Revista Mexicana de Neurociencia [PDF]

T Cy A ON nC e ra ho a ci uro e xN Me v Re

Vol. 18, núm. 5 (septiembre-octubre de 2017)

Revista Mexicana de

Neurociencia

Revista Mexicana de Neurociencia; 18,5 (2017):1-101

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

Órgano Oficial de Difusión de la AMN

www.revmexneuroci.com / ISSN 1665-5044

Academia Mexicana de Neurología, A.C.

Editorial committee 2017 Chief editor: Dr. C. Ildefonso Rodríguez Leyva [email protected] Co-editors: M.C. Carolina León Jimenez M.C. Antonio Arauz Góngora [email protected] Founding editor: Dra. Lilia Núñez Orozco Emeritus editor: Dr. C. Carlos Cantú Brito

National editorial comitee Dr. Sergio de Jesús Aguilar Castillo Dr. Marco Antonio Alegría Loyola Dra. Alma Yolanda Alvarado Gutierrez Dr. Carlos Gabriel Ascanio Rodríguez Dra. Catherine Boll Woehrlen Dr. Antonio Bravo Oro Dr. Jorge Burgos Centeno Dra. Graciela Cárdenas Hernández Dr. Paul Carrillo Mora Dra. Teresa Corona Vázquez Dra. Beatriz Chavez Dr. Bruno Estañol Vidal Dra. Agnes Fleury Dr. José Flores Rivera Dra. Silvia García Dr. Fernando Góngora Rivera Dra. Margarita González Cruz Dra. Alejandra González-Duarte Dr. Oscar González-Vargas

Dr. Rubén Haro Silva Dr. Juan Calixto Hernández Aguilar Dr. Héctor Gerardo Hernández Rodríguez Dr. Jesús Higuera Calleja Dr. Javier Jaramillo de la Torre Dr. Humberto Juárez Jiménez Dr. Rubén Martínez Hernández Dra. Iris E. Martínez Juárez Dra. Adriana Martínez Mayorga Dr. Francisco Mena-Barranco Dra. Roxana Millán Cepeda Dra. Rebeca Millán Guerrero Dr. Alberto Mimenza Alvarado Dra. Leticia Munive Baez Dr. Luis Manuel Murillo Bonilla Dr. Alfredo Ponce de León Dr. Guillermo Punzo Bravo Dra. Sandra Quiñones Aguilar Dra. María Teresa Reyes

International editorial comitee Dr. Anthony Amato Dr. José Biller Dr. Andre Kanner Dra. Farrah Mateen Dr. José Merino

Statistical Advisor Style corrector Translator Design

Dr. José Obeso Dr. Julio Pascual Dr. Marc Patterson Dr. Eduardo Tolosa Dr. Samuel Wiebe

Héctor Gerardo Hernández Rodríguez Maestro Alejandro García Rebeca Barroso Design Cortex

Dra. Mayela Rodríguez Violante Dr. Leopoldo Rivera Castaño Dr. Ulises Rodríguez Ortiz Dr. Francisco Rogel Ortiz Dr. Luis Ángel Ruano Calderón Dra. Angélica Ruiz-Franco Dr. José Luis Ruiz-Sandoval Dr. José Manuel Sandoval Rivera Dr. Daniel San Juan Dr. Horacio Sentíes Madrid Dra. Mónica Sierra del Rio Dra. Ana Luisa Sosa Ortiz Dr. José Luis Soto-Hernández Dr. Gersain Trujillo Alonso Dr. Steven Vargas Cañas Dr. Rubén Darío Vargas García Dra. Karina Vélez Jiménez Dr. Marco Zenteno Castellanos

Contenidos

Contents

CONTRIBUCIONES ORIGINALES

ORIGINAL CONTRIBUTIONS

• Perfil neuropsicológico de un grupo de adultos mayores diagnosticados con deterioro cognitivo leve • Caracterización fractal de ventrículos cerebrales normales en imágenes de resonancia Magnética ponderadas en T2 • Relación entre la enfermedad ateroesclerótica y hernia discal en pacientes con manejo conservador integral.

• Neuropsychological profile of a group of older adults diagnosed with mild cognitive impairment • Fractal characterization of normal cerebral ventricles in t2-wheigthed magnetic resonance imaging • Relationship between atherosclerotic disease and disc herniation in patients with integral conservative management.

REVISIONES

REVIEWS

• Revisión del trastorno del espectro autista: Actualización del diagnóstico y tratamiento • Fisiopatología del trauma raquimedular • ¿Dónde estamos y a dónde vamos? Nuevas estrategias integrales en el manejo de hernia de disco. • Consideraciones y reconceptualización de teorias del dolor crónico asociado a disfunciones musculoesqueleticas y su implicancia en la plasticidad y reorganización cerebral: una revisión de la literatura. • Celulas madres: una nueva alternativa en el manejo de la paralisis cerebral

REPORTES DE CASO

• Evaluación neuropsicológica de la pragmática de la comunicación en un paciente con daño cerebral adquirido • Tratamiento endovascular de pseudoaneurismas gigantes de la arteria carótida interna cervical: a propósito de un caso y revisión de la literatura

EDITORIAL

• Carta editorial por Dr. Miguel Osorno Guerra

• Autism spectrum disorder review: diagnosis and treatment update • Pathophysiology of spinal trauma • Where are we and where are we going? Review of strategies and new integral proposals in the management of herniated disc. • Considerations and reconceptualization of theories of chronic pain associated with musculoskeletal dysfunctions and its implication in plasticity and cerebral reorganization: a review of the literatura. • Stem cells: an alternative for the treatment of cerebral palsy

CASE REPORTS

• Neuropsychological evaluation of pragmatics in a patient with acquired brain injury • Endovascular treatment of giant pseudoaneurysms of the cervical internal carotid artery: Case report and Review of literature.acquired brain injury

EDITORIAL

• Editorial letter by Dr. Miguel Osorno Guerra

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Original contribution Mild cognitive impairment

Original contribution Ríos-Gallardo Ángela Magnolia,1 Muñoz-Bernal Luisa Fernanda,2 Aldana-Camacho Laura Victoria,3 SantamaríaÍñiguez María Fernanda,4 Villanueva-Bonilla Cristian5

Neuropsychological profile of a group of older adults diagnosed with mild cognitive impairment Neuropsychological profile of a group of older adults diagnosed with mild cognitive impairment

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PhD. Neurociencia Cognitiva. Grupo de Investigación Dneuropsy. Vicerrectora Investigación y Proyección Social Universidad Surcolombiana. 2 Esp. Evaluación Clínica y Tratamiento de Trastornos Emocionales y Afectivos. Fundación Universitaria Konrad Lorenz. 3 Psicóloga Universidad Surcolombiana. Grupo de Investigación Dneuropsy. 4 Mg. Psicología Clínica. Fundación Universitaria Konrad Lorenz. 5 Psicólogo Universidad Surcolombiana. Joven Investigador Colciencias. Grupo de Investigación Dneuropsy.

Abstract INTRODUCTION: Mild cognitive impairment (MCI) is a clinical

condition between normal aging and a probable dementia process such as Alzheimer’s disease (AD), which manifests itself as a loss of memory greater than expected for age, without meeting the diagnostic criteria Established for AD. This disease occurs in people with advanced ages. It is expected that by 2050 life expectancy in Colombia will exceed 79 years and with more than 20% of the population over 60 years.

OBJECTIVE: To describe the neuropsychological profile of a group of older adults with MCI.

METHODS:

The sample consisted of 69 elderly adults with an average age of 71.79 years. Mini-Mental State Examination and Neuropsychological Assessment (Grover and Buschke Verbal Memory and Cognitive Cerad) were used.

RESULTS: In all, 49% of older adults assessed had a predominance

of MCI-type amnestic multiple domains, 35% had non-amnestic MCI multiple domains and 8% met criteria for MCI-type amnestic single domain and non-amnesic single domain.

Keywords mild cognitive impairment, dementia, executive functions, attention, memory. Revista Mexicana de Neurociencia

CONCLUSION:

When comparing the results of other investigations and taking into account that the present study does not estimate prevalence, it is necessary to recognize the similarity in the results and the usefulness of the case study to make more accurate diagnoses. September-October, 2017; 18(5):1-13

Original contribution Mild cognitive impairment

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Resumen INTRODUCCIÓN:

El deterioro cognitivo leve (DCL) es una condición clínica entre el envejecimiento normal y un probable proceso demencial como la enfermedad de Alzheimer (EA), que se manifiesta por pérdida de memoria mayor a la esperada para la edad, sin cumplir con los criterios diagnósticos establecidos para la EA. Dicha enfermedad se presenta en personas con edades avanzadas. Se espera que para el 2050 la esperanza de vida en Colombia sea superior a 79 años y con más del 20% de la población por encima de los 60 años.

OBJETIVO:

Describir el perfil neuropsicológico de un grupo de adultos mayores con DCL.

MÉTODOS: La muestra fue conformada por 69 adultos mayores con una edad promedio de 71.79 años. Se utilizaron instrumentos de tamizaje (Mini-Mental State Examination, Escalas de memoria, depresión y actividades de la vida diaria) y de evaluación neuropsicológica (Memoria Verbal de Grober and Buschke y el Cerad Cognitivo).

RESULTADOS: El 49% de los adultos mayores valorados presenta

un predominio de DCL tipo amnésico múltiples dominios, el 35% presenta DCL tipo no amnésico múltiples dominios y el 8% cumple los criterios para DCL tipo amnésico único dominio y no amnésico único dominio.

CONCLUSIONES:

Al comparar los resultados de otras investigaciones y teniendo en cuenta que en el presente estudio no se estima prevalencia, es necesario reconocer la similitud en los resultados arrojados y la utilidad que presenta el estudio de caso para realizar diagnósticos más acertados.

Palabras clave deterioro cognitivo leve, demencia, funciones ejecutivas, atención, memoria.

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. Email: [email protected]

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Original contribution Mild cognitive impairment

Introduction Mild cognitive impairment (MCI) is a clinical condition between normal aging and Alzheimer’s disease (AD), which is manifested by memory loss greater than expected for the age, without complying with the diagnostic criteria established for AD.1 MCI is associated with an increased risk of developing dementia; additionally, neuropsychological deficits are more common and clinically important in intervention and rehabilitation processes.2 The increase in life expectancy represents one of the most relevant aspects of our current society, resulting from a series of factors such as disease control, better nutritional conditions, hygiene, birth control, and decrease of mortality. According to the last census performed in Colombia, 6.3% of the population is over 65 years of age, corresponding to 2,612,508 inhabitants. The general population increased by an average of 1.9% per year (in the period 1990-2003), while the population aged over 80 grew at a rate of 4%.3 It is expected that by 2050, life expectancy in Colombia will exceed 79 years, and more than 20% of the population will be over 60 years old.4 These figures suggest that, as the population ages, diseases of this age such as dementia will also increase. Taking into account that senescence involves a series of changes, especially at the cognitive level, it is necessary to analyze these changes because not all of them are particular to old age. When it comes to alterations in cognitive functions with a predominance of important changes in memory, language, perception, and attention, some are due to the appearance of dementia.5,6 However, there is interindividual variability due to external factors such as educational level, gender, socioeconomic status, and eating habits.7 Considering the aforementioned, and due to the lack of clarity about recognizing a pre-dementia process that begins with MCI, Petersen et al.8 proposed diagnostic criteria to identify cognitive impairments that do not affect daily life activities Revista Mexicana de Neurociencia

and suggest that MCI should be designated as a transition state between normal aging and dementia.9-12 This article presents the neuropsychological profile of a group of older adults with MCI at the Memory Clinic of the city of Neiva, Colombia. The objective of this clinic is to develop integral rehabilitation programs in mental health and offer a complementary treatment to the pharmacological, within the framework of investigative processes, led by a group at the Surcolombiana University. This approach includes the recovery or optimization of cognitive, occupational, social, and physical abilities, and is aimed at patients with cognitive disorders secondary to neurodegenerative diseases, vascular diseases, or sequelae of cranioencephalic trauma, and their families.

Methods Participants The sample consisted of 69 older adults with an average age of 71.79 years (SD=7.88) and 2.76 years of schooling (SD=1.04). The group consisted of 78% females and 22% males. Out of these participants, 74% presented medical history of risk of arterial hypertension (54%), diabetes (11%), cardiopathies (7%), and cerebrovascular disease (1%), and a family medical history of dementia (18%), Parkinson’s disease (7%), psychiatric background (3%), and other neurodegenerative conditions (2%). This sample of patients arises from the diagnostic process performed on 573 elderly people, of which 48% (275) did not present cognitive impairment, and 52% (298) were assessed in depth due to the suspicion of dementia in process. Of this remaining population (298), 23% were diagnosed with MCI according to the classification proposed by Petersen et al.8 The research protocol and September-October, 2017; 18(5):1-13

Original contribution Mild cognitive impairment

informed consent were approved by the Research Ethics Committee of the Faculty of Health of the Surcolombiana University.

Instruments Screening Instruments Mini-Mental State Examination (MMSE).13 A cut-off point between 23 and 24 was used, with a sensitivity and specificity of 87% and 82%, respectively. Subjective Memory Complaints Questionnaire.14 It is applied to one of the relatives and/or caregiver (who must be in permanent contact with the participant). The cut-off point is 19 and the maximum score is 45. Lawton and Brody Scale. It evaluates the subject’s ability to lead an independent life, and studies the patient’s performance in order to correlate it with the cognitive skills he uses to access the context in which he is developing.15 Yesavage Geriatric Depression Scale. Allows a differential diagnosis with pseudodementia.16

Complementary neuropsychological evaluation tests Grober-Buschke Test. Test of explicit verbal memory with controlled coding that allows to register free recall and cued recall, phonological and semantic, in the short and long term.17 Cognitive CERAD.18 Standardized in the Colombian population by the Neuroscience Research Group at the University of Antioquia.19 It evaluates the following cognitive domains:

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active search strategies for information and word production from an established category. Sustained attention. Search and visual tracking from the Trail Making Test (TMT) Part A, which allows to obtain the number of correct sequences in a maximum execution time of 120 seconds.21 Constructional apraxia and visual-spatial skills. Determined by the Rey-Osterrieth Complex Figure Test,22 which allows to evaluate the execution and to assess the capacity to generate planning strategies and imitative capacity. Executive functions. Categorization, conceptualization, planning, organization, and abstraction are evaluated with tests such as the Wisconsin, Raven, and WAIS (Wechsler Adult Intelligence Scale) subtests.

Procedures A screening process was initially performed to obtain the participants’ cognitive processes baseline. Once this was completed, if there was a suspected cognitive impairment in a participant (value less than 2 ± SD in each of the tests), we proceeded to a complementary neuropsychological evaluation with a protocol standardized by the Neuroscience group of the University of Antioquia,23 which was used in a study of the prevalence of dementia in Neiva’s population over 60 years of age.24 After the complementary neuropsychological assessment, all the cases were submitted to study by an interdisciplinary team (neurologist, psychiatrist, and neuropsychologist), whose purpose was to establish a diagnosis with the support of MCI international criteria.25

Language. It utilizes the 64 figures of the Boston Naming Test.20 The subject must name objects, and the errors are classified into six categories: visual, semantic, visual-semantic, phonological, descriptive, and others. Semantic fluency. It explores the generation of Revista Mexicana de Neurociencia

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Original contribution Mild cognitive impairment

Results First, the sociodemographic characteristics of the participants are described. Next, the scores obtained in the neuropsychological tests are evaluated, and the performance of the subjects is established with respect to the MCI subtype in which they are located. Finally, an inter- and intragroup comparison is performed for MCI subtypes in order to establish significant differences in the performance of the cognitive spheres evaluated.

