Rmn 2019 20 2.Pdf

Revista Mexicana de Neurociencia Publicación oficial de la Academia Mexicana de Neurología A.C. © Permanyer 2019

VOLUME 20 - NUMBER 2 / Marzo-Abril 2019 – ISSN: 1665-5044 . eISSN: 2604-6180 www.revmexneurociencia.com of the publisher 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 No part of this publication may be reproduced or photocopying without the prior written permission

PERMANYER www.permanyer.com Revista Mexicana de Neurociencia

Editorial

Clinical guidelines from the Priority Epilepsy Program of the public health sector in Mexico © Permanyer 2019 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 of the publisher

The Programa Prioritario de Epilepsia (PPE - Priority planned for this task. The national coordination is led Epilepsy Program) was created based on the accord by its creator and founder Francisco Rubio Donnadieu, published in the Mexican Official Gazette of the Fede- MD and by the author. ration on October 24th, 1984. This program has labored The development of the first Clinical Guidelines in an uninterrupted manner to regulate, coordinate, (CGs) has been a laborious effort, one that has been methodize, and optimize the strategies in favor of pa- finished due to the work of all the coordinators of the tients with epilepsy, as well as their families and socie- PPE, who are neurologists and pediatric neurologists ty. There are currently 78 centers of integral treatment certified by the Mexican Board of Neurology and who for epilepsy in Mexico, located in various hospitals be- work in one of the many institutions of the health sec- longing to Mexico’s health sector. tor in Mexico. To elaborate the CG, all the coordinators The headquarters for the national coordination is in of the PPE met in person in two meetings, the first in the Instituto Nacional de Neurología y Neurocirugía the city of Leon and the second in the city of Puebla, (National Institute of Neurology and Neurosurgery) where we formed workgroups for each CG. These “Dr. Manuel Velasco Suarez” (INNN due to its acronym meetings were possible due to the support of the fe- in Spanish) in Mexico City, from where all actions are deral government and the contributions of the

Correspondence: Date of reception: 01-02-2019 Available online: 12-04-2019 No part of this publication may be reproduced or photocopying without the prior written permission Juan Carlos Reséndiz-Aparicio Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):56-62 E-mail: [email protected] 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- cialists in making adequate decisions when approa- portant to state that there are no conflicts of interest in ching epileptic patients of different age groups and these CGs due to the fact that they are editorially inde- genders. These are the culmination of the experience pendent of any external funding. of their authors, who have followed the necessary Finally, I would like to thank the INNN for their hos- steps for proper and updated scientific research, using pitality and support in the coordination of the Program, the criterion of the American Epilepsy Society 2016 to the Mexican Academy of Neurology for the publication © Permanyer 2019 analyze the levels of evidence and recommendations in their magazine, the Mexican Society of Pediatric

. including the benefit for the patients. To evaluate the Neurology who supported the process of translating the quality of the CG, two experts coordinated each table CG to English, and the authorities of the Hospital Psi- and applied the Spanish version of the AGREE instru- quiátrico Infantil (Children’s Psychiatric Hospital) of ment of 2001. Mexico City who have allowed me to work as the ad- Due to the advances in the knowledge of epilepsy, junct executive member of the Priority Epilepsy Pro- the PPE group aims to update the CG every 5 years. gram and above all, thank you to the coordinators of of the publisher These CGs constitute a series of recommendations the Priority Epilepsy Program who worked on this pro- developed by a group of medical physicians that have ject; this work is dedicated to them and their families a particular interest in the field of epilepsy and work and to which I express my most ample recognition.

Juan Carlos Reséndiz Aparicio, MD, Adjunct Executive Member

American Epilepsy Society 2016

Article Classification: Evidence Class I: A randomized, prospective and controlled clinical trial with masked outcome assessment, in a representative 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. Class II: A randomized, prospective and controlled clinical trial with masked outcome assessment that lacks one or two criteria of Class I a-e above, or a prospective matched cohort study with masked objective 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. No part of this publication may be reproduced or photocopying without the prior written permission

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 One or more Class I trials or the specified population. two or more Class II trials. Recommendation: Level B Must be done or must not be done. One or more Class II trials or Conclusion, Level B three or more class III trials. Probably effective, ineffective, or harmful for the given condition in the © Permanyer 2019 Level C specified population.

Two or more Class III trials. Recommendation: . Level U It must be considered or must not be considered. Absence of trails that com- Conclusion, Level C plement levels A, B, or C. Possibly effective, ineffective, or harmful for the given condition in the Level R-PPE specified population. Recommendation: of the publisher 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 consensus 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 Channelopathies FBTCS: focal to bilateral tonic-clonic seizure 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 No part of this publication may be reproduced or photocopying without the prior written permission 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: Guía de Práctica Clínica del Programa Prioritario de Epilepsia or Clinical Guide- BBB: blood–brain barrier lines of the Priority Epilepsy Program CSF: cerebrospinal fluid CNS: central nervous system Additional neurological disorders D iagnostic tests CVD: cerebrovascular disease TBI: traumatic brain injury

fMRI: functional magnetic resonance imaging © Permanyer 2019 MRI: magnetic resonance imaging

PET: positron emission tomography D rug 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 S/L: sublingual of the publisher MEG: magnetoelectroencephalogram Video-EEG: video electroencephalogram PSG: polysomnogram Syndromes and types of epilepsy EKG: electrocardiogram BECTS: benign 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 No part of this publication may be reproduced or photocopying without the prior written permission Epilepsy Program LEV: levetiracetam SAdE: Sociedad Andaluza de Epilepsia or Andalusian LZP: lorazepam Epilepsy Society MDL: midazolam 59 Rev Mex Neuroci. 2019;20

MPH: methylphenidate CBT: carabersat (SB-204269) MPB: methylphenobarbital TBT: tonabersat (SB-220453) MSM: mesuximide/methsuximide SFM: safinamide (PNU-151774E) 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) © Permanyer 2019 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 TGB: tiagabine LiCBZ: licarbazepine of the publisher 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 No part of this publication may be reproduced or photocopying without the prior written permission

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

Centers of integral care for epilepsy “CAIE” in Mexico © Permanyer 2019

. of the publisher No part of this publication may be reproduced or photocopying without the prior written permission

61 Rev Mex Neuroci. 2019;20 © Permanyer 2019

. of the publisher

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

62 Revista Mexicana de Neurociencia

REVIEW ARTICLE

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 © Permanyer 2019 8

Jesús D. Rayo-Mares . 1PPE, Instituto Nacional de Neurología y Neurocirugía Dr. Manuel Velasco Suárez y Hospital Psiquiátrico Infantil Dr. Juan N. Navarro, Mexico City; 2Hospital Christus 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 of the publisher

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 symptoms 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 and its workgroups have strived to provide a standard This being a clinical guide, it is developed based on terminology to be used worldwide. 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- Question 1. What is an epileptic seizure? dence since the references used are current articles An epileptic seizure is defined as the transitory ma- from the International League Against Epilepsy (ILAE)1-3, nifestation of signs and/or symptoms caused by an which is the official agency for this disease worldwide, 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 No part of this publication may be reproduced or photocopying without the prior written permission Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):63-68 E-mail: [email protected] 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 The classification is divided into three, depending on seizure? the patient’s symptoms at seizure onset: Focal onset seizure/Generalized onset seizure/Unk- The term unprovoked implies the absence of a nown onset seizure. temporal or reversible factor that reduces the convulsive Focal onset seizures originate within a network limi- threshold and provokes a seizure at that moment. The ted to one hemisphere; they can be localized or more opposite of this type of phenomenon is an acute symp- widely distributed. Generalized seizures are those that tomatic seizure, defined as a seizure that occurs in tem- originate at one point with wide and rapid participation

poral relation during cerebral injury, which can be meta- of bilaterally distributed networks. Those seizures whe- © Permanyer 2019 4,5 bolic, infectious, toxic, structural, or inflammatory . re it cannot be distinguished whether they are of focal

. or generalized onset with a confidence level of 80%, Question 3. What is the current definition must be considered of unknown onset (Fig. 1). of epilepsy? A diagnosis of epilepsy is established after any of the Question 6. How are focal onset epileptic following situations4: seizures currently classified? of the publisher 1. Two or more unprovoked or reflex seizures occurring The state of awareness is a differentiating factor for with >24 h difference. the type of seizure in focal seizures1,2. Awareness refers 2. An unprovoked or reflex seizure with a probability of at to the relationship between oneself and the external least 60% of presenting a future seizure (similar range environment. In epilepsy, we establish awareness as the as the general risk of recurrence, after two unprovoked mental state, with both subjective and objective aspects, seizures that appear in the following 10 years). that encompasses the sense of self as a unique entity, 3. Diagnosed epileptic syndrome. capable of response, and memory. A focal seizure is classified by the degree of awareness during onset, Question 4. How is the risk of recurrence which can be altered at any time during the event. of an epileptic seizure defined? Focal seizures, with or without impaired awareness, can be subclassified depending on whether they initiate with The events that have been documented to increase motor or non-motor symptoms. In addition, the 2017 clas- the risk of recurrence of an epileptic seizure are cere- sification recommends adding what they call “descriptors,” brovascular disease, both ischemic and hemorrhagic, which are symptoms and signs that the patient presents cranioencephalic trauma, abnormal electric activity in during the seizure1,2. Descriptors have been divided into an EEG compatible with an epileptic seizure, or a cranial six groups: motor, automatisms, sensory, emotional, cog- magnetic resonance showing a lesion compatible with nitive, or autonomic. To remember these descriptors more a diagnosis of epilepsy5. If a patient, after a first unpro- easily, you can use the mnemotechny MASECA, which is voked seizure is predisposed to continued generation the most famous brand of tortilla dough in Mexico8. 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 Question 7. How are the symptoms and or more unprovoked seizures >24 h apart). signs divided into focal seizures? Epilepsy is considered as resolved in those patients Motor that have an age-dependent epileptic syndrome but have grown older than the corresponding age for the Involvement of the musculature in any way. An in- specific syndrome or in patients that have remained crease (positive) or decrease (negative) in muscular seizure-free for the past ten, without taking antiepileptic contraction to produce movement. The most frequent drugs in the last 5 years4. are: motor arrest, astatic, clonic, dysarthria, dystonic, pelvic thrusting, figure-of-4, hypokinetic, hyperkinetic, Question 5. What is the current incoordination, Jacksonian, myoclonic, paralysis, pare- classification by type of epileptic seizure? sis, pedaling, fencer’s posture, and versive. No part of this publication may be reproduced or photocopying without the prior written permission The most frequent clinical confusion is in differentia- The ILAE decided to modify the classification system ting clonic seizures from myoclonic seizures. A clonic for epileptic seizures in 19816, and update it in 20107. seizure is a repetitive, regular movement that can be 64 J.C. Reséndiz-Aparicio, et al.: Definition and classification of epilepsy

Focal OnsetGeneralized Onset Unknown Onset © Permanyer 2019

Aware Impaired

Awareness . MOTOR MOTOR tonic-clonic tonic-clonic clonic epileptic spasms tonic NON- MOTOR myoclonic MOTOR ONSET Behavior arrest myoclonic-tonic-clonic automatisms myoclonic-atonic atonic* of the publisher 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 oral-facial, perseveration, sexual, undressing, vocaliza- muscle groups. A myoclonic seizure is a brief (< 100 ms), tion, walking, or running. sudden, involuntary, single or multiple contractions of the muscles or muscle groups, with variable topography Sensory (axial, proximal, or distal extremities). The myoclonic seizure is less repetitive and sustained. Related with the senses, thus, in this case, are not signs but symptoms. The most frequently reported Automatisms symptoms are: auditory, gustatory, olfactory, somato- sensory, vestibular, visual, and pain. Motor activity, which is more or less coordinated, that generally occurs when awareness is deteriorated and Emotional No part of this publication may be reproduced or photocopying without the prior written permission after which the subject is generally (but not always) amnesiac. It commonly resembles a voluntary move- These are seizures that present as having an emotion ment. The most frequent include: aggression, manual, as a prominent initial feature, such as fear, pleasure or 65 Rev Mex Neuroci. 2019;20

spontaneous euphoria, laughter, crying, expressed in seizure. It frequently occurs in clusters or bursts. Epi- bursts, or flares. leptic spasms are more frequent in children but can occur at all ages. Cognitive Absence seizures can be divided into four types: Typical absence, atypical absence, myoclonic absence, The most frequently reported data from this group and absence with palpebral myoclonus. Typical absen- are: acalculia, aphasia, attention impairment, déjà vu ce seizures are of sudden onset, interrupting ongoing or jamais vu phenomena, dysphasia, illusions, memory activities, blank stare, does not respond when spoken

impairment, forced thinking, altered responsiveness, or to, lasting from seconds to half a minute, and with very © Permanyer 2019 hallucinations. quick recovery. It’s important to remember that the

. word “absence” is not synonymous with blank stare Autonomic since this can also be encountered in focal onset seizures2. Alteration of the autonomic nervous system function, Atypical absence seizures show changes in tone that which may involve the cardiovascular system, pupils, are more pronounced than in typical absence; the on- diaphoresis, the gastrointestinal tract, vasomotor and set and cessation are not abrupt. Myoclonic absence of the publisher thermoregulation functions. presents with sudden, brief (<100 ms), involuntary, In focal seizures, there are two sections that were not non-repetitive nor sustained, and absence. In absence included in previous classifications, the epileptic spasm with palpebral myoclonus, we observe eyelids jerking (previously only classified within generalized seizures) at a frequency under 3 per second, eyes commonly and behavior arrest1,2. deviated upward, generally lasting <10 s, frequently A focal onset seizure, with or without impaired awa- precipitated by ocular closure, with high possibility of reness, motor or non-motor, can progress to a bilateral photosensitivity. tonic-clonic activity. The term previously used for this type of seizure was a secondary generalized partial Question 9. When do we classify an seizure. At present, we must classify it as a focal onset epileptic seizure under the heading of seizure that evolves into a bilateral tonic-clonic unknown onset or unclassified? seizure. The term bilateral tonic-clonic is used for focal seizu- When there is no evidence about the onset of the res that propagate to both cerebral hemispheres, while seizure, focal or generalized, it may be classified under generalized is for seizures that originate simultaneously the heading of unknown onset seizure, and in this case, in both cerebral hemispheres. a limited classification can be carried out with the findings that were observed. Question 8. ¿How are generalized The heading “Unclassified” applies to the type of epileptic seizures currently classified? seizure when there are no data described in the ILAE classification of 2017, either because the information is They are divided into seizures with motor or inadequate or because of unusual characteristics1,2. non-motor symptoms. Among those with motor, symptoms are the generalized tonic-clonic, clonic, tonic, Question 10. How are epilepsy and myoclonic, myoclonic-tonic-clonic, myoclonic-atonic epileptic syndromes classified? seizures, and the epileptic spasm. For non-motor, there are absence seizures1,2. A myoclonic-tonic-clo- Since April 2017 the epilepsy classification set forth nic is a type of generalized seizure that was not in- by the ILAE establishes three levels of diagnosis: the cluded in the previous classification. These seizures first level is the type of seizure, which incorporates all imply one or various bilateral jerks (myoclonic) of the of the concepts in all diagnostic levels revised pre- extremities, followed by a tonic-clonic seizure1,2,8. Ato- viously, focal, generalized or of unknown onset, and nic seizures present sudden loss or reduction in mus- now we have added two important concepts at all

cle tone involving musculature of the head, trunk, diagnostic levels: patient comorbidities (associated No part of this publication may be reproduced or photocopying without the prior written permission mandible, or extremities. pathological entities) and etiology. Some patients can The epileptic spasm is usually more sustained than only stay at this diagnostic level because it is not pos- a myoclonic movement, but not as sustained as a tonic sible to study more, and this can be valid or be the 66 J.C. Reséndiz-Aparicio, et al.: Definition and classification of epilepsy

Type of seizure Etiology Focal Generalized Unknown Structural

Genetic s

Type of Epilepsy Infectious © Permanyer 2019 Combined, generalized

Focal Generalized and focal Unknown Metabolic . Comorbiditie

Immune

Unknown Epileptic Syndrome of the publisher

Figure 2. Classification of Epilepsy. ILAE 2017.

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

epilepsies No part of this publication may be reproduced or photocopying without the prior written permission but that is subject for another Guide.

67 Rev Mex Neuroci. 2019;20

Critically ill or with clinical suspicion Presentation

No seizure Video EEG (without EEG correlate) Diagnosis

Seizure (with EEG correlate) © Permanyer 2019 Without clinical signs with clinical science

(only electrographic) Manifestation .

MOTOR automatisms clonic epileptic spasms myoclonic of the publisher 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 de la Epilepsia. Epilepsia. 2014;55:475-82. In this article, there are no conflicts of interest by the 5. Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia. 2011;52 Suppl 7:2-6. authors or the source of funding. 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. References 7. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and con- 1. Fisher RS, Cross JH, French JA, et al. Operational classification of sei- cepts for organization of seizures and epilepsies: report of the ILAE zure types by the international league against epilepsy: position paper of commission on classification and terminology, 2005-2009. Epilepsia. the ILAE commission for classification and terminology. Epilepsia. 2010;51:676-85. 2017;58:522-30. 8. Rubio F, Resendiz JC, Alonso MA, Senties H. Epilepsia. 1st ed. México: 2. Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE Editorial Alfil; 2016. p. 27-42. 2017 operational classification of seizure types. Epilepsia. 2017;58:531-42. 9. Volpe JJ. Neonatal seizures: current concepts and revised classification. 3. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the Pediatrics. 1989;84:422-8. epilepsies: position paper of the ILAE commission for classification and 10. Mizrahi EM, Kellaway P. Characterization and classification of neonatal terminology. Epilepsia. 2017;58:512-21. seizures. Neurology. 1987;37:1837-44. No part of this publication may be reproduced or photocopying without the prior written permission

68 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: management of seizures in the emergency room © Permanyer 2019 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. of the publisher

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 direct and guarantee the assertiveness of medical at- Epilepsy is one of the diseases that affect the quality tention to improve the diagnosis and treatment of this of life of patients the most, due to its neurological, psy- disease1-3. chological, and social implications. Epileptic seizures Recommendations for scientific research were based (ES) are a common cause of admittance to the emer- on the selective location of keywords in PubMed-MED- gency room (ER), and they are responsible for 1 million LINE, The Cochrane Library, and other clinical practice or 1% of all the ER consults. The annual cost of care, guidelines, as well as recommendations by other scien- prehospital and within the ER, to treat ES is estimated 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 No part of this publication may be reproduced or photocopying without the prior written permission Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2018;20(2):69-75 E-mail: [email protected] 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? 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. © Permanyer 2019

. 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 of the publisher 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 No part of this publication may be reproduced or photocopying without the prior written permission − 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

Non-epileptic Yes No paroxysmal event © Permanyer 2019

Diagnostic support with Confirmed ES EEG or VEEG is suggested Recurrence risk assessment: of the publisher 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. No part of this publication may be reproduced or photocopying without the prior written permission

71 Rev Mex Neuroci. 2019;20 © Permanyer 2019

. of the publisher

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 No part of this publication may be reproduced or photocopying without the prior written permission ictal activity NICE, 20124 − Asses the risk of seizure recurrence R‑ SAdE, 20156 − Support therapeutic decisions

72 EEG: electroencephalography; ES: epileptic seizures, ER: emergency room. J. Visoso-Franco, et al.: Management of seizures in the emergency room

ES on patients previously diagnosed with epilepsy © Permanyer 2019 Typical ES

No Yes presentation .

