Revista Mexicana de NeurocienciaRevista Mexicana de Neurociencia Publicación oficial de la Academia...

EditorialClinical guidelines from the Priority Epilepsy Program of the public health sector in Mexico 56JC Reseacutendiz-Aparicio

Artiacuteculos de revisioacutenClinical guideline definition and classification of epilepsy 63JC Reseacutendiz-Aparicio JC Peacuterez-Garciacutea E Olivas-Pentildea E Garciacutea-Cuevas YL Roque-Villavicencio M Hernaacutendez-Hernaacutendez JI Castro-Maciacuteas and JD Rayo-Mares

Clinical guideline management of seizures in the emergency room 69J Visoso-Franco L Romero-Ocampo JA Santos-Zambrano A Serrano-Gonzaacutelez and E Castro-Martiacutenez

Clinical guideline management of the first unprovoked epileptic seizure in adults and children 76JA Gien-Loacutepez RA Cuevas-Escalante E Garciacutea-Cuevas MR Maacuterquez-Estudillo BE Villasentildeor-Anguiano R Leal-Cantuacute and RE Jimeacutenez-Arredondo

Clinical guideline antiepileptic drugs of choice for focal and generalized seizures in adult patients with epilepsy 82L Rivera-Castantildeo H Sentiacutees-Madrid J Berumen-Jaik and IE Martiacutenez-Juaacuterez

Clinical guideline antiepileptic drugs of choice for epileptic syndromes and epilepsies in pediatric patients 89JC Reseacutendiz-Aparicio JM Padilla-Huicab IE Martiacutenez-Juaacuterez G Hernaacutendez-Martiacutenez E Loacutepez-Correa B Vaacutezquez-Juaacuterez R Huerta-Albarraacuten and C Rivera-Acuntildea

Clinical guideline febrile seizures diagnosis and treatment 97C Aguirre-Velaacutezquez AM Huerta Hurtado H Ceja-Moreno K Salgado-Hernaacutendez R San Romaacuten-Tovar MA Ortiz-Villalpando Avril Molina-Garciacutea G Vargas-Ramiacuterez J Loacutepez-Rivera and R Huerta-Albarraacuten

Clinical guideline epilepsy in pregnancy and women of childbearing age 104PO Gonzaacutelez-Vargas Y Matuk-Peacuterez JL Sosa Hernaacutendez G Quintildeones-Canales SE Silva-Saacutenchez G Aguayo-Leytte S Medina-Benitez JM Ibarra-Puig LG Mariacutea del Consuelo and Elvira Castro-Martiacutenez

Clinical guideline status epilepticus in children and adults 110A Olmos-Loacutepez J Ibarra-Aguilar JO Cornelio-Nieto LA Ocantildea-Hernaacutendez MA Maacuterquez-Amaya N Luna-Loacutepez JC Reseacutendiz-Aparicio and I Rodriacuteguez-Leyva

Clinical guideline pre-operative evaluation of epilepsy surgery 116M Ruiz-Garciacutea MA Alonso-Vanegas SP Peacuterez-Reyes G Quintildeones-Canales I Rodriacuteguez-Leyva HR Martiacutenez-Rodriacuteguez and E Barragaacuten-Peacuterez

Clinical guide discontinuing chronic antiepileptic drug treatment 123MC Loy-Gerala OM Ibarra-Bravo MR Maacuterquez-Estudillo F Mena-Barranco FJ Rogel-Ortiz SE Silva-Saacutenchez H Villegas-Pentildea and A Molina-Garciacutea

PERMANYERwwwpermanyercom

VOLUME 20 - NUMBER 2 Marzo-Abril 2019 ndash ISSN 1665-5044

eISSN 2604-6180

wwwrevmexneurocienciacom

Revista Mexicana de

NeurocienciaPublicacioacuten oficial de la Academia Mexicana de Neurologiacutea AC

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56

Clinical guidelines from the Priority Epilepsy Program of the public health sector in MexicoJC Reseacutendiz-AparicioHospital Psiquiaacutetrico Infantil Dr Juan N Navarro y PPE Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez Mexico City Mexico

Revista Mexicana de Neurociencia

EditoRiAl

Correspondence Juan Carlos Reseacutendiz-Aparicio

E-mail jc_docyahoocom

Available online 12-04-2019

Rev Mex Neuroci 201920(2)56-62


Date of reception 01-02-2019

Date of acceptance 28-02-2019

DOI 1024875RMNM19000041

The Programa Prioritario de Epilepsia (PPE - Priority Epilepsy Program) was created based on the accord published in the Mexican Official Gazette of the Fede-ration on October 24th 1984 This program has labored in an uninterrupted manner to regulate coordinate methodize and optimize the strategies in favor of pa-tients with epilepsy as well as their families and socie-ty There are currently 78 centers of integral treatment for epilepsy in Mexico located in various hospitals be-longing to Mexicorsquos health sector

The headquarters for the national coordination is in the Instituto Nacional de Neurologiacutea y Neurocirugiacutea (National Institute of Neurology and Neurosurgery) ldquoDr Manuel Velasco Suarezrdquo (INNN due to its acronym in Spanish) in Mexico City from where all actions are

planned for this task The national coordination is led by its creator and founder Francisco Rubio Donnadieu MD and by the author

The development of the first Clinical Guidelines (CGs) has been a laborious effort one that has been finished due to the work of all the coordinators of the PPE who are neurologists and pediatric neurologists certified by the Mexican Board of Neurology and who work in one of the many institutions of the health sec-tor in Mexico To elaborate the CG all the coordinators of the PPE met in person in two meetings the first in the city of Leon and the second in the city of Puebla where we formed workgroups for each CG These meetings were possible due to the support of the fe-deral government and the contributions of the

1665-5044copy 2019 Academia Mexicana de Neurologiacutea AC Published by Permanyer Meacutexico This is an open access article under the CC BY-NC-ND license (httpcreativecommonsorglicensesby-nc-nd40)

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57

J C Reseacutendiz-Aparicio Clinical Guidelines of the Priority Epilepsy Program

pharmaceutical laboratories that aid in training primary health-care physicians These CGs are designed to aid the primary health-care physicians and the spe-cialists in making adequate decisions when approa-ching epileptic patients of different age groups and genders These are the culmination of the experience of their authors who have followed the necessary steps for proper and updated scientific research using the criterion of the American Epilepsy Society 2016 to analyze the levels of evidence and recommendations including the benefit for the patients To evaluate the quality of the CG two experts coordinated each table and applied the Spanish version of the AGREE instru-ment of 2001

Due to the advances in the knowledge of epilepsy the PPE group aims to update the CG every 5 years

These CGs constitute a series of recommendations developed by a group of medical physicians that have a particular interest in the field of epilepsy and work

throughout the various institutions of the health sector however it is understood that the application of said recommendations depends on many factors It is im-portant to state that there are no conflicts of interest in these CGs due to the fact that they are editorially inde-pendent of any external funding

Finally I would like to thank the INNN for their hos-pitality and support in the coordination of the Program the Mexican Academy of Neurology for the publication in their magazine the Mexican Society of Pediatric Neurology who supported the process of translating the CG to English and the authorities of the Hospital Psi-quiaacutetrico Infantil (Childrenrsquos Psychiatric Hospital) of Mexico City who have allowed me to work as the ad-junct executive member of the Priority Epilepsy Pro-gram and above all thank you to the coordinators of the Priority Epilepsy Program who worked on this pro-ject this work is dedicated to them and their families and to which I express my most ample recognition

Juan Carlos Reseacutendiz Aparicio Md Adjunct Executive Member

American Epilepsy Society 2016

Article Classification EvidenceClass i A randomized prospective and controlled clinical trial with masked outcome assessment in a repre-

sentative population The following are required

a No more than two specified primary resultsb Blind allocation of subjectsc Exclusioninclusion criteria are clearly definedd 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 objec-tive outcome assessment in a representative population that meets a-e

Class iii All other control trials in a representative population where outcome was independently assessed by objective outcome measurement

Class iV Evidence from non-controlled trials including series reports case reports consensus or expert opinion

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58

Rev Mex Neuroci 201920

In all of the CGs of the Priority Epilepsy Program (PPE) the abbreviations we published are the same as the book ldquoEpilepsiardquo by authors Rubio Reseacutendiz Alon-so and Sentiacutees by the editorial Alfil in 2016 page numbers IX X y XI ISBN 978-607-741-168-0

Glossary and Abbreviations

Channelopathies

SCN4A SCN2A SCN1BKCNA1 KCNQ2 KCNQ3CACNA1ACHRNA4 CHRNB2GLRA1GABRG2 Ion NA sodium K potassium CA calcium CH acetylcholine GL glycine GABA gamma-ami-nobutyric acid Channel or receptor CN channel R receptor N nicotinicSubunit A α B β Q M G γ

Seizure

ES epileptic seizureGS generalized seizureGTCS generalized tonic-clonic seizureFS focal seizure FIAS focal impaired awareness seizures (or discon-nection from medium)FAS focal aware seizuresimple partial seizureFBTCS focal to bilateral tonic-clonic seizureSE status epilepticusFeS febrile seizure

Electrolytes and neurotransmitters

Ca++ calciumClminus chlorineK+ potassiumMg++ magnesiumNa+ sodiumGABA gamma-aminobutyric acidNMDA N-methyl-D-aspartate AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepro-pionic acid

Evidence for the Recommendation

level AOne or more Class I trials or two or more Class II trials level BOne or more Class II trials or three or more class III trialslevel CTwo or more Class III trialslevel UAbsence of trails that com-plement levels A B or Clevel R-PPE

Conclusion and RecommendationConclusion level AEstablished as effective ineffective or harmful for the given condition in the specified population RecommendationMust be done or must not be doneConclusion level BProbably effective ineffective or harmful for the given condition in the specified population RecommendationIt must be considered or must not be consideredConclusion level CPossibly effective ineffective or harmful for the given condition in the specified populationRecommendationIt could be considered or should not be consideredConclusion level UData is insufficient or inadequate given current knowledge treatment is unprovenRecommendation Should not be performedConclusion level R-PPENo evidence from levels A B or C but it is a recommendation by con-sensus of the group that elaborated the Clinical Guidelines of the PPE

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59


Neurologic structures

BBB bloodndashbrain barrierCSF cerebrospinal fluidCNS central nervous system

diagnostic tests

fMRI functional magnetic resonance imagingMRI magnetic resonance imagingPET positron emission tomography SPECT single-photon emission computed tomographyCT computed tomography scan ECoG electrocorticographyintracranial

electroencephalographyEEG electroencephalogramMEG magnetoelectroencephalogramVideo-EEG video electroencephalogramPSG polysomnogramEKG electrocardiogramLP lumbar puncturespinal tap

Genetics

AD autosomal dominantAR autosomal recessivep short arm of a chromosomeq long arm of a chromosomeDNA deoxyribonucleic acidRNA ribonucleic acidNB newbornneonate

organizations

AAN American Academy of NeurologyAES American Epilepsy SocietyAAP American Academy of Pediatrics CAIE Centros de Atencioacuten Integral para la Epilepsia

or Comprehensive Care Centers for EpilepsyFDA Food and Drug AdministrationIBE International Bureau for EpilepsyILAE International League Against Epilepsy INNN Instituto Nacional de Neurologiacutea y Neurocirugiacutea

or National Institute for Neurology and Neurosurgery

WHO World Health OrganizationPAHO Pan American Health Organization PPE Programa Prioritario de Epilepsia or Priority

Epilepsy Program SAdE Sociedad Andaluza de Epilepsia or Andalusian

Epilepsy Society

GPC-PPE Guiacutea de Praacutectica Cliacutenica del Programa Prioritario de Epilepsia or Clinical Guide-lines of the Priority Epilepsy Program

Additional neurological disorders

CVD cerebrovascular diseaseTBI traumatic brain injury

drug administration routes

IM intramuscularIV intravenousPO oralSC subcutaneousSL sublingual

Syndromes and types of epilepsy

BECTS benign epilepsy with centrotemporal spikes (Rolandic Epilepsy)

IGE idiopathic generalized epilepsyPME progressive myoclonus epilepsyJME juvenile myoclonus epilepsyMTS mesial temporal sclerosisLGS Lennox-Gastaut syndromeDRE difficult to treat seizuresdrug-resistant epilepsy

Miscellaneous

AED antiepileptic drugsanti-seizure medicationsBZD benzodiazepines

Antiepileptic drugs

ACZ acetazolamideACTH adrenocorticotropic hormoneNE barbexacloneNE beclamideCBZ carbamazepineCLB clobazamCZP clonazepamCLP clorazepateDZP diazepamESM ethosuximideFBM felbamateGBP gabapentinLTG lamotrigineLEV levetiracetamLZP lorazepamMDL midazolam

No

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60


MPH methylphenidateMPB methylphenobarbitalMSM mesuximidemethsuximideNTZ nitrazepamOXC oxcarbazepinePAC phenacemidePTR pheneturidePB phenobarbitalPSM phensuximidePHT phenytoinNE fosphenytoinPGB pregabalinPRM primidonePRO progabideSTM sultiamesulthiameTGB tiagabineTPM topiramateNE trimethadioneVPA valproic acidVGB vigabatrinZNS zonisamideNE 4-amino-3-hydroxibutiric AcidFLN flunarizineLSG losigamoneRLT ralitoline (Cl-946)REM remacemideSTP stiripentolHRK harkoserideLCM lacosamideRET retigabine (D-23129)BRV brivaracetamSTM seletracetam (ucb 44212)

CBT carabersat (SB-204269)TBT tonabersat (SB-220453)SFM safinamide (PNU-151774E)RUF rufinamide (SGP33101)STL soretolide (D-2916)TLP talampanel (GYKI 53773)HUP huperzine AATM atipamezoleVLR valrocemide (TV1901)IVR isovaleramideVPG valproyl glycinamideVLT valnoctamideVPD valpromideVCD valrocemidePID propylisopropylacetamideLiCBZ licarbazepineEsliCBZ eslicarbazepine (BIA 2-093)FI-FBM fluorofelbamateNA ganaxolonecarisbamate (RWJ-333369)perampanelELB-139JZP-4NS-1209CGX-1007SPD-421ICA27243T2000XP-13512YKP3089NE not establishedNA not applicable

No

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61


Centers of integral care for epilepsy ldquoCAiErdquo in Mexico

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62


Thanks to Jetzabel Fragoso and Dr Francisco Loacutepez for their support in all the activities of the Priority Epilepsy Program

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63

Clinical guideline definition and classification of epilepsyJuan C Reseacutendiz-Aparicio1 Juan C Peacuterez-Garciacutea2 Efraiacuten Olivas-Pentildea3 Enrique Garciacutea-Cuevas4 Yuridia L Roque-Villavicencio5 Marisela Hernaacutendez-Hernaacutendez6 Jaime I Castro-Maciacuteas7 and Jesuacutes D Rayo-Mares8

1PPE Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez y Hospital Psiquiaacutetrico 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 Bajiacuteo Leoacuten Guanajuato 8Hospital de Pediatriacutea del Centro Meacutedico Nacional Siglo XXI IMSS Mexico City Mexico


REViEW ARtiClE

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 gt24 h the second an unprovoked or reflex seizure with at least a 60 probability of continuing to present seizures and the third the presence of an epileptic syndrome The classification of the type of seizure divides them into three possibilities depending on how they begin they can be of focal generalized or unknown onset Focal seizures can be subclassified into those that have or have not lost consciousness then categorized as to whether the symp-toms are motor or non-motor and further give a descriptor of the event which is nothing else but the description of symptoms and signs presented by the patient during his seizure The classification of the type of epilepsy proposes three diagnostic levels the first related to the type of seizure the second to the type of epilepsy and the third to the type of epileptic syndrome without forgetting etiology and comorbidity These concepts are basic for the approach of any patient who presents epilepsy

Key words Epilepsy Definition Classification


PPE Instituto Nacional de Neurologiacutea y

Neurocirugiacutea Dr Manuel Velasco Suaacuterez

Hospital Psiquiaacutetrico Infantil Dr Juan N Navarro

Mexico City Mexico


Disponible en internet 12-04-2019





DOI 1024875RMNM19000024

introduction

This being a clinical guide it is developed based on research questions under the PICO method answers are presented and it concludes with recommendations In this clinical guide we do not mention levels of evi-dence since the references used are current articles from the International League Against Epilepsy (ILAE)1-3 which is the official agency for this disease worldwide

and not a review of the available evidence The ILAE and its workgroups have strived to provide a standard terminology to be used worldwide

Question 1 What is an epileptic seizure

An epileptic seizure is defined as the transitory ma-nifestation of signs andor symptoms caused by an anomalous excessive neuronal activity in the brain4

1665-5044copy 2019 Academia Mexicana de Neurologiacutea AC Publicado por Permanyer Meacutexico Este es un artiacuteculo Open Access bajo la licencia CC BY-NC-ND (httpcreativecommonsorglicensesby-nc-nd40)

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64


Question 2 What is an unprovoked seizure

The term unprovoked implies the absence of a temporal or reversible factor that reduces the convulsive threshold and provokes a seizure at that moment The opposite of this type of phenomenon is an acute symp-tomatic seizure defined as a seizure that occurs in tem-poral relation during cerebral injury which can be meta-bolic infectious toxic structural or inflammatory45

Question 3 What is the current definition of epilepsy

A diagnosis of epilepsy is established after any of the following situations41 Two or more unprovoked or reflex seizures occurring

with gt24 h difference2 An unprovoked or reflex seizure with a probability of at

least 60 of presenting a future seizure (similar range as the general risk of recurrence after two unprovoked seizures that appear in the following 10 years)

3 Diagnosed epileptic syndrome

Question 4 How is the risk of recurrence of an epileptic seizure defined

The events that have been documented to increase the risk of recurrence of an epileptic seizure are cere-brovascular disease both ischemic and hemorrhagic cranioencephalic trauma abnormal electric activity in an EEG compatible with an epileptic seizure or a cranial magnetic resonance showing a lesion compatible with a diagnosis of epilepsy5 If a patient after a first unpro-voked seizure is predisposed to continued generation of seizures of at least 60 a diagnosis of epilepsy must be considered4 If this is not the case to establish a diagnosis of epilepsy one must consider option one (two or more unprovoked seizures gt24 h apart)

Epilepsy is considered as resolved in those patients that have an age-dependent epileptic syndrome but have grown older than the corresponding age for the specific syndrome or in patients that have remained seizure-free for the past ten without taking antiepileptic drugs in the last 5 years4

Question 5 What is the current classification by type of epileptic seizure

The ILAE decided to modify the classification system for epileptic seizures in 19816 and update it in 20107

The classification is divided into three depending on the patientrsquos symptoms at seizure onset

Focal onset seizureGeneralized onset seizureUnk-nown onset seizure

Focal onset seizures originate within a network limi-ted to one hemisphere they can be localized or more widely distributed Generalized seizures are those that originate at one point with wide and rapid participation of bilaterally distributed networks Those seizures whe-re it cannot be distinguished whether they are of focal or generalized onset with a confidence level of 80 must be considered of unknown onset (Fig 1)

Question 6 How are focal onset epileptic seizures currently classified

The state of awareness is a differentiating factor for the type of seizure in focal seizures12 Awareness refers to the relationship between oneself and the external environment In epilepsy we establish awareness as the mental state with both subjective and objective aspects that encompasses the sense of self as a unique entity capable of response and memory A focal seizure is classified by the degree of awareness during onset which can be altered at any time during the event

Focal seizures with or without impaired awareness can be subclassified depending on whether they initiate with motor or non-motor symptoms In addition the 2017 clas-sification recommends adding what they call ldquodescriptorsrdquo which are symptoms and signs that the patient presents during the seizure12 Descriptors have been divided into six groups motor automatisms sensory emotional cog-nitive or autonomic To remember these descriptors more easily you can use the mnemotechny MASECA which is the most famous brand of tortilla dough in Mexico8

Question 7 How are the symptoms and signs divided into focal seizures

Motor

Involvement of the musculature in any way An in-crease (positive) or decrease (negative) in muscular contraction to produce movement The most frequent are motor arrest astatic clonic dysarthria dystonic pelvic thrusting figure-of-4 hypokinetic hyperkinetic incoordination Jacksonian myoclonic paralysis pare-sis pedaling fencerrsquos posture and versive

The most frequent clinical confusion is in differentia-ting clonic seizures from myoclonic seizures A clonic seizure is a repetitive regular movement that can be

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65

JC Reseacutendiz-Aparicio et al Definition and classification of epilepsy

symmetrical or asymmetrical and that involves the same muscle groups A myoclonic seizure is a brief (lt 100 ms) sudden involuntary single or multiple contractions of the muscles or muscle groups with variable topography (axial proximal or distal extremities) The myoclonic seizure is less repetitive and sustained

Automatisms

Motor activity which is more or less coordinated that generally occurs when awareness is deteriorated and after which the subject is generally (but not always) amnesiac It commonly resembles a voluntary move-ment The most frequent include aggression manual

oral-facial perseveration sexual undressing vocaliza-tion walking or running

Sensory

Related with the senses thus in this case are not signs but symptoms The most frequently reported symptoms are auditory gustatory olfactory somato-sensory vestibular visual and pain

Emotional

These are seizures that present as having an emotion as a prominent initial feature such as fear pleasure or

Figure 1 Classification by type of seizure ILAE 2017

Focal Onset Generalized Onset Unknown Onset

Aware Impaired Awareness

MOTOR ONSETautomatismsatonic clonicepileptic spasmshyperkineticmyoclonictonicNON-MOTOR ONSETBehavior arrestautonomicsensoryemotionalcognitive

MOTORtonic-clonicclonictonicmyoclonicmyoclonic-tonic-clonicmyoclonic-atonicatonicepileptic spasmsABSENCEtypicalatypicalmyoclonicpalpebral myoclonia

MOTORtonic-clonicepileptic spasmsNON- MOTORBehavior arrest

UnclassifieddaggerFocal to bilateral toacutenico-cloacutenica

Can be focal or generalized with or without alteration of awareness dagger Due to inadequate information or inability to be included in another category

No

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may

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66


spontaneous euphoria laughter crying expressed in bursts or flares

Cognitive

The most frequently reported data from this group are acalculia aphasia attention impairment deacutejagrave vu or jamais vu phenomena dysphasia illusions memory impairment forced thinking altered responsiveness or hallucinations

Autonomic

Alteration of the autonomic nervous system function which may involve the cardiovascular system pupils diaphoresis the gastrointestinal tract vasomotor and thermoregulation functions

In focal seizures there are two sections that were not included in previous classifications the epileptic spasm (previously only classified within generalized seizures) and behavior arrest12

A focal onset seizure with or without impaired awa-reness motor or non-motor can progress to a bilateral tonic-clonic activity The term previously used for this type of seizure was a secondary generalized partial seizure At present we must classify it as a focal onset seizure that evolves into a bilateral tonic-clonic seizure

The term bilateral tonic-clonic is used for focal seizu-res that propagate to both cerebral hemispheres while generalized is for seizures that originate simultaneously in both cerebral hemispheres

Question 8 iquestHow are generalized epileptic seizures currently classified

They are divided into seizures with motor or non-motor symptoms Among those with motor symp-toms are the generalized tonic-clonic clonic tonic myoclonic myoclonic-tonic-clonic myoclonic-atonic seizures and the epileptic spasm For non-motor there are absence seizures12 A myoclonic-tonic-clo-nic is a type of generalized seizure that was not in-cluded in the previous classification These seizures imply one or various bilateral jerks (myoclonic) of the extremities followed by a tonic-clonic seizure128 Ato-nic seizures present sudden loss or reduction in mus-cle tone involving musculature of the head trunk mandible or extremities

The epileptic spasm is usually more sustained than a myoclonic movement but not as sustained as a tonic

seizure It frequently occurs in clusters or bursts Epi-leptic spasms are more frequent in children but can occur at all ages

Absence seizures can be divided into four types Typical absence atypical absence myoclonic absence and absence with palpebral myoclonus Typical absen-ce seizures are of sudden onset interrupting ongoing activities blank stare does not respond when spoken to lasting from seconds to half a minute and with very quick recovery Itrsquos important to remember that the word ldquoabsencerdquo is not synonymous with blank stare since this can also be encountered in focal onset seizures2

Atypical absence seizures show changes in tone that are more pronounced than in typical absence the on-set and cessation are not abrupt Myoclonic absence presents with sudden brief (lt100 ms) involuntary non-repetitive nor sustained and absence In absence with palpebral myoclonus we observe eyelids jerking at a frequency under 3 per second eyes commonly deviated upward generally lasting lt10 s frequently precipitated by ocular closure with high possibility of photosensitivity

Question 9 When do we classify an epileptic seizure under the heading of unknown onset or unclassified

When there is no evidence about the onset of the seizure focal or generalized it may be classified under the heading of unknown onset seizure and in this case a limited classification can be carried out with the fin-dings that were observed

The heading ldquoUnclassifiedrdquo applies to the type of seizure when there are no data described in the ILAE classification of 2017 either because the information is inadequate or because of unusual characteristics12

Question 10 How are epilepsy and epileptic syndromes classified

Since April 2017 the epilepsy classification set forth by the ILAE establishes three levels of diagnosis the first level is the type of seizure which incorporates all of the concepts in all diagnostic levels revised pre-viously focal generalized or of unknown onset and now we have added two important concepts at all diagnostic levels patient comorbidities (associated pathological entities) and etiology Some patients can only stay at this diagnostic level because it is not pos-sible to study more and this can be valid or be the

No

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67


first step in their evaluation The second diagnostic level applies when there is at least one encephalo-gram and a cerebral imaging study At this level one must establish the type of epilepsy which can be fo-cal generalized or combined this is for focal gene-ralized (which is common in various epileptic syndro-mes) or unknown type seizures The etiologic diagnosis can be in any of the following fields structural gene-tic infectious metabolic immune or unknown On occasion there can be gt1 etiology in the same patient for example a patient with tuberous sclerosis that has cortical tubers would suggest a structural etiology but also genetic due to the base disease The third diag-nostic level constitutes an epileptic syndrome A group of characteristics that incorporates types of seizure specific EEG findings characteristics form imaging studies age-dependent frequency age at onset and remission when applicable specific triggers varia-tions during the day on occasion prognosis distincti-ve comorbidities both intellectual and psychiatric and all can have implications on etiology and treatment This classification eliminates the term benign which has been substituted by the terms autolimited or drug responsive (Fig 2)

Epileptic syndromes can be classified by age groups as was established by the ILEA classification of 20107 but that is subject for another Guide

Question 11 How are seizures and epilepsy in the newborn classified

There are various classifications for neonatal seizu-res The Volpe classification9 considers the clinical fin-dings (mostly used by pediatricians and neonatologists) and the Mizrahi classification10 considers the physiopa-thologic origin be it epileptic or non-epileptic In 2018 the ILAE issued a new proposal to classify seizures in the newborn (Fig 3) that includes four parts the pre-sentation established in the critically ill newborn who must be under vigilance in view of the possibility of a seizure diagnosis by performing a video-EEG mani-festation which could be by clinical signs or only elec-troencephalographic data and fourth the type of sei-zure which could be with motor symptoms It is called sequential when the symptoms in the newborn show a motor sequence and the seizure is of a non-motor type

