Revista Mexicana de Neurocienciaprevious.revmexneurociencia.com/wp-content/uploads/... · / ISSN...

www.revmexneuroci.com / ISSN 1665-5044

Órgano Oficial de Difusión de la AMN

AcademiaMexicana deNeurología, A.C.

Rev Mex Neuroci ahora en CONACyT

Vol. 19, issue. 3 (may-june 2018)

Rev

ista

Mex

ican

a d

e N

euro

cien

cia;

19

,3 (2

01

8):

1-1

00

Revista Mexicana de

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

Editorial committee 2018Chief editor: Dr. en C. Ildefonso Rodríguez Leyva [email protected]: M.C. Carolina León Jimenez Dr. en C. Antonio Arauz Góngora [email protected] editor: Dra. Lilia Núñez OrozcoEmeritus editor: Dr. en C. Carlos Cantú Brito

International editorial comitee

National editorial comitee

Dr. Anthony Amato Dr. José BillerDr. Andre KannerDra. Farrah MateenDr. José Merino

Dr. Sergio de Jesús Aguilar Castillo Dr. Marco Antonio Alegría LoyolaDra. Alma Yolanda Alvarado GutierrezDr. Carlos Gabriel Ascanio RodríguezDra. Catherine Boll WoehrlenDr. Antonio Bravo OroDr. Jorge Burgos CentenoDra. Graciela Cárdenas HernándezDr. Paul Carrillo MoraDra. Teresa Corona VázquezDra. Beatriz ChavezDr. Bruno Estañol VidalDra. Agnes FleuryDr. José Flores RiveraDra. Silvia GarcíaDr. Fernando Góngora RiveraDra. Margarita González CruzDra. Alejandra González-DuarteDr. Oscar González-Vargas

Dr. Rubén Haro Silva Dr. Juan Calixto Hernández AguilarDr. Héctor Gerardo Hernández RodríguezDr. Jesús Higuera CallejaDr. Javier Jaramillo de la TorreDr. Humberto Juárez JiménezDr. Rubén Martínez HernándezDra. Iris E. Martínez JuárezDra. Adriana Martínez MayorgaDr. Francisco Mena-BarrancoDra. Roxana Millán CepedaDra. Rebeca Millán GuerreroDr. Alberto Mimenza AlvaradoDra. Leticia Munive BaezDr. Luis Manuel Murillo BonillaDr. Alfredo Ponce de LeónDr. Guillermo Punzo BravoDra. Sandra Quiñones AguilarDra. María Teresa Reyes

Héctor Gerardo Hernández RodríguezMaestro Alejandro GarcíaRebeca BarrosoDesign Cortex

Statistical AdvisorStyle corrector

TranslatorDesign

Dra. Mayela Rodríguez ViolanteDr. Leopoldo Rivera CastañoDr. Ulises Rodríguez OrtizDr. Francisco Rogel OrtizDr. Luis Ángel Ruano Calderón Dra. Angélica Ruiz-FrancoDr. José Luis Ruiz-SandovalDr. José Manuel Sandoval RiveraDr. Daniel San JuanDr. Horacio Sentíes MadridDra. Mónica Sierra del RioDra. Ana Luisa Sosa Ortiz Dr. José Luis Soto-HernándezDr. Gersain Trujillo AlonsoDr. Steven Vargas CañasDr. Rubén Darío Vargas GarcíaDra. Karina Vélez JiménezDr. Marco Zenteno Castellanos

Dr. José Obeso Dr. Julio PascualDr. Marc Patterson Dr. Eduardo TolosaDr. Samuel Wiebe

Contenidos ContentsEDITORIAL• Carta Editorial por Dra. Rivera Nava

IN MEMORIAM• Dr. Ladislao Olivares Larraguível

CONTRIBUCIONES ORIGINALES• Seguridad y efectividad de la Estimulación

Cerebral No Invasiva en el Trastorno del Espectro del Autismo: Resultados de un estudio de prueba de concepto

• Análisis tiempo-frecuencia del Potencial de disparidad (MMN) en niños preescolares mexicanos saludables

• Neumoencefalo como complicacion de bloqueo peridural: informe de un caso y tratamiento empleado

• Desarrollando habilidades emocionales, neurocognitivas y sociales en niños con autismo. Evaluación e intervención en juego de roles sociales

• Comparación de toxina botulínica tipo a y electroestimulación orofaríngea en sialorrea en niños con parálisis cerebral en el Centro de rehabilitación e inclusion infantil Teletón Estado de México

REVISIONES • Contexto histórico de los agonistas

dopaminérgicos

REPORTES DE CASO• Esclerosis Lateral Amiotrófica y Embarazo,

una asociación poco común • Vasculitis Primaria del Sistema Nervioso

Central Tratada Exitosamente con Rituximab: Reporte de Caso

EDITORIAL• Editorial letter by Dr. Rivera Nava

IN MEMORIAM• Dr. Ladislao Olivares Larraguível

ORIGINAL CONTRIBUTIONS• Safety and effectiveness of Non-Invasive Brain

Stimulation in Autism Spectrum Disorder: Results from a proof of concept study

• Time-frequency analysis of Mismatch Negativity (MMN) in healthy Mexican preschool children

• Pneumoencephalon as Complication of epidural Block: Case report

• Developing Emotional, Neurocognitive, and Social Skills in Children with Autism: Evaluation and Intervention through Social Role-Playing

• Comparison of botulinic toxin type a and oropharyngeal electrostimulation in sialorrhea in children with cerebral palsy

REVIEWS• Historical context of dopaminergic agonists

CASE REPORTS• Amyotrophic Lateral Sclerosis during

pregnancy an uncommon association • Primary Central Nervous System Vasculitis

Succesfully Treated With Rituximab: Case Report

Revista Mexicana de Neurociencia may-June 19,3 (2018): 1-3

Editorial2

REVISTA MEXICANA DE NEUROCIENCIA MAY 2018

Dear colleagues,

We live in a time of instant satisfaction. If we want to read a book or listen to music, we can download it in a matter of minutes. Unfortunately, we expect that same kind of speed when it comes to our personal growth. We want it to be easy or fast. That will never happen. So dear friends in the study of Neuroscience this growth takes time requires tenacity, courage and human warmth; but “it is worth the wait.”

However, remember, it is not possible to become a great leader overnight, but you can be a leader day by day. Nowadays, when our Mexican Academy of Neurology has grown both in number and intellectual development, as I would never have imagined, I realize that there are leaders who have advanced the perspectives of young neurologists in the country. However, we must adapt to the new times and challenges that the development of Neurosciences demands.

Therefore, “teamwork” is required, that strive to develop work friendships. Abraham Lincoln said: “If you would win a man to your cause, first convince him that you are a sincere friend.” Good relationships make influence possible, and friendship is the most positive relationship you can develop in employment, with your colleagues. Theodore Roosevelt said: the most important ingredient in the formula of success is knowing how to get along with people. Sometimes you have achievements, but you can “feel a vacuum.”

Friendship is the shelter of sudden storms, and real friends are a haven. So it is necessary to increase our teamwork, become leaders day by day, through the challenges that are pending in the progress of our discipline.

Let’s not be teammates, be friends with those with whom you work. Let’s incorporate the young neurologists into the study groups, let’s make them part of our friends. Let’s achieve values such as loyalty, gratitude, and integrity every day. We also need to visualize our progress, face the challenges but, as a team of friends, it is more comfortable.

Editorial

Revista Mexicana de Neurociencia may-June 19,3 (2018): 1-3

Editorial 3

Thomas Jefferson said that a candle loses nothing if it lights another candle.

Substantial changes are required in the practice of our professions, such as Insurance, or legal support a result of many unjustified demands to our work, and after this increase, we require to participate as a team to ensure that all of us are protected with life insurance, of unemployment and disability. Let’s make sure we deliver the relief for such priorities; that is to say that in teams we will obtain more significant results, a single person does not achieve the same as a team of friends working for a cause.

Remember that everything we know, we learned it from another person. Talent is never enough. Soften your attitude today, learn humility and be willing to learn, and if you do as a team, we will be doing the right thing.

I believe that we should be more active concerning our Mexican Journal of Neurology that, with so much effort, was formed and it is also a continuous effort that reflects our work in our Neurological Care Centers. We must work as a team of friends and share experiences through our Journal.

Dra. Cristina Rivera Nava Active member of the Mexican Academy Of Neurology

Revista Mexicana de Neurociencia may-june 19,3 (2018): 4-7

IN MEMORIAM4

DR. LADISLAO OLIVARES LARRAGUÍVELIN MEMORIAM

Dr. Ladislao Olivares Larraguível left unexpectedly on April 26, 2018, just over a month after his 87th birthday. The news were of great impact to all who knew him and especially to his family (he was the oldest of 5 siblings), his four children and six grandchildren. It is difficult to find where to start talking about a character who was a legend in the National Institute of Neurology and the National Medical Center “CMN 20 de Noviembre”, where after many years of not being active in either of the two places, people is still talking about him. Dr. Olivares made his specialty in the United States and in England, at a time when there was no Neurology residency in our country. Like other masters of that time who were trained abroad, he returned to Mexico as a new specialist, already married since 1956 during his stay in England, with Mrs. Jean Walker, with whom he formed a beautiful family of 4 children. Upon his return, he was placed in the Hospital 20 de Noviembre, founded in 1961 and in the National Institute of Neurology (INN), founded in 1964.

I met Dr. Olivares on my first day of undergraduate rotation at the National Institute of Neurology in 1973. At that time, Dr. Olivares was a case reviewer in the Pediatric Neurology department, which the INN had, since the specialty in our country had not been divided and neurologists were trained for all age groups. His penetrating gaze and inquisitive attitude were intimidating, but our first meeting followed up with an excellent relationship. There I noticed his acute intelligence and great clinical capacity that I never stopped learning from. By the 70s he wrote with Milton Alter in Archives of Neurology, his widely cited Multiple Sclerosis epidemiology papers, reporting a prevalence of 1.6 per 100,000 from patients seen at the Hospital Center November 20. Shortly after that, in 1975, he made a report on the clinical manifestations of neurocysticercosis with Tomás Alarcón (a distinguished neurologist from Guayaquil trained at the INN), published in the Journal of Clinical Research, both reasons for his great satisfaction as essential contributions to knowledge. When I arrived at the Hospital 20 de Noviembre in 1975 as a rotating resident, I met the Neurology service, where Dr. Olivares demanded all his members the most considerable effort and clearly stated what he thought when the expectation was not met, a situation that not everyone easily tolerates.

The Neurology service was an innovative world, where patient records were indispensable and without computers, high-value databases were made. At that time, Neurology treated patients of all ages in the outpatient clinic and as an interconsultant in hospitalization, since it did not have a section under its responsibility. Interaction with other hospital services was constant, especially with Pediatrics and Internal Medicine. The neurological patients were detected and registered in a service census so that the neurologists participated in their care and the residents could learn from them in their postgraduate course, existing since 1961. At the end of my residency in 1980, I received from Dr. Olivares the invitation to work in the Neurology service, where I continue till today.


IN MEMORIAM 5

During the following nine years I continued to learn from him, seeing how he approached and solved the medical problems, the organizational problems and also implemented rules for the benefit of patients, who received better care in all aspects. He had introduced an information program to the community, which we had to do to the neurologists on Saturdays so that our patients of various neurological diseases could learn to face them, and we as doctors learned to explain to patients their illnesses, talking to them in an accessible language. This situation led to the founding of a formal self-help group (Group Acceptance of Epilepsy) for people with epilepsy in 1991, which exists till today. Meanwhile, Dr. Olivares continued in charge of the training of new neurologists by teaching them a methodology to identify and solve problems, which is applicable not only to medicine but all aspects of life. He worked tirelessly to improve the world that he did not understand because he was years ahead of what was happening, and for that reason, he was considered a particular person, different and challenging, I would say a misunderstood genius. Thee entered the National Academy of Medicine with analytical and philosophical work on aphasia, wrote the books Diagram Decisions in Medicine, Analysis of Decisions in Medicine and Practical Neurology, this one addressed to the medical students that we had periodically in the Service and who understood even less the good intentions of Dr. Olivares. In the 80s, there was no training of neuropediatricians in our hospital, and with his visionary approach, in addition to continuing with the Adult Neurology residency, he began his residency in Pediatric Neurology, a very natural situation, given that the Neurology service attended to the patients of all ages.

From 1985, a section in hospitalization for the direct attention of patients was granted to various specialties, including Neurology, which greatly facilitated the organization and teaching. Due to the small number of residents, the guards were very heavy and were personally supervised by Dr. Olivares, who could appear in the hospital in the early hours at random. Always; very early every morning before the academic sessions, came to supervise that the vascular patients, who at that time were the first cause of neurological hospitalization, were sitting in the armchair with their lower limbs bandage and mattress and water donut, always with a next of kin, who was part of the care team for the sick, thus favoring a better evolution.

Towards the end of the 1980s, he was named Deputy Director of Regulations of the ISSSTE, where he ventured to propose plans and programs, which unfortunately did not have the echo they deserved, ending that assignment at the end of 1990, with his retirement from the institution. His last generation of residents as full professor ended in 1991 when having no clinical field, he had to leave this activity, which made him leave the hospital for years, but the service he formed remains as his most valuable legacy with all innovations that he made. Out of the “20 de Noviembre” Hospital and years before the National Institute of Neurology, he continued his clinical work in his private practice in the Hospital Médica Sur, where he was active from 1985 until the


IN MEMORIAM6

end of 2017. Another significant aspect, closely related to his innovative vision, was the foundation of the Mexican Academy of Neurology. The few neurologists who had recognized themselves as such upon the founding of the Mexican Council of Neurology in 1971, had only the recognition mentioned above of their specialty, but in developed countries, there were already academic associations such as the American Academy of Neurology, founded in 1948.

Thus, Dr. Olivares organized a meeting in Querétaro, which he called on the existing neurologists in 1976 to organize an association, which resulted in the founding of the Mexican Academy of Neurology that year. According to Dr. Olivares; much controversies were created on the matter, but in the end, Dr. Recaredo Rodríguez López was accepted and elected, with periods initially of one year and later of two, being Dr. Olivares the second president of this Academy, one which was born from his visionary ideas. His participation in the academic activities was legendary, as thee always questioned and frequently made devastating comments about what the speakers and coordinators said, and for that reason, he was very feared, as well as a synod of the certification exams of the Mexican Council of Neurology. Over the years he also retired from these activities, frequently attending the Annual Meetings of the Mexican Academy of Neurology, where he was invited as an ex-president and where he was the subject of several recognitions, such as being named member emeritus of the AMN and received a tribute with other teachers of Neurology, carried out in 2014.

The last years of his life, widowed since 2010, he faced some health problems, but especially being absent from the academic and teaching activities he enjoyed so much. His last loss was to close his private practice and retire from his favorite clinical activity entirely since last year, but always trying to keep his mind active, he then started learning something new, like playing the piano. I can not omit some of his famous phrases, which we do not stop remembering in the Service when they come to the case, which happens very frequently: “I have a pact with the devil”, he said this when he detected any failure in the processes, for which he had a huge talent. “Forgive me for speaking while you interrupt me,” he did not tolerate that his interlocutors stopped following the conversation and introduced distractors. “We do not have answers for questions we have not asked ourselves”:

He advocated analyze the situations and not collect information without order or meaning, which in the end also constituted a distraction in the clinical approach.


IN MEMORIAM 7

Dr. Olivares left in his way many students who admired and loved him very much, as well as some who once held some resentment, but all of us who had the fortune of knowing him and learning from him, we recognize him and thank him for his many valuable contributions and teachings.

Rest in peace.

Dra. Lilia Núñez OrozcoHead of the Neurology Service of CMN November 20, ISSSTE. President of the Mexican Society of Neurology and Psychiatry. One of the students of Dr. Ladislao Olivares Larraguível.

Revista Mexicana de Neurociencia mayo-june, 2018; 19(3):8-19

Original contributionNon-Invasive Brain Stimulation in Autism

8

Safety and effectiveness of non-invasive brain stimulation in autism spectrum disorder: results of a proof-of-concept study

Seguridad y efectividad de la estimulación cerebral no invasiva en el trastorno del espectro del autismo: resultados de un estudio de prueba de concepto

Original contribution

Lázaro Gómez-Fernández,1 Belkis Vidal-Martínez,2 Carlos Maragoto-Rizo,1 Lilia Morales-Chacón,1 Sheyla Berrillo-Batista,1 Héctor Vera-Cuesta,1 Maribel Selguera-Wilson,2 Marlén Denis-Vidal,1 Tairí Marín-Alvarez,1 Abel Sánchez-Coroneaux,1 Yaumara Cabrera-González,1 Margarita Báez-Martín,1 Celia Alarcón-Calaña,1 María Robinson-Agramonte,1 Yaima Llanez-García.1

1International Center for Neurological Restoration.2Borrás-Marfán Pediatric Teaching Hospital .

Abstract

Introduction. Autism Spectrum Disorder(ASD) still being a therapeutic challenge for neurosciences. Different pharmachological and non-pharmachological treatments have been developed inducing benefits in ASD patients in some degree, with cumulative effect; but more research is needed to improve clinical results. There are evidences about the potential positive effects of Non-Invasive Brain Stimulation(NIBS) in ASD patients.

Objective. To evaluate the safety and effectiveness of NIBS in patients with ASD.

Methods. We carried out a proof of concept study including 15 children with ASD according to DSM-5 diagnostic criteria. They proceeded from the ambulatory services of the International Center for Neurological Restoration and Borrás-Marfán Hospital(Havana, Cuba). Inclusion criteria established that children should had no change in their therapeutic approach one month before the intervention; and an equivalent period of stabilization of their symptoms. Repetitive Transcranial Magnetic Stimulation(rTMS) and Transcranial Direct Current Stimulation(tDCS) were used as stimulation methods; tDCS(cathode F3, anode right arm) was used in children under 10 years and 11 month; and 1 Hz rTMS for children over 11 years. Stimulation was focalized over the left dorsolateral prefrontal cortex, and a total of 20 session were applied. Patients were evaluated before and one week after the intervention applying the Autism Treatment Evaluation Checklist(ATEC), the Autism Diagnostic Interview(ADI-R) and the Autism Behavior Checklist(ABC).

Results. Only in one patient it was not possible to start the treatment because of poor collaboration. The other 14 completed



9

Corresponding author: Dr. Lázaro Gómez FernándezLaboratorio de EMG & TMS.Servicio de Neurofisiología Clínica y Unidad de Estimulación Cerebral No Invasiva. Centro Internacional de Restauración Neurológica.Calle 212, %19 y 19ª. Atabey. Playa. Habana. CubaPhone: 72736923 E-mail: [email protected]

the 20 sessions with a few adverse effects, basically local pain at the stimulation site. A significant change in clinical scales was observed, with lower scores in the second evaluation, (ADI-R: initial= 52±9, final=44.4±7; ATEC: 58±19.4 and 41±14.7; ABC: 108.4±23.7 and 89±17; p<0.05); indicating a clinical improvement in the group of patients.

Conclusions. NIBS was well tolerated and induced behavioral changes in our sample of patients in key aspects of autistic behavior.

KeywordsNIBS, rTMS, tDCS, Autism Spectrum Disorder.



10

Palabras claveECNI, rTMS, tDCS, Trastorno del Espectro del Autismo.

Resumen

Introducción. El Trastorno del Espectro del Autismo(TEA) es un desafío terapéutico para las neurociencias. Se han desarrollado diversas intervenciones farmacológicas y no farmacológicas con resultados beneficiosos; pero se requieren de más investigaciones para lograr mejores resultados clínicos. Existen evidencias sobre los beneficios potenciales de la Estimulación Cerebral No Invasiva(ECNI) en estos pacientes.

Objetivo. Evaluar la seguridad y la efectividad del uso de la ECNI en niños con TEA.

Métodos. Se realizó un estudio de prueba de concepto que incluyó 15 pacientes con diagnóstico de TEA según criterios del DSM-5, procedentes del Centro Internacional de Restauración Neurológica y del Hospital Pediátrico Borrás-Marfán(Habana, Cuba). Como criterio de inclusión se definió la no modificación del esquema terapéutico de los pacientes, y la existencia de estabilidad clínica 1 mes previo a la intervención. Se utilizaron dos métodos de ECNI: la estimulación magnética transcraneal repetitiva(rTMS) y la estimulación transcraneal con corriente directa(tDCS). Los pacientes hasta 10 años y 11 meses recibieron tDCS(cátodo F3; ánodo brazo derecho); a partir de 11 años de edad la rTMS(1 Hz). La estimulación se focalizó sobre la corteza prefrontal dorsolateral del hemisferio izquierdo, con un total de 20 sesiones. Los pacientes fueron evaluados antes y una semana después de la intervención mediante la Escala de Evaluación de la Respuesta Terapéutica en el Autismo(ATEC), la Entrevista Diagnóstica para el Autismo(ADI-R) y la Lista de la Conducta Autista(ABC).

Resultados. En un paciente no fue posible iniciar el tratamiento por poca colaboración. Los restantes 14 completaron la intervención con pocos efectos adversos, básicamente molestias locales en el sitio estimulado. Se observó una disminución significativa en la puntuación de las escalas clínicas en la segunda evaluación (ADI-R: inicial= 52±9, final=44.4±7; ATEC:58±19.4 y 41±14.7; ABC:108.4±23.7 y 89±17; p<0.05); indicando una mejoría clínica grupal.

Conclusiones. La ECNI fue bien tolerada e indujo cambios conductuales en la muestra de pacientes en aspectos claves de la conducta autista.



11

IntroductionAutism Spectrum Disorder (ASD), according to the current criteria defined in the DSM-5, includes a spectrum of manifestations characterized by severe deficits and generalized alterations in multiple areas of development. In these patients, there are alterations in social interaction, communication disorders, and the presence of restricted and stereotyped behaviors, interests, and activities. The term ASD currently encompasses four different diagnoses that existed in the previous DSM-IV classification but, in essence, it is a clinical picture whose diagnosis, in most cases, involves a high degree of disability.1 The figures for ASD prevalence fluctuate between different countries. In the USA, the prevalence in children aged up to 8 years old is 1 in 68;2 in France, it’s 0.36 per 100 children;3 and in Mexico, there is 1 case for every 115 children.4 In general, reliable epidemiological data regarding this disorder can be scarce in developing countries.

Recent advances in neuroscience have allowed us to know more about the pathophysiology of ASD, especially in terms of brain connectivity patterns that are far from what has been described in normal subjects.5 As in other diseases, unfortunately, there are no great advances in therapeutic approaches; although it is noteworthy that the use of various methods of fundamentally non-pharmacological treatments can be favorable in terms of controlling autistic symptoms, facilitating a better integration of the patient with their family and social environment.6 From the pharmacological point of view, there is still no single, specific drug for the treatment of ASD. The use of risperidone, aripiprazole, carbamazepine, valproic acid, and methylphenidate, among others, stand out internationally according to the prevailing symptoms and comorbidity with other pathologies.7,8 All the therapies described in the literature benefit patients with ASD and, although traditional or alternative medicine can be added, it is agreed by consensus that more scientific research is needed to define better therapeutic strategies that would allow achieving superior clinical results.9

Bailey et al. were among the first to point to the cerebral cortex as key in the pathophysiology of

ASD.10 Casanova et al. subsequently drew attention in a series of investigations to the existence of anomalies in the minicolumnar organization of the cerebral cortex, including the existence of smaller neurons increased in number and density per unit area, periventricular heterotopias, and cortical dysplasia, in addition to a significant reduction of the neuropil, which results in an inhibitory intracortical dysfunction, an aspect that possibly contributes significantly to much of the autistic symptomatology.11,12

A large amount of research has been developed in recent years using non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). These methods, depending on the specific protocol used, may have an effect that enhances cortical inhibition or an increase of excitability in the circuits to which they’re applied.13,14 Both rTMS and tDCS are methods that are widely used currently for the symptomatic control of various diseases with differences in the levels of scientific evidence. Major depression, chronic pain, post-traumatic stress, and fibromyalgia account for the highest levels of scientific evidence right now.15,16

Several articles have been published that provide evidence for the favorable effect that these methods can have on the control of autistic behavior even with changes in the expression of some electrophysiological responses, although mostly with the application of a low number of sessions to expect a significant and lasting clinical effect. In other diseases, where the clinical effect of these interventions is better known (e.g. depression), the use of at least 20 sessions is recommended to ensure greater efficacy.17-19 On the other hand, there are no data to differentiate the efficacy of rTMS and tDCS as neuromodulators, an aspect that is of great importance as a guide for the selection of one over another method for therapeutic use.

In this article, we start from the hypothesis that



12

the use of NIBS can have an adjuvant effect in the treatment of children with ASD, and we set as the main objective to demonstrate the safety of the use of rTMS and tDCS in this particular disorder, as well as to obtain proof-of-concept type of evidence on the effect of both methods for the better control of the clinical symptomatology.

Methods

Fifteen children diagnosed with ASD (13 males and 2 females, aged between 5 and 13 years), were included in this study. They were classified as moderate or mild according to the DSM-5 criteria and coincidental diagnostic impressions from the specialist in pediatric neurology and child and adolescent psychiatry. The patients came from the ambulatory care services of the Pediatric Teaching Hospital Borrás-Marfán and from the International Neurological Restoration Center, treated during the period of November 2015 to October 2016.

The criteria of inclusion included an agreement in diagnostic impression by the specialist in pediatric neurology and child and adolescent psychiatry, the maintenance of the same therapeutic scheme (pharmacological and psychopedagogical) during the month prior to starting the intervention, and stability of the symptomatology during that time. The clinical diagnosis was confirmed by applying the Childhood Autism Rating Scale (CARS)20

and the Autism Diagnostic Interview (diagnostic algorithm), Revised (ADI-R).21

Any patients in whom comorbidity with epilepsy existed were excluded from the initial selection, as well as any who had modifications in their pharmacotherapy (in dose or type of medication) in the month prior to the recruitment for this investigation. In no case was the basic therapeutic scheme interrupted for any patient, only the appropriate stimulation protocol was added according to their age.

Experimental designPatients were recruited through continuous

inclusion, as they visited their corresponding care services. The characteristics of the study were explained to the parents and the children were assigned a treatment group according to their age: 5 to 10 year-olds to the tDCS group, and 11 year-olds and older to the rTMS group. This differentiation was established because children older than 11 years of age generally collaborate better with the different evaluative procedures and more demanding technical requirements involved in the application of the rTMS. The tDCS was applied with a Neuroconn (GE) device, and the cathode was placed in the F3 position (10/20 system) as a projection guide for the left dorsolateral prefrontal cortex and the anode on the upper third of the right arm. Each session lasted 20 minutes and the stimulation had 1 mA of intensity. In each session of the other group, each patient received a total of 1500 pulses of 1 Hz rTMS at 90% of the motor threshold value (MagStim, UK), placing the center of the figure 8 coil on the same position. The patients sat comfortably during the stimulation sessions. They were shown cartoons of their choice on a television screen and, in some cases, they were also allowed to manipulate didactic toys and tablets with entertainment games to facilitate their cooperation. Every patient received 20 treatment sessions in total.

