful to
establish a differential diagnosis between an ES and
non-ES such as Psychogenic, syncope or migraine,
among other causes4. The medical history has always
been considered the cornerstone of the approach to
any disease, and patients with ES and epilepsy are not
the exception5.
2. What are the precipitating risk factors
after a first UES?
A systematic review published in 2015, consisting of
10 randomized control studies, revealed that treatment
versus lack of treatment of first ES resulted in early
recurrence within 2  years from 21% to 45% in the
1st  year, respectively6. Certain clinical characteristics
can determine seizure recurrence. This study demons-
trated that the majority of patients with UES are be-
tween 16 and 60  years of age, which implies that the
age groups before and after this age range have a
greater recurrence risk of 2.1  (95% confidence
interval = 1.0-4.3)7. Other risk factors for seizure recu-
rrence include positive family history, history of febrile
seizures, first prolonged seizure, initial suspicion of
epilepsy, unknown seizure etiology, abnormal physical
examination, and nocturnal seizures in patients aged
1-4  years when compared to patients who remain
awake during seizures7. A paroxysmal electroencepha-
logram (EEG), structural injury visible on magnetic re-
sonance imaging (MRI), and prolactin levels are highly
specific, yet a poorly sensitive test for ES. Prolactin
levels over 36  ng/mL are highly suggestive of ES;
however, these must be measured between 20 min and
4 h from the onset of the seizure8. A lumbar puncture
is useful when neuroinfection is suspected8.
 f the publisher.   © Permanyer 2019
Evidence Level Grade
Brain injury, epileptiform EEG pattern, 1 A
abnormal brain imaging, and nocturnal
crisis are factors that increase the degree
of recurrence and aid in the decision to
initiate treatment
3. Which diagnostic tests are useful for
the diagnosis and prognosis of a first
UES?
EEG – evidence demonstrates that all patients with
a first UES should be submitted to an EEG because
No part of this publication may be reproduced or photocopying without the prior written permission o
the data obtained are useful for diagnosing ES when
abnormalities are present. Determining the type of ES
also helps in identifying the etiology in some cases,
and establishing a differential diagnosis from NES8.
EEG data are also useful in the selection of the an-
ti-epileptic drugs (AED), whenever these are medically
indicated. It must be noted, however, that abnormal
EEG results without clinical manifestations are not con-
sidered epilepsy, and conversely, patients with epilepsy
may have a normal EEG9.
A meta-analysis of 16 studies established as a sei-
zure recurrence indicator for an UES epileptiform dis-
charges on the EEG (2.0; CI 95%: 1.6-2.6). If the EEG
showed non-epileptiform discharges, there was a recu-
rrence of seizures; however, no statistical significance
was found10. Records of brain electrical activity within
the first 24 h after the first UES increase the probability
of detecting interictal epileptiform discharges (IEDs).
The IED is most frequently recorded among temporal
epilepsies when compared to extratemporal epilep-
sies11, and they increase seizure recurrence risk.
The EEG must be carried out and interpreted by cer-
tified personnel, on patients under hyperventilation and
with at least 20  min of recorded patterns without
artifacts. Current guidelines suggest that an EEG is a
necessary test for the evaluation and treatment deter-
mination after a first ES6. EEGs are the most common
test used for diagnosing epilepsy. An epileptiform dis-
charge on an EEG was associated with a relative in-
crease in the recurrence rate of ESs when compared to
a normal EEG12. Patients with an abnormal EEG with
epileptiform discharges presented a recurrence risk of
60% after a first seizure. According to the ILAE 2017,
60% recurrence risk mandates that the first seizure
should be considered epilepsy. The probability of
77
 Rev Mex Neuroci. 2019;20
finding an abnormality on the EEG is higher after repeat
studies, where 39% of patients presented abnormalities
on the first test and 68% on their third test7. Patients
with epileptiform discharges have a 77% recurrence
rate on a first UES compared to 47% if the EEG is nor-
mal. These discharges are better detected if the EEG
is performed within the first 12 h after an ES13. Accor-
ding to the ILAE, the recommended window to perform
an EEG is within the first 72 h after a UES and within
the first 24 h after an ES14. If EEG results are normal,
it is recommended to perform EEG tests during sleep,
with sleep deprivation, photostimulation, and repeated
tests12-14. An unaltered routine EEG does not exclude
the presence of an ES. Other studies report that an
EEG performed within the first 6 h after an ES reveals
the presence of epileptiform discharges in 67% of ca-
ses, between 6-12 h in 52%, 12-24 h in 24%, 24-48 h
in 25%, 48-72 h in 22%, and 72-96 h in 18%13. Based
on the previous data, it can be concluded that prompt
EEG tests after onset of seizures are more likely to de-
tect epileptiform discharges and their efficacy of detec-
tion is progressively reduced in later tests15. The Ame-
rican Academy of Neurology (AAN) in 2007 established
a time-frame for EEGs within a window of 48 h after ES
onset and up to an average of 15 days afterward13.
EEG results from sleep-deprived patients improve
the sensibility and specificity of the epilepsy diagnosis.
Sleep induced by sleep deprivation is more likely to
provoke epileptiform discharges when compared to
physiological sleep16. Seizure recurrence after a first
ES with epileptiform discharges recorded on an EEG
was 73.2%, whereas a normal EEG was associated
with a 32.8% recurrence11; thus, EEG records with
epileptiform graphic patterns were established as a
recurrence factor. Seizure recurrence on patients with
generalized compared to focal epileptiform discharges
was 68.8% and 75%, respectively13. The recommenda-
tions of the AAN and the American Epilepsy Society
(AES) for patients with a first UES and an EEG with
epileptiform discharges are level A6.
Neuroimaging
A computed tomography scan (CT) of the skull is
performed in emergency cases on a patient with a first
ES; its primary indication is to determine the presence
of brain injuries that could cause an ES, such as a
stroke or TBI. A CT may also be performed when phy-
sical exploration demonstrates a focal neurological de-
ficit, a prolonged altered state of alertness and in febrile
patients or with findings that suggest a CNS infection.
78
MRIs detect more SNC alterations when compared to
CT scan; thus, without a need for an emergency image,
MRI is the technique of choice12. Neuroimaging tests
 f the publisher.   © Permanyer 2019
are necessary to predict the probability of recurrence
after the first UES6. They are indicated with the objec-
tive of identifying the etiology of the ES. The advanta-
ges of a CT are availability and the speed in which the
test is performed, and the results obtained can guide
the decision for the need of immediate medical atten-
tion, especially in emergency care12. Neuroimaging
tests have an important value in patients with epilepsy;
research shows recurrence rates a year after the first
seizure of 59% (95% CI 54-65%) if patients had an
No part of this publication may be reproduced or photocopying without the prior written permission o
epileptogenic lesion visible on a CT or MRI and 44%
(95% CI 41-48%) in patients without evident lesions by
neuroimaging (p=0.001)12.
The recurrence rate of UES within 1 year in patients
that demonstrated an epileptogenic lesion only by MRI
was 67% compared to 50% for patients without a visible
lesion. The MRI is superior to the CT in detecting epi-
leptogenic abnormalities13. If available, an MRI is the
preferred neuroimaging technique in patients with a first
UES. Neuroimaging tests should be performed fo-
llowing epilepsy protocol and interpreted by neuroradio-
logy specialists.
Evidence Level
Children or adults with a first UES should Class I (13)
undergo a thorough medical history and Class I C.II (14)
examination, followed by at least two
diagnostic tests: neuroimaging (CT/MRI)
and EEG
A standard EEG is a useful study for the Class III (15)
diagnosis of a first UES Class I (16)
An EEG with epileptogenic discharges is Class I (16)
the best predictor for recurrence of a first Class III (13)
UES, together with an abnormal
neurological examination and
corresponding etiology
An EEG helps to differentiate between an Class I (16)
ES and other events of non‑epileptic origin
A routine EEG does not demonstrate Class II (4)
evidence of brain abnormalities. A prolonged
EEG is useful for the diagnosis of a first UES
The VEEG is a useful test for the diagnosis of Class III (4)
a first UES; it predicts a seizure recurrence
of 46% in 12 months and 51% in 24 months
The CT is a useful test for the diagnosis of Class I (16)
a first UES

Focal lesions are more commonly found on
a CT in adults (18‑34%) compared to
children (0‑12%), with the exception of
infants under 6 months old where
abnormalities are found in 55% of cases
and in adults with HIV in 28% of cases
The following conditions are predictors of
abnormalities found on a CT: altered
neurological examination, infants under 6
months old, closed TBI, recent
manipulation of ventriculoperitoneal
shunting, cerebral tumor suspicion,
neurocutaneous syndromes, focal onset of
seizure, alcohol abuse history,
cysticercosis, and seizures over 15 min in
duration
An MRI is superior to the CT in establishing
the diagnosis of an epileptogenic lesion
The MRI is the preferred diagnostic test
alongside the EEG in children that present
a first non‑febrile seizure
The recurrence risk of an UES increases
by 2.16 (95% CI 1.44‑4.51) if epileptogenic
alterations are found on the EEG and by
2.1 (95% CI 1.09‑5.44) in an abnormal
neuroimaging test
Recommendations
The standard EEG should be considered a
useful test to diagnose UES since it
detects epileptogenic abnormalities in
12‑27% of cases, and if performed under
sleep deprivation, the probability of
detection increases up to 58%
A standard EEG performed within the first
24 h of seizure onset detects epileptogenic
abnormalities in 34‑51% of cases
A standard EEG detects the same
recurrence risk of a UES as a VEEG
A standard protocol MRI detects
epileptogenic lesions in 23% of cases that
are not detected by CT
UES: unprovoked epileptic seizure; CT/MRI: computed tomography/magnetic
resonance imaging; EEG: electroencephalogram; ES: epileptic seizure;
VEEG: video‑electroencephalogram.
4. What are recurrence factors for first
UESs?
The AAN has described four factors that result in
greater seizure recurrence: (1) an EEG with epileptiform
abnormalities, (2) cerebral injury such as stroke or TBI,
(3) a newly found lesion on neuroimaging, and (4) noc-
turnal seizures17. After a patient suffers a second sei-
zure, the patient has 60% of recurrence within the
1st year and 70% recurrence within the 2nd year17.
J. A. Gien-López, et al.: First unprovoked epileptic seizure
Class I (16)
If the seizure is of genetic etiology and the patient
Class I (14) has a sibling with seizures, the recurrence risk is 29%.
If the seizure is idiopathic with a spike and wave pattern
 f the publisher.   © Permanyer 2019
on EEG, the risk increases to 50%18. In children, a
5-year recurrence risk from the first seizure is 43%19.
Class I (14) In the presence of abnormalities on the EEG, the risk
increases to over 50%, up to 65%18.
An adult with epileptiform discharges on a routine
EEG after a UES has 77% probability of a second sei-
zure, while in children the probability is 66%20. Children
who present a seizure during sleep have a 75% proba-
bility of recurrence within 2 years compared to 49% in
children who did not21.
Class I (14)
5. What are the indications for
No part of this publication may be reproduced or photocopying without the prior written permission o
Class I (16)
pharmacological treatment?
Currently, the decision whether to treat a first UES is
Class I (6) a matter of controversy. It is generally accepted that
AEDs are indicated as of the second UES because
recurrence risk is greater (57% within the 1st year and
73% within 4  years)22. A  study performed by the AAN
Grade and the AES based on 10 level A trials determined that
the seizure recurrence risk of an adult with a first UES
Level B
was between 21% and 45% within the first 2 years, and
the cumulative risk of a second ES was 32% after a
year and 46% for 5 years1,4. In the Multicenter Epilepsy
and Single Seizures (MESS) study, it was concluded
that the recurrence of a first UES was 39% within
Level B
2 years and 51% within 5 years2.
The probability of presenting an isolated ES is 8-10%
Level B and 3% of developing epilepsy, revealing an incidence
rate of 61/100,000 individuals per year, resulting in a
Level B prediction that an estimated 4 million individuals each
year will experience a first UES that may be focal or
generalized1, because 30% of paroxysmal episodes are
inappropriately diagnosed1.
To initiate treatment, it is important to confirm the
presence of a first UES as there is no doubt that a
simulator event is ocurring5,23. The degree of certainty
of the diagnosis lies in an adequate interrogation, as
well as physical and neurological examination, directed
diagnostic tests, emphasizing important points of sei-
zure semiology, suspicion of ES or epilepsy establi-
shing a proper differential diagnosis, distinguishing
between provoked ES and UES using the definition
criteria for epilepsy, and investigating and classifying
the type of seizure, as well as the recurrence risk.
Treatment should be limited to observation and com-
plementary tests if recurrence risk is low. AED should
be initiated if the risk if moderate or high3,24. If patients
79
 Rev Mex Neuroci. 2019;20
have an ES while being alone, complementary labo-
ratory and other diagnostic tests such as the EEG must
be performed as soon as possible, because its useful-
ness is greater in the first 24 h after the seizure25. If
epilepsy debut is suspected in subclinical seizures, it
must be noted that <50% of seizures are detected by
a 30-min routine EEG; however, this detection rate is
increased to 90% if constant monitoring of 24-36 h is
performed26. Within the emergency care department,
the accepted initial test is a CT23, considering a sub-
sequent MRI, except if the CT demonstrates an impor-
tant pathology or if the patient must be sedated.
Other tests, such as serum prolactin, are not recom-
mended for the diagnosis of epilepsy; however, it is
important to quantify serum electrolytes and glucose to
identify potential causes or any comorbidities23. An
electrocardiogram or referral to a cardiologist must be
performed in cases of a doubtful diagnosis.
Neuropsychological evaluation is indicated when the
MRI demonstrates important alterations or declines in
the cognitive areas of the brain. To initiate treatment,
the level of certainty of the diagnosis, the degree of
alteration in the neurological examination, family history,
laboratory and imaging test results, electroencephalo-
graphy, the side effects of the AED indicated for the type
of seizure, quality of life, and cost of treatment must be
considered.
The treatment of the first UES reduces short-term
recurrence risk but not the long-term prognosis3. Thus,
it is important to counterweigh AED side effects on re-
currence risk when the risk is low3-5,23,24,26, considering
the possibility if recurrence is greater within the first
3-6 months.
Evidence Level Grade
Initial treatment should not be given after a 1 A
first seizure except if the recurrence risk is
high or under special circumstances
Pharmacological treatment should only be 1 A
initiated after the diagnosis of epilepsy is
confirmed
The decision to initiate treatment should 1 B
be taken by the treating physician together
with the patient or caregiver, after
explaining the recurrence risk, side effects,
and quality of life issues
The cornerstone of the diagnosis of an 1 B
epileptic seizure is the clinical feature
The EEG is useful for the decision to 1 B
initiate treatment
Neuroimaging tests, such as CT and MRI, 1 A
are necessary evaluations of a patient with
an isolated epileptic seizure
80
The treatment of the first unprovoked 1 B
epileptic seizure reduces the risk of
relapse but does not affect the long‑term
 f the publisher.   © Permanyer 2019
prognosis of epilepsy
CT/MRI: computed tomography/magnetic resonance imaging;
EEG: electroencephalogram.
6. What are the reference indications for a
first UES?
Every patient with a first UES must be examined by
a neurologist27. According to the regional infrastructure,
patients must be referred to a secondary or tertiary
medical facility if there is any doubt about the type of
No part of this publication may be reproduced or photocopying without the prior written permission o
provoked ES or if there is evidence of cerebral lesion
whether it consists of a tumor, hemorrhage, or infection
(cysticercosis, toxoplasmosis, or tuberculosis)28. Pa-
tients that debut with status epilepticus in their first ES
must be referred to a specialized facility for treatment
as soon as vital signs are stable. Approximately 6-7%
of long debut seizures are considered as status
epilepticus29,30.
The etiology of a provoked ES was found to be
stroke in 34.7%, TBI in 34.7%, and infection in the
CNS in 30.6%. Conversely, etiology for first UES was
a stroke in 68.2%, a TBI in 25%, and CNS infection
in 6.8%31.
It is important for patients to also undergo evaluation
for seizure simulator conditions, where studies de-
monstrate that the most common simulator is a synco-
pe reflex (74%) and psychogenic seizures (16%)32. The
most common symptoms for reference to a secondary
or tertiary medical facility are accompanying neurolo-
gical manifestations, such as cephalea, immediately
after the seizure28.
Mortality within the first 30 days from the first provoked
ES was 21.4% (95% CI = 16.9-26.9%), compared to
3.4% for the first UES (95% CI = 1.4-7.9%, p < 0.001)31.
It has been suggested that in locations where a spe-
cialized neurological consult is unavailable, a remote
consult by a specialist should be established by te-
lephone or by video conference2; this is a common
occurrence in subspecialties such as pediatric neurolo-
gy33. Every referral to a tertiary health-care facility must
include a complete medical history, specifying medica-
tion, semiology of neurological signs and symptoms that
may aid in classifying the type of seizure, and the di-
rected diagnostic evaluation28.
 J. A. Gien-López, et al.: First unprovoked epileptic seizure
Recommendations Grade
Every patient with a first epileptic seizure must be R‑PPE
evaluated in a secondary health‑care facility
Evidence Level
Hospitalization criteria for patients with a first UES: Class III
− Under 1 year of age (afebrile)
− Atypical or complex epileptic crisis
− Prolonged postictal state
− Onset status epilepticus
− Meningeal signs
− New neurological deficit (previously absent)
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81
 Revista Mexicana de Neurociencia

REVIEW ARTICLE

 f the publisher.   © Permanyer 2019

Clinical guideline: antiepileptic drugs of choice for focal and
generalized seizures in adult patients with epilepsy
Leopoldo Rivera-Castaño1, Horacio Sentíes-Madrid2, Jesús Berumen-Jaik3 and Iris E. Martínez-Juárez4
1Department of Neurology, Hospital Ángeles Chihuahua, Chihuahua; 2Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico
3Hospital
City; Infantil Universitario, Torreón, Coahuila; 4Instituto Nacional de Neurología y Neurocirugía Dr.  Manuel Velasco Suárez, Mexico City.
Mexico

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
The mainstay of treatment in patients with epilepsy is antiepileptic drugs (AEDs). Currently, there are a significant number of
AEDs in Mexico. For the pharmacological management of the patient with epilepsy, it is important to know the pharmacoki-
netics, dosage, mechanism of action, and formulations of the AED. 70-80% of patients with either focal or generalized seizu-
res are completely seizure free on AED monotherapy. When, despite the use of AED in monotherapy, seizure freedom is not
achieved, a second AED should be used; AEDs with different mechanisms of action are empirically combined for this pur-
pose. If a patient persists in having seizures with the use of an adequate AED, at appropriate doses and with therapeutic
adherence, a correct diagnosis of the seizure type and a differential diagnosis should be reconsidered, using a new clinical
evaluation and auxiliary diagnostic tests.

Key words: Antiepileptic drug. Monotherapy. Polytherapy. Adult.