Recommendation Level of recommendation

Itrsquos desirable for health professionals to know the current definition of epilepsy to be able to apply it

R‑PPE

Itrsquos desirable that health professionals know and apply the current classification of the types of epileptic seizures and epilepsies

R‑PPE

Figure 2 Classification of Epilepsy ILAE 2017

Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown

EtiologyFocal Generalized Unknown

Type of seizure

Focal Generalized UnknownCombinedgeneralizedand focal

Type of Epilepsy

Epileptic Syndrome

No

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68


Conflicts of interestIn this article there are no conflicts of interest by the

authors or the source of funding

References 1 Fisher RS Cross JH French JA et al Operational classification of sei-

zure types by the international league against epilepsy position paper of the ILAE commission for classification and terminology Epilepsia 201758522-30

2 Fisher RS Cross JH DrsquoSouza C et al Instruction manual for the ILAE 2017 operational classification of seizure types Epilepsia 201758531-42

3 Scheffer IE Berkovic S Capovilla G et al ILAE classification of the epilepsies position paper of the ILAE commission for classification and terminology Epilepsia 201758512-21

4 Fisher R Acevedo C Arzimanoglou A et al Definicioacuten cliacutenica practica de la Epilepsia Epilepsia 201455475-82

5 Thurman DJ Beghi E Begley CE et al Standards for epidemiologic studies and surveillance of epilepsy Epilepsia 201152 Suppl 72-6

6 Bancaud J Rubio-Donnadieu F Seino M Dreifuss F Penry K Proposal for revised clinical and electroencephalographic classification of epileptic seizures From the commission on classification and terminology of the international league against epilepsy Epilepsia 198122489-501

7 Berg AT Berkovic SF Brodie MJ et al Revised terminology and con-cepts for organization of seizures and epilepsies report of the ILAE commission on classification and terminology 2005-2009 Epilepsia 201051676-85

8 Rubio F Resendiz JC Alonso MA Senties H Epilepsia 1st ed Meacutexico Editorial Alfil 2016 p 27-42

9 Volpe JJ Neonatal seizures current concepts and revised classification Pediatrics 198984422-8

10 Mizrahi EM Kellaway P Characterization and classification of neonatal seizures Neurology 1987371837-44

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

Critically ill or with clinical suspicion

Video EEG

Seizure(with EEG correlate)

Without clinical signs(only electrographic)

MOTORautomatisms clonicepileptic spasmsmyoclonictonicsequentialNON-MOTORBehavior arrestautonomicUNCLASSIFIED

Presentation

Diagnosis

Manifestation

Seizure type

No seizure(without EEG correlate)

with clinical science

No

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69

Clinical guideline management of seizures in the emergency roomJoseacute Visoso-Franco1 Liliana Romero-Ocampo2 Joseacute A Santos-Zambrano3 Alberto Serrano-Gonzaacutelez4 and Elvira Castro-Martiacutenez5

1Hospital Regional de Especialidades ISSSTE Leoacuten Guanajuato 2Hospital Central Norte PEMEX y Hospital General de La Raza CMN Especialidades IMSS 3Instituto Nacional de Neurologiacutea y Neurocirugiacutea 4Hospital Pediaacutetrico Legaria 5Hospital General ldquoDr Manuel Gea Gonzaacutelezrdquo e Instituto Nacional de Neurologiacutea y Neurocirugiacutea Mexico City Mexico


REViEW ARtiClE

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

Correspondence Elvira Castro Martiacutenez

Hospital General ldquoDr Manuel Gea Gonzaacutelezrdquo e

Instituto Nacional de Neurologiacutea y Neurocirugiacutea

Mexico City Mexico

E-mail elviracastromyahoocommx






DOI 1024875RMNM19000025


introduction

Epilepsy is one of the diseases that affect the quality of life of patients the most due to its neurological psy-chological and social implications Epileptic seizures (ES) are a common cause of admittance to the emer-gency room (ER) and they are responsible for 1 million or 1 of all the ER consults The annual cost of care prehospital and within the ER to treat ES is estimated

to be 1 billion dollars Clinical guidelines attempt to direct and guarantee the assertiveness of medical at-tention to improve the diagnosis and treatment of this disease1-3

Recommendations for scientific research were based on the selective location of keywords in PubMed-MED-LINE The Cochrane Library and other clinical practice guidelines as well as recommendations by other scien-tific societies

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2019

70


Questions addressed within this guideline

1 What clinical data must be purposefully investigated during the anamnesis of a patient with ES in the ER2 Which laboratory tests must be performed in the ER on a patient with a first ES3 Under which conditions must electroencephalography be performed on a patient with ES in the ER4 Under which conditions must a neuroimaging test (CT or MRI) be performed on a patient with ES in the ER5 Under which conditions must anti‑epileptic drugs be initiated on patients with a first ES in the ER

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

What clinical data must be purposefully investigated during the anamnesis of a patient with ES in the ER

Recommendation (Figures 1-3) Level of recommendation

Identification of all possible triggering factors for the seizureminus Fever concomitant systemic infection or diseaseminus History of previous neurological diseaseminus Traumaminus Ingestion of drugs or toxic substancesminus Recent vaccinationsminus Family history of ES

DNICE 20124

R‑ Solari F 20115

Medical personnel performing an initial examination on a patient in the ER must identify and interrogateminus Alteration of the level of consciousnessminus Type and topography of altered motor activityminus Sensory symptomsminus Autonomic symptomsminus Cognitive symptomsminus Behavior during the preictal ictal and postictal periods

DNICE 20124

R‑ SAdE 20156

Additional information must be gathered for the diagnosis includingminus Perinatal pathologiesminus Characteristics of psychomotor development timelineminus Learning disabilitiesminus Other neurological or psychiatric diseases

3NICE 20124

R‑ SAdE 20156

A directed neurological examination is recommended in search of signs and symptoms ofminus Intracranial hypertensionminus Signs of meningeal irritationminus Focal neurological deficitminus Neurological emergency

DNICE 20124

R‑ SAdE 20156

ES epileptic seizures ER emergency room

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


Laboratory tests on a patient that has complete recovery after a first ES are not considered necessary unless there are specific findings that justify them

3NICE 20124

R‑SAdE 20156

Laboratory tests recommended for patients with ES that present with dehydration due to vomiting or diarrhea and demonstrate a progressive or persistent deterioration of consciousness are

minus Complete blood countminus Blood glucose sodium and electrolytesminus Serum pregnancy (qualitative hCG) test

DNICE 20124

R‑SAdE 20156

No

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71

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

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

DNICE 20124

R‑ SAdE 20156

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

R‑ SAdE 20156

To establish a differential diagnosis of non‑epileptic paroxysmal events individualization of cases is recommended when considering complementary tests

DNICE 20124

R‑SAdE 20156

If substance abuse of psychoactive drugs or exposure to toxic substances is suspected a toxicology screen is recommended

DNICE 20124

R‑ SAdE 20156

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

R‑SAdE 20156

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

Figure 1 Unprovoked Epileptic Seizure

Diagnosis of UES

Non-epileptic paroxysmal event

Yes No

Diagnostic support with EEG or VEEG is

suggested

Confirmed ES

A doubtful or uncertain diagnosis merits a referral to a specialist

(Psychiatrist or Neurologist)

Recurrence risk assessment 1 Family history of epilepsy2 Abnormal neurological examination3 Abnormal EEG4 Brain injury visible on cranial CT or MRI5 FS (focal epileptic seizures)6 ES during sleep7 Epileptic Syndrome

Commence individualized AED therapy

No

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72


Under which conditions must electroencephalography be performed on a patient with ES in the ER


There is no evidence that an emergency EEG has any implication on immediate therapy therefore there are few indications such as

minus Suspicion of subtle or non‑convulsive status epilepticusminus Comatose state of unknown originminus Suspicion of herpetic encephalitis

IVSAdE 20156

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

R‑SAdE 20156

An EEG is a useful diagnostic test in stabilized patients in the ER tominus Support the diagnosis of epilepsyminus Determine the type of epilepsy and epileptic syndrome in concordance with clinical findings and

ictal activityminus Asses the risk of seizure recurrenceminus Support therapeutic decisions

2+SIGN 20157

3NICE 20124

R‑ SAdE 20156

EEG electroencephalography ES epileptic seizures ER emergency room

Figure 2 Acute symptomatic epileptic seizure (provoked)

No

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73


Figure 3 Epileptic seizure on patients previously diagnosed with epilepsy

ES on patients previously diagnosed

with epilepsy

Typical ES presentation No Yes

1 Blood glucose and sodium2 Cranial CT

bull Lack of AED treatment adherence bull AED cessation due to adverse effectsbull AED drug interaction with concomitant treatment bull Insufficient AED dosagebull Sleep hygiene alterationbull Underlying infectionbull Alcohol or toxin ingestion

Correction of uncontrolled seizure trigger factors

Adjustment or modification of AED treatment

Outpatient consult follow-up

Hospitalization assessment

Identification of trigger factorsfor uncontrolled seizures

Repeat initial diagnostic tests

Under which conditions must a neuroimaging test (Ct or MRi) be performed on a patient with ES in the ER


A cranial CT must be performed on all emergency cases however it does not substitute a programmed cranial MRI

BSAdE 20156

An emergency cranial CT may be considered for previously healthy patients (pediatric or adult) if a programmed MRI cannot be performed within the following 3 days

R‑SAdE 20156

No

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74


Neuroimaging tests (cranial CT or MRI the latter being the first choice) are recommended for patients who present a first ES under the following circumstances

minus Focal seizuresminus Focal neurological deficitminus Persistent alteration in the level of consciousnessminus Recent traumatic brain injuryminus Cancerminus Suspicion of HIV infectionimmunosuppressionminus Hemorrhagic diathesisminus Children under 2 years of ageminus Persistent cephalea (headache)minus Meningeal signsminus Signs of intracranial hypertension

BSAdE 20156

CNICE 20124

R‑Ghofrani M 20138

R‑Aprahamian N 20149

R‑Michoulas AS 201110

Neuroimaging tests are not useful under the following circumstancesminus Febrile seizuresminus Focal impaired awareness seizuresminus ES with a proven metabolic origin

R‑SAdE 20156

CT computerized tomography MRI magnetic resonance imaging

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 considerminus The probability of recurrenceminus The drugs efficacy and toxicity

CNICE 20124

R‑Bergey G 201611

Treatment with AED after a first ES must be individualized and assessed by a qualified professional ANICE 20124

R‑ Leone MA 201612

CNICE 20124

R‑Bergey G 201611

It is recommended that AED treatment be initiated on patients with one or more of the following risk factors

minus History of previous brain injury with remote symptomatic seizuresminus Focal ESminus ES during sleepminus Family history of ESminus Abnormal neurological examinationminus Psychomotor delayminus Status epilepticusminus Abnormal EEGminus Neuroimaging abnormalities

CNICE 20124


R‑Bergey G 201611


R‑Krumholz A 201513

During the initiation of AED treatment it is recommended to consider the risk of seizure aggravationminus Phenytoin aggravates absence and myoclonic seizuresminus Carbamazepine and oxcarbamazepine exacerbate absence myoclonic and atonic seizures

DNICE 20124

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

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75


Algorithm Management of ES in the ER

ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus

Figure 1 Figure 2 Figure 3Refer to status

epilepticus guidelines

References 1 Cerdaacute JM Argani MT Llerda JA et al Guiacutea oficial de la sociedad espantildeola de neurologiacutea de praacutectica cliacutenica en epilepsia Neurologiacutea 201631121-9 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

2008197-105 3 Martindale JL Goldstein JN Pallin DJ Emergency department seizure epidemiology Emerg Med Clin North Am 20112915-27 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 epileacutepticas en la poblacioacuten infantil Rev Med Clin Condes 201122647-54 6 Sociedad Andaluza de Epilepsia Guiacutea 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 201371-5 9 Aprahamian N Harper MB Prabhu SP et al Pediatric first time non-febrile seizure with focal manifestations is emergent imaging indicated Seizure

201423740-5 10 Michoulas A Farrell K Connolly M Approach to a child with a first afebrile seizure BCMJ 201153274-7 11 Bergey GK Management of a first seizure Continuum (Minneap Minn) 20162238-50 12 Leone MA Giussani G Nolan SJ Marson AG Beghi E Immediate antiepileptic drug treatment versus placebo deferred or no treatment for first unpro-

voked seizure Cochrane Database Syst Rev 20165CD007144 13 Krumholz A Wiebe S Gronseth GS et al Evidence-based guideline management of an unprovoked first seizure in adults report of the guideline deve-

lopment subcommittee of the American academy of neurology and the American epilepsy society Epilepsy Curr 201515144-52

No

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76

Clinical guideline management of the first unprovoked epileptic seizure in adults and childrenJoseacute A Gien-Loacutepez1 Raymundo A Cuevas-Escalante2 Enrique Garciacutea-Cuevas3 Mariacutea R Maacuterquez-Estudillo4 Blanca E Villasentildeor-Anguiano5 Rauacutel Leal-Cantuacute6 and Ramoacuten E Jimeacutenez-Arredondo7

1Hospital Regional No 1 IMSS Meacuterida Yucataacuten 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 ldquoDr Miguel Silvardquo Morelia Michoacaacuten 7Hospital General de Zona No 1 ldquoLuis Ernesto Miramontes Caacuterdenasrdquo IMSS Tepic Nayarit Mexico City Mexico


REViEW ARtiClE

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

Correspondence Jose Antonio Gien-Loacutepez

Hospital Regional No 1 IMSS

Meacuterida Yucataacuten Mexico

E-mail neurologiameridagmailcom






DOI 1024875RMNM19000026

introduction

This guideline was developed based on research questions under the PICO method where questions are presented with their corresponding answer establishing levels of evidence to offer specific orientation regarding the international recommendations on the related sub-ject matter seeking the exposure and application of these same management criteria for first unprovoked seizures in children and adults The final objective of this guide is to aid health-care professionals in solving the initial questions when faced with a patient who has

suffered an epileptic seizure (ES) and to make deci-sions based on the best evidence available

1 What are the characteristics of acute symptomatic ESs and unprovoked ESs (UES)

An acute symptomatic ES provoked or reactive can be defined as seizures presented during the course of a disease which temporarily lowers the threshold of an ES this type of seizure is not considered epilepsy1


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2019

77

J A Gien-Loacutepez et al First unprovoked epileptic seizure

For the condition to be considered a provoked ES the required time span between a cerebral injury and onset of the seizure is 7 days for injuries such as trau-matic brain injury (TBI) brain surgery cerebrovascular disease and cerebral anoxia and for the acute phase of infections of the central nervous system (CNS) 24 h for patients with metabolic disorders and 7-48 h after the last ingestion of alcohol in patients with abstinence2

An UES is characterized by the lack of temporary or reversible risk factors that lower the threshold to pre-sent an ES3 The diagnosis of an ES and epilepsy is based on the patientrsquos medical history the information obtained during direct questioning when the patientrsquos consciousness is preserved and is able to describe the seizure or indirect questioning when information is ob-tained from a first-hand witness of the seizure A tho-rough medical history must be obtained to allow the clinician to identify if the event is an ES as well as the type of seizure This information will also be useful to establish a differential diagnosis between an ES and non-ES such as Psychogenic syncope or migraine among other causes4 The medical history has always been considered the cornerstone of the approach to any disease and patients with ES and epilepsy are not the exception5

2 What are the precipitating risk factors after a first UES

A systematic review published in 2015 consisting of 10 randomized control studies revealed that treatment versus lack of treatment of first ES resulted in early recurrence within 2 years from 21 to 45 in the 1st year respectively6 Certain clinical characteristics can determine seizure recurrence This study demons-trated that the majority of patients with UES are be-tween 16 and 60 years of age which implies that the age groups before and after this age range have a greater recurrence risk of 21 (95 confidence interval = 10-43)7 Other risk factors for seizure recu-rrence include positive family history history of febrile seizures first prolonged seizure initial suspicion of epilepsy unknown seizure etiology abnormal physical examination and nocturnal seizures in patients aged 1-4 years when compared to patients who remain awake during seizures7 A paroxysmal electroencepha-logram (EEG) structural injury visible on magnetic re-sonance imaging (MRI) and prolactin levels are highly specific yet a poorly sensitive test for ES Prolactin levels over 36 ngmL are highly suggestive of ES

however these must be measured between 20 min and 4 h from the onset of the seizure8 A lumbar puncture is useful when neuroinfection is suspected8

Evidence Level Grade

Brain injury epileptiform EEG pattern abnormal brain imaging and nocturnal crisis are factors that increase the degree of recurrence and aid in the decision to initiate treatment

1 A

3 Which diagnostic tests are useful for the diagnosis and prognosis of a first UES

EEG ndash evidence demonstrates that all patients with a first UES should be submitted to an EEG because the data obtained are useful for diagnosing ES when abnormalities are present Determining the type of ES also helps in identifying the etiology in some cases and establishing a differential diagnosis from NES8 EEG data are also useful in the selection of the an-ti-epileptic drugs (AED) whenever these are medically indicated It must be noted however that abnormal EEG results without clinical manifestations are not con-sidered epilepsy and conversely patients with epilepsy may have a normal EEG9

A meta-analysis of 16 studies established as a sei-zure recurrence indicator for an UES epileptiform dis-charges on the EEG (20 CI 95 16-26) If the EEG showed non-epileptiform discharges there was a recu-rrence of seizures however no statistical significance was found10 Records of brain electrical activity within the first 24 h after the first UES increase the probability of detecting interictal epileptiform discharges (IEDs) The IED is most frequently recorded among temporal epilepsies when compared to extratemporal epilep-sies11 and they increase seizure recurrence risk

The EEG must be carried out and interpreted by cer-tified personnel on patients under hyperventilation and with at least 20 min of recorded patterns without artifacts Current guidelines suggest that an EEG is a necessary test for the evaluation and treatment deter-mination after a first ES6 EEGs are the most common test used for diagnosing epilepsy An epileptiform dis-charge on an EEG was associated with a relative in-crease in the recurrence rate of ESs when compared to a normal EEG12 Patients with an abnormal EEG with epileptiform discharges presented a recurrence risk of 60 after a first seizure According to the ILAE 2017 60 recurrence risk mandates that the first seizure should be considered epilepsy The probability of

No

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2019

78


finding an abnormality on the EEG is higher after repeat studies where 39 of patients presented abnormalities on the first test and 68 on their third test7 Patients with epileptiform discharges have a 77 recurrence rate on a first UES compared to 47 if the EEG is nor-mal These discharges are better detected if the EEG is performed within the first 12 h after an ES13 Accor-ding to the ILAE the recommended window to perform an EEG is within the first 72 h after a UES and within the first 24 h after an ES14 If EEG results are normal it is recommended to perform EEG tests during sleep with sleep deprivation photostimulation and repeated tests12-14 An unaltered routine EEG does not exclude the presence of an ES Other studies report that an EEG performed within the first 6 h after an ES reveals the presence of epileptiform discharges in 67 of ca-ses between 6-12 h in 52 12-24 h in 24 24-48 h in 25 48-72 h in 22 and 72-96 h in 1813 Based on the previous data it can be concluded that prompt EEG tests after onset of seizures are more likely to de-tect epileptiform discharges and their efficacy of detec-tion is progressively reduced in later tests15 The Ame-rican Academy of Neurology (AAN) in 2007 established a time-frame for EEGs within a window of 48 h after ES onset and up to an average of 15 days afterward13

EEG results from sleep-deprived patients improve the sensibility and specificity of the epilepsy diagnosis Sleep induced by sleep deprivation is more likely to provoke epileptiform discharges when compared to physiological sleep16 Seizure recurrence after a first ES with epileptiform discharges recorded on an EEG was 732 whereas a normal EEG was associated with a 328 recurrence11 thus EEG records with epileptiform graphic patterns were established as a recurrence factor Seizure recurrence on patients with generalized compared to focal epileptiform discharges was 688 and 75 respectively13 The recommenda-tions of the AAN and the American Epilepsy Society (AES) for patients with a first UES and an EEG with epileptiform discharges are level A6

Neuroimaging

A computed tomography scan (CT) of the skull is performed in emergency cases on a patient with a first ES its primary indication is to determine the presence of brain injuries that could cause an ES such as a stroke or TBI A CT may also be performed when phy-sical exploration demonstrates a focal neurological de-ficit a prolonged altered state of alertness and in febrile patients or with findings that suggest a CNS infection

MRIs detect more SNC alterations when compared to

CT scan thus without a need for an emergency image

MRI is the technique of choice12 Neuroimaging tests

are necessary to predict the probability of recurrence

after the first UES6 They are indicated with the objec-

tive of identifying the etiology of the ES The advanta-

ges of a CT are availability and the speed in which the

test is performed and the results obtained can guide

the decision for the need of immediate medical atten-

tion especially in emergency care12 Neuroimaging

tests have an important value in patients with epilepsy

research shows recurrence rates a year after the first

seizure of 59 (95 CI 54-65) if patients had an

epileptogenic lesion visible on a CT or MRI and 44

(95 CI 41-48) in patients without evident lesions by

neuroimaging (p=0001)12

The recurrence rate of UES within 1 year in patients

that demonstrated an epileptogenic lesion only by MRI

was 67 compared to 50 for patients without a visible

lesion The MRI is superior to the CT in detecting epi-

leptogenic abnormalities13 If available an MRI is the

preferred neuroimaging technique in patients with a first

UES Neuroimaging tests should be performed fo-

llowing epilepsy protocol and interpreted by neuroradio-

logy specialists

Evidence Level

Children or adults with a first UES should undergo a thorough medical history and examination followed by at least two diagnostic tests neuroimaging (CTMRI) and EEG

Class I (13)Class I CII (14)

A standard EEG is a useful study for the diagnosis of a first UES

Class III (15)Class I (16)

An EEG with epileptogenic discharges is the best predictor for recurrence of a first UES together with an abnormal neurological examination and corresponding etiology

Class I (16)Class III (13)

An EEG helps to differentiate between an ES and other events of non‑epileptic origin

Class I (16)

A routine EEG does not demonstrate evidence of brain abnormalities A prolonged EEG is useful for the diagnosis of a first UES

Class II (4)

The VEEG is a useful test for the diagnosis of a first UES it predicts a seizure recurrence of 46 in 12 months and 51 in 24 months

Class III (4)

The CT is a useful test for the diagnosis of a first UES

Class I (16)

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Focal lesions are more commonly found on a CT in adults (18‑34) compared to children (0‑12) with the exception of infants under 6 months old where abnormalities are found in 55 of cases and in adults with HIV in 28 of cases

Class I (16)Class I (14)

The following conditions are predictors of abnormalities found on a CT altered neurological examination infants under 6 months old closed TBI recent manipulation of ventriculoperitoneal shunting cerebral tumor suspicion neurocutaneous syndromes focal onset of seizure alcohol abuse history cysticercosis and seizures over 15 min in duration

Class I (14)

An MRI is superior to the CT in establishing the diagnosis of an epileptogenic lesion

Class I (14)

The MRI is the preferred diagnostic test alongside the EEG in children that present a first non‑febrile seizure

Class I (16)

The recurrence risk of an UES increases by 216 (95 CI 144‑451) if epileptogenic alterations are found on the EEG and by 21 (95 CI 109‑544) in an abnormal neuroimaging test

Class I (6)

Recommendations Grade

The standard EEG should be considered a useful test to diagnose UES since it detects epileptogenic abnormalities in 12‑27 of cases and if performed under sleep deprivation the probability of detection increases up to 58

Level B

A standard EEG performed within the first 24 h of seizure onset detects epileptogenic abnormalities in 34‑51 of cases

Level B

A standard EEG detects the same recurrence risk of a UES as a VEEG

Level B

A standard protocol MRI detects epileptogenic lesions in 23 of cases that are not detected by CT

Level B

UES unprovoked epileptic seizure CTMRI computed tomographymagnetic resonance imaging EEG electroencephalogram ES epileptic seizure VEEG video‑electroencephalogram

4 What are recurrence factors for first UESs

The AAN has described four factors that result in greater seizure recurrence (1) an EEG with epileptiform abnormalities (2) cerebral injury such as stroke or TBI (3) a newly found lesion on neuroimaging and (4) noc-turnal seizures17 After a patient suffers a second sei-zure the patient has 60 of recurrence within the 1st year and 70 recurrence within the 2nd year17

If the seizure is of genetic etiology and the patient has a sibling with seizures the recurrence risk is 29 If the seizure is idiopathic with a spike and wave pattern on EEG the risk increases to 5018 In children a 5-year recurrence risk from the first seizure is 4319 In the presence of abnormalities on the EEG the risk increases to over 50 up to 6518

An adult with epileptiform discharges on a routine EEG after a UES has 77 probability of a second sei-zure while in children the probability is 6620 Children who present a seizure during sleep have a 75 proba-bility of recurrence within 2 years compared to 49 in children who did not21

5 What are the indications for pharmacological treatment

Currently the decision whether to treat a first UES is a matter of controversy It is generally accepted that AEDs are indicated as of the second UES because recurrence risk is greater (57 within the 1st year and 73 within 4 years)22 A study performed by the AAN and the AES based on 10 level A trials determined that the seizure recurrence risk of an adult with a first UES was between 21 and 45 within the first 2 years and the cumulative risk of a second ES was 32 after a year and 46 for 5 years14 In the Multicenter Epilepsy and Single Seizures (MESS) study it was concluded that the recurrence of a first UES was 39 within 2 years and 51 within 5 years2

The probability of presenting an isolated ES is 8-10 and 3 of developing epilepsy revealing an incidence rate of 61100000 individuals per year resulting in a prediction that an estimated 4 million individuals each year will experience a first UES that may be focal or generalized1 because 30 of paroxysmal episodes are inappropriately diagnosed1

To initiate treatment it is important to confirm the presence of a first UES as there is no doubt that a simulator event is ocurring523 The degree of certainty of the diagnosis lies in an adequate interrogation as well as physical and neurological examination directed diagnostic tests emphasizing important points of sei-zure semiology suspicion of ES or epilepsy establi-shing a proper differential diagnosis distinguishing between provoked ES and UES using the definition criteria for epilepsy and investigating and classifying the type of seizure as well as the recurrence risk Treatment should be limited to observation and com-plementary tests if recurrence risk is low AED should be initiated if the risk if moderate or high324 If patients

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have an ES while being alone complementary labo-ratory and other diagnostic tests such as the EEG must be performed as soon as possible because its useful-ness is greater in the first 24 h after the seizure25 If epilepsy debut is suspected in subclinical seizures it must be noted that lt50 of seizures are detected by a 30-min routine EEG however this detection rate is increased to 90 if constant monitoring of 24-36 h is performed26 Within the emergency care department the accepted initial test is a CT23 considering a sub-sequent MRI except if the CT demonstrates an impor-tant pathology or if the patient must be sedated