The patients were evaluated twice before starting the intervention. The ADI-R (algorithm for current condition),21 the Autism Behavior Checklist (ABC),22 and the Autism Treatment Evaluation Checklist (ATEC)23 were applied. These evaluations were performed again one week after completing the 20 treatment sessions. The evaluators did not directly participate in the application of the stimulation sessions in any of the cases.

Additionally, an electroencephalogram (EEG) was performed in the awake state before starting the treatment and one week after the end of the treatment, in order to corroborate whether changes in brain connectivity patterns were identified. An assembly of 19 active Ag-Cl electrodes was used on the scalp (Fp1, Fp2, F7, F8, F3, F4, C3, C4, T5, T6, T3, T4, P3, P4, O1, O2, Fz, Cz, Pz), according to the international 10/20



13

Results

Tolerance and adverse effectsThe final distribution of the sample according to the treatment method included a total of 9 children younger than 11 years old who received tDCS and 6 children older than 11 years who received rTMS; only 2 of them were female. The majority of patients showed good tolerance with both procedures, and only in an 8-year-old child (tDCS) therapy was not achieved due to lack of collaboration after several attempts to place the electrodes for stimulation on non-consecutive days. In the remaining patients it was possible to begin the treatment on the day it was proposed to start and complete it without interruption. The most frequent adverse effect reported or detected from the behavior of the children was the existence of local discomfort at the stimulation site (≈50%), which in all cases was slight and did not require any intervention, pharmacological or otherwise (Table 1).

Somnolence occupied the second place, which, according to the description of the parents, was expressed as the child sleeping one or two hours earlier than usual at night, with a quieter and more regular sleep, although this was not an aspect that was evaluated in depth.

Effects of the interventionIn all the cases individually, the parents identified behavioral changes they spontaneously described qualitatively, which were also transmitted indirectly by teachers and other relatives, who were often unaware that the child was receiving an experimental intervention. Standing out among these changes were those related mainly to the improvement in socialization and communication;

system, with references at the level of Cz and Pz. The impedance was kept below 5 k Ohm. For this analysis, 38 windows were selected free of artifacts from the electroencephalographic records in the awake state with open eyes in each patient’s registry. The functional connectivity was analyzed from the calculation of the spatial synchronization matrix (synchronization likelihood) between the electrodes.24,25 The following was determined for the five frequency bands: Alfa (8-12.9 Hz), Beta (13-29.9 Hz), Theta (4-7.9 Hz), Delta (1-3.9 Hz) and Gamma (only within the 30-35 Hz range). All the processing was performed using algorithms implemented on the MATLAB R2008b program, and the data matrices registered for each patient were compared before the intervention and after the intervention.

Adverse effectsThe children were closely observed during the stimulation sessions, looking for signs indicating local discomfort or any manifestation of abnormal cortical hyperexcitability induced by the intervention. The parents were questioned a day later about any behavioral changes they noticed in the child, especially in the first hours after the sessions ended.

Medical ethicsThe protocol was approved by the Scientific Council and the Institutional Ethics Committee of the International Center of Neurological Restoration. The informed consent was given in writing by the parents, who received an extensive oral and written explanation of the characteristics of the procedures. The ethical guidelines for human research included in the Code of Ethics of the World Medical Association (Declaration of Helsinki) were complied with for research involving humans.26

Statistical AnalysisA nonparametric statistical analysis was performed using the Wilcoxon series test to compare the behavior of the scales in the two evaluative moments and the Mann-Whitney U to define if there were differences in the therapeutic response between groups with different interventions. Both

cases considered an α=0.05 (Statistica 7.0, Stat Soft Inc. 2004). Connectivity analysis based on the EEG also considered an α=0.05 for the comparisons between the matrices of data extracted from the two evaluative moments, with the use of a Student’s t-test.



14

Table 1. General characteristics and adverse effects observed in the sample studied.

additionally, there was a decrease in the variety and amount of stereotypies from the first week after the end of the intervention.

The initial and post-intervention evaluations were developed maintaining exactly the same conditions, variety of toys, and interactions. Evaluators similarly described qualitative and quantitative behavioral changes regarding the child’s interactions during the interview, the characteristics of the game, and the degree of hyperactivity. These changes were reflected in the results of the statistical analysis of the scores of the clinical scales evaluated (Figure 1).

One week after completing the intervention there was a 15% reduction in the score of the scales compared to the initial score of the group. No differences were identified regarding the magnitude of the changes observed in the scales related to the method used (tDCS vs rTMS), even

without considering the differences in average age between the groups (tDCS=8.7 years; rTMS=12.6 years), showing both methods to be effective as modulators of autistic behavior (Figure 2).

Modifications in brain connectivity based on the analysis of the α activity of the electroencephalogram.

The EEG-based connectivity analysis showed significant changes after the intervention, with an increase in functional connectivity at the alpha, beta, and gamma frequencies, especially in the latter (p<0.05). The same analysis for the slower frequencies (θ and δ) had an opposite behavior with a decrease in connectivity, especially in anterior regions (p<0.05). The topographic distribution of this increase in functional connectivity for the faster frequencies had a more diffuse character, including all regions, with a wider distribution in the case of the gamma (Figure 3).

Patient1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Age5

5

8

10

13

13

13

7

13

9

10

8

10

7

11

SexM

M

M

M

M

M

M

F

M

M

F

M

M

M

M

NIBStDCS

tDCS

tDCS

tDCS

rTMS

rTMS

rTMS

tDCS

rTMS

tDCS

tDCS

tDCS

tDCS

tDCS

rTMS

Headache-

-

-

-

-

-

-

-

Yes

-

-

-

-

-

-

Somnolence----

Yes-

YesYesYes

-----

Yes

Pharmacological treatment

CBZ

CBZ, RPD

CBZ

CBZ, RPD

-

CBZ, RPD

CBZ

:

CBZ

RPD

CBZ

-

CBZ

CBZ

CBZ

Completedthe treatment

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Local discomfort

Yes

-

-

-

-

-

-

Yes

-

Yes

Yes

Yes

Yes

Yes

-

Degree of severity

Mild

Mild

Moderate

Moderate

Moderate

Moderate

Mild

Mild

Moderate

Mild

Mild

Mild

Moderate

Moderate

Mild

Comorbidity-

-

-

-

-

-

-

-

-

-

-

-

-

ADHD

-



15

Figure 1. Behavior of the scores on the clinical scales with the therapy (*p<0.05).

Figure 2. Differences between the scores of the clinical scales before and one week after completing treatment with tDCS and rTMS (p>0.05 in the three scales).

ADI-R ATEC ABC0

50

100

InitialOne week aftertreatment

* *

*Sc

ales

sco

res

50

40

30

20

10

0

tDCSrTMS

Var

iant

ions

in th

e sc

ales

sco

res

ADI-R dif ATEC dif ABC dif

Figure 3. . Increase in functional connectivity between the points selected for the frequencies analyzed >8 Hz α, β and γ (only significant changes are represented, p <0.05).

α β γ



16

The application of NIBS methods in the pediatric population has been limited in previous years due to the lack of data on their safety and potential adverse effects, to such an extent that the reference literature lists children under 18 years of age as a formal contraindication to the application of rTMS. The absence of evidence on their safety has not meant at any time that there is evidence that contraindicates its use in children under 18 years of age. Fortunately, it has only been a matter of time to demonstrate that the application of rTMS and tDCS is a safe, tolerable method and that it is associated with very few adverse effects, both in healthy subjects and in patients.27,28

The most frequent adverse effects described with these methods involve the presence of local discomfort, an observation we reported as one of the results of this work.29,30 Secondly, the changes observed by the parents regarding sleep (reported as somnolence), are limited in all cases to the child going to bed earlier than usual and sleeping most of the night without interruptions--even the patients who typically slept little or had a very restless sleep with frequent awakenings. This description is interpreted as an improvement in the structure and quality of sleep, even though this had not been one of the preconceived objectives of this research. It was a beneficial side effect in all the cases in which it was reported and, though not widely reported in the literature, it is a known effect.31 In no case did seizures or other phenomena of abnormal cortical hyperexcitability occur.

The most interesting result in this research was the significant improvement in autistic symptoms in all the children who received the intervention, achieving an additional reduction of 15% in the score of the clinical scales compared to just basic treatment. This coincided qualitatively with the overall clinical impression of the evaluators, the large majority of whom were also the specialists who had been following up with these patients since their initial diagnosis. As a prominent aspect, a very significant improvement in socialization

Discussionwas observed, although from the point of view of the clinical scales the effect was global; and in second place, all aspects of language improved. Unlike research published by other groups, our study used a much larger number of sessions than what has been used so far in patients with ASD,32,33

and the clinical results seem very consistent when contrasting the results of the scales and the qualitative behavioral change in the patients.No significant differences were identified in the modulatory effect between rTMS and tDCS in the expression of autistic symptomatology. The values for both groups moved in a similar range after treatment, even though the average age of the groups was different. Such an effect does not seem to be related to the age of the patients. This is an element that has not been addressed in the literature and can be an interesting starting point as it contrasts the use of a more expensive and technically demanding method (rTMS) with a cheaper, technically less demanding method, both yielding similar results, so that the cost-benefit ratio may be in favor of the extended use of tDCS. The rTMS is currently the NIBS method with the greater number of scientific evidence, so we just posit a hypothesis that requires more research to corroborate its veracity.34-36 NIBS cannot currently be recommended as a valid therapeutic alternative for ASD due to lack of sufficient scientific evidence, but there are several indications that allow us to believe it could be in the near future. The heterogeneity in terms of methods is striking when analyzing the results of small published clinical trials with good apparent results and with the use of inverted stimulation polarities in the case of tDCS.33,37

The limitation of this study was the absence of a control group and/or placebo, which does not completely rule out the subjective factor in patients, family members, and evaluators, though we did start from an experimental design in which the concomitant use of other therapies was controlled, while also requiring the patient to have a period of at least one month of stability



17

both in their therapeutic scheme as well as in their symptomatology. Hence, the patients receiving the intervention were their own controls, so there is a high probability that the observed changes were secondary to the intervention and not to another cause. A sample increase and a design that includes a control group and the use of a placebo would be key to reach solid conclusions regarding the effect of these interventions.

Considering the elements that have been described about the pathophysiology of ASD,12,38 which is based on an inhibitory intracortical dysfunction that motivates the alterations in the functional connectivity between brain areas, 39 the beneficial effect may be associated with the increase in functional connectivity between cortical areas dependent on the activity of the frequencies in the range of activity α, β and γ. Particularly with regard to this last band of frequency, this study only analyzed the lower component (30-35 Hz) in the

waking state, at rest with eyes open. It is known that the spectral power of the γ activity is dependent on the functional state of the brain and that its increase is generally associated with the process of attention in normal subjects, showing a high degree of interhemispheric coherence. It seems that in patients with ASD, although most of the studies describe the increase in the spectral energy of this frequency band, it differs from normal records precisely in their degree of coherence. It has been described that the increase in connectivity of the γ band, especially in posterior regions, is associated with a higher level of functioning in ASD.40 There seems to be a link between γ activity and ASD. In our case, the increase in functional connectivity dependent on gamma activity was associated with clinical improvement. There’s not much more to say about it at the moment, but it is an aspect that deserves more attention, pending a definition of the type of relationship between this functional change and the therapeutic effect of NIBS.

Conclusions

The use of Non-Invasive Brain Stimulation is tolerable in children with Autism Spectrum Disorder and induces significant changes in key aspects of autistic behavior, with increased functional connectivity between cortical areas depending primarily on the fastest frequencies.

Conflicts of interestThe authors state that there are no relevant conflicts of interest in this study.

Funding sourcesThere was no particular funding source for this scientific report.



18

1. American Psychiatric Association. Neurodevelopmental Disorders. In: American Psychiatric Association, ed. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ed. Washington DC: American Psychiatric Publishing. 2013:31-86.

2. Christensen D, Van Naarden BK, Doernberg NS, et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56:59-65.

3. van Bakel MM, Delobel-Ayoub M, Cans C, et al. Low but increasing prevalence of autism spectrum disorders in a French area from register-based data. J Autism Dev Disord. 2015 Oct;45:3255-3261.

4. Fombonne E, Marcin C, Manero AC, et al. Prevalence of Autism Spectrum Disorders in Guanajuato, Mexico: The Leon survey. J Autism Dev Disord. 2016 May;46:1669-1685.

5. Rane P, Cochran D, Hodge SM, Haselgrove C, Kennedy DN, Frazier JA. Connectivity in Autism: A Review of MRI Connectivity Studies. Harv Rev Psychiatry. 2015 Jul;23:223-244.

6. Mukherjee S, Rupani K, Dave M, Subramanyam A, Shah H, Kamath R. Evaluation of effectiveness of integrated intervention in autistic children. Indian J Pediatr. 2014 Apr;81:339-345.

7. Jobski K, Hofer J, Hoffmann F, Bachmann C. Use of psychotropic drugs in patients with autism spectrum disorders: a systematic review. Acta Psychiatr Scand. 2016 Sep 13;10.

8. Ruggieri VL, Arberas CL. [Therapeutic approaches in autism spectrum disorders]. Rev Neurol. 2015 Feb 25;60 Suppl 1:S45-9.:S45-S49.

9. Brondino N, Fusar-Poli L, Rocchetti M, Provenzani U, Barale F, Politi P. Complementary and Alternative Therapies for Autism Spectrum Disorder. Evid Based Complement Alternat Med. 2015;2015:258589. doi: 10.1155/2015/258589. Epub;%2015 May 7.:258589.

10. Bailey A, Luthert P, Dean A, et al. A clinicopathological study of autism. Brain. 1998 May;121:889-905.

11. Casanova MF, El-Baz AS, Kamat SS, et al. Focal cortical dysplasias in autism spectrum disorders. Acta Neuropathol Commun. 2013 Oct 11;1:67. doi: 10.1186/2051-5960-1-67.:67-1.

12. Frye RE, Casanova MF, Fatemi SH, et al. Neuropathological Mechanisms of Seizures in Autism Spectrum Disorder. Front Neurosci. 2016 May 10;10:192. doi: 10.3389/fnins.2016.00192. eCollection;%2016.:192.

13. Muller-Dahlhaus F, Vlachos A. Unraveling the cellular and molecular mechanisms of repetitive magnetic stimulation. Front Mol Neurosci. 2013 Dec 17;6:50. doi: 10.3389/fnmol.2013.00050. eCollection;%2013.:50.

14. Bikson M, Name A, Rahman A. Origins of specificity during tDCS: anatomical, activity-selective, and input-bias mechanisms. Front Hum Neurosci. 2013 Oct 21;7:688. doi: 10.3389/fnhum.2013.00688. eCollection;%2013.:688.

15. Berlim MT, Van den Eynde F, Daskalakis ZJ. Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: a systematic review and meta-analysis of randomized trials. Depress Anxiety. 2013 Jul;30:614-623.

16. Lefaucheur JP, Antal A, Ahdab R, et al. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain. Brain Stimul. 2008 Oct;1:337-344.

17. Casanova MF, Baruth JM, El-Baz A, Tasman A, Sears L, Sokhadze E. Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Event-Related Potential (ERP) Indices of Attention in Autism. Transl Neurosci. 2012 Jun 1;3:170-180.

18. Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB. Repetitive transcranial magnetic stimulation (rTMS) improves movement-related cortical potentials in autism spectrum disorders. Brain Stimul. 2012 Jan;5:30-37.

19. Sokhadze EM, Baruth JM, Sears L, Sokhadze GE, El-Baz AS, Casanova MF. Prefrontal neuromodulation using rTMS improves error monitoring and correction function in autism. Appl Psychophysiol Biofeedback. 2012 Jun;37:91-102.

20. Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord. 1980 Mar;10:91-103.

21. Lord C, Rutter M, Le CA. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994 Oct;24:659-685.

References



19

22. Volkmar FR, Cicchetti DV, Dykens E, Sparrow SS, Leckman JF, Cohen DJ. An evaluation of the Autism Behavior Checklist. J Autism Dev Disord. 1988 Mar;18:81-97.

23. Al Backer NB. Correlation between Autism Treatment Evaluation Checklist (ATEC) and Childhood Autism Rating Scale (CARS) in the evaluation of autism spectrum disorder. Sudan J Paediatr. 2016;16:17-22.

24. Niso G, Pereda E, Gutiérrez R, Bajo R, Maestrú F, et al. HERMES: towards an integrated toolbox to characterize functional and effective brain connectivity. Neuroinformatics. 2013;11:405-34.

25. Stam C. Synchronization likelihood: an unbiased measure of generalized synchronization in multivariate data sets. Physica D. 2002;163:236-241.

26. Nierdermeyer E. The Normal EEG of the waking adult. In: Niedermeyer E and Lopez da Silva, eds. Electroencephalography. Basic principles, clinical applications, and related fields. Fifth Edition. USA: Lippincott Williams & Wilkins, 2005: 167-192.

27. Asociación Médica Mundial. Declaración de Helsinki de La Asociación Médica Mundial. Principios éticos para las investigaciones médicas en seres humanos. Seúl, Corea: Asociación Médica Mundial; 2008. Report No.: 59.

28. Gomez L, Vidal B, Morales L, et al. Low frequency repetitive transcranial magnetic stimulation in children with attention deficit/hyperactivity disorder. Preliminary results. Brain Stimul. 2014 Sep;7:760-762.

29. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120:2008-2039.

30. Anderson B, Mishory A, Nahas Z, et al. Tolerability and safety of high daily doses of repetitive transcranial magnetic stimulation in healthy young men. J ECT. 2006 Mar;22:49-53.

31. Hadley D, Anderson BS, Borckardt JJ, et al. Safety, tolerability, and effectiveness of high doses of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation for treatment-resistant depression in a clinical setting. J ECT. 2011 Mar;27:18-25.

32. Misra UK, Kalita J, Bhoi SK. High-rate repetitive transcranial magnetic stimulation in migraine prophylaxis: a randomized, placebo-controlled study. J Neurol. 2013 Nov;260:2793-2801.

33. Enticott PG, Fitzgibbon BM, Kennedy HA, et al. A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation (rTMS) for autism spectrum disorder. Brain Stimul. 2014 Mar;7:206-211.

34. Amatachaya A, Auvichayapat N, Patjanasoontorn N, et al. Effect of anodal transcranial direct current stimulation on autism: a randomized double-blind crossover trial. Behav Neurol. 2014;2014:173073. doi: 10.1155/2014/173073. Epub;%2014 Oct 30.:173073.

35. Lefaucheur JP, Andre-Obadia N, Poulet E, et al. [French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. Neurophysiol Clin. 2011 Dec;41:221-295.

36. Butler AJ, Shuster M, O’Hara E, Hurley K, Middlebrooks D, Guilkey K. A meta-analysis of the efficacy of anodal transcranial direct current stimulation for upper limb motor recovery in stroke survivors. J Hand Ther. 2013 Apr;26:162-170.

37. Nizard J, Lefaucheur JP, Helbert M, de CE, Nguyen JP. Non-invasive stimulation therapies for the treatment of refractory pain. Discov Med. 2012 Jul;14:21-31.

38. D’Urso G, Bruzzese D, Ferrucci R, et al. Transcranial direct current stimulation for hyperactivity and noncompliance in autistic disorder. World J Biol Psychiatry. 2015;16:361-366.

39. Casanova MF, Sokhadze E, Opris I, Wang Y, Li X. Autism spectrum disorders: linking neuropathological findings to treatment with transcranial magnetic stimulation. Acta Paediatr. 2015 Apr;104:346-355.

40. Datko M, Gougelet R, Huang MX, Pineda JA. Resting State Functional Connectivity MRI among Spectral MEG Current Sources in Children on the Autism Spectrum. Front Neurosci. 2016 Jun 9;10:258. doi: 10.3389/fnins.2016.00258. eCollection;%2016.:258.

41. Takesaki N, Kikuchi M, Yoshimura Y, et al. The Contribution of Increased Gamma Band Connectivity to Visual Non-Verbal Reasoning in Autistic Children: A MEG Study. PLoS One. 2016 Sep 15;11:e0163133.

Revista Mexicana de Neurociencia may-june, 2018; 20(3):20-33

Original contributionTime-frequency analysis of MMN

20

Time-frequency analysis of Mismatch Negativity (MMN) in healthy Mexican preschool children

Análisis tiempo-frecuencia del Potencial de disparidad (MMN) en niños preescolares mexicanos saludables


Dora E. Granados-Ramos,1

Samuel Zamora-Lugo,1,2 Patricia Torres-Morales,1,3

Héctor J. Cervantes,1,4 Carmelita Vela-Baizabal,1,4

Norma Castañeda-Villa,5 Gabriela Romero-Esquiliano.6

1Laboratorio de Psicobiología, Facultad de Psicología-Xalapa, Universidad Veracruzana. Xalapa, Veracruz, México.2Maestría en Neuroetología, Instituto de Neuroetología-UV, Xalapa, Veracruz, México.3Doctorado en Investigaciones Cerebrales-UV, Xalapa, Veracruz, México. 4Doctorado en Ciencias Biomédicas-UV, Xalapa, Veracruz, México. 5Depto. Ingeniería Eléctrica, Universidad Autónoma Metropolitana-Iztapalapa. México.6Universidad Autónoma Metropolitana-Xochimilco. México.

Abstract

Introduction: The MMN is an Event-Related Potential frequently studied in auditory change detection tasks. Recent work using time frequency measures has proved promising in understanding the neurophysiology behind auditory change detection. These measures, unfortunately, have not been fully studied in children.

Objective: The purpose of this study was to describe the spectro-temporal characteristics of the MMN response using words in healthy Mexicans preschool children.

Method: 20 children (10 boys and 10 girls) of preschool age participated a neuropsychological evaluation and an auditory discrimination task during EEG recording. Event Related Spectral Perturbation (ERSP) and Inter-Trial Coherence (ITC) was obtained for frequent and infrequent trials.

Results: The ERP showed a typical MMN and LDN response. ERSP increases in the theta band corresponded to the auditory change detection, though no differences between boys and girls was found.

Conclusions: In Mexican preschool children, the MMN is like what has been previously reported in adults. However, in contrast to similar studies, sex did not influence the neurophysiological measures. Significance: We established parameters for future research in children using the MMN.

KeywordsElectroencephalogram, Event-Related Potentials, Event-Related Spectral Perturbations, Inter-Trial Coherence, Audition.



21

Resumen

Introducción: El MMN es un Potencial Relacionado a Eventos que frecuentemente se estudia ante tareas de detección de cambios auditivos. Trabajos recientes que han utilizado medidas de tiempo-frecuencia han demostrado lo prometedor de comprender la detección neurofisiológica del cambio auditivo, sin embargo, estas medidas no se han estudiado completamente en niños.

Objetivo: El propósito de este estudio fue describir las características espectro-temporales de la respuesta MMN utilizando palabras en niños preescolares sanos mexicanos.

Método: 20 niños (10 niños y 10 niñas) de edad preescolar participaron en una evaluación neuropsicológica y una tarea de discriminación auditiva durante el registro de EEG. La Perturbación Espectral Relacionada a Eventos (ERSP) y la Coherencia Inter-Ensayos (ITC) se obtuvieron para los estímulos frecuentes e infrecuentes. Resultados: El ERP mostró una respuesta típica de MMN y LDN. El incremento de ERSP en la banda theta correspondió a la detección de cambios auditivos, aunque no se encontraron diferencias entre niños y niñas.

Conclusiones: El MMN en niños preescolares mexicanos es similar al que se ha reportado en adultos. Sin embargo, en contraste con estudios similares, el sexo no tuvo efecto sobre las medidas neurofisiológicas. Significancia: Establecimos parámetros para la investigación futura en niños usando el MMN.

Palabras claveElectroencefalograma, Potencial Relacionados a Eventos, Perturbaciones Espectrales Relacionadas a Eventos, Coherencia Inter-Ensayos, Audición.

Corresponding author: Dra. Dora E. Granados RamosLaboratorio de Psicobiología, Facultad de Psicología de la Universidad Veracruzana-Xalapa, Manantial de San Cristóbal s/n; 91097, col. Xalapa 2000, Xalapa, México.Phone: (+52) 228 841 1700 Ext. 19518.email: [email protected]



22

IntroductionLiving organisms need to discriminate between the various characteristics of sound stimuli acquired from the environment to adapt their behavior, to provide answers and to learn. In the case of language, speech perception is associated with the identification and discrimination of the characteristics of auditory stimuli, such as phonemes and words that make up a language.1

To perform this auditory discrimination, an adaptation process is produced in which neurons decrease their response to certain stimuli that are presented regularly and give longer responses when the neurons detect a stimulus difference.2,3

Neurophysiological techniques such as Event-Related Potentials (ERPs) are useful for analyzing the cortical response to external stimuli. The Mismatch Negativity (MMN) is one of these ERPs and is described as a pre-attentional indicator of deviance detection that reflects a memory process. Each incoming sound is compared with an internal representation of previous stimulation when deviant stimuli are presented within a frequent stimuli sequence.3,4

Described for the first time by Näätänen, Gaillard and Mäntysalo,5 the MMN is a neurophysiological response represented as a negative deflection with certain characteristics: an amplitude of -0.5 to -5 µV; with a topographical scalp distribution around frontocentral; spectral power most prominent from 2 to 8.5 Hz;6 and cortical generators within the primary auditory and prefrontal cortex.7-10 In addition, deviant stimuli elicit a second negative deflection called the Late Discriminative Negativity (LDN) in children, which decreases with age.1,11

In previous studies, auditory phonological processing has been studied using speech stimuli in different languages. MMN responses in healthy children are elicited using complex tones, pseudowords and words. With words, greater amplitudes are found from 150 to 200 ms and 300 to 400 ms.1 Strotseva-Feinschmidt et al.12 found that the frequent forms

used in German evoked both the MMN and LDN, whereas infrequent forms evoked only the LDN response in 3-year-old children. Ahmadi et al.13

used the MMN to describe the discrimination of phonemes with three different words as deviant stimuli and found that the MMN was about 380-424 ms in healthy children.