Neuropsychological profile To determine the state of the cognitive functions of the participants, a descriptive analysis was performed for each of the cognitive domains evaluated. The classification of optimal and low performance was based on a conversion of the gross scores in each of the tests that constitute the protocol used, taking into consideration the age, schooling, and the standardized scales for the Colombian population proposed by the research group of the University of Antioquia.19 The direct scores that were below average for the age and schooling were considered low performance, and those that were above the mean were considered optimal performance. Table 1 presents the performance of the participants in the cognitive domains.

Language It was found that 56.8% of the evaluated subjects exhibited low performance in the tasks of denomination, semantic fluency, and phonological fluency, with only 43.2% presenting optimal performance.

Memory In the memory of constructional praxis, 64.9% of the evaluated subjects presented low performance; likewise, 70.3% obtained low performance in the Rey complex figure test. Meanwhile, 97.3% Revista Mexicana de Neurociencia

displayed optimal performance in the recognition of a list of words.

Attention In the Trail Making Test (TMT), 62.2% of those evaluated had low performance, and 86.5% used more time than expected for their age and schooling in the execution of the task, just as 78.4% did in the visual execution test.

Constructional abilities Though 62.2% had an optimal performance, the time spent for the execution of the test in the majority of the subjects was high, which is to say, there is a slowing down in this process.

Executive functions The 78.4% of the subjects obtained low performance in tests of calculation (WAIS) and the Wisconsin (64.9%); similarly, 62.2% of the population did not reach the number of categories indicated for age and schooling, and 59.5% had a low performance in the initial category index.

Functional status assessment The results of the functional status scales complement the diagnostic criteria for MCI proposed by Petersen et al.8 Participants must be totally independent in their basic activities of daily living. In the functional status assessment, 81.1% of the population shows no signs of depression, 64.9% of those evaluated are at level two of the functional state, and in relation to the other tests it is evident that the basic functions of daily life are not altered (100% of the population presents absence of disability), which is why they’re considered MCI.

Typifying the subtypes of MCI Taking into consideration the analysis of the cognitive domains and the description of the

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Original contribution Mild cognitive impairment

sample studied, participants were classified into subtypes of MCI. This was done through a rigorous review of the case and the standardized scales for the Colombian population, in order to verify the correspondence in 1.5 standard deviations of the expected mean for age and schooling in each of the tests, placing each subject in one of the sub-types to carry out an intragroup characterization with respect to age, schooling, origin, and gender. The distribution of the participants according to the classification of the subtypes of MCI is presented in Figure 1. According to the classification with respect to MCI subtypes, we found in the evaluated sample a predominance of amnestic multiple domains with 49% belonging to this sub-type; the percentage for non-amnestic multiple domains was 35%, and 8% met the criteria for amnestic single domain as well as non-amnestic single domain. In the amnestic single domain group, the most common age was that of 66.7% of participants, which were older than 70 years, and the remainder of the group’s age range was from 60 to 69 years old; the participants included in the amnestic multiple domains sub-type were 55.6% aged between 60 and 69 years, and 44.4% were over 70 years; within the non-amnestic single domain group, 33.3% were aged 60 to 69 years and 66.7% older than 70; with regards to non-amnestic multiple domains, the majority of the participants (76.69%) were over 70 years and the minority (23.1%) were in the range of 60 to 69 years of age. One hundred percent of the participants in the amnestic single domain group had basic primary schooling. In the group for amnestic multiple domains, 88.9% had basic primary schooling and 11.1% had some middle school. In the nonamnestic single domain group, the whole group had basic primary schooling. In the non-amnestic multiple domains group, 69.2% had basic primary and 30.8% had some middle school. Intraand inter-group comparison of neuropsychological characteristics (MCI subtypes) The statistical calculation was performed to know Revista Mexicana de Neurociencia

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the compliance with normality parameters; the calculated p value was p> 0.05 according to the Shapiro-Wilk and the ANOVA statistic was applied. Table 2 shows the comparison of intragroup neuropsychological characteristics. The ANOVA shows that there is a statistically significant difference between the groups in the tests that evaluate the field of visual execution and praxis; with p=0.001 in the recollection of constructional praxis, p=0.016 in the execution of constructional praxis, and p=0.027 in the execution of the Rey figure test, the significant difference clearly shows that the dependent variable is directly related to the independent variables in the study. With respect to the remaining tests, there are no significant differences between groups.

Discussion The human being, from the perspective of the life cycle, transits through different stages. In later adulthood, there are changes that relate to these stages, among which is the slowing down of cognitive processes such as attention, memory, visuoconstruction abilities, and executive functions. These changes can become significant and generate cognitive alterations that affect the older adult’s general performance. Experts in the subject have named these subtle changes MCI, which is characterized by a clinical picture consisting of the decrease of one or more cognitive functions without affectation in the activities of daily living.26 Petersen et al.8 propose as criteria for MCI diagnosis that there should be a cognitive concern on the part of the patient or an informant, a decline in cognitive functions, intact daily life activities, and no pathological, neurological, or psychiatric alteration to explain the deterioration. Furthermore, they classify MCI into four sub-types taking into consideration the cognitive domain: amnestic single domain MCI, amnestic multiple September-October, 2017; 18(5):1-13

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Original contribution Mild cognitive impairment

Table 1. Cognitive profile.

Language

Test applied Denomination Semantic Fluency Phonological Fluency Memory of a list of words

Memory

Total Intrusions of the Word Listing Recognition of the correct words list Recognition of the incorrect words list Recollection of constructional praxis Rey–Osterrieth complex figure test (Total score) Trail Making Test (Correct Answers)

Attention

Trail Making Test (Time) Visual Execution Test (Correct Answers) Visual Execution Test (Omissions)

Visuoconstruction abilities

Visual Execution Test (Time) Constructional Praxis Rey–Osterrieth complex figure test (Time) Rey–Osterrieth complex figure test (Total score)

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Performance Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal

Percentage 56.80% 43.20% 56.80% 43.20% 56.80% 43.20% 40.50% 59.50% 48.60% 51.40% 35.10% 64.90% 2.70% 97.30% 64.90% 35.10% 70.30% 29.70% 62.20% 37.80% 86.50% 13.50% 32.40% 67.60% 32.40% 67.60% 78.40% 21.60% 37.80% 62.20% 64.90% 35.10% 32.40% 67.60%

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Original contribution Mild cognitive impairment

Test applied Raven-A

Executive Functions

WAIS Arithmetic Wisconsin correct hits Wisconsin errors Wisconsin categories Wisconsin perseverative responses Wisconsin Initial Conceptualization Index Wisconsin Total Attempts

Performance Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Low Optimal Complete Incomplete

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Percentage 40.50% 59.50% 78.40% 21.60% 64.90% 35.10% 45.90% 54.10% 62.20% 37.80% 32.40% 67.60% 59.50% 40.50% 83.80% 16.20%

Table 2. ANOVA statistical values for the comparison of neuropsychological characteristics between the groups (MCI subtypes). Test Mini-Mental Denomination Memory of list of words Constructional Praxis Recollection of list of words Recollection of constructional praxis Trail Making Test (Time) Visual Execution Test (Time) Rey–Osterrieth complex figure test (Time) Rey–Osterrieth complex figure test (Total score) Semantic Fluency Phonological Fluency Raven-A WAIS Arithmetic Wisconsin correct hits Wisconsin errors Wisconsin perseverative responses

F 0.571 2.019 1.373 3.97 0.467 7.461 0.973 2.445 0.356 3.46 0.451 1.232 1.399 1.478 2.431 1.626 0.811

Sig. 0.638 0.13 0.268 0.016 0.707 0.001 0.417 0.081 0.785 0.027 0.719 0.314 0.26 0.238 0.083 0.202 0.497

F = Statistical Value Sig. = Statistical Significance

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Original contribution Mild cognitive impairment

domains MCI, non-amnestic single domain MCI, and non-amnestic multiple domains MCI.27

performance was evident in the WAIS arithmetic and the Wisconsin card classification tests.

The participants classified in the non-amnestic single domain MCI group had low grades in tests of denomination, semantic fluency, phonological fluency, and visuoconstruction execution, evidencing predominantly cognitive affectation of language. The group classified in the subtype non-amnestic multiple domains presented low performance in denomination tests, sustained attention, executive functions, and visuoconstruction execution, which indicate more than one altered cognitive sphere.

In different studies, it was found that patients with amnestic MCI had poor performance in memory tests (episodic predominance), while non-amnestic multiple domains had more difficulty with language tasks.31-33 These findings are similar to the present study because the evaluated subjects exhibited low performance in tests related with semantic and phonological fluency; in the amnestic multiple domains group, they had low performance in language, memory, and attention.

In the analysis performed with ANOVA at the inter- and intra-group level, we verified significant differences between the groups in the execution of constructional praxis tests as much in memory as in copying, and in the elaboration of the complex Rey figure; this shows that the dependent variable meets the criterion of being directly influenced by the independent variables present in the study. This verifies that the initial classification, product of case studies, gives an important value to the clinical findings and helps establish a clear diagnostic criterion.28 In Colombia, research has shown how, over the years, cognitive processes deteriorate and may become clinically significant.29,30 In these studies, the cognitive profile of a group of older adults was established and it was concluded that, at an older age, performance declines in attention, language, memory, and executive functions; similarly, the neuropsychological evaluation showed that the participants presented a decline in cognitive spheres, such as language, with low performance in the denomination, phonological fluency, and semantics tests.

Regarding schooling as a variable to be analyzed regarding cognitive decline, many studies show that the higher the schooling, the lower the impairment in cognitive performance.11,33,34 This is corroborated in the present investigation because the range of schooling is low, having been considered a risk factor and a trigger of this clinical picture. The affected areas in the participants in multiple domains MCI show decline in memory, attention, language, and visuoconstructional abilities, among others. These processes are also affected in the amnestic multiple domains MCI with a greater decline in amnestic processes. When comparing the aforementioned figures, and taking into account that the present study does not estimate prevalence, it is necessary to recognize the similarity in the results obtained and the usefulness of the case study to make more accurate diagnoses.28

With regards to memory, the remarkably inferior performance was presented at the recollection of constructional praxis and the complex Rey figure; as for attention, low results were found in the performance of the trail making test, the visual execution test (time), and the complex Rey figure test. With respect to the executive functions, a low Revista Mexicana de Neurociencia

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Original contribution Mild cognitive impairment

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Figure 1. Population distribution according to the classification of the MCI subtypes.

Conflict of interest statement

The authors declare there are no relevant conflicts of interest in this study.

Revista Mexicana de Neurociencia

Funding

There was no particular source of funding for this scientific report.

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Original contribution Mild cognitive impairment

References 1. 2. 3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Petersen R, Doody R, Kurz A, Mohs R, Morris J, Rabins P, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001; 58: 1985-1992. Yanhong O, Chandra M, Venkatesh D, Mild cognitive impairment in adult: A neuropsychological review. Ann Indian Acad Neurol. 2013; 16: 310-318. Ministerio de Salud y Protección Social. Diagnóstico preliminar sobre personas mayores, dependencia y servicios sociales en Colombia. 2008; Available from: https://www.minsalud.gov. co/proteccionsocial/Documents/Situacion%20Actual%20de%20las%20Personas%20adultas%20 mayores.pdf. Velásquez V, López L, López H, Cataño N, Muñoz. Efecto de un programa educativo para cuidadores de personas ancianas: una perspectiva cultural. Rev Salud Publica. 2011; 13: 610-619. Bocanegra Y, Trujillo-Orrego N, Pineda D. Demencia y deterioro cognitivo leve en la enfermedad de Parkinson: una revisión. Rev Neurol. 2014; 59: 555-569. Gainotti G, Quaranta D, Vita M, Marra C. Neuropsychological predictors of conversion from mild cognitive impairment to Alzheimer’s disease. J Alzheimers Dis. 2014; 38: 481-495. Cooper C, Sommerlad A, Lyketsos C, Livingston G. Modifiable predictors of dementia in mild cognitive impairment: A systematic review and meta-analysis. Am J Psychiatry. 2015; 172: 323-334. Petersen R, Smith G, Waring S, Ivnik R, Tangalos E, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999; 56: 303-308. Casanova-Sotolongo P, Casanova-Carrillo P, Casanova-Carrillo C. Deterioro cognitivo en la tercera edad. Rev Cubana Med Gen Integr. 2004; 20(5-6): 0-0. Figuera L, Mulet B, Sánchez-Casas R, Estragó M, Cardús M, Alquézar A. Deterioro cognitivo anterior a la enfermedad de Alzheimer: tipologías y evolución. Psicothema. 2005; 17: 250-256. Rodríguez N, Juncos-Rabadán O, Mayo D. Discriminación mediante marcadores cognitivos del deterioro cognitivo leve frente a envejecimiento normal. Rev Esp Geriatr Gerontol. 2008; 43: 291298. Valls-Pedret C, Molinuevo J, Rami L, Diagnóstico precoz de la enfermedad de Alzheimer: fase prodrómica y preclínica. Rev Neurol. 2010; 51: 471-480. Folstein M, Folstein S, McHugh P. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12: 189-198. Moreno A, Montañés P, Cano C, Plata S, Gámez A. Comparación de perfiles neuropsicológicos del Viejo-Joven (VJ) y el Viejo-Viejo (VV): envejecimiento normal y enfermedad de Alzheimer. Rev Asoc Colomb Gerontol Geriatr. 2005; 19: 776-796. Lawton M, Moss M, Fulcomer M, Kleban M. A research and service oriented multilevel assessment instrument. J Gerontol. 1982; 37: 91-99. Yesavage J, Sheikh J. 9/Geriatric Depression Scale (GDS) recent evidence and development of a shorter violence. Clin Gerontol. 1986; 5: 165-173. Grober E, Merling A, Heimlich T, Lipton R. Free and cued selective reminding and selective reminding in the elderly. J Clin Exp Neuropsychol.1997; 19: 643-654. Morris J, Heyman A, Mohs R, Hughes J, Van Belle G, Fillenbaum G, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD): I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology. 1989; 39: 1159-1165 Aguirre-Acevedo D, Gómez R, Moreno S, Henao-Arboleda E, Motta M, Muñoz C, et al. Validez y fiabilidad de la batería neuropsicológica CERAD-Col. Rev Neurol. 2007; 46: 655-660. García-Albea J, Del Viso S, Bernardos M. Test de Boston para el diagnóstico de la afasia: adaptación española. Bogotá: Editorial Medica Panamericana; 1996. Kortte K, Horner M, Windham W, The trail making test, part B: cognitive flexibility or ability to maintain set? Appl Neuropsychol Adult. 2002; 9: 106-109. Osterrieth P. The test of copying a complex figure: A contribution to the study of perception and memory. Arch Psychol. 1944; 30: 206-356. Henao-Arboleda E, Aguirre-Acevedo D, Muñoz C, Pineda D, Lopera F. Prevalencia de deterioro cognitivo leve de tipo amnésico en una población colombiana. Rev Neurol. 2008; 46: 709-713. Goodling M, Amaya E, Parra M, Ríos A. Prevalencia de las demencias en el municipio de Neiva 20032005. Acta Neurol Colomb 2006; 22: 243-248.

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Original contribution Mild cognitive impairment

13

25. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of 26. 27.

28. 29. 30. 31.

32. 33. 34.