Other tests such as serum prolactin are not recom-mended for the diagnosis of epilepsy however it is important to quantify serum electrolytes and glucose to identify potential causes or any comorbidities23 An electrocardiogram or referral to a cardiologist must be performed in cases of a doubtful diagnosis Neuropsychological evaluation is indicated when the MRI demonstrates important alterations or declines in the cognitive areas of the brain To initiate treatment the level of certainty of the diagnosis the degree of alteration in the neurological examination family history laboratory and imaging test results electroencephalo-graphy the side effects of the AED indicated for the type of seizure quality of life and cost of treatment must be considered

The treatment of the first UES reduces short-term recurrence risk but not the long-term prognosis3 Thus it is important to counterweigh AED side effects on re-currence risk when the risk is low3-5232426 considering the possibility if recurrence is greater within the first 3-6 months


Initial treatment should not be given after a first seizure except if the recurrence risk is high or under special circumstances

1 A

Pharmacological treatment should only be initiated after the diagnosis of epilepsy is confirmed

1 A

The decision to initiate treatment should be taken by the treating physician together with the patient or caregiver after explaining the recurrence risk side effects and quality of life issues

1 B

The cornerstone of the diagnosis of an epileptic seizure is the clinical feature

1 B

The EEG is useful for the decision to initiate treatment

1 B

Neuroimaging tests such as CT and MRI are necessary evaluations of a patient with an isolated epileptic seizure

1 A

The treatment of the first unprovoked epileptic seizure reduces the risk of relapse but does not affect the long‑term prognosis of epilepsy

1 B

CTMRI computed tomographymagnetic resonance imaging EEG electroencephalogram

6 What are the reference indications for a first UES

Every patient with a first UES must be examined by a neurologist27 According to the regional infrastructure patients must be referred to a secondary or tertiary medical facility if there is any doubt about the type of provoked ES or if there is evidence of cerebral lesion whether it consists of a tumor hemorrhage or infection (cysticercosis toxoplasmosis or tuberculosis)28 Pa-tients that debut with status epilepticus in their first ES must be referred to a specialized facility for treatment as soon as vital signs are stable Approximately 6-7 of long debut seizures are considered as status epilepticus2930

The etiology of a provoked ES was found to be stroke in 347 TBI in 347 and infection in the CNS in 306 Conversely etiology for first UES was a stroke in 682 a TBI in 25 and CNS infection in 6831

It is important for patients to also undergo evaluation for seizure simulator conditions where studies de-monstrate that the most common simulator is a synco-pe reflex (74) and psychogenic seizures (16)32 The most common symptoms for reference to a secondary or tertiary medical facility are accompanying neurolo-gical manifestations such as cephalea immediately after the seizure28

Mortality within the first 30 days from the first provoked ES was 214 (95 CI = 169-269) compared to 34 for the first UES (95 CI = 14-79 p lt 0001)31

It has been suggested that in locations where a spe-cialized neurological consult is unavailable a remote consult by a specialist should be established by te-lephone or by video conference2 this is a common occurrence in subspecialties such as pediatric neurolo-gy33 Every referral to a tertiary health-care facility must include a complete medical history specifying medica-tion semiology of neurological signs and symptoms that may aid in classifying the type of seizure and the di-rected diagnostic evaluation28

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Every patient with a first epileptic seizure must be evaluated in a secondary health‑care facility

R‑PPE

Evidence Level

Hospitalization criteria for patients with a first UESminus Under 1 year of age (afebrile)minus Atypical or complex epileptic crisisminus Prolonged postictal stateminus Onset status epilepticusminus Meningeal signsminus New neurological deficit (previously absent)

Class III

References 1 Martinez-Juarez IE Moreno J Ladino LD et al Diagnoacutestico y tratamien-

to de la crisis epileacuteptica uacutenica no provocada Rev Neurol 201663165-75 2 Sociedad Andaluza de Epilepsia Guia Andaluza de Epilepsia Viguera

Sociedad Andaluza de Epilepsia 2015 3 Guiacutea de Praacutectica Cliacutenica Diagnoacutestico y Tratamiento de la Epilepsia en

el Adulto en el Primer y Segundo Nivel de Atencioacuten Actualizacioacuten 2015 4 Tao JX Davis AM Management of an unprovoked first seizure in adults

JAMA 20163161590-1 5 Pohlmann-Eden B Beghi E Camfield C Camfield P The first seizure

and its management in adults and children BMJ 2006332339-42 6 Krumholz A Wiebe S Gronseth GS et al Evidence-based guideline

management of an unprovoked first seizure in adults report of the gui-deline development subcommittee of the American academy of neurolo-gy and the American epilepsy society Neurology 2015841705-13

7 Angus-Leppan H First seizures in adults BMJ 2014348g2470 8 Rosenow F Klein KM Hamer HM Non-invasive EEG evaluation in

epilepsy diagnosis Expert Rev Neurother 201515425-44 9 Britton JW Frey LC Hopp JL et al Electroencephalography (EEG) an

Introductory Text and Atlas of Normal and Abnormal Findings in Adults Children and Infants Chicago American Epilepsy Society 2016

10 Berg AT Shinnar S The risk of seizure recurrence following a first unprovoked seizure a quantitative review Neurology 199141965-72

11 Chen T Si Y Chen D et al The value of 24-hour video-EEG in evalua-ting recurrence risk following a first unprovoked seizure a prospective study Seizure 20164046-51

12 Ho K Lawn N Bynevelt M Lee J Dunne J Neuroimaging of first-ever seizure contribution of MRI if CT is normal Neurol Clin Pract 20133 398-403

13 Sofat P Teter B Kavak KS Gupta R Li P Time interval providing highest yield for initial EEG in patients with new onset seizures Epilepsy Res 2016127229-32

14 Askamp J van Putten MJ Diagnostic decision-making after a first and recurrent seizure in adults Seizure 201322507-11

15 Gavvala JR Schuele SU New-onset seizure in adults and adolescents a review JAMA 20163162657-68

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 futu-re directions Neurosci Biobehav Rev 201447533-48

17 Fisher RS Acevedo C Arzimanoglou A Bogacz A Cross JH Elger CE et al Appendix A summary of evidence-based guideline for clinicians management of an unprovoked first seizure in adults Continuum (Min-neap Minn) 201622281-2

18 Rizvi S Ladino LD Hernandez-Ronquillo L Teacutellez-Zenteno JF Epide-miology of early stages of epilepsy risk of seizure recurrence after a first seizure Seizure 20174946-53

19 Shinnar S Berg AT Moshe SL et al The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood an extended fo-llow-up Pediatrics 199698216-25

20 Bouma HK Labos C Gore GC Wolfson C Keezer MR The diagnostic accuracy of routine electroencephalography after a first unprovoked sei-zure Eur J Neurol 201623455-63

21 Ramos Lizana J Cassinello Garciaacute E Carrasco Marina LL et al Seizu-re recurrence after a first unprovoked seizure in childhood a prospective study Epilepsia 2000411005-13

22 Brown JW Lawn ND Lee J Dunne JW When is it safe to return to driving following first-ever seizure J Neurol Neurosurg Psychiatry 20158660-4

23 NICE Clinical Guideline 137 The Epilepsies the Diagnosis and Mana-gement of the Epilepsies in Adults and Children in Primary and Secon-dary Care 2012

24 Leone MA Giussani G Nolan SJ Marson AG Beghi E Immediate an-tiepileptic drug treatment versus placebo deferred or no treatment for first unprovoked seizure Cochrane Database Syst Rev 20165CD007144

25 Gloss DS Krumholz A Managing an unprovoked first seizure in adults CNS Drugs 201630179-83

26 Guiacutea de Practica Clinica IMSS Diagnoacutestico y Tratamiento de la Primera Crisis Convulsiva Nintildeas Nintildeos y Adolescentes Primero y Segundo Nivel de Atencioacuten 2017

27 Wilmshurst JM Gaillard WD Vinayan KP et al Summary of recommen-dations for the management of infantile seizures task force report for the ILAE commission of pediatrics Epilepsia 2015561185-97

28 Arkilo D Griesemer D Padulsky K et al Urgent referrals for seizure evaluation to a tertiary care neurology center a pilot study J Child Neu-rol 201227885-7

29 Huff JS Morris DL Kothari RU Gibbs MA Emergency Medicine Seizu-re Study Group Emergency department management of patients with seizures a multicenter study Acad Emerg Med 20018622-8

30 Krumholz A Grufferman S Orr ST Stern BJ Seizures and seizure care in an emergency department Epilepsia 198930175-81

31 Brinar V Bozicevic D Zurak N et al Epileptic seizures as a symptom of various neurological diseases Neurol Croat 19914093-101

32 Jackson A Teo L Seneviratne U Challenges in the first seizure clinic for adult patients with epilepsy Epileptic Disord 201618305-14

33 Millichap JJ Millichap JG Child neurology past present and future part 1 history Neurology 200973e31-3

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Clinical guideline antiepileptic drugs of choice for focal and generalized seizures in adult patients with epilepsyLeopoldo Rivera-Castantildeo1 Horacio Sentiacutees-Madrid2 Jesuacutes Berumen-Jaik3 and Iris E Martiacutenez-Juaacuterez4

1Department of Neurology Hospital Aacutengeles Chihuahua Chihuahua 2Instituto Nacional de Ciencias Meacutedicas y Nutricioacuten Salvador Zubiraacuten Mexico City 3Hospital Infantil Universitario Torreoacuten Coahuila 4Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez Mexico City Mexico


REViEW ARtiClE

Abstract

The mainstay of treatment in patients with epilepsy is antiepileptic drugs (AEDs) Currently there are a significant number of AEDs in Mexico For the pharmacological management of the patient with epilepsy it is important to know the pharmacoki-netics dosage mechanism of action and formulations of the AED 70-80 of patients with either focal or generalized seizu-res are completely seizure free on AED monotherapy When despite the use of AED in monotherapy seizure freedom is not achieved a second AED should be used AEDs with different mechanisms of action are empirically combined for this pur-pose If a patient persists in having seizures with the use of an adequate AED at appropriate doses and with therapeutic adherence a correct diagnosis of the seizure type and a differential diagnosis should be reconsidered using a new clinical evaluation and auxiliary diagnostic tests

Key words Antiepileptic drug Monotherapy Polytherapy Adult

Correspondence Leopoldo Rivera-Castantildeo

Hospital Aacutengeles Chihuahua

Chihuahua Chihuahua Mexico

E-mail drleopoldoriverayahoocom






DOI 1024875RMNM19000027

introduction

This is a clinical guide for the pharmacologic treat-ment of epilepsy in adults at first and second level treatment centers It consists of establishing PICO-ba-sed questions and setting forth answers The levels of evidence are based on articles published in peer-re-viewed indexed articles and other international guideli-nes such as the guides published by the International League Against Epilepsy and the National Institute for Health Care Excellence as well as emitting

recommendations from the programa prioritario de epi-lepsia (priority epilepsy program)

Question 1 What are the pharmacokinetics of antiepileptic drugs (AEds)

In general newer AEDs have more predictable ki-netics and lower risk of drug interaction This is becau-se serum protein binding is low or null they are mainly eliminated by renal excretion or metabolized by isoen-zymes lacking P450 and they have a lower potential


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L Rivera-Castantildeo et al Antiepileptic drugs in adult patients

AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

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n Ex

tend

ed r

elea

se

form

ulat

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Pare

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ion

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lity

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T M

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Hal

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dose

sSV

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le 22

9 3

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100‑

400

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2‑24

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5 m

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GN

oN

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DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

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600

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3 do

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13

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6‑8

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mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

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ses

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‑100

80

42‑0

75

45‑6

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‑140

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6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

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lt10

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63

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200‑

300

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Tabl

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of a

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AED

Initi

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ose

Fina

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nism

of

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n Ex

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nce

(Lk

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100‑

125

mg

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dose

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0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

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1500

mg

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200‑

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Yes

Yes

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01‑

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88‑9

215

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15

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vig

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rin V

PA v

alpr

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A an

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‑type

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M m

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ctio

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atio

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for a

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of A

EDs

avai

labl

e in

Mex

ico1 (Continued)

for inducinginhibiting various hepatic enzyme systems1 (Table 1)

Question 2 What are the advantages and limitations of monotherapy for the control of epilepsy in the adult

It was not until the 70s that the practice of beginning therapy with polypharmacy began to come into question due to its toxic effects and by recognizing that there was no scientific evidence that two or three AEDs were more effective than a single AED Conversely the first obser-vational studies of that era reported that when patients with epileptic seizures went from polytherapy to mono-therapy they tended to have fewer secondary effects and even better seizure control2

The ideal AED must be effective for controlling any type of epileptic seizure have perfectly known mecha-nisms of action simple pharmacokinetics and pharma-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 epilepsy78 (Tables 4 and 5) It must have an opti-mal efficacy and tolerabilitysafety relationship In addi-tion it should be inexpensive since it is of chronic use Currently AEDs are very far from the ideal AED profile3

In 2018 Brodie et al reported results from a pros-pective study including 1795 English patients with 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 637 of the patients without seizures 573 were seizure free on monotherapy and 64 were seizure-free on polytherapy The other 363 were considered as refractory and were taking two or more AEDs without control of their seizures with a Class IV level of evi-dence (Fig 1 and Table 2)3

Monotherapy is the gold standard to begin treat-ment of focal and generalized seizures in adults with the goal of obtaining 100 control however it is im-portant to realize that about 20-30 do not achieve this goal3

Question 3 What is the AEd of choice for focal onset seizures and what is the first-line AEd for generalized onset seizures in adults

To begin treatment based on pharmacokinetics and pharmacodynamics one must start with a gradually

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

Focal Seizures 1409 (785) Generalized Seizures 386 (215)

1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)

Monotherapy 1 AED 1028 (573) Seizure-free

Bitherapy 2 AEDs 116 (64) Seizure-free

Polytherapy ge 2 AEDs 651 (363) No control

CONTROL

1144 (637)

No Control

651 (363)

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 prescribed correctly for the syndrome or type of seizure

I and III A

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 therapeutic dose

IV R‑PPE

Consistency in taking the treatment is very important and the patient must be informed of the gravity of suspending it abruptly

IV R‑PPE

AEDs antiepileptic drugs PPE priority epilepsy program

progressive dose to arrive at the recommended thera-peutic dose In the adult you do not always calculate the milligrams per kilogram of weight especially for the new generation AED but must consider the aspects related to the particular AED the characteristics of the patient as well as cost and bioavailability6 (Table 3) The AED of

the first choice will fundamentally depend on clinical con-firmation of epilepsy First by recognizing the type of epileptic seizure second the type of epilepsy if possible third to determine a diagnosis of the epileptic syndrome presented by the patient and on a fourth level to be able to determine the etiology of the epilepsy

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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

Teratogenicity Ability to swallow

Interactions

Immediateextended release formulation

Modified form AED antiepileptic drug

Table 4 Data for monotherapy in focal onset seizures in adults9‑19


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 statistically significant differences compared with the adverse effects of CBZ and PHT

II and III C

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

I and IV C

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

IV U

The AEDs are in alphabetical order and are available in Mexico610‑18 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 adults9‑21


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

II and III A

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

II and III A

TPM can be useful as monotherapy in generalized onset motor seizures tonic‑clonic tonic and clonic

II and III B

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

IV R‑PPE

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

R‑PPE

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

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Question 4 When do you recognize that the first-line AEd is not effective to treat epilepsy in the adult patient and what are the recommendations for monotherapy with a second AEd

When despite taking a first-line AED at adequate do-ses and therapeutic adherence by the patient it is not effective to control epilepsy in the adult and we must reconsider the correct diagnosis of the type of seizure and the differential diagnosis by conducting a new cli-nical evaluation and clinical tests61220-22 (Table 5)

Question 5 At the moment when monotherapy with two or more drugs has not been enough to control all the seizures what AEds are adequate when you want to combine two AEds in the adult

The fact is that there are no existing Class I II or III studies for bitherapy The possibility that the 4-25 of patients who do not respond to monotherapy will be seizure free with bitherapy that is that they require administration of two AEDs to completely control their seizures only has class IV evidence323

Table 7 Data for bitherapy for focal onset seizures in adults2425


If monotherapy with one or various regimens of AED with A‑B recommendation was not effective two AEDs with recommendation A‑B and different mechanisms of action can be combined (SC)+(M) (SC)+(SV2) (SC)+(G) or (SV2)+(M)

I‑III A

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

I‑III A

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

IV U

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

IV R‑PPE

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

IV R‑PPE

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


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

IV R‑PPE

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

Table 6 Data for using a 2nd AED in monotherapy61220‑22


If the first AED is not well tolerated at low doses another AED from among those recommended for first‑line therapy must be used

IV R‑PPE

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

IV R‑PPE

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

IV R‑PPE

AED antiepileptic drug PPE priority epilepsy program

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Empirically a combination of AED with different me-chanisms of action minimum interaction between the AED and a different spectrum of adverse effects has been proposed2425 (Tables 1 and 6)

The bitherapy that has been demonstrated to be the most effective is the combination of a sodium channel blocker with a wide spectrum AED with multiple (M) mechanisms of action such as lamotrigine and valproa-te keeping in mind the teratogenic potential (Tables 7 and 8) 23-36

Acknowledgments

We thank Dr Mitzel del Carmen Peacuterez-Careta for her editorial help in preparing this guide

References 1 Patsalos PN Antiepileptic Drug Interactions A Clinical Guide 3rd ed

London UK Springer 2016 2 Genton P Roger J Antiepileptic drug monotherapy versus polytherapy

a historical perspective Epilepsia 199738(Suppl 5)S2-5 3 Chen Z Brodie MJ Liew D Kwan P Treatment outcomes in patients

with newly diagnosed epilepsy treated with established and new antiepi-leptic drugs a 30-year longitudinal cohort study JAMA Neurol 201875279-86

4 Brodie MJ Perucca E Ryvlin P et al Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy Neuro-logy 200768402-8

5 Baulac M Patten A Giorgi L Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy results of a phase III randomized double-blind study Epilepsia 2014551534-43

6 Glauser T Ben-Menachem E Bourgeois B et al ILAE treatment guide-lines evidence-based analysis of antiepileptic drug efficacy and effecti-veness as initial monotherapy for epileptic seizures and syndromes Epilepsia 2006471094-120



9 Freeman A Concannon B Cross H et al The epilepsies the diagnosis and management of the epilepsies in adults and children in primary and secondary care NICE Clin Guidel 201220121-177 Available from httpwwwniceorgukcg137

10 Glauser T Ben-Menachem E Bourgeois B Cnaan A Chadwick D Guerreiro C et al Update ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial immunotherapy for epileptic seizures and syndromes Epilepsies 2013 54(3)551-563

11 Nevitt SJ Sudell M Weston J Tudur Smith C Mason AG Antiepileptic drug immunotherapy for epilepsy a network meta-analysis of individual participant data Cochrane Epilepsy Group 2017

12 Xiao Y Gan L Wang J Luo M Luo H Vigabatrin versus carbamazepine monotherapy for epilepsy Cochrane Database Syst Rev 2015

13 Nolan SJ Marson AG Weston J Tudur Smith C Carbamazepine versus phenobarbitone monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 201612CD001904

14 Nolan SJ Sudell M Tudur Smith C Marson AG Topiramate versus carbamazepine monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 201612CD012065

15 Nolan SJ Tudur Smith C Weston J Marson AG Lamotrigine versus carbamazepine monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 201611CD001031

16 Nevitt SJ Marson AG Weston J Tudur Smith C Carbamazepine versus phenytoin monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 20172CD001911

17 Nolan SJ Marson AG Weston J Tudur Smith C Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures an individual participant data review Cochrane Database Syst Rev 20164CD001769

18 Nolan SJ Muller M Tudur Smith C Marson AG Oxcarbazepine versus phenytoin monotherapy for epilepsy Cochrane Database Syst Rev 2013 5CD003615

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 201840589-98

20 Genton P When antiepileptic drugs aggravate epilepsy Brain Dev 20002275-80

21 Somerville ER Some treatments cause seizure aggravation in idiopathic epilepsies (especially absence epilepsy) Epilepsia 200950 Suppl 831-6

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 against epilepsy Epilepsia 201859905-14

23 Joshi R Tripathi M Gupta P Gulati S Gupta YK Adverse effects and drug load of antiepileptic drugs in patients with epilepsy monotherapy versus polytherapy Indian J Med Res 2017145317-26

24 Stafstrom CE Mechanisms of action of antiepileptic drugs the search for synergy Curr Opin Neurol 201023157-63

25 Brodie MJ Sills GJ Combining antiepileptic drugs--rational polytherapy Seizure 201120369-75

26 Kumari S Mishra CB Tiwari M Polypharmacological drugs in the treat-ment of epilepsy the comprehensive review of marketed and new emer-ging molecules Curr Pharm Des 2016223212-25

27 Bonnett LJ Tudur Smith C Donegan S Marson AG Treatment outcome after failure of a first antiepileptic drug Neurology 201483552-60

28 Margolis JM Chu BC Wang ZJ Copher R Cavazos JE Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action JAMA Neurol 201471985-93

29 Beyenburg S Stavem K Schmidt D Placebo-corrected efficacy of mo-dern antiepileptic drugs for refractory epilepsy systematic review and meta-analysis Epilepsia 2010517-26

30 Brodie MJ Yuen AW Lamotrigine substitution study evidence for syner-gism with sodium valproate 105 study group Epilepsy Res 199726 423-32

31 Pisani F Oteri G Russo MF et al The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures evidence for a phar-macodynamic interaction Epilepsia 1999401141-6

32 Taing KD OrsquoBrien TJ Williams DA French CR Anti-epileptic drug com-bination efficacy in an in vitro seizure model-phenytoin and valproate lamotrigine and valproate PLoS One 201712e0169974

33 Ramaratnam S Panebianco M Marson AG Lamotrigine add-on for drug-resistant partial epilepsy Cochrane Database Syst Rev 20166CD001909

34 Poolos NP Castagna CE Williams S Miller AB Story TJ Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy Epilepsy Behav 20176959-68

35 Yasam VR Jakki SL Senthil V et al A pharmacological overview of lamotrigine for the treatment of epilepsy Expert Rev Clin Pharmacol 201691533-46

36 Lee BI No SK Yi SD et al Unblinded randomized multicenter trial comparing lamotrigine and valproate combination with controlled-release carbamazepine monotherapy as initial drug regimen in untreated epi-lepsy Seizure 20185517-22

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Clinical guideline antiepileptic drugs of choice for epileptic syndromes and epilepsies in pediatric patientsJuan C Reseacutendiz-Aparicio1 Jesuacutes M Padilla-Huicab2 Iris E Martiacutenez-Juaacuterez3 Gustavo Hernaacutendez-Martiacutenez4 Eunice Loacutepez-Correa5 Benjamiacuten Vaacutezquez-Juaacuterez6 Rosana Huerta-Albarraacuten7 and Claudia Rivera-Acuntildea8

1PPE Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez y Hospital Psiquiaacutetrico Infantil Dr Juan N Navarro Mexico City 2Hospital General de Especialidades Dr Javier Buenfil Osorio Campeche 3Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez Mexico City 4Centro de Alta Especialidad del Estado de Veracruz Dr Rafael Lucio Jalapa Veracruz 5Hospital General Dr Gaudencio Gonzaacutelez Garza Centro Meacutedico La Raza IMSS Mexico City 6Hospital para el Nintildeo Poblano Puebla 7Hospital General de Meacutexico Dr Eduardo Liceaga Mexico City 8Hospital Regional de Alta Especialidad ISSSTE Puebla Meacutexico


REViEW ARtiClE

Abstract

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

Key words Antiepileptic drug Monotherapy Polytherapy Childhood Pediatric

Correspondence Juan Carlos Reseacutendiz Aparicio




Mexico City Mexico







DOI 1024875RMNM19000028

introduction

This is a clinical guide for the pharmacologic treatment of epilepsy in pediatric patients It consists of establishing PICO-based questions and setting forth answers The levels of evidence are based on articles published in peer-reviewed indexed articles and other

international guidelines such as the guides published by the International League Against Epilepsy the National Institute for Health Care Excellence and the Guidelines from the Sociedad Andaluza de Epilepsia (Andalusian Epilepsy Society) In addition we emit re-commendations from the Programa Prioritario de Epi-lepsia (Priority Epilepsy Program)

1665-5044copy 2019 Academia Mexicana de Neurologiacutea AC Published by Permanyer Meacutexico This is an Open Access article under the CC BY-NC-ND license (httpcreativecommonsorglicensesby-nc-nd40)

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Question 1 What are the pharmacokinetic and pharmacodynamic differences in pharmacologic management of epilepsy between the pediatric patient and the adult

Pediatric patients have a broad range of variations in their ability for absorption distribution metabolism and clearance of antiepileptic drugs (AEDs) (Fig 1) Clea-rance of AED is much faster than in adults which makes it important to calculate the dose depending on the weight or body surface area and to be careful of the toxic effects (Tables 1 and 2)1-6

Question 2 Should treatment with antiepileptics be based on the type of epileptic syndrome that a patient presents

To establish a diagnosis of epilepsy it is sufficient if we can define an epileptic siacutendrome7 that in the current classification would correspond to a Level III diagno-sis8 By definition an epileptic syndrome presupposes a disease that incorporates characteristics in common such as the type of seizure the electroencephalogra-phic findings the shared imaging study results age of onset andor remission when applicable seizure

triggering factors diurnal variations and sometimes the prognosis8

Question 3 What is the evidence for treating epileptic syndromes described for newborns benign familial neonatal epilepsy (BFNE) early myoclonic encephalopathy (EME) and ohtahara syndrome

The first thing to understand is that neither systematic reviews nor clinical guides exist for the management of the syndromes that have been described in newborns thus the evidence for treatment is Level IV and in all these cases the recommendation is U

BFNE

For cases with frequent seizures or status epilepti-cus it could be necessary to provide therapy with drugs such as carbamazepine (CBZ) phenytoin (PHT) phe-nobarbital (PB) levetiracetam (LEV) oxcarbazepine (OXC) and valproate (VPA) CBZ even at low doses is considered to be a good option for BFNE even in status epilepticus910 In general patients require treat-ment during the first 6-12 months of life

Absorption

bull Agebull Gastric emptyingbull Intestinal Integritybull Intestinal transit time and pH

Distribution

bull Amount of body waterbull Amount of fat and musclebull Drug-Protein binding

Metabolismmbull Same as in adults

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

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J C Reseacutendiz-Aparicio et al Antiepileptic drugs in pediatric patients

Table 2 New antiepileptic drugs and their use in pediatric age patients

Drug Initial dose (mg kg day)

Maintenance Daily dose Secondary effects Formulation

Lacosamide 1‑2 6‑9 2 Dizziness cephalea double vision nausea

Tablets 50 and 100 mg

LamotriginemonotherapyWith enzyme inducing AEDWith Valproate

052

02

2‑105‑151‑5

22

1‑2

Skin rash drowsiness dizziness nausea double vision

Tablets 5 25 50 and 100 mg

Levetiracetam 10 20‑60 2 Cephalea anorexia drowsiness behavior problems

Tablets 250 500 and 1000 mgSuspension 100 mg1 ml

Oxcarbazepine 5‑8 10‑30 2 Dizziness ataxia drowsiness hyponatremia

Tablets 300 and 600 mgSuspension 300 mg5 ml

Topiramate 1 6‑9 2 Weight loss lethargy anorexia hyperthermia kidney stones

Tablets 25 50 and 100 mg

Vigabatrin 20‑50 50‑150 2 Hyperkinesis weight gain insomnia visual field defects

Tablets 500 mg

AED antiepileptic drugs

Table 1 Traditional antiepileptic drugs and their pediatric use

AED Initial dose (mgkgday) Maintenance dose Daily dose Presentation

Diazepam 2‑5 years 156‑11 years 09

SameSame

3 times Solution 5 mg5 mlTablets 10 mg

Carbamazepine 5‑10 15‑20 mgkgday 2 or 3 times Suspension 100 mg5 mlTablets 200 mg