Despite these investigations, there is no conclusion about the characteristics of MMN in healthy preschool children using words as stimulus. Ervast et al.14 for example, described the MMN and LDN but using only frequency change in the stimulation.Although the MMN has been described as one of the first cortical correlates of automatic auditory discrimination, current studies have shown that the MMN is not the earliest correlate of deviant stimuli detection in the human auditory cortex and is modulated by earlier ERPs.3,4,15 The MMN is consistently generated by a set of processes which detect deviant stimuli presentation that occur while auditory processing is performed at multiple levels within the human brain.3

The sensory ERPs that appear before the MMN include the exogenous components N1, P1 and N2, which are characterized as obligatory responses of the nervous system to external stimuli. This is supported by the fact that these components of the sensory modality differ in shape and cortical distribution depending on the type of sensory modality in which the stimulus is presented. The N1 component has generators in the dorsal area of the temporal hemispheres and in the superior temporal gyrus of the auditory cortex.10 The P1 component appears around 50 ms and its cortical generators are in the Heschl gyrus and in the temporal regions of the auditory cortex.16,17 The N2 component reflects active discrimination by the subject.18

The quantification of the MMN and earlier sensory ERPs helps evaluate dynamic changes in the auditory stimulation assessing system of children. This has not only theoretical but also clinical relevance. For example, the absence of a normal MMN in children of typical development could predict the presence of subsequent language disorders.19 We have also shown that children with language impairment elicit



23

Methods

The present study was prospective, observational, and transversal and was done in the Laboratorio de Psicobiología, Universidad Veracruzana, Xalapa, Veracruz-México.

Thirty-two Mexicans preschool children with an age ranging from 5 to 6.5 years were evaluated.

a MMN with later latencies compared to healthy children.20

Besides studying the phase-locked ERPs response, time-frequency analyses have been enjoying a surge in popularity when analyzing EEG. As has been previously stated by Cohen,21 oscillatory dynamics are more readily associable with their neurophysiological origins compared to ERPs. Time-frequency analyses also allow for the quantification of non-phase locked oscillations which average out in ERPs. This includes event related spectral perturbation (ERSP) and inter-trial phase coherence (ITC).22 Therefore, time-frequency analyses have shown promise for understanding the neural correlates of behavior and cognition, and complement and extend the findings of ERP-only studies.

Recently, Fujimoto et al.23 studied sex-related differences in gamma oscillation during an auditory oddball task. Using source localization, the authors found that ERSP in females increased in both paracentral regions at 625 ms. Additionally, ERSP in females increased in the medial orbitofrontal regions at 125 ms, and right caudal anterior cingulate cortex regions at 250 ms in both hemispheres, compared to males. Finally, they conclude that these findings indicate a more efficient network architecture in females, corresponding to higher overall cortical connectivity due to greater interhemispheric connectivity in the female brain.

The purpose of this study was to extend previous studies to describe the spectro-temporal characteristics of the MMN response using words in healthy Mexicans preschool children.

For the final sample, 20 children were selected (10 males and 10 females matched by age) with mean age of 5.5 months (SD±4.6 months) and paired by age (Appendix 1). The children did not have any diagnosis of developmental disorders and had normal Auditory Attention (AA), Auditory Perception (AP) and Auditory Memory-Coding (AMC), evaluated using the auditory tests included in the Children Neuropsychological Assessment ENI (Evaluación Neuropsicológica Infantil) (Table 1), a neuropsychological test standardized for use in the Mexican population.24

The parents or tutors signed a form of informed consent in which the aim of the current study was outlined. Parents were noted that they could suspend any part of the evaluation if they so desired.

ProcedureEEG was acquired using a Neuroscan System® with Curry 7.0.10. XS software and a cap with 60 active Ag/AgCl electrodes on the scalp, distributed according to the International System 10-20. This corresponds to the following derivations: FP1-FP2, AF3-AF4, F1-F2, F3-F4, F5-F6, F7-F8, FT7-FT8, FC1-FC2, FC3-FC4, FC5-FC6, C1-C2, C3-C4, C5-C6, T7-T8, TP7-TP8, CP1-CP2, CP3-CP4, CP5-CP6, P1-P2, P3-P4, P5-P6, P7-P8, PO3-PO4, PO5- PO6, PO7-PO8, O1-O2, FPz, Fz, FCz, Cz, CPz, Pz, POz and Oz. An electrode on the left mastoid served as the online reference, the ground electrode was placed in the forehead anterior to FPZ electrode. Four electrodes were used to record vertical and horizontal eye movements (VE1-VE2 and HO1-HO2), and two electrodes located below of collarbone to record cardiac activity (EKG1-EKG2).

A clinical EEG was used to determine if the children had normal electrical brain activity. The MMN was obtained from an auditory passive oddball paradigm (Figure 1), using 320 standard stimuli (/Ajos/) and 80 deviant stimuli (/Ojos/). We selected these stimuli from two word pairs: /Ajos-Ojos/ (Garlic-Eyes) and /Vaso-Paso/ (Glass-Step), since the morphology of the MMN had amplitudes and latencies like that of the reviewed literature.



24

Table 1. Mean (±SD) of the age, quantitative qualification of Auditory Attention (AA), Auditory Perception (AP) and Auditory Memory-Coding (AMC).

Figure 1. Odd-ball paradigm used to stimulus presentation. Word duration in ms: milliseconds, F1: First formant, F2: Second formant.

The clinical EEG and the MMN were performed in wakefulness with an average duration of 90 minutes. One day before the study, each child went to the registration area to familiarize himself with the place and know what was going to be done, he was told that it would not hurt him and that he should not move. The day of study, the children observed a video without sound so that they could ignore the auditory stimulation. The children were accompanied by their main caregiver, who made sure that the he did not move during the study.20

Data analysis The EEGLAB toolbox, version 13.5.4b, was used to analyze the data. Recorded data was resampled to 512 Hz, and offline re-referenced to the right mastoid (M2) electrode. Epochs consisted of -200 ms to 500 around stimulus onset. Any epoch that contained amplitude of ±75 µV was automatically rejected. The FASTICA algorithm was applied to remove eye and heartbeat components.25

Statistical analyses were done using a mixed factor ANOVA with gender and stimulus type as between

Subjects

BOYSGIRLS

AGE68.5 (4.6)

68.1 (4.9)

AA48.7 (35.3)

63.1 (36.7)

AP63.9 (23.1)

75.4 (21.2)

AMC52.6 (16.4)

44.4 (24.6)

MEAN (±SD)

and within factors, respectively. To account for multiple comparisons, we corrected for the False Discovery Rate (FDR) using the corresponding option in EEGLAB 13.5.4b.For the description of the temporal characteristics of the neurophysiological response of the sample of this research, we defined time-windows to determine the peaks of P1-N2, MMN and LDN. The P1 component was measured around 50 ms, while the N2 component around 150-200 ms.

The MMN was analyzed between 200-300 ms and the LDN between 350-500 ms based on previous studies with preschool children.1,11,26

With respect to spectrum characteristics, we analyzed two frequency domain measures: Inter-Trial Coherence (ITC) and the Event-Related Spectral Perturbation (ERSP). The ITC was defined as the degree of synchronization between the epochs (standard and deviant) within the odd-ball paradigm used in the study. The ERSP was the synchronization at specific frequencies over time, starting from the values observed in the baseline.

Standardn=320

Deviantn=80

Standard 632 msF1-1199Hz F2-3505 hz

Deviant 692 msF1-526Hz F2-3568 Hz

ISI1000 ms

/Ajos/ /Ajos/ /Ajos/ /Ajos/ /Ajos//Ojos/ /Ojos/



25

ms = milliseconds µV = microvolts

Results

MMN and LDNA general analysis of the frequent and infrequent stimuli was done at the FCz electrode to observe the P1 and N2 components characteristics (Table 2). The N1 component is not observed.

The electrodes FC3, FCz and FC4 were chosen for MMN and LDN analyses. For a comparison between anterior and posterior areas, O1, Oz and O2 were analyzed.

The MMN was observed at 287.1 ms, with amplitude of -0.51 µV, and the LDN was observed at 425.8 ms and -1.38 µV (Figure 2).

In boys, the MMN was found at 282.3 ms with amplitude -1.81 µV and the LDN was found at 431.2 ms with -1.78 µV. In girls, the MMN was observe at 288.6 ms with an amplitude of 0.43 µV and the LDN at 395.8 ms with -1.26 µV (Table 3).

Thus, we found the MMN to have greater amplitude in boys compared to girls, while the LDN showed no differences between the groups (Figure 3).

ERSP of the MMNBased on the individual ERSP values of the MMN an average was obtained (Appendix 2). A broadband event related synchronization was observed for frequencies below 20 Hz between 100-200 ms for boys and between 150-300 ms for girls (Figure 4).

While we found a significant difference between boys and girls at the FC4 electrode during early latencies, these differences did not survive correction for multiple comparisons. Theta band synchronization was found in the infrequent stimuli (/Ojos/) for girls only (Figure 5).

This low frequency band synchronization followed a frontocentral distribution in boys and girls (Figure 6).

ITC values showed synchronization for the frequent stimulus presentation between 100 and 200 ms, with frequencies ranging from 3 to 30Hz in both groups (Figure 7).

ITC values at Oz showed an increase in synchronization from 100 ms to 200 ms from 5 to 20 Hz for both boys and girls (Figure 8).

Electrode Stimuli

/Ajos/

/Ojos/

Latency(ms)

111.3

121.2

Amplitude(µV)2.96

2.96

Amplitude(µV)

-3.27

-3.67

Latency(ms)

304.7

289.1FCZ

P1 N2

Table 2. P1 and N2 components latencies and amplitudes at FCz (n=20).



26

Table 3. Average latencies and amplitudes of the MMN y LDN in anterior regions (n=20).

Figure 2. Grand average MMN and LDN latencies and amplitudes at FCz.

Figure 3. Grand average MMN and LDN at FC3, FCZ and FC4. The blue line corresponds to boys and the red to girls.

Sex

Boys

Girls

Boys

Girls

Boys

Girls

FC3

FCz

FC4

Electrode Latency (ms)273.2

(38.2)

288.4

(45.3)

282.3

(40.3)

288.6

(39.5)

265.4

(48.4)

293.7

(52.1)

Amplitude (µV)-2.01

(4.2)

0.52

(1.8)

-1.81

(1.4)

0.43

(3.01)

-1.86

(2.3)

0.03

(3.1)

Latency (ms)437.3

(37.6)

392.7

40.7)

431.2

(22.8)

395.8

(39.9)

418.8

(52.4)

393.7

(48.3)

Amplitude (µV)-2.03

(3.6)

-1.96

(3.4)

-1.78

(2.3)

-1.26

(2.1)

-2.02

(1.2)

-1.43

(1.8)

MMN MEAN (±SD) LDN MEAN (±SD)

ms = milliseconds µV = microVolts



27

Figure 4. ERSP of the MMN at FC3, FCz and FC4, of girls (middle) and boys (left). A statistically significant difference (p not corrected<0.05) was observed at the FC4 electrode.

Figure 5. ERSP of /Ajos/ and /Ojos/ at the FCZ.

Figure 6. Topographic map of 5 to 20 Hz power for frequent and infrequent stimuli.



28

DiscussionBehavioral and neurophysiological studies of development help attend different disorders, as well as adapt teaching methods. In Mexico, it is necessary to have its own behavioral and neurophysiological norms that permit the evaluation of a child’s development.

The EEG is a neurophysiological tool that helps discard alterations in brain electrical activity. It also establishes neurophysiological parameters through ERPs for cognitive tasks corresponding to different sensory modalities, so far focused mainly in vision and audition. Within the ERPs, the MMN is a neurophysiological response that has been found is a useful tool to analyze cognitive processes such as

Figure 7. ITC of /Ajos/ and /Ojos/ at the FCz.

Figure 8. ITC of /Ajos/ and /Ojos/ at the OZ.

language.27,28 Taken together, parameters of Mexican children in the preschool stage are necessary, being a relevant stage for the later acquisition of the reading-writing process. This includes the relevance of time-frequency analyses of EEG acquisition with previous studies with children of similar ages.20 The importance of ITC and ERSP is that these measures define the way different frequency bands of neuronal activity presents with an evoked and induced effect before specific cognitive events.

In children, we observed that although the auditory responses of behavioral tasks of perception, attention, and memory were adequate, between subject differences in language development with relation to the articulation of sounds may be due to perinatal risk factors and to the stimulation received at home or at school. However, the language of 80%



29

of the children was normal for both boys and girls, echoing several authors who found no differences between genders in language development at 5 years of age. In this way, children should be able to develop a structured language that will continue to develop in expression and comprehension with age.29

With regards to the MMN and LDN, we observed responses within expected latencies, amplitude and age distribution and with between-subject differences that were not significant by gender when correcting for multiple comparisons, which leads us to state that, at this stage, the Neurophysiological development among boys and girls was similar.

However, we can say that MMN in boys showed earlier latencies and higher amplitudes than in girls, which is related to better responses of speech language discrimination that has been previously described in cases of typical development.1 It will be necessary to evaluate how these latencies change throughout the child’s school education.

With the time-frequency analysis of event-related potentials we established the methodology to obtain MMN parameters from words previously validated in our laboratory with stimuli selected from a common neuropsychological evaluation for populations of Mexican children. Previous studies have shown data like this study, with an enhanced inter-trial coherence (ITC) in children with dyslexia aged around 6-11 years, but less event-related desynchronization in older children with dyslexia.30

As in other studies, we found no significant effect of sex on the theta power. Fujimoto and colleagues22 found an increase in faster frequencies such as gamma power in males. On the other hand, the MMN has been associated with an increase in theta power for the deviant trials;31 both results have been described in adults so that it is necessary to continue evaluating children of preschool ages which will allow for any necessary adjustments to have appropriate parameters for our population.

SubjectM1

M2

M3

M4

M5

M6

M7

M8

M9

M10

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Age in months62

62

65

66

68

70

71

72

74

75

61

62

65

66

65

70

71

72

74

75

PRMedium

High

High

Low

High

High

Low

Medium

Medium

Medium

High

Low

Low

Medium

Medium

High

Medium

Medium

Low

High

ArticulationNormal

Moderate

Normal

Normal

Normal

Severe

Normal

Normal

Mild

Normal

Normal

Mild

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

BOYS

GIRLS

Appendix 1. Individual data of age in months, perinatal risk (PR) and articulation in boys and girls.



30

Appendix 2. Individual Time-frequency analysis of MMN, in the left column the girls and in the right the boys.



31

Conclusions

With the time-frequency analysis of event-related potentials we established for future research, the methodology to obtain MMN parameters from words using the auditory perception tests included in the Children Neuropsychological Assessment ENI standardized for use in the Mexican population.

Conflicts of interestNone of the authors have potential conflicts of interest to be disclosed.

FundingThere was no source of funding for this research.



32

1. Korpilahti P, Krause CM, Holopainen I, Lang AH. Early and late Mismatch Negativity elicited by words and speech-like stimuli in children. Brain and Language. 2001: 76(3); 332-9. http://dx.doi.org/10.1006/brln.2000.2426

2. Ulanovsky N, Las L, Nelken I. Processing of low-probability sounds by cortical neurons. Nature Neuroscience. 2003; 6(4): 391-398. http://dx.doi.org/10.1038/nn1032

3. Grimm S, Escera C, Slabu L, Costa-Fadeilla J. Electrophysiological evidence for the hierarchical organization of auditory change detection in the human brain. Psychophysiology. 2011; 48(3): 377-84. http://dx.doi.org/10.1111/j.1469-8986.2010.01073.x

4. Shiga T, Althen H, Cornella M, Zarnowiec K, Yabe H, Escera, C. Deviance-related response along the auditory hierarchy: combined FFR, MLR and MMN evidence. PLoS ONE. 2015; 10(9): 1-14 e0136794. http://dx.doi.org/10.1371/journal.pone.0136794

5. Näätänen R, Gaillard AWK, Mäntysalo. Early selective-attention effect on evoked potential reinterpreted. Acta Psychologica. 1978: 42; 313–329. http://dx.doi.org/10.1016/0001-6918(78)90006-9

6. Cong F, Kalyakin I, Huttunnen-Scott T, Li H, Lyytinen H, Ristaniemi T. Singletrial based independent component analysis on Mismatch Negativity in children. International Journal of Neural Sciences. 2010; 20(49): 279-92. http://dx.doi.org/10.1142/S0129065710002413

7. Näätänen R, Paavilainen P, Rinne T, Alho K. The mismatch negativity (MMN) in basic research of central auditory processing: A review. Clinical Neurophysiology. 2007; 118(12): 2544-90. http://dx.doi.org/10.1016/j.clinph.2007.04.026

8. Näätänen R, Kujala T, Winkler I. Auditory processing that leads to conscious perception: a unique window to central auditory processing opened by the mismatch Negativity and related responses. Psychophysiology. 2011; 48: 4-22. http://dx.doi.org/10.1111/j.1469-8986.2010.01114.x

9. Näätänen R, Kujala T, Escera C, Baldeweg T, Kreegipuu K, Carlson S, Ponton C. The mismatch negativity (MMN). A unique to disturbed central auditory processing in ageing and different clinical conditions. Clinical Neurophysiology. 2012: 123(3); 424- 458. http://dx.doi.org/10.1016/j.clinph.2011.09.020

10. Luck, SJ. An introduction to the event-related potential technique. 2th ed. Cambridge, England: The MIT Press. 2014: 85-87.

11. Bishop DVM, Hardiman MJ, Barry JG. Is auditory discrimination mature by middle childhood? A study using time–frequency analysis of mismatch responses from 7 years to adulthood. Developmental Science. 2011: 14(2); 402–16. https://doi.org/10.1111/j.1467-7687.2010.00990.x

12. Strotseva-Feinschmidt A, Cunitz K, Friederici AD, Gunter TC. Auditory discrimination between function words in children and adults: a mismatch negativity study. Frontiers in Psychology. 2015; 6: 1-9. https://doi.org/10.3389/fpsyg.2015.01930

13. Ahmadi SZZ, Mahmoudian S, Ashayeri H, Allaeddini F, Farhadi M. Electrophysiological and phonological change detection measures of auditory word processing in normal Persian-speaking children. International Journal of Pediatric Otorhinolaryngology. 2016: 90; 220-226. https://doi.org/10.1016/j.ijporl.2016.09.014

14. Ervast L, Hämäläinen JA, Zachau S, Lohvansuud K, Heinänen K, Veijola M, Heikkinen E, Suominen K, Luotonen M, Lehtihalmes M, Leppänen, PHT. Event-related brain potentials to change in the frequency and temporal structure of sounds in typically developing 5–6-year-old children. International Journal of Psychophysiology. 2015: 98(3); 413–425. https://doi.org/10.1016/j.ijpsycho.2015.08.007

15. Costa-Faidella J, Baldeweg T, Grimm S, Escera C. Interactions between “what” and “when” in the auditory system: temporal predictability enhances repetition suppression. The Journal of Neuroscience. 2011; 31(50): 18590-7. http://dx.doi.org/0.1523/JNEUROSCI.2599-11.2011

16. Ponton CW, Eggermont JJ, Khosla D, Kwong B, Don, M. Maduration of human central auditory ystem activity: Separating auditory evoked potentials by dipole source 120 modeling. Clinical Neurophysiology. 2002; 113(3): 407-420. http://dx.doi.org/10.1016/S1388-2457(01)00733-7

17. Martin BA, Tremblay KL, Korczak P. Speech Evoked Potentials: From the laboratory to clinic. Ear and Hearing. 2009; 29(3): 285-313. http://dx.doi.org/10.1097/aud.0b013e3181662c0e

18. Nuñez-Peña MI, Corral MJ, Escera C. Potenciales evocados cerebrales en el contexto de la investigación psicológica: una actualización. Anuario de Psicología. 2004; 35: 3-21.

References



33

19. Sussman A, Steinscheneider M, Lee W, Lawson, K. Auditory scene analysis in school-aged children with developmental language disorders. International Journal of Psychophisiology. 2014; 95: 13-24. http://dx.doi.org/1016/j.ijpsycho.2014.02.002

20. Granados-Ramos D, Torres-Morales P, Cervantes-Méndez HJ, Castañeda-Villa N, Romero-Esquiliano G. Mismatch Negativity (MMN) y el lenguaje en niños preescolares hablantes del idioma español. Revista Chilena de Neuropsicología. 2013; 8: 1-5, http://dx.doi.org/10.5839/rcnp.2013.0801.01

21. Cohen MX. Analyzing neural time series data: Theory and practice. Cambridge, England: The MIT Press. 2014: 55-57.

22. Shanin AJ, Picton TW, Miller LL. Brain oscillations during semantic evaluation of speech. Brain and cognition. 2009; 70(3): 259-266. https://doi.org/10.1016/j.bandc.2009.02.008

23. Fujimoto T, Okumurab E, Kodabashia A, Takeuchia K, Otsuboa T, Nakamuraa K, Yatsushiroa K, Sekinec M, Kamiyaa S, Shimookia, S. Tamurac T. Sex Differences in Gamma Band Functional Connectivity Between the Frontal Lobe and Cortical Areas During an Auditory Oddball Task, as Revealed by Imaginary Coherence Assessment. The Open Neuroimaging Journal. 2016; 10: 85-101. https://doi.org/10.2174/1874440001610010085

24. Matute E, Rosselli M, Ardila A, Ostrosky-Solís F. Evaluación Neuropsicológica Infantil (ENI): Manual de Aplicación. México: Manual Moderno. 2007: 13-19.

25. De Lathauwer L, De Moor B, Vandewalle J. An introduction to independent component analysis. Journal of Chemometrics. 2000; 14: 123-49. http://dx.doi.org/10.20982/tqmp.06.1.p031

26. Kuuluvainen S, Alku P, Makkonen T, Lipsanen J, Kujala T. Cortical speech and non-speech discrimination in relation to cognitive measures in preschool children. European Journal of Neuroscience. 2016; 43: 738–50. http://dx.doi.org/10.1111/ejn.13141

27. Näätanen R, Gaillard AWK, Mantysalo S. Brain potential correlates of voluntary and involuntary attention. In Kornhuber AHM, Deecke L. (Eds.). Motivation, motor and sensoryprocesses of the brain: elecrricalporentials, behavior and clinical use. Amsterdam: Elsevier, 1980: 343-348

28. Garrido MI, Kilner JM, Stephan KE, Friston KJ. The mismatch negativity: a review of underlying mechanisms. Clinical Neurophysiology. 2009; 120(3): 453-63. http://dx.doi.org/10.1016/j.clinph.2008.11.029

29. Cervera-Mérida JF, Ygual-Fernández A. Evaluación de la discriminación de habla en preescolares: comparación de las pruebas ABX y AX. Revista de Logopedia, Foniatria y Audiología. 2013; 33(2): 69-82. http://dx.doi.org/10.1016/j.rlfa.2013.04.003

30. Power AJ, Mead N, Barnes L, Goswami U. Neural entrainment to rhythmic speech in children with developmental dyslexia. Frontiers in Human Neuroscience. 2013; 7(777): 16-34. http://dx.doi.org/10.3389/fnhum.2013.00777

31. Fuentemilla LI, Marco-Pallarésa J, Münte TF, Grau C. Theta EEG oscillatory activity and auditory change detection. Brain Research. 2008; 1220: 93-101. http://dx.doi.org/10.1016/j.brainres.2007.07.079


Case reportPneumocephalus as Complication of Epidural Block

34

Pneumocephalus as complication of epidural block: report of a case and its treatment

Neumoencefalo como complicacion de bloqueo peridural: informe de un caso y tratamiento empleado

Case report

Gabriel Miranda Nava,1 Adriana Aguirre Alvarado,2

Francisco Alejandro López Jiménez,3

José Luis Ojeda Delgado.4

1Neurologist and Clinical Neurophysiologist. Chief of Neurology at the Centro Hospitalario del Estado Mayor Presidencial. Mexico City.2Department of Hyperbaric Medicine. Central Military Hospital. Mexico City3Head of the Anesthesiology Service at the Centro Hospitalario del Estado Mayor Presidencial. Mexico City.4Director, Centro Hospitalario del Estado Mayor Presidencial.

AbstractComplications arising from regional anesthesia and, in this case, the central blocks (epidural and subarachnoid) cause sympathetic blockade, sensory analgesia, and motor block at greater or lesser extent depending on the technique used, the dose, concentration, and volume of drug used. These are very useful techniques in many surgical procedures and for prolonged and effective postoperative analgesia, but the debate about the safety, effectiveness, and benefits of these techniques has increased with its widespread use. Major complications are rare, but when they appear they result in serious developments. This is especially unusual in the obstetrical and gynecological procedures, where patients are young and healthy and in which a complication or irreversible injury will be hardly understandable. There are very few recorded series of cases of patients affected by the complications related to neuraxial blockades. One of the largest includes 500,000 patients who underwent epidural block for labor, estimating 1/47,000 complications. The aforementioned complications are diverse in literature and the severity may vary.

A female 38-year-old patient with an extensive history of diagnosis of diabetes mellitus and hypertension, undergoing hysterectomy after two childbirths, goes through her operation and postoperative period without problems, but after 24 hours reports a severe headache that won't yield to the usual analgesics and its intensity increases in the next few hours. The Neurology service detects meningeal signs and severe pain, a CT scan of the skull is performed, and pneumocephalus is reported.

KeywordsEpidural block, regional anesthesia, pneumoencephalus.



35

ResumenLas complicaciones derivadas del procedimiento del grupo de la anestesia regional, y en este caso los bloqueos centrales (epidurales y subaracnoideos) causan bloqueo simpático, analgesia sensitiva y bloqueo motor en mayor o menor medida dependiendo de la técnica utilizada, la dosis, la concentración, el volumen de fármaco utilizado. Son técnicas muy útiles en gran cantidad de procedimientos quirúrgicos, así como para obtener una analgesia prolongada y eficaz en el postoperatorio. El debate acerca de la seguridad, la eficacia y los beneficios de estas técnicas ha aumentado desde finales del siglo XX, cuando se ha generalizado su uso. Las complicaciones mayores no son muy frecuentes, pero cuando aparecen suelen ser graves. Esto es especialmente llamativo en los procedimientos obstétricos y ginecológicos, en los que las pacientes son jóvenes y sanas y en las que una complicación o lesión irreversible será difícilmente entendible. No existen grandes series de pacientes en las que se hayan valorado las complicaciones ligadas a los bloqueos neuroaxiales. Una de las mayores es la que incluye a 500,000 pacientes sometidas a bloqueo epidural para el parto, estimando las complicaciones en 1/47000. Son diversas las complicaciones referidas en la literatura y su gravedad es muy variable.