Alzheimer’s disease Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984; 34: 939-939. Henao-Arboleda E, Moreno-Carrillo C, Ramos V, Aguirre-Acevedo D, Pineda D, Lopera F. Caracterización de síntomas neuropsiquiátricos en pacientes con DCL de tipo amnésico en una población colombiana. Revista Chilena de Neuropsicología. 2010; 5: 153-159. Albert M, DeKosky S, Dickson D, Dubois B, Feldman H, Fox N, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on AgingAlzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7: 270-279. Fisk J, Merry H, Rockwood K. Variations in case definition affect prevalence but not outcomes of mild cognitive impairment. Neurology. 2003; 61: 1179-1184. Montañés P, Cano C, Pedraza O, Peñalosa M, Rubiano L, Gamez A. Demencia no Alzheimer: variante frontal de la demencia fronto-temporal. Revista de la Asociación Colombiana de Gerontología y Geriatría. 2003; 17: 539-583. Hernández L, Montañés P, Gámez A, Cano C, Núñez E. Neuropsicología del envejecimiento normal. Revista de la Asociación Colombiana de Gerontología y Geriatría. 2007; 21: 992-1004. Frutos-Alegría M, Moltó-Jordà J, Morera-Guitart J, Sánchez-Pérez A, Ferrer-Navajas M. Perfil neuropsicológico del deterioro cognitivo leve con afectación de múltiples áreas cognitivas. Importancia de la amnesia en la distinción de dos subtipos de pacientes. Rev Neurol. 2007; 44: 455459. López O. Clasificación del deterioro cognitivo leve en un estudio poblacional. Rev Neurol. 2003; 37: 140-144. Migliacci, M., D. Scharovsky, and S. Gonorazky, Deterioro cognitivo leve: características neuropsicológicas de los distintos subtipos. Rev Neurol. 2009; 48: 237-241. Mías C, Sassi M, Masih M, Querejeta A, Krawchik R. Deterioro cognitivo leve: estudio de prevalencia y factores sociodemográficos en la ciudad de Córdoba, Argentina. Rev Neurol. 2007; 44: 733-738.

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Original contribution Fractal characterization of normal cerebral ventricles

Original contribution Alejandro Velasco,1 Javier O Rodríguez,2 Edgar G OrdonezRubiano,3 Signed E Prieto,4 Catalina S Correa,4 Germán Forero,5 Laura Mendez,1 Hebert Bernal,1 Laura P Valero,1 Natalia Hoyos.1

Fractal characterization of normal cerebral ventricles in t2-wheigthed magnetic resonance imaging Caracterización fractal de ventrículos cerebrales normales en imágenes de resonancia magnética ponderadas en T2

1

Faculty of Medicine – Universidad Militar Nueva Granada. Bogotá, D.C. Colombia. 2 Faculty of Medicine – Universidad Militar Nueva Granada, Centro de Investigaciones Clínica del Country. Bogotá, D.C. Colombia. 3 Fundación Universitaria de Ciencias de la Salud (FUCS) – Hospital de San José, Hospital Infantil Universitario de San José. Bogotá, D.C. Colombia. 4 Universidad Militar Nueva Granada, Centro de Investigaciones Clínica del Country. Bogotá, D.C. Colombia. 5 Universidad Militar Nueva Granada. Bogotá, D.C. Colombia.

Abstract Introduction:

The fractal geometry describes adequately the irregularity of the natural objects such as the cerebral ventricles, which are irregular structures that can be characterized through the Box-Counting method.

Objective: This research aims to develop a new methodology of

geometric characterization of the cerebral ventricles, based on the fractal geometry for the analysis of normal cerebral ventricles.

Methods:

Based on the Box-Counting method, the fractal dimensions of the both lateral ventricles of a normal adult were obtained. Sequential cephalic-caudal 4mm axial slices were acquired on T2-WI, and the differences and similarities of the lateral ventricles were established using the Ventricular Intrinsic Mathematical Harmony.

Results:

The fractal dimension of the left lateral ventricle had values between 1.0641 and 1.3599, and in the right lateral ventricle had values between 0.8931 and 1.3219.

Conclusion:

A new morphometric measure of the cerebral ventricles was developed based on the fractal geometry for its use as an objective and reproducible measure.

Keywords brain, cerebral ventricle, fractal, fractal geometry, lateral ventricles. Revista Mexicana de Neurociencia

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Original contribution Fractal characterization of normal cerebral ventricles

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Resumen Introducción:

Las dimensiones fractales permiten caracterizar matemáticamente la irregularidad de las formas naturales como los son las estructuras cerebrales. Los ventrículos cerebrales son objetos irregulares que pueden ser estudiados mediante esta geometría.

Objetivo: La investigación pretende desarrollar una caracterización en el espacio fractal de Box-Counting del ventrículo cerebral normal del adulto.

Métodos: Con fundamento en el método Box-Counting, se analizó

la estructura geométrica de las imágenes obtenidas mediante TAC de un sujeto normal. Para ello se tomaron las imágenes de cortes cada 4mm y se midieron las dimensiones fractales de los ventrículos cerebrales, determinando además la Armonía Matemática Intrínseca Ventricular entre las imágenes consecutivas de cada ventrículo.

Resultados: Las dimensiones fractales presentaron valores entre

0.8931 y 1.3599, con valores de AMIV entre 0 y 2, mostrando la capacidad de la metodología de caracterizar la estructura irregular de los ventrículos cerebrales.

Conclusiones:

: Los resultados constituyen una nueva medida morfométrica para los ventrículos cerebrales, que permitió establecer medidas características de normalidad de utilidad como referencia para determinar la presencia de alteraciones ventriculares.

Palabras clave cerebro, ventrículo cerebral, fractal, geometría fractal, ventrículos laterales.

Corresponding author: Edgar G Ordóñez-Rubiano Phone: (+57)-300-643-9837, (+57)-(1)-287-0087 Fax: (+57)-(1)-287-5878 E-mail: [email protected]

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Original contribution Fractal characterization of normal cerebral ventricles

Introduction Due to an impossibility to perform trustable Euclidian measures that could be associated with structures with complex and irregular shapes in different scales,1,2 Benoit Mandelbrot in 1975 developed the fractal geometry, geometry that allows characterization of the irregular objects. This advance allowed him to work in a measure of the irregularity of objects, denominated as Fractal Dimension (FD). For non-mathematical fractals, characterized by superposition between its parts, considered as wild fractals, the FD is calculated with the Box-Counting method.3,4 There are different examples of application of fractal geometry in medicine, including laboratory and clinical sets: evaluation of diagnosis, followups, and results of any therapeutic intervention.5–9 Even though, in many cases, determining the FD by itself is not enough to establish differences for clinical practice, making it necessary to establish mathematical concepts for its evaluation. For example, like it was in an experimental model of coronary re-stenosis, where the morphometric of histology was evaluated, based on the processing of the FDs of the arterial layers, using the term of Arterial Intrinsic Mathematical Harmony (AIMH),10 that can differentiate healthy versus sick arteries, with an accuracy of 10^30. This made place to a generalization of all possible fractal arterial structures, from the normal lumen to the total occlusion of the arterial lumen.11 In other clinical project, the fractal dimension of the branching of the left coronary artery from diastole to systole in angiography was evaluated, differentiating patients with and without severe arterial occlusive disease.12 Likewise, different diagnoses of the left cardiac ventricle in ventriculogram13 and echocardiography14 have been established, relating its FDs. Different authors have also shown its clinical applications in erythrocytary diagnosis,15 cervical uterine paraneoplastic lesions,16 and cardiac hemodynamics.17 Fractal geometry has been applied to the measurement of cerebral structures, analysis of electroencephalograms, Revista Mexicana de Neurociencia

and functional Magnetic Resonance Imaging (MRI) as well.18,19 Thus, demonstrating that the fractal geometry is a complementary important tool able to characterize states of normality and disease.20,21 The cerebral ventricles are evaluated with MRI for clinical practice through the use of lines for determining lengths and using Euclidian formulas for establishing volumes or approximated areas. Clinical MRI is based on the electromagnetic activity of spins of active atomic nuclei of hydrogen (protons and neutrons). Voxel-based MRI, by the way, could be very accurate for establishing measures, based on three-dimensional occupation of matter.22 However, these measurements do not take into account completely the irregularity of cerebral structures, thus some important information can be ignored that could be determinant for clinical decisions and are based on statistic probabilistic significance. There is no other published work regarding the fractal characterization of the cerebral ventricles. This paper aims to develop a new objective and reproducible histological morphometric measurement for the characterization of the cerebral ventricles with the application of the fractal geometry.

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Original contribution Fractal characterization of normal cerebral ventricles

Methods and Materials Definitions

Fractal: Irregular object, from the Latin “fractus”: irregular, fractioned.

measurement that determines the degree of the irregularity of a fractal. For this work, it was used the definition for FD of Box-Counting: LogN ( 2 ( K 1) ) LogN ( 2 K ) Log 2k 1  Log 2k

but differentiate between each other in the first significant digit, as it is with 1,242 and 1,433; therefore, an IVMH of 2 will correspond to equal values to the unit and the first significant digit, as it is the case of 1,563 and 1,543, and then in the same way sequentially.

Bioethical considerations

Fractal dimension: A not-dimensional numeric

D

17

 Log 2

N ( 2 ( k 1) ) N ( 2 k )

Where N (2-k) is a function of the grade of partition of the k grid, and corresponds to the number of squares occupied by the object in the grid with partition 2-k.

Procedure Sequential cephalic-caudal 4mm axial slices of a T2-WI sequence of a non-contrast MRI of the head were acquired from a healthy patient with a General Electric SIGNA HD.XT. 1.5 Tesla. All images were processed in software developed by previous researches for the calculation of FDs with the Box Counting method.12,11 The borders of the both lateral ventricles were delineated. Posteriorly, the number of squares occupied by the ventricles in the different slices was established. Based on these values the FD of the Box-Counting was obtained for each ventricle in the different slices using the equation D (see definitions). Finally, the Ventricular Intrinsic Mathematical Harmony (VIMH) was calculated, mathematically defined as the degree of similarity or difference between two FDs when comparing the two units and its significant digits. Two FDs present a VIMH of 0 if they have differences between the units. For example with 0,786 and 1,234: there is a VIMH of 1 if they have an equal value between the units Revista Mexicana de Neurociencia

This work meets the standards of medical ethics committees of the sponsoring institution of research and with the Helsinki Declaration of 1975, updated in 2000. It complies with the scientific, technical and administrative standards for health research, based on the resolution No. 008430 of 1993, and specifically title 11 concerning research on human beings, to be classified in the category of research without risk, as mathematical calculations on results of tests are done made a voluntary without coercion, not affecting the patient and respect their integrity and anonymity.23

Results It was found that the cerebral lateral ventricles were observed in 4 out of 8 the adapted MRI slices. (Figure 1) For the both lateral ventricles of each 4 images the FD was obtained. The FD presented variations between 0,8931 and 1,3598. For the right lateral ventricles FDs ranged between 0,8931 and 1,3219 (Table 1), while the values of the degree of irregularity of the left ventricles were between 1.0641 and 1.3598. The degree of similarity between the parts of the ventricles were obtained when finding the VIMH for each ventricle in the different slices, as each image is a section of a three dimensional object. The values of the VIMH (Table 2) were higher for the lateral left ventricle on two of the three comparisons, showing that there is a greater degree of similarity between the parties to the left ventricle compared with the right. Additionally, the comparison of the images of the right ventricle of the slices 7 and 8 showed a greater self-organization than those of the left ventricle of the same slice, but in the other two comparisons the left ventricles had greater VIHM values. September-October, 2017; 18(5):14-22

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Original contribution Fractal characterization of normal cerebral ventricles

Figure 1. Images adapted to process of Box-Counting. a. Limits of the ventricles are outlined. b. Superposition de la rejilla de 20 pixels.

Figure 2. Image adapted to process of Box-Counting. a. This is an example of the measurements; both lateral ventricles are outlined (corresponding to the slice 5). b. Superposition of a 20-pixel Grillage.

Table 1. The fractal dimensions of the right al lateral ventricles for each of the studied slices.

Image (#) 5 6 7 8

Left DF 1,0780 1,0641 1,3599 1,2283

Right DF 1,3219 0,8931 1,1793 1,1829

Table 2. Ventricular Intrinsic Mathematical Harmony values for comparisons between the images. VIHM between the images # 5 and 6 6 and 7 7 and 8

Left 2 1 1

Right 0 0 2

VIMH= Ventricular Intrinsic Mathematical Harmony.

FD = Fractal Dimension.

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Original contribution Fractal characterization of normal cerebral ventricles

Discussion This is the first work where the Box-Counting method was applied for quantification of the degree of irregularity of the cerebral ventricles. This can be useful as a new reference for future studies of measuring of ventricles in patients with different diseases. Therewith, a new measurement for evaluation of the self-organization between the measures of the same ventricle in different slices was performed. This can also be a reference of normality in the future, for detecting the presence of ventricular alterations. However, this measure should be performed in larger series of healthy individuals to increase accuracy. The measures conventionally used in a clinical fashion, especially in the Emergency Room, are based on Euclidean measurements and on the use of formulas to make approximations regarding the volume or size of specific structures. Even though, because of the irregularity of the structures, there is potentially important clinical information that can be lost by using Euclidean geometry on irregular objects. Additionally, the objectivity and the reproducibility of the measurements are difficult, which may involve variations in inter- and intra-observer interpretation. In contrast, the measurements obtained by fractal geometry are an objective and reproducible method suited to the characteristics of brain structures, which provides clinical information that can be useful not only to assess the initial state of a patient but also for the purpose of monitoring their changes over time. Fractal geometry has been successfully used for the objective characterization of different cellular and histological structures in medicine. For example, Hayano et al. 6, 24 performed fractal measures over Computed Tomography Angiography images of the liver, and made direct correlations with the degree of heterogeneity of tumors, for the evaluation of anti-angiogenic treatment, and for the survival of patients with hepatocellular carcinoma. In the same way, Fiz et al.7 used fractal measures of ultrasound images of pulmonary nodules, differentiating benign and malignant nodules. Meanwhile, Talu Revista Mexicana de Neurociencia

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performed fractal measures that could differentiate the microvasculature of the retina of patients with diabetic macular edema, which allowed making an earlier diagnosis of the disease.9 Other comparisons between fractal dimensions of parts of a structure, or the whole structure, or its dynamics have been studied in other experimental and clinical phenomena.10, 12-14, 25 In the brain, the fractal characterization was performedwithMRI,obtainingimportantinformation regarding normal changes that occur during aging.26 Reishofer et al.27 also observed differences between FDs of cerebral structures in MRI of healthy patients and patients with arteriovenous malformations, giving information about the clinical behavior of these lesions. Besides, Wang et al. made fractal analysis of electroencephalograms of ictal and interictal states, achieving a characterization of each one, with a high sensibility (>90%), demonstrating that it can be used for the automatic identification of seizures.28 In this paper, we present a fractal characterization of cerebral lateral ventricles. Furthermore, the concept of VIMH is implemented, whereby variations of fractal auto-organization of the cerebral ventricles can be observed in different slices. In further studies, there should be an implementation of this methodological analysis of different neurological diseases and cerebral lesions demonstrating changes in geometry of cerebral structures, in order to develop diagnostic and therapeutic clinical applications. This work is based on a form of physical-mathematical non-causal thinking, which seeks to establish the underlying laws of the different phenomena within the cerebral ventricles. This research perspective has established diagnoses and predictions in areas such as immunology,29 molecular biology,30 infectology,31,32 neonatal and adult cardiology,33,34 and predicting epidemics,35 obtaining results of clinical, experimental and public health utility. Further studies are needed to implement the fractal characterization of the cerebral ventricles and VIMH in the clinical context of patients with diseases of the central nervous system. September-October, 2017; 18(5):14-22

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Original contribution Fractal characterization of normal cerebral ventricles

Conclusions This research is based on physical and mathematical theories that provide a new tool for clinical practice for a future adequate evaluation of the irregularity of the cerebral ventricles using the BoxCounting method and the VIMH.