Clobazam 025 1 mgkgday Once or twice Tablets 10 mg

Clonazepam 001 01 mgkgday 2 or 3 times Suspension 01 mg1mlTablets 2 mg

Phenytoin 4‑5 4‑8 mgkgday 2 or 3 times Suspension 375 mg5 mlTablets 100 mg

Phenobarbital 5 Same Once or twice Tablets 100 mg

Gabapentin 10‑15 30‑100 mgkgday 2 or 3 times Capsules 300 and 400 mg

Lamotrigine 05 2‑10 mgkgday Twice Tablets 25 50 and 100 mg

Levetiracetam 10 40‑60 mgday Twice Solution 100 mgmlTablets 250 500 and 1000 mg500 mg extended release

Oxcarbazepine 5‑10 20‑30 mgkgday Once or twice Suspension 300 mg5 mlTablets 300 and 600 mg150 300 and 600 mg extended release

Pregabalin 35‑5 15‑20 mgkgday Twice Capsules 75 and 150 mg

Topiramate 05‑10 4‑8 mgkgday Twice Tablets 25 50 and 100 mg

Valproic acid 10‑15 15‑30 mgkgday 2 or 3 times Syrup 250 mg5 mlSprinkle 125 mgCapsules 250 mg and 500 mg250 mg and 500 mg extended release

Vigabatrin 40 80‑100 mgkgday (150 mgkgper day for

childhood spasms)

2 or 3 times Tablets 500 mg

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EME

Early onset with a burst suppression pattern in the EEG various types of seizures and psychomotor re-tardation Metabolic etiologies are often a cause of EME The burst suppression pattern in EME is different from that of Ohtahara since in general the burst is shorter and the suppression is longer The use of ste-roids and ACTH may be effective in some cases11

Ohtahara syndrome

It has been calculated that 75 of these cases evolve into West syndrome between the 2nd and 6th months of age Treatment is difficult but in some cases ACTH LEV and high doses of PB have been shown to be effective11

Question 4 What is the evidence for treating West syndrome

There are insufficient data to determine the effecti-veness of ketogenic diet intravenous immunoglobulin LEV nitrazepam topiramate (TPM) VPA or Vitamin B6 for treating infantile spasms12

Early control of spasms could improve development in those who do not have a proven underlying etiology13 For West of unknown cause providing treatment quickly with ACTH or prednisolone above using vigabatrin (VGB) can improve cognitive results in the long term12 Both steroids and VGB have potentially serious secondary effects and the patient must be carefully observed

The current studies are not enough to establish whe-ther other types of corticosteroids such as prednisolo-ne dexamethasone or methylprednisolone may be as effective or recommendable as ACTH for short-term treatment of infantile spasms12

First-line treatment medications are considered to be ACTH steroids or VGB while second-line treatment can be benzodiazepines ketogenic diet TPM and VPA although the long-term benefits of the different therapies are still uncertain and more research is nee-ded on this subject (Table 3)13

Question 5 What is the evidence for treating lennox-Gastaut syndrome

To choose the treatment one must consider the be-havioral and psychiatric comorbidities such as depres-sion anxiety and psychosis One must also take into account that the patient may have different types of seizures and some drugs may diminish some types of seizures while increasing others Some combinations can be synergistic and reduce the number of seizures but it is important to monitor the possible increase in adverse effects (Table 4)1415

Valproate is a first-line drug while CLB ketogenic diet lamotrigine (LTG) LEV and TPM are effective as adjunct (add-on) therapies15-19 Other options for resis-tant seizures are cannabidiol resective surgery stimu-lation of the vagus nerve callosotomy or transcranial stimulation20-22

Table 3 Treatment for west syndrome

Evidence Recommendation

Insufficient data to determine whether ketogenic diet immunoglobulin LEV NZP TPM VPA or vitamin B6 are effective for treating infantile spasms

III and IV U

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

II and III C

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

III and IV U

Low‑dose ACTH (20‑30 UI) versus high dose (150 UIm2) 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 TPM and VPA

IV R‑PPE

The AEDs are in alphabetical order and are available in Mexico1213 LEV levetiracetam NZP nitrazepam TPM topiramate VPA valproate VGB vigabatrin BZD benzodiazepines TPM topiramate VPA valproate

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Question 6 What drugs are the most effective for pediatric patients with myoclonic astatic epilepsy or doose syndrome

VPA is considered the first choice AED and it can be combined with BZD ethosuximide (ESM) LTG LEV and TPM23

The ketogenic diet can be very effective The an-ti-epileptics that should be avoided are CBZ gabapen-tin (GBP) OXC pregabalin (PGB) tiagabine and VGB since these increase myoclonic epileptic seizures (ES) (Table 5)2425

Question 7 What pharmacological treatment is recommended for pediatric patients with dravet syndrome

ESs in these patients are refractory A good combination is VPA with TPM which has shown impro-vement especially for focal seizures and generalized tonic-clonic ES In some cases ACTH or corticoids ketogenic diet ESM or intravenous immunoglobulin has shown satisfactory results26 CBZ GBP LTG OXC

PHT PGB and VGB should not be used as they can aggravate myoclonic ES (Table 6)15

Question 8 What drugs should be used for early onset occipital epilepsy or Panayiotopoulos syndrome

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-cyeffectiveness as initial monotherapy in children with focal onset epilepsy that have been recently diagnosed or without previous therapy27

Question 9 What drug must be used for juvenile myoclonic epilepsy

TPM and VPA are potentially effective (Level D) for any type of seizure within this syndrome Avoid admi-nistering CBZ GBP OXC PHT and VGB since they can aggravate or trigger absence seizures myoclonus and in some cases generalized tonic-clonic seizures Furthermore LTG may exacerbate myoclonic seizures in some cases (Level F)2829

Question 10 What is the evidence for treating generalized epilepsy with generalized tonic-clonic ES in pediatric patients

There are no Class I or II studies on pediatric-aged patients leaving us with only class III studies and thus Level C evidence that suggests that monotherapy with CLB LTG LEV TPM and VPA may be effective30-33

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

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

Table 5 Treatment in Doose syndrome23‑25


LTG II B

VPA IV R‑PPE

Ketogenic diet IV U

LTG Lamotrigine VPA valproate

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CBZ and PHT must be avoided since they can aggra-vate or trigger GTCS (Table 7)29

Question 11 Which AEd is considered to be first choice for recently diagnosed focal epilepsy in the pediatric patient

Around 65 of children with recently diagnosed epi-lepsy achieve sustained control of their ES with the

AED prescribed initially An additional 15-20 of these patients require combination with other AEDs to achie-ve control The remaining percentage does not achieve control with the available medicines becoming a drug-resistant focal epilepsy3435

For childhood focal seizures first-line monotherapy with GBP LCM LEV LTG OXC PGB and TPM is recommended Alternative monotherapy includes CBZ or VPA and as coadjuvant therapy CLB or LCM or one

Table 6 Treatment in Dravet syndrome


VPA is effective for myoclonic seizures IV R‑PPE

LTG may worsen or trigger myoclonic ES in patients with Juvenile myoclonic epilepsy or Dravet syndrome

IV R‑PPE

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

The AED are in alphabetical order and are available in Mexico1526 VPA valproate LTG lamotrigine CLB clobazam CNZ clonazepam LTG lamotrigine LEV levetiracetam TPM topiramate ES Epileptic seizures

Table 7 Treatment in epilepsy for generalized tonic‑clonic epileptic seizures only in pediatric age patients

Level of evidence Recommendation

Initial CLB monotherapy may be slightly more effective in treating epilepsy with GTCS than PHT No advantage over CBZ

II B

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

II B

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

II B

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 2003Tudur 2007

PB is less tolerated than CBZ (with similar effectiveness)

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 evidenceVPA show efficacy and effectiveness with low‑quality evidence

The AEDs are in alphabetical order and are available in Mexico283742‑44 CBZ carbamazepine PHT phenytoin ES epileptic seizures PB phenobarbital PHT phenytoin VPA valproate

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of the AEDs used as monotherapy can be used When using VPA remember the teratogenic risks for ferti-le-aged patients especially when used in high doses (Tables 8-10)2836-44

Question 12 Which AEds are considered to be the first choice for recently diagnosed generalized epilepsy in the pediatric patient

Choosing an AED for generalized seizures must be personalized according to age type of seizure tolera-bility availability for use and other aspects

VPA continues to be the drug of choice as monothe-rapy for all types of generalized ES in children after assessing the risk-benefit and taking into special con-sideration patients with cognitive deficits risk of overwei-ght and teratogenic effects in fertile-aged adolescents Other options include LEV and TPM Administration of CBZ GBP LTG OXC PHT and VGB should be avoi-ded since they could precipitate generalized tonic-clonic seizures and myoclonic seizures152935

Acknowledgments

We thank Dr Mitzel del Carmen Peacuterez-Careta for editorial assistance in preparing this Guide

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

Privitera 2003 TPM (doses 100 or 200 mgday) CBZ (600 mgday) and VPA (1250 mgday) show similar efficacy results

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

Nolan 2013Arya 2013

OXC shows similar efficacy compared to PHT but it is tolerated better

Koch 2009 OXC presents similar efficacy and effectiveness compared with CBZ

Marson 2007Tudur 2007

LTG shows greater effectiveness over CBZ GBP and TPM but not over OXCCBZ demonstrates greater efficacy in seizure remission during 12 months compared to GBP but not greater than that observed with LTG OXC and TPMThe AED with the lowest efficacy is GBP and the least tolerated is TPMCBZ LTG and OXC show better adherence and better control during treatment of focal ESVPA shows similar adherence as CBZ but with lower efficacyPHT and TPM are less effective than LTG and have lower efficacy than CBZ

Brodie 2007Perry 2008

LEV demonstrates similar efficacy and tolerability CBZ for recently diagnosed focal epilepsy

CSGCE 1998Bawden 1999

CLB shows similar efficacy as PHT and CBZ as monotherapy for the control of focal ES and GTCSThere 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 Mexico283742‑52 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 treatment of focal onset ES in children

A

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 Mexico283742‑52 GBP gabapentin LTG lamotrigine LEV levetiracetam TPM topiramate VPA valproate OXC oxcarbazepine PB phenobarbital PHT phenytoin LEV levetiracetam

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References 1 Donovan MD Griffin BT Kharoshankaya L Cryan JF Boylan GB Phar-

macotherapy for neonatal seizures current knowledge and future pers-pectives Drugs 201676647-61

2 Sankaraneni R Lachhwani D Antiepileptic drugs a review Pediatr Ann 201544e36-42

3 Pellock JM Arzimanoglou A DrsquoCruz O et al Extrapolating evidence of antiepileptic drug efficacy in adults to children ge2 years of age with focal seizures the case for disease similarity Epilepsia 2017581686-96

4 Yozawitz E Stacey A Pressler RM Pharmacotherapy for seizures in neonates with hypoxic ischemic encephalopathy Paediatr Drugs 2017 19553-67

5 Linder C Wide K Walander M et al Comparison between dried blood spot and plasma sampling for therapeutic drug monitoring of antiepileptic drugs in children with epilepsy a step towards home sampling Clin Biochem 201750418-24

6 Landmark CJ Johannessen SI Tomson T Dosing strategies for antiepi-leptic drugs from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring Epileptic Disord 2016 18367-83

7 Fisher RS Acevedo C Arzimanoglou A et al ILAE official report a practical clinical definition of epilepsy Epilepsia 201455475-82


9 Shellhaas RA Wusthoff CJ Tsuchida TN et al Profile of neonatal epi-lepsies characteristics of a prospective US cohort Neurology 2017 89893-9

10 Sands TT Balestri M Bellini G et al Rapid and safe response to low-do-se carbamazepine in neonatal epilepsy Epilepsia 2016572019-30

11 Yamamoto H Okumura A Fukuda M Epilepsies and epileptic syndromes starting in the neonatal period Brain Dev 201133213-20

12 Go CY Mackay MT Weiss SK et al Evidence-based guideline update medical treatment of infantile spasms Report of the guideline develop-ment subcommittee of the American academy of neurology and the practice committee of the child neurology society Neurology 2012 781974-80

13 Hancock EC Osborne JP Edwards SW Treatment of Infantile Spasms Copyright copy 2014 the Cochrane Collaboration Hoboken Publicado Por John Wiley and Sons Ltd 2014

14 Tournay AE DynaMed Plus patients with Lennox-Gastaut Siacutendrome Spain Marzo 2018

15 Epilepsies Diagnosis and Management Clinical Guideline Publicada 11 Enero 2012 httpwwwniceorgukguidancecg137

16 Lemmon ME Kossoff EH New treatment options for lennox-gastaut syndrome Curr Treat Options Neurol 201315519-28

17 Hancock EC Cross H Treatment of Lennox-Gastaut syndrome Copyri-ght copy 2013 the Cochrane Collaboration Hoboken Publicado Por John Wiley and Sons Ltd 2013

18 Motte J Trevathan E Arvidsson JF et al Lamotrigine for generalized seizures associated with the lennox-gastaut syndrome Lamictal len-nox-gastaut study group N Engl J Med 19973371807-12

19 Kossoff EH Shields WD Nonpharmacologic care for patients with len-nox-gastaut syndrome ketogenic diets and vagus nerve stimulation Epilepsia 201455 Suppl 429-33

20 Lancman G Virk M Shao H et al Vagus nerve stimulation vs Corpus callosotomy in the treatment of lennox-gastaut syndrome a meta-analy-sis Seizure 2013223-8

21 Thiele EA Marsh ED French JA et al Cannabidiol in patients with seizures associated with lennox-gastaut syndrome (GWPCARE4) a ran-domised double-blind placebo-controlled phase 3 trial Lancet 2018 3911085-96

22 Tzadok M Uliel-Siboni S Linder I et al CBD-enriched medical cannabis for intractable pediatric epilepsy the current israeli experience Seizure 20163541-4

23 Kilaru S Bergqvist AG Current treatment of myoclonic astatic epilepsy clinical experience at the childrenrsquos hospital of Philadelphia Epilepsia 2007481703-7

24 Kelley SA Kossoff EH Doose syndrome (myoclonic-astatic epilepsy) 40 years of progress Dev Med Child Neurol 201052988-93

25 von Stuumllpnagel C Coppola G Striano P et al First long-term experien-ce with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome) Eur J Paediatr Neurol 201216459-63

26 Mizrahi EM Watanabe K Symptomatic neonatal seizures In Roger J Bureau M Dravet CH editors Epileptic Syndromes in Infancy Childhood and Adolescencie 3rd ed London John Libbey 2002

27 Weir E Gibbs J Appleton R Panayiotopoulos syndrome and benign partial epilepsy with centro-temporal spikes a comparative incidence study Seizure 20185766-9


29 Glauser T Ben-Menachem E Bourgeois B et al Updated ILAE eviden-ce review of antiepileptic drug efficacy and effectiveness as initial mono-therapy for epileptic seizures and syndromes Epilepsia 201354551-63


31 Arya R Giridharan N Anand V Garg SK Clobazam monotherapy for focal or generalized seizures Cochrane Database Syst Rev 2018 7CD009258

32 Nevitt SJ Marson AG Weston J Smith CT Carbamazepine versus phenytoin monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 20172CD001911

33 Nevitt SJ Smith CT Weston J Marson AG Lamotrigine versus carba-mazepine monotherapy for epilepsy an individual participant data review Cochrane Database Syst Rev 20186CD001031

34 Aneja S Sharma S Newer anti-epileptic drugs Indian Pediatr 2013 501033-40

35 Saacutenchez-Aacutelvarez JC Ramos-Lizana J Machado-Casas IS et al Com-bined treatment with antiepileptic drugs Andalusian epilepsy guide 2015 Rev Neurol 201560365-79

36 Marson AG Al-Kharusi AM Alwaidh M et al The SANAD study of effectiveness of carbamazepine gabapentin lamotrigine oxcarbazepine or topiramate for treatment of partial epilepsy an unblinded randomised controlled trial Lancet 20073691000-15

37 Smith CT Marson AG Chadwick DW Williamson PR Multiple treatment comparisons in epilepsy monotherapy trials Trials 2007834


39 Wechsler RT Li G French J et al Conversion to lacosamide monothe-rapy in the treatment of focal epilepsy results from a historical-controlled multicenter double-blind study Epilepsia 2014551088-98

40 Lang N Lange M Schmitt FC et al Intravenous lacosamide in clinical practice-results from an independent registry Seizure 2016395-9

41 Maguire M Marson AG Ramaratnam S Epilepsy (partial) BMJ Clin Evid 201120111214

42 Smith CT Marson AG Williamson PR Carbamazepine versus pheno-barbitone monotherapy for epilepsy Cochrane Database Syst Rev 2003 1CD001904

43 Nolan SJ Smith CT Pulman J Marson AG Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures Cochrane Database Syst Rev 20131CD002217

44 Nolan SJ Marson AG Pulman J Smith CT Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures Cochrane Database Syst Rev 20138CD001769

45 Privitera MD Brodie MJ Mattson RH et al Topiramate carbamazepine and valproate monotherapy double-blind comparison in newly diagnosed epilepsy Acta Neurol Scand 2003107165-75

46 Gamble CL Williamson PR Marson AG Lamotrigine versus carbamaze-pine monotherapy for epilepsy Cochrane Database Syst Rev 2006 1CD001031

47 Arya R Glauser TA Pharmacotherapy of focal epilepsy in children a systematic review of approved agents CNS Drugs 201327273-86

48 Koch MW Polman SK Oxcarbazepine versus carbamazepine monothe-rapy for partial onset seizures Cochrane Database Syst Rev 2009 4CD006453

49 Perry S Holt P Benatar M Levetiracetam versus carbamazepine mono-therapy for partial epilepsy in children less than 16 years of age J Child Neurol 200823515-9

50 Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy Canadian study group for childhood epilepsy Epilepsia 199839952-9

51 Bawden HN Camfield CS Camfield PR et al The cognitive and beha-vioural effects of clobazam and standard monotherapy are comparable Canadian study group for childhood epilepsy Epilepsy Res 1999 33133-43

52 Rosenow F Schade-Brittinger C Burchardi N et al The laLiMo trial lamotrigine compared with levetiracetam in the initial 26 weeks of mono-therapy for focal and generalised epilepsy an open-label prospective randomised controlled multicenter study J Neurol Neurosurg Psychiatry 2012831093-8 N

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Clinical guideline febrile seizures diagnosis and treatmentCarlos Aguirre-Velaacutezquez1 Alma M Huerta Hurtado2 Hugo Ceja-Moreno3 Karina Salgado-Hernaacutendez4 Roberto San Romaacuten-Tovar5 Martha A Ortiz-Villalpando6 Avril Molina-Garciacutea7 Guadalupe Vargas-Ramiacuterez8 Jaime Loacutepez-Rivera9 and Rosana Huerta-Albarraacuten10

1Escuela Nacional de Medicina TEC de Monterrey Monterrey 2Hospital de Pediatriacutea Centro Meacutedico 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 Rehabilitacioacuten Infantil e Inclusioacuten Infantil de Occidente CRIT Guadalajara Jalisco 7Hospital Infantil de Especialidades de Chihuahua Chihuahua 8Hospital Pediaacutetrico de Leoacuten Leoacuten Guanajuato 9Hospital Universitario Saltillo Coahuila 10Hospital General de Meacutexico Dr Eduardo Liceaga Mexico City Mexico


REViEW ARtiClE

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

Correspondence Alma Maritza Huerta Hurtado

Guadalajara Jalisco Mexico

E-mail almamaritzahotmailcom






DOI 1024875RMNM19000029

1 What is a simple febrile seizure (SFeS)

SFeS happen in children 3-5 months old1-4 They are generalized tonic-clonic seizures accompanied by fe-ver without central nervous system (CNS) infection metabolic disorder or history of FeS5-8 Fever is considered as a rectal temperature greater than 38degC axillary temperature greater than 375degC or tympanic temperature greater than 382degC9 SFeS can occur be-fore or after the fever becomes apparent within 24 h during the course of a febrile illness10-12 SFeS affect 2-5 of the pediatric population and they are reported to be more frequent in some ethnic Asian groups31314

They are benign seizures since they are induced con-vulsions and not related to epilepsy713

2 What is a complex FeS (CFeS)

A CFeS is a focal or generalized FeS lasting more than 15 min recurrent (more than once in 24 h) andor associated with postictal neurologic abnormalities most commonly a postictal paralysis (Toddrsquos paralysis) or when the patient presents with previous neurological impairment15-17

The child that presents with a prolonged FeS which was interrupted with anticonvulsant therapy (such as


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diazepam [DZP]) before 15th min must also be classified within this group1518

It is considered a febrile status epilepticus when a complex FeS lasts gt30 min or when there are shorter serial FeS without recovering consciousness during the interictal state6101516

3 When do you carry out a lumbar puncture in the first SFeS

In children of any age that have their first FeS it is important to discard an infection in the CNS (encepha-litismeningitis) Pay special attention when children are younger than 6 months seizures last more than 15 min there are more than two seizures within a 24-h time period when there are focal motor or non-motor seizu-res with affected alertness andor when the child pre-sents the following clinical datandash Sleepiness alternating with irritability or Glasgow

scale below 15 pointsndash Neck stiffness Kernigrsquos sign and Brudzinskirsquos signndash Vomit tense or bulging fontanelle and papilledemandash Presence of macular or petechial exanthemndash Abnormal postures during the postictal state or if stu-

por remains for over an hour after a seizure619-21The risk of bacterial meningitis in children that pre-

sent with fever and seizures is about 3 but in a CFeS it is 9 Thus lumbar puncture must be carried out in all children with CFeS and suspected CNS infection In the case of CFeS without clinical signs of meningitis they must be closely observed and checked after 2 h

by a pediatrician to then decide again whether to carry out a lumbar puncture15 (Table 1)

4 How are SFeS or CFeS treated during the acute ictal phase

Managing SFeS begins with training the parents for home management22 (Table 2) Informing the parents that their child will not die that association with epi-lepsy is rare and that the frequency of SFeS is reduced with age13162324 Warning them that if the seizure lasts 5 min or more they must call an ambulance provide emergent initial therapy or go to the emergency room Various authors support that intervention during the acute phase is rarely required1228

In the case of recurrent seizures administer emer-gent initial therapy with the knowledge that the use of benzodiazepine may cause respiratory depression24 Benzodiazepine intravenous (IV) intramuscular oral intranasal or rectal can be used to abort the crisis but is not recommended for prophylactic treatment125 (Table 3)

In a systematic review about the use of AEDs for on-going convulsive seizures including epileptic status they analyzed the efficacy and safety of using Midazolam (MDL) DZP lorazepam (LZP) phenytoin (PHT) pheno-barbital (PB) and paraldehyde concluding that IV or rectal LZP is as effective or more effective than DZP26 Oral MDL is more effective than rectal DZP and the in-tranasal form is as effective as IV DZP Oral or nasal MDL is the treatment of choice when there is no access to IV or for home management by the parents26-28 (Table 4)

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

III B

Lumbar puncture must be obtained from children of any age with FeS that present with altered alertness andor meningeal symptoms

II B

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

III C

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

I A

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 without signs or symptoms that require diagnostic studies

I A

FeS febrile seizures

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C Aguirre-Velaacutezquez 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 gt 5 min

7 Administer oral or nasal midazolam as first‑line treatment Rectal diazepam 05mgkg when midazolam is not available

8 Seek medical attention if the seizure lasts gt5 min Contact your pediatrician or other health professional

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


Table 3 Emergent initial therapy for acute (ictal) management of FeS in children25

Antiepileptic Administration route Dose

Midazolam (15mg3 ml vial) OralNasalIVIM

05 mgkg repeat in 10 min if necessary02‑05 mgkg divided in each nostril maximum 10 mg02 mgkg or 015mgkg by infusion02mgkg or 5‑10 mg sole dose

Diazepam (10 mg3 ml vial) RectalIV

05mgkg03‑05 mgkg bolus speed of 5mgminute repeat in 10 min if necessary001 mgkgmin by infusion

Lorazepam (2 mg3 ml vial) IV 01 mgkg (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 lt 90)

6 Administer an intravenous bolus of Diazepam at a dose of 05 mgkg and a maximum infusion speed of 5 mgmin discontinue when the seizure stops The dose can be repeated if necessary after an interval of 10 min (consider that Diazepam takes about 10 m to reach an effective concentration in the brain even using intravenous administration) Other benzodiazepines like Lorazepam are equally effective

7 Monitor excess base and glucose in blood

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

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

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

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100


Hospitalization criteria

Independently of the length of the seizure the patient must be assessed by medical history documentation of SFeS history epilepsy immunizations duration of the seizure postictal phase and any focal symptom4 The American Academy of Pediatrics recommends that hospitalization is unnecessary for clinically stable pa-tients older than 18 months without signs or symptoms that require diagnostic studies29 Parents are trained for home management (Table 1)22 Hospitalization recommended for children younger than 18 months for observation and possible lumbar puncture Patients previously diagnosed with recurrent FeS do not require hospitalization1229 (Table 1)

5 is long-term antiepileptic treatment required for FeS

Simple FeS SFeS

A systematic review that assesses the use of conser-vative and antipyretic measures concluded that there is no evidence that they have any usefulness in pre-venting SFeS reccurences30 There is no evidence for the clinical usefulness of continuous or intermittent use of antiepileptic drugs (oral or rectal DZP PB diphenylhydantoin or valproate) in SFeS23 There is no evidence that continuous or intermittent treatment with antiepileptic drugs in SFeS can prevent the subsequent development of epilepsy61831

Complex FeS CFeS

Long-term routine prophylaxis with antiepileptic drugs is not recommended since there is no clear information about their use in complex FeS23 There is evidence that supports intermittent use of PB and antipyretics clobazam or rectal DZP to prevent recurrence of com-plex FeS However the information does not clearly distinguish simple from complex seizures and there may be bias due to the relative incidence of both types of seizures32

Regular use of antiepileptic drugs can be considered for patients with long or repetitive FeS despite the pro-phylactic use of DZP33 Carbamazepine and PHT are not effective for preventing the recurrence of FeS and thus should be avoided24

A prospective study carried out in 2014 compared the efficacy of intermittent use of clobazam versus DZP to prevent recurrence of FeS (both simple and

complex) as well as the adverse effects The results showed that clobazam is safe effective requires a lower dose and has fewer adverse effects than DZP suggesting it as a good alternative for preventing recu-rrence of FeS34 In addition in 2017 another group demonstrated a significant difference in the prevention of recurrence after treatment with levetiracetam versus no treatment after 50 weeks14 Table 5