Paciente femenina de 38 años de edad con antecedente de diabetes mellitus e hipertensión arterial, secundigesta, que se somete a histerectomía, cursa su trans y postoperatorio inmediato sin mayores problemas, pero a las 24 horas inicia con cefalea intensa que no cede ante los analgésicos habituales, e incluso aumenta conforme pasan las horas siguientes, por lo que se interconsulta a Neurología, detectando datos meníngeos y dolor intenso, por lo que se realiza una tomografía de cráneo y se detecta neumoencéfalo.

Palabras claveBloqueo epidural, anestesia regional, neumoencéfalo.

Corresponding autor:Dr. Gabriel Miranda Nava Av. Constituyentes 240, Miguel Hidalgo, Daniel Garza, 11840 Ciudad de México.Neurología Clínica. Centro Hospitalario del Estado Mayor Presidencial.E-mail: [email protected]



36

Introduction

Epidural anesthesia-analgesia (AAED) techniques have been used for many years. The technique of choice for certain cases, such as analgesia for women in labor, is other times selected for the benefits it can offer in major surgery, such as better pain control (superior to any other analgesia technique) and the reduction of postoperative morbidity and mortality in high-risk patients. However, it is necessary to assess the risk-benefit ratio because this technique is not free of complications. Some may be considered only adverse effects of the drugs used, while others are direct complications from a neurological injury inflicted by needle trauma, infections, toxic effect of the drugs applied, or a compromised spinal cord due to ischemia or compression due to bruises or abscesses, and may be serious.1

It is necessary to assess the risk-benefit ratio at decision-making time. Historically, the reported probability of a serious injury has been of 0.005% to 0.7%. Recent series, however, report that although serious injuries derived from an epidural hematoma or an abscess can be observed in 0.6 obstetric cases out of 100,000, up to 17 cases per 100,000 occur in non-obstetric cases.2 In another recent series, it was documented that the joint probability of hematoma or epidural abscess occurred in up to 1 in every 1,026 blocks.

The following are some of the most important complications:

a. Post-dural-puncture headache (25%) - is more frequent in young patients after accidental meningeal puncture. Its incidence has decreased due to the use of smaller, non-cutting trocars.

b. Back pain (18-25%) - is a frequent cause of discomfort and of patient rejection of future regional anesthesia. It is usually an acute self-limiting pain.

c. Hypotension (12-23%) - presents a systolic pressure below 100mmHg or a decrease in

systolic pressure by 20%.(1) It is produced by the blockage of sympathetic preganglionic fibers, causing distal vasodilatation and accentuated by the position that the patient must maintain after the application (dorsal decubitus).

d. Neurological complications - they have the lowest incidence but are the main source of fear before the procedure is performed. Clinically, they are characterized by nuchal rigidity, intense headache, local pain, fever, leukocytosis, weakness of the lower extremities (after the fourth day) and paraplegia (24 hours after weakness of the extremities). It is defined as permanent damage to the spinal cord and/or its nerve roots. The main etiological factors are the (direct or indirect) damage produced by a trocar or catheter, neurotoxicity of local anesthetics, spinal cord ischemia due to hematoma or vasoconstriction, and infection producing temporary or permanent paralysis.

e. Pneumocephalus is a collection of air in the intracranial compartments, intraventricular, subarachnoid, subdural, or extradural. It is a rare complication of epidural anesthesia that occurs when air is injected accidentally into the subarachnoid space with the loss-of-resistance technique. This technique has been associated with other complications such as compression of the cauda equina and a high rate of dural puncture. Clinical manifestations of pneumocephalus include frontal headache, paresthesias, meningeal signs, changes in blood pressure, loss of consciousness, and mydriasis. The diagnosis is confirmed with CT or MRI. It usually reabsorbs spontaneously in less than 3 days if its origin was an epidural anesthesia.



37

Case report

A 38-year-old female patient underwent a hysterectomy due to the presence of uterine fibroids. For the anesthetic procedure, a regional block using an epidural was performed. The immediate postoperative period went without complications for both the surgical operation and the anesthetic procedure. At 24 hours, in the hospital ward, the patient suffered a severe headache of a 9/10 scale, dizziness, and unsteadiness when walking. The Anesthesiology service counteracted those symptoms. Not yielding to intravenous analgesia like local patches, they requested interconsultation with the Neurology service. The patient was examined and a meningeal sign associated with intense headache was detected. A cranial tomography was indicated and the presence of air

in the skull and spine was observed. (Figures 1-3) Pneumocephalus was diagnosed and treatment started consisting of hydration, antibiotic therapy, intravenous steroids, and consultation with the hyperbaric medicine service of the Central Military Hospital. At 72 hours from onset, a session was performed using hyperbaric oxygen at 3 ATAS for 90 minutes in a multi-place chamber twice a day, resulting in improvement of the symptomatology by diminishing the headache at 30 minutes into the session and decreasing the rigidity at 60 minutes into the session. She was discharged without complications. A control tomography of the skull showed a reduction in the amount of intracranial air that had been observed in the first study. (Figures 4-6)

Figure 1,2 y 3. Neuro-axis tomography with the presence of air before therapeutic measures.



38

Figure 4,5 y 6. Tomography after therapeutic measures, including the hyperbaric chamber.



39

DiscussionIt is important that the patients are well informed about the epidural procedure and its possible complications so they can fully cooperate at the time the puncture is performed. It should be applied only in the cases when it is indicated so that it really is a useful tool and not an added complication. Risk-benefit ratios should always be considered.

Although multiple and varied complications have been reported, it should be noted that they are rare, so patients and practitioners should not be afraid to use epidural anesthesia since it is a great advance in the branch of anesthesia and a great help to both the patient and the treating doctor. With respect to hyperbaric medicine, it is a complementary systemic treatment in which 100% oxygen is breathed at an atmospheric pressure higher than normal (760 mmHg at sea level) in a pressurized environment (hyperbaric chamber) at pressures of 1.5-3.0 ATA (Atmosphere Absolute). It is a safe procedure with few side effects when used safely by qualified medical and technical personnel and with an appropriate selection of patients. The first indications regarding the usefulness of the Hyperbaric Oxygen Therapy were for decompression sickness and gas embolism related to the practice of scuba diving and carbon monoxide poisoning, with subsequent applications in different fields of medicine. The hyperbaric chamber is currently one of the most effective options to treat pneumocephalus that occurs as a complication of surgical, diagnostic, and therapeutic events (iatrogenic gas embolism), or diving (which is less frequent).



40

Conclusions

Epidural anesthesia is a safe and effective technique, though not without risks such as the ones we have mentioned. Many of these complications can be avoided by having a qualified and knowledgeable practitioner perform the most appropriate technique for its specific case. In special cases, the use of hyperbaric oxygen for the adequate management of, in this case, pneumocephalus, is an effective and safe therapy to treat air embolisms and their complications.





41

1. Kane RE. Neurologic deficits following epidural or espinal anesthesia. Anest. Analg. 60:150-161, 1981.

2. Kenjiro M, Koh S. Correspondence: Epidural Ketamine does not produce analgesia. Anesthesiology. 68:296-297, 1988.

3. Miller, Ronald D. Anesthesia. Fourth edition. Churchill Livingstone Inc. Estados Unidos. 1994, pags 1527-153.

4. Parras MT, García PL, Ceballos J. Neumoencéfalo como complicación de punción dural inadvertida en analgesia epidural. Rev Esp Anestesiol Reanim. 2010; 57: 259-61.

5. Kozikowski GP, Cohen SP. Lumbar puncture associated with pneumocephalus: report of a case. Anesth Analg. 2004; 98:524-6.

6. K.K. Jain, Cerebral Air Embolism, Textbook of Hyperbaric Medicine. 5th revised and updated edition. 2009: 103-110.

7. Gupta R, Vora N, Thomas A (2007) Symptomatic cerebral air embolism during neuro-angiophic procedures: incidence and problem avoidance. Neurocritic Care. 7:241-246.

8. Jorgensen TB, Sorensen AM, Jansen EC (2008) Iatrogernic systemic air embolism treated with hyperbaric oxygen therapy. Acta Anaesthesiol Scand. 52: 566-568.

9. V. Romero Laguna, A. Rodríguez Molina, L. Domínguez Gómez, M.J. Regaña Feijoó, T. Díaz Antonio y M.M. García Gallardo Hospital Clínico Virgen de la Victoria, Málaga, España. Radiología. 2016;58(Espec Cong):1466.

References


Original contributionAutism and Theory of Mind

42

Developing Emotional, Neurocognitive, and Social Skills in Children with Autism: Evaluation and Intervention through Social Role-Playing

Desarrollando habilidades emocionales, neurocognitivas y sociales en niños con autismo. Evaluación e intervención en juego de roles sociales


Cristian Villanueva-Bonilla,1 Jasmín Bonilla-Santos,2 Ángela Magnolia Ríos-Gallardo,3 Yulia Solovieva.4

1Psychologist, South Colombian University. Young Researcher at Colciencias. Dneuropsy Research Group. South Colombian University.2PhD. Cognitive Neuroscience. Psicosaberes Research Group. Cooperative University of Colombia.3PhD. Cognitive Neuroscience. Dneuropsy Research Group. Vice-Rector Research and Social Projection, South Colombian University.4Master's Degree in Neuropsychology, School of Psychology, Autonomous University of Puebla, Mexico.

AbstractIntroduction: Autism is a neurodevelopmental disorder that is characterized by difficulties with socialization, communication, and cognition as well as repetitive and unusual behaviors. Social role-playing is a guiding activity that produces positive changes in children’s development in terms of imagination, voluntary activity, language, reflexive thought, and conversational abilities.

Objective: To describe the effect of an intervention program on emotional, neurocognitive and social skills in three children with autism spectrum disorder (ASD).

Methods: A multiple-case design, based on the principles of the microgenetic method, was used to determine the emotional, neurocognitive, and social characteristics of three children with autism following the application of an intervention program involving social role-playing. Case 1: A 9-year-old child with poor identification and emotional expression, as well as difficulties in maintaining fluent and coherent conversations. Case 2: A 10-year-old child with mechanical language, poor fluency, and difficulty initiating and maintaining conversation. Case 3: An 8-year-old girl presents deficits in nonverbal communicative behaviors used in social interaction and difficulties in adapting to non-daily situations.

Results: Positive changes in emotional identification, understanding, and expression as well as mental states and social language. The children also demonstrated improvements in their cognitive and social abilities following the intervention program. The above results should be interpreted carefully because of the preliminary character of the study. A larger sample that allows the generalization of the results is suggested for future investigations.

KeywordsAutism, emotional abilities, social abilities, role-playing, theory of mind.



43

Resumen

Introducción: El autismo es un trastorno del neurodesarrollo, se caracteriza por dificultades en la socialización, comunicación, cognición y conductas repetitivas e inusuales. Por su parte, el juego de roles sociales es la actividad rectora que propicia cambios positivos en el desarrollo de los niños en aspectos como la imaginación, actividad voluntaria, lenguaje, pensamiento reflexivo y habilidades conversacionales.

Objetivo: Describir el efecto de un programa de intervención sobre las habilidades emocionales, neurocognitivas y sociales en tres niños con trastorno del espectro autista (TEA).

Métodos: Se utilizó un diseño de caso múltiple, orientado por principios de metodología microgenética para determinar las características emocionales, neurocognitivas y sociales de tres niños con autismo posterior a la aplicación de un programa de intervención basado en el juego de roles sociales. Caso 1: Niño de 9 años de edad, con escasa identificación y expresión emocional, así como dificultades para mantener conversaciones fluidas y coherentes. Caso 2: Niño de 10 años de edad, con lenguaje mecánico, poco fluido y dificultades para iniciar y mantener una conversación. Caso 3: Niña de 8 años de edad, presenta déficits en conductas comunicativas no verbales usadas en la interacción social y dificultades para adaptarse a situaciones no cotidianas.

Resultados: Se evidencian cambios positivos en la identificación, comprensión y expresión emocional, estados mentales y lenguaje social. Además, los niños presentaron mejoría en sus habilidades cognitivas y sociales después del programa de intervención. Los resultados mencionados se deben interpretar cuidadosamente debido al carácter preliminar del estudio. Se sugiere para futuras investigaciones una muestra mayor que permita la generalización de los resultados.

Palabras claveAutismo, habilidades emocionales, habilidades sociales, juego de rol, teoría de la mente.

Corresponding Author: Ps. Cristian Villanueva-Bonilla. Facultad de Salud de la Universidad Surcolombiana, contiguo Hospital Universitario Hernando Moncaleano. Calle 9 carrero 4. Neiva, Huila, Colombia. Phone.: (57) (8) 8718310. Ext. 3137. E-mail: [email protected]



44

Introduction

Methods

Autism is a neurodevelopment disorder characterized by difficulties in socialization, communication, cognition, and repetitive and unusual behaviors with different levels of severity that occur in the first years of life.1 In 1985, autism was related to difficulties specific to Theory of Mind (ToM). The research conducted allowed inferring that this process was part of one of the deficits that people with autism have. ToM is a complex process, which requires skills to make inferences about what other people may be thinking or feeling and the difficulties in perceiving such mental states are manifested in communication and social interaction problems.2,3 Investigations grew exponentially from the aforementioned studies, as evidenced by some reviews.4,5 ToM is currently defined as the ability to understand and predict other people's behavior, knowledge, intentions, and beliefs and has different levels of complexity.6

The social difficulties associated with the ToM deficits in children with autism raise the need for a progressive and comprehensive evaluation and intervention, including the assessment of psychological, cognitive, and emotional processes in order to characterize the essential aspects of its stage of development in terms of strengths and difficulties. The intervention process was performed with social role-play, which is defined as the preschool activity that allows consolidating important formations such as directed social communication, reflection, and shared actions, formations which occur to a lesser extent in children with autism.7 Role-play is an essential activity for the development of peer contact, which shares a single objective among everyone and does not require isolated participation from each individual.7 The game must be initiated and regulated independently by the children to make way for the development of their creativity. The child develops the ability to understand the representation of a specific role and its interaction with the other, learning to see himself through the eyes of others, which is an essential component of ToM.8

ParticipantsThe databases of the possible participants were provided by institutions providing health services specialized in caring for people with autism, Down syndrome, pervasive developmental disorders, attention-deficit/hyperactivity disorders, and other pathologies that affect behavior through professionals in the branches of physiotherapy, speech therapy, psychology, occupational therapy, and special education. Six children fulfilling the characteristics required by the study (inclusion criteria) were pre-selected. The relatives of these children were contacted and informed about the research and the possibility of participation. Three children were finally selected, with the signature and authorization of the parents.

Inclusion criteria• Diagnosis of autism. A consensus of professionals in pediatrics, clinical psychology, neuropsychology, neurology, and psychiatry. Diagnostic criteria of the DSM-V.12

• Age between 7 and 11 years old. The authors indicate this age range as the appropriate one to generate changes in the cognitive and communicative areas from social role-play.7

The methodology of social role-play and the ToM are the axes of the intervention program developed in this study. The scientific evidence of the methodology indicates positive changes in cognitive and social areas.9-11 In addition, numerous investigations that specifically intervene in components or precursors of ToM cited in a systematic review, empirically support the creation and implementation of the intervention program.4

The objective of this research is to describe the effect of an intervention program on emotional, neurocognitive, and social skills in three children with autism spectrum disorder (ASD).



45

• Level 1 and Level 2 of the three ranges of severity of autism established in the DSM-V.12

Clinical casesCase 1 (J1)A nine-year-old boy with a diagnosis of autism. In the prenatal history, the mother reported anemia and headache during the last month of pregnancy. The delivery was natural and full term. The motor development (head control, sitting, crawling, standing, walking, sphincter control) and language (eye contact, babbling, joined two words, said three words, constructed sentences) were appropriate until 24 months, after which a progressive involution was generated in the child's psychomotor development. The child received physical, language, and behavioral therapy from age six. History of recurrent difficulties of adaptation to the school environment. Currently, there are difficulties in interaction and social communication in his daily life, expressed through scarce emotional identification and expression as well as deficits in the proper maintenance of fluent and coherent conversations with other people. According to the clinical history and the initial cognitive evaluation for this study, the child had difficulties in the cognitive domains of attention and understanding of language, which were evidenced in inappropriate resolutions of tasks that required follow-up of instructions and cognitive effort. J1 presented simple stereotyped movements, extreme discomfort with small changes related to subjects of his taste, restricted interests, and sensory hyperreactivity to auditory stimuli. He was not in school during the development of this intervention program.

Case 2 (J2)A 10-year-old boy with a diagnosis of autism. The prenatal history reported that the mother suffered from toxoplasmosis. The delivery was natural and full term. The motor and language development was appropriate until 24 months, after which a progressive involution was generated in the child's psychomotor development. The child started to

receive behavioral therapy at four years of age. Adaptation to the school environment with the permanent accompaniment of a therapist. Currently presented difficulties in communication and social interaction, simple stereotyped movements, and sensory hyperreactivity to olfactory and visual stimuli. Presented aggressive behaviors due to the inability to perform some tasks that required cognitive effort (cognitive flexibility, behavior planning and organization). Maintained a constant attention level with academic tasks and adapted with difficulty to everyday situations.

Case 3 (J3)An eight-year-old girl with a diagnosis of autism. The prenatal history reported there was a threat of miscarriage. The birth was natural and full term. The motor development was appropriate. Language acquisition presented the following characteristics: babbling at two months, joined two words at 12 months, said three words at 18 months and built sentences at four years ("the girl was quiet all the time"). J3 received phonoaudiology therapy since the age of two. She currently had difficulties with non-verbal communicative behaviors used in social interaction in different areas of her daily life, expressed as difficulties maintaining eye contact and expressing emotions. Her expressive language was automatic, poorly articulated, and dysprosodic, presenting poor emotional control, simple stereotyped movements, extreme discomfort to changes in routine, and difficulties adapting to non-everyday situations. Adopted a rigid and strict thinking pattern. During the research, she was in second grade of primary school, without any type of school support. Her behavior and inflexible thinking caused her difficulties in her school environment.

DesignThis was a within-subjects, quasi-experimental, pre-post research design guided by principles of microgenetic methodology.8 It allowed a detailed approach to the emotional, neurocognitive, and social processes of the children through the



46

intervention program.13 This design was used in order to record the greatest number of behaviors in a sequence of time and, in turn, to identify the occurrence of changes in emotional and social skills.

The research protocol and informed consent were approved by the Research Ethics Committee of the Faculty of Health of the South Colombian University.

Evaluation instrumentsPediatric Neuropsychological Evaluation (PNE)Assesses the neurocognitive component (construction skills, memory, attention, and executive functions, among others) in children between 5 and 16 years of age.14 Inter-rater reliability ranged between .874 and .987 and statistically significant correlations were recorded with most of the subtests of the Wechsler Intelligence Scale for Children (WISC-R).15

Emotion recognition test of facial expressionsThe test consists of 36 videos that represent the basic emotions (joy, sadness, anger, surprise, fear, and disgust) used to evaluate the identification of basic emotions. It does not have psychometric properties.6

Autonomous Scale for the Detection of Asperger Syndrome and High Functioning Autism (ASDA)This instrument was given to the relatives and teachers. It is composed of 18 items evaluating six dimensions: social skills, fiction and imagination, cognitive processes, mentalistic abilities, executive functions, language and communication and the scores range from 1 to 4 (1 represents the appropriate level expected of a child of this age). Reliability, internal consistency =.97; Inter-rater reliability =.87; Test-retest reliability =.94 and .97 in parents and teachers respectively.16

Australian Scale for Asperger Syndrome (ASAS)Designed to identify social and emotional skills, communication, cognitive skills, specific interests, and motor skills that may be indicative of Asperger syndrome in children during their early school years.17 Consists of 24 questions to apply to

parents or teachers which are scored from 0 to 6 (0 represents the appropriate level expected of a child of this age). Reliability of 0.88 through the Cronbach alpha test.18

Observational Instrument of Emotional Behaviors (OIEB)It assesses the level of identification, expression, and comprehension of six dimensions or basic emotions in contextual situations (joy, sadness, anger, surprise, fear, and disgust) and allows registering defined behaviors in a fixed period of time. It was designed for this investigation based on the levels of complexity of the ToM6 and was validated by expert judges in the areas of research, autism, and ToM (content validity). One researcher listed in each of the sessions the frequency in which the corresponding behavior was presented.

ProceduresTaking into account the aforementioned classification by levels, the ToM skills intervention program (Figure 1) was structured as follows:1. Basic emotions (joy, sadness, anger, fear, surprise, disgust). Objective: to enable children to recognize, understand, and express verbally and with a facial expression each of the basic emotions through play activities. 2. Mental states of belief (first and second order).Objective: to enable children to recognize, understand, and express mental states of belief of first and second order through play activities.3. Social language (lie, pious lie, and irony).Objective: to enable children to recognize, understand, and appropriately use social language through play activities.

The program consisted of 25 face-to-face sessions of play activities, 24 pencil and paper activities that were developed by the children with the help of their family members in order to appropriate and reinforce what they learned in face-to-face activities, and three sessions of psychoeducation aimed at people who share daily life with the child (family, therapists, teachers). The implementation of the program was performed throughout 13 weeks. Face-to-face activities were held twice



47

a week at the facilities of the South Colombian University, in a place conditioned according to the didactic specifications required for the activities. Each week consisted of two face-to-face activities and one or two "at home" activities. At the end of the last session every week, the child's family member or companion was given a paper and pencil "at home" task for the next meeting. Each "at home" activity was directly related to the contents reviewed in the face-to-face play sessions. Over the course of the 13 weeks, the three psychoeducational sessions were distributed equally among the children's family members, therapists, and teachers.

An active game with rules was used in the first phase of the program. It was characterized by not having roles distributed among the participants and by having clear rules about their execution. To fulfill the study's objectives for each of the phases, children's games that could be adapted to teach

ToM skills were taken into consideration, such as a collage of emotions, a roulette of emotions, and the mural of emotions, among others.

Social role-playing was performed with themes and characters proposed by the researchers according to the tastes and interests of the participants and adapted to fulfill the objectives set out in the final phase of the program (the circus, the soccer match, the hospital, the birthday party, the school, and the chef, among others). For example, in "the chef," the children were invited to a TV show where the chef asked them to prepare a fruit salad. The children had to identify the fruits that were in good condition but, if any were not, they needed to make the expression of disgust, and the chef thanked them for their participation. The children took different roles during the session: chef, assistants, and spectators.

All the group activities included the three children

Figure 1. IDEAS - Intelligence, Emotional Development, and Social Activity Intervention Program.

OBJETIVETo help children with autism develop the ability to recognize, understand, and express basic emotions as well as to recognize, understand, and express mental states of belief and the practical use of social lenguage. (Theory of Mind skills.)

Twenty activities (45-60 minutes per activity):

Ten object play and social role-play activitiesNine pencil and paper activitiesOne psychoeducational activity

BASIC EMOTIONS(Joy, sadness, anger, surprise,

fear, disgust)

MENTAL STATES OF BELIEF

(First and second order)

SOCIAL LENGUAGE(Lie, while lie, irony)

DRAWING OBJECT PLAY

GUIDING PRINCIPALES

SOCIAL ROLE PLAY

E.g. Guided by the researches, the children draw and color, step by step, one of the stories about social use of

lenguage (irony).

E.g. “How do you express the emotion of...?” Facing a mirror, “How do you express the emotion of...?”“Most people express the emotion of... in this way.” “How do you feel?” Faces with the basics emotions distributed all over the place.

E. g. Roulette with each of the six emotions to work on. Each child

comes forward and spins the roulette. When the roulette stops,

the child represents the corresponding emotion.

E. g. The circus. Purchasing tickets. Going into the circus. Locating the

seats. The ringmaster making an entrance.

Presenting the clowns.Spectators participating (children)

In the role of clowns.

Sixteen activities (45-60 minutes per activity):

Eight object play and social role-play activitiesSeven pencil and paper activitiesOne psychoeducational activity

Sixteen activities (45-60 minutes per activity):

Eight object play and social role-play activitiesSeven pencil and paper activitiesOne psychoeducational activity

“IDEAS”INTERVENTION

PROGRAM



48

ResultsThe results obtained in the emotional skills, cognitive abilities, and social skills of the three children participating in the research are described next.

Emotional skillsEmotional identificationThe three children presented a greater number of correct answers after the execution of the first phase (Posttest 1) and at the end of the intervention program (Posttest 2) compared to the initial evaluation (Figure 2). J1 and J2 showed positive inter-phase changes (Posttest 1-Posttest 2).

participating in the research and, on several occasions, the relatives or companions and the researchers participated as well. The roles within each activity were distributed in a coherent manner corresponding to each child's stage of development within the program, always geared towards each child's learning benefit. The concept of a guiding principle, defined as "the theoretical and practical information that helps a subject perform a specific action," was taken into account while planning the game activities.7 The guiding principle was focused on achieving the proposed objectives, for example: in order to enable the children to identify the facial expression of each emotion, images of the expressions were distributed in the play area (images that guided the course of the action).

The researchers determined the roles considering the characteristics of each participant and their level of cognitive development; in addition, the roles were redistributed each session based on the progress and performance achieved in previous sessions by each child. During all the face-to-face activities, the people who lived with the child had the opportunity to observe and take an active role in the activity in order to generate an appropriation of the strategies used during the course of the program. Each child was accompanied by a researcher during each session to facilitate the learning process.

Identification, understanding, and emotional expressionA positive overall change in the basic emotions behavior was evidenced (name the emotion, express the emotion verbally, and express the emotion facially, denominate the emotion in images, and recognize the emotion in other people, identify-justify adequately the emotional situation). In general, the ascending tendency for each of the emotions in the three children was evident (Figure 3).

Cognitive skillsThe percentage of correct responses by neurocognitive subdomain in pre- and posttest evaluation was recorded (Table 1).

A percentage increase in neurocognitive subdomains was observed after the execution of the IDEAS program. The three children presented the highest percentage of correct answers in tasks that evaluated construction skills, perceptual skills, attention, conceptual skills, and reading. In addition to the percentage increase in successes in the subdomains mentioned above, J1 showed positive changes in memory (coding and evocation), language (expression and comprehension), metalinguistic and spatial skills, graphic fluency, cognitive flexibility, planning and organization, writing, and arithmetic. J2 also showed positive changes in memory (evocation), metalinguistic abilities, and arithmetic (counting). J3 presented a higher percentage of successes in planning and organization.

Social skillsThe ASDA showed a decrease in the average score in the three cases (Figure 4). J1 presented positive changes in social and mental skills according to parents and therapist, and the mother reported improvement in language and communication. In addition, the total average score of the scale decreased according to the parents. J2 presented positive changes in language and communication, social skills, mentalistic abilities, and in the total scale according to the mother. The therapist scored positively on social skills, language and



49

Figure 2. Pre-, Post-1, and Post-2 evaluations in facial recognition of emotions. In parentheses, total number of possible correct hits.