Aknowledgements Thanks to the Asociación Colombiana de Neurocirugía. Thanks to the Universidad Militar Nueva Granada. Special thanks to Elsa Cardenas, Vice President of Research, Dr. Yanneth Méndez Academic Vice Chancellor, Dr. Jorge Luque, dean of the Faculty of Medicine and to Nydia Rojas, director of the Research Center of the Faculty of Medicine for his constant support and cooperation in our research. We also thank the Research Center of the Clínica del Country, especially to Doctors Tito Tulio Roa, Director of Medical Education, Jorge Ospina, Medical Director, Alfonso Correa, Director of the Research Center, and Dr. Adriana Lizbeth, epidemiologist. To Sandra Rodriguez, nurse, and Silvia Ortiz, Head Nurse research Center, for their constant support to our research. In dedication to our children. In dedication to Laura Rivera-Osorio.

Conflict of interest

The authors declare no conflict of interest.

Revista Mexicana de Neurociencia

Funding Source

Product of MED-1344, project funded by the Research Vice-Rector of the Military University Nueva Granada. Validity 2014. Bogotá, Colombia.

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Bibliography 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Mandelbrot B. ¿Cuánto Mide la Costa de Gran Bretaña? Los Objetos Fractales. Barcelona: Tusquets Editores; 1987. 27–50. Mandelbrot B. The Fractal Geometry of Nature. Barcelona: Tusquets Editores; 2000. Peitgen H-O, Jürgens H, Saupe D. Limits And Self Similarity. Chaos and Fractals. New York: SpringerVerlag; 1992. 135–82. Peitgen H, Jürgens H, Saupe D. Length, Area and Dimension: Measuring Complexity and Scaling Properties. In: Peitgen H, Jürgens H, Saupe D, eds. Chaos and Fractals. New York: Springer-Verlag; 1992. 183–228. Al-Kadi OS. A multiresolution clinical decision support system based on fractal model design for classification of histological brain tumours. Comput Med Imaging Graph. 2015;41:67-79. Hayano K, Yoshida H, Zhu AX, Sahani D V. Fractal analysis of contrast-enhanced CT images to predict survival of patients with hepatocellular carcinoma treated with sunitinib. Dig Dis Sci. 2014;59(8):1996–2003. Fiz JA, Monte-Moreno E, Andreo F, et al. Fractal dimension analysis of malignant and benign endobronchial ultrasound nodes. BMC Med Imaging. 2014;14:22. Metze K. Fractal dimension of chromatin: potential molecular diagnostic applications for cancer prognosis. Expert Rev Mol Diagn. 2013;13(7):719-735. Tălu S. Multifractal geometry in analysis and processing of digital retinal photographs for early diagnosis of human diabetic macular edema. Curr Eye Res. 2013;38(7):781–792. Rodriguez J, Mariño M, Avilan N, et al. Medidas fractales de arterias coronarias en un modelo experimental de reestenosis. Armonía matemática intrínseca de la estructura arterial. Rev Colomb Cardiol. 2002;10:65–72. Rodríguez J, Prieto S, Correa C, et al. Theoretical generalization of normal and sick coronary arteries with fractal dimensions and the arterial intrinsic mathematical harmony. BMC Med Phys. 2010;10(1):1–6. Rodríguez J, Prieto S, Correa C, et al. Fractal diagnosis of severe cardiac dysfunction Fractal dynamic of the left coronary branching. Rev Colomb Cardiol. 2012;19(5):225–32. Rodríguez J, Prieto S, Correa C, et al. Fractal diagnosis of left heart ventriculograms Fractal geometry of ventriculogram during cardiac dynamics. Rev Colomb Cardiol. 2011;19(1):18–24. Rodríguez J, Prieto S, Ortiz L, et al. Mathematical diagnosis of pediatric echocardiograms with fractal dimension measures evaluated through intrinsic mathematical harmony. Rev Colomb Cardiol. 2010;17(2):79–86. Correa C, Rodríguez J, Prieto S, et al. Geometric diagnosis of erythrocyte morphophysiology. Int J Med Med Sci. 2012;3(11):715–720. Prieto S, Rodríguez J, Correa C, et al. Diagnosis of cervical cells based on fractal and Euclidian geometrical measurements: Intrinsic Geometric Cellular Organization. BMC Med Phys. 2014;14(1):2. Rodríguez J, Correa C, Melo M, et al. Chaotic cardiac law : Developing predictions of clinical application. Int J Med Med Sci. 2013;4(2):79–84. Spasic S, Culic M, Grbic G, et al. Spectral and fractal analysis of cerebellar activity after single and repeated brain injury. Bull Math Biol. 2008;70(4):1235–1249. Lahmiri S, Boukadoum M. Alzheimer’s disease detection in brain magnetic resonance images using multiscale fractal analysis. ISRN Radiol. 2013;2013:627303. Di Ieva A, Grizzi F, Jelinek H, et al. Fractals in the Neurosciences, Part I: General Principles and Basic Neurosciences. Neuroscientist. 2013;20(4):403–417. Di Ieva A, Esteban FJ, Grizzi F, et al. Fractals in the Neurosciences, Part II: Clinical Applications and Future Perspectives. Neuroscientist. 2015;21(1):30–43. Bitar R, Leung G, Perng R, et al. MR Pulse Sequences : What Every Radiologist Wants to Know but Is Afraid to Ask. Radio Graphics. 2006;26(2):513–538. Ministerio de Salud de Colombia. Resolución número 8430 DE 1993. 1–19. Hayano K, Lee SH, Yoshida H, et al. Fractal analysis of CT perfusion images for evaluation of antiangiogenic treatment and survival in hepatocellular carcinoma. Acad Radiol. 2014;21(5):654– 660. Rodríguez J. New diagnosis aid method with fractal geometry for pre-neoplasic cervical epithelial cells. Rev UDCA Actual y Divulg Científica. 2011;1(14):15–22.

Revista Mexicana de Neurociencia

September-October, 2017; 18(5):14-22

22

Original contribution Fractal characterization of normal cerebral ventricles

26. Liu JZ, Zhang LD, Yue GH. Fractal dimension in human cerebellum measured by magnetic resonance imaging. Biophys J. 2003;85(6):4041–4016.

27. Reishofer G, Koschutnig K, Enzinger C, et al. Fractal dimension and vessel complexity in patients with cerebral arteriovenous malformations. PLoS One. 2012;7(7):e4114–4118.

28. Wang Y, Zhou W, Yuan Q, et al. Comparison of ictal and interictal EEG signals using fractal features. Int J Neural Syst. 2013;23(6):1350028.

29. Rodríguez J, Bernal P, Álvarez L, et al. Plasmodium falciparum MSP-1 and EBA-140 peptides 30. 31. 32. 33. 34. 35.

prediction of binding to HLA class II probability, combinatory and entropy applied to peptide sequences. Inmunología. 2010;29(3):91–9. Rodríguez J, Bernal P, Prieto S, et al. Theory of malaria peptides with high-affinity binding to red blood cells. Theoretical predictions of new binding peptides and predictive mutations of critical amino acids. Inmunología. 2010;29(1):7–19. Rodríguez J, Prieto S, Correa C, et al. Predictions of CD4 lymphocytes’ count in HIV patients from complete blood count. BMC Med Phys. 2013;13(1):3. Rodríguez J, Prieto S, Correa C, et al. Teoría de conjuntos aplicada al recuento de linfocitos y leucocitos: predicción de linfocitos T CD4 de pacientes con virus de la inmunodeficiencia humana/ sida. Inmunología. 2013;32(2):50–56. Rodríguez J, Prieto S, Domínguez D, et al. Mathematical-physical prediction of cardiac dynamics using the proportional entropy of dynamic systems. Int J Med Med Sci. 2013;4(9):370–381. Rodríguez J, Prieto S, Flórez M, et al. Physical-mathematical diagnosis of cardiac dynamic on neonatal sepsis : predictions of clinical application. Int J Med Med Sci. 2014;5(5):102–108. Rodríguez J. A method for forecasting the seasonal dynamic of malaria in the municipalities of Colombia. Rev Panam Salud Pública. 2010;27(3):211–218.

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Original contribution Atherosclerosis and herniated disc

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Original contribution Jorge Rendón-Félix,1* Diana Paola Urias-Valdez,1 David Gustavo Rodriguez-Cisneros,1 Eloy Ovando-Sanders.1 1

Centro de la Columna Vertebral. Zapopan, Jalisco, México.

Relationship between atherosclerotic disease and disc herniation in patients with integral conservative management Relación entre la enfermedad ateroesclerótica y hernia discal en pacientes con manejo conservador integral

Abstract Introduction:

Atherosclerosis is the leading cause of general mortality and hospital morbidity. The prevalence of lumbar intervertebral disc degeneration related to atherothrombotic pathology has been increasing, and the incidence of low back pain reaches its peak after 45 years. A relationship between the decrease in apolipoprotein A1 and hypertriglyceridemia as related factors, as well as hypertension, elevated LDL levels and a high Framingham score, but it has yet to be seen if the treatment is compromised in that aspect.

Methods:

Retrospective observational study in patients with herniated disc treated with combined conservative therapy, comparing their effectiveness depending on the cardiovascular risk presented.

Results: A total of 171 patients were analyzed. 25.7% presented

adequate weight, 41.5% overweight and 32.8%, obesity. In all, 42.7% had hypertension, 19.3% diabetes mellitus, 15.3% smoked, no patients had physical activity and 24% had a high or very high cardiovascular risk. There was no difference between the results presented with the combined conservative treatment.

Keywords atherosclerosis, herniated disk, conservative treatment.

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Conclusion: In addition to the physical components that cause disc

herniation, there is a compromised circulatory component, which was not affected after the combined conservative treatment, which is why it is recommended the timely treatment of the herniated disk and its risk factors. September-October, 2017; 18(5):23-30

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Original contribution Atherosclerosis and herniated disc

Resumen Introducción:

La aterosclerosis constituye la primera causa de mortalidad general y morbilidad hospitalaria. La prevalencia de la degeneración del disco intervertebral lumbar relacionada a la patología aterotrombótica ha ido creciendo, y la incidencia de dolor lumbar alcanza su pico después de los 45 años. Se ha encontrado una relación entre la disminución de la apolipoproteína A1 y la hipertrigliceridemia como factores relacionados, así como la hipertensión, niveles elevados de LDL y un puntaje elevado en el Score Framingham, pero no se ha visto si el tratamiento está comprometido en ese aspecto.

Métodos:

Estudio observacional retrospectivo en pacientes con hernia discal tratados con terapia conservadora combinada, comparando su efectividad dependiendo del riesgo cardiovascular que presentaran.

Resultados: Un total de 171 pacientes fueron analizados. 25.7%

presentaban peso adecuado, 41.5% sobrepeso y 32.8%, obesidad. Un 42.7% tenían hipertensión arterial, 19.3% diabetes mellitus, 15.3% tabaquismo, ningún paciente realizaba actividad física y 24% tuvieron un riesgo cardiovascular alto o muy alto. No hubo diferencia entre los resultados presentados con el tratamiento conservador combinado.

Conclusión: Además de los componentes físicos que causan hernia

discal, se aprecia un componente circulatorio comprometido, el cual no se vio afectado tras el tratamiento conservador combinado, por lo que se recomienda el tratamiento oportuno de la patología y de los factores de riesgo.

Palabras clave aterosclerosi, hernia discal, tratamiento conservador.

Corresponding Author: Jorge Rendón-Félix. Centro de la Columna Vertebral. Av. San Ignacio 123, Col. Jardines de San Ignacio. Zapopan, Jalisco. C.P. 45040 México. e-mail: [email protected]

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Original contribution Atherosclerosis and herniated disc

Introduction Atherosclerosis is the leading cause of general mortality and hospital morbidity. It is a disease of the metabolism that responds to the persistent aggression and exponential intensity that affects the connective tissue of the arterial wall, in which a series of physical, hemodynamic, biochemical, metabolic, humoral, inflammatory, and coagulation alterations finally end up damaging the arterial wall with a scar, which is the atherosclerotic lesion.1 Since this ischemic injury is capable of causing pain and degeneration of the structures involved, atherothrombotic disease of the arteries that irrigate the spine has received increased consideration as one of the possible underlying factors for both lower back pain and herniated discs. Atheromatous plaques begin to appear in the abdominal aorta in adulthood, and 20 years later, 10% of the population in developed countries will have advanced lesions in the abdominal aorta. The prevalence of lumbar intervertebral disc degeneration (IDD) related to atherothrombotic pathology has been increasing steadily in early adulthood, and the incidence of lumbar pain (LP) increases linearly to reach its highest prevalence after the age of 45. Although IDD and LP are fairly common, one can develop without the other. The most rapid increase in the number of complications (necrosis, ulcerations, thrombi, calcifications) occurs between the ages of 4464 years old.2,3 These lesions tend to accumulate at the bifurcation and around the orifices of the branched arteries. The lumbar spine, supplied by these branched arteries, may be affected if the arteries become clogged. The segmental lumbar arteries supply the first to the fourth lumbar segments. The fifth lumbar segment is supplied by branches of the middle sacra, and by tributaries of the iliolumbar arteries. In addition to the lumbar vertebrae, these arteries also irrigate surrounding structures such as intervertebral discs, nerve roots, and paraspinal muscles. The spinal cord is less dependent on these arteries because its main supply of blood does not come from the lumbar Revista Mexicana de Neurociencia

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spine.4 In contrast, the intervertebral disc,5 as the largest avascular structure in the body, relies on the passive diffusion of the peripheral arteries for nourishment. Therefore, the disc may be a risk zone for anyone with atherosclerotic disease. Computed tomography angiography (CTA) offers better spatial resolution to visualize the atherosclerotic narrowing of small arteries, such as the lumbar artery. After the preliminary findings of a necropsy study in 1993,5,6 suggesting an association between decreased blood supply to the lumbar spine and lower back pain, atherosclerosis and cardiovascular risk factors have received increased consideration as possible underlying factors for back disorders. Lifestyle factors, such as smoking or diet, may play a significant role in spinal problems as they promote vascular disease and play an underlying role in degenerative changes and pain. Other cardiovascular risk factors have been studied concerning lumbar intervertebral disc degeneration and lower back pain’s relationship with atherosclerosis. Hemingway7 found a considerable decrease in Apolipoprotein A1 (Apo 1, the major protein component of highdensity lipoproteins (HDL) which is responsible for the activation of the lecithin-cholesterol acyltransferase (LCAT) which binds to the HDL receptor to stimulate inverse cholesterol transport and to intervene in the structure) in a sample of 4,886 office workers between 35 and 55 years old, in both genders; and in men an important hypertriglyceridemia associated with incapacity for work due to a disease secondary to back pain. Leino-Arjas8-10 found an association between elevated triglycerides and lower back pain in three separate studies. In addition, high blood pressure, high cholesterol, elevated LDL, and increased carotid intima and middle layers have been found to be significantly associated with lower back pain. An increase in the investigation of modifiable and non-modifiable risk factors in patients September-October, 2017; 18(5):23-30

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Original contribution Atherosclerosis and herniated disc

with cardiovascular risk leads to a reduction in morbidity and mortality. This risk assessment uses the Framingham model, tables, and SCORE, which can easily be adapted to the conditions, resources, and priorities of different countries, and take into account the heterogeneity in cardiovascular disease mortality, as can be seen in Figure 1.11 In an effort to seek a more rapid and effective recovery for patients, the combined conservative strategies achieve an accelerated recovery of patients in a more effective and less invasive way (through anti-inflammatory drugs, ozone therapy, and targeted rehabilitation),12-15 leaving surgery as a last resort and obtaining good results in the majority of patients with herniated disc.

diagnosis were excluded, as well as patients who did not complete the 15 combination treatment induction sessions or who have been inconstant, patients who presented an inconvenience or an adverse event in their treatment or in their condition, patients with incomplete records or who did not authorize the review of their clinical file through the informed consent. Response variables were assessed after administration of 15 sessions of conservative combined treatment using an visual analogue scale for pain (VAS; 0 = no pain and 10 = most severe pain) and the search for a relationship between weight, body mass index (BMI), and risk of cardiovascular event related to the present symptomatology.