6 What paraclinical tests are necessary after the first FeS

Diagnostic tests (analytic electroencephalogram (EEG) and cerebral imaging) are usually unnecessary and currently are not routinely recommended for pa-tients with simple FeS1517

Electroencephalogram

Not indicated for the assessment of a neurologically healthy child with simple FeS6 In a focal andor prolon-ged convulsion it is recommended to carry out an EEG and neurologic follow-up due to the greater risk of deve-loping epilepsy A short generalized convulsion that is repeated twice in 24 h is by definition a complex con-vulsion but it is also not necessary to conduct an EEG unless the neurologic examination shows alterations

The EEG does not allow prediction of which children are at greater risk to suffer new seizures Epileptiform alterations in the EEG are relatively frequent in children with FeS Few retrospective cohort case and control studies show a possible association between the epi-leptiform discharges in the EEG and a high risk of afe-brileepileptic seizures35 The EEG has low sensitivity in children under 3 years of age after an unprovoked convulsion35-37

Laboratory tests

They can be considered under certain clinical condi-tions but are not routinely carried out in a child after his first FeS with an evident source of infection They will only identify the source of the childrsquos fever and are not necessary as part of the assessment of the seizure617

Neuroimaging

Highly recommended for patients with FeS that do not regain complete consciousness in hours with pro-longed Toddrsquos paralysis (post-critical) or with other

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focal alterations found in the neurologic exploration1516 (Table 6)

7 What are the risk and recurrence factors for SFeS and CFeS

Population risk of a FeS is 27-3136 The reported risk of recurrence after a first FeS is 27-32 of which 75 happen during the 1st year after the first crisis18 The risk of recurrence is similar between simple and complex FeS38 The risk factors for FeS are enlisted in Table 7 The frequency of recurrence is 10 among patients with no risk factors 25-50 in the presence of 1-2 risk factors and 50-100 when there are three or more risk factors15 The risk of developing epilepsy

after a SFeS is 15-24 while for complex FeS it is estimated to be 4-1539 and in the case of focal FeS up to 2940

8 When should cases of SFeS and CFeS be referred to the neuropediatrician

FeS is a benign condition they are not associated with neurodevelopmental damage nor do they cause secondary neurologic consequences6 The only asso-ciation found was between repeated FeS and a delay in language development thus new studies and lon-ger-term follow-up will be required42 Hippocampal mal-formations do not appear to be a consequence of FeS but can be a predisposing factor for the development

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 prevention of recurrences of FeS

I A

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

I A

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

I A

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

I II B

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 and should be avoided

II B

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

I A

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 magnesium) are not useful for the management of children with FeS

III C

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

II‑III C

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

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102


of epilepsy7 Providing the family with information about the illness and the risk of recurrence during the illness or in the future should be carried out by the pediatri-cian However if the clinical history shows gt2 risk factors of seizure recurrence or the patient fulfills the requirements for complex FeS we recommend he be referred to the neuropediatrician

Conclusion

FeS is an age-dependent phenomenon related to individual genetic predisposition and with a special vul-nerability of the developing CNS to the effects of fever The continued or intermittent prophylactic treatment with antiepileptic drugs does not reduce the risk of subsequent epilepsy and although it is effective to reduce recurrences its toxicity surpasses the few risks of FeS

Informed and responsible parental counseling are the greatest contribution that the physician can make for the care of children with FeS

References 1 Pavone P Corsello G Ruggieri M et al Benign and severe early-life

seizures a round in the first year of life Ital J Pediatr 20184454 2 Takasu M Kubota T Tsuji T et al The semiology of febrile seizures

focal features are frequent Epilepsy Behav 20177359-63 3 Martiacutenez C Herraacuteiz-Martiacutenez M Crisis febriles complejas debemos cam-

biar nuestro modo de actuacioacuten Rev Neurol 201459449-58 4 Chung S Febrile seizures Korean J Pediatr 201457384-95

5 Auvin S Antonios M Benoist G et al Evaluating a child after a febrile seizure insights on three important issues Arch Pediatr 201724 1137-46

6 American Academy of Pediatrics Clinical practice guideline Febrile sei-zures guideline for the neurodiagnostic evaluation of the child with a simple febrile seizure Pediatrics 2011127389-94

7 Frascari F Dreyfus I Chaix Y Tison-Chambellan C Efficacy of an inter-ventional educational programme in mitigating posttraumatic stress in parents who have witnessed a febrile seizure a pilot before-and-after study BMJ Paediatr Open 2017121-6

8 Assogba K Balaka B Touglo FA Apetsegrave KM Kombateacute D Febrile sei-zures in one-five aged infants in tropical practice frequency etiology and outcome of hospitalization J Pediatr Neurosci 2015109-12

9 Guiacutea de Practica Cliacutenica diagnoacutestico y Tratamiento de la Fiebre en Nintildeos de 3 Meses a 5 Antildeos CENETEC 2013

10 Moreno N Crisis febriles simples y complejas epilepsia generalizada con crisis febriles plus FIRES y nuevos siacutendromes Medicina 201373 63-70

11 Zeballos J Cerisola A Peacuterez W Primera convulsioacuten febril en nintildeos asistidos en un servicio de emergencia pediaacutetrica Arch Pediatr Urug 20138418-25

12 Gupta A Febrile seizures Continuum (Minneap Minn) 20162251-9 13 Byeon JH Kim GH Eun BL Prevalence incidence and recurrence of

febrile seizures in Korean children based on national registry data J Clin Neurol 20181443-7

14 Li XC Lu LL Wang JZ et al Clinical characteristics and electroencepha-logram analysis of levetiracetam in the treatment of children with febrile seizure recurrence Exp Ther Med 2017142015-20

15 Capovilla G Mastrangelo M Romeo A Vigevano F Recommendations for the management of ldquofebrile seizuresrdquo ad hoc task force of LICE guidelines commission Epilepsia 200950 Suppl 12-6

16 Blanco M Gascoacuten J Evaluacioacuten y Tratamiento de las Convulsiones Fe-briles en guiacutea de la Sociedad Andaluza de Epilepsia 2015 p 161-70

17 Loacutepez RB Fernaacutendez JM Antoacuten JM Fernaacutendez MG Cardona AU Complex febrile seizures study of the associated pathology and practical use of complementary tests An Pediatr (Barc) 201480365-9

18 Knudsen FU Febrile seizures treatment and prognosis Epilepsia 2000412-9

19 Sugai K Current management of febrile seizures in Japan an overview Brain Dev 20103264-70

20 Kimia AA Ben-Joseph E Prabhu S et al Yield of emergent neuroima-ging among children presenting with a first complex febrile seizure Pe-diatr Emerg Care 201228316-21

21 Shaked O Pentildea BM Linares MY Baker RL Simple febrile seizures are the AAP guidelines regarding lumbar puncture being followed Pediatr Emerg Care 2009258-11

Table 7 FeS risk factors153541

Recurrence after an initial FeS Factors for developing epilepsy

Early onset (lt12 months) Age during the first FeS lt12 months or gt37 months

Epilepsy in first‑grade family members

FeS in first‑grade family members Family history of epilepsy

Frequent febrile illnesses Fever lasting lt1 h before the seizure

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

Fever lasting lt 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

Neurologic abnormalities (retarded development or CCP)

Focal epileptogenic discharges

CFeS complex febrile seizure FeS febrile seizure

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103


22 Silverman EC Sporer KA Lemieux JM et al Prehospital care for the adult and pediatric seizure patient current evidence-based recommen-dations West J Emerg Med 201718419-36

23 Offringa M Newton R Prophylactic drug management for febrile seizures in children Evid Based Child Health 201381376-485

24 Patel AD Vidaurre J Complex febrile seizures a practical guide to evaluation and treatment J Child Neurol 201328762-7

25 Zhao ZY Wang HY Wen B et al A comparison of midazolam loraze-pam and diazepam for the treatment of status epilepticus in children a network meta-analysis J Child Neurol 2016311093-107

26 McTague A Martland T Appleton R Drug management for acute to-nic-clonic convulsions including convulsive status epilepticus in children Cochrane Database Syst Rev 20181CD001905

27 Mewasingh LD Febrile seizures BMJ Clin Evid 20142014324 28 Sirsi D Is intranasal midazolam better than rectal diazepam for home

management of acute seizures Arch Neurol 201168120-1 29 American Academy of Pediatrics Provisional committee on quality im-

provement subcommittee on febrile seizures Practice parameter the neurodiagnostic evaluation of the child with a first simple febrile seizure Pediatrics 199697769-75

30 Rosenbloom E Finkelstein Y Adams-Webber T Kozer E Do antipyretics prevent the recurrence of febrile seizures in children A systematic re-view of randomized controlled trials and meta-analysis Eur J Paediatr Neurol 201317585-8

31 Baumann RJ Duffner PK Treatment of children with simple febrile sei-zures the AAP practice parameter American academy of pediatrics Pediatr Neurol 20002311-7

32 Salehiomran M Hoseini SM Juibary AG Intermittent diazepam versus continuous phenobarbital to prevent recurrence of febrile seizures a randomized controlled trial Iran J Child Neurol 20161021-4

33 Natsume J Hamano SI Iyoda K et al New guidelines for management of febrile seizures in Japan Brain Dev 2017392-9

34 Sattar S Saha SK Parveen F et al Intermittent prophylaxis of recurrent febrile seizures with clobazam versus diazepam Mymensingh Med J 201423676-85

35 Cappellari AM Brizio C Mazzoni MB et al Predictive value of EEG for febrile seizure recurrence Brain Dev 201840311-5

36 Armon K Stephenson T MacFaul R et al An evidence and consensus based guideline for the management of a child after a seizure Emerg Med J 20032013-20

37 Harini C Nagarajan E Kimia AA et al Utility of initial EEG in first com-plex febrile seizure Epilepsy Behav 201552200-4

38 Graves R Oehler K Febrile seizures risks evaluation and prognosis Am Fam Phys 201285149-53

39 Gencpinar P Yavuz H Bozkurt Ouml Haspolat Ş Duman Ouml The risk of subsequent epilepsy in children with febrile seizure after 5 years of age Seizure 20175362-5

40 Pavlidou E Panteliadis C Prognostic factors for subsequent epilepsy in children with febrile seizures Epilepsia 2013542101-7

41 Olson H Rudloe T Loddenkemper T Harper MB Kimia AA Should patients with complex febrile seizure be admitted for further manage-ment Am J Emerg Med 2018361386-90

42 Visser AM Jaddoe VW Ghassabian A et al Febrile seizures and beha-vioural and cognitive outcomes in preschool children the generation R study Dev Med Child Neurol 2012541006-11

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104

Clinical guideline epilepsy in pregnancy and women of childbearing agePerfecto O Gonzaacutelez-Vargas1 Yamil Matuk-Peacuterez2 Joseacute L Sosa Hernaacutendez3 Gerardo Quintildeones-Canales4 Sandra E Silva-Saacutenchez5 Geroacutenimo Aguayo-Leytte6 Sergio Medina-Benitez7 Jorge M Ibarra-Puig8 Mariacutea del Consuelo Loy-Gerala9 and Elvira Castro-Martiacutenez10

1Hospital Perinatal Moacutenica Pretelini Toluca Mexico State 2Hospital General de Quereacutetaro Quereacutetaro 3Hospital General de Alta Especialidad Dr Juan Graham Casasus Villahermosa Tabasco 4Hospital Dr Santiago Ramoacuten y Cajal ISSSTE Durango 5Hospital Central del Estado de Chihuahua Chihuahua 6Hospital Miguel Hidalgo Aguascalientes Aguascalientes 7Hospital General ISSSTE Zacatecas Zacatecas 8Instituto Nacional de Perinatologiacutea Ciudad de Meacutexico 9Hospital General de Puebla ldquoDr Eduardo Vaacutezquez Navarrordquo Puebla 10Hospital General Dr Manuel Gea Gonzaacutelez e Instituto Nacional de Neurologiacutea y Neurocirugiacutea ldquoManuel Velascoldquo Mexico City Mexico


REViEW ARtiClE

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

Correspondence Perfecto Oscar Gonzaacutelez-Vargas

Hospital Perinatal Moacutenica Pretelini

Toluca Mexico State Mexico

E-mail ogv1804yahoocom

Yamil Matuk Peacuterez

Hospital General de Quereacutetaro Mexico

E-mail dryamilmatukhotmailcom






DOI 1024875RMNM19000030

introduction

Epilepsy in reproductive-aged and pregnant women entails a series of reproductive changes such as inte-raction of antiepileptic drugs (AEDs) with contracepti-ves changes in fertility changes inherent to pregnancy and hormonal modification a series of risks for conge-nital malformation caused by AEDs and obstetric and lactation modifications that require knowledge and re-commendations necessary for an adequate control of epileptic seizures (ES) in women with epilepsy (WWE) This is the main reason for the PPE to write these guidelines

What are the recommendations for childbearing-aged WWE

According to statistics published by the National Institute of Statistics and Geography in Mexico there are 614 million women and they represent more than half of the nationrsquos population (514)1 Many of them are of childbearing age and have high probabilities of becoming pregnant

The AEDs that are enzymatic inducers (EI-AED) (PHT TPM PB OXC and CBZ) directly modify hormo-ne concentrations Virtual payment address (VPA) is associated with an increase in serum testosterone


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105

P O Gonzaacutelez-Vargas et al Epilepsy in women

and risk of hirsutism central cause amenorrhea hype-randrogenemia and infertility The risk of infertility can be up to 10 greater than those of the general popula-tion and is greater with polytherapy with temporal lobe epilepsy and the use of PB2 AEDs have a bidirectional relationship with hormonal contraceptives3 There are variations in serum concentration of AED depending on the mechanism of action of the drug and the type of contraceptive4 According to the WHO and the CDC progesterone and combined oral contraceptives as well as contraceptive patches and vaginal rings are not re-commended as first-line contraceptives for women that take EI-AED Medroxyprogesterone and levonorgestrel implants can be used by women who take EI-AED It is recommended to avoid combining LMT and contracep-tive methods that contain estrogens due to the risk of loss of control of ES The IUD is recommended as the contraceptive of choice for WWE5

Should AEd treatment be suspended in pregnant WWE (PWWE)

A review published by the AAN in 2009 did not find studies with high levels of evidence that indicate changes in the frequency of ES during pregnancy but information is limited There is between 84 and 92 probability that the pregnancy will continue normally with proper control if the WWE has been seizure-free for 9-12 months before getting pregnant6

For PWWE the use of AED in monotherapy and at low doses is suggested Preferably AEDs with a grea-ter risk of teratogenicity should be avoided such as VPA which has been demonstrated to increase this risk up to 1387 The greatest risk of congenital mal-formations is considered to be during the first trimester of pregnancy so once neural tube formation is comple-ted (second and third trimester of pregnancy) the con-traindication to suspend VPA is relative and generally the change of an AED during pregnancy is not recom-mended due to the risk of uncontrolled ES8 PHT PB and TPM have been demonstrated to have an interme-diate risk of congenital malformations whereas LTG CBZ and LEV show low rates of such malformations7 The frequency of ES is increased when patients dis-continue the use of their AED so patients must have control of the ES and discipline in taking their AED It is frequent that PWWE suspend their AED for fear of the risk of congenital malformations of the fetus due to nausea and vomiting associated to pregnancy the pharmacokinetic changes of the AED and insomnia it is even frequent that treating physicians suspend AED

even in spite of this being counterproductive since it has been demonstrated that during a ES the fetus su-ffers anoxia fetal tachycardia uterine contractions in-creased risk of preterm labor and low birth weight One Canadian study demonstrated that up to 30 of neu-rologists are unaware of the obstetric complications of PWWE Thus we can infer that the OBGYN is also unaware of treatment complications for PWWE9-11

A planned pregnancy demonstrates that there is be-tter control of the ES and shows apparent improvement in the obstetric complications of labor

Which AEd should be used for the PWWE

There is no first choice AED for the PWWE and the AED must be adequate for the type of epilepsy suffered by the patient There have been major congenital mal-formations (CM) described in products of those PWWE that took EAD during their pregnancy In these cases structural CM have been reported such as hypospa-dias neural tube defects (NTD) congenital cardiopathy and cleft palate Long-term cognitive teratogenic effects are also observed in children whose mothers took AED during pregnancy although the studies are not conclu-sive7 The risk of CM with AED varies depending on the type of AED used the dose and whether it was used in mono or polytherapy In general the average risk of CM with AED varies between 4 and 14 while in the open population risk of CM is about 3 The risk of CM with CBZ is about 22 LMT is 32 PHT is 37 and it is gt13 for VPA It must be pointed out that combining CBZ with LMT has a 3 risk of CM When polytherapy includes VPA the risk of CM can increase to up to 138 especially for NTD For WWE who have had a product with a CM the risk of CM in subsequent pregnancies with the use of AED increases up to 168 During pregnancy serum levels of CBZ LMT PHT and LEV are reduced thus serum concentrations of these AED must be determined before conception and during the first trimester of pregnancy In develo-ped countries the most commonly used AED are LMT and LEV and in our Country CBZ is considered to be the most commonly used as well as paradoxically VPA11-13

What is the approach and treatment for uncontrolled ES in PWWE

The presence of ES during pregnancy could be due to three circumstances uncontrolled ES in PWWE

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106


debut of ES and obstetric problems The first of these circumstances is the most common and the main re-ason is the lack of compliance with the antiepileptic treatment this commonly happens to PWWE and so one must investigate and persuade therapeutic adhe-rence Other factors must be taken into consideration such as genetic factors changes in serum concentra-tions of AED sleep suppression stress and hyperemesis gravidarum induced by pregnancy The management of uncontrolled ES in PWWE must follow the same protocol as that of any other patient with epi-lepsy Despite the seriousness of ES they do not in-crease in frequency in PWWE

Once the ES are controlled one must restart the AED the patient was taking if the motive was lack of disci-pline In this case adjust the AED treatment depending on the type of epilepsy and with the adequate dose1415

What are the obstetric complications for PWWE

There is a dilemma in terms of the increase in obstetric risk in PWWE Previously there was no evidence that confirmed it but recent studies have demonstrated a risk of presenting preeclampsia maternal infection placental abruption emergency cesarean sections risk of fetal death abortions neonatal infections risk of neonatal asphyxia with Apgar lower than 5 points in the 1st min neonatal hypoglycemia and neonatal hypoxia1617

What is the utility of folic acid and Vitamin K in PWWE

One of the most frequent congenital malformations of the CNS is NTD Folate receptors are critical for fetal neural tube and neural crest formation Folate deficien-cy causes a reduction in the mitotic capacity of neural crest or neural tube cells Folic acid is the synthetic form of folate (Vitamin B9) Mexico is one of the coun-tries with the greatest frequency of NTD The worldwide recommendation (WHO) is that childbearing-aged wo-men supplement with 04-08 mg of folic acid daily since it is calculated that 75 of them do not consume the optimal dose of folic acid However for NTD pre-vention the dose is greater There is no consensus on the larger dose the objective is to achieve high tissue levels of folic acid in the 1st weeks of pregnancy during the time that the neural tube is formed

As a large percentage of WWE have unplanned preg-nancies it is recommended to take folic acid daily it should be taken for at least 1 month before conception

if pregnancy is planned and should continue at least during the first trimester It is considered that in addition to the reduction of NTD the development of other mal-formations such as cleft palate can also be reduced

If there is a history of an infant with NTD the daily recommendation is 4 or even 5 mg of folic acid since there are no adverse effects related to this vitamin It has been calculated that this results in a reduction in NTD of up to 85 This recommendation is especially important for WWE that take polytherapy or use VPA18-20

As for Vitamin K it was previously proposed that by giving doses of the said vitamin to PWWE during the third trimester you could prevent intracranial hemorrhaging in neonates It was thought that PWWE that took enzymatic inducing AED (CBZ PG and PHT) had increased risk of this hemorrhagic complication in their products In a study of more than 600 patients it was demonstrated that there was no increase in the risk of hemorrhages in the products of PWWE that took these AED compared to controls thus there is not sufficient evidence to recom-mend the use of Vitamin K in PWWE721

is breastfeeding safe in WWE

The benefits of maternal breastfeeding are well de-monstrated itrsquos even beneficial for the mother since it reduces the risk of postpartum depression as well as generating a psychologic bond with the infant conver-sely the BBB in neonates has not been completely formed thus it is susceptible to drugs Therefore there must be an adequate risk-benefit analysis

Patients get confused because they receive informa-tion from the obstetrician the neonatologist or the neu-rologist this in conjunction with the social concept that the WWE cannot breastfeed Studies show that breas-tfeeding has geographical variations at educational levels and is lower among WWE that take LMT or are receiving polytherapy

The concentration of an AED in maternal milk is de-pendent on the serum levels of the drug and the me-tabolism of the infant Although there are mathematical formulas to calculate AED concentrations in maternal milk it is not practical to use this method in daily prac-tice Furthermore the AED concentrations are different and individual for each AED

There are studies that aim to investigate the cognitive effects on children exposed to AEDs during breastfee-ding but the results are contradictory

The recommendations from the AAN in 2009 about breastfeeding were not conclusive and later studies have not demonstrated the existence of contraindications for

No

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may

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107


breastfeeding by WWE What is clear is that the serum levels of AED that the WWE is taking must be measured that there is the option of supplementary feeding if se-condary effects are suspected for the infant and that breastfeeding is preferred when the newborn has long

sleep patterns The infant should be observed to deter-mine excessive sleepiness and both the benefits to the mother of avoiding postpartum depression and the harm that sleep deprivation may cause to the WWE must be assessed22-24

Evidence tables and recommendations

Evidence and PPE recommendations Levelrecommendation

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

The presence of polycystic ovaries hirsutism galactorrhea and central cause amenorrhea is more frequent in WWE

R‑PPE

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


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 information to reproductive‑aged WWE about the effects of AED on the infant

II

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

I

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

R‑PPE

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 uncontrolled seizures

R‑PPE

Management of WWE must be multidisciplinary and all physicians must be aware of the risk of teratogenicity from AED

R‑PPE

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

R‑PPE

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 138 and occurs more often with VPA II

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

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

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

No

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108


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

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


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

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 diagnose it due to its gravity

R‑PPE


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

III

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

III

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 born of a non‑epileptic mother

R‑PPE

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

R‑PPE


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 recommended nutritional requirement

I

A daily dose of 04‑08 mg of folic acid reduces the risk of NTD In WWE with a history of NTD use of polytherapy or VPA greater doses are required

I

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

III

All PWWE should consume 04‑08 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 to reduce the risk of NTD

R‑PPE

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

No

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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 suspend breastfeeding

III

WWE must breastfeed without clinical contraindications unless the neonate presents secondary effects R‑PPE

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 should not be suspended in WWE

R‑PPE

References 1 Instituto Nacional de Estadiacutestica y Geografiacutea Poblacioacuten 2015 https

wwwinegiorgmxtemasestructura [Last accessed 2018 May] 2 Yang Y Wang X Sexual dysfunction related to antiepileptic drugs in

patients with epilepsy Expert Opin Drug Saf 20161531-42 3 Harden CL Pennell PB Neuroendocrine considerations in the treatment

of men and women with epilepsy Lancet Neurol 20131272-83 4 Mandle HB Cahill KE Fowler KM et al Reasons for discontinuation of

reversible contraceptive methods by women with epilepsy Epilepsia 201758907-14

5 Espinera AR Gavvala J Bellinski I et al Counseling by epileptologists affects contraceptive choices of women with epilepsy Epilepsy Behav 2016651-6

6 Harden CL Hopp J Ting TY et al Practice parameter update manage-ment issues for women with epilepsy focus on pregnancy (an eviden-ce-based review) Obstetrical complications and change in seizure fre-quency report of the quality standards subcommittee and therapeutics and technology assessment subcommittee of the American academy of neurology and American epilepsy society Neurology 200973126-32

7 Gerard EE Meador KJ Managing epilepsy in women Continuum (Min-neap Minn) 201622204-26

8 Bromley RL Baker GA Fetal antiepileptic drug exposure and cognitive outcomes Seizure 2017 44225-31

9 Tomson T Battino D Bonizzoni E et al Withdrawal of valproic acid treatment during pregnancy and seizure outcome observations from EURAP Epilepsia 201657e173-7

10 Herzog AG Mandle HB Cahill KE Fowler KM Hauser WA Predictors of unintended pregnancy in women with epilepsy Neurology 2017 88728-33

11 Roberts JI Metcalfe A Abdulla F et al Neurologistslsquo and neurology residentslsquo knowledge of issues related to pregnancy for women with epilepsy Epilepsy Behav 201122358-63

12 Tomson T Xue H Battino D Major congenital malformations in children of women with epilepsy Seizure 20152846-50

13 Bollig KJ Jackson DL Seizures in pregnancy Obstet Gynecol Clin North Am 201845349-67

14 Aya AG Ondze B Ripart J Cuvillon P Seizures in the peripartum period epidemiology diagnosis and management Anaesth Crit Care Pain Med 201635 Suppl 1S13-S21

15 Vajda FJ Hitchcock A Graham J et al Seizure control in antiepileptic drug-treated pregnancy Epilepsia 200849172-6

16 Razaz N Tomson T Wikstroumlm AK Cnattingius S Association between pregnancy and perinatal outcomes among women with epilepsy JAMA Neurol 201774983-91

17 MacDonald SC Bateman BT McElrath TF Hernaacutendez-Diacuteaz S Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States JAMA Neurol 201572981-8

18 Gonzaacutelez-Vargas PO Savery D Gerrelli D Defectos del tubo neural Experiencia en un hospital de Toluca Meacutexico Arch Neurocien (Mex) 200712171-5

19 Ban L Fleming KM Doyle P et al Congenital anomalies in children of mothers taking antiepileptic drugs with and without periconceptional high dose folic acid use a population-based cohort study PLoS One 201510e131130

20 US Preventive Services Task Force Bibbins-Domingo K Grossman DC et al Folic acid supplementation for the prevention of neural tube defects US preventive services task force recommendation statement JAMA 2017317183-9

21 Kaaja E Kaaja R Matila R Hiilesmaa V Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate Neurology 200258549-53

22 Harden CL Meador KJ Pennell PB et al Practice parameter upda-te management issues for women with epilepsy focus on pregnan-cy (an evidence-based review) Teratogenesis and perinatal outco-mes report of the quality standards subcommittee and therapeutics and technology assessment subcommittee of the American aca-demy of neurology and American epilepsy society Neurology 200973133-41

23 Veiby G Bjoslashrk M Engelsen BA Gilhus NE Epilepsy and recommenda-tions for breastfeeding Seizure 20152857-65

24 Lavi-Blau T Ekstein D Neufeld MY Eyal S Use of antiepileptic drugs during pregnancy and lactation type of information provided by searching google Epilepsy Behav 201655113-9

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110

Clinical guideline status epilepticus in children and adultsAlejandro Olmos-Loacutepez1 Jorge Ibarra-Aguilar2 Joseacute O Cornelio-Nieto3 Luis A Ocantildea-Hernaacutendez4 Mario A Maacuterquez-Amaya5 Norberto Luna-Loacutepez6 Juan C Reseacutendiz-Aparicio7 and Ildefonso Rodriacuteguez-Leyva8