50

Figure 3. Total trend for basic emotion behaviors (J1-J2-J3). J1 did not attend three activities. J2 and J3 did not attend one activity.



51

Table 1. Percentage of hits per neurocognitive subdomain.

Domains, subdomains

Skills constructionConstruction with sticks

Skills graphic

Memory (coding)Verbal-auditory

Visual

Memory (evocation)Verbal-auditory

Visual

Skills perceptualTactile

Visual

Auditory

LanguageRepetition

Expression

Understanding

Skills metalinguistic Skills spatialAttentionVisual

Auditory

Skills conceptualExecutive functionsGraphic fluency

Cognitive flexibilityCorrect answers

Perseverative answers

Number of categories

Planning and organization

ReadingPrecision

Understanding

WritingPrecision

Narrative understanding

ArithmeticCounting

Arithmetic handling

Calculus

Mathematical reasoning

Pretest

50 %

72 %

33 %

38 %

25 %

30 %

81 %

42 %

44 %

78 %

1 %

33 %

0 %

45 %

2 %

7 %

0 %

6 %

61 %

19 %

33 %

82 %

97 %

8 %

26 %

0%

38 %

22 %

0 %

0 %

Posttest

88 %

70 %

38 %

50 %

38 %

38 %

88 %

62 %

56 %

75 %

4 %

61 %

25 %

75 %

20 %

13 %

3 %

14 %

61 %

35 %

67 %

94 %

100 %

23 %

78 %

0 %

50 %

22 %

0 %

13 %

Pretest

50 %

68 %

29 %

38 %

22 %

22 %

94 %

50 %

53 %

84 %

2 %

61 %

44%

33 %

15 %

27 %

6 %

28%

50%

64 %

52%

94%

97 %

8 %

85 %

0%

38 %

53 %

43 %

13 %

Posttest

88 %

66 %

19 %

31%

25 %

30 %

88 %

66 %

81 %

81 %

2 %

59%

75 %

28%

26%

60%

28 %

26%

46 %

45 %

48 %

92 %

100%

31 %

67 %

0 %

63 %

53 %

40 %

13 %

Pretest

38 %

55 %

100 %

48 %

97 %

27 %

53 %

31 %

29 %

48 %

95%

Posttest

75%

59%

88 %

70 %

84 %

79 %

42 %

40 %

50 %

25%

84 %

100%

62%

Case 1 Case 2 Case 3a

a Professional external assessment prior to the investigation.



52

communication, and full scale. J3 presented improvement in social skills and total scale according to the mother. The therapist scored positively on language, communication, and full scale.

The results of the ASAS showed a decrease in the average score in the three cases (Figure 5). J1 presented positive changes in social and emotional skills, communication, and full scale according to the father and the therapist. J2 presented positive changes in all the areas evaluated by the scale according to the mother. J3 also presented positive changes in all the areas evaluated according to mother and therapist.

The individual differences of children diagnosed with autism create difficulties when determining whether interventions have an impact on their social skills. For this reason, multiple case designs are a viable option to evaluate the changes in children over time and during each of the phases of the intervention program.19 Trends in each of the assessments suggest that the effect of the intervention generated positive changes in the children's emotional, cognitive, and social skills.

Children with autism present difficulties establishing social contact with other people, which are related to the inability to recognize, understand and express emotions, intentions, thoughts, and beliefs.4 These difficulties are reflected in the activities they perform in their daily lives, generating problems at school, at home, and at other social spaces.5,20 The children who took part in this research presented similar characteristics, creating difficulties when trying to adapt to their school environment. The essential purpose of the research was to generate positive changes in the social skills of the children and, therefore, in the different capacities that contribute to the establishment of an optimal social relationship (emotions, mental states of belief, social language, attention, memory, and executive functions among others).

Discussion

The intervention program was designed to promote ToM skills in children diagnosed with autism, taking into account their individual characteristics. Different game strategies were implemented (active game, drawing, and role-play) in an environment of inclusion, where the child's family played an active role. The external activity (the game) determined the psychic development (created the zone of proximal development) and constituted the guiding activity.21 The accompaniment of the adult is essential in the development and consolidation of abilities in the children. It's important to involve the family in the phase of psychoeducation and treatment in order to generate lasting changes over time.22,23 Children live in a social and cultural space that includes their family and educators. The learning process must be holistic and integrated as established in the research.

Some reviews suggest implementing intervention programs that affect the communicative and social aspects of children with autism.20,24 For this reason, the role-play methodology was used, allowing the simulation of habitual situations in order to achieve the generalization of the skills learned by children in their social context. In addition, a group intervention program was implemented together with an individualized accompaniment, establishing the progressive evolution of learning and possibly favoring the development of social skills in children with autism.25,26

These social skills must be measured over time in the child's clinical, social, and family situations. The evaluative and formative process must be continuous and framed in the individual differences, therefore, differences should not be measured only in pre- and post-intervention evaluations because communicative, cognitive, and emotional changes are constant in early stages of development.27-29 The assessment made during the execution of the program indicated positive changes in the identification, comprehension and emotional expression and these changes positively influenced the social skills of the children according to the adaptive scales applied to parents and therapists (ASDA, ASAS).



53

Figure 4. Pre-Post evaluation. Autonomous Scale for the Detection of Asperger Syndrome and High Functioning Autism (ASDA).

Average score. Father (P), Mother (M), and Therapist (T).



54

Figure 5. Pre-Post evaluation. Australian Scale for Asperger Syndrome (ASAS).Average score. Father (P), Mother (M), and Therapist (T).



55

The children increased their number of successes in the identification of emotions after the first phase of the program and at the end of the intervention. They also presented a greater number of expressive behaviors and understanding of emotions during the development of the program. From there, a generalization of these behaviors was presented in the social context of the children, according to the results of the adaptive scales. Recent research indicates that emotional skills have a positive impact on the social skills of people with autism, which is why the results obtained in this research are highlighted.30,31

The changes generated in the emotional and social abilities of the children opened the possibility of changes at the neurocognitive level. The interaction within a social context requires the joint effort of different cognitive abilities that seek to adjust to the complex norms of a social organization. The development of ToM skills possibly influenced the improvement of such abilities, considering the functional interdependence of the attentional, executive, and metacognitive processes described in the literature.32,33

Finally, the results obtained indicate that the emotional and social abilities of the children participating in the research increased, in addition to generating positive changes in attentional, visual-construction, comprehensive, and executive processes. The group intervention programs based on flexible play activities adapted to the individual characteristics of each child, which focus on emotional, cognitive and social areas and included the family and people from their social environment, reported positive results in other investigations.4,5,20,22,23 However, these results must be interpreted carefully due to the preliminary nature of the study. A larger sample that allows a generalization of the results is suggested for future investigations.



56

Conclusion

In this study, we described the effect of an intervention program on emotional, neurocognitive, and social skills in three children with ASD of eight, nine, and ten years of age. We used a pre-post quasi-experimental within-subject design, guided by principles of microgenetic methodology in order to address in detail the social skills of children during the intervention program. Neuropsychological assessment instruments, emotional recognition tests, and behavioral and social measurement scales were used. The intervention program consisted of 25 face-to-face sessions of play activities, 24 pencil and paper activities, and three sessions of psychoeducation aimed at the people who share everyday life with the child (family, therapists, teachers). In conclusion, the program generated changes in the identification, expression, and comprehension of basic emotions in the children and had a positive impact on their social skills according to the perception of their parents, teachers, or therapists, measured through behavioral scales. In addition, attentional, visual-construction, comprehensive, and executive changes were presented after the end of the program

Conflicto de interesesThe authors declare there are no relevant conflicts of interest in this study.

Fuentes de financiamientoVice-presidency of research and social projection of the South Colombian University, Colombia. Cooperative University of Colombia, Neiva headquarters.



57

1. Volkmar F, Siegel M, Woodbury-Smith M, King B, McCracken J, State M. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2014; 53: 237-257.

2. Baron-Cohen S, Leslie AM, Frith U. Does the autistic child have a ´theory of mind´? Cognition. 1985; 21: 37-46.

3. Baron-Cohen S. Theory of mind in normal development and autism. Prisme. 2001; 34: 174-183.4. Fletcher-Watson S, McConnell F, Manola E, McConachie H. Interventions based on the Theory of

Mind cognitive model for autism spectrum disorder. Cochrane Database Syst Rev. 2014; 3: CD0087855. Bishop-Fitzpatrick L, Minshew N, Eack S. A systematic review of psychosocial interventions for

adults with autism spectrum disorders. J Autism Dev Disord. 2013; 43: 687-694.6. Tirapu J, Pérez G, Erekatxo M, Pelegrín C. ¿Que es la teoria de la mente? Rev Neurol. 2007; 44: 479-

489.7. Solovieva Y, Quintanar L. La actividad de juego en la edad preescolar. México DF: Trillas; 2012.8. González-Moreno CX, Solovieva Y, Quintanar L. Actividad reflexiva en preescolares: perspectivas

psicológicas y educativas. Universitas Psychologica. 2011; 10: 423-440.9. Morales M, Lázaro E, Solovieva Y, Quintanar L. Evaluación y corrección neuropsicológica del

lenguaje en la infancia. Pensamiento Psicológico. 2014; 12: 39-53.10. Solovieva Y, Mata A, Quintanar L. Vías de corrección alternativa para el Trastorno de Déficit de

Atención en la edad preescolar. CES Psicología. 2014; 7: 95-112.11. Solovieva Y, González-Moreno CX, Quintanar L. Developmental analysis of symbolic perceptual

actions in preschools. British Journal of Education, Society & Behavioural Science. 2016; 15: 1-13.12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.).

Arlington, VA: American Psychiatric Association; 2013.13. Garcia-Mila M, Gilabert S, Rojo N. El cambio estratégico en la adquisición del conocimiento: la

metodología microgenética. Infancia y Aprendizaje. 2011; 34: 169-180.14. Rosselli-Cock M, Matute-Villaseñor E, Ardila-Ardila A, Botero-Gómez VE, Tangarife-Salazar

GA, Echeverría-Pulido SE, et al. Evaluación Neuropsicológica Infantil (ENI): Una batería para la evaluación de niños entre 5 y 16 años de edad. Estudio normativo colombiano. Rev Neurol. 2004; 38: 720-731.

15. Matute E, Rosselli-Cock M, Ardila A, Ostrosky-Solís F. Evaluación Neuropsicológica Infantil. México DF: Manual Moderno; 2007.

16. Belinchón M, Hernández J, Sotilo M. Personas con síndrome de Asperger: funcionamiento, detección y necesidades. Madrid: CPA-UAM; 2008.

17. Attwood T. El síndrome de Asperger. Barcelona: Paidós; 2002.18. Ojea M, Diéguez N. Programa de desarrollo de habilidades sociales “PDHS” aplicado a estudiantes

con síndrome de Asperger. Revista Galego-Portuguesa de Psicoloxía e Educación. 2011; 19: 227-242.19. Wang SY, Parrila R, Cui Y. Meta-analysis of social skills interventions of single-case research for

individuals with autism spectrum disorders: Results from three-level HLM. J Autism Dev Disord. 2013; 43: 1701-1716.

20. Warren Z, McPheeters ML, Sathe N, Foss-Feig JH, Glasser A, Veenstra-VanderWeele J. A systematic review of early intensive intervention for autism spectrum disorders. Pediatrics. 2011; 127: e1303-1111.

21. Vygotsky L. The methods of reflexological and psychological investigation. Selected Works, Vol 1. Madrid: Visor; 1991.

22. Karst JS, Van Hecke AV, Carson AM, Stevens S, Schohl K, Dolan B. Parent and Family Outcomes of PEERS: A Social Skills Intervention for Adolescents with Autism Spectrum Disorder. J Autism Dev Disord. 2015; 45: 752-765.

23. Woodman AC, Smith LE, Greenberg JS, Mailick MR. Change in Autism Symptoms and Maladaptive Behaviors in Adolescence and Adulthood: The Role of Positive Family Processes. J Autism Dev Disord. 2014; 45: 111-126.

24. Reichow B, Volkmar FR. Social skills interventions for individuals with autism: Evaluation for evidence-based practices within a best evidence synthesis framework. J Autism Dev Disord. 2010; 40: 149-66.

References



58

25. Kasari C, Dean M, Kretzmann M, Shih W, Orlich F, Whitney R, et al. Children with autism spectrum disorder and social skills groups at school: a randomized trial comparing intervention approach and peer composition. J Child Psychol Psychiatry. 2016; 57: 171-179.

26. Wolfberg P, DeWitt M, Young GS, Nguyen T. Integrated Play Groups: Promoting Symbolic Play and Social Engagement with Typical Peers in Children with ASD Across Settings. J Autism Dev Disord. 2015; 45: 830-845.

27. Kasari C, Smith T. Interventions in schools for children with autism spectrum disorder: Methods and recommendations. Autism. 2013; 17: 2542-2567.

28. Artigas J. Atención precoz de los trastornos del neurodesarrollo. A favor de la intervención precoz de los trastornos del neurodesarrollo. Rev Neurol. 2007; 44(Supl 3): S31-34.

29. Bradshaw J, Steiner AM, Gengoux G, Koegel LK. Feasibility and Effectiveness of Very Early Intervention for Infants At-Risk for Autism Spectrum Disorder: A Systematic Review. J Autism Dev Disord. 2015; 45: 778-794.

30. Rice LM, Wall CA, Fogel A, Shic F. Computer-Assisted Face Processing Instruction Improves Emotion Recognition, Mentalizing, and Social Skills in Students with ASD. J Autism Dev Disord. 2015; 45: 2176-2186.

31. Williams BT, Gray KM, Tonge BJ. Teaching emotion recognition skills to young children with autism: a randomised controlled trial of an emotion training programme. J Child Psychol Psychiatry. 2012; 53: 1268-1276.

32. Ardila A. On the evolutionary origins of executive functions. Brain Cogn. 2008; 68: 92-99.33. Ardila A. Development of metacognitive and emotional executive functions in children. Appl

Neuropsychology Child. 2013; 2: 82-87.


Original contributionBotulinum Toxin A and Oropharyngeal Electrostimulation for Children Sialorrhea

59

Comparing Type A Botulinum Toxin and Oropharyngeal Electrostimulation on Sialorrhea in Children with Cerebral Palsy at the Teletón Center for Rehabilitation and Inclusion for Children in the State of Mexico

Comparación de Toxina Botulínica Tipo A y Electroestimulación Orofaríngea en Sialorrea en Niños con Parálisis CerebralEn el Centro de Rehabilitación e Inclusión Infantil Teletón Estado de México


Maria Adriana Mariscal-Ramos,1 Alejandro Parodi-Carbajal,1 Blanca Gabriel-Legorreta Ramirez,1 Oscar Gabriel Rolón-Lacarriere.1

1 Teletón Center for Rehabilitation and Inclusion for Children in the State of Mexico.

AbstractThis work compares two alternative techniques in the treatment of sialorrhea in children with cerebral palsy: botulinum toxin and oropharyngeal electrical stimulation (VitalStim). There were two study groups, one with botulinum toxin type A and the other with oropharyngeal electrical stimulation, and both groups received motor oral therapy. The drooling measurement form from the Department of Plastic and Maxillofacial Surgery of the Royal Children’s Hospital was used, quantifying the amount of saliva by weighing intraoral cotton rolls placed inside the mouth for two minutes.

Statistical analysis was performed using the SPSS-18 packets and the Mann Whitney and Wilcoxon tests. Thirty-two children were included, 16 in the botulinum toxin group (50%) and 16 in the oropharyngeal electrostimulation group (50%). The study showed that the use of botulinum toxin in the salivary glands (parotid and submaxillary) and treatment with oropharyngeal electrostimulation are useful in the treatment of sialorrhea in children with cerebral palsy with a positive impact on the quality of life; however, there was superiority in results with the use of botulinum toxin.

KeywordsBotulinic toxin, sialorrhea, cerebral palsy.



60

Resumen

Este trabajo compara dos técnicas alternativas en el tratamiento de niños con parálisis cerebral y sialorrea, como lo es la toxina botulínica y la estimulación eléctrica orofaríngea (Vital Stim), Hubo dos grupos de estudio, uno donde se utilizó toxina botulínica tipo A y en el otro estimulación eléctrica orofaríngea, ambos grupos con terapia oral motora; se aplicó el Formulario de medida de babeo del Department of Plastic and Maxillofacial Surgery of the Royal Children’s Hospital, se cuantificó la cantidad de saliva pesando rollos de algodón intraorales colocados dentro de la boca por 2 minutos.

El análisis estadístico se realizó mediante los paquetes de SPSS-18 y las pruebas de Mann Whitney y Wilcoxon. Se incluyeron 32 niños, 16 para el grupo con toxina botulínica (50%) y 16 en el grupo de electroestimulación orofaríngea (50%). El estudio realizado mostró que el uso de toxina botulínica en las glándulas salivales (parótida y submaxilares) y el tratamiento con electroestimulación orofaringea son útiles en el tratamiento de la sialorrea en niños con parálisis cerebral con un impacto positivo en la calidad de vida, sin embargo hubo superioridad en los resultados con el empleo de la toxina botulínica.

Palabras claveToxina botulínica, sialorrea, parálisis cerebral.

Correspondence: Maria Adriana Mariscal RamosAvenida Gustavo Baz 219 Colonia San Pedro Barrientos, C.P.: 54010, Delegación Tlalnepantla. Estado de MéxicoE-mail: [email protected]



61

Introduction

Material and method

Sialorrhea is a symptom that generates disability with a multifactorial etiology: neuromuscular/sensory dysfunction, hypersalivation, and anatomical alterations. Within the first is cerebral palsy (CP), a neurological condition prevalent in pediatrics,22 especially in children with moderate to severe disability5,11 where it can reach up to 58% and become profuse in 33%, the majority of which is spastic quadriplegia.37,40,43

Physical and psychosocial complications include maceration of the skin around the mouth, secondary bacterial infection, bad smell, dehydration, and social stigmatization. There is also a greater risk of aspiration of saliva, food, or liquid into the lungs, especially when there is deterioration of the gag and cough reflexes. All this has a negative impact on the quality of life of the patient and their family or caregivers.11

There is also a deficient mechanism of control of the orofacial, palate, tongue, and head muscles, with aggravating factors such as spasticity, decreased frequency of swallowing, decreased intraoral tactile sensitivity, prolonged protrusion of the tongue, poor dental occlusion, poor head control, and moderate to severe mental retardation.2,5

At rest, 70% of the saliva is produced by the submandibular and sublingual glands. Under stimulation, the flow of saliva increases up to five times, with the parotid gland as the main provider. An adult produces between 1,000-1,500 ml of saliva per day. Children before puberty produce significantly less (750-900 ml per day).4,22,45

Saliva’s functions include mechanical cleaning of the mouth, contribution to oral homeostasis, and pH regulation. It has bacteriostatic and bactericidal properties that contribute to dental health and decrease bad odor. It is important in the lubrication of the food bolus as the amylase it contains starts the digestion of carbohydrates.

Indications for sialorrhea include anticholinergics, tricyclic antidepressants, speech therapy, desensitization techniques, intraoral techniques, elimination of drooling aggravators (such as certain drugs that depress the level of alertness or with muscarinic effect), optimizing the vertical positioning of the head, and achieving the active participation of the subject according to their own cognitive level.5,19,24 In certain cases, surgery is an option.

Intraglandular botulinum toxin type A and oropharyngeal electrostimulation are new treatment options. Several studies have shown the effects are beneficial, very well tolerated, and without reports of significant adverse effects.9,12,14,21-23,26

The effect of botulinum toxin is temporary and, with oral motor therapy, resembles oropharyngeal electrostimulation.

The aim of the study is to compare the application of botulinum toxin type A and oropharyngeal electrical stimulation in the treatment of moderate to severe sialorrhea in children with cerebral palsy, and their impact on the quality of life of the child and the caregiver.

The sialorrhea form of the Department of Plastic and Maxillofacial Surgery of the Royal Children’s Hospital was applied in both groups, using the Thomas-Stonell scale with five severity items and four frequency items, and Likert-type questions.19

To measure the salivation as objectively as possible, the amount of saliva was quantified by weighing intraoral cotton rolls.

It was a quasi-experimental study carried out from July to October 2014 at the Teletón Children Rehabilitation Center in the State of Mexico of children from 4 to 17 years of age who met the requirements and informed consents of their tutors.

There were two study groups, one with botulinum toxin type A and the other with oropharyngeal



62

Figure 1. Sialorrhea according to type of cerebral palsy and study group.

electrical stimulation. Both groups had oral motor therapy. The botulinum toxin type A dose was 60 units distributed in parotid glands and 40 units sublingual bilaterally.

The electrodes placement used were 1, 3a or 3b according to the manual.26 The intensity of the stimulus was between 7 and 25 mA, symmetrical biphasic waveforms, a maximum voltage of 100 volts, pulse of 80 Hz, and pulse duration of 700 ms. During the stimulation, the patient practiced swallowing. Ten sessions were prescribed.

In both groups, the clinical assessment was performed by the specialist in pediatric rehabilitation medicine and by the researcher, applying the sialorrhea form of the Department of Plastic and Maxillofacial Surgery of the Royal Children’s Hospital (annex 1). The amount of saliva

Mixed CP

Hypnotic CP

Dyskinetic CP

Spastic CP-spastic diplegia

Spastic CP-spastic hemiplegia

Spastic CP-spastic quadriplegia

Oropharyngeal electrostimulation group Botulinum toxin group

1

1

11

0

4

33

2

57

4

was quantified by weighing intraoral cotton rolls placed inside the mouth for two minutes. The assessment happened in two stages for both study groups: one at the initial contact and the other in the fourth month of intervention.

This study complied with the Nuremberg Code, the Belmont Report’s ethical principles and guidelines for the protection of human subjects of research, the Declaration of Helsinki’s ethical principles for medical research involving human subjects, the General Health Law regarding health research, and the guidelines and policies of the Teletón Foundation in Mexico.

The statistical analysis was performed with the SPSS-18 program and the Mann Whitney and Wilcoxon tests.

n = 32 patients



63

ResultsThe study included 32 children, 16 for group A (botulinum toxin type A) and 16 for group B (oropharyngeal electrostimulation). The average age was 9 years for both groups, with a range of 4 to 14 years in group A and 4 to 16 years in group B. Both groups presented a homogeneous distribution regarding number, age, and sex.

Spastic quadriplegia was the most common type of cerebral palsy in both groups. (Figure 1) Table 1 shows that the frequency of sialorrhea decreased after the fourth month of intervention in both groups. Botulinum toxin showed clinical superiority but with no significant statistical difference (p=0.05). Regarding the severity of the sialorrhea, there was a decrease in the averages in both groups; however, there was no statistically significant difference between them (p=0.216). (Figure 2)

Frequency of sialorrheaBeginning

After 4 months

Botulinum toxin type A group

3.69

2.13

Oropharyngeal electrostimulation

group3.56

2.50

Table 1. Average frequency of sialorrhea in the study.

n = 32 patients.Source: Sialorrhea measurement form from the Department of Plastic and Maxillofacial Surgery, Royal Children’s Hospital (sialorrhea frequency and severity

scale measured with Thomas-Stonell scale).19

Table 2 shows that botulinum toxin showed significantly fewer bib changes compared with the oropharyngeal electrostimulation group (p=0.05).

It was reported that there was no significant difference between the study groups (p=0.085) in the variable of changes of clothes per day. (Figure 3)

Table 3 shows that in both groups the degree of discomfort towards the saliva odor decreased: 5.56 points on the Likert scale for the group with

botulinum toxin and 2.19 points for the group with oropharyngeal electrostimulation.

Table 4 shows that the intensity of perioral dermatitis had no statistically significant change in the groups (p=0.426).

Table 5 shows a decrease in the average of mouth cleaning frequency in both study groups, but without significance (p=0.075).

Table 6 shows a decrease in the impact on the social affectation of the caregivers at the end of the intervention in both groups, with superiority in group A (botulinum toxin type A).

Figure 4 shows that, according to the Wilcoxon and U Mann Whitney test, botulinum toxin type A shows a statistically significant change in terms of

the concern regarding other people’s reaction to the child’s drooling compared to the oropharyngeal electrostimulation group (p=0.038).

Table 7 shows there is no significance in the frequency of saliva cleaning from toys and furniture between the study groups (p=0.135).

Table 8 shows that botulinum toxin type A had a significant decrease in coughing/drowning sensation due to the child’s drooling compared to the oropharyngeal electrostimulation group (p=0.05).



64

Changes of bibsper day

Beginning

After 4 months


4.81

1.75


group5.5

3.81

Table 2. Average number of changes of bibs per day by study groups.

Figure 2. Average severity of sialorrhea by study groups. Thomas-Stonell scale.

Figure 3. Average number of changes of clothes per day by study groups.

Source: Sialorrhea measurement form from the Department of Plastic and

Maxillofacial Surgery, Royal Children’s Hospital.19

FSource: Sialorrhea measurement form from the Department of Plastic and Maxillofacial Surgery, Royal Children’s Hospital (sialorrhea frequency and

severity scale measured with Thomas-Stonell scale).19

FSource: Sialorrhea measurement form from the Department of Plastic and


Botulinum toxin group Oropharyngeal electrostimulation group

4,44

2,63

4,13

3,06

Beginning After 4 months


3,38

0,94

3,06

1,56




65

Table 3. Average discomfort at the smell of saliva by study groups.

Table 4. Average intensity of perioral dermatitis by study groups.

Table 5. Average frequency of mouth cleaning by study groups.

Table 6. Average social affectation of the child’s constant drooling by study groups.









Scale of discomfort at the smell of the salivaBeginningAfter 4 months

GroupBT type A

8.75

3.19


group7.38

5.19

Scale of intensity of perioral dermatitisBeginningAfter 4 months


7.69

2.88


group5.25

3.81

Scale of frequency of mouth cleaningBeginningAfter 4 months


9.38

3.94


group7.63

5

Scale of social affecta-tion by the child's droolingBeginningAfter 4 months

Botulinum Toxin Type A

6.94

2.5


5.5

4.13



66

Table 7. Average cleaning of saliva from toys and furniture by study groups.

Table 8. Average drooling necessary to provoke coughing or drowning by study groups.





Figure 4. Average concern about the reaction of other people to the child’s drooling.