Due to the tendency for combined conservative treatment of the herniated disc and to the relationship of the disease with vascular diseases, it was decided to seek a relationship between both and to seek benefits through conservative combined treatment of disc herniation.

All patients were standardized in each session with intravenous medications (analgesics, antiinflammatories, multivitamins and homotoxicology), ozone therapy and physical therapy sessions (electrotherapy, local ultrasound, massage therapy, thermotherapy, hydrotherapy, traction, Williams exercises, and neuromuscular bandaging).

Material and methods

Ethical considerations

A retrospective observational study was performed in patients with herniated disc undergoing conservative combined treatment at the Spine Center in 2015, with the objective of comparing the effectiveness of the technique used in different groups of patients depending on cardiovascular risk and presented comorbidities.

The study was conducted in accordance with the principles of the 1989 Declaration of Helsinki, with all its modifications, and under the norms and guidelines of Mexico’s General Health Law. As this was a retrospective observational study, it did not require a review by the Institution’s Ethics Committee. All the patients gave their informed consent duly signed.

Inclusion criteria were: 18-65 years old patients with clinical and imaging diagnosis of herniated disc, who completed a minimum of 15 sessions of combined treatment of parenteral therapy, rehabilitation, and ozone therapy in the Spine Center. Additionally, they duly signed an informed consent to an anonymous review of their progress with this therapeutic modality. Patients outside this age range or with a different Revista Mexicana de Neurociencia

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Original contribution Atherosclerosis and herniated disc

Figure 1. Cardiovascular risk using Framingham Score.11

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Hard CHD Risk STEP 1

30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74

STEP 6 AGE SCORE Man -1 0 1 2 3 4 5 6 7

Woman -9 -4 0 3 6 7 8 8 8

DIABETES SCORE Man 0 2

Woman 0 4

STEP 2

NO YES STEP 3

NO YES

SMOKER SCORE Man 0 2

STEP 5

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BLOOD PRESSURE WOMEN Systolic Diastolic 100 160 When the systolic and diastolic blood pressure throw different scores, the higher value is used.

Table for the quantification of the risk in function of the score Woman 0 2

STEP 4

280

BLOOD PRESSURE MEN Diastolic Systolic 100 160

Total Cholesterol SCORE Woman Man -2 -3 0 0 1 1 1 2 3 3 HDL CHOLESTEROL SCORE Woman Man 5 2 2 1 1 0 0 0 -3 -2

Risk of serious cardiovascular event or “hard” event (10 years) Points 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 45% >45% >45% 20%

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Original contribution Atherosclerosis and herniated disc

Results Out of 593 patients treated in 2015, 171 met the inclusion criteria. The average age of the patients was 59.7 ± 13.7 years, their weight 75.7 ± 15.9 kg, the pain (measured by VAS) at the beginning was of 7.3 ± 1.9, and 2.4 ± 2 at the end, and there was no discernible difference related to the risk factors. Cholesterol levels were 193.4 ± 40.8, LDL levels of 116.2 ± 81.8, HDL levels of 52.4 ± 13, and the average risk of cardiovascular event was 14.8 ± 13.3.

adequate weight, 41.5% were overweight, and the remaining 32.8% had some degree of obesity (22.2% obesity type I, 5.8% obesity type II and 4.7% obesity type III). It should be mentioned that 42.7% of the patients suffered arterial hypertension, 19.3% had diabetes mellitus, 15.3% used tobacco, no patient performed any physical activity prior to the radiculopathy, and 24% presented a high or very high cardiovascular risk (Framingham score >20). These results are better illustrated in Figure 2.

Out of the 171 patients, 25.7% presented an

Figure 2. Comorbidities in the study group. DM: diabetes mellitus.

Comorbidity (%) 45 40 35 30 25 20 15 10 5

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ty ivi Ac t

e us ac co To b

pe ty D M

H yp er

te n

sio

2

n

y sit O be

gh t w ei ve r O

No r

m

al

w ei

gh t

0

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Original contribution Atherosclerosis and herniated disc

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Discussion It is increasingly common to hear the term “herniated disc” and the increase in the incidence of cases with this pathology is alarming because the onset of symptoms is occurring at an earlier age and the patient seeks treatment until the disease worsens, which makes its handling much more complicated. Simultaneously, atherosclerosis has become one of the great epidemics of the 21st century. Twenty-five years ago, when the International Conference on Primary Care was held by the World Health Organization (WHO), a list of eight essential elements was drawn up, where no reference was made to the treatment or prevention of conditions such as heart disease or stroke. At the time, cardiovascular diseases and other non-communicable diseases were considered characteristic of industrialized countries (in fact, they were called “diseases of the rich”) were attributable to ways of life radically different from those prevailing in most parts of Africa, Asia and many other places of the developing world, but the reality is quite different: cardiovascular diseases have not only appeared in practically all countries but have also spread remarkably; this increasing burden poses a real threat of hindering social and economic development. Risk factors serve as indicators of future health status, and five out of ten of the main global threats are related to non-communicable diseases such as arterial hypertension, tobacco use, alcohol use, hypercholesterolemia, obesity, or overweight.16 Results show there is a correlation between atherosclerosis, metabolic syndrome, and

Conflict of interest statement

The authors of this manuscript declare no conflict of interest with the subjects mentioned here.

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microcirculation ailments such as herniated discs. The fact that more prevalence of arterial hypertension has been observed (42.7%) than that of diabetes mellitus (19.3%), and the fact that the patients respond to intravenous treatment indicates that the circulation of the intervertebral disc can be more compromised by atherosclerosis than by ischemia (without ruling out the latter), but more circulation studies have to be done to confirm it and to be able to regulate approaches to future treatments.

Conclusion It can be observed that the herniated disc, in addition to the physical factors that cause it, has an important circulatory component, which was not so affected when comparing the results after the combined conservative treatment. Adequate recognition of symptoms caused by disc herniation, together with a correct diagnosis, timely treatment, and control of comorbidities, is indispensable for a favorable prognosis; therefore, a timely and adequate diagnosis and comprehensive treatment of the patient’s condition and its underlying circulatory diseases, is highly recommended.

Funding

The authors of this manuscript declare that they have received no funding whatsoever that could interfere with the subjects mentioned herein.

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References 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Santana-López, S., Montero-Díaz, R., Sánchez-Fuentes, A.L., Valdés-Vento, A.C, Vidal Vega, I. Caracterización de los factores de riesgo de la aterosclerosis. Rev. Ciencias Médicas de Pinar del Río. Enero-febrero, 2016; vol 20 (1):136-141 Vihert AM. Atherosclerosis of the aorta in five towns. Bull World Health Organ. 1976;53:501e8. Zhdanov VS, Sternby NH, Vikhert AM, Galakhov IE. Development of atherosclerosis over a 25 year period: an epidemiological autopsy study in males of 11 towns. Int J Cardiol. 1999;68:95e106. Chiras J, Morvan G, Merland JJ. The angiographic appearances of the normal intercostal and lumbar arteries. Analysis and the anatomic correlation of the lateral branches. J Neuroradiol. 1979;6:169e96. Beckworth WJ, Holbrook JF, Ward L, Welle JR, Foster LG. (2016). Atherosclerotic Diseaseand Its Relationship to Lumbar Degenerative Disc Disease, Facet Arthritis and Stenosis Using CT Angiography. 05/12/2016, de EMORY University School of Medicine Sitio web: http://www. painmed.org/2016posters/poster101.pdf Kauppila LI, Tallroth K. Postmortem angiographic findings for arteries supplying the lumbar spine: their relationship to lowback symptoms. J Spinal Disord. 1993;6:124e9. Hemingway H, Shipley M, Stansfeld S, Shannon H, Frank J, Brunner E, et al. Are risk factors for atherothrombotic disease associated with back pain sickness absence? The whitehall II study. J Epidemiol Community Health. 1999;53:197e203. Leino-Arjas P, Kaila-Kangas L, Solovieva S, Riihima¨ki H, Kirjonen J, Reunanen A. Serum lipids and low back pain: an association? A follow-up study of a working population sample. Spine. 2006;31:1032e7. Leino-Arjas P, Solovieva S, Kirjonen J, Reunanen A, Riihima¨ki H. Cardiovascular risk factors and low-back pain in a long-term follow-up of industrial employees. Scand J Work Environ Health. 2006;32:12e9. Leino-Arjas P, Kauppila L, Kaila-Kangas L, Shiri R, Heistaro S, Helio¨vaara M. Serum lipids in relation to sciatica among Finns. Atherosclerosis. 2008;197:43e9. Guía de Práctica clínica: Detección y estratificación de factores de riesgo cardiovascular. México: Secretaria de Salud; 2009. Ernst E1, Schmidt K. Homotoxicology--a review of randomised clinical trials. Eur J Clin Pharmacol. 2004 Jul;60(5):299-306. Andreula CF, Simonetti L, de Santis F, Agati R, Ricci R, Leonardi M. Minimally Invasive OxygenOzone Therapy for Lumbar Disk Herniation. AJNR Am J Neuroradiol. 2003;24:996-1000. Zhang Y, Ma Y, Jiang J, Ding T, Wang J. Treatment of the lumbar disc herniation with intradiscal and intraforaminal injection of oxygen-ozone. J Back Musculoskelet Rehabil. 2013;26(3):317-22. Ovando-Sanders E, Salazar-García JL, Ortiz-Watson LA. Reporte de 147 casos de éxito en el Centro de la Columna Vertebral a base de colchicina homeopática, ozono y terapia física. Rev Mex Med Fis Rehab. 2014;26(1):24-37. Yusuf S. Global burden of cardiovascular diseases. Circulation. 2001, 104:2746-53.

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Revision Review of Autism Spectrum Disorder

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Revision Lucía Lisseth VázquezVillagrán,1 Carlos Daniel Moo-Rivas,1 Elisael MeléndezBautista,1 Juan Sebastián Magriñá-Lizama,1 Nina Isabel Méndez-Domínguez.2

Autism spectrum disorder review: diagnosis and treatment update Revisión del trastorno del espectro autista: Actualización del diagnóstico y tratamiento

1

Estudiante de Medicina. Campus ciencias de la salud. Universidad Marista de Mérida. 2 Médico Cirujano, Maestra de ciencias de Ecología Humana, Dra. En Ciencias de la Salud Investigadora Posdoctorante en Centro de investigación y de Estudios Avanzados del IPN. Profesora Titular, Universidad Marista de Mérida, Campus de Ciencias de la Salud.

Abstract Autism spectrum disorder (ASD) is considered a multifactorial etiology during child’s neurodevelopmental process covering the following clinical groups including: a) autistic disorder b) Rett´s Syndrome c) childhood disintegrative and d) widespread development. Affects 1 to 2/1000 people and is characterized by impaired in: a) social behavior b) deficit verbal and nonverbal c) restricted interests and repetitive behaviors, and d) changes in the scope of activities. The TEA persists lifelong and shows heterogeneity, ranging from mild personality changes to severe disability. The importance of this review is to provide a timely diagnosis in order to obtain a more favorable prognosis for the patient. The sections to treat are the symptoms, diagnosis and treatment. The relevance of this review is to provide and update information about ASD, so that it could guide the reader to fully understand the characteristics of this disease and the advances that have been developed to take appropriate treatment and improve the quality of patient’s life.

Keywords ASD, Autism spectrum disorder, Review, Diagnosis, Treatment.

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Revision Review of Autism Spectrum Disorder

Resumen El Trastorno del Espectro Autista (TEA) es considerado una etiología multifactorial del neurodesarrollo infantil que abarca los siguientes grupos clínicos entre ellos: a) el trastorno autista b) los trastornos de Rett c) desintegrativo infantil y d) generalizado del desarrollo. Afecta entre 1 a 2/1000 personas y se caracteriza por alteración en: a) comportamiento social b) déficit verbal y no verbal c) intereses restrictivos y conductas repetitivas, así como d) alteraciones en el margen de actividades. El TEA persiste toda la vida y muestra una gran heterogeneidad, que varía desde modificaciones leves de la personalidad hasta discapacidad grave. La importancia de la siguiente revisión es procurar un diagnóstico oportuno con el fin de obtener un pronóstico más favorable para el paciente. Las secciones a tratar serán la sintomatología, diagnóstico y tratamiento. La relevancia del presente artículo radica en proporcionar al lector información ampliada y actualizada sobre el TEA, de manera que sirva como una herramienta para que el lector comprenda en su totalidad las características de esta patología y los avances que se han desarrollado para poder llevar un tratamiento adecuado y mejorar la calidad de vida del paciente.

Palabras clave TEA, Trastornos del espectro autista, Revisión, Diagnóstico, Tratamiento.