1Hospital General de Cuernavaca ldquoDr Joseacute G Parresrdquo Morelos 2Hospital del Nintildeo del DIF Pachuca Hidalgo 3Hospital de Alta Especialidad del Nintildeo ldquoDr Rodolfo Nieto Padroacutenrdquo Villahermosa Tabasco 4Unidad Meacutedica de Alta Especialidad HENo71 IMSS Torreoacuten Coahuila 5Hospital Regional Delicias Chihuahua 6Facultad de Medicina de Minatitlan Veracruz 7PPE Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez y Hospital Psiquiaacutetrico Infantil Dr Juan N Navarro Mexico City 8Hospital Central ldquoDr Ignacio Morones Prietordquo San Luis Potosiacute San Luis Potosiacute Mexico


REViEW ARtiClE

Abstract

A generalized epileptic seizure lasting 5 or more minutes or the presence of two or more seizures without recovering cons-ciousness within 30 min or a focal seizure that persists for gt10 min or with altered consciousness lasting for 60 min or more is called status epilepticus (SE) It can be classified into generalized and focal and motor and non-motor Its etiology may or may not be recognized The electroencephalographic pattern shows focal or generalized persistent epileptic activity It is a dangerous situation which requires algorithmic management from the time it is detected in the emergency room and if re-quired in intensive care In-hospital management would include the initial ABCDE hypertonic glucose solution and thiamin if hypoglycemia was detected Lorazepam (midazolam [MDZ] or diazepam) to stop seizures followed by phenytoin valproa-te or levetiracetam in impregnation and maintenance If the SE persists for more than an hour the patient will be admitted to an intensive care unit with intubation and continuous administration of MDZ propofol or thiopental with continuous moni-toring If it does not yield with two drugs it is called refractory epileptic status and if it continues for 24 h or more it is re-cognized as super-refractory A third of patients die

Key words Status epilepticus Seizures Focal Generalized Motor Acute treatment

Correspondence Ildefonso Rodriacuteguez-Leyva

E-mail ilroleyahoocommx






DOI 1024875RMNM19000031

1 How is status epilepticus (SE) defined

The ILAE proposes an operational definition as a generalized epileptic seizure in children and adults that lasts 5 or more minutes two or more seizures without recovering awareness within 30 min (here we include the majority of generalized epileptic seizures) It is a condition that results from a failure in initiating the in-hibitory mechanisms responsible for terminating an epi-leptic seizure and the persistence of mechanisms that favor the extension of a seizure

A generalized motor SE is defined as 5 or more mi-nutes of generalized motor activity or recurrent seizure without returning to baseline These represent 45-75 of all epileptic states

There is insufficient information about focal SE with altered level of awareness However it has been pro-posed to define it as an epileptic seizure that lasts 10 min or two or more epileptic seizures without re-covering a state of awareness within 60 min For ab-sence SE there is not enough scientific evidence to define the times but it has been proposed that it be


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111

A Olmos-Loacutepez et al Status epilepticus in children and adults

defined as an absence epileptic seizure lasting 10-15 min or more

2 How is SE classified

It can be classified based on four main axes which cannot always be determined semiology etiology electroencephalographic correlation and age

Axis 1 (semiology) two criteria are considered the presence or absence of motor symptoms and signs and the degree (qualitative or quantitative) of altered awa-reness (Table 1)

Axis 2 (etiology) on occasion it is difficult to deter-mine the cause of the SE so they are divided into two groups known and unknown cause (Table 2)

Axis 3 (electroencephalographic correlation) most of the first or second level hospitals do not have elec-troencephalogram (EEG) equipment but if the study can be carried out it should be done immediately Ba-sed on descriptive series and consensus we can des-cribe six electrical activity patterns (Table 3)

Axis 4 (age) important axis since the clinical mani-festations of SE can vary (Table 4)

3 What are the pre-hospitalization measures in SE management

Pre-hospitalization measures begin with the family and generally with paramedics that will help maintain the airway permeable avoid trauma (placing the patient in a place where he will not get hurt) and place the 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-tole andor apnea

The paramedic or first contact physician can admi-nister a standard dose (Table 5) diazepam or loraze-pam by intrarectal nasal intramuscular or intravenous administration

As soon as the situation is stabilized in the quickest manner possible the patient must be sent to a hospital that ideally will have an adequate service of emergen-cy care and intensive care

Stepsndash Immediate protection of the airway ensure gaseous

exchange and place the head properly (avoid snoring

Table 1 Axis 1 ndash SE classification

A With motor symptomsA1 Motor SE (generalized tonic‑clonic SE)

A1 a Generalized motor SEA1 b focal onset with secondary bilateral spreading (focal

to bilateral)A1 c unknown onset focal or generalized

A2 Myoclonic SE (predominance of myoclonic seizures)A2 a with a comatose stateA2 b without a comatose state

A3 Focal motorA3 a Repetitive focal motor seizures (Jacksonian)A3 b Continuous partial seizureA3 c Versive stateA3 d Ocular clonic stateA3 e Ictal paralysis

A4 Tonic SEA5 Hyperkinetic SE

B Without motor symptoms (Non‑motor or non‑convulsive SE ‑ NCSE)

B1 NCSE with coma (subtle SE)B2 NCSE without coma

B2 a GeneralizedB2 aa Typical absence SEB2 ab Atypical absence SEB2 ac Myoclonic absence SE

B2 b FocalB2 ba Without loss of awareness (Continuous aura with autonomic sensory olfactory visual auditory psychological and emotional symptoms)B2 bb AphasiaB2 bc With impaired awareness

B2 c Unknown onset focal or generalizedB2 ca Autonomic SE

SE status epilepticus

Table 2 Axis 2 ndash Etiology

Known cause (symptomatic)AcuteRemoteProgressiveSE in defined electroclinical syndromes

Of unknown cause (cryptogenic)


Table 3 Axis 3 ndash Electroencephalographic correlation

1 Location generalized (including bilateral synchronic patterns) lateralized bilateral independent and multifocal

2 By electric pattern periodic discharges rhythmic delta activity or subtypes of a paroxysmal pattern of spike‑wave and sharp‑wave

3 By morphology wave acuteness triphasic waves absolute and relative amplitude and polarity

Table 4 Axis 4 ndash Age

Neonatal 0‑30 days

Lactating 1 month‑2 years

Infancy 2 years‑12 years

Adolescence and adulthood 12 years‑59 years

Senile gt 60 years

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112


and lingual obstruction) and if necessary and avai-lable administer oxygen

ndash Monitor vital signsndash Test for glycemia using a Destrostix if possiblendash Administer a standard dose (child or adult) of benzo-

diazepine by rectal nasal intramuscular or intrave-nous administration

4 What are the initial measures that must be taken for the management of SE

0-5 minndash ABCDEndash Durationndash Oxygenndash Monitorizationndash Determination of glycemia (in adults if glucose was

lower than 60 mg administer thiamine and 50 ml 50 glucose for children older than 2 years 2 mlkg of 25 glucose solution

ndash Place venous access and take blood for laboratory tests (complete blood count serum electrolytes drug serum levels and toxicologic screen)

ndash If it is considered necessary place the urinary catheterndash Complete diagnostic approach continuous EEG

computed axial tomography lumbar puncture and magnetic resonance imaging (preferred over cranial computed tomography)

5 What is the initial pharmacologic treatment to manage generalized motor SE

Benzodiazepines are the first-line treatment for the management of SE (Table 5)

Othersndash Phenytoin (fosphenytoin) 20 mgkg IV to 50 mgmin

physiological solutionndash Phenobarbital 20 mgKg IV (5-10 mgkg can be

added)ndash Valproate (VPA) 20-40 mgkg IVndash Levetiracetam 60 mgKg (1-3 g) IVndash Lacosamide 100 mg IV every 6 h

6 What is the second-line pharmacologic treatment to manage generalized motor SE

Second-line drugs or urgent control therapy are added when SE has been established that is when benzodiazepines alone have not been effective in sub-verting the crisis124

In adults intravenous levetiracetam phenytoin or VPA can be used (level A)12 In children the guidelines from the American Epilepsy Society state that there is insufficient evidence to evaluate phenytoin and leveti-racetam as second-line treatments (level U) however valproic acid has similar efficacy and better tolerability than intravenous phenobarbital (level B)3 The US Na-tional Institutes of Health have implemented a protocol for the treatment of SE comparing phenytoin VPA and levetiracetam in children and adults contributing rele-vant information about these drugs (level C)5

In some studies67 phenytoin and fosphenytoin are the most commonly used drugs if SE persists in spite of benzodiazepine administration A recent meta-analy-sis8 of drugs administered for SE refractory to benzo-diazepines demonstrated the efficacy of phenytoin (50) levetiracetam (69) phenobarbital (74) and VPA (76) (all C)

8 What is the initial pharmacologic treatment for other SE (Focal and non-motor)

Non-motor SE (NCSE) is an entity that is difficult to recognize clinically due to its heterogeneity Its diagnosis results from its suspicion mainly due to an altered state of consciousness and persistence of clinical changes after a convulsive event or convulsive epileptic state has finished NCSE must be considered for any patients with altered consciousness presenting one or more of these situations coma lethargy and confusion For focal SE Toddrsquos paralysis which is a neurologic focal deficit of the last hours or days especially if it is after a seizure

Table 5 Benzodiazepines In SE

Doses in adults Doses in children

Lorazepam 01 mgkg IV up to 4 mg

004 mgkg IV

MDZ 02 mgkg IM or IV up to 10 mg

Heavier than 40 kg 02 mgkg up to 10 mgLighter than 40 kg 02 mgkg up to 5 mg

Diazepam 015 mgkg IV up to 10 mg IV

IV 03 mgkg up to 5 mg in younger than 5 years and 10 mg in older than 5 yearsRectal 05 mgkg From 1 to 3 years 5 mg older than 3 years 10 mg standard dose

SE status epilepticus MDZ midazolam

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113


It presents in up to 30 of patients with previous convulsive SE and requires discovery of compatible electroencephalic changes persisting for gt10 min1011

Diagnostic criteria

ndash Alterations in consciousness or other neurological deficit

ndash Epileptiform EEG discrete epileptic paroxysms or continuous discharges

ndash Response to anticonvulsants clinical or electroence- phalographicThe most frequent types of NCSE are the focal

non-convulsive the absence status the continuous partial epilepsy the continuous aura persistent hemi-paresis and others of lesser frequency It is classified as followsndash Comatose form generalized or focal (must be treated

if it lasts gt30 min) May or may not be preceded by a convulsive SE

ndash NCSE proper form absence status (typical absence atypical absence and late-onset absence) treatment is recommended after 15 min Focal SE with or wi-thout altered consciousness initiating treatment is recommended after 10 minFor treatment there are two recommended methods

ndash Aggressive treatment similar to management of con-vulsive SE preferred for patients that have had a symptomatic convulsive event (after an event of as-phyxia or acute hypoxia perinatal hypoxic encepha-lopathy Cardiovascular disease automated external defibrillator suppression etc) since the morbimorta-lity is high in these patients

ndash For the rest of the primary non-convulsive SE mor-bimortality is low and less aggressive management using oral or parenteral administration is preferred which reduces the morbimortality inherent in the use of central nervous system depressant drugs used to manage SEInstructions for administration (IV) and pharmacoki-

netics of anti-epileptic drugs in refractory SEMDZ 02-03 mgkg or 4 mg2 min 01-05 mgkg

hour 02-1 microgml in bolus Propofol 1-2 mgkg Slowly 5-10 mgkgh Thiopental 100-200 mg 30s 3-5 mgkgh 25-50 microgml in bolus followed by 50 mg every 2-3 mi-nutes until the ES is controlled Ketamine 05-45 mgKg (up to 5 mgKgh)

The patient must be closely monitored to avoid hypo-tension sepsis atelectasis pneumonia or cerebral venous thrombosis to the extent possible On occa-sion parenteral feeding for the patient may be necessary

Table 7 Second‑line drugs in SE treatment

Patient Intervention Comparison Result

Pediatric patient with tonic‑clonic SE

Second line drugs PhenytoinVPALevetiracetamPhenobarbital

Phenytoin fosphenytoin and Levetiracetam (Level U)VPA phenobarbital (Level B)

Adult patient with tonic‑clonic SE

Levetiracetam phenytoin or VPA (level A)

SE status epilepticus VPA valproate

Table 6 First line drugs in SE treatment

AED Doses in adults Doses in children Infusion speed

Phenytoin 20 mgkg IV 18 a 20 mgkg IV up to 1 g 1 mgkgmin for at least 20 min

Phenobarbital 20 mgkg IV 15 a 20 mgkg IV up to 1 g 1 mgkgmin for at least 20 min

Valproic acid 20‑40 mgkg IV 20‑40 mgkg IV up to 15 g Infusion for 15 min

Levetiracetam 1 g‑3 gkg IV 20‑60 mgkg IV up to 25 g Infusion for 15 min

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

AED automated external defibrillator Not available in Mexico

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9 iquestWhen is a generalized convulsive SE considered to be refractory to treatment

Refractory SE is defined as a generalized epileptic seizure that persists despite the use of two anti-epileptic drugs at least one first-line drug (benzodiazepine) and another second-line drug The super-refractory SE is defined as a SE that continues or recurs in 24 h or more once anesthesia has been initiated when it is removed or when it is completely terminated It can also be con-sidered when there are clinical or encephalographic seizures after benzodiazepine treatment and an ade-quately selected anti-epileptic drug

Predictors of a Refractory SEndash Non-structural causes hypoxia toxic-metabolic and

infectionndash Hyponatremia in the previous 24 h

ndash Delay in diagnosis and treatmentndash Non-convulsive or subtle SEndash Convulsive focal onset seizuresndash Young patient11-18

Complicationsndash Prolonged ventilator use and its complicationsndash Refractory bradycardia with metabolic acidosis

ndash Hyperlipidemiandash Fatty liverTriggering factors

ndash Sepsis assisted ventilation and subject submitted to hemodynamic monitoring

ndash Use of beta-lactams (cefepime and meropenem)Myocardial infarction with global anoxia

ndash Suppression syndromesndash Delirium (non-convulsive crises)

Management

ndash MDZ initial 02 mgkg IV in 2-5 min repeat in bolus of 02-04 mg every 5 min until the seizure stops Maintenance at 005-29 mgKgh

ndash Propofol initial 1-2 mgkg IV in 3-5 min repeat bolus every 3-5 min until the seizure stops Initial infu-sion at 20 mcgkgminute with maintenance of 30-200 mcgKgminute

ndash VPA 40 mgKg IV with an additional 20 mgkg main-tenance of 40 mgkgday

ndash Pentobarbital initial 5 mgkg IV up to 50 mgminute repeat in bolus of 5 mgkg until the seizure stops maintenance of 05-10 mgkgh (Tables 6-9)

ndash Ketamine 1-2 mgkg IV in 1 minute maintenance of 001-003 mgkgminute IV (adjust in the case of he-patic insufficiency)

ndash Corticosteroids It is recommended especially in ca-ses of super-refractory cases associated with Hashi-motorsquos encephalitis or Rasmussenrsquos encephalitis

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

Mean 55

AED automated external defibrillator

Table 9 Levels of Evidence of drugs in SE (modified from Yasiry et al2014)10

Evidence and level of recommendation

Treatment for SELorazepamMDZDiazepamPhenytoinPhenobarbitalVPALevetiracetam

Class ILevel AClass ILevel AClass IIaLevel AClass IIbLevel AClass IIbLevel AClass IIbLevel AClass IIbLevel A

Treatment for RSEMDZPropofolThiopentalVPALevetiracetamPhenytoin

The PPE recommends reviewing the complete guide

Class IIaLevel BClass IIbLevel BClass IIbLevel BClass IIbLevel BClass IIbLevel BClass IIbLevel BR‑PPE

SE status epilepticus MDZ midazolam VPA valproate

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A ketogenic diet could be an alternative especially for children with catastrophic epilepsy Vagus nerve stimulation is another alternative for super-refractory SE in children with catastrophic epilepsy

Hemispherectomy is used in children with Rasmus-senrsquos encephalitis

10 What type of patient follow-up must be carried out after remission from SE

About two-thirds of the patients respond to the first treatment if it was opportune and adequate In general the prognosis for those patients is good and with a good selection of anti-epileptic drugs to individualize the diagnostic approach to the patient good control of the seizure can be achieved Patient management and observation must be maintained as with any individual that suffers from epilepsy Unfortunately between 3 and 33 die from the SE itself or the complications caused by this problem

References 1 Trinka E Cock H Hesdorffer D et al A definition and classification of

status epilepticus report of the ILAE task force on classification of status epilepticus Epilepsia 2015561515-23

3 Meierkord H Boon P Engelsen B et al EFNS guideline on the mana-gement of status epilepticus in adults Eur J Neurol 201017348-55

2 Brophy GM Bell R Claassen J et al Guidelines for the evaluation and management of status epilepticus Neurocrit Care 2012173-23

4 Meierkord H Boon P Engelsen B et al EFNS guideline on the mana-gement of status epilepticus Eur J Neurol 200613445-50

5 Glauser T Shinnar S Gloss D et al Evidence-based guideline treatment of convulsive status epilepticus in children and adults report of the guideline committee of the American epilepsy society Epilepsy Curr 20161648-61

6 Treiman DM Meyers PD Walton NY et al A comparison of four treat-ments for generalized convulsive status epilepticus Veterans affairs status epilepticus cooperative study group N Engl J Med 1998339792-8

7 Alldredge BK Gelb AM Isaacs SM et al A comparison of lorazepam diazepam and placebo for the treatment of out-of-hospital status epilep-ticus N Engl J Med 2001345631-7

8 Mayer SA Claassen J Lokin J et al Refractory status epilepticus fre-quency risk factors and impact on outcome Arch Neurol 200259205-10

9 Bleck TP Management approaches to prolonged seizures and status epilepticus Epilepsia 199940 s59-s63

10 Yasiry Z and Shorvon SD The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilep-ticus a meta-analysis of published studies Seizure 201423(3)167-74

11 Lowenstein DH Alldredge BK Status epilepticus N Engl J Med 1998 338970-6

12 Appleton R Choonara I Martland T et al The treatment of convulsive status epilepticus in children Arch Dis Childhood 200083415-9

13 Kinney MO Craig JJ Kaplan PW Non-convulsive status epilepticus mimics and chameleons Pract Neurol 201818291-305

14 Lowenstein DH Alldredge BK Status epilepticus at an urban public hospital in the 1980s Neurology 199343483-8

15 Young GB Jordan KG Doig GS An assessment of nonconvulsive sei-zures in the intensive care unit using continuous EEG monitoring an investigation of variables associated with mortality Neurology 199647 83-9

16 Holtkamp M Othman J Buchheim K Meierkord H Predictors and prog-nosis of refractory status epilepticus treated in a neurological intensive care unit J Neurol Neurosurg Psychiatry 200576534-9

17 Holtkamp M Othman J Buchheim K et al A ldquomalignantrdquo variant of status epilepticus Arch Neurol 2005621428-31

18 Vasquez A Farias-Moeller R Tatum W Pediatric refractory and super-re-fractory status epilepticus Seizure 2018S1059-311

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116

Clinical guideline pre-operative evaluation of epilepsy surgeryMatilde Ruiz-Garciacutea1 Mario A Alonso-Vanegas2 Sara P Peacuterez-Reyes3 Gerardo Quintildeones-Canales4 Ildefonso Rodriacuteguez-Leyva5 Heacutector R Martiacutenez-Rodriacuteguez6 and Eduardo Barragaacuten-Peacuterez7

1Instituto Nacional de Pediatriacutea Mexico City 2Hospital HGM Mexico City 3Hospital Regional de Alta Especialidad del Bajiacuteo Leoacuten Guanajuato 4Hospital General del ISSSTE Durango 5Facultad de Medicina Universidad Autoacutenoma de San Luis Potosiacute and Hospital Central ldquoDr Ignacio Morones Prietordquo San Luis Potosiacute 6Instituto de Neurologiacutea y Neurocirugiacutea Hospital Zambrano Hellion TecSalud Tecnoloacutegico de Monterrey Nuevo Leoacuten 7Hospital Infantil de Meacutexico ldquoFederico Goacutemezrdquo Mexico City Mexico


REViEW ARtiClE

Abstract

Epilepsy surgery is an approved treatment for the management of drug-resistant epilepsy or refractory epilepsy (RE) Approxi-mately one-third of patients with epilepsy will develop RE RE is considered a serious public health threat carrying important biopsychosocial consequences including seizure-related accidents professional limitations and increased risk of sudden death Epilepsy surgery is associated with seizure remission in approximately 65 of patients after a 5 year follow-up Patients with drug-resistant epilepsy should be referred to a specialized center for a pre-operative evaluation Pre-operative evaluation requires at least a detailed clinical analysis an electroencephalogram (EEG) and video-EEG a cranial magnetic resonance imaging test as well as neuropsychological developmental and psychiatric evaluations The most common surgical proce-dures are temporal lobe resections extratemporal and multilobar resections lesionectomy hemispherectomies callosotomies and multiple subpial transections in descending order of frequency

Key words Surgery Epilepsy Pre-operative evaluation

Correspondence Matilde Ruiz-Garciacutea

Instituto Nacional de Pediatriacutea

Insurgentes Sur 3700-C

Mexico City Mexico

E-mail matilderuizggmailcom






DOI 1024875RMNM19000032

introduction

Epilepsy surgery is an approved treatment for the management of drug-resistant or refractory epilepsy (RE)1-3

RE is responsible for approximately 80 of the direct and indirect annual costs attributed to epilepsy4 The majority of surgical candidates are referred for surgery on average 20-25 years after their initial diagnosis at which time their prognosis is less favorable

When do patients with epilepsy require surgical treatment

According to the criteria established by International League Against Epilepsy (ILAE) approximately 17-33 of patients with epilepsy develop RE throughout the course of the disease (level of evidence III)5 A variable portion of patients are able to achieve seizure remission through epilepsy surgery depending on the type of crisis under-lying pathologies and the type of series consulted


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117

M Ruiz-Garciacutea et al Surgical evaluation in refractory epilepsy

Surgery generates significant improvements in the patientsrsquo behavior cognition and quality of life and the cost effectiveness of epilepsy has been demonstrated in pediatric as well as adult patients6

Early identification of patients with RE that meet cri-teria for epilepsy surgery candidacy optimizes seizure control and reduces cognitive long-term adverse effects7 The age at the time of surgery has been iden-tified as an important modulator of the patientsrsquo capa-city for cognitive reserve where the most unfavorable results are in patients with prolonged RE58

In 2003 the American Academy of Neurology publi-shed recommendations for the surgical management of epilepsy in adults Clinical trials demonstrated that pa-tients with focal epilepsy in the temporal lobe with or without evolution to bilateral tonic-clonic seizures who develop resistance to first-line pharmacological treat-ment must be examined as surgical candidates (consi-dering the new classification of seizures previously cited in 2003 as incapacitating complex partial seizu-res and with or without progression to generalized seizures)9


Patients with temporal lobe focal epilepsy with or without progression to bilateral tonic‑clonic seizures who develop resistance to first‑line pharmacological treatment must be examined as surgical candidates (AAN)

A

Studies with 5 year follow-up showed that surgery achieved seizure remission in 65 of cases1011

All subjects with RE must be submitted to a preoperati-ve evaluation to identify or discard well-circumscribed epileptogenic zones (EZ) and assess the potential be-nefit of a neurosurgical procedure7

Patients must meet certain requirements to be con-sidered candidates for epilepsy surgery the following criteria are indispensable1 Confirmed diagnosis of ER2 A systematic pre-operative evaluation with specific and

staggered stages that discard an epileptogenic zone susceptible to surgical resection without provoking ma-jor neurological deficits Published studies lack a com-parative analysis of pre-operative algorithms The spe-cialist consensus is that it must include a rigorous stratified outline followed by a multidisciplinary team that includes a neurologist sub-specialized in epilepsy a neurophysiologist electroencephalographist neuro-radiologist neuropsychologist neuropsychiatrist and

neurosurgeon trained in epileptic surgery procedures The pre-operative evaluation is carried out in con-gruent and concurrent stages The evaluation of each neurological subspecialty has independent value in localizing potential EZ which is an indispensable ob-jective of the pre-operative evaluation as well as post-operative care Even when the EZ cannot be out-lined or resected due to its location on or nearby a functional or eloquent area of the brain cortex it is important to consider that a thorough pre-operative evaluation is highly valuable in offering a meaningful diagnosis or prognosis to the patient as well as gui-ding alternative therapeutic measures

Epilepsy surgery is defined as any neurosurgical in-tervention with the objective of improving the quality of life through the control of epileptic seizures (ES) with minimum secondary side effects7

Can epilepsy develop resistance to pharmaceutical treatment

Epilepsy affects approximately 70 million people worldwide1213 one-third of this population develops RE5 In these cases epilepsy surgery has the potential to eliminate recurrence of ES and improves quality of life114 Certain epileptic syndromes present better prog-nosis with surgical treatment when compared to phar-maceutical treatment alone It is not easy to predict which patients will develop resistance to pharmaceuti-cal treatment the probability of developing RE varies according to the type of epileptic syndrome and the etiology this last factor being the most consistently reported in trails predicting the prognosis of epilepsy The prevalence of RE is higher among patients with symptomatic or cryptogenic epilepsy compared to tho-se with idiopathic epilepsy A trial including 2200 pa-tients studied for a period between 1 and 7 years achieved complete control of ES in 82 of patients with generalized idiopathic epilepsy 45 of cryptogenic fo-cal epilepsy and 35 of symptomatic focal epilepsy Another negative factor for the development of RE is an early age of onset A significant amount of patients with RE also presents hippocampal sclerosis malfor-mations of cortical development and dysembryoplastic neuroepithelial tumors

Temporal lobe epilepsy (TLE) is the most common cause of focal RE1516 therefore the most frequent type of epilepsy surgery on adults are temporal lobe resec-tions (level of evidence class I compared to conti-nuous pharmaceutical treatment alone)217

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118


Different definitions of RE have emerged throughout the years where multiple factors have been taken into account such as diagnostic certainty the number of failed anti-epileptic drugs (AEDs) attempted for seizure control the frequency of seizures and other aspects relating to the time span of the seizure pattern In fact different terms have been established such as untrea-table epilepsy uncontrollable epilepsy difficult to control epilepsy resistant to pharmaceutical treatment or RE Terminology diversity and the lack of definition of spe-cified criteria to conceptualize RE complicates the com-parison of studies and series thus rendering incomplete conclusions regarding the epidemiology diagnosis management and treatment of RE The ILAE is the association responsible for establishing a structured de-finition applicable for both clinical practice and scientific research of RE Thus RE was defined as the sustained failure or the lack of ES remission despite adequate attempts with at least two first-line AEDs as monothe-rapy or combined therapy that is well tolerated by the patient and was administered in their appropriate co-rresponding dosages5 ES remission or sustained sei-zure termination was defined as the absence of seizures for at least 12 months or for a period 3 times greater than the longest period of ES remission5 This definition may be used to justify a complete evaluation within a epilepsy center to establish a pre-operative evaluation for epilepsy surgery or to design a randomized contro-lled trial for AED or other research purposes thus emphasizing the importance of encouraging the con-nection between clinical practice and research scien-tists with a unified epilepsy criteria obtained through consensus and endorsed by the ILAE