Bolulinum toxin group Oropharyngeal electrostimulation group

6,69

2,38

6,13

4,75


Scale cleaning of saliva from toys and furnitureBeginningAfter 4 months


7.25

2.75


group5.75

4

In Table 9, botulinum toxin type A shows a statistically significant change in the decrease in the affectation of drooling in the child’s life and family compared to the oropharyngeal electrostimulation group (p=0.010).

In Figure 5 it was observed that botulinum toxin type A had a statistically significant change in the

decrease of drooling on close relatives of the child as compared to the oropharyngeal electrostimulation group (p=0.05).

Table 10 shows that botulinum toxin type A had significance in the weight reduction of intraoral cotton (p=0.002).

Scale of drooling necessary to provoke coughing or drowningBeginningAfter 4 months


4.38

1.69


group4

2.56



67

Table 9. Average affectation of the life of the child and the family due to drooling by study groups.

Tabla 10. Average weight of intraoral cotton by study groups..

FSource: Sialorrhea measurement form from the Department of Plastic and


*weight in decigramsSource: Reid SM, Johnstone MB. Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders. Developmental Medicine and Child Neurology; Feb 2008; 50,2; ProQuest Hospital

Collection pg 123-128.11

Scale of affectation of the life of the child and the family due to droolingBeginningAfter 4 months


7.94

2.69


group6

4.06


7,06

2,13

4,63

3,25


Figure 5. Average drooling on close relatives by study groups.



Weight of intraoral cotton

BeginningAfter 4 months


23.125*

14.81*


group21*

17*



68

Discussionvarious studies in the Manual of Oropharyngeal Electrostimulation26 report an improvement in drooling secondary to the treatment. This research work has also shown an improvement of this picture.

There are no studies comparing the results between botulinum toxin and oropharyngeal electrostimulation regarding the social affectation that drooling has on the child, the caregivers, and their concern in the presence of other people. Hockstein and Narbona review the different options for the treatment of sialorrhea. They mention that social stigmatization itself can be devastating for patients and their families. In describing the therapeutic alternatives, they noted the benefits of botulinum toxin, which is safe and effective, but its effects decline after several months. In our study, both botulinum toxin and oropharyngeal electrostimulation have a positive effect on quality of life; however, botulinum toxin has greater superiority, corroborating the result of that study.

When studying the quality of life, our study took into account the variable of drooling on nearby objects. Zeppa2 and the systematic review by Benson and Daugherty9 report botulinum toxin improves this aspect, corroborating the result of our study. There is no research on this variable in similar studies with oropharyngeal electrostimulation.

In general, according to the results obtained in this research, both botulinum toxin type A and oropharyngeal electrostimulation are minimally invasive alternatives for the treatment of moderate to severe sialorrhea in pediatric patients with cerebral palsy, which has a positive impact on the quality of life of the patient and the caregivers.

No adverse effects were observed during the procedure of the application of botulinum toxin type A or oropharyngeal electrostimulation.

According to Tahmassebi in Prevalence of Drooling in Children with Cerebral Palsy Attending Special Schools,7 sialorrhea is a prevalent symptom in cerebral palsy that is barely considered and difficult to treat, yet with a negative impact on the quality of life of the patient, the family, and/or the caregivers.

According to Banerjee, sialorrhea can occur in up to a third of children with cerebral palsy, particularly the moderate and severe types, and most frequently in spastic quadriplegia, which correlates with our study.5 The objective of his study was to determine if the injection of botulinum toxin in the parotid and submandibular glands in children between 6 and 16 years decreased salivation and improved their quality of life. He reported that the frequency of sialorrhea and the severity scores had a statistically significant decrease at four weeks (p<0.001) and at 12 weeks (p<0.006), improving the quality of life of the child and the family. These findings are confirmed in our study.

According to Reid, in a randomized study, Peter and Benson mentioned that children with sialorrhea have different secondary problems, such as odor, dermatitis, cough, and presence of saliva in toys, computers, clothes, etc, causing social isolation in school and even with their family. They reported the effectiveness in reduction of these discomforts with a significant difference after six months of application. These studies support the results of our study.8,10,11

Alferai and Dressler concluded that botulinum toxin is effective in the treatment of sialorrhea12,13

adding that there were some children who did not respond to the first infiltration but improved after the second.13 In our study, only one infiltration was contemplated, observing a better result in severe sialorrhea compared to the response to oropharyngeal stimulation.

There are no studies comparing the efficacy of botulinum toxin and oropharyngeal electrostimulation. The research of Madrigal17 and



69

Conclusions

This study shows that the use of botulinum toxin in the salivary glands (parotid and submaxillary) and the treatment with oropharyngeal electrostimulation are useful in the treatment of sialorrhea in children with cerebral palsy with a positive impact on the quality of life, and there was superiority in the results with the use of botulinum toxin.

Conflicts of interestWe declare that this research has no conflicts of interest.

FundingNo funding was received for the realization of this work.



70

1. Hockstein NG, Samadi DS, Gendron K. Sialorrhea: a management challege. Am FamPhysician. 2004 Jun 1; 69 (11): 2688-34

2. Zeppa Guillermo. Tratamiento de la sialorrea con toxina botulínica. En: Micheli, Dressler. Toxina Botulínica-Nuevas indicaciones terapéuticas. Editorial Médica Panamericana S.A, 2010. p 285-290.

3. Aguilar Rebolledo F. Tratamiento e sialorrea en enfermedades neurológicas más frecuentes del adulto. Medigraphic, Plasticidad y Restauración neurológica. 2006 julio-diciembre. Vol. 5 Núm. 2. Disponible en : http://www.medigraphic.com/pdfs/plasticidad/prn-2006/prn062b.pdf

4. Araneda I, Cortés P., Gonzáles K.. Medición de la cantidad de Saliva en personas con enfermedad de Parkinson y su impacto en la calidad de vida. Tesis. (Universidad de Chile. Facultad de Medicina. Escuela de Fonoaudiología, 2011. Disponible en : http://www.tesis.uchile.cl/bitstream/handle/2250/114902/Medici%C3%B3n%20Saliva%20en%20personas%20con%20EP.pdf?sequence=1

5. Banerjee K.J. Parotid and submandibular botulinum toxin A injections for sialorrhoea in children with cerebral palsy. Developmental Medicine and Child Neurology; Nov 2006; 48, 11 ProQuest Hospital Collection pg 883-887. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/17044954

6. Peter. H. Jongerius. Botulinum toxin A: a new option for treatment of drooling in children with cerebral palsy. Presentation of a case series. European Journal of pediatrics (2001); 160: 509-512. Disponible en: http://connection.ebscohost.com/c/articles/5350714/botulinum-toxin-a-new-option-treatment-drooling-children-cerebral-palsy-presentation-case-series

7. J.F. Tahmassebi. Prevalence of drooling in children with cerecbral palsy attending special schools. Develpmental Medicine & Child Neurology. 2003,45:613-617. Disponible en: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2003.tb00965.x/pdf

8. Sharon Hassin-Baer. Botulinum Toxin Injections for children with excessive drooling. Journal of child Neurology. 2005; 20:120-123. Disponible en: http://connection.ebscohost.com/c/articles/16734699/botulinum-toxin-injections-children-excessive-drooling

9. Jennifer Benson. BotulinumToxin A in the treatment of sialorrhea. The Annals of Pharmacotherapy(2007) 41: 79-85. Disponible en: http://aop.sagepub.com/content/41/1/79.abstract.es

10. Peter H. Botulinum toxin in the treatment of drooling: a controlled clinical trial. Pediatrics. (2004);114:620-627. Disponible en: http://onlinelibrary.wiley.com/doi/10.1017/S0012162206000235/pdf

11. Reid S.M, Johnstone MB. Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders. Developmental Medicine and Child Neurology; Feb 2008; 50,2; ProQuest Hospital Collection pag 123-128. Disponible en http://www.ncbi.nlm.nih.gov/pubmed/18201301

12. Dressler Dirk. Botulinum toxin therapy: its use for neurological disorders of autonomic nervous system. J Neurol. (2013) 260:701-713. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/22878428

13. Alrefai Ali, Aburahma S, Khader Y. Treatment of sialorrhea in children with Cerebral Palsy: A double-blind placebo controlled trial. Clinical Neurology and Neurosurgery. 111 (2009) 79-82. Disponible en: http://www.clineu-journal.com/article/S0303-8467(08)00302-8/abstract

14. Troung DD, Bhidayasiri R. Evidence for the effectiveness of botulinum toxin for sialorrhoea. J Neural Transm. 2008:115(4):631-5. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/18250951

15. Lee J.H., Lee B.N. Kwon O. Anatomical localization of submadibular gland for botulinum toxin injection. SurgRAdiolAnat. (2010) 32: 945-949. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/20221760

16. Colver A., Fairhurst C., Pharoah P. Cerebral Palsy. Lancet. 2014; 383: 1240-9. Disponible en : http://www.ncbi.nlm.nih.gov/pubmed/24268104

17. Madrigal R.L, Sanchez E, García L, Hernandez L. Tratamiento en alteraciones de deglución con estímulo eléctrico comparado con terapia habitual en pacientes con daño neurológico moderado. Revista Mexicana de Medicina Física y Rehabilitación. 2010; 22 (4):118-122. Disponible en : http://new.medigraphic.com/cgi-bin/resumen.cgi?IDREVISTA=28&IDARTICULO=27615&IDPUBLICACION=2945

References



71

18. Tahmassebi J.F, Curzon M.E. Prevalence of drooling in children with cerebral palsy attending special schools. Developmental Medicina and child Neurology. 2003, 45:613-617. Disponible en : http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=169933&fileId=S0012162203001117

19. Saliva control in children. Department of Plastic and Maxillofacial Surgery.The Royal Chyildren’s Hospital, Melbourne, Australia. En: http://www.rch.org.au/uploadedFiles/Main/Content/plastic/salivabook.pdf

20. Parra K. Enfoque de Sara Rosenfeld-Johnson para la alimentación oromotora y la terapia del habla (Traducción). En http://www.talktools.com/content/Sar%20Rosenfeld-Johnson’s%20Approach%20to%20Oral-Motor%20Feeding%20and%20Speech_Spanish.pdf

21. León F, León r, Bravo G. Aplicaciones de la toxina botulínica en glándulas salivales. Revista Hospital Clínicas – Universidad de Chile 2011; 22: 355-60. Disponible en : http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&src=google&base=LILACS&lang=p&nextAction=lnk&exprSearch=647647&indexSearch=ID

22. Chahuán S, Espinoza T, Cruzat L. Sialorrea neurogénica infantil y el manejo con la toxina botulínica: Revisión de la literatura y reporte del caso de un niño con traqueostomía y ventilación mecánica crónica. Rev Neumología Pediátrica. 2012;7 (I):13-18. Caso clínico

23. Amrita A, Moghimi N, Jbbari B. Sialorrhea: Anatomy, Pthophysiology and Treatment with Emphasis on the Role of Botulinum Toxins. Toxins. 2013, 5(5),1010-1031. Disponible en : www.mdpi.com/journal/toxins

24. Narbona J, Concejo C. Tratamiento de la incontinencia salival en el niño con patología neurológica. Acta Pediatría Esp. 2007; 65(2):56-60

25. Paredes Martínez E. Problemas de salud oral en pacientes con parálisis cerebral y estrategias para su tratamiento. Revista Odontología Pediátrica. 2010 julio-diciembre. Vol 9 No 2. Disponible en : http://revistas.concytec.gob.pe/pdf/op/v9n2/a05v9n2.pdf

26. VitalStimtherapy. Programa de Certificación de VitalStim. Manual de Entrenamiento para el uso de Estimulación eléctrica en el Tratamiento de disfagia. En: www.vitalstimtherapy.com ; www.interferenciales.com.mx

27. Tortora G.J, Derrickson B.(2006). Principios de Anatomía y Fisiología. México:Editorial Panamericana. 11ª Edición.

28. Gisel E, Applegate-Ferrante, T., Benson J. Oral-Motor Skills following Sensoriomotor Therapy in Two Groups of Moderately Dysphagic Children with Cerebral Palsy: Aspiration vs Nonaspiration. Rev. Dysphagia. 1996; 11:59-71. Disponible en: http://link.springer.com/article/10.1007/BF00385801

29. Del Águila A, Áibar P. Características nutrionales de niños con parálisis cerebral. ARIE- Villa El Salvador, 2004. Rev. Anales de la Facultad de Medicina Lima. 2006;67 (2). Disponible en : http://www.scielo.org.pe/pdf/afm/v67n2/a03v67n2.pdf

30. Guía de Práctica Clínica. Alimentación en Niños con dificultad para masticar y deglutir derivada de alteración en el Sistema Nervioso. Ministerio de Salud 2010. Subsecretaria de Salud Pública. División de Prevención y control de Enfermedades. Departamento de discapacidad y Rehabilitación. Chile.

31. Bacco J.L, Araya F. Flores E, Peña N. Trastornos de la alimentación y deglución en niños y jóvenes portadores de Parálisis cerebral: abordaje multidisciplinario. REV. MED. CLIN. CONDES 2014; 25(2) 330-342. Disponible en: http://www.clinicalascondes.cl/Dev_CLC/media/Imagenes/PDF%20revista%20m%C3%A9dica/2014/2%20marzo/Rev.Med_marzo2014.pdf

32. Food for Thought. Mealtime Strategies For Children with special Needs. Disponible en: http://www.pisp.ca/strategies/documents/food forThought

33. Gisel E. Oral-motor Skills Following Sensorimotor intervention in the Moderately Eating-Impaired Child with Cerebral Palsy. Rev. Dysphagia. 1994 ; 9:180-192 . Disponible en : http://www.ncbi.nlm.nih.gov/pubmed/8082327

34. Araneda O, Canales P, Curihual P, Quintana M. Tratamientos fonoaudiológicos para el manejo de la sialorrea en usuarios con enfermedad de Parkinson. Tesis. Universidad de Chile. Facultad de Medicina. Escuela de Fonoaudiología, 2012. Disponible en : http://www.tesis.uchile.cl/bitstream/handle/2250/114930/TRATAMIENTOS%20FONOAUDIOLOGICOS%20PARA%20EL%20MANEJO%20DE%20LA%20SIALORREA.pdf?sequence=1

35. Moyano A, Cubillos F, Maldonado P. Toxina botulínica y su importancia en el campo de la rehabilitación. Revista Hospital de Clínicas-Universidad de Chile. 2010; 21:319-25. Disponible en : https://www.redclinica.cl/Portals/0/Users/014/14/14/Publicaciones/Revista/toxina_butolimica_y_su_import.pdf



72

36. BerkerN,Yalçin S. THE HELP GUIDE TO CEREBRAL PALSY. Publicación de Global-HELP. Marzo 2005.37. Espinosa J, Arroyo O, Martín P. Guía esencial de Rehabilitación Infantil. Editorial médicaPanamerican,

S.A. 2010. 38. Flórez J. Farmacología Humana. Editorial ELSERVIER MASSON. QuintaEdición. 39. Freeman M. Cerebral Palsy. Editorial Springer. 2005.40. Monografìa Dysport-Toxinabotulínica tipo A. IPSEN Innovation for patient care.41. Dysport-Toxina botulínica tipo A única con 500U. Guía de aplicacao-Bloqueio Nuromuscular Quìmico.

Material tècnic-cientìfico exclusivo a clase Médica. Agosto 2009.42. Malagón J. Parálisis Cerebral. Actualizaciones en Neurología Infantil. Actualizaciones en Neurología

Infantil. MEDICINA. (Buenos Aires) 2007; 67 (6/1): 586-59243. Velázquez, Lorenzo P, Moreno A. Farmacología Básica y Clínica. 18a Edición . Editorial

MédicaPanamericana. 44. Regulación de la función gastrointestinal. En: Ganong William. Fisiología médica. Editorial Manual

Moderno, 2004. 19 Edición. p 532-534. 45. Arellano ME, Rodriguez J, Morales MG, Arenas-Sordo M. Eficacia clínica de la aplicación de toxina

botulínica tipo A en las glándulas submaxilares para el tratamiento de la sialorrea profusa en paciantes pediátricos con parálsis cerebral, 2014. Vol., Núm3, Julio-septiembre. p 101-105


RevisionHistory of dopamine agonists

73

Historical context of dopamine agonists

Contexto histórico de los agonistas dopaminérgicos

Revision

Ingrid Estrada-Bellmann,1

Carlos Cámara-Lemarroy,1 Guillermo Delgado-García,2

Christopher Cerda-Contreras.1

1Neurology Service, University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, Mexico. 2National Institute of Neurology and Neurosurgery, Tlalpan, Mexico.

Abstract

Introduction: Shortly after the introduction of levodopa in the therapeutics of Parkinson's disease (PD), it became clear that its chronic use was associated with some adverse effects. Considering that dopamine agonists (DAs) act directly on the nigrostriatal system and that their half-lives are longer, it was hypothesized that using them could prevent these adverse effects.

Objective: To conduct a narrative review about the historical development of DAs.

Results: Even though DAs have been used in the treatment of PD only since the seventies, there were already reports on the effects of apomorphine at the beginning of the last century. The search for drugs that modulate prolactin led to the discovery of bromocriptine, a DA derived from ergocryptine, in the 1960s. Its effectiveness in PD was established in the following decade. In the last two decades of the last century there was a marked advance in the development of non-ergotamine DAs (e.g., ropinirole, pramipexole and rotigotine). Currently the use of these is increasing due to its more favorable profile. However, these DAs are associated with other adverse effects.

Conclusions: As monotherapy, non-ergotamine DAs are a safe alternative in early PD and in young patients. However, they are usually administered together with levodopa in advanced PD. The development of new DAs continues and this has allowed to deepen our knowledge on dopaminergic receptors, thus enabling the creation of more selective and specific drugs.

KeywordsParkinson disease, dopamine, dopamine agonists, levodopa, history of medicine, pharmacology.



74

Resumen

Introducción: Al corto tiempo de la introducción de la levodopa en la terapéutica de la EP, se volvió claro que su uso crónico se asociaba con efectos adversos. Considerando que los agonistas dopaminérgicos (AD) actúan directamente sobre el sistema nigroestriado y que sus vidas medias son más prolongadas, se hipotetizó que utilizándolos podrían evitarse estos efectos adversos.

Objetivo: Realizar una revisión narrativa acerca del desarrollo históricos de los AD.

Desarrollo: Aun cuando los AD han sido utilizados en el tratamiento de la EP sólo desde la década de los setenta, a principios del siglo pasado ya existían reportes sobre los efectos de la apomorfina. La búsqueda de fármacos moduladores de la prolactina llevo al descubrimiento de la bromocriptina, un AD derivado del ergot, en los años sesenta. Su utilidad en la EP se estableció en la década siguiente. En las últimas dos décadas del siglo pasado hubo un marcado avance con el desarrollo de AD no ergotamínicos (e.g., ropinirol, pramipexol y rotigotina). Actualmente el uso de éstos está en aumento gracias a su perfil más favorable. Sin embargo, estos AD se asocian a otras complicaciones.

Conclusiones: Como monoterapia, los AD no ergotamínicos son una alternativa segura en la EP temprana y en pacientes jóvenes. No obstante, suelen administrarse conjuntamente con levodopa en la EP avanzada. El desarrollo de nuevos AD continúa y esto ha permitido profundizar en el conocimiento de los receptores dopaminérgicos, posibilitando así la creación de fármacos más selectivos y específicos.

Palabras claveEnfermedad de Parkinson, dopamina, agonistas dopaminérgicos, levodopa, Historia de la medicina, Farmacología.

Corresponding author:Dr. Ingrid Estrada-BellmannServicio de Neurología, Hospital Universitario “Dr. José Eleuterio González”, Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460Monterrey, Nuevo León, México. E-mail: [email protected]



75

Introduction

In the classic essay An Essay on the Shaking Palsy, published in 1817, the English physician James Parkinson documented the symptoms of six patients with tremor at rest, slow movements, and changes in gait and posture.1 This was the first clinical description of what Jean-Martin Charcot baptized as "Parkinson disease" about fifty years later.2 Towards the end of that century, the first observations relating alterations of the substantia nigra (SN) with Parkinson disease (PD) appeared in the medical literature.2 In France, cases of patients with parkinsonism induced by lesions in the SN were reported.3 Later, Friedrich Lewy reported the presence of eosinophilic inclusions in the brainstem of patients with PD,4 and other authors subsequently found them in the SN.5,6

The link with dopamineAfter having established the anatomical relationship between PD and SN, evidence about a physiological relationship with the neurotransmitter dopamine emerged in the middle of the last century.7 In this period, the existence of dopamine in the brain was demonstrated along with its location, mainly in the neostriatum and SN, and that it has effects on the motor system.8-11 Based on these data, as well as other observations of his own, Carlsson was the first to suggest that the administration of the dopamine precursor DOPA might be effective in the treatment of PD.12 His work in the area earned him the Nobel Prize in Physiology or Medicine (2000). Some years after Carlsson's publications, Cotzias and colleagues reported the successful use of DOPA in patients with PD.13,14 This started the dopaminergic era of treatment of PD, which is still the cornerstone of the therapeutic arsenal.

Need for alternativesShortly after the introduction of levodopa in PD therapeutics, it became clear that chronic therapy was associated with dyskinesia and motor fluctuations due to the loss of neurons responsible for the metabolism of levodopa in the basal ganglia. Considering that dopaminergic agonists (DAs) can

act directly on the nigrostriatal system and that their half-lives are longer, it was hypothesized that using them could avoid these adverse effects to some degree.15,16

However, the complexity of the study of DAs is clear when recognizing that there is more than one dopaminergic receptor. It has been more than thirty years since the dopaminergic receptors were classified as D1 and D2 according to their post-receptor effects on the production of cyclic AMP.17 Today we know of three additional subtypes of receptors (D3-D5). The dopaminergic receptors have different locations in the central nervous system (CNS), but it is recognized that D1 and D2 receptors are the predominant types in the nigrostriatal system. The differential modulation of this complex system may in principle have regulatory effects on the symptoms of PD. Thus, in conjunction with the discovery of DAs, their physiological and pharmacological properties were described.

History of dopamine agonistsApomorphineSince antiquity, human beings have known about the beneficial (or harmful) effects of substances from various plants. The history goes back to the preclassic period (from 2000 BC to 250 AD) when the Egyptians and the Mayans knew the clinical effects of Nymphaea, mainly of the varieties N. caerulea and N. ampla, which are plants containing apomorphine and growing very close to rivers and lakes.18

Apomorphine, a derivative of morphine, was probably the first known dopamine agonist. Apomorphine was synthesized for the first time in 1845 by Arppe from morphine and sulfuric acid. Later, Mathiesen and Wright created it artificially using morphine and hydrochloric acid.19,20 Around 1874, Eric Harnack published Ueber die Wirkungen des Apomorphins am Saugerthier und am Frosch (Effects of Apomorphine in Mammals and Frogs), in which he described the emetic effects in dogs, cats, and humans, hemodynamic changes in children when using low doses, and motor effects in dogs and cats.21 He noticed that higher doses could cause hyperexcitation of the CNS resulting in psychomotor agitation, seizures,



76

muscle paralysis, and/or respiratory failure. The first reference of apomorphine as antiparkinsonian treatment dates from 1884, when Weill suggested it for patients with this disease;22 previously, he had used it with very good results in the management of Sydenham chorea.

In 1951, Schwab et al. reported the benefits of apomorphine in Parkinson disease.23 They studied thirty patients with PD, who after the administration of apomorphine showed a decrease in tremor and rigidity, noticing a greater effect using the subcutaneous route. In 1967, Ernst noted that apomorphine was structurally similar to dopamine.24 Also, Cotzias demonstrated the similarities of the neurological effects of levodopa and apomorphine.25 Later experimental studies confirmed that apomorphine is a potent D1 and D2 agonist. The oral formulation never proved to be practical. Cotzias developed an oral apomorphine that was provided to fifteen patients in order to decrease the toxicity and adverse effects of its parenteral counterpart, but this was later abandoned due to dose-dependent nephrotoxicity.26

The discovery of levodopa did not diminish the interest in apomorphine.

In 1970, Braham determined that the effect of apomorphine on parkinsonian tremor was superior to that of levodopa. Thirteen patients were injected with 0.5-2 mg of subcutaneous apomorphine, of which eight presented total effect and three partial effects. The responses took 5-10 min to appear and the therapeutic effects lasted approximately 1-2 hours.27 It was shown later that apomorphine was able to decrease the "off" and the required doses of levodopa28 and its rapid effect made it attractive as a rescue medicine. In the last twenty years, the usefulness of apomorphine has been established in certain groups of patients, in the treatment of "off", in advanced stages in the form of infusions, and as a rescue medicine.

ErgotamineErgot is a fungal disease caused by the parasitic organism Claviceps purpurea that affects multiple

types of cereals and herbs.29 In 1906, Dale showed that ergot (derived from C. purpurea) inhibited the vasopressor effect of adrenaline, and Stoll isolated ergotamine in 1918.30 Stoll himself (together with Hofmann) isolated the psychotropic agent lysergic acid diethylamide (LSD) from ergot preparations. However, Fluckinger (in Sandoz) was the one who, searching for an ergotamine alkaloid that could inhibit the secretion of prolactin in the pituitary, isolated bromocriptine from ergocryptine in the 1960s.31

Fuxe and Hökfelt demonstrated that, in humans, bromocriptine reduced the recapture of dopamine in hypothalamic and nigrostriatal neurons. Thereafter, ergot pharmacology was established.32

Shortly after it was demonstrated that bromocriptine had dopaminergic properties, it was reported that it also had favorable effects on PD.33

In this way bromocriptine became the first ergot agonist useful in the treatment of PD, approved by the Food and Drug Administration (FDA) in 1978. Subsequent studies showed beneficial effects on patients treated with levodopa, with reduction of "off" and dyskinesias.

By the 1980s, other ergot-derived dopamine agonists had been discovered. Kehr detailed the effects of lisuride and other ergot derivatives (e.g. LSD and methysergide) on monoaminergic mechanisms in rat brains in 1976,34 and found that lisuride stimulated pre- and post-synaptic DA receptors and also the 5-HT receptors, but that it was an antagonist of the noradrenergic (NA) receptors of the CNS. As early as 1980, Goldstein et al. tested the activity of pergolide, an N-propylergoline derivative found to act on the D1 and D2 receptors in the CNS.35 Two years later, Lieberman et al. demonstrated that pergolide was effective as adjuvant therapy in patients with motor complications.36 In 1983, Calde presented the effects of lisuride and pergolide in Lisuride and Other Dopamine Agonists: Basic Mechanisms and Endocrine and Neurological Effects.37 He reported that both stimulated the presynaptic DA receptors, and also reported sexual hyperactivity associated with the use of lisuride in rats. That same year, DAs began to be used in the monotherapy of early PD.