Introduction recommendations from the programa prioritario de epi-

This is a clinical guide for the pharmacologic treat-
ment of epilepsy in adults at first and second level
treatment centers. It consists of establishing PICO-ba-
sed questions and setting forth answers. The levels of
evidence are based on articles published in peer-re-
viewed indexed articles and other international guideli-
nes, such as the guides published by the International
League Against Epilepsy and the National Institute for
Health Care Excellence, as well as emitting
lepsia (priority epilepsy program).
Question 1. What are the pharmacokinetics
of antiepileptic drugs (AEDs)?
In general, newer AEDs have more predictable ki-
netics and lower risk of drug interaction. This is becau-
se serum protein binding is low or null, they are mainly
eliminated by renal excretion or metabolized by isoen-
zymes lacking P450, and they have a lower potential

Correspondence:
Leopoldo Rivera-Castaño
Hospital Ángeles Chihuahua Date of reception: 30-01-2019 Disponible en internet: 12-04-2019
Chihuahua, Chihuahua, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):82-88
E-mail: drleopoldo.rivera@yahoo.com DOI: 10.24875/RMN.M19000027 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Publicado por Permanyer México. Este es un artículo Open Access bajo la licencia CC BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

82
 Table 1. Dose, mechanism of action, formulation, and pharmacokinetics for adults of AEDs available in Mexico 1
AED Initial dose Final dose Mechanism of Extended release Parenteral Bioavailability (%) T. Max (h) Distribution PP binding Half‑life Clearance
action formulation formulation volume (L/kg) 37°C (%) (h) (L/kg/h)

BRV 50 mg 25‑100 mg SV2 No Yes 100 0.25‑3 0.5 ≤ 22 9 3.6 L/h

1 dose 2 doses

CBZ 100‑400 mg 600‑1200 SC Yes No 75‑85 2‑24 0.8‑2 70‑80 16‑24 0.133
2‑3 doses 2‑3 doses

CLB 5 mg 5 mg G No No 90‑100 2 0.9‑0.4 87‑90 20 ‑

2 doses 2 doses

CLZ ‑ 1‑20 mg G No No 80‑90 1‑4 3 80‑90 20‑60 0.09

1‑3 doses

DZP Oral and ‑ G No Yes 75‑100 1-4 1.1 95 32‑47 ‑

intravenous
0.15‑0.2 mg/kg
maximum
10 mg/dose

ESM 250 mg 1500 CC No No 90‑95 3‑7 0.65 0 30‑60 0.01‑0.015

2 doses 2‑3 doses

GBP 300 mg 600 mg G No No 60 2‑4 0.9 0 4‑6 0.12‑0.13

3 doses 3 doses

LCS 100 mg 200 mg SC No Yes

2 doses 2 doses

LEV 125‑500 mg 1000‑3000 mg SV2 Yes Yes 95‑100 0.6‑1.3 0.5‑0.7 < 10 6‑8 0.6 mL/min/kg
2 doses 2 doses

LTG 12.50 mg 100‑600 mg SC No No 95‑100 2‑5 0.9‑1.22 55 24‑35 0.044‑0.84

1‑2 doses 1‑2 doses

OXC 300‑600 mg 600‑2400 mg SC Yes No 95‑100 4.5 0.7‑0.8 40 4‑9 ‑

2 doses 2 doses

PB 25‑50 mg 100‑200 mg G No yes 95‑100 8 0.42‑0.75 45‑60 50‑140 0.006‑0.009

1‑2 doses 1‑2 doses

PGB 150 mg 200‑600 mg G No No 90‑100 <1 0.56 0 6.3 0.083

2 or 3 doses 2 or 3 doses

PHT 200‑300 mg 300‑500 mg SC No Yes 85‑90 10‑15 0.5‑0.8 70‑95 7‑48 0.003‑0.02
2 or 3 doses 2 or 3 doses
L. Rivera-Castaño, et al.: Antiepileptic drugs in adult patients

(continue)

83
No part of this publication may be reproduced or photocopying without the prior written permission o
 f the publisher.   © Permanyer 2019
 Rev Mex Neuroci. 2019;20

for inducing/inhibiting various hepatic enzyme systems1

AED: antiepileptic drug; BRV: brivaracetam; CBZ: carbamazepine; CLB: clobazam; CLZ: clonazepam; DZP: diazepam; ESM: ethosuximide; GBP: gabapentin; LCS: lacosamide; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PB: phenobarbital;
0.006‑0.009

0.022‑0.036

0.102‑0.114
Clearance

0.01‑0.115
(Table 1).
(L/kg/h)

 f the publisher.   © Permanyer 2019

Question 2. What are the advantages and
limitations of monotherapy for the control
Half‑life

15‑23 of epilepsy in the adult?

15‑17
5‑18

4‑7
(h)

It was not until the 70s that the practice of beginning

therapy with polypharmacy began to come into question
PP binding
37°C (%)

due to its toxic effects and by recognizing that there was

20‑30

88‑92
9‑17

no scientific evidence that two or three AEDs were more

effective than a single AED. Conversely, the first obser-
vational studies of that era reported that when patients
volume (L/kg)
Distribution

with epileptic seizures went from polytherapy to mono-

0.55‑0.8

0.1‑0.4
0.6‑1

0.8

therapy, they tended to have fewer secondary effects

Table 1. Dose, mechanism of action, formulation, and pharmacokinetics for adults of AEDs available in Mexico 1 (Continued)

No part of this publication may be reproduced or photocopying without the prior written permission o
and even better seizure control2.
The ideal AED must be effective for controlling any
T. Max (h)

type of epileptic seizure, have perfectly known mecha-

3‑4

2‑3

1‑8
3.7

nisms of action, simple pharmacokinetics and pharma-

Mechanism of action: SV2: protein binding SV2; SC: sodium channel blocker; G: GABA analogue; CC: T-type calcium channel blocker; M: multiple mechanism.

codynamics, no plasma protein binding, and without

active metabolites to avoid interactions with other AEDs
Bioavailability (%)

or other drugs, given the comorbidities found in people

90‑100

80‑100

with epilepsy7,8 (Tables 4 and 5). It must have an opti-

60‑80

<100

mal efficacy and tolerability/safety relationship. In addi-

tion, it should be inexpensive, since it is of chronic use.
Currently, AEDs are very far from the ideal AED
profile3.
formulation
Parenteral

In 2018, Brodie et al. reported results from a pros-

pective study including 1795 English patients, with
Yes
No

No

No

an average age of 32  years (range 9-93  years), wi-

thout previous treatment that received their first
Extended release

PGB pregabalin; PHT: phenytoin; PRM: primodone; TPM; topiramate; VGB: vigabatrin; VPA: valproate.

AED, followed from 1982 to 2012. Of the 63.7% of

formulation

the patients without seizures, 57.3% were seizure

free on monotherapy and 6.4% were seizure-free on
Yes

Yes
No

No

polytherapy. The other 36.3% were considered as

refractory and were taking two or more AEDs without
Mechanism of

control of their seizures, with a Class IV level of evi-

dence (Fig. 1 and Table 2)3.
action

Monotherapy is the gold standard to begin treat-

M

M
G

ment of focal and generalized seizures in adults, with

the goal of obtaining 100% control; however, it is im-
1000‑3000 mg
750‑2000 mg

portant to realize that about 20-30% do not achieve

125‑200 mg
Final dose

1‑2 doses

2‑3 doses
1500 mg
2 doses

2 doses

this goal3.

Question 3. What is the AED of choice for

focal onset seizures and what is the
Initial dose

100‑125 mg

200‑500 mg
1‑2 doses

2‑3 doses
25‑50 mg

first-line AED for generalized onset

2 doses

2 doses
500 mg

seizures in adults?
To begin treatment, based on pharmacokinetics and
PRM

TPM

VGB
AED

VPA

pharmacodynamics, one must start with a gradually

84
 L. Rivera-Castaño, et al.: Antiepileptic drugs in adult patients

Patients with recent diagnosis of Epilepsy: 1795 (100%) 1982-2014

Focal Seizures: 1409 (78.5%) / Generalized Seizures: 386 (21.5%)

 f the publisher.   © Permanyer 2019

1st AED MONOTHERAPY

CONTROL No Control CONTROL No Control

820 (45.7%) 116 (6.4%) 651 (36.3%)

2nd AED ≥2 AEDs POLYTHERAPY

CONTROL No Control
208 (11.6%)
CONTROL No Control

No part of this publication may be reproduced or photocopying without the prior written permission o
1144 (63.7%) 651 (36.3%)

Monotherapy 1 AED 1,028 (57.3%) Seizure-free

Bitherapy 2 AEDs 116 (6.4%) Seizure-free

Polytherapy ≥ 2 AEDs 651 (36.3%) No control

Figure 1. Pharmacologic control of epileptic seizures.

Table 2. Data for monotherapy in adults

Data Evidence Recommendation

The goal of AEDs is the complete control of epileptic seizures, and they are effective if I and III A
prescribed correctly for the syndrome or type of seizure

The recommendation is to begin treatment with a single AED I and III A

The dose of the AED must be reached slowly and progressively until arriving at the recommended IV R‑PPE
therapeutic dose

Consistency in taking the treatment is very important, and the patient must be informed of the IV R‑PPE
gravity of suspending it abruptly

AEDs: antiepileptic drugs; PPE: priority epilepsy program.

progressive dose to arrive at the recommended thera-
peutic dose. In the adult, you do not always calculate the
milligrams per kilogram of weight, especially for the new
generation AED, but must consider the aspects related
to the particular AED, the characteristics of the patient,
as well as cost and bioavailability6 (Table 3). The AED of
the first choice will fundamentally depend on clinical con-
firmation of epilepsy. First, by recognizing the type of
epileptic seizure; second, the type of epilepsy, if possible,
third to determine a diagnosis of the epileptic syndrome
presented by the patient, and on a fourth level, to be able
to determine the etiology of the epilepsy.

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 Rev Mex Neuroci. 2019;20

Table 3. Variables to consider when choosing the AED as first‑line monotherapy 6

Variables related to the AED Variables related to the patient Other variables

Primary AED for the type of seizure Genetic history Availability of the AED

 f the publisher.   © Permanyer 2019

Idiosyncratic Reactions Age at seizure onset Cost of the AED

Dose dependent adverse effects Gender

Pharmacokinetics Comorbidities

Pharmacodynamics Concomitant medication

Teratogenicity Ability to swallow

Interactions

Immediate/extended release formulation

Modified form. AED: antiepileptic drug.

No part of this publication may be reproduced or photocopying without the prior written permission o
Table 4. Data for monotherapy in focal onset seizures in adults*9-19
Data Evidence Recommendation

The AEDs of choice to begin monotherapy treatment in focal onset seizures are CBZ, PHT, LTG and LEV I and III A

The evidence level for VPA is from Class II and III studies for control of focal onset seizures II and III B

Evidence for monotherapy for focal onset seizures with PB or with PRM is class II and III, without II and III C
statistically significant differences compared with the adverse effects of CBZ and PHT

VGB, currently having only one Class I study, has insufficient data to recommend it for monotherapy I and IV C
in focal onset seizures, given the risk‑benefit of visual field affectation

For BRV, GBP, OXC, PGB, and TPM, the data are insufficient to recommend as monotherapy for IV U
epilepsy with focal onset seizures

*The AEDs are in alphabetical order and are available in Mexico6,10‑18. PHT: phenytoin; CBZ: carbamazepine; LEV: levetiracetam; VPA: valproate; PB: phenobarbital;
PRM: primidone; VGB: vigabatrin; BRV: brivaracetam; GBP: gabapentin; OXC: oxcarbazepine; PGB: pregabalin; TPM: topiramate; AEDs: antiepileptic drugs; LTG: lamotrigine

Table 5. Data for monotherapy in generalized onset seizures in adults*9-21

Data Evidence Recommendation

LTG, LEV, and VPA are first choice AEDs for monotherapy management of generalized onset motor II and III A
and non‑motor seizures in adults

To treat generalized onset non‑motor seizures, first‑line AEDs are ESM and VPA; LTG may also be II and III A
useful

TPM can be useful as monotherapy in generalized onset motor seizures: tonic‑clonic, tonic, and II and III B
clonic

Generalized onset seizures, motor (myoclonic), and non‑motor (absences) are aggravated with IV R‑PPE
CBZ, GBP, PTH, OXC and VGB

When treating childbearing‑aged women, the teratogenic potential of the AED must be R‑PPE
considered, especially for TPM and VPA

*The AEDs are in alphabetical order and are available in Mexico19‑21. LTG: lamotrigine; LEV: levetiracetam; VPA: valproate; AEDs: antiepileptic drugs; ESM: ethosuximide;
TPM: topiramate; CBZ: carbamazepine; GBP: gabapentin; PHT: phenytoin; OXC: oxcarbazepine; VGB: vigabatrin.

86
 L. Rivera-Castaño, et al.: Antiepileptic drugs in adult patients

Table 6. Data for using a 2nd AED in monotherapy6,12,20‑22

Data Evidence Recommendation

If the first AED is not well tolerated at low doses, another AED from among those recommended IV R‑PPE

 f the publisher.   © Permanyer 2019

for first‑line therapy must be used

When an average therapeutic dose of the chosen AED is reached, without achieving 100% control in IV R‑PPE
a maximum period of 6 months, another AED with a different pharmacological profile must be used

When changing the AED is necessary, the other AED must be introduced gradually at the IV R‑PPE
recommended dose, and the gradual and progressive suspension of the first AED must be
evaluated

AED: antiepileptic drug; PPE: priority epilepsy program.

Table 7. Data for bitherapy for focal onset seizures in adults24,25

Data Evidence Recommendation

No part of this publication may be reproduced or photocopying without the prior written permission o
If monotherapy with one or various regimens of AED with A‑B recommendation was not effective, I‑III A
two AEDs with recommendation A‑B and different mechanisms of action can be
combined: (SC)+(M), (SC)+(SV2), (SC)+(G) or (SV2)+(M)

VPA inhibits the glucuronidation process, increasing the half‑life of LTG. Thus, when combined with I‑III A
valproate, the dose of LTG must be increased slowly until arriving at a minimal therapeutic dose to
avoid adverse effects

There are insufficient data for combining 2 AEDs with the same mechanism of action, like two with IV U
multiple mechanisms (M)+(M)

Combination of 2 AEDs with the same mechanism of action, such as SC blockers (SC)+(SC) or GABA IV R‑PPE
analogs (G)+(G), is not recommended because of reports of inefficacy and increase in adverse effects

The most effective combination of two AEDs with different mechanisms of action to control focal IV R‑PPE
onset seizures in adults that did not respond to monotherapy is (SC)+(M): LTG (LTG)
recommendation A + VPA recommendation B

SC: sodium channel; VPA: valproate; AED: antiepileptic drug; PPE: priority epilepsy program; LTG: lamotrigine.

Table 8. Data for bitherpay in generalized onset seizures in adults

Data Evidence Recommendation

If monotherapy with one or more regimens of AED with recommendation A was not enough, IV R‑PPE
two AEDs with recommendation A, with different mechanisms of action, must be
combined: (SC)+(M), (SC)+(SV2), or (SV2)+(M)

Modified from3. AED: antiepileptic drug; PPE: priority epilepsy program; SC: sodium channel.

Question 4. When do you recognize that Question 5. At the moment when

the first-line AED is not effective to treat
epilepsy in the adult patient and what are
the recommendations for monotherapy
with a second AED?
When despite taking a first-line AED at adequate do-
ses and therapeutic adherence by the patient, it is not
effective to control epilepsy in the adult, and we must
reconsider the correct diagnosis of the type of seizure
and the differential diagnosis by conducting a new cli-
nical evaluation and clinical tests6,12,20-22 (Table 5).
monotherapy with two or more drugs has
not been enough to control all the seizures,
what AEDs are adequate when you want to
combine two AEDs, in the adult?
The fact is that there are no existing Class I, II, or III
studies for bitherapy. The possibility that the 4-25% of
patients who do not respond to monotherapy will be
seizure free with bitherapy, that is, that they require
administration of two AEDs to completely control their
seizures, only has class IV evidence.3,23
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 Rev Mex Neuroci. 2019;20
Empirically, a combination of AED with different me-
chanisms of action, minimum interaction between the
AED, and a different spectrum of adverse effects has
been proposed24,25 (Tables 1 and 6).
The bitherapy that has been demonstrated to be the
most effective is the combination of a sodium channel
blocker with a wide spectrum AED with multiple (M)
mechanisms of action: such as lamotrigine and valproa-
te, keeping in mind the teratogenic potential (Tables 7
and 8) 23-36
Acknowledgments
We thank Dr. Mitzel del Carmen Pérez-Careta for her
editorial help in preparing this guide.
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Revista Mexicana de Neurociencia

REVIEW ARTICLE

 f the publisher.   © Permanyer 2019

Clinical guideline: antiepileptic drugs of choice for epileptic
syndromes and epilepsies in pediatric patients
Juan C. Reséndiz-Aparicio1, Jesús M. Padilla-Huicab2, Iris E. Martínez-Juárez3,
Gustavo Hernández-Martínez4, Eunice López-Correa5, Benjamín Vázquez-Juárez6,
Rosana Huerta-Albarrán7 and Claudia Rivera-Acuña8
1PPE, Instituto
Nacional de Neurología y Neurocirugía Dr. Manuel Velasco Suárez y Hospital Psiquiátrico Infantil Dr. Juan N. Navarro, Mexico City;
2HospitalGeneral de Especialidades Dr. Javier Buenfil Osorio, Campeche; 3Instituto Nacional de Neurología y Neurocirugía Dr. Manuel Velasco
Suárez Mexico City; 4Centro de Alta Especialidad del Estado de Veracruz Dr.  Rafael Lucio, Jalapa, Veracruz; 5Hospital General Dr.  Gaudencio
González Garza, Centro Médico La Raza, IMSS, Mexico City; 6Hospital para el Niño Poblano, Puebla; 7Hospital General de México Dr Eduardo

No part of this publication may be reproduced or photocopying without the prior written permission o
Liceaga, Mexico City; 8Hospital Regional de Alta Especialidad ISSSTE, Puebla. México

Abstract
Approximately 65% of children with newly diagnosed epilepsy achieve sustained control of their epileptic seizures with the
antiepileptic drug (AED) initially prescribed, and 15-20% require the combination of other AEDs. To begin treatment with an
AED, basic aspects should be considered, such as the capacity for absorption, distribution, metabolism, and elimination of
each AED. Treatment with an AED in pediatric patients, as for any age, must be personalized, but in these cases, the biolo-
gical age and its degree of development are fundamental. Furthermore, the type of seizure, type of epileptic syndrome, co-
morbidity, in many cases the etiology, and even other aspects such as tolerability and availability of use must be considered.
If adequate seizure control is not achieved, synergistic combinations could be used, making sure that adverse effects are
not increased. Remember that a high percentage of patients initiate their epilepsy in the pediatric stage, which is why ma-
nagement in this age group is fundamental, and doses must always be calculated in relation to the weight of the patient.

Key words: Antiepileptic drug. Monotherapy. Polytherapy. Childhood. Pediatric.

Introduction international guidelines, such as the guides published

This is a clinical guide for the pharmacologic
treatment of epilepsy in pediatric patients. It consists of
establishing PICO-based questions and setting forth
answers. The levels of evidence are based on articles
published in peer-reviewed indexed articles and other
by the International League Against Epilepsy, the
National Institute for Health Care Excellence, and the
Guidelines from the Sociedad Andaluza de Epilepsia
(Andalusian Epilepsy Society). In addition, we emit re-
commendations from the Programa Prioritario de Epi-
lepsia (Priority Epilepsy Program).

Correspondence:
Juan Carlos Reséndiz Aparicio
PPE, Instituto Nacional de Neurología y
Neurocirugía Dr. Manuel Velasco Suárez
Hospital Psiquiátrico Infantil Dr. Juan N. Navarro Date of reception: 08-02-2019 Available online: 12-04-2019
Mexico City, Mexico Date of acceptance: 02-02-2019 Rev Mex Neuroci. 2019;20(2):89-96
E-mail: jc_doc@yahoo.com DOI: 10.24875/RMN.M19000028 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

89
 Rev Mex Neuroci. 2019;20

• Age
• Gastric emptying

 f the publisher.   © Permanyer 2019

• Intestinal Integrity
Absorption • Intestinal transit time and pH

• Amount of body water

• Amount of fat and muscle
Distribution • Drug-Protein binding

• Same as in adults

No part of this publication may be reproduced or photocopying without the prior written permission o
Metabolism
m

Figure 1. Pharmacokinetic and pharmacodynamic variables in pediatric age and use of antiepileptic drugs 1-6.