Corresponding author: Nina Isabel Méndez Domínguez. Antigua carretera a Progreso Km 6, Cordemex, 97310 Mérida, Yucatán, México. Phone: +52 (999) 942-9400. E-mail: [email protected]

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Revision Review of Autism Spectrum Disorder

Introduction Autistic spectrum disorder (ASD) affects one in every 700 to 1000 people; one in every 1000 presents classic autism symptomatology, generally affecting three to four boys per each girl at a global level. Autism disorder is a neurodevelopmental disorder under whose autism spectrum disorder umbrella encompasses five clinical groups including Rett syndrome, Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorder; it affects cognitive, emotional, and social skills and competency. The specific etiologies and neural bases of autism remain largely unknown; it has been proposed that alterations in multiple genes in combination with environmental factors constitute the cause for the development of the autism phenotype.1,2,3 Its manifestations are mainly cognitive and behavioral of variable severity, characterized by early dysfunction in communication and social interactions, presenting with repetitive, restrictive, stereotyped patterns of behavior and loss of interest in diverse activities. Additionally, it is frequently accompanied by impairments in adaptive functioning, sensory processing disorder, aggression, or self-injury. It is generally diagnosed clinically with the presence of central symptoms based on the criteria established by the DSM-V. Treatment of ASD must be individualized and there has been growing interest in the role of various pharmacological treatments.4,5,6,7 The importance of early detection and diagnosis by primary care physicians is that they know the disease and, should there be clinical suspicion, to refer the patient to a specialist or be treated, aside from supporting the adaptation of the patient with ASD to their environment. The social impact of timely intervention of patients has a positive effect on their environment and community when receiving the necessary support; the prognosis is very variable. It has been observed that patients with autism and their families have a lower quality of life directly related to higher traits of autism and deficits of executive functions.8,9,10 Revista Mexicana de Neurociencia

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Definition

Autism spectrum disorder occurs in the early years of life. It is considered a multifactorial origin etiology, where genetics play an important role. Included in the category of ASD, based on the update of the DSM-V, are all generalized developmental disorders under the same diagnosis. These include autism disorder or Kanner syndrome, Rett syndrome, childhood disintegrative disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified / atypical autism.8,9,11 The ASD comprise a heterogeneous group of clinical expressions, whose main cause is unknown. Autism’s clinical manifestations include social interaction and communication deficiencies with persistent deterioration, restricted and repetitive patterns of behavior, as well as deficiencies in social-emotional reciprocity, deficits in nonverbal communicative behaviors, and in the ability to develop, maintain, and understand relationships. Intellectual disability is frequent, with or without affecting of the cognitive competence and skills. It should be noted that the manifestations of ASD vary according to the severity of the autistic condition, level of development, and chronological age.12,13,2

Classification

Based on the classification of ICD.10 and the new update of the DSM-V regarding the types of autism (see Table 1), the ASD encompasses all generalized developmental disorders under a single diagnosis (except for Asperger disorder, which has been excluded from ASD in the DSM-V) that varies in age of onset, as well as in clinical presentation considering variations in cognitive, linguistic, behavioral and social skills.13 (See Table 2) The heterogeneity of the autistic disorder is due to different etiologies or combination of factors believed, according to the DSM-V, to be associated with known medical or genetic conditions, environmental factors, or other neurodevelopmental, mental or behavioral disorders. Primary autism is considered to be likely caused by an indeterminate genetic factor, and September-October, 2017; 18(5):31-45

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Table 1. ASD Classification (Difference between DSM-IV and DSM-V)13

DSM-IV-TR Disorders of early childhood and adolescence Mental retardation Generalized Developmental Disorders Autism Disorder Rett Syndrome Childhood Disintegrative Disorder Asperger Syndrome Pervasive Developmental Disorder Not Otherwise Specified

DSM-V Neurodevelopmental Disorders Intellectual disabilities Intellectual disability Global development delay Intellectual disability not specified Autism spectrum disorder Autism spectrum disorder

Table 2. Classification and characteristics of generalized developmental disorders included in ASD1

Classification

Rett syndrome

Characteristics It mainly affects pediatric female patients. Motor development is normal in the first six months. Later, there is a progressive loss of cognitive and motor skills, loss of positive pressure, language, social interaction, and interest in the environment. Stereotypies that characterize the syndrome appear later.

Childhood disintegrative disorder

Development is normal until two years of age. Before turning ten there is a loss of previously acquired language, social, interactive, and motor skills.

Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS)

Patients who do not meet all the manifestations of the autism disorder. (See Table 2)

Autism Disorder

Meet all criteria for autism disorder. (See Table 3)

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Revision Review of Autism Spectrum Disorder

secondary autism associated with known genetic alterations.13

Prevalence

It has been observed that the male-to-female ratio of incidence of this disorder is of 4:1, regardless of social or cultural classes. In Spain, during the seventies, autism was considered a disorder of low prevalence; however, it has since increased to 60/10,000 inhabitants suffering from ASD. American sources mention this number has increased from 1/1000 in 1998 to a 2002 accepted prevalence of 1/150-1/200 patient with ASD.14,15

Clinical manifestations

The clinical manifestations of patients with ASD are divided into three areas: a) deterioration in social interactions, b) verbal and nonverbal communication, and c) behavioral patterns and restricted and repetitive interests.16 (See Table 3)

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The clinical manifestations of autism are usually present between the year and a half and two years of age that remain stable during the preschool and school years. Typically, the average interval from the time parents begin to worry until they ask for help can be more than a year. During the first year the most consistent behavior in children with autism is: not responding to their name and not looking at faces or doing so rarely. During the second year, there is absence of interest in sharing experiences and inability to pay attention. The following are considered precocious signs: a) frequent tantrums and low tolerance to change; b) absence of babbling at nine months old; c) no signaling or gesticulation at one year of age, unresponsive when called by name; d) won’t utter single words at sixteen months of age; e) absence of symbolic play at a year and a half; f) absence of two-word phrases at two years old. Any of the aforementioned findings should motivate a thorough investigation, considering

Table 3. Manifestations of autism.16 Manifestations

Deterioration in social interactions

Deterioration in communication

Deterioration in patterns of behavior, and restricted and repetitive interests

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Characteristics • Patients may or may not show affection when interacting socially. • Older pediatric patients often do not point things out, instead, use eye contact. • They present lack of social interest, with an absence of friends, according to their age, or prefer to play alone. • In early childhood, some children do not babble and cannot compensate for this language deficit with facial expressions or gestures. • Immediate or delayed echolalia. • Concern about specific parts of toys. • Behavior is restricted, repetitive, with stereotyped interests (child does not change toys or objects). • They can demonstrate atypical and impulsive behavior such as with objects, through unusual gestures, or with self-harming actions. • They repeat the same question several times, regardless of having received an answer, or participate in repetitive games. • They are concerned about their family, school environment, or routines.

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Revision Review of Autism Spectrum Disorder

autism one of the possible diagnoses. In a third of cases, the development is normal between the first and second year, and may later experience a gradual or unexpected regression, backtracking on previous development. Symptoms may also not be apparent to parents or teachers until four or six years of age.17 Patients may have cognitive abilities with moderate, severe, or profound mental retardation in IQ tests. With normal intellectual ability, the cognitive and language skills are often preserved; characteristically, they tend to misunderstand nonverbal messages, show difficulty in interpersonal relationships, especially when in a group, and possess few manipulative skills, are expressionless, speak with an abnormal tone, and focus on repetitive conversation topics that are interesting only to them.17

Diagnosis

Autistic spectrum disorder can be reliably diagnosed in children from the age of two years, with early intervention being beneficial for these patients. However, the average age for diagnosis is between three and six years. It has been postulated that one of the causes of this delay has to do with the great difficulty inherent in diagnosing these disorders at very early ages. Several factors contribute to this: a) symptom presentation is very variable and changes with age, b) social deficits and language delays may not be identified until the child begins to relate to peers in preschool.6,16 It is evident that the early detection of this disorder is crucial to aid the prognosis, the child’s subsequent development, and the family’s ability to adequately handle the difficulties that arise from this situation. We currently consider that around the year of life, and even earlier, the red flags for this disorder can already be identified. These signs are: little or no interest in visual contact, absence of orientation response when the child is named, absence of pointing, and absence of showing objects. This is fundamental because the earlier the diagnosis is made, the faster the child and his family can be given adequate help in order to promote an increase of achievements in Revista Mexicana de Neurociencia

functional abilities, communication, and intellectual processes.2,18 In early care, the diagnostic process of ASD should be based on the child’s evolutionary history information, for which interviews will be conducted with parents, educators, and significant people in the child’s life. Information will be collected regarding the child’s neurobiological development, communicative, social, and motor developmental milestones, and on the appearance of the first autistic symptoms, as well as on their environment, their relationship style, behavior patterns, interactions with adults and children of the same age, level of participation in structured group dynamics, and their adaptation in the nursery or pre-school.18 The American Academy of Neurology (AAN) in their report on identification and diagnosis of ASD, emphasize that a double approach is required. (See Algorithm 1) The first level deals with the strict monitoring of the neurodevelopment of children to discover any change or deviation from normal, for which it is desirable that doctors remain alert from the birth of the child. The second level in the diagnosis is to define the clinical characteristics of the child and then carry out three phases of evaluation.19 Phase 1, Identification of possible cases: the objective is to recognize the manifestations or to verify the observations of the parents regarding their child’s communication, behavior, and social interaction.19 Phase 2, Global evaluation: seeks to observe the consistency and the significance of the child’s neurological and behavioral manifestations, and to confirm the observations and concerns of the parents or physicians who referred the child to the specialist.19 Phase 3, Specific diagnosis: establishes the definitive diagnosis of ASD and defines its type. For this purpose the information provided by the parents and the specialists who have seen the patient is contrasted, applying the necessary tests

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Algorithm 1. Diagnostic Levels for Autism.1

Level 1 Routine developmental review (pediatric follow-up) Absolute indication for immediate evaluation: • No babbling, no signaling or other gestures at 12 months; • No unique word utterances at 16 months. • No use of spontaneous 2-word phrases (no echolalia) at 24 months. • Any loss of language or social skills at any age.

Reevaluate at next consult

Level 1. Lab Investigation Audiologist final assessment Lead detection (if there are signs of pica)

Specific evaluation to detect autism (E.g. CHAT, PDDST-stage1, Australian scale, etc.)

Refer to early intervention or to the local school district. Proceed to level 2

Refer to level 2, as indicated

Level 2. Diagnosis and evaluation of autism Formal diagnostic procedures. Interview tools: GARS, PIA, PDDST-stage3, ADI-R. Observation instruments: CARS, STAT, ADOS-G. Clinical diagnosis: DSM-V. Extended medical and neurological evaluation. Specific evaluations to determine the development profil.e Speech-language-communication, cognitive and adaptive behavior, occupational therapy, evaluation of family resources, and neuropsychological, behavioral, and academic evaluation. Extended laboratory evaluation (only if indicated). Pruebas metabólicas y genéticas, electrofisiología, imágenes neurológicas.

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Revision Review of Autism Spectrum Disorder

to correlate the data with the criteria of the DSM-V diagnostic manual.19 Caution is advised in the diagnosis of ASD due to nonspecific manifestations in different age groups. Early non-specific signs in infancy or small children include irritability, passivity, and difficulty sleeping and eating.16 Since autism does not have a diagnostic biological marker the judgment is strictly clinical, based on the behavioral manifestations given by the criteria of the DSM-V (see Table 4). The DSM-V manual mentions that the main features of autistic spectrum disorder are the persistent deterioration of social and reciprocal communication and social interaction (criteria A), and the behavioral patterns, interests, or restrictive and repetitive activities (criteria B). These symptoms are present since early childhood and limit or impede daily functioning (criteria C and D). The stage in which functional deterioration is obvious will vary according to the characteristics of the individual and his/her environment. The manifestations of the disorder also vary greatly depending on the severity of the autistic condition, the level of development, and the chronological age.13, 20 There is a wide variety of instruments for the diagnosis of autism spectrum disorder. The three most prominent are: a) The Modified Checklist for Autism in Toddlers (M-CHAT) is best applied in pediatric primary care during the recognition of the healthy child at a year and a half of age, the moment at which the symptoms become measurable and remain stable until preschool age between 16 and 30 months. It is a questionnaire addressed entirely to the parents consisting of 23 questions (see Table 5). b) The Autism Observation Scale for Infants (AOSI) studies children who have an older sibling with autism. c) The Childhood Autism Spectrum Test (CAST), for children between four and six years of age, is also a diagnostic tool.17 For definitive diagnostic confirmation there is a broad consensus on the use of validated tools such as The Autism Diagnostic Interview-Revised (ADI-R) and The Autism Diagnostic Observation Schedule (ADOS).17 Revista Mexicana de Neurociencia

Complementary tests

Laboratory. Laboratory tests almost never provide data for diagnosis, but in many cases are performed to rule out the symptomatic forms of autism, especially if there is an associated history of lethargy, cyclic vomiting, early epileptic seizures, dysmorphic features, and mental retardation.1 Neurophysiology. The electroencephalogram (EEG) tends to be normal in autistic children who do not have convulsions or clinical evidence of concomitant cerebral pathology.17 Neuroimaging. In idiopathic forms of autism, neuroimaging is usually normal; in some cases it observes hypoplasia of the posterior vermis and cerebellar hemispheres, reduction of the volume of the cerebral parietal lobes, and thinning of the corpus callosum.1 Genetic testing is not a routine study method for autism, and neither is metabolic screening, because less than 5% of patients will have an underlying metabolic disorder.8

Differential diagnosis

When a patient has some of the symptoms, a differential diagnosis should be made to rule out pathologies that may present similar symptoms, such as sensory anomalies, genetic or physical illnesses, since certain disorders or diseases may be accompanied by symptoms of autism and may require specific treatments. Among the most common are mental retardation / developmental delay, language developmental disorders, learning disabilities, hearing disorders, Landau-Kleffner syndrome, anxiety, and obsessive-compulsive disorder.16

Treatment

The objectives to keep in mind, in order to correctly treat children with autism spectrum disorder, should include: the patient’s functional independence and quality of life, seeking to reduce the negative consequences of the disorder itself, facilitate development and learning of the individual, promote socialization, reduce disruptive

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Table 4. DSM-V Diagnostic criteria.13

A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested in the following symptoms, whether current or past (examples are illustrative, not exhaustive): 1. Deficiencies in social-emotional reciprocity vary, for example, from an abnormal social approach and failure of normal conversation in both directions, to a decrease in shared interests, emotions, or affections, to failure to initiate or respond to social interactions. 2. Deficiencies in nonverbal communicative behavior used in social interaction vary, for example, from poorly integrated verbal and non-verbal communication, to anomalies of visual contact and body language, or deficiencies in the understanding and use of gestures, to a total lack of facial expression and non-verbal communication. 3. Deficiencies in the development, maintenance, and understanding of a relationship range from, for instance, difficulties adjusting behavior in various social contexts, to difficulties sharing imaginative games, the ability to make friends, or even a lack of interest in other people. Specify current severity: Magnitude is based on impairments of social communication and repetitive and restricted behaviors. B. Repetitive and restricted patterns of behaviors, activities, and interests, manifested in at least two of the following symptoms, whether current or past (examples are illustrative, not exhaustive): 1. Motor movements, stereotyped or repetitive use of objects or speech (e.g., simple stereotyped motor movements, aligning objects, spinning objects, echolalia, idiosyncratic phrases). 2. Insistence on sameness, inflexible adherence to routines or patterns of verbal and non-verbal ritualized behavior (e.g., extreme discomfort in the face of small changes, difficulties with transitions, rigid thought patterns, greeting rituals, need to always follow the same path, or eat always the same thing). 3. Highly restricted, obsessive interests that are abnormal because of their intensity or focus (e.g., excessive attachment or preoccupation with unusual objects, overly circumscribed or persevering interests). 4. Sensory hyper or hypo-reactivity or unusual interest in sensory aspects of the environment (e.g., apparent indifference to pain or temperature, adverse response to sounds or specific textures, excessive smelling or touching of objects, fascination with lights or rotating objects). Specify current severity: Magnitude is based on social and communicative disturbances and on the presence of repetitive and restricted patterns of behavior. C. Symptoms must be present in the early developmental period (although they may not fully manifest until the demands of the environment exceed the child's abilities, or can be dissimulated in later life through learned skills). D. Symptoms cause clinically significant changes in social, occupational, or other important areas of current functioning. E. These alterations are not best explained by the presence of an intellectual disability (intellectual development disorder) or a global developmental delay. Intellectual disability and autism spectrum disorder often co-occur; to make a diagnosis of comorbidity of autism spectrum disorder and intellectual disability, social communication must be below expectations as a function of the general level of development.