77

The study of the combination of several agonists (or agonists together with levodopa) gained strength in the same decade. Goetz and colleagues conducted a clinical trial using bromocriptine and pergolide as chronic agonist therapy, which was published in 1985.38 For their part, Lieberman and Goldstein reviewed the use of bromocriptine versus the combined use of bromocriptine and levodopa, reporting that the dual therapy mentioned was more effective.39 In 1989, pergolide was approved by the FDA. Later, evidence would emerge on how the use of DAs in early phases of PD could delay the onset of motor complications.40,41 Rabey reported in 1990 the beneficial effects of a new ergot derivative (cabergoline) in the treatment of PD with motor fluctuations.42

Non-ergot In recent years, ergot derivatives (which have diverse and potentially important side effects at the cardiovascular level) have been almost completely replaced by synthetic DAs such as ropinirole, pramipexole, and rotigotine. Ropinirole is a D2/D3 DA with greater affinity for the D3 receptor in central and peripheral receptors.43 Pramipexole is a highly selective agonist with intrinsic activity for receptors of the D2 family (D2, D3, and D4, with preference for D3).44 There are standard and prolonged release formulations. Rotigotine is unique given its administration via transdermal patch. It was withdrawn from the market for a while, but is now available again. This drug is the levorotatory enantiomer of an aminotetralin derivative 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin, and is structurally similar to dopamine.45 It is also unique for its D1 activity, with greater affinity towards D3, although it also activates the rest of the dopaminergic receptors.

In 1990, The Lancet published that the administration of ropinirole was as effective as its combination with levodopa46 and, a year later, the pharmacology of this drug was reported: selective DA of D2 receptors.47 The beneficial effect of the joint therapy (ropinirole with levodopa) was also demonstrated. Likewise, the effectiveness of pramipexole was reported in de novo patients and patients with fluctuations.48 The Journal of

Neurology published a report on the pathological mechanisms of PD and the role of piribedil.49 This drug acts on the SN and the nucleus accumbens, but not on the striatum, and produces improvement in symptoms such as tremor, nausea, and dizziness.

In 1994, a multicentre clinical trial comparing the use of Sinemet® (carbidopa-levodopa) versus Sinemet® with pergolide was reported.50 In this study, three hundred and twenty-six patients with advanced PD were evaluated for six months and found significant improvement in the pergolide group. This allowed reducing the dose of levodopa by 24.7% without showing adverse effects. In 1995, Jenner published in Neurology an article on the rational use of DAs in PD and their possible neuroprotective actions.51 This last point is still a source of controversy. Pramipexole was approved in 1997 by the FDA. Shannon52 demonstrated its efficacy as monotherapy in mild to moderate PD and, in the same year, the Journal of the American Medical Association (JAMA) documented its safety and efficacy in early PD.53

In 1998, the FDA approved ropinirole for use in PD. Subsequently, in 2000, JAMA published another clinical trial evaluating pramipexole: Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial.54 The objective was to determine motor complications after initial treatment, for which three hundred patients with early PD were studied. One hundred and fifty-one received levodopa and the rest pramipexole. The results showed that the use of pramipexole was associated with fewer dyskinesias (9.9%) and wearing-off phenomena (23.8%) than levodopa (30.7% and 38%, respectively). However, improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) was greater in the levodopa group. In 2005, an article about the use of rotigotine in a transdermal patch to control motor symptoms of PD was published in Neurology.55 In that same year, a multicenter study conducted in Sydney by Hely and colleagues56 indicated the presence of symptoms that did not respond to levodopa in patients with more than fifteen years of PD, which were (in order of frequency): cognitive deterioration, falls, depression, hallucinations, and dementia, among others.



78

In 2006, Movement Disorders published a double-blind clinical trial evaluating the efficacy of piribedil as monotherapy in patients with early PD.57 This study reported a superior response to piribedil (42%) compared to placebo (14%), and it was determined that piribedil was an effective and safe treatment for early PD. The following year, Jankovic and Watts in their work Transdermal rotigotine: Double-blind, placebo-controlled trial in Parkinson Disease58 and Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease59 demonstrated the superiority of the transdermal patch of rotigotine over placebo in terms of tolerance and efficacy in early PD, and also reported adverse effects similar to other DAs.

Dopamine Agonists in the Era of Evidence-Based MedicineRecent studies suggest the presence of pleiotropic effects in DAs. In 2010, a study on the antidepressant effect of pramipexole was published in The Lancet Neurology.60 Yasui and colleagues also reported an improvement in depressive symptoms with the use of pramipexole.61 On the other hand, the DOMINION62 study indicated the relationship of DAs with impulse control disorders, and their findings reported a 2 to 3.5 times higher risk in patients receiving DAs: 13.6% of patients had one impulse control disorder, and 3.9% had more than one. The most prevalent disorders were: compulsive shopping (5.7%), gambling (5%), compulsive eating disorder (4.3%), and impulsive sexual behavior (3.5%).

In 2011, Ghys et al. described in a post hoc analysis of the RECOVER63 study the beneficial effects of transdermal rotigotine using the PDSS-2 scale and the PDQ-8 questionnaire. Among their findings they reported improvement in pain, depression, quality of life, and sleep. Simultaneously, another post hoc analysis of the same study64 was presented at the 84th Annual Congress of the German Society of Neurology. In this study, they evaluated the effect of rotigotine on pain in patients with PD. The authors reported an improvement in patients with moderate to severe pain attributable to improvement in motor symptoms and sleep disorders.

Movement Disorders published in 2011 The Movement Disorder Society Evidence-based Medicine Review Update: Treatments for the Motor Symptoms of Parkinson's Disease.65 This document reviewed several articles related to the effects of different treatments used in PD, including CALM-PD and REAL-PET. The first one indicated that the use of pramipexole in the initial treatment delayed the complications and the loss of the dopamine transporter (DAT). However, in this study, levodopa showed greater improvement in UPDRS. The second study compared ropinirole against levodopa and showed a delay in motor complications and loss of DAT, however, levodopa was also more effective. Both studies suggested a neuroprotective role for these two DAs.

In 2013 it was reported in the journal Brain that the use of piribedil (a D2-D3 agonist) significantly relieved postoperative apathy in patients who had undergone deep brain stimulation with bilateral subthalamic implants.66 A European Multicentre Survey of Impulse Control Behaviours in Parkinson’s Disease Patients Treated with Short- and Long-acting Dopamine Agonists67 was published in early 2016, which determined the association of impulse control disorders with the use of short and prolonged action agonists. This study collected data from different European centers that reported a lower rate of impulse control disorders in patients who used transdermal rotigotine or long-acting agonists.

DAs are the drug of choice in patients with early-onset PD at young ages. Their higher plasma half-lives possibly lead to continuous dopaminergic stimulation, which decreases the occurrence and severity of motor fluctuations and dyskinesias. However, the fear of dyskinesias has led to the concept of "levodopaphobia."68,69 When considering the side effects associated with DAs (such as drowsiness, orthostasis, hallucinations and impulse-control disorders), a moderate position has been taken nowadays, where it is recognized that there is as much a place for levodopa (still the most potent antiparkinsonian) as there is for dopamine agonists in the treatment of Parkinson disease.68,69



79

ConclusionsThroughout history, the evolution of antiparkinsonian therapy has been documented from the use of apomorphine and levodopa to dopamine agonists and deep brain stimulation. Considering their prolonged half-life and high degrees of specificity in the recipients, the DAs would theoretically offer more advantages than levodopa, which is why they have been investigated for use as monotherapy with varying degrees of success. However, studies such as CALM-PD and REAL-PET have shown that although the use of DAs delays the motor complications of PD and the loss of DAT, levodopa is clinically more effective. Many patients who receive DAs will end up needing levodopa to control their parkinsonism.

The ergot-derived DAs are not considered a first-line treatment because of their fibrotic effects at cardiac and pulmonary level. Although an association with impulse control disorders has been reported, the use of non-ergot derived DAs is preferable because of their wide margin of safety and tolerance. The ergot-derived DAs today have fallen into disuse and have been replaced by synthetic DAs that are not ergot-derived. As monotherapy, DAs are a safe alternative in early PD and in young patients. However, they are usually administered together with levodopa in advanced PD. Due to these great contributions, the development of new dopamine agonists continues, allowing to deepen the knowledge of dopaminergic receptors and enabling the creation of drugs that are more selective and specific. It would be worthwhile to ask ourselves, could dopamine agonists be the Parkinson disease treatment of the 21st century?





80

1. Parkinson J. An Essay on the Shaking Palsy. Londres: Whittingham and Rowland; 1817.2. Lanska DJ. Chapter 33: the history of movement disorders. Handb Clin Neurol. 2010;95:501-46.3. Blocq P, Marinescu G. Sur un cas de tremblement parkinsonien hémiplégique : symptomatique d'une

tumeur du pédoncule cérébral. Comp Rend Soc Biol. 1893;5:105-11.4. Lewy FH. Zur pathologischen Anatomie der Paralysis agitans. Dtsch Z Nervenheilk. 1913;50:50-5.5. Tretiakoff KN. Contribution à l'étude de l'anatomie pathologique du Locus Niger de Soemmering avec

quelques déductions relatives à la pathogénie des troubles du tonus musculaire et de la maladie de Parkinson. París: Jouve et Cie.; 1919.

6. Tretiakoff KN. Contribution à l'étude de l'anatomie du locus niger. Rev Neurol. (Paris) 1921;28: 592-600.

7. Kopin IJ. Parkinson's disease: past, present, and future. Neuropsychopharmacology. 1993;9:1-12.8. Bertler A, Rosengren E. Occurrence and distribution of catechol amines in brain. Acta Physiol Scand.

1959;47:350-61.9. Carlsson A. The occurrence, distribution and physiological role of catecholamines in the nervous

system. Pharmacol Rev. 1959;11:490-93.10. Sano I, Gamo T, Kakimoto Y, Taniguchi K, Takesada M, Nishinuma K. Distribution of catechol

compounds in human brain. Biochim Biophys Acta. 1959;32:586-7. 11. Foley P. The L-DOPA story revisited. Further surprises to be expected? The contribution of Isamu

Sano to the investigation of Parkinson’s disease. J Neural Transm Suppl. 2000;60:1-20.12. Carlsson A. A half-century of neurotransmitter research: impact on neurology and psychiatry. In

Jornvall H, ed. Nobel Lectures: Physiology or Medicine. 1996-2000. Singapur: World Scientific; 2003. p. 303-22.

13. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic acids and modification of parkinsonism. N Engl J Med. 1967;276:374-79.

14. Fahn S. The medical treatment of Parkinson disease from James Parkinson to George Cotzias. Mov Disord. 2015;30:4-18.

15. Tolosa E, Martí MJ, Valldeoriola F, Molinuevo JL. History of levodopa and dopamine agonists in Parkinson's disease treatment. Neurology. 1998;50:S2-10; discussion S44-8.

16. Horowski R. A history of dopamine agonists. From the physiology and pharmacology of dopamine to therapies for prolactinomas and Parkinson's disease - a subjective view. J Neural Transm. (Vienna) 2007;114:127-34.

17. Kebabian JW, Calne DB. Multiple receptor mechanism for dopamine. Nature. 1979;227:93-6.18. Bertol E, Fineschi V, Karch SB, Mari F, Riezzo I (2004). Nymphaea cults in ancient Egypt and the New

World: a lesson in empirical pharmacology. J R Soc Med. 2004;97:84-5. 19. Mathiesen A, Wright CR. Apomorphine. Proc R Soc Med. 1869;17:455.20. Subramony JA. Apomorphine in dopaminergic therapy. Mol Pharm. 2006;3:380-5. 21. Taba P, Lees A, Stern G. Erich Harnack (1852-1915) and a short history of apomorphine. Eur Neurol.

2013;69:321-4. 22. Weill E. De l'apomorphine dans certains troubles nerveux. Lyon Med. 1884;48:411-19.23. Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Trans Am Neurol Assoc.

1951;56:251-3.24. Ernst AM. Mode of Action of Apomorphine and Dexamphetamine on Gnawing Compulsion in Rats.

Psychopharmacologia. 1967;10:316-23.25. Cotzias GC, Papavisiliou PS. Similarities between neurologic effects of L-dopa and apomorphine. N.

Engl J Med. 1970;282:31-3.26. Cotzias GC, Papavasiliou PS, Tolosa ES, Mendez JS, Bellmidura M. Treatment of Parkinson disease

with apomorphines: possible role of growth hormone. N Engl J Med. 1976;294:567-72.27. Braham J, Sarova-Pinhas I, Goldhammer Y. Apomorphine in Parkinsonian tremor. Br Med J.

1970;3:768.28. Rascol O, Lozano A, Stern M, Poewe W. Milestones in Parkinson's disease therapeutics. Mov Disord.

2011;26:1072-82.29. Tfelt-Hansen PC, Koehler PJ. History of the use of ergotamine and dihydroergotamine in migraine

from 1906 and onward. Cephalalgia. 2008;28:877-86.30. Lee MR. The history of ergot of rye (Claviceps purpurea) I: from antiquity to 1900. J R Coll Physicians

Edinb. 2009;39:179-84.

References



81

31. Lee MR. The history of ergot of rye (Claviceps purpurea) III: 1940-80. J R Coll Physicians Edinb. 2010;40:77-80.

32. Fuxe K, Hokfelt T. Central monoaminergic system and hypothalamic function. In Martini TL, Motta M, Fraschini F, eds. The hypothalamus. Nueva York: Academic Press; 1970. p. 123-38.

33. Calne DB, Teychenne PF, Claveria LE, Eastman R, Greenacre JK, Petrie A. Bromocriptine in parkinsonism. Br Med J. 1974;4:442-44.

34. Kehr W. Effect of lisuride and other ergot derivations on monoaminergic mechanism in rat brain. Eur J Pharmacol. 1976;41:261-73.

35. Goldstein M, Lieberman A, Lew JY, Asano T, Rosenfeld MR, Makman NH. Interaction of pergolide with central dopaminergic receptors. Proc Natl Acad Sci. USA 1980;77:3725-8.

36. Lieberman AN, Goldstein M, Gopinathan G. Further studies with pergolide in Parkinson’s disease. Neurology. 1982;32:1181-4.

37. Lieberman AN, Goldstein M, Gopinathan G, Neophytides A, Leibowitz M, Walker R, et al. Lisuride in Parkinson’s disease and related disorders. In Calne DB, Horowski R, McDonald RJ, Wuttke W, eds. Lisuride and other dopamine agonists: basic mechanisms and endocrine and neurological effects. Nueva York: Raven Press; 1983. p. 419-29.

38. Goetz CG, Tanner CM, Glantz RH, Klawans HL. Chronic agonist therapy for Parkinson’s disease: a 5-year study of bromocriptine and pergolide. Neurology. 1985;35:749-51.

39. Lieberman AN, Goldstein M. Bromocriptine in Parkinson disease. Pharmacol Rev. 1985;37:217-27.40. Rinne UK. Early combination of bromocriptine and levodopa in the treatment of Parkinson’s disease:

a 5-year follow-up. Neurology. 1987;37:826-8.41. Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Marti Masso JF, et al. Early treatment of

Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs. 1998;55:23-30.

42. Rabey JM, Nissipenau P, Inzelberg R, et al. (1990). Beneficial effect of cabergoline in the treatment of Parkinson’s disease. Preliminary data. Adv Neurol. 1990;53:451-5.

43. Nashatizadeh MM, Lyons KE, Pahwa R. A review of ropinirole prolonged release in Parkinson's disease. Clin Interv Aging. 2009;4:179-86.

44. Frampton JE. Pramipexole extended-release: a review of its use in patients with Parkinson's disease. Drugs. 2014;74:2175-90.

45. Waters C. The development of the rotigotine transdermal patch: a historical perspective. Neurol Clin. 2013;31:S37-50.

46. Vidailhet MJ, Bonnet AM, Belal S, Dubois B, Marle C, Agid Y. Ropinirole without levodopa in Parkinson's disease. Lancet. 1990;336:316-7.

47. Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist. Pharmacol Biochem Behav. 1991;38:147-54.

48. Albani C, Popescu R, Lacher R, et al. Single dose response to pramipexole in patients with Parkinson’s disease. Mov Disord. 1992;7:98.

49. Jenner P. Parkinson's disease. Pathological mechanisms and actions of piribedil. J Neurol. 1992;239:S2-8.

50. Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M, et al. A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Mov Disord. 1994;9:40-7.

51. Jenner P. The rationale for the use of dopamine agonists in Parkinson's disease. Neurol. 1995;45:S6-12.

52. Shannon KM, Bennett JP Jr, Friedman JH. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group. Neurology. 1997;49:724-8.

53. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. JAMA. 1997;278:125-30.

54. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA. 2000;284:1931-8.

55. Jenner P. A novel dopamine agonist for the transdermal treatment of Parkinson's disease. Neurology. 2005;65:S3-5.

56. Hely MA, Morris JGL, Reid WGJ, Trafficante R. Sydney Multicenter Study of Parkinson's disease: non-L-dopa responsive problems dominate at 15 years. Mov Disord. 2005;20:190-9.



82

57. Rascol O, Dubois B, Caldas AC, Senn S, Del Signore S, Lees A. Early piribedil monotherapy of Parkinson’s disease: A planned seven-month report of the REGAIN study. Mov Disord. 2006;21:2110-5.

58. Jankovic J, Watts RL, Martin W, Boroojerdi B. Transdermal rotigotine: double-blind, placebo-controlled trial in Parkinson disease. Arch Neurol. 2007;64:676-82.

59. Watts R, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007;68:272-6.

60. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9:573-80.

61. Yasui N1, Sekiguchi K, Hamaguchi H, Kanda F. The effect of pramipexole on depressive symptoms in Parkinson's disease. Kobe J Med Sci. 2010;56:214-9.

62. Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse Control Disorders in Parkinson Disease: A Cross-Sectional Study of 3090 Patients. Arch Neurol. 2010;67:589-95.

63. Ghys L, Surmann E, Whitesides J, Boroojerdi B. Effect of rotigotine on sleep and quality of life in Parkinson's disease patients: post hoc analysis of RECOVER patients who were symptomatic at baseline. Expert Opin Pharmacother. 2011;12:1985-98.

64. Kassubek J, Ghys L, Chaudhuri KR, et al; on behalf of the RECOVER study investigators. Transdermal rotigotine improves pain in patients with Parkinson’s disease: a post hoc analysis of the RECOVER Study. Poster presented at: Deutschen Gesellschaft für Neurologie (DGN), 84th Annual Congress; September 28-October 1, 2011; Wiesbaden, Germany.

65. Fox SH, Katzenschlager R, Lim SY, Ravina B, Seppi K, Coelho M, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2011;26:S2-41.

66. Thobois S, Lhommée E, Klinger H, Ardouin C, Schmitt E, Bichon A, et al. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain. 2013;136:1568-77.

67. Rizos A, Sauerbier A, Antonini A, Weintraub D, Martinez-Martin P, Kessel B, et al. A European multicentre survey of impulse control behaviours in Parkinson's disease patients treated with short- and long-acting dopamine agonists. Eur J Neurol. 2016;23:1255-61.

68. Zhang J, Tan LC. Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist. Curr Neuropharmacol. 2016;14:356-63.

69. Reichmann H. Modern treatment in Parkinson's disease, a personal approach. J Neural Transm. (Vienna) 2016;123:73-80.


Case reportPACNS successfully treated with Rituximab

83

Primary Angiitis of the Central Nervous System Successfully Treated with Rituximab: Case Report

Vasculitis Primaria del Sistema Nervioso Central Tratada Exitosamente con Rituximab: Reporte de Caso

Case report

Fernando Morales-Ramírez,1 Brenda Bertado-Cortés,2 Raúl Carrera-Pineda.3

1Third year Neurology Resident at the Centro Médico Nacional Siglo XXI Specialties Hospital. 2Medical Assistant at the Neurology Service at the Centro Médico Nacional Siglo XXI Specialties Hospital.3Head of the Neurology Service at the Centro Médico Nacional Siglo XXI Specialties Hospital.

Abstract

Background. Primary Central Nervous System Vasculitis (VPSNC) is an heterogeneous and infrequent disease characterized for vasculitis limited to the brain and spinal cord. The diagnosis is oriented by angiography and confirmed by biopsy. The treatment of VPSNC is based on the combination of steroids and cyclophosphamide, but nevertheless, some patients are intolerant or do not have favorable response to this treatment. To our knowledge there is only two other reports ( three patients total) of VPSNC treated with Rituximab.

Case report. We document the case of a female patient, 28 years old with diagnosis of VPSNC pseudotumoral variant, angiographically negative. In consideration of refractoriness of pseudotumoral variant with first-line treatment, we decided to administer treatment with Rituximab.

Conclusions. Rituximab can be considered in a future to be a fist-line treatment for VPSNC.

KeywordsVasculitis, central nervous system, rituximab.



84

Resumen

Introducción. La vasculitis primaria del sistema nervioso central (VPSNC) es una entidad heterogénea e infrecuente caracterizada por vasculitis limitada al cerebro y médula espinal. El diagnóstico es orientado por angiografía y establecido mediante biopsia. El tratamiento se basa en la combinación de esteroides y ciclofosfamida, sin embargo, algunos pacientes son intolerantes a este esquema de tratamiento o no obtienen respuesta favorable. En nuestro conocimiento sólo existen dos reportes (con tres pacientes en total) de VPSNC tratados con Rituximab.

Reporte de caso. Documentamos el caso de un paciente femenino de 28 años de edad en la que se establece diagnóstico de VPSNC variante pseudotumoral con angiografía normal. Ante los reportes de refractariedad en la variante pseudotumoral con el manejo de primera línea se decide manejo con Rituximab.

Conclusiones. El Rituximab puede ser considerado en un futuro como tratamiento de primera línea para VPSNC por su efectividad y seguridad.

Palabras claveVasculitis, sistema nervioso central, rituximab.

Corresponding author: Dr. Brenda Bertado CortésDemyelinating disease clinic. Neurology ServiceCentro Médico Nacional Siglo XXI Specialties HospitalAvenida Cuauhtemoc 330, Colonia Doctores, Delegación Cuauhtemoc, C.P. 06720 Ciudad de México.Phone: 56 27 69 00 E-mail: [email protected]



85

Introduction Clinic case

Primary angiitis of the central nervous system (PACNS) is a rare disease of unknown cause, with exclusive involvement of the brain and spinal cord.1 Its recognition dates back to the mid-1950s when Carvioto and Feigin described several cases of noninfectious granulomatous angiitis. The largest series of patients was published by Salvarani et al. and it included 163 patients.2-5 The incidence is estimated at 2.4 cases per million inhabitants per year, it occurs in the same frequency in both sexes, and the average age of diagnosis is 50 years.6 The pathogenesis is unknown. It has been proposed that infection with varicella-zoster virus has a leading role in the disease.7 We do not know of any randomized trials for the medical management of central nervous system vasculitis, the current strategies are derived from those used in other vasculitis.8 Corticosteroids alone or in combination with cyclophosphamide achieve a favorable response in most cases, however, some patients respond poorly to this scheme or are intolerant to the treatment.9 We report a case of PACNS treated with rituximab in our hospital.

Female patient, 28 years old, with a history of hypothyroidism, four years since diagnosis, in treatment with levothyroxine. She presented with right palpebral ptosis in 2010. In 2015 she had an episode of language arrest lasting three hours, spontaneously remitting. She later reported a left hemicranial headache, oppressive, of moderate intensity, for which she sought assessment by the neurology service at our hospital. Upon evaluation, a right palpebral ptosis and generalized hyperreflexia were found; otherwise, the neurological examination was normal. Magnetic resonance imaging of the brain was performed, the presence of three parenchymal lesions at the frontal lobe and left parietal lobes were observed. The lesions were isointense in T1 weight, hyperintense in T2, and upon administration of contrast medium presented irregular ring reinforcement. The spectroscopy of the larger lesion showed an increase in choline with a decrease in N-acetylaspartate (Figure 1 A, B, C). A diagnostic approach was performed that included the following tests: ANA, ANCA-c, ANCA-p, Anti-DS, Anti Smith, Anti-Ro, Anti-La, Anticardiolipin IgG, IgM, which were all negative. Cerebrospinal fluid clear and colorless, cells 4, glucose 50, proteins 37. Polymerase chain reaction in cerebrospinal fluid for tuberculosis negative. Brain angiography (Figure 2) and renal without alterations. It was decided to perform a biopsy where perivascular lymphocytic infiltration, gliosis, edema and multiple zones of ischemia with microinfarcts were found without observing acid-fast bacilli or neoplastic cells. Treatment was started with intravenous methylprednisolone and subsequent cycles of rituximab at a dose of 2 grams every six months for one year. No further clinical progression, resolution of the edema, decrease in the size of the lesions and lower gadolinium uptake were evidenced by magnetic resonance (Figure 1 D, E, F). Eighteen months after starting treatment there was no evidence of clinical or radiological progression (Figure 1 G, H, I). Later, she underwent plication of aponeurosis of the eyelid with partial functional recovery of it.



86

Figure 1. 1 Magnetic resonance imaging of the brain in T2, FLAIR, and T1Gad weights (A, B, and C, respectively) show ring-enhancing lesions with significant perilesional edema. Eight weeks after treatment with rituximab (D, E, F) resolution of the edema is observed and, after administration of gadolinium, there are no abnormal

enhancements. Eighteen months after starting treatment (G, H, I), no evidence of progression.



87

Figure 2. Normal cerebral angiography. Angiography can be negative in up to 50% of patients. A negative angiogram is associated with recurrence after treatment.