Repeat initial diagnostic Identification of trigger factors tests: for uncontrolled seizures: of the publisher 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 No part of this publication may be reproduced or photocopying without the prior written permission 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

73 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 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 © Permanyer 2019 − 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. of the publisher

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. No part of this publication may be reproduced or photocopying without the prior written permission

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

Algorithm: Management of ES in the ER

ES in ER © Permanyer 2019

Acute . Unprovoked ES on patients Symptomatic Status ES previously diagnosed ES Epilepticus with epilepsy of the publisher

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 unprovoked 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 development subcommittee of the American academy of neurology and the American epilepsy society. Epilepsy Curr. 2015;15:144-52. No part of this publication may be reproduced or photocopying without the prior written permission

75 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: management of the first unprovoked epileptic seizure in adults and children © Permanyer 2019 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 . 1Hospital Regional 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. of the publisher

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 decisions based on the best evidence available. This guideline was developed based on research questions under the PICO method, where questions are presented with their corresponding answer, establishing 1. What are the characteristics of acute levels of evidence to offer specific orientation regarding symptomatic ESs and unprovoked ESs the international recommendations on the related sub- (UES)? ject matter, seeking the exposure and application of these same management criteria for first unprovoked An acute symptomatic ES, provoked or reactive, can seizures in children and adults. The final objective of be defined as seizures presented during the course of this guide is to aid health-care professionals in solving a disease which temporarily lowers the threshold of an the initial questions when faced with a patient who has 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 No part of this publication may be reproduced or photocopying without the prior written permission Mérida, Yucatán, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):76-81 E-mail: [email protected] 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, however, these must be measured between 20 min and the required time span between a cerebral injury and 4 h from the onset of the seizure8. A lumbar puncture onset of the seizure is 7 days for injuries such as trau- is useful when neuroinfection is suspected8. matic brain injury (TBI), brain surgery, cerebrovascular Evidence Level Grade disease, and cerebral anoxia and for the acute phase Brain injury, epileptiform EEG pattern, 1 A of infections of the central nervous system (CNS); 24 h abnormal brain imaging, and nocturnal for patients with metabolic disorders; and 7-48 h after crisis are factors that increase the degree the last ingestion of alcohol in patients with of recurrence and aid in the decision to initiate treatment abstinence2. © Permanyer 2019 An UES is characterized by the lack of temporary or

. reversible risk factors that lower the threshold to pre- 3. Which diagnostic tests are useful for sent an ES3. The diagnosis of an ES and epilepsy is the diagnosis and prognosis of a first based on the patient’s medical history, the information UES? obtained during direct questioning when the patient’s consciousness is preserved and is able to describe the EEG – evidence demonstrates that all patients with seizure, or indirect questioning when information is ob- a first UES should be submitted to an EEG because of the publisher tained from a first-hand witness of the seizure. A tho- the data obtained are useful for diagnosing ES when rough medical history must be obtained to allow the abnormalities are present. Determining the type of ES clinician to identify if the event is an ES as well as the also helps in identifying the etiology in some cases, 8 type of seizure. This information will also be useful to and establishing a differential diagnosis from NES . establish a differential diagnosis between an ES and EEG data are also useful in the selection of the an- non-ES such as Psychogenic, syncope or migraine, ti-epileptic drugs (AED), whenever these are medically among other causes4. The medical history has always indicated. It must be noted, however, that abnormal been considered the cornerstone of the approach to EEG results without clinical manifestations are not con- any disease, and patients with ES and epilepsy are not sidered epilepsy, and conversely, patients with epilepsy 9 the exception5. may have a normal EEG . A meta-analysis of 16 studies established as a seizure recurrence indicator for an UES epileptiform dis- 2. What are the precipitating risk factors charges on the EEG (2.0; CI 95%: 1.6-2.6). If the EEG after a first UES? showed non-epileptiform discharges, there was a recu- A systematic review published in 2015, consisting of rrence of seizures; however, no statistical significance 10 randomized control studies, revealed that treatment was found10. Records of brain electrical activity within versus lack of treatment of first ES resulted in early the first 24 h after the first UES increase the probability recurrence within 2 years from 21% to 45% in the of detecting interictal epileptiform discharges (IEDs). 1st year, respectively6. Certain clinical characteristics The IED is most frequently recorded among temporal can determine seizure recurrence. This study demons- epilepsies when compared to extratemporal epilep- trated that the majority of patients with UES are be- sies11, and they increase seizure recurrence risk. tween 16 and 60 years of age, which implies that the The EEG must be carried out and interpreted by cer- age groups before and after this age range have a tified personnel, on patients under hyperventilation and greater recurrence risk of 2.1 (95% confidence with at least 20 min of recorded patterns without interval = 1.0-4.3)7. Other risk factors for seizure recu- artifacts. Current guidelines suggest that an EEG is a rrence include positive family history, history of febrile necessary test for the evaluation and treatment deter- seizures, first prolonged seizure, initial suspicion of mination after a first ES6. EEGs are the most common epilepsy, unknown seizure etiology, abnormal physical test used for diagnosing epilepsy. An epileptiform dis- examination, and nocturnal seizures in patients aged charge on an EEG was associated with a relative in- 1-4 years when compared to patients who remain crease in the recurrence rate of ESs when compared to awake during seizures7. A paroxysmal electroencepha- a normal EEG12. Patients with an abnormal EEG with

logram (EEG), structural injury visible on magnetic re- epileptiform discharges presented a recurrence risk of No part of this publication may be reproduced or photocopying without the prior written permission sonance imaging (MRI), and prolactin levels are highly 60% after a first seizure. According to the ILAE 2017, specific, yet a poorly sensitive test for ES. Prolactin 60% recurrence risk mandates that the first seizure levels over 36 ng/mL are highly suggestive of ES; should be considered epilepsy. The probability of 77 Rev Mex Neuroci. 2019;20

finding an abnormality on the EEG is higher after repeat MRIs detect more SNC alterations when compared to studies, where 39% of patients presented abnormalities CT scan; thus, without a need for an emergency image, 7 on the first test and 68% on their third test . Patients MRI is the technique of choice12. Neuroimaging tests with epileptiform discharges have a 77% recurrence are necessary to predict the probability of recurrence rate on a first UES compared to 47% if the EEG is nor- 6 mal. These discharges are better detected if the EEG after the first UES . They are indicated with the objec- is performed within the first 12 h after an ES13. Accor- tive of identifying the etiology of the ES. The advanta- ding to the ILAE, the recommended window to perform ges of a CT are availability and the speed in which the

an EEG is within the first 72 h after a UES and within test is performed, and the results obtained can guide © Permanyer 2019 the first 24 h after an ES14. If EEG results are normal,

the decision for the need of immediate medical atten- . it is recommended to perform EEG tests during sleep, tion, especially in emergency care12. Neuroimaging with sleep deprivation, photostimulation, and repeated tests12-14. An unaltered routine EEG does not exclude tests have an important value in patients with epilepsy; the presence of an ES. Other studies report that an research shows recurrence rates a year after the first EEG performed within the first 6 h after an ES reveals seizure of 59% (95% CI 54-65%) if patients had an of the publisher the presence of epileptiform discharges in 67% of ca- epileptogenic lesion visible on a CT or MRI and 44% ses, between 6-12 h in 52%, 12-24 h in 24%, 24-48 h (95% CI 41-48%) in patients without evident lesions by in 25%, 48-72 h in 22%, and 72-96 h in 18%13. Based neuroimaging (p=0.001)12. on the previous data, it can be concluded that prompt EEG tests after onset of seizures are more likely to de- The recurrence rate of UES within 1 year in patients tect epileptiform discharges and their efficacy of detec- that demonstrated an epileptogenic lesion only by MRI tion is progressively reduced in later tests15. The Ame- was 67% compared to 50% for patients without a visible rican Academy of Neurology (AAN) in 2007 established lesion. The MRI is superior to the CT in detecting epi- a time-frame for EEGs within a window of 48 h after ES leptogenic abnormalities13. If available, an MRI is the onset and up to an average of 15 days afterward13. preferred neuroimaging technique in patients with a first EEG results from sleep-deprived patients improve the sensibility and specificity of the epilepsy diagnosis. UES. Neuroimaging tests should be performed fo- Sleep induced by sleep deprivation is more likely to llowing epilepsy protocol and interpreted by neuroradio- provoke epileptiform discharges when compared to logy specialists. physiological sleep16. Seizure recurrence after a first Evidence Level ES with epileptiform discharges recorded on an EEG was 73.2%, whereas a normal EEG was associated Children or adults with a first UES should Class I (13) 11 undergo a thorough medical history and Class I C.II (14) with a 32.8% recurrence ; thus, EEG records with examination, followed by at least two epileptiform graphic patterns were established as a diagnostic tests: neuroimaging (CT/MRI) recurrence factor. Seizure recurrence on patients with and EEG generalized compared to focal epileptiform discharges A standard EEG is a useful study for the Class III (15) was 68.8% and 75%, respectively13. The recommenda- diagnosis of a first UES Class I (16) tions of the AAN and the American Epilepsy Society An EEG with epileptogenic discharges is Class I (16) (AES) for patients with a first UES and an EEG with the best predictor for recurrence of a first Class III (13) 6 UES, together with an abnormal epileptiform discharges are level A . neurological examination and corresponding etiology Neuroimaging An EEG helps to differentiate between an Class I (16) ES and other events of non‑epileptic origin A computed tomography scan (CT) of the skull is A routine EEG does not demonstrate Class II (4) performed in emergency cases on a patient with a first evidence of brain abnormalities. A prolonged ES; its primary indication is to determine the presence EEG is useful for the diagnosis of a first UES of brain injuries that could cause an ES, such as a The VEEG is a useful test for the diagnosis of Class III (4) a first UES; it predicts a seizure recurrence

stroke or TBI. A CT may also be performed when phy- No part of this publication may be reproduced or photocopying without the prior written permission sical exploration demonstrates a focal neurological de- of 46% in 12 months and 51% in 24 months ficit, a prolonged altered state of alertness and in febrile The CT is a useful test for the diagnosis of Class I (16) patients or with findings that suggest a CNS infection. a first UES 78 J. A. Gien-López, et al.: First unprovoked epileptic seizure

If the seizure is of genetic etiology and the patient Focal lesions are more commonly found on Class I (16) a CT in adults (18‑34%) compared to Class I (14) has a sibling with seizures, the recurrence risk is 29%. children (0‑12%), with the exception of If the seizure is idiopathic with a spike and wave pattern infants under 6 months old where 18 abnormalities are found in 55% of cases on EEG, the risk increases to 50% . In children, a and in adults with HIV in 28% of cases 5-year recurrence risk from the first seizure is 43%19.

The following conditions are predictors of Class I (14) In the presence of abnormalities on the EEG, the risk abnormalities found on a CT: altered increases to over 50%, up to 65%18. neurological examination, infants under 6 An adult with epileptiform discharges on a routine months old, closed TBI, recent manipulation of ventriculoperitoneal EEG after a UES has 77% probability of a second sei- © Permanyer 2019 shunting, cerebral tumor suspicion, zure, while in children the probability is 66%20. Children

. neurocutaneous syndromes, focal onset of who present a seizure during sleep have a 75% proba- seizure, alcohol abuse history, cysticercosis, and seizures over 15 min in bility of recurrence within 2 years compared to 49% in duration children who did not21. An MRI is superior to the CT in establishing Class I (14) the diagnosis of an epileptogenic lesion 5. What are the indications for of the publisher The MRI is the preferred diagnostic test Class I (16) pharmacological treatment? alongside the EEG in children that present a first non‑febrile seizure Currently, the decision whether to treat a first UES is The recurrence risk of an UES increases Class I (6) a matter of controversy. It is generally accepted that by 2.16 (95% CI 1.44‑4.51) if epileptogenic AEDs are indicated as of the second UES because alterations are found on the EEG and by st 2.1 (95% CI 1.09‑5.44) in an abnormal recurrence risk is greater (57% within the 1 year and neuroimaging test 73% within 4 years)22. A study performed by the AAN Recommendations Grade and the AES based on 10 level A trials determined that the seizure recurrence risk of an adult with a first UES The standard EEG should be considered a Level B useful test to diagnose UES since it was between 21% and 45% within the first 2 years, and detects epileptogenic abnormalities in the cumulative risk of a second ES was 32% after a 12‑27% of cases, and if performed under year and 46% for 5 years1,4. In the Multicenter Epilepsy sleep deprivation, the probability of detection increases up to 58% and Single Seizures (MESS) study, it was concluded that the recurrence of a first UES was 39% within A standard EEG performed within the first Level B 2 24 h of seizure onset detects epileptogenic 2 years and 51% within 5 years . abnormalities in 34‑51% of cases The probability of presenting an isolated ES is 8-10% A standard EEG detects the same Level B and 3% of developing epilepsy, revealing an incidence recurrence risk of a UES as a VEEG rate of 61/100,000 individuals per year, resulting in a A standard protocol MRI detects Level B prediction that an estimated 4 million individuals each epileptogenic lesions in 23% of cases that year will experience a first UES that may be focal or are not detected by CT generalized1, because 30% of paroxysmal episodes are UES: unprovoked epileptic seizure; CT/MRI: computed tomography/magnetic inappropriately diagnosed1. resonance imaging; EEG: electroencephalogram; ES: epileptic seizure; VEEG: video‑electroencephalogram. 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 4. What are recurrence factors for first well as physical and neurological examination, directed UESs? diagnostic tests, emphasizing important points of seizure semiology, suspicion of ES or epilepsy establi- The AAN has described four factors that result in shing a proper differential diagnosis, distinguishing greater seizure recurrence: (1) an EEG with epileptiform between provoked ES and UES using the definition abnormalities, (2) cerebral injury such as stroke or TBI, criteria for epilepsy, and investigating and classifying

(3) a newly found lesion on neuroimaging, and (4) noc- the type of seizure, as well as the recurrence risk. No part of this publication may be reproduced or photocopying without the prior written permission turnal seizures17. After a patient suffers a second sei- Treatment should be limited to observation and com- zure, the patient has 60% of recurrence within the plementary tests if recurrence risk is low. AED should 1st year and 70% recurrence within the 2nd year17. 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- The treatment of the first unprovoked 1 B ratory and other diagnostic tests such as the EEG must epileptic seizure reduces the risk of be performed as soon as possible, because its useful- relapse but does not affect the long‑term prognosis of epilepsy ness is greater in the first 24 h after the seizure25. If epilepsy debut is suspected in subclinical seizures, it CT/MRI: computed tomography/magnetic resonance imaging; EEG: electroencephalogram. 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, © Permanyer 2019 the accepted initial test is a CT23, considering a sub- 6. What are the reference indications for a

. sequent MRI, except if the CT demonstrates an impor- first UES? tant pathology or if the patient must be sedated. Every patient with a first UES must be examined by Other tests, such as serum prolactin, are not recom- a neurologist27. According to the regional infrastructure, mended for the diagnosis of epilepsy; however, it is important to quantify serum electrolytes and glucose to patients must be referred to a secondary or tertiary identify potential causes or any comorbidities23. An medical facility if there is any doubt about the type of of the publisher electrocardiogram or referral to a cardiologist must be provoked ES or if there is evidence of cerebral lesion performed in cases of a doubtful diagnosis. whether it consists of a tumor, hemorrhage, or infection Neuropsychological evaluation is indicated when the (cysticercosis, toxoplasmosis, or tuberculosis)28. Pa- MRI demonstrates important alterations or declines in tients that debut with status epilepticus in their first ES the cognitive areas of the brain. To initiate treatment, must be referred to a specialized facility for treatment the level of certainty of the diagnosis, the degree of as soon as vital signs are stable. Approximately 6-7% alteration in the neurological examination, family history, of long debut seizures are considered as status laboratory and imaging test results, electroencephalo- epilepticus29,30. graphy, the side effects of the AED indicated for the type The etiology of a provoked ES was found to be of seizure, quality of life, and cost of treatment must be stroke in 34.7%, TBI in 34.7%, and infection in the considered. CNS in 30.6%. Conversely, etiology for first UES was The treatment of the first UES reduces short-term a stroke in 68.2%, a TBI in 25%, and CNS infection 3 recurrence risk but not the long-term prognosis . Thus, in 6.8%31. it is important to counterweigh AED side effects on re- It is important for patients to also undergo evaluation 3-5,23,24,26 currence risk when the risk is low , considering for seizure simulator conditions, where studies de- the possibility if recurrence is greater within the first monstrate that the most common simulator is a synco- 3-6 months. pe reflex (74%) and psychogenic seizures (16%)32. The Evidence Level Grade most common symptoms for reference to a secondary Initial treatment should not be given after a 1 A or tertiary medical facility are accompanying neurolo- first seizure except if the recurrence risk is gical manifestations, such as cephalea, immediately high or under special circumstances after the seizure28. Pharmacological treatment should only be 1 A Mortality within the first 30 days from the first provoked initiated after the diagnosis of epilepsy is confirmed 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. The decision to initiate treatment should 1 B be taken by the treating physician together It has been suggested that in locations where a spe- with the patient or caregiver, after cialized neurological consult is unavailable, a remote explaining the recurrence risk, side effects, and quality of life issues consult by a specialist should be established by te- lephone or by video conference2; this is a common The cornerstone of the diagnosis of an 1 B epileptic seizure is the clinical feature occurrence in subspecialties such as pediatric neurolo- gy33. Every referral to a tertiary health-care facility must The EEG is useful for the decision to 1 B include a complete medical history, specifying medica-

initiate treatment No part of this publication may be reproduced or photocopying without the prior written permission tion, semiology of neurological signs and symptoms that Neuroimaging tests, such as CT and MRI, 1 A are necessary evaluations of a patient with may aid in classifying the type of seizure, and the di- an isolated epileptic seizure rected diagnostic evaluation28. 80 J. A. Gien-López, et al.: First unprovoked epileptic seizure

14. Askamp J, van Putten MJ. Diagnostic decision-making after a first and Recommendations Grade recurrent seizure in adults. Seizure. 2013;22:507-11. 15. Gavvala JR, Schuele SU. New-onset seizure in adults and adolescents: Every patient with a first epileptic seizure must be R‑PPE a review. JAMA. 2016;316:2657-68. evaluated in a secondary health‑care facility 16. Giorgi FS, Guida M, Caciagli L, et al. What is the role for EEG after sleep deprivation in the diagnosis of epilepsy? Issues, controversies, and future directions. Neurosci Biobehav Rev. 2014;47:533-48. Evidence Level 17. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. Appendix A: summary of evidence-based guideline for clinicians: Hospitalization criteria for patients with a first UES: Class III management of an unprovoked first seizure in adults. Continuum (Min- − Under 1 year of age (afebrile) neap Minn). 2016;22:281-2. − Atypical or complex epileptic crisis 18. Rizvi S, Ladino LD, Hernandez-Ronquillo L, Téllez-Zenteno JF. Epide- miology of early stages of epilepsy: risk of seizure recurrence after a first − Prolonged postictal state seizure. Seizure. 2017;49:46-53. © Permanyer 2019 − Onset status epilepticus 19. Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recurrence − Meningeal signs after a first unprovoked afebrile seizure in childhood: an extended fo-