Question 1. What are the pharmacokinetic
and pharmacodynamic differences in
pharmacologic management of epilepsy
between the pediatric patient and the
adult?
Pediatric patients have a broad range of variations in
their ability for absorption, distribution, metabolism, and
clearance of antiepileptic drugs (AEDs) (Fig.  1). Clea-
rance of AED is much faster than in adults, which
makes it important to calculate the dose depending on
the weight or body surface area and to be careful of
the toxic effects (Tables 1 and 2)1-6.
Question 2. Should treatment with
antiepileptics be based on the type of
epileptic syndrome that a patient presents? BFNE
To establish a diagnosis of epilepsy, it is sufficient if
we can define an epileptic síndrome7 that, in the current
classification, would correspond to a Level III diagno-
sis8. By definition, an epileptic syndrome presupposes
a disease that incorporates characteristics in common
such as the type of seizure, the electroencephalogra-
phic findings, the shared imaging study results, age
of  onset and/or remission, when applicable, seizure
90
triggering factors, diurnal variations, and sometimes the
prognosis8.
Question 3. What is the evidence for
treating epileptic syndromes described
for newborns: benign familial neonatal
epilepsy (BFNE), early myoclonic
encephalopathy (EME), and Ohtahara
syndrome?
The first thing to understand is that neither systematic
reviews nor clinical guides exist for the management of
the syndromes that have been described in newborns;
thus, the evidence for treatment is Level IV, and in all
these cases, the recommendation is U.
For cases with frequent seizures or status epilepti-
cus, it could be necessary to provide therapy with drugs
such as carbamazepine (CBZ), phenytoin (PHT), phe-
nobarbital (PB), levetiracetam (LEV), oxcarbazepine
(OXC), and valproate (VPA). CBZ, even at low doses,
is considered to be a good option for BFNE, even in
status epilepticus9,10. In general, patients require treat-
ment during the first 6-12 months of life.
 J. C. Reséndiz-Aparicio, et al.: Antiepileptic drugs in pediatric patients

Table 1. Traditional antiepileptic drugs and their pediatric use

AED Initial dose (mg/kg/day) Maintenance dose Daily dose Presentation

Diazepam 2‑5 years: 1.5 Same 3 times Solution: 5 mg/5 ml

 f the publisher.   © Permanyer 2019

6‑11 years: 0.9 Same Tablets: 10 mg

Carbamazepine 5‑10 15‑20 mg/kg/day 2 or 3 times Suspension: 100 mg/5 ml

Tablets: 200 mg

Clobazam 0.25 1 mg/kg/day Once or twice Tablets: 10 mg

Clonazepam 0.01 0.1 mg/kg/day 2 or 3 times Suspension: 0.1 mg/1ml

Tablets: 2 mg

Phenytoin 4‑5 4‑8 mg/kg/day 2 or 3 times Suspension: 37.5 mg/5 ml

Tablets: 100 mg

Phenobarbital 5 Same Once or twice Tablets: 100 mg

Gabapentin 10‑15 30‑100 mg/kg/day 2 or 3 times Capsules: 300 and 400 mg

Lamotrigine 0.5 2‑10 mg/kg/day Twice Tablets: 25, 50, and 100 mg

No part of this publication may be reproduced or photocopying without the prior written permission o
Levetiracetam 10 40‑60 mg/day Twice Solution: 100 mg/ml
Tablets: 250, 500, and 1000 mg
500 mg extended release

Oxcarbazepine 5‑10 20‑30 mg/kg/day Once or twice Suspension: 300 mg/5 ml

Tablets: 300 and 600 mg
150, 300, and 600 mg extended release

Pregabalin 3.5‑5 15‑20 mg/kg/day Twice Capsules: 75 and 150 mg

Topiramate 0.5‑1.0 4‑8 mg/kg/day Twice Tablets: 25, 50, and 100 mg

Valproic acid 10‑15 15‑30 mg/kg/day 2 or 3 times Syrup: 250 mg/5 ml

Sprinkle: 125 mg
Capsules: 250 mg and 500 mg
250 mg and 500 mg extended release

Vigabatrin 40 80‑100 mg/kg/day 2 or 3 times Tablets: 500 mg

(150 mg/kg/per day for
childhood spasms)

Table 2. New antiepileptic drugs and their use in pediatric age patients
Drug Initial dose Maintenance Daily dose Secondary effects Formulation
(mg, kg, day)

Lacosamide 1‑2 6‑9 2 Dizziness, cephalea, Tablets: 50 and 100 mg

double vision, nausea

Lamotrigine/monotherapy 0.5 2‑10 2 Skin rash, drowsiness, Tablets: 5, 25, 50, and
With enzyme inducing AED 2 5‑15 2 dizziness, nausea, 100 mg
With Valproate 0.2 1‑5 1‑2 double vision

Levetiracetam 10 20‑60 2 Cephalea, anorexia, Tablets: 250, 500, and

drowsiness, behavior 1000 mg
problems Suspension: 100 mg/1 ml

Oxcarbazepine 5‑8 10‑30 2 Dizziness, ataxia, Tablets: 300 and 600 mg

drowsiness, Suspension: 300 mg/5 ml
hyponatremia

Topiramate 1 6‑9 2 Weight loss, lethargy, Tablets: 25, 50, and 100 mg
anorexia, hyperthermia,
kidney stones

Vigabatrin 20‑50 50‑150 2 Hyperkinesis, weight Tablets: 500 mg

gain, insomnia, visual
field defects

AED: antiepileptic drugs

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 Rev Mex Neuroci. 2019;20

Table 3. Treatment for west syndrome*

Evidence Recommendation

Insufficient data to determine whether ketogenic diet, immunoglobulin, LEV, NZP, TPM, VPA, or III and IV U

 f the publisher.   © Permanyer 2019

vitamin B6 are effective for treating infantile spasms

Using rapid ACTH or prednisolone in unknown cause West syndrome improves long‑term II and III C
cognitive results

Insufficient studies to establish what other forms of corticosteroids are as effective and III and IV U
recommended as ACTH to treat short‑term infantile spasms

Low‑dose ACTH (20‑30 UI) versus high dose (150 UI/m2) shows similar efficacy I and II B

ACTH is more effective than VGB for infantile spasms not associated with tuberous sclerosis III C

VGB is more effective for infantile spasms associated with tuberous sclerosis III C

First‑line drugs are ACTH, steroids, or VGB and second‑line drugs are BZD, ketogenic diet, IV R‑PPE
TPM, and VPA

*The AEDs are in alphabetical order and are available in Mexico12,13, LEV: levetiracetam, NZP: nitrazepam, TPM: topiramate, VPA: valproate, VGB: vigabatrin,

No part of this publication may be reproduced or photocopying without the prior written permission o
BZD: benzodiazepines, TPM: topiramate, VPA: valproate

EME The current studies are not enough to establish whe-

Early onset with a burst suppression pattern in the
EEG, various types of seizures, and psychomotor re-
tardation. Metabolic etiologies are often a cause of
EME. The burst suppression pattern in EME is different
from that of Ohtahara since, in general, the burst is
shorter and the suppression is longer. The use of ste-
roids and ACTH may be effective in some cases11.
Ohtahara syndrome
It has been calculated that 75% of these cases evolve
into West syndrome between the 2nd and 6th months of
age. Treatment is difficult, but in some cases, ACTH,
LEV, and high doses of PB have been shown to be
effective11.
Question 4. What is the evidence for
treating West syndrome?
There are insufficient data to determine the effecti-
veness of ketogenic diet, intravenous immunoglobulin,
LEV, nitrazepam, topiramate (TPM), VPA, or Vitamin
B6, for treating infantile spasms12.
Early control of spasms could improve development in
those who do not have a proven underlying etiology13. For
West of unknown cause, providing treatment quickly with
ACTH or prednisolone, above using vigabatrin (VGB),
can improve cognitive results in the long term12. Both
steroids and VGB have potentially serious secondary
effects, and the patient must be carefully observed.
92
ther other types of corticosteroids, such as prednisolo-
ne, dexamethasone, or methylprednisolone, may be as
effective or recommendable as ACTH for short-term
treatment of infantile spasms12.
First-line treatment medications are considered to be
ACTH, steroids, or VGB, while second-line treatment
can be benzodiazepines, ketogenic diet, TPM, and
VPA, although the long-term benefits of the different
therapies are still uncertain, and more research is nee-
ded on this subject (Table 3)13.
Question 5. What is the evidence for
treating Lennox-Gastaut syndrome?
To choose the treatment, one must consider the be-
havioral and psychiatric comorbidities, such as depres-
sion, anxiety, and psychosis. One must also take into
account that the patient may have different types of
seizures and some drugs may diminish some types of
seizures while increasing others. Some combinations
can be synergistic and reduce the number of seizures,
but it is important to monitor the possible increase in
adverse effects (Table 4)14,15.
Valproate is a first-line drug, while CLB, ketogenic
diet, lamotrigine (LTG), LEV, and TPM are effective as
adjunct (add-on) therapies15-19. Other options for resis-
tant seizures are cannabidiol, resective surgery, stimu-
lation of the vagus nerve, callosotomy, or transcranial
stimulation20-22.
 J. C. Reséndiz-Aparicio, et al.: Antiepileptic drugs in pediatric patients

Table 4. Treatment for LGS*

Level evidence Recommendation

VPA is the first‑line drug for LGS II and III B

 f the publisher.   © Permanyer 2019

CLB, LTG, LEV, and TPM are effective as adjunct therapy II and III B

Ketogenic diet is recommended for drug‑resistant seizures in LGS III C

Cannabidiol is useful for resistant seizures in LGS I and III A

Callosotomy is useful for atonic seizures in LGS III C

Vagus nerve stimulation is useful for drug‑resistant seizures in LGS III C

The use of CBZ, GBP, OXC, PGB, or VGB is not recommended in LGS IV R‑PPE

*The AED are in alphabetical order and are available in Mexico15‑22. LGS: Lennox‑Gastaut syndrome, VPA: valproate, CLB: clobazam, LTG: lamotrigine, LEV: levetiracetam,
TPM: topiramate, CBZ: carbamazepine, GBP: gabapentin, OXC: oxcarbazepine, PGB: pregabalin, VGB: vigabatrin

No part of this publication may be reproduced or photocopying without the prior written permission o
Table 5. Treatment in Doose syndrome23‑25 PHT, PGB, and VGB should not be used, as they can
Evidence Recommendation aggravate myoclonic ES (Table 6)15.
LTG II B

VPA IV R‑PPE Question 8. What drugs should be used

for early onset occipital epilepsy or
Ketogenic diet IV U
Panayiotopoulos syndrome?
LTG: Lamotrigine, VPA: valproate
Evidence places OXC at Level A, while CBZ, PB,
PHT, TPM, VPA, and VGB are Level C, and CLB, CZP,
and LTG are potentially Level D, with respect to effica-
Question 6. What drugs are the most cy/effectiveness, as initial monotherapy in children with
effective for pediatric patients with focal onset epilepsy that have been recently diagnosed
myoclonic astatic epilepsy or Doose or without previous therapy27.
syndrome?
VPA is considered the first choice AED, and it can
Question 9. What drug must be used for
be combined with BZD, ethosuximide (ESM), LTG, LEV,
juvenile myoclonic epilepsy?
and TPM23. TPM and VPA are potentially effective (Level D) for
The ketogenic diet can be very effective. The an- any type of seizure within this syndrome. Avoid admi-
ti-epileptics that should be avoided are CBZ, gabapen- nistering CBZ, GBP, OXC, PHT and VGB, since they
tin (GBP), OXC, pregabalin (PGB), tiagabine, and VGB can aggravate or trigger absence seizures, myoclonus,
since these increase myoclonic epileptic seizures (ES) and in some cases, generalized tonic-clonic seizures.
(Table 5)24,25. Furthermore, LTG may exacerbate myoclonic seizures
in some cases (Level F)28,29.
Question 7. What pharmacological
treatment is recommended for pediatric Question 10. What is the evidence for
patients with Dravet syndrome? treating generalized epilepsy with
generalized tonic-clonic ES in pediatric
ESs in these patients are refractory. A  good
patients?
combination is VPA with TPM, which has shown impro-
vement, especially for focal seizures and generalized There are no Class I or II studies on pediatric-aged
tonic-clonic ES. In some cases, ACTH or corticoids, patients, leaving us with only class III studies, and thus,
ketogenic diet, ESM, or intravenous immunoglobulin Level C evidence that suggests that monotherapy with
has shown satisfactory results26. CBZ, GBP, LTG, OXC, CLB, LTG, LEV, TPM and VPA may be effective30-33.
93
 Rev Mex Neuroci. 2019;20

Table 6. Treatment in Dravet syndrome*

Level evidence Recommendation

VPA is effective for myoclonic seizures IV R‑PPE

 f the publisher.   © Permanyer 2019

LTG may worsen or trigger myoclonic ES in patients with Juvenile myoclonic IV R‑PPE
epilepsy or Dravet syndrome

CLB, CNZ, LTG, LEV, and TPM are also effective for myoclonic seizures IV U

*The AED are in alphabetical order and are available in Mexico15,26, VPA: valproate, LTG: lamotrigine, CLB: clobazam, CNZ: clonazepam, LTG: lamotrigine,
LEV: levetiracetam, TPM: topiramate, ES: Epileptic seizures

Table 7. Treatment in epilepsy for generalized tonic‑clonic epileptic seizures only in pediatric age patients*
Level of evidence Recommendation

Initial CLB monotherapy may be slightly more effective in treating epilepsy II B

No part of this publication may be reproduced or photocopying without the prior written permission o
with GTCS than PHT. No advantage over CBZ

CBZ and LTG may be effective as monotherapy for epilepsy with GTCS. II B
There is greater treatment failure with CBZ but quicker response in
controlling seizures (6 months)

CBZ and PHT can be effective as monotherapy for treating epilepsy with II B
GTCS, no difference between them when comparing effectiveness and
adverse effects

LEV, TPM, and VPA can be effective in treating epilepsy with GTCS III R‑PPE

*The AED are in alphabetical order and are available in Mexico 29‑33
, CLB: Clobazam, PHT: phenytoin, CBZ: carbamazepine, LTG: lamotrigine, LEV: levetiracetam,
TPM: topiramate, VPA: valproate

Table 8. Meta‑analysis from the Cochrane library among first‑generation AEDs for the treatment of focal ES*
Study Conclusions

Tudur 2002 CBZ and PHT show similar effectiveness in treating focal ES

Tudur 2003 PB is less tolerated than CBZ (with similar effectiveness)

Tudur 2007

Nolan 2013 PB is less tolerated than PHT (with similar effectiveness)

Nolan 2013 PHT and VPA present similar effectiveness to control ES

Glauser 2006 CBZ and PHT show efficacy and effectiveness with good quality evidence
VPA show efficacy and effectiveness with low‑quality evidence

*The AEDs are in alphabetical order and are available in Mexico28,37,42‑44, CBZ: carbamazepine, PHT: phenytoin, ES: epileptic seizures, PB: phenobarbital, PHT: phenytoin,
VPA: valproate

CBZ and PHT must be avoided since they can aggra- AED prescribed initially. An additional 15-20% of these
vate or trigger GTCS (Table 7)29. patients require combination with other AEDs to achie-
ve control. The remaining percentage does not achieve
control with the available medicines, becoming a
Question 11. Which AED is considered to
drug-resistant focal epilepsy34,35.
be first choice for recently diagnosed
For childhood focal seizures, first-line monotherapy
focal epilepsy in the pediatric patient?
with GBP, LCM, LEV, LTG, OXC, PGB, and TPM is
Around 65% of children with recently diagnosed epi- recommended. Alternative monotherapy includes CBZ
lepsy achieve sustained control of their ES with the or VPA, and as coadjuvant therapy CLB or LCM or one
94
 J. C. Reséndiz-Aparicio, et al.: Antiepileptic drugs in pediatric patients

Table 9. Comparative studies between traditional and new AEDs in treating focal ES*
Study Conclusions

Glauser 2006 Second‑generation AEDs (GBP, LTG, OXC, and TPM) are not inferior in effectiveness compared with first‑generation AEDs

 f the publisher.   © Permanyer 2019

Second‑generation AEDs (GBP, LTG, OXC, and TPM) show similar efficacy

Privitera 2003 TPM (doses 100 or 200 mg/day), CBZ (600 mg/day), and VPA (1250 mg/day) show similar efficacy results

Gamble 2006 LTG has better tolerability and adherence to treatment than CBZ

Nolan 2013 OXC shows similar efficacy compared to PHT, but it is tolerated better
Arya 2013

Koch 2009 OXC presents similar efficacy and effectiveness compared with CBZ

Marson 2007 LTG shows greater effectiveness over CBZ, GBP, and TPM but not over OXC
Tudur 2007 CBZ demonstrates greater efficacy in seizure remission during 12 months compared to GBP but not greater than that
observed with LTG, OXC, and TPM
The AED with the lowest efficacy is GBP and the least tolerated is TPM
CBZ, LTG, and OXC show better adherence and better control during treatment of focal ES
VPA shows similar adherence as CBZ but with lower efficacy

No part of this publication may be reproduced or photocopying without the prior written permission o
PHT and TPM are less effective than LTG and have lower efficacy than CBZ

Brodie 2007 LEV demonstrates similar efficacy and tolerability CBZ for recently diagnosed focal epilepsy
Perry 2008

CSGCE 1998 CLB shows similar efficacy as PHT and CBZ as monotherapy for the control of focal ES and GTCS
Bawden 1999 There are no differences in the results of cognitive tests applied to children at 12 months of treatment receiving CBZ
or CLB

Rosenow 2012 There are no differences in efficacy or tolerability with LEV or LTG for control of focal ES or GS as monotherapy at
26 weeks of treatment in patients older than 12 years

*The AEDs are in alphabetical order and are available in Mexico28,37,42‑52, AEDs: antiepileptic drugs, CBZ: carbamazepine, PHT: phenytoin, OXC: oxcarbazepine,
VPA: valproate, GBP: gabapentin, LTG: lamotrigine, LEV: levetiracetam, TPM: topiramate, CLB: clobazam

Table 10. Treatment for epilepsy with focal epileptic seizures in pediatric age patients*
Level of recommendation

CBZ, GBP, LTG, OXC, PB, PHT, TPM, and VPA can be used as monotherapy for the initial A
treatment of focal onset ES in children

LEV can be used as monotherapy for initial treatment of focal onset ES in children C

*The AEDs are in alphabetical order and are available in Mexico28,37,42‑52,

GBP: gabapentin, LTG: lamotrigine, LEV: levetiracetam, TPM: topiramate, VPA: valproate,
OXC: oxcarbazepine, PB: phenobarbital, PHT: phenytoin, LEV: levetiracetam

of the AEDs used as monotherapy can be used. When
using VPA, remember the teratogenic risks for ferti-
le-aged patients, especially when used in high doses
(Tables 8-10)28,36-44.
Question 12. Which AEDs are considered
to be the first choice for recently
diagnosed generalized epilepsy in the
pediatric patient?
Choosing an AED for generalized seizures must be
personalized according to age, type of seizure, tolera-
bility, availability for use, and other aspects.
VPA continues to be the drug of choice as monothe-
rapy for all types of generalized ES in children, after
assessing the risk-benefit and taking into special con-
sideration patients with cognitive deficits, risk of overwei-
ght, and teratogenic effects in fertile-aged adolescents.
Other options include LEV and TPM. Administration of
CBZ, GBP, LTG, OXC, PHT, and VGB should be avoi-
ded since they could precipitate generalized tonic-clonic
seizures and myoclonic seizures15,29,35.
Acknowledgments
We thank Dr.  Mitzel del Carmen Pérez-Careta for
editorial assistance in preparing this Guide.
95
 Rev Mex Neuroci. 2019;20
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Revista Mexicana de Neurociencia

REVIEW ARTICLE

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Clinical guideline: febrile seizures, diagnosis and treatment
Carlos Aguirre-Velázquez1, Alma M. Huerta Hurtado2, Hugo Ceja-Moreno3, Karina Salgado-Hernández4,
Roberto San Román-Tovar5, Martha A. Ortiz-Villalpando6, Avril Molina-García7,
Guadalupe Vargas-Ramírez8, Jaime López-Rivera9 and Rosana Huerta-Albarrán10
1Escuela Nacional de Medicina TEC de Monterrey, Monterrey; 2Hospital de Pediatría Centro Médico Nacional De Occidente IMSS, Guadalajara,

Jalisco; 3Hospital Civil Viejo Fray Antonio Alcalde, Guadalajara, Jalisco; 4Hospital Materno Infantil ISSEMYM, Toluca; 5Hospital General de Occidente
Zoquipan, Zapopan, Jalisco; 6Centro de Rehabilitación Infantil e Inclusión Infantil de Occidente, CRIT, Guadalajara, Jalisco; 7Hospital Infantil de
Especialidades de Chihuahua, Chihuahua; 8Hospital Pediátrico de León; León, Guanajuato; 9Hospital Universitario, Saltillo, Coahuila; 10Hospital
General de México Dr. Eduardo Liceaga, Mexico City, Mexico

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
Febrile seizures (FeS) are the most common problem in pediatric neurological practice. They are convulsive episodes during
the course of febrile illness in the absence of epilepsy, severe hydroelectrolytic imbalance or neuroinfection. Its diagnosis is
clinical and classified as simple and complex. Febrile status epilepticus occurs in approximately 5% of cases. It is convenient
to teach parents how to act in a seizure and clarify that a FeS is not epilepsy, it is a benign process that usually does not
leave neurological sequelae, and in which mortality is zero. In this clinical guide, we indicate risk factors for recurrence,
management instructions for the first FeS, as well as criteria for hospital admission and treatment for prolonged seizures.