88

Figure 3. Hemotoxilin-Eosin preparation of a brain parenchyma sample obtained from the largest lesion. It is observed perivascular lymphocytic infiltrate



89

PACNS is an uncommon disease, of unknown cause, with exclusive involvement of the brain and spinal cord. Clinically, it has varied and unspecific manifestations, often insidious and progressive. The most common manifestation is headache, which is of nonspecific characteristics. Cognitive impairment is the second most common manifestation. Neurological focality is frequent, with or without evidence of cerebral infarction, while systemic symptoms such as fever or weight loss are uncommon, unlike in secondary vasculitis.2-5 There are different clinical-radiological varieties of the disease, which differ in prognosis and treatment.2-5 PACNS with normal angiography is characterized by affecting the smaller intracerebral arteries. These patients frequently present cognitive deterioration, hyperproteinorrachia (118 mg/dl), and meningeal enhancement or gadolinium-enhancing lesions in magnetic resonance. This form is associated with recurrence after treatment.10

Patients with leptomeningeal enhancement usually have a rapid response to treatment, although relapses are frequent.11

There is a rapidly progressive form of PACNS, which represents the most ominous form and frequently has a fatal outcome. It is characterized by multiple lesions visible on magnetic resonance, along with bilateral cerebral infarcts. The response to immunosuppressive treatment is poor.12

Spinal abnormalities occur in 5% of patients with PACNS, mainly affecting the thoracic spinal cord, presenting as partial or complete myelopathy.2-5

Four percent of patients present a single lesion with mass effect, named the pseudotumoral variant. In some cases, surgical resection of the lesion is curative, while in other cases it has been reported that aggressive immunosuppressive therapy has a favorable response, obviating the need for surgery.14

Intracranial hemorrhage occurs in 12% of patients, mainly as intraparenchymal hemorrhage, although cases of subarachnoid hemorrhage have been reported.15

The diagnosis of PACNS is based on three aspects: neurological deficit without explanation after comprehensive approach, vascular abnormalities in the central nervous system evidenced by angiography or histopathology, and exclusion of other causes.16

Magnetic resonance is the first study to be performed; its sensitivity is reported to be close to 100%. The findings are not specific and vary from cortical or subcortical infarcts, pachymeningeal and/or leptomeningeal enhancement, intracranial hemorrhage, pseudotumoral lesions, and hyperintense areas in T2/FLAIR.13

The typical images of cerebral angiography are alternating areas of narrowing and dilation of the cerebral arteries or occlusions affecting several brain vessels in the absence of abnormalities at the proximal level. When the affected vessels are less than 500 micrometers in diameter, the angiography is usually reported as normal.14

Cerebral and meningeal biopsies are the gold standard for the diagnosis of primary central nervous system vasculitis, since they confirm the diagnosis and discard its imitators. An optimal sample should include dura mater, leptomeningeal, cortex and white matter samples, and should preferably be taken from a site with radiological abnormality.2,7 Biopsy is especially important in the differential diagnosis of pseudotumoral lesions.17 Three histological patterns are known: granulomatous (56%), lymphocytic (28%), and necrotizing (14%).2

Several diagnostic criteria have been established. The most common are Birnbaum and Hellmann, based on clinical findings, angiography, and biopsy.2 (Table 1)

Discussion



90

As mentioned before, there are no randomized trials for the treatment of PACNS and the strategies derive from those used in other vasculitis.8 Corticosteroids alone or in combination with cyclophosphamide achieve a favorable response in the majority of cases, however, there are patients who respond poorly or are intolerant to this scheme so it is necessary to evaluate the efficacy of other immunomodulatory treatments.9 Azathioprine, methotrexate, mycophenolate mofetil, infliximab, and etanercept have been used with variable results.8,18,19

In the related literature, there are only three reported cases of PACNS treated with rituximab, the first published by Salvarani et al in 2014, in which the patient presented intolerance to cyclophosphamide. The other two cases were published by Boyson and colleagues in 2015. One of them found refractoriness to the treatment with a combination of cyclophosphamide and steroids.

The other had decided to use rituximab instead of cyclophosphamide due to a history of vesical polyps. In all three cases, a sustained improvement of 8-12 months post-treatment was reported.1,16

Our case was a woman in the third decade of life with pseudotumoral lesions in imaging studies. Biopsy was performed with data concordant with lymphocytic vasculitis. Secondary causes of vasculitis were ruled out and a brain angiography was performed without alterations. PACNS with pseudotumoral variant and a normal angiography was concluded; these variants are associated with refractoriness to the standard treatment. Considering the patient was of reproductive age, rituximab was preferred over cyclophosphamide because of its better safety profile and lesser effect on fertility. The clinical progression stopped after the treatment and improvement of the lesions was observed in magnetic resonance 18 months post-treatment.

Modified from Salvarani C, Brown RD, Hunder GG, 2012.

Table 1. Diagnostic criteria for Primary Angiitis of the Central Nervous System.

History or clinical findings of an acquired neurological deficit that remains unexplained after an

initial rigorous approach.

Classical findings by angiography or histopathological characteristics of vasculitis within the

central nervous system.

No evidence of vasculitis or any other systemic condition where angiographic and/or

pathological findings may be secondary.

The diagnosis of primary central nervous system vasculitis is established if it meets all the

aforementioned criteria.

Definitive: Confirmation of vasculitis by biopsy.

Probable: In the absence of a biopsy, if there are highly compatible findings in angiography

along with concordant abnormal findings in MRI of the brain and cerebrospinal fluid.

Diagnostic criteria proposed by Calabrese and Mallek

Diagnostic criteria proposed by Brinbaum and Hellmann



91

ConclusionsPACNS is an infrequent and poorly understood disorder of the CNS. The optimal treatment has not yet been defined. It is reported in the international literature that the combination of prednisone and cyclophosphamide is the treatment of choice; however, some patients have contraindications, intolerance to the adverse effects, or little response to this treatment scheme. In our experience, the use of rituximab showed regression of the brain lesions and stopped the clinical progression without the occurrence of adverse effects.





92

1. Salvarani C, Brown RD, Huston J, Morris JM, Hunder GG. Treatment of Primary CNS Vasculitis With Rituximab: Case Report. Neurology. 2014; 82:1287-1288.

2. Salvarani C, Brown RD, Hunder GG. Adult primary central nervous system vasculitis. Lancet. 2012; 380:767-77.

3. Salvarani C, Brown RD, Christianson TJ, Huston J, Giannini C, Miller DV et al. Adult Primary Central Nervous System Vasculitis Treatment and Course.. Arthritis & Rheumatology. 2015; 6:1637-1645.

4. Salvarani C, Brown RD, Christianson TJ, Huston J, Giannini C, Miller DV et al. An update of the Mayo Clinic Cohort of Patients With Adult Primary Central Nervous System Vasculitis. Medicine. 2015; 94:738.

5. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Weigand SD, Miller DV et al. Primary Central Nervous System Vasculitis: Analysis of 101 Patients. Ann Neurol. 2017: 62: 442-451.

6. Salvarani C, Brown RD, Hunder GG. Adult primary central nervoys system vasculitis: an update. Curr Opin Rheumatol. 2012, 24:46-52.

7. Gioannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous system vasculitis: Pathology and mechanisms.. Acta neuropathol. 2012. 123: 759-772.

8. Salvarani C, Brown RD, Christianson T, Huston J, Giannini C, Miller DV et al. Mycophenolate mofetil in primary central nervous system vasculitis. Seminars in Arthritis and Rheumatism. 2015; 45:55-59.

9. Salvarani C, Pipirone N, Hunder GG. Management of primary and secondary central nervous system vasculitis. Curr opin Rheumatol. 2016; 28:21-28.

10. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Huston J, Meschia JF et al. Angiography-Negative Primary Central Nervous System Vasculitis. Medicine. 2008;87:264-271.

11. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Huston J, Meschia JF et al. Primary Central Nervous System Vasculitis With Prominent Leptomeningeal Enhancement. Arthritis & Rheumatism. 2008; 58(2): 595-603.

12. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Huston J, Meschia JF, et al. Rapidly progressive primary central nervous system vasculitis. Rheumatology. 2011;50:349-358.

13. Goyanna-Lyra T, Morais-Martin MG, Carmo-Carvalho R, Oliveira-Mendes CR, Souza Godoy LF, Sousa-Delgado D, et al. Pseudotumoral presentation of primary central nervous system vasculitis. Arq Neuropsiquiatr. 2013; 71(5): 330-335.

14. Kraemer M, Berlit P. Primary central nervous system vasculitis. clinical experiences with 21 new European cases. Rheumatol int. 2011; 31:463-472.

15. Salvarani C, Brown RD, Calamia KT, Christianson TJ, Huston J, Meschia JF et al. Primary Central Nervous System Vasculitis Presenting With Intracranial Hemorrhage. Arthritis & Rheumatism. 2011;63:3598-3606.

16. De Boysson H, Arquizan C, Guillevin L, Pagnoux C. Rituximab for Primary Angiitis of the central Nervous System: Report of 2 patients from the French COVAC Cohort and Review of the Literature. J Rheumatol. 2013; 40:2012-2103.

17. Qu SB, Khan S, Liu H. Primary central nervous system vasculitis mimicking brain tumour: Case report and literature review Rheumatol Int. 2009; 30:127-134.

18. Batthish M, Banwell B, Laughlin S, Halliday W, Peschken C, Paras E, et al. Refractory Primary Central Nervous System Vasculitis of Childhood: Successful treatment with Infliximab. J Rheumatol. 2012;39;2227-2229.

19. Salvarani C, Brown R, Calamia KT, Huston J, Meschia JF, Giannini C et al. Efficacy Of Tumor Necrosis Factor Alfa Blockade in Primary Central Nervous System Vasculitis Resistant to Immunosuppressive Treatment. Arthritis & Rheumatism. 2008; 2:291-296.

References


Case report ALS and Pregnancy

93

Amyotrophic Lateral Sclerosis during pregnancy: an uncommon association

Esclerosis Lateral Amiotrófica y Embarazo: una asociación poco común

Case report

Jaime Iván Castro-Macías,1

Gabriel Santos-Vázquez,2 Marcos Oswaldo Díaz-Campos,2 Iván Quijas-Aldana,2 Ricardo García-Cázarez.1

1Neurosciences Service, High Specialty Regional Hospital of Bajío, León, Gto. México.2Department of Medicine and Nutrition, University of Guanajuato, León, Gto. México.

AbstractBackground: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that shows a combination of upper and lower motor neurons signs and symptoms. The association of ALS and pregnancy has low prevalence due to demographic characteristics of the disease.

Case: A 29-year-old woman, healthy, who comes to the clinic at week 29 of gestation, manifests progressive weakness, distal hypotrophy, and dysphagia. On examination signs of upper and lower motor neuron with involvement in cervical, bulbar, thoracic and lumbar segments. The pregnancy developed without complications; adequate prenatal control, and cesarean section as resolution of pregnancy.

Conclusion: Pregnancy may be associated with the development of latent ALS due to hormonal factors related to the increase of progestogens, which would decrease the neuroprotective effect of estrogens, being the trigger of the disease. Vaginal delivery is facilitated, but respiratory compromise would determine the cesarean delivery.

KeywordsAmyotrophic lateral sclerosis, pregnancy, motor neuron disease, neurodegeneration.



94

ResumenIntroducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa progresiva, con afección de las neuronas motoras superior e inferior, caracterizada por debilidad, atrofia y fasciculaciones. La asociación de ELA y embarazo tiene baja prevalencia debido a las características demográficas de la enfermedad.

Caso clínico: Mujer de 29 años, sana, la cual acude a consulta en la semana 29 de gestación manifestando debilidad progresiva, hipotrofia distal y disfagia. A la exploración signos de afección de motoneurona superior e inferior en segmentos cervical, bulbar, torácico y lumbar. El embarazo se desarrolló sin complicaciones; control prenatal adecuado, y resolución del embarazo por cesárea.

Conclusión: El embarazo podría estar asociado al desarrollo de una ELA latente debido a factores hormonales relacionados al aumento de los progestágenos, los cuales disminuirían el efecto neuroprotector de los estrógenos, siendo el gatillo de la enfermedad. El parto vaginal se ve facilitado, pero el compromiso respiratorio determinaría la vía cesárea.

Palabras claveEsclerosis lateral amiotrófica, embarazo, enfermedad de neurona motora, neurodegeneración.

Corresponding author: Dr. Jaime Iván Castro MacíasServicio de Neurociencias, Hospital Regional de Alta Especialidad del Bajío, León, Gto. México. Boulevard Milenio 130, San Carlos la Roncha, 37660 León, Guanajuato.Phone: +52 477 267 2000E-mail: [email protected]



95

Introduction

Case report

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons manifested by progressive weakness, atrophy, spasticity, fasciculations, and abnormal reflexes with a survival of three to five years after diagnosis.1 The incidence is higher in men with a 1.2-1.5:1 ratio. The age of onset is usually between the fifth and sixth decade of life.1,2 ALS during pregnancy is uncommon, only 18 cases have been described worldwide.3-13 The largest series of cases with this association was described on the island of Guam in 1956 with a higher prevalence of the familial variant of the disease.6,15 In Mexico, there are two cases reported.14 We describe a case in this article.

Female, twenty-nine years old, right-handed, primiparous, with no family history of neuromuscular diseases, drug use, or toxic exposure had pregestational diabetes documented at week 14. At week 29, she sought assessment due to asymmetric weakness predominantly in the upper extremities. Onset of symptoms was one month prior to the diagnosis of pregnancy. The lower extremities were involved three months later. She also presented dysphagia and spastic dysarthria. The physical examination found a globose abdomen with a single live product in cephalic presentation and a fetal heart rate of 140 beats per minute. The neurological exploration found spastic dysarthria, dysphagia, and Vernet's syndrome effects. Muscular strength was 3/5 proximal and 4/5 distal in upper extremities, and 4/5 proximal and distal in lower extremities on the Medical Research Council (MRC) grading system. Additionally, there was generalized atrophy of distal predominance (Aran-Duchenne hands), spasticity, generalized hyperreflexia, extensor plantar response (Babinski), Hoffmann, and bilateral Trömner. Basic laboratory studies, thyroid

Despite the low prevalence, hormonal factors have an impact on the incidence, as well as on the evolution of the disease. Estrogens have a neuroprotective effect, not only in ALS, but also in Alzheimer and Parkinson.3 The possible mechanisms of neuroprotection of these hormones are related to the potentiation of the release of neurotrophins, as well as the interaction with various neurotransmitters.17 Recently, the molecular pathways of estrogen-mediated neuroprotection have been described through inactivation of the NADPH-oxidase complex and reduction of oxidative damage in motoneurons.18 Despite this, it has been observed that the effects of estrogen are contrasting regarding its neuroprotective qualities. In a group of postmenopausal women

profile, cytochemical, cytological analysis, and cerebrospinal fluid (CSF) cultures were normal. VDRL (Venereal Disease Research Laboratory), ELISA (Enzyme-Linked Immunosorbent Assay) and HIV (Human Immunodeficiency Virus) were negative. Antiganglioside antibodies (GM1) were not found. Magnetic resonance imaging (MRI) of the brain and spinal cord were normal. Electromyography (EMG) showed a neuronal-neuropathic pattern with acute and chronic denervation, as well as indirect affection of the upper motor neuron by F-wave facilitation. These findings support the diagnosis of defined ALS, according to the revised criteria of El Escorial and Airlie House, with neurophysiological support in the Awajishima criteria.16 Resolution of the pregnancy was via cesarean section, using regional anesthesia, obtaining one single live product. The evolution of the patient during the puerperium was torpid due to respiratory compromise 30 days after the obstetric event, warranting advanced management of the airway, nevertheless presenting cardiorespiratory arrest and death. The development of the product had a normal evolution from birth until the first six months of postnatal follow-up.

Discussion



96

who received hormone replacement therapy, early signs of the disease were documented without an impact on the onset and progression of symptoms related to ALS.17 The proposed theory regarding this failure in neuroprotection is attributed to the fact that receptors for estrogens are located in the dorsal horn of the spinal cord, while the androgen receptors are located in its motor neurons.17

However, exposure to exogenous estrogens and progestogens, due to the use of combined hormonal contraceptives and hormone replacement therapy, decreases the risk of developing ALS.19

It has also been observed that every extra year of the reproductive period in women, due to the greater exposure of endogenous estrogens, decreases the risk of developing ALS, increasing survival.20 In in vitro studies, estrogen pretreatment protected cortical neurons from glutamate toxicity.21 In transgenic mice, carriers of the mutation in the SOD-1 gene which were ovariectomized, there was an accelerated progression of the disease and a decrease in survival. In another group of ovariectomized mice treated with 17 β-estradiol, the progression of the disease decreased significantly.22

It is important to consider the high levels of progesterone during pregnancy, since it was observed in in vitro studies that this hormone decreases the expression of the estrogen receptor in neuronal cultures, decreasing therefore the neuroprotective effects of estrogen regardless of its concentration.23 However, in nonpregnant women, endogenous progesterone levels have been shown to be correlated with a better prognosis and survival of patients with ALS, since they have a neuroprotective and promyelinating effect.24

The proposed mechanism is due to activation of autophagy in cortical astrocytes. In murine models the autophagy induced by progesterone in the medullary neurons protects them from the neurodegeneration induced by the mutation in the gene G93A-SOD1.25

The relatively higher concentrations of progesterone with respect to estrogen during pregnancy could be related to the mechanisms

previously proposed to trigger ALS during pregnancy, since in more developed models it has been described that the molecular pathways of neuroprotection in this disease are mediated mainly by estrogens.18

In addition to the potential hormonal effect, the activation of cytokines and neuroinflammation mediated by other routes may increase the susceptibility to develop ALS during pregnancy, since, during this state, there is an increase in the concentration of cytokines that have a toxic effect on motor neurons in susceptible patients.26 These neurons can degenerate if they also have mutations in the SOD-1 gene or other neuroprotective molecules such as vascular endothelial growth factor (VEGF), since polymorphisms in the gene of this molecule are related to the development of ALS during pregnancy.27 Based on these findings, it could be speculated that pregnancy could act as a trigger for a preexisting but clinically silent ALS in genetically susceptible patients, in addition to epigenetic factors involved.28,29

Phenotypic differences have been reported: spinal variants predominate in men, while bulbar variants predominate in women.30 One possible explanation is due to the vulnerability of the bulbar cranial nerves related to the increase in the expression of the receptor for N-methyl-D-aspartate (NMDA), which is promoted by estrogenic activity, which favors glutamate toxicity.31

During pregnancy, there is a physiological increase in ventilatory requirements of 40% because pregnancy causes a deterioration of respiratory function related to uterine growth.4 Therefore, in patients with this association, ventilatory support is required during the gestational period and delivery,12 especially in advanced cases of the disease, since there is a limitation in the respiratory reserve with respect to diaphragmatic function.4

The treatment during advanced stages represents a serious problem. Bulbar involvement, in addition to affecting respiration, affects swallowing and this is additional to the physiological hypermetabolism inducing malnutrition and cachexia in final stages.4



97

Treatment with riluzole is considered class C during pregnancy due to teratogenic effects reported in animal tests; however, the risk in humans has not been evaluated in appropriate clinical studies. There is a report of a woman with ALS during pregnancy who received this treatment without deleterious effects on the product.32

Regional anesthesia offers advantages over general anesthesia, since it reduces pain intensity, while preserving bulbar function.10

There is no consensus regarding the resolution of pregnancy via vaginal birth or cesarean section. Because the uterine musculature is not affected, but the pelvic floor is, which lacks tone, this could facilitate vaginal delivery. Since the sensitivity is preserved in ALS, the patient would have no difficulty perceiving uterine contractions.32 Bulbar compromise, as well as of the respiratory musculature, would determine the resolution of pregnancy via cesarean section.3,15

Regarding the association of ALS and pregnancy, the frequency of congenital malformations has only been reported in two cases: anencephaly and cleft palate. It has not been determined, however, if they have a direct relationship with ALS.6,15



98

Conclusion

The association of ALS and pregnancy is uncommon, but the diagnostic suspicion is important. Data of upper and lower motor neuron involvement should be taken into account since it impacts the gestational care of the mother and the product, as well as the resolution of the pregnancy.





99

1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-55.

2. Al-Chalabi A, Hardiman O, Kiernan MC, Chiò A, Rix-Brooks B, van den Berg LH. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol. 2016;15(11):1182-94.

3. Chiò A, Calvo A, Di Vito N, Vercellino M, Ghiglione P, Terreni AA, et al. Amyotrophic lateral sclerosis associated with pregnancy: report of four new cases and review of the literature. Amyotroph Lateral Scler Other Mot Neuron Disord. 2003;4(1):45-48.

4. Sarafov S, Doitchinova M, Karagiozova Z, Slancheva B, Dengler R, Petri S, et al. Two consecutive pregnancies in early and late stage of amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10(5-6):483-6.

5. Scalco RS, Vieira MC, da Cunha Filho EV, Lago EG, da Silva IG, Becker J. Amyotrophic lateral sclerosis and riluzole use during pregnancy: A case report. Amyotroph Lateral Scler. 2012;13(5):471-2.

6. Huston J, Lingenfelder J, Mulder D, Kurland L. Pregnancy complicated by amyotrophic lateral sclerosis. Am J Obstet Gynecol. 1956;72(1):93-9.

7. Levine MC, Michels RM. Pregnancy and amyotrophic lateral sclerosis. Ann Neurol. 1977;1(4):408.8. Lupo VR, Rusterholz JH, Reichert JA, Hanson SA. Amyotrophic lateral sclerosis in pregnancy. Obstet

Gynecol. 1993;82(4):682-5.9. Vincent O, Rodriguez-Ithurralde D. Amyotrophic lateral sclerosis and pregnancy. J Neurol Sci.

1995;129:42-3.10. Jacka MJ, Sanderson F. Amyotrophic lateral sclerosis presenting during pregnancy. Anesth Analg.

1998;86(3):542-3.11. Sobrino-bonilla Y. Caring for a Laboring Women With Amyotrophic Lateral Sclerosis: A CASE

REPORT. MCN Am J Matern Child Nurs. 2004;29(4):243-7.12. Leveck DE, Davies GA. Rapid progression of amyotrophic lateral sclerosis presenting during

pregnancy: a case report. J Obstet Gynaecol Can. 2005;27(4):360-2.13. Ahmed WA, Morsy A, Hunter A. Motor neurone disease in pregnancy: A case report. SCU-MJ.

2008:137-9.14. Martínez HR, Marioni SS, Ocañas CEE, Garza MTG, Moreno-Cuevas JE. Amyotrophic lateral sclerosis

in pregnancy: clinical outcome during the post-partum period after stem cell transplantation into the frontal motor cortex. Cytotherapy. 2014;16(3):402-5.

15. Tyagi A, Sweeney B, Connolly S. Amyotrophic lateral sclerosis associated with pregnancy. Neurol India. 2001;49(4):413.

16. Hardiman O, Al-Chalabi A, Chio A, Corr E, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Prim. 2017;3:17071.

17. Rudnicki SA. Estrogen replacement therapy in women with amyotrophic lateral sclerosis. J Neurol Sci. 1999;169(1):126-7.

18. Klemann CJHM, Visser JE, Van Den Bosch L, Martens GJM, Poelmans G. Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology. Brain Pathol. 2017; 28(2): 203-211.

19. Rooney JPK, Visser AE, D’Ovidio F, Vermeulen R, Beghi E, Chio A, et al. A case-control study of hormonal exposures as etiologic factors for ALS in women. Neurology. 2017;89(12):1283-1290.

20. de Jong S, Huisman M, Sutedja N, van der Kooi A, de Visser M, Schelhaas J, et al. Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis. J Neurol. 2013;260(2):507-12.

21. Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM. The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci. 1999;19(7):2455-63.

22. Groeneveld G, Van Muiswinkel F, Sturkenboom J, Wokke J, Bär P, Van den Berg L. Ovariectomy and

17β-estradiol modulate disease progression of a mouse model of ALS. Brain Res. 2004;1021(1):128-31.

23. Jayaraman A, Pike CJ. Progesterone attenuates oestrogen neuroprotection via downregulation of oestrogen receptor expression in cultured neurones. J Neuroendocrinol. 2009;21(1):77-81.

24. Monachelli GG, Meyer M, Rodríguez G, Garay L, Sica RE, De Nicola AF, et al. Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors. Horm Mol Biol Clin Investig. 2011;6(1):167-173.

References



100

25. Kim J, Kim TY, Cho KS, Kim HN, Koh JY. Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2013;59:80-85.

26. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10(3):253-63.

27. Lunetta C, Sansone V, Penco S, Mosca L, Tarlarini C, Avemaria F, et al. Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype. Eur J Neurol. 2014;21(4):594-8.

28. Paez-Colasante X, Figueroa-Romero C, Sakowski SA, Goutman SA, Feldman EL. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol. 2015;11(5):266-279.

29. Jimenez-Pacheco A, Franco JM, Lopez S, Gomez-Zumaquero JM, Leal-Lasarte MM, Caballero-Hernandez DE et al. Epigenetic mechanisms of gene regulation in amyotrophic lateral sclerosis. Neuroepigenomics in Aging and Disease. 2017:255-275.

30. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gend Med. 2010;7(6):557-70.

31. Fuller PI, Reddrop C, Rodger J, Bellingham MC, Phillips JK. Differential expression of the NMDA NR2B receptor subunit in motoneuron populations susceptible and resistant to amyotrophic lateral sclerosis. Neurosci Lett. 2006;399(1):157-61.

32. Kawamichi Y, Makino Y, Matsuda Y, Miyazaki K, Uchiyama S, Ohta H. Riluzole use during pregnancy in a patient with amyotrophic lateral sclerosis: a case report. J Int Med Res. 2010;38(2):720-6.

Revista Mexicana de Neurociencia

Estimado académico:

Por medio de la presente, es un gusto saludarle y extenderle la más cordial invitación a colaborar con la publicación de artículos de investigación original, básica, tradicional o aplicada, casos clínicos o artículos de revisión en la Revista Mexicana de Neurociencia, órgano oficial de difusión científica de la Academia Mexicana de Neurología.

La publicación ha sido incluida recientemente en el índice de revistas de CONACyT, y se trabaja para que en breve esté disponibleen las plataformas OVID y SciELO, especialmente en PubMed.

Estamos seguros que con su amplia trayectoria académica le permitirá participar e invitar a colaborar a sus distinguidos colegas, que con su participación enriquecerán nuestra revista.

El Comité Editorial está formado por investigadores de diversas instituciones de nuestro país y del extranjero, quienes cuentan con reconocida calidad académica.

Esperamos que usted y cada integrante de la Academia Mexicana de Neurología se sientan parte y sumamente orgullosos de la Revista Mexicana de Neurociencia.

Reciba un cordial saludo.Atentamente,

Dra. Carolina LeónCo-Editor

Dr. Ildefonso RodríguezEditor

Dr. Antonio ArauzCo-Editor

Revista Mexicana de Neurociencia

San francisco 1384 Torre B 7, Col. Del Valle, Ciudad de México, C.P. 03100Teléfonos: +52 (55) 5559 9833 / +52 (55) 5575 9312

www.neurologia.org.mx www.revmexneuroci.com

Revista Mexicana de

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

Revista Mexicana de Neurociencia, 2018; 19(3): 1-100

www.revmexneuroci.com

Revista Mexicana de Neurocienciaprevious.revmexneurociencia.com/wp-content/uploads/... · / ISSN...

Documents

Transcript of Revista Mexicana de Neurocienciaprevious.revmexneurociencia.com/wp-content/uploads/... · / ISSN...