− New neurological deficit (previously absent) llow-up. Pediatrics. 1996;98:216-25. . 20. Bouma HK, Labos C, Gore GC, Wolfson C, Keezer MR. The diagnostic accuracy of routine electroencephalography after a first unprovoked seizure. Eur J Neurol. 2016;23:455-63. References 21. Ramos Lizana J, Cassinello Garciá E, Carrasco Marina LL, et al. Seizu- re recurrence after a first unprovoked seizure in childhood: a prospective 1. Martinez-Juarez IE, Moreno J, Ladino LD, et al. Diagnóstico y tratamien- study. Epilepsia. 2000;41:1005-13. to de la crisis epiléptica única no provocada. Rev Neurol. 2016;63:165-75. 22. Brown JW, Lawn ND, Lee J, Dunne JW. When is it safe to return to driving 2. Sociedad Andaluza de Epilepsia. Guia Andaluza de Epilepsia. Viguera: following first-ever seizure? J Neurol Neurosurg Psychiatry. 2015;86:60-4. of the publisher Sociedad Andaluza de Epilepsia; 2015. 23. NICE Clinical Guideline 137, The Epilepsies: the Diagnosis and Mana- 3. Guía de Práctica Clínica, Diagnóstico y Tratamiento de la Epilepsia en gement of the Epilepsies in Adults and Children in Primary and Secon- el Adulto en el Primer y Segundo Nivel de Atención. Actualización; 2015. dary Care; 2012. 4. Tao JX, Davis AM. Management of an unprovoked first seizure in adults. 24. Leone MA, Giussani G, Nolan SJ, Marson AG, Beghi E. Immediate an- JAMA. 2016;316:1590-1. tiepileptic drug treatment, versus placebo, deferred, or no treatment for 5. Pohlmann-Eden B, Beghi E, Camfield C, Camfield P. The first seizure first unprovoked seizure. Cochrane Database Syst Rev. 2016;5:CD007144. and its management in adults and children. BMJ. 2006;332:339-42. 25. Gloss DS, Krumholz A. Managing an unprovoked first seizure in adults. 6. Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: CNS Drugs. 2016;30:179-83. management of an unprovoked first seizure in adults: report of the gui- 26. Guía de Practica Clinica IMSS. Diagnóstico y Tratamiento de la Primera deline development subcommittee of the American academy of neurolo- Crisis Convulsiva Niñas, Niños y Adolescentes Primero y Segundo Nivel gy and the American epilepsy society. Neurology. 2015;84:1705-13. de Atención; 2017. 7. Angus-Leppan H. First seizures in adults. BMJ. 2014;348:g2470. 27. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommen- 8. Rosenow F, Klein KM, Hamer HM. Non-invasive EEG evaluation in dations for the management of infantile seizures: task force report for the epilepsy diagnosis. Expert Rev Neurother. 2015;15:425-44. ILAE commission of pediatrics. Epilepsia. 2015;56:1185-97. 9. Britton JW, Frey LC, Hopp JL, et al. Electroencephalography (EEG): an 28. Arkilo D, Griesemer D, Padulsky K, et al. Urgent referrals for seizure Introductory Text and Atlas of Normal and Abnormal Findings in Adults, evaluation to a tertiary care neurology center: a pilot study. J Child Neu- Children, and Infants. Chicago: American Epilepsy Society; 2016. rol. 2012;27:885-7. 10. Berg AT, Shinnar S. The risk of seizure recurrence following a first 29. Huff JS, Morris DL, Kothari RU, Gibbs MA, Emergency Medicine Seizu- unprovoked seizure: a quantitative review. Neurology. 1991;41:965-72. re Study Group. Emergency department management of patients with 11. Chen T, Si Y, Chen D, et al. The value of 24-hour video-EEG in evalua- seizures: a multicenter study. Acad Emerg Med. 2001;8:622-8. ting recurrence risk following a first unprovoked seizure: a prospective 30. Krumholz A, Grufferman S, Orr ST, Stern BJ. Seizures and seizure care study. Seizure. 2016;40:46-51. in an emergency department. Epilepsia. 1989;30:175-81. 12. Ho K, Lawn N, Bynevelt M, Lee J, Dunne J. Neuroimaging of first-ever 31. Brinar V, Bozicevic D, Zurak N, et al. Epileptic seizures as a symptom of seizure: contribution of MRI if CT is normal. Neurol Clin Pract. 2013;3: various neurological diseases. Neurol Croat. 1991;40:93-101. 398-403. 32. Jackson A, Teo L, Seneviratne U. Challenges in the first seizure clinic 13. Sofat P, Teter B, Kavak KS, Gupta R, Li P. Time interval providing highest for adult patients with epilepsy. Epileptic Disord. 2016;18:305-14. yield for initial EEG in patients with new onset seizures. Epilepsy Res. 33. Millichap JJ, Millichap JG. Child neurology: past, present, and future: 2016;127:229-32. part 1: history. Neurology. 2009;73:e31-3. No part of this publication may be reproduced or photocopying without the prior written permission

81 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: antiepileptic drugs of choice for focal and generalized seizures in adult patients with epilepsy © Permanyer 2019 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 . City; 3Hospital Infantil Universitario, Torreón, Coahuila; 4Instituto Nacional de Neurología y Neurocirugía Dr. Manuel Velasco Suárez, Mexico City. Mexico of the publisher 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 pharmacokinetics, dosage, mechanism of action, and formulations of the AED. 70-80% of patients with either focal or generalized seizures 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 epilepsia (priority epilepsy program). This is a clinical guide for the pharmacologic treatment of epilepsy in adults at first and second level treatment centers. It consists of establishing PICO-ba- Question 1. What are the pharmacokinetics sed questions and setting forth answers. The levels of of antiepileptic drugs (AEDs)? evidence are based on articles published in peer-re- In general, newer AEDs have more predictable ki- viewed indexed articles and other international guideli- netics and lower risk of drug interaction. This is becau- nes, such as the guides published by the International se serum protein binding is low or null, they are mainly League Against Epilepsy and the National Institute for eliminated by renal excretion or metabolized by isoen- Health Care Excellence, as well as emitting 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 No part of this publication may be reproduced or photocopying without the prior written permission Chihuahua, Chihuahua, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):82-88 E-mail: [email protected] 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 L. Rivera-Castaño, et al.: Antiepileptic drugs in adult patients ‑ ‑ ‑ 3.6 L/h (continue) (L/kg/h) Clearance 0.6 mL/min/kg life ‑ 9 (h) 6.3 0.083 6‑8 4‑6 0.12‑0.13 4‑9 30‑60 0.01‑0.015 Half © Permanyer 2019 0 0 0

95 32‑47 40 . ≤ 22 < 10 80‑90 20‑60 0.09 37°C (%) PP binding 3 1.1 0.9 0.65 0.56 0.9‑0.4 87‑90 20 0.42‑0.75 45‑60 50‑140 0.006‑0.009 of the publisher Distribution Distribution volume (L/kg) 1 4 - 2 8 <1 4.5 0.7‑0.8 1‑4 1 3‑7 2‑5 0.9‑1.22 55 24‑35 0.044‑0.84 2‑4 2‑24 0.8‑2 70‑80 16‑24 0.133 10‑15 0.5‑0.8 70‑95 7‑48 0.003‑0.02 0.25‑3 0.5 T. Max (h) T. 60 100 75‑85 80‑90 90‑95 85‑90 90‑100 75‑100 95‑10095‑100 0.6‑1.3 0.5‑0.7 95‑100 95‑100 90‑100 Bioavailability (%) Parenteral Parenteral formulation Yes No No No Yes No No Yes Yes No No yes No Yes Extended release Extended release formulation No Yes No No No No No No Yes No Yes No No No action action SV2 SC G G G CC G SC SV2 SC SC G G SC 25‑100 mg 2 doses 600‑1200 2‑3 doses 1‑20 mg 1‑3 doses 5 mg 2 doses ‑ 1500 2‑3 doses 600 mg 3 doses 200 mg 2 doses 1000‑3000 mg 2 doses 100‑600 mg 1‑2 doses 600‑2400 mg 2 doses 100‑200 mg 1‑2 doses 200‑600 mg 2 or 3 doses 300‑500 mg 2 or 3 doses No part of this publication may be reproduced or photocopying without the prior written permission Initial dose Final dose Mechanism of 50 mg 1 dose 100‑400 mg 2‑3 doses ‑ 5 mg 2 doses Oral and Oral and intravenous 0.15‑0.2 mg/kg maximum 10 mg/dose 250 mg 2 doses 300 mg 3 doses 100 mg 2 doses 125‑500 mg 2 doses 12.50 mg 1‑2 doses 300‑600 mg 2 doses 25‑50 mg 1‑2 doses 150 mg 2 or 3 doses 200‑300 mg 2 or 3 doses AED BRV CBZ CLZ CLB DZP ESM GBP LCS LEV LTG OXC PB PGB PHT Dose, mechanism of action, formulation, and pharmacokinetics for adults AEDs available in Mexico Table 1. 83 Rev Mex Neuroci. 2019;20

for inducing/inhibiting various hepatic enzyme systems1 (Table 1). (L/kg/h) Clearance Question 2. What are the advantages and limitations of monotherapy for the control life ‑ (h)

4‑7 0.102‑0.114 of epilepsy in the adult? Half It was not until the 70s that the practice of beginning

therapy with polypharmacy began to come into question © Permanyer 2019

‑ due to its toxic effects and by recognizing that there was

37°C (%) no scientific evidence that two or three AEDs were more PP binding effective than a single AED. Conversely, the first obser- vational studies of that era reported that when patients with epileptic seizures went from polytherapy to mono- 0.8 0.6‑1 20‑30 5‑18 0.006‑0.009 therapy, they tended to have fewer secondary effects of the publisher

Distribution Distribution 2 volume (L/kg) and even better seizure control . The ideal AED must be effective for controlling any

(Continued) type of epileptic seizure, have perfectly known mecha- 1 3.7 0.55‑0.8 9‑17 15‑23 0.022‑0.036 3‑4 2‑3 1‑8 0.1‑0.4 88‑92nisms 15‑17 of 0.01‑0.115 action, simple pharmacokinetics and pharma- T. Max (h) T. codynamics, no plasma protein binding, and without active metabolites to avoid interactions with other AEDs or other drugs, given the comorbidities found in people with epilepsy7,8 (Tables 4 and 5). It must have an opti- <100 60‑80 90‑100 80‑100 mal efficacy and tolerability/safety relationship. In addition, it should be inexpensive, since it is of chronic use. Bioavailability (%) Currently, AEDs are very far from the ideal AED profile3. In 2018, Brodie et al. reported results from a prospective study including 1795 English patients, with Parenteral Parenteral formulation No No No Yes

type calcium channel blocker; M: multiple mechanism. an average age of 32 years (range 9-93 years), wi- - thout previous treatment that received their first AED, followed from 1982 to 2012. Of the 63.7% of the patients without seizures, 57.3% were seizure free on monotherapy and 6.4% were seizure-free on Extended release Extended release formulation No Yes No Yes polytherapy. The other 36.3% were considered as refractory and were taking two or more AEDs without control of their seizures, with a Class IV level of evidence (Fig. 1 and Table 2)3. Monotherapy is the gold standard to begin treat- action action G M G M ment of focal and generalized seizures in adults, with the goal of obtaining 100% control; however, it is important to realize that about 20-30% do not achieve this goal3. 750‑2000 mg 1‑2 doses 125‑200 mg 2 doses 1500 mg 2 doses 1000‑3000 mg 2‑3 doses Question 3. What is the AED of choice for focal onset seizures and what is the first-line AED for generalized onset No part of this publication may be reproduced or photocopying without the prior written permission Initial dose Final dose Mechanism of 100‑125 mg 1‑2 doses 25‑50 mg 2 doses 500 mg 2 doses 200‑500 mg 2‑3 doses seizures in adults? To begin treatment, based on pharmacokinetics and AED PRM TPM VGB VPA 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; lamotrigine; OXC: oxcarbazepine; PB: phenobarbital; levetiracetam; LTG: brivaracetam; CBZ: carbamazepine; CLB: clobazam; CLZ: clonazepam; DZP: diazepam; ESM: ethosuximide; GBP: gabapentin; LCS: lacosamide; LEV: AED: antiepileptic drug; BRV: valproate. phenytoin; PRM: primodone; TPM; topiramate; VGB: vigabatrin; VPA: PGB pregabalin; PHT: Mechanism of action: SV2: protein binding SV2; SC: sodium channel blocker; G: GABA analogue; CC: T Dose, mechanism of action, formulation, and pharmacokinetics for adults AEDs available in Mexico Table 1. 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%)

1st AED MONOTHERAPY

CONTROL No Control CONTROL No Control © Permanyer 2019 820 (45.7%) 116 (6.4%) 651 (36.3%)

2nd AED ≥2 AEDs POLYTHERAPY

CONTROL No Control 208 (11.6%) CONTROL No Control of the publisher

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- the first choice will fundamentally depend on clinical con- peutic dose. In the adult, you do not always calculate the firmation of epilepsy. First, by recognizing the type of milligrams per kilogram of weight, especially for the new epileptic seizure; second, the type of epilepsy, if possible, generation AED, but must consider the aspects related third to determine a diagnosis of the epileptic syndrome No part of this publication may be reproduced or photocopying without the prior written permission to the particular AED, the characteristics of the patient, presented by the patient, and on a fourth level, to be able as well as cost and bioavailability6 (Table 3). The AED of to determine the etiology of the epilepsy.

85 Rev Mex Neuroci. 2019;20

Table 3. Variables to consider when choosing the AED as first‑line monotherapy6 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

Idiosyncratic Reactions Age at seizure onset Cost of the AED

Dose dependent adverse effects Gender

Pharmacokinetics Comorbidities

Pharmacodynamics Concomitant medication © Permanyer 2019

Teratogenicity Ability to swallow

. Interactions

Immediate/extended release formulation

Modified form. AED: antiepileptic drug. of the publisher

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. No part of this publication may be reproduced or photocopying without the prior written permission

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 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 © Permanyer 2019

AED: antiepileptic drug; PPE: priority epilepsy program. .

Table 7. Data for bitherapy for focal onset seizures in adults24,25 Data Evidence Recommendation of the publisher 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 monotherapy with two or more drugs has epilepsy in the adult patient and what are not been enough to control all the seizures, the recommendations for monotherapy what AEDs are adequate when you want to with a second AED? combine two AEDs, in the adult? When despite taking a first-line AED at adequate do- The fact is that there are no existing Class I, II, or III ses and therapeutic adherence by the patient, it is not studies for bitherapy. The possibility that the 4-25% of

effective to control epilepsy in the adult, and we must patients who do not respond to monotherapy will be No part of this publication may be reproduced or photocopying without the prior written permission reconsider the correct diagnosis of the type of seizure seizure free with bitherapy, that is, that they require and the differential diagnosis by conducting a new cli- administration of two AEDs to completely control their nical evaluation and clinical tests6,12,20-22 (Table 5). seizures, only has class IV evidence.3,23 87 Rev Mex Neuroci. 2019;20

Empirically, a combination of AED with different me- 14. Nolan SJ, Sudell M, Tudur Smith C, Marson AG. Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data chanisms of action, minimum interaction between the review. Cochrane Database Syst Rev. 2016;12:CD012065. 15. Nolan SJ, Tudur Smith C, Weston J, Marson AG. Lamotrigine versus AED, and a different spectrum of adverse effects has carbamazepine monotherapy for epilepsy: an individual participant data been proposed24,25 (Tables 1 and 6). review. Cochrane Database Syst Rev. 2016;11:CD001031. 16. Nevitt SJ, Marson AG, Weston J, Tudur Smith C. Carbamazepine versus The bitherapy that has been demonstrated to be the phenytoin monotherapy for epilepsy: an individual participant data review. most effective is the combination of a sodium channel Cochrane Database Syst Rev. 2017;2:CD001911. 17. Nolan SJ, Marson AG, Weston J, Tudur Smith C. Phenytoin versus blocker with a wide spectrum AED with multiple (M) valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review. Cochrane mechanisms of action: such as lamotrigine and valproa- Database Syst Rev. 2016;4:CD001769.

te, keeping in mind the teratogenic potential (Tables 7 18. Nolan SJ, Muller M, Tudur Smith C, Marson AG. Oxcarbazepine versus © Permanyer 2019 phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev. 2013; and 8) 23-36 5:CD003615. 19. Campos MS, Ayres LR, Morelo MR, Carizio FA, Pereira LR. Comparati- . ve efficacy of antiepileptic drugs for patients with generalized epileptic seizures: systematic review and network meta-analyses. Int J Clin Pharm. Acknowledgments 2018;40:589-98. 20. Genton P. When antiepileptic drugs aggravate epilepsy. Brain We thank Dr. Mitzel del Carmen Pérez-Careta for her Dev. 2000;22:75-80. 21. Somerville ER. Some treatments cause seizure aggravation in idiopathic editorial help in preparing this guide. epilepsies (especially absence epilepsy). Epilepsia. 2009;50 Suppl 8:31-6. of the publisher 22. Thurman DJ, Begley CE, Carpio A, et al. The primary prevention of epilepsy: a report of the prevention task force of the international league References against epilepsy. Epilepsia. 2018;59:905-14.

rd 23. Joshi R, Tripathi M, Gupta P, Gulati S, Gupta YK. Adverse effects and 1. Patsalos PN. Antiepileptic Drug Interactions. A Clinical Guide. 3 ed. drug load of antiepileptic drugs in patients with epilepsy: monotherapy London, UK: Springer; 2016. versus polytherapy. Indian J Med Res. 2017;145:317-26. 2. Genton P, Roger J. Antiepileptic drug monotherapy versus polytherapy: 24. Stafstrom CE. Mechanisms of action of antiepileptic drugs: the search a historical perspective. Epilepsia. 1997;38(Suppl 5):S2-5. for synergy. Curr Opin Neurol. 2010;23:157-63. 3. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients 25. Brodie MJ, Sills GJ. Combining antiepileptic drugs--rational polytherapy? with newly diagnosed epilepsy treated with established and new antiepi- Seizure. 2011;20:369-75. leptic drugs: a 30-year longitudinal cohort study. JAMA 26. Kumari S, Mishra CB, Tiwari M. Polypharmacological drugs in the treat- Neurol. 2018;75:279-86. ment of epilepsy: the comprehensive review of marketed and new emer- 4. Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and ging molecules. Curr Pharm Des. 2016;22:3212-25. controlled-release carbamazepine in newly diagnosed epilepsy. Neuro- 27. Bonnett LJ, Tudur Smith C, Donegan S, Marson AG. Treatment outcome logy. 2007;68:402-8. after failure of a first antiepileptic drug. Neurology. 2014;83:552-60. 5. Baulac M, Patten A, Giorgi L. Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in 28. Margolis JM, Chu BC, Wang ZJ, Copher R, Cavazos JE. Effectiveness adults with newly diagnosed epilepsy: results of a phase III, randomized, of antiepileptic drug combination therapy for partial-onset seizures based double-blind study. Epilepsia. 2014;55:1534-43. on mechanisms of action. JAMA Neurol. 2014;71:985-93. 6. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guide- 29. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of mo- lines: evidence-based analysis of antiepileptic drug efficacy and effecti- dern antiepileptic drugs for refractory epilepsy: systematic review and veness as initial monotherapy for epileptic seizures and syndromes. meta-analysis. Epilepsia. 2010;51:7-26. Epilepsia. 2006;47:1094-120. 30. Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for syner- 7. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the gism with sodium valproate? 105 study group. Epilepsy Res. 1997;26: epilepsies: position paper of the ILAE commission for classification and 423-32. terminology. Epilepsia. 2017;58:512-21. 31. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate-lamotrigine 8. Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE comedication in refractory complex partial seizures: evidence for a phar- 2017 operational classification of seizure types. Epilepsia. 2017;58:531-42. macodynamic interaction. Epilepsia. 1999;40:1141-6. 9. Freeman A, Concannon B, Cross H, et al. The epilepsies: the diagnosis 32. Taing KD, O’Brien TJ, Williams DA, French CR. Anti-epileptic drug com- and management of the epilepsies in adults and children in primary and bination efficacy in an in vitro seizure model-phenytoin and valproate, secondary care. NICE Clin Guidel. 2012;2012:1-177. Available from: lamotrigine and valproate. PLoS One. 2017;12:e0169974. http://www.nice.org.uk/cg137. 33. Ramaratnam S, Panebianco M, Marson AG. Lamotrigine add-on for 10. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, drug-resistant partial epilepsy. Cochrane Database Syst Guerreiro C, et al. Update ILAE evidence review of antiepileptic drug Rev. 2016;6:CD001909. efficacy and effectiveness as initial immunotherapy for epileptic seizures 34. Poolos NP, Castagna CE, Williams S, Miller AB, Story TJ. Association and syndromes. Epilepsies 2013; 54(3):551-563. between antiepileptic drug dose and long-term response in patients with 11. Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Mason AG. Antiepileptic refractory epilepsy. Epilepsy Behav. 2017;69:59-68. drug immunotherapy for epilepsy: a network meta-analysis of individual 35. Yasam VR, Jakki SL, Senthil V, et al. A pharmacological overview of participant data. Cochrane Epilepsy Group 2017. lamotrigine for the treatment of epilepsy. Expert Rev Clin 12. Xiao Y, Gan L, Wang J, Luo M, Luo H. Vigabatrin versus carbamazepine Pharmacol. 2016;9:1533-46. monotherapy for epilepsy. Cochrane Database Syst Rev 2015. 36. Lee BI, No SK, Yi SD, et al. Unblinded, randomized multicenter trial 13. Nolan SJ, Marson AG, Weston J, Tudur Smith C. Carbamazepine versus comparing lamotrigine and valproate combination with controlled-release phenobarbitone monotherapy for epilepsy: an individual participant data carbamazepine monotherapy as initial drug regimen in untreated epi- review. Cochrane Database Syst Rev. 2016;12:CD001904. lepsy. Seizure. 2018;55:17-22. No part of this publication may be reproduced or photocopying without the prior written permission

88 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: antiepileptic drugs of choice for epileptic syndromes and epilepsies in pediatric patients © Permanyer 2019 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; 2Hospital General 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 Liceaga, Mexico City; 8Hospital Regional de Alta Especialidad ISSSTE, Puebla. México of the publisher

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, comorbidity, 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 management 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 by the International League Against Epilepsy, the This is a clinical guide for the pharmacologic National Institute for Health Care Excellence, and the treatment of epilepsy in pediatric patients. It consists of Guidelines from the Sociedad Andaluza de Epilepsia establishing PICO-based questions and setting forth (Andalusian Epilepsy Society). In addition, we emit re- answers. The levels of evidence are based on articles commendations from the Programa Prioritario de Epi- published in peer-reviewed indexed articles and other 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 No part of this publication may be reproduced or photocopying without the prior written permission Mexico City, Mexico Date of acceptance: 02-02-2019 Rev Mex Neuroci. 2019;20(2):89-96 E-mail: [email protected] 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 •Intestinal Integrity Absorption •Intestinal transit time and pH

• Amount of body water © Permanyer 2019 • Amount of fat and muscle

Distribution •Drug- Protein binding . •Same as in adults of the publisher Metabolismm

Figure 1. Pharmacokinetic and pharmacodynamic variables in pediatric age and use of antiepileptic drugs1-6.