Key words: Febrile Seizures. Diagnosis. Treatment.

1. What is a simple febrile seizure (SFeS)?
SFeS happen in children 3-5 months old1-4. They are
generalized tonic-clonic seizures accompanied by fe-
ver, without central nervous system (CNS) infection,
metabolic disorder, or history of FeS5-8. Fever is
considered as a rectal temperature greater than 38°C,
axillary temperature greater than 37.5°C, or tympanic
temperature greater than 38.2°C9. SFeS can occur be-
fore or after the fever becomes apparent, within 24 h,
during the course of a febrile illness10-12. SFeS affect
2-5 % of the pediatric population and they are reported
to be more frequent in some ethnic Asian groups3,13,14.
They are benign seizures, since they are induced con-
vulsions and not related to epilepsy7,13.
2. What is a complex FeS (CFeS)?
A CFeS is a focal or generalized FeS lasting more
than 15 min, recurrent (more than once in 24 h), and/or
associated with postictal neurologic abnormalities, most
commonly a postictal paralysis (Todd’s paralysis), or
when the patient presents with previous neurological
impairment15-17.
The child that presents with a prolonged FeS which
was interrupted with anticonvulsant therapy (such as

Correspondence:
Alma Maritza Huerta Hurtado Date of reception: 01-02-2019 Available online: 12-04-2019
Guadalajara, Jalisco, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):97-103
E-mail: almamaritza@hotmail.com DOI: 10.24875/RMN.M19000029 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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 Rev Mex Neuroci. 2019;20

Table 1. Lumbar puncture in FeS and criteria for hospitalization

Data Level of evidence Recommendation

Lumbar puncture must be obtained from children with FeS, younger than 12 months old, III B

 f the publisher.   © Permanyer 2019

who have not completed their immunizations or have received previous antibiotic
treatment

Lumbar puncture must be obtained from children of any age with FeS that present with II B
altered alertness and/or meningeal symptoms

Children younger than 6 months with a simple FeS must be punctured unless an experienced III C
pediatrician evaluates the patient and declines, but he must reevaluate the patient in 2 h

All patients under 18 months with their first simple FeS must be admitted to the I A
emergency room.

Patients previously diagnosed with a recurrence of FeS do not require hospitalization I A

Hospitalization is not necessary in children older than 18 months that are clinically stable, I A
without signs or symptoms that require diagnostic studies

No part of this publication may be reproduced or photocopying without the prior written permission o
FeS: febrile seizures

diazepam [DZP]) before 15th min must also be classified
within this group15,18.
It is considered a febrile status epilepticus when a
complex FeS lasts >30 min, or when there are shorter
serial FeS without recovering consciousness during the
interictal state6,10,15,16.
3. When do you carry out a lumbar
puncture in the first SFeS?
In children of any age that have their first FeS, it is
important to discard an infection in the CNS (encepha-
litis/meningitis). Pay special attention when children are
younger than 6 months, seizures last more than 15 min,
there are more than two seizures within a 24-h time
period when there are focal motor or non-motor seizu-
res with affected alertness, and/or when the child pre-
sents the following clinical data:
– Sleepiness alternating with irritability or Glasgow
scale below 15 points.
– Neck stiffness, Kernig’s sign, and Brudzinski’s sign.
– Vomit, tense or bulging fontanelle, and papilledema.
– Presence of macular or petechial exanthem.
– Abnormal postures during the postictal state or if stu-
por remains for over an hour after a seizure6,19-21.
The risk of bacterial meningitis in children that pre-
sent with fever and seizures is about 3%, but in a CFeS
it is 9%. Thus, lumbar puncture must be carried out in
all children with CFeS and suspected CNS infection. In
the case of CFeS without clinical signs of meningitis,
they must be closely observed and checked after 2 h
98
by a pediatrician to then decide again whether to carry
out a lumbar puncture15 (Table 1).
4. How are SFeS or CFeS treated during
the acute ictal phase?
Managing SFeS begins with training the parents for
home management22 (Table  2). Informing the parents
that their child will not die, that association with epi-
lepsy is rare, and that the frequency of SFeS is reduced
with age13,16,23,24. Warning them that if the seizure lasts
5  min or more, they must call an ambulance, provide
emergent initial therapy, or go to the emergency room.
Various authors support that intervention during the
acute phase is rarely required12,28.
In the case of recurrent seizures, administer emer-
gent initial therapy with the knowledge that the use of
benzodiazepine may cause respiratory depression24.
Benzodiazepine intravenous (IV), intramuscular, oral,
intranasal, or rectal can be used to abort the crisis but
is not recommended for prophylactic treatment1,25
(Table 3).
In a systematic review about the use of AEDs for on-
going convulsive seizures, including epileptic status, they
analyzed the efficacy and safety of using Midazolam
(MDL), DZP, lorazepam (LZP), phenytoin (PHT), pheno-
barbital (PB), and paraldehyde, concluding that IV or
rectal LZP is as effective or more effective than DZP26.
Oral MDL is more effective than rectal DZP, and the in-
tranasal form is as effective as IV DZP. Oral or nasal MDL
is the treatment of choice when there is no access to IV
or for home management by the parents26-28 (Table 4).
 C. Aguirre-Velázquez, et al.: Febrile seizures, diagnosis, and treatment

Table 2. Initial management of FeS at home22

1. Remain calm. Loosen clothes, especially around the neck. Protect the child from injury during the FeS

2. Do not introduce fingers or objects, or obstruct the mouth of the child. Do not force the mouth to open

 f the publisher.   © Permanyer 2019

3. Once the seizure has passed, make sure the child is in an adequate lateral position for recovery, where the airway is not obstructed

4. Observe the type of seizure or movement and its duration

5. Explain that after the seizure the child will be asleep for up to 1 h

6. In the case of recurrent FeS, administer a emergent initial therapy drug if there is a tonic‑clonic seizure that lasts > 5 min

7. Administer oral or nasal midazolam as first‑line treatment. Rectal diazepam 0.5mg/kg when midazolam is not available

8. Seek medical attention if the seizure lasts >5 min. Contact your pediatrician or other health professional

9. The parents of children at high‑risk for recurrence should receive the necessary training.

FeS: febrile seizures

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Table 3. Emergent initial therapy for acute (ictal) management of FeS in children 25
Antiepileptic Administration route Dose

Midazolam (15mg/3 ml vial) Oral 0.5 mg/kg, repeat in 10 min if necessary

Nasal 0.2‑0.5 mg/kg divided in each nostril, maximum 10 mg
IV 0.2 mg/kg or 0.15mg/kg by infusion
IM 0.2mg/kg or 5‑10 mg, sole dose

Diazepam (10 mg/3 ml vial) Rectal 0.5mg/kg

IV 0.3‑0.5 mg/kg, bolus speed of 5mg/minute, repeat in 10 min if necessary
0.01 mg/kg/min by infusion

Lorazepam (2 mg/3 ml vial) IV 0.1 mg/kg (maximum 4 mg in children heavier than 40 kg)

IV: intravenous, IM: intramuscular, Oral Midazolam is more effective than rectal Diazepam, and the intranasal route is equally effective as IV diazepam (Level I evidence),
Oral or nasal Midazolam is the treatment of choice when there is no access to IV or for home management by the parents (Level III evidence), FeS: febrile seizures

Table 4. SF treatment in a hospital environment

1 Assess A, B, C

2 Open the airway, aspirate secretions, maintain adequate ventilation, and ensure perfusion

3 Obtain venous access

4 Monitor vital signs (heart rate, respiratory rate, arterial pressure, and pulse oximetry)

5 Administer oxygen, if necessary (SaO2 < 90%)

6 Administer an intravenous bolus of Diazepam at a dose of 0.5 mg/kg and a maximum infusion speed of 5 mg/min,
discontinue when the seizure stops. The dose can be repeated, if necessary, after an interval of 10 min (consider that
Diazepam takes about 10 m to reach an effective concentration in the brain, even using intravenous administration). Other
benzodiazepines, like Lorazepam, are equally effective

7 Monitor excess base and glucose in blood

8 If the convulsion does not subside, ask for advice from a specialist to determine treatment

9 The Febrile Status Epilepticus must be treated under the same treatment considerations as pediatric Afebrile Status
Epilepticus

10 The measures taken for fever reduction must begin after benzodiazepine administration, as long as it does not interfere
with routine attention

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 Rev Mex Neuroci. 2019;20
Hospitalization criteria
Independently of the length of the seizure, the patient
must be assessed by medical history, documentation
of SFeS history, epilepsy, immunizations, duration of
the seizure, postictal phase, and any focal symptom4.
The American Academy of Pediatrics recommends that
hospitalization is unnecessary for clinically stable pa-
tients older than 18 months, without signs or symptoms
that require diagnostic studies29. Parents are trained
for  home management (Table  1)22. Hospitalization
recommended for children younger than 18 months, for
observation and possible lumbar puncture. Patients
previously diagnosed with recurrent FeS do not require
hospitalization12,29 (Table 1).
5. Is long-term antiepileptic treatment
required for FeS?
Simple FeS, SFeS
A systematic review that assesses the use of conser-
vative and antipyretic measures concluded that there
is no evidence that they have any usefulness in pre-
venting SFeS reccurences30. There is no evidence for
the clinical usefulness of continuous or intermittent use
of antiepileptic drugs (oral or rectal DZP, PB,
diphenylhydantoin, or valproate) in SFeS23. There is no
evidence that continuous or intermittent treatment with
antiepileptic drugs in SFeS can prevent the subsequent
development of epilepsy6,18,31.
Complex FeS CFeS
Long-term routine prophylaxis with antiepileptic drugs
is not recommended since there is no clear information
about their use in complex FeS23. There is evidence
that supports intermittent use of PB and antipyretics,
clobazam, or rectal DZP, to prevent recurrence of com-
plex FeS. However, the information does not clearly
distinguish simple from complex seizures, and there
may be bias due to the relative incidence of both types
of seizures32.
Regular use of antiepileptic drugs can be considered
for patients with long or repetitive FeS despite the pro-
phylactic use of DZP33. Carbamazepine and PHT are
not effective for preventing the recurrence of FeS and
thus, should be avoided24.
A prospective study, carried out in 2014, compared
the efficacy of intermittent use of clobazam versus DZP
to prevent recurrence of FeS (both simple and
100
complex), as well as the adverse effects. The results
showed that clobazam is safe, effective, requires a
lower dose, and has fewer adverse effects than DZP,
 f the publisher.   © Permanyer 2019
suggesting it as a good alternative for preventing recu-
rrence of FeS34. In addition, in 2017, another group
demonstrated a significant difference in the prevention
of recurrence after treatment with levetiracetam versus
no treatment after 50 weeks14 Table 5.
6. What paraclinical tests are necessary
after the first FeS?
Diagnostic tests (analytic, electroencephalogram
(EEG), and cerebral imaging) are usually unnecessary
and, currently, are not routinely recommended for pa-
No part of this publication may be reproduced or photocopying without the prior written permission o
tients with simple FeS15,17.
Electroencephalogram
Not indicated for the assessment of a neurologically
healthy child with simple FeS6. In a focal and/or prolon-
ged convulsion, it is recommended to carry out an EEG
and neurologic follow-up, due to the greater risk of deve-
loping epilepsy. A  short, generalized convulsion that is
repeated twice in 24 h is, by definition, a complex con-
vulsion, but it is also not necessary to conduct an EEG
unless the neurologic examination shows alterations.
The EEG does not allow prediction of which children
are at greater risk to suffer new seizures. Epileptiform
alterations in the EEG are relatively frequent in children
with FeS. Few retrospective, cohort, case and control
studies show a possible association between the epi-
leptiform discharges in the EEG and a high risk of afe-
brile/epileptic seizures35. The EEG has low sensitivity
in children under 3 years of age, after an unprovoked
convulsion35-37.
Laboratory tests
They can be considered under certain clinical condi-
tions but are not routinely carried out in a child after his
first FeS with an evident source of infection. They will
only identify the source of the child’s fever and are not
necessary as part of the assessment of the seizure6,17.
Neuroimaging
Highly recommended for patients with FeS that do
not regain complete consciousness in hours, with pro-
longed Todd’s paralysis (post-critical), or with other
 C. Aguirre-Velázquez, et al.: Febrile seizures, diagnosis, and treatment

Table 5. Long‑term treatment for simple FeS and Complex SF

Data Level of Evidence Recommendation

Intermittent antipyretics, zinc, pyridoxin, or antiepileptic drugs are not useful for the I A

 f the publisher.   © Permanyer 2019

prevention of recurrences of FeS

The continuous or intermittent use of antiepileptic drugs, such as DZP, PHT, PB, or VPA, I A
is not useful

The continuous or intermittent use of antiepileptic drugs in FeS does not prevent the I A
subsequent development of epilepsy

The regular use of antiepileptic drugs can be considered for patients with prolonged or I, II B
repeated FeS despite the prophylactic use of diazepam

Levetiracetam could work as an antiepileptic drug for prevention of recurrence of FeS III C

Clobazam is safe, effective and requires a lower dose than diazepam II‑III C

Carbamazepine and phenytoin are not effective for the prevention of recurrence of FeS II B
and should be avoided

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Children with FeS should receive the complete recommended immunization program for I A
their age

FeS: febrile seizures, DZP: diazepam, PHT: phenytoin, PB: phenobarbital

Table 6. Indications to carry out paraclinical tests in FeS

Data Evidence level Recommendation

Conducting analytic tests routinely (CBC, blood glucose, electrolytes, calcium, and III C
magnesium), are not useful for the management of children with FeS

Routine cerebral imaging tests are not recommended for children with SFeS or CFeS. II‑III C
Neuroimaging is indicated for patients that do not regain complete consciousness in
hours, with prolonged Todd’s paralysis (post‑critical), or other focal alterations found in
the neurologic exploration

Routine EEG is not recommended for children with SFeS II B

EEG in the case of focal FeS to discard seizures unleashed by fever III R‑PPE

FeS: febrile seizure, SFeS: simple febrile seizure

focal alterations found in the neurologic exploration15,16 after a SFeS is 1.5-2.4% while for complex FeS it is
(Table 6). estimated to be 4-15%39, and in the case of focal FeS
up to 29%40.
7. What are the risk and recurrence factors
for SFeS and CFeS? 8. When should cases of SFeS and CFeS
36 be referred to the neuropediatrician?
Population risk of a FeS is 2.7-3.1% . The reported
risk of recurrence after a first FeS is 27-32% of which FeS is a benign condition; they are not associated
75% happen during the 1st  year after the first crisis18. with neurodevelopmental damage nor do they cause
The risk of recurrence is similar between simple and secondary neurologic consequences6. The only asso-
complex FeS38. The risk factors for FeS are enlisted in ciation found was between repeated FeS and a delay
Table  7. The frequency of recurrence is 10% among in language development; thus, new studies and lon-
patients with no risk factors; 25-50% in the presence ger-term follow-up will be required42. Hippocampal mal-
of 1-2 risk factors; and 50-100% when there are three formations do not appear to be a consequence of FeS
or more risk factors15. The risk of developing epilepsy but can be a predisposing factor for the development
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 Rev Mex Neuroci. 2019;20

Table 7. FeS risk factors15,35,41

Recurrence after an initial FeS Factors for developing epilepsy

Early onset (<12 months) Age during the first FeS: <12 months or >37 months

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Epilepsy in first‑grade family members

FeS in first‑grade family members Family history of epilepsy

Frequent febrile illnesses Fever lasting <1 h before the seizure

Temperature in the lower range of fever at the moment of the FeS

Fever lasting < 1 h before the seizure. Low Apgar at 5 min

History of at least 1 CFeS

Febrile status epilepticus

Multiple seizures in 24 h

Focal seizures

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Neurologic abnormalities (retarded development or CCP)

Focal epileptogenic discharges

CFeS: complex febrile seizure, FeS: febrile seizure

of epilepsy7. Providing the family with information about
the illness and the risk of recurrence during the illness
or in the future should be carried out by the pediatri-
cian. However, if the clinical history shows >2 risk
factors of seizure recurrence or the patient fulfills the
requirements for complex FeS, we recommend he be
referred to the neuropediatrician.
Conclusion
FeS is an age-dependent phenomenon, related to
individual genetic predisposition and with a special vul-
nerability of the developing CNS to the effects of fever.
The continued or intermittent prophylactic treatment
with antiepileptic drugs does not reduce the risk of
subsequent epilepsy and, although it is effective to
reduce recurrences, its toxicity surpasses the few risks
of FeS.
Informed and responsible parental counseling are the
greatest contribution that the physician can make for
the care of children with FeS.
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REVIEW ARTICLE

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Clinical guideline: epilepsy in pregnancy and women of
childbearing age
Perfecto O. González-Vargas1, Yamil Matuk-Pérez2, José L. Sosa Hernández3, Gerardo Quiñones-Canales4,
Sandra E. Silva-Sánchez5, Gerónimo Aguayo-Leytte6, Sergio Medina-Benitez7, Jorge M. Ibarra-Puig8,
María del Consuelo Loy-Gerala9 and Elvira Castro-Martínez10
1Hospital Perinatal Mónica Pretelini, Toluca, Mexico State; 2Hospital General de Querétaro, Querétaro; 3Hospital General de Alta Especialidad
Dr.  Juan Graham Casasus, Villahermosa, Tabasco; 4Hospital Dr.  Santiago Ramón y Cajal, ISSSTE, Durango; 5Hospital Central del Estado de
Chihuahua, Chihuahua; 6Hospital Miguel Hidalgo, Aguascalientes, Aguascalientes; 7Hospital General ISSSTE Zacatecas, Zacatecas; 8Instituto
Nacional de Perinatología Ciudad de México; 9Hospital General de Puebla “Dr. Eduardo Vázquez Navarro,” Puebla; 10Hospital General Dr. Manuel

No part of this publication may be reproduced or photocopying without the prior written permission o
Gea González e Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco“. Mexico City, Mexico.

Abstract
Childbearing-aged and pregnant women undergo physiological modifications that make them think in a particular way about
epilepsy and the management of taking antiepileptic drugs. These guidelines address both the effects of epilepsy in the
gynecological, obstetric, and perinatal aspect of the woman, with a series of recommendations based on evidence-based
medicine.

Key words: Epilepsy. Woman. Childbearing age. Pregnancy.