For patients to be considered surgical candidates for epilepsy surgery adults must present confirmed diagno-sis of RE for at least 2 years however in life-threatening situations this required interval may be less In pediatric patients the required interval is lt2 years due to the potential long-term effects that ES can have if present during important stages of neurodevelopment10

Candidates for epilepsy surgery are usually between 1 and 60 years of age however there are no defined age limits51014 According to the Andalusian Epilepsy Guide of 20157 surgical candidate selection criteria includea Confirmed diagnosis of RE Epilepsy that is not con-

trolled with AED after 2 years Unsuccessful treat-ment after prescribing two AEDs with adequate do-sage respective to each type of ES and adequate treatment compliance Patient under 2 years of age High risk of presenting adverse effects on several AEDs

b Presence of a single unilateral and excisable structural brain lesion

c Presence of a non-resectable epileptogenic zone If a non-excisable zone is identified neurosurgical te-chniques such as disconnection procedures vagus nerve stimulation (VNS) or deep brain stimulation (DBS) are recommended if surgery is considered to reduce the severity of epilepsy and the proceduresrsquo side effects are considered acceptable

d Presence of psychological or psychiatric comorbiditiese Presence of diagnostic doubt regarding etiology or

epileptic syndromef Positive patient motivation to accept pre-operative

evaluation procedures surgical intervention and fo-llow-up protocol

g Age psychiatric pathology or disabilities are not contraindications for surgical candidacy however they must be analyzed on an individual basis11

What are the characteristics of patients that are submitted to surgical treatment

Patients that must be submitted to epilepsy surgery are (a) those that present refractory ES (b) patients with physical disabilities due to uncontrolled seizures and (c) patients with focal RE low morbidity risk and potential for rehabilitation and social integration

A randomized control study demonstrated the superiority of surgical treatment over continuous phar-macological treatment in patients with refractory TLE 80 patients with mesial temporal lobe sclerosis (mTLS) where randomly distributed into groups of pharmacolo-gical or surgical treatment respectively after a pre-operative evaluation Authors discovered that 58 of patients in the surgical group presented seizure re-mission for 1 year compared to 8 of the patients in the pharmacology group (p lt 0001) Authors also found that patients in the surgical group demonstrated better quality of life when compared to the pharmacology group as measured by reduced work or school absen-ces In addition one death was reported within the pharmacology group compared to no deaths in the surgical group2 Epilepsy surgery has curative potential when an epileptogenic lesion or zone is completely excised In other situations surgery will only serve a palliative function as is the case for the DBS or colos-tomy procedures for atonic seizures in patients with Lennox-Gastaut syndrome The curative potential of surgery is maximized with complete excision of a pri-mary cerebral tumor vascular malformation malforma-tion of cortical development or mTLS18

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119


Extratemporal epilepsy surgeries are significantly less frequent in surgical series because they represent a greater surgical challenge they require frequent eva-luation through multimodal imaging tests or invasive monitoring In addition the EZ in extratemporal epi-lepsy are more commonly diffuse and poorly cir-cumscribed they present a faster rate of extension in the seizure propagation and superposition with elo-quent areas thus frequently requiring invasive monito-ring to locate the epileptogenic zone(s)19 There lacks sufficient evidence to provide definite recommenda-tions for extratemporal epilepsy surgeries in patients without defined lesions or in symptomatic patients with poorly circumscribed lesions A meta-analysis publi-shed by Teacutellez-Zenteno11 reported a 60 and 35 re-mission rate in extratemporal and non-defined lesion epilepsies respectively

Which epileptic syndromes should be managed with surgical treatment

Epileptic syndromes that should be managed by sur-gery includea Mesial temporal epilepsyb Neocortical epilepsy with a single well-defined lesion

without compromise of other eloquent areas of the brain

c Hemispheric epilepsy syndromes such as hemime-galencephaly (HME) Sturge-Weber syndrome Rasmussenrsquos encephalitis and other unilateral he-mispheric lesions

Patients that generally do not require invasive proce-dures include

a Mesial temporal epilepsy associated with hippocam-pal sclerosis

b Circumscribed epileptogenic lesions including be-nign neoplasias such as ganglioma dysembryoplas-tic neuroepithelial tumors low-grade astrocytoma oligodendroglioma vascular malformations and atrophic brain lesions

c Hemispheric lesions hemiplegic hemiconvulsive epilepsy such as Sturge-Weber syndrome HME and Rasmussenrsquos encephalitis

d Epileptic encephalopathies and multifocal diseases such as Lennox-Gastaut Syndrome

Patients that require functional neuroimagingmapping andor invasive tests include

e Dual pathologies with discordant electroclinical bilateral mesial temporal sclerosis poorly circumscribed epilep-togenic lesions malformations of cortical development

with normal magnetic resonance imaging (MRI) in or near eloquent areas

What are the primary modalities of surgical treatment

Modalities of resection include techniques where the EZ are excised without producing a significant functio-nal deficit In addition there are modalities of non-re-section techniques including disconnection or palliative procedures3 The most frequently performed procedu-res are temporal lobe resections extratemporal and multilobar resections lesionectomy hemispherectomy callostomies and multiple subpial transections7a Anterior temporal lobectomy or anterior medial tem-

poral resection it is the most commonly practiced procedure consisting of the excision of medial tem-poral structures (amygdala hippocampus and para-hippocampal gyrus) up to 6 cm of anterior temporal lobe cortex in the non-dominant hemisphere and up to 45 cm in the dominant hemisphere To avoid neuropsychological side effects and superior qua-drantanopsia the resection of the anterior temporal lobe is limited

b Lesionectomy it is indicated in neocortical epilepsy with single well-circumscribed epileptic zone super-posed or in proximity to structural lesions this allows superior surgical results and ES control The proce-dure consists of selective resection of an epilepto-genic structural lesion such as certain types of focal cortical dysplasia cavernomas circumscribed glio-sis and certain types of developmental tumors such as dysembryoplastic neuroepithelial tumors gan-gliogliomas and some low-grade gliomas In some cases the epileptogenic zone may extend beyond the visible lesion thus requiring an invasive elec-troencephalogram (EEG) test to locate and determi-ne the extension as well as to improve the results of the surgery

c Neocortical resections resections of the single or multilobar cortical lesion This type of surgery requi-res electrocorticography (intracranial electroen-cephalography) to establish the extension and the limits of the epileptogenic zone

d Functional hemispherectomy this procedure has substituted the anatomic hemispherectomy due to the risk of residual cerebral hemosiderosis and post-operative hemorrhaging It consists of total dis-connection of the brain hemispheres with limited cerebral tissue resection It is the indicated proce-dure for patients with severe hemispheric damage

No

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2019

120


and refractory motor ES of diverse etiology whether congenital or postnatal The causes may be disor-ders of brain development such as HME long-term effects of the perinatal vascular event or traumatic brain injury progressive autoimmune disease such as Rasmussenrsquos encephalitis Sturge-Weber syndro-me and among others

e Callostomy palliative procedure in which hemisphe-ric disconnection is achieved through the section of the corpus collosum in the prevention of interhemis-pheric seizure propagation and generalization This procedure is indicated in cases of severe epilepsy with drop attacks

f Multiple subpial transections this procedure is re-served for non-excisable EZ due to their proximity to eloquent areas of the brain cortex It is frequently associated with cortical resection

g Other techniques stereotactic radiosurgery VNS trigeminal nerve stimulation and DBS220

What are the minimum tests required for the preoperative evaluation of epilepsy surgery

Phase 1 of the pre-operative evaluation is the non-in-vasive portion of the evaluation and it requires at leasta Extensive clinical evaluation with expert review of

patientrsquos clinical history and previous laboratory and imaging tests The identification of associated prog-nostic factors at the time of seizure onset and throu-ghout the evolution of the disease must be empha-sized as well as seizure semiology during the course of disease with particular interest in the previous 12 months including frequency intensity duration aura and associated trigger factors (emotional stress sleep-deprivation menstruation) medica-tions dosages combinations side-effects memory and language alteration cognitive deterioration and psychiatric comorbidities An exhaustive review of previous laboratory and imaging tests as well as previous hospital records must be performed whe-never possible for example finding the activity or epileptic discharge zones in the patientrsquos first EEG will have focalizing or lateralizing value A large quan-tity of patients referred to surgical epilepsy centers present pseudoresistance to AEDs The most com-mon causes include incorrect diagnosis inadequate pharmaceutical drug selection for the seizure type inadequate or insufficient dosages and ldquoirresponsi-ble patient lifestyle choices Initially the diagnosis of ES must be corroborated according to international

criteria Subsequently the diagnosis of RE must be identified and confirmed ideally based on a thorough review of patientrsquos history and disease evolution

b EEG compatible and consistent serialized EEG and video ndash EEG (vEEG) monitored by superficial electrodes

c MRI high-resolution cranial MRI that identifies brain anatomy and structural lesions It is recommended to use resonance equipment in the 15-30 Tesla range and FLAIR sequences to identify cortical dys-plasia In addition tractography is recommended to identify Meyerrsquos loop and prevent post-operative quadrantanopsia in temporal lobe surgeries The Wada test or functional MRI (fMRI) can be perfor-med if the identification of the verbal dominant he-misphere is required

d Neuropsychology or developmental evaluation faci-litates the identification of possible lateralization and localization of the epileptogenic zone as well as determining the pre-operative cognitive status to an-ticipate possible cognitive surgical side effects

e Psychiatric evaluation necessary to evaluate the pa-tientrsquos comorbidities as well as the patientrsquos expec-tations of surgical outcome and quality of life

In 2006 the sub-commission of pediatric epilepsy surgery of the ILAE concluded that a superficial EEG that includes a record of sleeping cortical electrical activity an MRI with specific epilepsy protocol and neuropsychological evaluation are required to consider a pediatric patient for epilepsy surgery A 12-24 h su-perficial vEEG must record at least one paroxysm and a brain fMRI must be performed whenever possible6

What are the main complications of drug-resistant or RE

A mortality rate of 2-3 times higher has been recor-ded for the population with epilepsy The mortality rate is even more critical in the subgroup of patients with RE where the standardized mortality rate has been calculated up to 469 to 5 times higher than the general population In addition within this group of patients a large proportion of the causes of death are directly related to epilepsy such as sudden unexpected death Conversely when epilepsy surgery is successful in controlling seizures reduced epilepsy-related mortality risk has been recorded21

RE is associated with non-fatal injuries such as trau-matic brain injury burns fractures work-related accidents and accidents during recreational and every-day life activities among others In addition RE is

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121


associated to disabilities and a low quality of life which can cause a low academic performance cognitive de-cline and social isolation The rate of employment matrimony and fertility is considerably reduced in pa-tients with poorly controlled ES2

The majority of patients with RE has significant res-trictions on their everyday life such as driving motor vehicles The complications of RE can originate throu-gh a combination of effects such as recurrent ES drug toxicity and other psychological associated factors

such as depression anxiety psychosis and excessive dependence on a care-taker9 In addition to the direct and indirect costs of ES most patients are referred to surgical evaluation over 20 years after the diagnosis of epilepsy it is highly likely that this delay in referral is responsible for a significant quantity of deaths related to ES10 Finally the probability of postsurgical seizure remission and favorable quality of life is indirectly rela-ted to the time span between RE onset to the moment of epilepsy surgery10

levels of evidence of epilepsy surgery

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 alone for temporal lobe epilepsy and results in greater control of epileptic seizures and improved quality of live

I

Patients with medial temporal lobe RE subjected to early surgery (lt2 years) achieve seizure remission more frequently than patients who do not undergo surgery

II

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

II

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

III

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

III

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

IV

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 must be sequential and staggered beginning with basic tests and subject to amplification if necessary

IV

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

IV

Video‑EEG monitoring with intracranial electrodes is a safe procedure that is associated with minimum permanent morbidity andor mortality rate

II

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

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122


References 1 Rathore C Radhakrishnan K Concept of epilepsy surgery and presurgi-

cal evaluation Epileptic Disord 20151719-31 2 Wiebe S Blume WT Girvin JP Eliasziw M Effectiveness efficiency of

surgery for temporal lobe epilepsy study group A randomized controlled trial of surgery for for temporal-lobe epilepsy N Engl J Med 2001 345(5)311-8

3 Pindrik J Hoang N Smith L et al Preoperative evaluation and surgical management of infants and toddlers with drug-resistant epilepsy Neuro-surg Focus 201845E3

4 Begley CE Annegers JF Lairson DR Reynolds TF Hauser WA Cost of epilepsy in the United States a model based on incidence and prog-nosis Epilepsia 1994351230-43

5 Kwan P Arzimanoglou A Berg AT et al Definition of drug resistant epilepsy Consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies Epilepsia 2010511069-77

6 Ryvlin P Cross JH Rheims S Epilepsy surgery in children and adults Lancet Neurol 2014131114-26

7 Andaluza G Epilepsia D Diagnoacutestico y Tratamiento de la Epilepsia en Nintildeos y Adultos Sociedad Andaluza de Epilepsia Viguera Editores Saint Louis Saint Louis University 2015

8 Helmstaedter C Neuropsychological aspects of epilepsy surgery Epi-lepsy Behav 20045 Suppl 1S45-55

9 Helmstaedter C Cognitive outcomes of different surgical approaches in temporal lobe epilepsy Epileptic Disord 201315221-39

10 Engel J Jr Wiebe S French J et al Practice parameter temporal lobe and localized neocortical resections for epilepsy report of the quality standards subcommittee of the American academy of neurology in

association with the American epilepsy society and the American asso-ciation of neurological surgeons Neurology 200360538-47

11 Teacutellez-Zenteno JF Dhar R Wiebe S Long-term seizure outcomes fo-llowing epilepsy surgery a systematic review and meta-analysis Brain 20051281188-98

12 West S Nolan SJ Cotton J et al Surgery for epilepsy Cochrane Data-base Syst Rev 20157CD010541

13 Sander JW Shorvon SD Epidemiology of the epilepsies J Neurol Neu-rosurg Psychiatry 199661433-43

14 Kalilani L Sun X Pelgrims B Noack-Rink M Villanueva V The epide-miology of drug-resistant epilepsy a systematic review and meta-analy-sis Epilepsia 2018592179-93

15 Pre-surgical evaluation for epilepsy surgery European standards Euro-pean federation of neurological societies task force Eur J Neurol 2000 7119-22

16 Engel J Jr Mesial temporal lobe epilepsy what have we learned Neu-roscientist 20017340-52

17 Semah F Picot MC Adam C et al Is the underlying cause of epilepsy a major prognostic factor for recurrence Neurology 1998511256-62

18 Jayakar P Gaillard WD Tripathi M et al Diagnostic test utilization in evaluation for resective epilepsy surgery in children Epilepsia 2014 55507-18

19 Wyllie E Comair YG Kotagal P et al Seizure outcome after epilepsy surgery in children and adolescents Ann Neurol 199844740-8

20 Engel J Jr McDermott MP Wiebe S et al Early surgical therapy for drug-resistant temporal lobe epilepsy a randomized trial JAMA 2012 307922-30

21 Ryvlin P Kahane P Does epilepsy surgery lower the mortality of drug-re-sistant epilepsy Epilepsy Res 200356105-20

No

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ub

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ion

may

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2019

123

Clinical guide discontinuing chronic antiepileptic drug treatmentMariacutea del C Loy-Gerala1 Octavio M Ibarra-Bravo2 Mariacutea del R Maacuterquez-Estudillo3 Francisco Mena-Barranco4 Francisco J Rogel-Ortiz5 Sandra E Silva-Saacutenchez6 Hilda Villegas-Pentildea7 and Avril Molina-Garciacutea8

1Hospital General de Puebla ldquoDr Eduardo Vaacutezquez Navarrordquo SSA Puebla 2Hospital General ldquo Dr Miguel Silvardquo Morelia Michoacaacuten 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


REViEW ARtiClE

Abstract

The decision to continue or withdraw the antiepileptic drugs (AEDs) should be taken jointly by the patient family andor 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 patientrsquos 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






DOI 1024875RMNM19000033

Question 1 How long must the patient be seizure free before considering antiepileptic drug (AEd) withdrawal

In 1996 the American Academy of Neurology propo-sed a guide for discontinuing antiepileptics in patients that are seizure free with the following criteria seizure free after 2-5 years of treatment only one type of epi-lepsy normal neurological examination and a normal electroencephalogram (EEG)1 There have been very few changes with respect to the previous proposal

There are a number of prospective studies and me-ta-analyses in this respect but there has not been a uniform consensus about how long the patient must be in remission before treatment can be discontinued these studies propose from 1 to 5 years of remission2-8 The risk of recurrence is greater when the epileptic seizu-re-free period before discontinuing the medication is lt2 years than when itrsquos longer9 For patients that have been seizure free for 2 or more years the risk of recu-rrence after discontinuing medications is lower the lon-ger the patient has been seizure free Furthermore the


Correspondence Mariacutea del Consuelo Loy-Gerala

Hospital General de Puebla ldquoDr Eduardo

Vaacutezquez Navarrordquo SSA

Puebla Mexico City Mexico

E-mail marialoy1gmailcom

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124


risk of recurrence is lower for patients that did not have a seizure after beginning their treatment with AEDs2

Various studies have demonstrated that one of three patients relapse within a period of 2 years after suspen-ding antiepileptics The risk of seizure recurrence in the same period of time is 2 or 3 times that observed for patients that remain on AEDs The 2015 Cochrane re-view10 of randomized controlled trials about epileptic drug withdrawal defines withdrawal of antiepileptics af-ter lt 2 years of treatment as ldquoearly withdrawalrdquo and ldquolate withdrawalrdquo when they are discontinued after 2 years of treatment The seizure-free period for children neces-sary to consider antiepileptic withdrawal is considerably shorter compared to that of adults and depends on the epileptic syndrome This is true for those cases with favorable evolution such as benign childhood epilepsy and Rolandic epilepsy11 In these cases treatment can be suspended after a maximum of 1 year12

Recommendation Level of recommendation and level of evidence

Consider withdrawing medication in patients with at least 2 years in complete seizure remission

Evidence level 1Recommendation level A

Question 2 What are the risk factors for recurrence of epileptic seizures after AEd withdrawal in pediatric patients

ndash Generalized non-motor absence seizures 20-30 relapse

ndash Focal seizures 44 relapse Focal seizures with di-minished awareness have greater risk of relapse

ndash Juvenile myoclonic epilepsy recurs in 33-78 only 25-26 can undergo treatment withdrawal

ndash West Lennox-Gastaut and Dravet syndromes have a high risk of recurrenceOther factors

ndash Symptomatic epilepsies 41-42 riskndash Neurological anomalies present at birthndash Average of five seizures per year 68 relapsendash Prolonged seizuresndash History of febrile seizures has 2 times the risk of

relapsendash Prolonged epilepsy before remissionndash Age of onset of epilepsy younger than 2 or older than

12 years oldndash ge 10 seizures before remissionndash Impaired neurodevelopment intellectual quotient lt 70ndash EEG with epileptiform activity before withdrawalndash lt 2 years without seizures10

There are a few studies that show that female gender and family history of epilepsy are risk factors that in-crease the probability of relapse13-19

Recommendations when faced with risk factors for recurrence of epileptic seizures in children

Level recommendation

Antiepileptic drugs can be suspended in cases of focal epilepsy and most generalized genetic epilepsiesAssess whether or not to withdraw treatment in generalized symptomatic or unknown cause epilepsies juvenile myoclonic epilepsy and partial symptomatic epilepsy due to a high risk of relapse

B

In children the main risk factor is etiology Continued treatment does not guarantee the absence of recurrence

A

An abnormal electroencephalogram age of onset of seizures intellectual disability abnormal neurological examination at birth altered neuroimaging studies family history of epilepsy and febrile seizures alone should not be taken as justification to avoid suspending treatment if there are no other associated negative predictors

B

Gender should not be an isolated factor to decide not to withdraw antiepileptic drug treatment

C

Inform the patient that two or more epileptic drugs at the onset of withdrawal may be associated with increased risk of relapse However this does not contraindicate withdrawal

C

The decision to stop or continue treatment does not depend on the type of drug that will be withdrawn

C

Question 3 What are the risk factors for recurrence of epileptic seizures in adult patients after suspending antiepileptic

There are multiple studies that assess the risk factors for recurrence of epileptic seizures in adults In 2017 a predictive model for recurrence was published which described the most important factors9 This was based on multiple studies considering that the methodology the types of patients and types of epileptic seizures are very varieda Age One study reported a greater possibility of re-

mission when withdrawing AED at an older age (p = 002) finding remission in 45 of the patients Various other studies demonstrated that the earlier the age of onset of epilepsy before the period of con-trol of seizures the greater the risk of recurrence as well as a greater risk of recurrence when the age of onset is late infancy or adolescence191620

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125

MC Loy-Gerala et al Discontinuing chronic antiepileptic treatment

b Mental retardation An intelligence quotient lt 70 and motor deficits are independent predictors of recurrence1620

c Abnormal neurological examination A 15 seizure recurrence is reported during the 1st month in pa-tients with abnormal neurological examinations2122

d Abnormal interictal encephalogram (EEG) The pre-sence of an abnormal EEG before AED withdrawal or during the 1st year after AED withdrawal indicates greater risk of recurrence12223

e Focal and generalized symptomatic tonic-clonic epi-lepsies have a greater risk of recurrence920

f Age of onset of epilepsy920g Family history of epilepsy Increased risk of

recurrence920h Number of AEDs The greater the number of AED the

greater the risk of recurrence after withdrawal920


For patients with epilepsy that has been seizure free for gt2 years without risk factors the gradual withdrawal of antiepileptic drugs is recommended The decision should be made in conjunction with the patient andor the caretakers

Evidence level 1Recommendation level B

For patients with epilepsy that has been seizure free for gt2 years with risk factors the riskbenefit of AED withdrawal should be assessed


Question 4 What are the risk factors for recurrence of epileptic seizures after withdrawing AEds in patients following epilepsy surgery

In 2011 a prospective study was published with 311 patients after mesial temporal epilepsy surgery who underwent AED withdrawal after being seizure free be-tween 3 months and 1 year The results showed that the absence of hippocampal sclerosis and the presence of interictal discharges in the EEG were independent predictors of seizure recurrence24 The majority of stu-dies report the same requirement of 1-2 years seizure free without increase in recurrence in up to 10 years of follow-up2526 A Class II prospective randomized study published in 2009 which included post-surgical patients that were seizure free for 1 year demonstrated a greater rate of recurrence for patients with hippocampal sclero-sis compared with those with lesional epilepsy27 The only work that included extratemporal surgery is a re-trospective study with 106 patients diagnosed with

epilepsy that presented evident lesions by magnetic resonance imaging which evidenced greater risk for older patients longer course of epilepsy abnormal post-operative EEG early post-operative seizures glio-sis or cortical focal dysplasia and interictal discharges in the EEG and during the 1st year after surgery28

The largest study in pediatric population is a European multicentric retrospective uncontrolled study that inclu-ded 766 patients under 18 years of age that was seizure free after surgery (temporal and extratemporal) who were subjected to AED withdrawal Results showed a seizure recurrence of 12 and of these patients 30 did not achieve seizure control after reintroducing medication29

Good prognosis Bad prognosis

Surgery at an early age Surgery after 30 years of age

Hippocampal sclerosis Long‑term epilepsy

Anterior temporal lobectomy

Normal anatomopathological examination

Seizure free for 1‑2 years after surgery

Neocortical resection

Question 5 What is the usefulness of an EEG to decide on AEd withdrawal

Although there are no examinations that are comple-tely reliable to predict the recurrence of seizures many studies have demonstrated that abnormalities in the EEG before or after AED withdrawal increase the risk of recurrence1516 A recent meta-analysis reported that the presence of EEG paroxysms before AED withdrawal predicts a high percentage of recurrences (Table 1) 23


In patients that are seizure free but show paroxysmal EEG patterns and other risk factors AED withdrawal is not recommended due to a high risk or recurrence

IA

Question 6 What are the probabilities of the recurrence of epileptic seizures for patients undergoing AEd withdrawal

The probability for seizure recurrence after stopping treatment varies among different studies and oscillates from 20 to 469 Different studies have found risk fac-tors that significantly impact the probability of recurrence These risk factors are as follows duration of epilepsy before achieving control total number of seizures (fewer or more than 10) time in remission age at seizure onset

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(with a discreetly greater risk when epilepsy begins in adolescence or adulthood) intellectual quotient lt 70 abnormal EEG at the time of AED withdrawal remote symptomatic epilepsy (defined as epilepsy caused by an old brain lesion) absence of an epileptic syndrome rela-ted to age and history of febrile seizures13-1930-32

These risk factors have different prognostic weight The most important are as follows duration of epilepsy total number of seizures intellectual disability remote symptomatic epilepsy and absence of an autolimited epileptic syndrome Tables that assign a numeric value for each of these risk factors have been developed9 The information found in these tables is simple the greater the high significance risk factors the greater the risk of seizure recurrence (Level I)

Regarding epilepsy of genetic origin it must be poin-ted out that juvenile myoclonic epilepsy has a very high risk of recurrence after treatment withdrawal (Relative Risk RR of 70 up to 95) even after very long periods of remission3334 Itrsquos very important that the patient receives clear information during the decision-making process (R-PPE) (Level I)

Question 7 How should AEd be withdrawn

There is no clear consensus among different studies that analyze this aspect since the period of time pro-posed for AED withdrawal varies from 4 weeks to 12 months In a controlled randomized study with 149 children no differences were found with regard to re-currence of seizures when AEDs were withdrawn in a period between 6 weeks and 9 months In another study involving 56 children no differences in RR were found after assessing periods of AED withdrawal las-ting 1-6 months Finally another study with 216 children that assessed AED withdrawal periods of 4-6 weeks versus 4-6 months also did not find significant differen-ces in RR Thus we recommend gradual withdrawal of AED in an interval of 4-6 months3536


Gradual withdrawal of AED in an interval of 4‑6 months is recommended

Level of evidence 2Level of recommendation PPE consensus

Question 8 What other risks besides recurrence are there when withdrawing AEds

In addition to the risk of recurrence other factors must be considered adverse effects of the drugs risk

of physical lesions or death quality of life and social and psychological problems Always consider the risk of losing a driverrsquos license or a job since this is a de-terminant factor for some adults137

A prospective study found that after AED withdrawal and relapse of epileptic seizures there is little risk of epileptic seizures resistant to treatment This risk co-rresponds to 1 compared to 97 of recurring after treatment is reinitiated A review from 2005 reported treatment refractory epilepsy in 19 of the patients that had previously undergone treatment withdrawal which was associated with a symptomatic etiology location of the epilepsy and abnormal neurological examina-tions In some patients with controlled epilepsy and associated comorbidity this can be increased under AED withdrawal since valproic acid and lamotrigine are indicated for stabilizing emotional states as in bipolar disorder and topiramate is also used as prophylactic treatment for migraines1737