Question 1. What are the pharmacokinetic triggering factors, diurnal variations, and sometimes the and pharmacodynamic differences in prognosis8. pharmacologic management of epilepsy between the pediatric patient and the Question 3. What is the evidence for adult? treating epileptic syndromes described Pediatric patients have a broad range of variations in for newborns: benign familial neonatal their ability for absorption, distribution, metabolism, and epilepsy (BFNE), early myoclonic clearance of antiepileptic drugs (AEDs) (Fig. 1). Clea- encephalopathy (EME), and Ohtahara rance of AED is much faster than in adults, which syndrome? makes it important to calculate the dose depending on The first thing to understand is that neither systematic the weight or body surface area and to be careful of reviews nor clinical guides exist for the management of the toxic effects (Tables 1 and 2)1-6. the syndromes that have been described in newborns; thus, the evidence for treatment is Level IV, and in all Question 2. Should treatment with these cases, the recommendation is U. antiepileptics be based on the type of epileptic syndrome that a patient presents? BFNE To establish a diagnosis of epilepsy, it is sufficient if For cases with frequent seizures or status epilepti- we can define an epileptic síndrome7 that, in the current cus, it could be necessary to provide therapy with drugs classification, would correspond to a Level III diagno- such as carbamazepine (CBZ), phenytoin (PHT), phe- sis8. By definition, an epileptic syndrome presupposes nobarbital (PB), levetiracetam (LEV), oxcarbazepine

a disease that incorporates characteristics in common (OXC), and valproate (VPA). CBZ, even at low doses, No part of this publication may be reproduced or photocopying without the prior written permission such as the type of seizure, the electroencephalogra- is considered to be a good option for BFNE, even in phic findings, the shared imaging study results, age status epilepticus9,10. In general, patients require treat- of onset and/or remission, when applicable, seizure ment during the first 6-12 months of life. 90 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 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 © Permanyer 2019 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 of the publisher

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 No part of this publication may be reproduced or photocopying without the prior written permission gain, insomnia, visual field defects

AED: antiepileptic drugs 91 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 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 © Permanyer 2019 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

12,13 *The AEDs are in alphabetical order and are available in Mexico , LEV: levetiracetam, NZP: nitrazepam, TPM: topiramate, VPA: valproate, VGB: vigabatrin, of the publisher BZD: benzodiazepines, TPM: topiramate, VPA: valproate

EME The current studies are not enough to establish whether other types of corticosteroids, such as prednisolo- Early onset with a burst suppression pattern in the ne, dexamethasone, or methylprednisolone, may be as EEG, various types of seizures, and psychomotor re- effective or recommendable as ACTH for short-term tardation. Metabolic etiologies are often a cause of 12 EME. The burst suppression pattern in EME is different treatment of infantile spasms . from that of Ohtahara since, in general, the burst is First-line treatment medications are considered to be shorter and the suppression is longer. The use of ste- ACTH, steroids, or VGB, while second-line treatment roids and ACTH may be effective in some cases11. 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- Ohtahara syndrome ded on this subject (Table 3)13. It has been calculated that 75% of these cases evolve into West syndrome between the 2nd and 6th months of Question 5. What is the evidence for age. Treatment is difficult, but in some cases, ACTH, LEV, and high doses of PB have been shown to be treating Lennox-Gastaut syndrome? effective11. To choose the treatment, one must consider the behavioral and psychiatric comorbidities, such as depres- Question 4. What is the evidence for sion, anxiety, and psychosis. One must also take into treating West syndrome? account that the patient may have different types of seizures and some drugs may diminish some types of There are insufficient data to determine the effecti- seizures while increasing others. Some combinations veness of ketogenic diet, intravenous immunoglobulin, can be synergistic and reduce the number of seizures, LEV, nitrazepam, topiramate (TPM), VPA, or Vitamin but it is important to monitor the possible increase in B6, for treating infantile spasms12. 14,15 Early control of spasms could improve development in adverse effects (Table 4) . those who do not have a proven underlying etiology13. For Valproate is a first-line drug, while CLB, ketogenic West of unknown cause, providing treatment quickly with diet, lamotrigine (LTG), LEV, and TPM are effective as adjunct (add-on) therapies15-19. Other options for resis-

ACTH or prednisolone, above using vigabatrin (VGB), No part of this publication may be reproduced or photocopying without the prior written permission can improve cognitive results in the long term12. Both tant seizures are cannabidiol, resective surgery, stimu- steroids and VGB have potentially serious secondary lation of the vagus nerve, callosotomy, or transcranial effects, and the patient must be carefully observed. stimulation20-22. 92 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

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 © Permanyer 2019

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 of the publisher

Table 5. Treatment in Doose syndrome23‑25 PHT, PGB, and VGB should not be used, as they can 15 Evidence Recommendation aggravate myoclonic ES (Table 6) .

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 27 myoclonic astatic epilepsy or Doose or without previous therapy . 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 improvement, especially for focal seizures and generalized There are no Class I or II studies on pediatric-aged No part of this publication may be reproduced or photocopying without the prior written permission 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

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 © Permanyer 2019

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 of the publisher 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 Mexico29‑33, 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 achieve control. The remaining percentage does not achieve control with the available medicines, becoming a Question 11. Which AED is considered to 34,35 be first choice for recently diagnosed drug-resistant focal epilepsy . focal epilepsy in the pediatric patient? For childhood focal seizures, first-line monotherapy No part of this publication may be reproduced or photocopying without the prior written permission 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 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 © Permanyer 2019

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 PHT and TPM are less effective than LTG and have lower efficacy than CBZ of the publisher

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 VPA continues to be the drug of choice as monothe- using VPA, remember the teratogenic risks for ferti- rapy for all types of generalized ES in children, after le-aged patients, especially when used in high doses assessing the risk-benefit and taking into special con- (Tables 8-10)28,36-44. sideration patients with cognitive deficits, risk of overwei- ght, and teratogenic effects in fertile-aged adolescents. Other options include LEV and TPM. Administration of Question 12. Which AEDs are considered CBZ, GBP, LTG, OXC, PHT, and VGB should be avoi- to be the first choice for recently ded since they could precipitate generalized tonic-clonic diagnosed generalized epilepsy in the seizures and myoclonic seizures15,29,35. pediatric patient? No part of this publication may be reproduced or photocopying without the prior written permission Choosing an AED for generalized seizures must be Acknowledgments personalized according to age, type of seizure, tolera- We thank Dr. Mitzel del Carmen Pérez-Careta for bility, availability for use, and other aspects. editorial assistance in preparing this Guide. 95 Rev Mex Neuroci. 2019;20

27. Weir E, Gibbs J, Appleton R. Panayiotopoulos syndrome and benign References partial epilepsy with centro-temporal spikes: a comparative incidence 1. Donovan MD, Griffin BT, Kharoshankaya L, Cryan JF, Boylan GB. Phar- study. Seizure. 2018;57:66-9. macotherapy for neonatal seizures: current knowledge and future pers- 28. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guide- pectives. Drugs. 2016;76:647-61. lines: evidence-based analysis of antiepileptic drug efficacy and effecti- 2. Sankaraneni R, Lachhwani D. Antiepileptic drugs a review. Pediatr Ann. veness as initial monotherapy for epileptic seizures and syndromes. 2015;44:e36-42. Epilepsia. 2006;47:1094-120. 3. Pellock JM, Arzimanoglou A, D’Cruz O, et al. Extrapolating evidence of 29. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE eviden- antiepileptic drug efficacy in adults to children ≥2 years of age with focal ce review of antiepileptic drug efficacy and effectiveness as initial mono- seizures: the case for disease similarity. Epilepsia. 2017;58:1686-96. therapy for epileptic seizures and syndromes. Epilepsia. 2013;54:551-63. 4. Yozawitz E, Stacey A, Pressler RM. Pharmacotherapy for seizures in 30. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommen- neonates with hypoxic ischemic encephalopathy. Paediatr Drugs. 2017; dations for the management of infantile seizures: task force report for the 19:553-67. ILAE commission of pediatrics. Epilepsia. 2015;56:1185-97. 5. Linder C, Wide K, Walander M, et al. Comparison between dried blood 31. Arya R, Giridharan N, Anand V, Garg SK. Clobazam monotherapy for © Permanyer 2019 spot and plasma sampling for therapeutic drug monitoring of antiepileptic focal or generalized seizures. Cochrane Database Syst Rev. 2018; 7:CD009258. drugs in children with epilepsy: a step towards home sampling. Clin . Biochem. 2017;50:418-24. 32. Nevitt SJ, Marson AG, Weston J, Smith CT. Carbamazepine versus 6. Landmark CJ, Johannessen SI, Tomson T. Dosing strategies for antiepi- phenytoin monotherapy for epilepsy: an individual participant data review. leptic drugs: from a standard dose for all to individualised treatment by Cochrane Database Syst Rev. 2017;2:CD001911. 33. Nevitt SJ, Smith CT, Weston J, Marson AG. Lamotrigine versus carba- implementation of therapeutic drug monitoring. Epileptic Disord. 2016; mazepine monotherapy for epilepsy: an individual participant data review. 18:367-83. Cochrane Database Syst Rev. 2018;6:CD001031. 7. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a 34. Aneja S, Sharma S. Newer anti-epileptic drugs. Indian Pediatr. 2013; practical clinical definition of epilepsy. Epilepsia. 2014;55:475-82. 50:1033-40. 8. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the 35. Sánchez-Álvarez JC, Ramos-Lizana J, Machado-Casas IS, et al. Com- of the publisher epilepsies: position paper of the ILAE commission for classification and bined treatment with antiepileptic drugs. Andalusian epilepsy guide 2015. terminology. Epilepsia. 2017;58:512-21. Rev Neurol. 2015;60:365-79. 9. Shellhaas RA, Wusthoff CJ, Tsuchida TN, et al. Profile of neonatal epi- 36. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of lepsies: characteristics of a prospective US cohort. Neurology. 2017; effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, 89:893-9. or topiramate for treatment of partial epilepsy: an unblinded randomised 10. Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-do- controlled trial. Lancet. 2007;369:1000-15. se carbamazepine in neonatal epilepsy. Epilepsia. 2016;57:2019-30. 37. Smith CT, Marson AG, Chadwick DW, Williamson PR. Multiple treatment 11. Yamamoto H, Okumura A, Fukuda M. Epilepsies and epileptic syndromes comparisons in epilepsy monotherapy trials. Trials. 2007;8:34. starting in the neonatal period. Brain Dev. 2011;33:213-20. 38. Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and 12. Go CY, Mackay MT, Weiss SK, et al. Evidence-based guideline update: controlled-release carbamazepine in newly diagnosed epilepsy. Neuro- medical treatment of infantile spasms. Report of the guideline develop- logy. 2007;68:402-8. ment subcommittee of the American academy of neurology and the 39. Wechsler RT, Li G, French J, et al. Conversion to lacosamide monothe- practice committee of the child neurology society. Neurology. 2012; rapy in the treatment of focal epilepsy: results from a historical-controlled, 78:1974-80. multicenter, double-blind study. Epilepsia. 2014;55:1088-98. 13. Hancock EC, Osborne JP, Edwards SW. Treatment of Infantile Spasms. 40. Lang N, Lange M, Schmitt FC, et al. Intravenous lacosamide in clinical Copyright © 2014 the Cochrane Collaboration. Hoboken: Publicado Por practice-results from an independent registry. Seizure. 2016;39:5-9. John Wiley and Sons, Ltd.; 2014. 41. Maguire M, Marson AG, Ramaratnam S. Epilepsy (partial). BMJ Clin Evid. 14. Tournay AE. DynaMed Plus: patients with Lennox-Gastaut Síndrome. 2011;2011:1214. Spain: Marzo; 2018. 42. Smith CT, Marson AG, Williamson PR. Carbamazepine versus pheno- 15. Epilepsies: Diagnosis and Management. Clinical Guideline Publicada: 11 barbitone monotherapy for epilepsy. Cochrane Database Syst Rev. 2003; Enero; 2012. http://www.nice.org.uk/guidance/cg137. 1:CD001904. 16. Lemmon ME, Kossoff EH. New treatment options for lennox-gastaut 43. Nolan SJ, Smith CT, Pulman J, Marson AG. Phenobarbitone versus syndrome. Curr Treat Options Neurol. 2013;15:519-28. phenytoin monotherapy for partial onset seizures and generalised onset 17. Hancock EC, Cross H. Treatment of Lennox-Gastaut syndrome. Copyri- tonic-clonic seizures. Cochrane Database Syst Rev. 2013;1:CD002217. ght © 2013 the Cochrane Collaboration. Hoboken: Publicado Por John 44. Nolan SJ, Marson AG, Pulman J, Smith CT. Phenytoin versus valproate Wiley and Sons, Ltd.; 2013. monotherapy for partial onset seizures and generalised onset tonic-clonic 18. Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalized seizures. Cochrane Database Syst Rev. 2013;8:CD001769. seizures associated with the lennox-gastaut syndrome. Lamictal len- 45. Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine nox-gastaut study group. N Engl J Med. 1997;337:1807-12. and valproate monotherapy: double-blind comparison in newly diagnosed 19. Kossoff EH, Shields WD. Nonpharmacologic care for patients with len- epilepsy. Acta Neurol Scand. 2003;107:165-75. nox-gastaut syndrome: ketogenic diets and vagus nerve stimulation. 46. Gamble CL, Williamson PR, Marson AG. Lamotrigine versus carbamaze- Epilepsia. 2014;55 Suppl 4:29-33. pine monotherapy for epilepsy. Cochrane Database Syst Rev. 2006; 20. Lancman G, Virk M, Shao H, et al. Vagus nerve stimulation vs. Corpus 1:CD001031. callosotomy in the treatment of lennox-gastaut syndrome: a meta-analy- 47. Arya R, Glauser TA. Pharmacotherapy of focal epilepsy in children: a sis. Seizure. 2013;22:3-8. systematic review of approved agents. CNS Drugs. 2013;27:273-86. 21. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with 48. Koch MW, Polman SK. Oxcarbazepine versus carbamazepine monothe- seizures associated with lennox-gastaut syndrome (GWPCARE4): a ran- rapy for partial onset seizures. Cochrane Database Syst Rev. 2009; domised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018; 4:CD006453. 391:1085-96. 49. Perry S, Holt P, Benatar M. Levetiracetam versus carbamazepine mono- 22. Tzadok M, Uliel-Siboni S, Linder I, et al. CBD-enriched medical cannabis therapy for partial epilepsy in children less than 16 years of age. J Child for intractable pediatric epilepsy: the current israeli experience. Seizure. Neurol. 2008;23:515-9. 2016;35:41-4. 50. Clobazam has equivalent efficacy to carbamazepine and phenytoin as 23. Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: monotherapy for childhood epilepsy. Canadian study group for childhood clinical experience at the children’s hospital of Philadelphia. Epilepsia. epilepsy. Epilepsia. 1998;39:952-9. 2007;48:1703-7. 51. Bawden HN, Camfield CS, Camfield PR, et al. The cognitive and beha- 24. Kelley SA, Kossoff EH. Doose syndrome (myoclonic-astatic epilepsy): vioural effects of clobazam and standard monotherapy are comparable. 40 years of progress. Dev Med Child Neurol. 2010;52:988-93. Canadian study group for childhood epilepsy. Epilepsy Res. 1999; 25. von Stülpnagel C, Coppola G, Striano P, et al. First long-term experien- 33:133-43. ce with the orphan drug rufinamide in children with myoclonic-astatic 52. Rosenow F, Schade-Brittinger C, Burchardi N, et al. The laLiMo trial: epilepsy (Doose syndrome). Eur J Paediatr Neurol. 2012;16:459-63. lamotrigine compared with levetiracetam in the initial 26 weeks of mono- 26. Mizrahi EM, Watanabe K, Symptomatic neonatal seizures. In: Roger J, therapy for focal and generalised epilepsy an open-label, prospective, Bureau M, Dravet CH, editors Epileptic Syndromes in Infancy, Childhood randomised controlled multicenter study. J Neurol Neurosurg Psychiatry. and Adolescencie. 3rd ed. London: John Libbey; 2002. 2012;83:1093-8. No part of this publication may be reproduced or photocopying without the prior written permission

96 Revista Mexicana de Neurociencia

REVIEW ARTICLE

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, © Permanyer 2019 8 9 10

Guadalupe Vargas-Ramírez , Jaime López-Rivera and Rosana Huerta-Albarrán . 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 of the publisher

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

Correspondence: Alma Maritza Huerta Hurtado Date of reception: 01-02-2019 Available online: 12-04-2019 No part of this publication may be reproduced or photocopying without the prior written permission Guadalajara, Jalisco, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):97-103 E-mail: [email protected] 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/). 97 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 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 © Permanyer 2019

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 FeS: febrile seizures of the publisher

diazepam [DZP]) before 15th min must also be classified by a pediatrician to then decide again whether to carry within this group15,18. out a lumbar puncture15 (Table 1). It is considered a febrile status epilepticus when a complex FeS lasts >30 min, or when there are shorter 4. How are SFeS or CFeS treated during serial FeS without recovering consciousness during the the acute ictal phase? interictal state6,10,15,16. Managing SFeS begins with training the parents for home management22 (Table 2). Informing the parents 3. When do you carry out a lumbar that their child will not die, that association with epi- puncture in the first SFeS? lepsy is rare, and that the frequency of SFeS is reduced 13,16,23,24 In children of any age that have their first FeS, it is with age . Warning them that if the seizure lasts important to discard an infection in the CNS (encepha- 5 min or more, they must call an ambulance, provide litis/meningitis). Pay special attention when children are emergent initial therapy, or go to the emergency room. Various authors support that intervention during the younger than 6 months, seizures last more than 15 min, acute phase is rarely required12,28. there are more than two seizures within a 24-h time In the case of recurrent seizures, administer emer- period when there are focal motor or non-motor seizu- gent initial therapy with the knowledge that the use of res with affected alertness, and/or when the child pre- benzodiazepine may cause respiratory depression24. sents the following clinical data: Benzodiazepine intravenous (IV), intramuscular, oral, – Sleepiness alternating with irritability or Glasgow intranasal, or rectal can be used to abort the crisis but scale below 15 points. is not recommended for prophylactic treatment1,25 – Neck stiffness, Kernig’s sign, and Brudzinski’s sign. (Table 3). – Vomit, tense or bulging fontanelle, and papilledema. In a systematic review about the use of AEDs for on- – Presence of macular or petechial exanthem. going convulsive seizures, including epileptic status, they – Abnormal postures during the postictal state or if stu- analyzed the efficacy and safety of using Midazolam 6,19-21 por remains for over an hour after a seizure . (MDL), DZP, lorazepam (LZP), phenytoin (PHT), pheno- The risk of bacterial meningitis in children that pre- barbital (PB), and paraldehyde, concluding that IV or sent with fever and seizures is about 3%, but in a CFeS rectal LZP is as effective or more effective than DZP26. it is 9%. Thus, lumbar puncture must be carried out in

Oral MDL is more effective than rectal DZP, and the in- No part of this publication may be reproduced or photocopying without the prior written permission all children with CFeS and suspected CNS infection. In tranasal form is as effective as IV DZP. Oral or nasal MDL the case of CFeS without clinical signs of meningitis, is the treatment of choice when there is no access to IV they must be closely observed and checked after 2 h or for home management by the parents26-28 (Table 4). 98 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