Introduction What are the recommendations for

Epilepsy in reproductive-aged and pregnant women
entails a series of reproductive changes, such as inte-
raction of antiepileptic drugs (AEDs) with contracepti-
ves, changes in fertility, changes inherent to pregnancy
and hormonal modification, a series of risks for conge-
nital malformation caused by AEDs, and obstetric and
lactation modifications that require knowledge and re-
commendations necessary for an adequate control of
epileptic seizures (ES) in women with epilepsy (WWE).
This is the main reason for the PPE to write these
guidelines.
childbearing-aged WWE?
According to statistics published by the National
Institute of Statistics and Geography, in Mexico, there
are 61.4 million women, and they represent more than
half of the nation’s population (51.4%)1. Many of them
are of childbearing age and have high probabilities of
becoming pregnant.
The AEDs that are enzymatic inducers (EI-AED)
(PHT, TPM, PB, OXC, and CBZ) directly modify hormo-
ne concentrations. Virtual payment address (VPA) is
associated with an increase in serum testosterone

Correspondence:
Perfecto Oscar González-Vargas
Hospital Perinatal Mónica Pretelini
Toluca, Mexico State, Mexico
E-mail: ogv1804@yahoo.com
Yamil Matuk Pérez Date of reception: 31-01-2019 Available online: 12-04-2019
Hospital General de Querétaro, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):104-109
E-mail: dryamilmatuk@hotmail.com DOI: 10.24875/RMN.M19000030 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

104

and risk of hirsutism, central cause amenorrhea, hype-
randrogenemia, and infertility. The risk of infertility can
be up to 10% greater than those of the general popula-
tion and is greater with polytherapy, with temporal lobe
epilepsy, and the use of PB2. AEDs have a bidirectional
relationship with hormonal contraceptives3. There are
variations in serum concentration of AED, depending on
the mechanism of action of the drug and the type of
contraceptive4. According to the WHO and the CDC,
progesterone and combined oral contraceptives, as well
as contraceptive patches and vaginal rings are not re-
commended as first-line contraceptives for women that
take EI-AED. Medroxyprogesterone and levonorgestrel
implants can be used by women who take EI-AED. It is
recommended to avoid combining LMT and contracep-
tive methods that contain estrogens, due to the risk of
loss of control of ES. The IUD is recommended as the
contraceptive of choice for WWE5.
Should AED treatment be suspended in
pregnant WWE (PWWE)?
A review published by the AAN in 2009, did not find
studies with high levels of evidence that indicate
changes in the frequency of ES during pregnancy, but
information is limited. There is between 84 and 92%
probability that the pregnancy will continue normally
with proper control if the WWE has been seizure-free
for 9-12 months before getting pregnant6.
For PWWE, the use of AED in monotherapy and at
low doses is suggested. Preferably, AEDs with a grea-
ter risk of teratogenicity should be avoided, such as
VPA, which has been demonstrated to increase this
risk up to 13.8%7. The greatest risk of congenital mal-
formations is considered to be during the first trimester
of pregnancy, so once neural tube formation is comple-
ted (second and third trimester of pregnancy), the con-
traindication to suspend VPA is relative, and generally,
the change of an AED during pregnancy is not recom-
mended due to the risk of uncontrolled ES8. PHT, PB,
and TPM have been demonstrated to have an interme-
diate risk of congenital malformations, whereas LTG,
CBZ, and LEV show low rates of such malformations7.
The frequency of ES is increased when patients dis-
continue the use of their AED, so patients must have
control of the ES and discipline in taking their AED. It
is frequent that PWWE suspend their AED for fear of
the risk of congenital malformations of the fetus, due
to nausea and vomiting associated to pregnancy, the
pharmacokinetic changes of the AED, and insomnia; it
is even frequent that treating physicians suspend AED,
P. O. González-Vargas, et al.: Epilepsy in women
even in spite of this being counterproductive, since it
has been demonstrated that during a ES the fetus su-
ffers anoxia, fetal tachycardia, uterine contractions, in-
 f the publisher.   © Permanyer 2019
creased risk of preterm labor, and low birth weight. One
Canadian study demonstrated that up to 30% of neu-
rologists are unaware of the obstetric complications of
PWWE. Thus, we can infer that the OB/GYN is also
unaware of treatment complications for PWWE9-11.
A planned pregnancy demonstrates that there is be-
tter control of the ES and shows apparent improvement
in the obstetric complications of labor.
Which AED should be used for the
PWWE?
No part of this publication may be reproduced or photocopying without the prior written permission o
There is no first choice AED for the PWWE, and the
AED must be adequate for the type of epilepsy suffered
by the patient. There have been major congenital mal-
formations (CM) described in products of those PWWE
that took EAD during their pregnancy. In these cases,
structural CM have been reported, such as hypospa-
dias, neural tube defects (NTD), congenital cardiopathy,
and cleft palate. Long-term cognitive teratogenic effects
are also observed in children whose mothers took AED
during pregnancy, although the studies are not conclu-
sive7. The risk of CM with AED varies depending on the
type of AED used, the dose, and whether it was used
in mono or polytherapy. In general, the average risk of
CM with AED varies between 4 and 14%, while in the
open population risk of CM is about 3%. The risk of CM
with CBZ is about 2.2%, LMT is 3.2%, PHT is 3.7%,
and it is >13% for VPA. It must be pointed out that
combining CBZ with LMT has a 3% risk of CM. When
polytherapy includes VPA, the risk of CM can increase
to up to 13.8%, especially for NTD. For WWE who have
had a product with a CM, the risk of CM in subsequent
pregnancies with the use of AED increases up to
16.8%. During pregnancy, serum levels of CBZ, LMT,
PHT, and LEV are reduced; thus, serum concentrations
of these AED must be determined before conception
and during the first trimester of pregnancy. In develo-
ped countries, the most commonly used AED are LMT,
and LEV, and in our Country, CBZ is considered to be
the most commonly used as well as, paradoxically,
VPA11-13.
What is the approach and treatment for
uncontrolled ES in PWWE?
The presence of ES during pregnancy could be due
to three circumstances: uncontrolled ES in PWWE,
105
 Rev Mex Neuroci. 2019;20
debut of ES, and obstetric problems. The first of these
circumstances is the most common, and the main re-
ason is the lack of compliance with the antiepileptic
treatment; this commonly happens to PWWE, and so
one must investigate and persuade therapeutic adhe-
rence. Other factors must be taken into consideration,
such as genetic factors, changes in serum concentra-
tions of AED, sleep suppression, stress, and
hyperemesis gravidarum induced by pregnancy. The
management of uncontrolled ES in PWWE must follow
the same protocol as that of any other patient with epi-
lepsy. Despite the seriousness of ES, they do not in-
crease in frequency in PWWE.
Once the ES are controlled, one must restart the AED
the patient was taking, if the motive was lack of disci-
pline. In this case, adjust the AED treatment depending
on the type of epilepsy and with the adequate dose14,15.
What are the obstetric complications for
PWWE?
There is a dilemma in terms of the increase in obstetric
risk in PWWE. Previously, there was no evidence that
confirmed it, but recent studies have demonstrated a risk
of presenting preeclampsia, maternal infection, placental
abruption, emergency cesarean sections, risk of fetal
death, abortions, neonatal infections, risk of neonatal
asphyxia with Apgar lower than 5 points in the 1st min,
neonatal hypoglycemia, and neonatal hypoxia16,17.
What is the utility of folic acid and
Vitamin K in PWWE?
One of the most frequent congenital malformations
of the CNS is NTD. Folate receptors are critical for fetal
neural tube and neural crest formation. Folate deficien-
cy causes a reduction in the mitotic capacity of neural
crest or neural tube cells. Folic acid is the synthetic
form of folate (Vitamin B9). Mexico is one of the coun-
tries with the greatest frequency of NTD. The worldwide
recommendation (WHO) is that childbearing-aged wo-
men supplement with 0.4-0.8  mg of folic acid daily
since it is calculated that 75% of them do not consume
the optimal dose of folic acid. However, for NTD pre-
vention, the dose is greater. There is no consensus on
the larger dose; the objective is to achieve high tissue
levels of folic acid in the 1st weeks of pregnancy, during
the time that the neural tube is formed.
As a large percentage of WWE have unplanned preg-
nancies, it is recommended to take folic acid daily; it
should be taken for at least 1 month before conception
106
if pregnancy is planned and should continue at least
during the first trimester. It is considered that, in addition
to the reduction of NTD, the development of other mal-
 f the publisher.   © Permanyer 2019
formations, such as cleft palate, can also be reduced.
If there is a history of an infant with NTD, the daily
recommendation is 4 or even 5  mg of folic acid, since
there are no adverse effects related to this vitamin. It has
been calculated that this results in a reduction in NTD of
up to 85%. This recommendation is especially important
for WWE that take polytherapy or use VPA18-20.
As for Vitamin K, it was previously proposed that by
giving doses of the said vitamin to PWWE during the third
trimester, you could prevent intracranial hemorrhaging in
neonates. It was thought that PWWE that took enzymatic
inducing AED (CBZ, PG, and PHT) had increased risk of
No part of this publication may be reproduced or photocopying without the prior written permission o
this hemorrhagic complication in their products. In a
study of more than 600 patients, it was demonstrated that
there was no increase in the risk of hemorrhages in the
products of PWWE that took these AED compared to
controls; thus, there is not sufficient evidence to recom-
mend the use of Vitamin K in PWWE7,21.
Is breastfeeding safe in WWE?
The benefits of maternal breastfeeding are well de-
monstrated, it’s even beneficial for the mother since it
reduces the risk of postpartum depression as well as
generating a psychologic bond with the infant conver-
sely, the BBB in neonates has not been completely
formed; thus, it is susceptible to drugs. Therefore, there
must be an adequate risk-benefit analysis.
Patients get confused because they receive informa-
tion from the obstetrician, the neonatologist or the neu-
rologist, this in conjunction with the social concept that
the WWE cannot breastfeed. Studies show that breas-
tfeeding has geographical variations, at educational
levels, and is lower among WWE that take LMT or are
receiving polytherapy.
The concentration of an AED in maternal milk is de-
pendent on the serum levels of the drug and the me-
tabolism of the infant. Although there are mathematical
formulas to calculate AED concentrations in maternal
milk, it is not practical to use this method in daily prac-
tice. Furthermore, the AED concentrations are different
and individual for each AED.
There are studies that aim to investigate the cognitive
effects on children exposed to AEDs during breastfee-
ding, but the results are contradictory.
The recommendations from the AAN, in 2009, about
breastfeeding were not conclusive, and later studies have
not demonstrated the existence of contraindications for
 P. O. González-Vargas, et al.: Epilepsy in women

breastfeeding by WWE. What is clear is that the serum sleep patterns. The infant should be observed to deter-
levels of AED that the WWE is taking must be measured, mine excessive sleepiness, and both the benefits to the
that there is the option of supplementary feeding if se- mother of avoiding postpartum depression and the harm

 f the publisher.   © Permanyer 2019

condary effects are suspected for the infant, and that that sleep deprivation may cause to the WWE must be
breastfeeding is preferred when the newborn has long assessed22-24.

Evidence tables and recommendations

Evidence and PPE recommendations Level/recommendation

There is increased infertility and sexual dysfunction in WWE. III

The frequency of gynecologic disorders is greater in WWE. III

WWE that take hormonal contraceptives must be under medical surveillance. III

Health professionals must be aware that WWE have reduced fertility and libido. R‑PPE

No part of this publication may be reproduced or photocopying without the prior written permission o
The presence of polycystic ovaries, hirsutism, galactorrhea, and central cause amenorrhea is R‑PPE
more frequent in WWE.

IUD is recommended as a contraceptive method for WWE. R‑PPE

Evidence and PPE recommendations Level/recommendation

There are no modifications in ES in WWE during pregnancy if the patient does not suspend treatment. III

Planned pregnancy for WWE reduces the risk of ES during pregnancy. III

Most pregnancies in WWE are not planned; thus, it is recommended to provide preconception II
information to reproductive‑aged WWE about the effects of AED on the infant.

Uncontrolled ES occur due to discontinued AED treatment, basically due to a lack of awareness about I
the risks of teratogenicity of these drugs.

WWE can have a normal pregnancy, especially if before conception (at least 9 months) there is good R‑PPE
control of ES.

WWE must not suspend their antiepileptic treatment during pregnancy. R‑PPE

Changing the epileptic treatment scheme during pregnancy is not recommended due to the risk of R‑PPE
uncontrolled seizures.

Management of WWE must be multidisciplinary, and all physicians must be aware of the risk of R‑PPE
teratogenicity from AED.

Determining the serum concentrations of AED during the first trimester of pregnancy is recommended. R‑PPE
There is no consensus for the following trimesters.

Evidence Level

There is no AED of choice for the PWWE, and the adequate AED for the subtype of epilepsy suffered by the patient must be used. I

Monotherapy and lower effective therapeutic doses are preferable. II

After the first trimester of pregnancy, there is no evidence that the use of AED poses a greater risk of CM. II

The risk of CM with AEDs varies between 2% and 13.8% and occurs more often with VPA. II

There is no sufficient data on the safety of the new AED and the risk of CM. II

A reduction in the dose of AED in PWWE must be after having been seizure free for a minimum of 3 years. II

The ideal AED must be used for the type of epilepsy suffered by the PWWE. R‑PPE

107
 Rev Mex Neuroci. 2019;20

All AEDs have some risk of CM. R‑PPE

The knowledge of the risk of CM is greater for the classic AED than for the new AED. R‑PPE

 f the publisher.   © Permanyer 2019

The main risk for CM with AED happens during the first trimester of pregnancy; during the rest of the pregnancy, risks are low. R‑PPE

The use of VPA is not recommended for PWWE; if used, it must be at the lowest therapeutic dose. R‑PPE

For WWE that plan to get pregnant, using CBZ, OXC, LEV, or LMT is recommended. R‑PPE

Evidence and PPE recommendations Level/recommendation

The main cause of ES during pregnancy is due to a lack of pharmacologic discipline. II

If focal neurologic data exist, the PWWE must undergo a profound investigation (MRI, EEG, and NS) I

Control of ES during pregnancy must adhere to the same recommendations as conventional ES. III

The frequency of ES does not increase in PWWE. III

No part of this publication may be reproduced or photocopying without the prior written permission o
It is recommended to insist that the PWWE be disciplined in taking the antiepileptic treatment. R‑PPE

Management of ES in PWWE must adhere to the same guidelines as in non‑pregnant patients. R‑PPE

One must pay attention to the neurologic integrity of the PWWE that has ES. R‑PPE

The frequency of ES in PWWE is the same as in the epileptic patient, but its important to know how to R‑PPE
diagnose it due to its gravity.

Evidence and PPE recommendations Level/recommendation

The risk of presenting obstetric complications (placenta previa, preterm labor, cesarean section, and III
preeclampsia) during pregnancy in the PWWE, does not appear to differ from the rest of the obstetric
patients.

The risk of presenting complications to the infant (neonatal hypoxia and hypoglycemia, and risk of III
infection) of the PWWE, does not appear to differ from the rest of the obstetric patients.

There is no certainty about the increased risk of obstetric complications in PWWE. R‑PPE

There is no certainty about the increased risks to a newborn child of a WWE in relation to neonates R‑PPE
born of a non‑epileptic mother.

Its recommended to keep close vigilance on PWWE during gestation, labor and puerperium, faced with R‑PPE
the possible risk of complications. The same must apply for the children of a PWWE.

Evidence and PPE recommendations Level/recommendation

Folic acid is necessary for the formation of the neural tube. I

Daily ingestion of folic acid in reproductive‑aged women is much lower than the daily I
recommended nutritional requirement.

A daily dose of 0.4‑0.8 mg of folic acid reduces the risk of NTD. In WWE with a history of NTD, I
use of polytherapy or VPA, greater doses are required.

There is no evidence to support that prophylactic doses of Vitamin K in PWWE protect their III
neonates from intracranial hemorrhages.

All PWWE should consume 0.4‑0.8 mg of folic acid every day. R‑PPE

All WWE and a history of NTD, polytherapy, and VPA use must consume 4‑5 mg of folic acid daily R‑PPE
to reduce the risk of NTD.

Prophylactic doses of Vitamin K are not recommended for PWWE. R‑PPE

108

Evidence and PPE recommendations
Evidence
The benefits of breast milk are accepted worldwide.
The concentration of AED in breast milk of a WWE, essentially depends on the serum concentration of the drug.
Unless there is clinical evidence of neonatal secondary effects (sleepiness and others), WWE should not
suspend breastfeeding.
WWE must breastfeed without clinical contraindications unless the neonate presents secondary effects.
One must be careful about breastfeeding when WWE are taking PB, BZD, or are undergoing polytherapy.
Unless there is clinical evidence of neonatal secondary effects (sleepiness and others) breastfeeding
should not be suspended in WWE.
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 Revista Mexicana de Neurociencia

REVIEW ARTICLE

 f the publisher.   © Permanyer 2019

Clinical guideline: status epilepticus in children and adults
Alejandro Olmos-López1, Jorge Ibarra-Aguilar2, José O. Cornelio-Nieto3, Luis A. Ocaña-Hernández4,
Mario A. Márquez-Amaya5, Norberto Luna-López6, Juan C. Reséndiz-Aparicio7 and
Ildefonso Rodríguez-Leyva8
1Hospital General de Cuernavaca “Dr. José G. Parres,” Morelos; 2Hospital del Niño del DIF, Pachuca, Hidalgo; 3Hospital de Alta Especialidad del
Niño “Dr. Rodolfo Nieto Padrón” , Villahermosa,Tabasco; 4Unidad Médica de Alta Especialidad H.E.No.71, IMSS Torreón, Coahuila; 5Hospital Regional,
Delicias, Chihuahua; 6Facultad de Medicina de Minatitlan, Veracruz; 7PPE, Instituto Nacional de Neurología y Neurocirugía Dr.  Manuel Velasco
Suárez y Hospital Psiquiátrico Infantil Dr. Juan N. Navarro, Mexico City; 8Hospital Central “Dr. Ignacio Morones Prieto” San Luis Potosí, San Luis
Potosí, Mexico

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
A generalized epileptic seizure lasting 5 or more minutes, or the presence of two or more seizures without recovering cons-
ciousness within 30 min, or a focal seizure that persists for >10 min, or with altered consciousness lasting for 60 min or more
is called status epilepticus (SE). It can be classified into generalized and focal and motor and non-motor. Its etiology may or
may not be recognized. The electroencephalographic pattern shows focal or generalized persistent epileptic activity. It is a
dangerous situation, which requires algorithmic management from the time it is detected in the emergency room and if re-
quired, in intensive care. In-hospital management would include the initial ABCDE, hypertonic glucose solution, and thiamin;
if hypoglycemia was detected. Lorazepam (midazolam [MDZ] or diazepam) to stop seizures, followed by phenytoin, valproa-
te, or levetiracetam in impregnation and maintenance. If the SE persists for more than an hour, the patient will be admitted
to an intensive care unit with intubation and continuous administration of MDZ, propofol or thiopental with continuous moni-
toring. If it does not yield with two drugs, it is called refractory epileptic status, and if it continues for 24 h or more, it is re-
cognized as super-refractory. A third of patients die.

Key words: Status epilepticus. Seizures. Focal. Generalized. Motor. Acute treatment.

1. How is status epilepticus (SE) defined?
The ILAE proposes an operational definition as a
generalized epileptic seizure in children and adults that
lasts 5 or more minutes, two or more seizures without
recovering awareness within 30 min (here, we include
the majority of generalized epileptic seizures). It is a
condition that results from a failure in initiating the in-
hibitory mechanisms responsible for terminating an epi-
leptic seizure and the persistence of mechanisms that
favor the extension of a seizure.
A generalized motor SE is defined as 5 or more mi-
nutes of generalized motor activity, or recurrent seizure
without returning to baseline. These represent 45-75%
of all epileptic states.
There is insufficient information about focal SE with
altered level of awareness. However, it has been pro-
posed to define it as an epileptic seizure that lasts
10  min or two or more epileptic seizures without re-
covering a state of awareness within 60 min. For ab-
sence SE, there is not enough scientific evidence to
define the times, but it has been proposed that it be

Correspondence: Date of reception: 01-02-2019 Available online: 12-04-2019

Ildefonso Rodríguez-Leyva Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):110-115
E-mail: ilrole@yahoo.com.mx DOI: 10.24875/RMN.M19000031 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

110
 A. Olmos-López, et al.: Status epilepticus in children and adults

Table 1. Axis 1 – SE classification Table 3. Axis 3 – Electroencephalographic correlation

A. With motor symptoms 1. Location: generalized (including bilateral synchronic
A.1 Motor SE (generalized tonic‑clonic SE) patterns), lateralized, bilateral, independent, and multifocal

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A.1 a Generalized motor SE 2. By electric pattern: periodic discharges, rhythmic delta
A.1 b focal onset with secondary bilateral spreading (focal activity, or subtypes of a paroxysmal pattern of spike‑wave
to bilateral) and sharp‑wave
A.1 c unknown onset, focal, or generalized 3. By morphology: wave acuteness, triphasic waves, absolute
A.2 Myoclonic SE (predominance of myoclonic seizures) and relative amplitude, and polarity
A.2 a with a comatose state
A.2 b without a comatose state
A.3 Focal motor
Table 4. Axis 4 – Age
A.3 a Repetitive focal motor seizures (Jacksonian)
A.3 b Continuous partial seizure Neonatal: 0‑30 days
A.3 c Versive state
A.3 d Ocular clonic state Lactating: 1 month‑2 years
A.3 e Ictal paralysis
A.4 Tonic SE Infancy: 2 years‑12 years
A.5 Hyperkinetic SE
Adolescence and adulthood: 12 years‑59 years
B. Without motor symptoms (Non‑motor or non‑convulsive
Senile: > 60 years

No part of this publication may be reproduced or photocopying without the prior written permission o
SE ‑ NCSE)
B.1 NCSE with coma (subtle SE)
B.2 NCSE without coma
B.2 a Generalized Axis 2 (etiology): on occasion, it is difficult to deter-
B.2 a.a Typical absence SE
mine the cause of the SE, so they are divided into two
B.2 a.b Atypical absence SE
B.2 a.c Myoclonic absence SE groups: known and unknown cause (Table 2).
B.2 b Focal Axis 3 (electroencephalographic correlation): most of
B.2 b.a Without loss of awareness (Continuous aura with
autonomic, sensory, olfactory, visual, auditory,
the first or second level hospitals do not have elec-
psychological, and emotional symptoms) troencephalogram (EEG) equipment, but if the study
B.2 b.b Aphasia can be carried out, it should be done immediately. Ba-
B.2 b.c With impaired awareness
B.2 c. Unknown onset, focal or generalized sed on descriptive series and consensus, we can des-
B.2 c.a Autonomic SE cribe six electrical activity patterns (Table 3).
SE: status epilepticus. Axis 4 (age): important axis since the clinical mani-
festations of SE can vary (Table 4).