Relapse of epileptic seizures after AED withdrawal may have psychosocial repercussions and important financial effects Depending on the legislation regula-ting the area where the patient resides this situation indicates that he will be restricted from driving for a period of 3-12 months as well as a greater risk of ha-ving epileptic seizures during work and repercussions on quality of life and social stigma since everyday ac-tivities may have to be modified22

Question 9 What are the benefits of withdrawing epileptic drugs

AEDs are associated with long-term adverse effects that may include cognitive and behavioral alterations Suspending antiepileptics can benefit persons in long-term remission if the benefit of withdrawing treatment is greater than the alterations caused by taking the antiepileptics

Some of these effects are attention reduction alterations in memory and mood and depression In addition they can cause problems in daily activities resulting in an affected quality of life although these may be slight Their daily chronic use offers other risk factors such as teratogenesis possibility of infertility in males interactions with other drugs and long-term to-xicity and pseudodementia as can be caused by phenytoin even at therapeutic doses Conversely sei-zure recurrence can also be devastating from the emo-tional point of view and in social life there is risk of losing work and autonomy and especially for obtaining a driverrsquos license1

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Taking AEDs imply a continuous economic expense for the individual and their families as well for the public health system when they are administered unnecessa-rily (World Health Organization 2012) Therefore when epilepsy is in remission withdrawing antiepileptics can favor quality of life17

In general cognitive function is improved In a prospective placebo-controlled double-blind study 139 patients that were seizure free for at least 2 years un-derwent neuropsychological tests before and after AED withdrawal finding better performance after stopping treatment In addition there were lower levels of depres-sion and irritability after withdrawing the medication22

In a retrospective study that included 766 patients under 18 years of age with pre- and post-surgical neu-ropsychological assessment and at least 1 year after AED withdrawal results showed that withdrawal of phe-nobarbital and primidone was associated with an in-crease in intellectual quotient of 10 or more points The fact of reducing the doses of antiepileptics and comple-te withdrawal of the drugs predicted better results in psychometric tests compared to children that continued their antiepileptic treatment before surgery Verbal me-mory developed better in children that underwent drug withdrawal These cognitive and behavioral effects were also observed with the new AEDs3839

References 1 Practice parameter a guideline for discontinuing antiepileptic drugs in seizu-

re-free patients summary statement Report of the quality standards subcom-mittee of the American academy of neurology Neurology 199647600-2

2 Epilepsies the Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary Care Withdrawal of Pharmaco-logical Treatment NICE Clinical Guideline 137 Clinical Guideline [CG137] Fecha de Publicacioacuten Enero 2012 Fecha de Uacuteltima Actualiza-cioacuten 2018 Available from httpswwwniceorgukguidancecg137

3 Guiacuteas Diagnoacutesticas y Terapeacuteuticas de la Sociedad Espantildeola de Neuro-logiacutea 2012 Guiacutea Oficial de Praacutectica Cliacutenica en Epilepsia Sociedad Es-pantildeola de Neurologiacutea 2012

4 Olmez A Arslan U Turanli G Aysun S Risk of recurrence after drug withdrawal in childhood epilepsy Seizure 200918251-6

5 Shinnar S Berg AT Mosheacute SL et al Discontinuing antiepileptic drugs in children with epilepsy a prospective study Ann Neurol 199435534-45

6 Berg AT Shinnar S Relapse following discontinuation of antiepileptic drugs a meta-analysis Neurology 199444601-8

7 Camfield P Camfield C When is it safe to discontinue AED treatment Epilepsia 200849 Suppl 925-8

8 Beghi E Giussani G Grosso S et al Withdrawal of antiepileptic drugs guidelines of the Italian league against epilepsy Epilepsia 201354 Suppl 72-12

9 Lamberink HJ Otte WM Geerts AT et al Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepi-leptic drugs in seizure-free patients a systematic review and individual participant data meta-analysis Lancet Neurol 201716523-31

10 Sirven JI Sperling M Wingerchuk DM Early versus late antiepileptic drug withdrawal for people with epilepsy in remission Cochrane Database Syst Rev 20013CD001902

11 Capovilla MD Vigevano MD Topical review benign idiopathic partial epilepsies in infancy Child Neurol 200116874-81

12 Peters AC Brouwer OF Geerts AT et al Randomized prospective study of early discontinuation of antiepileptic drugs in children with epilepsy Neurology 199850724-30

13 Camfield CS Camfield PR Juvenile myoclonic epilepsy 25 years after seizure onset a population-based study Neurology 2009731041-5

14 Geithner J Schneider F Wang Z et al Predictors for long-term seizure outcome in juvenile myoclonic epilepsy 25-63 years of follow-up Epilep-sia 2012531379-86

15 Specchio LM Tramacere L La Neve A Beghi E Discontinuing antiepi-leptic drugs in patients who are seizure free on monotherapy J Neurol Neurosurg Psychiatry 20027222-5

16 Hixson JD Stopping antiepileptic drugs when and why Curr Treat Options Neurol 201012434-42

17 Tang X Yu P Ding D et al Risk factors for seizure reoccurrence after withdrawal from antiepileptic drugs in individuals who have been seizu-re-free for over 2 years PLoS One 201712e0181710

18 Giussani G Bianchi E Canelli V et al Antiepileptic drug discontinuation by people with epilepsy in the general population Epilepsia 201758 1524-32

19 Incecik F Herguner OM Altunbasak S Mert G Kiris N Risk of recurren-ce after discontinuation of antiepileptic drug therapy in children with epilepsy J Pediatr Neurosci 20149100-4

20 Schachter SC Determining when to stop antiepileptic drug treatment Curr Opin Neurol 201831211-5

21 Lossius MI Hessen E Mowinckel P et al Consequences of antiepileptic drug withdrawal a randomized double-blind study (Akershus study) Epilepsia 200849455-63

22 Lamberink HJ Otte WM Geleijns K Braun KP Antiepileptic drug with-drawal in medically and surgically treated patients a meta-analysis of seizure recurrence and systematic review of its predictors Epileptic Di-sord 201517211-28

23 Tang L Xiao Z Can electroencephalograms provide guidance for the with-drawal of antiepileptic drugs a meta-analysis Clin Neurophysiol 2017 128297-302

24 Rathore C Panda S Sarma PS Radhakrishnan K How safe is it to withdraw antiepileptic drugs following successful surgery for mesial tem-poral lobe epilepsy Epilepsia 201152627-35

25 Berg AT Langfitt JT Spencer SS Vickrey BG Stopping antiepileptic drugs after epilepsy surgery a survey of US Epilepsy center neurolo-gists Epilepsy Behav 200710219-22

26 McIntosh AM Kalnins RM Mitchell LA et alTemporal lobectomy long-term seizure outcome late recurrence and risks for seizure recurrence Brain 20041272018-30

27 Kerling F Pauli E Lorber B et al Drug withdrawal after successful epilepsy surgery how safe is it Epilepsy Behav 200915476-80

28 Menon R Rathore C Sarma SP Radhakrishnan K Feasibility of antiepi-leptic drug withdrawal following extratemporal resective epilepsy surgery Neurology 201279770-6

29 Boshuisen K Uiterwaal C The timetostop study I Antiepileptic drug wi-thdrawal policies after childhood epilepsia surgery in Europe Epilepsia 201051181-9

30 Prognostic index for recurrence of seizures after remission of epilepsy Medical research council antiepileptic drug withdrawal study group BMJ 19933061374-8

31 Gherpelli JL Kok F dal Forno S et al Discontinuing medication in epileptic children a study of risk factors related to recurrence Epilepsia 199233681-6

32 Dooley J Gordon K Camfield P Camfield C Smith E Discontinuation of anticonvulsant therapy in children free of seizures for 1 year a pros-pective study Neurology 199646969-74

Table 1 Prognostic factors for recurrence after epileptic surgery


Considering withdrawal of AED is recommended for patients having had epilepsy surgery after 1‑2 years seizure free with good prognostic factors

Level of evidence IILevel of recommendation B

In patients with bad prognostic factors seizure free for 1‑2 years withdrawal of AED is not recommended after epilepsy surgery

Level of evidence IILevel of recommendation C

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33 Pavlović M Jović N Pekmezović T Antiepileptic drugs withdrawal in patients with idiopathic generalized epilepsy Seizure 201120520-5

34 Martiacutenez-Juaacuterez IE Alonso ME Medina MT et al Juvenile myoclonic epilepsy subsyndromes family studies and long-term follow-up Brain 2006 1291269-80

35 Tennison M Greenwood R Lewis D Thorn M Discontinuing antiepilep-tic drugs in children with epilepsy A comparison of a six-week and a nine-month taper period N Engl J Med 19943301407-10

36 Serra JG Montenegro MA Guerreiro MM Antiepileptic drug withdrawal in childhood does the duration of tapering off matter for seizure recu-rrence J Child Neurol 200520624-6

37 Bonnett LJ Shukralla A Tudur-Smith C Williamson PR Marson AG Seizure recurrence after antiepileptic drug withdrawal and the implications for driving further results from the MRC antiepileptic drug withdrawal study and a systematic review J Neurol Neurosurg Psychiatry 201182 1328-33

38 Overweg J Withdrawal of antiepileptic drugs (AEDs) in seizure-free pa-tients risk factors for relapse with special attention for the EEG Seizure 1995419-36

39 Tinuper P Avoni P Riva R et al The prognostic value of the electroen-cephalogram in antiepileptic drug withdrawal in partial epilepsies Neuro-logy 19964776-8

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_Hlk1465528

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_GoBack

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_Hlk514635593

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56

Clinical guidelines from the Priority Epilepsy Program of the public health sector in MexicoJC Reseacutendiz-AparicioHospital Psiquiaacutetrico Infantil Dr Juan N Navarro y PPE Instituto Nacional de Neurologiacutea y Neurocirugiacutea Dr Manuel Velasco Suaacuterez Mexico City Mexico


EditoRiAl








DOI 1024875RMNM19000041

The Programa Prioritario de Epilepsia (PPE - Priority Epilepsy Program) was created based on the accord published in the Mexican Official Gazette of the Fede-ration on October 24th 1984 This program has labored in an uninterrupted manner to regulate coordinate methodize and optimize the strategies in favor of pa-tients with epilepsy as well as their families and socie-ty There are currently 78 centers of integral treatment for epilepsy in Mexico located in various hospitals be-longing to Mexicorsquos health sector

The headquarters for the national coordination is in the Instituto Nacional de Neurologiacutea y Neurocirugiacutea (National Institute of Neurology and Neurosurgery) ldquoDr Manuel Velasco Suarezrdquo (INNN due to its acronym in Spanish) in Mexico City from where all actions are

planned for this task The national coordination is led by its creator and founder Francisco Rubio Donnadieu MD and by the author

The development of the first Clinical Guidelines (CGs) has been a laborious effort one that has been finished due to the work of all the coordinators of the PPE who are neurologists and pediatric neurologists certified by the Mexican Board of Neurology and who work in one of the many institutions of the health sec-tor in Mexico To elaborate the CG all the coordinators of the PPE met in person in two meetings the first in the city of Leon and the second in the city of Puebla where we formed workgroups for each CG These meetings were possible due to the support of the fe-deral government and the contributions of the

1665-5044copy 2019 Academia Mexicana de Neurologiacutea AC Published by Permanyer Meacutexico This is an open access article under the CC BY-NC-ND license (httpcreativecommonsorglicensesby-nc-nd40)

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57


















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58




Channelopathies


Seizure







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59




diagnostic tests



Genetics


organizations






Epilepsy Society









Miscellaneous


Antiepileptic drugs


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60




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61



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62



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63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






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ion

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uce

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64





















Motor



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65



Automatisms



Sensory


Emotional










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66



Cognitive


Autonomic
















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67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

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68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



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69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




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may

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rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

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n o

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70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

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sio

n o

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e p

ub

lish

er

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71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

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Per

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72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

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75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

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76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

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77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

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e p

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lish

er

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Per

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85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

f th

e p

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Per

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2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

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Per

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2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

man

yer

2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

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sio

n o

f th

e p

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lish

er

copy

Per

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2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

117







A










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

118















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

121









I


II


II


III


III


IV



IV


IV


II



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

125





























IA



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

126


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

127












































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

128









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

_Hlk1465528

_Hlk1465829

_GoBack

_Hlk514719573

_Hlk514917121

_Hlk514635593

_Hlk514656185

57


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

58




Channelopathies


Seizure







No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

59




diagnostic tests



Genetics


organizations






Epilepsy Society









Miscellaneous


Antiepileptic drugs


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

60




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

61



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

62



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

64





















Motor



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

65



Automatisms



Sensory


Emotional










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

66



Cognitive


Autonomic
















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

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sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

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ut

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116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






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f th

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licat

ion

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be

rep

rod

uce

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r p

ho

toco

pyi

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117







A










No

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t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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118















No

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t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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tten

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lish

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119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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Per

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120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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or

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tten

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121









I


II


II


III


III


IV



IV


IV


II



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t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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or

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tten

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123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

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ut

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Per

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124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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e p

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Per

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125





























IA



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

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Per

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126


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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127












































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

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e p

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lish

er

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Per

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128









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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n o

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Per

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_Hlk1465528

_Hlk1465829

_GoBack

_Hlk514719573

_Hlk514917121

_Hlk514635593

_Hlk514656185

58




Channelopathies


Seizure







No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

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sio

n o

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e p

ub

lish

er

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Per

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2019

59




diagnostic tests



Genetics


organizations






Epilepsy Society









Miscellaneous


Antiepileptic drugs


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

man

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60




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

61



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

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62



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

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e p

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lish

er

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Per

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64





















Motor



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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65



Automatisms



Sensory


Emotional










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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lish

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66



Cognitive


Autonomic
















No

par

t o

f th

is p

ub

licat

ion

may

be

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rod

uce

d o

r p

ho

toco

pyi

ng

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ut

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or

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tten

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67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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Per

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68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



No

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t o

f th

is p

ub

licat

ion

may

be

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rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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or

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tten

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n o

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er

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Per

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69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

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73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

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sio

n o

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lish

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74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

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75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

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e p

ub

lish

er

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Per

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2019

76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

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2019

81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

ub

lish

er

copy

Per

man

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2019

83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

117







A










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

118















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

121









I


II


II


III


III


IV



IV


IV


II



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

125





























IA



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

126


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

127












































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

128









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

_Hlk1465528

_Hlk1465829

_GoBack

_Hlk514719573

_Hlk514917121

_Hlk514635593

_Hlk514656185

59




diagnostic tests



Genetics


organizations






Epilepsy Society









Miscellaneous


Antiepileptic drugs


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

60




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

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61



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

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62



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

64





















Motor



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

65



Automatisms



Sensory


Emotional










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

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Per

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2019

66



Cognitive


Autonomic
















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

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n o

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Per

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67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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lish

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Per

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68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

er

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Per

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69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

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n o

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70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

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n o

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e p

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lish

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Per

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71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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lish

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72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

ub

lish

er

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Per

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73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

er

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Per

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2019

74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

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e p

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lish

er

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75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

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e p

ub

lish

er

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Per

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yer

2019

76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

er

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Per

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77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

er

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Per

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2019

78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

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Per

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79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

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sio

n o

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Per

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85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

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86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

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lish

er

copy

Per

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2019

87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

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e p

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lish

er

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Per

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88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

mis

sio

n o

f th

e p

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2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

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94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

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2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

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2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

117







A










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

118















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

121









I


II


II


III


III


IV



IV


IV


II



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

125





























IA



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

126


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

127












































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

128









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

_Hlk1465528

_Hlk1465829

_GoBack

_Hlk514719573

_Hlk514917121

_Hlk514635593

_Hlk514656185

60




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

61



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

62



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

64





















Motor



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

65



Automatisms



Sensory


Emotional










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

66



Cognitive


Autonomic
















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

mis

sio

n o

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e p

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Per

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78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

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sio

n o

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e p

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Per

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79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

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e p

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Per

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80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

man

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2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

wri

tten

per

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n o

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e p

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Per

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83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

f th

e p

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lish

er

copy

Per

man

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2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

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pri

or

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tten

per

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n o

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85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

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e p

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er

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Per

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86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

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tten

per

mis

sio

n o

f th

e p

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lish

er

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Per

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87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

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lish

er

copy

Per

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88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

117







A










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

118















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

121









I


II


II


III


III


IV



IV


IV


II



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

125





























IA



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

126


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

127












































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

128









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

_Hlk1465528

_Hlk1465829

_GoBack

_Hlk514719573

_Hlk514917121

_Hlk514635593

_Hlk514656185

61



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

62



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

63




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000024

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

64





















Motor



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

65



Automatisms



Sensory


Emotional










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

66



Cognitive


Autonomic
















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

67








R‑PPE


R‑PPE


Com

orbi

ditie

sStructural

Genetic

Infectious

Metabolic

Immune

Unknown


Type of seizure


Type of Epilepsy

Epileptic Syndrome

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

68

















Video EEG




Presentation

Diagnosis

Manifestation

Seizure type



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

69




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000025


introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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70








DNICE 20124

R‑ Solari F 20115


DNICE 20124

R‑ SAdE 20156


3NICE 20124

R‑ SAdE 20156


DNICE 20124

R‑ SAdE 20156





3NICE 20124

R‑SAdE 20156



DNICE 20124

R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

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Per

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71



DNICE 20124

R‑ SAdE 20156


R‑ SAdE 20156


DNICE 20124

R‑SAdE 20156


DNICE 20124

R‑ SAdE 20156


R‑SAdE 20156



Diagnosis of UES


Yes No


suggested

Confirmed ES





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

72






IVSAdE 20156


R‑SAdE 20156



2+SIGN 20157

3NICE 20124

R‑ SAdE 20156



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

73




with epilepsy













BSAdE 20156


R‑SAdE 20156

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

74




BSAdE 20156

CNICE 20124





R‑SAdE 20156





CNICE 20124

R‑Bergey G 201611



CNICE 20124

R‑Bergey G 201611



CNICE 20124


R‑Bergey G 201611




DNICE 20124

R‑SAdE 20156



par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

75



ES in ER

Unprovoked ES

Acute Symptomatic

ES


with epilepsy

Status Epilepticus










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

76




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000026

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

77









1 A





No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

78




Neuroimaging


























logy specialists

Evidence Level








Class I (16)


Class II (4)


Class III (4)


Class I (16)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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2019

79





Class I (14)


Class I (14)


Class I (16)


Class I (6)



Level B


Level B


Level B


Level B










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

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yer

2019

80







1 A


1 A


1 B


1 B


1 B


1 A


1 B








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

81




R‑PPE

Evidence Level


Class III



































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

82




REViEW ARtiClE

Abstract












DOI 1024875RMNM19000027

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

83


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

BRV

50 m

g1

dose

25‑1

00 m

g2

dose

sSV

2N

oYe

s10

00

25‑3

05

le 22

9 3

6 L

h

CBZ

100‑

400

mg

2‑3

dose

s60

0‑12

002‑

3 do

ses

SCYe

sN

o75

‑85

2‑24

08‑

270

‑80

16‑2

40

133

CLB

5 m

g2

dose

s 5

mg

2 do

ses

GN

oN

o90

‑100

20

9‑0

487

‑90

20‑

CLZ

‑1‑

20 m

g1‑

3 do

ses

GN

oN

o80

‑90

1‑4

380

‑90

20‑6

00

09

DZP

Oral

and

in

trave

nous

0

15‑0

2 m

gkg

max

imum

10 m

gdo

se

‑G

No

Yes

75‑1

001‑

41

195

32‑4

7‑

ESM

250

mg

2 do

ses

1500

2‑3

dose

sCC

No

No

90‑9

53‑

70

650

30‑6

00

01‑0

015

GBP

300

mg

3 do

ses

600

mg

3 do

ses

GN

oN

o60

2‑4

09

04‑

60

12‑0

13

LCS

100

mg

2 do

ses

200

mg

2 do

ses

SCN

oYe

s

LEV

125‑

500

mg

2 do

ses

1000

‑300

0 m

g2

dose

sSV

2Ye

sYe

s95

‑100

06‑

13

05‑

07

lt 10

6‑8

06

mL

min

kg

LTG

125

0 m

g1‑

2 do

ses

100‑

600

mg

1‑2

dose

sSC

No

No

95‑1

002‑

50

9‑1

2255

24‑3

50

044‑

084

OXC

300‑

600

mg

2 do

ses

600‑

2400

mg

2 do

ses

SCYe

sN

o95

‑100

45

07‑

08

404‑

9‑

PB25

‑50

mg

1‑2

dose

s10

0‑20

0 m

g1‑

2 do

ses

GN

oye

s95

‑100

80

42‑0

75

45‑6

050

‑140

000

6‑0

009

PGB

150

mg

2 or

3 d

oses

200‑

600

mg

2 or

3 d

oses

GN

oN

o90

‑100

lt10

560

63

008

3

PHT

200‑

300

mg

2 or

3 d

oses

300‑

500

mg

2 or

3 d

oses

SCN

oYe

s85

‑90

10‑1

50

5‑0

870

‑95

7‑48

000

3‑0

02

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1

(continue)

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

84


AED

Initi

al d

ose

Fina

l dos

eM

echa

nism

of

actio

n Ex

tend

ed r

elea

se

form

ulat

ion

Pare

nter

al

form

ulat

ion

Bio

avai

labi

lity

()

T M

ax (h

)D

istr

ibut

ion

volu

me

(Lk

g)PP

bin

ding

37degC

()

Hal

f-lif

e(h

)Cl

eara

nce

(Lk

gh)

PRM

100‑

125

mg

1‑2

dose

s75

0‑20

00 m

g1‑

2 do

ses

GN

oN

o90

‑100

3‑4

06‑

120

‑30

5‑18

000

6‑0

009

TPM

25‑5

0 m

g2

dose

s12

5‑20

0 m

g2

dose

sM

Yes

No

80‑1

003

70

55‑0

89‑

1715

‑23

002

2‑0

036

VGB

500

mg

2 do

ses

1500

mg

2 do

ses

GN

oN

o60

‑80

2‑3

08

‑4‑

70

102‑

011

4

VPA

200‑

500

mg

2‑3

dose

s10

00‑3

000

mg

2‑3

dose

sM

Yes

Yes

lt100

1‑8

01‑

04

88‑9

215

‑17

001

‑01

15

AED

ant

iepi

lept

ic d

rug

BRV

briv

arac

etam

CBZ

car

bam

azep

ine

CLB

clo

baza

m C

LZ c

lona

zepa

m D

ZP d

iaze

pam

ESM

eth

osux

imid

e G

BP g

abap

entin

LCS

lac

osam

ide

LEV

lev

etira

ceta

m L

TG l

amot

rigin

e O

XC o

xcar

baze

pine

PB

phe

noba

rbita

l PG

B pr

egab

alin

PHT

phe

nyto

in P

RM p

rimod

one

TPM

top

iram

ate

VGB

vig

abat

rin V

PA v

alpr

oate

M

echa

nism

of a

ctio

n S

V2 p

rote

in b

indi

ng S

V2 S

C s

odiu

m c

hann

el b

lock

er G

GAB

A an

alog

ue C

C T

‑type

cal

cium

cha

nnel

blo

cker

M m

ultip

le m

echa

nism

Tabl

e 1

Dos

e m

echa

nism

of a

ctio

n fo

rmul

atio

n a

nd p

harm

acok

inet

ics

for a

dults

of A

EDs

avai

labl

e in

Mex

ico1 (Continued)









No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

85




1st AED MONOTHERAPY

CONTROL CONTROL

CONTROL

820 (457)

No Control

2nd AED

208 (116)

116 (64)

ge2 AEDs

No Control

No Control

POLYTHERAPY

651 (363)




CONTROL

1144 (637)

No Control

651 (363)





I and III A



IV R‑PPE


IV R‑PPE




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

86










Interactions








II and III C


I and IV C


IV U





II and III A


II and III A


II and III B


IV R‑PPE


R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

87









I‑III A


I‑III A


IV U


IV R‑PPE


IV R‑PPE





IV R‑PPE





IV R‑PPE


IV R‑PPE


IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

88




Acknowledgments







































No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

89




REViEW ARtiClE

Abstract







Mexico City Mexico







DOI 1024875RMNM19000028

introduction




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

90









BFNE


Absorption


Distribution




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

91








052

02

2‑105‑151‑5

22

1‑2










Tablets 500 mg





SameSame















childhood spasms)


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

92


EME


Ohtahara syndrome













III and IV U


II and III C


III and IV U





IV R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

93


























LTG II B

VPA IV R‑PPE

Ketogenic diet IV U


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

94











IV R‑PPE






II B


II B


II B




Study Conclusions








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

95






Acknowledgments



Study Conclusions




Nolan 2013Arya 2013














A



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

96























































o p

art

of

this

pu

blic

atio

n m

ay b

e re

pro

du

ced

or

ph

oto

cop

yin

g w

ith

ou

t th

e p

rio

r w

ritt

en p

erm

issi

on

of

the

pu

blis

her

copy P

erm

anye

r 20

19

97




REViEW ARtiClE

Abstract











DOI 1024875RMNM19000029








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

98

















III B


II B


III C


I A



I A


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

99






















1 Assess A B C










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

100





Simple FeS SFeS


Complex FeS CFeS










Laboratory tests


Neuroimaging


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

101











I A


I A


I A


I II B




II B


I A





III C


II‑III C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

102



Conclusion



































Focal seizures




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

103























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

104




REViEW ARtiClE

Abstract















DOI 1024875RMNM19000030

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

105












No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

106


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

107











R‑PPE






II


I


R‑PPE



R‑PPE


R‑PPE


R‑PPE

Evidence Level








No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

108
















R‑PPE



III


III



R‑PPE


R‑PPE




I


I


III



R‑PPE


No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

109



Evidence Level




III




R‑PPE


























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

110




REViEW ARtiClE

Abstract










DOI 1024875RMNM19000031






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

111









































Senile gt 60 years

No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

112

























004 mgkg IV






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

113



Diagnostic criteria




























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

114












Management









LRZ 65 14 28 12

PB 58 13 34 3

DZP + PHT 56 19 33 2

PHT 44 11 29 9

Mean 55










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

115

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

116




REViEW ARtiClE

Abstract






Mexico City Mexico







DOI 1024875RMNM19000032

introduction






No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

117







A










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

118















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

119





















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

120


















No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

121









I


II


II


III


III


IV



IV


IV


II



No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

122

























No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

123




REViEW ARtiClE

Abstract








DOI 1024875RMNM19000033










No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

124



















B


A


B


C


C


C




No

par

t o

f th

is p

ub

licat

ion

may

be

rep

rod

uce

d o

r p

ho

toco

pyi

ng

wit

ho

ut

the

pri

or

wri

tten

per

mis

sio

n o

f th

e p

ub

lish

er

copy

Per

man

yer

2019

125





























IA



No

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Revista Mexicana de NeurocienciaRevista Mexicana de Neurociencia Publicación oficial de la Academia...

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Transcript of Revista Mexicana de NeurocienciaRevista Mexicana de Neurociencia Publicación oficial de la Academia...