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 © Permanyer 2019

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 of the publisher

Table 3. Emergent initial therapy for acute (ictal) management of FeS in children25 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 No part of this publication may be reproduced or photocopying without the prior written permission

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

99 Rev Mex Neuroci. 2019;20

Hospitalization criteria complex), as well as the adverse effects. The results showed that clobazam is safe, effective, requires a Independently of the length of the seizure, the patient lower dose, and has fewer adverse effects than DZP, must be assessed by medical history, documentation suggesting it as a good alternative for preventing recu- of SFeS history, epilepsy, immunizations, duration of rrence of FeS34. In addition, in 2017, another group the seizure, postictal phase, and any focal symptom4. demonstrated a significant difference in the prevention The American Academy of Pediatrics recommends that of recurrence after treatment with levetiracetam versus hospitalization is unnecessary for clinically stable pa- no treatment after 50 weeks14 Table 5.

tients older than 18 months, without signs or symptoms © Permanyer 2019 that require diagnostic studies29. Parents are trained

for home management (Table 1)22. Hospitalization 6. What paraclinical tests are necessary . recommended for children younger than 18 months, for after the first FeS? observation and possible lumbar puncture. Patients Diagnostic tests (analytic, electroencephalogram previously diagnosed with recurrent FeS do not require (EEG), and cerebral imaging) are usually unnecessary hospitalization12,29 (Table 1). and, currently, are not routinely recommended for pa- of the publisher tients with simple FeS15,17. 5. Is long-term antiepileptic treatment required for FeS? Electroencephalogram Simple FeS, SFeS Not indicated for the assessment of a neurologically 6 A systematic review that assesses the use of conser- healthy child with simple FeS . In a focal and/or prolon- vative and antipyretic measures concluded that there ged convulsion, it is recommended to carry out an EEG is no evidence that they have any usefulness in pre- and neurologic follow-up, due to the greater risk of deve- venting SFeS reccurences30. There is no evidence for loping epilepsy. A short, generalized convulsion that is the clinical usefulness of continuous or intermittent use repeated twice in 24 h is, by definition, a complex con- of antiepileptic drugs (oral or rectal DZP, PB, vulsion, but it is also not necessary to conduct an EEG diphenylhydantoin, or valproate) in SFeS23. There is no unless the neurologic examination shows alterations. evidence that continuous or intermittent treatment with The EEG does not allow prediction of which children antiepileptic drugs in SFeS can prevent the subsequent are at greater risk to suffer new seizures. Epileptiform development of epilepsy6,18,31. 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- Complex FeS CFeS leptiform discharges in the EEG and a high risk of afe- Long-term routine prophylaxis with antiepileptic drugs brile/epileptic seizures35. The EEG has low sensitivity is not recommended since there is no clear information in children under 3 years of age, after an unprovoked about their use in complex FeS23. There is evidence convulsion35-37. that supports intermittent use of PB and antipyretics, clobazam, or rectal DZP, to prevent recurrence of com- Laboratory tests plex FeS. However, the information does not clearly distinguish simple from complex seizures, and there They can be considered under certain clinical condi- may be bias due to the relative incidence of both types tions but are not routinely carried out in a child after his of seizures32. first FeS with an evident source of infection. They will Regular use of antiepileptic drugs can be considered only identify the source of the child’s fever and are not for patients with long or repetitive FeS despite the pro- necessary as part of the assessment of the seizure6,17. phylactic use of DZP33. Carbamazepine and PHT are not effective for preventing the recurrence of FeS and 24 Neuroimaging

thus, should be avoided . No part of this publication may be reproduced or photocopying without the prior written permission A prospective study, carried out in 2014, compared Highly recommended for patients with FeS that do the efficacy of intermittent use of clobazam versus DZP not regain complete consciousness in hours, with pro- to prevent recurrence of FeS (both simple and longed Todd’s paralysis (post-critical), or with other 100 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 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 © Permanyer 2019 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 of the publisher 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 be referred to the neuropediatrician? Population risk of a FeS is 2.7-3.1%36. 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- No part of this publication may be reproduced or photocopying without the prior written permission 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 101 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

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 © Permanyer 2019

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 of the publisher

Neurologic abnormalities (retarded development or CCP)

Focal epileptogenic discharges

CFeS: complex febrile seizure, FeS: febrile seizure

of epilepsy7. Providing the family with information about 5. Auvin S, Antonios M, Benoist G, et al. Evaluating a child after a febrile seizure: insights on three important issues. Arch Pediatr. 2017;24: the illness and the risk of recurrence during the illness 1137-46. 6. American Academy of Pediatrics. Clinical practice guideline. Febrile sei- or in the future should be carried out by the pediatri- zures: guideline for the neurodiagnostic evaluation of the child with a cian. However, if the clinical history shows >2 risk simple febrile seizure. Pediatrics. 2011;127:389-94. 7. Frascari F, Dreyfus I, Chaix Y, Tison-Chambellan C. Efficacy of an inter- factors of seizure recurrence or the patient fulfills the ventional educational programme in mitigating posttraumatic stress in requirements for complex FeS, we recommend he be parents who have witnessed a febrile seizure: a pilot before-and-after study. BMJ Paediatr Open. 2017;12:1-6. referred to the neuropediatrician. 8. Assogba K, Balaka B, Touglo FA, Apetsè KM, Kombaté D. Febrile seizures in one-five aged infants in tropical practice: frequency, etiology and outcome of hospitalization. J Pediatr Neurosci. 2015;10:9-12. 9. Guía de Practica Clínica: diagnóstico y Tratamiento de la Fiebre en Niños Conclusion de 3 Meses a 5 Años. CENETEC; 2013. 10. Moreno N. Crisis febriles simples y complejas, epilepsia generalizada con crisis febriles plus, FIRES y nuevos síndromes. Medicina. 2013;73: FeS is an age-dependent phenomenon, related to 63-70. individual genetic predisposition and with a special vul- 11. Zeballos J, Cerisola A, Pérez W. Primera convulsión febril en niños asistidos en un servicio de emergencia pediátrica. Arch Pediatr Urug. nerability of the developing CNS to the effects of fever. 2013;84:18-25. 12. Gupta A. Febrile seizures. Continuum (Minneap Minn). 2016;22:51-9. The continued or intermittent prophylactic treatment 13. Byeon JH, Kim GH, Eun BL. Prevalence, incidence, and recurrence of with antiepileptic drugs does not reduce the risk of febrile seizures in Korean children based on national registry data. J Clin Neurol. 2018;14:43-7. subsequent epilepsy and, although it is effective to 14. Li XC, Lu LL, Wang JZ, et al. Clinical characteristics and electroencepha- reduce recurrences, its toxicity surpasses the few risks logram analysis of levetiracetam in the treatment of children with febrile seizure recurrence. Exp Ther Med. 2017;14:2015-20. of FeS. 15. Capovilla G, Mastrangelo M, Romeo A, Vigevano F. Recommendations for the management of “febrile seizures”: ad hoc task force of LICE Informed and responsible parental counseling are the guidelines commission. Epilepsia. 2009;50 Suppl 1:2-6. greatest contribution that the physician can make for 16. Blanco M, Gascón J. Evaluación y Tratamiento de las Convulsiones Fe- briles. en: guía de la Sociedad Andaluza de Epilepsia; 2015. p. 161-70. the care of children with FeS. 17. López RB, Fernández JM, Antón JM, Fernández MG, Cardona AU. Complex febrile seizures: study of the associated pathology and practical use of complementary tests. An Pediatr (Barc). 2014;80:365-9. 18. Knudsen FU. Febrile seizures: treatment and prognosis. Epilepsia. References 2000;41:2-9. 19. Sugai K. Current management of febrile seizures in Japan: an overview. 1. Pavone P, Corsello G, Ruggieri M, et al. Benign and severe early-life Brain Dev. 2010;32:64-70. seizures: a round in the first year of life. Ital J Pediatr. 2018;44:54. 20. Kimia AA, Ben-Joseph E, Prabhu S, et al. Yield of emergent neuroima- 2. Takasu M, Kubota T, Tsuji T, et al. The semiology of febrile seizures: ging among children presenting with a first complex febrile seizure. Pe- No part of this publication may be reproduced or photocopying without the prior written permission focal features are frequent. Epilepsy Behav. 2017;73:59-63. diatr Emerg Care. 2012;28:316-21. 3. Martínez C, Herráiz-Martínez M. Crisis febriles complejas: debemos cam- 21. Shaked O, Peña BM, Linares MY, Baker RL. Simple febrile seizures: are biar nuestro modo de actuación? Rev Neurol. 2014;59:449-58. the AAP guidelines regarding lumbar puncture being followed? Pediatr 4. Chung S. Febrile seizures. Korean J Pediatr. 2014;57:384-95. Emerg Care. 2009;25:8-11. 102 C. Aguirre-Velázquez, et al.: Febrile seizures, diagnosis, and treatment

. 22 Silverman EC, Sporer KA, Lemieux JM, et al. Prehospital care for the 32. Salehiomran M, Hoseini SM, Juibary AG. Intermittent diazepam versus adult and pediatric seizure patient: current evidence-based recommen- continuous phenobarbital to prevent recurrence of febrile seizures: a dations. West J Emerg Med. 2017;18:419-36. randomized controlled trial. Iran J Child Neurol. 2016;10:21-4. 23. Offringa M, Newton R. Prophylactic drug management for febrile seizures 33. Natsume J, Hamano SI, Iyoda K, et al. New guidelines for management in children. Evid Based Child Health. 2013;8:1376-485. of febrile seizures in Japan. Brain Dev. 2017;39:2-9. 24. Patel AD, Vidaurre J. Complex febrile seizures: a practical guide to 34. Sattar S, Saha SK, Parveen F, et al. Intermittent prophylaxis of recurrent evaluation and treatment. J Child Neurol. 2013;28:762-7. febrile seizures with clobazam versus diazepam. Mymensingh Med J. 25. Zhao ZY, Wang HY, Wen B, et al. A comparison of midazolam, loraze- 2014;23:676-85. pam, and diazepam for the treatment of status epilepticus in children: a 35. Cappellari AM, Brizio C, Mazzoni MB, et al. Predictive value of EEG for network meta-analysis. J Child Neurol. 2016;31:1093-107. febrile seizure recurrence. Brain Dev. 2018;40:311-5. 26. McTague A, Martland T, Appleton R. Drug management for acute to- 36. Armon K, Stephenson T, MacFaul R, et al. An evidence and consensus nic-clonic convulsions including convulsive status epilepticus in children. based guideline for the management of a child after a seizure. Emerg Med J. 2003;20:13-20. Cochrane Database Syst. Rev 2018;1:CD001905.

37. Harini C, Nagarajan E, Kimia AA, et al. Utility of initial EEG in first com- © Permanyer 2019 27. Mewasingh LD. Febrile seizures. BMJ Clin Evid. 2014;2014:324. plex febrile seizure. Epilepsy Behav. 2015;52:200-4. 28. Sirsi D. Is intranasal midazolam better than rectal diazepam for home 38. Graves R, Oehler K. Febrile seizures: risks, evaluation, and prognosis.

management of acute seizures? Arch Neurol. 2011;68:120-1. Am Fam Phys. 2012;85:149-53. . 29. American Academy of Pediatrics. Provisional committee on quality im- 39. Gencpinar P, Yavuz H, Bozkurt Ö, Haspolat Ş, Duman Ö. The risk of provement, subcommittee on febrile seizures. Practice parameter: the subsequent epilepsy in children with febrile seizure after 5 years of age. neurodiagnostic evaluation of the child with a first simple febrile seizure. Seizure. 2017;53:62-5. Pediatrics. 1996;97:769-75. 40. Pavlidou E, Panteliadis C. Prognostic factors for subsequent epilepsy in 30. Rosenbloom E, Finkelstein Y, Adams-Webber T, Kozer E. Do antipyretics children with febrile seizures. Epilepsia. 2013;54:2101-7. prevent the recurrence of febrile seizures in children? A systematic re- 41. Olson H, Rudloe T, Loddenkemper T, Harper MB, Kimia AA. Should view of randomized controlled trials and meta-analysis. Eur J Paediatr patients with complex febrile seizure be admitted for further manage- Neurol. 2013;17:585-8. ment? Am J Emerg Med. 2018;36:1386-90. of the publisher 31. Baumann RJ, Duffner PK. Treatment of children with simple febrile sei- 42. Visser AM, Jaddoe VW, Ghassabian A, et al. Febrile seizures and beha- zures: the AAP practice parameter. American academy of pediatrics. vioural and cognitive outcomes in preschool children: the generation R Pediatr Neurol. 2000;23:11-7. study. Dev Med Child Neurol. 2012;54:1006-11. No part of this publication may be reproduced or photocopying without the prior written permission

103 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: epilepsy in pregnancy and women of childbearing age © Permanyer 2019 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 Gea González e Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco“. Mexico City, Mexico. of the publisher

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

Correspondence: Perfecto Oscar González-Vargas Hospital Perinatal Mónica Pretelini Toluca, Mexico State, Mexico E-mail: [email protected] Yamil Matuk Pérez Date of reception: 31-01-2019 Available online: 12-04-2019 No part of this publication may be reproduced or photocopying without the prior written permission Hospital General de Querétaro, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):104-109 E-mail: [email protected] 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 P. O. González-Vargas, et al.: Epilepsy in women and risk of hirsutism, central cause amenorrhea, hype- even in spite of this being counterproductive, since it randrogenemia, and infertility. The risk of infertility can has been demonstrated that during a ES the fetus su- be up to 10% greater than those of the general popula- ffers anoxia, fetal tachycardia, uterine contractions, in- tion and is greater with polytherapy, with temporal lobe creased risk of preterm labor, and low birth weight. One epilepsy, and the use of PB2. AEDs have a bidirectional Canadian study demonstrated that up to 30% of neu- relationship with hormonal contraceptives3. There are rologists are unaware of the obstetric complications of variations in serum concentration of AED, depending on PWWE. Thus, we can infer that the OB/GYN is also the mechanism of action of the drug and the type of unaware of treatment complications for PWWE9-11. contraceptive4. According to the WHO and the CDC, A planned pregnancy demonstrates that there is be- © Permanyer 2019 progesterone and combined oral contraceptives, as well tter control of the ES and shows apparent improvement

. as contraceptive patches and vaginal rings are not re- in the obstetric complications of labor. commended as first-line contraceptives for women that take EI-AED. Medroxyprogesterone and levonorgestrel Which AED should be used for the implants can be used by women who take EI-AED. It is PWWE? recommended to avoid combining LMT and contraceptive methods that contain estrogens, due to the risk of There is no first choice AED for the PWWE, and the of the publisher loss of control of ES. The IUD is recommended as the AED must be adequate for the type of epilepsy suffered contraceptive of choice for WWE5. by the patient. There have been major congenital malformations (CM) described in products of those PWWE that took EAD during their pregnancy. In these cases, Should AED treatment be suspended in structural CM have been reported, such as hypospa- pregnant WWE (PWWE)? dias, neural tube defects (NTD), congenital cardiopathy, A review published by the AAN in 2009, did not find and cleft palate. Long-term cognitive teratogenic effects studies with high levels of evidence that indicate are also observed in children whose mothers took AED changes in the frequency of ES during pregnancy, but during pregnancy, although the studies are not conclu- information is limited. There is between 84 and 92% sive7. The risk of CM with AED varies depending on the probability that the pregnancy will continue normally type of AED used, the dose, and whether it was used with proper control if the WWE has been seizure-free in mono or polytherapy. In general, the average risk of for 9-12 months before getting pregnant6. CM with AED varies between 4 and 14%, while in the For PWWE, the use of AED in monotherapy and at open population risk of CM is about 3%. The risk of CM low doses is suggested. Preferably, AEDs with a grea- with CBZ is about 2.2%, LMT is 3.2%, PHT is 3.7%, ter risk of teratogenicity should be avoided, such as and it is >13% for VPA. It must be pointed out that VPA, which has been demonstrated to increase this combining CBZ with LMT has a 3% risk of CM. When risk up to 13.8%7. The greatest risk of congenital mal- polytherapy includes VPA, the risk of CM can increase formations is considered to be during the first trimester to up to 13.8%, especially for NTD. For WWE who have of pregnancy, so once neural tube formation is comple- had a product with a CM, the risk of CM in subsequent ted (second and third trimester of pregnancy), the con- pregnancies with the use of AED increases up to traindication to suspend VPA is relative, and generally, 16.8%. During pregnancy, serum levels of CBZ, LMT, the change of an AED during pregnancy is not recom- PHT, and LEV are reduced; thus, serum concentrations mended due to the risk of uncontrolled ES8. PHT, PB, of these AED must be determined before conception and TPM have been demonstrated to have an interme- and during the first trimester of pregnancy. In develo- diate risk of congenital malformations, whereas LTG, ped countries, the most commonly used AED are LMT, CBZ, and LEV show low rates of such malformations7. and LEV, and in our Country, CBZ is considered to be The frequency of ES is increased when patients dis- the most commonly used as well as, paradoxically, continue the use of their AED, so patients must have VPA11-13. control of the ES and discipline in taking their AED. It is frequent that PWWE suspend their AED for fear of What is the approach and treatment for

the risk of congenital malformations of the fetus, due No part of this publication may be reproduced or photocopying without the prior written permission uncontrolled ES in PWWE? to nausea and vomiting associated to pregnancy, the pharmacokinetic changes of the AED, and insomnia; it The presence of ES during pregnancy could be due is even frequent that treating physicians suspend AED, to three circumstances: uncontrolled ES in PWWE, 105 Rev Mex Neuroci. 2019;20

debut of ES, and obstetric problems. The first of these if pregnancy is planned and should continue at least circumstances is the most common, and the main re- during the first trimester. It is considered that, in addition ason is the lack of compliance with the antiepileptic to the reduction of NTD, the development of other mal- treatment; this commonly happens to PWWE, and so formations, such as cleft palate, can also be reduced. one must investigate and persuade therapeutic adhe- If there is a history of an infant with NTD, the daily rence. Other factors must be taken into consideration, recommendation is 4 or even 5 mg of folic acid, since such as genetic factors, changes in serum concentra- there are no adverse effects related to this vitamin. It has tions of AED, sleep suppression, stress, and been calculated that this results in a reduction in NTD of

hyperemesis gravidarum induced by pregnancy. The up to 85%. This recommendation is especially important © Permanyer 2019 management of uncontrolled ES in PWWE must follow for WWE that take polytherapy or use VPA18-20.

. the same protocol as that of any other patient with epi- As for Vitamin K, it was previously proposed that by lepsy. Despite the seriousness of ES, they do not in- giving doses of the said vitamin to PWWE during the third crease in frequency in PWWE. trimester, you could prevent intracranial hemorrhaging in Once the ES are controlled, one must restart the AED neonates. It was thought that PWWE that took enzymatic the patient was taking, if the motive was lack of disci- inducing AED (CBZ, PG, and PHT) had increased risk of pline. In this case, adjust the AED treatment depending this hemorrhagic complication in their products. In a of the publisher on the type of epilepsy and with the adequate dose14,15. study of more than 600 patients, it was demonstrated that there was no increase in the risk of hemorrhages in the What are the obstetric complications for products of PWWE that took these AED compared to PWWE? controls; thus, there is not sufficient evidence to recommend the use of Vitamin K in PWWE7,21. There is a dilemma in terms of the increase in obstetric risk in PWWE. Previously, there was no evidence that Is breastfeeding safe in WWE? confirmed it, but recent studies have demonstrated a risk of presenting preeclampsia, maternal infection, placental The benefits of maternal breastfeeding are well de- abruption, emergency cesarean sections, risk of fetal monstrated, it’s even beneficial for the mother since it death, abortions, neonatal infections, risk of neonatal reduces the risk of postpartum depression as well as asphyxia with Apgar lower than 5 points in the 1st min, generating a psychologic bond with the infant conver- neonatal hypoglycemia, and neonatal hypoxia16,17. sely, the BBB in neonates has not been completely formed; thus, it is susceptible to drugs. Therefore, there What is the utility of folic acid and must be an adequate risk-benefit analysis. Vitamin K in PWWE? Patients get confused because they receive information from the obstetrician, the neonatologist or the neu- One of the most frequent congenital malformations rologist, this in conjunction with the social concept that of the CNS is NTD. Folate receptors are critical for fetal the WWE cannot breastfeed. Studies show that breas- neural tube and neural crest formation. Folate deficien- tfeeding has geographical variations, at educational cy causes a reduction in the mitotic capacity of neural levels, and is lower among WWE that take LMT or are crest or neural tube cells. Folic acid is the synthetic receiving polytherapy. form of folate (Vitamin B9). Mexico is one of the coun- The concentration of an AED in maternal milk is de- tries with the greatest frequency of NTD. The worldwide pendent on the serum levels of the drug and the me- recommendation (WHO) is that childbearing-aged wo- tabolism of the infant. Although there are mathematical men supplement with 0.4-0.8 mg of folic acid daily formulas to calculate AED concentrations in maternal since it is calculated that 75% of them do not consume milk, it is not practical to use this method in daily prac- the optimal dose of folic acid. However, for NTD pre- tice. Furthermore, the AED concentrations are different vention, the dose is greater. There is no consensus on and individual for each AED. the larger dose; the objective is to achieve high tissue There are studies that aim to investigate the cognitive levels of folic acid in the 1st weeks of pregnancy, during effects on children exposed to AEDs during breastfee-

the time that the neural tube is formed. ding, but the results are contradictory. No part of this publication may be reproduced or photocopying without the prior written permission As a large percentage of WWE have unplanned preg- The recommendations from the AAN, in 2009, about nancies, it is recommended to take folic acid daily; it breastfeeding were not conclusive, and later studies have should be taken for at least 1 month before conception not demonstrated the existence of contraindications for 106 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 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.