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Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified should be diagnosed with autism spectrum disorder. Individuals who have marked deficits in social communication but whose symptoms do not meet the criteria for autism spectrum disorder should be evaluated for social (pragmatic) communication disorder. Specify if: It is accompanied or not by intellectual disability. It is accompanied or not by a language disorder. It is associated with a medical or genetic condition or with a known environmental factor (coding note: use an additional code to identify the medical or genetic condition). It is associated with another mental or behavioral neurodevelopmental disorder (coding note: use additional code(s) to identify the associated mental or behavioral neurodevelopmental disorder). With catatonia (coding note: use additional code 293.89 [F06.1] catatonia associated with autism spectrum disorder to indicate the presence of concurrent catatonia).

behaviors, and educate relatives and teachers to have an active participation in these during the intervention.21 It is necessary, in order to carry out the treatment, the participation of a multidisciplinary team that includes specialists with knowledge of diagnosis and treatment of autistic spectrum disorders, relatives, teachers, and people who maintain direct contact with the child that generate some influence through interactions.21 Intervention-based practices include clinicaleducational strategies based on research of relevant interest groups, which can be taken into consideration while planning appropriate treatment for the patient.22 (See Table 6). There are global models of treatment that have shown positive results when applied; however, each of these models differ in terms such as the age of onset in which to start the application, the influence of the environment, actions regarding the answers obtained, individualization of the child, and reinforcements to apply. It is necessary to evaluate all variables that influence the way the treatment will be handled to be able to choose an adequate model to apply in order to achieve an adequate interaction of the child with its environment, developing as well the language and socialization skills.22 Revista Mexicana de Neurociencia

Appropriate pharmacological treatment for children with autism spectrum disorder should take into consideration the general basic care that any pediatric patient receives, such as prevention and immunization campaigns. Recommendations directed to a specific pharmacological treatment are based only on case studies and literature, which can be taken into consideration during the selection of the appropriate drug in each case.21 The main symptoms to be treated in patients with autism spectrum disorder are: epilepsy, aggression, hyperactivity, irritability, attention deficit, poor social interaction, obsessions, and anxiety. Individual treatment should take into account factors such as: to start with monotherapy to avoid the occurrence of any adverse drug reaction; administer low doses and adjust them according to the effect it produces in the patient; follow-up; take into consideration the pharmacokinetic and pharmacodynamic factors of each drug.23 A pharmacological treatment administering oxytocin, a neuropeptide related to social attachment and the development of bonding via a single intranasal dose, was linked to facilitation in the processing and retention of social information and recognition of emotion in relation with language intonation; however, this type of therapy is still subject to investigation and hasn’t produced sufficient data to verify its effectiveness and to consider it an adequate treatment.24 September-October, 2017; 18(5):31-45

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Table 5. M-CHAT. 6 1. Does your child enjoy being rocked, bounced on your knees, etc.? 2. Is your child interested in other children? * 3. Does your child like to climb to places, such as to the top of the stairs? 4. Does your child enjoy playing peekaboo, hide-and-seek, or other similar games? 5. Does your child pretend to, for example, serve a cup of tea or simulate other things? * 6. Does your child use the index finger to signal, to ask for something? 7. Does your child use the index finger to point, to show interest in something? * 8. Does your child know how to play with small toys (such as cars or blocks) and not just put them in their mouth, touch them, or throw them away? 9. Has your child ever brought an object to show you something? * 10. Does your child look into your eyes for more than a second or two? 11. Has your child shown hypersensitivity to noise (for instance, covering the ears)? 12. Does your child laugh in response to your face or your smile? 13. Does your child imitate you (for example, when you make a face)? 14. Does your child answer to his/her name when called? * 15. If you point to a toy in the room, does your child look at it? * 16. Does your child walk? 17. Does your child make strange movements with the fingers close to his/her face? 18. Does your child look at the things you’re looking at? 19. Does your child try to call attention towards his/her own activities? 20. Have you ever wondered if your child is deaf? 21. Does your child understand what people say? 22. Does your child sometimes stare ahead or wander aimlessly? 23. Does your child look at your face to check your reaction when finding something unfamiliar? * These are the critical questions, the most indicative of the existence of autistic features.

Table 6. Intervention Practices.22

Preventive behavioral Behavioral intervention Molding Joint attention Natural context Parental intervention Peer learning Pivotal behaviors Strategies for autonomy Work systems Visual support

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Give different types of visual, physical and verbal stimuli to achieve the desired response. Look for alternatives to reduce behavioral problems. Reinforce the desired behavior by imitating it. Increase the response to the perceived behavior of other people. Teaching of daily activities. Family participation. Interactions with other children. Motivation, spontaneous initiation, response to multiple signals, and autonomy. Favor the child’s independence. Organize areas for play and other activities. Use visual cues to maintain a behavior or ability.

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Another treatment of interest is secretin, which is a gastrointestinal polypeptide involved in digestion, and that in intravenous infusion therapies has been associated with an improvement in socialization, cognitive, and communication skills thanks to its intervention as a neurotransmitter; however, like other hormonal therapies, there isn’t enough evidence to be able to demonstrate its true therapeutic value. On the other hand, melatonin is a neurotransmitter whose main therapeutic function is the induction of sleep in patients with insomnia problems. Specific effects of its application in autism have not been demonstrated, its use is based on simply treating sleep disorders in children with autism to produce a sedative effect, but its excessive use can cause adverse effects such as dizziness, lethargy, and headache.25 Among the main drugs used in the treatment of autism are typical antipsychotics such as haloperidol, thioridazine, chlorpromazine and the atypical risperidone, olanzapine and clozapine, whose use is more common. These are used with the objective to treat the child’s behavioral problems by blocking the D2 dopaminergic channels, causing a diminished reaction to stimuli known as “neuroleptic syndrome,” observed as calm and quiet behavior in the child. In turn, some atypical antipsychotics also exhibit an antagonism of type 2A receptors for serotonin, aside from their effect on the D2 channels. It is important to individualize the patient when these drugs are administered, since there are no pre-established criteria for dosing and could present extrapyramidal adverse effects such as tremors, sialorrhea, sedation, impaired liver function, etc. This therapy should be suspended if no changes are perceived in the patient’s behavior within six weeks.23,25 Risperidone is now considered the safest and most effective antipsychotic in the short-term treatment of autism, although it has been linked to a significant increase in weight of about two kilograms when used in 12-week trials. The effects of haloperidol have also been shown to be as effective as those produced by risperidone. Caution should be exercised when using clozapine in treatment because of the high risk of granulocytosis as an Revista Mexicana de Neurociencia

adverse effect; olanzapine is useful to treat children and adults but with minor adverse effects such as increased appetite and weight gain. Even with limitations in its study, intramuscular application of paliperidone has shown improvements in suppressing irritability and aggression in patients with autism, and its only adverse effect is the increase in appetite. Treatment with aripiprazole can be extended up to one year due to its safety and good tolerance in children and adolescents with autism.25,26 Olanzapine also produces an improvement in the treatment of irritability and hyperactivity in autism with lesser effects than risperidone, but with more marked adverse effects such as weight gain, so its use is recommended more for the treatment of adolescents rather than of children.25 Attempts have been made to test the efficacy of a placebo treatment for autism in order to avoid some of the adverse effects of drugs such as haloperidol and risperidone; however, placebos have not shown any favorable outcome against any other type of pharmacological therapy.25 Serotonin reuptake inhibitors such as fluoxetine, paroxetine and sertraline are given to children with autism because they have been found to increase 25% of serotonin levels in platelets and serum. This treatment is based on suppressing symptoms such as anxiety, depression, obsessive-compulsive disorders, and self-injurious behavior.23 Clomipramine has shown favorable results in reducing symptoms such as repetitive behaviors in children with autism with effectiveness similar to haloperidol; however, the intensity of the effect varies with each patient and the doses have to be individualized to avoid adverse effects such as dry mouth, constipation, lethargy, depression, and sleep and behavior problems. Fluvoxamine is effective in treating repetitive and aggressive behavior, but the percentage of effectiveness in patients is very low and very poorly tolerated leading to anxiety, irritability, lack of concentration, and aggressive behavior, among other adverse effects.27 September-October, 2017; 18(5):31-45

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The effects of fluoxetine are more effective during adolescence than at any other age. Sertraline has been shown to be well tolerated and moderately effective in treating repetitive and aggressive behavior with a minimum amount of adverse effects such as weight gain and anxiety. The use of citalopram brings a wide range of adverse effects such as hyperactivity, impulsivity, insomnia, diarrhea, and dry skin, and is merely used to treat symptoms secondary to behavioral problems. Effective therapy in children for hyperactivity may require the use of multiple drugs such as venlafaxine with serotonin and noradrenaline receptor inhibitors. Mirtazapine is a tricyclic antidepressant which antagonizes serotonin receptors and α-2 adrenergic receptors, showing a very low incidence of adverse effects during its use to treat anxiety, irritability, and hyperactivity.27 A series of indistinguishable behaviors may be associated with variable epileptic seizures in children with autism. The administration of antiepileptic drugs such as sodium valproate, carbamazepine, lamotrigine and topiramate, among others have action mechanisms focusing on blocking sodium and calcium channels, reducing excitatory glutamatergic activity, and increasing inhibition by GABA. The administration of these drugs is directed towards the resolution of these crises without taking into consideration the presence of autism in children. Electroencephalogram studies may associate the presence of autism with the manifestations of seizures by finding temporary unilateral or bilateral paroxysms in the temporal lobes.23,25 Studies have investigated a possible increase in the permeability of the intestinal barrier, so specific diets have been considered for children with autism. Such diets involve the elimination of products such as gluten or casein, found in products such as wheat and milk, since their activity has been linked to opioid effects. The ketogenic diet includes a high fat content and a low amount of carbohydrates that leads to the formation of ketone bodies by the liver and these are linked to a lower incidence of epileptic seizures. Revista Mexicana de Neurociencia

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The proposal to include supplements in this type of diets such as magnesium and vitamin B6 has also been evaluated, but there is no evidence that any specific diet plan has beneficial effects in children with autism.25

Prognosis

In general, patients’ prognoses are variable, they depend on the early attention given and also on the severity of the underlying etiologies. The best prognoses belong to patients who have access to different treatments and with socio-familial conditions that favor their development. Some factors are associated with better prognoses: the development of some communicative language before the age of six, presence of slight or no mental retardation in nonverbal intelligence tests, and psychotherapeutic intervention as early and as intensive as possible. The cooperation between specialists such as neurologists, psychiatrists, neuroscientists, psychologists, speech therapists, occupational therapists, and educators is crucial to continue to promote understanding and allow a more adequate approach to patients.28,8,29

Quality of life

In studies evaluating IQ, early language development, daily executive functions, and their influence on quality of life, children with ASD were found to have a lower quality of life than children with normal development. This inferior quality of life is related to higher levels of autistic features and deficits of executive functions. It is recorded that, in addition to the patient, the family has a significant reduction in the quality of life affecting different domains (economic, social, educational, and psychological). It is recommended to work with the aggravating factors in autism and the deficits of executive functions that are more associated to an inferior quality of life. The intention is to improve the interventions and, together with the individualized treatments, to improve the quality of life in patients and their families and, in turn, become a useful tool for evaluating treatment outcomes.10,30

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Conclusion The present article analyzed the main tools available with the objective of providing information for the early diagnosis and intervention for patients with ASD. It is essential to recognize its main and early clinical manifestations in the first years of life, so that the physician is able to offer the optimal clinical-educational and pharmacological treatment to improve the patients’ prognosis and quality of life.

Conflict of interest

There are no conflicts of interest for any of the authors in this scientific report.

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Funding

The authors have not declared any funding source for this scientific report.

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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Camino-León R, López-Laso E. El espectro autista. Vox pediátrica. 2006; 14, 2: 7-15 Millá MG, Mulas F. Atención temprana y programas de intervención específica en el trastorno del espectro autista. Rev Neurol. 2009; 48 (Supl 2): S47-S52 Oviedo N, Manuel-Apollinar L, De la Chesnaye E, Guerra-Araiza C. Aspectos genéticos y neuroendocrinos en el trastorno del espectro autista. Bol Med Hosp Infant Mex. 2015; 72 (1): 5-14 Yoo H. Genetics of Autism Spectrum Disorder: Current Status and Possible Clinical Applications. Exp Neurobiol. 2015; 4: 257-272. Kong MYF. Diagnosis and history taking in children with autism spectrum disorder: dealing with the challenges. Front. Pediatr. 2015; 3:55. Caretti-Giangaspro E, Alcamí-Pertejo M. Instrumentos para la detección precoz de los trastornos del espectro autista. Rev Pediatr Aten Primaria. 2007;9: 301-15 Hye-Ran P, Jae-Meen L, Hyo-Eun M, Dong-Soo L, Bung-Nyun K, Jinhyun K, et al. A short review on the current understanding of autism spectrum disorders. Exp Neurobiol. 2016; 25(1):1-13. Rogel-Ortiz F. Autismo. Gac Méd Méx. 2005; 141 (2): 143-147. Díez-Cuervo A, Muñoz-Yunta J, Fuentes-Biggic J, Canal-Bedia R, Idiazábal-Aletxae M, Ferrari-Arroyo M, et al. Guía de buena práctica para el tratamiento de los trastornos del espectro autista. Rev Neurol. 2006; 43(7), 425-38. De Vries M, Geurts H. Influence of autism traits and executive functioning on quality of life in children with an autism spectrum disorder. Journal of autism and developmental disorders. 2015; 45(9), 2734-2743. Lopez-Gómez S, Cajal-Cernuda C. Curso y pronóstico del trastorno autista Balbuena F. Etiología del autismo: el continuo idiopático- sindrómico como tentativa explicativa. Rev chil neuro-psiquiatr. 2015; 53(4): 269- 276 Blazer-Dan G, Burke-Jack D. Carpenter William, T. Xavier Castellanos, F. Dimsdale Joel, E. et al. Trastorno del espectro autista. Manual diagnóstico y estadístico de los trastornos mentales. España 2014. P. 50-59 Ministerio de sanidad y política social. Guía de prática clínica para el manejo de pacientes con trastornos del espectro autista en atención primaria. Ministerio de ciencia e innovación. España 2009.p.13-31. Geschwind D. Advances in autism. NIH Annu Rev Med. 2009; 60: 367-380 Sung-Koo Kim. Recent update of autism spectrum disorders. Korean J pediatr. 2015; 58(1): 8-14 Ruiz-Lázaro P, Posada de la Paz M, Hijano-Bandera F. Trastornos del espectro autista. Detección precoz, herramientas de cribado. Rev Pediatr Aten Primaria. 2009; 11 (17): 381-s397 Sampedro-Tobón ME, González-González M, Vélez-Vieira S, Lemos-Hoyos M. Detección temprana en trastornos del espectro autista: una decisión responsable para un mejor pronóstico. Bol Med Hosp Infant Mex. 2013;70(6): 456-466 Álvarez-Alcántara E. Trastornos del espectro autista. Rev Mex Pediatr. 2007;74(6); 269-276 Cabrera D. Generalidades sobre el autismo. Rev Colomb Psiquiat. 2007; vol. 36 (1) 208-220s Moyano MB, Alonso M, Aspitarte A, Brío MC, Cleffi V, Cukier S, et al. Guía para el tratamiento de los trastornos del espectro autista. CAP y N. 2013. Salvadó-Salvadó B, Palau-Baduell M, Clofent-Torrentó M, Montero-Camacho M, Hernández-Latorre M. A. Modelos de intervención global en personas con trastorno del espectro autista. Revista de Neurología. 2012; 54 (Supl 1) S63-71. Morant A, Mulas F, Hernandez S. Abordaje farmacológico en el espectro autista. Rev Neurol. 2002; 34 (Supl 1) S64-S67. Ruggieri VL., Arberas CL. Abordajes terapéuticos en los trastornos del espectro autista. Revista de Neurología. 2015; 60 (Supl. 1) S45-S49. The British Psycological Society and The Royal College of Psychiatrist. Recognition, referral, diagnosis and management of adults on the autism spectrum. Great Britain. National Collaborating Centre for Mental Health. 2012 Fuentes-Biggi J, Ferrari-Arroyo MJ, Boada-Muñoz L, Touriño-Aguilera E, Artigas-Pallarés J, Belinchón-Carmona M, et al. Guía de buena práctica para el tratamiento de los trastornos del espectro autista. Rev Neurol. 2006; 43(7) 425-38. Doyle CA, McDougle CJ. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan. Dialogues Clin Neurosci. 2012; 14(3), 263-279. Soto-Calderón R. El síndrome autista: un acercamiento a sus características y generalidades. Revista Educación. 2002; 26(1): 47-61. Gadia C, Tuchman R. Manejo de los niños con trastornos del espectro autista. Rev Neurol. 2003; 36 (2): 166-173. Dietert R, Dietert J, DeWitt J. Environmental risk factors for autism. Emerging Health Threats Journal. 2011; Vol. 4, 1-11.