Table 2. Axis 2 – Etiology 3. What are the pre-hospitalization

Known cause (symptomatic) measures in SE management?
Acute
Remote Pre-hospitalization measures begin with the family
Progressive
SE in defined electroclinical syndromes
and generally, with paramedics that will help maintain
the airway permeable, avoid trauma (placing the patient
Of unknown cause (cryptogenic)
in a place where he will not get hurt), and place the
SE: status epilepticus head on its side. Ideally, the paramedic or extra-hospital
first contact physician must be prepared to give car-
diopulmonary resuscitation if the patient presents asys-
defined as an absence epileptic seizure lasting 10- tole and/or apnea.
15 min or more. The paramedic or first contact physician can admi-
nister a standard dose (Table  5) diazepam or loraze-
pam by intrarectal, nasal, intramuscular, or intravenous
2. How is SE classified?
administration.
It can be classified based on four main axes, which As soon as the situation is stabilized in the quickest
cannot always be determined: semiology, etiology, manner possible, the patient must be sent to a hospital
electroencephalographic correlation, and age. that, ideally, will have an adequate service of emergen-
Axis 1 (semiology): two criteria are considered: the cy care and intensive care.
presence or absence of motor symptoms and signs and Steps:
the degree (qualitative or quantitative) of altered awa- – Immediate protection of the airway, ensure gaseous
reness (Table 1). exchange and place the head properly (avoid snoring
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 Rev Mex Neuroci. 2019;20

Table 5. Benzodiazepines In SE Others:

Doses in adults Doses in children – Phenytoin (fosphenytoin): 20 mg/kg IV to 50 mg/min/
physiological solution
Lorazepam 0.1 mg/kg IV up 0.04 mg/kg IV

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to 4 mg – Phenobarbital: 20  mg/Kg IV (5-10  mg/kg can be
added)
MDZ 0.2 mg/kg IM or Heavier than 40 kg: 0.2 mg/kg
IV up to 10 mg up to 10 mg – Valproate (VPA): 20-40 mg/kg IV
Lighter than 40 kg: 0.2 mg/kg – Levetiracetam: 60 mg/Kg (1-3 g) IV
up to 5 mg
– Lacosamide: 100 mg IV every 6 h
Diazepam 0.15 mg/kg IV IV 0.3 mg/kg up to 5 mg in
up to 10 mg IV younger than 5 years and
10 mg in older than 5 years
Rectal: 0.5 mg/kg. From 1 to
6. What is the second-line pharmacologic
3 years 5 mg, older treatment to manage generalized motor
than 3 years 10 mg SE?
standard dose

SE: status epilepticus, MDZ: midazolam

Second-line drugs or urgent control therapy are
added when SE has been established, that is, when

and lingual obstruction), and if necessary and avai-
lable, administer oxygen.
– Monitor vital signs.
– Test for glycemia using a Destrostix, if possible.
– Administer a standard dose (child or adult) of benzo-
diazepine by rectal, nasal, intramuscular, or intrave-
nous administration.
4. What are the initial measures that must
be taken for the management of SE?
0-5 min:
– ABCDE.
– Duration.
– Oxygen.
– Monitorization.
– Determination of glycemia (in adults, if glucose was
lower than 60  mg, administer thiamine, and 50  ml
50% glucose; for children older than 2 years, 2 ml/kg
of 25% glucose solution.
– Place venous access and take blood for laboratory
tests (complete blood count, serum electrolytes, drug
serum levels, and toxicologic screen).
– If it is considered necessary, place the urinary catheter.
– Complete diagnostic approach: continuous EEG,
computed axial tomography, lumbar puncture, and
magnetic resonance imaging (preferred over cranial
computed tomography).
5. What is the initial pharmacologic
treatment to manage generalized motor
SE?
Benzodiazepines are the first-line treatment for the
management of SE (Table 5).
112
No part of this publication may be reproduced or photocopying without the prior written permission o
benzodiazepines alone have not been effective in sub-
verting the crisis1,2,4.
In adults, intravenous levetiracetam, phenytoin, or
VPA can be used (level A)1,2. In children, the guidelines
from the American Epilepsy Society state that there is
insufficient evidence to evaluate phenytoin and leveti-
racetam as second-line treatments (level  U), however
valproic acid has similar efficacy and better tolerability
than intravenous phenobarbital (level B)3. The US Na-
tional Institutes of Health have implemented a protocol
for the treatment of SE comparing phenytoin, VPA, and
levetiracetam in children and adults, contributing rele-
vant information about these drugs (level C)5.
In some studies6,7, phenytoin, and fosphenytoin are
the most commonly used drugs if SE persists in spite
of benzodiazepine administration. A recent meta-analy-
sis8 of drugs administered for SE refractory to benzo-
diazepines demonstrated the efficacy of phenytoin
(50%), levetiracetam (69%), phenobarbital (74%), and
VPA (76%) (all C).
8. What is the initial pharmacologic
treatment for other SE (Focal and
non-motor)?
Non-motor SE (NCSE) is an entity that is difficult to
recognize clinically due to its heterogeneity. Its diagnosis
results from its suspicion, mainly due to an altered state
of consciousness and persistence of clinical changes
after a convulsive event or convulsive epileptic state has
finished. NCSE must be considered for any patients with
altered consciousness presenting one or more of these
situations: coma, lethargy, and confusion. For focal SE:
Todd’s paralysis, which is a neurologic focal deficit of the
last hours or days, especially if it is after a seizure.
 A. Olmos-López, et al.: Status epilepticus in children and adults

Table 6. First line drugs in SE treatment

AED Doses in adults Doses in children Infusion speed

Phenytoin 20 mg/kg IV 18 a 20 mg/kg IV up to 1 g 1 mg/kg/min for at least 20 min

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Phenobarbital* 20 mg/kg IV 15 a 20 mg/kg IV up to 1 g 1 mg/kg/min for at least 20 min

Valproic acid 20‑40 mg/kg IV 20‑40 mg/kg IV up to 1.5 g Infusion for 15 min

Levetiracetam 1 g‑3 g/kg IV 20‑60 mg/kg IV up to 2.5 g Infusion for 15 min

Lacosamide 200‑400 mg IV No established pediatric dose Infusion for 15 min

AED: automated external defibrillator, * Not available in Mexico.

Table 7. Second‑line drugs in SE treatment

Patient Intervention Comparison Result

No part of this publication may be reproduced or photocopying without the prior written permission o
Pediatric patient with Second line drugs Phenytoin, Phenytoin, fosphenytoin, and Levetiracetam (Level U).
tonic‑clonic SE VPA, VPA, phenobarbital (Level B)
Levetiracetam,
Phenobarbital

Adult patient with Levetiracetam, phenytoin or VPA (level A)

tonic‑clonic SE

SE: status epilepticus, VPA: valproate.

It presents in up to 30% of patients with previous
convulsive SE and requires discovery of compatible
electroencephalic changes persisting for >10 min10,11.
Diagnostic criteria
– Alterations in consciousness or other neurological
deficit.
– Epileptiform EEG: discrete epileptic paroxysms or
continuous discharges.
– Response to anticonvulsants: clinical or electroence-
phalographic.
The most frequent types of NCSE are the focal
non-convulsive, the absence status, the continuous
partial epilepsy, the continuous aura, persistent hemi-
paresis, and others of lesser frequency. It is classified
as follows:
– Comatose form: generalized or focal (must be treated
if it lasts >30 min). May or may not be preceded by
a convulsive SE.
– NCSE proper form: absence status (typical absence,
atypical absence, and late-onset absence), treatment
is recommended after 15 min. Focal SE, with or wi-
thout altered consciousness, initiating treatment is
recommended after 10 min.
For treatment, there are two recommended methods:
– Aggressive treatment, similar to management of con-
vulsive SE, preferred for patients that have had a
symptomatic convulsive event (after an event of as-
phyxia or acute hypoxia, perinatal hypoxic encepha-
lopathy, Cardiovascular disease, automated external
defibrillator suppression, etc.) since the morbimorta-
lity is high in these patients.
– For the rest of the primary non-convulsive SE, mor-
bimortality is low and less aggressive management,
using oral or parenteral administration is preferred,
which reduces the morbimortality inherent in the use
of central nervous system depressant drugs used to
manage SE.
Instructions for administration (IV) and pharmacoki-
netics of anti-epileptic drugs in refractory SE:
MDZ 0.2-0.3  mg/kg or 4  mg/2  min, 0.1-0.5  mg/kg/
hour, 0.2-1 µg/ml in bolus. Propofol 1-2 mg/kg. Slowly,
5-10 mg/kg/h. Thiopental 100-200 mg 30s 3-5 mg/kg/h,
25-50 µg/ml in bolus, followed by 50 mg every 2-3 mi-
nutes until the ES is controlled. Ketamine 0.5-4.5 mg/
Kg (up to 5 mg/Kg/h).
The patient must be closely monitored to avoid hypo-
tension, sepsis, atelectasis, pneumonia, or cerebral
venous thrombosis, to the extent possible. On occa-
sion, parenteral feeding for the patient may be
necessary.
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 Rev Mex Neuroci. 2019;20

Table 8. Possibilities of success and complications with drugs (modified from Bleck, 1999) 9
AED Success (%) APNEA (%) Hypotension (%) Arrhythmias (%)

LRZ 65 14 28 12

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PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55

AED: automated external defibrillator.

Table 9. Levels of Evidence of drugs in SE (modified from – Delay in diagnosis and treatment.
Yasiry, et al.,2014)10 – Non-convulsive or subtle SE.

No part of this publication may be reproduced or photocopying without the prior written permission o
Evidence and level of – Convulsive focal onset seizures.
recommendation
– Young patient11-18.
Treatment for SE Complications:
Lorazepam Class I/Level A
MDZ Class I/Level A
– Prolonged ventilator use and its complications.
Diazepam Class IIa/Level A – Refractory bradycardia with metabolic acidosis.
Phenytoin Class IIb/Level A – Hyperlipidemia
Phenobarbital Class IIb/Level A
VPA Class IIb/Level A – Fatty liver
Levetiracetam Class IIb/Level A Triggering factors:
Treatment for RSE – Sepsis, assisted ventilation, and subject submitted to
MDZ Class IIa/Level B hemodynamic monitoring.
Propofol Class IIb/Level B
Thiopental Class IIb/Level B – Use of beta-lactams (cefepime and meropenem).
VPA Class IIb/Level B Myocardial infarction with global anoxia:
Levetiracetam Class IIb/Level B
– Suppression syndromes.
Phenytoin Class IIb/Level B
The PPE recommends reviewing the R‑PPE – Delirium (non-convulsive crises?).
complete guide

SE: status epilepticus, MDZ: midazolam, VPA: valproate

9. ¿When is a generalized convulsive SE
considered to be refractory to treatment?
Refractory SE is defined as a generalized epileptic
seizure that persists despite the use of two anti-epileptic
drugs: at least one first-line drug (benzodiazepine) and
another second-line drug. The super-refractory SE is
defined as a SE that continues or recurs in 24 h or more
once anesthesia has been initiated, when it is removed,
or when it is completely terminated. It can also be con-
sidered when there are clinical or encephalographic
seizures after benzodiazepine treatment and an ade-
quately selected anti-epileptic drug.
Predictors of a Refractory SE:
– Non-structural causes: hypoxia, toxic-metabolic, and
infection.
– Hyponatremia in the previous 24 h.
114
Management
– MDZ: initial 0.2 mg/kg IV in 2-5 min, repeat in bolus
of 0.2-0.4  mg every 5  min until the seizure stops.
Maintenance at 0.05-2.9 mg/Kg/h.
– Propofol: initial 1-2 mg/kg IV in 3-5 min, repeat bolus
every 3-5  min until the seizure stops. Initial infu-
sion  at  20  mcg/kg/minute, with maintenance of
30-200 mcg/Kg/minute.
– VPA: 40 mg/Kg IV with an additional 20 mg/kg, main-
tenance of 40 mg/kg/day.
– Pentobarbital: initial 5 mg/kg IV up to 50 mg/minute,
repeat in bolus of 5  mg/kg until the seizure stops,
maintenance of 0.5-10 mg/kg/h (Tables 6-9).
– Ketamine: 1-2 mg/kg IV in 1 minute, maintenance of
0.01-0.03 mg/kg/minute IV (adjust in the case of he-
patic insufficiency).
– Corticosteroids: It is recommended especially in ca-
ses of super-refractory cases associated with Hashi-
moto’s encephalitis or Rasmussen’s encephalitis.
 A. Olmos-López, et al.: Status epilepticus in children and adults
A ketogenic diet could be an alternative, especially
for children with catastrophic epilepsy. Vagus nerve
stimulation is another alternative for super-refractory
SE in children with catastrophic epilepsy.
Hemispherectomy is used in children with Rasmus-
sen’s encephalitis.
10. What type of patient follow-up must be
carried out after remission from SE?
About two-thirds of the patients respond to the first
treatment if it was opportune and adequate. In general,
the prognosis for those patients is good and, with a
good selection of anti-epileptic drugs to individualize
the diagnostic approach to the patient, good control of
the seizure can be achieved. Patient management and
13. Kinney MO, Craig JJ, Kaplan PW. Non-convulsive status epilepticus:
observation must be maintained, as with any individual
14. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public
that suffers from epilepsy. Unfortunately, between 3
and 33% die from the SE itself or the complications
caused by this problem.
References
17. Holtkamp M, Othman J, Buchheim K, et  al. A  “malignant” variant of
1. Trinka E, Cock H, Hesdorffer D, et  al. A  definition and classification of
status epilepticus report of the ILAE task force on classification of status
epilepticus. Epilepsia 2015;56:1515-23.
3. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the mana-
gement of status epilepticus in adults. Eur J Neurol. 2010;17:348-55.
2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and
management of status epilepticus. Neurocrit Care. 2012;17:3-23.
4. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the mana-
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gement of status epilepticus. Eur J Neurol. 2006;13:445-50.
5. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment
of convulsive status epilepticus in children and adults: report of the guideline
committee of the American epilepsy society. Epilepsy Curr. 2016;16:48-61.
6. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treat-
ments for generalized convulsive status epilepticus. Veterans affairs
status epilepticus cooperative study group. N Engl J Med. 1998;339:792-8.
7. Alldredge BK, Gelb AM, Isaacs SM, et  al. A  comparison of lorazepam,
diazepam, and placebo for the treatment of out-of-hospital status epilep-
ticus. N Engl J Med. 2001;345:631-7.
8. Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: fre-
quency, risk factors, and impact on outcome. Arch Neurol. 2002;59:205-10.
9. Bleck TP. Management approaches to prolonged seizures and status
epilepticus. Epilepsia. 1999;40, s59-s63.
10. Yasiry Z and Shorvon SD. The relative effectiveness of five antiepileptic
drugs in treatment of benzodiazepine-resistant convulsive status epilep-
ticus: a meta-analysis of published studies. Seizure. 2014;23(3):167-74.
11. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;
338:970-6.
12. Appleton R, Choonara I, Martland T, et al. The treatment of convulsive
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status epilepticus in children. Arch Dis Childhood. 2000;83:415-9.
mimics and chameleons. Pract Neurol. 2018;18:291-305.
hospital in the 1980s. Neurology. 1993;43:483-8.
15. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive sei-
zures in the intensive care unit using continuous EEG monitoring: an
investigation of variables associated with mortality. Neurology. 1996;47:
83-9.
16. Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prog-
nosis of refractory status epilepticus treated in a neurological intensive
care unit. J Neurol Neurosurg Psychiatry. 2005;76:534-9.
status epilepticus. Arch Neurol. 2005;62:1428-31.
18. Vasquez A, Farias-Moeller R, Tatum W. Pediatric refractory and super-re-
fractory status epilepticus. Seizure. 2018:S1059-311.
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 Revista Mexicana de Neurociencia

REVIEW ARTICLE

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Clinical guideline: pre-operative evaluation of epilepsy surgery
Matilde Ruiz-García1, Mario A. Alonso-Vanegas2, Sara P. Pérez-Reyes3, Gerardo Quiñones-Canales4,
Ildefonso Rodríguez-Leyva5, Héctor R. Martínez-Rodríguez6 and Eduardo Barragán-Pérez7
1Instituto
Nacional de Pediatría, Mexico City; 2Hospital HGM, Mexico City; 3Hospital Regional de Alta Especialidad del Bajío, León, Guanajuato;
4HospitalGeneral del ISSSTE Durango; 5Facultad de Medicina, Universidad Autónoma de San Luis Potosí and Hospital Central “Dr.  Ignacio
Morones Prieto”, San Luis Potosí; 6Instituto de Neurología y Neurocirugía, Hospital Zambrano Hellion, TecSalud, Tecnológico de Monterrey, Nuevo
León; 7Hospital Infantil de México “Federico Gómez”, Mexico City. Mexico.

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
Epilepsy surgery is an approved treatment for the management of drug-resistant epilepsy or refractory epilepsy (RE). Approxi-
mately one-third of patients with epilepsy will develop RE. RE is considered a serious public health threat carrying important
biopsychosocial consequences including seizure-related accidents, professional limitations, and increased risk of sudden
death. Epilepsy surgery is associated with seizure remission in approximately 65% of patients after a 5 year follow-up. Patients
with drug-resistant epilepsy should be referred to a specialized center for a pre-operative evaluation. Pre-operative evaluation
requires at least a detailed clinical analysis, an electroencephalogram (EEG) and video-EEG, a cranial magnetic resonance
imaging test, as well as neuropsychological, developmental, and psychiatric evaluations. The most common surgical proce-
dures are temporal lobe resections, extratemporal and multilobar resections, lesionectomy, hemispherectomies, callosotomies,
and multiple subpial transections, in descending order of frequency.

Key words: Surgery. Epilepsy. Pre-operative evaluation.

Introduction When do patients with epilepsy require

Epilepsy surgery is an approved treatment for the
management of drug-resistant or refractory epilepsy
(RE)1-3.
RE is responsible for approximately 80% of the direct
and indirect annual costs attributed to epilepsy4. The
majority of surgical candidates are referred for surgery
on average 20-25 years after their initial diagnosis, at
which time their prognosis is less favorable.
surgical treatment?
According to the criteria established by International
League Against Epilepsy (ILAE), approximately 17-33% of
patients with epilepsy develop RE throughout the course
of the disease (level of evidence III)5. A variable portion
of patients are able to achieve seizure remission through
epilepsy surgery, depending on the type of crisis, under-
lying pathologies, and the type of series consulted.