. 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 of the publisher 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 No part of this publication may be reproduced or photocopying without the prior written permission

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

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

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 of the publisher

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 No part of this publication may be reproduced or photocopying without the prior written permission to reduce the risk of NTD.

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

108 P. O. González-Vargas, et al.: Epilepsy in women

Evidence and PPE recommendations Level/recommendation

Evidence Level

The benefits of breast milk are accepted worldwide. I

The concentration of AED in breast milk of a WWE, essentially depends on the serum concentration of the drug. II

Unless there is clinical evidence of neonatal secondary effects (sleepiness and others), WWE should not III suspend breastfeeding.

WWE must breastfeed without clinical contraindications unless the neonate presents secondary effects. R‑PPE © Permanyer 2019

One must be careful about breastfeeding when WWE are taking PB, BZD, or are undergoing polytherapy. R‑PPE

. Unless there is clinical evidence of neonatal secondary effects (sleepiness and others) breastfeeding R‑PPE should not be suspended in WWE. of the publisher 14. Aya AG, Ondze B, Ripart J, Cuvillon P. Seizures in the peripartum period: References epidemiology, diagnosis and management. Anaesth Crit Care Pain Med. 1. Instituto Nacional de Estadística y Geografía. Población; 2015. https:// 2016;35 Suppl 1:S13-S21. www.inegi.org.mx/temas/estructura. [Last accessed 2018 May]. 15. Vajda FJ, Hitchcock A, Graham J, et al. Seizure control in antiepileptic 2. Yang Y, Wang X. Sexual dysfunction related to antiepileptic drugs in drug-treated pregnancy. Epilepsia. 2008;49:172-6. patients with epilepsy. Expert Opin Drug Saf. 2016;15:31-42. 16. Razaz N, Tomson T, Wikström AK, Cnattingius S. Association between 3. Harden CL, Pennell PB. Neuroendocrine considerations in the treatment pregnancy and perinatal outcomes among women with epilepsy. JAMA of men and women with epilepsy. Lancet Neurol. 2013;12:72-83. Neurol. 2017;74:983-91. 4. Mandle HB, Cahill KE, Fowler KM, et al. Reasons for discontinuation of 17. MacDonald SC, Bateman BT, McElrath TF, Hernández-Díaz S. Mortality reversible contraceptive methods by women with epilepsy. Epilepsia. and morbidity during delivery hospitalization among pregnant women with 2017;58:907-14. epilepsy in the United States. JAMA Neurol. 2015;72:981-8. 5. Espinera AR, Gavvala J, Bellinski I, et al. Counseling by epileptologists 18. González-Vargas PO, Savery D, Gerrelli D. Defectos del tubo neural. affects contraceptive choices of women with epilepsy. Epilepsy Behav. Experiencia en un hospital de Toluca, México. Arch Neurocien (Mex) 2016;65:1-6. 2007;12:171-5. 6. Harden CL, Hopp J, Ting TY, et al. Practice parameter update: manage- 19. Ban L, Fleming KM, Doyle P, et al. Congenital anomalies in children of ment issues for women with epilepsy focus on pregnancy (an eviden- mothers taking antiepileptic drugs with and without periconceptional high ce-based review): Obstetrical complications and change in seizure fre- dose folic acid use: a population-based cohort study. PLoS One. quency: report of the quality standards subcommittee and therapeutics 2015;10:e131130. and technology assessment subcommittee of the American academy of 20. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, neurology and American epilepsy society. Neurology. 2009;73:126-32. et al. Folic acid supplementation for the prevention of neural tube defects: 7. Gerard EE, Meador KJ. Managing epilepsy in women. Continuum (Min- US preventive services task force recommendation statement. JAMA neap Minn). 2016;22:204-26. 2017;317:183-9. 8. Bromley RL, Baker GA. Fetal antiepileptic drug exposure and cognitive 21. Kaaja E, Kaaja R, Matila R, Hiilesmaa V. Enzyme-inducing antiepileptic outcomes. Seizure. 2017; 44:225-31. drugs in pregnancy and the risk of bleeding in the neonate. Neurology. 9. Tomson T, Battino D, Bonizzoni E, et al. Withdrawal of valproic acid 2002;58:549-53. treatment during pregnancy and seizure outcome: observations from 22. Harden CL, Meador KJ, Pennell PB, et al. Practice parameter upda- EURAP. Epilepsia. 2016;57:e173-7. te: management issues for women with epilepsy focus on pregnan- 10. Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA. Predictors cy (an evidence-based review): Teratogenesis and perinatal outco- of unintended pregnancy in women with epilepsy. Neurology. 2017; mes: report of the quality standards subcommittee and therapeutics 88:728-33. and technology assessment subcommittee of the American aca- 11. Roberts JI, Metcalfe A, Abdulla F, et al. Neurologists‘ and neurology demy of neurology and American epilepsy society. Neurology. residents‘ knowledge of issues related to pregnancy for women with 2009;73:133-41. epilepsy. Epilepsy Behav. 2011;22:358-63. 23. Veiby G, Bjørk M, Engelsen BA, Gilhus NE. Epilepsy and recommenda- 12. Tomson T, Xue H, Battino D. Major congenital malformations in children tions for breastfeeding. Seizure. 2015;28:57-65. of women with epilepsy. Seizure. 2015;28:46-50. 24. Lavi-Blau T, Ekstein D, Neufeld MY, Eyal S. Use of antiepileptic drugs 13. Bollig KJ, Jackson DL. Seizures in pregnancy. Obstet Gynecol Clin during pregnancy and lactation: type of information provided by searching North Am. 2018;45:349-67. google. Epilepsy Behav. 2016;55:113-9. No part of this publication may be reproduced or photocopying without the prior written permission

109 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: status epilepticus in children and adults

Alejandro Olmos-López1, Jorge Ibarra-Aguilar2, José O. Cornelio-Nieto3, Luis A. Ocaña-Hernández4,

Ildefonso Rodríguez-Leyva . 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 of the publisher

Abstract

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

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 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 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 of the publisher 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 the first or second level hospitals do not have elec- autonomic, sensory, olfactory, visual, auditory, 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 manifestations 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 and generally, with paramedics that will help maintain SE in defined electroclinical syndromes 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 administer a standard dose (Table 5) diazepam or lorazepam 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. No part of this publication may be reproduced or photocopying without the prior written permission 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 111 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 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

10 mg in older than 5 years 6. What is the second-line pharmacologic . Rectal: 0.5 mg/kg. From 1 to 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 of the publisher benzodiazepines alone have not been effective in sub- and lingual obstruction), and if necessary and avai- verting the crisis1,2,4. lable, administer oxygen. In adults, intravenous levetiracetam, phenytoin, or – Monitor vital signs. VPA can be used (level A)1,2. In children, the guidelines – Test for glycemia using a Destrostix, if possible. from the American Epilepsy Society state that there is – Administer a standard dose (child or adult) of benzo- insufficient evidence to evaluate phenytoin and leveti- diazepine by rectal, nasal, intramuscular, or intrave- racetam as second-line treatments (level U), however nous administration. valproic acid has similar efficacy and better tolerability than intravenous phenobarbital (level B)3. The US Na- 4. What are the initial measures that must tional Institutes of Health have implemented a protocol be taken for the management of SE? for the treatment of SE comparing phenytoin, VPA, and levetiracetam in children and adults, contributing rele- 0-5 min: vant information about these drugs (level C)5. – ABCDE. In some studies6,7, phenytoin, and fosphenytoin are – Duration. the most commonly used drugs if SE persists in spite – Oxygen. of benzodiazepine administration. A recent meta-analy- – Monitorization. sis8 of drugs administered for SE refractory to benzo- – Determination of glycemia (in adults, if glucose was diazepines demonstrated the efficacy of phenytoin lower than 60 mg, administer thiamine, and 50 ml (50%), levetiracetam (69%), phenobarbital (74%), and 50% glucose; for children older than 2 years, 2 ml/kg VPA (76%) (all C). of 25% glucose solution. – Place venous access and take blood for laboratory tests (complete blood count, serum electrolytes, drug 8. What is the initial pharmacologic serum levels, and toxicologic screen). treatment for other SE (Focal and – If it is considered necessary, place the urinary catheter. non-motor)? – Complete diagnostic approach: continuous EEG, computed axial tomography, lumbar puncture, and Non-motor SE (NCSE) is an entity that is difficult to magnetic resonance imaging (preferred over cranial recognize clinically due to its heterogeneity. Its diagnosis computed tomography). 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 5. What is the initial pharmacologic finished. NCSE must be considered for any patients with treatment to manage generalized motor altered consciousness presenting one or more of these No part of this publication may be reproduced or photocopying without the prior written permission SE? situations: coma, lethargy, and confusion. For focal SE: Benzodiazepines are the first-line treatment for the Todd’s paralysis, which is a neurologic focal deficit of the management of SE (Table 5). last hours or days, especially if it is after a seizure. 112 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

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

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

Table 7. Second‑line drugs in SE treatment Patient Intervention Comparison Result of the publisher 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 – Aggressive treatment, similar to management of con- convulsive SE and requires discovery of compatible vulsive SE, preferred for patients that have had a electroencephalic changes persisting for >10 min10,11. symptomatic convulsive event (after an event of asphyxia or acute hypoxia, perinatal hypoxic encepha- Diagnostic criteria lopathy, Cardiovascular disease, automated external defibrillator suppression, etc.) since the morbimorta- – Alterations in consciousness or other neurological lity is high in these patients. deficit. – For the rest of the primary non-convulsive SE, mor- – Epileptiform EEG: discrete epileptic paroxysms or bimortality is low and less aggressive management, continuous discharges. using oral or parenteral administration is preferred, – Response to anticonvulsants: clinical or electroence- which reduces the morbimortality inherent in the use phalographic. of central nervous system depressant drugs used to The most frequent types of NCSE are the focal manage SE. non-convulsive, the absence status, the continuous Instructions for administration (IV) and pharmacoki- partial epilepsy, the continuous aura, persistent hemi- netics of anti-epileptic drugs in refractory SE: paresis, and others of lesser frequency. It is classified MDZ 0.2-0.3 mg/kg or 4 mg/2 min, 0.1-0.5 mg/kg/ as follows: hour, 0.2-1 µg/ml in bolus. Propofol 1-2 mg/kg. Slowly, – Comatose form: generalized or focal (must be treated 5-10 mg/kg/h. Thiopental 100-200 mg 30s 3-5 mg/kg/h, if it lasts >30 min). May or may not be preceded by 25-50 µg/ml in bolus, followed by 50 mg every 2-3 mi- a convulsive SE. nutes until the ES is controlled. Ketamine 0.5-4.5 mg/ – NCSE proper form: absence status (typical absence, Kg (up to 5 mg/Kg/h). atypical absence, and late-onset absence), treatment The patient must be closely monitored to avoid hypo-

is recommended after 15 min. Focal SE, with or wi- tension, sepsis, atelectasis, pneumonia, or cerebral No part of this publication may be reproduced or photocopying without the prior written permission thout altered consciousness, initiating treatment is venous thrombosis, to the extent possible. On occa- recommended after 10 min. sion, parenteral feeding for the patient may be For treatment, there are two recommended methods: necessary. 113 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

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

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. of the publisher Evidence and level of – Convulsive focal onset seizures. recommendation – Young patient11-18. Treatment for SE Complications: Lorazepam Class I/Level A – Prolonged ventilator use and its complications. MDZ Class I/Level A 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 Management – MDZ: initial 0.2 mg/kg IV in 2-5 min, repeat in bolus 9. ¿When is a generalized convulsive SE of 0.2-0.4 mg every 5 min until the seizure stops. considered to be refractory to treatment? Maintenance at 0.05-2.9 mg/Kg/h. – Propofol: initial 1-2 mg/kg IV in 3-5 min, repeat bolus Refractory SE is defined as a generalized epileptic every 3-5 min until the seizure stops. Initial infu- seizure that persists despite the use of two anti-epileptic sion at 20 mcg/kg/minute, with maintenance of drugs: at least one first-line drug (benzodiazepine) and 30-200 mcg/Kg/minute. another second-line drug. The super-refractory SE is – VPA: 40 mg/Kg IV with an additional 20 mg/kg, main- defined as a SE that continues or recurs in 24 h or more tenance of 40 mg/kg/day. once anesthesia has been initiated, when it is removed, – Pentobarbital: initial 5 mg/kg IV up to 50 mg/minute, or when it is completely terminated. It can also be con- repeat in bolus of 5 mg/kg until the seizure stops, sidered when there are clinical or encephalographic maintenance of 0.5-10 mg/kg/h (Tables 6-9). seizures after benzodiazepine treatment and an ade- – Ketamine: 1-2 mg/kg IV in 1 minute, maintenance of quately selected anti-epileptic drug. 0.01-0.03 mg/kg/minute IV (adjust in the case of he- Predictors of a Refractory SE: patic insufficiency). No part of this publication may be reproduced or photocopying without the prior written permission – Non-structural causes: hypoxia, toxic-metabolic, and – Corticosteroids: It is recommended especially in ca- infection. ses of super-refractory cases associated with Hashi- – Hyponatremia in the previous 24 h. moto’s encephalitis or Rasmussen’s encephalitis. 114 A. Olmos-López, et al.: Status epilepticus in children and adults

A ketogenic diet could be an alternative, especially 3. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol. 2010;17:348-55. for children with catastrophic epilepsy. Vagus nerve 2. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17:3-23. stimulation is another alternative for super-refractory 4. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the mana- SE in children with catastrophic epilepsy. gement of status epilepticus. Eur J Neurol. 2006;13:445-50. 5. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment Hemispherectomy is used in children with Rasmus- of convulsive status epilepticus in children and adults: report of the guideline committee of the American epilepsy society. Epilepsy Curr. 2016;16:48-61. sen’s encephalitis. 6. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments 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,

10. What type of patient follow-up must be diazepam, and placebo for the treatment of out-of-hospital status epilep- © Permanyer 2019 ticus. N Engl J Med. 2001;345:631-7. carried out after remission from SE? 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. . About two-thirds of the patients respond to the first 9. Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia. 1999;40, s59-s63. treatment if it was opportune and adequate. In general, 10. Yasiry Z and Shorvon SD. The relative effectiveness of five antiepileptic the prognosis for those patients is good and, with a drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies. Seizure. 2014;23(3):167-74. good selection of anti-epileptic drugs to individualize 11. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998; the diagnostic approach to the patient, good control of 338:970-6. 12. Appleton R, Choonara I, Martland T, et al. The treatment of convulsive of the publisher the seizure can be achieved. Patient management and status epilepticus in children. Arch Dis Childhood. 2000;83:415-9. 13. Kinney MO, Craig JJ, Kaplan PW. Non-convulsive status epilepticus: observation must be maintained, as with any individual mimics and chameleons. Pract Neurol. 2018;18:291-305. 14. Lowenstein DH, Alldredge BK. Status epilepticus at an urban public that suffers from epilepsy. Unfortunately, between 3 hospital in the 1980s. Neurology. 1993;43:483-8. and 33% die from the SE itself or the complications 15. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an caused by this problem. investigation of variables associated with mortality. Neurology. 1996;47: 83-9. 16. Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive References care unit. J Neurol Neurosurg Psychiatry. 2005;76:534-9. 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. Arch Neurol. 2005;62:1428-31. status epilepticus report of the ILAE task force on classification of status 18. Vasquez A, Farias-Moeller R, Tatum W. Pediatric refractory and super-re- epilepticus. Epilepsia 2015;56:1515-23. fractory status epilepticus. Seizure. 2018:S1059-311. No part of this publication may be reproduced or photocopying without the prior written permission

115 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guideline: pre-operative evaluation of epilepsy surgery

Matilde Ruiz-García1, Mario A. Alonso-Vanegas2, Sara P. Pérez-Reyes3, Gerardo Quiñones-Canales4,

Instituto Nacional de Pediatría, Mexico City; Hospital HGM, Mexico City; Hospital Regional de Alta Especialidad del Bajío, León, Guanajuato; . 4Hospital General 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. of the publisher

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 procedures 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 surgical treatment? Epilepsy surgery is an approved treatment for the management of drug-resistant or refractory epilepsy According to the criteria established by International (RE)1-3. League Against Epilepsy (ILAE), approximately 17-33% of RE is responsible for approximately 80% of the direct patients with epilepsy develop RE throughout the course and indirect annual costs attributed to epilepsy4. The of the disease (level of evidence III)5. A variable portion majority of surgical candidates are referred for surgery of patients are able to achieve seizure remission through on average 20-25 years after their initial diagnosis, at epilepsy surgery, depending on the type of crisis, under- which time their prognosis is less favorable. 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 No part of this publication may be reproduced or photocopying without the prior written permission Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):116-122 E-mail: [email protected] 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 neurosurgeon trained in epileptic surgery procedures. patients’ behavior, cognition, and quality of life and the The pre-operative evaluation is carried out in con- cost effectiveness of epilepsy has been demonstrated gruent and concurrent stages. The evaluation of each in pediatric as well as adult patients6. neurological subspecialty has independent value in Early identification of patients with RE that meet cri- localizing potential EZ, which is an indispensable ob- teria for epilepsy surgery candidacy optimizes seizure jective of the pre-operative evaluation as well as control and reduces cognitive long-term adverse post-operative care. Even when the EZ cannot be out- effects7. The age at the time of surgery has been iden- lined or resected due to its location on or nearby a tified as an important modulator of the patients’ capa- functional or eloquent area of the brain cortex, it is © Permanyer 2019

city for cognitive reserve, where the most unfavorable important to consider that a thorough pre-operative . results are in patients with prolonged RE5,8. evaluation is highly valuable in offering a meaningful In 2003, the American Academy of Neurology publi- diagnosis or prognosis to the patient, as well as gui- shed recommendations for the surgical management of ding alternative therapeutic measures. epilepsy in adults. Clinical trials demonstrated that pa- Epilepsy surgery is defined as any neurosurgical in- tients with focal epilepsy in the temporal lobe, with or tervention with the objective of improving the quality of of the publisher without evolution to bilateral tonic-clonic seizures, who life through the control of epileptic seizures (ES) with develop resistance to first-line pharmacological treat- minimum secondary side effects7. ment must be examined as surgical candidates (considering the new classification of seizures, previously cited in 2003, as incapacitating complex partial seizu- Can epilepsy develop resistance to res, and with or without progression to generalized pharmaceutical treatment? 9 seizures) . Epilepsy affects approximately 70 million people 12,13 Recommendation Level of recommendation worldwide ; one-third of this population develops RE5. In these cases, epilepsy surgery has the potential Patients with temporal lobe A focal epilepsy, with or without to eliminate recurrence of ES and improves quality of progression to bilateral life1,14. Certain epileptic syndromes present better prog- tonic‑clonic seizures, who nosis with surgical treatment when compared to phar- develop resistance to first‑line pharmacological treatment, maceutical treatment alone. It is not easy to predict must be examined as surgical which patients will develop resistance to pharmaceuti- candidates (AAN) cal treatment; the probability of developing RE varies Studies with 5 year follow-up showed that surgery according to the type of epileptic syndrome and the achieved seizure remission in 65% of cases10,11. etiology, this last factor being the most consistently All subjects with RE must be submitted to a preoperati- reported in trails predicting the prognosis of epilepsy. ve evaluation to identify or discard well-circumscribed The prevalence of RE is higher among patients with epileptogenic zones (EZ) and assess the potential be- symptomatic or cryptogenic epilepsy compared to tho- nefit of a neurosurgical procedure7. se with idiopathic epilepsy. A trial including 2200 pa- Patients must meet certain requirements to be con- tients studied for a period between 1 and 7 years, sidered candidates for epilepsy surgery; the following achieved complete control of ES in 82% of patients with criteria are indispensable: generalized idiopathic epilepsy, 45% of cryptogenic fo- 1. Confirmed diagnosis of ER cal epilepsy, and 35% of symptomatic focal epilepsy. 2. A systematic pre-operative evaluation with specific and Another negative factor for the development of RE is staggered stages that discard an epileptogenic zone an early age of onset. A significant amount of patients susceptible to surgical resection without provoking ma- with RE also presents hippocampal sclerosis, malfor- jor neurological deficits. Published studies lack a com- mations of cortical development, and dysembryoplastic parative analysis of pre-operative algorithms. The spe- neuroepithelial tumors. cialist consensus is that it must include a rigorous Temporal lobe epilepsy (TLE) is the most common 15,16

stratified outline followed by a multidisciplinary team cause of focal RE ; therefore, the most frequent type No part of this publication may be reproduced or photocopying without the prior written permission that includes a neurologist sub-specialized in epilepsy, of epilepsy surgery on adults are temporal lobe resec- a neurophysiologist electroencephalographist, neuro- tions (level of evidence: class I, compared to conti- radiologist, neuropsychologist, neuropsychiatrist, and nuous pharmaceutical treatment alone)2,17. 117 Rev Mex Neuroci. 2019;20

Different definitions of RE have emerged throughout b. Presence of a single, unilateral, and excisable structural the years where multiple factors have been taken into brain lesion. account, such as diagnostic certainty, the number of c. Presence of a non-resectable epileptogenic zone. If failed anti-epileptic drugs (AEDs) attempted for seizure a non-excisable zone is identified, neurosurgical te- control, the frequency of seizures, and other aspects chniques such as disconnection procedures, vagus relating to the time span of the seizure pattern. In fact, nerve stimulation (VNS), or deep brain stimulation different terms have been established, such as untrea- (DBS) are recommended if surgery is considered to table epilepsy, uncontrollable epilepsy, difficult to control reduce the severity of epilepsy and the procedures’

epilepsy, resistant to pharmaceutical treatment, or RE. side effects are considered acceptable. © Permanyer 2019 Terminology diversity and the lack of definition of spe- d. Presence of psychological or psychiatric comorbidities.