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Revision Spinal cord trauma

Revision Huber Padilla-Zambrano,1 YanCarlos Ramos-Villegas,2 Hernando Raphael AlvisMiranda,3 Andrei F. Joaquin. MD,4 Luis Rafael MoscoteSalazar5 1

Facultad de Medicina, Universidad de Cartagena, Cartagena de Indias, Colombia. 2 Facultad de Medicina, Universidad de Cartagena, Cartagena de Indias, Colombia. 3 Residente de Neurocirugia, Universidad de Cartagena, Cartagena de Indias, Colombia. 4 Department of Neurology, Neurosurgery Division, State University of Campinas, CampinasSao Paulo, Brazil. 5 Neurocirujano, Universidad de Cartagena, Cartagena de Indias, Colombia.

Keywords Spinal cord injury, spinal cord injury, primary spinal cord injury, pathophysiology, neurogenic shock, spinal shock.

Palabras clave trauma raquimedular, lesión medular secundaria, lesión medular primaria, fisiopatología, shock neurogénico, shock espinal.

Pathophysiology of spinal trauma Fisiopatología del trauma raquimedular

Abstract Spinal trauma (TRM) includes traumatic lesions characterized by fractures of the spine and may also have deficits in motor and / or sensory functions due to complete or partial involvement of the spinal cord. Pathophysiologically, it occurs by two mechanisms: primary spinal cord injury and secondary spinal cord injury; The first involves the initial mechanical injury due to local deformation and energy transformation, while the second involves a cascade of biochemical and cellular processes. The evolution of these processes has been divided into 5 phases: Immediate, Acute, Subacute, Intermediate and Chronic; The study of these phases is important because it allows the selection of interventions that may possibly improve the patient’s neurological prognosis.

Resumen El Trauma Raquimedular (TRM) engloba las lesiones de origen traumático que se caracterizan por fracturas de la columna vertebral y pueden tener también déficits de las funciones motoras y/ o sensoriales por la afectación completa o parcial de la medula espinal. Fisiopatológicamente, se produce por dos mecanismos: lesión medular primaria y lesión medular secundaria; la primera implica en la lesión mecánica inicial debido a la deformación local y la transformación de energía, mientras que la segunda abarca una cascada de procesos bioquímicos y celulares. La evolución de estos procesos se ha dividido en 5 fases: Inmediata, Aguda, Subaguda, Intermedia y Crónica. El estudio de esas fases es importante pues permite la selección de las intervenciones que pueden posiblemente mejorar el pronóstico neurológico del paciente. Corresponding author: Dr. Luis Rafael Moscote Universidad de Cartagena , Cartagena de Indias, Colombia e-mail: [email protected]

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Introduction Descriptions of traumatic injury to the spine and its treatment were reported between 3000-2500 BC on a parchment written by Edwin Smith, who mentioned 48 cases of traumatic lesions affecting the Central Nervous System (CNS), of which 12.5% corresponded to spinal injuries. Writings by Hippocrates were later found, reporting traumatic and non-traumatic lesions of the spine. And in the second century AD, Galen was among the first to experiment with animals and report the changes observed by affecting a part of the spinal cord.1 Spinal Cord Injuries (SCI) include injuries of traumatic origin affecting the bony, cartilaginous, muscular, vascular, meningeal, radicular, and medullary structures of the spine -in a joint or isolated way- at any of its levels.1-3 Medullary Lesions (ML) are a devastating neurological problem characterized by the deficit of motor, sensory, and anatomical functions due to a complete or partial involvement of the spinal cord, mainly caused by trauma, occurring in about 15 to 25% of SCI.4,5 SCI present mainly due to traffic or work accidents, accompanied by multiple traumatic injuries such as cranial, thoracic and pelvic. Additionally, they can also be related to injuries by firearm, falling from heights, and by an explosion, among others.1 This medullary traumatic pathology affects mostly men at a male: female-and-young-people ratio of 4:1,3 and has become a public health problem because it involves long-term treatment, high costs in care, and leads to a negative affectation in the patient and his family. The majority of patients affected with SCI cannot recover lost functions because the CNS, unlike the Peripheral Nervous System (PNS) once affected presents irreversible changes that hinder nerve regeneration.2,5 This article intends to describe a review of the pathophysiological considerations found in the scientific literature, which are developed in patients with SCI. Revista Mexicana de Neurociencia

Physiopathology

To describe the pathophysiology of SCI, the types of lesions that the spinal cord can undergo must be known, classified as follows: solid cord injury, contusion, laceration, and massive compression; with contusion being the most common SCI representing between 25% and 40% of the cases. In the majority of these, the anatomic severity of the damage does not correlate with the degree of loss of functional abilities presented by the patient.6,7 SCI are a two-step process involving primary and secondary mechanisms, the latter being first described by Allen in 1911.8 The primary process includes the initial mechanical trauma due to the observed displacement of the structures of the vertebral column caused by direct energy, which causes axonal disruption, vascular damage, and cellular apoptosis. In the secondary process, progressive vascular changes are observed; these are caused by the initial trauma leading to the presence of edema and ischemia, accompanied by the liberation of free radicals and ionic alterations, with excitotoxicity as consequence.8,9 The evolution of SCI undergo a series of changes divided into phases: immediate, acute, subacute, intermediate, and chronic.9

Primary injury

There are four mechanisms of primary injury: 1) impact with transient compression, 2) lacerationtransection, 3) distraction, and 4) impact plus persistent compression; the last being the most common presentation.10 The first mechanism presents in patients with degenerative disease of the cervical spine suffering from hyperextension trauma. The lacerationtransection may be due to firearm shot, displaced fracture, or stabbing wound. Distraction is the forced stretching of the spinal cord secondary to flexion, extension, rotation, or dislocation; it is more frequent in people with degenerative disease September-October, 2017; 18(5):46-52

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Revision Spinal cord trauma

of the cervical spine. Finally, the mechanism of impact plus persistent compression is observed in fractures with burst of vertebral body and retropulsion of bone fragments that exert compression in the spinal cord.10 Initial mechanical trauma includes tension and compression forces, causing penetrating injuries, strains, or tears in neural tissues and vascular structures.5 The initial impact results in the development of a hemorrhage that alters the blood flow, producing local infarcts due to hypoxia and ischemia, which harms the gray matter due to its metabolic requirements and differences in irrigation.5,10 The neurons located in the affected area suffer structural alterations and the myelin sheath diminishes, this, additional to the edema and the macrophages present in the area, are the factors that lead to the deterioration of the nervous transmission.5

Secondary injury

Theories about the secondary mechanisms have evolved in the last 30 years. In the 70s, the free radical hypothesis was crucial to the injury process as Demopoulos et al. stated. Later, in the 80s, they centered on the importance of calcium and lipid peroxidation. Presently, however, we’re exploring the involvement of apoptosis, inhibition of intracellular protein synthesis, and glutaminergic mechanisms in the injury process.8 In 1911, Allen et al. observed there was a harmful agent present in the hemorrhagic fluid that could be causing damage to the spinal cord. This aroused the interest of different authors, which postulated physiological and biochemical mechanisms to explain the post-traumatic damage of the spinal cord tissue, such as: vascular changes, free radical formation, ionic imbalance, apoptosis, and inflammatory responses, among others.8,11 Secondary spinal cord injury begins immediately, or minutes after injury, and can be extended for several days and even weeks.6,12 The tissue damage increases progressively, affecting the different levels of the spinal cord. In addition, endothelial damage leads to increased permeability and the Revista Mexicana de Neurociencia

presence of intracellular edema, an important factor for the extravasation of the cells of the immune system.6 Trauma triggers a series of pathophysiological processes that induce secondary spinal cord injury. To achieve an adequate understanding, this process has been divided into phases taking into account the events that occur in each one of them.13

Immediate phase

This phase occurs within the first two hours. It begins at the time of trauma with detectable changes such as general inflammation in the spinal cord followed by hemorrhage in the central gray matter. The cells present necrosis by the mechanical disruption of the membranes and, in turn, ischemia due to vascular disruption. Sudden microvascular disruption causes bleeding in the white matter, aggravating the lesion due to the fact that it can spread and affect the adjacent or distal segments.13

Acute phase

This phase happens within 2 to 48 hours. In the acute phase the primary damage occurs as a direct result of trauma, and once the structural thresholds are overcome, immediate cellular and biochemical alterations begin to happen.12,13 This phase is marked by systemic and local alterations such as alterations of the vascular mechanisms, ionic imbalance, and immune system response, among others, which will be described next.12,13

Free radicals

The production of radicals from the lipid peroxidation of the cell membrane in the lesions of the central nervous system causes enzymatic deterioration dependent on phospholipids, alterations in the ionic gradients, and even lysis of the membranes.8 In addition, they play an important role in post-traumatic hypoperfusion since there is a reduction of the blood flow of the spinal cord leading to the appearance of edema and an inflammatory response.11 Oxidative stress disables key mitochondrial enzymes in processes such as the respiratory chain,8 production of DNAassociated-proteins due to their nitration,6 and September-October, 2017; 18(5):46-52

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inhibition of Na+ /K+ -ATPase inducing a metabolic collapse and, therefore, the necrotic or apoptotic death of the cell.14

and apoptosis secondary to the activation of caspases, calpain, phospholipase A2, lipoxygenase, and cyclooxygenase.10–12

The use of high doses of methylprednisolone within the first eight hours has been found to improve spinal cord blood flow and microvascular perfusion, contributing to clinical neurological recovery.8 In this way, their routine use in clinical practice is still questionable. On the other hand, the cytoprotection through inhibitors of lipid peroxidation facilitates the maintenance of neuronal excitability and inhibits the vasoconstrictor effect produced by prostaglandins.8,11

The failure of the Na+/ K+ -ATPase bombs, the activation of voltage-dependent Na+ channels, and the massive depolarization impede the mobilization of intracellular Na+ to extracellular space, producing, as a result, an activation of NMDA, AMPA, and Kainate glutamate receptors generating an excitotoxicity that damages oligodendrocytes and axons.6,14

Vascular mechanisms

The injury causes a reduction of the blood flow, and therefore progressive ischemia, during the first hours, possibly associated to the vasospasm induced by mechanical damage.8,10 White matter perfusion decreases the first five minutes, reestablishing at approximately 15 minutes; however, in the gray matter there are multiple hemorrhages and intravascular thrombosis absenting flow during the first hour, and maintaining this the first 24 hours.12 The systemic hypotension resulting from the loss of hemodynamic self-regulation of the microvasculature may cause additional decreases in the blood flow of the spinal cord with induced hypertension that does not necessarily reverse ischemia but produces marked hyperemia at adjacent sites.10,14 After the ischemic period, the medulla can present a period of reperfusion, which can exacerbate the injury due to the generation of free radicals and other toxic products that contribute to oxidative stress.10,14

Ionic imbalance

Unregulated ion flow is detrimental to cell function and survival since the permeability of the cell membrane is compromised by the activation of the protease.12 In addition, high concentrations of intracellular Ca+ cause mitochondrial damage, enzymatic activation, changes in gene expression, Revista Mexicana de Neurociencia

The increase of the extracellular potassium produces an excessive depolarization of the neurons, which affects the nervous conduction, being an important factor in the spinal shock. On the other hand, the decrease in magnesium affects metabolic processes such as glycolysis, oxidative phosphorylation, and protein synthesis.10

Lipid peroxidation

After the increase in levels of intracellular Ca+, the mitochondrial dysfunction, the degradation of arachidonic acid, and the activation of inducible nitric oxide synthase, the formation of reactive species of oxygen and nitrogen is produced, causing the peroxidation of lipids, damage of proteins and nucleic acids, inducing alterations in the cytoskeleton and organelles that lead to lysis and, therefore, to neuronal loss.12

Inflammatory response

After the trauma, the microglia cells induce leukocyte extravasation, which begins to release cytokines (such as tumor necrosis factor α, interleukin-6, and interleukin-1β) complement and reactive species of the oxygen, allowing a greater extravasation and greater tissue damage.6,11,12,14 These cytokines induce cyclooxygenase-2 expression by promoting the degradation of arachidonic acid in prostaglandins, prostacyclin, and thromboxanes that mediate permeability, vascular resistance, and platelet aggregation and adhesion. Excess cytoplasmic Ca+ activates the phospholipases so that they can produce arachidonic acid from the lipids of the cell membrane.6,14 September-October, 2017; 18(5):46-52

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The inflammatory response is important for the elimination of cell debris, which may be vital in the regeneration of surviving neurons; however, an exaggerated response damages healthy tissue and exacerbates the lesion.12 Microglial cells, neutrophils, and macrophages offer innate immunity, and lymphocytes offer adaptive immunity. Neutrophils enter the damaged spinal cord immediately after the injury and peaks at six hours. Macrophages remain elevated within two to seven days and persist for up to two weeks after the injury.6

Apoptosis

Apoptosis is a form of programmed cell death characterized by cellular shrinkage, chromatin aggregation, and nuclear pyknosis, mediated by the activation of enzymes called caspases.14 During the acute phase the process of cellular inflammation and then rupture of the cell membrane lead to cell death by necrosis immediately; after several hours the caspase cascade is activated in neurons, oligodendrocytes, microglia, and astrocytes.10,12 In trauma, apoptosis occurs at the epicenter of the lesion and areas of Wallerian degeneration in the white matter, even after several weeks, contributing to post-injury demyelination.8,11,14 Inhibition of protein synthesis with cycloheximide has been found to inhibit apoptosis, reduce secondary damage, and improve functional outcome after spinal cord injury, which demonstrates the requirement for the cell to actively contribute to its own apoptotic disappearance stemming from the synthesis of new proteins.14

Subacute phase

The phase lasts approximately from two days to two weeks, in which the phagocytic response increases in order to achieve a removal of the débrided tissue in the area of the lesion, allowing a possible axonal regeneration.15 In addition, the astrocytic response occurs late due to hyperplasia and hypertrophy of the astrocyte population around the lesion, which will form the glial scar, which represents the physical and chemical barrier to axonal regeneration and promotes the restoration of ionic maintenance.16 Revista Mexicana de Neurociencia

Intermediate phase

This phase lasts approximately from two weeks to six months, characterized by the maturation of the glial scar produced by the late astrocytic response. In addition, this reaction of the astrocytes allows the possible regeneration of the affected axons to continue, but is insufficient for recovery in severe lesions.17

Chronic phase

The degenerative process continues and extends to the areas surrounding the lesion, which present depressed electrical and functional activity evolving to what is known as secondary injury and thus a subsequent loss of neuronal function. The trauma -in addition to producing neuronal deathprovokes lysis of glial cells, destruction of blood vessels, and lesions in axonal tracts that, when unable to regenerate, cause the alterations to be permanent.18 The process of demyelination begins 24 hours after injury, increasing two weeks later due to the effect of inflammatory cells entering a second phase of migration.19 At the third week, some fibers present Wallerian degeneration and loss of axonal diameter. The immature forms of healthy oligodendrocytes are able to re-myelinate some axons; additionally, the Schwann cells release trophic factors that collaborate with this process.18,20

Neurogenic shock

It is defined as a systolic blood pressure