Correspondence:
Matilde Ruiz-García
Instituto Nacional de Pediatría
Insurgentes Sur 3700-C Date of reception: 29-01-2019 Available online: 12-04-2019
Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):116-122
E-mail: matilderuizg@gmail.com DOI: 10.24875/RMN.M19000032 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

116
 M. Ruiz-García, et al.: Surgical evaluation in refractory epilepsy
Surgery generates significant improvements in the
patients’ behavior, cognition, and quality of life and the
cost effectiveness of epilepsy has been demonstrated
in pediatric as well as adult patients6.
Early identification of patients with RE that meet cri-
teria for epilepsy surgery candidacy optimizes seizure
control and reduces cognitive long-term adverse
effects7. The age at the time of surgery has been iden-
tified as an important modulator of the patients’ capa-
city for cognitive reserve, where the most unfavorable
results are in patients with prolonged RE5,8.
In 2003, the American Academy of Neurology publi-
shed recommendations for the surgical management of
epilepsy in adults. Clinical trials demonstrated that pa-
tients with focal epilepsy in the temporal lobe, with or
without evolution to bilateral tonic-clonic seizures, who
develop resistance to first-line pharmacological treat-
ment must be examined as surgical candidates (consi-
dering the new classification of seizures, previously
cited in 2003, as incapacitating complex partial seizu-
res, and with or without progression to generalized
seizures)9.
Recommendation Level of recommendation
Patients with temporal lobe A
focal epilepsy, with or without
progression to bilateral
tonic‑clonic seizures, who
develop resistance to first‑line
pharmacological treatment,
must be examined as surgical
candidates (AAN)
Studies with 5  year follow-up showed that surgery
achieved seizure remission in 65% of cases10,11.
All subjects with RE must be submitted to a preoperati-
ve evaluation to identify or discard well-circumscribed
epileptogenic zones (EZ) and assess the potential be-
nefit of a neurosurgical procedure7.
Patients must meet certain requirements to be con-
sidered candidates for epilepsy surgery; the following
criteria are indispensable:
1. Confirmed diagnosis of ER
2. A systematic pre-operative evaluation with specific and
staggered stages that discard an epileptogenic zone
susceptible to surgical resection without provoking ma-
jor neurological deficits. Published studies lack a com-
parative analysis of pre-operative algorithms. The spe-
cialist consensus is that it must include a rigorous
stratified outline followed by a multidisciplinary team
that includes a neurologist sub-specialized in epilepsy,
a neurophysiologist electroencephalographist, neuro-
radiologist, neuropsychologist, neuropsychiatrist, and
neurosurgeon trained in epileptic surgery procedures.
The pre-operative evaluation is carried out in con-
gruent and concurrent stages. The evaluation of each
 f the publisher.   © Permanyer 2019
neurological subspecialty has independent value in
localizing potential EZ, which is an indispensable ob-
jective of the pre-operative evaluation as well as
post-operative care. Even when the EZ cannot be out-
lined or resected due to its location on or nearby a
functional or eloquent area of the brain cortex, it is
important to consider that a thorough pre-operative
evaluation is highly valuable in offering a meaningful
diagnosis or prognosis to the patient, as well as gui-
ding alternative therapeutic measures.
Epilepsy surgery is defined as any neurosurgical in-
tervention with the objective of improving the quality of
No part of this publication may be reproduced or photocopying without the prior written permission o
life through the control of epileptic seizures (ES) with
minimum secondary side effects7.
Can epilepsy develop resistance to
pharmaceutical treatment?
Epilepsy affects approximately 70 million people
worldwide12,13; one-third of this population develops
RE5. In these cases, epilepsy surgery has the potential
to eliminate recurrence of ES and improves quality of
life1,14. Certain epileptic syndromes present better prog-
nosis with surgical treatment when compared to phar-
maceutical treatment alone. It is not easy to predict
which patients will develop resistance to pharmaceuti-
cal treatment; the probability of developing RE varies
according to the type of epileptic syndrome and the
etiology, this last factor being the most consistently
reported in trails predicting the prognosis of epilepsy.
The prevalence of RE is higher among patients with
symptomatic or cryptogenic epilepsy compared to tho-
se with idiopathic epilepsy. A  trial including 2200  pa-
tients studied for a period between 1 and 7  years,
achieved complete control of ES in 82% of patients with
generalized idiopathic epilepsy, 45% of cryptogenic fo-
cal epilepsy, and 35% of symptomatic focal epilepsy.
Another negative factor for the development of RE is
an early age of onset. A significant amount of patients
with RE also presents hippocampal sclerosis, malfor-
mations of cortical development, and dysembryoplastic
neuroepithelial tumors.
Temporal lobe epilepsy (TLE) is the most common
cause of focal RE15,16; therefore, the most frequent type
of epilepsy surgery on adults are temporal lobe resec-
tions (level of evidence: class  I, compared to conti-
nuous pharmaceutical treatment alone)2,17.
117
 Rev Mex Neuroci. 2019;20
Different definitions of RE have emerged throughout
the years where multiple factors have been taken into
account, such as diagnostic certainty, the number of
failed anti-epileptic drugs (AEDs) attempted for seizure
control, the frequency of seizures, and other aspects
relating to the time span of the seizure pattern. In fact,
different terms have been established, such as untrea-
table epilepsy, uncontrollable epilepsy, difficult to control
epilepsy, resistant to pharmaceutical treatment, or RE.
Terminology diversity and the lack of definition of spe-
cified criteria to conceptualize RE, complicates the com-
parison of studies and series, thus rendering incomplete
conclusions regarding the epidemiology, diagnosis,
management, and treatment of RE. The ILAE is the
association responsible for establishing a structured de-
finition applicable for both clinical practice and scientific
research of RE. Thus, RE was defined as the sustained
failure or the lack of ES remission, despite adequate
attempts with at least two first-line AEDs as monothe-
rapy or combined therapy that is well tolerated by the
patient and was administered in their appropriate co-
rresponding dosages5. ES remission or sustained sei-
zure termination was defined as the absence of seizures
for at least 12  months or for a period 3  times greater
than the longest period of ES remission5. This definition
may be used to justify a complete evaluation within a
epilepsy center, to establish a pre-operative evaluation
for epilepsy surgery or to design a randomized contro-
lled trial for AED or other research purposes, thus
emphasizing the importance of encouraging the con-
nection between clinical practice and research scien-
tists with a unified epilepsy criteria, obtained through
consensus and endorsed by the ILAE.
For patients to be considered surgical candidates for
epilepsy surgery, adults must present confirmed diagno-
sis of RE for at least 2 years; however, in life-threatening
situations, this required interval may be less. In pediatric
patients, the required interval is <2  years, due to the
potential long-term effects that ES can have if present
during important stages of neurodevelopment10.
Candidates for epilepsy surgery are usually between 1
and 60 years of age; however, there are no defined age
limits5,10,14. According to the Andalusian Epilepsy Guide
of 20157, surgical candidate selection criteria include:
a. Confirmed diagnosis of RE. Epilepsy that is not con-
trolled with AED after 2  years. Unsuccessful treat-
ment after prescribing two AEDs with adequate do-
sage respective to each type of ES and adequate
treatment compliance. Patient under 2 years of age.
High risk of presenting adverse effects on several
AEDs.
118
b. Presence of a single, unilateral, and excisable structural
brain lesion.
c. Presence of a non-resectable epileptogenic zone. If
 f the publisher.   © Permanyer 2019
a non-excisable zone is identified, neurosurgical te-
chniques such as disconnection procedures, vagus
nerve stimulation (VNS), or deep brain stimulation
(DBS) are recommended if surgery is considered to
reduce the severity of epilepsy and the procedures’
side effects are considered acceptable.
d. Presence of psychological or psychiatric comorbidities.
e. Presence of diagnostic doubt, regarding etiology, or
epileptic syndrome.
f. Positive patient motivation to accept pre-operative
evaluation procedures, surgical intervention, and fo-
llow-up protocol.
No part of this publication may be reproduced or photocopying without the prior written permission o
g. Age, psychiatric pathology, or disabilities are not
contraindications for surgical candidacy; however,
they must be analyzed on an individual basis11.
What are the characteristics of patients
that are submitted to surgical treatment?
Patients that must be submitted to epilepsy surgery
are: (a) those that present refractory ES, (b) patients
with physical disabilities due to uncontrolled seizures,
and (c) patients with focal RE, low morbidity risk, and
potential for rehabilitation and social integration.
A randomized control study demonstrated the
superiority of surgical treatment over continuous phar-
macological treatment in patients with refractory TLE.
80 patients with mesial temporal lobe sclerosis (mTLS)
where randomly distributed into groups of pharmacolo-
gical or surgical treatment, respectively, after a
pre-operative evaluation. Authors discovered that 58%
of patients in the surgical group presented seizure re-
mission for 1  year compared to 8% of the patients in
the pharmacology group (p < 0.001). Authors also found
that patients in the surgical group demonstrated better
quality of life when compared to the pharmacology
group, as measured by reduced work or school absen-
ces. In addition, one death was reported within the
pharmacology group compared to no deaths in the
surgical group2. Epilepsy surgery has curative potential
when an epileptogenic lesion or zone is completely
excised. In other situations, surgery will only serve a
palliative function as is the case for the DBS or colos-
tomy procedures for atonic seizures in patients with
Lennox-Gastaut syndrome. The curative potential of
surgery is maximized with complete excision of a pri-
mary cerebral tumor, vascular malformation, malforma-
tion of cortical development, or mTLS18.
 M. Ruiz-García, et al.: Surgical evaluation in refractory epilepsy
Extratemporal epilepsy surgeries are significantly
less frequent in surgical series because they represent
a greater surgical challenge; they require frequent eva-
luation through multimodal imaging tests or invasive
monitoring. In addition, the EZ in extratemporal epi-
lepsy are more commonly diffuse and poorly cir-
cumscribed, they present a faster rate of extension in
the seizure propagation and superposition with elo-
quent areas, thus frequently requiring invasive monito-
ring to locate the epileptogenic zone(s)19. There lacks
sufficient evidence to provide definite recommenda-
tions for extratemporal epilepsy surgeries in patients
without defined lesions or in symptomatic patients with
poorly circumscribed lesions. A  meta-analysis publi-
shed by Téllez-Zenteno11 reported a 60% and 35% re-
mission rate in extratemporal and non-defined lesion
epilepsies, respectively.
Which epileptic syndromes should be
managed with surgical treatment?
Epileptic syndromes that should be managed by sur-
gery include:
a. Mesial temporal epilepsy.
b. Neocortical epilepsy with a single well-defined lesion
without compromise of other eloquent areas of the
brain.
c. Hemispheric epilepsy syndromes such as hemime-
galencephaly (HME), Sturge-Weber syndrome,
Rasmussen’s encephalitis, and other unilateral he-
mispheric lesions.
Patients that generally do not require invasive proce-
dures include:
a. Mesial temporal epilepsy associated with hippocam-
pal sclerosis
b. Circumscribed epileptogenic lesions including be-
nign neoplasias such as ganglioma, dysembryoplas-
tic neuroepithelial tumors, low-grade astrocytoma,
oligodendroglioma, vascular malformations, and
atrophic brain lesions.
c. Hemispheric lesions, hemiplegic hemiconvulsive
epilepsy such as Sturge-Weber syndrome, HME,
and Rasmussen’s encephalitis.
d. Epileptic encephalopathies and multifocal diseases
such as Lennox-Gastaut Syndrome.
Patients that require functional neuroimaging/mapping
and/or invasive tests include:
e. Dual pathologies with discordant electroclinical, bilateral
mesial temporal sclerosis, poorly circumscribed epilep-
togenic lesions, malformations of cortical development
with normal magnetic resonance imaging (MRI) in or
near eloquent areas.
 f the publisher.   © Permanyer 2019
What are the primary modalities of
surgical treatment?
Modalities of resection include techniques where the
EZ are excised without producing a significant functio-
nal deficit. In addition, there are modalities of non-re-
section techniques including disconnection or palliative
procedures3. The most frequently performed procedu-
res are temporal lobe resections, extratemporal and
multilobar resections, lesionectomy, hemispherectomy,
callostomies, and multiple subpial transections7.
a. Anterior temporal lobectomy or anterior medial tem-
No part of this publication may be reproduced or photocopying without the prior written permission o
poral resection: it is the most commonly practiced
procedure consisting of the excision of medial tem-
poral structures (amygdala, hippocampus, and para-
hippocampal gyrus), up to 6 cm of anterior temporal
lobe cortex in the non-dominant hemisphere and up
to 4.5  cm in the dominant hemisphere. To avoid
neuropsychological side effects and superior qua-
drantanopsia, the resection of the anterior temporal
lobe is limited.
b. Lesionectomy: it is indicated in neocortical epilepsy
with single well-circumscribed epileptic zone super-
posed or in proximity to structural lesions; this allows
superior surgical results and ES control. The proce-
dure consists of selective resection of an epilepto-
genic structural lesion, such as certain types of focal
cortical dysplasia, cavernomas, circumscribed glio-
sis, and certain types of developmental tumors such
as dysembryoplastic neuroepithelial tumors, gan-
gliogliomas, and some low-grade gliomas. In some
cases, the epileptogenic zone may extend beyond
the visible lesion, thus requiring an invasive elec-
troencephalogram (EEG) test to locate and determi-
ne the extension, as well as to improve the results
of the surgery.
c. Neocortical resections: resections of the single or
multilobar cortical lesion. This type of surgery requi-
res electrocorticography (intracranial electroen-
cephalography) to establish the extension and the
limits of the epileptogenic zone.
d. Functional hemispherectomy: this procedure has
substituted the anatomic hemispherectomy due to
the risk of residual cerebral hemosiderosis and
post-operative hemorrhaging. It consists of total dis-
connection of the brain hemispheres with limited
cerebral tissue resection. It is the indicated proce-
dure for patients with severe hemispheric damage
119
 Rev Mex Neuroci. 2019;20
and refractory motor ES of diverse etiology, whether
congenital or postnatal. The causes may be disor-
ders of brain development such as HME, long-term
effects of the perinatal vascular event or traumatic
brain injury, progressive autoimmune disease such
as Rasmussen’s encephalitis, Sturge-Weber syndro-
me, and among others.
e. Callostomy: palliative procedure in which hemisphe-
ric disconnection is achieved through the section of
the corpus collosum in the prevention of interhemis-
pheric seizure propagation and generalization. This
procedure is indicated in cases of severe epilepsy
with drop attacks.
f. Multiple subpial transections: this procedure is re-
served for non-excisable EZ due to their proximity
to eloquent areas of the brain cortex. It is frequently
associated with cortical resection.
g. Other techniques: stereotactic radiosurgery, VNS,
trigeminal nerve stimulation, and DBS2,20.
What are the minimum tests required for
the preoperative evaluation of epilepsy
surgery?
Phase 1 of the pre-operative evaluation is the non-in-
vasive portion of the evaluation, and it requires at least:
a. Extensive clinical evaluation with expert review of
patient’s clinical history and previous laboratory and
imaging tests. The identification of associated prog-
nostic factors at the time of seizure onset and throu-
ghout the evolution of the disease must be empha-
sized, as well as seizure semiology during the course
of disease, with particular interest in the previous
12  months, including frequency, intensity, duration,
aura, and associated trigger factors (emotional
stress, sleep-deprivation, menstruation), medica-
tions, dosages, combinations, side-effects, memory
and language alteration, cognitive deterioration and
psychiatric comorbidities. An exhaustive review of
previous laboratory and imaging tests, as well as
previous hospital records, must be performed whe-
never possible; for example, finding the activity or
epileptic discharge zones in the patient’s first EEG
will have focalizing or lateralizing value. A large quan-
tity of patients referred to surgical epilepsy centers
present pseudoresistance to AEDs. The most com-
mon causes include incorrect diagnosis, inadequate
pharmaceutical drug selection for the seizure type,
inadequate or insufficient dosages, and “irresponsi-
ble patient lifestyle choices. Initially, the diagnosis of
ES must be corroborated according to international
120
criteria. Subsequently, the diagnosis of RE must be
identified and confirmed, ideally based on a thorough
review of patient’s history and disease evolution.
 f the publisher.   © Permanyer 2019
b. EEG: compatible and consistent serialized EEG and
video – EEG (vEEG) monitored by superficial
electrodes.
c. MRI: high-resolution cranial MRI that identifies brain
anatomy and structural lesions. It is recommended
to use resonance equipment in the 1.5-3.0 Tesla
range and FLAIR sequences to identify cortical dys-
plasia. In addition, tractography is recommended to
identify Meyer’s loop and prevent post-operative
quadrantanopsia in temporal lobe surgeries. The
Wada test or functional MRI (fMRI) can be perfor-
med if the identification of the verbal dominant he-
No part of this publication may be reproduced or photocopying without the prior written permission o
misphere is required.
d. Neuropsychology or developmental evaluation: faci-
litates the identification of possible lateralization and
localization of the epileptogenic zone, as well as
determining the pre-operative cognitive status to an-
ticipate possible cognitive surgical side effects.
e. Psychiatric evaluation: necessary to evaluate the pa-
tient’s comorbidities, as well as the patient’s expec-
tations of surgical outcome and quality of life.
In 2006, the sub-commission of pediatric epilepsy
surgery of the ILAE concluded that a superficial EEG
that includes a record of sleeping cortical electrical
activity, an MRI with specific epilepsy protocol and
neuropsychological evaluation are required to consider
a pediatric patient for epilepsy surgery. A  12-24 h su-
perficial vEEG must record at least one paroxysm, and
a brain fMRI must be performed whenever possible6.
What are the main complications of drug-
resistant or RE?
A mortality rate of 2-3 times higher has been recor-
ded for the population with epilepsy. The mortality rate
is even more critical in the subgroup of patients with
RE, where the standardized mortality rate has been
calculated up to 4.69 to 5 times higher than the general
population. In addition, within this group of patients, a
large proportion of the causes of death are directly
related to epilepsy, such as sudden unexpected death.
Conversely, when epilepsy surgery is successful in
controlling seizures, reduced epilepsy-related mortality
risk has been recorded21.
RE is associated with non-fatal injuries such as trau-
matic brain injury, burns, fractures, work-related
accidents, and accidents during recreational and every-
day life activities, among others. In addition, RE is
 M. Ruiz-García, et al.: Surgical evaluation in refractory epilepsy

associated to disabilities and a low quality of life which such as depression, anxiety, psychosis, and excessive
can cause a low academic performance, cognitive de- dependence on a care-taker9. In addition to the direct
cline, and social isolation. The rate of employment, and indirect costs of ES, most patients are referred to

 f the publisher.   © Permanyer 2019

matrimony, and fertility is considerably reduced in pa-
tients with poorly controlled ES2.
The majority of patients with RE has significant res-
trictions on their everyday life, such as driving motor
vehicles. The complications of RE can originate throu-
gh a combination of effects such as recurrent ES, drug
toxicity, and other psychological associated factors
surgical evaluation over 20 years after the diagnosis of
epilepsy; it is highly likely that this delay in referral is
responsible for a significant quantity of deaths related
to ES10. Finally, the probability of postsurgical seizure
remission and favorable quality of life is indirectly rela-
ted to the time span between RE onset to the moment
of epilepsy surgery10.