. cified criteria to conceptualize RE, complicates the com- e. Presence of diagnostic doubt, regarding etiology, or parison of studies and series, thus rendering incomplete epileptic syndrome. conclusions regarding the epidemiology, diagnosis, f. Positive patient motivation to accept pre-operative management, and treatment of RE. The ILAE is the evaluation procedures, surgical intervention, and fo- association responsible for establishing a structured de- llow-up protocol. finition applicable for both clinical practice and scientific g. Age, psychiatric pathology, or disabilities are not of the publisher research of RE. Thus, RE was defined as the sustained contraindications for surgical candidacy; however, failure or the lack of ES remission, despite adequate they must be analyzed on an individual basis11. attempts with at least two first-line AEDs as monotherapy or combined therapy that is well tolerated by the What are the characteristics of patients patient and was administered in their appropriate co- that are submitted to surgical treatment? rresponding dosages5. ES remission or sustained seizure termination was defined as the absence of seizures Patients that must be submitted to epilepsy surgery for at least 12 months or for a period 3 times greater are: (a) those that present refractory ES, (b) patients than the longest period of ES remission5. This definition with physical disabilities due to uncontrolled seizures, may be used to justify a complete evaluation within a and (c) patients with focal RE, low morbidity risk, and epilepsy center, to establish a pre-operative evaluation potential for rehabilitation and social integration. for epilepsy surgery or to design a randomized contro- A randomized control study demonstrated the lled trial for AED or other research purposes, thus superiority of surgical treatment over continuous phar- emphasizing the importance of encouraging the con- macological treatment in patients with refractory TLE. nection between clinical practice and research scien- 80 patients with mesial temporal lobe sclerosis (mTLS) tists with a unified epilepsy criteria, obtained through where randomly distributed into groups of pharmacolo- consensus and endorsed by the ILAE. gical or surgical treatment, respectively, after a For patients to be considered surgical candidates for pre-operative evaluation. Authors discovered that 58% epilepsy surgery, adults must present confirmed diagno- of patients in the surgical group presented seizure resis of RE for at least 2 years; however, in life-threatening mission for 1 year compared to 8% of the patients in situations, this required interval may be less. In pediatric the pharmacology group (p < 0.001). Authors also found patients, the required interval is <2 years, due to the that patients in the surgical group demonstrated better potential long-term effects that ES can have if present quality of life when compared to the pharmacology during important stages of neurodevelopment10. group, as measured by reduced work or school absen- Candidates for epilepsy surgery are usually between 1 ces. In addition, one death was reported within the and 60 years of age; however, there are no defined age pharmacology group compared to no deaths in the limits5,10,14. According to the Andalusian Epilepsy Guide surgical group2. Epilepsy surgery has curative potential of 20157, surgical candidate selection criteria include: when an epileptogenic lesion or zone is completely a. Confirmed diagnosis of RE. Epilepsy that is not con- excised. In other situations, surgery will only serve a trolled with AED after 2 years. Unsuccessful treat- palliative function as is the case for the DBS or colos- ment after prescribing two AEDs with adequate do- tomy procedures for atonic seizures in patients with

sage respective to each type of ES and adequate Lennox-Gastaut syndrome. The curative potential of No part of this publication may be reproduced or photocopying without the prior written permission treatment compliance. Patient under 2 years of age. surgery is maximized with complete excision of a pri- High risk of presenting adverse effects on several mary cerebral tumor, vascular malformation, malforma- AEDs. tion of cortical development, or mTLS18. 118 M. Ruiz-García, et al.: Surgical evaluation in refractory epilepsy

Extratemporal epilepsy surgeries are significantly with normal magnetic resonance imaging (MRI) in or less frequent in surgical series because they represent near eloquent areas. a greater surgical challenge; they require frequent evaluation through multimodal imaging tests or invasive What are the primary modalities of monitoring. In addition, the EZ in extratemporal epi- surgical treatment? lepsy are more commonly diffuse and poorly circumscribed, they present a faster rate of extension in Modalities of resection include techniques where the the seizure propagation and superposition with elo- EZ are excised without producing a significant functio- quent areas, thus frequently requiring invasive monito- nal deficit. In addition, there are modalities of non-re- © Permanyer 2019 19 section techniques including disconnection or palliative ring to locate the epileptogenic zone(s) . There lacks 3 . sufficient evidence to provide definite recommenda- procedures . The most frequently performed procedu- tions for extratemporal epilepsy surgeries in patients res are temporal lobe resections, extratemporal and without defined lesions or in symptomatic patients with multilobar resections, lesionectomy, hemispherectomy, 7 poorly circumscribed lesions. A meta-analysis publi- callostomies, and multiple subpial transections . 11 a. Anterior temporal lobectomy or anterior medial tem- shed by Téllez-Zenteno reported a 60% and 35% re- of the publisher mission rate in extratemporal and non-defined lesion poral resection: it is the most commonly practiced epilepsies, respectively. procedure consisting of the excision of medial temporal structures (amygdala, hippocampus, and para- hippocampal gyrus), up to 6 cm of anterior temporal Which epileptic syndromes should be lobe cortex in the non-dominant hemisphere and up managed with surgical treatment? to 4.5 cm in the dominant hemisphere. To avoid neuropsychological side effects and superior qua- Epileptic syndromes that should be managed by sur- drantanopsia, the resection of the anterior temporal gery include: lobe is limited. a. Mesial temporal epilepsy. b. Lesionectomy: it is indicated in neocortical epilepsy b. Neocortical epilepsy with a single well-defined lesion with single well-circumscribed epileptic zone super- without compromise of other eloquent areas of the posed or in proximity to structural lesions; this allows brain. superior surgical results and ES control. The proce- c. Hemispheric epilepsy syndromes such as hemime- dure consists of selective resection of an epilepto- galencephaly (HME), Sturge-Weber syndrome, genic structural lesion, such as certain types of focal Rasmussen’s encephalitis, and other unilateral he- cortical dysplasia, cavernomas, circumscribed glio- mispheric lesions. sis, and certain types of developmental tumors such Patients that generally do not require invasive proce- as dysembryoplastic neuroepithelial tumors, gan- dures include: gliogliomas, and some low-grade gliomas. In some a. Mesial temporal epilepsy associated with hippocam- cases, the epileptogenic zone may extend beyond pal sclerosis the visible lesion, thus requiring an invasive elec- b. Circumscribed epileptogenic lesions including be- troencephalogram (EEG) test to locate and determi- nign neoplasias such as ganglioma, dysembryoplas- ne the extension, as well as to improve the results tic neuroepithelial tumors, low-grade astrocytoma, of the surgery. oligodendroglioma, vascular malformations, and c. Neocortical resections: resections of the single or atrophic brain lesions. multilobar cortical lesion. This type of surgery requi- c. Hemispheric lesions, hemiplegic hemiconvulsive res electrocorticography (intracranial electroen- epilepsy such as Sturge-Weber syndrome, HME, cephalography) to establish the extension and the and Rasmussen’s encephalitis. limits of the epileptogenic zone. d. Epileptic encephalopathies and multifocal diseases d. Functional hemispherectomy: this procedure has such as Lennox-Gastaut Syndrome. substituted the anatomic hemispherectomy due to Patients that require functional neuroimaging/mapping the risk of residual cerebral hemosiderosis and

and/or invasive tests include: post-operative hemorrhaging. It consists of total dis- No part of this publication may be reproduced or photocopying without the prior written permission e. Dual pathologies with discordant electroclinical, bilateral connection of the brain hemispheres with limited mesial temporal sclerosis, poorly circumscribed epilep- cerebral tissue resection. It is the indicated proce- togenic lesions, malformations of cortical development dure for patients with severe hemispheric damage 119 Rev Mex Neuroci. 2019;20

and refractory motor ES of diverse etiology, whether criteria. Subsequently, the diagnosis of RE must be congenital or postnatal. The causes may be disor- identified and confirmed, ideally based on a thorough ders of brain development such as HME, long-term review of patient’s history and disease evolution. effects of the perinatal vascular event or traumatic b. EEG: compatible and consistent serialized EEG and brain injury, progressive autoimmune disease such video – EEG (vEEG) monitored by superficial as Rasmussen’s encephalitis, Sturge-Weber syndro- electrodes. me, and among others. c. MRI: high-resolution cranial MRI that identifies brain e. Callostomy: palliative procedure in which hemisphe- anatomy and structural lesions. It is recommended

ric disconnection is achieved through the section of to use resonance equipment in the 1.5-3.0 Tesla © Permanyer 2019 the corpus collosum in the prevention of interhemis- range and FLAIR sequences to identify cortical dys-

. pheric seizure propagation and generalization. This plasia. In addition, tractography is recommended to procedure is indicated in cases of severe epilepsy identify Meyer’s loop and prevent post-operative with drop attacks. quadrantanopsia in temporal lobe surgeries. The f. Multiple subpial transections: this procedure is re- Wada test or functional MRI (fMRI) can be perfor- served for non-excisable EZ due to their proximity med if the identification of the verbal dominant he- to eloquent areas of the brain cortex. It is frequently misphere is required. of the publisher associated with cortical resection. d. Neuropsychology or developmental evaluation: faci- g. Other techniques: stereotactic radiosurgery, VNS, litates the identification of possible lateralization and trigeminal nerve stimulation, and DBS2,20. localization of the epileptogenic zone, as well as determining the pre-operative cognitive status to an- What are the minimum tests required for ticipate possible cognitive surgical side effects. the preoperative evaluation of epilepsy e. Psychiatric evaluation: necessary to evaluate the pa- surgery? tient’s comorbidities, as well as the patient’s expec- tations of surgical outcome and quality of life. Phase 1 of the pre-operative evaluation is the non-in- In 2006, the sub-commission of pediatric epilepsy vasive portion of the evaluation, and it requires at least: surgery of the ILAE concluded that a superficial EEG a. Extensive clinical evaluation with expert review of that includes a record of sleeping cortical electrical patient’s clinical history and previous laboratory and activity, an MRI with specific epilepsy protocol and imaging tests. The identification of associated prog- neuropsychological evaluation are required to consider nostic factors at the time of seizure onset and throu- a pediatric patient for epilepsy surgery. A 12-24 h su- ghout the evolution of the disease must be empha- perficial vEEG must record at least one paroxysm, and sized, as well as seizure semiology during the course a brain fMRI must be performed whenever possible6. of disease, with particular interest in the previous 12 months, including frequency, intensity, duration, What are the main complications of drug- aura, and associated trigger factors (emotional resistant or RE? stress, sleep-deprivation, menstruation), medications, dosages, combinations, side-effects, memory A mortality rate of 2-3 times higher has been recor- and language alteration, cognitive deterioration and ded for the population with epilepsy. The mortality rate psychiatric comorbidities. An exhaustive review of is even more critical in the subgroup of patients with previous laboratory and imaging tests, as well as RE, where the standardized mortality rate has been previous hospital records, must be performed whe- calculated up to 4.69 to 5 times higher than the general never possible; for example, finding the activity or population. In addition, within this group of patients, a epileptic discharge zones in the patient’s first EEG large proportion of the causes of death are directly will have focalizing or lateralizing value. A large quan- related to epilepsy, such as sudden unexpected death. tity of patients referred to surgical epilepsy centers Conversely, when epilepsy surgery is successful in present pseudoresistance to AEDs. The most com- controlling seizures, reduced epilepsy-related mortality mon causes include incorrect diagnosis, inadequate risk has been recorded21.

pharmaceutical drug selection for the seizure type, RE is associated with non-fatal injuries such as trau- No part of this publication may be reproduced or photocopying without the prior written permission inadequate or insufficient dosages, and “irresponsi- matic brain injury, burns, fractures, work-related ble patient lifestyle choices. Initially, the diagnosis of accidents, and accidents during recreational and every- ES must be corroborated according to international day life activities, among others. In addition, RE is 120 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 matrimony, and fertility is considerably reduced in pa- surgical evaluation over 20 years after the diagnosis of tients with poorly controlled ES2. epilepsy; it is highly likely that this delay in referral is The majority of patients with RE has significant res- responsible for a significant quantity of deaths related trictions on their everyday life, such as driving motor to ES10. Finally, the probability of postsurgical seizure vehicles. The complications of RE can originate throu- remission and favorable quality of life is indirectly rela- gh a combination of effects such as recurrent ES, drug ted to the time span between RE onset to the moment © Permanyer 2019 toxicity, and other psychological associated factors of epilepsy surgery10.

Levels of evidence of epilepsy surgery of the publisher

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

121 Rev Mex Neuroci. 2019;20

association with the American epilepsy society and the American asso- References ciation of neurological surgeons. Neurology. 2003;60:538-47. 1. Rathore C, Radhakrishnan K. Concept of epilepsy surgery and presurgi- 11. Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes focal evaluation. Epileptic Disord. 2015;17:19-31. llowing epilepsy surgery: a systematic review and meta-analysis. Brain. 2. Wiebe S, Blume WT, Girvin JP, Eliasziw M, Effectiveness, efficiency of 2005;128:1188-98. surgery for temporal lobe epilepsy study group. A randomized, controlled 12. West S, Nolan SJ, Cotton J, et al. Surgery for epilepsy. Cochrane Data- trial of surgery for for temporal-lobe epilepsy. N Engl J Med. 2001; base Syst Rev. 2015;7:CD010541. 345(5):311-8. 13. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neu- 3. Pindrik J, Hoang N, Smith L, et al. Preoperative evaluation and surgical rosurg Psychiatry. 1996;61:433-43. management of infants and toddlers with drug-resistant epilepsy. Neuro- 14. Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epide- surg Focus. 2018;45:E3. miology of drug-resistant epilepsy: a systematic review and meta-analy- 4. Begley CE, Annegers JF, Lairson DR, Reynolds TF, Hauser WA. Cost sis. Epilepsia. 2018;59:2179-93. of epilepsy in the United States: a model based on incidence and prog- 15. Pre-surgical evaluation for epilepsy surgery European standards. Euro-

nosis. Epilepsia. 1994;35:1230-43. pean federation of neurological societies task force. Eur J Neurol. 2000; © Permanyer 2019 5. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant 7:119-22.

epilepsy: Consensus proposal by the ad hoc task force of the ILAE 16. Engel J Jr. Mesial temporal lobe epilepsy: what have we learned? Neu- commission on therapeutic strategies. Epilepsia. 2010;51:1069-77. roscientist. 2001;7:340-52. . 6. Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. 17. Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy Lancet Neurol. 2014;13:1114-26. a major prognostic factor for recurrence? Neurology. 1998;51:1256-62. 7. Andaluza G, Epilepsia D. Diagnóstico y Tratamiento de la Epilepsia en 18. Jayakar P, Gaillard WD, Tripathi M, et al. Diagnostic test utilization in Niños y Adultos. Sociedad Andaluza de Epilepsia. Viguera Editores. Saint evaluation for resective epilepsy surgery in children. Epilepsia. 2014; Louis: Saint Louis University; 2015. 55:507-18. 8. Helmstaedter C. Neuropsychological aspects of epilepsy surgery. Epi- 19. Wyllie E, Comair YG, Kotagal P, et al. Seizure outcome after epilepsy lepsy Behav. 2004;5 Suppl 1:S45-55. surgery in children and adolescents. Ann Neurol. 1998;44:740-8. 9. Helmstaedter C. Cognitive outcomes of different surgical approaches in 20. Engel J Jr., McDermott MP, Wiebe S, et al. Early surgical therapy for of the publisher temporal lobe epilepsy. Epileptic Disord. 2013;15:221-39. drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012; 10. Engel J Jr., Wiebe S, French J, et al. Practice parameter: temporal lobe 307:922-30. and localized neocortical resections for epilepsy: report of the quality 21. Ryvlin P, Kahane P. Does epilepsy surgery lower the mortality of drug-re- standards subcommittee of the American academy of neurology, in sistant epilepsy? Epilepsy Res. 2003;56:105-20. No part of this publication may be reproduced or photocopying without the prior written permission

122 Revista Mexicana de Neurociencia

REVIEW ARTICLE

Clinical guide: discontinuing chronic antiepileptic drug treatment © Permanyer 2019 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 of the publisher

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 There are a number of prospective studies and me- seizure free before considering ta-analyses in this respect, but there has not been a antiepileptic drug (AED) withdrawal? uniform consensus about how long the patient must be in remission before treatment can be discontinued; these In 1996, the American Academy of Neurology propo- studies propose from 1 to 5 years of remission2-8. The sed a guide for discontinuing antiepileptics in patients risk of recurrence is greater when the epileptic seizu- that are seizure free, with the following criteria: seizure re-free period before discontinuing the medication is free after 2-5 years of treatment, only one type of epi- <2 years than when it’s longer9. For patients that have lepsy, normal neurological examination, and a normal been seizure free for 2 or more years, the risk of recu- electroencephalogram (EEG)1. There have been very rrence after discontinuing medications is lower; the lon- few changes with respect to the previous proposal. 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 No part of this publication may be reproduced or photocopying without the prior written permission Puebla, Mexico City, Mexico Date of acceptance: 28-02-2019 Rev Mex Neuroci. 2019;20(2):123-128 E-mail: [email protected] 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 There are a few studies that show that female gender a seizure after beginning their treatment with AEDs2. and family history of epilepsy are risk factors that in- Various studies have demonstrated that one of three crease the probability of relapse13-19. patients relapse within a period of 2 years after suspen- Recommendations when faced with risk Level ding antiepileptics. The risk of seizure recurrence in the factors for recurrence of epileptic recommendation seizures in children same period of time is 2 or 3 times that observed for patients that remain on AEDs. The 2015 Cochrane re- Antiepileptic drugs can be suspended in B cases of focal epilepsy and most 10 view of randomized controlled trials about epileptic generalized genetic epilepsies. drug withdrawal defines withdrawal of antiepileptics af- Assess whether or not to withdraw © Permanyer 2019 treatment in generalized symptomatic or

ter < 2 years of treatment as “early withdrawal” and “late unknown cause epilepsies, juvenile . withdrawal” when they are discontinued after 2 years of myoclonic epilepsy, and partial symptomatic treatment. The seizure-free period for children neces- epilepsy, due to a high risk of relapse. sary to consider antiepileptic withdrawal is considerably In children, the main risk factor is etiology. A shorter compared to that of adults and depends on the Continued treatment does not guarantee the absence of recurrence. epileptic syndrome. This is true for those cases with of the publisher favorable evolution, such as benign childhood epilepsy An abnormal electroencephalogram, age B 11 of onset of seizures, intellectual disability, and Rolandic epilepsy . In these cases, treatment can abnormal neurological examination at be suspended after a maximum of 1 year12. birth, altered neuroimaging studies, family history of epilepsy, and febrile seizures, Recommendation Level of recommendation alone, should not be taken as justification and level of evidence to avoid suspending treatment if there are no other associated negative predictors. Consider withdrawing Evidence level 1 medication in patients with at Recommendation level A Gender should not be an isolated factor C least 2 years in complete to decide not to withdraw antiepileptic seizure remission. drug treatment.

Inform the patient that two or more C epileptic drugs at the onset of withdrawal Question 2. What are the risk factors for may be associated with increased risk of recurrence of epileptic seizures after AED relapse. However, this does not withdrawal in pediatric patients? contraindicate withdrawal. The decision to stop or continue C – Generalized non-motor absence seizures: 20-30% treatment does not depend on the type of relapse. drug that will be withdrawn. – Focal seizures: 44% relapse. Focal seizures with di- minished awareness have greater risk of relapse. – Juvenile myoclonic epilepsy: recurs in 33-78%, only Question 3. What are the risk factors for 25-26% can undergo treatment withdrawal. recurrence of epileptic seizures in adult – West, Lennox-Gastaut, and Dravet syndromes have patients after suspending antiepileptic? a high risk of recurrence. There are multiple studies that assess the risk factors Other factors: for recurrence of epileptic seizures in adults. In 2017, a – Symptomatic epilepsies: 41-42% risk predictive model for recurrence was published which – Neurological anomalies present at birth. described the most important factors9. This was based – Average of five seizures per year: 68% relapse on multiple studies, considering that the methodology, – Prolonged seizures the types of patients and types of epileptic seizures are – History of febrile seizures has 2 times the risk of very varied. relapse. a. Age. One study reported a greater possibility of re- – Prolonged epilepsy before remission. mission when withdrawing AED at an older age – Age of onset of epilepsy younger than 2 or older than (p = 0.02), finding remission in 45% of the patients. 12 years old. Various other studies demonstrated that the earlier

– ≥ 10 seizures before remission the age of onset of epilepsy before the period of con- No part of this publication may be reproduced or photocopying without the prior written permission – Impaired neurodevelopment, intellectual quotient < 70 trol of seizures, the greater the risk of recurrence, as – EEG with epileptiform activity before withdrawal. well as a greater risk of recurrence when the age of – < 2 years without seizures10 onset is late infancy or adolescence1,9,16,20. 124 M.C. Loy-Gerala, et al.: Discontinuing chronic antiepileptic treatment b. Mental retardation. An intelligence quotient < 70 and epilepsy that presented evident lesions by magnetic motor deficits are independent predictors of resonance imaging, which evidenced greater risk for recurrence16,20. older patients, longer course of epilepsy, abnormal c. Abnormal neurological examination. A 15% seizure post-operative EEG, early post-operative seizures, glio- recurrence is reported during the 1st month in pa- sis or cortical focal dysplasia, and interictal discharges tients with abnormal neurological examinations21,22. in the EEG and during the 1st year after surgery28. d. Abnormal interictal encephalogram (EEG). The pre- The largest study in pediatric population is a European sence of an abnormal EEG before AED withdrawal multicentric, retrospective, uncontrolled study that inclu-

or during the 1st year after AED withdrawal indicates ded 766 patients under 18 years of age that was seizure © Permanyer 2019 greater risk of recurrence1,22,23. free after surgery (temporal and extratemporal) who were

. e. Focal and generalized symptomatic tonic-clonic epi- subjected to AED withdrawal. Results showed a seizure lepsies have a greater risk of recurrence9,20. recurrence of 12%, and of these patients, 30% did not f. Age of onset of epilepsy9,20. achieve seizure control after reintroducing medication29. g. Family history of epilepsy. Increased risk of Good prognosis Bad prognosis recurrence9,20. Surgery at an early age Surgery after 30 years of age of the publisher h. Number of AEDs. The greater the number of AED, the greater the risk of recurrence after withdrawal9,20. Hippocampal sclerosis Long‑term epilepsy

Recommendation Level of Anterior temporal Normal anatomopathological recommendation lobectomy examination and level of evidence Seizure free for 1‑2 years Neocortical resection after surgery 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 Question 5. What is the usefulness of an antiepileptic drugs is recommended. The decision should be made in conjunction EEG to decide on AED withdrawal? with the patient and/or the caretakers. Although there are no examinations that are comple- For patients with epilepsy that has been Evidence level 1 tely reliable to predict the recurrence of seizures, many seizure free for >2 years, with risk factors, Recommendation the risk/benefit of AED withdrawal should level A studies have demonstrated that abnormalities in the be assessed. 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 Question 4. What are the risk factors for predicts a high percentage of recurrences (Table 1) 23. recurrence of epileptic seizures after Recommendation Level of recommendation withdrawing AEDs in patients following and level of evidence epilepsy surgery? In patients that are seizure IA In 2011, a prospective study was published with 311 free but show paroxysmal EEG patients after mesial temporal epilepsy surgery, who patterns and other risk factors, AED withdrawal is not underwent AED withdrawal after being seizure free be- recommended due to a high tween 3 months and 1 year. The results showed that risk or recurrence. the absence of hippocampal sclerosis and the presence of interictal discharges in the EEG were independent Question 6. What are the probabilities of predictors of seizure recurrence24. The majority of stu- the recurrence of epileptic seizures for dies report the same requirement of 1-2 years seizure patients undergoing AED withdrawal? free, without increase in recurrence in up to 10 years of follow-up25,26. A Class II, prospective, randomized study The probability for seizure recurrence after stopping published in 2009, which included post-surgical patients treatment varies among different studies and oscillates that were seizure free for 1 year demonstrated a greater from 20% to 46%9. Different studies have found risk fac-

rate of recurrence for patients with hippocampal sclero- tors that significantly impact the probability of recurrence. No part of this publication may be reproduced or photocopying without the prior written permission sis compared with those with lesional epilepsy27. The These risk factors are as follows: duration of epilepsy only work that included extratemporal surgery is a re- before achieving control, total number of seizures (fewer trospective study with 106 patients diagnosed with 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 of physical lesions or death, quality of life, and social adolescence or adulthood), intellectual quotient < 70, and psychological problems. Always consider the risk abnormal EEG at the time of AED withdrawal, remote of losing a driver’s license or a job, since this is a de- symptomatic epilepsy (defined as epilepsy caused by an terminant factor for some adults1,37. old brain lesion), absence of an epileptic syndrome rela- A prospective study found that after AED withdrawal ted to age, and history of febrile seizures13-19,30-32. and relapse of epileptic seizures, there is little risk of These risk factors have different prognostic weight. epileptic seizures resistant to treatment. This risk co- The most important are as follows: duration of epilepsy, rresponds to 1%, compared to 97% of recurring after

total number of seizures, intellectual disability, remote treatment is reinitiated. A review from 2005 reported © Permanyer 2019 treatment refractory epilepsy in 19% of the patients that

symptomatic epilepsy, and absence of an autolimited . epileptic syndrome. Tables that assign a numeric value had previously undergone treatment withdrawal, which for each of these risk factors have been developed9. was associated with a symptomatic etiology, location The information found in these tables is simple: the of the epilepsy, and abnormal neurological examina- greater the high significance risk factors, the greater tions. In some patients with controlled epilepsy and the risk of seizure recurrence (Level I). associated comorbidity, this can be increased under of the publisher Regarding epilepsy of genetic origin, it must be poin- AED withdrawal since valproic acid and lamotrigine are ted out that juvenile myoclonic epilepsy has a very high indicated for stabilizing emotional states, as in bipolar risk of recurrence after treatment withdrawal (Relative disorder, and topiramate is also used as prophylactic Risk RR: of 70 up to 95%), even after very long periods treatment for migraines17,37. of remission33,34. It’s very important that the patient Relapse of epileptic seizures after AED withdrawal receives clear information during the decision-making may have psychosocial repercussions and important process (R-PPE) (Level I). 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 Question 7. How should AED be withdrawn? period of 3-12 months, as well as a greater risk of ha- There is no clear consensus among different studies ving epileptic seizures during work, and repercussions that analyze this aspect since the period of time pro- on quality of life and social stigma since everyday ac- posed for AED withdrawal varies from 4 weeks to tivities may have to be modified22. 12 months. In a controlled randomized study with 149 children, no differences were found with regard to re- Question 9. What are the benefits of currence of seizures when AEDs were withdrawn in a withdrawing epileptic drugs? period between 6 weeks and 9 months. In another study involving 56 children, no differences in RR were AEDs are associated with long-term adverse effects found after assessing periods of AED withdrawal las- that may include cognitive and behavioral alterations. ting 1-6 months. Finally, another study with 216 children Suspending antiepileptics can benefit persons in long- that assessed AED withdrawal periods of 4-6 weeks term remission if the benefit of withdrawing treatment versus 4-6 months also did not find significant differen- is greater than the alterations caused by taking the ces in RR. Thus, we recommend gradual withdrawal of antiepileptics. AED in an interval of 4-6 months35,36. Some of these effects are attention reduction, alterations in memory and mood, and depression. In Recommendation Level of recommendation and level of evidence addition, they can cause problems in daily activities resulting in an affected quality of life, although these Gradual withdrawal of AED in Level of evidence 2 an interval of 4‑6 months is Level of recommendation: PPE may be slight. Their daily, chronic use offers other risk recommended consensus factors such as teratogenesis, possibility of infertility in males, interactions with other drugs and long-term to- Question 8. What other risks, besides xicity, and pseudodementia as can be caused by recurrence, are there when withdrawing phenytoin, even at therapeutic doses. Conversely, sei- AEDs? zure recurrence can also be devastating from the emo- No part of this publication may be reproduced or photocopying without the prior written permission tional point of view, and in social life, there is risk of In addition to the risk of recurrence, other factors losing work and autonomy, and especially for obtaining must be considered: adverse effects of the drugs, risk a driver’s license1. 126 M.C. Loy-Gerala, et al.: Discontinuing chronic antiepileptic treatment

Table 1. Prognostic factors for recurrence after epileptic surgery Recommendation Level of recommendation and level of evidence

Considering withdrawal of AED is recommended for patients having had Level of evidence II epilepsy surgery, after 1‑2 years seizure free with good prognostic factors. Level of recommendation B

In patients with bad prognostic factors, seizure free for 1‑2 years, withdrawal Level of evidence II of AED is not recommended after epilepsy surgery. Level of recommendation C © Permanyer 2019 Taking AEDs imply a continuous economic expense 9. Lamberink HJ, Otte WM, Geerts AT, et al. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepi- for the individual and their families, as well for the public leptic drugs in seizure-free patients: a systematic review and individual . health system, when they are administered unnecessa- participant data meta-analysis. Lancet Neurol. 2017;16:523-31. 10. Sirven JI, Sperling M, Wingerchuk DM. Early versus late antiepileptic drug rily (World Health Organization, 2012). Therefore, when withdrawal for people with epilepsy in remission. Cochrane Database Syst Rev. 2001;3:CD001902. epilepsy is in remission, withdrawing antiepileptics can 11. Capovilla MD, Vigevano MD. Topical review: benign idiopathic partial favor quality of life17. epilepsies in infancy. Child Neurol. 2001;16:874-81. 12. Peters AC, Brouwer OF, Geerts AT, et al. Randomized prospective study In general, cognitive function is improved. In a of early discontinuation of antiepileptic drugs in children with epilepsy. of the publisher Neurology. 1998;50:724-30. prospective, placebo-controlled, double-blind study, 139 13. Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after patients that were seizure free for at least 2 years, un- seizure onset: a population-based study. Neurology. 2009;73:1041-5. 14. Geithner J, Schneider F, Wang Z, et al. Predictors for long-term seizure derwent neuropsychological tests before and after AED outcome in juvenile myoclonic epilepsy: 25-63 years of follow-up. Epilep- withdrawal finding better performance after stopping sia. 2012;53:1379-86. 15. Specchio LM, Tramacere L, La Neve A, Beghi E. Discontinuing antiepi- treatment. In addition, there were lower levels of depres- leptic drugs in patients who are seizure free on monotherapy. J Neurol 22 Neurosurg Psychiatry. 2002;72:22-5. sion and irritability after withdrawing the medication . 16. Hixson JD. Stopping antiepileptic drugs: when and why? Curr Treat In a retrospective study that included 766 patients Options Neurol. 2010;12:434-42. 17. Tang X, Yu P, Ding D, et al. Risk factors for seizure reoccurrence after under 18 years of age, with pre- and post-surgical neu- withdrawal from antiepileptic drugs in individuals who have been seizu- ropsychological assessment and at least 1 year after re-free for over 2 years. PLoS One. 2017;12:e0181710. 18. Giussani G, Bianchi E, Canelli V, et al. Antiepileptic drug discontinuation AED withdrawal, results showed that withdrawal of phe- by people with epilepsy in the general population. Epilepsia. 2017;58: 1524‑32. nobarbital and primidone was associated with an in- 19. Incecik F, Herguner OM, Altunbasak S, Mert G, Kiris N. Risk of recurren- crease in intellectual quotient of 10 or more points. The ce after discontinuation of antiepileptic drug therapy in children with epilepsy. J Pediatr Neurosci. 2014;9:100-4. fact of reducing the doses of antiepileptics and comple- 20. Schachter SC. Determining when to stop antiepileptic drug treatment. te withdrawal of the drugs predicted better results in Curr Opin Neurol. 2018;31:211-5. 21. Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic psychometric tests compared to children that continued drug withdrawal: a randomized, double-blind study (Akershus study). Epilepsia. 2008;49:455-63. their antiepileptic treatment before surgery. Verbal me- 22. Lamberink HJ, Otte WM, Geleijns K, Braun KP. Antiepileptic drug with- mory developed better in children that underwent drug drawal in medically and surgically treated patients: a meta-analysis of seizure recurrence and systematic review of its predictors. Epileptic Di- withdrawal. These cognitive and behavioral effects were sord. 2015;17:211-28. 38,39 23. Tang L, Xiao Z. Can electroencephalograms provide guidance for the with- also observed with the new AEDs . drawal of antiepileptic drugs: a meta-analysis. Clin Neurophysiol. 2017; 128:297-302. 24. Rathore C, Panda S, Sarma PS, Radhakrishnan K. How safe is it to withdraw antiepileptic drugs following successful surgery for mesial tem- References poral lobe epilepsy? Epilepsia. 2011;52:627-35. 1. Practice parameter: a guideline for discontinuing antiepileptic drugs in seizu- 25. Berg AT, Langfitt JT, Spencer SS, Vickrey BG. Stopping antiepileptic re-free patients summary statement. Report of the quality standards subcom- drugs after epilepsy surgery: a survey of U.S. Epilepsy center neurolo- mittee of the American academy of neurology. Neurology. 1996;47:600-2. gists. Epilepsy Behav. 2007;10:219-22. 2. Epilepsies: the Diagnosis and Management of the Epilepsies in Adults 26. McIntosh AM, Kalnins RM, Mitchell LA, et al.Temporal lobectomy: long- and Children in Primary and Secondary Care. Withdrawal of Pharmaco- term seizure outcome, late recurrence and risks for seizure recurrence. logical Treatment. NICE Clinical Guideline 137. Clinical Guideline Brain. 2004;127:2018-30. [CG137] Fecha de Publicación: Enero 2012 Fecha de Última Actualiza- 27. Kerling F, Pauli E, Lorber B, et al. Drug withdrawal after successful ción; 2018. Available from: https://www.nice.org.uk/guidance/cg137. epilepsy surgery: how safe is it? Epilepsy Behav. 2009;15:476-80. 3. Guías Diagnósticas y Terapéuticas de la Sociedad Española de Neuro- 28. Menon R, Rathore C, Sarma SP, Radhakrishnan K. Feasibility of antiepi- logía 2012. Guía Oficial de Práctica Clínica en Epilepsia. Sociedad Es- leptic drug withdrawal following extratemporal resective epilepsy surgery. pañola de Neurología; 2012. Neurology. 2012;79:770-6. 4. Olmez A, Arslan U, Turanli G, Aysun S. Risk of recurrence after drug 29. Boshuisen K, Uiterwaal C. The timetostop study I. Antiepileptic drug wi- withdrawal in childhood epilepsy. Seizure. 2009;18:251-6. thdrawal policies after childhood epilepsia surgery in Europe. Epilepsia. 5. Shinnar S, Berg AT, Moshé SL, et al. Discontinuing antiepileptic drugs in 2010;51:181-9. children with epilepsy: a prospective study. Ann Neurol. 1994;35:534-45. 30. Prognostic index for recurrence of seizures after remission of epilepsy. 6. Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic Medical research council antiepileptic drug withdrawal study group. BMJ. drugs: a meta-analysis. Neurology. 1994;44:601-8. 1993;306:1374-8. No part of this publication may be reproduced or photocopying without the prior written permission 7. Camfield P, Camfield C. When is it safe to discontinue AED treatment? 31. Gherpelli JL, Kok F, dal Forno S, et al. Discontinuing medication in epileptic Epilepsia. 2008;49 Suppl 9:25-8. children: a study of risk factors related to recurrence. Epilepsia. 1992;33:681-6. 8. Beghi E, Giussani G, Grosso S, et al. Withdrawal of antiepileptic drugs: 32. Dooley J, Gordon K, Camfield P, Camfield C, Smith E. Discontinuation guidelines of the Italian league against epilepsy. Epilepsia. 2013;54 Suppl of anticonvulsant therapy in children free of seizures for 1 year: a pros- 7:2-12. pective study. Neurology. 1996;46:969-74. 127 Rev Mex Neuroci. 2019;20

33. Pavlović M, Jović N, Pekmezović T. Antiepileptic drugs withdrawal in 37. Bonnett LJ, Shukralla A, Tudur-Smith C, Williamson PR, Marson AG. patients with idiopathic generalized epilepsy. Seizure. 2011;20:520-5. Seizure recurrence after antiepileptic drug withdrawal and the implications 34. Martínez-Juárez IE, Alonso ME, Medina MT, et al. Juvenile myoclonic for driving: further results from the MRC antiepileptic drug withdrawal epilepsy subsyndromes: family studies and long-term follow-up. Brain. 2006; study and a systematic review. J Neurol Neurosurg Psychiatry. 2011;82: 129:1269-80. 1328-33. 35. Tennison M, Greenwood R, Lewis D, Thorn M. Discontinuing antiepilep- 38. Overweg J. Withdrawal of antiepileptic drugs (AEDs) in seizure-free patic drugs in children with epilepsy. A comparison of a six-week and a tients, risk factors for relapse with special attention for the EEG. Seizure. nine-month taper period. N Engl J Med. 1994;330:1407-10. 1995;4:19-36. 36. Serra JG, Montenegro MA, Guerreiro MM. Antiepileptic drug withdrawal 39. Tinuper P, Avoni P, Riva R, et al. The prognostic value of the electroen- in childhood: does the duration of tapering off matter for seizure recu- cephalogram in antiepileptic drug withdrawal in partial epilepsies. Neuro- rrence? J Child Neurol. 2005;20:624-6. logy. 1996;47:76-8. © Permanyer 2019

. of the publisher No part of this publication may be reproduced or photocopying without the prior written permission

128