Levels of evidence of epilepsy surgery

No part of this publication may be reproduced or photocopying without the prior written permission o
Data Levels of evidence

Approximately 17‑33% of patients with epilepsy develop RE. (ILAE) III

Combined surgical and pharmacological treatment are more effective compared to pharmacological treatment I
alone for temporal lobe epilepsy, and results in greater control of epileptic seizures and improved quality of live

Patients with medial temporal lobe RE subjected to early surgery (<2 years) achieve seizure remission more II
frequently than patients who do not undergo surgery

Complete hippocampal resection is more effective than partial resection in patients with medial temporal lobe II
epilepsy

Combined surgical plus rational pharmacological treatment is more effective than pharmacological treatment III
alone in patients with neocortical epilepsy, a single well‑circumscribed lesion and no contraindications of
surgery

Functional hemispherectomy, or its variants, is safe and efficient surgical techniques for the control of epileptic III
seizures in patients with hemispheric epilepsy syndromes

Multiple subpial transections, with or without resections, reduces the frequency of different types of epileptic IV
seizures

Callostomies can reduce the frequency of drop attack epileptic seizures in a sustained fashion over time IV

There is no consensus over the quantity of information necessary for pre‑operative evaluations, although it IV
must be sequential and staggered, beginning with basic tests and subject to amplification if necessary

The basic information of a pre‑operative evaluation includes a detailed clinical evaluation, prolonged record of IV
epileptic seizures through EEG monitor, magnetic resonance imaging with specific epilepsy protocol and
neuropsychological/neuropsychiatric evaluations

Video‑EEG monitoring with intracranial electrodes is a safe procedure that is associated with minimum II
permanent morbidity and/or mortality rate

The risk of complications is less with deep electrodes compared to subdural sheets III

When subdural electrodes are used, the risk of complications increases by the number of electrodes II

121
 Rev Mex Neuroci. 2019;20
References
1. Rathore C, Radhakrishnan K. Concept of epilepsy surgery and presurgi-
cal evaluation. Epileptic Disord. 2015;17:19-31.
2. Wiebe S, Blume WT, Girvin JP, Eliasziw M, Effectiveness, efficiency of
surgery for temporal lobe epilepsy study group. A randomized, controlled
trial of surgery for for temporal-lobe epilepsy. N Engl J Med. 2001;
345(5):311-8.
3. Pindrik J, Hoang N, Smith L, et al. Preoperative evaluation and surgical
management of infants and toddlers with drug-resistant epilepsy. Neuro-
surg Focus. 2018;45:E3.
4. Begley CE, Annegers JF, Lairson DR, Reynolds TF, Hauser WA. Cost
of epilepsy in the United States: a model based on incidence and prog-
nosis. Epilepsia. 1994;35:1230-43.
5. Kwan P, Arzimanoglou A, Berg AT, et  al. Definition of drug resistant
epilepsy: Consensus proposal by the ad hoc task force of the ILAE
commission on therapeutic strategies. Epilepsia. 2010;51:1069-77.
6. Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults.
Lancet Neurol. 2014;13:1114-26.
7. Andaluza G, Epilepsia D. Diagnóstico y Tratamiento de la Epilepsia en
Niños y Adultos. Sociedad Andaluza de Epilepsia. Viguera Editores. Saint
Louis: Saint Louis University; 2015.
8. Helmstaedter C. Neuropsychological aspects of epilepsy surgery. Epi-
lepsy Behav. 2004;5 Suppl 1:S45-55.
9. Helmstaedter C. Cognitive outcomes of different surgical approaches in
temporal lobe epilepsy. Epileptic Disord. 2013;15:221-39.
10. Engel J Jr., Wiebe S, French J, et al. Practice parameter: temporal lobe
and localized neocortical resections for epilepsy: report of the quality
standards subcommittee of the American academy of neurology, in
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association with the American epilepsy society and the American asso-
ciation of neurological surgeons. Neurology. 2003;60:538-47.
11. Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes fo-
llowing epilepsy surgery: a systematic review and meta-analysis. Brain.
2005;128:1188-98.
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12. West S, Nolan SJ, Cotton J, et al. Surgery for epilepsy. Cochrane Data-
base Syst Rev. 2015;7:CD010541.
13. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neu-
rosurg Psychiatry. 1996;61:433-43.
14. Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epide-
miology of drug-resistant epilepsy: a systematic review and meta-analy-
sis. Epilepsia. 2018;59:2179-93.
15. Pre-surgical evaluation for epilepsy surgery European standards. Euro-
pean federation of neurological societies task force. Eur J Neurol. 2000;
7:119-22.
16. Engel J Jr. Mesial temporal lobe epilepsy: what have we learned? Neu-
roscientist. 2001;7:340-52.
17. Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy
a major prognostic factor for recurrence? Neurology. 1998;51:1256-62.
18. Jayakar P, Gaillard WD, Tripathi M, et  al. Diagnostic test utilization in
evaluation for resective epilepsy surgery in children. Epilepsia. 2014;
55:507-18.
19. Wyllie E, Comair YG, Kotagal P, et  al. Seizure outcome after epilepsy
surgery in children and adolescents. Ann Neurol. 1998;44:740-8.
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20. Engel J Jr., McDermott MP, Wiebe S, et  al. Early surgical therapy for
drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;
307:922-30.
21. Ryvlin P, Kahane P. Does epilepsy surgery lower the mortality of drug-re-
sistant epilepsy? Epilepsy Res. 2003;56:105-20.
Revista Mexicana de Neurociencia

REVIEW ARTICLE

 f the publisher.   © Permanyer 2019

Clinical guide: discontinuing chronic antiepileptic drug
treatment
María del C. Loy-Gerala1, Octavio M. Ibarra-Bravo2, María del R. Márquez-Estudillo3,
Francisco Mena-Barranco4, Francisco J. Rogel-Ortiz5, Sandra E. Silva-Sánchez6, Hilda Villegas-Peña7 and
Avril Molina-García8
1Hospital General de Puebla “Dr.  Eduardo Vázquez Navarro” SSA, Puebla; 2Hospital General “ Dr.  Miguel Silva”, Morelia, Michoacán; 3Hospital
Regional de Alta Especialidad, ISSSTE, Puebla; 4Hospital General ISSSTE, La Paz, Baja California Sur; 5PPE, Veracruz, Veracruz; 6Hospital Central
Universitario, Chihuahua, Chihuhua; 7PPE Guadalajara, Jalisco; 8Hospital Infantil de Especialidades, Chihuahua, Mexico City. Mexico

No part of this publication may be reproduced or photocopying without the prior written permission o
Abstract
The decision to continue or withdraw the antiepileptic drugs (AEDs) should be taken jointly by the patient, family and/or
caregivers, and the specialist physician, after extensive information and discussion about the risks and benefits of withdrawing
the AED. The patient and family members must understand that there is a risk of the recurrence of seizures with and without
AED. The type of epilepsy, the prognosis, and the patient’s lifestyle should be taken into account. Withdrawal should be carried
out under the supervision of a specialist (clinical neurologist) and will be considered when the patient has been seizure free
for at least 2 years. The treatment must be withdrawn gradually for a period of at least 2-3 months and the antiepileptics
must be removed one by one. Withdrawal of benzodiazepines and barbiturates should be slower, in 6 months or more. An
agreement must be made that in the event of a seizure relapse, the patient must return to taking the last dose before the
dose in which the relapse was presented and request assessment by clinical neurologist.

Key words: Withdraw. Antiepileptic drugs. Stop antiepileptic drugs.

Question 1. How long must the patient be
seizure free before considering
antiepileptic drug (AED) withdrawal?
In 1996, the American Academy of Neurology propo-
sed a guide for discontinuing antiepileptics in patients
that are seizure free, with the following criteria: seizure
free after 2-5 years of treatment, only one type of epi-
lepsy, normal neurological examination, and a normal
electroencephalogram (EEG)1. There have been very
few changes with respect to the previous proposal.
There are a number of prospective studies and me-
ta-analyses in this respect, but there has not been a
uniform consensus about how long the patient must be
in remission before treatment can be discontinued; these
studies propose from 1 to 5 years of remission2-8. The
risk of recurrence is greater when the epileptic seizu-
re-free period before discontinuing the medication is
<2 years than when it’s longer9. For patients that have
been seizure free for 2 or more years, the risk of recu-
rrence after discontinuing medications is lower; the lon-
ger the patient has been seizure free. Furthermore, the

Correspondence:
María del Consuelo Loy-Gerala
Hospital General de Puebla “Dr. Eduardo
Vázquez Navarro”, SSA Date of reception: 28-01-2019 Available online: 12-04-2019
Puebla, Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):123-128
E-mail: marialoy1@gmail.com DOI: 10.24875/RMN.M19000033 www.revmexneurociencia.com
1665-5044/© 2019. Academia Mexicana de Neurología A.C. Published by Permanyer México. This is an Open Access article under the CC BY‑NC‑ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

123
 Rev Mex Neuroci. 2019;20
risk of recurrence is lower for patients that did not have
a seizure after beginning their treatment with AEDs2.
Various studies have demonstrated that one of three
patients relapse within a period of 2 years after suspen-
ding antiepileptics. The risk of seizure recurrence in the
same period of time is 2 or 3 times that observed for
patients that remain on AEDs. The 2015 Cochrane re-
view10 of randomized controlled trials about epileptic
drug withdrawal defines withdrawal of antiepileptics af-
ter < 2 years of treatment as “early withdrawal” and “late
withdrawal” when they are discontinued after 2 years of
treatment. The seizure-free period for children neces-
sary to consider antiepileptic withdrawal is considerably
shorter compared to that of adults and depends on the
epileptic syndrome. This is true for those cases with
favorable evolution, such as benign childhood epilepsy
and Rolandic epilepsy11. In these cases, treatment can
be suspended after a maximum of 1 year12.
Recommendation Level of recommendation
and level of evidence
Consider withdrawing Evidence level 1
medication in patients with at Recommendation level A
least 2 years in complete
seizure remission.
Question 2. What are the risk factors for
recurrence of epileptic seizures after AED
withdrawal in pediatric patients?
– Generalized non-motor absence seizures: 20-30%
relapse.
– Focal seizures: 44% relapse. Focal seizures with di-
minished awareness have greater risk of relapse.
– Juvenile myoclonic epilepsy: recurs in 33-78%, only
25-26% can undergo treatment withdrawal.
– West, Lennox-Gastaut, and Dravet syndromes have
a high risk of recurrence.
Other factors:
– Symptomatic epilepsies: 41-42% risk
– Neurological anomalies present at birth.
– Average of five seizures per year: 68% relapse
– Prolonged seizures
– History of febrile seizures has 2 times the risk of
relapse.
– Prolonged epilepsy before remission.
– Age of onset of epilepsy younger than 2 or older than
12 years old.
– ≥ 10 seizures before remission
– Impaired neurodevelopment, intellectual quotient < 70
– EEG with epileptiform activity before withdrawal.
– < 2 years without seizures10
124
There are a few studies that show that female gender
and family history of epilepsy are risk factors that in-
crease the probability of relapse13-19.
 f the publisher.   © Permanyer 2019
Recommendations when faced with risk Level
factors for recurrence of epileptic recommendation
seizures in children
Antiepileptic drugs can be suspended in B
cases of focal epilepsy and most
generalized genetic epilepsies.
Assess whether or not to withdraw
treatment in generalized symptomatic or
unknown cause epilepsies, juvenile
myoclonic epilepsy, and partial symptomatic
epilepsy, due to a high risk of relapse.
In children, the main risk factor is etiology. A
Continued treatment does not guarantee
the absence of recurrence.
No part of this publication may be reproduced or photocopying without the prior written permission o
An abnormal electroencephalogram, age B
of onset of seizures, intellectual disability,
abnormal neurological examination at
birth, altered neuroimaging studies, family
history of epilepsy, and febrile seizures,
alone, should not be taken as justification
to avoid suspending treatment if there are
no other associated negative predictors.
Gender should not be an isolated factor C
to decide not to withdraw antiepileptic
drug treatment.
Inform the patient that two or more C
epileptic drugs at the onset of withdrawal
may be associated with increased risk of
relapse. However, this does not
contraindicate withdrawal.
The decision to stop or continue C
treatment does not depend on the type of
drug that will be withdrawn.
Question 3. What are the risk factors for
recurrence of epileptic seizures in adult
patients after suspending antiepileptic?
There are multiple studies that assess the risk factors
for recurrence of epileptic seizures in adults. In 2017, a
predictive model for recurrence was published which
described the most important factors9. This was based
on multiple studies, considering that the methodology,
the types of patients and types of epileptic seizures are
very varied.
a. Age. One study reported a greater possibility of re-
mission when withdrawing AED at an older age
(p = 0.02), finding remission in 45% of the patients.
Various other studies demonstrated that the earlier
the age of onset of epilepsy before the period of con-
trol of seizures, the greater the risk of recurrence, as
well as a greater risk of recurrence when the age of
onset is late infancy or adolescence1,9,16,20.
 M.C. Loy-Gerala, et al.: Discontinuing chronic antiepileptic treatment
b. Mental retardation. An intelligence quotient < 70 and
motor deficits are independent predictors of
recurrence16,20.
c. Abnormal neurological examination. A 15% seizure
recurrence is reported during the 1st month in pa-
tients with abnormal neurological examinations21,22.
d. Abnormal interictal encephalogram (EEG). The pre-
sence of an abnormal EEG before AED withdrawal
or during the 1st year after AED withdrawal indicates
greater risk of recurrence1,22,23.
e. Focal and generalized symptomatic tonic-clonic epi-
lepsies have a greater risk of recurrence9,20.
f. Age of onset of epilepsy9,20.
g. Family history of epilepsy. Increased risk of
recurrence9,20.
h. Number of AEDs. The greater the number of AED, the
greater the risk of recurrence after withdrawal9,20.
Recommendation Level of
recommendation
and level of
evidence
For patients with epilepsy that has been Evidence level 1
seizure free for >2 years, without risk Recommendation
factors, the gradual withdrawal of level B
antiepileptic drugs is recommended. The
decision should be made in conjunction
with the patient and/or the caretakers.
For patients with epilepsy that has been Evidence level 1
seizure free for >2 years, with risk factors, Recommendation
the risk/benefit of AED withdrawal should level A
be assessed.
Question 4. What are the risk factors for
recurrence of epileptic seizures after
withdrawing AEDs in patients following
epilepsy surgery?
In 2011, a prospective study was published with 311
patients after mesial temporal epilepsy surgery, who
underwent AED withdrawal after being seizure free be-
tween 3 months and 1 year. The results showed that
the absence of hippocampal sclerosis and the presence
of interictal discharges in the EEG were independent
predictors of seizure recurrence24. The majority of stu-
dies report the same requirement of 1-2 years seizure
free, without increase in recurrence in up to 10 years of
follow-up25,26. A Class II, prospective, randomized study
published in 2009, which included post-surgical patients
that were seizure free for 1 year demonstrated a greater
rate of recurrence for patients with hippocampal sclero-
sis compared with those with lesional epilepsy27. The
only work that included extratemporal surgery is a re-
trospective study with 106 patients diagnosed with
epilepsy that presented evident lesions by magnetic
resonance imaging, which evidenced greater risk for
older patients, longer course of epilepsy, abnormal
 f the publisher.   © Permanyer 2019
post-operative EEG, early post-operative seizures, glio-
sis or cortical focal dysplasia, and interictal discharges
in the EEG and during the 1st year after surgery28.
The largest study in pediatric population is a European
multicentric, retrospective, uncontrolled study that inclu-
ded 766 patients under 18 years of age that was seizure
free after surgery (temporal and extratemporal) who were
subjected to AED withdrawal. Results showed a seizure
recurrence of 12%, and of these patients, 30% did not
achieve seizure control after reintroducing medication29.
Good prognosis Bad prognosis
Surgery at an early age Surgery after 30 years of age
No part of this publication may be reproduced or photocopying without the prior written permission o
Hippocampal sclerosis Long‑term epilepsy
Anterior temporal Normal anatomopathological
lobectomy examination
Seizure free for 1‑2 years Neocortical resection
after surgery
Question 5. What is the usefulness of an
EEG to decide on AED withdrawal?
Although there are no examinations that are comple-
tely reliable to predict the recurrence of seizures, many
studies have demonstrated that abnormalities in the
EEG, before or after AED withdrawal, increase the risk
of recurrence15,16. A recent meta-analysis reported that
the presence of EEG paroxysms before AED withdrawal
predicts a high percentage of recurrences (Table 1) 23.
Recommendation Level of recommendation
and level of evidence
In patients that are seizure IA
free but show paroxysmal EEG
patterns and other risk factors,
AED withdrawal is not
recommended due to a high
risk or recurrence.
Question 6. What are the probabilities of
the recurrence of epileptic seizures for
patients undergoing AED withdrawal?
The probability for seizure recurrence after stopping
treatment varies among different studies and oscillates
from 20% to 46%9. Different studies have found risk fac-
tors that significantly impact the probability of recurrence.
These risk factors are as follows: duration of epilepsy
before achieving control, total number of seizures (fewer
or more than 10), time in remission, age at seizure onset
125
 Rev Mex Neuroci. 2019;20
(with a discreetly greater risk when epilepsy begins in
adolescence or adulthood), intellectual quotient < 70,
abnormal EEG at the time of AED withdrawal, remote
symptomatic epilepsy (defined as epilepsy caused by an
old brain lesion), absence of an epileptic syndrome rela-
ted to age, and history of febrile seizures13-19,30-32.
These risk factors have different prognostic weight.
The most important are as follows: duration of epilepsy,
total number of seizures, intellectual disability, remote
symptomatic epilepsy, and absence of an autolimited
epileptic syndrome. Tables that assign a numeric value
for each of these risk factors have been developed9.
The information found in these tables is simple: the
greater the high significance risk factors, the greater
the risk of seizure recurrence (Level I).
Regarding epilepsy of genetic origin, it must be poin-
ted out that juvenile myoclonic epilepsy has a very high
risk of recurrence after treatment withdrawal (Relative
Risk RR: of 70 up to 95%), even after very long periods
of remission33,34. It’s very important that the patient
receives clear information during the decision-making
process (R-PPE) (Level I).
Question 7. How should AED be withdrawn?
There is no clear consensus among different studies
that analyze this aspect since the period of time pro-
posed for AED withdrawal varies from 4 weeks to
12 months. In a controlled randomized study with 149
children, no differences were found with regard to re-
currence of seizures when AEDs were withdrawn in a
period between 6 weeks and 9 months. In another
study involving 56 children, no differences in RR were
found after assessing periods of AED withdrawal las-
ting 1-6 months. Finally, another study with 216 children
that assessed AED withdrawal periods of 4-6 weeks
versus 4-6 months also did not find significant differen-
ces in RR. Thus, we recommend gradual withdrawal of
AED in an interval of 4-6 months35,36.
Recommendation Level of recommendation and
level of evidence
Gradual withdrawal of AED in Level of evidence 2
an interval of 4‑6 months is Level of recommendation: PPE
recommended consensus
Question 8. What other risks, besides
recurrence, are there when withdrawing
AEDs?
In addition to the risk of recurrence, other factors
must be considered: adverse effects of the drugs, risk
126
of physical lesions or death, quality of life, and social
and psychological problems. Always consider the risk
of losing a driver’s license or a job, since this is a de-
 f the publisher.   © Permanyer 2019
terminant factor for some adults1,37.
A prospective study found that after AED withdrawal
and relapse of epileptic seizures, there is little risk of
epileptic seizures resistant to treatment. This risk co-
rresponds to 1%, compared to 97% of recurring after
treatment is reinitiated. A review from 2005 reported
treatment refractory epilepsy in 19% of the patients that
had previously undergone treatment withdrawal, which
was associated with a symptomatic etiology, location
of the epilepsy, and abnormal neurological examina-
tions. In some patients with controlled epilepsy and
associated comorbidity, this can be increased under
No part of this publication may be reproduced or photocopying without the prior written permission o
AED withdrawal since valproic acid and lamotrigine are
indicated for stabilizing emotional states, as in bipolar
disorder, and topiramate is also used as prophylactic
treatment for migraines17,37.
Relapse of epileptic seizures after AED withdrawal
may have psychosocial repercussions and important
financial effects. Depending on the legislation regula-
ting the area where the patient resides, this situation
indicates that he will be restricted from driving for a
period of 3-12 months, as well as a greater risk of ha-
ving epileptic seizures during work, and repercussions
on quality of life and social stigma since everyday ac-
tivities may have to be modified22.
Question 9. What are the benefits of
withdrawing epileptic drugs?
AEDs are associated with long-term adverse effects
that may include cognitive and behavioral alterations.
Suspending antiepileptics can benefit persons in long-
term remission if the benefit of withdrawing treatment
is greater than the alterations caused by taking the
antiepileptics.
Some of these effects are attention reduction,
alterations in memory and mood, and depression. In
addition, they can cause problems in daily activities
resulting in an affected quality of life, although these
may be slight. Their daily, chronic use offers other risk
factors such as teratogenesis, possibility of infertility in
males, interactions with other drugs and long-term to-
xicity, and pseudodementia as can be caused by
phenytoin, even at therapeutic doses. Conversely, sei-
zure recurrence can also be devastating from the emo-
tional point of view, and in social life, there is risk of
losing work and autonomy, and especially for obtaining
a driver’s license1.
 M.C. Loy-Gerala, et al.: Discontinuing chronic antiepileptic treatment
Table 1. Prognostic factors for recurrence after epileptic surgery
Recommendation
Considering withdrawal of AED is recommended for patients having had
epilepsy surgery, after 1‑2 years seizure free with good prognostic factors.
In patients with bad prognostic factors, seizure free for 1‑2 years, withdrawal
of AED is not recommended after epilepsy surgery.
Taking AEDs imply a continuous economic expense
for the individual and their families, as well for the public
health system, when they are administered unnecessa-
rily (World Health Organization, 2012). Therefore, when
epilepsy is in remission, withdrawing antiepileptics can
favor quality of life17.
In general, cognitive function is improved. In a
prospective, placebo-controlled, double-blind study, 139
patients that were seizure free for at least 2 years, un-
derwent neuropsychological tests before and after AED
withdrawal finding better performance after stopping
treatment. In addition, there were lower levels of depres-
sion and irritability after withdrawing the medication22.
In a retrospective study that included 766 patients
under 18 years of age, with pre- and post-surgical neu-
ropsychological assessment and at least 1 year after
AED withdrawal, results showed that withdrawal of phe-
nobarbital and primidone was associated with an in-
crease in intellectual quotient of 10 or more points. The
fact of reducing the doses of antiepileptics and comple-
te withdrawal of the drugs predicted better results in
psychometric tests compared to children that continued
their antiepileptic treatment before surgery. Verbal me-
mory developed better in children that underwent drug
withdrawal. These cognitive and behavioral effects were
also observed with the new AEDs38,39.
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